CN103030646B

CN103030646B - Benzodioxane analog derivative, its preparation method and in application pharmaceutically

Info

Publication number: CN103030646B
Application number: CN201210300982.7A
Authority: CN
Inventors: 吕贺军; 董庆; 费洪博; 蒋宏健; 宋鹏
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Ruishi biomedical Co., Ltd
Priority date: 2011-09-29
Filing date: 2012-08-22
Publication date: 2016-08-24
Anticipated expiration: 2032-08-22
Also published as: CN103030646A

Abstract

The present invention relates to benzodioxane analog derivative, its preparation method and in application pharmaceutically.Specifically, the present invention relates to the new benzodioxane analog derivative shown in a kind of logical formula (I) and pharmaceutically useful salt thereof or containing its pharmaceutical composition, and preparation method thereof, the invention further relates to described benzodioxane analog derivative and pharmaceutically useful salt thereof or the pharmaceutical composition containing it is preparing therapeutic agent, particularly GPR40 agonist, with the purposes in the medicine of the preparation treatment disease such as diabetes and metabolic disorder, each substituent group of its formula of (I) is identical with the definition in description.

Description

Benzodioxane analog derivative, its preparation method and in application pharmaceutically

Technical field

The present invention relates to a kind of new benzodioxane analog derivative and pharmaceutically useful salt thereof or the medicine group containing it Compound, and preparation method thereof.The invention further relates to described benzodioxane analog derivative and pharmaceutically useful salt thereof or contain The pharmaceutical composition having it is preparing therapeutic agent, particularly GPR40 agonist, and at preparation treatment diabetes and metabolic disorder Etc. the purposes in the medicine of disease.

Background technology

Type ii diabetes, also known as non-insulin-dependent diabetes mellitus or maturity-onset diabetes, mainly shows as pancreas in patient Island element secretory volume is very little or body can not effectively utilize insulin (insulin resistant).The existing diabetics in the whole world at present About 1.85 hundred million, wherein type ii diabetes patient accounts for the 90 ~ 95% of diabetics sum, continues with the rate of increase of 6% simultaneously Rise.In China in 2010 crowd of more than 20 years old, the overall prevalence of type ii diabetes has reached 9.7%.

At present, the Therapeutic Method of type ii diabetes includes: Insulin secretagogues such as sulfonylurea, promotes pancreatic beta cell Generate more insulin；Hypoglycemic agent such as metformin class, reduces the formation of glucose in liver；Peroxisome proliferator activates Receptor y (PPAR-γ) activator such as thiazolidinediones, improves insulin sensitivity, strengthens the Purificatiou of insulin；α- Glucosidase inhibitor, the production of glucose in interference intestinal.But, the Therapeutic Method of present has certain lacking Fall into.Such as sulfonylurea and injection of insulin agent, may increase with hypoglycemic episodes and body weight.Additionally, patient in the course of time Body often loses response to sulfonylureas, produces tolerance.Metformin class and alpha-glucosidase inhibitor can frequently result in Gastrointestinal problems, PPAR-gamma agonist easily causes body weight to increase and edema.

For the research well afoot in multiple fields, to bringing more effective newly-developed hypoglycemic agent for market.Such as, Inventor is exploring minimizing liver glucose production too much at present, strengthens insulin and causes this signal path of glucose absorption Conduction, improve the insulin secretion (GSIS) that glucose stimulates in pancreatic beta cell, for fat and lipid metabolism, accumulate different The research of aspect such as often.

Free fatty (FFA) plays pivotal role in metabolic many aspects, including conduct in the fasted state Pancreatic beta cell strengthens the insulin " fuse cord " to glucose response, and as the starting point of lipid synthesis.Initially, GPR40 is first Find from human genome with the form of an orphan receptor.GPR40 is in pancreatic beta cell and the cell line of excreting insulin Middle high expressed.GPR40, also known as FAA 1 (FFAR1), is the one of g protein coupled receptor (" GPCRs ") gene superfamilies Member.GPCRs is the memebrane protein that a class has seven membrane spaning domains, different kinds of molecules can be produced response, thus in active cell Signal transduction pathway, to realizing, multiple physiological function is most important.The activation of GPR40 is related to regulate intracellular signal egg White Gq family, and attend by with induction calcium ion level rising.GPR40 is identified first fatty acid cell surface receptor, Can be in conjunction with such as palmitic acid, oleic acid, stearic acid, fatty acid the most universal in the blood plasma such as linoleic acid plus linolenic acid.GPR40 can also It is considered " nutrition sensing " receptor, plays multiple tissue dependence effect, total glucose utilization and/or fat may be affected therebetween Matter fat metabolism.Such as, long-chain free fatty acids is activated by GPR40, amplifies GSIS in pancreatic beta cell.

GPR40 modulator plays incretin effect and promotes GSIS, the most also can multiple treatment Rezulin Internet of Things Close and use.More than based on, GPR40 agonist can treat diabetes and relevant indication, especially type ii diabetes, fat, Glucose intolerance, insulin resistant, Metabolic syndrome X, hyperlipidemia, hypercholesterolemia, atherosclerosis, nerve moves back Row disease (such as Alzheimer's disease), and other indications such as apoplexy.Be potential therapy target with GPR40, find and The compound of transformation GPR40 has very important researching value and application prospect.

Disclose the patent application of a series of GPR40 agonist at present, including WO2005087710, WO2007106469, WO2004106276 and WO2010143733 etc..

Although the GPR40 agonist of the diseases such as a series for the treatment of diabetes and metabolic disease is had been disclosed at present, but Remain a need for developing new have more preferable drug effect, more long half-lift compound, through being continually striving to, present invention design has logical The compound of the structure shown in formula (I), and find that the compound with this class formation shows excellent effect and effect.

Summary of the invention

It is an object of the invention to provide the compound shown in a kind of logical formula (I) or its tautomer, mesomer, outer Raceme, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof.

Wherein:

R¹And R²It is each independently selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl, cycloalkyl, heterocycle Base, aryl, heteroaryl ,-OR⁷、-C(O)OR⁷、-OC(O)R⁷、-C(O)R⁷、-NHC(O)R⁷、-NR⁷R⁸、-OC(O)NR⁷R⁸、-NHC (O)NR⁷R⁸Or-S (O)_mR⁷, wherein said alkyl, alkoxyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optionally the most further by One or more selected from halogen, hydroxyl, carboxyl, cyano group, nitro, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR⁷、-C (O)OR⁷、-OC(O)R⁷、-C(O)R⁷、-NHC(O)R⁷、-NR⁷R⁸、-OC(O)NR⁷R⁸、-NHC(O)NR⁷R⁸Or-S (O)_mR⁷Replacement Base is replaced；

Or, R¹And R²Being fused into a cycloalkyl or heterocyclic radical with phenyl, wherein said cycloalkyl or heterocyclic radical optionally enter One step by one or more selected from R⁶Substituent group replaced；

R³、R⁴And R⁵It is each independently selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkyl, thiazolinyl, alkynyl, cycloalkanes Base, heterocyclic radical, aryl, heteroaryl ,-OR⁷、-C(O)OR⁷、-OC(O)R⁷、-C(O)R⁷、-NHC(O)R⁷、-NR⁷R⁸、-OC(O) NR⁷R⁸、-NHC(O)NR⁷R⁸Or-S (O)_mR⁷, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl The most further by one or more selected from halogen, hydroxyl, cyano group, nitro, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, virtue Base, heteroaryl ,-OR⁷、-C(O)OR⁷、-OC(O)R⁷、-C(O)R⁷、-NHC(O)R⁷、-NR⁷R⁸、-OC(O)NR⁷R⁸、-NHC(O) NR⁷R⁸Or-S (O)_mR⁷Substituent group replaced；

Or, R³、R⁴And R⁵Both middle arbitrary neighborhoods, such as R³And R⁴Or R⁴And R⁵, it is fused into a cycloalkanes with phenyl Base or heterocyclic radical, wherein said cycloalkyl or heterocyclic radical optionally the most further by one or more selected from R⁶Substituent group replaced；

R⁶It is each independently selected from halogen, hydroxyl, cyano group, nitro, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, virtue Base, heteroaryl ,-OR⁷、-C(O)OR⁷、-OC(O)R⁷、-C(O)R⁷、-NHC(O)R⁷、-NR⁷R⁸、-OC(O)NR⁷R⁸、-NHC(O) NR⁷R⁸Or-S (O)_mR⁷, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are further By one or more selected from halogen, hydroxyl, cyano group, nitro, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl Base ,-OR⁷、-C(O)OR⁷、-OC(O)R⁷、-C(O)R⁷、-NHC(O)R⁷、-NR⁷R⁸、-OC(O)NR⁷R⁸、-NHC(O)NR⁷R⁸Or-S (O)_mR⁷Substituent group replaced；

R⁷And R⁸It is each independently selected from hydrogen atom, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, Wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optionally the most further by one or more selected from halogen Element, hydroxyl, cyano group, nitro, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical or-S (O)_mR⁹Substituent group replaced；

R⁹For alkyl；And

M is 0,1 or 2.

In one embodiment of the invention, the compound shown in a kind of logical formula (I) or its tautomer, meso Body, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, it is logical formula (II) Described compound or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its mixture Form and pharmaceutically useful salt thereof:

Wherein:

Y is C, O, N or S atom；

L is cycloalkyl, heterocyclic radical, aryl or heteroaryl；

R⁹For alkyl；

M is 0,1 or 2；And

N is 0,1,2,3 or 4.

In one embodiment of the invention, the compound shown in a kind of logical formula (I) or its tautomer, meso Body, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, it is logical formula (III) Described compound or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its mixture Form and pharmaceutically useful salt thereof:

Wherein:

L is cycloalkyl, heterocyclic radical, aryl or heteroaryl；

R⁹For alkyl；

M is 0,1 or 2；And

N is 0,1,2,3 or 4.

In another embodiment of the present invention, the compound shown in a kind of logical formula (I) or its tautomer, meso Body, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, it is logical formula (IV) Described compound or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its mixture Form and pharmaceutically useful salt thereof:

Wherein: ring L, R³~R⁵Definition as described in logical formula (I).

In another embodiment of the present invention, the compound shown in a kind of logical formula (I) or its tautomer, meso Body, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, it is logical formula V institute The compound stated or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its mixture shape Formula and pharmaceutically useful salt thereof:

Wherein: ring L, R³~R⁵Definition as described in logical formula (I).

In another embodiment of the present invention, the compound shown in a kind of logical formula (I) or its tautomer, meso Body, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, wherein L is aryl, Preferably phenyl.

In another embodiment of the present invention, the compound shown in a kind of logical formula (I) or its tautomer, meso Body, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, wherein:

R³Selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or Heteroaryl, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further by one or many Individual selected from halogen, hydroxyl, cyano group, nitro, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or-OR⁷Take Replaced for base；

R⁴、R⁵For hydrogen atom or halogen；

R⁷For hydrogen atom or alkyl, wherein said alkyl is optionally further by one or more-S (O)_mR⁹Replaced；

R⁹For alkyl.

In another embodiment of the present invention, the compound shown in a kind of logical formula (I) or its tautomer, meso Body, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, wherein: R¹And R²Respectively From independently selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl Base, wherein said alkyl, alkoxyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optionally the most further by one or more selected from halogen The group of element, hydroxyl, carboxylic acid group, cyano group, nitro, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl is replaced.

In another embodiment of the present invention, the compound shown in a kind of logical formula (I) or its tautomer, meso Body, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, wherein R⁶For alkyl, Wherein said alkyl is further by one or more-C (O) OR⁷Replaced, R⁷For hydrogen atom or alkyl.

The typical compound of the present invention includes, but are not limited to:

Or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its mixture shape Formula and pharmaceutically useful salt thereof.

The invention further relates to a kind of compound shown in logical formula (I) or its tautomer, mesomer, outer prepared Raceme, enantiomer, diastereomer, its form of mixtures and the method for officinal salt thereof, the method includes following Step:

By being catalyzed in the presence of compound (IA) catalyst in the basic conditions, the product obtained is hydrolyzed the most further, Obtain general formula compound (I)；

Wherein: X is halogen, preferably bromine or iodine；R¹～R⁵, L definition as described in logical formula (I).

The invention further relates to a kind of pharmaceutical composition, it contains the compound shown in logical formula (I) of therapeutically effective amount Or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its form of mixtures and can Medicinal salt and pharmaceutically acceptable carrier.

Another aspect of the present invention relates to logical compound shown in formula (I) or its tautomer, mesomer, raceme Body, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, or the pharmaceutical composition comprising it exists Prepare the purposes in GPR40 agonist.

Another aspect of the present invention relates to logical compound shown in formula (I) or its tautomer, mesomer, raceme Body, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, or the pharmaceutical composition comprising it exists Preparation treatment diabetes and metabolic syndrome disease medicine in purposes, wherein said diabetes be preferably II type sugar Urine disease.

A kind of method that the invention still further relates to disease treating diabetes and metabolic syndrome, the method includes needing The compound shown in logical formula (I) of bacterium for the treatment of or its tautomer, mesomer, racemic modification, right Reflect isomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof or the pharmaceutical composition comprising it.

Another aspect of the present invention relates to as treatment diabetes and the logical formula (I) institute of the medicine of the disease of metabolic syndrome The compound shown or its tautomer, mesomer, racemic modification, enantiomer, diastereomer, its mixture shape Formula and pharmaceutically useful salt thereof, wherein said diabetes are preferably type ii diabetes.

Another aspect of the present invention relates to a kind of method regulating insulin, and the method includes that the patient that needs are treated is effective The compound shown in logical formula (I) of therapeutic dose or its tautomer, mesomer, racemic modification, enantiomer, diastereomeric Isomer, its form of mixtures and pharmaceutically useful salt thereof.

Another aspect of the present invention relates to the compound shown in the logical formula (I) of the medicine as regulation insulin or its change Isomer, mesomer, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof.

Detailed description of the invention

Unless stated to the contrary, the most following have following implication with term in the specification and in the claims." alkane Base " refer to saturated aliphatic hydrocarbon group, including straight chain and the branched group of 1 to 20 carbon atom.Preferably comprise 1 to 10 carbon atom Alkyl, more preferably contain the alkyl of 1 to 6 carbon atom.Non-limiting example includes methyl, ethyl, n-pro-pyl, isopropyl Base, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-diformazan Base propyl group, 1-ethyl propyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1,1,2-trimethyl Propyl group, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethyl amyl group, 2,4-dimethyl amyl group, 2,2-dimethyl amyl group, 3,3-dimethyl Amyl group, 2-ethyl pentyl group, 3-ethyl pentyl group, n-octyl, 2,3-dimethylhexanyl, 2,4-dimethylhexanyl, 2,5-dimethyl are own Base, 2,2-dimethylhexanyl, 3,3-dimethylhexanyl, 4,4-dimethylhexanyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl, 2-methyl-2-ethyl pentyl group, 2-methyl-3-ethyl pentyl group, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-second Base hexyl, 2,2-diethyl amyl group, positive decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomer Deng.The more preferably low alkyl group containing 1 to 6 carbon atom, non-limiting example includes methyl, ethyl, n-pro-pyl, different Propyl group, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-bis- Methyl-propyl, 1-ethyl propyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1,1,2-front three Base propyl group, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethyl fourth Base, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2,3-dimethylbutyl etc..Alkyl can be substituted or unsubstituted , when substituted, substituent group can be replaced on any spendable junction point, the most one or more following bases Group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, Cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo ,- OR⁷、-C(O)OR⁷、-OC(O)R⁷、-C(O)R⁷、-NHC(O)R⁷Or-S (O)_mR⁸。

" alkylidene " refers to that saturated aliphatic hydrocarbon formally eliminates the group that two hydrogen atoms are formed, including 1 to 20 The straight chain of individual carbon atom and branched group.Preferably comprise the alkyl of 1 to 10 carbon atom, more preferably contain 1 to 6 carbon atom Alkyl.The non-limiting example of alkylidene includes methylene, ethylidene, isopropylidene, 1-methyl propylene, butylidene, Asia Amyl group, hexylidene, 1,2-ethylidene, 1,3-propylidene, 1,6-hexylidene etc..Alkylidene can be substituted or unsubstituted, When substituted, substituent group can be replaced on any spendable junction point, the most one or more following groups, solely On the spot selected from alkyl, thiazolinyl, alkynyl, alkoxyl, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkanes Base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo ,-OR⁷、-C (O)OR⁷、-OC(O)R⁷、-C(O)R⁷、-NHC(O)R⁷Or-S (O)_mR⁸。

" cycloalkyl " refers to the saturated or unsaturated monocycle of part or multi-ring cyclic hydrocarbon substituent, and it includes 3 to 20 carbon atoms, Preferably include 3 to 12 carbon atoms, more preferably cycloalkyl ring to comprise 3 to 10 carbon atoms, most preferably cycloalkyl ring and comprise 3 to 6 Individual carbon atom, such as, can be 3,4,5,6 rings.The non-limiting example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, ring Amyl group, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, ring octyl group etc..Polycyclic naphthene Base includes the cycloalkyl of volution, condensed ring and bridged ring.

" spiro cycloalkyl group " refers to 5 to 20 yuan, shares the polycyclic moiety of a carbon atom (title spiro-atom) between monocycle, and these can With containing one or more double bonds, but neither one ring has the pi-electron system of total conjugated.It is preferably 6 to 14 yuan, more preferably It is 7 to 10 yuan.Spiro cycloalkyl group is divided into single spiro cycloalkyl group, double spiro cycloalkyl group base by the number according to spiro-atom shared between ring and ring Or many spiro cycloalkyl group, it is preferably single spiro cycloalkyl group and double spiro cycloalkyl group.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 Unit/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl group.The non-limiting example of spiro cycloalkyl group comprises

" cycloalkyl " refers to 5 to 20 yuan, and it is former that each ring in system and other rings in system share a pair carbon adjoined The full carbon polycyclic moiety of son, wherein one or more rings can contain one or more double bonds, but neither one ring has completely The pi-electron system of conjugation.It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three Ring, Fourth Ring or polycyclic fused ring alkyl, preferably dicyclo or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 yuan bicyclic alkyls.Condensed ring The non-limiting example of alkyl comprises

" bridge ring alkyl " refers to 5 to 20 yuan, and any two ring shares the many ring groups of full carbon of two carbon atoms not being directly connected to Group, these can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.It is preferably 6 to 14 Unit, more preferably 7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or multi-ring bridge ring alkyl, preferably For dicyclo, three rings or Fourth Ring, more elect dicyclo or three rings as.The non-limiting example of bridge ring alkyl comprises

Described cycloalkyl ring can condense on aryl, heteroaryl or heterocycloalkyl ring, is wherein connected to precursor structure Ring together is cycloalkyl, and non-limiting example includes indanyl, tetralyl, benzocyclohepta alkyl etc..Cycloalkyl is permissible Being optionally substituted or unsubstituted, when substituted, substituent group is preferably one or more following group, independently selected from alkane Base, thiazolinyl, alkynyl, alkoxyl, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, Aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo ,-OR⁷、-C(O)OR⁷、-OC(O) R⁷、-C(O)R⁷、-NHC(O)R⁷Or-S (O)_mR⁸。

" heterocyclic radical " refers to the saturated or unsaturated monocycle of part or multi-ring cyclic hydrocarbon substituent, and it includes 3 to 20 annular atomses, Wherein one or more annular atomses are selected from nitrogen, oxygen or S (O)_mThe hetero atom of (wherein m is integer 0 to 2), but do not include-O-O-,- The loop section of O-S-or-S-S-, remaining annular atoms is carbon.Preferably including 3 to 12 annular atomses, wherein 1～4 is hetero atom, More preferably heterocycloalkyl ring comprises 3 to 10 annular atomses, most preferably 5 rings or 6 rings.The non-limiting enforcement of monocyclic heterocycles base Example comprises pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base etc..Multiring heterocyclic include volution, Condensed ring and the heterocyclic radical of bridged ring." spiro heterocyclic radical " refers to 5 to 20 yuan, shares the multi-ring miscellaneous of an atom (title spiro-atom) between monocycle Cyclic group, wherein one or more annular atomses are selected from nitrogen, oxygen or S (O)_mThe hetero atom of (wherein m is integer 0 to 2), remaining ring is former Son is carbon.These can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.It is preferably 6 To 14 yuan, more preferably 7 to 10 yuan.Spiro cycloalkyl group is divided into single spiroheterocyclic by the number according to spiro-atom shared between ring and ring Base, double spiro heterocyclic radical or many spiro heterocyclic radicals, be preferably single spiro cycloalkyl group and double spiro cycloalkyl group.More preferably 4 yuan/4 yuan, 4 yuan/5 Unit, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl group.The non-limiting example of spiro cycloalkyl group comprises

" condensed hetero ring base " refers to 5 to 20 yuan, and each ring in system shares, with other rings in system, a pair atom adjoined Polycyclic heterocyclic group, one or more rings can contain one or more double bonds, but neither one ring has the π of total conjugated Electronic system, wherein one or more annular atomses are selected from nitrogen, oxygen or S (O)_mThe hetero atom of (wherein m is integer 0 to 2), remaining ring Atom is carbon.It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring Or multi-ring fused heterocycloalkyl, preferably dicyclo or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 yuan fused bicyclic heterocycle bases.Condensed hetero ring The non-limiting example of base comprises

" bridge heterocyclic radical " refers to 5 to 14 yuan, and any two ring shares the polycyclic heterocyclic group of two atoms not being directly connected to, These can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated, wherein one or more Annular atoms is selected from nitrogen, oxygen or S (O)_mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atoms is carbon.It is preferably 6 to 14 yuan, More preferably 7 to 10 yuan.7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or multi-ring bridge ring alkyl, It is preferably dicyclo, three rings or Fourth Ring, more elects dicyclo or three rings as.The non-limiting example of bridge ring alkyl comprises:

Described heterocyclic ring can condense on aryl, heteroaryl or cycloalkyl ring, is wherein connected to one with precursor structure The ring risen is heterocyclic radical, and non-limiting example comprises:

Deng.Heterocyclic radical can be optionally substituted or unsubstituted, and when substituted, substituent group is the most one or more Following group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, Cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxygen Generation ,-OR⁷、-C(O)OR⁷、-OC(O)R⁷、-C(O)R⁷、-NHC(O)R⁷Or-S (O)_mR⁸。

" cycloalkylidene " refers to that the saturated or unsaturated monocycle of part or multi-ring cyclic hydrocarbon formally eliminate two hydrogen atom institutes The group formed, it includes 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, more preferably monocycle cycloalkylidene ring and comprise 3 to 10 carbon atoms.The non-limiting example of monocycle cycloalkylidene comprises cyclopropylidene, sub-cyclobutyl, cyclopentylene, sub-ring Hexyl, cycloheptylidene, cyclooctylene, 1,2-cyclopropylidene, 1,3-Asia cyclobutyl, 1,4-cyclohexylidene etc..Multi-ring cycloalkylidene Including sub-volution, sub-condensed ring and the cycloalkylidene of sub-bridged ring.

" aryl " refers to 6 to 14 yuan of full carbon monocycles or fused polycycle (namely sharing the ring of adjacent carbon atoms pair) group, tool There is multi-ring (i.e. it is with the ring of phase adjacency pair carbon atom) group of the pi-electron system of conjugation, preferably 6 to 10 yuan, such as phenyl And naphthyl, most preferably phenyl.Described aryl rings can condense on heteroaryl, heterocyclic radical or cycloalkyl ring, wherein ties with parent The ring that structure links together is aryl rings, and non-limiting example comprises:

Aryl can be substituted or unsubstituted, and when substituted, substituent group is preferably one or more following group, Independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkanes Base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group ,-OR⁷、-C(O) OR⁷、-OC(O)R⁷、-C(O)R⁷、-NHC(O)R⁷Or-S (O)_mR⁸。

" heteroaryl " refers to comprise 1 to 4 hetero atom, and the heteroaromatic system of 5 to 14 annular atomses, wherein hetero atom includes Oxygen, sulfur and nitrogen.It is preferably 5 to 10 yuan.More preferably heteroaryl is 5 yuan or 6 yuan, such as furyl, thienyl, pyridine radicals, pyrroles Base, N-alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical, oxazolyl, isoxazolyl etc., preferably thienyl, pyridine Base, pyrimidine radicals, isoxazolyl.Described heteroaryl ring can condense on aryl, heterocyclic radical or cycloalkyl ring, wherein ties with parent The ring that structure links together is heteroaryl ring, and non-limiting example comprises:

Heteroaryl can be optionally substituted or unsubstituted, when substituted, substituent group be preferably one or more with Lower group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyanogen Base, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group ,-OR⁷、- C(O)OR⁷、-OC(O)R⁷、-C(O)R⁷、-NHC(O)R⁷Or-S (O)_mR⁸。

" alkoxyl " refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), and wherein alkyl is as defined above.Non-limit Property embodiment processed comprises methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy Deng.Alkoxyl can be optionally substituted or unsubstituted, and when substituted, substituent group is preferably one or more following base Group, independently selected from for alkyl, thiazolinyl, alkynyl, alkoxyl, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyanogen Base, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group ,-OR⁷、- C(O)OR⁷、-OC(O)R⁷、-C(O)R⁷、-NHC(O)R⁷Or-S (O)_mR⁸。

Term " thiazolinyl " refers to by the alkane as defined above being at least made up of two carbon atoms and at least one carbon-to-carbon double bond Base, such as vinyl, 1-acrylic, 2-acrylic, 1-, 2-or 3-cyclobutenyl etc..Preferably C_2-10Thiazolinyl, more preferably C_2-6Thiazolinyl, Most preferably C_2-4Thiazolinyl.Thiazolinyl can be substituted or non-substituted, when substituted, substituent group be preferably one or more with Lower group, its independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, Cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group ,-C (O)R⁷、-C(O)OR⁷、-S(O)_mR⁷、-NR⁸R⁹、-C(O)NR⁸R⁹、-NR⁸C(O)R⁹、-NR⁸S(O)_mR⁹Or-S (O)_mNR⁸R⁹。

Term " alkynyl " refers to the alkane as defined above being at least made up of two carbon atoms and at least one carbon-to-carbon triple bond Base, such as acetenyl, 1-propinyl, 2-propynyl, 1-, 2-or 3-butynyl etc..Preferably C_2-10Alkynyl, more preferably C_2-6Alkynyl, Most preferably C_2-3Alkynyl.Alkynyl can be substituted or non-substituted, when substituted, substituent group be preferably one or more with Lower group, its independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, Cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group ,-C (O)R⁷、-C(O)OR⁷、-S(O)_mR⁷、-NR⁸R⁹、-C(O)NR⁸R⁹、-NR⁸C(O)R⁹、-NR⁸S(O)_mR⁹Or-S (O)_mNR⁸R⁹。

" haloalkyl " refers to that alkyl is by one or more halogen substiuted.

" hydroxyl " refers to-OH group.

" halogen " refers to fluorine, chlorine, bromine or iodine.

" amino " refers to-NH₂。

" cyano group " refers to-CN.

" nitro " refers to-NO₂。

" benzyl " refers to-CH₂-phenyl.

" oxo " refers to=O.

" carboxylic acid group " refers to-C (O) OH.

" carboxylic acid ester groups " refers to-C (O) O (alkyl) or (cycloalkyl), and wherein alkyl is as defined above.

" optionally " or " optionally " mean ground described later event or environment can but need not occur, this explanation includes This event or environment occur or not spot occasion.Such as, " heterocyclic group optionally replaced by alkyl " means that alkyl is permissible But necessarily existing, this explanation includes situation that heterocyclic group replaced by alkyl and the situation that heterocyclic group is not replaced by alkyl.

" substituted " refers to the one or more hydrogen atoms in group, is preferably at most 5, more preferably 1～3 hydrogen atom Replaced by the substituent group of respective number independently of one another.Self-evident, substituent group is only in their possible chemical position, this Skilled person can not pay too much make great efforts in the case of determine that (by experiment or theoretical) may or impossible take Generation.Such as, amino or the hydroxyl with free hydrogen are probably shakiness when the carbon atom with unsaturation (such as olefinic) key is combined Fixed.

" pharmaceutical composition " represent containing one or more compounds described herein or its physiologically/pharmaceutically useful salt or The mixture of prodrug and other chemical constituents, and other components such as physiology/pharmaceutically useful carrier and excipient.Medicine The purpose of compositions is to promote the absorption of the administration to organism, beneficially active component and then play biological activity.

M and R⁷～R⁸Definition as described in logical formula (I) compound.

