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New method for preparing omarigliptin key intermediate

An intermediate and key technology are applied in the field of preparation of key intermediates of aulogliptin, can solve the problems of low synthesis yield, expensive catalyst and high cost, and achieve the advantages of few synthesis steps, avoiding column chromatography separation operation and short time. Effect

Inactive Publication Date: 2018-12-21
CHANGSHA UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The problem to be solved by the present invention is that the synthesis yield of the key intermediate of alogliptin is low, the cost is high, the catalyst used in the reaction is expensive, and the product needs column chromatography

Method used

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  • New method for preparing omarigliptin key intermediate
  • New method for preparing omarigliptin key intermediate
  • New method for preparing omarigliptin key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Embodiment 1: the preparation method of alogliptin intermediate.

[0023] Dissolve 31.2g (0.78mol) of NaOH in a mixture of water and methanol, cool the ethanol refrigerant to 0°C, and add 57.3ml (0.52mol) of 2,5-difluorobenzaldehyde and 42.6ml of nitromethane ( 0.78mol) of methanol solution, neutralized with glacial acetic acid after the reaction, added ethyl acetate and stirred, then layered, the organic phase was washed successively with sodium carbonate solution and saturated brine, then dried with anhydrous sodium sulfate, filtered, concentrated, 112g of 2-nitro-1(2,5-difluorophenyl)-ethanol (intermediate I) was obtained, with a yield of 97% and an HPLC of 91.4%. 1 H NMR (500MHz, CDCl 3 ), δ (ppm): 6.88 (m, 3H), 4.76 (d, 2H), 4.5 (m, 1H), 2.0 (d, 1H).

[0024] Dissolve 100g (0.45mol) of intermediate I in 200ml of acetone and cool down to 0°C, add dropwise 90g (0.9mol) of Jones reagent, keep the temperature of the reaction solution at 3°C, after the completion of t...

Embodiment 2

[0030] Embodiment 2: the preparation method of alogliptin intermediate.

[0031] Dissolve 15.6g (0.39mol) NaOH in a mixture of water and methanol, cool the ethanol refrigerant to 0°C, and add 28.8ml (0.26mol) of 2,5-difluorobenzaldehyde and 21.3ml of nitromethane ( 0.39mol) of methanol solution, neutralized with glacial acetic acid after the reaction, added ethyl acetate and stirred, then layered, the organic phase was washed successively with sodium carbonate solution and saturated brine, then dried with anhydrous sodium sulfate, filtered, concentrated, 55.9 g of 2-nitro-1(2,5-difluorophenyl)-ethanol (intermediate I) was obtained, with a yield of 98% and an HPLC of 92.6%. 1 H NMR (500MHz, CDCl 3 ), δ (ppm): 6.88 (m, 3H), 4.76 (d, 2H), 4.5 (m, 1H), 2.0 (d, 1H).

[0032] Dissolve 50g (0.23mol) of intermediate I in 100ml of acetone and cool down to 0°C, add 46g (0.46mol) of Jones reagent dropwise, the temperature of the reaction solution is maintained at 2°C, after the complet...

Embodiment 3

[0038] Embodiment 3: the preparation method of alogliptin intermediate.

[0039] Dissolve 46.8g (1.17mol) of NaOH in a mixture of water and methanol, cool the ethanol refrigerant to 0°C, and add 86.4ml (0.78mol) of 2,5-difluorobenzaldehyde and 63.9ml of nitromethane ( 1.17mol) of methanol solution, neutralized with glacial acetic acid after the reaction, added ethyl acetate and stirred, then layered, the organic phase was washed successively with sodium carbonate solution and saturated brine, then dried with anhydrous sodium sulfate, filtered, concentrated, 164 g of 2-nitro-1(2,5-difluorophenyl)-ethanol (intermediate I) was obtained, with a yield of 96% and an HPLC of 92.7%. 1 H NMR (500MHz, CDCl 3 ), δ (ppm): 6.88 (m, 3H), 4.76 (d, 2H), 4.5 (m, 1H), 2.0 (d, 1H).

[0040] Dissolve 149g (0.68mol) of intermediate I in 300ml of acetone and cool down to 0°C, add dropwise 137g (1.36mol) of Jones reagent, the temperature of the reaction solution is maintained at 3°C, after the com...

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Abstract

The invention provides a new method for preparing an omarigliptin key intermediate. The method comprises the following steps that 2,5-difluorobenzaldehyde is used as a raw material, and through a 7-step reaction, the omarigliptin key intermediate is obtained. According to the method for preparing the omarigliptin key intermediate disclosed by the invention, a new synthesis route for preparing theomarigliptin key intermediate is provided, the cost of raw materials and the cost of reagents are reduced, the yield of the omarigliptin intermediate is increased, the reaction operation is simple, the condition is mild, and the method is environmentally friendly and suitable for industrial production.

Description

technical field [0001] The invention relates to a new method for preparing the key intermediate of alogliptin. Background technique [0002] Diabetes is a group of metabolic diseases characterized by high blood sugar, which seriously endangers people's health. my country is a big country with diabetes. According to the latest research results, among the adult samples aged 18 and above in my country, the estimated prevalence of diabetes is 11.6%, or 113.9 million people; among them, the prevalence of prediabetes (IGT) is 50.1%. , that is, half of the people are the reserve army of diabetes. This set of figures profoundly reveals the grim situation of diabetes in my country. [0003] Alogliptin (MK-3102) is an ultra-long-acting dipeptidyl peptidase-4 (DPP-4) inhibitor oral hypoglycemic drug developed by Merck & Co., Ltd., which can be taken orally once a week to produce sustained DPP -4 inhibitory effect, has a brand-new hypoglycemic mechanism, and has the advantages of not ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/30
CPCC07D309/30
Inventor 黄朋勉周智慧陈金星王梓鉴
Owner CHANGSHA UNIVERSITY OF SCIENCE AND TECHNOLOGY
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