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Preparation method for vildagliptin impurity

A vildagliptin impurity and compound technology, which is applied in the field of preparation of vildagliptin impurity vildagliptin diketopiperazine, can solve the problems of high cost and complex process, reduce research and development costs, and simplify the synthesis method , the effect of mild reaction conditions

Active Publication Date: 2015-12-16
SHANGHAI PHARMA GRP QINGDAO GROWFUL PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Vildagliptin diketopiperazine is a specific degraded impurity in vildagliptin preparations. The synthesis method of this impurity has not been reported in the literature so far. The process is complicated and the cost is extremely high

Method used

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  • Preparation method for vildagliptin impurity
  • Preparation method for vildagliptin impurity
  • Preparation method for vildagliptin impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] The preparation of embodiment 1 compound 1

[0035] Add 16.9g (0.15mol) of chloroacetyl chloride to a 1000ml four-necked flask equipped with a mechanical stirrer, a condenser, a thermometer, and a heating device, then add 70ml of dichloromethane, and then add 12.9g (0.1mol) of L-proline Acetate methyl ester and 10.1g (0.1mol) triethylamine were dissolved in 200ml of dichloromethane and slowly added dropwise to the reaction flask, stirred and reacted for 1 hour, added 200ml of water to extract and separate the layers, and then washed the organic phase with 200ml of water, The organic phase was dried and spin-dried to obtain compound 1.

Embodiment 2

[0036] The preparation of embodiment 2 compound 2

[0037] Add 25g (0.15mol) of 3-amino-1-adamantanol, 13.8g (0.1mol) of potassium carbonate, 0.85g of potassium iodide and 200ml of acetone in a 1000ml four-necked flask equipped with mechanical stirring, condenser, thermometer and heating device , heated to reflux, dissolved 20.5g (0.1mol) of compound 1 in 200ml of acetone and slowly added dropwise to the reaction flask, stirred for 1 hour, filtered while hot, spin the filtrate to dryness, added 200ml of water to dissolve, and then added 200ml of di Extract with methyl chloride, wash the organic phase with 200 ml of water, dry the organic phase and spin dry to obtain compound 2.

Embodiment 3

[0038] The preparation of embodiment 3 vildagliptin diketopiperazine

[0039] Add 33.6g (0.1mol) of compound 2 to a 1000ml four-necked flask equipped with a mechanical stirrer, a condenser, a thermometer, and a heating device, then add 13.8g (0.1mol) of potassium carbonate and 200ml of DMF, stir and react at 50°C for 3 hours, filter , adding 300ml of water and 200ml of dichloromethane to extract and separate the layers, wash the organic phase with 200ml of water, separate the layers, dry and spin the organic phase to obtain vildagliptin diketopiperazine with a yield of 80%.

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Abstract

A disclosed preparation method for a vildagliptin impurity comprises the following steps: (1) reacting methyl L-prolinate with chloroacetyl chloride under an alkali condition to generate a compound I; (2) performing condensation reaction on the compound 1 and 3-amino-1-hydroxyadamantane to generate a compound 2; and (3) performing a self condensation reaction on the compound 2 under an alkali condition to obtain vildagliptin related compound 2. According to the vildagliptin related compound 2 synthetic method, methyl L-prolinate is taken as the raw material and is reacted with chloroacetyl chloride under the alkali condition for preparing the compound 1, the compound 1 is condensed with 3-amino-1-hydroxyadamantane for generating the compound 2, and the compound 2 is subjected to the self condensation reaction under the alkali condition for obtaining the vildagliptin related compound 2. The synthetic method is simple, reaction conditions are mild, operationality is high, a product according with quality standard is obtained through simple purification, and research and development cost is effectively reduced.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a preparation method of an impurity of vildagliptin, vildagliptin diketopiperazine. 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 vildagliptin diketopiperazine [0004] [000...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 刘振玉祖金祥周振宇卢伟伸
Owner SHANGHAI PHARMA GRP QINGDAO GROWFUL PHARMA CO LTD
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