The synthetic method of the compounds of this invention

In order to complete the purpose of the present invention, the present invention adopts the following technical scheme that

The present invention leads to the compound described in formula (I) or the preparation method of its pharmaceutically useful salt, comprises the following steps:

Wherein: PG is the silicon-based protecting group of hydroxyl, the silicon-based protecting group of wherein said hydroxyl selected from trimethyl silica-based, three Ethyl is silica-based, t-Butyldimethylsilyl, triisopropylsilyl or tert-butyl diphenyl silica-based；

X is selected from halogen, preferably bromine or iodine；R¹～R⁵, L definition identical with the definition of logical formula (I).

Aldehyde radical substituted ring L compound a reacts with wittig reagent (Wei Dixi reagent) in the basic conditions, obtains ethylene Base substituted ring L compound b；The ring L compound b of vinyl substituted reacts with oxidant, obtains dihydroxy compounds c；Dihydroxy Based compound c in the basic conditions, reacts with substituted chlorosilane, obtains siloxy compound d；

Hydroxyl substituted phenyl compound e reacts with halogenating agent, obtains the phenyl compound f of hydroxyl, halogen substiuted；Hydroxyl Base, halogen substiuted phenyl compound f and siloxy compound d in a solvent with Phosphine ligands and azodicarbonic acid ester or azo formyl Amine etc. occur Mitsunobu reaction to obtain compound g；Compound g is under the conditions of acid reagent or fluorization agent, and in solvent, hydrolysis is de- Fall silylation, obtain compound (IA)；Compound (IA) is catalyzed the most in the presence of a catalyst, the product that will obtain Hydrolysis, obtains general formula compound (I) the most further.

The acid providing acid condition includes but not limited to formic acid, acetic acid, hydrochloric acid, sulphuric acid, methanesulfonic acid, tetrabutylammonium chloride.

The alkali providing alkalescence condition includes that organic base and inorganic base, described organic bases include but not limited to three second Amine, DMAP, imidazoles, DIPEA, n-BuLi, potassium tert-butoxide, tetrabutyl ammonium bromide, it is preferably Triethylamine；Described inorganic base includes but not limited to sodium hydride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or carbonic acid Caesium, preferably potassium carbonate or cesium carbonate.

Wittig reagent includes but not limited to methyltriphenylphospbromide bromide or methyltriphenylphosphonium iodide.

Catalyst includes but not limited to tetra-triphenylphosphine palladium, triphenylphosphine, palladium chloride, palladium, 1,1 '-bis-(dibenzyls Base phosphorus) dichloro diamyl ferrum palladium, three (dibenzalacetone) two palladium, palladium/carbon or Raney Ni.

The Phosphine ligands that Phosphine ligands is three substituent groups related in Mitsunobu reaction, includes but not limited to triphenyl Phosphine, tributylphosphine or methyldiphenyl base phosphine, triphenylphosphine.

The azodicarbonic acid ester or the azodicarbonamide that relate in Mitsunobu reaction include but not limited to azoformic acid two Methyl ester, diethyl azodiformate or azodicarbonamide two piperidines.

Oxidant includes but not limited to Osmic acid., phosphorus oxychloride.

Halogenating agent includes but not limited to bromine water or halogenide；It is preferably lodine chloride.

Solvent for use includes but not limited to: acetic acid, methanol, ethanol, acetone, the tert-butyl alcohol, ether, oxolane, dichloromethane Alkane, dimethyl sulfoxide, toluene, 1,4-dioxane, water or N,N-dimethylformamide.

Detailed description of the invention

It is used for further describing the present invention below in conjunction with embodiment, but these embodiments not limit the model of the present invention Enclose.

Embodiment

The structure of compound is determined by nuclear magnetic resonance, NMR (NMR) or mass spectrum (MS).The mensuration of NMR is to use Bruker AVANCE-400 nuclear magnetic resonance spectrometer, measuring solvent is deuterated dimethyl sulfoxide (DMSO-d₆), deuterochloroform (CDCl₃), deuterated methanol (CD₃OD), being inside designated as tetramethylsilane (TMS), chemical shift is with 10^-6(ppm) be given as unit.

The mensuration of MS FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Thermo, model: Finnigan LCQ advantage MAX)。

The mensuration of HPLC uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150 × 4.6mm chromatograph Post) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150 × 4.6mm chromatographic column).

Kinases average inhibition and IC₅₀The mensuration of value is with NovoStar microplate reader (Germany BMG company).

Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, and thin layer chromatography (TLC) makes Silica gel plate use specification be 0.15mm～0.2mm, the isolated and purified product of thin layer chromatography use specification be 0.4mm～ 0.5mm silica gel plate.

It is carrier that column chromatography generally uses the Yantai Huanghai Sea 200 ~ 300 mesh silica gel.

The known initiation material of the present invention can use or synthesize according to methods known in the art, or commercially available from ABCR GmbH&Co.KG, Acros Organnics, Aldrich Chemical Company, splendid remote chemistry science and technology (Accela ChemBio Inc), reach the companies such as auspicious chemicals.

In embodiment if no special instructions, reaction is all carried out under argon atmospher or blanket of nitrogen.

Argon atmospher or blanket of nitrogen refer to that reaction bulb connects argon or the nitrogen balloon of an about 1L volume.

Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 1L volume.

Pressure hydration reaction uses Parr 3916EKX type hydrogenation instrument and clear blue QL-500 type hydrogen generator or HC2-SS Type hydrogenation instrument.

The usual evacuation of hydrogenation, is filled with hydrogen, repeatable operation 3 times.

Microwave reaction uses CEM Discover-S 908860 type microwave reactor.

In embodiment if no special instructions, the solution in reaction refers to aqueous solution.

In embodiment if no special instructions, the temperature of reaction is room temperature, and temperature range is 20 DEG C～30 DEG C.

The monitoring of the reaction process in embodiment uses thin layer chromatography (TLC), the system of the developing solvent that reaction is used Have: A: dichloromethane and methanol system, B: normal hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: acetone, The volume ratio of solvent is adjusted according to the polarity difference of compound.

The system of the system of the eluant of the column chromatography that purification compound uses and the developing solvent of thin layer chromatography includes: A: Dichloromethane and methanol system, B: normal hexane and ethyl acetate system, C: normal hexane and acetone system, D: normal hexane, E: acetic acid Ethyl ester, the volume ratio of solvent is adjusted according to the polarity difference of compound, it is also possible to add a small amount of triethylamine and acidity Or alkaline reagent etc. is adjusted.

Embodiment 1

2-((8S)-3-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxyl group) biphenyl-3-base)-2,3,7,8-tetrahydrochysene Benzofuran also [5,6-b] [1,4] two English-8-base) acetic acid

The first step

2,6-dimethyl-4-(3-(methylsulfonyl) propoxyl group)-3 '-vinyl biphenyl

By 2 ', (10g, 28.90mmol use 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxyl group) biphenyl-3-formaldehyde 1a Known method " patent WO2008001931 " is prepared) it is dissolved in 155mL dioxane and water (V/V=30:1) mixes molten In agent, add potassium carbonate (10g, 72.30mmol) and methyltriphenylphosphonium iodide (23.40g, 57.80mmol), be warming up to 100 DEG C, stirring reaction 12 hours.Pour in 200mL water, be extracted with ethyl acetate (150mL × 3), merge organic facies, use saturated chlorine Changing sodium solution washing (50mL × 3), anhydrous magnesium sulfate is dried, and filters, and concentrating under reduced pressure filtrate, with silica gel column chromatography with eluant System B purification gained residue, obtains title product 2,6-dimethyl-4-(3-(methylsulfonyl) propoxyl group)-3 '-vinyl biphenyl 1b (8g, white solid), productivity: 80.0%.

Second step

1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxyl group) biphenyl-3-base) ethane-1,2-glycol

N-methyl morpholine oxide (3.10g, 26.10mmol) and Osmic acid. (112mg, 0.44mmol) are dissolved in 40mL In the mixed solvent of water, acetone and the tert-butyl alcohol (V/V/V=5:2:1), add 13mL 2,6-dimethyl-4-(3-(methylsulfonyl) third Epoxide) acetone of-3 '-vinyl biphenyl 1b (3g, 8.70mmol) and the mixed solvent of dichloromethane (V/V=10:3), stirring is anti- Answer 2 hours.Add 100mL sodium thiosulfate, be extracted with ethyl acetate (100mL × 3), merge organic facies, successively with sulfur for sulfur Acid sodium (100mL × 2), saturated nacl aqueous solution washing (50mL × 3), anhydrous magnesium sulfate is dried, and filters, concentrating under reduced pressure filtrate, Obtain crude title product 1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxyl group) biphenyl-3-base) ethane-1,2-glycol 1c (3g, gray solid), product is the most purified directly carries out next step reaction.

MS m/z(ESI):361.1[M-18]

3rd step

2-(tertiary butyl dimethyl Si base)-1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxyl group) biphenyl-3- Base) ethanol

By crude product 1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxyl group) biphenyl-3-base) ethane-1,2-glycol 1c (2.80g, 7.40mmol), imidazoles (136mg, 14.80mmol) and DMAP (90mg, 0.74mmol) are dissolved in 20mLN, in dinethylformamide, adds tert-butyl chloro-silicane (1.20g, 7.77mmol), stirring reaction 1 hour. Add 100mL water, be extracted with ethyl acetate (50mL × 3), merge organic facies, wash (50mL × 3) with saturated nacl aqueous solution, Anhydrous magnesium sulfate is dried, and filters, concentrating under reduced pressure filtrate, purifies gained residue with silica gel column chromatography with eluant system B, To title product 2-(tertiary butyl dimethyl Si base)-1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxyl group) biphenyl-3- Base) ethanol 1d (2.60g, white oil thing), productivity: 72.2%.

4th step

(S)-2-(6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate

By 2-(6-hydroxyl-2,3-Dihydrobenzofuranes-3-base) methyl acetate 1e, (1g, 4.80mmol use known side Method " patent CN101616913 " is prepared) carry out chiral separation, use HPLC method, chiral with Preparation equipment and chiral column Isomer carry out separating (separation condition: chiral column Chiralpak IA, flow phase: normal hexane: oxolane=80:20, flow velocity: 1.0mL/ minute), collect its respective components, rotary evaporation removes solvent, obtains (S)-2-(6-hydroxyl-2,3-dihydrobenzo furan Mutter-3-base) methyl acetate (500mg, 2.40mmol), under ice bath, reactant is dissolved in 15mL ether, adds lodine chloride (390mg, 2.40mmol), stirring reaction 12 hours.Add 20mL water and 20mL ethyl acetate, add 30mL five and be hydrated sulfur generation Aqueous sodium persulfate solution, separatory, it is extracted with ethyl acetate (50mL × 3), merges organic facies, use sodium thiosulfate solution successively (20mL × 3), water (20mL × 3), saturated nacl aqueous solution washing (20mL × 3), anhydrous magnesium sulfate is dried, and filters, reduces pressure dense Contracting filtrate, purifies gained residue with silica gel column chromatography with eluant system B, obtains title product (S)-2-(6-hydroxyl-5- Iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 1f (530mg, yellow oil), productivity: 66.0%.

MS m/z(ESI):333.0[M-1]

5th step

2-((3S)-6-(2-(tertiary butyl dimethyl Si base)-1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) the third oxygen Base) biphenyl-3-base) ethyoxyl)-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate

By (S)-2-(6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 1f (200mg, 0.60mmol), 2-(tertiary butyl dimethyl Si base)-1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxyl group) biphenyl-3- Base) ethanol 1d (295mg, 0.60mmol) and azodicarbonyldipiperidine (242mg, 0.96mmol) be dissolved in 10mL toluene, Add tri-butyl phosphine (194mg, 0.96mmol), be heated to 50 DEG C, stirring reaction 12 hours.Add 5mL methanol, concentrating under reduced pressure Reactant liquor, purifies gained residue with silica gel column chromatography with eluant system B, obtains title product 2-((3S)-6-(2-(uncle Butyldimethylsilanyloxy)-1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxyl group) biphenyl-3-base) ethyoxyl)-5- Iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 1g (410mg, yellow liquid), productivity: 84.7%.

MS m/z(ESI):826.6[M+18]

6th step

2-((3S)-6-(1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxyl group) biphenyl-3-base)-2-'-hydroxyethoxy Base)-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate

By 2-((3S)-6-(2-(tertiary butyl dimethyl Si base)-1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) third Epoxide) biphenyl-3-base) ethyoxyl)-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 1g (390mg, 0.48mmol) Being dissolved in 10mL oxolane, add the tetrahydrofuran solution of 1M tetrabutyl ammonium fluoride (0.5mL, 0.50mmol), stirring is anti- Answer 2 hours.Concentrating under reduced pressure reactant liquor, purifies gained residue with silica gel column chromatography with eluant system B, obtains title product 2-((3S)-6-(1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxyl group) biphenyl-3-base)-2-hydroxyl-oxethyl)-5- Iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 1h (260mg, white solid), productivity: 77.6%.

MS m/z(ESI):712.4[M+18]

7th step

2-((8S)-3-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxyl group) biphenyl-3-base)-2,3,7,8-tetrahydrochysene Benzofuran also [5,6-b] [1,4] two English-8-base) methyl acetate

By 2-((3S)-6-(1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxyl group) biphenyl-3-base)-2-hydroxyl second Epoxide)-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 1h (215mg, 0.31mmol), acid chloride (10mg, 0.05mmol), 2-(di-t-butyl phosphorus)-1,1'-dinaphthalene (37mg, 0.09mmol) and cesium carbonate (201mg, 0.62mmol) dissolve In 10mL toluene, it is heated to 50 DEG C, stirring reaction 12 hours.Filtering, concentrating under reduced pressure filtrate, with silica gel column chromatography with eluting Agent system B purification gained residue, obtains title product 2-((8S)-3-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) the third oxygen Base) biphenyl-3-base)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 1j (80mg, Yellow liquid), productivity: 45.7%.

MS m/z(ESI):584.2[M+18]

8th step

By 2-((8S)-3-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxyl group) biphenyl-3-base)-2,3,7,8-four Hydrogen benzofuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 1j (80mg, 0.14mmol) is dissolved in 6mL tetrahydrochysene furan Mutter and in methanol (V/V=1:5) mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 68 DEG C, stirring reaction 1 hour.Adding 10mL water and 10mL ethyl acetate, dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, is extracted with ethyl acetate (30mL × 3), merging organic facies, wash (30mL) with saturated nacl aqueous solution, anhydrous magnesium sulfate is dried, and filters, concentrating under reduced pressure filtrate, Purify gained residue by HPLC preparative chromatography with eluant system A, obtain title product 2-((8S)-3-(2 ', 6 '-diformazan Base-4 '-(3-(methylsulfonyl) propoxyl group) biphenyl-3-base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English- 8-yl) acetic acid 1 (54mg, white solid), productivity: 64.1%.

MS m/z(ESI):551.5[M-1]

¹H NMR(400MHz,CDCl₃)δ7.45-7.49(m,1H),7.37-7.38(m,1H),7.14-7.18(m,2H), 6.77(s,1H),6.66(s,2H),6.47(s,1H),5.12-5.14(m,1H),4.71-4.76(m,1H),4.31-4.34(m, 1H),4.23-4.27(m,1H),4.12-4.15(m,2H),3.94-3.99(m,1H),3.81(m,1H),3.26-3.30(m, 2H),2.98(s,3H),2.78-2.83(m,1H),2.60-2.66(m,1H),2.33-2.39(m,2H),2.02(s,3H), 2.00(s,3H).

Embodiment 2

2-((3R, 8S)-3-(2 ', 6 '-dimethyl-4 '-(3-(mesyl) propoxyl group) biphenyl-3-base)-2,3,7,8- Tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid

By 2-((8S)-3-(2 ', 6 '-dimethyl-4 '-(3-(mesyl) propoxyl group) biphenyl-3-base)-2,3,7,8- Tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 1 (0.19g, 0.35mmol) carries out chiral separation, uses HPLC method, carries out separating (separation condition: chiral column Chiralpak IA, stream with the chiral isomer of Preparation equipment and chiral column Dynamic phase: ethanol: acrylonitrile: acetic acid=85:15:0.1, flow velocity: 1.0mL/ minute), collect its respective components, rotary evaporation removes Solvent, obtains title product 2-((3R, 8S)-3-(2 ', 6 '-dimethyl-4 '-(3-(mesyl) propoxyl group) biphenyl-3- Base)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 2 (0.09g, white solid).

Embodiment 3

2-((3S, 8S)-3-(2 ', 6 '-dimethyl-4 '-(3-(mesyl) propoxyl group) biphenyl-3-base)-2,3,7,8- Tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid

By 2-((8S)-3-(2 ', 6 '-dimethyl-4 '-(3-(mesyl) propoxyl group) biphenyl-3-base)-2,3,7,8- Tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 1 (0.19g, 0.35mmol) carries out chiral separation, uses HPLC method, carries out separating (separation condition: chiral column Chiralpak IA, stream with the chiral isomer of Preparation equipment and chiral column Dynamic phase: ethanol: acrylonitrile: acetic acid=85:15:0.1, flow velocity: 1.0mL/ minute), collect its respective components, rotary evaporation removes Solvent, obtains title product 2-((3S, 8S)-3-(2 ', 6 '-dimethyl-4 '-(3-(mesyl) propoxyl group) biphenyl-3- Base)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 3 (0.10g, white solid).

Embodiment 4

2-(3-(2'-chlorodiphenyl-3-base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8- Base) acetic acid

The first step

1-bromo-3-vinyl benzene

3-bromobenzaldehyde 4a (10g, 54.05mmol) is dissolved in 102mL dioxane and water (V/V=50:1) mixes molten In agent, add potassium carbonate (18.64g, 135mmol) and methyltriphenylphosphonium iodide (43.70g, 108.11mmol), be warming up to 100 DEG C, stirring reaction 12 hours.Filtering, filter cake 200mL normal hexane and ethyl acetate (V/V=50:1) mixed solvent wash, Filtrate reduced in volume, purifies gained residue with silica gel column chromatography with eluant system B, obtains title product 1-bromo-3-second Alkenyl benzene 4b (10g, yellow liquid), productivity: 100.0%.

Second step

1-(3-bromophenyl) ethane-1,2-glycol

N-methyl morpholine oxide (9.59g, 81.90mmol) and Osmic acid. (350mg, 1.37mmol) are dissolved in 40mL In the mixed solvent of water, acetone and the tert-butyl alcohol (V/V/V=5:2:1), addition 13mL 1-bromo-3-vinyl benzene 4b (5g, Acetone 27.30mmol) and the mixed solvent of dichloromethane (V/V=10:3), stirring reaction 30 minutes.Add the saturated sulfur of 30mL Sodium thiosulfate solution, stirs 30 minutes, is extracted with ethyl acetate (30mL × 3), merges organic facies, successively with water (20mL × 2), Saturated nacl aqueous solution washing (20mL × 2), anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, obtains crude title product 1-(3-bromophenyl) ethane-1,2-glycol 4c (4.70g, yellow solid), product is the most purified directly carries out next step reaction.

MS m/z(ESI):236.34[M+18]

3rd step

1-(3-bromophenyl)-2-((t-butyldimethyl silane) oxygen) ethanol

By crude product 1-(3-bromophenyl) ethane-1,2-glycol 4c (4.50g, 20.73mmol), imidazoles (2.82g, 41.46mmol) it is dissolved in 30mL DMF with DMAP (253mg, 2.07mmol), then adds Enter tert-butyl chloro-silicane (3.75g, 24.88mmol), stirring reaction 1 hour.Add 100mL water and 100mL acetic acid second Ester, extracts separatory, organic phase washed with water (30mL × 3), saturated nacl aqueous solution washing (30mL × 3), and anhydrous sodium sulfate is done Dry, filter, filtrate reduced in volume, purify gained residue with silica gel column chromatography with eluant system B, obtain title product 1- (3-bromophenyl)-2-((t-butyldimethyl silane) oxygen) ethanol 4d (5g, yellow liquid), productivity: 72.8%.

MS m/z(ESI):329.1[M-1]

4th step

2-(6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate

Under ice bath, by molten for 2-(6-hydroxyl-2,3-Dihydrobenzofuranes-3-base) methyl acetate 1e (12g, 57.70mmol) Solution, in 100mL ether, adds lodine chloride (9.40g, 57.70mmol), is warmed to room temperature, stirring reaction 2 hours.Add 100mL water, Being extracted with ethyl acetate (50mL × 3), merge organic facies, wash (50mL × 3) with saturated nacl aqueous solution, anhydrous magnesium sulfate is done Dry, filter, filtrate reduced in volume, with n-hexane and ethyl acetate system recrystallization purifying gained residue, obtain crude title Product 2-(6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 4e (8.50g, gray solid), product without Purification directly carries out next step reaction.

5th step

2-(6-(1-(3-bromophenyl)-2-((tert-butyldimethyl silyl) oxygen) ethyoxyl)-5-iodo-2,3-dihydrobenzo furan Mutter-3-base) methyl acetate

By 1-(3-bromophenyl)-2-((t-butyldimethyl silane) oxygen) ethanol 4d (3.70g, 11.18mmol), crude product 2- (6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 4e (3.73g, 11.18mmol) and azo two formyl two Piperidines (4.51g, 17.89mmol) is dissolved in 50mL toluene, adds tri-butyl phosphine (4.5mL, 17.89mmol), is heated to 50 DEG C, stirring reaction 30 minutes.Addition 20mL methanol, reactant liquor concentrating under reduced pressure is pure with eluant system B with silica gel column chromatography Change gained residue, obtain title product 2-(6-(1-(3-bromophenyl)-2-((tert-butyldimethyl silyl) oxygen) ethyoxyl)-5- Iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 4f (8g, yellow liquid), productivity: 100.0%.

6th step

2-(6-(1-(3-bromophenyl)-2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate

By 2-(6-(1-(3-bromophenyl)-2-((tert-butyldimethyl silyl) oxygen) ethyoxyl)-5-iodo-2,3-dihydrobenzo Furan-3-base) methyl acetate 4f (8g, 12.36mmol) is dissolved in 50mL oxolane, adds tetrabutyl ammonium fluoride (13.6mL, 13.60mmol), stirring reaction 1 hour.Reactant liquor concentrating under reduced pressure is pure with eluant system B with silica gel column chromatography Change gained residue, obtain title product 2-(6-(1-(3-bromophenyl)-2-hydroxyl-oxethyl)-5-iodo-2,3-dihydrobenzo furan Mutter-3-base) methyl acetate 4g (5g, yellow liquid), productivity: 75.9%.

MS m/z(ESI):552.1[M-1]

7th step

2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid first Ester

By 2-(6-(1-(3-bromophenyl)-2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-base) acetic acid first Ester 4g (1g, 1.87mmol), acid chloride (63mg, 0.28mmol), 2-(di-t-butyl phosphorus)-1,1'-dinaphthalene (224mg, 0.56mmol) being dissolved in 6mL toluene with cesium carbonate (1.22g, 3.74mmol), microwave heating to 130 DEG C, stirring reaction 3 is little Time.Filtering, filter cake ethyl acetate washs (5mL × 3), and filtrate reduced in volume is pure with eluant system B with silica gel column chromatography Change gained residue, obtain title product 2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 4h (310mg, yellow liquid), productivity: 40.8%.

MS m/z(ESI):424.2[M+18]

8th step

2-(3-(2'-chlorodiphenyl-3-base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8- Base) methyl acetate

By 2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid Methyl ester 4h (150mg, 0.37mmol), (2-chlorphenyl) boric acid (69mg, 0.44mmol), tetra-triphenylphosphine palladium (21.40mg, 0.02mmol) it is dissolved in 5.5mL dioxane and water (V/V=10:1) mixed solvent with cesium carbonate (361mg, 1.11mmol), It is heated to 90 DEG C, stirring reaction 3 hours.Filtering, filter cake ethyl acetate washs (5mL × 3), and anhydrous magnesium sulfate is dried, and filters, Filtrate reduced in volume, purifies gained residue with silica gel column chromatography with eluant system B, obtains title product 2-(3-(2'- Chlorodiphenyl-3-base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) methyl acetate 4i (100mg, yellow liquid), productivity: 62.1%.

MS m/z(ESI):454.3[M+18]

9th step

By 2-(3-(2'-chlorodiphenyl-3-base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8- Base) methyl acetate 4i (100mg, 0.23mmol) is dissolved in 5mL methanol and oxolane (V/V=4:1) mixed solvent, adds Sodium hydroxide (92mg, 2.30mmol), is heated to 50 DEG C, stirring reaction 30 minutes.Reactant liquor concentrating under reduced pressure, add 10mL water and 10mL ethyl acetate, dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, extraction separatory, and organic phase washed with water (10mL × 2) is saturated Sodium chloride solution washing (10mL × 2), anhydrous sodium sulfate is dried, and filters, and filtrate reduced in volume, with silica gel column chromatography with eluting Agent system A purification gained residue, obtains title product 2-(3-(2'-chlorodiphenyl-3-base)-2,3,7,8-tetrahydro benzo furans Mutter also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 4 (100mg, white solid), productivity: 100.0%.

MS m/z(ESI):440.2[M+18]

¹H NMR(400MHz,CDCl₃)δ7.42-7.50(m,5H),7.29-7.38(m,3H),6.79(s,1H),6.49 (s,1H),5.15-5.18(m,1H),4.72-4.76(m,1H),4.35-4.38(m,1H),4.24-4.28(m,1H),3.99- 4.04(m,1H),3.78-3.84(m,1H),2.78-2.84(m,1H),2.60-2.67(m,1H).

Embodiment 5

2-(3-(3-(3-chloropyridine-4-base) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid

The first step

Methyl ester

By 2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid Methyl ester 4h (130mg, 0.32mmol), (3-chloropyridine-4-base) boric acid (61mg, 0.39mmol), tetra-triphenylphosphine palladium (19mg, 0.02mmol) it is dissolved in 4.5mL dioxane and water (V/V=8:1) mixed solvent with cesium carbonate (312mg, 0.96mmol), It is heated to 95 DEG C, stirring reaction 12 hours.Filtering, filter cake ethyl acetate washs (5mL × 3), and anhydrous magnesium sulfate is dried, mistake Filter, filtrate reduced in volume, purify gained residue with silica gel column chromatography with eluant system B, obtain title product 2-(3- (3-(3-chloropyridine-4-base) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid first Ester 5a (28mg, yellow liquid), productivity: 20.0%.

MS m/z(ESI):438.3[M+1]

Second step

By 2-(3-(3-(3-chloropyridine-4-base) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) methyl acetate 5a (28mg, 0.23mmol) is dissolved in 5mL methanol and oxolane (V/V=4:1) mixed solvent, Add sodium hydroxide (2.60mg, 0.64mmol), be heated to 50 DEG C, stirring reaction 1 hour.Reactant liquor concentrating under reduced pressure, adds 10mL water and 10mL ethyl acetate, dropping 1M hydrochloric acid be 3 ~ 4 to reactant liquor pH, separatory, aqueous phase be extracted with ethyl acetate (5mL × 3), merging organic facies, successively with water (10mL × 3), saturated nacl aqueous solution washing (10mL × 3), anhydrous sodium sulfate is dried, mistake Filter, filtrate reduced in volume, purify gained residue with silica gel column chromatography with eluant system A, obtain title product 2-(3- (3-(3-chloropyridine-4-base) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid 5 (25mg, white solid), productivity: 92.6%.

MS m/z(ESI):422.2[M-1]

¹H NMR(400MHz,CDCl₃)δ8.70(s,1H),8.55-8.56(m,1H),7.51-7.57(m,4H),7.32- 7.33(m,1H),6.80(s,1H),6.49(s,1H),5.18-5.20(m,1H),4.73-4.77(m,1H),4.35-4.38(m, 1H),4.25-4.29(m,1H),3.98-4.03(m,1H),3.83(m,1H),2.78-2.84(m,1H),2.61-2.67(m, 1H).

Embodiment 6

2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) second Acid

The first step

2-((3S)-6-(1-(3-bromomethyl)-2-(tertiary butyl dimethyl Si base) ethyoxyl)-5-iodo-2,3-dihydrobenzene And furan-3-base) methyl acetate

By (S)-2-(6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 1f (4.50g, 13.47mmol), 1-(3-bromomethyl)-2-(tertiary butyl dimethyl Si base) ethanol 4d (4.46g, 13.47mmol) and azo two Formyl two piperidines (25.43g, 21.56mmol) is dissolved in 60mL toluene, adds tri-butyl phosphine (4.36g, 21.56mmol), It is heated to 50 DEG C, stirring reaction 12 hours.Adding 5mL methanol, concentrating under reduced pressure reactant liquor, with silica gel column chromatography with eluant body It is B purification gained residue, obtains title product 2-((3S)-6-(1-(3-bromomethyl)-2-(tertiary butyl dimethyl Si base) Ethyoxyl)-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 6a (4.80g, yellow liquid), productivity: 55.2%.

