WO2011080749A1

WO2011080749A1 - Process for purification of ziprasidone

Info

Publication number: WO2011080749A1
Application number: PCT/IN2009/000748
Authority: WO
Inventors: Bandi Parthasaradhi Reddy; Kura Rathnakar Reddy; Dasari Muralidhara Reddy; Rapolu Raji Reddy; Itiyala Srinivas Reddy; Bandi Vamsi Krishna
Original assignee: Hetero Research Foundation
Priority date: 2009-12-29
Filing date: 2009-12-29
Publication date: 2011-07-07

Abstract

The present invention relates to a process for the preparation of pure ziprasidone. Thus, for example, ziprasidone tosylate was added to water and aqueous ammonia at room temperature, the contents were heated to 65 °C and maintained for 30 minutes, filtered, washed with water to obtain a wet solid, tetrahydrofuran was added to wet solid and maintained at reflux for 30 minutes. The separated solid was filtered and dried at 65 °C to obtain pure ziprasidone.

Description

PROCESS FOR PURIFICATION OF ZIPRASIDONE

Field of the Invention

The present invention relates to a process for the preparation of pure ziprasidone.

Background of the Invention

Ziprasidone of formula (I) :

or 5 - [2- [4-( 1 ,2-Benzisothiazol-3 -yl)- 1 -piperazinyl] ethyl] -6-chloro- 1 ,3 -dihydro- 2H-indol-2-one and its salts are antipsychotic agents. Ziprasidone hydrochloride and related compounds and their therapeutic uses were disclosed in U.S. Patent No. 4,831,031, which are hereby incorporated by reference. According to U.S. Patent No. 4,831,031, ziprasidone can be prepared by reacting 1-(1,2- benzisothiazol-3-yl)piperazine and 5-(2-chloroethyl)-6-chloro-oxindole in a polar solvent, such as a lower alcohol, dimethylformamide or methylisobutyl ketone in the presence of a weak base.

U.S. Patent No. 5,206,366 and U.S. Patent No. 5,338,846 are described a process for preparing ziprasidone by reacting l-(l,2-benzisothiazol-3- yl)piperazine with 5-(2-chloroethyl)-6-chloro-oxindole in water with a neutralizing agent such as sodium carbonate under reflux.

U.S. Patent No. 5,359,068 disclosed a process for the preparation of ziprasidone. According to J, Med. Chem. 1996, 39, 143 - 148, ziprasidone is prepared by reacting l -(l,2-benzisothiazol-3-yl)piperazine with 5-(2-bromoethyl)-6-chloro- oxindole in isoamyl alcohol solvent in the presence of sodium carbonate.

U.S. Patent Application No. 2008/0214816 described a process for the preparation ziprasidone maleate, acetate or hydrochloride can be prepared by treating solution or suspension of ziprasidone base with the maleic acid or acetic acid or hydrochloric acid. Process of ziprasidone tosylate was mentioned, but preparation of tosylate is not specifically described.

U.S. Patent Application No. 2009/0163513 disclosed a process for the preparation of ziprasidone by reacting silylated l -(l,2-benzisothiazol-3- yl)piperazine with 5~(2-chloroethyl)-6-chloro-oxindole in water, followed by neutralization under reflux.

Despite various processes disclosed in the prior art for the preparation of ziprasidone and salts thereof, still there is a need for producing ziprasidone and pharmaceutically acceptable acid addition salts of ziprasidone in high purity.

An object of the present invention is to provide a process for the preparation of pure ziprasidone.

Detailed Description of the Invention

In accordance with the present invention there is provided a process for the preparation of pure ziprasidone, which comprises:

a) providing a solution of ziprasidone in alcohol solvent at reflux;

b) adding an organic acid to the solution obtained in step (a) and isolating ziprasidone organic acid salt from the solution as solid;

c) mixing ziprasidone organic acid salt obtained in step (b) with aqueous ammonia;

d) heating the contents obtained in step (c) at 60 to 80°C for at least 15 minutes;

e) isolating ziprasidone from the contents as solid;

f) refluxing ziprasidone obtained in step (e) with tertrahydrofuran; and g) isolating pure ziprasidone. The term "pure ziprasidone" refers to ziprasidone having the HPLC purity is more than 99.5%. Preferable HPLC purity is 99.8%.

The alcohol solvent used in step (a) is a solvent or mixture of solvents selected from methanol, ethanol, n-propyl alcohol, isopropyl alcohol, isobutanol, n-butanol and tertiary butanol. Preferable alcohol solvent is methanol.

