Saxagliptin and saxagliptin salt preparation method

A compound and reaction technology, applied in the field of preparing saxagliptin and its salts, can solve the problems of not being suitable for large-scale industrial production, serious environmental impact, complicated post-treatment, etc., and achieve cheap raw materials, simple post-reaction treatment, and high reaction efficiency. Mild and easy-to-control effects

Inactive Publication Date: 2015-12-09
SHANGHAI DESANO CHEM PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But this method needs to use excessive trifluoroacetic anhydride and pyridine, especially needs a large amount of pyridine, and aftertreatment is comparatively complicated, and has serious impact on environment, and utilizes the reaction of trifluoroacetic anhydride and pyridine dehydration to produce more By-products, including trifluoroacetic anhydride and hydroxyl to generate ester groups (amide groups are not converted to cyano groups), or products of tert-butoxycarbonyl removal
In U.S. Patent No. 7214702B2, a method for converting amides into cyano groups using phosphorus oxychloride is disclosed. In this method, phosphorus oxychloride is a dangerous reagent, and the reaction is violent and difficult to operate. Therefore, the current prior art is not suitable for industrialized large-scale production requirements.

Method used

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  • Saxagliptin and saxagliptin salt preparation method
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  • Saxagliptin and saxagliptin salt preparation method

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Experimental program
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Effect test

Embodiment 1

[0023] Embodiment 1: the preparation of formula II compound

[0024]

[0025] The compound of formula III (43.3g, 0.1mol) was dissolved in a mixed solvent formed by 100mL N,N-dimethylformamide and 330mL ethyl acetate, then lowered to 0-10°C, and cyanuric chloride (14.8g , 0.08mol), keep warm at 0-10°C and stir for 2-6 hours, add 400mL of water, stir for 2-3 hours, adjust the pH ≈ 8 in the reaction system with sodium hydroxide solution, separate the liquid, and use dichloromethane for the water layer Extract, combine the organic phases, and concentrate under reduced pressure to obtain 34.46 g of the compound of formula II with a molar yield of 83.3% and an HPLC purity of 96.8%.

Embodiment 2

[0026] Embodiment 2: the preparation of formula II compound

[0027] The compound of formula III (43.3g, 0.1mol) was dissolved in a mixed solvent formed by 100mL N,N-dimethylformamide and 330mL dichloromethane, then lowered to 0-10°C, and cyanuric chloride (14.8g, 0.08mol), keep warm at 0-10°C and stir for 2-6 hours, add 400mL water, stir for 2-3 hours, adjust the pH ≈ 8 in the reaction system with sodium hydroxide solution, separate the layers, and extract the water layer with dichloromethane , the organic phases were combined and concentrated under reduced pressure to obtain 35.9 g of the compound of formula II with a molar yield of 86.5% and an HPLC purity of 97.6%.

Embodiment 3

[0028] Embodiment 3: the preparation of formula I compound

[0029]

[0030] Dissolve the compound of formula II (34.5g, 0.1mol) in 100mL of dichloromethane, add hydrochloric acid-diethyl ether solution dropwise at 0-5°C, after dropping, keep warm at 0-5°C and stir for 1-2 hours, then concentrate under reduced pressure The reaction liquid obtained 34.9 g of saxagliptin hydrochloride, and the molar yield was 99.2%.

[0031] Dissolve the above-mentioned saxagliptin hydrochloride in 30 mL of water, add dropwise sodium hydroxide solution at 0-10°C to adjust the pH to ≈8.0, then extract with dichloromethane for 3 times, collect the organic phase, and concentrate under reduced pressure. 30.1 g of saxagliptin was obtained with a molar yield of 96.0% and an HPLC purity of 97.8%.

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Abstract

The present invention discloses a saxagliptin and saxagliptin salt preparation method, which includes the following reaction shown in the specification, and is characterized in that: according reaction a, a compound of formula III is reacted with cyanuric chloride in an organic solvent to produce a compound of formula II. The method has the advantages of safe and easy operation, available and cheap raw materials, easy-control and mild reaction conditions, simple reaction post-processing, high yield, and the like, can achieve the requirements of low-cost, large-scale production of high purity saxagliptin, and has significant industrial value.

Description

technical field [0001] The invention relates to a method for preparing saxagliptin and a salt thereof, belonging to the technical field of medicinal chemistry. Background technique [0002] Saxagliptin is a highly efficient, selective and competitive dipeptidyl peptidase-IV (DPP-IV) inhibitor jointly developed by Bristol-Myers Squibb and AstraZeneca. Preclinical and clinical studies have confirmed its The curative effect is outstanding and the effect is long-lasting. In 2009, the FDA approved it for the treatment of type 2 diabetes. Its chemical structure is as follows: [0003] [0004] JournalofMedicinalChemistry, 2005,48(15), discloses the method for preparing saxagliptin in 5025-5037, and reaction scheme is as follows: [0005] [0006] It can be seen from the above route that converting amide into cyano is a relatively critical step. Among them, US2013012723 discloses the use of trifluoroacetic anhydride and pyridine for dehydration to convert amides into cyano...

Claims

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Application Information

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IPC IPC(8): C07D209/52
Inventor 李竟鹏赵楠曾振亚
Owner SHANGHAI DESANO CHEM PHARMA
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