Process for the preparation of teneligliptin

1. A process for the preparation of teneligliptin, a compound of formula I or salt or hydrate thereof, the process comprising:

(a)(i) reacting a compound of formula 11, with bis (2-chloroethyl) amine or N-protected derivative or salt thereof to obtain a compound of formula Int-B or an N-protected derivative or salt thereof,

 Or

(a)(ii) reacting 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde, a compound of formula 30 with piperazine or N-protected derivative thereof,

to obtain a compound of formula Int-B or an N-protected derivative or salt thereof;

(b) reacting the compound of formula Int-B or N-protected derivative or salt thereof with a compound of formula 13 to obtain a compound of formula 14,

wherein R is an amino protecting group selected from the group consisting of aralkyl, acyl, lower alkoxycarbonyl, aralkyloxycarbonyl, lower alkanesulfonyl, aryl sulfonyl, tri-(loweralkyl) silyl, and triphosgene; and

(c) deprotecting the compound of formula 14 to obtain teneligliptin, a compound of formula I or salt or hydrate thereof.

2. The process according to claim 1 , wherein in step (a)(ii) 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde, the compound of formula 30

is reacted with piperazine-1-carboxylic acid tert-butyl ester to obtain tert-butyl 4-(4-formyl-3-methyl-1-phenyl-1H-pyrazol-5-yOpiperazine-1-carboxylate, a compound of formula 31 which is further deprotected to obtain the compound of formula Int-B.

3. The process according to claim 1 , wherein in step (b) R is acetyl, and the process further comprises reacting a compound of formula 29 with a compound of formula Int-B to obtain a compound of formula 32

or reacting a compound of formula 19 with a compound of formula Int-B to obtain a compound of formula 20

4. The process according to claim 1 , wherein the teneligliptin is treated with hydrobromic acid to obtain teneligliptin 2.5 hydrobromide hydrate.

5. The process according to claim 4 , comprising crystallizing teneligliptin 2.5 hydrobromide or a hydrate thereof from a solvent selected from the group consisting of methanol, n-butanol, tertiary butanol, dimethyl acetamide, dimethyl formamide, tetrahydrofuran, propyl acetate, isopropyl acetate, methyl ethyl ketone, methyl isobutyl ketone and mixtures thereof.

6. The process according to claim 5 , wherein teneligliptin 2.5 hydrobromide hydrate is crystallised from methanol.

7. The process according to claim 5 , wherein the obtained teneligliptin 2.5 hydrobromide hydrate is substantially pure teneligliptin 2.5 hydrobromide hydrate having a purity of at least 99% and having less than 0.1% of any of the below compounds

as measured by high performance liquid chromatography.

8. The process according to claim 1 wherein the step of deprotecting is carried out with a reagent selected from the group consisting of acid, reducing agents and base.

9. The process according to claim 1 , wherein step b involves either reacting Int-B with the compound of formula 19 which is selected from the compound of formula 13 when R is 9-fluorenylmethyloxycarbonyl to obtain the compound of formula 20; or reacting Int-B with the compound of formula 29 which is selected from the compound of formula 13 when R is acetyl to obtain the compound of formula 32

10. The process according to claim 1 , comprising step (a)(ii) wherein 5 chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde is reacted with piperazine or N-protected derivative thereof to obtain the compound of formula Int-B or an N-protected derivative or salt thereof.