Sitagliptin phosphate impurities, method for preparing same and application of sitagliptin phosphate impurities

A technology of sitagliptin phosphate and sitagliptin impurities, which is applied in the field of drug synthesis to achieve the effects of strong safety, simple and efficient operation, and moderate reaction conditions

Active Publication Date: 2017-01-25
CHONGQING ZEN PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are not many studies on its impurities at home and abroad, so it is of great practical significance to study the synthesis of sitagliptin phosphate impurities.

Method used

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  • Sitagliptin phosphate impurities, method for preparing same and application of sitagliptin phosphate impurities
  • Sitagliptin phosphate impurities, method for preparing same and application of sitagliptin phosphate impurities
  • Sitagliptin phosphate impurities, method for preparing same and application of sitagliptin phosphate impurities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Example 1 Preparation of sitagliptin phosphate impurity A

[0057] Add (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid (SM1, 23.3g, 0.1mol) into 250ml of dichloromethane at room temperature, and then add di-tert-butyl dicarbonate Esters (Boc anhydride, 98.22g, 0.45mol) and triethylamine (100g, 0.99mol) were stirred and reacted at room temperature for 5 hours, the reaction system was concentrated, and the concentrate was purified by silica gel column (dichloromethane:methanol volume ratio: 20:1) , the eluate containing impurity A was collected and concentrated to dryness to obtain a white solid (impurity A, 26 g, 60%). The purity is 97.84%.

[0058] 1 H-NMR (600HZ, DMSO-d6): δ7.49 (m , 1H), 7.45 (m , 1H), 6.83 (d , 1H), 4.01 (s, 1H), 2.82 (m , 1H), 2.41( m, 1H), 2.33 (m, 1H), 1.39 (s, 9H), 1.27 (s, 9H). MS (m / z): 433.42. [M-C4H9 / +K] + :412.

Embodiment 2

[0059] The preparation of embodiment 2 sitagliptin phosphate impurity B

[0060] 1. Preparation of Compound II

[0061] Add (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid (SM1, 46.6g, 0.20mol) into 500ml of dichloromethane at room temperature, and then add di-tert-butyl dicarbonate Esters (Boc anhydride, 43.65 g, 0.2 mol) and triethylamine (60.71 g, 0.60 mol) were stirred and reacted at room temperature for 3 hours. Add 100ml of 5% dilute hydrochloric acid to the system to wash, then wash the organic layer with water, separate the layers, wash the organic layer with saturated brine, dry over anhydrous magnesium sulfate, filter, concentrate the filtrate to dryness, add 200ml of n-hexane to crystallize to obtain a white solid (i.e. Compound II, 56.7 g, 85%).

[0062] , Preparation of Sitagliptin Phosphate Impurity B

[0063] Compound II (35g, 0.11mol), N,N-dicyclohexylcarbodiimide (DCC, 74.22g, 0.36mol) and triethylamine (33.39g, 0.33mol) were added to 250ml N,N- In dime...

Embodiment 3

[0065] The preparation of embodiment 3 sitagliptin phosphate impurity C

[0066] 1. Preparation of compound III

[0067] Compound II (20g, 0.06mol), N,N-dicyclohexylcarbodiimide (DCC, 24.74g, 0.12mol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro -[1,2,4]triazolo[4,3,α]pyrazine hydrochloride (SM2, 13.72g, 0.06mol) was added to 300ml N,N-dimethylformamide, and then added at room temperature Triethylamine (18.21g, 0.18mol) and N,N-dimethylaminopyridine (0.73g, 0.006mol) were stirred at room temperature for 24 hours. Filter the reaction system, add 200ml dichloromethane and 50ml water to the filtrate, separate the layers, extract the water layer three times with 100ml dichloromethane, separate the layers, wash the organic layer with saturated sodium bicarbonate and saturated brine respectively, add anhydrous sulfuric acid to the organic layer Dry over magnesium for 1 h, filter, and concentrate the filtrate to dryness to obtain a white solid (ie compound III, 24.36 g, 80%).

[0068] ...

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PUM

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Abstract

The invention discloses sitagliptin phosphate impurities, a method for preparing the same and application of the sitagliptin phosphate impurities. The sitagliptin phosphate impurities are sitagliptin phosphate impurities A, sitagliptin phosphate impurities B and sitagliptin phosphate impurities C. The relevant sitagliptin phosphate impurities, the method and the application have the advantage of important monitoring significance on industrial production of sitagliptin phosphate crude medicines.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a sitagliptin phosphate impurity and a preparation method and application thereof. Background technique [0002] Sitagliptin phosphate is the first dipeptidyl peptidase (DPP-IV) inhibitor developed by Merck in the United States and approved by the FDA in October 2006. It was released on November 6, 2009 on the 13th At the annual meeting of the Diabetes Society of the Chinese Medical Association, the State Food and Drug Administration has officially approved the listing of Januvia in China under the trade name. Its structure is as follows: [0003] [0004] Sitagliptin phosphate is mainly used for the treatment of type II diabetes mellitus. It has obvious hypoglycemic effect when used alone or in combination with metformin and pioglitazone. It is safe to take, well tolerated, and has few adverse reactions. Sitagliptin phosphate has always been one of the ho...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07C227/16C07C249/02C07C229/34C07C257/10
CPCC07C227/16C07C249/02C07D487/04C07C229/34C07C257/10
Inventor 邓祥林肖玉梅夏军
Owner CHONGQING ZEN PHARMACEUTICAL CO LTD
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