[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

CN111302968B - 一种酰胺氮三氟甲基化合物的合成方法 - Google Patents

一种酰胺氮三氟甲基化合物的合成方法 Download PDF

Info

Publication number
CN111302968B
CN111302968B CN202010201894.6A CN202010201894A CN111302968B CN 111302968 B CN111302968 B CN 111302968B CN 202010201894 A CN202010201894 A CN 202010201894A CN 111302968 B CN111302968 B CN 111302968B
Authority
CN
China
Prior art keywords
alkyl
cdcl
nmr
formula
benzyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202010201894.6A
Other languages
English (en)
Other versions
CN111302968A (zh
Inventor
李超忠
张珍珍
何嘉彦
朱林
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Organic Chemistry of CAS
Original Assignee
Shanghai Institute of Organic Chemistry of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Organic Chemistry of CAS filed Critical Shanghai Institute of Organic Chemistry of CAS
Priority to CN202010201894.6A priority Critical patent/CN111302968B/zh
Publication of CN111302968A publication Critical patent/CN111302968A/zh
Application granted granted Critical
Publication of CN111302968B publication Critical patent/CN111302968B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D313/12—[b,e]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C07J41/0061—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives one of the carbon atoms being part of an amide group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明公开了一种酰胺氮三氟甲基化合物的合成方法，包括如下反应：

