CN105924390A

CN105924390A - Synthesis method of metafenib

Info

Publication number: CN105924390A
Application number: CN201610332374.2A
Authority: CN
Inventors: 林寨伟; 胡盼; 张世喜
Original assignee: Guangzhou Xin Xin Pharmaceutical Co Ltd; GUANGZHOU NANXIN PHARMACEUTICAL CO Ltd
Current assignee: Guangzhou Xin Xin Pharmaceutical Co Ltd; GUANGZHOU NANXIN PHARMACEUTICAL CO Ltd
Priority date: 2016-05-19
Filing date: 2016-05-19
Publication date: 2016-09-07
Anticipated expiration: 2036-05-19
Also published as: CN105924390B

Abstract

The invention relates to a synthesis method of an anti-cancer active compound-metafenib. The chemical name of metafenib is 4-4{4-[3-(4-chloro-3-trifluoromethylphenyl)urea]-3-flrophenoxy}pyridine-2-methnamide (the compound 1). Metafenib is prepared by taking 4-chloropyridine-2-carboxamide as a raw material through the two synthesis steps of a metal catalytic coupling reaction and an isocyanate addition reaction. Compared with existing methods reported in literatures, the method is effective and practical and can be enlarged for massive production, and the total yield of the product is obviously increased.

Description

A kind of synthetic method of Mei Tafeini

Technical field

The present invention relates to pharmaceutical synthesis field, be specifically related to the conjunction of the β-elemene Mei Tafeini of VEGFR, RAF targeting One-tenth method.

Background technology

VEGF (VEGF) is one of most important cell growth factor during tumor-blood-vessel growth, Tumor vessel is extremely sensitive to VEGF, and in a lot of tumor cells, VEGF mRNA concentration is significantly higher than normal cell, these Tumor includes pulmonary carcinoma.Mei Tafeini, chemical name is 4-{4-[3-(4-chloro-3-trifluoromethyl) urea]-3-fluorophenoxy } Pyridine-2-carboxamide, shown in structure such as following formula (compound 1), is a kind of effective VEGF and RAF inhibitors of kinases, thus is Potential effective β-elemene (evaluates weekly 2015.7.19-2015.7.25 see CDE).Meanwhile, according to Japan's Miyagi cancer Research center is reported, before clinic in Anticancer Activities, Mei Tafei you have and listed cancer therapy drug Rui Gefeini (Regorafenib) similar active anticancer.The research of domestic Preclinical Drug also demonstrate that it is real at people's liver tumor nude mice model Obvious antitumous effect (patent application CN102885814A) is had in testing.

Domestic Hunan Nan Xin pharmaceutical Co. Ltd independent development Mei Tafeini is as anti-lung cancer drug candidate, the most as 1 Kind new medicine obtains clinical official written reply.Therefore, pilot scale research sample the most from now on produces or production of raw medicine after listing, Technically have and improve technique further, reduce production cost, increase the requirement friendly spent of process environments.

In terms of the synthesis technique that existing and document describe, the rarely complete synthesis report of Mei Tafeini.Patent The method of CN102885814A report, relates to 4-chloropyridine-2-Methanamide and with the fluoro-PAP of 3-in DMF, at t- In the presence of BuOK, 165⁰C reacts, yield about 45%.It is apparent that this severe reaction conditions, relate to high temperature, highly basic reaction, Especially reaction dissolvent DMF Partial digestion with this understanding, it is difficult to recovery, causes environmental protection pressure.Meanwhile, yield is the most on the low side, When being not suitable for large-scale production.Foreign patent US 20050245530, it was recently reported that 4-chloropyridine-2-Methanamide and and the fluoro-4-of 3- Amino-phenol is at NMP(N-methylpiperidone) in, 250 0C compound 3 is synthesized, yield 50%, reaction condition is the most severe Carving, yield is the highest.

