Preparation method of bosutinib

A technology of methoxyl and quinolinecarbonitrile, applied in the field of medicine and chemical industry, can solve the problems of low yield, achieve the effects of improving reaction conditions, stable properties, and facilitating the control of drug quality standards

Active Publication Date: 2016-04-20
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method is one of the current mainstream preparation methods, but the yield is low, especially for the preparation of the key intermediate 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy- The yield of 7-(3-chloropropoxy)-3-quinolinecarbonitrile (formula III) is only about 50%

Method used

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  • Preparation method of bosutinib
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  • Preparation method of bosutinib

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Embodiment 1: Preparation of 4-chloro-6-methoxy-7-(3-chloropropoxy)-3-quinolinecarbonitrile

[0035] Under nitrogen protection, add 33L of 1-methyl-2-pyrrolidone into a 50L enamel reaction kettle, and then add 3.30kg of 4-chloro-6-methoxy-7-hydroxy-3-quinolinecarbonitrile, 6.65kg of 1-bromo -3-chloropropane, 5.83kg anhydrous potassium carbonate, 99g dibenzo-18-crown-6-ether (4-chloro-6-methoxy-7-hydroxyl-3-quinolinecarbonitrile and 1-bromo The molar ratio of -3-chloropropane is 1:3); Under the protection of nitrogen, the temperature is controlled at 30°C-40°C and the reaction is stirred for more than 4 hours. TLC tracking monitors to 4-chloro-6-methoxy-7-hydroxyl-3- The quinolinecarbonitrile spots disappeared; the reaction solution was transferred to a 200L glass-lined reactor, and 66L of purified water I was slowly added under stirring at a temperature of 25-40°C; after the addition, the temperature was controlled at 25-35°C and stirred for 30 minutes; Wash with 10 L ...

Embodiment 2

[0036] Example 2: 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-(3-chloropropoxy)-3-quinolinecarbonitrile preparation

[0037] Under the protection of nitrogen, 20L dimethylacetamide was added to a 30L glass reactor, and 3.70kg2,4-dichloro-5-methoxyaniline, 1.48kg pyridine hydrochloride, 4.00kg4-chloro- 6-Methoxy-7-(3-chloropropoxy)-3-quinolinecarbonitrile (4-chloro-6-methoxy-7-(3-chloropropoxy)-3-quinolinecarbonitrile The molar ratio of nitrile to 2,4-dichloro-5-methoxyaniline is 2:3), stirred and heated at 90-100°C for more than 3 hours, followed by TLC until the spot of intermediate 1 disappeared. Cool the reaction solution to 20-30°C, transfer it to a 200L glass-lined reactor, add 40L ethyl acetate, slowly add 75L purified water under stirring, add 1M hydrochloric acid (prepared by 400mL concentrated hydrochloric acid and 4.5L purified water) to adjust the pH value to 2 , stirred for 30 min, filtered by rejection, and the filter cake was washed with 12L of purified...

Embodiment 3

[0038] Example 3: 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-(3-chloropropoxy)-3-quinolinecarbonitrile preparation

[0039] Under the protection of nitrogen, 20L of 1-methyl-2-pyrrolidone was added to a 30L glass reactor, and 3.70kg of 2,4-dichloro-5-methoxyaniline, 1.48kg of pyridine hydrochloride, 4.00kg of 4- Chloro-6-methoxy-7-(3-chloropropoxy)-3-quinolinecarbonitrile (4-chloro-6-methoxy-7-(3-chloropropoxy)-3-quinonitrile The molar ratio of phenonitrile to 2,4-dichloro-5-methoxyaniline is 2:3), stirred, heated and controlled at 90-100°C for more than 3 hours, followed by TLC until the spot of intermediate 1 disappeared. Cool the reaction solution to 20-30°C, transfer it to a 200L glass-lined reactor, add 40L ethyl acetate, slowly add 75L purified water under stirring, add 1M hydrochloric acid (prepared by 400mL concentrated hydrochloric acid and 4.5L purified water) to adjust the pH value to 2 , stirred for 30 min, filtered by rejection, and the filter cake was ...

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Abstract

The invention relates to a preparation method of bosutinib. According to the preparation method, 4-chloro-6-methoxyl-7-hydroxyl-3-quinoline formonitrile and 2,4-dichloro-5-methoxyl aniline are taken as the initial raw materials, 1-methyl-2-pyrrolidone is taken as the solvent, and a crude product of bosutinib is obtained through three steps. The preparation method has the advantages of few steps and mild conditions. The reaction conditions of the prior art are improved, the yield is prominently increased, the cost is reduced, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of bosutinib. Background technique [0002] Bosutinib is a potent protein kinase (Src / Abl) inhibitor. The drug was developed by Wyeth Pharmaceuticals, a subsidiary of Pfizer in the United States, and it was first launched in the United States on September 4, 2012. It was approved for chronic granulocytes with positive Philadelphia chromosome in chronic, accelerated phase or blast phase Treatment of adult patients with leukemia (CML) who have previously been treated with one or more tyrosine kinase inhibitors and are not eligible for imatinib, nilotinib, and dasatinib. The chemical structure of bosutinib is shown in formula I. [0003] [0004] Chinese patent CN101792416A discloses that aniline derivatives of o-formate and cyanoacetaldehyde diethyl acetal are condensed to generate imine derivatives, and the intermediates are cycli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/54
Inventor 陈程李阳孟庆义赵锐张喜全
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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