Description

一种酰胺氮三氟甲基化合物的合成方法
技术领域
本发明是涉及一种酰胺氮三氟甲基化合物的合成方法，属于有机合成技术领域。
背景技术
酰胺氮三氟甲基化合物在医药、材料等领域有重要的作用，目前通过三氟甲基化反应合成酰胺氮三氟甲基化合物的报道较少。
2009年，Shlomo Rozen课题组(Hagooly,Y.；Gatenyo,J.；Hagooly,A.；Rozen,S.；J.Org.Chem.2009,74,8578-8582)使用商业可用的三氟化溴与烷基硫代酰胺反应得到酰胺氮三氟甲基化合物以及N-二氟烷基-N-三氟甲基胺化合物，这是迄今为止报道的最早一例酰胺氮三氟甲基化合物的合成方法，但是该方法使用的三氟化溴不稳定，遇水容易产生有毒物质：
Figure GDA0002953696060000011
2019年，Schoenebeck小组(Scattolin,T.；Gervais,S.B.；Schoenebeck,F.；Nature2019,573,102-107)在Nature杂志上报道了酰胺的氮三氟甲基化反应，间接实现了酰胺氮三氟甲基化合物的合成，他们以二(三氯甲基)碳酸酯与异硫氰基化物为原料在氟化银的作用下先合成各种官能团的氟酰胺氮三氟甲基化合物，然后再用这些氟酰胺氮三氟甲基化物发生各种后续转化反应，从而间接实现了各种酰胺氮三氟甲基化合物的合成，但是该方法步骤繁琐，操作复杂，且他们使用大量的昂贵的氟化银(5当量)，这无疑给合成酰胺氮三氟甲基化合物造成了极大的限制：
Figure GDA0002953696060000012
综上所述，目前通过三氟甲基化反应合成酰胺氮三氟甲基化合物的方法比较少，且使用条件苛刻，从而阻碍了酰胺氮三氟甲基化合物的规模化生产和广泛使用。并且，迄今为止，还未见有通过酰胺化合物直接进行三氟甲基化反应制备酰胺氮三氟甲基化合物的相关报道。
发明内容
针对现有技术存在的上述问题，本发明的目的是提供一种酰胺氮三氟甲基化合物的合成方法，以促使具有该类化合物的应用。
为实现上述目的，本发明采用的技术方案如下：
一种酰胺氮三氟甲基化合物的合成方法，包括如下反应：
Figure GDA0002953696060000021
即：由式a1或式a2化合物与三氟甲基化试剂在有机溶剂中、在氟化试剂、氧化剂、含氧酸银盐和吡啶类配体的作用下进行三氟甲基化反应，从而得到式b1或式b2所示的目标化合物；其中：
R1和R2分别独立选自C1-C20的烷基、ORa、取代或未取代的苯基、芳基、杂芳基、
Figure GDA0002953696060000022
Figure GDA0002953696060000023
中的任意一种；Ra选自C1-C6的烷基、苄基中的任意一种；R3选自C1-C6的烷基、苄基中的任意一种；R4选自氢、C1-C6的烷基、苯基、苄基中的任意一种；R5选自C1-C6的烷基；R6选自氢、C1-C6的烷基、苄基中的任意一种；R7选自C1-C6的烷基中的任意一种；R8选自C1-C6的烷基、苄基、取代或未取代的苯基中的任意一种；R9选自C1-C6的烷基中的任意一种；R10选自C1-C6的烷基、苄基中的任意一种；R11和R12分别独立选自C1-C6的烷基中的任意一种；R13选自C1-C6的烷基中的任意一种；R14选自C1-C6的烷基、苄基中的任意一种。
一种优选方案，R1和R2分别独立选自C1-C16的烷基、ORa、苯基、
Figure GDA0002953696060000024
Figure GDA0002953696060000031
Figure GDA0002953696060000032
中的任意一种；Ra选自C1-C6的烷基、苄基中的任意一种；Rb选自卤素、氰基、C1-C6的烷基、C1-C6的烷氧基、苄氧基、三氟甲氧基、三氟甲基、COORc中的任意一种，Rc选自C1-C6的烷基中的任意一种；R3选自C1-C6的烷基、苄基中的任意一种；R4选自氢、C1-C6的烷基、苯基、苄基中的任意一种；R5选自C1-C6的烷基、苄基中的任意一种；R6选自氢、C1-C6的烷基、苄基中的任意一种；R7选自C1-C6的烷基中的任意一种；R8选自C1-C6的烷基、苄基、苯基或C1-C6的烷基取代的苯基中的任意一种；R9选自C1-C6的烷基中的任意一种；R10选自C1-C6的烷基、苄基中的任意一种；R11和R12分别独立选自C1-C6的烷基中的任意一种；R13选自C1-C6的烷基中的任意一种；R14选自C1-C6的烷基、苄基中的任意一种。
一种优选方案，Rb选自氟、氯、溴、氰基、甲基、甲氧基、苄氧基、三氟甲氧基、三氟甲基、COOCH3中的任意一种；R3选自C1-C6的甲基、乙基、叔丁基、苄基中的任意一种；R4选自氢、甲基、乙基、叔丁基、苯基、苄基中的任意一种；R5选自甲基、乙基、叔丁基、苄基中的任意一种；R6选自氢、苄基中的任意一种；R7为甲基；R8选自甲基、乙基、叔丁基、苄基、苯基、
Figure GDA0002953696060000033
中的任意一种；R9选自甲基、乙基、异丙基中的任意一种；R10为苄基中；R11和R12分别为甲基；R13选自甲基、乙基、
Figure GDA0002953696060000034
中的任意一种；R14选自甲基、乙基、叔丁基、苄基中的任意一种。
一种优选方案，所述式a1、a2化合物和式b1、b2化合物分别选自具有如下结构的化合物中的任意一种：
Figure GDA0002953696060000041
Figure GDA0002953696060000051
Figure GDA0002953696060000061
Figure GDA0002953696060000071
Figure GDA0002953696060000081
一种优选方案，所述三氟甲基化试剂为三氟甲基三氟硅烷(即：TMSCF3)。
一种优选方案，所述三氟甲基化试剂与式a1或式a2化合物的摩尔比为1:1-5:1。
一种优选方案，所述有机溶剂为非配位性有机溶剂，选自二氯甲烷、氯苯、三氟甲基苯中的至少一种，进一步优选，二氯甲烷：氯苯体积比为1:1-6:1的复合溶剂，以二氯甲烷：氯苯体积比为3:1的复合溶剂为最佳。
一种优选方案，所述式a1或式a2化合物的浓度为0.01-0.1mol/L。
一种优选方案，所述氟化试剂为碱金属氟化物，优选，氟化铯(即：CsF)。
一种优选方案，所述氟化试剂与式a1或式a2化合物的摩尔比为1:1-5:1。
一种优选方案，所述氧化剂为Selectfluor(即：1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)盐)。
一种优选方案，所述氧化剂与式a1或式a2化合物的摩尔比为1:1-5:1。
一种优选方案，所述吡啶类配体选自4-氰基吡啶、2-三氟甲基吡啶、2,4,6-三甲基吡啶、2,3,4,5,6-五氟吡啶、2-氟吡啶、吡啶、2-氟-5-溴吡啶、2-氟-4-氯吡啶、2-氰基-5-氟吡啶、2-氰基-6-氟吡啶、2-氰基-5-溴吡啶、2-氰基-6-甲氧基吡啶中的任意一种，进一步优选，2-氟吡啶。
一种优选方案，所述含氧酸银盐选自三氟甲烷磺酸银(AgOTf)、硝酸银(AgNO3)、三氟醋酸银(AgTFA)中的任意一种，进一步优选，三氟甲烷磺酸银。
一种优选方案，所述含氧酸银盐与式a1或式a2化合物的摩尔比为1:1-2:1，所述吡啶类配体与式a1或式a2化合物的摩尔比为1:1-2:1。
一种优选方案，吡啶类配体与含氧酸银盐的摩尔比为1:1。
一种优选方案，所述合成方法包括如下操作步骤：
将式a1或式a2化合物、氧化剂、含氧酸银盐、氟化试剂加入到反应器中，抽换气使反应器中处于惰性气体保护氛围；在惰性气体保护下，加入适宜有机溶剂、三氟甲基化试剂和吡啶类配体；使反应体系混合均匀，室温反应；反应结束后，向反应体系中加入水，然后使用有机溶剂萃取，对萃取液进行饱和食盐水洗涤，对洗涤后的有机相进行干燥、浓缩和柱层析，即得到式b1或式b2所示的目标化合物。
与现有技术相比，本发明具有如下显著性有益效果：
本发明通过创造性地由式a1所示的酰胺化合物或式a2所示的磺酰胺化合物与三氟甲基化试剂在有机溶剂中、在氟化试剂、氧化剂、含氧酸银盐和吡啶类配体的作用下进行三氟甲基化反应，从而得到式b1所示的酰胺氮三氟甲基化合物或式b2所示的磺酰胺氮三氟甲基化合物，可直接构建酰胺(磺酰胺)N-CF3键，所述方法具有操作简单、原料易得、成本低廉、安全环保、反应条件温和、易于实现规模化生产等优点，对酰胺氮三氟甲基化合物的工业化应用具有重要意义。
具体实施方式
下面结合具体实施例和对比例对本发明技术方案做进一步详细、完整地说明。
实施例1：式a1化合物的制备
1.1化合物a1-15、a1-21、a1-23、a1-27、a1-34、a1-43的制备
Figure GDA0002953696060000091
将化合物2(甲胺盐酸盐，0.6112g，7.5mmol)和碳酸钾(1.38g，10mmol)加入反应器中，然后向体系中加入10mL乙酸乙酯和5mL水，搅拌使之混合均匀，冰浴冷却至0度，随后将化合物1(4-卞氧基苯甲酰氯，1.23g，5mmol)滴加到体系中，加完后至室温搅拌半个小时，结束反应，向体系中加入1M/L的盐酸10mL淬灭，然后用乙酸乙酯与水萃取，合并有机相之后用无水硫酸钠干燥，过滤浓缩后即得到目标产物a1-15。
化合物a1-21、a1-23、a1-27、a1-34、a1-43都是由相对应的酰氯与对应的胺缩合的到的，步骤同a1-15的合成。
经测试：
Figure GDA0002953696060000101
(化合物a1-21)：收率，95％，白色固体，熔点：100.1-100.8℃；1HNMR(400MHz,CDCl3):δ7.48-7.25(m,8H),7.12-7.05(m,1H),6.29(br,1H),5.08(s,2H),2.99(d,J＝4.8Hz,3H)；13C NMR(100MHz,CDCl3):δ168.0,158.9,136.5,136.1,129.5,128.6,128.0,127.5,118.9,118.3,113.2,70.1,26.8；IR(KBr):v(cm-1)3322,3065,3033,2939,1640,1582,1547,1485,1435,1410,1383,1311,1241,1156 1137,1081,1040,1028,1011,992,904,874,797,751,697；ESI-MS:(m/z)(M++H)242.1；HRMS calcd for C15H16NO2(M+H)242.1176,found 242.1177。
Figure GDA0002953696060000102
(化合物a1-21)：收率，94％，无色油状物；1H NMR(400MHz,CDCl3):δ7.30-7.22(m,2H),7.20-7.12(m,3H),6.19(br,1H),3.22(q,J＝5.6Hz,2H),2.61(t,J＝7.6Hz,2H),1.93(s,3H),1.68-1.58(m,2H),1.57-1.46(m,2H)；13C NMR(100MHz,CDCl3):δ170.2,141.7,128.0,127.9,125.4,39.0,35.1,28.7,28.3,22.6；IR(KBr):v(cm-1)3291,3084,3026,2934,2859,1710,1652,1559,1496,1453,1369,1293,1177,1104,1030,1002,909,747,699；ESI-MS:(m/z)(M++H)192.2；HRMS calcd for C12H18NO(M+H)192.1383,found 192.1383。
Figure GDA0002953696060000103
(化合物a1-23)：收率，91％，无色油状物；1H NMR(400MHz,CDCl3):δ6.15(br,1H),4.18(q,J＝6.8Hz,2H),3.99(d,J＝5.2Hz,2H),2.21(t,J＝7.6Hz,2H),1.67-1.56(m,2H),1.35-1.20(m,7H),0.86(t,J＝6.4Hz,3H)；13C NMR(100MHz,CDCl3):δ173.5,169.8,60.9,40.9,35.8,31.0,25.0,22.0,13.7,13.5；IR(KBr):v(cm-1)3304,3077,2958,2933,2872,1755,1656,1543,1466,1407,1376,1354,1197,1028,860,707；ESI-MS:(m/z)(M++H)202.2；HRMS calcd for C10H20NO3(M+H)202.1438,found202.1439。
Figure GDA0002953696060000111
(化合物a1-27)：收率，95％，白色固体，熔点：27.1-27.3℃；1H NMR(400MHz,CDCl3):δ5.64(br,1H),3.20(q,J＝6.8Hz,2H),2.52-2.41(m,1H),1.87-1.63(m,6H),1.60-1.40(m,4H),1.33-1.20(m,6H),0.85(t,J＝6.8Hz,3H)；13C NMR(100MHz,CDCl3):δ176.1,45.9,39.4,31.4,30.4,29.6,26.5,25.8,22.5,13.9；IR(KBr):v(cm-1)3295,3083,2956,2930,2869,1644,1550,1452,1378,1315,1240,693；ESI-MS:(m/z)(M++H)198.2；HRMS calcd for C12H24NO(M+H)198.1852,found 198.1853。
Figure GDA0002953696060000112
(化合物a1-34)：收率，93％，白色固体，熔点：96.5-96.9℃；1HNMR(400MHz,CDCl3):δ7.86-7.81(m,2H),7.55-7.40(m,3H),7.04-6.99(m,2H),6.97-6.91(m,1H),6.75(d,J＝8.4Hz,1H),4.62-4.52(m,1H),3.93(dd,J＝8.8Hz,J＝4.0Hz,1H),3.82(dd,J＝9.2Hz,J＝2.8Hz,1H),2.28(s,6H),1.53(d,J＝6.4Hz,3H)；13C NMR(100MHz,CDCl3):δ166.9,154.8,134.6,131.4,130.7,129.0,128.5,126.9,124.1,73.8,45.9,17.8,16.1；IR(KBr):v(cm-1)3307,3060,2974,2923,2874,1636,1579,1538,1477,1456,1386,1345,1326,1263,1203,1093,1027,987,769,713,694,668；ESI-MS:(m/z)(M++H)284.2；HRMS calcd for C18H22NO2(M+H)284.1645,found284.1647。
Figure GDA0002953696060000113
(化合物a1-43)：收率，85％，白色固体，熔点：33.5-33.9℃；1HNMR(400MHz,CDCl3):δ6.92(br,1H),2.61-2.51(m,1H),2.03(t,J＝7.6Hz,2H),1.55-1.41(m,2H),1.25-1.07(m,4H),0.81-0.65(m,3H),0.61-0.52(m,2H),0.42-0.35(m,2H)；13C NMR(100MHz,CDCl3):δ175.0,36.4,31.2,25.2,22.3,22.1,13.6,5.9；IR(KBr):v(cm-1)3253,3086,3060,2953,2871,2856,1651,1550,1462,1440,1424,1362,1290,1268,1219,1193,1106,1038,1008,995,881,821,735,585,505；ESI-MS:(m/z)(M++H)156.2；HRMS calcd forC9H18NO(M+H)156.1383,found 156.1383。
1.2化合物a1-32、a1-38、a1-39、a1-40的制备
Figure GDA0002953696060000121
将化合物3(果糖二丙酮，1.30g,5.0mmol)，DMAP(122mg,1.0mmol)，化合物4(N-乙酰-L-苯丙氨酸，1.24g,6.0mmol)加入反应器中，抽空换氮三次之后加入DCM(50mL)并用冰浴冷却至0℃，随后缓慢加入DCC(1.24g,6.0mmol)，加完后回至室温搅拌过夜，结束反应，加入一定量的水淬灭反应，并用DCM反复萃取水相，合并后的有机相用无水Na2SO4干燥，过滤旋干后，过柱分离得到目标产物a1-39。
化合物a1-32、a1-38、a1-40都是由相应的酸与对应的胺缩合的到的，步骤同a1-39的合成。
经测试：
Figure GDA0002953696060000122
(化合物a1-32)：收率，91％，白色固体，熔点：202.1-202.4℃；[]D＝-16.0(c＝1.000,CHCl3,25℃)；1H NMR(400MHz,CDCl3):δ5.89(br,1H),5.12(br,1H),3.82-3.70(m,2H),2.13-2.00(m,1H),1.93-1.81(m,2H),1.73-1.54(m,3H),1.42(s,9H),1.40-1.25(m,2H),1.20-1.05(m,3H),0.91(dd,J＝13.6Hz,J＝6.8Hz,6H)；13C NMR(100MHz,CDCl3):δ170.6,155.9,79.5,60.1,48.1,33.0,32.8,30.9,28.2,25.4,24.7,19.2,18.0；IR(KBr):v(cm-1)3315,3084,2961,2929,2854,1683,1640,1524,1450,1390,1365,1296,1248,1176,1043,1018,998,881,636；ESI-MS:(m/z)(M++H)299.2；HRMS calcdfor C16H30N2O3Na(M+Na)321.2149,found 321.2150。
