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Method for synthesizing 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

A technology of methylphenyl and aminothiazole, applied in the field of medicine, can solve the problems of difficult raw materials, high cost, unfavorable production and the like, and achieve the effect of simplifying difficulties

Active Publication Date: 2015-06-03
SHANDONG BOYUAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The technical problem to be solved in the present invention is to overcome the low yield, high cost and large pollution in the preparation of 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide in the prior art , raw materials are rare and unfavorable to production, etc., providing a simple and efficient preparation method

Method used

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  • Method for synthesizing 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Suspend 172g (1mol) of ethyl 2-aminothiazole-5-carboxylate in 1000g of dichloromethane, add 168g (2mol) of sodium bicarbonate, stir evenly, and at the same time lower the temperature to 10-15°C, and control the dropping rate at 3 Within 1 hour, 255g (1.5mol) of benzyl chloroformate was dropped into the mixture, and bubbles appeared during the dropwise addition. After the dropwise addition, it was raised to room temperature and reacted for 5 hours. Dichloromethane was recovered under reduced pressure in a water bath at 40°C. After evaporating to dryness, add 2000g of purified water for beating for 30 minutes, filter and wash with water, put the filter cake into 1000g of methanol, add 100g of glacial acetic acid, beat for 30 minutes at room temperature, lower to 0-5°C and stir for 1 hour, and suction filter to obtain an off-white solid. Air-dried at 50°C to obtain 275 g of compound II, with a yield of 90%.

Embodiment 2

[0029] Put 100g of sodium hydroxide into 1500g of 30% ethanol aqueous solution, and control the temperature below 30°C. Stir to dissolve until clear, and drop 308 g (1 mol) of the product of Example 1 at this temperature. Incubate at 30°C for 8 hours. Cool down to 0-5°C, add 2N concentrated hydrochloric acid dropwise to adjust the pH to 3, a large amount of off-white solid precipitates, stir at 0-5°C for 1 hour, then filter with suction, wash the filter cake with 1000g of purified water, and dry it with air at 80°C to obtain the compound Ⅲ dry product 260g, yield 93%.

Embodiment 3

[0031] Put 280g (1mol) of the product of Example 2 into 1000g of pyridine, lower the temperature to 0-5°C, add 125g (1.1mol) of methanesulfonyl chloride dropwise within 1 hour, keep the temperature for 5 hours after the drop, and then Add 156 g (1.1 mol) of 2-chloro-6-methylaniline and slowly raise the temperature to 80° C., keep the reaction at this temperature for 8 hours, recover pyridine under reduced pressure, and evaporate to nearly dryness. Add 2000 g of 50% methanol water and beat at room temperature for 3 hours, filter with suction, and air-dry at 80°C to obtain 350 g of compound IV as a dry product, with a yield of 85%.

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Abstract

The invention discloses a method for synthesizing 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide. The method comprises the following steps: performing amino protection on 2-aminothiazole-5-ethyl formate as a raw material by adopting CBZ (carbamazepine) to obtain a compound II, and performing decarboxylation protection on the compound II to obtain a compound III; adding the compound III into methylsufonyl chloride activated carboxyl, then adding 2-chloro-6-methylaniline for amidation so as to obtain a compound IV, and removing CBZ protection of the compound IV by using aluminum trichloride-anisole to obtain a product of the 2-amino-N-(2-chloro-6-methylphenyl) thiazole-5-carboxamide. The method has the characteristics of mild condition, simplification after treatment, environment friendliness, suitability for industrial production and the like.

Description

technical field [0001] The invention relates to a synthesis method of a dasatinib intermediate 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide, which belongs to the technical field of medicine. Background technique [0002] Dasatinib, trade name SPRYCEL TM , is an oral tyrosine kinase inhibitor developed by BMS for the treatment of adult chronic myelogenous leukemia (CML) and also for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. 2-amino-N-(2-chloro-6-methylphenyl) thiazole-5-carboxamide as shown in formula (1) is a key intermediate for the synthesis of dasatinib, and its synthetic process accuracy will be It directly affects the purity of dasatinib, and has a direct impact on the cost of raw materials of dasatinib. [0003] [0004] Many synthesis methods of 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide have been published. The synthesis route of this intermediate in the Dasatinib synthesis diagram reviewed in Ch...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/56
CPCC07D277/56
Inventor 吕红超赵孝杰王超朱义胜
Owner SHANDONG BOYUAN PHARM CO LTD
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