Improved process for the preparation of lurasidone and its intermediate

Patent metadata

Field	Value
Publication number	US-2017349601-A1
Application number	US-201615541568-A
Country	US
Kind code	A1
Filing date	Jan 5, 2016
Priority date	Jan 8, 2015
Publication date	Dec 7, 2017
Grant date	—

Abstract

The present invention provides an improved process for preparation of the substantially pure (3aR,7aR)-4′-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1′-piperazin]-1′-ium methanesulfonate (referred to as compound-II), which is useful as a key intermediate for the synthesis of lurasidone ((3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1ylmethyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione). The process comprises reaction of the compound-III (as described herein) with the compound-IV (as described herein) in the presence of a solvent mixture selected from an alcohol and water; and a base The improved process for the preparation of compound II provides the product with total amount of unreacted compound-IV as impurity in less than 0.06% and the product with HPLC purity as ≧99.8%. The process further refers purification of Lurasidone hydrochloride, wherein the product contains the residual acetone <5000 ppm.

First claim

We claim:

1 . A process for the preparation of (3aR,7aR)-4′-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1′-piperazin]-1′-ium methanesulfonate (II) of the following formula,

comprising; reacting the compound-III of the following formula;

with the compound-IV of the following formula;

in a mixture of protic solvents and a base.

2 . The process according to claim 1 , wherein the solvent mixture consists of an organic solvent and water.

3 . The process according to claim 1 , wherein the solvent mixture consists of an alcoholic solvent and water.

4 . The process according to claim 1 , wherein the solvent mixture comprises alcoholic solvent and water, wherein the ratio of alcoholic solvent to water ranges from 1:1 to 10:10 as v/v (volume/volume)

5 . The process according to claim 1 , wherein the solvent mixture comprises alcoholic solvent and water, wherein the ratio of alcoholic solvent to water ranges from 1:1 to 10:5 as v/v (volume/volume).

6 . The process according to claim 1 , wherein the solvent mixture comprises isopropyl alcohol (IPA) and water, wherein the ratio of IPA to water is 3:1 v/v (volume/volume).

7 . The process according to claim 1 , wherein the base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.

8 . The process according to claim 1 , wherein the compound II is obtained in a yield of about 85-90%.

9 . The process according to claim 1 , wherein the compound II is obtained with a purity of at least 99% (HPLC).

10 . The process according to claim 1 , wherein the compound II contains total amount of unreacted compound-IV as impurities in less than 0.06%.

11 . The process according to claim 1 , wherein the compound II is further converted to Lurasidone free base or a pharmaceutically acceptable salt thereof.

12 . A process for the purification of Lurasidone salt comprising;
(w) preparing a solvent mixture consisting of an organic solvent and water; (x) adding the Lurasidone salt to the solvent mixture of step (w); (y) heating the mixture of step (x); (z) cooling the reaction mixture of step (y) and isolating the precipitated product.

13 . The process according to claim 12 , wherein the organic solvent in step (w) is selected from alcoholic solvent, halogenated solvent, cyclic solvent, protic solvent, aromatic solvent, ketone, ester, hydrocarbon, nitrile or ether.

14 . The process according to claim 12 , wherein the organic solvent in step (w) is an alcoholic solvent selected from ethyl alcohol, n-propyl alcohol, isopropyl alcohol (IPA), isobutyl alcohol or methanol, or a mixture thereof.

15 . The process according to claim 12 , wherein the heating temperature in step (y) ranges from 75° C. to 90° C.

16 . The process according to claim 12 , wherein the cooling temperature in step (z) ranges from 20° C. to 35° C.

17 . The process according to claim 12 , wherein the product pure Lurasidone salt contains the residual acetone less than 5000 ppm.

18 . A process for the purification of Lurasidone hydrochloride comprising;
(i) preparing a solvent mixture of isopropyl alcohol (IPA) and water; (ii) adding the Lurasidone hydrochloride to the solvent mixture of step (i); (iii) heating the mixture of step (ii) at temperature about 85° C.; (iv) cooling the reaction mixture of step (iii) at temperature about 20-30° C.; and (v) isolating the precipitated product.

Assignees

• Piramal Entpr Ltd

Inventors

• Gharpure Milind
• Tiwari Shashi Kant
• Wagh Ganesh
• Revanappa Galge
• Warpe Manikrao
• Zalte Yogesh
• Krishnmurthy Dhileepkumar

Classifications

• C07D487/10 Primary

  Spiro-condensed systems · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title