Figure GDA0002953696060000123
(化合物a1-38)：收率，78％，白色固体，熔点：133.6-133.9℃；1H NMR(400MHz,CDCl3):δ8.05(d,J＝2.0Hz,1H),7.86-7.80(m,1H),7.56-7.49(m,1H),7.46-7.38(m,2H),7.35-7.30(m,1H),7.02-7.97(m,1H),5.99(br,1H),5.13(s,2H),3.53(s,2H),2.73(d,J＝4.8Hz,3H)；13C NMR(100MHz,CDCl3):δ190.8,171.3,160.4,140.2,136.4,135.4,132.8,132.2,129.3,129.2,128.8,127.7,125.1,121.3,73.5,42.3,26.4；IR(KBr):v(cm-1)3300,3068,2940,2874,1648,1610,1567,1489,1454,1412,1379,1301,1255,1163,1138,1121,1016,995,859,831,801,761,736,701；ESI-MS:(m/z)(M++H)282.1；HRMScalcd for C17H16NO3(M+H)282.1125,found282.1127。
Figure GDA0002953696060000131
(化合物a1-39)：收率，85％，白色固体，熔点:49.8-52.0℃；[]D＝-1.6(c＝1.000,CHCl3,25℃).1H NMR(400MHz,CDCl3):δ7.28-7.16(m,3H),7.11-7.05(m,2H),6.23-6.14(m,1H),4.95-4.85(m,1H),4.61-4.52(m,1H),4.41-3.93(m,4H),3.92-3.82(m,1H),3.77-3.67(m,1H),3.17-3.02(m,2H),1.93(s,1H),1.92(s,2H),1.52(s,2H),1.47(d,J＝6.8Hz,2H),1.43(s,2H),1.39(s,2H),1.33(s,1H),1.30(s,3H)；13C NMR(100MHz,CDCl3):δ171.0,170.9,169.5,169.4,135.6,135.5,129.2,129.2,128.4,127.0,126.9,109.0,108.9,108.8,108.7,100.9,100.9,70.6,70.5,70.1,70.0,69.8,69.7,66.0,65.6,61.1,61.1,53.2,52.9,38.1,37.4,30.7,26.3,26.3,25.7,25.7,25.2,25.1,23.9,23.9,22.9,22.8；IR(KBr):v(cm-1)3281,3063,3030,2990,2937,1749,1658,1538,1455,1381,1252,1211,1164,1120,1072,1021,981,913,886,865,756,738,701；ESI-MS:(m/z)(M++H)450.2；HRMS calcd for C23H31NO8Na(M+Na)472.1942,found 472.1943。
Figure GDA0002953696060000132
(化合物a1-40)：收率，80％，白色固体，熔点:262.8-263.8℃；[]D＝19.1(c＝1.000,CHCl3,25℃).1H NMR(400MHz,CDCl3):δ5.60(br,1H),2.95-2.77(m,6H),2.40-2.17(m,7H),2.17-2.06(m,3H),2.06-1.91(m,4H),1.91-1.76(m,3H),1.66-1.54(m,1H),1.56(s,3H),1.40-1.19(m,5H),1.06(s,3H),0.83(d,J＝5.6Hz,3H)；13CNMR(100MHz,CDCl3):δ212.0,209.1,208.7,173.9,56.8,51.7,48.9,46.8,45.5,45.5,44.9,42.7,38.6,36.4,35.9,35.4,35.2,33.4,31.1,27.5,26.2,25.1,21.8,18.7,11.8；IR(KBr):v(cm-1)3269,3092,2961,2869,1704,1640,1567,1469,1425,1383,1336,1319,1297,1277,1228,1183,1159,1140,1117,1027,955,926,738,686；ESI-MS:(m/z)(M++H)416.3；HRMS calcd for C25H38NO4(M+H)416.2795,found416.2799。
1.3化合物a1-36、a1-41的制备
Figure GDA0002953696060000141
将化合物5(N-(叔丁氧羰基)-L-2-苯基甘氨酸，1.26g,5.0mmol)，苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU,2.09g,5.5mmol)，化合物6(N,N-二甲基-L-苯丙酰胺，821mg,5.0mmol)加入反应器中，加入20mL二氯甲烷，然后再加入N,N-二异丙基乙胺(DIEA,1.65mL,10mmol)，室温搅拌搅拌半小时，结束反应，加入一定量的水淬灭反应，并用DCM反复萃取水相，合并后的有机相用无水Na2SO4干燥，过滤旋干后，过柱分离得到底物1-36a。
化合物1-41a也是相应的酸与对应的胺缩合的到的，步骤同1-36a的合成。
经测试：
Figure GDA0002953696060000142
(化合物a1-36)：收率，85％，白色固体，熔点：160.1-160.4℃；[]D＝85.3(c＝1.000,CHCl3,25℃).1H NMR(400MHz,CDCl3):δ7.38-7.11(m,11H),5.78(br,1H),5.23(br,1H),5.09-5.00(m,1H),3.08-2.94(m,2H),2.79(s,3H),2.52(s,3H),1.42(s,9H)；13C NMR(100MHz,CDCl3):δ170.4,169.5,154.9,138.1,136.1,129.4,128.8,128.4,128.1,127.0,79.9,58.6,50.6,39.7,36.7,35.5,28.2；IR(KBr):v(cm-1)3295,3062,3030,2977,2932,1715,1633,1495,1454,1420,1392,1366,1246,1169,1090,1024,888,851,737,700,522；ESI-MS:(m/z)(M++H)426.2；HRMS calcd for C24H32N3O4(M+H)426.2387,found 426.2388。
Figure GDA0002953696060000143
(化合物a1-41)：收率，75％，白色固体，熔点：70.6-72.3℃；[]D＝-11.2(c＝1.000,CHCl3,25℃)；1H NMR(400MHz,CDCl3):δ7.36-7.26(m,5H),6.80(br,1H),5.68(d,J＝7.6Hz,1H),5.09(q,J＝10.4Hz,2H),4.37-4.27(m,1H),3.88(d,J＝4.4Hz,2H),1.44(s,9H),1.37(d,J＝6.8Hz,3H)；13C NMR(100MHz,CDCl3):δ172.3,168.7,155.9,136.1,128.5,128.1,128.0,82.3,67.0,50.4,41.9,28.0,18.6；IR(KBr):v(cm-1)3318,3065,3034,2979,2936,1728,1667,1531,1455,1393,1368,1295,1249,1158,1070,1043,946,918,846,778,738,698；ESI-MS:(m/z)(M++Na)359.1；HRMS calcd forC17H24N2O5Na(M+Na)359.1577,found359.1577。
1.4化合物1-42a的合成
Figure GDA0002953696060000151
将化合物7(Boc-L-异亮氨酸，1.16g,5.0mmol)，苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU,2.09g,5.5mmol)，化合物8(L-脯氨酸苄酯，1.03g,5.0mmol)加入反应器中，加入20mL二氯甲烷，然后再加入N,N-二异丙基乙胺(DIEA,1.65mL,10mmol)，室温搅拌半小时，结束反应，加入一定量的水淬灭反应，并用DCM反复萃取水相，合并后的有机相用无水Na2SO4干燥，过滤旋干后，过柱分离得到中间体化合物9；将该中间体化合物9溶到二氯甲烷中，加入三氟乙酸(10equiv)将Boc保护的胺基水解，1小时之后，TCL板监测，待反应完全后，向体系中加入饱和碳酸钾溶液，将体系PH值调节至9-10左右，加水淬灭，并用二氯甲烷和水萃取，合并后的有机相用无水Na2SO4干燥，过滤旋干，得到中间体化合物10；所得中间体化合物10直接与化合物11进行下一步反应(反应操作如化合物7和化合物8的反应)，即得到目标产物三肽分子a1-42。
经测试：
Figure GDA0002953696060000152
(化合物a1-42)：收率，73％，黄色油状物，[]D＝-40.8(c＝1.620,CHCl3,25℃).1H NMR(400MHz,CDCl3):δ7.36-7.26(m,5H),6.94-6.85(m,1H),5.21(br,1H),5.13(q,J＝5.6Hz,2H),4.65-4.56(m,1H),4.56-4.45(m,1H),3.90-3.56(m,4H),2.25-2.13(m,1H),2.05-1.88(m,3H),1.87-1.74(m,1H),1.60-1.45(m,1H),1.41(s,9H),1.14-1.00(m,1H),0.94(d,J＝6.8Hz,3H),0.83(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3):δ171.6,170.8,169.2,155.7,135.5,128.5,128.2,128.1,79.9,66.8,59.0,54.6,47.3,44.0,37.7,29.0,28.2,24.8,24.3,15.0,10.9；IR(KBr):v(cm-1)3295,3062,2967,2877,1751,1715,1633,1504,1455,1366,1322,1248,1170,1096,1049,1027,942,915,865,782,736,699；ESI-MS:(m/z)(M++H)476.3；HRMS calcd for C25H38N6O3(M+H)476.2755,found 476.2757。
其余式a1化合物和式a2化合物直接采用市售产品即可。
实施例2：式b1和b2化合物的制备
Figure GDA0002953696060000161
将式a1-1化合物(13.5mg,0.1mmol)，Selectfluor(141.7mg,0.4mmol)，AgOTf(28.3mg,0.11mmol)，CsF(76.0mg，0.5mmol)加入到反应器中，抽换气使反应器中处于惰性气体保护氛围；在惰性气体保护下，加入DCM(1.5mL)，氯苯(0.5mL)，TMSCF3(74uL,0.5mmol)，2-氟吡啶(9uL,0.11mmol)，搅拌使反应体系混合均匀，室温反应24小时；结束反应，向反应体系中加入水，然后使用乙酸乙酯萃取，对萃取液进行饱和食盐水洗涤，对洗涤后的有机相进行无水硫酸钠干燥、浓缩和柱层析，即得到式b1-1所示的目标化合物。
其余的式b1化合物和式b2化合物都是由相应的式a1化合物和式a2化合物与TMSCF3反应得到，操作步骤同b1-1的合成。
经测试：
Figure GDA0002953696060000162
(化合物b1-1)：收率，74％，无色油状物；1H NMR(400MHz,CDCl3):δ7.57-7.48(m,3H),7.47-7.40(m,2H),3.17(q,J＝2.0Hz,3H)；13C NMR(100MHz,CDCl3):δ170.6,134.7,131.5,128.4,127.6,121.2(q,J＝261.0Hz),32.2；19F NMR(376MHz,CDCl3):δ-55.69(s,3F)；IR(KBr):v(cm-1)3065,2968,1694,1603,1582,1479,1449,1347,1275,1227,1156,1099,1053,1024,887,855,795,721,698；EIMS:m/z(rel intensity)203(M+,25),173(20),145(12),106(25),105(100),77(97),69(22),51(49)；HRMS calcd forC9H8F3NO(M):203.0558,found:203.0559。
Figure GDA0002953696060000163
(化合物b1-2)：收率，76％，无色油状物；1H NMR(400MHz,CDCl3):δ7.10(d,J＝8.0Hz,2H),7.64(d,J＝8.0Hz,2H),3.20(q,J＝2.0Hz,3H)；13C NMR(100MHz,CDCl3):δ169.0,138.3,133.1(q,J＝32.8Hz),127.7,125.5(q,J＝3.7Hz),123.5(q,J＝271.3Hz),121.0(q,J＝261.0Hz),31.7(q,J＝1.4Hz)；19F NMR(376MHz,CDCl3):δ-54.70(s,3F),-63.10(s,3F)；IR(KBr):v(cm-1)1697,1517,1480,1438,1410,1324,1166,1128,1109,1068,1017,852；IMS:m/z(rel intensity)271(M+,22),252(31),173(99),145(100),139(16),125(24),95(31),75(26),69(23)；HRMS calcd for C10H7F6NO(M):271.0432,found:271.0433。
Figure GDA0002953696060000171
(化合物b1-3)：收率，63％，无色油状物；1H NMR(400MHz,CDCl3):δ7.77-7.72(m,2H),7.61(d,J＝8.4Hz,2H),3.21(q,J＝1.6Hz,3H)；13C NMR(100MHz,CDCl3):δ168.4,139.0,132.2,127.8,120.9(q,J＝261.4Hz),117.8,115.0,31.5；19F NMR(376MHz,CDCl3):δ-54.33(s,3F)；IR(KBr):v(cm-1)2233,1697,1479,1437,1406,1352,1319,1271,1157,1100,1053,1851,765；EIMS:m/z(rel intensity)228(M+,13),131(9),130(100),102(42),76(6),75(10),69(6),51(4)；HRMS calcd for C10H7F3N2O(M):228.0510,found:228.0511。
Figure GDA0002953696060000172
(化合物b1-4)：收率，61％，白色固体，熔点：64.4-64.8℃；1H NMR(400MHz,CDCl3):δ7.52-7.47(m,2H),7.44-7.39(m,2H),3.17(q,J＝1.6Hz,3H)；13C NMR(100MHz,CDCl3):δ169.5,137.8,133.1,129.0,128.8,121.1(q,J＝260.9Hz),32.1；19F NMR(376MHz,CDCl3):δ-55.31(s,3F)；IR(KBr):v(cm-1)1694,1595,1344,1274,1156,1090,1051,1014,841,759；EIMS:m/z(rel intensity)237(M+,27),203(4),141(56),139(100),113(22),111(58),105(22),77(14),75(33),69(13),50(12)；HRMS calcd for C9H7ClF3NO(M):237.0168,found:237.0171。
Figure GDA0002953696060000173
(化合物b1-5)：收率，62％，无色油状物；1H NMR(400MHz,CDCl3):δ7.61-7.55(m,2H),7.16-7.09(m,2H),3.17(q,J＝1.6Hz,3H)；13C NMR(100MHz,CDCl3):δ169.6,164.58(d,J＝250.9Hz),130.8,130.2(d,J＝8.1Hz),121.2(q,J＝260.3Hz),115.7(d,J＝21.9Hz),32.2(q,J＝2.2Hz)；19F NMR(376MHz,CDCl3):δ-55.57(s,3F),107.17(m,1F)；IR(KBr):v(cm-1)3079,1698,1605,1511,1344,1236,1155,1098,1050,850,766；EIMS:m/z(rel intensity)221(M+,11),124(9),123(100),95(45),75(16),69(7),50(3)；HRMScalcd for C9H7F4NO(M):221.0464,found:221.0469。
Figure GDA0002953696060000174
