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Preparation method of DP-IV inhibitor omarigliptin intermediate

A technology of intermediates and organic solvents, which is applied in the field of preparation of alogliptin intermediates, can solve the problems of time-consuming and low process yield, and achieve the effect of good purity and simple post-treatment

Active Publication Date: 2019-04-19
HENAN MEDICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Some responses are particularly time-consuming
[0004] CN105392772B discloses a variety of alogliptin intermediates and processes for further synthesizing downstream products, but some processes have problems such as low yields

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] To an ice-cold solution of benzyl 2-(2,5-difluorophenyl)-2-oxoethylcarbamate (0.1 mmol) in dimethylformamide (DMF) was added NaH (0.14 mmol), and the solution was Leave it in the ice bath for 20 minutes; continue to add propargyl ethanesulfonate (0.11 mmol) to the solution, and stir the mixture in the ice bath for 2 h. Add 10ml of water and wash with Et 2 O (3×5ml) extraction, the obtained organic phase was concentrated, and then purified by silica gel chromatography (eluent: cyclohexane / ether) to obtain 31.3 mg of a white solid product, 1-(2,5-difluorophenyl) The molar yield of benzyl-1-oxopent-4-yn-2-ylcarbamate was 91%. 1 H-NMR (CDCl 3 ),δ:

[0018] 7.55-7.59(m,1H),7.23-7.39(m,6H),7.12-7.18(m,1H),6.03(d,1H),5.28-5.34(m,1H),5.14(s,2H), 3.00(dm,1H), 2.71(dm,,1H), 2.00(t,1H).

Embodiment 2

[0020] To an ice-cold solution of benzyl 2-(2,5-difluorophenyl)-2-oxoethylcarbamate (0.1 mmol) in dimethylformamide (DMF) was added NaH (0.14 mmol), and the solution was It was left in the ice bath for 20 minutes; propargyl mesylate (0.11 mmol) was continued to be added to the solution, and the mixture was stirred in the ice bath for 2 h. Add 10ml of water and wash with Et 2 O (3×5ml) extraction, the obtained organic phase was concentrated, and then purified by silica gel chromatography (eluent: cyclohexane / ether) to obtain 27.9 mg of a white solid product, 1-(2,5-difluorophenyl) The molar yield of benzyl-1-oxopent-4-yn-2-ylcarbamate was 81%.

Embodiment 3

[0022] To an ice-cold solution of benzyl 2-(2,5-difluorophenyl)-2-oxoethylcarbamate (0.1 mmol) in dimethylformamide (DMF) was added NaH (0.14 mmol), and the solution was Leave it in the ice bath for 20 minutes; continue to add propargyl ethanesulfonate (0.12 mmol) to the solution, and stir the mixture in the ice bath for 2 h. Add 10ml of water and wash with Et 2 O (3×5ml) extraction, the obtained organic phase was concentrated, and then purified by silica gel chromatography (eluent: cyclohexane / ether) to obtain 33.0 mg of a white solid product, 1-(2,5-difluorophenyl) The molar yield of benzyl-1-oxopent-4-yn-2-ylcarbamate was 96%.

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Abstract

The invention provides a preparation method of a DP-IV inhibitor omarigliptin intermediate. The preparation method includes the step that a raw material A which is 2-(2,5-difluorophenyl)-(2-oxoethyl)carbamate reacts with a raw material B which is alkyl propargyl sulfonate, so that a product C which is 1-(2,5- difluorophenyl)-1-oxopent-4-yne-2-yl carbamate is obtained. The preparation method is new, the specific omarigliptin intermediate is selected as a problem-solving direction, an efficient technology is provided, and the yield of a one-step reaction is up to 96%.

Description

technical field [0001] The invention relates to a preparation method of an alogliptin intermediate. Background technique [0002] Alogliptin is a novel dipeptidyl peptidase-IV (DP-IV) inhibitor that can be used in the treatment of type 2 diabetes, obesity and hypertension. [0003] Since Merck disclosed the drug, after a comprehensive search, dozens of families of patents around the world have disclosed its synthesis process, some of which require many synthesis steps and use quite expensive starting materials such as 2,5-difluorobenzaldehyde or 2- Bromo-1,4-difluorobenzene, preparation of Weinreb amides and use of carbonyldiimidazole (CDI). Some responses are particularly time-consuming. [0004] CN105392772B discloses a variety of alogliptin intermediates and processes for further synthesizing downstream products, but some processes have problems such as low yields. Contents of the invention [0005] The present invention has a unique approach, selects a specific alog...

Claims

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Application Information

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IPC IPC(8): C07C269/06C07C271/18
CPCC07C269/06C07C271/18
Inventor 刘岩李苏颖梁金英安硕黄丽珍
Owner HENAN MEDICAL COLLEGE
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