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2-methylpyrazolo[1,5-a]pyrimidyl-6-carboxylic acid derivative and application thereof

A technology of carboxylic acid derivatives and methylpyrazole, which is applied in the field of key intermediates in the synthesis of anagliptin, can solve the problems of expensive hydroxybenzotriazole condensing agent, difficult industrial scale-up, and harsh reaction conditions. Achieve stable and controllable quality, reduce preparation costs, and achieve good stability

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

AI Technical Summary

Problems solved by technology

[0016] Among them, method one is prepared by activating intermediate 1 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, and the reaction yield is low
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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  • 2-methylpyrazolo[1,5-a]pyrimidyl-6-carboxylic acid derivative and application thereof
  • 2-methylpyrazolo[1,5-a]pyrimidyl-6-carboxylic acid derivative and application thereof
  • 2-methylpyrazolo[1,5-a]pyrimidyl-6-carboxylic acid derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] O-2,5-dicarbonylpyrrolyl-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (I-1)

[0067] 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 O-2,5-dicarbonylpyrrolyl-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (I-1) was obtained as a white solid, with a yield of 86%.

[0068] 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

[0070] O-3,5-dimethoxy-2,4,6-triazinyl-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (I-2)

[0071] According to the general method 1, (I-2) was prepared as a white solid by using triethylamine in dichloromethane, and the yield was 95%.

[0072] 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

[0074] O-3-Chloro-5-methoxy-2,4,6-triazinyl-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (I-3)

[0075] According to general method 1, (I-3) was prepared as a white solid in THF with pyridine, and the yield was 84%.

[0076] 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 2-methylpyrazolo[1,5-a]pyrimidyl-6-carboxylic acid derivative and application thereof. The 2-methylpyrazolo[1,5-a]pyrimidyl-6-carboxylic acid derivative (I) can be used for synthesizing anagliptin. The compound (I) has high stability, and avoids using expensive reagents and harsh reaction conditions in the anagliptin synthesis process. The compound (I) has the advantages of mild reaction conditions, high reaction yield and stable and controllable quality, is simple to operate, avoids column chromatography, low-temperature reaction and other complex after-treatment processes, greatly lowers the anagliptin preparation cost, and is suitable for industrialized mass preparation. The 2-methylpyrazolo[1,5-a]pyrimidyl-6-carboxylic acid derivative is the compound disclosed as Formula (I).

Description

technical field [0001] The invention relates to a key intermediate for synthesizing anagliptin, in particular to 2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid derivatives. 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 [0005] 2-Methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (1) 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 (1) [0008] Paten...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 李建其倪峰张怡张树新张瑾吴夏冰杜振新卢秀莲
Owner CISEN PHARMA
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