MS m/z(ESI):666.3[M+18]

Second step

2-((3S)-6-(1-(3-bromophenyl)-2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-base) acetic acid Methyl ester

By 2-((3S)-6-(1-(3-bromomethyl)-2-(tertiary butyl dimethyl Si base) ethyoxyl)-5-iodo-2,3-dihydro Benzofuran-3-base) methyl acetate 6a (4.80g, 7.42mmol) is dissolved in 50mL oxolane, adds the fluorination of the 1M tetrabutyl The tetrahydrofuran solution of ammonium (8.2mL, 8.16mmol), stirring reaction 2 hours.Concentrating under reduced pressure reactant liquor, uses silica gel column chromatography With eluant system B purification gained residue, obtain title product 2-((3S)-6-(1-(3-bromophenyl)-2-'-hydroxyethoxy Base)-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 6b (2.53g, yellow liquid), productivity: 64.1%.

MS m/z(ESI):533.0[M+1]

3rd step

2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) second Acid methyl ester

By 2-((3S)-6-(1-(3-bromophenyl)-2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-base) second Acid methyl ester 6b (1g, 1.87mmol), acid chloride (63mg, 0.28mmol), 2-(di-t-butyl phosphorus)-1,1'-dinaphthalene (224mg, 0.56mmol) being dissolved in 6mL toluene with cesium carbonate (1.22g, 3.74mmol), microwave heating to 130 DEG C, stirring reaction 3 is little Time.Filter, wash (5mL × 4) by ethyl acetate, concentrating under reduced pressure filtrate, purifies institute with silica gel column chromatography with eluant system B Obtain residue, obtain title product 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] Two English-8-bases) methyl acetate 6c (390mg, yellow liquid), productivity: 51.3%.

MS m/z(ESI):422.2[M+18]

4th step

By 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) Methyl acetate 6c (90mg, 0.22mmol) is dissolved in 5mL oxolane and methanol (V/V=1:4) mixed solvent, adds 1M hydrogen Sodium hydroxide solution (1mL, 1mmol), is heated to 50 DEG C, stirring reaction 1 hour.Concentrating under reduced pressure reactant liquor, add 15mL water and 15mL ethyl acetate, dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, is extracted with ethyl acetate (5mL × 2), merges organic facies, with full Washing (30mL) with sodium chloride solution, anhydrous magnesium sulfate is dried, and filters, and concentrating under reduced pressure filtrate, by HPLC preparative chromatography to wash De-agent system A purification gained residue, obtains title product 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfurans And [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 6 (35mg, white solid), productivity: 40.2%.

MS m/z(ESI):389.0[M-1]

¹H NMR(400MHz,CDCl₃)δ7.58(s,1H),7.50-7.52(m,1H),7.29-7.35(m,2H),6.79 (s,1H),6.48(s,1H),5.07-5.09(m,1H),4.72-4.77(m,1H),4.25-4.32(m,2H),3.90-3.96 (m,1H),3.78-3.86(m,1H),2.78-2.85(m,1H),2.61-2.68(m,1H).

Embodiment 7

2-((8S)-3-(3-cyclopropyl phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8- Base) acetic acid

The first step

2-((8S)-3-(3-cyclopropyl phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8- Base) methyl acetate

By 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) Methyl acetate 6c (150mg, 0.37mmol), cyclopropylboronic acid (38mg, 0.44mmol), tetra-triphenylphosphine palladium (21mg, 0.02mmol) it is dissolved in 5.5mL dioxane and water (V/V=10:1) mixed solvent with cesium carbonate (361g, 1.11mmol), It is heated to 95 DEG C, stirring reaction 2 hours.Filtering, wash (5mL × 3) by ethyl acetate, anhydrous magnesium sulfate is dried, and filters, decompression Concentrated filtrate, purifies gained residue by HPLC preparative chromatography with eluant system B, obtains title product 2-((8S)-3- (3-cyclopropyl phenyl)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 7a (59mg, Yellow liquid), productivity: 43.4%.

MS m/z(ESI):367.2[M+1]

Second step

By 2-((8S)-3-(3-cyclopropyl phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English- 8-yl) methyl acetate 7a (59mg, 0.16mmol) is dissolved in 5mL oxolane and methanol (V/V=1:4) mixed solvent, adds 1M sodium hydroxide solution (1mL, 1mmol), is heated to 50 DEG C, stirring reaction 1 hour.Concentrating under reduced pressure reactant liquor, adds 10mL water With 10mL ethyl acetate, dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, is extracted with ethyl acetate (5mL × 2), merges organic facies, uses Saturated nacl aqueous solution washing (30mL), anhydrous magnesium sulfate is dried, filter, concentrating under reduced pressure filtrate, with HPLC preparative chromatography with Eluant system A purification gained residue, obtains title product 2-((8S)-3-(3-cyclopropyl phenyl)-2,3,7,8-tetrahydrochysene benzene And furo [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 7 (35mg, white solid), productivity: 61.4%.

MS m/z(ESI):353.0[M+1]

¹H NMR(400MHz,CDCl₃)δ7.28-7.32(m,1H),7.17-7.19(m,1H),7.13(s,1H),7.05- 7.07(m,1H),6.78(s,1H),6.49(s,1H),5.05-5.07(m,1H),4.72-4.76(m,1H),4.24-4.31(m, 2H),3.93-3.98(m,1H),3.80-3.84(m,1H),2.78-2.84(m,1H),2.61-2.67(m,1H),1.90-1.96 (m,1H),0.97-1.01(m,2H),0.70-0.75(m,2H).

Embodiment 8

2-((8S)-3-(2', 4', 6'-trimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-bases) acetic acid

The first step

2-((8S)-3-(2', 4', 6'-trimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-bases) methyl acetate

By 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) Methyl acetate 6c (50mg, 0.12mmol), trimethylbenzene boric acid (20mg, 0.12mmol), tetra-triphenylphosphine palladium (7mg, 0.006mmol) it is dissolved in 5.5mL dioxane and water (V/V=10:1) mixed solvent with cesium carbonate (120mg, 0.37mmol) In, it is heated to 90 DEG C, stirring reaction 2 hours.Filtering, wash (5mL × 3) by ethyl acetate, anhydrous magnesium sulfate is dried, and filters, Concentrating under reduced pressure filtrate, purifies gained residue with silica gel column chromatography with eluant system B, obtains title product 2-((8S)-3- (2', 4', 6'-trimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) second Acid methyl ester 8a (40mg, yellow liquid), productivity: 72.4%.

MS m/z(ESI):445.4[M+1]

Second step

By 2-((8S)-3-(2', 4', 6'-trimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6- B] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 8a (40mg, 0.09mmol) is dissolved in 3mL oxolane and methanol (V/V=1:2) In mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 DEG C, stirring reaction 0.5 hour.Concentrating under reduced pressure Reactant liquor, adds 10mL water and 10mL ethyl acetate, and dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, extracts separatory, and organic facies is successively With water (10mL × 3), saturated nacl aqueous solution washing (10mL × 3), anhydrous magnesium sulfate is dried, and filters, concentrating under reduced pressure filtrate, uses Silica gel column chromatography, with eluant system A purification gained residue, obtains title product 2-((8S)-3-(2', 4', 6'-front three Base-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 8 (35mg, white Solid), productivity: 92.1%.

MS m/z(ESI):429.1[M-1]

¹H NMR(400MHz,CDCl₃)δ7.37-7.49(m,3H),7.16-7.20(m,1H),6.96(s,2H),6.78 (s,1H),6.48(s,1H),5.13-5.15(m,1H),4.72-4.76(m,1H),4.26-4.35(m,2H),3.95-4.00 (m,1H),3.82(m,1H),2.79-2.84(m,1H),2.61-2.67(m,1H),2.34(s,3H),2.00-2.02(m,6H).

Embodiment 9

2-((8S)-3-(2', 6'-dimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1, 4] two English-8-base) acetic acid

The first step

2-((8S)-3-(2', 6'-dimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1, 4] two English-8-base) methyl acetate

By 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) Methyl acetate 6c (50mg, 0.12mmol), (2,6-dimethyl benzene) boric acid (19mg, 0.12mmol), tetra-triphenylphosphine palladium (7mg, 0.006mmol) it is dissolved in 3.3mL dioxane and water (V/V=10:1) mixed solvent with cesium carbonate (120mg, 0.37mmol) In, it is heated to 90 DEG C, stirring reaction 2 hours.Filtering, wash (2mL × 2) by ethyl acetate, anhydrous magnesium sulfate is dried, and filters, Concentrating under reduced pressure filtrate, purifies gained residue with silica gel column chromatography with eluant system B, obtains title product 2-((8S)-3- (2', 6'-dimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid Methyl ester 9a (33mg, yellow liquid), productivity: 62.3%.

Second step

By 2-((8S)-3-(2', 6'-dimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 9a (33mg, 0.08mmol) is dissolved in 4mL oxolane and methanol (V/V=1:3) mixes In bonding solvent, add 1M sodium hydroxide solution (0.5mL, 0.50mmol), be heated to 50 DEG C, stirring reaction 0.5 hour.Reduce pressure dense Contracting reactant liquor, adds 10mL water and 10mL ethyl acetate, and dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, extracts separatory, and organic facies depends on Secondary water (10mL × 3), saturated nacl aqueous solution washing (10mL × 3), anhydrous magnesium sulfate is dried, and filters, concentrating under reduced pressure filtrate, Purify gained residue with silica gel column chromatography with eluant system A, obtain title product 2-((8S)-3-(2', 6'-diformazan Base-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 9 (28mg, white Solid), productivity: 87.5%.MS m/z(ESI):415.1[M-1]

¹H NMR(400MHz,CDCl₃)δ7.47-7.50(m,1H),7.38-7.42(m,2H),7.13-7.21(m,4H), 6.78(s,1H),6.48(s,1H),5.13-5.15(m,1H),4.71-4.76(m,1H),4.24-4.35(m,2H),3.95- 4.00(m,1H),3.82(m,1H),2.79-2.83(m,1H),2.61-2.67(m,1H),2.02-2.05(m,6H).

Embodiment 10

2-(3-([1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid

The first step

2-(3-([1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid Methyl ester

By 2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid Methyl ester 4h (90mg, 0.22mmol), phenylboric acid (27mg, 0.22mmol), tetra-triphenylphosphine palladium (13mg, 0.01mmol) and carbon Acid caesium (215mg, 0.66mmol) is dissolved in 5mL dioxane and water (V/V=10:1) mixed solvent, is heated to 90 DEG C, stirring React 2 hours.Filtering, filter cake ethyl acetate washs (5mL × 3), and anhydrous magnesium sulfate is dried, and filters, filtrate reduced in volume, uses Silica gel column chromatography, with eluant system B purification gained residue, obtains title product 2-(3-([1,1'-xenyl]-3- Base)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 10a (60mg, colourless liquid), productivity: 67.4%.

MS m/z(ESI):420.3[M+18]

Second step

By 2-(3-([1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) second Acid methyl ester 10a (60mg, 0.15mmol) is dissolved in 5mL methanol and oxolane (V/V=4:1) mixed solvent, adds 1M hydrogen-oxygen Change sodium solution (1mL, 1mmol), be heated to 50 DEG C, stirring reaction 1 hour.Reactant liquor concentrating under reduced pressure, adds 10mL water and 10mL Ethyl acetate, dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, extracts separatory, organic phase washed with water (10mL × 3), saturated chlorination Sodium solution washing (10mL × 3), anhydrous sodium sulfate is dried, and filters, and filtrate reduced in volume, with silica gel column chromatography with eluant body It is A purification gained residue, obtains title product 2-(3-([1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 10 (60mg, white solid), productivity: 100.0%.

MS m/z(ESI):387.1[M-1]

¹H NMR(400MHz,CDCl₃)δ7.58-7.62(m,3H),7.38-7.50(m,6H),6.80(s,1H),6.51 (s,1H),5.17-5.19(m,1H),4.72-4.77(m,1H),4.25-4.38(m,2H),4.00-4.05(m,1H),3.83 (m,1H),2.79-2.85(m,1H),2.62-2.68(m,1H).

Embodiment 11

2-(3-(2'-methyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8- Base) acetic acid

The first step

2-(3-(2'-methyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8- Base) methyl acetate

By 2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid Methyl ester 4h (90mg, 0.22mmol), o-methyl-benzene boric acid (30mg, 0.22mmol), tetra-triphenylphosphine palladium (13mg, 0.01mmol) It is dissolved in 5mL dioxane and water (V/V=10:1) mixed solvent with cesium carbonate (215mg, 0.66mmol), is heated to 90 DEG C, Stirring reaction 2 hours.Filtering, filter cake ethyl acetate washs (5mL × 3), and anhydrous magnesium sulfate is dried, and filters, and filtrate decompression is dense Contracting, purifies gained residue with silica gel column chromatography with eluant system B, obtains title product 2-(3-(2'-methyl-[1,1'- Xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 11a (48mg, yellow liquid Body), productivity: 52.2%.

MS m/z(ESI):434.3[M+18]

Second step

By 2-(3-(2'-methyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English- 8-yl) methyl acetate 11a (48mg, 0.12mmol) is dissolved in 5mL methanol and oxolane (V/V=4:1) mixed solvent, adds Enter 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 DEG C, stirring reaction 1 hour.Reactant liquor concentrating under reduced pressure, adds 10mL Water and 10mL ethyl acetate, dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, extraction separatory, organic phase washed with water (10mL × 3), Saturated nacl aqueous solution washing (10mL × 3), anhydrous sodium sulfate is dried, filter, filtrate reduced in volume, with silica gel column chromatography with Eluant system A purification gained residue, obtains title product 2-(3-(2'-methyl-[1,1'-xenyl]-3-base)-tetrahydrochysene Benzofuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 11 (42mg, white solid), productivity: 91.3%.

MS m/z(ESI):401.1[M-1]

¹H NMR(400MHz,CDCl₃)δ7.26-7.47(m,8H),6.79(s,1H),6.49(s,1H),5.15(m,1H), 4.74-4.76(m,1H),4.26-4.37(m,2H),4.01-4.03(m,1H),3.82(m,1H),2.79-2.83(m,1H), 2.61-2.67(m,1H),2.28(s,3H).

Embodiment 12

2-(3-(2', 4'-dimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid

The first step

2-(2,4-3,5-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring

By bromo-for 1-2,4-dimethyl benzene 12a (1.0g, 5.40mmol), double valeryl two boron (1.90g, 8.10mmol), 1, Double (diphenylphosphine) ferrocene of 1'-] palladium chloride (198mg, 0.27mmol) and potassium acetate (1.30g, 13.50mmol) dissolving In 50mL glycol dimethyl ether, it is heated to return stirring and reacts 3 hours.Filter, filtrate reduced in volume, use silica gel column chromatography With eluant system B purification gained residue, obtain title product 2-(2,4-3,5-dimethylphenyl)-4,4,5,5-tetramethyl-1, 3,2-dioxy boron penta ring 12b (700mg, yellow oil), productivity: 56.0%.

Second step

2-(3-(2', 4'-dimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) methyl acetate

By 2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid Methyl ester 4h (90mg, 0.22mmol), 2-(2,4-3,5-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring 12b (62mg, 0.27mmol), tetra-triphenylphosphine palladium (13mg, 0.01mmol) and sodium carbonate (47mg, 0.44mmol) are dissolved in 5mL bis- In oxygen six ring and water (V/V=10:1) mixed solvent, it is heated to 90 DEG C, stirring reaction 2 hours.Filtering, filter cake ethyl acetate is washed Washing (5mL × 3), anhydrous magnesium sulfate is dried, and filters, filtrate reduced in volume, purifies institute with silica gel column chromatography with eluant system B Residue, obtain title product 2-(3-(2', 4'-dimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5, 6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 12c (50mg, yellow liquid), productivity: 52.1%.Generate by-product 2-(3-benzene Base-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 12d (20mg, yellow liquid).

MS m/z(ESI):448.3[M+18]

3rd step

By 2-(3-(2', 4'-dimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) methyl acetate 12c (50mg, 0.12mmol) is dissolved in 5mL methanol and oxolane (V/V=4:1) mixed solvent In, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 DEG C, stirring reaction 1 hour.Reactant liquor concentrating under reduced pressure, adds 10mL water and 10mL ethyl acetate, dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, extraction separatory, organic phase washed with water (5mL × 3), saturated nacl aqueous solution washing (5mL × 3), anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, uses silica gel column chromatography With eluant system A purification gained residue, obtain title product 2-(3-(2', 4'-dimethyl-[1,1'-xenyl]-3- Base)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 12 (45mg, white solid), productivity: 93.7%.

MS m/z(ESI):415.1[M-1]

¹H NMR(400MHz,CDCl₃)δ7.27-7.58(m,6H),7.08-7.15(m,1H),6.78(s,1H),6.48 (s,1H),5.07-5.16(m,1H),4.72-4.76(m,1H),4.25-4.36(m,2H),3.91-4.03(m,1H),3.82 (m,1H),2.79-2.84(m,1H),2.61-2.68(m,1H),2.37(s,3H),2.25(s,3H).

Embodiment 13

2-(3-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] Two English-8-bases) acetic acid

The first step

2,5-bis-chloro-2,5-dimethylhexane

By 2,5-dimethylhexane-2,5-glycol 13a (102.20g, 0.70mol) adds to 700mL concentrated hydrochloric acid, then adds Enter 50mL normal hexane, stirring reaction 12 hours.Filtering, filter cake washes (50mL × 3) with water, and filtrate is extracted with ethyl acetate (200mL × 3), merge organic facies, and anhydrous sodium sulfate is dried, and filter, filtrate reduced in volume, merge filter cake, obtain title product Crude product 2,5-bis-chloro-2,5-dimethylhexane 13b (124.20g, white powder), product is the most purified, and directly to carry out next step anti- Should.

Second step

6-bromo-1,1,4,4-tetramethyl-1,2,3,4-naphthane

Under ice bath, by crude product 2,5-bis-chloro-2,5-dimethylhexane 13b (5.0g, 27.30mmol) are dissolved in 50mL dichloro In methane, add bromobenzene (8.45g, 53.80mmol), then be dividedly in some parts aluminum chloride (728mg, 5.46mmol), stir 10 points Clock, more naturally it is warmed to room temperature stirring reaction 0.5 hour.Reactant liquor is poured into 100mL frozen water, adds 50mL ethyl acetate, extraction Separatory, aqueous phase is extracted with ethyl acetate (50mL × 3), merges organic facies, successively with water (30mL × 3), saturated nacl aqueous solution Washing (30mL × 3), anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, pure with eluant system B with silica gel column chromatography Change gained residue, obtain title product 6-bromo-1, Isosorbide-5-Nitrae, 4-tetramethyl-1,2,3,4-naphthane 13c (7.10g, yellow liquid Body), productivity: 97.4%.

3rd step

5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-formaldehyde

At-78 DEG C, by bromo-for 6-1, Isosorbide-5-Nitrae, 4-tetramethyl-1,2,3,4-naphthane 13c (7.0g, 26.20mmol) are dissolved in In 70mL oxolane, drip 12.6mL2.5M n-BuLi, stir 30 minutes, then drip DMF (2.87g, 39.30mmol), stirring reaction 0.5 hour.Reactant liquor is poured into 50mL saturated ammonium chloride solution, adds 50mL acetic acid Ethyl ester and 50mL water, extract separatory, organic phase washed with water (30mL × 3), saturated nacl aqueous solution washing (30mL × 3), nothing Aqueous sodium persulfate is dried, and filters, filtrate reduced in volume, purifies gained residue with silica gel column chromatography with eluant system B, obtains Title product 5,5,8,8-tetramethyl-5,6,7,8-naphthanes-2-formaldehyde 13d (2.97g, yellow liquid), productivity: 52.5%.

MS m/z(ESI):217.2[M+1]

4th step

1,1,4,4-tetramethyl-6-vinyl-1,2,3,4-naphthane

By 5,5,8,8-tetramethyl-5,6,7,8-naphthanes-2-formaldehyde 13d (2.82g, 13.06mmol) are dissolved in 51mL In dioxane and water (V/V=50:1) mixed solvent, add potassium carbonate (4.50g, 32.65mmol) and triphenylphosphine iodomethane (10.55g, 26.11mmol), is warming up to 100 DEG C, stirring reaction 12 hours.Filter, filtrate reduced in volume, use silica gel column chromatography Method, with eluant system B purification gained residue, obtains title product 1, Isosorbide-5-Nitrae, 4-tetramethyl-6-vinyl-1, and 2,3,4-tetra- Hydrogen naphthalene 13e (2.60g, colourless liquid), productivity: 93.2%.

5th step

1-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-base) ethane-1,2-glycol

N-methyl morpholine oxide (2.46g, 21.02mmol) and Osmic acid. (89mg, 0.35mmol) are dissolved in 20mL In water, acetone and the tert-butyl alcohol (V/V/V=5:2:1) mixed solvent, addition 13mL 1, Isosorbide-5-Nitrae, 4-tetramethyl-6-vinyl-1,2, The acetone of 3,4-naphthane 13e (1.50g, 7mmol) and dichloromethane (V/V=10:3) mixed solvent, stirring reaction 1.5 hours. Add 30mL saturated sodium thiosulfate solution, stir 30 minutes, be extracted with ethyl acetate (30mL × 3), merge organic facies, successively With saturated sodium carbonate solution (20mL × 2), water (20mL × 2), saturated nacl aqueous solution washing (20mL × 2), anhydrous sodium sulfate It is dried, filters, filtrate reduced in volume, purify gained residue with silica gel column chromatography with eluant system B, obtain title product 1-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-bases) ethane-1,2-glycol 13f (1.53g, white solid), productivity: 88.0%.

6th step

2-((t-butyldimethyl silane) oxygen)-1-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-base) ethanol

By 1-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-bases) ethane-1,2-glycol 13f (1.53g, 6.17mmol), imidazoles (839mg, 12.34mmol) and DMAP (75mg, 0.62mmol) are dissolved in 30mLN, N- In dimethylformamide, add tert-butyl chloro-silicane (1.12g, 7.40mmol), stirring reaction 0.5 hour.Add 30mL water and 30mL ethyl acetate, extract separatory, organic phase washed with water (20mL × 3), saturated nacl aqueous solution washing (20mL × 3), anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, purifies gained with silica gel column chromatography with eluant system B remaining Thing, obtains title product 2-((t-butyldimethyl silane) oxygen)-1-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2- Base) ethanol 13g (1.99g, yellow liquid), productivity: 89.2%.

7th step

2-(6-(2-((tert-butyldimethyl silyl) oxygen)-1-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-base) second Epoxide)-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate

By 2-((t-butyldimethyl silane) oxygen)-1-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-base) ethanol 13g (250mg, 0.69mmol), crude product 2-(6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 4e (230mg, 0.69mmol) and azodicarbonyldipiperidine (278mg, 1.10mmol) are dissolved in 10mL toluene, add three positive fourths Base phosphine (0.27mL, 1.10mmol), is heated to 50 DEG C, stirring reaction 30 minutes.Addition 10mL methanol, reactant liquor concentrating under reduced pressure, Purify gained residue with silica gel column chromatography with eluant system B, obtain title product 2-(6-(2-((fert-butyidimethylsilyl Silicon) oxygen)-1-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-base) ethyoxyl)-5-iodo-2,3-Dihydrobenzofuranes-3- Base) methyl acetate 13h (430mg, yellow liquid), productivity: 91.9%.

MS m/z(ESI):696.5[M+18]

8th step

2-(6-(2-hydroxyl-1-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-base) ethyoxyl) the iodo-2,3-of-5- Dihydrobenzofuranes-3-base) methyl acetate

By 2-(6-(2-((tert-butyldimethyl silyl) oxygen)-1-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-base) Ethyoxyl)-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 13h (390mg, 0.57mmol) is dissolved in 10mL tetrahydrochysene In furan, add tetrabutyl ammonium fluoride (0.63mL, 0.63mmol), stirring reaction 0.5 hour.Reactant liquor concentrating under reduced pressure, uses silicon Glue column chromatography, with eluant system B purification gained residue, obtains title product 2-(6-(2-hydroxyl-1-(5,5,8,8-tetra- Methyl-5,6,7,8-naphthane-2-base) ethyoxyl)-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 13i (240mg, yellow liquid), productivity: 74.0%.

9th step

2-(3-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] Two English-8-bases) methyl acetate

By 2-(6-(2-hydroxyl-1-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-base) ethyoxyl)-5-iodo-2, 3-Dihydrobenzofuranes-3-base) methyl acetate 13i (190mg, 0.34mmol), acid chloride (11mg, 0.05mmol), 2-(two uncles Butyl phosphorus)-1,1'-dinaphthalene (40mg, 0.10mmol) and cesium carbonate (219mg, 0.68mmol) are dissolved in 10mL toluene, heating React 16 hours to 50 DEG C of stirrings.Filter, filtrate reduced in volume, purify gained with silica gel column chromatography with eluant system B residual Excess, obtain title product 2-(3-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-bases)-tetrahydrochysene benzfuran also [5, 6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 13j (115mg, white solid), productivity: 78.2%.

MS m/z(ESI):454.3[M+18]

Tenth step

By 2-(3-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-base)-tetrahydrochysene benzfuran also [5,6-b] [1, 4] two English-8-base) methyl acetate 13j (135mg, 0.31mmol) is dissolved in 7.5mL methanol and oxolane (V/V=4:1) mixes In bonding solvent, add 1.5M sodium hydroxide solution (2mL, 3mmol), be heated to 50 DEG C, stirring reaction 1 hour.Reactant liquor reduces pressure Concentrating, add 10mL water and 10mL ethyl acetate, dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, extracts separatory, and organic facies is used successively Water (15mL × 3), saturated nacl aqueous solution washing (15mL × 3), anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, uses silicon Glue column chromatography with eluant system A purification gained residue, obtain title product 2-(3-(and 5,5,8,8-tetramethyl-5,6,7, 8-naphthane-2-base)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 13 (130mg, white solid), Productivity: 100.0%.

MS m/z(ESI):421.2[M-1]

¹H NMR(400MHz,CDCl₃)δ7.34-7.36(m,1H),7.31(m,1H),7.15-7.17(m,1H),6.78 (s,1H),6.48(s,1H),5.03-5.05(m,1H),4.71-4.76(m,1H),4.24-4.31(m,2H),3.96-4.01 (m,1H),3.80-3.81(m,1H),2.79-2.84(m,1H),2.60-2.67(m,1H),1.70(s,4H),1.29(s, 12H).

Embodiment 14

2-(3-(2', 5'-dimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid

The first step

2-(2,5-3,5-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring

By bromo-for 2-Isosorbide-5-Nitrae-dimethyl benzene 14a (1.02g, 5.50mmol), double valeryl two boron (1.95g, 8.30mmol), 1, Double (diphenylphosphine) ferrocene of 1'-] palladium chloride (202mg, 0.30mmol) and potassium acetate (1.35g, 13.80mmol) be dissolved in In 20mL glycol dimethyl ether, it is heated to return stirring and reacts 3 hours.Filter, filtrate reduced in volume, with silica gel column chromatography with Eluant system B purification gained residue, obtains title product 2-(2,5-3,5-dimethylphenyl)-4,4,5,5-tetramethyl-1, and 3, 2-dioxy boron penta ring 14b (538mg, colorless oil), productivity: 42.1%.

Second step

2-(3-(2', 5'-dimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) methyl acetate

By 2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid Methyl ester 4h (150mg, 0.37mmol), 2-(2,5-3,5-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring 14b (103mg, 0.44mmol), tetra-triphenylphosphine palladium (21mg, 0.021mmol) and sodium carbonate (78mg, 0.74mmol) are dissolved in 5mL In dioxane and water (V/V=10:1) mixed solvent, it is heated to 90 DEG C, stirring reaction 3 hours.Filter, filter cake ethyl acetate Washing (10mL × 3), anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, pure with eluant system B with silica gel column chromatography Change gained residue, obtain title product 2-(3-(2', 5'-dimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran And [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 14c (80mg, yellow liquid), productivity: 50.3%.

MS m/z(ESI):448.2[M+18]

3rd step

By 2-(3-(2', 5'-dimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) methyl acetate 14c (80mg, 0.19mmol) is dissolved in 5mL methanol and oxolane (V/V=4:1) mixed solvent In, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 DEG C, stirring reaction 1 hour.Reactant liquor concentrating under reduced pressure, adds 10mL water and 10mL ethyl acetate, dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, extraction separatory, organic phase washed with water (10mL × 2), saturated nacl aqueous solution washing (10mL × 2), anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, uses silica gel column chromatography Method, with eluant system A purification gained residue, obtains title product 2-(3-(2', 5'-dimethyl-[1,1'-xenyl]-3- Base)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 14 (70mg, white solid), productivity: 90.9%.

