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Intermediate for preparing Sitagliptin and preparation method and application of intermediate

A technology for sitagliptin and its use, which is applied to the preparation of an intermediate for sitagliptin and the field of preparation thereof, can solve the problems of complex reaction, harsh operating conditions, expensive starting materials and the like, and achieves high purity and high application value. Effect

Active Publication Date: 2016-11-23
ZHEJIANG JIUZHOU PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] From the above literature, we can see that their common disadvantages are that the starting materials are expensive, the reaction is very complicated, the reaction route is long, the operating conditions are harsh, and it is difficult to process.

Method used

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  • Intermediate for preparing Sitagliptin and preparation method and application of intermediate
  • Intermediate for preparing Sitagliptin and preparation method and application of intermediate
  • Intermediate for preparing Sitagliptin and preparation method and application of intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Embodiment 1: the preparation of compound b

[0074]

[0075] Add the compound of formula 7 (1.3g, 0.01mol) and compound 9 (1.9g, 0.01mol) into a 50ml two-necked flask, add 20ml of dichloromethane to stir the solvent, add HOBt (1.49, 0.011mol) and EDC.HCl (2.9g, 0.015mol) the reaction mixture was stirred at room temperature for 8 hours, after the reaction was completed, 15mL NaHCO was added3 The aqueous solution and the organic phase were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 2.67 g of the compound of formula b with a yield of 89.1%.

[0076] LC-MS m / z=303(M-H) + .

Embodiment 2

[0077] Embodiment 2: the preparation of compound c

[0078]

[0079] Catalyst preparation:

[0080] N 2 Under protection, put 4g Dppp (1mmol, 0.1eq), 0.11g (0.5mmol, 0.05eq) palladium acetate, 4ml acetonitrile into a 20ml one-mouth bottle, replace with nitrogen for 3 times, stir, heat in a water bath to 58-62°C, keep warm 2.5 to 3.5 hours. After the heat preservation is completed, cool to 30-35°C to obtain the catalyst.

[0081] N 2 Under protection, put 3.0g (0.01mol, 1.0eq) of compound b and 10ml of acetonitrile into a 50ml two-neck flask, stir and mix evenly; add DBU: 3.8g (0.025mol, 2.5eq), dissolve clear; add 2,4, 5-trifluorobromobenzene: 2.32g (0.011mol, 1.1eq), stirring; N 2 Replaced 3 times, adding the catalyst prepared above, N 2 Replacement 3 times, N 2 Under protection, keep warm at 80°C for 20-26 hours. After the heat preservation is completed, TLC detects that the reaction is complete until the raw material point disappears. The reaction solution was wa...

Embodiment 3

[0083] Embodiment 3: the preparation of compound e

[0084]

[0085] Put 4.4g (0.01mol, 1.0eq) of compound d and 20ml of dichloromethane into the four-neck flask, cool down to 0-5°C, slowly add 1.8g (0.015mol, 1.5eq) of thionyl chloride dropwise, and control the temperature 0~5℃, after dropping, raise the temperature to 35~40℃ and keep it for 4~6h, the reaction is over. A dichloromethane solution of compound e was obtained.

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Abstract

The invention relates to the technical filed of organic chemistry, in particular to an intermediate for preparing Sitagliptin and a preparation method and application of the intermediate. The structure of the intermediate is as shown in a formula A (Please see the formula A in the description.), wherein R adopts hydrogen or a formula as shown in the description.

Description

technical field [0001] The invention relates to the technical field of organic chemistry, in particular to an intermediate for preparing sitagliptin, a preparation method and application thereof. Background technique [0002] Sitagliptin, the chemical name is (2R)-4-oxo-4-[3-trifluoromethyl-5,6-dihydro[1,2,4]triazol[4,3- a] pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)-butan-2-amine, the structural formula of its hydrochloride salt is as follows: [0003] [0004] It is the first product of the dipeptidyl peptidase-VI (DPP-VI) inhibitor developed by Merck (Merck). In October 2006, its phosphate, as the first dipeptidyl peptidase-Ⅵ (DPP-Ⅵ) inhibitor, was approved by the US FDA for marketing and clinically used for the treatment of type 2 diabetes. The advantages of this drug are few adverse reactions, low risk of hypoglycemia and no weight gain. [0005] However, at present, the synthetic route of sitagliptin has disadvantages such as high cost, cumbersome operation, and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
Inventor 朱国良何前钱灵峰许营洲严普查
Owner ZHEJIANG JIUZHOU PHARM CO LTD
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