WO2014102834A2 - Process for lurasidone - Google Patents

Abstract

The present invention provides a novel process for the purification of lurasidone substantially free of isomeric impurity.

Description

PROCESS FOR LURASIDONE

This application claims the benefit of Indian patent Application No. 5539/CHE/2012, filed on December 31, 2012, which is incorporated herein by reference.

Filed of the Invention

The present invention provides a novel process for the purification of lurasidone substantially free of isomeric impurity. Background of the Invention

Lurasidone hydrochloride is chemically, (38Λ,45,7Λ,785)-2-[((1Λ,2Λ)-2-{[4-(1,2- benzisothiazol-3-yl)-piperazin-l-yl]methyl}cyclohexyl)methyl]hexahydro-lH-4,7- methanisoindol-l ,3-dione hydrochloride and has the structural formula:

Lurasidone hydrochloride is a typical antipsychotic developed by Dainippon Sumitomo Pharma under the trade name Latuda®.

Lurasidone and its salts were disclosed in US patent No. 5,532,372 ('372 patent).

According to the '372 patent also described a process for the preparation of lurasidone.

U.S. patent no. 7,605,260 disclosed a process for the preparation of lurasidone hydrochloride.

(3aS,4S,7i?,7a£)-2-[(( 1 R,2R)-2- { [4-( 1 ,2-benzisoth iazol-3-y l)-piperazin- 1 - yl]methyl}cyclohexyl)methyl]hexahydro-lH-4,7-methanisoindol-l ,3-dione (isomeric impurity) is potential impurity in lurasidone formed by procedures described in the art. In particular, the present invention is directed to reduce or remove (3aS,4S,7i?,7afl)-2-[(( 1 R,2R)-2- { [4-( 1 ,2-benzisothiazol-3-yl)-piperazin- 1 - yl]methyl}cyclohexyl)methyl]hexahydro-lH-4,7-methanisoindol-l,3-dione impurity from lurasidone. The process of the invention may be used for obtaining lurasidone in high purity with less than 0.1% of any individual impurities, in particular (3aS,4S,7tf,7atf)-2-[(( li?,2i?)-2- { [4-( 1 ,2-benzisothiazol-3-yl)-piperazin- 1 - yl]methyl}cyclohexyl)methyl]hexahydro-lH-4,7-methanisoindol-l,3-dione impurity.

The chemical formula of (3aS,45,7i?,7ai?)-2-[((li?,2i?)-2-{[4-(l,2-benzisothiazol- 3-yl)-piperazin-l-yl]methyl}cyclohexyl)methyl]hexahydro-lH-4,7-methanisoindol-l,3- dione (isomeric impurity) impurity may be represented as:

Thus, an object of the present invention is to provide a novel process for the purification of lurasidone substantially free of isomeric impurity.

Detailed Description of the Invention

The term "room temperature" refers to temperature at about 25 to 35°C.

According to one aspect of the present invention, there is provided a novel process for the purification of lurasidone substantially free of isomeric impurity, which comprises crystallizing the lurasidone substantially free of isomeric impurity from a solution of lurasidone containing isomeric impurity in an ester solvent or a chlorinated solvent.

The term "lurasidone substantially free of isomeric impurity" refers to lurasidone having the content of isomeric impurity in equal to or less than about 0.2% by weight, preferably equal to or less than about 0.1% by weight, more preferably equal to or less than about 0.05% by weight and still more preferably not detected. The contents of lurasidone and the impurities are determined by High performance liquid chromatography (HPLC).

HPLC conditions for analysis are:

Column : Qualisil BDS CI 8, 150 x 4.6 mm, 5.0 μη or equivalent

(Make: LC GC, Part No: US0601-15)

Flow rate : 1.0 ml/minute

Detector wavelength : 230 nm

Injection volume : 10 μΐ

Column temperature : 35°C

Run time : 50 minutes

Elution mode : Gradient

Diluent : Prepare a mixture of buffer and methanol in the ratio of

50:50 (v/v).

