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A kind of preparation method of nilotinib and its intermediate

A nilotinib and volumetric technology, applied in the field of drug synthesis, can solve the problems of expensive reagents, cumbersome processes, and many side reactions

Active Publication Date: 2021-03-30
SHANGHAI SUNTECH PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The problem to be solved by the present invention is to provide a kind of nilotinib in order to overcome the defects of expensive reagents, potential safety hazards, cumbersome process, many side reactions, low product yield and purity in the existing method for preparing nilotinib. The preparation method of Lotinib and its intermediate

Method used

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  • A kind of preparation method of nilotinib and its intermediate
  • A kind of preparation method of nilotinib and its intermediate
  • A kind of preparation method of nilotinib and its intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Add respectively 3-amino-4-methylbenzoic acid methyl ester (16.5 grams, 0.10mol, 1.0 equivalents), di-tert-butyl dicarbonate (Boc 2 O, 21.8 g, 0.10 mol, 1.0 equivalent) and 100 ml of n-butanol. The reaction mixture was heated to 50-55° C. and stirred for 5-8 hours. High-efficiency liquid chromatography monitors that the reaction is complete. After adding 1000 grams of water to the reaction mixture, the system is concentrated to 100 milliliters. After the concentration is completed, it is filtered, and the filter cake is dried to obtain the nilotinib intermediate 3-((tert-butoxycarbonyl)amino) -25.5 g of methyl 4-methylbenzoate (Intermediate A), white to yellow solid, molar yield 96%.

Embodiment 2

[0085] Add respectively 3-amino-4-methylbenzoic acid methyl ester (33 grams, 0.2mol, 1.0 equivalents), di-tert-butyl dicarbonate (Boc2 O, 65.5 g, 0.3 mol, 1.5 equiv) and methanol 200 ml. The reaction mixture was heated to 60-65° C. and stirred for 6-10 hours. High-efficiency liquid chromatography monitors that the reaction is complete. After adding 3000 grams of water to the reaction mixture, the system is concentrated to 200 milliliters. After the concentration is completed, it is filtered, and the filter cake is dried to obtain the nilotinib intermediate 3-((tert-butoxycarbonyl)amino) - 47.8 g of methyl 4-methylbenzoate (Intermediate A), white to yellow solid, molar yield 90%.

Embodiment 3

[0087] Add respectively 3-amino-4-methylbenzoic acid methyl ester (16.5 grams, 0.1mol, 1.0 equivalents), di-tert-butyl dicarbonate (Boc 2 O, 24.0 g, 0.11 mol, 1.1 equiv) and 100 ml of ethanol. The reaction mixture was heated to 55-60° C. and stirred for 6-8 hours. High-efficiency liquid chromatography monitors that the reaction is complete. After adding 1000 grams of water to the reaction mixture, the system is concentrated to 100 milliliters. After the concentration is completed, it is filtered, and the filter cake is dried to obtain the nilotinib intermediate 3-((tert-butoxycarbonyl)amino) - 25.4 g of methyl 4-methylbenzoate (Intermediate A), white to yellow solid, molar yield 91%.

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Abstract

The invention discloses a nilotinib preparation method and an intermediate of nilotinib. The preparation method comprises: in a solvent, carrying out a reaction defined in the specification on a compound D or a hydrochloride salt thereof, and a compound SM3 under the action of an inorganic base to obtain the compound E nilotinib. According to the present invention, the preparation method has characteristics of simple reaction, easy operation, safe and environmentally friendly reagent, less side reaction and short reaction time. The reaction formula is defined in the specification.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of nilotinib and an intermediate thereof. Background technique [0002] Nilotinib is an oral tyrosine kinase inhibitor developed by Novartis. The monohydrochloride monohydrate of nilotinib was approved by the U.S. Food and Drug Administration (FDA) in October 2007 under the trade name Tasigna. Clinically used for the treatment of chronic myeloid leukemia resistant to imatinib mesylate. The drug can selectively inhibit Philadelphia chromosome-positive chronic myeloid leukemia caused by tyrosinase and its encoding gene mutation through targeted action, or has good tolerance and remarkable curative effect. [0003] In the existing research, many literatures and patents have reported different synthetic methods of nilotinib. [0004] Patent US 7169791 reports the synthesis method of nilotinib. The method adopts ethyl 3-amino-4-methylbenzoate (1) as a starting ma...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14C07D233/61C07C271/28
CPCC07C271/28C07D233/61C07D401/14
Inventor 刘学军陈晓冬郝璐吴锋
Owner SHANGHAI SUNTECH PHARMA