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Preparation method of omarigliptin intermediate

An intermediate and time technology, applied in the field of drug synthesis, can solve the problems of difficult control of reaction, long synthesis steps, complicated operation, etc., and achieve the effect of low price, simple operation and high yield

Active Publication Date: 2017-11-07
GUANGXI UNIVERSITY OF TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the technique disclosed above for the preparation of compounds of formula (II), there are long synthetic steps, the use of expensive starting materials such as 2,5-difluorobenzaldehyde or 2-bromo-1,4-difluorobenzene, the preparation of Weinreb amide and Use defects such as carbonyldiimidazole (CDI), and the operation is complicated and the yield is low
[0008] Patent document CN 105392772 discloses a method for preparing a compound of formula (II) using 1,4-difluorobenzene as a starting material. The method has simple reaction conditions and low cost of raw materials, but flammable and explosive The chemical sodium hydride has the disadvantages of difficult control of the reaction and low yield.

Method used

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  • Preparation method of omarigliptin intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0031] Dissolve the compound of formula (III) (X=Br) (23.5 g, 0.10 mol) in dichloromethane (100 mL), add diisopropylethylamine (21 mL, 0.15 mol) at room temperature, stir for 10 min, and slowly drop Dibenzimide (21.7 g, 0.12 mol) was dissolved in dichloromethane solution (100 mL), and stirred for 5 h. After the reaction, 100 mL of water was added to stir and separate the liquids. The organic phase was washed with dilute hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was recovered under reduced pressure to obtain the compound of formula (IV). The yield was 93%.

Embodiment 2

[0033] Dissolve the compound of formula (III) (X=Br) (23.5g, 0.10mol) in acetonitrile (100mL), add diisopropylethylamine (21mL, 0.15mol) at room temperature, stir for 10min, slowly drop into the solution Acetonitrile solution (100 mL) of dibenzimide (21.7 g, 0.12 mol) was stirred for 5 h. After the reaction, the solvent was removed under reduced pressure, and the residue was added with dichloromethane (100mL) / water (100mL) to stir and separate the liquids. The organic phase was washed with dilute hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine, and dried over anhydrous sodium sulfate. , and recover the solvent under reduced pressure to obtain the compound of formula (IV). The yield was 93%.

Embodiment 3

[0035]Dissolve the compound of formula (III) (X=Cl) (19.1g, 0.10mol) in acetone (100mL), add diisopropylethylamine (21mL, 0.15mol) at room temperature, stir for 10min, slowly drop into the solution A solution of dibenzimide (21.7g, 0.12mol) in acetone (100mL) was stirred for 5h. After the reaction, the solvent was removed under reduced pressure, and the residue was added with dichloromethane (100mL) / water (100mL) to stir and separate the liquids. The organic phase was washed with dilute hydrochloric acid, washed with saturated sodium bicarbonate solution, washed with saturated brine, and dried over anhydrous sodium sulfate. , and recover the solvent under reduced pressure to obtain the compound of formula (IV). The yield was 89%.

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Abstract

The invention relates to a preparation method of an omarigliptin intermediate. The omarigliptin intermediate is tert-butyl [1-(2,5-difluorophenyl)-1-oxopent-4-yn-2-yl] carbamate. The method comprises the following steps: a compound I shown as the formula (III) is prepared from 1,4-difluorobenzene as a starting material; the compound I is subjected to a reaction with dibenzimide, and a compound II shown as the formula (IV) is obtained; the compound II is subjected to a substitution reaction with a propargyl compound, and a compound III shown as the formula (V) is prepared; the compound III is subjected to acidolysis and Boc protection, and the compound, namely, the omarigliptin intermediate, shown as the formula (II) is obtained. According to the preparation method, technical defects of long synthesis steps, quite expensive starting materials such as 2,5-difluorobenzaldehyde or 2-bromo-1,4-difluorobenzene, preparation of Weinreb amides, use of CDI (1,1'-Carbonyldiimidazole) and the like in the prior art are overcome; the preparation method has the advantages of simple operation, high yield, low cost and wide source of raw materials and the like, and is applicable to industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of an alogliptin intermediate. Background technique [0002] The present invention relates to a convenient method for the preparation of important intermediates for the synthesis of dipeptidyl peptidase-IV inhibitors (DP-IV). Specifically, the name alogliptin or (2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6- Compounds of dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine, formula (I): [0003] [0004] Alogliptin is a drug developed by Merck and approved in Japan on September 30, 2015 for the treatment of type II diabetes. It is a long-acting DPP-IV inhibitor that only needs to be taken once a week (25mg). Produces continuous DPP-IV inhibitory effect, has a brand-new hypoglycemic mechanism, and has the advantages of not gaining weight, not causing hypoglycemic reactions, and not causing edema. Patent document WO2010 / 0...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C249/02C07C251/24C07C269/04C07C271/18
CPCY02P20/55C07C249/02C07C269/04C07C251/24C07C271/18
Inventor 蒋旭东冯军邓琦
Owner GUANGXI UNIVERSITY OF TECHNOLOGY
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