Piramal Enterprises Limited

Dhileepkumar Krishnmurthy

Milind Moreshwar Gharpure

Ashutosh Jagtap

Changdev Raut

Navnath Patil

Navnath Shinde

Chirag Anilkumar Shah

Galge Revanappa

Manikrao Warpe

Yogesh Zalte

Shashi Kant Tiwari

Ganesh Wagh

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&#x2032;-piperazin]-1&#x2032;-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 &#x2265;99.8%. The process further refers purification of Lurasidone hydrochloride, wherein the product contains the residual acetone &#x3c;5000 ppm.

Process for the preparation of lurasidone and its intermediate

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).

Process for the preparation of clobazam and its intermediate

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Maharashtra, India

Dhileepkumar Krishnmurthy