阅读说明：本技术 卡博替尼中间体的制备方法 (Preparation method of cabozantinib intermediate ) 是由 谷琦琦 金子 邱新光 张增梅 徐海莉 毛宏伟 于 2019-07-09 设计创作，主要内容包括：本发明提供了一种卡博替尼中间体的制备方法,包括,1-(甲氧羰基)环丙烷甲酸与4-((6,7-二甲氧基喹啉-4-基)氧基)苯胺进行成酰胺反应,得到1-((4-((6,7-二甲氧基喹啉-4-基)氧基)苯基氨甲酰基)环丙烷甲酸甲酯。该方法可在一锅中进行,本发明克服了现有技术的偏见,从酰卤法中筛选到一种制备酰胺的方法,该方法的摩尔收率反而可高达95％,纯度可高达98％,后处理亦非常简单。(The invention provides a preparation method of a cabozantinib intermediate, which comprises the step of carrying out amide forming reaction on 1- (methoxycarbonyl) cyclopropane formic acid and 4- ((6, 7-dimethoxyquinoline-4-yl) oxy) aniline to obtain 1- ((4- ((6, 7-dimethoxyquinoline-4-yl) phenylcarbamoyl) cyclopropane methyl formate.)

1. A preparation method of cabozantinib intermediate comprises the steps of carrying out acyl chlorination reaction on 1- (methoxycarbonyl) cyclopropane carboxylic acid and trichloromethyl carbonate, and then carrying out amide forming reaction on the 1- (methoxycarbonyl) cyclopropane carboxylic acid and 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) aniline to obtain 1- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenylcarbamoyl) cyclopropane carboxylic acid methyl ester.

2. The process according to claim 1, wherein the molar ratio of 1- (methoxycarbonyl) cyclopropanecarboxylic acid to trichloromethyl carbonate is 1:0.4-0.5, such as 1: 0.45-0.5.

3. The process according to claim 1 or 2, wherein the acid chlorination is carried out in the presence of imidazole.

4. A process according to claim 3, wherein the molar ratio of imidazole to 1- (methoxycarbonyl) cyclopropanecarboxylic acid is from 0.03 to 0.05:1, e.g. 0.04: 1.

5. The process according to any one of the preceding claims, characterized in that the acylchlorination reaction is carried out at a melting temperature of, for example, 100 ℃ and 120 ℃ and then, for example, 110 ℃.

6. A process according to any preceding claim, wherein the molar ratio of 1- (methoxycarbonyl) cyclopropanecarboxylic acid to 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) aniline is from 1.05 to 1.15:1, such as from 1.05 to 1.1: 1.

7. a process according to any preceding claim, wherein 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) aniline is subjected to the amide-forming reaction in the presence of water and an inorganic base, such as sodium carbonate.

8. The process according to any one of the preceding claims, wherein the molar ratio of 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) aniline to the inorganic base is from 1:1 to 2, such as 1: 1.5.

9. A process according to any preceding claim, wherein the post-treatment of the amide-forming reaction comprises: the reaction mixture was extracted with ethyl acetate.

Technical Field

The invention relates to a preparation method of a cabozantinib intermediate.

Background

The research of metabolites has important significance in many fields of medical pharmacy, such as (1) research, development and design of new drugs, (2) clinical drug detection, (3) research on bioavailability and bioequivalence of pharmaceutical preparations, and (4) toxicology research, L u Anthony Y.H indicates that one of the most challenging research subjects in drug metabolism is to clarify the reasons of individual reaction difference in drug treatment and the mechanism that individual difference in drug metabolism influences treatment effect and causes toxic and side effects, so as to really realize safety, reasonability and individualization of clinical medication.

Cabozantinib has been approved to be marketed abroad several years ago and is currently used for treating medullary thyroid cancer, renal cell carcinoma, liver cancer and the like, but has not been approved to be marketed domestically so far. In the future, patients with advanced and recurrent medullary thyroid cancer have no standard treatment scheme, and China has clinical blank in the treatment field. The data show that the sense metabolite of cabozantinib includes methyl 1- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) carbamoyl) cyclopropanecarboxylate, which is an amide. At present, the method for synthesizing amide is very many, the most traditional acyl halide method is not popular due to the fact that the reaction steps are many, the yield is low, the reaction control is complex and the like, and the most popular method is a condensing agent method, and the method is high in yield and simple in reaction condition.

Disclosure of Invention

The invention overcomes the prejudice of the prior art, and the method for preparing the amide by screening in the acyl halide method has the advantages that the molar yield can reach 95 percent, the purity can reach 98 percent, and the post treatment is very simple.

In order to achieve the purpose, the invention adopts the technical scheme that:

a preparation method of a cabozantinib intermediate comprises the amide forming reaction of 1- (methoxycarbonyl) cyclopropane carboxylic acid and 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) aniline, i.e. a reaction aimed at the preparation of an amide product, to give methyl 1- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenylcarbamoyl) cyclopropanecarboxylate, which process may be carried out in one pot, optionally, the amide-forming reaction comprises, 1- (methoxycarbonyl) cyclopropanecarboxylic acid is first acylchlorinated with trichloromethyl carbonate before reaction with 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) aniline, after which it can be filtered and used directly in the next reaction.

Optionally, the molar ratio of 1- (methoxycarbonyl) cyclopropanecarboxylic acid to trichloromethyl carbonate is 1:0.4-0.5, such as 1: 0.45.

optionally, the acid chlorination reaction is carried out in the presence of imidazole.

Optionally, the molar ratio of imidazole to 1- (methoxycarbonyl) cyclopropanecarboxylic acid is from 0.03 to 0.05:1, such as 0.04: 1.

Optionally, the acid chlorination reaction is conducted at a melt temperature, such as 100 ℃ to 120 ℃, and further such as 110 ℃. The reaction time may be 2 h.

Optionally, the molar ratio of 1- (methoxycarbonyl) cyclopropanecarboxylic acid to 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) aniline is 1.05-1.15:1, such as 1.1: 1.

optionally, the 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) aniline is subjected to an amide forming reaction in the presence of water and inorganic base, and the reaction time can be 2 h; optionally, the inorganic base may be sodium carbonate.

Optionally, the molar ratio of the 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) aniline to the inorganic base is from 1:1 to 2, such as 1: 1.5.

Optionally, the post-treatment of the amide forming reaction comprises: extracting the reactant mixed liquor by using ethyl acetate, and then crystallizing in a system containing acetone and water (for example, using the mixed liquor of acetone and water, the volume ratio of acetone to water can be 1:1), so as to obtain the 1- ((4- ((6, 7-dimethoxyquinoline-4-yl) phenylcarbamoyl) cyclopropane methyl formate.

The invention has the beneficial effects that:

the invention overcomes the prejudice of the prior art, and the method for preparing the amide by screening from the acyl halide method has the advantages that the molar yield can reach 95 percent, the purity can reach 98 percent, the post-treatment is very simple, and the effects are far superior to those of the prior art and are unexpected.

Detailed Description