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.
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.
| # | 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 |
| 1 | 5018CHE2015SEARCHREPORT-convertedE_24-07-2020.pdf |