(化合物b1-6)：收率，70％，无色油状物；1H NMR(400MHz,CDCl3):δ7.58(d,J＝8.4Hz,2H),7.42(d,J＝8.4Hz,2H),3.17(q,J＝1.6Hz,3H)；13C NMR(100MHz,CDCl3):δ169.6,133.6,131.7,129.1,126.2,121.1(q,J＝261.2Hz),32.0(q,J＝1.6Hz)；19FNMR(376MHz,CDCl3):δ-55.31(s,3F)；IR(KBr):v(cm-1)1701,1590,1479,1436,1397,1346,1273,1156,1099,1011,838,757；EIMS:m/z(rel intensity)283/281(M+,18),185(100),183(100),157(31),155(32),139(13),105(27),77(12),76(21),69(9),50(13)；HRMScalcd for C9H7BrF3NO(M):280.9663,found:280.9665。
Figure GDA0002953696060000181
(化合物b1-7)：收率，27％，白色油状物；1H NMR(400MHz,CDCl3):δ7.62-7.58(m,1H),7.40-7.35(m,1H),7.33-7.26(m,2H),3.18(q,J＝1.6Hz,3H)；13C NMR(100MHz,CDCl3):δ167.7,137.2,132.9,131.1,127.4,127.3,120.7(q,J＝261.2Hz),118.9,30.8；19F NMR(376MHz,CDCl3):δ-55.65(s,3F)；IR(KBr):v(cm-1)3069,2966,2863,1700,1591,1566,1473,1432,1353,1320,1267,1161,1104,1072,1026,890,855,772,745,690,675,634；EIMS:m/z(rel intensity)283(18),281(M+,19),185(100),183(99),173(11),157(30),155(30),139(13),105(42),77(17),76(23),75(22),69(11),50(14)；HRMScalcd for C9H7BrF3NO(M):280.9663,found:280.9665。
Figure GDA0002953696060000182
(化合物b1-8)：收率，66％，无色油状物；1H NMR(400MHz,CDCl3):δ7.69-7.62(m,2H),7.46(d,J＝7.6Hz,1H),7.31(t,J＝7.6Hz,1H),3.17(q,J＝2.0Hz,3H)；13C NMR(100MHz,CDCl3):δ168.8,136.6,134.4,130.5,130.0,125.9,122.4,121.0(q,J＝261.8Hz),32.0(q,J＝1.8Hz)；19F NMR(376MHz,CDCl3):δ-55.33(s,3F)；IR(KBr):v(cm-1)3067,1698,1569,1478,1436,1415,1347,1270,1158,1101,898,802,747,709；EIMS:m/z(rel intensity)283/281(M+,23),185(100),183(97),157(40),155(40),123(8),105(7),77(5),76(24),75(21),69(10),50(13)；HRMS calcd for C9H7BrF3NO(M):280.9663,found:280.9667。
Figure GDA0002953696060000183
(化合物b1-9)：收率，70％，无色油状物；1H NMR(400MHz,CDCl3):δ7.60-7.55(m,2H),6.95-6.91(m,2H),3.86(s,3H),3.15(q,J＝1.6Hz,3H)；13C NMR(100MHz,CDCl3):δ170.5,162.4,130.2,126.6,121.4(q,J＝260.5Hz),113.7,55.4,32.7(q,J＝1.4Hz)；19F NMR(376MHz,CDCl3):δ-56.38(s,3F)；IR(KBr):v(cm-1)1693,1607,1578,1514,1339,1259,1153,1095,1051,1027,861,768；EIMS:m/z(rel intensity)233(M+,18),185(7),183(7),136(11),135(100),121(9),107(13),92(14),77(17),69(5)；HRMS calcdfor C10H10F3NO2(M):233.0664,found:233.0671。
Figure GDA0002953696060000184
(化合物b1-10)：收率，41％，无色油状物；1H NMR(400MHz,CDCl3):δ7.43-7.37(m,1H),7.28-7.24(m,1H),6.99(dt,J＝0.8,7.6Hz,1H),6.93(d,J＝8.4Hz,1H),3.84(s,3H),3.14(q,J＝2.0Hz,3H)；13C NMR(100MHz,CDCl3):δ168.3,155.8,131.5,127.9,125.0,120.9(q,J＝260.3Hz),120.5,111.0,55.6,30.9(q,J＝1.5Hz)；19F NMR(376MHz,CDCl3):δ-56.26(s,3F)；IR(KBr):v(cm-1)1698,1602,1585,1493,1466,1438,1351,1255,1161,1117,1057,1036,1023,891,756；EIMS:m/z(rel intensity)233(M+,18),203(4),182(5),136(10),135(100),97(16),92(13),77(22),69(19),64(5)；HRMS calcd forC10H10F3NO2(M):233.0664,found:233.0656。
Figure GDA0002953696060000191
(化合物b1-11)：收率，78％，白色固体，熔点：56.0-56.2℃；1H NMR(400MHz,CDCl3):δ8.12-8.08(m,2H),7.60-7.56(m,2H),3.94(s,3H),3.18(q,J＝2.0Hz,3H)；13C NMR(100MHz,CDCl3):δ169.5,166.1,138.9,132.5,129.6,127.3,121.0(q,J＝260.9Hz),52.4,31.7；19F NMR(376MHz,CDCl3):δ-54.98(s,3F)；IR(KBr):v(cm-1)1727,1677,1610,1573,1482,1442,1406,1370,1271,1162,1108,1058,1015,877,732；EIMS:m/z(rel intensity)261(M+,7),230(13),164(10),163(100),135(25),121(4),104(8),103(12),92(3),77(7),76(9),50(5)；HRMS calcd for C11H10F3NO3(M):261.0613,found:261.0615。
Figure GDA0002953696060000192
(化合物b1-12)：收率，31％，白色油状物；1H NMR(400MHz,CDCl3):δ7.56(d,J＝0.8Hz,1H),7.20(d,J＝3.6Hz,1H),6.53(dd,J＝3.6Hz,J＝1.6Hz,1H),3.76(qq,J＝6.8Hz,J＝2.0Hz,2H),1.35(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3):δ159.0,146.5,145.4,121.4(q,J＝261.8Hz),118.7,111.9,40.8,15.0；19F NMR(376MHz,CDCl3):δ-54.61(s,3F)；IR(KBr):v(cm-1)3145,2988,2945,2885,1682,1575,1471,1373,1330,1293,1240,1147,1106,1066,1014,962,932,886,841,758；EIMS:m/z(rel intensity)207(M+,41),179(11),178(22),138(10),123(10),112(8),96(17),95(100),69(13),67(8)；HRMScalcd for C8H8F3NO2(M):207.0507,found:207.0511。
Figure GDA0002953696060000193
(化合物b1-13)：收率，72％，无色油状物；1H NMR(400MHz,CDCl3):δ7.46(d,J＝8.0Hz,2H),7.23(d,J＝8.0Hz,2H),3.15(q,J＝2.0Hz,3H),2.40(s,3H)；13C NMR(100MHz,CDCl3):δ170.8,142.1,131.8(q,J＝1.5Hz),129.0,127.8,121.3(q,J＝260.3Hz),32.4(q,J＝1.5Hz),21.5；19F NMR(376MHz,CDCl3):δ-56.02(s,3F)；IR(KBr):v(cm-1)3035,1694,1612,1479,1437,1340,1276,1155,1098,1050,833,756；EIMS:m/z(relintensity)217(M+,28),187(13),159(3),123(31),120(17),119(100),95(13),91(64),89(12),69(11),65(23),63(9)；HRMS calcd for C10H10F3NO(M):217.0714,found:217.0720。
Figure GDA0002953696060000201
(化合物b1-14)：收率，60％，无色油状物；1H NMR(400MHz,CDCl3):δ7.38-7.29(m,4H),3.16(q,J＝2.0Hz,3H),2.39(s,3H)；13C NMR(100MHz,CDCl3):δ170.9,138.4,134.6(q,J＝1.5Hz),132.2,128.2,128.1,124.6,121.2(q,J＝260.3Hz),32.3(q,J＝2.2Hz),21.3；19F NMR(376MHz,CDCl3):δ-55.88(s,3F)；IR(KBr):v(cm-1)1698,1607,1588,1479,1437,1344,1276,1147,1100,1054,797,748；EIMS:m/z(rel intensity)217(M+,21),185(5),120(9),119(100),105(2),91(49),69(5),65(13)；HRMS calcd forC10H10F3NO(M):217.0714,found:217.0717。
Figure GDA0002953696060000202
(化合物b1-15)：收率，53％，无色油状物；1H NMR(400MHz,CDCl3):δ7.46-7.31(m,6H),7.16-7.09(m,3H),5.09(s,2H),3.14(q,J＝1.6Hz,3H)；13C NMR(100MHz,CDCl3):δ170.4,158.6,136.4,135.9(d,J＝1.5Hz),129.6,128.7,128.1,127.5,121.2(q,J＝260.4Hz),120.1,118.4,113.8,70.2,32.3(q,J＝1.5Hz)；19F NMR(376MHz,CDCl3):δ-56.06(s,3F)；IR(KBr):v(cm-1)3067,3035,1698,1582,1487,1439,1347,1264,1211,1146,1099,1025,754,697；EIMS:m/z(rel intensity)309(M+,13),211(9),177(4),161(4),131(9),105(8),91(100),77(6),65(10),51(3)；HRMS calcd for C16H14F3NO2(M):309.0977,found:309.0973。
Figure GDA0002953696060000203
(化合物b1-16)：收率，56％，无色油状物；1H NMR(400MHz,CDCl3):δ7.15(dd,J＝7.6,1.6Hz,1H),7.05(d,J＝1.6Hz,1H),6.84(d,J＝8.0Hz,1H),6.04(s,2H),3.14(q,J＝1.2Hz,3H)；13C NMR(100MHz,CDCl3):δ170.1,150.7,147.7,128.1,123.3,121.3(q,J＝260.3Hz),108.5,108.1,101.8,32.7(q,J＝1.4Hz)；19F NMR(376MHz,CDCl3):δ-56.50(s,3F)；IR(KBr):v(cm-1)1749,1695,1609,1506,1491,1441,1333,1253,1227,1038,933,849,762；EIMS:m/z(rel intensity)247(M+,28),217(12),187(4),177(5),149(100),135(7),131(11),123(23),121(27),119(50),104(11),95(9),91(38),69(9),65(19)；HRMS calcd for C10H8F3NO3(M):247.0456,found:247.0457。
Figure GDA0002953696060000204
(化合物b1-17)：收率，69％，白色固体，熔点：85.3-85.5℃；1HNMR(400MHz,CDCl3):δ8.09(s,1H),7.95-786(m,3H),7.65-7.53(m,3H),3.23(q,J＝1.6Hz,3H)；13C NMR(100MHz,CDCl3):δ170.8,134.6,132.3,131.9,128.9,128.4,128.0,127.8,127.0,124.1,121.3(q,J＝260.9Hz),32.5；19F NMR(376MHz,CDCl3):δ-55.86(s,3F)；IR(KBr):v(cm-1)1690,1476,1334,1271,1256,1149,1124,907,873,834,811,758,481；EIMS:m/z(rel intensity)253(M+,31),223(55),195(30),156(12),155(100),153(31),135(8),127(67),126(20),77(9),69(5),63(5),51(4)；HRMS calcd for C13H10F3NO(M):253.0714,found:253.0710。
Figure GDA0002953696060000211
(化合物b1-18)：收率，52％，无色油状物；1H NMR(400MHz,CDCl3):δ7.55-7.46(m,3H),7.45-7.39(m,2H),3.91-3.79(m,1H),2.02-1.80(m,6H),1.68-1.60(m,1H),1.35-1.08(m,3H)；13C NMR(100MHz,CDCl3):δ171.1,136.3,131.2,128.3,127.1,121.9(q,J＝262.5Hz),59.3,31.1,26.4,25.2；19F NMR(376MHz,CDCl3):δ-49.84(s,3F)；IR(KBr):v(cm-1)3065,2939,2858,1692,1602,1449,1409,1329,1288,1261,1233,1211,1150,1077,699；EIMS:m/z(rel intensity)271(M+,2),202(5),190(49),161(2),106(8),105(100),96(2),82(8),77(32),67(6),51(6)；HRMS calcd for C14H16F3NO(M):271.1184,found:271.1191。
Figure GDA0002953696060000212
(化合物b1-19)：收率，58％，无色油状物；1H NMR(400MHz,CDCl3):δ7.55-7.47(m,3H),7.45-7.39(m,2H),4.31(qq,J＝7.2,1.2Hz,1H),1.45(qd,J＝1.2,6.8Hz,6H)；13C NMR(100MHz,CDCl3):δ171.0,136.1,131.2,128.4,127.1,122.0(q,J＝261.8Hz),50.7,21.0(q,J＝1.8Hz)；19F NMR(376MHz,CDCl3):δ-50.15(s,3F)；IR(KBr):v(cm-1)1693,1603,1449,1406,1333,1280,1255,1236,1140,1093,1024,698；EIMS:m/z(relintensity)231(M+,51),230(32),162(10),119(8),106(23),105(100),96(6),92(7),77(74),69(11),51(25)；HRMS calcd for C11H12F3NO(M):231.0871,found:231.0874。
Figure GDA0002953696060000213
(化合物b1-20)：收率，65％，无色油状物；1H NMR(400MHz,CDCl3):δ7.16(d,J＝8.4Hz,2H),6.87(d,J＝8.8Hz,2H),3.80(s,5H),3.10(q,J＝2.0Hz,3H)；13C NMR(100MHz,CDCl3):δ171.0,158.8,130.4,125.5,121.7(q,J＝259.1Hz),114.0,55.2,40.8(q,J＝4.7Hz),30.0(q,J＝1.6Hz)；19F NMR(376MHz,CDCl3):δ-52.55(s,3F)；IR(KBr):v(cm-1)1712,1614,1586,1515,1465,1436,1360,1319,1250,1179,1090,1034,823,792；EIMS:m/z(rel intensity)247(M+,22),185(2),148(2),122(10),121(100),105(2),91(5),78(9),77(8),69(4),51(3)；HRMS calcd for C11H12F3NO2(M):247.0820,found:247.0811。
