Process for the preparation of sitagliptin phosphate
AssigneeCadila Healthcare Limited
InventorsShri prakash Dhar DWIVEDI, Kumar Kamlesh SINGH, Sunil Dnyaneshwar NARODE, Dhaval Jashvantbhai PATEL, Kirtipalsinh Sajjansinh SOLANKI
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Abstract
The present invention relates to a method for the preparation of sitagliptin phosphate and sitagliptin phosphate anhydrous of Formula (I′) and monohydrate of Formula (I),
Claims14
A process for the preparation of sitagliptin phosphate anhydrous of Formula (I′) or monohydrate of Formula (I),
- the process comprising the steps of:
- (a) coupling (3R)-N-(tert-butoxycarbonyl)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid of Formula (V),
- with 3-trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo-[4,3-a]pyrazine or its hydrochloride of Formula (IV),
- in presence of coupling agent TBTU and a base in first organic solvent to obtain (R)-tert-butyl 4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-ylcarbamate of Formula (III);
- b) deprotecting the compound of Formula (III) with suitable acid in second organic solvent to obtain sitagliptin free base of Formula (II) by removal of organic solvent;
- and
- (c) treating the sitagliptin free base of Formula (II) with at least 1.4 mole equivalent of phosphoric acid in second organic solvent to obtain sitagliptin phosphate anhydrous of Formula (I′);
- or
- (d) treating the sitagliptin free base of Formula (II) with at least 1.4 mole equivalent of phosphoric acid in second organic solvent optionally in presence of seed crystals to obtain sitagliptin phosphate monohydrate of Formula (I).
A process for the preparation of sitagliptin phosphate anhydrous of Formula (I′) or monohydrate of Formula (I)
- the process comprising the steps of:
- (a) treating the sitagliptin free base of Formula (II)
- with at least 1.4 mole equivalent of phosphoric acid in organic solvent to obtain sitagliptin phosphate anhydrous of Formula (I′);
- or
- (b) treating the sitagliptin free base of Formula (II) with at least 1.4 mole equivalent of phosphoric acid in organic solvent optionally in presence of seed crystals to obtain sitagliptin phosphate monohydrate of Formula (I).
A process for the preparation of (R)-tert-butyl 4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-ylcarbamate of Formula (III), an intermediate for sitagliptin phosphate anhydrous of Formula (I′) or monohydrate of Formula (I),
- the process comprising the steps of:
- coupling (3R)-N-(tert-butoxycarbonyl)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid of Formula (V) with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo-[4,3-a]pyrazine or its hydrochloride of Formula (IV),
- in presence of coupling agent TBTU and a base in organic solvent to obtain reaction mixture and obtaining compound (III) by addition of water in the reaction mixture.
A process for the preparation of sitagliptin phosphate anhydrous of Formula (I′)
- or monohydrate of Formula (I)
- comprising coupling (3R)-N-(tert-butoxycarbonyl)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid of Formula (V) with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo-[4,3-a]pyrazine or its hydrochloride of Formula (IV),
- in presence of coupling agent TBTU of Formula (A) to obtain (R)-tert-butyl 4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluoro phenyl)butan-2-ylcarbamate of Formula (III) and converting (R)-tert-butyl 4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluoro phenyl)butan-2-ylcarbamate of Formula (III) to sitagliptin phosphate anhydrous of Formula (I′) or monohydrate of Formula (I).
Dependencies are inferred from the claim text.