MS m/z(ESI):415.5[M-1]

¹H NMR(400MHz,CDCl₃)δ7.33-7.48(m,4H),7.16-7.18(m,1H),7.08-7.10(m,1H), 7.06(m,1H),6.79(s,1H),6.49(s,1H),5.14-5.16(m,1H),4.72-4.76(m,1H),4.24-4.37(m, 2H),3.98-4.03(m,1H),3.81-3.84(m,1H),2.78-2.84(m,1H),2.61-2.67(m,1H),2.36(s, 3H),2.23(s,3H).

Embodiment 15

2-(3-(3', 5'-dimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid

The first step

2-(3,5-3,5-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring

By bromo-for 2-3,5-dimethyl benzene 15a (1.06g, 5.70mmol), double valeryl two boron (2.0g, 8.60mmol), 1, Double (diphenylphosphine) ferrocene of 1'-] palladium chloride (210mg, 0.20mmol) and potassium acetate (1.40g, 14.30mmol) be dissolved in In 20mL glycol dimethyl ether, it is heated to return stirring and reacts 3 hours.Filter, filtrate reduced in volume, with silica gel column chromatography with Eluant system B purification gained residue, obtains title product 2-(3,5-3,5-dimethylphenyl)-4,4,5,5-tetramethyl-1, and 3, 2-dioxy boron penta ring 15b (538mg, colorless oil), productivity: 42.1%.

Second step

2-(3-(3', 5'-dimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) methyl acetate

By 2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid Methyl ester 4h (150mg, 0.37mmol), 2-(3,5-3,5-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring 15b (103mg, 0.44mmol), tetra-triphenylphosphine palladium (21mg, 0.021mmol) and sodium carbonate (78mg, 0.74mmol) are dissolved in 5mL In dioxane and water (V/V=10:1) mixed solvent, it is heated to 90 DEG C, stirring reaction 3 hours.Filter, filter cake ethyl acetate Washing (10mL × 3), anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, pure with eluant system B with silica gel column chromatography Change gained residue, obtain title product 2-(3-(3', 5'-dimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran And [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 15c (77mg, yellow liquid), productivity: 48.4%.

MS m/z(ESI):448.2[M+18]

3rd step

By 2-(3-(3', 5'-dimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) methyl acetate 15c (77mg, 0.18mmol) is dissolved in 5mL methanol and oxolane (V/V=4:1) mixed solvent In, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 DEG C, stirring reaction 0.5 hour.Reactant liquor concentrating under reduced pressure, adds Entering 10mL water and 10mL ethyl acetate, dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, extracts separatory, organic phase washed with water (10mL × 2), saturated nacl aqueous solution washing (10mL × 2), anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, uses silicagel column color Spectrometry with eluant system A purification gained residue, obtain title product 2-(3-(3', 5'-dimethyl-[1,1'-xenyl]- 3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 15 (75mg, white solid), productivity: 100.0%.

MS m/z(ESI):415.5[M-1]

¹H NMR(400MHz,CDCl₃)δ7.58-7.60(m,2H),7.45-7.49(m,1H),7.37-7.38(m,1H), 7.21(s,2H),7.02(s,1H),6.80(s,1H),6.51(s,1H),5.16-5.18(m,1H),4.72-4.77(m,1H), 4.25-4.37(m,2H),3.99-4.04(m,1H),3.81-3.84(m,1H),2.79-2.85(m,1H),2.61-2.68(m, 1H),2.40(s,6H).

Embodiment 16

(S)-2-(3-(2'-methyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid

The first step

(S)-2-(3-(2'-methyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) methyl acetate

By 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) Methyl acetate 6c (150mg, 0.37mmol), o-methyl-benzene boric acid (60mg, 0.44mmol), tetra-triphenylphosphine palladium (21mg, 0.021mmol) it is dissolved in 5.5mL dioxane and water (V/V=10:1) mixed solvent with cesium carbonate (361mg, 1.11mmol) In, it is heated to 90 DEG C, stirring reaction 3 hours.Filtering, filter cake ethyl acetate washs (5mL × 3), and anhydrous sodium sulfate is dried, mistake Filter, filtrate reduced in volume, purify gained residue with silica gel column chromatography with eluant system B, obtain title product (S)-2- (3-(2'-methyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid first Ester 16a (115mg, yellow liquid), productivity: 74.6%.

MS m/z(ESI):434.3[M+18]

Second step

By (S)-2-(3-(2'-methyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) methyl acetate 16a (115mg, 0.28mmol) is dissolved in 7.5mL methanol and oxolane (V/V=4:1) mixes molten In agent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 DEG C, stirring reaction 1 hour.Reactant liquor concentrating under reduced pressure, adds Entering 10mL water and 10mL ethyl acetate, dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, extracts separatory, organic phase washed with water (10mL × 3), saturated nacl aqueous solution washing (10mL × 3), anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, uses silicagel column color Spectrometry with eluant system A purification gained residue, obtain title product (S)-2-(3-(2'-methyl-[1,1'-xenyl]- 3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 16 (105mg, white solid), productivity: 94.6%.

MS m/z(ESI):401.3[M-1]

¹H NMR(400MHz,CDCl₃)δ7.29-7.59(m,8H),6.80(s,1H),6.50(s,1H),5.16(m,1H), 4.75(m,1H),4.28-4.38(m,2H),4.02(m,1H),3.83(m,1H),2.81-2.85(m,1H),2.67-2.69(m, 1H),2.29(s,3H).

Embodiment 17

2-((3R, 8S)-3-(2', 6'-dimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-bases) acetic acid

By 2-((8S)-3-(2', 6'-dimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 9 (90mg, 0.22mmol) carries out chiral separation, uses HPLC method, by Preparation equipment and chirality The chiral isomer of post carry out separating (separation condition: chiral column AD-s Chiralpak 4.6, flow phase: ethanol/acrylonitrile/ Acetic acid=90/10/0.1, flow velocity: 0.5mL/ minute), collect its respective components, rotary evaporation removes solvent, obtains title product 2-((3R, 8S)-3-(2', 6'-dimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid 17 (39mg, white solid).

¹H NMR(400MHz,CDCl₃)δ7.41-7.49(m,3H),7.13-7.21(m,4H),6.78(s,1H),6.48 (s,1H),5.14(m,1H),4.74(m,1H),4.26-4.35(m,2H),3.98(m,1H),3.82(m,1H),2.79(m, 1H),2.65(m,1H),2.02-2.05(m,6H).

Embodiment 18

2-((3R, 8S)-3-(2'-methyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] Two English-8-bases) acetic acid

By (S)-2-(3-(2'-methyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid 16 (105mg, 0.26mmol) carries out chiral separation, uses HPLC method, with Preparation equipment and chiral column pair Chiral isomer carry out separating (separation condition: chiral column AD-H Chiralpak 4.6, flow phase: ethanol: acrylonitrile: acetic acid= 90/10/0.1 (v/v/v), flow velocity: 0.5mL/ minute), collect its respective components, rotary evaporation removes solvent, obtains title and produces Thing 2-((3R, 8S)-3-(2'-methyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English- 8-yl) acetic acid 18 (34mg, white solid).

¹H NMR(400MHz,CDCl₃)δ7.27-7.58(m,8H),6.78(s,1H),6.48(s,1H),5.14(m,1H), 4.73(m,1H),4.26-4.36(m,2H),4.00(m,1H),3.81(m,1H),2.79-2.83(m,1H),2.65-2.67(m, 1H),2.27(s,3H).

Embodiment 19

2-(3-phenyl-tetrahydro benzofuran also [5,6-b] [1,4] two English-8-base) acetic acid

By 2-(3-phenyl-tetrahydro benzofuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 12d (20mg, 0.06mmol) it is dissolved in 5mL methanol and oxolane (V/V=4:1) mixed solvent, addition 1M sodium hydroxide solution (1mL, 1mmol), it is heated to 50 DEG C, stirring reaction 1 hour.Reactant liquor concentrating under reduced pressure, adds 10mL water and 10mL ethyl acetate, dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, extracts separatory, organic phase washed with water (5mL × 3), saturated nacl aqueous solution washing (5mL × 3), anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, purifies gained with silica gel column chromatography with eluant system A remaining Thing, obtain title product 2-(3-phenyl-tetrahydro benzofuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 19 (10mg, in vain Color solid), productivity: 52.6%.

MS m/z(ESI):313.3[M+1]

¹H NMR(400MHz,CDCl₃)δ7.42(m,5H),6.78(s,1H),6.49(s,1H),5.10-5.12(m,1H), 4.72-4.76(m,1H),4.24-4.33(m,2H),3.95-4.00(m,1H),3.82(m,1H),2.79-2.83(m,1H), 2.61-2.67(m,1H).

Embodiment 20

2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid

By 2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid Methyl ester 4h (30mg, 0.07mmol) is dissolved in 5mL methanol and oxolane (V/V=4:1) mixed solvent, adds 1M hydroxide Sodium solution (1mL, 1mmol), is heated to 50 DEG C, stirring reaction 1 hour.Reactant liquor concentrating under reduced pressure, adds 10mL water and 10mL second Acetoacetic ester, dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, extracts separatory, and organic phase washed with water (5mL × 3), saturated sodium-chloride is molten Liquid washing (5mL × 3), anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, pure with eluant system A with silica gel column chromatography Change gained residue, obtain title product 2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 20 (20mg, white solid), productivity: 74.1%.

MS m/z(ESI):389.1[M-1]

¹H NMR(400MHz,CDCl₃)δ7.58(m,1H),7.50-7.52(m,1H),7.29-7.35(m,2H),6.78 (s,1H),6.48(s,1H),5.07-5.09(m,1H),4.72-4.77(m,1H),4.24-4.32(m,2H),3.91-3.96 (m,1H),3.82(m,1H),2.79-2.83(m,1H),2.60-2.67(m,1H).

Embodiment 21

2-((3S, 8S)-3-(2', 6'-dimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-bases) acetic acid

By 2-((8S)-3-(2', 6'-dimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 9 (90mg, 0.22mmol) carries out chiral separation, uses HPLC method, by Preparation equipment and chirality The chiral isomer of post carry out separating (separation condition: chiral column AD-s Chiralpak 4.6, flow phase: ethanol/acrylonitrile/ Acetic acid=90/10/0.1, flow velocity: 0.5mL/ minute), collect its respective components, rotary evaporation removes solvent, obtains title product 2-((3S, 8S)-3-(2', 6'-dimethyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid 21 (54mg, white solid).

¹H NMR(400MHz,CDCl₃)δ7.42-7.49(m,3H),7.13-7.21(m,4H),6.78(s,1H),6.48 (s,1H),5.14(m,1H),4.74(m,1H),4.26-4.35(m,2H),3.98(m,1H),3.82(m,1H),2.79(m, 1H),2.65(m,1H),2.05(s,3H),2.02(s,3H).

Embodiment 22

2-((3S, 8S)-3-(2'-methyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] Two English-8-bases) acetic acid

By (S)-2-(3-(2'-methyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid 16 (105mg, 0.26mmol) carries out chiral separation, uses HPLC method, with Preparation equipment and chiral column pair Chiral isomer carry out separating (separation condition: chiral column AD-H Chiralpak 4.6, flow phase: ethanol: acrylonitrile: acetic acid= 90/10/0.1 (v/v/v), flow velocity: 0.5mL/ minute), collect its respective components, rotary evaporation removes solvent, obtains title and produces Thing 2-((3S, 8S)-3-(2'-methyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English- 8-yl) acetic acid 22 (39mg, white solid).

¹H NMR(400MHz,CDCl₃)δ7.27-7.58(m,8H),6.79(s,1H),6.49(s,1H),5.15(m,1H), 4.74(m,1H),4.26-4.37(m,2H),4.01(m,1H),3.82(m,1H),2.80-2.83(m,1H),2.65-2.68(m, 1H),2.28(s,3H).

Embodiment 23

2-(3-(4'-fluoro-2'-methyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid

The first step

2-(3-(4'-fluoro-2'-methyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) methyl acetate

By 2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid Methyl ester 4h (100mg, 0.25mmol), (4-fluoro-2-methylbenzene base) boric acid (46mg, 0.30mmol), tetra-triphenylphosphine palladium (14mg, 0.01mmol) and cesium carbonate (241mg, 0.74mmol) are dissolved in 5.5mL dioxane and water (V/V=10:1) mixing In solvent, it is heated to 95 DEG C, stirring reaction 2 hours.Filtering, filter cake ethyl acetate washs (10mL × 2), and anhydrous magnesium sulfate is done Dry, filter, filtrate reduced in volume, purify gained residue with silica gel column chromatography with eluant system B, obtain title product 2- (3-(4'-fluoro-2'-methyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) Methyl acetate 23a (74mg, yellow liquid), productivity: 69.2%.

MS m/z(ESI):452.2[M+18]

Second step

By 2-(3-(4'-fluoro-2'-methyl-[1,1'-xenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [1,4] Two English-8-bases) methyl acetate 23a (74mg, 0.17mmol) is dissolved in 5mL methanol and oxolane (V/V=4:1) mixes molten In agent, add 3M sodium hydroxide solution (0.5mL, 1.5mmol), be heated to 50 DEG C, stirring reaction 1 hour.Reactant liquor decompression is dense Contracting, adds 10mL water and 10mL ethyl acetate, and dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, extracts separatory, organic phase washed with water (10mL × 2), saturated nacl aqueous solution washing (10mL × 2), anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, uses silica gel Column chromatography, with eluant system A purification gained residue, obtains title product 2-(3-(4'-fluoro-2'-methyl-[1,1'-connection Phenyl]-3-base)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 23 (62mg, white solid), productivity: 86.6%.

MS m/z(ESI):419.3[M-1]

¹H NMR(400MHz,CDCl₃)δ7.45-7.49(m,1H),7.38-7.42(m,1H),7.29-7.33(m,2H), 7.17-7.21(m,1H),6.93-7.00(m,2H),6.79(s,1H),6.48(s,1H),5.14-5.16(m,1H),4.72- 4.76(m,1H),4.24-4.37(m,2H),3.98-4.03(m,1H),3.82(m,1H),2.78-2.84(m,1H),2.61- 2.67(m,1H),2.26(s,3H).

Embodiment 24

2-((8S)-3-(2 '-methyl-4 '-(3-(methylsulfonyl) propoxyl group)-[1,1'-xenyl]-3-base)-2,3,7,8- Tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid

The first step

3-(methyl sulphonyl) propyl group toluenesulfonate

Under ice bath, 3-(methyl mercapto) propyl group toluenesulfonate 24a (10.0g, 38.40mmol) is dissolved in 100mL In methanol, the dropping 100mL aqueous solution containing Oxone reagent (35.42g, 57.60mmol), naturally it is warmed to room temperature stirring reaction 2 little Time.Reactant liquor concentrating under reduced pressure, adds 100mL water and 100mL ethyl acetate, extracts separatory, and aqueous phase is extracted with ethyl acetate (50mL × 2), organic facies is merged, successively with water (30mL × 3), saturated nacl aqueous solution washing (30mL × 3), anhydrous sodium sulfate is dried, Filter, filtrate reduced in volume, obtain crude title product 3-(methyl sulphonyl) propyl group toluenesulfonate 24b (8.0g, in vain Color solid), product is the most purified directly carries out next step reaction.

MS m/z(ESI):310.1[M+18]

Second step

1-bromo-2-methyl-4-(3-(mesyl) propoxyl group) benzene

By crude product 3-(methyl sulphonyl) propyl group toluenesulfonate 24b (1.87g, 6.42mmol), 4-bromo-3-methyl Phenol (1.0g, 5.34mmol) and potassium carbonate (1.47g, 10.68mmol) are dissolved in 20mLN, in dinethylformamide, and heating To 95 DEG C, stirring reaction 2 hours.Add 50mL water and 50mL ethyl acetate, stir 30 minutes, extract separatory, aqueous phase acetic acid Ethyl ester extraction (30mL × 2), merges organic facies, successively with water (30mL × 3), and saturated nacl aqueous solution washing (30mL × 3), nothing Aqueous sodium persulfate is dried, and filters, filtrate reduced in volume, purifies gained residue with silica gel column chromatography with eluant system B, obtains Title product 1-bromo-2-methyl-4-(3-(mesyl) propoxyl group) benzene 24c (1.27g, yellow solid), productivity: 77.4%.

3rd step

4,4,5,5-tetramethyl-2-(2-methyl-4-(3-(mesyl) propoxyl group) phenyl)-1,3,2-dioxy boron penta ring

By bromo-for 1-2-methyl-4-(3-(mesyl) propoxyl group) benzene 24c (640mg, 2.08mmol), double valeryl two boron (738mg, 3.12mmol), 1, double (diphenylphosphine) ferrocene of 1'-] palladium chloride (76mg, 0.10mmol) and potassium acetate (510mg, 5.20mmol) is dissolved in 15mL glycol dimethyl ether, is heated to 90 DEG C, stirring reaction 3 hours.Filtering, filtrate subtracts Pressure concentrates, and purifies gained residue with silica gel column chromatography with eluant system B, obtains title product 4, and 4,5,5-tetramethyls- 2-(2-methyl-4-(3-(mesyl) propoxyl group) phenyl)-1,3,2-dioxy boron penta ring 24d (930mg, brown liquid), produce Rate: 100.0%.

MS m/z(ESI):372.2[M+18]

4th step

2-((8S)-3-(2 '-methyl-4 '-(3-(methylsulfonyl) propoxyl group)-[1,1'-xenyl]-3-base)-2,3,7,8- Tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) methyl acetate

By 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) Methyl acetate 6c (150mg, 0.37mmol), 4,4,5,5-tetramethyl-2-(2-methyl-4-(3-(mesyl) propoxyl group) benzene Base)-1,3,2-dioxy boron penta ring 24d (157mg, 0.44mmol), tetra-triphenylphosphine palladium (21mg, 0.021mmol) and sodium carbonate (118mg, 1.11mmol) is dissolved in 4.5mL dioxane and water (V/V=8:1) mixed solvent, is heated to 90 DEG C, and stirring is anti- Answer 12 hours.Filtering, filter cake ethyl acetate washs (5mL × 4), and anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, uses Silica gel column chromatography, with eluant system B purification gained residue, obtains title product 2-((8S)-3-(2 '-methyl-4 '-(3- (methylsulfonyl) propoxyl group)-[1,1'-xenyl]-3-base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English- 8-yl) methyl acetate 24e (170mg, yellow liquid), productivity: 83.3%.

MS m/z(ESI):570.3[M+18]

5th step

By 2-((8S)-3-(2 '-methyl-4 '-(3-(methylsulfonyl) propoxyl group)-[1,1'-xenyl]-3-base)-2,3,7, 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 24e (65mg, 0.12mmol) is dissolved in 5mL first In alcohol and oxolane (V/V=4:1) mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 DEG C, stirring React 1 hour.Reactant liquor concentrating under reduced pressure, adds 10mL water and 10mL ethyl acetate, and dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, Extraction separatory, organic phase washed with water (5mL × 3), saturated nacl aqueous solution washing (5mL × 3), anhydrous sodium sulfate is dried, mistake Filter, filtrate reduced in volume, purify gained residue with silica gel column chromatography with eluant system A, obtain title product 2- ((8S)-3-(2 '-methyl-4 '-(3-(methylsulfonyl) propoxyl group)-[1,1'-xenyl]-3-base)-2,3,7,8-tetrahydro benzo furan Mutter also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 24 (24mg, white solid), productivity: 38.1%.

MS m/z(ESI):537.4[M-1]

¹H NMR(400MHz,CDCl₃)δ7.42-7.45(m,1H),7.30-7.38(m,3H),7.16-7.18(m,1H), 6.79-6.82(m,3H),6.48(s,1H),5.13-5.15(m,1H),4.72-4.76(m,1H),4.24-4.36(m,2H), 4.14-4.17(m,2H),3.98-4.03(m,1H),3.82(m,1H),3.27-3.31(m,2H),2.98(s,3H),2.78- 2.82(m,1H),2.60-2.67(m,1H),2.38-2.39(m,2H),2.26(s,3H).

Embodiment 25

2-((8S)-3-(2 '-chloro-4 '-(3-(methylsulfonyl) propoxyl group)-[1,1'-xenyl]-3-base)-2,3,7,8-four Hydrogen benzofuran also [5,6-b] [1,4] two English-8-base) acetic acid

The first step

The chloro-4-of the bromo-2-of 1-(3-(mesyl) propoxyl group) benzene

By crude product 3-(methyl sulphonyl) propyl group toluenesulfonate 24b (676mg, 2.31mmol), 4-bromo-3-chlorobenzene Phenol (400mg, 1.93mmol) and potassium carbonate (532mg, 3.86mmol) are dissolved in 10mLN, in dinethylformamide, are heated to 90 DEG C, stirring reaction 2 hours.Adding 50mL water and 50mL ethyl acetate, extract separatory, aqueous phase is extracted with ethyl acetate (30mL × 3), organic facies is merged, successively with water (30mL × 3), saturated nacl aqueous solution washing (30mL × 3), anhydrous sodium sulfate is dried, Filter, filtrate reduced in volume, purify gained residue with silica gel column chromatography with eluant system B, obtain title product 1-bromo- The chloro-4-of 2-(3-(mesyl) propoxyl group) benzene 25a (540mg, white solid), productivity: 85.6%.

Second step

4,4,5,5-tetramethyl-2-(the chloro-4-of 2-(3-(mesyl) propoxyl group) phenyl)-1,3,2-dioxy boron penta ring

By bromo-for the 1-chloro-4-of 2-(3-(mesyl) propoxyl group) benzene 25a (300mg, 0.92mmol), double valeryl two boron (324mg, 1.37mmol), 1, double (diphenylphosphine) ferrocene of 1'-] palladium chloride (34mg, 0.05mmol) and potassium acetate (225mg, 2.29mmol) is dissolved in 10mL glycol dimethyl ether, is heated to 90 DEG C, stirring reaction 3 hours.Filtering, filtrate subtracts Pressure concentrates, and purifies gained residue with silica gel column chromatography with eluant system B, obtains title product 4, and 4,5,5-tetramethyls- 2-(the chloro-4-of 2-(3-(mesyl) propoxyl group) phenyl)-1,3,2-dioxy boron penta ring 25b (190mg, yellow liquid), productivity: 55.4%。

MS m/z(ESI):392.0[M+18]

3rd step

2-((8S)-3-(2 '-chloro-4 '-(3-(methylsulfonyl) propoxyl group)-[1,1'-xenyl]-3-base)-2,3,7,8-four Hydrogen benzofuran also [5,6-b] [1,4] two English-8-base) methyl acetate

By 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) Methyl acetate 6c (85mg, 0.21mmol), 4,4,5,5-tetramethyl-2-(the chloro-4-of 2-(3-(mesyl) propoxyl group) phenyl)- 1,3,2-dioxy boron penta ring 25b (94mg, 0.25mmol), tetra-triphenylphosphine palladium (12mg, 0.01mmol) and sodium carbonate (67mg, 0.63mmol) being dissolved in 4.5mL dioxane and water (V/V=8:1) mixed solvent, be heated to 90 DEG C, stirring reaction 12 is little Time.Filtering, filter cake ethyl acetate washs (5mL × 2), and anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, uses silicagel column Chromatography, with eluant system B purification gained residue, obtains title product 2-((8S)-3-(2 '-chloro-4 '-(3-(methylsulfonyl) Propoxyl group)-[1,1'-xenyl]-3-base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) second Acid methyl ester 25c (82mg, yellow liquid), productivity: 68.3%.

MS m/z(ESI):590.5[M+18]

4th step

By 2-((8S)-3-(2 '-chloro-4 '-(3-(methylsulfonyl) propoxyl group)-[1,1'-xenyl]-3-base)-2,3,7,8- Tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 25c (82mg, 0.14mmol) is dissolved in 5mL methanol With in oxolane (V/V=4:1) mixed solvent, adding 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 DEG C, stirring is anti- Answer 1 hour.Reactant liquor concentrating under reduced pressure, adds 10mL water and 10mL ethyl acetate, and dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, extraction Taking separatory, organic phase washed with water (5mL × 3), saturated nacl aqueous solution washing (5mL × 3), anhydrous sodium sulfate is dried, and filters, Filtrate reduced in volume, purifies gained residue with silica gel column chromatography with eluant system A, obtains title product 2-((8S)-3- (2 '-chloro-4 '-(3-(methylsulfonyl) propoxyl group)-[1,1'-xenyl]-3-base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6- B] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 25 (66mg, white solid), productivity: 82.5%.

MS m/z(ESI):557.3[M-1]

¹H NMR(400MHz,CDCl₃)δ7.40-7.49(m,4H),7.27-7.29(m,1H),7.02-7.03(m,1H), 6.86-6.89(m,1H),6.79(s,1H),6.49(s,1H),5.14-5.16(m,1H),4.72-4.76(m,1H),4.24- 4.37(m,2H),4.15-4.18(m,2H),3.98-4.03(m,1H),3.82(m,1H),3.26-3.30(m,2H),2.99(s, 3H),2.78-2.84(m,1H),2.61-2.67(m,1H),2.36-2.42(m,2H).

Embodiment 26

3-(3-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-2,3-two Hydrogen benzo [b] [1,4] two English-6-base) propanoic acid

The first step

3-(4-hydroxyl-3-iodophenyl) methyl propionate

Under ice bath, 3-(4-hydroxy phenyl) methyl propionate 26a (1.0g, 5.60mmol) is dissolved in 15mL glacial acetic acid, Add 0.5mL concentrated sulphuric acid, then drip the 5mL glacial acetic acid solution containing N-N-iodosuccinimide (1.2g, 5.60mmol), naturally rise To reaction 12 hour is stirred at room temperature.Reactant liquor is poured in 100mL water, be extracted with ethyl acetate (100mL × 3), merge organic Phase, successively with saturated sodium thiosulfate solution (100mL × 2), saturated nacl aqueous solution washing (100mL × 2), anhydrous sodium sulfate It is dried, filters, filtrate reduced in volume, purify gained residue with silica gel column chromatography with eluant system B, obtain title product 3-(4-hydroxyl-3-iodophenyl) methyl propionate 26b (700mg, white solid), productivity: 41.0%.

Second step

2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxyl group)-[1,1'-xenyl]-3-base) oxirane

By 2,6-dimethyl-4-(3-(methylsulfonyl) propoxyl group)-3 '-vinyl biphenyl 1b (3.10g, 9mmol) is dissolved in In 50mL dichloromethane, add sodium bicarbonate (3.0g, 36mmol) and metachloroperbenzoic acid (5.40g, 31.50mmol), stir Mix reaction 12 hours.Reactant liquor is poured into 100mL saturated sodium thiosulfate solution, extracts (100mL × 2) with dichloromethane, close And organic facies, washing (100mL × 3) with saturated nacl aqueous solution, anhydrous magnesium sulfate is dried, and filters, concentrating under reduced pressure filtrate, uses silicon Glue column chromatography, with eluant system B purification gained residue, obtains title product 2-(2', 6'-dimethyl-4'-(3-(MSM Base) propoxyl group)-[1,1'-xenyl]-3-base) oxirane 26c (980mg, white oil), productivity: 30.6%.

3rd step

3-(4-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-2- Hydroxyl-oxethyl)-3-iodophenyl) methyl propionate

By 2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxyl group)-[1,1'-xenyl]-3-base) oxirane 26c (400mg, 1.10mmol), 3-(4-hydroxyl-3-iodophenyl) methyl propionate 26b (440mg, 1.10mmol), Red copper oxide (24mg, 0.17mmol), cesium carbonate (720mg, 2.20mmol) and 1,10-phenanthrolene (59mg, 0.33mmol) is dissolved in 10mLN, in dinethylformamide, is warming up to 110 DEG C, stirring reaction 12 hours.Reactant liquor is poured in 100mL water, use second Acetoacetic ester extraction (80mL × 2), merges organic facies, washs (50mL × 3) with saturated nacl aqueous solution, and anhydrous magnesium sulfate is dried, Filter, concentrating under reduced pressure filtrate, purify gained residue with silica gel column chromatography with eluant system B, obtain title product 3-(4- (2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-2-hydroxyl-oxethyl)-3- Iodophenyl) methyl propionate 26d (200mg, yellow oily), productivity: 41.0%.

