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Novel Crystalline Polymorphs Of 1 [2 (2,4 Dimethyl Phenylsulfanyl) Phenyl] Piperazine Hydrobromide And Process For Preparation Thereof

Abstract: The present invention relates to novel crystalline polymorphs of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide represented by the following structural formula-1 a and process for preparation thereof.

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Notices, Deadlines & Correspondence

Patent Information

Application #
Filing Date
21 September 2015
Publication Number
26/2017
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application

Applicants

MSN LABORATORIES PRIVATE LIMITED
FACTORY: Sy.No.317 & 323, RUDRARAM (VIL), PATANCHERU (MDL), MEDAK (DIST) - 502 329,

Inventors

1. SRINIVASAN THIRUMALAI RAJAN
MSN LABORATORIES LIMITED, FACTORY: Sy.No.317 & 323, RUDRARAM (VIL), PATANCHERU (MDL), MEDAK (DIST) - 502 329,
2. SAJJA ESWARAIAH
MSN LABORATORIES LIMITED, FACTORY: Sy.No.317 & 323, RUDRARAM (VIL), PATANCHERU (MDL), MEDAK (DIST) - 502 329,
3. GHOJALA VENKAT REDDY
MSN LABORATORIES LIMITED, FACTORY: Sy.No.317 & 323, RUDRARAM (VIL), PATANCHERU (MDL), MEDAK (DIST) - 502 329,
4. BOGE RAJESHAM
MSN LABORATORIES LIMITED, FACTORY: Sy.No.317 & 323, RUDRARAM (VIL), PATANCHERU (MDL), MEDAK (DIST) - 502 329,
5. BEKKAM MARKONDAIAH
MSN LABORATORIES LIMITED, FACTORY: Sy.No.317 & 323, RUDRARAM (VIL), PATANCHERU (MDL), MEDAK (DIST) - 502 329,

Specification

We Claim:
1. An improved process for the preparation of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la, comprising of; a) Reacting the 2,4-dimethylbenzenethiol with compound of general formula-2
wherein 'X' represents a suitable leaving group;
in presence of a suitable base in a suitable solvent to provide (2,4-dimethylphenyl)(2-
nitrophenyl)sulfane compound of formula-3,
b) reducing the compound of formula-3 with a suitable reducing agent in a suitable solvent to provide 2-(2,4-dimethylphenylthio)aniline compound of formula-4,
c) cyclization of compound of formula-4 by reacting it with protected amine compound of general formula-5 or its acid-addition salt

d) deprotecting the compound of general formula-6 with a suitable deprotecting agent optionally in a suitable solvent to provide compound of formula-1,
e) optionally purifying the compound of formula-1,
f) treating the compound of formula-1 with HBr optionally in a suitable solvent to provide compound of formula-la.

2. The process according to claim 1, wherein,
in step-a) & step-c) the suitable base is selected from inorganic bases, orgar bases, organosilicon bases, organolithium bases or their mixtures;
in step-b) the suitable reducing agent is selected from Pd, Pt, PtC>2, Raney Ni presence of hydrogen gas; Fe, Zn, Sn in presence of NH4CI or a suitable acid such HC1, acetic acid; SnC^-HCl, sodium borohydride, lithium borohydride, lithiu aluminium hydride, sodium aluminium hydride, diborane, hydrazine hydra1 sodiumdithionate, thiourea dioxide, sodium sulfide, ammonium sulfide;
in step-c) the suitable catalyst is selected from alkali metal halides such as sodiu bromide, potassium bromide, lithium bromide, sodium iodide, potassium iodide, lithiu iodide, methanesulfonic acid, p-toluenesulfonic acid (PTSA); and the reaction is carri out optionally in presence of a suitable phase transfer catalyst;
in step-d) the suitable deprotecting agent is selected from acids, bases ai hydrogenating agents;
in step-a) to step-f) wherever necessary the suitable solvent is selected fro hydrocarbon solvents, alcohol solvents, ether solvents, ester solvents, chloro solven polar solvents, polar-aprotic solvents, ketone solvents, nitrile solvents, formic acid, acei acid, alkyl ethers of ethylene glycol or propylene glycol or their mixtures.
3. An improved process for the preparation of l-[2-(2,4-dimethyl-phenylsulfanyl)-pheny
piperazine hydrobromide compound of formula-la, comprising of;
a) Reacting the 2,4-dimethylbenzenethiol with compound of general formula-2
wherein 'X' represents a suitable leaving group;
in presence of a suitable base in a suitable solvent to provide (2,4-dimethylphenyl)(2-nitrophenyl)sulfane compound of formula-3, b) reducing the compound of formula-3 with a suitable reducing agent in a suitable solvent to provide 2-(2,4-dimethylphenylthio)aniline compound of formula-4,

