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Method for producing pyrazine carboxamide compound, and synthetic intermediate thereof

A manufacturing method and compound technology, which can be used in organic chemistry, drug combination, anti-tumor drugs, etc., and can solve problems such as low yield

Inactive Publication Date: 2017-09-26
ASTELLAS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, the production method of the compound (1) and its monomethanesulfonate (9) disclosed in Patent Document 1 includes, for example, steps in which the yield of the product is low, for example, the yield is 17%, as shown in Table 3 below. The step (the first step of reaction scheme 1), the total yield until the monomethanesulfonate of compound (1) as the final target object ends at 5%.

Method used

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  • Method for producing pyrazine carboxamide compound, and synthetic intermediate thereof
  • Method for producing pyrazine carboxamide compound, and synthetic intermediate thereof
  • Method for producing pyrazine carboxamide compound, and synthetic intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] The first step 5-chloro-6-ethyl-3-{4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino}pyrazine-2-carboxamide( Synthesis of compound (6))

[0078] Add 3,5-dichloro-6-ethylpyrazine-2-carboxamide (13.0kg), 4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline ( 17.8kg), N,N-diisopropylethylamine (15.3kg) in 2-butanol (105.0kg) solution was stirred at 80℃~85℃ for 1 hour. After adding seed crystals (2.6 g) of compound (6), the reaction was performed at 84°C to 88°C for 15 hours. After aging for 24 hours at 22°C to 30°C, the solid was filtered and washed with 2-butanol. Dry under reduced pressure to obtain 5-chloro-6-ethyl-3-{4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino}pyrazine as a solid -2-carboxamide (21.7 kg). It should be noted that the seed crystals can be produced by the following method to obtain compound (6), that is, after cooling to room temperature under the same reaction conditions without adding seed crystals, the solids are filtered, and 2-butanol Afte...

Embodiment 2

[0104] The first step 5-chloro-6-ethyl-3-{4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino}pyrazine-2-carboxamide( Synthesis of compound (6))

[0105] Add 3,5-dichloro-6-ethylpyrazine-2-carboxamide (34.0kg), 4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline ( 44.5kg), N,N-diisopropylethylamine (39.9kg), and 2-butanol (274.7kg) were stirred at 83°C to 86°C for 1 hour. After adding seed crystals (7 g) of compound (6), the reaction was carried out at 85°C to 86°C for 20 hours. A mixed solvent of 2-butanol (82.4 kg) and dimethyl sulfoxide (486.2 kg) was added, stirred at 84°C to 85°C for 2 hours, cooled, and stirred at 20°C to 30°C for 19 hours. The solid was filtered out and washed with dimethyl sulfoxide and 2-butanol. Dry under reduced pressure to obtain 5-chloro-6-ethyl-3-{4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino}pyrazine as a solid -2-carboxamide (55.7 kg).

[0106] The second step (3R)-3-{[5-carbamoyl-3-ethyl-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl] ...

reference example 1

[0119] The first step (3R)-3-[(5-carbamoyl-6-chloro-3-ethylpyrazin-2-yl)oxy]pyrrolidine-1-carboxylic acid tert-butyl ester (Compound (10) )Synthesis

[0120] In the mixture of (3R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (2600mg) and N,N-dimethylformamide (60mL), add 55% oily sodium hydride (540mg ), stirring for 1 hour. 3,5-Dichloro-6-ethylpyrazine-2-carboxamide (3000 mg) was added to the reaction solution under ice cooling, and the mixture was further stirred for 30 minutes. The reaction liquid was poured into ice water, and then extracted with ethyl acetate. After the organic layer was washed with saturated brine, it was dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate). The obtained solid was washed with diisopropyl ether to obtain (3R)-3-[(5-carbamoyl-6-chloro-3-ethylpyrazin-2-yl)oxy] as a solid Tert-Butyl pyrrolidi...

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Abstract

The invention provides: a novel method for producing a pyrazine carboxamide compound as a production material of pharmaceutical products, etc.; and a synthetic intermediate that is useful in said production method. As a result of diligent research on production methods in industrially producing a pyrazine carboxamide compound, the inventors have found that, by using a predetermined material and synthetic intermediate, a pyrazine carboxamide compound can be produced according to a method that is suitable for industrial production as a pharmaceutical product, does not require purification by silica gel column chromatography, and in which overall yield is greatly improved, thus accomplishing the present invention.

Description

Technical field [0001] The present invention relates to 5-{[(3R)-1-acryloylpyrrolidin-3-yl]oxy}-6-ethyl-3-({4-[4-(4-methylpiperazine-1- (Yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (hereinafter, sometimes referred to as "compound (1)") production method and its synthesis intermediate. Background technique [0002] We have reported that compound (1) or a pharmaceutically acceptable salt thereof is useful as an active ingredient of a pharmaceutical composition for cancer treatment (Patent Document 1). In Patent Document 1, the compound (1) is described as Example 54, and the monomethanesulfonate (9) of the compound (1) is described as Example 261. [0003] [0004] The method for producing compound (1) described in Patent Document 1 (Example 54 of Patent Document 1) and its monomethanesulfonate (9) is shown in Reaction Scheme 1. [0005] (Reaction Roadmap 1) [0006] [0007] It is the following method: using 3,5-dichloro-6-ethylpyrazine-2-carboxamide (hereinafter, sometimes...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61K31/497A61P35/00
CPCA61K31/497C07D401/14
Inventor 秋叶贤宏星井博昭岛田逸郎米之井孝辅西川贤太郎森永泰浩
Owner ASTELLAS PHARMA INC
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