4th step

3-(4-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-2- Hydroxyl-oxethyl)-3-iodophenyl) propanoic acid

By 3-(4-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)- 2-hydroxyl-oxethyl)-3-iodophenyl) methyl propionate 26d (150mg, 0.30mmol) is dissolved in 10mL methanol, adds hydroxide Lithium (72mg, 3mmol), is warming up to return stirring and reacts 3 hours.It is cooled to room temperature, by reactant liquor concentrating under reduced pressure, pours 50mL water into In, dropping 1M hydrochloric acid is 1 ~ 2 to reactant liquor pH, is extracted with ethyl acetate (50mL × 3), merges organic facies, uses saturated sodium-chloride Solution washing (50mL × 3), anhydrous magnesium sulfate is dried, and filters, and concentrating under reduced pressure filtrate, with silica gel column chromatography with eluant system A purification gained residue, obtain title product 3-(4-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1, 1'-xenyl]-3-base)-2-hydroxyl-oxethyl)-3-iodophenyl) propanoic acid 26e (70mg, yellow oily), productivity: 50.0%.

5th step

By 3-(4-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)- 2-hydroxyl-oxethyl)-3-iodophenyl) propanoic acid 26e (70mg, 0.11mmol), Red copper oxide (3mg, 0.02mmol), cesium carbonate (72mg, 0.22mmol) and 1,10-phenanthrolene (5.40mg, 0.03mmol) is dissolved in 10mLN, dinethylformamide In, it is warming up to 110 DEG C, stirring reaction 12 hours.Reactant liquor is poured in 100mL water, is extracted with ethyl acetate (20mL × 3), Merging organic facies, wash (20mL × 3) with saturated nacl aqueous solution, anhydrous magnesium sulfate is dried, and filters, concentrating under reduced pressure filtrate, uses Silica gel column chromatography, with eluant system A purification gained residue, obtains title product 3-(3-(2', 6'-dimethyl-4'-(3- (mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-2,3-dihydrobenzo [b] [1,4] two English-6-base) propanoic acid 26 (8mg, white solid), productivity: 14.0%.

MS m/z(ESI):523.2[M-1]

¹H NMR(400MHz,CDCl₃) δ 7.49-7.45 (m, 1H), 7.39-7.38 (m, 1H), 7.27 (s, 1H), 7.19 (s,1H),7.16-7.14(d,1H),6.85(s,1H),6.74-6.72(d,1H),6.66(s,2H),5.15-5.14(m,1H), 4.38-4.35(m,1H),4.15-4.12(m,2H),4.04-3.99(m,1H),3.30-3.26(m,2H),2.97(s,3H), 2.90-2.86(m,2H),2.67-2.63(m,2H),2.39-2.32(m,2H),2.02-1.99(d,6H).

Embodiment 27

3-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-2,3-two Hydrogen benzo [b] [1,4] two English-6-base) propanoic acid

The first step

(E)-3-(3-hydroxy phenyl) ethyl acrylate

By 3-bromophenol 27a (3.46g, 20.0mmol), acid chloride (220mg, 1mmol), triphenylphosphine (1.05g, 4mmol) it is dissolved in 50mLN, in dinethylformamide, adds ethyl acrylate (6.0g, 60mmol) and triethylamine (7.07g, 70mmol), is warming up to 100 DEG C, stirring reaction 12 hours.Add 20mL water and 100mL ethyl acetate, extract separatory, Organic phase washed with water (50mL × 3), saturated nacl aqueous solution washing (50mL × 3), anhydrous sodium sulfate is dried, and filters, decompression Concentrated filtrate, purifies gained residue with silica gel column chromatography with eluant system B, obtains title product (E)-3-(3-hydroxyl Phenyl) ethyl acrylate 27b (2.97g, yellow solid), productivity: 77.3%.

MS m/z(ESI):193.0[M+1]

Second step

3-(3-hydroxy phenyl) ethyl propionate

(E)-3-(3-hydroxy phenyl) ethyl acrylate 27b (500mg, 2.60mmol) is dissolved in 20mL ethanol, adds Enter palladium/carbon (50mg, 10%), hydrogen exchange three times, stirring reaction 12 hours.Filter, filtrate reduced in volume, obtain crude title Product 3-(3-hydroxy phenyl) ethyl propionate 27c (470mg, yellow oil), product is the most purified, and directly to carry out next step anti- Should.

MS m/z(ESI):193.1[M-1]

3rd step

3-(3-hydroxyl-4-iodophenyl) ethyl propionate

Under ice bath, crude product 3-(3-hydroxy phenyl) ethyl propionate 27c (460mg, 2.37mmol) is dissolved in 10mL ice vinegar In acid, the dropping 5mL glacial acetic acid solution containing N-N-iodosuccinimide (533mg, 2.37mmol), add 10 concentrated sulphuric acids, Naturally stirring reaction 12 hours it is warmed to room temperature.Reactant liquor is poured in 100mL water, be extracted with ethyl acetate (100mL × 3), close And organic facies, successively with saturated sodium thiosulfate solution (20mL × 3), saturated nacl aqueous solution washing (20mL × 3), anhydrous sulfur Acid sodium is dried, and filters, filtrate reduced in volume, purifies gained residue with silica gel column chromatography with eluant system B, obtains title Product 3-(3-hydroxyl-4-iodophenyl) ethyl propionate 27d (270mg, yellow liquid), productivity: 35.6%.

MS m/z(ESI):318.9[M-1]

4th step

By 2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxyl group)-[1,1'-xenyl]-3-base) oxirane 26c (563mg, 1.56mmol), 3-(3-hydroxyl-4-iodophenyl) ethyl propionate 27d (250mg, 0.78mmol), Red copper oxide (18mg, 0.12mmol), cesium carbonate (477mg, 1.56mmol) and 1,10-phenanthrolene (42mg, 0.23mmol) is dissolved in 10mLN, in dinethylformamide, is warming up to 110 DEG C, stirring reaction 12 hours.Add 30mL water and 30mL ethyl acetate, extraction Taking separatory, aqueous phase is extracted with ethyl acetate (15mL × 3), merges organic facies, and successively with water (20mL × 3), saturated sodium-chloride is molten Liquid washing (20mL × 3), anhydrous magnesium sulfate is dried, and filters, and concentrating under reduced pressure filtrate, with silica gel column chromatography with eluant system A Purification gained residue, obtains title product 3-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'- Xenyl]-3-base)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two English-6-base) propanoic acid 27 (15mg, yellow solid), productivity: 3.6%.

MS m/z(ESI):523.26[M-1]

¹H NMR(400MHz,CDCl₃)δ7.46-7.49(m,1H),7.38-7.40(m,1H),7.14-7.19(m,2H), 6.79-6.92(m,2H),6.72-6.74(m,1H),6.66(s,2H),5.13-5.15(m,1H),4.36-4.39(m,1H), 4.12-4.15(m,2H),4.00-4.06(m,1H),3.26-3.30(m,2H),2.98(s,3H),2.87-2.91(m,2H), 2.64-2.68(m,2H),2.33-2.40(m,2H),2.03(s,3H),2.00(s,3H).

Embodiment 28

2-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-2,3-two Hydrogen benzo [b] [1,4] two English-6-base) cyclopropanecarboxylic acid

The first step

(E)-3-(3-methoxyphenyl) ethyl acrylate

By bromo-for 1-4-methoxybenzene 28a (10.0g, 57.80mmol), acid chloride (649mg, 2.89mmol), triphenylphosphine (3.03g, 11.56mmol) is dissolved in 50mLN, in dinethylformamide, add ethyl acrylate (17.34g, 173.40mmol) with triethylamine (20.43g, 202.30mmol), it is warming up to 90 DEG C, stirring reaction 12 hours.Reactant liquor is poured into In 100mL water, it is extracted with ethyl acetate (100mL × 2), merges organic facies, wash (100mL × 2) with saturated nacl aqueous solution, Anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure filtrate, purifies gained residue with silica gel column chromatography with eluant system B, To title product (E)-3-(3-methoxyphenyl) ethyl acrylate 28b (6.50g, white oil), productivity: 58.5%.

Second step

2-(4-methoxyphenyl) cyclopropanecarboxylic acid ethyl ester

Sodium hydride (464mg, 11.60mmol) and Trimethylsulfoxonium Iodide (2.60g, 11.60mmol) are dissolved in 20mL In dimethyl sulfoxide, stir 1 hour, add (E)-3-(3-methoxyphenyl) ethyl acrylate 28b (1.20g, 5.80mmol), Stirring reaction 1 hour.Reactant liquor is poured in 100mL water, be extracted with ethyl acetate (50mL × 2), merge organic facies, with saturated Sodium chloride solution washing (50mL × 3), anhydrous sodium sulfate is dried, and filters, and concentrating under reduced pressure filtrate, with silica gel column chromatography with eluting Agent system B purification gained residue, obtains title product 2-(4-methoxyphenyl) cyclopropanecarboxylic acid ethyl ester 28c (160mg, white Solid), productivity: 12.7%.

3rd step

2-(4-hydroxy phenyl) cyclopropanecarboxylic acid ethyl ester

At-78 DEG C, 2-(4-methoxyphenyl) cyclopropanecarboxylic acid ethyl ester 28c (160mg, 0.77mmol) is dissolved in 20mL bis- In chloromethanes, the dichloromethane solution of dropping 0.8mL2M Boron tribromide, stirring reaction 15 minutes, then rise to 0 DEG C of stirring reaction 12 Hour.Reactant liquor is poured in 100mL saturated ammonium chloride solution, be extracted with ethyl acetate (50mL × 2), merge organic facies, use Saturated nacl aqueous solution washing (50mL × 2), anhydrous sodium sulfate is dried, and filters, and concentrating under reduced pressure filtrate, by thin layer chromatography to wash De-agent system B purification gained residue, obtains title product 2-(4-hydroxy phenyl) cyclopropanecarboxylic acid ethyl ester 28d (195mg, white Solid), productivity: 57.8%.

4th step

2-(4-hydroxyl-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester

Under ice bath, 2-(4-hydroxy phenyl) cyclopropanecarboxylic acid ethyl ester 28d (195mg, 0.95mmol) is dissolved in 20mL ice vinegar In acid, add N-N-iodosuccinimide (202mg, 0.90mmol), add 1mL concentrated sulphuric acid, be naturally warmed to room temperature stirring anti- Answer 12 hours.Reactant liquor is poured in 50mL water, be extracted with ethyl acetate (50mL × 2), merge organic facies, use saturated sodium-chloride Solution washing (50mL × 3), anhydrous sodium sulfate is dried, and filters, and filtrate reduced in volume, with silica gel column chromatography with eluant system B purification gained residue, obtains title product 2-(4-hydroxyl-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 28e (230mg, white liquid Body), productivity: 73.0%.

5th step

2-(4-(2-((tert-butyldimethyl silyl) epoxide)-1-(2', 6'-dimethyl-4'-(3-(mesyl) the third oxygen Base)-[1,1'-xenyl]-3-base) ethyoxyl)-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester

By 2-(4-hydroxyl-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 28e (230mg, 0.69mmol), 2-(fert-butyidimethylsilyl Siloxy)-1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxyl group) biphenyl-3-base) ethanol 1d (340mg, 0.69mmol) It is dissolved in 10mL toluene with azodicarbonyldipiperidine (277mg, 1.10mmol), addition tri-n-butyl phosphine (222mg, 1.10mmol), it is heated to 50 DEG C, stirring reaction 12 hours.Reactant liquor is poured in 50mL water, be extracted with ethyl acetate (50mL × 2), merging organic facies, wash (50mL × 2) with saturated nacl aqueous solution, anhydrous sodium sulfate is dried, and filters, and filtrate decompression is dense Contracting, purifies gained residue with silica gel column chromatography with eluant system B, obtains title product 2-(4-(2-((tert-butyl group diformazan Base silicon) epoxide)-1-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base) ethoxy Base)-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 28f (320mg, white liquid), productivity: 57.0%.

6th step

2-(4-(1-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-2- Hydroxyl-oxethyl)-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester

By 2-(4-(2-((tert-butyldimethyl silyl) epoxide)-1-(2', 6'-dimethyl-4'-(3-(mesyl) the third oxygen Base)-[1,1'-xenyl]-3-base) ethyoxyl)-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 28f (320mg, 0.40mmol) is dissolved in In 10mL oxolane, add the tetrahydrofuran solution of 0.44mL1M tetrabutyl ammonium fluoride, stirring reaction 2 hours.Reactant liquor subtracts Pressure concentrates, and purifies gained residue with silica gel column chromatography with eluant system B, obtains title product 2-(4-(1-(2', 6'- Dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-2-hydroxyl-oxethyl)-3-iodophenyl) ring Third Ethyl formate 28g (220mg, white solid), productivity: 80.3%.

7th step

2-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-2,3-two Hydrogen benzo [b] [1,4] two English-6-base) cyclopropanecarboxylic acid ethyl ester

By 2-(4-(1-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)- 2-hydroxyl-oxethyl)-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 28g (215mg, 0.31mmol), acid chloride (11mg, 0.05mmol), 2-(di-t-butyl phosphorus)-1,1'-dinaphthalene (37mg, 0.09mmol) and cesium carbonate (302mg, 0.93mmol) are dissolved in 10mL toluene In, it is heated to 50 DEG C, stirring reaction 12 hours.Reactant liquor is poured in 50mL water, be extracted with ethyl acetate (50mL × 2), close And organic facies, washing (50mL × 2) with saturated nacl aqueous solution, anhydrous sodium sulfate is dried, and filters, and filtrate reduced in volume, with thin Layer chromatography, with eluant system B purification gained residue, obtains title product 2-(2-(2', 6'-dimethyl-4'-(3-(first Sulfonyl) propoxyl group)-[1,1'-xenyl]-3-base)-2,3-dihydrobenzo [b] [1,4] two English-6-base) cyclopropanecarboxylic acid second Ester 28h (130mg, white liquid), productivity: 74.3%.

MS m/z(ESI):582.54[M+18]

8th step

By 2-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-2,3- Dihydrobenzo [b] [Isosorbide-5-Nitrae] two English-6-base) cyclopropanecarboxylic acid ethyl ester 28h (130mg, 0.23mmol) is dissolved in 16mL oxolane With in methanol (V/V=1:15) mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 70 DEG C, stir reaction 1 Hour.Reactant liquor concentrating under reduced pressure, adds 50mL water, and dropping 1M hydrochloric acid is 1 ~ 2 to reactant liquor pH, is extracted with ethyl acetate (50mL × 2), merging organic facies, wash (50mL × 2) with saturated nacl aqueous solution, anhydrous magnesium sulfate is dried, and filters, and concentrating under reduced pressure is filtered Liquid, purifies gained residue by thin layer chromatography with eluant system A, obtains title product 2-(2-(2', 6'-dimethyl-4'- (3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-2,3-dihydrobenzo [b] [1,4] two English-6-base) ring third Formic acid 28 (85mg, white solid), productivity: 69.0%.

MS m/z(ESI):535.49[M-1]

¹H NMR(400MHz,CDCl₃)δ7.49-7.46(m,1H),7.39-7.37(m,1H),7.18-7.14(m,2H), 6.91-6.89(d,1H),6.68-6.65(m,4H),5.14-5.11(m,1H),4.39-4.35(m,1H),4.15-4.12(m, 2H),4.04-4.02(m,1H),3.30-3.26(m,2H),2.98(s,3H),2.54-2.52(m,1H),2.38-2.34(m, 2H),2.02-1.99(d,6H),1.83-1.82(m,1H),1.64-1.59(m,1H),1.36-1.33(m,1H).

Embodiment 29

(R)-3-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-2, 3-dihydrobenzo [b] [1,4] two English-6-base) propanoic acid

By 3-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-2,3- Dihydrobenzo [b] [Isosorbide-5-Nitrae] two English-6-base) propanoic acid 27 (95mg, 0.18mmol) carries out chiral separation, uses HPLC method, by system Standby equipment and the chiral isomer of chiral column carry out separating (separation condition: chiral column AD-H Chiralpak 4.6, flow phase: (methanol: ethanol 1:1) (0.1%TFA): normal hexane=60:40, flow velocity: 0.5mL/ minute), collect its respective components, rotary evaporation Remove solvent, obtain title product (R)-3-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-connection Phenyl]-3-base)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two English-6-base) propanoic acid 29 (40mg, white solid).

Embodiment 30

(S)-3-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-2, 3-dihydrobenzo [b] [1,4] two English-6-base) propanoic acid

By 3-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-2,3- Dihydrobenzo [b] [Isosorbide-5-Nitrae] two English-6-base) propanoic acid 27 (95mg, 0.18mmol) carries out chiral separation, uses HPLC method, by system Standby equipment and the chiral isomer of chiral column carry out separating (separation condition: chiral column AD-H Chiralpak 4.6, flow phase: (methanol: ethanol 1:1) (0.1%TFA): normal hexane=60:40, flow velocity: 0.5mL/ minute), collect its respective components, rotary evaporation Remove solvent, obtain title product (S)-3-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-connection Phenyl]-3-base)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two English-6-base) propanoic acid 30 (32mg, colourless liquid).

Embodiment 31

(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-7-is fluoro-for 3- 2,3-dihydrobenzo [b] [1,4] two English-6-base) propanoic acid

The first step

(E)-3-(2-fluoro-4-hydroxy phenyl) ethyl acrylate

By bromo-for 4-3-fluorophenol 31a (5.0g, 26.18mmol), acid chloride (588mg, 2.62mmol), triphenylphosphine (1.37g, 5.24mmol) is dissolved in 30mLN, in dinethylformamide, add ethyl acrylate (5.23g, 52.36mmol) with triethylamine (7.93g, 78.54mmol), it is warming up to 100 DEG C, stirring reaction 72 hours.Add 100mL water and 100mL ethyl acetate, extract separatory, aqueous phase is extracted with ethyl acetate (50mL × 3), merge organic facies, successively with water (50mL × 3), saturated nacl aqueous solution washing (50mL × 3), anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure filtrate, uses silica gel column chromatography Method, with eluant system B purification gained residue, obtains title product (E)-3-(2-fluoro-4-hydroxy phenyl) ethyl acrylate 31b (4.80g, yellow solid), productivity: 87.3%.

MS m/z(ESI):209.1[M-1]

Second step

3-(2-fluoro-4-hydroxy phenyl) ethyl propionate

(E)-3-(2-fluoro-4-hydroxy phenyl) ethyl acrylate 31b (2.0g, 9.52mmol) is dissolved in 15mL methanol and In oxolane (V/V=2:1) mixed solvent, add palladium/carbon (200mg, 10%), hydrogen exchange three times, stirring reaction 12 is little Time.Filter, filtrate reduced in volume, obtain crude title product 3-(2-fluoro-4-hydroxy phenyl) ethyl propionate 31c (2.0g, yellow Grease), product is the most purified directly carries out next step reaction.

MS m/z(ESI):211.45[M-1]

3rd step

3-(2-fluoro-4-hydroxyl-5-iodophenyl) ethyl propionate

Under ice bath, crude product 3-(2-fluoro-4-hydroxy phenyl) ethyl propionate 31c (500mg, 2.36mmol) is dissolved in 10mL In glacial acetic acid, the dropping 5mL glacial acetic acid solution containing N-N-iodosuccinimide (530mg, 2.36mmol), add 4 dense sulfur Acid, is warmed to room temperature stirring reaction 12 hours naturally.Adding 150mL water and 150mL ethyl acetate, extract separatory, organic facies is successively With saturated sodium bicarbonate solution (100mL × 3), water (100mL × 3), saturated nacl aqueous solution washing (100mL × 3), anhydrous sulfur Acid sodium is dried, and filters, concentrating under reduced pressure filtrate, purifies gained residue with silica gel column chromatography with eluant system B, obtains title Product 3-(2-fluoro-4-hydroxyl-5-iodophenyl) ethyl propionate 31d (600mg, yellow liquid), productivity: 75.3%.

4th step

3-(4-(2-((tert-butyldimethyl silyl) epoxide)-1-(2', 6'-dimethyl-4'-(3-(mesyl) the third oxygen Base)-[1,1'-xenyl]-3-base) ethyoxyl)-2-fluoro-5-iodophenyl) ethyl propionate

By 3-(2-fluoro-4-hydroxyl-5-iodophenyl) ethyl propionate 31d (150mg, 0.44mmol), 2-(fert-butyidimethylsilyl Siloxy)-1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxyl group) biphenyl-3-base) ethanol 1d (218mg, 0.44mmol) It is dissolved in 15mL toluene with azodicarbonyldipiperidine (179mg, 0.71mmol), addition tri-n-butyl phosphine (143mg, 0.71mmol), it is heated to 50 DEG C, stirring reaction 1.5 hours.Add 20mL methanol cancellation reaction, reactant liquor concentrating under reduced pressure, use silicon Glue column chromatography, with eluant system B purification gained residue, obtains title product 3-(4-(2-((tert-butyldimethyl silyl) oxygen Base)-1-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base) ethyoxyl)-2-is fluoro- 5-iodophenyl) ethyl propionate 31e (220mg, yellow liquid), productivity: 61.1%.

MS m/z(ESI):830.2[M+18]

5th step

3-(4-(1-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-2- Hydroxyl-oxethyl)-2-fluoro-5-iodophenyl) ethyl propionate

By 3-(4-(2-((tert-butyldimethyl silyl) epoxide)-1-(2', 6'-dimethyl-4'-(3-(mesyl) the third oxygen Base)-[1,1'-xenyl]-3-base) ethyoxyl)-2-fluoro-5-iodophenyl) ethyl propionate 31e (210mg, 0.26mmol) dissolving In 3mL oxolane, add the tetrahydrofuran solution of 0.28mL1M tetrabutyl ammonium fluoride, stirring reaction 2 hours.Reactant liquor subtracts Pressure concentrates, and purifies gained residue with silica gel column chromatography with eluant system B, obtains title product 3-(4-(1-(2', 6'- Dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-2-hydroxyl-oxethyl)-2-fluoro-5-iodobenzene Base) ethyl propionate 31f (110mg, yellow liquid), productivity: 61.1%.

6th step

(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-7-is fluoro-for 3- 2,3-dihydrobenzo [b] [1,4] two English-6-base) ethyl propionate

By 3-(4-(1-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)- 2-hydroxyl-oxethyl)-2-fluoro-5-iodophenyl) ethyl propionate 31f (110mg, 0.16mmol), acid chloride (5mg, 0.02mmol), 2-(di-t-butyl phosphorus)-1,1'-dinaphthalene (19mg, 0.05mmol) and cesium carbonate (102mg, 0.31mmol) are dissolved in 10mL toluene In, it is heated to 80 DEG C, stirring reaction 12 hours.Filter, filtrate reduced in volume, pure with eluant system B with silica gel column chromatography Change gained residue, obtain title product 3-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-connection Phenyl]-3-base)-7-fluoro-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two English-6-base) ethyl propionate 31g (70mg, yellow liquid), Productivity: 77.8%.

MS m/z(ESI):588.57[M+18]

7th step

By 3-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-7- Fluoro-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two English-6-base) ethyl propionate 31g (70mg, 0.12mmol) is dissolved in 6mL tetrahydrochysene furan Mutter and in methanol (V/V=1:5) mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 70 DEG C, stirring reaction 1 hour.Reactant liquor concentrating under reduced pressure, adds 30mL water and 30mL ethyl acetate, and dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, uses second Acetoacetic ester extraction (10mL × 2), merges organic facies, successively with water (10mL × 3), and saturated nacl aqueous solution washing (10mL × 3), Anhydrous magnesium sulfate is dried, and filters, concentrating under reduced pressure filtrate, purifies gained residue with silica gel column chromatography with eluant system A, To title product 3-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-7- Fluoro-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two English-6-base) propanoic acid 31 (80mg, white solid), productivity: 100.0%.

MS m/z(ESI):541.3[M-1]

¹H NMR(400MHz,CDCl₃)δ7.46-7.49(m,1H),7.36-7.38(m,1H),7.15-7.17(m,2H), 6.76-6.782(m,1H),6.68-6.71(m,1H),6.66(s,2H),5.12-5.15(m,1H),4.34-4.37(m,1H), 4.12-4.15(m,2H),3.97-4.02(m,1H),3.26-3.30(m,2H),2.98(s,3H),2.88-2.92(m,2H), 2.64-2.68(m,2H),2.33-2.40(m,2H),2.02(s,3H),2.00(s,3H).

Embodiment 32

3-((S)-2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-2, 3-dihydrobenzo [b] [1,4] two English-6-base)-4-acetylenic acid

The first step

4-hydroxyl-3-benzaldehyde iodine

4-hydroxy benzaldehyde 32a (5.0g, 40.90mmol) is dissolved in 30mL glacial acetic acid, adds N-iodo succinyl The glacial acetic acid solution of imines (9.20g, 40.90mmol), adds 1mL concentrated sulphuric acid, stirring reaction 12 hours.Reactant liquor is poured into In 50mL water, it is extracted with ethyl acetate (50mL × 3), merges organic facies, wash (50mL × 3) with saturated nacl aqueous solution, nothing Aqueous sodium persulfate is dried, and filters, concentrating under reduced pressure filtrate, purifies gained residue with silica gel column chromatography with eluant system A, obtains Title product 4-hydroxyl-3-benzaldehyde iodine 32b (5.0g, yellow liquid), productivity: 49.0%.

Second step

5-(4-hydroxyl-3-iodine benzal)-2,2-dimethyl-1,3-dioxane-4,6-diketone

4-hydroxyl-3-benzaldehyde iodine 32b (2.0g, 8.10mmol) is dissolved in 20mL water, is warming up to 75 DEG C, add 10mL contains 2, and 2-dimethyl-1,3-dioxane-4, the aqueous solution of 6-diketone (1.20g, 40.98.50mmol), stirring reaction 2 is little Time.Reactant liquor is poured in 50mL water, with 1M sulfuric acid solution regulation pH value to 1～2, be extracted with ethyl acetate (50mL × 3), close And organic facies, washing (50mL × 3) with saturated nacl aqueous solution, anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, obtains Crude title product 5-(4-hydroxyl-3-iodine benzal)-2,2-dimethyl-1,3-dioxane-4,6-diketone 32c (2.60g, yellow Color solid), product is the most purified directly carries out next step reaction.

3rd step

5-(1-(4-hydroxyl-3-iodophenyl)-2-butyne-1-base)-2,2-dimethyl-1,3-dioxane-4,6-diketone

By crude product 5-(4-hydroxyl-3-iodine benzal)-2,2-dimethyl-1,3-dioxane-4,6-diketone 32c (1.0g, 2.70mmol) it is dissolved in 20mL oxolane, adds 20mL2M1-propinyl magnesium bromide, stirring reaction 2 hours.By reactant liquor Pour in 50mL water, with 1M sulfuric acid solution regulation pH value to 1～2, ethyl acetate extraction (50mL × 2), merge organic facies, with full Washing (50mL × 2) with sodium chloride solution, anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, obtains crude title product 5- (1-(4-hydroxyl-3-iodophenyl)-2-butyne-1-base)-2,2-dimethyl-1,3-dioxane-4,6-diketone 32d (1.10g, yellow Color solid), product is the most purified directly carries out next step reaction.

MS m/z(ESI):413.1[M-1]

4th step

3-(4-hydroxyl-3-iodophenyl)-4-hexin ethyl ester

By crude product 5-(1-(4-hydroxyl-3-iodophenyl)-2-butyne-1-base)-2,2-dimethyl-1,3-dioxane-4,6- Diketone 32d (1.10g, 2.70mmol) is dissolved in 1.5mL ethanol, adds 4.5mL pyridine, is warming up to 80 DEG C, stirs reaction 12 Hour.Reactant liquor concentrating under reduced pressure, purifies gained residue with silica gel column chromatography with eluant system B, obtains title product 3- (4-hydroxyl-3-iodophenyl)-4-hexin ethyl ester 32e (600mg, yellow liquid), productivity: 63.0%.

5th step

(R)-1-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base) ethane- At 1,2-glycol 0 DEG C, by 2,6-dimethyl-4-(3-(methylsulfonyl) propoxyl group)-3 '-vinyl biphenyl 1b (3.0g, 8.70mmol) it is dissolved in the 200mL tert-butyl alcohol and water (V/V=1:1) mixed solvent, adds AD-mix-beta (13.0g), stirring React 3 hours.Reactant liquor is poured in 100mL saturated sodium thiosulfate solution, be extracted with ethyl acetate (100mL × 2), merge Organic facies, washs (50mL × 3) with saturated nacl aqueous solution, and anhydrous magnesium sulfate is dried, and filters, filtrate reduced in volume, uses silica gel Column chromatography, with eluant system B purification gained residue, obtains title product (R)-1-(2', 6'-dimethyl-4'-(3-(first Sulfonyl) propoxyl group)-[1,1'-xenyl]-3-base) ethane-1,2-glycol 32f (1.20g, white solid), productivity: 36.0%.

