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Sitagliptin impurity and preparation and detection method thereof

A technology for sitagliptin impurities and impurities, which is applied in the field of sitagliptin impurities and preparation, and achieves the effects of mild reaction conditions, guaranteed safety and reliability, and simple operation.

Active Publication Date: 2017-03-08
NANJING CHIA TAI TIANQING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, in the process of drug development, we found an impurity with a new structure and high content, which cannot be avoided by optimizing the preparation process

Method used

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  • Sitagliptin impurity and preparation and detection method thereof
  • Sitagliptin impurity and preparation and detection method thereof
  • Sitagliptin impurity and preparation and detection method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] 10g of 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-trifluoro Methyl-1,2,4-triazolo[4,3-a]pyrazine, 8.2g (R)-3-(tert-butoxycarbonyl)amino-4-(2,4,5-trifluorobenzene Base) butyric acid and 200mL methanol were added to a 500mL reaction flask, stirred and dissolved, then cooled to -10~-5°C, and 6.8g 4-(4,6-dimethoxytriazin-2-yl)-4-methanol was added Morpholine hydrochloride, 4.9g of triethylamine were reacted for 3 hours. Put the reaction bottle at room temperature, add 150mL of water, stir for 45min, filter, and dry the filter cake to obtain 16.2g of compound II.

[0040] 16.2 g of compound II obtained above, 200 mL of dichloromethane, and 15 g of trifluoroacetic acid were added into a 500 mL reaction flask and heated to reflux for reaction, and monitored by TLC until the reaction of the raw materials was completed. Lower the reaction temperature to room temperature, add 200% water to the reaction bottle, adjust the pH to about 8-9 with 2mol...

Embodiment 2

[0042] 10g of 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-trifluoro Methyl-1,2,4-triazolo[4,3-a]pyrazine, 9.7g (R)-3-(tert-butoxycarbonyl)amino-4-(2,4,5-trifluorobenzene Base) butyric acid, 200mL acetonitrile were added to a 500mL reaction flask, stirred and dissolved, then cooled to -8°C, and 7.3g of 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine salt was added Acetate, 5.6g triethylamine back reaction 2.5 hours. Put the reaction bottle at room temperature, add 150mL of water, stir for 45min, filter, and dry the filter cake to obtain 16.4g of compound II.

[0043] Add 16.4 g of compound II obtained above, 180 mL of toluene, and 6 g of hydrochloric acid into a 500 mL reaction flask and heat to reflux for reaction. TLC monitors until the reaction of the raw materials is complete. Lower the reaction temperature to room temperature, add 180% water to the reaction bottle, adjust the pH to about 8-9 with 2mol / L sodium hydroxide, extract, extract the...

Embodiment 3

[0045] 10g of 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-trifluoro Methyl-1,2,4-triazolo[4,3-a]pyrazine, 10.2g (R)-3-(tert-butoxycarbonyl)amino-4-(2,4,5-trifluorobenzene base) butyric acid and 230mL acetone were added to a 500mL reaction flask, stirred and dissolved, then cooled to -5°C, and 4.8g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 3.6g Ethylenediamine post reaction for 3.5 hours. Put the reaction bottle at room temperature, add 170mL of water, stir for 45min, filter, and dry the filter cake to obtain 16.1g of compound II.

[0046] Add 16.1 g of Compound II obtained above, 180 mL of toluene, and 10.3 g of formic acid into a 500 mL reaction flask and heat to reflux for reaction. TLC monitors until the reaction of the raw materials is complete. Lower the reaction temperature to room temperature, add 180% water to the reaction bottle, adjust the pH to about 8-9 with 2mol / L sodium hydroxide, extract, extract the dichlorom...

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PUM

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Abstract

The present invention provides sitagliptin impurity compound I and a preparation method and application thereof in the quality control study of sitagliptin. The sitagliptin impurity compound I is as follows: (R)-3-amino-N-[(R)-4-oxy-4-(3-(trifluoromethyl)-5, 6-dihydro-[1, 2, 4] triazole[ 4, 3-a] pyrazine-7(8H)-yl)-1-(2, 4, 5-trifluorophenyl) butyl-2-yl)-4-(2, 4, 5-trifluorophenyl) butyramide.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to an impurity of sitagliptin, a preparation method and a detection method thereof. Background technique [0002] Diabetes is a series of diseases such as sugar, protein, fat, water and electrolyte caused by genetic factors, immune dysfunction, microbial infection and its toxins, free radical toxins, mental factors and other pathogenic factors acting on the body to cause hypofunction of pancreatic islets. Metabolic disorder syndrome is clinically characterized by hyperglycemia. In typical cases, symptoms such as polyuria, polydipsia, polyphagia, and weight loss may occur, namely "three excesses and one deficiency". [0003] Sitagliptin Phosphate, the chemical name is 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6, 7,8-Tetrahydro-3-trifluoromethyl-1,2,4-triazolo[4,3-a]pyrazine phosphate monohydrate, an oral antihyperglycemic agent for DPP-IV inhibitors The d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04G01N30/02
CPCC07D487/04G01N30/02
Inventor 李志华单海霞吴舰柴雨柱王华萍徐丹朱春霞田舟山
Owner NANJING CHIA TAI TIANQING PHARMA
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