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Simple environment-friendly synthesis process of vildagliptin

A synthetic method and hydroxyl technology, applied in the field of high-purity vildagliptin, can solve the problems of poor crystallization separation effect, unfavorable industrialization, and many by-products, and achieve green production procedures, large economic and social benefits, and equipment simple effect

Active Publication Date: 2014-05-21
ZHANG JIA GANG VINSCE BIO PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] (1) The solubility of carbonic acid in organic solvents is extremely low, so a large excess of potassium carbonate must be added to maintain the reaction pH for condensation amination; (2) After adding more potassium carbonate, in order to increase the pH value, it must be heated Facilitates the dissolution of potassium carbonate, which leads to possible hydrolysis of the amide bond, and at high temperature, 3-hydroxy-adamantanamine may react with two molecules of (S)-1-(2-chloroacetyl)pyrrolidine-2-cyanide , many by-products are produced; (3) a large amount of potassium iodide is used in the catalyst of the reaction system, which becomes one of the main pollutants; (4) due to the low reaction conversion rate and many by-products, the final yield of vildagliptin is low, The separation effect of cutting crystallization is poor, and there is even a column chromatography separation process, the cost is too high, which is not conducive to industrialization

Method used

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  • Simple environment-friendly synthesis process of vildagliptin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 1 Synthesis of Vildagliptin 1

[0022]In No. 1 500 L stainless steel reaction kettle, add (S)-1-(2-chloroacetyl)pyrrolidine-2-cyanide 20.0 kg and 3-hydroxy-adamantanamine 22.0 kg, then add dichloromethane 160 L stirred to dissolve. Add 10.0 kg of neutral alkali potassium carbonate and 1.1 kg of tetrabutylammonium bromide into No. 2 stainless steel reaction kettle, and stir and dissolve with 80.0 kg of water. The jacket is passed cold brine to control the temperature of No. 1 reactor below 10°C, and the aqueous solution of No. 2 reactor is slowly introduced, and the addition is completed in about 2 hours. Then the temperature was slowly raised to room temperature, and the stirring reaction was continued for 10 h until the raw material (S)-1-(2-chloroacetyl)pyrrolidine-2-cyanide was completely reacted as monitored by thin-layer chromatography, and the reaction was terminated. The reaction solution was transferred to an extraction tank to stand for stratification...

Embodiment 2

[0023] Example 2 Synthesis of Vildagliptin 2

[0024] In No. 1 500 L stainless steel reaction kettle, add (S)-1-(2-bromoacetyl)pyrrolidine-2-cyanide 21.5 kg and 3-hydroxy-adamantanamine 22.0 kg, add dichloromethane 160 L stirred to dissolve. Add 9.0 kg of neutral alkali sodium carbonate and 1.2 kg of tetrabutylammonium bromide into No. 2 stainless steel reaction kettle, and stir and dissolve with 80.0 kg of water. The jacket is passed cold brine to control the temperature of No. 1 reactor below 10°C, and the aqueous solution of No. 2 reactor is slowly introduced, and the addition is completed in about 2 hours. Then the temperature was raised slowly to 20-22°C, and the stirring reaction was continued for 5 h until the raw material (S)-1-(2-bromoacetyl)pyrrolidine-2-cyanide was completely reacted as monitored by thin layer chromatography, and the reaction was terminated. The reaction solution was transferred to an extraction tank to stand for stratification, the dichloromethan...

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Abstract

The invention discloses a synthesis method of vildagliptin, which comprises the steps of performing a condensation reaction of (S)-1-(2-chloroacetyl)pyrrolidine-2-methylcyanogen or (S)-1-(2-bromoacetyl)pyrrolidine-2-methylcyanogen and 3-hydroxyl-amantadine as raw materials in a mixed system of an organic solvent and water in the presence of a catalyst; after the reaction, performing extraction separation, concentration and crystallization to obtain a product with high content, high purity and high yield. The method is simple in process, simple to operate, environment-friendly and suitable for industrial mass production.

Description

technical field [0001] The present invention relates to the synthesis of vildagliptin, a medicine for treating diabetes, in particular to the synthesis of 3-hydroxy-amantadine and (S)-1-(2-haloacetyl)pyrrolidine-2-cyanide as raw materials. The high-purity vildagliptin product was obtained through condensation, crystallization and purification under a mild and green process. Background technique [0002] Vildagliptin, English name: Vildgliptin, also known as Vildagliptin. It was launched by Novartis Pharmaceuticals in 2008 as a new oral drug for treating diabetes. Its mechanism of action is that it can effectively selectively, competitively and reversibly inhibit dipeptidyl peptidase IV, enhance the activity of glucagon-like peptide I and reduce the symptoms of hyperglycemia in patients with type 2 diabetes. Vildagliptin inhibits the activity of the enzyme by combining with dipeptidyl peptidase IV to form a dipeptidyl peptidase IV complex, increasing the concentration of gl...

Claims

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Application Information

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IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 彭学东张梅赵金召闫勇义
Owner ZHANG JIA GANG VINSCE BIO PHARM