6th step

(R)-2-((tert-butyldimethyl silyl) epoxide)-1-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)- [1,1'-xenyl]-3-base) ethanol

By (R)-1-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base) second Alkane-1,2-glycol 32f (1.10g, 2.90mmol), imidazoles (395mg, 5.80mmol) and DMAP (26mg, 0.29mmol) it is dissolved in 20mLN, in dinethylformamide, adds tert-butyl chloro-silicane (482mg, 3.20mmol), Stirring reaction 2 hours.Add 100mL water, be extracted with ethyl acetate (50mL × 2), merge organic facies, use saturated nacl aqueous solution Washing (50mL × 2), anhydrous magnesium sulfate is dried, and filters, concentrating under reduced pressure filtrate, pure with eluant system A with silica gel column chromatography Change gained residue, obtain title product (R)-2-((tert-butyldimethyl silyl) epoxide)-1-(2', 6'-dimethyl-4'-(3- (mesyl) propoxyl group)-[1,1'-xenyl]-3-base) ethanol 32g (900mg, white oil thing), productivity: 62.9%.

7th step

3-(4-((S)-2-((t-Butyldimethylsilyl) epoxide)-1-(2', 6'-dimethyl-4'-(3-(mesyl) Propoxyl group)-[1,1'-xenyl]-3-base) ethyoxyl)-3-iodophenyl)-4-hexin ethyl ester

By 3-(4-hydroxyl-3-iodophenyl)-4-hexin ethyl ester 32e (240mg, 0.67mmol), (R)-2-((tert-butyl group two Methyl silicon) epoxide)-1-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base) ethanol 32g (300mg, 0.61mmol) and azodicarbonyldipiperidine (247mg, 0.98mmol) are dissolved in 10mL toluene, add three Normal-butyl phosphine (198mg, 0.98mmol), is heated to 50 DEG C, stirring reaction 12 hours.Add 50mL water, be extracted with ethyl acetate (25mL × 2), merge organic facies, wash (25mL × 3) with saturated nacl aqueous solution, and anhydrous magnesium sulfate is dried, and filter, reduce pressure dense Contracting filtrate, obtain crude title product 3-(4-((S)-2-((t-Butyldimethylsilyl) epoxide)-1-(2', 6'-dimethyl- 4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base) ethyoxyl)-3-iodophenyl)-4-hexin ethyl ester 32h (500g, yellow liquid), product is the most purified directly carries out next step reaction.

8th step

3-(4-((S)-1-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3- Base)-2-hydroxyl-oxethyl-3-iodophenyl)-4-hexin ethyl ester

By crude product 3-(4-((S)-2-((t-Butyldimethylsilyl) epoxide)-1-(2', 6'-dimethyl-4'-(3-(first Sulfonyl) propoxyl group)-[1,1'-xenyl]-3-base) ethyoxyl)-3-iodophenyl)-4-hexin ethyl ester 32h (500mg, 0.60mmol) being dissolved in 10mL oxolane, the oxolane adding 1M tetrabutyl ammonium fluoride (0.66mL, 0.66mmol) is molten Liquid, stirring reaction 1 hour.Add 25mL water, be extracted with ethyl acetate (20mL × 2), merge organic facies, molten with saturated sodium-chloride Liquid washing (20mL × 3), anhydrous magnesium sulfate is dried, and filters, filtrate reduced in volume, pure with eluant system B by thin layer chromatography Change gained residue, obtain title product 3-(4-((S)-1-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)- [1,1'-xenyl]-3-base)-2-hydroxyl-oxethyl-3-iodophenyl)-4-hexin ethyl ester 32i (300mg, yellow oily), produces Rate: 77.9%.

MS m/z(ESI):736.4[M+18]

9th step

3-((S)-2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-2, 3-dihydrobenzo [b] [1,4] two English-6-base)-4-acetylenic acid ethyl ester

By 3-(4-((S)-1-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3- Base)-2-hydroxyl-oxethyl-3-iodophenyl)-4-hexin ethyl ester 32i (300mg, 0.42mmol), acid chloride (14mg, 0.06mmol), 2-(di-t-butyl phosphorus)-1,1'-dinaphthalene (52mg, 0.13mmol) and cesium carbonate (409mg, 1.26mmol) dissolve In 10mL toluene, it is heated to 50 DEG C, stirring reaction 12 hours.Add 20mL water, be extracted with ethyl acetate (20mL × 3), close And organic facies, washing (20mL × 3) with saturated nacl aqueous solution, anhydrous magnesium sulfate is dried, and filters, and filtrate reduced in volume, with thin Layer chromatography, with eluant system B purification gained residue, obtains title product 3-((S)-2-(2', 6'-dimethyl-4'-(3- (mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-2,3-dihydrobenzo [b] [1,4] two English-6-base)-4-acetylene Acetoacetic ester 32j (180mg, yellow oily), productivity: 72.9%.

Tenth step

By 3-((S)-2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)- 2,3-dihydrobenzos [b] [Isosorbide-5-Nitrae] two English-6-base)-4-acetylenic acid ethyl ester 32j (180mg, 0.31mmol) is dissolved in 16mL tetra- In hydrogen furan and methanol (V/V=1:15) mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 70 DEG C, stir Mix reaction 1 hour.Reactant liquor concentrating under reduced pressure, adds 25mL water, and dropping 1M hydrochloric acid is 1 ~ 2 to reactant liquor pH, extracts by ethyl acetate Taking (25mL × 2), merge organic facies, wash (25mL × 2) with saturated nacl aqueous solution, anhydrous magnesium sulfate is dried, and filters, filtrate Concentrating under reduced pressure, purifies gained residue with silica gel column chromatography with eluant system A, obtain title product 3-((S)-2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-2,3-dihydrobenzo [b] [1,4] two English-6-base)-4-acetylenic acid 32 (140mg, white solid), productivity: 81.9%.

MS m/z(ESI):580.4[M+18]

¹H NMR(400MHz,CDCl₃)δ7.49-7.45(m,1H),7.39-7.37(m,1H),7.18-7.14(m,2H), 7.00-6.99(m,1H),6.92-6.89(m,2H),6.65(s,2H),5.15-5.13(m,1H),4.39-4.36(m,1H), 4.15-4.10(m,2H),4.04-4.00(m,2H),3.30-3.26(m,2H),2.97(s,3H),2.83-2.69(m,2H), 2.39-2.34(m,2H),2.02-1.99(m,6H),1.84(m,3H).

Embodiment 33

(R)-3-((S)-2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3- Base)-2,3-dihydrobenzo [b] [1,4] two English-6-base)-4-acetylenic acid

By 3-((S)-2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)- 2,3-dihydrobenzos [b] [Isosorbide-5-Nitrae] two English-6-base)-4-acetylenic acid 32 (140mg, 0.25mmol) carries out chiral separation, uses HPLC method, carries out separating (separation condition: chiral column ADH with the chiral isomer of Preparation equipment and chiral column CHIRALPAK4.6, flow phase: ethanol/acrylonitrile/acetic acid=95/5/0.1, flow velocity: 0.8mL/ minute), collect its respective sets Point, rotary evaporation removes solvent, obtains title product (R)-3-((S)-2-(2', 6'-dimethyl-4'-(3-(mesyl) third Epoxide)-[1,1'-xenyl]-3-base)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two English-6-base)-4-acetylenic acid 33 (60mg, in vain Color solid).

Embodiment 34

(S)-3-((S)-2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3- Base)-2,3-dihydrobenzo [b] [1,4] two English-6-base)-4-acetylenic acid

By 3-((S)-2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)- 2,3-dihydrobenzos [b] [Isosorbide-5-Nitrae] two English-6-base)-4-acetylenic acid 32 (140mg, 0.25mmol) carries out chiral separation, uses HPLC method, carries out separating (separation condition: chiral column ADH CHIRALPAK with the chiral isomer of Preparation equipment and chiral column 4.6, flow phase: ethanol/acrylonitrile/acetic acid=95/5/0.1, flow velocity: 0.8mL/ minute), collect its respective components, rotary evaporation Remove solvent, obtain title product (S)-3-((S)-2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1, 1'-xenyl]-3-base)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two English-6-base)-4-acetylenic acid 34 (76mg, white solid).

Embodiment 35

2-(2-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-base)-2,3-dihydrobenzo [b] [1,4] two English- 6-yl) cyclopropanecarboxylic acid

The first step

2-(4-(2-((tert-butyldimethyl silyl) epoxide)-1-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-base) Ethyoxyl)-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester

By 2-(4-hydroxyl-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 28e (230mg, 0.69mmol), 2-((fert-butyidimethylsilyl Silane) oxygen)-1-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-bases) ethanol 13g (250mg, 0.69mmol) and azo Two formyls two piperidines (277mg, 1.10mmol) are dissolved in 10mL toluene, add tri-butyl phosphine (223mg, 1.10mmol), It is heated to 50 DEG C, stirring reaction 2 hours.Reactant liquor concentrating under reduced pressure, obtains crude title product 2-(4-(2-((tert-butyl group diformazan Base silicon) epoxide)-1-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-base) ethyoxyl)-3-iodophenyl) cyclopropanecarboxylic acid second Ester 35a (460mg, white liquid), product is the most purified directly carries out next step reaction.

Second step

2-(4-(2-hydroxyl-1-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-base) ethyoxyl)-3-iodophenyl) Cyclopropanecarboxylic acid ethyl ester

By crude product 2-(4-(2-((tert-butyldimethyl silyl) epoxide)-1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydrochysene Naphthalene-2-base) ethyoxyl)-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 35a (500mg, 0.74mmol) is dissolved in 10mL oxolane, Add the tetrahydrofuran solution of 0.82mL1M tetrabutyl ammonium fluoride, stirring reaction 2 hours.Reactant liquor concentrating under reduced pressure, uses silicagel column Chromatography with eluant system B purification gained residue, obtain title product 2-(4-(2-hydroxyl-1-(5,5,8,8-tetramethyls- 5,6,7,8-naphthane-2-bases) ethyoxyl)-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 35b (170mg, white oil), productivity: 41.0%.

3rd step

2-(2-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-base)-2,3-dihydrobenzo [b] [1,4] two English- 6-yl) cyclopropanecarboxylic acid ethyl ester

By 2-(4-(2-hydroxyl-1-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-base) ethyoxyl)-3-iodobenzene Base) cyclopropanecarboxylic acid ethyl ester 35b (170mg, 0.30mmol), acid chloride (11mg, 0.05mmol), 2-(di-t-butyl phosphorus)-1,1'- Dinaphthalene (36mg, 0.09mmol) and cesium carbonate (195mg, 0.60mmol) are dissolved in 10mL toluene, are heated to 50 DEG C, and stirring is anti- Answer 12 hours.Filter, filtrate reduced in volume, purify gained residue by thin layer chromatography with eluant system B, obtain title and produce Thing 2-(2-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-base)-2,3-dihydrobenzo [b] [1,4] two English-6-base) Cyclopropanecarboxylic acid ethyl ester 35c (120mg, white liquid), productivity: 90.0%.

MS m/z(ESI):452.2[M+18]

4th step

By 2-(2-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-base)-2,3-dihydrobenzo [b] [1,4] two English-6-base) cyclopropanecarboxylic acid ethyl ester 35c (120mg, 0.30mmol) is dissolved in 15mL methanol, adds 1M sodium hydroxide solution (1mL, 1mmol), is heated to return stirring and reacts 0.5 hour.Reactant liquor concentrating under reduced pressure, adds 25mL water, and dropping 1M hydrochloric acid is extremely Reactant liquor pH is 1 ~ 2, is extracted with ethyl acetate (25mL × 2), merge organic facies, with saturated nacl aqueous solution washing (20mL × 3), anhydrous magnesium sulfate is dried, and filters, concentrating under reduced pressure filtrate, purifies gained residue by thin layer chromatography with eluant system B, Obtain title product 2-(2-(5,5,8,8-tetramethyl-5,6,7,8-naphthane-2-base)-2,3-dihydrobenzo [b] [1,4] two English-6-base) cyclopropanecarboxylic acid 35 (70mg, white solid), productivity: 62.5%.

MS m/z(ESI):405.3[M-1]

¹H NMR(400MHz,CDCl₃)δ7.36-7.32(m,2H),7.17-7.15(m,1H),6.91-6.89(m,1H), 6.69-6.65(m,2H),5.04-5.02(m,1H),4.35-4.32(m,1H),4.06-4.01(m,1H),2.57-2.53(m, 1H),1.86-1.84(m,1H),1.70(s,4H),1.64-160(m,1H),1.36-1.25(m,13H).

Embodiment 36

(R)-3-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-7- Fluoro-2,3-dihydrobenzo [b] [1,4] two English-6-base) propanoic acid

By 3-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-7- Fluoro-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two English-6-base) propanoic acid 31 (80mg, 0.15mmol) carries out chiral separation, uses HPLC Method, carries out separating (separation condition: chiral column OJ-H CHIRALCEL4.6, stream with the chiral isomer of Preparation equipment and chiral column Dynamic phase: ethanol: normal hexane: methanol=45:10:45, flow velocity: 0.5mL/ minute), collect its respective components, rotary evaporation removes molten Agent, obtain title product (R)-3-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]- 3-yl)-7-fluoro-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two English-6-base) propanoic acid 36 (40mg, brown solid).

Embodiment 37

(S)-3-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-7- Fluoro-2,3-dihydrobenzo [b] [1,4] two English-6-base) propanoic acid

By 3-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]-3-base)-7- Fluoro-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two English-6-base) propanoic acid 31 (80mg, 0.15mmol) carries out chiral separation, uses HPLC Method, carries out separating (separation condition: chiral column OJ-H CHIRALCEL4.6, stream with the chiral isomer of Preparation equipment and chiral column Dynamic phase: ethanol: normal hexane: methanol=45:10:45, flow velocity: 0.5mL/ minute), collect its respective components, rotary evaporation removes molten Agent, obtain title product (S)-3-(2-(2', 6'-dimethyl-4'-(3-(mesyl) propoxyl group)-[1,1'-xenyl]- 3-yl)-7-fluoro-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two English-6-base) propanoic acid 37 (44mg, brown solid).

Embodiment 38

2-(2-(2'-methyl-[1,1'-xenyl]-3-base)-2,3-dihydrobenzo [b] [1,4] two English-6-base) ring Third formic acid

The first step

2-(4-(1-(3-bromophenyl)-2-((tert-butyldimethyl silyl) epoxide) ethyoxyl)-3-iodophenyl) cyclopropanecarboxylic acid Ethyl ester

By 1-(3-bromophenyl)-2-((t-butyldimethyl silane) oxygen) ethanol 4d (745mg, 2.25mmol), 2-(4-hydroxyl Base-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 28e (750mg, 2.25mmol) and azodicarbonyldipiperidine (907mg, 3.60mmol) It is dissolved in 20mL toluene, adds tri-n-butyl phosphine (728mg, 3.60mmol), be heated to 50 DEG C, stirring reaction 30 minutes.Instead Answer liquid concentrating under reduced pressure, purify gained residue with silica gel column chromatography with eluant system B, obtain title product 2-(4-(1- (3-bromophenyl)-2-((tert-butyldimethyl silyl) epoxide) ethyoxyl)-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 38a (1.25g, yellow Color liquid), productivity: 86.2%.

Second step

2-(4-(1-(3-bromophenyl)-2-hydroxyl-oxethyl)-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester

By 2-(4-(1-(3-bromophenyl)-2-((tert-butyldimethyl silyl) epoxide) ethyoxyl)-3-iodophenyl) ring the third first Acetoacetic ester 38a (1.25g, 1.93mmol) is dissolved in 10mL oxolane, adds the tetrahydrochysene furan of 2.1mL1M tetrabutyl ammonium fluoride Mutter solution, stirring reaction 2 hours.Add 20mL water, be extracted with ethyl acetate (20mL × 2), merge organic facies, use saturated chlorination Sodium solution washing (20mL × 2), anhydrous sodium sulfate is dried, and filters, and filtrate reduced in volume, with silica gel column chromatography with eluant body It is B purification gained residue, obtains title product 2-(4-(1-(3-bromophenyl)-2-hydroxyl-oxethyl)-3-iodophenyl) ring third Ethyl formate 38b (600mg, colorless oil), productivity: 58.3%.

3rd step

2-(2-(3-bromophenyl)-2,3-dihydrobenzo [b] [1,4] two English-6-base) cyclopropanecarboxylic acid ethyl ester

By 2-(4-(1-(3-bromophenyl)-2-hydroxyl-oxethyl)-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 38b (200mg, 0.38mmol), acid chloride (15mg, 0.06mmol), 2-(di-t-butyl phosphorus)-1,1'-dinaphthalene (48mg, 0.12mmol) and carbonic acid Caesium (123mg, 0.38mmol) is dissolved in 10mL toluene, is heated to 50 DEG C, stirring reaction 12 hours.Add 20mL water, use second Acetoacetic ester extraction (20mL × 2), merges organic facies, washs (20mL × 2) with saturated nacl aqueous solution, and anhydrous sodium sulfate is dried, Filter, filtrate reduced in volume, purify gained residue by thin layer chromatography with eluant system B, obtain title product 2-(2- (3-bromophenyl)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two English-6-base) cyclopropanecarboxylic acid ethyl ester 38c (120mg, colourless liquid), produces Rate: 59.2%.

MS m/z(ESI):405.1[M+1]

4th step

2-(2-(2'-methyl-[1,1'-xenyl]-3-base)-2,3-dihydrobenzo [b] [1,4] two English-6-base) ring Third Ethyl formate

By 2-(2-(3-bromophenyl)-2,3-dihydrobenzo [b] [1,4] two English-6-base) cyclopropanecarboxylic acid ethyl ester 38c (85mg, 0.21mmol), 2-toluene boric acid (35mg, 0.25mmol), tetra-triphenylphosphine palladium (14mg, 0.01mmol) and cesium carbonate (204mg, 0.63mmol) is dissolved in 5.5mL dioxane and water (V/V=10:1) mixed solvent, is heated to 90 DEG C, and stirring is anti- Answer 3 hours.Add 30mL water, be extracted with ethyl acetate (20mL × 2), merge organic facies, wash with saturated nacl aqueous solution (20mL × 2), anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, purifies institute with silica gel column chromatography with eluant system B Obtain residue, obtain title product 2-(2-(2'-methyl-[1,1'-xenyl]-3-base)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two English-6-base) cyclopropanecarboxylic acid ethyl ester 38d (80mg, yellow liquid), productivity: 90.0%.

MS m/z(ESI):432.5[M+18]

5th step

By 2-(2-(2'-methyl-[1,1'-xenyl]-3-base)-2,3-dihydrobenzo [b] [1,4] two English-6-base) Cyclopropanecarboxylic acid ethyl ester 38d (80mg, 0.19mmol) is dissolved in 5.5mL methanol and oxolane (V/V=10:1) mixed solvent, Add 1M sodium hydroxide solution (2mL, 2mmol), be heated to return stirring and react 1 hour.Reactant liquor concentrating under reduced pressure, adds 20mL Water, dropping 1M hydrochloric acid is 1 ~ 2 to reactant liquor pH, is extracted with ethyl acetate (25mL × 2), merges organic facies, uses saturated sodium-chloride Solution washing (20mL × 2), anhydrous magnesium sulfate is dried, and filters, and filtrate reduced in volume, by thin layer chromatography with eluant system A Purification gained residue, obtains title product 2-(2-(2'-methyl-[1,1'-xenyl]-3-base)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] two English-6-base) cyclopropanecarboxylic acid 38 (20mg, white solid), productivity: 26.6%.

MS m/z(ESI):385.1[M-1]

¹H NMR(400MHz,CDCl₃)δ7.49-7.47(m,1H),7.40-7.36(m,3H),7.28-7.25(m,4H), 6.92-6.90(m,1H),6.70-6.66(m,2H),5.16-5.13(m,1H),4.41-4.38(m,1H),4.08-4.03(m, 1H),2.55-2.52(m,1H),2.27(s,3H),1.84(m,1H),1.65-1.60(m,1H),1.36-1.33(m,1H).

Embodiment 39

2-((8S)-3-(3-(3 methyl thiophene-2-base) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1, 4] two English-8-base) acetic acid

The first step

2-((8S)-3-(3-(3 methyl thiophene-2-base) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1, 4] two English-8-base) methyl acetate

By 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) Methyl acetate 6c (85mg, 0.21mmol), (3 methyl thiophene-2-base) boric acid (36mg, 0.25mmol), tetra-triphenylphosphine palladium (12mg, 0.01mmol) and cesium carbonate (205mg, 0.63mmol) are dissolved in 4.5mL dioxane and water (V/V=8:1) mixes molten In agent, it is heated to 90 DEG C, stirring reaction 12 hours.Filtering, filter cake ethyl acetate washs (5mL × 2), and anhydrous magnesium sulfate is done Dry, filter, filtrate reduced in volume, purify gained residue with silica gel column chromatography with eluant system B, obtain title product 2- ((8S)-3-(3-(3 methyl thiophene-2-base) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8- Base) methyl acetate 39a (60mg, yellow liquid), productivity: 68.2%.

MS m/z(ESI):440.3[M+18]

Second step

By 2-((8S)-3-(3-(3 methyl thiophene-2-base) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 39a (60mg, 0.14mmol) is dissolved in 5mL methanol and oxolane (V/V=4:1) mixes In bonding solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 DEG C, stirring reaction 1 hour.Reactant liquor decompression is dense Contracting, adds 10mL water and 10mL ethyl acetate, and dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, extracts separatory, organic phase washed with water (5mL × 3), saturated nacl aqueous solution washing (5mL × 3), anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, uses silicagel column Chromatography, with eluant system A purification gained residue, obtains title product 2-((8S)-3-(3-(3 methyl thiophene-2-base) Phenyl)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 39 (26mg, white solid), produces Rate: 44.8%.

MS m/z(ESI):407.3[M-1]

¹H NMR(400MHz,CDCl₃)δ7.44-7.50(m,3H),7.36-7.37(m,1H),7.23-7.27(m,1H), 6.94-6.95(m,1H),6.79(s,1H),6.50(s,1H),5.15-5.17(m,1H),4.72-4.77(m,1H),4.25- 4.37(m,2H),3.99-4.04(m,1H),3.79-3.86(m,1H),2.79-2.85(m,1H),2.62-2.69(m,1H), 2.33(s,3H).

Embodiment 40

2-((8S)-3-(3-bromo-5-fluorophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8- Base) acetic acid

The first step

3-bromo-5-fluorobenzaldehyde

Under ice bath, being dissolved in 5mL oxolane by 2M isopropylmagnesium chloride (10mL, 20mmol), dropping 5mL is containing 1,3- The tetrahydrofuran solution of two bromo-5-fluorobenzene 40a (4.0g, 15.70mmol), stirs 2 hours, then is warming up to 20 DEG C of reactions 30 points Clock.It is cooled to 0 DEG C, dropping DMF (2.5mL, 31.50mmol), stirring reaction 1.5 hours, it is warmed to room temperature and stirs Mix reaction 12 hours.Add 20mL saturated ammonium chloride solution cancellation reaction, be extracted with ethyl acetate (50mL × 3), merge organic Phase, anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, purifies gained with silica gel column chromatography with eluant system B remaining Thing, obtains title product 3-bromo-5-fluorobenzaldehyde 40b (2.57g, yellow liquid), productivity: 81.0%.

Second step

The bromo-3-of 1-fluoro-5-vinyl benzene

Methyltriphenylphospbromide bromide phosphorus (3.70g, 10.30mmol) and potassium tert-butoxide (867mg, 7.70mmol) are dissolved in In 40mL oxolane, stirring 1 hour, ice bath is cooled to 0 DEG C, dropping 20mL containing 3-bromo-5-fluorobenzaldehyde 40b (1.50g, Tetrahydrofuran solution 7.40mmol), is warmed to room temperature stirring reaction 3.5 hours.Add 20mL saturated ammonium chloride solution cancellation anti- Should, extracting (50mL × 3) with n-hexane, merge organic facies, anhydrous magnesium sulfate is dried, and filters, filtrate reduced in volume, uses silicagel column Chromatography with eluant system B purification gained residue, obtain the bromo-3-of title product 1-fluoro-5-vinyl benzene 40c (680mg, Colourless liquid), productivity: 46.0%.

3rd step

1-(3-bromo-5-fluorophenyl) ethane-1,2-glycol

N-methyl morpholine oxide (2.55g, 21.70mmol) and Osmic acid. (500mg, 1.96mmol) are dissolved in 30mL In water, acetone and the tert-butyl alcohol (V/V/V=19:8:3) mixed solvent, add 13mL fluoro-5-vinyl benzene 40c Han the bromo-3-of 1- The dichloromethane of (1.45g, 7.25mmol) and acetone (V/V=10:3) mixed solvent, stirring reaction 2 hours.Add 30mL saturated Hypo solution cancellation is reacted, and is extracted with ethyl acetate (50mL × 3), merges organic facies, and anhydrous sodium sulfate is dried, mistake Filter, filtrate reduced in volume, purify gained residue with silica gel column chromatography with eluant system B, obtain title product 1-(3- Bromo-5-fluorophenyl) ethane-1,2-glycol 40d (1.25g, colourless liquid), productivity: 73.0%.

4th step

1-(3-bromo-5-fluorophenyl)-2-((t-butyldimethyl silane) oxygen) ethanol

By 1-(3-bromo-5-fluorophenyl) ethane-1,2-glycol 40d (1.25g, 5.30mmol), imidazoles (0.54g, 7.90mmol) being dissolved in 30mL dichloromethane, add tert-butyl chloro-silicane (0.84g, 5.60mmol), stirring is anti- Answer 12 hours.Reactant liquor concentrating under reduced pressure, purifies gained residue with silica gel column chromatography with eluant system B, obtains title and produces Thing 1-(3-bromo-5-fluorophenyl)-2-((t-butyldimethyl silane) oxygen) ethanol 40e (1.0g, colourless liquid), productivity: 54.0%.

5th step

2-((3S)-6-(1-(3-bromo-5-fluorophenyl)-2-((tert-butyldimethyl silyl) oxygen) ethyoxyl) the iodo-2,3-of-5- Dihydrobenzofuranes-3-base) methyl acetate

By 1-(3-bromo-5-fluorophenyl)-2-((t-butyldimethyl silane) oxygen) ethanol 40e (172mg, 0.49mmol), (S)-2-(6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 1f (150mg, 0.45mmol) and azo diformazan Acyl two piperidines (181mg, 0.72mmol) is dissolved in 5mL toluene, adds tri-n-butyl phosphine (145mg, 0.72mmol), is heated to 50 DEG C, stirring reaction 1 hour.Reactant liquor concentrating under reduced pressure, purifies gained residue with silica gel column chromatography with eluant system B, ((3S)-6-(1-(3-bromo-5-fluorophenyl)-2-((tert-butyldimethyl silyl) oxygen) ethyoxyl)-5-is iodo-to obtain title product 2- 2,3-Dihydrobenzofuranes-3-bases) methyl acetate 40f (260mg, colourless liquid), productivity: 87.0%.

6th step

2-((3S)-6-(1-(3-bromo-5-fluorophenyl)-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-base) Methyl acetate

By 2-((3S)-6-(1-(3-bromo-5-fluorophenyl)-2-((tert-butyldimethyl silyl) oxygen) ethyoxyl)-5-iodo-2, 3-Dihydrobenzofuranes-3-base) methyl acetate 40f (260mg, 0.39mmol) is dissolved in 20mL oxolane, adds 1M tetra- Butyl ammonium fluoride (0.6mL, 0.60mmol), stirring reaction 0.5 hour.Reactant liquor concentrating under reduced pressure, with silica gel column chromatography to wash De-agent system B purification gained residue, obtain title product 2-((3S)-6-(1-(3-bromo-5-fluorophenyl)-hydroxyl-oxethyl)- 5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 40g (178mg, white liquid), productivity: 82.7%.

7th step

2-((8S)-3-(3-bromo-5-fluorophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8- Base) methyl acetate

By 2-((3S)-6-(1-(3-bromo-5-fluorophenyl)-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3- Base) methyl acetate 40g (178mg, 0.32mmol), acid chloride (22mg, 0.10mmol), 2-(di-t-butyl phosphorus)-1,1'-dinaphthalene (77mg, 0.19mmol) and cesium carbonate (210mg, 0.65mmol) are dissolved in 5mL toluene, are heated to 50 DEG C, stir reaction 12 Hour.Filter, filtrate reduced in volume, purify gained residue by thin layer chromatography with eluant system B, obtain title product 2- ((8S)-3-(3-bromo-5-fluorophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid first Ester 40h (26mg, colourless liquid), productivity: 19.0%.

