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Preparation method of anagliptin

The technology of a compound and a basic substance is applied in the field of preparing an antidiabetic drug Analiptin, which can solve the problems of expensive hydroxybenzotriazole condensing agent, difficult industrial scale-up, harsh reaction conditions, etc., and achieves great practical application value, The effect of high overall yield and easy purification

Inactive Publication Date: 2015-10-14
CISEN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] Among them, method 1 is prepared by activating intermediate 2 with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (ECDI) and hydroxybenzotriazole (HOBT) condensing agent Anagliptin, the hydroxybenzotriazole condensing agent used is more expensive, and it is difficult to realize industrial scale-up
Method 2 Anagliptin is prepared by N, N'-carbonyldiimidazole (CDI) condensing agent, the reaction yield is low and the reproducibility is poor
Method 3 The preparation of anagliptin by acid chloride needs to be carried out at an ultra-low temperature of -78°C, and the reaction conditions are harsh and difficult to meet in industry

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0075] O-2,5-dicarbonylpyrrolyl-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (5-1)

[0076] Suspend the compound of formula (1) (30g) and N-hydroxysuccinimide (19.5g) in 200mL of dichloromethane, add EDCI (36g) in dichloromethane mixture in batches under ice-cooling, and stir at room temperature after adding 8 hours. After filtration, 40 g of white solid O-2,5-dicarbonylpyrrolyl-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (5-1) was obtained, with a yield of 86%.

[0077] 1 HNMR (DMSO-d6): δ1.90-2.05 (m, 4H), 2.51 (s, 3H), 6.66 (s, 1H), 8.81 (s, 2H), 9.36 (s, 1H).

Embodiment 2

[0079] O-3,5-dimethoxy-2,4,6-triazinyl-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (5-2)

[0080] According to General Method 1, triethylamine was used to prepare (5-2) white solid in dichloromethane, and the yield was 95%.

[0081] 1 HNMR (DMSO-d6): δ2.51 (s, 3H), 3.90 (s, 6H), 6.66 (s, 1H), 8.81 (s, 2H), 9.36 (s, 1H).

Embodiment 3

[0083] O-3-Chloro-5-methoxy-2,4,6-triazinyl-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (5-3)

[0084] According to General Method 1, (5-3) was prepared as a white solid with pyridine in THF, and the yield was 84%.

[0085] 1 HNMR (DMSO-d6): δ2.55 (s, 3H), 3.91 (s, 3H), 6.68 (s, 1H), 8.71 (s, 2H), 9.46 (s, 1H).

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Abstract

The invention discloses a preparation method of anagliptin, which comprises the following steps: 1. activating a compound disclosed as Formula (2) to prepare a compound disclosed as Formula (5); and 2. condensing the compound disclosed as Formula (5) with a compound disclosed as Formula (3) or salts thereof to obtain the compound disclosed as Formula (1). The method has the advantages of cheap and accessible raw materials, mild reaction conditions, high reaction yield and easily purified intermediate, is simple to operate and suitable for industrial production, avoids the complex after-treatment processes, such as column chromatography, low-temperature reaction and the like, and greatly lowers the preparation cost. The intermediate (5) is subjected to condensation reaction and refined to obtain the anagliptin. The target product has the advantages of high purity and stable and controllable quality. The method overcomes the defects in the reported anagliptin preparation processes, and has great aggressive advancement effect and practical application value. Besides, the method is suitable for industrial production. The reaction general formula is disclosed in the specification.

Description

technical field [0001] The invention relates to a method for preparing antidiabetic medicine anagliptin. Background technique [0002] Anagliptin was developed by Sanwa Chemical Research Institute of Japan Co., Ltd. in November 2012, it was approved for marketing in Japan for the treatment of type II diabetes, and in December 2012 it was approved by the US FDA for the treatment of type II diabetes. Anagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor, oral tablets one a day, good for the treatment and prevention of type II diabetes, and the treatment and prevention of complications of type II diabetes Effect. [0003] [0004] Anagliptin (1) [0005] 2-Methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (2) is the key intermediate for the preparation of anagliptin, and its chemical structure is as follows: [0006] [0007] 2-Methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (2) [0008] The original research patent WO2004067509 (same family patent CN100434420C...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 李建其倪峰张怡张树新吴夏冰张瑾杜振新卢秀莲
Owner CISEN PHARMA
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