Indian Patents. 271004:AN IMPROVED PROCESS FOR THE PREPARATION AND PURIFICATION OF ZIPRASIDONE

Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION AND PURIFICATION OF ZIPRASIDONE
Abstract	The present invention relates to a process for the preparation and purification of 5-[2-[4-(l, 2- benzisothiazol-3-yl)-l-piperazinyl] ethyl]-6- chloro-1, 3-dihydro-2 H -indol-2-one, also known as ziprasidone.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 OF 1970) & PATENTS RULES, 2006 PROVISIONAL SPECIFICATION (SECTION 10; RULE 13) "AN IMPROVED PROCESS FOR THE PREPARATION AND PURIFICATION OF ZIPRASIDONE" ALKEM LABORATORIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE. OFFICE AT ALKEM HOUSE, DEVASHISH, ADJACENT TO MATULYA CENTRE, S.B.MARG, LOWER PAREL, MUMBAI - 400013, MAHARASHTRA, INDIA THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED FIELD OF THE INVENTION The present invention relates to an improved process for the preparation and purification of ziprasidone. BACKGROUND OF THE INVENTION Ziprasidone is an antipsychotic agent with the following chemical name: 5-[2-[4-(l, 2- benzisothiazol-3-yl)-l-pi perazinyl] ethyl]-6- chloro-l,3-dihydro-2 H -indol-2-one of formula (I) o> — J*, i "VoN H (1) Ziprasidone is disclosed in U.S. Patent no. 4,831,031 and 5,312,925 (assigned to Pfizer). Ziprasidone inhibits synaptic reuptake of serotonin and norepinephrine. No appreciable affinity was exhibited for other receptor/binding sites tested, including the cholinergic muscarinic receptor. The mechanism of action of ziprasidone, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that this drug's efficacy in schizophrenia is mediated through a combination of dopamine type 2 (D 2) and serotonin type 2 (5HT 2) antagonism. Ziprasidone's antagonism of histamine H receptors may explain the somnolence observed with this drug. US 5,312,925 (Pfizer Inc.) describes a process for the synthesis of monohydrate of 5-(2- (4-(l,2-benzisothiazol-3-yl)piperazinyl)ethyl)-G-chloro-l,3-dihydro-2H-indol-2-one hydrochloride and its characterization based on IR, XRD and moisture content,. The '925 patent also discloses that the he mi hydrate may be obtained by the process described in Example 10 of US Patent No. 4,831,031 and their characterization by IR, XRD and moisture content. It also discloses the IR, XRD and moisture content of anhydrous Ziprasidone hydrochloride. According to the invention in the '925 patent, water content having 3.97, 2.55 and 0.37 % were used for the IR and XRD study of Ziprasidone hydrochloride monohydrate, hemihydrate and anhydrous. In this invention, the monohydrate of Ziprasidone hydrochloride was prepared by reacting anhydrous 5- (2-(4-l,2-benzisothiazol-3-yl)piperazinyl)ethyl)-6-chloro-l,3-dihydro-2H-indol-2-one with aqueous hydrochloric acid. The temperature range of the reaction was maintained between 60 to 65 °C and aqueous hydrochloride used for salt formation was around 0.7 M. Depending on the reaction temperature and other conditions, the reaction times were set around 3 to 24 hours. The final product thus obtained was dried carefully monitored conditions to make certain that water content was from about 3.8 % to about 4.5 % to obtain the stable monohydrate. US Patent No. 6,150,366, discloses a manufacturing process of ziprasidone hydrochloride monohydrate, which states: 1) dissolving ziprasidone free base in a solvent comprising THF and water, in a volume ratio of about 22-35 unit volumes of THF to about 1.5-8 volumes of water; 2) heating the solution resulting from step (1); 3) adding HC1 to the solution resulting from step (2); and 4) cooling the solution resulting from step (3) and crystals were collected by filtration and drying. j US 5,206,366 and US 5,338,846 describe a process for preparing ziprasidone by reacting 1-(1, 2-benzisothiazol-3-yl) piperazine with 5-(2-chloroethyl)-6-chloro-oxindole in water with a neutralizing agent such as sodium carbonate under reflux. J. Med. Chem. 1996, 39, 143-148 discloses preparation of ziprasidone 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. Some salts of ziprasidone, and in particular, its hydrochloride salt is a potent commercial antipsychotic agent useful in the treatment of various disorders, including schizophrenia and anxiety diseases. Ziprasidone hydrochloride is currently marketed under the proprietary name of Geodon. Other salts of ziprasidone are also reported to be effective for the treatment of the same type of diseases. Some of the processes described in the aforementioned patents necessitate the