8th step

By 2-((8S)-3-(3-bromo-5-fluorophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English- 8-yl) methyl acetate 40h (26mg, 0.06mmol) is dissolved in 5mL methanol, oxolane and water (V/V/V=1:3:1) and mixes molten In agent, add Lithium hydrate (13mg, 0.31mmol), be heated to 50 DEG C, stirring reaction 1.5 hours.Reactant liquor concentrating under reduced pressure, adds Entering 10mL water, dropping 1M hydrochloric acid is 1 to reactant liquor pH, extracts (20mL × 3) with dichloromethane, and anhydrous sodium sulfate is dried, and filters, Filtrate reduced in volume, purifies gained residue by thin layer chromatography with eluant system B, obtains title product 2-((8S)-3- (3-bromo-5-fluorophenyl)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) and acetic acid 40 (16mg, in vain Color solid), productivity: 64.0%.

MS m/z(ESI):409.1[M+1]

¹H NMR(400MHz,CDCl₃)δ7.40(s,1H),7.29(d,1H),7.13(d,1H),6.81(s,1H),6.51 (s,1H),5.12(d,1H),4.78(t,1H),4.28-4.36(m,2H),3.94-3.97(m,1H),3.84-3.86(m,1H), 2.81-2.87(m,1H),2.64-2.71(m,1H).

Embodiment 41

2-((3S, 8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8- Base) acetic acid

By 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) Acetic acid 6 (212mg, 0.54mmol) carries out chiral separation, uses HPLC method, enters with the chiral isomer of Preparation equipment and chiral column Row separates (separation condition: chiral column OJ-RH CHIRALCEL4.6, flowing phase: normal hexane/ethanol/acetic acid=80/20/0.1 (V/ V/V), flow velocity: 1.0mL/ minute), collect its respective components, rotary evaporation removes solvent, obtain title product 2-((3S, 8S)- 3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) (79mg, white is solid for acetic acid 41 Body).

Embodiment 42

2-((3R, 8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8- Base) acetic acid

By 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) Acetic acid 6 (212mg, 0.54mmol) carries out chiral separation, uses HPLC method, enters with the chiral isomer of Preparation equipment and chiral column Row separates (separation condition: chiral column OJ-RH CHIRALCEL4.6, flowing phase: normal hexane/ethanol/acetic acid=80/20/0.1 (V/ V/V), flow velocity: 1.0mL/ minute), collect its respective components, rotary evaporation removes solvent, obtain title product 2-((3R, 8S)- 3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) (65mg, white is solid for acetic acid 42 Body).

Embodiment 43

2-((8S)-3-(3-(3,5-dimethyl isoxazole-4-base) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6- B] [1,4] two English-8-bases) acetic acid

The first step

2-((8S)-3-(3-(3,5-dimethyl isoxazole-4-base) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6- B] [1,4] two English-8-bases) methyl acetate

By 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) Methyl acetate 6c (100mg, 0.25mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring-2- Base) isoxazole (66mg, 0.30mmol), tetra-triphenylphosphine palladium (14mg, 0.01mmol) and sodium carbonate (79mg, 0.74mmol) are molten Solution, in 5.5mL dioxane and water (V/V=10:1) mixed solvent, is heated to 90 DEG C, stirring reaction 12 hours.Filter, filter cake Washing (5mL × 2) by ethyl acetate, anhydrous magnesium sulfate is dried, and filters, and filtrate reduced in volume, with silica gel column chromatography with eluting Agent system B purification gained residue, obtain title product 2-((8S)-3-(3-(3,5-dimethyl isoxazole-4-base) phenyl)- 2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 43a (70mg, yellow liquid), produces Rate: 67.3%.

MS m/z(ESI):422.4[M+1]

Second step

By 2-((8S)-3-(3-(3,5-dimethyl isoxazole-4-base) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5, 6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 43a (70mg, 0.17mmol) be dissolved in 5mL methanol and oxolane (V/V=4: 1), in mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 DEG C, stirring reaction 1 hour.Reactant liquor subtracts Pressure concentrates, and adds 10mL water and 10mL ethyl acetate, and dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, extracts separatory, and organic facies is successively With water (10mL × 2), saturated nacl aqueous solution washing (10mL × 2), anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, uses Silica gel column chromatography, with eluant system A purification gained residue, obtains title product 2-((8S)-3-(3-(3,5-dimethyl Isoxazole-4-base) phenyl)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 43 (63mg, White solid), productivity: 92.6%.

MS m/z(ESI):406.3[M-1]

¹H NMR(400MHz,CDCl₃)δ7.48-7.52(m,1H),7.39-7.41(m,1H),7.27-7.30(m,2H), 6.79(s,1H),6.49(s,1H),5.16-5.18(m,1H),4.72-4.77(m,1H),4.25-4.37(m,2H),3.98- 4.03(m,1H),3.81-3.82(m,1H),2.78-2.84(m,1H),2.61-2.68(m,1H),2.41(s,3H),2.28(s, 3H),.

Embodiment 44

2-((8S)-3-(2'-chloro-[1,1'-xenyl]-3-base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1, 4] two English-8-base) acetic acid

The first step

2-((8S)-3-(2'-chloro-[1,1'-xenyl]-3-base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1, 4] two English-8-base) methyl acetate

By 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) Methyl acetate 6c (200mg, 0.50mmol), (2-chlorphenyl) boric acid (93mg, 0.60mmol), tetra-triphenylphosphine palladium (29mg, 0.02mmol) it is dissolved in 11mL dioxane and water (V/V=10:1) mixed solvent with cesium carbonate (482mg, 1.48mmol), It is heated to 90 DEG C, stirring reaction 12 hours.Filtering, anhydrous magnesium sulfate is dried, and filters, filtrate reduced in volume, uses silica gel column chromatography Method, with eluant system B purification gained residue, obtains title product 2-((8S)-3-(2'-chloro-[1,1'-xenyl]-3- Base)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 44a (144mg, yellow liquid Body), productivity: 66.7%.

MS m/z(ESI):454.3[M+18]

Second step

By 2-((8S)-3-(2'-chloro-[1,1'-xenyl]-3-base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 44a (144mg, 0.33mmol) is dissolved in 10mL methanol and oxolane (V/V=4:1) In mixed solvent, add 2M sodium hydroxide solution 1.5mL, be heated to 50 DEG C, stirring reaction 1 hour.Reactant liquor concentrating under reduced pressure, adds Entering 20mL water and 20mL ethyl acetate, dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, extracts separatory, and aqueous phase is extracted with ethyl acetate (10mL × 3), merge organic facies, successively with water (10mL × 3), and saturated nacl aqueous solution washing (10mL × 3), anhydrous sodium sulfate It is dried, filters, filtrate reduced in volume, purify gained residue with silica gel column chromatography with eluant system A, obtain title product 2-((8S)-3-(2'-chloro-[1,1'-xenyl]-3-base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid 44 (112mg, white solid), productivity: 80.6%.

MS m/z(ESI):421.3[M-1]

¹H NMR(400MHz,CDCl₃)δ7.43-7.50(m,5H),7.31-7.35(m,3H),6.79(s,1H),6.49 (s,1H),5.16-5.18(m,1H),4.72-4.76(m,1H),4.24-4.38(m,2H),3.99-4.04(m,1H),3.82 (m,1H),2.79-2.84(m,1H),2.61-2.68(m,1H).

Embodiment 45

2-((8S)-3-(3-(trifluoromethyl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid

The first step

1-(trifluoromethyl)-3-vinyl benzene

By 3-(trifluoromethyl) benzaldehyde 45a (5.0g, 28.70mmol), methyltriphenylphospbromide bromide phosphorus (20.50g, 57.50mmol) it is dissolved in 152mL dioxane and water (V/V=75:1) mixed solvent with potassium carbonate (9.90g, 71.75mmol) In, it is heated to 95 DEG C, stirring reaction 12 hours.Add 250mL water and 50mL normal hexane, stir 10 minutes, extract separatory, aqueous phase Extract (30mL × 3) with n-hexane, merge organic facies, successively with water (30mL × 3), saturated nacl aqueous solution washing (30mL × 3), anhydrous magnesium sulfate is dried, and filters, filtrate reduced in volume, purifies gained with silica gel column chromatography with eluant system B remaining Thing, obtains title product 1-(trifluoromethyl)-3-vinyl benzene 45b (1.35g, colourless liquid), productivity: 27.3%.

Second step

1-(3-(trifluoromethyl) phenyl) ethane-1,2-glycol

N-methyl morpholine oxide (2.66g, 22.68mmol) and Osmic acid. (96mg, 0.38mmol) are dissolved in 40mL In water, acetone and the tert-butyl alcohol (V/V/V=5:2:1) mixed solvent, add 13mL vinyl benzene 45b Han 1-(trifluoromethyl)-3- The dichloromethane of (1.30g, 7.56mmol) and acetone (V/V=10:3) mixed solvent, stirring reaction 2 hours.Add 10mL saturated Hypo solution cancellation is reacted, and is extracted with ethyl acetate (50mL × 3), merges organic facies, uses saturated thiosulfuric acid successively Sodium solution (30mL × 3), water (30mL × 3), saturated nacl aqueous solution washing (30mL × 3), anhydrous sodium sulfate is dried, and filters, Filtrate reduced in volume, purifies gained residue with silica gel column chromatography with eluant system B, obtains title product 1-(3-(trifluoro Methyl) phenyl) ethane-1,2-glycol 45c (1.40g, yellow liquid), productivity: 90.5%.

3rd step

2-((t-butyldimethyl silane) oxygen)-1-(3-(trifluoromethyl) phenyl) ethanol

By 1-(3-(trifluoromethyl) phenyl) ethane-1,2-glycol 45c (1.40g, 6.80mmol), imidazoles (925mg, 13.60mmol) it is dissolved in 15mL DMF with DMAP (83mg, 0.68mmol), adds Tert-butyl chloro-silicane (1.23g, 8.16mmol), stirring reaction 1 hour.Add 50mL water and 50mL ethyl acetate, stir Mixing 30 minutes, extract separatory, aqueous phase is extracted with ethyl acetate (20mL × 3), merges organic facies, successively with water (20mL × 3), full Washing (20mL × 3) with sodium chloride solution, anhydrous magnesium sulfate is dried, and filters, and filtrate reduced in volume, with silica gel column chromatography to wash De-agent system B purification gained residue, obtains title product 2-((t-butyldimethyl silane) oxygen)-1-(3-(trifluoromethyl) Phenyl) ethanol 45d (1.99g, yellow liquid), productivity: 91.7%.

MS m/z(ESI):338.3[M+18]

4th step

2-((3S)-6-(2-((tert-butyldimethyl silyl) oxygen)-1-(3-(trifluoromethyl) phenyl) ethyoxyl)-5-iodo-2, 3-Dihydrobenzofuranes-3-base) methyl acetate

By 2-((t-butyldimethyl silane) oxygen)-1-(3-(trifluoromethyl) phenyl) ethanol 45d (144mg, 0.45mmol), (S)-2-(6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 1f (150mg, 0.45mmol) It is dissolved in 5mL toluene with azodicarbonyldipiperidine (181mg, 0.72mmol), addition tri-n-butyl phosphine (145mg, 0.72mmol), it is heated to 50 DEG C, stirring reaction 1 hour.Add 10mL methanol, reactant liquor concentrating under reduced pressure, use silica gel column chromatography With eluant system B purification gained residue, obtain title product 2-((3S)-6-(2-((tert-butyldimethyl silyl) oxygen)-1- (3-(trifluoromethyl) phenyl) ethyoxyl)-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 45e (250mg, yellow liquid Body), productivity: 87.4%.

MS m/z(ESI):654.4[M+18]

5th step

2-((3S)-6-(2-hydroxyl-1-(3-(trifluoromethyl) phenyl) ethyoxyl)-5-iodo-2,3-Dihydrobenzofuranes- 3-yl) methyl acetate

By 2-, ((3S)-6-(2-((tert-butyldimethyl silyl) oxygen)-1-(3-(trifluoromethyl) phenyl) ethyoxyl)-5-is iodo- 2,3-Dihydrobenzofuranes-3-bases) methyl acetate 45e (250mg, 0.39mmol) is dissolved in 10mL oxolane, adds 1M Tetrabutyl ammonium fluoride (0.5mL, 0.50mmol), stirring reaction 1 hour.Reactant liquor concentrating under reduced pressure, with silica gel column chromatography to wash De-agent system B purification gained residue, obtains title product 2-((3S)-6-(2-hydroxyl-1-(3-(trifluoromethyl) phenyl) second Epoxide)-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 45f (160mg, yellow liquid), productivity: 78.0%.

MS m/z(ESI):523.1[M+1]

6th step

2-((8S)-3-(3-(trifluoromethyl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) methyl acetate

By 2-((3S)-6-(2-hydroxyl-1-(3-(trifluoromethyl) phenyl) ethyoxyl)-5-iodo-2,3-dihydrobenzo furan Mutter-3-base) methyl acetate 45f (160mg, 0.31mmol), acid chloride (21mg, 0.10mmol), 2-(di-t-butyl phosphorus)-1, 1'-dinaphthalene (73mg, 0.18mmol) and cesium carbonate (199mg, 0.61mmol) are dissolved in 15mL toluene, are heated to 50 DEG C, stir Mix reaction 12 hours.Adding 30mL water and 30mL ethyl acetate, extract separatory, aqueous phase is extracted with ethyl acetate (10mL × 3), closes And organic facies, successively with water (15mL × 3), saturated nacl aqueous solution washing (15mL × 3), anhydrous magnesium sulfate is dried, and filters, filter Liquid concentrating under reduced pressure, purifies gained residue with silica gel column chromatography with eluant system B, obtains title product 2-((8S)-3- (3-(trifluoromethyl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) methyl acetate 45g (100mg, yellow liquid), productivity: 82.6%.

MS m/z(ESI):412.1[M+1]

7th step

By 2-((8S)-3-(3-(trifluoromethyl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) methyl acetate 45g (100mg, 0.25mmol) is dissolved in 6mL methanol and oxolane (V/V=5:1) mixed solvent In, add 2M sodium hydroxide solution 1mL, be heated to 50 DEG C, stirring reaction 1 hour.Reactant liquor concentrating under reduced pressure, add 10mL water and 10mL ethyl acetate, dropping 1M hydrochloric acid is 3～4 to reactant liquor pH, is extracted with ethyl acetate (10mL × 3), merges organic facies, depends on Secondary water (10mL × 3), saturated nacl aqueous solution washing (10mL × 3), anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, Purify gained residue with silica gel column chromatography with eluant system A, obtain title product 2-((8S)-3-(3-(trifluoromethyl) Phenyl)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 45 (80mg, white solid), produces Rate: 83.3%.

MS m/z(ESI):379.2[M-1]

¹H NMR(400MHz,CDCl₃)δ7.55-7.69(m,4H),6.79(s,1H),6.50(s,1H),5.17-5.19 (m,1H),4.73-4.77(m,1H),4.25-4.35(m,2H),3.93-3.98(m,1H),3.83(m,1H),2.80-2.84 (m,1H),2.62-2.69(m,1H).

Embodiment 46

2-((8S)-3-(3-chlorphenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) second Acid

The first step

1-chloro-3-vinyl benzene

By 3-chlorobenzaldehyde 46a (10.0g, 71.10mmol), methyltriphenylphospbromide bromide phosphorus (50.80g, 142.20mmol) It is dissolved in 160mL dioxane and water (V/V=15:1) mixed solvent with potassium carbonate (24.50g, 178mmol), is heated to 95 DEG C, stirring reaction 12 hours.Add 100mL water, be extracted with ethyl acetate (100mL × 3), merge organic facies, use saturated chlorination Sodium solution washing (100mL × 3), anhydrous sodium sulfate is dried, and filters, and filtrate reduced in volume, with silica gel column chromatography with eluant System B purification gained residue, obtains title product 1-chloro-3-vinyl benzene 46b (7.0g, colourless liquid), productivity: 71.0%.

Second step

1-(3-chlorphenyl) ethane-1,2-glycol

N-methyl morpholine oxide (12.30g, 108.30mmol) and Osmic acid. (500mg, 1.97mmol) are dissolved in In 100mL water, acetone and the tert-butyl alcohol (V/V/V=5:2:1) mixed solvent, add 50mL chloro-3-vinyl benzene 46b Han 1- The dichloromethane of (5.0g, 36.10mmol) and acetone (V/V=10:3) mixed solvent, stirring reaction 2 hours.Add 100mL to satisfy With hypo solution cancellation react, be extracted with ethyl acetate (50mL × 3), merge organic facies, successively with water (50mL × 3), saturated nacl aqueous solution washing (50mL × 3), anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, uses silica gel column chromatography Method, with eluant system B purification gained residue, obtains title product 1-(3-chlorphenyl) ethane-1,2-glycol 46c (4.30g, Colourless liquid), productivity: 69.4%.

3rd step

2-((t-butyldimethyl silane) oxygen)-1-(3-chlorphenyl) ethanol

By 1-(3-chlorphenyl) ethane-1,2-glycol 46c (4.30g, 24.90mmol), imidazoles (3.40g, 49.80mmol) It is dissolved in 30mLN with DMAP (305mg, 2.50mmol), in dinethylformamide, adds tert-butyl group diformazan Base chlorosilane (4.50g, 29.90mmol), stirring reaction 2 hours.Add 100mL water, be extracted with ethyl acetate (60mL × 2), Merging organic facies, wash (50mL × 3) with saturated nacl aqueous solution, anhydrous magnesium sulfate is dried, and filters, filtrate reduced in volume, uses Silica gel column chromatography with eluant system B purification gained residue, obtain title product 2-((t-butyldimethyl silane) oxygen)- 1-(3-chlorphenyl) ethanol 46d (5.0g, colourless liquid), productivity: 70.0%.

MS m/z(ESI):288.2[M+1]

4th step

2-((3S)-6-(2-((tert-butyldimethyl silyl) oxygen)-1-(3-chlorphenyl) ethyoxyl)-5-iodo-2,3-dihydrobenzene And furan-3-base) methyl acetate

By 2-((t-butyldimethyl silane) oxygen)-1-(3-chlorphenyl) ethanol 46d (150mg, 0.52mmol), (S)-2- (6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 1f (174mg, 0.52mmol) and azo two formyl two piperazine Pyridine (209mg, 0.83mmol) is dissolved in 5mL toluene, adds tri-n-butyl phosphine (168mg, 0.83mmol), is heated to 50 DEG C, Stirring reaction 2 hours.Reactant liquor concentrating under reduced pressure, purifies gained residue with silica gel column chromatography with eluant system B, is marked Topic product 2-((3S)-6-(2-((tert-butyldimethyl silyl) oxygen)-1-(3-chlorphenyl) ethyoxyl)-5-iodo-2,3-dihydrobenzo Furan-3-base) methyl acetate 46e (220mg, colourless liquid), productivity: 69.8%.

MS m/z(ESI):620.4[M+18]

5th step

2-((3S)-6-(1-(3-chlorphenyl)-2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-base) acetic acid Methyl ester

By 2-((3S)-6-(2-((tert-butyldimethyl silyl) oxygen)-1-(3-chlorphenyl) ethyoxyl)-5-iodo-2,3-dihydro Benzofuran-3-base) methyl acetate 46e (220mg, 0.36mmol) is dissolved in 20mL oxolane, adds 1M tetrabutyl fluorine Change ammonium (0.4mL, 0.40mmol), stirring reaction 2 hours.Reactant liquor concentrating under reduced pressure, with silica gel column chromatography with eluant system B Purification gained residue, obtains title product 2-((3S)-6-(1-(3-chlorphenyl)-2-hydroxyl-oxethyl)-5-iodo-2,3-bis- Hydrogen benzofuran-3-base) methyl acetate 46f (130mg, colourless liquid), productivity: 73.0%.

6th step

2-((8S)-3-(3-chlorphenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) second Acid methyl ester

By 2-((3S)-6-(1-(3-chlorphenyl)-2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-base) second Acid methyl ester 46f (130mg, 0.27mmol), acid chloride (18mg, 0.08mmol), 2-(di-t-butyl phosphorus)-1,1'-dinaphthalene (64mg, 0.16mmol) and cesium carbonate (176mg, 0.54mmol) are dissolved in 15mL toluene, are heated to 50 DEG C, stir reaction 12 Hour.Add 50mL water, be extracted with ethyl acetate (30mL × 3), merge organic facies, wash (30mL with saturated nacl aqueous solution × 3), anhydrous magnesium sulfate is dried, and filters, filtrate reduced in volume, purifies gained by thin layer chromatography with eluant system B remaining Thing, obtain title product 2-((8S)-3-(3-chlorphenyl)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English- 8-yl) methyl acetate 46g (70mg, colourless liquid), productivity: 72.9%.

7th step

By 2-((8S)-3-(3-chlorphenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) Methyl acetate 46g (70mg, 0.19mmol) is dissolved in 10mL methanol, adds 1M sodium hydroxide solution 1mL, is heated to 60 DEG C, Stirring reaction 1 hour.Reactant liquor concentrating under reduced pressure, adds 20mL water, and dropping 1M hydrochloric acid is 1～2 to reactant liquor pH, uses ethyl acetate Extraction (20mL × 3), merges organic facies, washs (20mL × 3) with saturated nacl aqueous solution, and anhydrous sodium sulfate is dried, and filters, filter Liquid concentrating under reduced pressure, purifies gained residue by thin layer chromatography with eluant system A, obtains title product 2-((8S)-3-(3- Chlorphenyl)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 46 (50mg, white solid), Productivity: 74.6%.

MS m/z(ESI):345.2[M-1]

¹H NMR(400MHz,CDCl₃)δ7.42(s,1H),7.36-7.35(m,2H),7.30-7.28(m,1H),6.78 (s,1H),6.48(s,1H),5.10-5.08(m,1H),4.76-4.72(m,1H),4.32-4.24(m,2H),3.96-3.92 (m,1H),3.82(m,1H),2.85-2.78(m,1H),2.68-2.62(m,1H).

Embodiment 47

2-((8S)-3-(the chloro-4'-of 2'-fluoro-[1,1'-xenyl]-3-base)-2,3,7,8-tetrahydrochysene benzfuran also [5, 6-b] [1,4] two English-8-bases) acetic acid

The first step

2-((8S)-3-(the chloro-4'-of 2'-fluoro-[1,1'-xenyl]-3-base)-2,3,7,8-tetrahydrochysene benzfuran also [5, 6-b] [1,4] two English-8-bases) methyl acetate

By 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) Methyl acetate 6c (100mg, 0.25mmol), (2-chloro-4-fluorophenyl) boric acid (52mg, 0.30mmol), tetra-triphenylphosphine palladium (14mg, 0.01mmol) and cesium carbonate (241mg, 0.74mmol) are dissolved in 11mL dioxane and water (V/V=10:1) mixes molten In agent, it is heated to 90 DEG C, stirring reaction 12 hours.Filtering, anhydrous magnesium sulfate is dried, and filters, filtrate reduced in volume, uses silicagel column Chromatography, with eluant system B purification gained residue, obtains title product 2-((8S)-3-(fluoro-[1,1'-connection of the chloro-4'-of 2'- Phenyl]-3-base)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 47a (100mg, Yellow liquid), productivity: 89.3%.

MS m/z(ESI):472.3[M+18]

Second step

By 2-, (-2,3,7,8-tetrahydrochysene benzfuran is also for (8S)-3-(the chloro-4'-of 2'-fluoro-[1,1'-xenyl]-3-base) [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 47a (100mg, 0.22mmol) is dissolved in 6mL methanol and oxolane (V/ V=5:1), in mixed solvent, add 2M sodium hydroxide solution 1mL, be heated to 50 DEG C, stirring reaction 1 hour.Reactant liquor decompression is dense Contracting, adds 15mL water and 15mL ethyl acetate, and dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, extracts separatory, aqueous phase ethyl acetate Extraction (10mL × 3), merges organic facies, successively with water (10mL × 3), and saturated nacl aqueous solution washing (10mL × 3), anhydrous sulfur Acid sodium is dried, and filters, filtrate reduced in volume, purifies gained residue with silica gel column chromatography with eluant system A, obtains title Product 2-((8S)-3-(the chloro-4'-of 2'-fluoro-[1,1'-xenyl]-3-base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 47 (90mg, white solid), productivity: 92.8%.

MS m/z(ESI):438.9[M-1]

¹H NMR(400MHz,CDCl₃)δ7.45(m,4H),7.27-7.33(m,2H),7.07(m,1H),6.79(s,1H), 6.49(s,1H),5.15-5.17(m,1H),4.74(m,1H),4.26-4.37(m,2H),4.01-4.03(m,1H),3.83(m, 1H),2.79-2.84(m,1H),2.66-2.68(m,1H).

Embodiment 48

The first step

4,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring-2-base) pyrimidine

By bromo-for 5-4, (470mg, 2.51mmol use known method " document to 6-dimethyl pyrimidine 48a Heterocycles, vol, 38, NO.6,1994, " be prepared), double valeryl two boron (3.56g, 15.06mmol), 1,1'-is double (diphenylphosphine) ferrocene] palladium chloride (184mg, 0.28mmol) and potassium acetate (617mg, 6.28mmol) be dissolved in 10mL second In glycol dimethyl ether, it is heated to 90 DEG C, stirring reaction 2 hours.Filtering, filtrate reduced in volume, with silica gel column chromatography with eluting Agent system B purification gained residue, obtains title product 4,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxy boron penta Ring-2-base) pyrimidine 48b (545mg, yellow solid), productivity: 92.6%.

MS m/z(ESI):235.2[M+1]

Second step

2-((8S)-3-(3-(4,6-dimethyl pyrimidine-5-base) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-bases) methyl acetate

By 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) Methyl acetate 6c (60mg, 0.14mmol), 4,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring-2-bases) Pyrimidine 48b (120mg, 0.52mmol), tetra-triphenylphosphine palladium (40mg, 0.03mmol) and sodium carbonate (70mg, 0.66mmol) are molten Solution, in 5.5mL dioxane and water (V/V=10:1) mixed solvent, is heated to 90 DEG C, stirring reaction 12 hours.Filter, filter cake Washing (5mL × 2) by ethyl acetate, anhydrous sodium sulfate is dried, and filters, and filtrate reduced in volume, with silica gel column chromatography with eluting Agent system B purification gained residue, obtain title product 2-((8S)-3-(3-(4,6-dimethyl pyrimidine-5-base) phenyl)-2, 3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 48c (60mg, yellow liquid), productivity: 74.7%.

MS m/z(ESI):433.4[M+1]

3rd step

2-((8S)-3-(3-(4,6-dimethyl pyrimidine-5-base) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-bases) acetic acid

By 2-((8S)-3-(3-(4,6-dimethyl pyrimidine-5-base) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6- B] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 48c (80mg, 0.18mmol) is dissolved in 3mL methanol and oxolane (V/V=5:1) In mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 DEG C, stirring reaction 1 hour.Reactant liquor reduces pressure Concentrating, add 10mL water and 10mL ethyl acetate, dropping 2M hydrochloric acid is 2 to reactant liquor pH, extracts separatory, organic phase washed with water (5mL × 3), saturated nacl aqueous solution washing (5mL × 3), anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, uses silicagel column Chromatography, with eluant system A purification gained residue, obtains title product 2-((8S)-3-(3-(4,6-dimethyl pyrimidine-5- Base) phenyl)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 48 (28mg, white solid), Productivity: 36.2%.

MS m/z(ESI):417.3[M-1]

¹H NMR(400MHz,CDCl₃)δ8.96(s,1H),7.51-7.55(m,1H),7.44-7.46(m,1H),7.18- 7.23(m,2H),6.76(s,1H),6.44(s,1H),5.11-5.16(m,1H),4.67-4.69(m,1H),4.22-4.32(m, 2H),3.92-3.99(m,1H),3.78(m,1H),2.73-2.76(m,1H),2.58(m,1H),2.24-2.29(m,6H).

Embodiment 49

2-((8S)-3-(2'-fluoro-[1,1'-xenyl]-3-base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1, 4] two English-8-base) acetic acid

The first step

2-((8S)-3-(2'-fluoro-[1,1'-xenyl]-3-base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1, 4] two English-8-base) methyl acetate

By 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) Methyl acetate 6c (50mg, 0.12mmol), (2-fluorophenyl) boric acid (21mg, 0.15mmol), tetra-triphenylphosphine palladium (7mg, 0.006mmol) it is dissolved in 5.5mL dioxane and water (V/V=10:1) mixed solvent with cesium carbonate (120mg, 0.37mmol) In, it is heated to 90 DEG C, stirring reaction 12 hours.Filtering, anhydrous magnesium sulfate is dried, and filters, filtrate reduced in volume, uses silicagel column color Spectrometry, with eluant system B purification gained residue, obtains title product 2-((8S)-3-(2'-fluoro-[1,1'-xenyl]-3- Base)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 49a (52mg, yellow liquid), Productivity: 100.0%.