Buffer : Mix 1.36 gm of potassium dihydrogen orthophosphate,

2.16 gm of octane 1 -sulfonic acid, 1000 ml of water and 2.0 ml of triethylamine. Adjust pH to 2.45 to 2.55 with dilute orthophosphoric acid.

The ester solvent used in the process may preferably be a solvent or mixture of solvents selected from ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate and ethyl formate, and more preferably the ester solvent is ethyl acetate.

The chlorinated solvent used in the process may preferably be a solvent or a mixture of solvents selected from methylene chloride, chloroform, carbon tetrachloride and ethylene dichloride, and more preferable chlorinated solvent is methylene chloride.

Crystallization of lurasidone substantially free of isomeric impurity from the solution of lurasidone containing isomeric impurity in an ester solvent can be performed by conventional methods such as cooling, partial removal of solvents, seeding or a combination thereof. The separated solid may be collected by the method known such as centrifugation or filtration. The invention will now be further described by the following example, which is illustrative rather than limiting.

Examples

Example 1 :

Preparation of lurasidone

Toluene (500 ml) was added to trans-3a,7a-octahydroisoindolium-2-spiro-l'-[4'- (l,2-benzisothiazol-3-yl)]piperazine methane sulfonate (100 gm) and then added bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide (66 gm) under stirring. To the reaction mass was added potassium hydroxide (48 gm) and dibenzo 18-crown ether (2 gm). The contents were heated to 1 10°C and maintained for 8 hours. To the reaction mass was then cooled to room temperature and then added water (1000 ml). The layers were separated and the aqueous layer was extracted with toluene. Combined organic layers were dried with sodium sulfate and then treated with carbon. The reaction mass was filtered through hy-flow bed and then concentrated to obtain 65 gm of lurasidone.

Chromatographic purity of lurasidone: 98.5%;

Content of isomeric impurity: 0.5%.

Example 2:

Purification of lurasidone

Lurasidone (50 gm; HPLC Purity: 98.5%) as obtained in example 1 was dissolved in ethyl acetate (150 ml) at room temperature. The solution was stirred for 28 hours at room temperature and filtered. The solid obtained was dried to obtain 40 gm of pure lurasidone.

Chromatographic purity of lurasidone: 99.5%;

Content of isomeric impurity: 0.03%.

Example 3:

Purification of lurasidone

Lurasidone (10 gm) was dissolved in methylene chloride (25 ml) at room temperature. The solution was stirred for 28 hours at room temperature and filtered. The solid obtained was dried to obtain 7 gm of pure lurasidone. Chromatographic purity of lurasidone: 99.3%;

Content of isomeric impurity: 0.05%.

Example 4:

Purification of lurasidone

Example 2 was repeated using tert-butyl methyl acetate solvent instead of ethyl acetate solvent to obtain pure lurasidone.

Example 5:

Preparation of lurasidone y rochlor de

Lurasidone (65 gm) was dissolved in water (650 ml) and then heated to 50°C. To the solution was added concentrated hydrochloride (65 ml) slowly for 20 minutes at 45 to 50°C and maintained for 1 hour. The contents were then cooled to room temperature, filtered and then dried to obtain 69 gm of lurasidone hydrochloride.

Claims

We claim:

1. A process for the purification of lurasidone substantially free of isomeric impurity, which comprises crystallizing the lurasidone substantially free of isomeric impurity from a solution of lurasidone containing isomeric impurity in an ester solvent or a chlorinated solvent.

2. The process as claimed in claim 1, wherein the ester solvent used in the process is a solvent or mixture of solvents selected from ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate and ethyl formate.

3. The process as claimed in claim 2, wherein the ester solvent is ethyl acetate.

4. The process as claimed in claim 1 , wherein the chlorinated solvent used in the process is a solvent or a mixture of solvents selected from methylene chloride, chloroform, carbon tetrachloride and ethylene dichloride.

5. The process as claimed in claim 4, wherein the chlorinated solvent is methylene chloride.