Figure GDA0002953696060000221
(化合物b1-21)：收率，59％，无色油状物；1H NMR(400MHz,CDCl3):δ7.31-7.25(m,2H),7.21-7.14(m,3H),3.62-3.55(m,2H),2.63(t,J＝7.8Hz,2H),2.28(q,J＝1.6Hz,2H),1.65-1.58(m,4H)；13C NMR(100MHz,CDCl3):δ169.3,141.9,128.4,125.9,122.0(q,J＝259.6Hz),43.3,35.4,28.5,28.3,23.3(q,J＝4.3Hz)；19F NMR(376MHz,CDCl3):δ-51.99(s,3F)；IR(KBr):v(cm-1)3028,2941,2863,1709,1604,1497,1454,1375,1317,1166,1132,1080,969,747,670；EIMS:m/z(rel intensity)259(M+,16),239(16),216(35),213(21),177(38),152(5),131(79),117(18),104(61),99(52),91(100),78(11),71(18),65(17),55(7)；HRMS calcd for C13H16F3NO(M):259.1184,found:259.1182。
Figure GDA0002953696060000222
(化合物b1-22)：收率，63％，无色油状物；1H NMR(400MHz,CDCl3):δ7.56-7.50(m,2H),7.15-7.08(m,2H),3.62(tq,J＝7.6,1.2Hz,2H),1.70-1.60(m,2H),1.39-1.24(m,2H),0.91(t,J＝7.6Hz,3H)；13C NMR(100MHz,CDCl3):δ169.5,164.3(d,J＝250.5Hz),131.5,129.6(d,J＝8.4Hz),121.4(q,J＝260.3Hz),115.5(d,J＝22.2Hz),45.4,31.0,19.8,13.5；19F NMR(376MHz,CDCl3):δ-52.58(s,3F),107.90(m,1F)；IR(KBr):v(cm-1)2964,2938,2878,1694,1605,1510,1469,1370,1336,1211,1147,1098,848,764；EIMS:m/z(rel intensity)263(M+,3),262(3),231(3),208(7),152(20),135(5),124(13),123(100),105(6),95(37),75(12),69(6)；HRMS calcd for C12H13F4NO(M):263.0933,found:263.0940。
Figure GDA0002953696060000223
(化合物b1-23)：收率，60％，无色油状物；1H NMR(400MHz,CDCl3):δ4.30(q,J＝2.4Hz,2H),4.21(q,J＝7.2Hz,2H),2.59(t,J＝8.0Hz,3H),1.74-1.64(m,2H),1.37-1.22(m,7H),0.90(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3):δ172.4,167.8(q,J＝1.5Hz),121.4(q,J＝260.3Hz),61.7,44.1(q,J＝1.5Hz),34.5(q,J＝3.6Hz),31.1,24.4,22.3,14.0,13.8；19F NMR(376MHz,CDCl3):δ-51.50(s,3F)；IR(KBr):v(cm-1)2961,2936,2875,1760,1715,1467,1423,1359,1217,1144,1028；EIMS:m/z(relintensity)224(18),213(44),193(3),171(7),165(8),152(8),124(7),99(100),98(18),78(5),71(37),55(13)；HRMS calcd for C11H18F3NO3(M):269.1239,found:269.1234。
Figure GDA0002953696060000224
(化合物b1-24)：收率，85％，无色油状物；1H NMR(400MHz,CDCl3):δ7.60-7.55(m,2H),7.54-7.48(m,1H),7.45-7.40(m,2H),4.34(q,J＝1.6Hz,2H),4.26(q,J＝6.8Hz,2H),1.30(t,J＝6.8Hz,3H)；13C NMR(100MHz,CDCl3):δ169.9,167.6,134.4(q,J＝1.6Hz),131.4,128.4,127.2,120.9(q,J＝261.9Hz),61.9,45.7(q,J＝1.5Hz),14.0；19F NMR(376MHz,CDCl3):δ-52.62(s,3F)；IR(KBr):v(cm-1)1755,1698,1603,1449,1425,1359,1212,1129,1086,1025,988,972,700；ESI-MS:(m/z)(M++H)276.1；HRMScalcd for C12H12F3NNaO3(M+Na)298.0661,found 298.0664。
Figure GDA0002953696060000231
(化合物b1-25)：收率，54％，无色油状物；1H NMR(400MHz,CDCl3):δ7.34-7.27(m,2H),7.25-7.19(m,3H),3.57(tq,J＝7.2,1.2Hz,2H),3.00(t,J＝8.4Hz,2H),2.84(t,J＝7.6Hz,2H),1.58-1.47(m,2H),1.35-1.25(m,2H),0.93(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3):δ171.5,140.5,128.5,128.4,126.3,122.0(q,J＝260.5Hz),43.4,36.7(q,J＝3.8Hz),31.0,30.8,19.8,13.6；19F NMR(376MHz,CDCl3):δ-51.37(s,3F)；IR(KBr):v(cm-1)3065,3030,2963,2936,2875,1705,1605,1497,1455,1380,1313,1215,1131,749,700；EIMS:m/z(rel intensity)273(M+,14),231(38),224(5),183(9),182(8),135(64),133(26),105(100),104(42),97(25),91(76),77(30),69(35),51(9)；HRMS calcd for C14H18F3NO(M):273.1340,found:273.1345。
Figure GDA0002953696060000232
(化合物b1-26)：收率，57％，无色油状物；1H NMR(400MHz,CDCl3):δ7.33-7.27(m,2H),7.24-7.19(m,3H),3.09(q,J＝2.4Hz,3H),3.00(t,J＝7.2Hz,2H),2.84(t,J＝8.0Hz,2H)；13C NMR(100MHz,CDCl3):δ171.7,140.4,128.5,128.4,126.3,121.7(q,J＝258.9Hz),36.8(q,J＝3.8Hz),30.8,29.6(q,J＝2.3Hz)；19F NMR(376MHz,CDCl3):δ-53.02(s,3F)；IR(KBr):v(cm-1)3065,3030,2961,1709,1604,1497,1454,1436,1382,1318,1141,1095,751,700；EIMS:m/z(rel intensity)231(M+,69),135(12),133(30),105(100),104(48),103(16),91(81),79(13),78(14),77(22),69(17),51(10)；HRMScalcd for C11H12F3NO(M):231.0871,found:231.0874。
Figure GDA0002953696060000233
(化合物b1-27)：收率，47％，无色油状物；1H NMR(400MHz,CDCl3):δ3.55(tq,J＝7.6,2.0Hz,2H),3.08-2.97(m,1H),1.94-1.72(m,6H),1.65-1.48(m,4H),1.34-1.24(m,6H),0.88(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3):δ176.7,122.1(q,J＝259.7Hz),43.7,43.5(q,J＝3.1Hz),31.5,31.3,29.0,26.2,22.5,13.9；19F NMR(376MHz,CDCl3):δ-50.53(s,3F)；IR(KBr):v(cm-1)2959,2936,2873,1702,1455,1382,1357,1303,1250,1195,1131,1038；EIMS:m/z(rel intensity)265(M+,3),224(21),196(9),182(32),140(5),135(6),98(11),97(100),69(100),55(13)；HRMS calcd for C13H22F3NO(M):265.1653,found:265.1660。
Figure GDA0002953696060000241
(化合物b1-28)：收率，34％，无色油状物；H NMR(400MHz,CDCl3):δ7.32(s,4H),2.10(s,3H)；13C NMR(100MHz,CDCl3):δ169.7,149.9(q,J＝1.6Hz),134.0,130.9,122.0(q,J＝1.5Hz),120.3(q,J＝256.7Hz),120.0(q,J＝262.2Hz),24.0(q,J＝2.3Hz)；19F NMR(376MHz,CDCl3):δ-53.72(s,3F),-57.96(s,3F)；IR(KBr):v(cm-1)1732,1511,1437,1374,1341,1318,1263,1170,1004,980,922,856；EIMS:m/z(rel intensity)287(M+,1),273(3),245(100),225(9),202(5),176(28),156(10),135(17),123(9),121(9),105(12),91(8),77(6),69(15)；HRMS calcd for C10H7F6NO2(M):287.0381,found:287.0378。
Figure GDA0002953696060000242
(化合物b1-29)：收率，66％，无色油状物；1H NMR(400MHz,CDCl3):δ7.52-7.46(m,3H),7.45-7.39(m,2H),3.62(tq,J＝7.6,1.2Hz,2H),1.72-1.62(m,2H),1.36-1.21(m,4H),0.88(t,J＝7.2,3H)；13C NMR(100MHz,CDCl3):δ170.6,135.5,131.0,128.3,127.1,121.9(q,J＝261.0Hz),45.6,28.7,28.6,22.1,13.8；19F NMR(376MHz,CDCl3):δ-52.85(s,3F)；IR(KBr):v(cm-1)3064,2960,2935,2874,1695,1603,1467,1448,1369,1338,1260,1197,1147,1102,722,698；EIMS:m/z(rel intensity)259(M+,3),237(3),219(2),190(8),173(16),148(12),145(9),139(23),111(8),105(100),77(36),51(8)；HRMS calcd for C13H16F3NO(M):259.1184,found:259.1187。
Figure GDA0002953696060000243
(化合物b1-30)：收率，35％，白色油状物；1H NMR(400MHz,CDCl3):δ7.50-7.46(m,3H),7.31-7.26(m,2H),2.00(s,3H)；13C NMR(100MHz,CDCl3):δ170.2,136.0,129.9,129.8,129.3(q,J＝1.5Hz),120.1(q,J＝261.8Hz),24.0(q,J＝2.2Hz)；19F NMR(376MHz,CDCl3):δ-54.32(s,3F)；IR(KBr):v(cm-1)3068,1730,1595,1493,1456,1431,1372,1312,1270,1238,1147,1075,1035,1005,977,927,914,774,744,699,669；EIMS:m/z(rel intensity)203(M+,1),183(3),162(20),161(100),142(17),141(63),119(18),114(5),95(9),91(24),77(11),69(12),65(11),51(8)；HRMS calcd for C9H8F3NO(M)203.0558,found:203.0550。
Figure GDA0002953696060000244
(化合物b1-31)：收率，39％，白色固体，熔点：34.6-34.9℃；1H NMR(400MHz,CDCl3):δ7.51-7.45(m,3H),7.30-7.26(m,2H),2.10(t,J＝7.6Hz,2H),1.63-1.52(m,2H),1.35-1.15(m,20H),0.88(t,J＝6.8Hz,3H)；13C NMR(100MHz,CDCl3):δ173.1,135.7,129.9,129.8,129.5,120.1(q,J＝262.7Hz),35.6(q,J＝2.7Hz),31.9,29.6,29.6,29.6,29.5,29.3,29.3,29.2,28.9,24.3,22.7,14.1；19F NMR(376MHz,CDCl3):δ-54.48(s,3F)；IR(KBr):v(cm-1)2925,2854,1727,1594,1493,1456,1412,1370,1304,1249,1151,1074,1005,975,773,702,667,521；EIMS:m/z(rel intensity)371(M+,1),211(28),203(4),178(3),161(100),141(6),123(13),95(38),85(9),71(11),69(10),57(15),55(12)；HRMS calcd for C21H32F3NO(M)371.2436,found:371.2441。
Figure GDA0002953696060000251
(化合物b1-32)：收率，66％，无色油状物；[α]D＝-1.1(c＝1.300,CHCl3,25℃).1H NMR(400MHz,CDCl3):δ6.26(br,1H),3.90(d,J＝10.0Hz,1H),3.82-3.70(m,1H),2.60-2.46(m,1H),1.85(d,J＝11.2Hz,2H),1.73-1.61(m,2H),1.61-1.53(m,1H),1.51(s,9H),1.42-1.30(m,2H),1.27-1.08(m,3H),1.04(d,J＝6.8Hz,3H),0.90(d,J＝6.8Hz,3H)；13C NMR(100MHz,CDCl3):δ168.0,152.2,121.0(q,J＝260.9Hz),84.5,66.1,47.9,32.7,27.8,27.4,25.5,24.6,24.5,21.2,19.1；19F NMR(376MHz,CDCl3):δ-53.55(s,3F)；IR(KBr):v(cm-1)3338,2976,2933,2856,1735,1719,1664,1534,1475,1451,1370,1350,1255,1155,1055,1027,937,849,777；ESI-MS:(m/z)(M++H)367.2；HRMS calcd forC17H29F3N2NaO3(M+Na)389.2022,found 389.2025。
Figure GDA0002953696060000252
(化合物b1-33)：收率，94％，无色油状物；[α]D＝-84.8(c＝1.220,CHCl3,25℃).1H NMR(400MHz,CDCl3):δ7.32-7.20(m,3H),7.19-7.14(m,2H),5.03(dd,J＝10.4,5.2Hz,1H),3.77(s,3H),3.52(dd,J＝14.4,5.2Hz,1H),3.13(dd,J＝14.4,10.4Hz,1H),2.21(q,J＝2.0Hz,3H)；13C NMR(100MHz,CDCl3):δ169.6,169.2,136.8,129.2,128.5,126.9,121.4(q,J＝260.9Hz),58.1,52.7,35.6,22.9(q,J＝4.6Hz)；19F NMR(376MHz,CDCl3):δ-51.03(s,3F)；IR(KBr):v(cm-1)3031,2955,1751,1712,1606,1497,1438,1374,1331,1291,1266,1229,1140,1041,1006,758,748,700；EIMS:m/z(rel intensity)289(M+,2),258(2),188(21),162(100),161(26),131(44),123(6),117(5),103(8),91(38),77(6),65(8)；HRMS calcd for C13H14F3NO3(M):289.0926,found:289.0920。
Figure GDA0002953696060000261