MS m/z(ESI):438.4[M+18]

Second step

By 2-((8S)-3-(2'-fluoro-[1,1'-xenyl]-3-base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 49a (52mg, 0.12mmol) is dissolved in 6mL methanol and oxolane (V/V=5:1) mixes In bonding solvent, add 1M sodium hydroxide solution 1mL, be heated to 50 DEG C, stirring reaction 1 hour.Reactant liquor concentrating under reduced pressure, adds 15mL water and 15mL ethyl acetate, dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, extracts separatory, and aqueous phase is extracted with ethyl acetate (10mL × 2), merge organic facies, successively with water (10mL × 2), and saturated nacl aqueous solution washing (10mL × 2), anhydrous sodium sulfate It is dried, filters, filtrate reduced in volume, purify gained residue with silica gel column chromatography with eluant system A, obtain title product 2-((8S)-3-(2'-fluoro-[1,1'-xenyl]-3-base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid 49 (47mg, white solid), productivity: 94.0%.

MS m/z(ESI):405.1[M-1]

¹H NMR(400MHz,CDCl₃)δ7.42-7.59(m,5H),7.15-7.35(m,3H),6.79(s,1H),6.50 (s,1H),5.16-5.18(m,1H),4.72-4.77(m,1H),4.24-4.38(m,2H),3.99-4.04(m,1H),3.82 (m,1H),2.79-2.83(m,1H),2.61-2.68(m,1H).

Embodiment 50

(-2,3,7,8-tetrahydrochysene benzfuran is also for (8S)-3-(2'-(trifluoromethyl)-[1,1'-xenyl]-3-base) for 2- [5,6-b] [1,4] two English-8-base) acetic acid

The first step

(-2,3,7,8-tetrahydrochysene benzfuran is also for (8S)-3-(2'-(trifluoromethyl)-[1,1'-xenyl]-3-base) for 2- [5,6-b] [1,4] two English-8-base) methyl acetate

By 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) Methyl acetate 6c (50mg, 0.12mmol), (2-(trifluoromethyl) phenyl) boric acid (28mg, 0.15mmol), tetra-triphenylphosphine palladium (7mg, 0.006mmol) and cesium carbonate (120mg, 0.37mmol) are dissolved in 5.5mL dioxane and water (V/V=10:1) mixing In solvent, it is heated to 90 DEG C, stirring reaction 12 hours.Filtering, anhydrous magnesium sulfate is dried, and filters, filtrate reduced in volume, uses silica gel Column chromatography with eluant system B purification gained residue, obtain title product 2-((8S)-3-(2'-(trifluoromethyl)-[1, 1'-xenyl]-3-base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) methyl acetate 50a (57mg, yellow liquid), productivity: 98.3%.

MS m/z(ESI):488.4[M+18]

Second step

By 2-, (-2,3,7,8-tetrahydrochysene benzfuran is also for (8S)-3-(2'-(trifluoromethyl)-[1,1'-xenyl]-3-base) [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 50a (57mg, 0.12mmol) is dissolved in 6mL methanol and oxolane (V/V =5:1) in mixed solvent, add 1M sodium hydroxide solution 1mL, be heated to 50 DEG C, stirring reaction 1 hour.Reactant liquor decompression is dense Contracting, adds 15mL water and 15mL ethyl acetate, and dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, extracts separatory, aqueous phase ethyl acetate Extraction (10mL × 3), merges organic facies, successively with water (10mL × 3), and saturated nacl aqueous solution washing (10mL × 3), anhydrous sulfur Acid sodium is dried, and filters, filtrate reduced in volume, purifies gained residue with silica gel column chromatography with eluant system A, obtains title Product 2-((8S)-3-(2'-(trifluoromethyl)-[1,1'-xenyl]-3-base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6- B] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 50 (50mg, white solid), productivity: 90.9%.

MS m/z(ESI):455.1[M-1]

¹H NMR(400MHz,CDCl₃)δ7.75-7.77(m,1H),7.57-7.60(m,1H),7.45-7.51(m,3H), 7.35-7.38(m,3H),6.78(s,1H),6.48(s,1H),5.14-5.16(m,1H),4.72-4.76(m,1H),4.24- 4.36(m,2H),3.96-4.01(m,1H),3.82(m,1H),2.79-2.84(m,1H),2.61-2.67(m,1H).

Embodiment 51

2-((8S)-3-(3-(4-picoline-3-base) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1, 4] two English-8-base) acetic acid

The first step

2-((8S)-3-(3-(4-picoline-3-base) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1, 4] two English-8-base) methyl acetate

By 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) Methyl acetate 6c (50mg, 0.12mmol), (4-picoline-3-base) boric acid (20mg, 0.15mmol), tetra-triphenylphosphine palladium (7mg, 0.006mmol) and cesium carbonate (120mg, 0.37mmol) are dissolved in 5.5mL dioxane and water (V/V=10:1) mixing In solvent, it is heated to 90 DEG C, stirring reaction 12 hours.Filtering, anhydrous magnesium sulfate is dried, and filters, filtrate reduced in volume, uses silica gel Column chromatography, with eluant system B purification gained residue, obtains title product 2-((8S)-3-(3-(4-picoline-3- Base) phenyl)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 51a (80mg, yellow Liquid), productivity: 100.0%.

MS m/z(ESI):418.3[M+1]

Second step

By 2-((8S)-3-(3-(4-picoline-3-base) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 51a (80mg, 0.19mmol) is dissolved in 6mL methanol and oxolane (V/V=5:1) mixes In bonding solvent, add 2M sodium hydroxide solution 1mL, be heated to 50 DEG C, stirring reaction 1 hour.Reactant liquor concentrating under reduced pressure, adds 15mL water and 15mL ethyl acetate, dropping 1M hydrochloric acid is 3 ~ 4 to reactant liquor pH, extracts separatory, and aqueous phase is extracted with ethyl acetate (10mL × 2), merge organic facies, successively with water (10mL × 2), and saturated nacl aqueous solution washing (10mL × 2), anhydrous sodium sulfate It is dried, filters, filtrate reduced in volume, purify gained residue with silica gel column chromatography with eluant system A, obtain title product 2-((8S)-3-(3-(4-picoline-3-base) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English- 8-yl) acetic acid 51 (11mg, white solid), productivity: 14.3%.

MS m/z(ESI):402.2[M-1]

¹H NMR(400MHz,CDCl₃)δ8.37-8.46(m,2H),7.43-7.54(m,2H),7.33-7.37(m,2H), 7.26(m,1H),6.80(s,1H),6.47-6.48(m,1H),5.16-5.22(m,1H),4.72-4.76(m,1H),4.24- 4.38(m,2H),3.98-4.07(m,1H),3.82-3.85(m,1H),2.75-2.82(m,1H),2.60-2.68(m,1H), 2.32-2.33(m,3H).

Embodiment 52

2-((8S)-3-(3,4-Dichlorobenzene base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8- Base) acetic acid

The first step

1,2-bis-chloro-4-vinyl benzene

By 3,4-dichlorobenzaldehyde 52a (5.0g, 28.60mmol), methyltriphenylphospbromide bromide phosphorus (20.40g, 57.20mmol) it is dissolved in 110mL dioxane and water (V/V=10:1) mixed solvent with potassium carbonate (9.90g, 71.50mmol) In, it is heated to 95 DEG C, stirring reaction 12 hours.Add 100mL water, be extracted with ethyl acetate (50mL × 3), merge organic facies, Washing (50mL × 3) with saturated nacl aqueous solution, anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, uses silica gel column chromatography With eluant system B purification gained residue, obtain title product 1,2-bis-chloro-4-vinyl benzene 52b (4.0g, colourless liquid Body), productivity: 80.9%.

Second step

1-(3,4-Dichlorobenzene base) ethane-1,2-glycol

N-methyl morpholine oxide (2.0g, 17.40mmol) and Osmic acid. (74mg, 0.29mmol) are dissolved in 50mL In water, acetone and the tert-butyl alcohol (V/V/V=5:2:1) mixed solvent, add 13mL containing 1,2-bis-chloro-4-vinyl benzene 52b (1.0g, Dichloromethane 5.80mmol) and acetone (V/V=10:3) mixed solvent, stirring reaction 12 hours.Add the saturated sulfur of 50mL for sulfur Acid sodium solution cancellation is reacted, and is extracted with ethyl acetate (30mL × 3), merges organic facies, washs (30mL with saturated nacl aqueous solution × 3), anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, purifies gained with silica gel column chromatography with eluant system B remaining Thing, obtains title product 1-(3,4-Dichlorobenzene base) ethane-1,2-glycol 52c (750mg, colourless liquid), productivity: 62.5%.

3rd step

2-((t-butyldimethyl silane) oxygen)-1-(3,4-Dichlorobenzene base) ethanol

By 1-(3,4-Dichlorobenzene base) ethane-1,2-glycol 52c (750mg, 3.62mmol), imidazoles (492mg, 7.24mmol) it is dissolved in 30mL DMF with DMAP (45mg, 0.40mmol), adds Tert-butyl chloro-silicane (655mg, 4.34mmol), stirring reaction 2 hours.Add 50mL water, be extracted with ethyl acetate (30mL × 3), merge organic facies, wash (30mL × 3) with saturated nacl aqueous solution, and anhydrous magnesium sulfate is dried, and filter, and filtrate subtracts Pressure concentrates, and purifies gained residue with silica gel column chromatography with eluant system B, obtains title product 2-((fert-butyidimethylsilyl Silane) oxygen)-1-(3,4-Dichlorobenzene base) ethanol 52d (770mg, colourless liquid), productivity: 70.0%.

4th step

2-((3S)-6-(2-((tert-butyldimethyl silyl) oxygen)-1-(3,4-Dichlorobenzene base) ethyoxyl) the iodo-2,3-of-5-bis- Hydrogen benzofuran-3-base) methyl acetate

By 2-((t-butyldimethyl silane) oxygen)-1-(3,4-Dichlorobenzene base) ethanol 52d (211mg, 0.66mmol), (S)-2-(6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 1f (220mg, 0.66mmol) and azo diformazan Acyl two piperidines (267mg, 1.06mmol) is dissolved in 5mL toluene, adds tri-n-butyl phosphine (214mg, 1.06mmol), is heated to 50 DEG C, stirring reaction 3 hours.Reactant liquor concentrating under reduced pressure, purifies gained residue with silica gel column chromatography with eluant system B, Obtain title product 2-((3S)-6-(2-((tert-butyldimethyl silyl) oxygen)-1-(3,4-Dichlorobenzene base) ethyoxyl)-5-iodo-2, 3-Dihydrobenzofuranes-3-base) methyl acetate 52e (350mg, colourless liquid), productivity: 80.0%.

5th step

2-((3S)-6-(1-(3,4-Dichlorobenzene base)-2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-base) Methyl acetate

By 2-((3S)-6-(2-((tert-butyldimethyl silyl) oxygen)-1-(3,4-Dichlorobenzene base) ethyoxyl) the iodo-2,3-of-5- Dihydrobenzofuranes-3-base) methyl acetate 52e (350mg, 0.55mmol) is dissolved in 20mL oxolane, adds 1M tetra-fourth Base ammonium fluoride (0.6mL, 0.60mmol), stirring reaction 2 hours.Reactant liquor concentrating under reduced pressure, with silica gel column chromatography with eluant System B purification gained residue, obtains title product 2-((3S)-6-(1-(3,4-Dichlorobenzene base)-2-hydroxyl-oxethyl)-5- Iodo-2,3-Dihydrobenzofuranes-3-base) methyl acetate 52f (200mg, colourless liquid), productivity: 70.0%.

6th step

2-((8S)-3-(3,4-Dichlorobenzene base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8- Base) methyl acetate

By 2-((3S)-6-(1-(3,4-Dichlorobenzene base)-2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3- Base) methyl acetate 52f (200mg, 0.38mmol), acid chloride (26mg, 0.11mmol), 2-(di-t-butyl phosphorus)-1,1'-dinaphthalene (91mg, 0.23mmol) and cesium carbonate (247mg, 0.76mmol) are dissolved in 20mL toluene, are heated to 50 DEG C, stir reaction 12 Hour.Add 30mL water, be extracted with ethyl acetate (30mL × 2), merge organic facies, wash (30mL with saturated nacl aqueous solution × 2), anhydrous magnesium sulfate is dried, and filters, filtrate reduced in volume, purifies gained by thin layer chromatography with eluant system B remaining Thing, obtains title product 2-((8S)-3-(3,4-Dichlorobenzene base)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) methyl acetate 52g (120mg, yellow liquid), productivity: 79.5%.

7th step

By 2-((8S)-3-(3,4-Dichlorobenzene base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English- 8-yl) methyl acetate 52g (120mg, 0.30mmol) is dissolved in 10mL methanol, adds 1.5M sodium hydroxide solution 1mL, heating To 60 DEG C, stirring reaction 1 hour.Reactant liquor concentrating under reduced pressure, adds 30mL water, and dropping 1M hydrochloric acid is 1～2 to reactant liquor pH, uses Ethyl acetate extraction (30mL × 2), merges organic facies, washs (20mL × 3) with saturated nacl aqueous solution, and anhydrous sodium sulfate is done Dry, filter, filtrate reduced in volume, purify gained residue by thin layer chromatography with eluant system A, obtain title product 2- ((8S)-3-(3,4-Dichlorobenzene base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid 52 (60mg, white solid), productivity: 51.7%.

MS m/z(ESI):379.2[M-1]

¹H NMR(400MHz,CDCl₃)δ7.52-7.48(m,2H),7.25-7.24(m,1H),6.77-6.76(m,1H), 6.47-6.46(m,1H),5.09-5.06(m,1H),4.76-4.72(m,1H),4.30-4.24(m,2H),3.92-3.81(m, 2H),2.82-2.77(m,1H),2.67-2.61(m,1H).

Embodiment 53

2-((3R, 8S)-3-(3-trifluoromethyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid

By 2-((8S)-3-(3-trifluoromethyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid 45 (70mg, 0.18mmol) carries out chiral separation, uses HPLC method, chiral with Preparation equipment and chiral column Isomer carries out separating (separation condition: chiral column AD-H CHIRALPAK4.6, flowing phase: methanol/acrylonitrile/acetic acid=80/ 20/0.1, flow velocity: 1.0mL/ minute), collect its respective components, rotary evaporation removes solvent, obtain title product 2-((3R, 8S)-3-(3-trifluoromethyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid 53 (25mg, white solid).

MS m/z(ESI):379.2[M-1]

Embodiment 54

2-((3S, 8S)-3-(3-trifluoromethyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid

By 2-((8S)-3-(3-trifluoromethyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid 6 (70mg, 0.18mmol) carries out chiral separation, uses HPLC method, chiral with Preparation equipment and chiral column Isomer carries out separating (separation condition: chiral column AD-H CHIRALPAK 4.6, flowing phase: methanol/acrylonitrile/acetic acid=80/ 20/0.1, flow velocity: 1.0mL/ minute), collect its respective components, rotary evaporation removes solvent, obtain title product 2-((3S, 8S)-3-(3-trifluoromethyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid 54 (22mg, white solid).

MS m/z(ESI):379.2[M-1]

Embodiment 55

2-((3R, 8S)-3-(3-chlorphenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8- Base) acetic acid

By 2-((8S)-3-(3-chlorphenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) Acetic acid 46 (50mg, 0.21mmol) carries out chiral separation, uses HPLC method, enters with the chiral isomer of Preparation equipment and chiral column Row separation (separation condition: chiral column AY-H CHIRALPAK 4.6, flow phase: normal hexane/isopropanol/acetic acid=80/20/0.1, Flow velocity: 1.0mL/ minute), collect its respective components, rotary evaporation removes solvent, obtains title product 2-((3R, 8S)-3-(3- Chlorphenyl)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 55 (25mg, white solid).

MS m/z(ESI):345.2[M-1]

Embodiment 56

2-((3S, 8S)-3-(3-chlorphenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8- Base) acetic acid

By 2-((8S)-3-(3-chlorphenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) Acetic acid 46 (80mg, 0.21mmol) carries out chiral separation, uses HPLC method, enters with the chiral isomer of Preparation equipment and chiral column Row separation (separation condition: chiral column AY-H CHIRALPAK4.6, flow phase: normal hexane/isopropanol/acetic acid=80/20/0.1, Flow velocity: 1.0mL/ minute), collect its respective components, rotary evaporation removes solvent, obtains title product 2-((3S, 8S)-3-(3- Chlorphenyl)-2,3,7,8-tetrahydrochysene benzfurans also [5,6-b] [Isosorbide-5-Nitrae] two English-8-base) acetic acid 56 (24mg, white solid).

MS m/z(ESI):345.2[M-1]

Embodiment 57

2-((3R, 8S)-3-(3,4-Dichlorobenzene base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English- 8-yl) acetic acid

By 2-((8S)-3-(3,4-Dichlorobenzene base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English- 8-yl) acetic acid 52 (65mg, 0.16mmol) carries out chiral separation, uses HPLC method, chiral different with Preparation equipment and chiral column Structure body carries out separating (separation condition: chiral column IA CHIRALPAK 4.6, flowing phase: isopropanol/acrylonitrile/acetic acid=80/20/ 0.1 (v/v/v), flow velocity: 1.0mL/ minute), collect its respective components, rotary evaporation removes solvent, obtains title product 2- ((3R, 8S)-3-(3,4-Dichlorobenzene base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid 57 (31mg, white solids).

MS m/z(ESI):379.2[M-1]

Embodiment 58

2-((3S, 8S)-3-(3,4-Dichlorobenzene base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English- 8-yl) acetic acid

By 2-((8S)-3-(3,4-Dichlorobenzene base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English- 8-yl) acetic acid 52 (65mg, 0.16mmol) carries out chiral separation, uses HPLC method, chiral different with Preparation equipment and chiral column Structure body carries out separating (separation condition: chiral column IA CHIRALPAK 4.6, flowing phase: isopropanol/acrylonitrile/acetic acid=80/20/ 0.1 (v/v/v), flow velocity: 1.0mL/ minute), collect its respective components, rotary evaporation removes solvent, obtains title product 2- ((3S, 8S)-3-(3,4-Dichlorobenzene base)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] two English-8-base) acetic acid 58 (33mg, white solids).

MS m/z(ESI):379.2[M-1]

Utilize suitable reactant with reference to operating procedure synthetic example 59-71 of embodiment 9 and 25.

The following is embodiment to number, structure and sign data:

Utilize suitable reactant with reference to operating procedure synthetic example 72-88 of embodiment 9,13,45 and 64.

The following is embodiment to number, structure and sign data:

Test case

Biological assessment

Test case 1 the compounds of this invention agonist activity to CHO-K1/GPR40 cell

Following methods is used for measuring the compounds of this invention agonist activity to GPR40.

Experimental technique is summarized as follows:

CHO-K1/GPR40 cell is inoculated (by Retroviral Transfer method construction expression P2Y12's in 96 orifice plates CHO-K1 cell line, is called for short CHO-K1/GPR40 cell, and wherein, CHO-K1 cell is purchased from Chinese Academy of Sciences's cell bank, catalog number (Cat.No.) GNHa 7；GPR40cDNA is purchased from Guangzhou FulenGen Co., Ltd., catalog number (Cat.No.) EX-U0270-M02), inoculum density is 25000/hole. Cell at 37 DEG C, 5%CO₂Under the conditions of cultivate 24 hours.After experiment, discard cell culture fluid, by cell buffer (1x HBSS+20mM HEPES pH7.4) wash once after, in every hole, add rapidly 100 μ L Fluo-4 calcium ion dyestuffs, and 37 DEG C lucifuge is hatched 30 minutes, then continues to hatch 30 minutes in room temperature.During mensuration, first read every hole baseline value, then in hole Add variable concentrations medicine (50 μ L/ hole), continue to read fluorescent value.Fluorescence madam's excitation wavelength is 494nm, and transmitted wave is a length of 516nm.The increase of fluorescence intensity is directly proportional to intracellular calcium ion level.Obtain every porocyte responsiveness=(maximum fluorescence Value-minimum fluorescent value)/minimum fluorescent value, computerized compound EC₅₀Value.

Compound number	EC₅₀(CHO-K1/GPR40)/(nM)
		Embodiment 2	54
Embodiment 3	156
		Embodiment 4	50
Embodiment 5	46
		Embodiment 6	54
Embodiment 7	36
		Embodiment 8	61
Embodiment 9	25
		Embodiment 10	65
Embodiment 11	11
		Embodiment 12	38
Embodiment 13	56
		Embodiment 14	88
Embodiment 15	132
		Embodiment 16	37
Embodiment 17	52
		Embodiment 18	39
Embodiment 19	85
		Embodiment 20	43
Embodiment 21	30

Embodiment 22	19
		Embodiment 23	35
Embodiment 24	122
		Embodiment 25	64
Embodiment 27	71
		Embodiment 29	45
Embodiment 30	62
		Embodiment 31	80
Embodiment 32	116
		Embodiment 33	64
Embodiment 35	65
		Embodiment 36	35
Embodiment 37	99
		Embodiment 38	35
Embodiment 40	47
		Embodiment 42	32
Embodiment 43	89
		Embodiment 44	31
Embodiment 45	44
		Embodiment 46	37
Embodiment 47	74
		Embodiment 49	73
Embodiment 50	74
		Embodiment 51	136
Embodiment 52	36
		Embodiment 53	11
Embodiment 54	30
		Embodiment 56	23
Embodiment 57	15
		Embodiment 59	128
Embodiment 60	94
		Embodiment 61	81
Embodiment 64	56
		Embodiment 66	95
Embodiment 67	56
		Embodiment 68	46
Embodiment 69	67
		Embodiment 70	82

Embodiment 71	120
		Embodiment 72	66
Embodiment 73	56
		Embodiment 75	62
Embodiment 77	63
		Embodiment 78	100
Embodiment 79	125
		Embodiment 81	101
Embodiment 82	33
		Embodiment 83	44
Embodiment 84	35
		Embodiment 85	98
Embodiment 86	54
		Embodiment 88	125

Conclusion: the compounds of this invention has obvious agonist activity to GPR40.

Pharmacokinetics is tested

1, summary

Drug level in blood plasma the most in the same time after the oral embodiment of the present invention compound of research.Research the compounds of this invention Pharmacokinetics behavior in rat body, evaluates its characteristics of pharmacokinetics.

2, testing program

2.1 test drug

Embodiment 1 compound, embodiment 4 compound, embodiment 5 compound, embodiment 6 compound, embodiment 42 chemical combination Thing, embodiment 53 compound, embodiment 56 compound, embodiment 57 compound and embodiment 60 compound.

2.2 experimental animal

Healthy adult SD rat 36, is divided into 9 groups, often group 4, male and female half and half, dynamic purchased from Shanghai western pul-Bi Kai experiment Thing company limited, animal productiong credit number: SCXK (Shanghai) 2008-0016.

2.3 medicine preparations

Weigh a certain amount of medicine, add 0.5% sodium carboxymethyl cellulose, ultrasonic make 0.5mg/mL suspension.

2.4 are administered and sample collecting

Fasting one distinguishes gastric infusion after night, and dosage is 5.0mg/kg, is administered volume 10mL/kg.In be administered before and give Blood sampling of each moment in 24 hours after medicine, anticoagulant heparin, separated plasma preserves in 20 ° of C.It is administered feed in latter 2 hours.

3, method is analyzed

Before being administered and after administration 1.0,2.0,3.0,4.0,6.0,8.0,11.0,24.0,48.0h take a blood sample 0.1mL, be placed in In heparinised tubes, 3500 revs/min of centrifugal 5 minutes separated plasmas, preserve in 20 ° of C.It is administered feed in latter 2 hours.

With the testing compound content in rat plasma after the different compound gastric infusion of LC/MS/MS method mensuration.Method The range of linearity is 25.0 ~ 5000ng/mL, and plasma sample is analyzed after methanol extraction albumen processes.

4, pharmacokinetic parameter result

The pharmacokinetic parameter of the compounds of this invention such as following table:

Conclusion: in the compounds of this invention rat body after oral administration, blood drug level and exposure level are the highest, the half-life Long, there is good medicine dynamic characteristic.

Claims

1. the compound shown in a logical formula (I) and pharmaceutically useful salt thereof:

Wherein:

Ring L is phenyl；

R¹And R²It is asynchronously hydrogen atom, is each independently selected from hydrogen atom, halogen, C_1-6Alkyl or C_3-6Cycloalkyl, wherein said C_1-6Alkyl or C_3-6Cycloalkyl optionally the most further by one or more selected from C_1-6The substituent group of alkynyl or carboxyl is replaced；

Or, R¹And R²One such as the heterocyclic radical of logical formula (IV) structure it is fused into adjacent phenyl；

R³、R⁴And R⁵It is each independently selected from hydrogen atom, halogen, C_1-6Alkyl, C_3-6Cycloalkyl, phenyl or heteroaryl, wherein said C_1-6Alkyl is optionally replaced by one or more halogens further, and wherein said heteroaryl is the most one or more Selected from halogen or C_1-6The substituent group of alkyl is replaced, wherein said phenyl optionally the most further by one or more selected from halogen, C_1-6Alkyl or-OR⁷Substituent group replaced；

Condition is, works as R¹And R²It is asynchronously hydrogen atom, is each independently selected from hydrogen atom, halogen, C_1-6Alkyl or C_3-6Cycloalkanes Base, wherein said C_1-6Alkyl or C_3-6Cycloalkyl optionally the most further by one or more selected from C_1-6Alkynyl or the substituent group of carboxyl Time replaced, R³、R⁴And R⁵It it is asynchronously hydrogen atom；

Or, R³、R⁴And R⁵Both and phenyl L of middle arbitrary neighborhood are fused into a C_3-6Cycloalkyl, wherein said C_3-6Cycloalkyl Optionally further by one or more R⁶Replaced；

R⁶Selected from halogen or C_1-6Alkyl；

R⁷Selected from hydrogen atom or C_1-6Alkyl, wherein said C_1-6Alkyl optionally the most further by one or more selected from halogen, hydroxyl Or-S (O)_mR⁹Substituent group replaced；

R⁹For C_1-6Alkyl；

M is 0,1 or 2；And

Described heteroaryl is that 5-6 unit comprises 1-4 selected from nitrogen, sulfur or the heteroatomic hetero-aromatic ring of oxygen.

Compound shown in a kind of logical formula (I) the most according to claim 1 and pharmaceutically useful salt thereof, it is logical formula V institute The compound stated and pharmaceutically useful salt thereof:

Wherein: ring L, R³～R⁵Definition as described in the appended claim 1.

Compound shown in logical formula (I) the most according to claim 1 and pharmaceutically useful salt thereof, wherein:

R³For phenyl or heteroaryl, wherein said phenyl the most further by one or more selected from halogen, C_1-6Alkyl or-OR⁷ Substituent group replaced, wherein said heteroaryl optionally the most further by one or more selected from halogen or C_1-6The substituent group of alkyl Replaced；

R⁴And R⁵It is independently selected from hydrogen atom, C_1-6Alkyl or halogen；

R⁷For hydrogen atom or C_1-6Alkyl, wherein said C_1-6Alkyl is optionally further by-S (O)_mR⁹Replaced；

R⁹For C_1-6Alkyl；

Compound shown in logical formula (I) the most according to claim 1 and pharmaceutically useful salt thereof, wherein this compound is:

5. prepare the compound shown in logical formula (I) according to claim 1 and a method for officinal salt, the method Comprise the following steps:

It is catalyzed in the presence of compound (IA) catalyst in the basic conditions, the product obtained is hydrolyzed the most further, Obtain logical formula (I) compound；

Wherein:

X is halogen；

Ring L, R¹～R⁵Definition as described in the appended claim 1.

6., according to the preparation method described in claim 5, wherein said X is bromine or iodine.

7. a pharmaceutical composition, described pharmaceutical composition contain therapeutically effective amount according to claim 1-4 any one institute The compound shown in logical formula (I) stated and pharmaceutically useful salt thereof and pharmaceutically acceptable carrier, diluent and excipient.

8. according to the compound shown in the logical formula (I) described in claim 1-4 any one and pharmaceutically useful salt thereof or according to power Profit requires the purposes in preparing GPR40 agonist of the pharmaceutical composition described in 7.

9. according to the compound shown in the logical formula (I) described in claim 1-4 any one and pharmaceutically useful salt thereof or according to power Profit requires the purposes in the medicine of the disease of preparation treatment metabolic syndrome of the pharmaceutical composition described in 7.

Purposes the most according to claim 9, the disease of wherein said metabolism syndrome is diabetes.

11. purposes according to claim 10, wherein said diabetes are type ii diabetes.