Metallic catalyst, as having the title of organic synthesis " welding apparatus " containing Ni metal, Pd compound or complex, can have Effect promotes the formation of C-C, C-N, C-O key in drug synthetic reaction, and some catalyst can also be some organic solvent reaction conversions For aqueous solvent phase reaction, become the important member in green chemistry (see document " copper catalysis aqueous phase Ullmann type couple Repercussion study is in progress ", organic chemistry, 2013,33,760-770), have in modern medicines and intermediate synthesize and extensively should With.In our invention, in Mei Tafeini synthesis step 1, the coupling reaction to aryl alkyl halide Yu phenol, have employed Buchwald Types of metals catalyst, result is effectively increased reaction yield, and the cost of catalyst own is the highest.In the 2nd step reaction, By compound 3 and 4-chloro-3-trifluoromethylbenzene based isocyanate reacting by heating in ethyl acetate, obtain through silica column purification Product, the yield moon 18%, hence it is evident that on the low side, is not suitable for industrialized production.The method that we use, uses instead at dichloromethane solvent, adds Hunig base catalysis, room temperature reaction, extend the response time, make yield bring up to 60%.2 step overall yield of reaction are compared CN102885814A(2 walks total recovery 8%), bring up to 40%, beneficially environmental protection.

Summary of the invention

Because situation described above, it is an object of the invention to overcome and ask present in existing Mei Tafeini synthetic method Topic, it is provided that a kind of react more effectively, Mei Tafeini synthetic method that cost is less expensive, more environmentally friendly.In order to realize this purpose, I For raw material, prepare Mei Tafeini through metal catalysed reaction with 4-chloropyridine-2-Methanamide (compound 2, commercially available).Work CuI, Cs in skill step₂CO₃, Phen or Me₄Phen(structure sees below formula) it is commercially available raw material.The synthesis road that we use Line such as following formula:

Wherein, organic ligand Phen, Me₄Phen has a following chemical structural formula:

Specifically comprise the following steps that

With raw material 4-chloropyridine-2-Methanamide (commercially available) as raw material, prepare 4-{4-[3-(4-through following process steps Chloro-3-trifluoromethyl) urea]-3-fluorophenoxy } pyridine-2-carboxamide (Mei Tafeini, compound 1):

Step 1: in dry reaction bulb, put into CuI, Cs₂CO₃, organic ligand Me₄Phen, compound 2, toluene.Mixing Under an argon atmosphere, the lower reaction of heating generates target product to thing.It is qualified that product crude product is recrystallized to give purity in ethyl acetate Intermediate.

Step 2: put into 4-chloro-3-trifluoromethylbenzene based isocyanate, DMF in reaction bulb.2-ammonia is dripped to reaction bulb Base formoxyl-4-((3-fluoro-4-amino) phenoxy group) dichloromethane solution of pyridine.Reactant liquor is stirred at room temperature reaction.Reaction Solvent is boiled off after completing.Remain in re-crystallizing in ethyl acetate and obtain compound 1 finished product.

In a preferred embodiment of the present invention, the solvent described in step 1 is toluene, DMF.Preferably toluene.Used urges Agent be mol ratio be 5%-10%CuI, 5-10% part Phen, Me₄Phen, preferably 5%CuI, 10%Me₄Phen.Reaction temperature For 70-120⁰C, preferably 80-85⁰C.Step 2 reaction dissolvent is dichloromethane, DMF, dichloromethane and DMF mixed solvent, excellent Selecting dichloromethane-DMF mixed solvent, catalysts is triethylamine, N, N-diisopropyl ethyl amine, preferably N, N-diisopropyl Ethylamine, the preferred 25-30 of reaction temperature⁰C。

Compared with prior art, the Advantageous Effects of the present invention is embodied in:

Compound 1 synthesizes through metal catalysed reaction step, mild condition, and yield is significantly improved, and improves yield, decreases Solvent usage amount, makes technical process more " green " environmental protection.And, these Optimal improvements so that always receive from compound I to finished product Rate reaches about 40%, compares the method that patent CN103058922 B describes, from compound 2 to Mei Tafeini synthesis total recovery only About 8%, yield is significantly improved.