(化合物b1-34)：收率，66％，无色油状物；1H NMR(400MHz,CDCl3):δ7.64-7.60(m,2H),7.54-7.48(m,1H),7.46-7.40(m,2H),7.03-6.99(m,2H),6.96-6.91(m,1H),4.56-4.46(m,1H),4.29-4.23(m,1H),3.85-3.79(m,1H),2.25(s,6H),1.58(d,J＝6.8Hz,3H)；13C NMR(100MHz,CDCl3):δ171.0,155.1,135.9,131.3,130.8,128.9,128.3,127.3,124.1,121.7(q,J＝261.8Hz),72.3,54.5,16.4,16.2；19F NMR(376MHz,CDCl3):δ-51.00(s,3F)；IR(KBr):v(cm-1)3062,2981,2944,1694,1602,1477,1449,1380,1335,1200,1136,1092,1028,1004,871,791,770,725,699；ESI-MS:(m/z)(M++H)352.2；HRMS calcdfor C19H21F3NO2(M+H)352.1519,found352.1521。
Figure GDA0002953696060000262
(化合物b1-35)：收率，23％，无色油状物；1H NMR(400MHz,CDCl3):δ7.58-7.53(m,2H),7.52-7.46(m,1H),7.44-7.38(m,2H),7.19-7.15(m,1H),7.02-6.97(m,1H),6.89(s,1H),3.00-2.78(m,3H),2.34-2.27(m,1H),1.94-1.86(m,1H),1.84-1.25(m,9H),1.24(s,6H),1.22(s,3H),1.02(s,3H)；13C NMR(100MHz,CDCl3):δ171.8,147.2,145.7,135.8,134.6,131.3,128.2,127.7,126.9,123.9,123.8,121.8(q,J＝259.6Hz),53.7,46.2,39.1,38.2,37.7,36.5,33.4,30.0,25.6,24.0,23.9,19.4,18.5,18.1；19F NMR(376MHz,CDCl3):δ-47.97(s,3F)；IR(KBr):v(cm-1)3060,2959,2869,1695,1602,1497,1448,1419,1378,1352,1243,1167,1139,1059,975,951,822,793,729,697,669,650,629；ESI-MS:(m/z)(M++H)458.3；HRMS calcd for C28H35F3NO(M+H)458.2665,found 458.2670。
Figure GDA0002953696060000263
(化合物b1-36)：收率，87％，无色油状物；[α]D＝87.6(c＝0.330,CHCl3,25℃).1H NMR(400MHz,CDCl3):δ7.40-7.23(m,8H),7.18-7.14(m,2H),6.69(d,J＝7.6Hz,1H),5.63(s,1H),5.20-5.13(m,1H),3.05(dd,J＝5.2,12.8Hz,2H),2.95(dd,J＝8.8,12.8Hz,1H),2.83(s,3H),2.60(s,3H),1.46(s,9H)；13C NMR(100MHz,CDCl3):δ170.4,166.7,151.2,136.0,134.5,129.5,128.9,128.8,128.6,128.5,127.1,121.0(q,J＝260.9Hz),84.5,62.6,50.7,39.5,36.8,35.5,27.9；19F NMR(376MHz,CDCl3):δ-53.17(s,3F)；IR(KBr):v(cm-1)3392,3293,3030,2980,2934,1740,1687,1647,1497,1454,1397,1352,1253,1153,1049,1031,848,746,700；ESI-MS:(m/z)(M++H)494.3；HRMS calcd forC25H31F3N3O4(M+H)494.2261,found 494.2265。
Figure GDA0002953696060000271
(化合物b1-37)：收率，63％，无色油状物；[α]D＝-69.3(c＝0.600,CHCl3,25℃).1H NMR(400MHz,CDCl3):δ7.32-7.19(m,5H),6.43(br,1H),4.91(dd,J＝10.4,5.2Hz,1H),4.23(q,J＝7.2Hz,2H),4.07(qd,J＝10.4,4.8Hz,2H),3.60(dd,J＝14.4,4.8Hz,1H),3.07(dd,J＝14.4,10.4Hz,1H),1.38(s,9H),1.29(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3):δ169.4,169.1,150.9,137.0,129.4,128.5,126.9,120.8(q,J＝261.8Hz),84.7,61.6,60.5,41.7,35.2(q,J＝1.4Hz),27.7,14.1；19F NMR(376MHz,CDCl3):δ-52.85(s,3F)；IR(KBr):v(cm-1)3369,3031,2982,2938,1743,1683,1522,1456,1396,1351,1251,1155,1057,1032,848,752,701；ESI-MS:(m/z)(M++Na)441.2；HRMS calcdfor C19H25F3N2NaO5(M+Na)441.1608,found 441.1610。
Figure GDA0002953696060000273
(化合物b1-38)：收率，56％，白色固体，熔点：122.1-122.5℃；1H NMR(400MHz,CDCl3):δ8.07(d,J＝2.4Hz,1H),7.88(dd,J＝8.0,1.2Hz,1H),7.58-7.52(m,1H),7.49-7.43(m,1H),7.41-7.34(m,2H),7.04(d,J＝8.4Hz,1H),5.19(s,2H),3.88(s,2H),3.12(q,J＝2.0Hz,3H)；13C NMR(100MHz,CDCl3):δ190.7,170.4,160.5,140.4,136.6,135.5,132.7,132.6,129.5,129.2,127.8,127.2,125.1,121.7(q,J＝260.0Hz),121.0,73.6,40.6(q,J＝4.5Hz),29.9(q,J＝1.8Hz)；19F NMR(376MHz,CDCl3):δ-52.56(s,3F)；IR(KBr):v(cm-1)1716,1639,1612,1595,1571,1493,1457,1422,1362,1290,1197,1143,1089,1014,943,771；EIMS:m/z(rel intensity)349(M+,40),224(19),223(100),195(7),194(7),177(4),165(16),152(9),115(4),89(5),77(3),69(3),51(2)；HRMScalcd for C18H14F3NO3(M):349.0926,found:349.0932。
Figure GDA0002953696060000272
(化合物b1-39)：收率，75％，无色油状物；[α]D＝-39.5(c＝1.400,CHCl3,25℃).1H NMR(400MHz,CDCl3):δ7.31-7.20(m,3H),7.18-7.12(m,2H),5.20-5.12(m,1H),4.62-4.53(m,1.7H),4.33(AB,J＝16.4Hz,0.65H),4.26(d,J＝2.4Hz,1H),4.23(d,J＝8.0Hz,1H),4.04(d,J＝11.6Hz,0.65H),3.91(dd,J＝13.2Hz,J＝2.0Hz,1H),3.76(d,J＝12.8Hz,1H),3.59-3.50(m,1H),3.21-3.07(m,1H),2.18(s,3H),1.54-1.45(m,6H),1.36-1.31(m,6H)；13C NMR(100MHz,CDCl3):δ206.9,169.0/168.9,168.5/168.4,136.5,129.3/129.2,128.5,127.0,121.4(q,J＝260.9Hz),109.2/109.1,108.8,101.1,70.7,70.3,69.9,66.2/66.0,61.3,58.0/57.8,35.7,30.9,26.4,25.8,25.2,24.0,22.8(m)；19F NMR(376MHz,CDCl3):δ-50.46(s,1.89F),-50.61(s,1.11F)；IR(KBr):v(cm-1)1755,1712,1606,1497,1455,1375,1329,1254,1208,1072,1019,886,739,701；ESI-MS:(m/z)(M++NH4)535.3；HRMS calcd for C24H30F3NNaO8(M+Na)540.1816,found540.1820。
Figure GDA0002953696060000281
(化合物b1-40)：收率，40％，白色固体，熔点：269.1-269.6℃；[α]D＝18.6(c＝2.520,CHCl3,25℃).1H NMR(400MHz,CDCl3):δ3.06(q,J＝2.0Hz,3H),2.95-2.78(m,3H),2.63-2.40(m,2H),2.40-1.79(m,14H),1.66-1.54(m,1H),1.44-1.20(m,7H),1.06(s,3H),0.83(d,J＝6.4Hz,3H)；13C NMR(100MHz,CDCl3):δ211.9,209.0,208.7,172.8,121.7(q,J＝260.0Hz),56.8,51.7,48.9,46.8,45.6,45.5,44.9,42.7,38.6,36.4,35.9,35.4,35.2,32.1(q,J＝4.6Hz),30.3,29.6(q,J＝2.8Hz),27.5,25.1,21.8,18.6,11.8；19F NMR(376MHz,CDCl3):δ-52.96(s,3F)；IR(KBr):v(cm-1)1705,1470,1434,1383,1343,1317,1288,1139,1117,1088,1005；ESI-MS:(m/z)(M++H)484.3；HRMS calcd for C26H36F3NNaO4(M+Na)506.2489,found 506.2494。
Figure GDA0002953696060000282
(化合物b1-41)：收率，40％，无色油状物；[α]D＝-7.7(c＝1.780,CHCl3,25℃).1H NMR(400MHz,CDCl3):δ7.40-7.32(m,5H),6.33(br,1H),5.27(AB,J＝14.8Hz,2H),4.79(q,J＝7.2Hz,1H),3.95-3.82(m,2H),1.56(d,J＝6.8Hz,3H),1.46(s,9H)；13C NMR(100MHz,CDCl3):δ169.0,168.5,152.4,134.6,128.7,128.6,128.0,120.8(q,J＝262.7Hz),82.5,69.2,54.7,42.2,28.0,15.0；19F NMR(376MHz,CDCl3):δ-53.53(s,3F)；IR(KBr):v(cm-1)3369,3067,3035,2981,2947,1732,1682,1537,1456,1393,1337,1153,1068,1020,845,752,698；ESI-MS:(m/z)(M++Na)427.1；HRMS calcd forC18H23F3N2NaO5(M+Na)427.1451,found 427.1454。
Figure GDA0002953696060000283
(化合物b1-42)：收率，72％，无色油状物；[α]D＝-63.7(c＝2.830,CHCl3,25℃).1H NMR(400MHz,CDCl3):δ7.38-7.28(m,5H),6.80(d,J＝8.8Hz,1H),5.22-5.07(m,2H),4.71-4.64(m,1H),4.54(dd,J＝8.4,4.8Hz,1H),4.12(q,J＝1.6Hz,2H),3.88-3.78(m,1H),3.70-3.62(m,1H),2.28-2.15(m,1H),2.08-1.90(m,3H),1.90-1.75(m,1H),1.60-1.50(m,1H),1.49(s,9H),1.17-1.02(m,1H),0.96(d,J＝6.8Hz,3H),0.85(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3):δ171.6,170.6,167.0,151.1,135.5,128.5,128.3,128.1,120.6(q,J＝260.4Hz),84.2,66.8,59.0,54.7,47.4,46.9,38.0,29.0,27.9,24.8,24.2,15.1,11.0；19F NMR(376MHz,CDCl3):δ-54.98(s,3F)；IR(KBr):v(cm-1)3288,3066,2971,2935,2879,1747,1697,1627,1542,1455,1369,1262,1216,1162,1054,857,737；ESI-MS:(m/z)(M++H)544.3；HRMS calcd for C26H37F3N3O6(M+H)544.2629,found 544.2629。
Figure GDA0002953696060000291
(化合物b1-43)：收率，61％，无色油状物；1H NMR(400MHz,CDCl3):δ2.64-2.56(m,1H),2.52(t,J＝7.6Hz,2H),1.71-1.61(m,2H),1.39-1.24(m,4H),1.04-0.97(m,2H),0.90(t,J＝7.2Hz,3H),0.79-0.73(m,2H)；13C NMR(100MHz,CDCl3):δ174.5,121.7(q,J＝261.0Hz),35.8(q,J＝2.9Hz),31.2,25.9,24.4,22.4,13.9,8.9(q,J＝2.2Hz)；19F NMR(376MHz,CDCl3):δ-52.43(s,3F)；IR(KBr):v(cm-1)3021,2960,2934,2874,1721,1461,1416,1364,1328 1269,1203,1135,1040,1029,955,883,833,726,689,598；ESI-MS:(m/z)(M++H)223.1；HRMS calcd for C10H16F3NO(M+H)223.1184,found 223.1193。
Figure GDA0002953696060000292
(化合物b2-1)：收率，16％，无色油状物；1H NMR(400MHz,CDCl3):δ7.93-7.88(m,2H),7.71-7.64(m,1H),7.60-7.54(m,2H),3.11(q,J＝1.6Hz,3H)；13C NMR(100MHz,CDCl3):δ138.3,134.0,129.3,127.7,120.5(q,J＝261.8Hz),32.2；19F NMR(376MHz,CDCl3):δ-56.26(s,3F)；IR(KBr):v(cm-1)3071,2961,1586,1480,1450,1378,1313,1260,1177,1152,1089,1070,1026,920,747,718,688,595,566,507；ESI-MS:(m/z)(M++H)239；HRMS calcd for C8H8F3NO2S(M+H)239.0228,found 239.0232。
此外，本实施例还可进行以下演变：
1)所使用的2-氟吡啶可替换为4-氰基吡啶、2-三氟甲基吡啶、2,4,6-三甲基吡啶、2,3,4,5,6-五氟吡啶、吡啶、2-氟-5-溴吡啶、2-氟-4-氯吡啶、2-氰基-5-氟吡啶、2-氰基-6-氟吡啶、2-氰基-5-溴吡啶、2-氰基-6-甲氧基吡啶中的任意一种，其余条件保持不变。
2)所使用的三氟甲烷磺酸银可替换为硝酸银、三氟醋酸银中的任意一种，其余条件保持不变。
3)所使用的二氯甲烷和氯苯可以替换为二氯甲烷、氯苯、三氟甲基苯中的至少一种，其余条件保持不变。
对比例
对比例1
本对比例与实施例2中化合物b1-1制备方法的区别仅在于：反应体系中未加吡啶类配体：2-氟吡啶和含氧酸银盐：AgOTf，其余条件完全相同，结果无目标产物的生成，说明在没有吡啶类配体和含氧酸银盐参与下，本发明所述反应将不能发生。
对比例2
本对比例与实施例2中化合物b1-1制备方法的区别仅在于：反应体系中未加含氧酸银盐：AgOTf，其余条件完全相同，结果无目标产物的生成，说明在没有含氧酸银盐参与下，本发明所述反应将不能发生。
对比例3
本对比例与实施例2中化合物b1-1制备方法的区别仅在于：反应体系中未加氟化试剂：CsF，其余条件完全相同，结果无目标产物的生成，说明在没有氟化试剂参与下，本发明所述反应将不能发生。
对比例4
本对比例与实施例2中化合物b1-1制备方法的区别仅在于：反应体系中未加氧化剂：Selectfluor，其余条件完全相同，结果无目标产物的生成，说明在没有氧化剂参与下，本发明所述反应将不能发生。
对比例5
本对比例与实施例2中化合物b1-1制备方法的区别仅在于：反应体系中的银盐为非含氧酸银盐：AgBF4，配体为非吡啶类配体：胺配体
Figure GDA0002953696060000301
结果基本无目标产物的生成，说明只有在含氧酸银盐+吡啶类配体的体系下，本发明所述反应才能顺利进行。
最后需要在此指出的是：以上仅是本发明的部分优选实施例，不能理解为对本发明保护范围的限制，本领域的技术人员根据本发明的上述内容做出的一些非本质的改进和调整均属于本发明的保护范围。

