# US 9,518,047 B2 · Process for the industrial synthesis of lurasidone

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- Number: US 9,518,047 B2
- Document ID: US9518047B2
- Status: Granted
- Kind: B2
- Application number: 15/028,962
- Filed: 2014-10-16
- Published: 2016-08-18
- Granted: 2016-12-13
- Earliest claimed: 2013-10-17
- Assignees: Procos S.P.A.
- Applicants: Procos S.P.A.
- Inventors: Tommaso Angelini; Piergiorgio Bettoni; Jacopo Roletto; Paolo Paissoni
- Web page: https://patentgrep.com/patent/US9518047B2

## CPC

- C07D 417/12: linked by a chain containing hetero atoms as chain links
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed is a process for the industrial synthesis of Lurasidone from (1R,2R)-cyclohexane-1,2-diyldimethanol (1), 3-(piperazin-1-yl)benzo[d]isothiazole (3) and (3aR,4R,7R,7aS)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1,3-dione (6).). Said process is optimised to obtain Lurasidone with high yields and high purities by preparing highly pure synthesis intermediates, using critical raw materials and reagents in amounts close to the stoichiometric amounts, increasing productivity and reducing the costs and environmental impact of the process.

## Claims

### Claim 1

A process for the preparation of Lurasidone starting from (1R,2R)-cyclohexane-1,2-diyldimethanol 1 which comprises the following steps:
a) mesylating 1 to give (1R,2R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane 2;
b) reacting 2 with 3-(piperazin-1-yl)benz[d]isothiazole 3 in an organic solvent in the presence of a calcium or magnesium oxide or hydroxide, to give (3aR,7aR)-4′-(benz[d]isothiazol-3-yl)octahydrospiro[2H-isoindol-2,1′-piperazinium] methanesulfonate 4;
c) reacting 4 obtained in step b) with (3aR,4S,7R,7aS)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione 5 to give Lurasidone.

### Claim 2 (depends on 1)

The process according to claim 1 wherein step b) is effected in the presence of calcium hydroxide.

### Claim 3 (depends on 1)

The process according to claim 1 wherein in step b) 0.9-1.1 molar equivalents of 3 with respect to 2, are used.

### Claim 4 (depends on 1)

The process according to claim 1 wherein in step b) the organic solvent is selected from the group consisting of acetonitrile, ethanol, propanol, isopropanol, or a mixture of methyl isobutyl ketone, isopropanol and acetonitrile.

### Claim 5 (depends on 1)

The process according to claim 1 wherein intermediate 5 used in step c) is obtained with a process comprising the following steps:
d) reacting (3aR,4R,7R,7aS)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1,3-dione 6 in the presence of one or more ammonium C1-C6 carboxylates in the absence of solvents at the mixture melting temperature, to give (3aR,4S,7R,7aS)tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione 7;
e) hydrogenating 7 to give 5.

### Claim 6 (depends on 5)

The process according to claim 5 wherein in step d) 0.9-10 molar equivalents of one or more ammonium C1-C6 carboxylates, for 1 molar equivalent of 6, are used.