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Preparation method of vildagliptin cyclic amidine impurity

A vildagliptin cycloamidine and impurity technology, applied in the field of medicinal chemistry, can solve problems such as high cost and complicated process, and achieve the effects of reducing research and development costs, high yield and easy operation

Active Publication Date: 2018-07-27
SHANGHAI PHARMA GRP QINGDAO GROWFUL PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The vildagliptin cyclic amidine impurity is a specific degradation impurity in vildagliptin preparations. The synthesis method of this impurity has not been reported in the literature so far. It can only be extracted from the preparation during the current research and development process, and the impurity is extracted from the preparation The process is complicated and the cost is extremely high

Method used

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  • Preparation method of vildagliptin cyclic amidine impurity
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  • Preparation method of vildagliptin cyclic amidine impurity

Examples

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Embodiment 1

[0024] Embodiment 1: Preparation of vildagliptin cyclic amidine impurity

[0025]

[0026] Add 30.3g vildagliptin (I) (0.1mol) and 200ml ethanol to a 1000ml four-necked bottle equipped with mechanical stirring, condenser, thermometer and heating device, and then add 200ml aqueous solution of 20g sodium hydroxide (0.5mol) , the temperature was raised to 40° C., and the reaction was carried out for 5 hours, and the reaction was completed. Cool to room temperature and filter, evaporate the filtrate to dryness, then add 500ml of a mixed solution of methanol and dichloromethane (methanol:dichloromethane=1:10 (v:v)), stir to dissolve, filter, and evaporate the filtrate to obtain a white solid , which is the degradation impurity (II) of vildagliptin amide, with a yield of 85%.

Embodiment 2

[0027] Embodiment 2: Preparation of vildagliptin cyclic amidine impurity

[0028] Add 30.3g vildagliptin (I) (0.1mol) and 200ml methanol to a 1000ml four-necked bottle equipped with mechanical stirring, condenser, thermometer and heating device, then add 200ml aqueous solution of 28g potassium hydroxide (0.5mol) , the temperature was raised to 60° C., and the reaction was carried out for 5 hours, and the reaction was completed. Cool to room temperature and filter, evaporate the filtrate to dryness, then add 500ml of a mixed solution of methanol and dichloromethane (methanol:dichloromethane=1:10 (v:v)), stir to dissolve, filter, and evaporate the filtrate to obtain a white solid , which is the degradation impurity (II) of vildagliptin amide, with a yield of 80%.

Embodiment 3

[0029] Embodiment 3: Preparation of vildagliptin cyclic amidine impurity

[0030] Add 30.3g vildagliptin (I) (0.1mol) and 200mlDMF in the 1000ml four-necked bottle equipped with mechanical stirring, condenser, thermometer, heating device, add 200ml aqueous solution of 28g potassium hydroxide (0.5mol) again, The temperature was raised to 70° C., and the reaction was completed for 5 hours. Cool to room temperature and filter, evaporate the filtrate to dryness, then add 500ml of a mixed solution of methanol and dichloromethane (methanol:dichloromethane=1:10 (v:v)), stir to dissolve, filter, and evaporate the filtrate to obtain a white solid , which is the degradation impurity (II) of vildagliptin amide, with a yield of 90%.

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Abstract

The invention discloses a preparation method of a vildagliptin cyclic amidine impurity. The preparation method comprises the following steps: adding a reaction solvent into vildagliptin (I) and addingalkali; raising the temperature to 30 to 180 DEG C, wherein the reaction time is 2 to 8h; purifying a reaction solution to obtain the vildagliptin cyclic amidine impurity (II). The invention providesa synthesis method of the vildagliptin cyclic amidine impurity for the first time; the vildagliptin is used as a raw material and the vildagliptin cyclic amidine impurity is prepared by adopting one-step ring-forming reaction; the preparation method is moderate in reaction conditions, is easy to operate and high in yield. A product, which accords with quality standards, can be obtained through simple purification and the research and development cost is effectively reduced.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of vildagliptin cyclic amidine impurity. Background technique [0002] Vildagliptin was developed by Novartis and was approved for marketing by the European Union in 2007. On August 15, 2011, CFDA officially approved vildagliptin to be launched in China. Vildagliptin can be used in combination with biguanides, thiazolidinediones, and sulfonylureas to treat type 2 diabetes. Vildagliptin can reduce fasting and postprandial blood glucose levels, postprandial glucagon secretion and improve β-cell function, which provides a new option for the treatment of type Ⅱ diabetes patients. Vildagliptin's sales grew strongly after its launch, reaching US$677 million in 2011, and the total sales in the first three quarters of 2012 were close to US$655 million. [0003] The following is the structure of the degradation impurity of vildagliptin cyclic amidine:...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 卢伟伸周振宇祖金祥张欣
Owner SHANGHAI PHARMA GRP QINGDAO GROWFUL PHARMA CO LTD
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