Claims (5)

1.一种酰胺氮三氟甲基化合物的合成方法，其特征在于，包括如下反应：
Figure FDA0002953696050000011
即：由式a1或式a2化合物与三氟甲基化试剂在有机溶剂中、在氟化试剂、氧化剂、含氧酸银盐和吡啶类配体的作用下进行三氟甲基化反应，从而得到式b1或式b2所示的目标化合物；其中：
R1和R2分别独立选自C1-C20的烷基、ORa、取代或未取代的苯基、芳基、杂芳基、
Figure FDA0002953696050000012
Figure FDA0002953696050000013
中的任意一种；Ra选自C1-C6的烷基、苄基中的任意一种；R3选自C1-C6的烷基、苄基中的任意一种；R4选自氢、C1-C6的烷基、苯基、苄基中的任意一种；R5选自C1-C6的烷基；R6选自氢、C1-C6的烷基、苄基中的任意一种；R7选自C1-C6的烷基中的任意一种；R8选自C1-C6的烷基、苄基、取代或未取代的苯基中的任意一种；R9选自C1-C6的烷基中的任意一种；R10选自C1-C6的烷基、苄基中的任意一种；R11和R12分别独立选自C1-C6的烷基中的任意一种；R13选自C1-C6的烷基中的任意一种；R14选自C1-C6的烷基、苄基中的任意一种；
所述三氟甲基化试剂为三氟甲基三氟硅烷；所述氟化试剂为碱金属氟化物；所述氧化剂为Selectfluor；所述吡啶类配体选自4-氰基吡啶、2-三氟甲基吡啶、2,4,6-三甲基吡啶、2,3,4,5,6-五氟吡啶、2-氟吡啶、吡啶、2-氟-5-溴吡啶、2-氟-4-氯吡啶、2-氰基-5-氟吡啶、2-氰基-6-氟吡啶、2-氰基-5-溴吡啶、2-氰基-6-甲氧基吡啶中的任意一种；所述含氧酸银盐选自三氟甲烷磺酸银、硝酸银、三氟醋酸银中的任意一种。
2.根据权利要求1所述的合成方法，其特征在于：R1和R2分别独立选自C1-C16的烷基、ORa、苯基、
Figure FDA0002953696050000021
Figure FDA0002953696050000022
Figure FDA0002953696050000023
中的任意一种；Ra选自C1-C6的烷基、苄基中的任意一种；Rb选自卤素、氰基、C1-C6的烷基、C1-C6的烷氧基、苄氧基、三氟甲氧基、三氟甲基、COORc中的任意一种，Rc选自C1-C6的烷基中的任意一种；R3选自C1-C6的烷基、苄基中的任意一种；R4选自氢、C1-C6的烷基、苯基、苄基中的任意一种；R5选自C1-C6的烷基、苄基中的任意一种；R6选自氢、C1-C6的烷基、苄基中的任意一种；R7选自C1-C6的烷基中的任意一种；R8选自C1-C6的烷基、苄基、苯基或C1-C6的烷基取代的苯基中的任意一种；R9选自C1-C6的烷基中的任意一种；R10选自C1-C6的烷基、苄基中的任意一种；R11和R12分别独立选自C1-C6的烷基中的任意一种；R13选自C1-C6的烷基中的任意一种；R14选自C1-C6的烷基、苄基中的任意一种。
3.根据权利要求1所述的合成方法，其特征在于：所述有机溶剂为非配位性有机溶剂，选自二氯甲烷、氯苯、三氟甲基苯中的至少一种。
4.根据权利要求1所述的合成方法，其特征在于：所述含氧酸银盐与式a1或式a2化合物的摩尔比为1:1-2:1，所述吡啶类配体与式a1或式a2化合物的摩尔比为1:1-2:1。
5.根据权利要求1所述的合成方法，其特征在于，包括如下操作步骤：
将式a1或式a2化合物、氧化剂、含氧酸银盐、氟化试剂加入到反应器中，抽换气使反应器中处于惰性气体保护氛围；在惰性气体保护下，加入适宜有机溶剂、三氟甲基化试剂和吡啶类配体；使反应体系混合均匀，室温反应；反应结束后，向反应体系中加入水，然后使用有机溶剂萃取，对萃取液进行饱和食盐水洗涤，对洗涤后的有机相进行干燥、浓缩和柱层析，即得到式b1或式b2所示的目标化合物。
CN202010201894.6A 2020-03-20 2020-03-20 一种酰胺氮三氟甲基化合物的合成方法 Active CN111302968B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010201894.6A CN111302968B (zh) 2020-03-20 2020-03-20 一种酰胺氮三氟甲基化合物的合成方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010201894.6A CN111302968B (zh) 2020-03-20 2020-03-20 一种酰胺氮三氟甲基化合物的合成方法

Publications (2)

Publication Number Publication Date
CN111302968A CN111302968A (zh) 2020-06-19
CN111302968B true CN111302968B (zh) 2021-06-08

Family

ID=71162268

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010201894.6A Active CN111302968B (zh) 2020-03-20 2020-03-20 一种酰胺氮三氟甲基化合物的合成方法

Country Status (1)

Country Link
CN (1) CN111302968B (zh)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0057588A2 (en) * 1981-02-02 1982-08-11 Monsanto Company Process for producing N-(halomethyl)acylamides
KR850001601B1 (ko) * 1980-12-01 1985-10-24 몬산토 캄파니 N-(할로메틸)아씰아미드류의 제조방법

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3906034A (en) * 1972-03-21 1975-09-16 Hoechst Ag Trifluoromethyl-salicylanilides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR850001601B1 (ko) * 1980-12-01 1985-10-24 몬산토 캄파니 N-(할로메틸)아씰아미드류의 제조방법
EP0057588A2 (en) * 1981-02-02 1982-08-11 Monsanto Company Process for producing N-(halomethyl)acylamides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CuCl-catalyzed ortho trifluoromethylation of arenes and heteroarenes with a pivalamido directing group;Chanjuan Xi等;《Chem. Commun.》;20131231;第49卷;第4552-4554页 *

Also Published As

Publication number Publication date
CN111302968A (zh) 2020-06-19

Similar Documents

Publication Publication Date Title
CN106279074B (zh) 一种化合物及其制备方法和在合成布瓦西坦中的用途
CN116478022A (zh) 一种炔酰胺介导的酮类化合物的制备方法
CN107325018B (zh) β-三氟甲基烯胺衍生物及其制备方法
CN111302968B (zh) 一种酰胺氮三氟甲基化合物的合成方法
CN106749071B (zh) 一种芳香类1,2,4,5-四嗪化合物的制备方法
CN111925356B (zh) 手性喹啉-咪唑啉配体的合成方法及其应用
RU2414449C2 (ru) Новый способ получения 6-[3-(1-адамантил)-4-метоксифенил]-2-нафтойной кислоты
Ishizuka et al. An efficient method for the preparation of enantiomerically pure N-acylarylsulfonamides having an asymmetric center at the α-position: Condensation of acid chlorides and arylsulfonamides under solid-liquid two-phase conditions
CN110790689B (zh) 一种1,1-二氟-2-异腈-乙基苯基砜类化合物的合成方法
CN110003081B (zh) 一种多氟烷基取代的吲哚啉和四氢异喹啉的合成方法
CN113416162B (zh) 一种双手性联萘o-n-n三齿配体及其制备方法
CN111566116B (zh) 新型金属配合物、其制造方法及利用其的γ-内酰胺化合物的制造方法
CN110028448B (zh) 一种3-羟基-2,3-二氢异喹啉-1,4-二酮化合物的制备方法
CN111116420B (zh) 一种对称脲类化合物的制备方法
JP5928971B2 (ja) カルボン酸アミドの製法
CN103613513B (zh) 盐酸米那普仑中间体及其制备方法和应用
CN112898202A (zh) 一种杂环基并环丙烷化合物、合成方法
CN113214104A (zh) 一种合成芳香乙酰胺的方法
JP2544926B2 (ja) 新規なホスフイノピロリジン化合物およびそれを用いた不斉合成法
US6284912B1 (en) Process for synthesizing para-and/or meta-substituted cyanophenyalanine derivatives
JP6588924B2 (ja) ルテニウムの触媒作用によってアニリド類からビフェニルアミン類を製造する方法
CN114560838B (zh) 一种2-氨基-3-甲酰基色酮类化合物的制备方法
CN107954886A (zh) 一种制备抗心衰脑啡肽酶抑制剂沙库必曲中间体的方法
CN1055460C (zh) C-取代二亚乙基三胺的制备方法
CN110590641B (zh) 一种3-羟基异吲哚-1-酮系列化合物的绿色制备方法

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant