# US 9,518,048 B2 · Process for the preparation of teneligliptin

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- Number: US 9,518,048 B2
- Document ID: US9518048B2
- Status: Granted
- Kind: B2
- Application number: 14/423,550
- Filed: 2013-08-28
- Published: 2015-07-23
- Granted: 2016-12-13
- Earliest claimed: 2012-08-31
- Assignees: Glenmark Pharmaceuticals S.A.
- Applicants: Glenmark Pharmaceuticals Limited; Glenmark Generics Limited
- Inventors: Suresh Mahadev Kadam; Bipin Parsottam Kansagra; Ramchandran Vishnue Kale; Jayant Prakashrao Patil; Venkataramana Reddy Yemireddy; Shailendra Nilkanth Bhadane; Uddhav Popat Chaudhar; Ulhas Digambar Patil; Shekhar Bhaskar Bhirud
- Web page: https://patentgrep.com/patent/US9518048B2

## CPC

- C07D 417/14: containing three or more hetero rings
- C07D 231/40: Acylated on said nitrogen atom
- C07D 295/205: Radicals derived from carbonic acid
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

A process for the preparation of teneligliptin.

## Claims

### Claim 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.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 4)

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.

### Claim 6 (depends on 5)

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

### Claim 7 (depends on 5)

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.

### Claim 8 (depends on 1)

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.

### Claim 9 (depends on 1)

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

### Claim 10 (depends on 1)

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.