Process for the preparation of clobazam and its intermediate

Patent metadata

Field	Value
Publication number	US-10150745-B2
Application number	US-201615559987-A
Country	US
Kind code	B2
Filing date	Mar 21, 2016
Priority date	Mar 24, 2015
Publication date	Dec 11, 2018
Grant date	Dec 11, 2018

Abstract

The present invention provides an improved process for the preparation of 8-chloro-1-phenyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (hereafter referred to as the compound (IV)), which is useful as a key intermediate for the synthesis of Clobazam (referred to as the compound (I)) 7-chloro-1-methyl-5-phenyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione. The process of the present invention further involves transformation of the compound (IV) into Clobazam (I), comprising (a) reacting the compound (II) (as described herein) with monoalkyl malonate in the presence of a coupling agent to obtain the compound (III) (as described herein); followed by the cyclization using a base; (b) reacting the compound-IV (as described herein) obtained from step (a) with methylating agent. The process of the present invention involves formation of novel intermediates methyl 3-((4-chloro-2-(phenylamino)phenyl)amino)-3-oxopropanoate (IIIa) and 3-((4-chloro-2-(phenylamino)phenyl)amino)-3-oxopropanoic acid (V).

First claim

We claim:

1. A process for the preparation of Clobazam (compound-I) of the following formula,

comprising the steps;
(a) reacting 5-chloro-N 1 -phenylbenzene-1,2-diamine (II) of the following formula with mono alkyl malonate in the presence of a coupling agent; to obtain alkyl 3-((4-chloro-2-(phenylamino)phenyl)amino)-3-oxopropanoate (III);

wherein, the compound (III) is optionally isolated,
(b) cyclizing the compound (III) of step (a) in the presence of a base to obtain 8-chloro-1-phenyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (IV) of the following formula;

(c) reacting the compound (IV) obtained from step (b) with a methylating agent.

2. The process according to claim 1 , wherein the base used in step (b) is selected from the group consisting of metal alkoxide selected from potassium tert-butoxide or sodium tert-butoxide.

3. A process for the preparation of Clobazam (compound-I) of the following formula,

comprising the steps;
(a-i) reacting 5-chloro-N 1 -phenylbenzene-1,2-diamine (II) of the following formula with mono alkyl malonate in the presence of a coupling agent; to obtain alkyl 3-((4-chloro-2-(phenylamino)phenyl)amino)-3-oxopropanoate (III);

wherein, the compound (III) is optionally isolated,
(b-i) hydrolyzing the compound (III) obtained from step (a-i) using a base, to obtain 3-((4-chloro-2-(phenylamino)phenyl)amino)-3-oxopropanoic acid (V) of the following formula;

(c-i) cyclizing the compound (V) of step (b-i) in the presence of a coupling agent to obtain 8-chloro-1-phenyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (IV) of the following formula;

(d-i) reacting the compound-IV obtained from step (c-i) with a methylating agent.

4. The process according to claim 1 , wherein the mono alkyl malonate used in step (a) of claims 1 is a C 1 -C 10 mono alkyl malonate.

5. The process according to claim 1 , wherein the coupling agent used in step (a) of claim 1 is selected from the group consisting of dicyclohexylcarbodiimide (DCC), diethyl cyanophosphate and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide.

6. The process according to claim 1 , wherein the methylating agent used in step (c) of claim 1 is selected from methyl iodide or dimethyl sulphate.

7. The process according to claim 1 , wherein the methylation step (c) of claim 1 is in the absence of a phase transfer catalyst.

8. The process according to claim 3 , wherein the base used in step (b-i) is an alkali hydroxide selected from potassium hydroxide or sodium hydroxide.

9. A compound: methyl 3-((4-chloro-2-(phenylamino)phenyl)amino)-3-oxopropanoate (IIIa) of following formula;

10. A compound: 3-((4-chloro-2-(phenylamino)phenyl)amino)-3-oxopropanoic acid (V) of following formula;

11. A crystalline Form-P of Clobazam, characterized by an XRPD pattern having peaks at 7.4, 13.2, 14.4, 17.7, 18.3, 19.3, 19.6, 20.6, 21.9, 22.3, 23.0, 24.2, 24.6, 26.7, 28.4, 28.7, 28.9, 29.4, 30.5, 31.2, 32.1, 33.8, 34.0 and 38.5 ±0.2 degrees 2θ.

12. A process for preparation of the crystalline Form-P of Clobazam according to claim 11 , comprising the steps of;
(s) suspending/dissolving Clobazam in a halogenated hydrocarbon solvent,
(t) heating the reaction mixture of step (s) at reflux temperature,
(u) cooling the reaction mixture of step (t) to a lower temperature of about 15-25° C., and
(v) isolating the precipitated solid.

13. The process according to claim 3 , wherein the mono alkyl malonate used in step (a-i) of claim 3 is a C 1 -C 10 mono alkyl malonate.

14. The process according to claim 3 , wherein the coupling agent used in step (a-i) of claim 3 or step (c-i) of claim 3 is selected from the group consisting of dicyclohexylcarbodiimide (DCC), diethyl cyanophosphate and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide.

15. The process according to claim 3 , wherein the methylating agent used in step (d-i) of claim 3 is selected from methyl iodide or dimethyl sulphate.

16. The process according to claim 3 , wherein the methylation step (d-i) of claim 3 is in the absence of a phase transfer catalyst.

Assignees

• Piramal Entpr Ltd

Inventors

• Jagtap Ashutosh
• Gharpure Milind
• Shinde Navnath
• Patil Navnath
• Shah Chirag
• Raut Changdev
• Krishnmurthy Dhileepkumar

Classifications

• C07D243/12 Primary

  1,5-Benzodiazepines; Hydrogenated 1,5-benzodiazepines · CPC title

• C07B37/10

  Cyclisation · CPC title

• C07C233/43

  having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07C231/02

  from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines · CPC title