Method used for preparing 4-chloropyrrolo[2,3-d]pyrimidine

A hydroxypyrrolopyrimidine and 3-d technology, which is applied in the field of industrial preparation of high-purity 4-chloropyrrolo[2,3-d]pyrimidine, can solve problems such as difficult production and amplification, highly toxic reagents, and complicated processes, and achieve The effect of moderate reaction temperature, high product purity and simple process

Inactive Publication Date: 2015-08-26
CHONGQING PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Aiming at the deficiencies in the prior art, the present invention provides a method for preparing 4-chloropyrrole[2,3-d]pyrimidine, which is suitable for industrial scale It overcomes the shortcomings or deficiencies in the prior art that require high-vacuum distillation or column chromatography purification, high temperature, high-risk and high-toxic reagents, long routes, complicated processes, and difficult production and scale-up.

Method used

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  • Method used for preparing 4-chloropyrrolo[2,3-d]pyrimidine

Examples

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Embodiment 1

[0027] (1) Synthesis of ethyl 2-cyano-4,4-diethoxybutyrate (A)

[0028] Weigh 24.5Kg of N,N dimethylformamide, 1147g of sodium hydride (60% content, containing mineral oil), stir and suspend to cool down, add 3520g of ethyl cyanoacetate dropwise at 0~5°C, return to temperature after the dropwise addition is completed Stir at 25°C for 1.0h, add 5000g of bromoacetaldehyde diethyl acetal dropwise, raise the temperature to 95°C and stir for 4.0h, distill N,N dimethylformamide under reduced pressure at 60°C until the flow is cut off, add 20L of water and 15L Extract the liquid with methyl tert-butyl ether, extract the water phase with methyl tertiary ether twice (10L×2), combine the organic phases and wash with water to separate the liquid, stir and dry with 500g of anhydrous sodium sulfate for 3.0h, and distill under reduced pressure at 40°C After concentrating the solvent, the crude ethyl 2-cyano-4,4-diethoxybutyrate was obtained, which was directly used in the next reaction....

Embodiment 2

[0034] (1) Synthesis of ethyl 2-cyano-4,4-diethoxybutyrate (A)

[0035] Weigh 24.5Kg of N,N dimethylformamide, 1065g of sodium hydride (60% content, containing mineral oil), stir and suspend to cool down, add 3148g of ethyl cyanoacetate dropwise at 0-5°C, return to temperature after the dropwise addition is completed Stir to room temperature, add 5000 g of bromoacetaldehyde diethyl acetal dropwise, raise the temperature to 95°C and stir until the reaction is complete, distill N,N dimethylformamide under reduced pressure at 60°C until the flow is cut off, add 20L of water and 15L of methyl Extract the liquid with tert-butyl ether, extract the water phase twice with tert-methyl ether (10L×2), combine the organic phases and wash with water to separate the liquid, stir and dry with 500g of anhydrous sodium sulfate for 3.0h, and concentrate under reduced pressure at 40°C to After drying, the crude product of ethyl 2-cyano-4,4-diethoxybutyrate was obtained, which was directly used i...

Embodiment 3

[0041] (1) Synthesis of ethyl 2-cyano-4,4-diethoxybutyrate (A)

[0042] Weigh 24.5Kg of N,N dimethylformamide, 1166g of sodium hydride (60% content, containing mineral oil), stir and suspend to cool down, add 3720g of ethyl cyanoacetate dropwise at 0~5°C, return to temperature after the dropwise addition is completed Stir to room temperature, add 5000g of bromoacetaldehyde diethyl acetal dropwise, raise the temperature to 95°C and stir until the reaction is complete, distill the solvent under reduced pressure at 60°C until the flow is cut off, add 20L of water and 20L of methyl tert-butyl ether for extraction and separation , the aqueous phase was extracted twice with tertiary methyl ether (10L×2), the organic phases were combined, washed with water and separated, stirred and dried with 500g of anhydrous sodium sulfate for 3.0h, and concentrated to dryness by distillation under reduced pressure at 40°C to obtain 2-cyano - The crude product of ethyl 4,4-diethoxybutyrate was dir...

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Abstract

The invention discloses a novel method used for preparing high-purity 4-chloropyrrolo[2,3-d]pyrimidine in industrialization scale. According to the method, ethyl cyanoacetate, bromo-acetal, formamidine acetate, and sodium alcoholate are taken as raw materials; N,N-dimethylformamide, ethyl alcohol, and phosphorus oxychloride are taken as solvents; and 4-chloropyrrolo[2,3-d]pyrimidine is obtained via three-step approach. The process route of the method is simple; time is short; next step feed can be carried out directly without complex purification process of intermediates; no toxic agent is used; the method is safe and reliable, and is low in cost; total yield is higher than 30%; and the purity of obtained products is as high as 99.2%.

Description

[0001] technical field [0002] The invention belongs to the field of organic chemistry and relates to a method for industrially preparing high-purity 4-chloropyrrolo[2,3-d]pyrimidine. Background technique [0003] 4-Chloropyrrole[2,3-d]pyrimidine is an important pharmaceutical and chemical intermediate used in the preparation of the anti-rheumatic arthritis drug Tofacitinib. [0004] In 2007, Mibenmei et al. disclosed a method for the gram-scale synthesis of 4-chloropyrrole[2,3-d]pyrimidine in "Chemical Reagents". The first step needs to be purified by high vacuum fractionation to obtain 2-cyano Base-4,4-diethoxybutyric acid ethyl ester makes it difficult to scale up the process. In the second and third steps, a large amount of high-risk metal sodium and Raney nickel are used. A total of 5 steps are required, and the steps are lengthy Complexity, long preparation period, and high potential safety hazards in the process, it is difficult to apply it in production. Patent CN...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 潘元张耀春但春燕全继平院兴龚恒源郑德平左小勇
Owner CHONGQING PHARMA RES INST
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