The organic acid used in step (b) may preferably be selected from p- toluenesulfonic acid, acetic acid, methane sulfonic acid, ethane sulfonic acid, tartaric acid and benzenesulfonic acid. More preferable organic acid is p- toluenesulfonic acid.

The addition and isolation in step (b) may be carried out at reflux.

The heating in step (d) may preferably carried out at 60 to 70 C for 30 minutes.

The precipitated solid may be isolated from the contents by methods such as filtration or centrifugation. If required the isolation of the pure ziprasidone may be performed by the methods known in the art such as by cooling, using an antisolvent, by partial evaporation or a combination thereof followed by filtration or a centrifugation.

Optionally, the pure ziprasidone is converted to ziprasidone pharmaceutical acceptable salts such as ziprasidone hydrochloride.

The invention will now be further described by the following examples, which are illustrative rather than limiting.

Preparative example

Preparation of Ziprasidone

Sodium carbonate (50 gm) was dissolved in water (1225 ml) at 25 to 30°C and then added l -(l ,2-benzisothiazol-3-yl)piperazine (47 gm). The reaction mass was stirred for 10 minutes and 6-chloro-5-(2-chloroethyl)oxindole (50 gm) was added to reaction mass at 25 to 30°C. To the reaction mass was added sodium iodide (1 gm) and tetrabutylammonium chloride (1 gm) at 25 to 30°C, and then heated to reflux for 9 hours. The reaction mass was poured into ice and added water (1000 ml), filtered and washed with water (200 ml). The solid obtained was dissolved in methanol (700 ml) and heated to reflux for 1 hour, filtered. The solid obtained was washed with methanol (100 ml) and dried at 50 to 55°C for 5 hours to obtain 70 gm of ziprasidone (HPLC Purity: 98%).

Examples

Example 1 :

Preparation of pure ziprasidone

Ziprasidone (100 gm) as obtained in preparative example was dissolved in methanol (3000 ml) and heated to reflux, and then added p-toluenesulfonic acid (150 gm) at reflux. The reaction mixture was maintained for 30 minutes at reflux, filtered, dried at 65°C to obtain ziprasidone tosylate.

Ziprasidone tosylate was added to water (1200 ml) and aqueous ammonia (15%, 150 ml) at room temperature. The contents were heated to 65°C and maintained for 30 minutes, filtered. The solid obtained was washed with water to obtain a wet solid.

To the above wet solid was added tetrahydrofuran (100 ml) and heated to reflux, maintained for 30 minutes at reflux. The separated solid was filtered and dried at 65°C to obtain 65 gm of pure ziprasidone (HPLC Purity: 99.8%).

Example 2:

Preparation of ziprasidone hydrochloride

Pure ziprasidone (65 gm) as obtained in example 1 was added methylene dichloride (100 ml) at room temperature. The contents were cooled to 0°C and stirred for 35 minutes. Isopropylalcohol hydrochloride (100 ml) was added to reaction mass at 0°C and maintained for 10 minutes, filtered. The solid obtained was washed with methylene dichloride and dried at 65°C to obtain 60 gm of ziprasidone hydrochloride.

Claims

We claim

1. A process for the preparation of pure ziprasidone, which comprises:

a. providing a solution of ziprasidone in alcohol solvent at reflux; b. adding an organic acid to the solution obtained in step (a) and isolating ziprasidone organic acid salt from the solution as solid; c. mixing ziprasidone organic acid salt obtained in step (b) with aqueous ammonia;

d. heating the contents obtained in step (c) at 60 to 80°C for at least 15 minutes;

e. isolating ziprasidone from the contents as solid;

f. refluxing ziprasidone obtained in step (e) with tertrahydrofuran; and g. isolating pure ziprasidone.

2. The process according to claim 1, wherein the alcohol solvent used in step (a) is a solvent or mixture of solvents selected from methanol, ethanol, n-propyl alcohol, isopropyl alcohol, isobutanol, n-butanol and tertiary butanol.

3. The process according to claim 2, wherein the alcohol solvent is methanol.

4. The process according to claim 1, wherein the organic acid used in step (b) is selected from p-toluenesulfonic acid, acetic acid, methane sulfonic acid, ethane sulfonic acid, tartaric acid and benzenesulfonic acid.

5. The process according to claim 4, wherein the organic acid is p- toluenesulfonic acid.

6. The process according to claim 1, wherein the addition and isolation in step (b) is carried out at reflux.

7. The process according to claim 1, wherein the heating in step (d) is carried out at 60 to 70°C for 30 minutes.