c) cyclization of compound of formula-4 by reacting it with N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide compound of formula-5a or its salt
in a suitable solvent optionally in presence of a suitable base and/or a suitable catalyst to provide l-(2-(2,4-dimethylphenylthio)phenyl)-4-tosylpiperazine compound of formula-6a,
d) deprotecting the compound of formula-6a with HBr in acetic acid to directly provide hydrobromide salt compound of formula-1 a,
e) purifying the compound of formula-1 a to provide pure compound of formula-1 a.
4. *A process for the preparation of l-[2-(254-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la, comprising of deprotecting the compound of general formula-6
wherein, CP' represents amine protecting group;
with HBr in acetic acid to provide compound of formula-la.
5. A process according to claim 4, wherein T' represents preferably acid sensitive protecting group and the reaction is carried out optionally in presence of phenol.

6. A process for the preparation of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la, comprising of reacting the l-(2-(2,4-dimethylphenylthio)phenyl)-4-tosylpiperazine compound of formula-6a with HBr in acetic acid.
7. Crystalline form-M of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide characterized by its PXRD pattern having peaks at 3.7, 4.3, 13.0, 17.3, 18.6, 19.7, 20.4, 22.5, 26.9 ± 0.2° of 20 and its PXRD pattern as illustrated in figure-1.
8. Crystalline form-S of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide characterized by its PXRD pattern having peaks at 3.9, 7.7, 9.9, 10.7, 12.6, 14.6, 18.3, 18.9, 20.0, 21.5, 24.5, 27.4 ± 0.2° of 20 and its PXRD pattern as illustrated in figure-2.
9. Crystalline form-N of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide characterized by its PXRD pattern having peaks at 3.7, 4.4, 8.9, 12.2, 17.0, 18.6, 23.5, 27.0 ± 0.2° of 20 and its PXRD pattern as illustrated in figure-3.
10. Pharmaceutical composition comprising crystalline form of l-[2-(2,4-dimethyl-phenyl sulfanyl)-phenyl]-piperazine hydrobromide according to any of the claims 7, 8 or 9.

Documents

Application Documents

# Name Date
1 5018-CHE-2015-FER.pdf 2021-10-17
1 5018-CHE-2015-Other Patent Document-210915.pdf 2015-10-15
2 5018-CHE-2015-FORM28-210915.pdf 2015-10-15
2 5018-che-2015-FORM 18 [16-09-2019(online)].pdf 2019-09-16
3 5018-CHE-2015-FORM 3 [03-05-2018(online)].pdf 2018-05-03
3 5018-CHE-2015-Form 2(Title Page)-210915.pdf 2015-10-15
4 5018-CHE-2015-Form 1-210915.pdf 2015-10-15
4 5018-CHE-2015-Abstract-190916.pdf 2016-11-28
5 5018-CHE-2015-Claims-190916.pdf 2016-11-28
5 5018-CHE-2015 FORM-28.pdf 2016-09-06
6 5018-CHE-2015-Form 5-190916.pdf 2016-11-28
6 5018-CHE-2015-Correspondence-190916.pdf 2016-11-28
7 5018-CHE-2015-Form 2(Title Page)-190916.pdf 2016-11-28
7 5018-CHE-2015-Description(Complete)-190916.pdf 2016-11-28
8 5018-CHE-2015-Drawing-190916.pdf 2016-11-28
9 5018-CHE-2015-Form 2(Title Page)-190916.pdf 2016-11-28
9 5018-CHE-2015-Description(Complete)-190916.pdf 2016-11-28
10 5018-CHE-2015-Correspondence-190916.pdf 2016-11-28
10 5018-CHE-2015-Form 5-190916.pdf 2016-11-28
11 5018-CHE-2015-Claims-190916.pdf 2016-11-28
11 5018-CHE-2015 FORM-28.pdf 2016-09-06
12 5018-CHE-2015-Form 1-210915.pdf 2015-10-15
12 5018-CHE-2015-Abstract-190916.pdf 2016-11-28
13 5018-CHE-2015-FORM 3 [03-05-2018(online)].pdf 2018-05-03
13 5018-CHE-2015-Form 2(Title Page)-210915.pdf 2015-10-15
14 5018-CHE-2015-FORM28-210915.pdf 2015-10-15
14 5018-che-2015-FORM 18 [16-09-2019(online)].pdf 2019-09-16
15 5018-CHE-2015-Other Patent Document-210915.pdf 2015-10-15
15 5018-CHE-2015-FER.pdf 2021-10-17

Search Strategy

1 5018CHE2015SEARCHREPORT-convertedE_24-07-2020.pdf