use of ion-exchange catalyst (i.e. sodium iodide) and/or phase transfer catalysts (for example tetra butyl ammonium bromide or tetra butyl phosphoriium bromide) in order for the coupling reaction producing ziprasidone to take place. For example, U.S. Patent No. 4,831, 031 indicates that arylpiperazinyl-ethyl (or butyl)-heterocydic compounds may be prepared by reacting piperazines of the formula II with compounds of the formula III as follows: Ar—N Nli+hai(t>>li,)'/- \ K ii in Wherein Hal is fluoro, chioro, bromo or iodo; and Ar is naphthyl optionally substituted by fluoro, chioro, tritluoromethyl, methoxy, cyano or nitro; quinolyl; isoquinolyl; 6-hydroxy-8-quinolyl; benzoisothiazolyl or an oxide or dioxide thereof, each optionally substituted by fluoro, chioro, trifluoromethyl, methoxy, cyano, or nitro; benzothiazolyl; benzothiadiazolyl; benzotriazolyl; benzoxazolyl; benzoxazolonyl; indolyl; indanyl optionally substituted by one or two fluoro; 3-indazolyl optionally substituted by 1-trifluoromethylphenyl; or phthalazinyl; n is 1 or 2; and X and Y together with the phenyl to which they are attached form quinolyl; 2-hydroxyquinolyl; benzothiazolyl; 2-aminobenzothiazolyl; benzoisothiazolyl; indazolyl; 3-hydroxyindazolyl; indolyl; spiro[cyclopentane-l,3'-indolinyl]; oxindolyl; optionally substituted by one to three of (Ci-O,) alkyl, or one of chioro, fluoro or phenyl, said phenyl optionally substituted by one chioro or fluoro; benzoxazolyl; 2-aminobenzoxazolyl; benzoxazolonyl; 2-aminobenzoxazoimyl; benzol hiazolony I; bonzoimidazolonyl; or benzotriazolyl. According to the '031 patent the coupling reaction is generally conducted in a polar solvent, such as a lower alcohol, dimethylformamide or methylisobutylketone, and in the presence of a weak base and that, preferably, the reaction is in the further presence of a catalytic amount of sodium iodide, and a neutralizing agent for hydrochloride such as sodium carbonate. Another process uses potentially explosive gases such as hydrogen in the presence of catalysts, for example zinc, palladium on carbon, followed by acid treatment to carry out a reduction and cyclization of an intermediate, in order to obtain ziprasidone. Other processes utilize very large volumes of solvents such as tetrahydrofuran to accomplish the clarification and purification of crude ziprasidone (nearly 40 times the amount of crude ziprasidone, i.e. 40 volumes), thus severely limiting the utility of the process for large-scale manufacturing purposes. In some instances, the ziprasidone obtained in those manners was purified by column chromatography, thus making the process impractical for large-scale preparations. Purification of ziprasidone base is revealed in various solvents. The solubility of ziprasidone free base is poor in most of the organic solvents. Normally huge volumes of solvents are used for purification. United Sates Patent Application No. 2005/0049295A1 uses 18.75 times of methanol and G.25 volumes of chloroform. PCTApplication No. WO03/099198 uses 20 times by volume THF for the purification of 1PA wet free base. PCT Application No. WO03/070246 uses 52 times by volumes for the purification. The above references indicate the need for suitable purification procedure for the manufacture of pure ziprasidone free base. 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 thereof in high purity and yield. The present invention provides a process for the preparation and purification of ziprasidone in high yields and purity, suitable for large-scale manufacturing, which helps to overcome some of the deficiencies of the prior art. SUMMARY OF THE INVENTION The present invention relates to a process for the preparation and purification of 5-[2-[4-(l, 2- benzisothiazol-3-yl)-l-piperazinyl] ethyl]-6- chloro-1, 3-dihydro-2 H -indol-2-one, also known as ziprasidone, of formula I. DETAILED DESCRIPTION OF THE INVENTION This present invention provides a process for the preparation and purification of 5-[2-[4-(l, 2- benzisothiazol-3-yl)-l-piperazinyl] ethyl]-6- chloro-1, 3-dihydro-2 H -indol-2-one, also known as ziprasidone, of formula I. Surprisingly, we have found that by using a dispersing agent in the prior art process, we were able to produce pharmaceutical grade ziprasidone in an efficient manner with a yield and purity higher than the prior art processes. The purpose of using dispersing agent under nitrogen atmosphere, in the reaction is to overcome the problem of sticky mass that is generated during the reaction. This sticky mass is not easily soluble in