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Method for purifying L-prolinamide

A prolineamide, a selected technology, applied in the field of purifying L-prolineamide, can solve problems such as inability to meet requirements, difficulty in refining, unsatisfactory color and impurity refining effect, and achieve good product quality, low operating cost, Easy to use effect

Active Publication Date: 2014-07-02
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Since L-prolinamide has a chiral structure, a part of the generated isomer D-prolinamide remains in the product, and the isomer impurity is very close to the polarity of the product, resulting in difficulty in refining
CN102432616A reports that ethyl acetate is used as a solvent to refine L-prolineamide, but the effect of refining the color and impurities is not very satisfactory, and cannot meet the requirements of vildagliptin for high-quality L-prolineamide

Method used

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  • Method for purifying L-prolinamide

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Example 1: Purification of L-prolineamide

[0030] 30g of crude L-prolineamide was added to a 250ml four-necked flask. 15 g of methanol was added and stirred, the temperature was raised to 40° C. to dissolve, and the temperature was maintained at 40° C., 1.5 g of diatomaceous earth was added, and the mixture was stirred for 1 hour. Filter while hot, pour the filtrate back into a new four-necked flask, keep the temperature at 40°C, and add 90 g of n-heptane dropwise under stirring. After the dropwise addition is completed, ensure that the material solution is clearly dissolved. The temperature was lowered to 0 to 5°C at a rate of decreasing 1°C every 5 minutes, kept stirring for 3 hours, and filtered. Keep the temperature at 50-60°C, and vacuum dry for 28 hours to obtain a white crystalline solid, yield: 75%. Purity: 99.82%, L-proline: 0.10%, D-prolineamide: 0.09%.

Embodiment 2

[0031] Example 2: Purification of L-prolineamide

[0032] 30g of crude L-prolineamide was added to a 250ml four-necked flask. 15 g of ethanol was added and stirred, the temperature was raised to 40° C. to dissolve, and the temperature was maintained at 40° C., 1.5 g of diatomaceous earth was added, and the mixture was stirred for 1 hour. Filter while hot, pour the filtrate back into a new four-necked flask, keep the temperature at 40°C, and add 90 g of n-heptane dropwise under stirring. After the dropwise addition is completed, ensure that the material solution is clearly dissolved. The temperature was lowered to 0 to 5°C at a rate of decreasing 1°C every 5 minutes, kept stirring for 3 hours, and filtered. Keep the temperature at 50-60°C, and vacuum dry for 28 hours to obtain a white crystalline solid, yield: 77%. Purity: 99.88%, L-proline: 0.08%, D-prolineamide: 0.08%.

Embodiment 3

[0033] Example 3: Purification of L-prolineamide

[0034] 30g of crude L-prolineamide was added to a 250ml four-necked flask. 15 g of isopropanol was added and stirred, the temperature was raised to 40° C. to dissolve, and the temperature was maintained at 40° C., 1.5 g of diatomaceous earth was added, and the mixture was stirred for 1 hour. Filter while hot, pour the filtrate back into a new four-necked flask, keep the temperature at 40°C, and add 90 g of n-heptane dropwise under stirring. After the dropwise addition is completed, ensure that the material solution is clearly dissolved. The temperature was lowered to 0 to 5°C at a rate of decreasing 1°C every 5 minutes, kept stirring for 3 hours, and filtered. Keep the temperature at 50-60°C and vacuum dry for 28 hours to obtain a white crystalline solid with a yield of 79%. Purity: 99.87%, L-proline: 0.08%, D-prolineamide: 0.08%.

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Abstract

The invention provides a method for purifying L-prolinamide. The method comprises the following steps of: a, stirring L-prolinamide crude product into alcohols and dissolving until the solution is clear; adding adsorbent, keeping warm and stirring, and filtering; b, dropwise adding an anti-solvent into filter liquor, cooling and crystallizing; c, filter, drying and thus obtaining the L-prolinamide. The method provided by the invention is simple and convenient to operate, and the obtained product is good in quality.

Description

technical field [0001] The present invention relates to a method for purifying L-prolineamide. Background of the Invention [0002] L-prolineamide is an important intermediate of the antidiabetic drug vildagliptin, the structural formula is as follows: [0003] [0004] (Chemical Reagents, 2005, Vol.27, No.7, 441-442) reported that L-proline methyl ester was prepared from L-proline, and then the methyl ester solution was subjected to ammonia under pressure and low temperature conditions. The L-prolineamide produced is yellowish in color, and a large amount of large polar impurities (L-proline) are brought into the product. [0005] Since L-prolineamide has a chiral structure, a part of the generated isomer D-prolineamide will remain in the product, and the isomer impurity is very close to the product in polarity, which leads to difficulty in purification. CN102432616A reported that L-prolineamide was purified by using ethyl acetate as a solvent, but the color and impuri...

Claims

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Application Information

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IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 朱晓仁张文灵王鹏
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD