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Preparation method of saxagliptin intermediate

An intermediate and volume technology, applied in organic chemistry and other directions, can solve the problems of high industrialization cost, harsh reaction conditions, expensive process raw materials, etc., and achieve the effects of low cost, simple operation and less environmental pollution.

Active Publication Date: 2021-07-30
SHANGHAI SHYNDEC PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The technical problem to be solved by the present invention is to provide a kind of saxagliptin in order to overcome the problems of expensive raw materials, high industrialization cost, harsh reaction conditions, and unfriendly environment in the preparation of saxagliptin intermediates in the prior art. The preparation method of Ting intermediate

Method used

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  • Preparation method of saxagliptin intermediate
  • Preparation method of saxagliptin intermediate
  • Preparation method of saxagliptin intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0045]

[0046] Add 20g of compound 5 (N-boc-4,5-dehydroproline ethyl ester), 20g of zinc powder, 11.2g of CuBr, 400ml of tetrahydrofuran into a 500mL three-necked flask, stir at 25°C, and 2 Protection, adding CH dropwise 2 Br 2 135g, heat up to 40°C, slowly add trifluoroacetic acid (2ml) dropwise, the color of the reaction solution changes from gray-green to purple-black, the reaction is triggered, the temperature rises from 40°C to 47°C, and reacts at 40°C-50°C for 18 hours, The raw materials were basically reacted completely, concentrated under reduced pressure, added 1L ethyl acetate, 400ml water, 100ml saturated aqueous sodium bicarbonate solution, stirred, filtered with suction, separated phases, concentrated the ethyl acetate phase, and used n-heptane / ethyl acetate=30: 1 was passed through the column to obtain 7 g of compound 6 (yield 32.5%). 1 H-NMR (CDCl 3 , 400MHz): 4.5-4.6(m, 1H), 4.16-4.20(m, 2H), 3.47-3.51(m, 1H), 2.50-2.56(m, 1H), 2.20-2.36(m, 1H), 1.55 -1...

Embodiment 2

[0049] Add 4g of compound 5 (N-boc-4,5-dehydroproline ethyl ester), 4g of zinc powder, 2.2g of CuBr, 80ml of tetrahydrofuran into a 100mL three-necked flask, stir at 0°C, and 2 Protection, adding CH dropwise 2 Br 2 27g, slowly add trifluoroacetic acid (2ml) dropwise, react at 0°C for 72h, concentrate under reduced pressure, add 200ml ethyl acetate, 80ml water, 20ml saturated aqueous sodium bicarbonate solution, stir, filter with suction, separate phases, concentrate ethyl acetate The phase was passed through the column with n-heptane / ethyl acetate=30:1 to obtain 0.6 g of compound 6 (yield 14.4%).

Embodiment 3

[0051] Add 4g of compound 5 (N-boc-4,5-dehydroproline ethyl ester), 4g of zinc powder, 2.2g of CuBr, 80ml of tetrahydrofuran into a 100mL three-necked flask, and stir at 66°C under N 2 Protection, adding CH dropwise 2 Br 2 27g, slowly add trifluoroacetic acid (2ml) dropwise, react at 66°C for 3h, concentrate under reduced pressure, add 200ml ethyl acetate, 80ml water, 20ml saturated aqueous sodium bicarbonate solution, stir, suction filter, separate phases, concentrate ethyl acetate Phase was passed through the column with n-heptane / ethyl acetate=30:1 to obtain 0.3 g of compound 6 (yield 7.08%).

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Abstract

The invention discloses a preparation method of a saxagliptin intermediate compound. The method comprises the following steps: in an ether organic solvent, in the presence of an acid, under the catalysis of cuprous catalyst and zinc powder, react compound I with dibromomethane. The preparation method has low cost, less environmental pollution and simple operation, and can be applied to industrialized industries.

Description

technical field [0001] The invention relates to a preparation method of a saxagliptin intermediate. Background technique [0002] Saxagliptin ONGLYZA TM (saxagliptin saxagliptin tablets) is a highly effective DPP-4 receptor inhibitor, which can increase endogenous glucagon-like peptide-1 (Glucagon-like Peptide-1) by selectively inhibiting dipeptidylase-4 -1, GLP-1) and glucose-dependent insulinotropic peptide (GIP) levels, thereby regulating blood sugar. A number of clinical studies on saxagliptin have been published one after another, consistently confirming its ability to lower HbA1c, fasting blood glucose (FPG), and postprandial blood glucose (PPG) levels, as well as its good tolerance and safety. [0003] Patents CN102070451A and CN200380109631 report that the chemical name of saxagliptin (saxagliptin) is (1S, 3S, 5S)-2-{(2S)-2-amino-2-(3-hydroxytricyclic-1-adamantyl) Acetyl}2-azabicyclo[3.1.0]hexane-3-carbonitrile via key intermediate (1S,3S,5S)-3-(aminocarbonyl)-2-a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/52
CPCC07D209/52
Inventor 李春刚占轶鹏黄文武刘超鲍丰足孙一平王国平李辉姜碧波张杰
Owner SHANGHAI SHYNDEC PHARMA CO LTD
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