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Process for preparing bosutinib

A preparation process, the technology of bosutinib, applied in the chemical and pharmaceutical field, can solve the problems of harshness, increase the reaction route, and low yield, and achieve the effect of short route, high yield and mild cyclization conditions

Inactive Publication Date: 2010-08-04
NANJING MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route is deisopropylated after hydroxyl protection, which increases the reaction route, and the temperature at the time of ring closure is -78°C, which is relatively harsh and the yield is low

Method used

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  • Process for preparing bosutinib
  • Process for preparing bosutinib
  • Process for preparing bosutinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] The preparation process of bosutinib, the preparation steps are: take 4-hydroxy-3-methoxybenzoic acid as raw material, react with methanol to form an ester, and obtain methyl 4-hydroxy-3-methoxybenzoate; Hydroxy-3-methoxybenzoic acid methyl ester reacts with 1-bromo-3-chloropropane to obtain 4-(3-chloropropoxy)-3-methoxybenzoic acid methyl ester after alkylation; 4 The molar ratio of -hydroxy-3-methoxymethylbenzoate to 1-bromo-3-chloropropane is 1:1, and the reaction temperature is 50°C; 4-(3-chloropropoxy)-3-methoxy Methyl benzoate was nitrated to obtain methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate, 4-(3-chloropropoxy)-3-methoxy The molar ratio of methyl benzoate and fuming nitric acid is 1:1, and the reaction temperature is 40°C; methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate is obtained by reduction 4-(3-chloropropoxy)-5-methoxy-2-aminobenzoic acid methyl ester, the reducing agent used is iron powder, zinc powder or palladium carbon, wherein 4-(3-chlor...

Embodiment 2

[0019]The preparation process of bosutinib, the preparation steps are: take 4-hydroxy-3-methoxybenzoic acid as raw material, react with methanol to form an ester, and obtain methyl 4-hydroxy-3-methoxybenzoate; Hydroxy-3-methoxybenzoic acid methyl ester reacts with 1-bromo-3-chloropropane to obtain 4-(3-chloropropoxy)-3-methoxybenzoic acid methyl ester after alkylation; 4 The molar ratio of -hydroxy-3-methoxybenzoic acid methyl ester to 1-bromo-3-chloropropane is 1:3, and the reaction temperature is 80°C; 4-(3-chloropropoxy)-3-methoxy Methyl benzoate was nitrated to obtain methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate, 4-(3-chloropropoxy)-3-methoxy The molar ratio of methyl benzoate and fuming nitric acid is 1:2, and the reaction temperature is 60°C; methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate is obtained by reduction 4-(3-chloropropoxy)-5-methoxy-2-aminobenzoic acid methyl ester, the reducing agent used is iron powder, zinc powder or palladium carbon, wherein ...

Embodiment 3

[0021] The preparation process of bosutinib, the preparation steps are: take 4-hydroxy-3-methoxybenzoic acid as raw material, react with methanol to form an ester, and obtain methyl 4-hydroxy-3-methoxybenzoate; Hydroxy-3-methoxybenzoic acid methyl ester reacts with 1-bromo-3-chloropropane to obtain 4-(3-chloropropoxy)-3-methoxybenzoic acid methyl ester after alkylation; 4 The molar ratio of -hydroxy-3-methoxybenzoic acid methyl ester to 1-bromo-3-chloropropane is 1:5, and the reaction temperature is 110°C; 4-(3-chloropropoxy)-3-methoxy Methyl benzoate was nitrated to obtain methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate, 4-(3-chloropropoxy)-3-methoxy The molar ratio of methyl benzoate to fuming nitric acid is 1:3, and the reaction temperature is 80°C; methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate is obtained by reduction 4-(3-chloropropoxy)-5-methoxy-2-aminobenzoic acid methyl ester, the reducing agent used is iron powder, zinc powder or palladium carbon, wherein...

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Abstract

The invention discloses a process for preparing bosutinib, which simplifies reaction steps, optimizes reaction conditions, improves yield and paves the way for industrial production. The bosutinib is prepared from 4-hydroxy-3-methoxybenzoic acid serving as a raw material and the raw materials required in the reaction process have already been industrially produced, so the cost is low and can be saved; the process flow is relatively short and the yield is relatively high; and the cyclization conditions are mild and cyclization is only carried out at room temperature, so the process is suitable for industrial production.

Description

1. Technical field [0001] The present invention belongs to the field of chemical industry and pharmacy, especially relates to 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1- The preparation technology of piperazine) propoxy]-3-quinolinecarbonitrile (bosutinib, bosutinib). 2. Background technology [0002] Bosutinib (code name: SKI-606), developed by Wyeth Pharmaceuticals of the United States, is a potent dual protein kinase Src / Abl inhibitor, which can inhibit the autophosphorylation of Src protein in a variety of human tumor cells, Also inhibits phosphorylation of Src and Abl substrates. [0003] [0004] In a completed Phase II clinical trial, one with 69 patients with CML or acute lymphoblastic leukemia (ALL), which included treatment with imatinib, dasatinib, and nilotinib (nilotinib) and other patients who have already developed drug resistance participated in the clinical trials, and the patients took bosutinib 400, 500 or 600mg orally every da...

Claims

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Application Information

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IPC IPC(8): C07D215/54
Inventor 李飞殷晓佳江珂孙旭许贯虹
Owner NANJING MEDICAL UNIV
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