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Synthesizing method of sitagliptin key intermediate

A synthesis method and technology of sitagliptin, applied in the field of medicine, can solve the problems of increasing protection and deprotection steps, expensive use, etc., and achieve the effects of easy control, mild synthesis process conditions, and improved optical purity

Active Publication Date: 2016-01-20
GENCHEM & GENPHARM CHANGZHOU CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Although the prior art has reported several methods for the preparation of sitagliptin, they have one or more disadvantages, such as using expensive reagents, increasing protection and deprotection steps, etc.

Method used

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  • Synthesizing method of sitagliptin key intermediate
  • Synthesizing method of sitagliptin key intermediate
  • Synthesizing method of sitagliptin key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Preparation of α,α-dichloro-2,4,5-trifluoroacetophenone:

[0029] Add 14.7g (110mmol) of aluminum trichloride and 13.2g (100mmol) of 1,2,4-trifluorobenzene in a 250ml three-necked flask, and add 16.2g (120mmol) of dichloroacetyl chloride dropwise under stirring, and the reaction temperature is controlled at Between 40°C and 45°C; after the reaction is completed, lower the reaction solution to room temperature, slowly add 200ml of ice water to remove residual aluminum trichloride, stir the reaction solution and let it stand for stratification; the water phase is extracted three times with dichloromethane and combined Organic layer, the organic layer was washed with water and saturated sodium bicarbonate solution, then dried over anhydrous magnesium sulfate, dichloromethane was evaporated under normal pressure to obtain α,α-dichloro-2,4,5-trifluoroacetophenone 23.6g, purity 98%, yield 95.2%. 1 HNMR (300MHz, CDCl 3 )6.73(m,1H),6.92(s,1H),7.45(m,1H). MS:m / z244(M+H) + . ...

Embodiment 2

[0031] Preparation of 2-hydroxy-2-(2,4,5-trifluorophenyl)acetic acid:

[0032] Add 24.3g (100mmol) of 2,4,5-trifluoro-dichloroacetophenone into a 500ml three-necked flask, slowly add 200ml of 10% aqueous sodium hydroxide solution under stirring at room temperature, and keep the reaction temperature at 0-5°C. After the reaction was completed, the pH was adjusted to 1-3 with 10% dilute hydrochloric acid, and a light yellow solid was precipitated, which was recrystallized from ethyl acetate to obtain 18.2 g of a light yellow solid with a purity of 97% and a yield of 85.6%. 1 HNMR (300MHz, CDCl 3 )3.65(s,1H),5.38(s,1H),6.48(m,1H),6.76(m,1H),10.1(s,1H). MS:m / z207(M+H) + .

Embodiment 3

[0034] Preparation of 2-chloro-2-(2,4,5-trifluorophenyl)acetic acid:

[0035] Add 100ml of anhydrous dichloromethane, 20.6g (100mmol) of 2-hydroxy-2-(2,4,5-trifluorophenyl)acetic acid, and 36.3ml (500mmol) of thionyl chloride into a 250ml three-necked flask under stirring. , reflux reaction for 10 hours, TLC thin layer monitoring to the end of the reaction; after the reaction is completed, add the reaction solution to a 10% sodium carbonate solution cooled with an ice-salt bath, stir for 1 hour, adjust the pH to 1 to 3 with dilute hydrochloric acid, and let the reaction solution stand Layering; the aqueous phase was extracted three times with dichloromethane and the organic layer was combined, the organic layer was dried over anhydrous magnesium sulfate, and the dichloromethane was evaporated under normal pressure to obtain 2-chloro-2-(2,4,5-trifluorophenyl ) acetic acid solid, recrystallized from methanol to obtain 21.7 g of a light yellow body with a purity of 98% and a yiel...

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Abstract

The invention relates to the technical field of medicine, in particular to a synthesizing method of a sitagliptin key intermediate. The sitagliptin key intermediate (R)-4-chloro-3-amino-4-(2,4,5-trifluoro-phenyl)butyrate after the raw material trifluoro-benzene is subjected to friedel-crafts acylation, hydrolysis, helium atom replacement, condensation, ammonolysis, hydrogenation reduction and hydrolysis. The method has the advantages that low-price trifluoro-benzene serves as the initial raw material and is wide in source; the chiral center is established through a hydrogenation reduction in which metal rhodium and chiral ferrocenyl diphosphine participate, helium atoms are introduced to the left side of a reaction locus, and therefore the optical purity of the product is effectively improved; the synthesis process conditions are mild and easy to control.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a method for synthesizing a sitagliptin key intermediate. Background technique [0002] 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl Base)-1,2,4-triazolo[4,3-a]pyrazine, also known as sitagliptin, is a new type of anti-diabetic drug developed by Merck in the United States. It was released in October 2006 Approved by the US FDA in March, it is the first dipeptidyl peptidase-IV (DPP-IV) inhibitor drug for the treatment of type 2 diabetes, and is often used in the form of phosphate. Sitagliptin can increase the activity of GLP-1 and GIP in plasma, slightly increase its content and weaken the antagonism of GLP-1 metabolites. At the same time, sitagliptin stimulates insulin secretion with blood sugar dependence, so it can Greatly reduce the incidence of hypoglycemic side effects of traditional oral hypoglycemic drugs. [0003] During ...

Claims

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Application Information

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IPC IPC(8): C07C229/34C07C227/18
Inventor 王玉琴詹玉进
Owner GENCHEM & GENPHARM CHANGZHOU CO LTD
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