Abstract: The present invention relates to a single pot process for the manufacture of Linagliptin (I) by reacting 8-bromo-7-(but-2-ynyl)-1H-purine-2,6(3H,7H)-dione (XII) with 2-(chloromethyl)-4-methylquinazoline (XIII) followed by amination using (R)-piperidine-3-amine or HCI salt thereof in the presence of base in polar organic solvent to yield Linagliptin of formula (I).
1. A process for preparing Linagliptin a compound of the formula (I) in a single pot comprising of:
(I) a) N-alkylation of 7-but-2-yn-1-yl-8-bromo-3-methyl-3,7-dihydro-purine-2,6-dione represented by the formula (XI);
with 2-chloromethyl-4-methyl-quinazoline represented by the formula(XII),
in the presence of base and suitable solvent at ambient temperature:
b) Further treating the reaction mass with (R)-3-aminopiperidine represented by the formula (VIII) or its salt namely (R)-3-aminopiperidinedihydrochloride,
in presence of a base and a suitable solvent at ambient temperature to yield compound of formula (I).
The process as claimed in claim-1b represents, preferably (R)-3-aminopiperidine.
The process as claimed in claim-1 wherein, the base is selected from a group base or a mixture of bases, selected from a group consists of trialkyl amine, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates and alkali metal hydrides, more preferably alkali metal carbonates, most preferably potassium carbonate.
The process as claimed in claim-1, the polar solvent or mixture of solvents is selected from the group consist of THF, methyl THF, DMF, DMSO, sulfolane and dimethylacetamide more preferably from the group consist of DMSO and DMF most preferably DMSO.
The process as claimed in claim-4, wherein the polar solvent is DMSO.
The process as claimed in claim-1 wherein, the ambient temperature range is selected from the range of 10 to 130°C more preferably between from the range of 50 to 100°C, most preferably between from the range of 75 to 85°C.
| # | Name | Date |
|---|---|---|
| 1 | 202041001116-Abstract_(As Filed)_10-01-2020.pdf | 2020-01-10 |
| 1 | 202041001116_Correspondence_10-01-2020.pdf | 2020-01-10 |
| 2 | 202041001116-Claims_(As Filed)_10-01-2020.pdf | 2020-01-10 |
| 2 | 202041001116-Form5_(As Filed)_10-01-2020.pdf | 2020-01-10 |
| 3 | 202041001116-Description Complete_As Filed_10-01-2020.pdf | 2020-01-10 |
| 3 | 202041001116-Form3_(As Filed)_10-01-2020.pdf | 2020-01-10 |
| 4 | 202041001116-Form1_(As Filed)_10-01-2020.pdf | 2020-01-10 |
| 4 | 202041001116-Form2 (Title Page)_Complete_10-01-2020.pdf | 2020-01-10 |
| 5 | 202041001116-Form1_(As Filed)_10-01-2020.pdf | 2020-01-10 |
| 5 | 202041001116-Form2 (Title Page)_Complete_10-01-2020.pdf | 2020-01-10 |
| 6 | 202041001116-Description Complete_As Filed_10-01-2020.pdf | 2020-01-10 |
| 6 | 202041001116-Form3_(As Filed)_10-01-2020.pdf | 2020-01-10 |
| 7 | 202041001116-Claims_(As Filed)_10-01-2020.pdf | 2020-01-10 |
| 7 | 202041001116-Form5_(As Filed)_10-01-2020.pdf | 2020-01-10 |
| 8 | 202041001116-Abstract_(As Filed)_10-01-2020.pdf | 2020-01-10 |
| 8 | 202041001116_Correspondence_10-01-2020.pdf | 2020-01-10 |