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Method for preparing midbody (2S)-N-chloracetyl-2-cyano tetrahydropyrrole of vildagliptin

A technology of cyanotetrahydropyrrole and chloroacetyl, which is applied in the field of medicine, can solve the problems of high toxicity, unsuitable for industrialization, and cumbersome post-processing, and achieve the effects of low pollution, low raw material cost, and small damage

Inactive Publication Date: 2014-06-11
成都诺维尔生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] Method 2. Although the route of this synthetic method is short, when the first step reacts with thionyl chloride to generate acid chloride, proline self-condensation reaction will occur to generate proline dimers, etc., and when there is conversion of amide to cyano group Phosphorus oxychloride and DMF are used, the toxicity is high, and the post-treatment is cumbersome. Due to the existence of these shortcomings, the process is not suitable for industrialization

Method used

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  • Method for preparing midbody (2S)-N-chloracetyl-2-cyano tetrahydropyrrole of vildagliptin
  • Method for preparing midbody (2S)-N-chloracetyl-2-cyano tetrahydropyrrole of vildagliptin
  • Method for preparing midbody (2S)-N-chloracetyl-2-cyano tetrahydropyrrole of vildagliptin

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Embodiment 1

[0033] Embodiment 1: A preparation method of vildagliptin intermediate (2S)-N-chloroacetyl-2-cyanotetrahydropyrrole, specifically comprising the following steps:

[0034] S1. Synthesis of intermediate Ⅰ (2S)-N-chloroacetyl-2-carboxylic acid tetrahydropyrrole:

[0035] Suspend 50 g of L-proline in the solvent toluene, add the acid-binding agent triethylamine, slowly add chloroacetyl chloride at room temperature, stir and react in an oil bath at 0°C for 1 hour, track the reaction by TLC, and cool the reaction solution to At room temperature, add 200ml of ethyl acetate for separation and extraction, the organic phase was first washed with saturated brine, then dried with anhydrous sodium sulfate, and finally concentrated to obtain the crude product intermediate Ⅰ (2S)-N-chloroacetyl-2-carboxylic acid Tetrahydropyrrole, the crude product intermediate I was recrystallized with ethyl acetate to obtain 65.3 g of refined intermediate I (2S)-N-chloroacetyl-2-carboxylic acid tetrahydrop...

Embodiment 2

[0040] Embodiment 2: A preparation method of vildagliptin intermediate (2S)-N-chloroacetyl-2-cyanotetrahydropyrrole, specifically comprising the following steps:

[0041] S1. Synthesis of intermediate Ⅰ (2S)-N-chloroacetyl-2-carboxylic acid tetrahydropyrrole:

[0042] Suspend 50 g of L-proline in the solvent chloroform, add the acid-binding agent diisopropylamine, slowly add chloroacetyl chloride at room temperature, stir and react in an oil bath at 150°C for 72 hours, track the reaction by TLC, and cool the reaction solution to At room temperature, 200ml of ethyl acetate was added for separation and extraction, the organic phase was first washed with saturated brine, then dried with anhydrous sodium sulfate, and finally concentrated to obtain the crude product intermediate Ⅰ (2S)-N-chloroacetyl-2-carboxylic acid Tetrahydropyrrole, the crude product intermediate I was recrystallized with ethyl acetate to obtain 50 g of refined intermediate I (2S)-N-chloroacetyl-2-carboxylic ac...

Embodiment 3

[0047] Embodiment 3: A preparation method of vildagliptin intermediate (2S)-N-chloroacetyl-2-cyanotetrahydropyrrole, specifically comprising the following steps:

[0048] S1. Synthesis of intermediate Ⅰ (2S)-N-chloroacetyl-2-carboxylic acid tetrahydropyrrole:

[0049] Suspend 50g of L-proline in the solvent methanol, add the acid-binding agent diisopropylethylamine, slowly add chloroacetyl chloride at room temperature, stir and react in an oil bath at 15°C for 10h, follow the reaction by TLC, and after the reaction is completed, the reaction The solution was cooled to room temperature, and 200ml of ethyl acetate was added for separation and extraction. The organic phase was first washed with saturated brine, then dried with anhydrous sodium sulfate, and finally concentrated to obtain the crude product intermediate Ⅰ (2S)-N-chloroacetyl-2 -Carboxylic acid tetrahydropyrrole, the crude product intermediate I was recrystallized with ethyl acetate to obtain refined intermediate I (...

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Abstract

The invention discloses a method for preparing a midbody (2S)-N-chloracetyl-2-cyano tetrahydropyrrole of vildagliptin, belonging to the field of medical technology. According to the method, L-proline is taken as the main starting material, the L-proline and chloroacetyl chloride are amidated so as to produce a midbody I(2S)-N-chloracetyl-2-carboxylic acid tetrahydropyrrole, the midbody I is amidated by carboxyl so as to obtain a midbody II (2S)-N-chloracetyl-2-amide tetrahydropyrrole, the midbody II is further dehydrated by amide so as to obtain the (2S)-N-chloracetyl-2-cyano tetrahydropyrrole. The method for preparing the midbody (2S)-N-chloracetyl-2-cyano tetrahydropyrrole of vildagliptin has advantages of short synthetic route, mild reaction conditions, environment protection, and low cost, and is applicable to mass production in factories.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of a vildagliptin intermediate (2S)-N-chloroacetyl-2-cyanotetrahydropyrrole. Background technique [0002] Diabetes mellitus (Diabetes Inellitus) is a metabolic disease of multiple etiologies characterized by chronic hyperglycemia accompanied by disturbances in carbohydrate, fat, and protein metabolism due to defects in insulin secretion and / or action. Diabetes can occur at any age. As the course of the disease prolongs, it is easy to cause histopathological damage such as systemic nerve, microvascular and macrovascular lesions, and can lead to chronic and progressive lesions of the heart, brain, kidney, nerves and eyes and other tissues and organs, resulting in Blindness, lower extremity gangrene, uremia, stroke or myocardial infarction will eventually occur, and even life-threatening. With the improvement of living standards, diabetes has beco...

Claims

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Application Information

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IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 支永刚赵玉燕张振吴德志李桃桃
Owner 成都诺维尔生物医药有限公司
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