Detailed description of the invention

Embodiment 1 2-carbamoyl-4-((3-fluoro-4-amino) phenoxy group) synthesis of pyridine (compound 4)

In dry reaction bulb, put into CuI(9.5g, 49.9mmoL), Cs₂CO₃(490.0g, 1504.0mmoL), Me₄Phen (24.0g, 101.6mmoL), compound 2(247.2 g, 1000mmoL), toluene (500mL).Mixture under an argon atmosphere, 80 - 85 ⁰24h is reacted under C oil bath.Being cooled to room temperature, add ethyl acetate (1500mL), reactant liquor is through one section of silicagel column Filtering, and wash filter cake, merging filtrate by ethyl acetate 500mL, decompression boils off filtrate solvent.Concentrated residues thing is at appropriate acetic acid In ethyl ester-petroleum ether, crystallization obtains white solid 173.1 g.Yield 70%.¹H NMR(400MHz, DMSO-d ₆): δ 5.21 (s, 2 H), 6.77 (dd, 1 H), 6.85 (t, 1 H), 7.01 (dd, 1 H), 7.10 (dd, 1 H), 7.34 (d, 1 H), 7.68 (br s, 1 H), 8.10 (br s, 1 H), 8.45 (d, 1 H); MS (ESI) m/z: 248.1 (M + H⁺)。

Embodiment 2 4-{4-[3-(4-chloro-3-trifluoromethyl) urea]-3-fluorophenoxy } pyridine-2-carboxamide (change Compound 1) synthesis

In reaction bulb, put into 4-chloro-3-trifluoromethylbenzene based isocyanate (26.6g, 120mmoL), DMF(50mL), N, N-bis- Diisopropylethylamine (2.6g, 20mmoL).It is slowly added dropwise 2-carbamoyl-4-((3-fluoro-4-amino to reaction bulb) benzene oxygen Base) dichloromethane (350mL) solution of pyridine (24.7g, 100mmoL).Reactant liquor is stirred at room temperature 24h to reaction completely.Steam Remove solvent.Remain in re-crystallizing in ethyl acetate and obtain 28.1 g white solids (compound 1), yield 60%.¹H NMR (400 MHz, DMSO-d ₆): δ 7.18 (d, 1H), 7.20 (m, 1H), 7.32 (m, 1H), 7.40 (d, 1H), 7.61 (d, 2H), 7.72(s, 1H), 8.18(m, 3H), 8.52(d, 1H), 8.73(s, 1H),9.51(s, 1H); MS(ESI) m/z: 469.1(M+H)⁺。

Claims

1. the synthetic method of Yi Zhong Mei Tafeini, it is characterised in that comprise the steps:

Step 1, synthesizes compound 3 by Buchwald catalytic coupling method: with the fluoro-PAP of compound 2 and 3-as raw material, With toluene or DMF as solvent, at CuI, Cs₂CO₃, organic ligand 1,10-phenanthroline (Phen) or 3,4,7,8-tetramethyl- 1,10-phenanthroline (Me₄Phen) under effect, 70⁰C – 120 ⁰C reacting generating compound 3；

Step 2, compound 3 and isocyanates carry out additive reaction synthesis compound 1: the chloro-3-trifluoromethylbenzene of compound 3 and 4- Based isocyanate is in DMF or dichloromethane, under triethylamine or N, N-diisopropyl ethyl amine (Hunig alkali) catalysis, in room Temperature is reacted and to be obtained thick product, obtains compound 1 after refining.

2. according to the synthetic method described in claim 1, it is characterised in that organic solvent described in step 1 is toluene.

3. according to the synthetic method described in claim 1, it is characterised in that catalyst described in step 1 is about 5% (mol ratio) CuI and 10% (mol ratio) Me₄Phen and 150%(mol ratio) Cs₂CO₃。

4. according to the synthetic method described in claim 1, it is characterised in that step 1 reaction temperature is 80 85⁰C。

5. according to the synthetic method described in claim 1, it is characterised in that the reaction dissolvent described in step 2 be dichloromethane with The mixed solvent of DMF, catalysts be Hunig alkali, reaction temperature be 25 30⁰C。