FIELD OF INVENTION
The present invention relates to an improved method for the manufacture of Ziprasidone of the formula (I), chemically known as 5-(2-(4-(l,2-benzisothiazol-3-yl)-l-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one and identified by the CAS registration number [146939-27-7], which is an antipsychotic agent used for the treatment of schizophrenia.
BACKGROUND OF THE INVENTION
Ziprasidone of formula (I) is generically covered in the US Patent 4,831,031 that discloses its synthesis by the reaction of 3-piperazinylbenzo[d]isothiazole of formula (II) (hereinafter, PBT) and 6-chloro-5-(2-chloroethyl)indolin-2-one of formula (III) (hereinafter, CEOI) in a polar organic solvent such as ethanol, dimethylformamide or methylisobutyl ketone; in the presence of a tertiary amine base such as triethylamine or diisopropylethylamine or alkali metal base such as sodium carbonate, and in the further presence of catalytic amount of sodium iodide. The final product is purified by chromatography. This method suffers from the following disadvantages,
1) Longer reaction time of 24 to 72 hours,
2) Formation of considerable quantities of by products,
3) Special purification techniques like chromatography and,
Moreover, when practiced in the laboratory, the process of US 4,831,031 resulted in low yield from 14 to 22%.
US Patent 5,206,366 discloses and claims a process for making Ziprasidone (I) by reacting PBT free base and CEOI in water and in the presence of neutralizing agent sodium carbonate, at refluxing temperature for about 9 to 12 hours.
US Patent 5,338,846, which is a continuation-in-part of US 5,206,366, discloses and claims a process for the preparation of hydrochloride salt of Ziprasidone (I). The Ziprasidone free base is prepared by reacting PBT hydrochloride and CEOI by refluxing hydrochloride salt of (II) with (III) in water and in presence of a neutralizing agent sodium carbonate for about 8 to 16 hours.
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WO 2005/040160 discloses and claims a process of similar coupling in various solvents that include water, alcohols, glycols, sulfolane and tolune, in presence of bases like sodium carbonate.
WO 2005/085240 discloses and claims similar coupling in water, without employing any base.
The above-mentioned methods have the following disadvantages,
1) Require tedious purification procedures such as chromatographic separation.
2) The present inventors have found that the presence of base, as per the prior art
disclosed methods discussed hereinbefore, increases impurity level of the reaction
mass so that it becomes a dark, thick gummy mass which does not allow
precipitation of the product as a filterable solid mass. The residue needs further
tedious purification that increases the cost of the process and decreases process
efficiency.
Surprisingly, the present inventors have found that the above coupling reaction to manufacture Ziprasidone (I) can be effectively carried out by mixing 3-piperazinylbenzo[d]isothiazole (II) and 6-chloro-5-(2-chloroethyl)indolin-2-one (III) and heating in a non-aqueous medium, for instance sulfolane, without employing such external bases, thus overcoming the limitations of the prior art discussed hereinbefore.
SUMMARY OF THE INVENTION
The scope of the present invention is to provide an improved method to manufacture Ziprasidone (I) by the coupling of free base piperazine derivative (II) with oxindole derivative of formula (III) by heating in a non-aqueous suspending liquid, for example, sulfolane, without the need of any external base and optionally in presence of a catalyst.
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DETAILED DESCRIPTION OF THE INVENTION
The coupling reaction of this instant invention is an equimolecular condensation reaction between an amine (piperazine derivative, a nitrogen containing organic base) and a chloroethyl oxindole derivative. During the condensation hydrochloric acid (HC1) is liberated which needs to be scavenged.
Accordingly, this instant invention provides a process wherein the piperazine derivative of formula (II) is used in a molar ratio excess to the oxindole derivative of formula (III). The preferred molar ratio of the piperazine derivative of formula (II) and the oxindole derivative of formula (III) ranges between 1:1 and 2.5:1, more preferably between 1.2:1 and 2:1. The excess quantity of the piperizine derivative (II) captures the HC1. Hence the reaction takes place even without the addition of any external inorganic or organic base.
The said coupling of the free base piperazine derivative (II) with oxindole derivative of formula (III) is effected by heating the mixture of (II) and (III) in a non-aqueous suspending liquid, for example, sulfolane, at a temperature in the range of 50° to 150°C. The most preferred temperature is 80-90°C.
Alkali metal halides, for example, sodium or potassium iodides, are optionally used in the reaction as a catalyst.
The process of the present invention results in a pure Ziprasidone, which precipitates as a filterable solid mass. The product may be purified by washing with acetone.
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The ziprasidone obtained by the process of the present invention can be converted to its hydrochloride or other pharmaceutically acceptable salts by known methods.
The invention is further illustrated by the following non-limiting example. Example 1
Preparation of 5-(2-(4-(l,2-benzisothiazol-3-yl)-l-piperazinyl)ethyl)-6-chloro-l,3-dihydro-2H-indol-2-one (Ziprasidone)
To a solution of sulfolane (69 ml), 5-(2-chloroethyl)-6-chloro-oxindole (23 g, 0.1 mole) and l-(l,2-benzothiozol-3-yl) piperazine (43.7 g, 0.2 mole), KI (1.15 g, 5%) was added at 30-35°C. The mixture was slowly heated under stirring to 80-90°C over 60-90min. The mixture was stirred for 24-26 hr, after completion of the reaction as monitored by HPLC, the reaction mass was cooled to room temperature. Added water (230 ml) and stirred the reaction mass for 60 min. The solid was filtered and washed with water (115 ml). Suck dry the solid for 2 hr. The wet solid was stirred with acetone (230 ml) for 60 min. Filtered the solid with acetone (50 ml) dried the solid under vacuum at 40°C for 4-5 hr. Yield: 24 g (57%) Purity by HPLC: ~ 90%
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WE CLAIM
1. A process for preparing the compound of formula (I)

comprising of reacting a piperazine derivative of formula (II) and an oxindole derivative of formula (III),

in a non-aqueous suspending liquid, in the absence of an external base, optionally in presence of a catalyst.
2. The process as claimed in claim 1, wherein the molar ratio of the piperazine
derivative of formula (II) and the oxindole derivative of formula (III) ranges
between 1:1 and 2.5:1.
3. The process as claimed in claim 1, wherein the molar ratio of the piperazine
derivative of formula (II) and the oxindole derivative of formula (III) ranges
between 1.2:1 and 2:1.
4. The process as claimed in any of the preceding claims wherein the temperature of
the reaction is in the range of 50° to 150°C.
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5. The process as claimed in any of the preceding claims wherein the non-aqueous
suspending liquid is sulfolane.
6. The process as claimed in any of the preceding claims wherein the catalyst is
selected from sodium iodide and potassium iodide.
Dated this 8th day of December 2006

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An improved method for preparing a compound of formula (I)
which comprises of coupling the piperazine derivative of formula (II) with oxindole derivative of formula (III)
by heating in a non-aqueous medium, in the absence of an external base and optionally in presence of a catalyst.