water and may cause problems in the reaction during manufacture. Additionally the use of a dispersing agent results in pharmaceutical grade ziprasidone in an efficient manner with a yield and purity higher than the prior art processes. The compounds that can be used as dispersing agent are for example polymers of the arylsulphonate type, in particvilar the alkaline polynaphthalene sulphonates obtained by condensation of (alkyl) aryl sulphonate derivatives with formaldehyde, lignosulphonates (for example: sodium lignosulfonate and calcium lignosulphate), the polyphenol sulphonates, the salts of polyacrylic acids, the sails of lignosulphonic acids (for example: the sodium salt of polymerized lignosuiphonic acids of the Kraft type), the salts of sulphonic phenol acids or sulphonic naphthalenes, the phosphoric esters of alcohols or of polyethoxylated phenols, the esters of fatty acids and of polyols, derivatives with a sulphates, sulphonafces and phosphates function of the preceding compounds. Suitable for use as dispersants are, for example, modified sodium lignosulfonates, such as Borresperse Na.RTM., Ufoxane 3A.RTM and Ultrazine Na.RTM. (Borregard), Craft sodium lignosulfonates, such as Reax 88 B.RTM. (Westvaco) or naphthaline-formaldehyde condensates, such as Dispersing Agent SI.RTM. (Clariant GmbH), Morwet D425. (Witco Corporation) and Galoryl DT 201. RTM (CFPI). Preferred dispersants are sodium salts of alkylnaphthylsulfonic acid/formaldehyde condensates and sodium lignosulfonate which are commercially available, for example, under the trade names Morwet D425 and having the structure below:. / SO-.iSa \J^™r Wherein n ranges from 2 to 9, Therefore based on the object of discovering that the dispersing agents particularly Morwet D425 was found to give a product with lesser impurities, an efficient, high-yield and being a significantly cheaper raw material, it becomes an excellent source for the production of 5-[2-[4-(l,2- benzisothiazol-3-yl)-l-pi perazinyl] ethyl]-6- chloro-l,3-dihydro-2 H -indol-2-one. The invention accordingly provides, in a first aspect, use of dispersing agent such as Morwet D425 in the prior art process in presence of a base such as for example sodium hydroxide or sodium carbonate. The invention accordingly provides, in another aspect, use of dispersing agent such as Morwet D425 in the prior art process in absence of any base. In an embodiment of the present invention, piperazine benzisothiazole hydrochloride, 5-(2-chloroefchyl)-6-chlorooxindole, Sodium hydroxide in which water is added 20 times based on oxindole weight and 1 % of dispersing agent Morwet D425 is mixed. All these reactants are charged in to the flask and refluxed under nitrogen, under stirring for 12-16hr. After the completion of the reaction, the reaction mass is then cooled to room temperature and the resulting mass is filtered. It is slurried in IPA and then in water and isolated by filtration. The solid is dried at 95-100°C As previously stated, this invention provides improvement in processes known to those skilled in the art, for normally, huge volumes of solvents are used for purification in the various patent applications for the purification. Therefore this invention is particularly applicable to the commercially significant process of purifying the Ziprasidone that may otherwise severely limit the utility of the process for large-scale manufacturing purposes. The improved purification process of the instant invention provides increased efficiency through improved and suitable purification procedure for the manufacture of pure ziprasidone free base by the soxhlet extraction using tetrahydrofuran as solvent. Pure compound is obtained after G-10 extractions depending on the purity of the product. The following example illustrates the [(reparation of ziprasidone and is not to be construed as limiting the scope of the invention in any manner. EXAMPLE 1 1 mole of l-(l,2-bonzisothiazol-;5-yI)pipera/.ine hydrochloride, 1 mole of 5-(2-ehloroethyI)-(5-chlorooxindole, ',).'.) mole of Sodium carbonate, water 5.2 times based on oxindole weight, and 1 % of dispersing agent Morwet. All the reactants are charged in to the flask and refluxed under nitrogen, under stirring for 12-16hr. After the completion of the reaction, the reaction mass is cooled to room temperature and the resulting mass is filtered. It is slurred in IPA and then in water and isolated by filtration. The solid is dried at 95-100°C and purified as per the procedure given in example 5. Yield: 90 %; Purity: 100.30% EXAMPLE 2 1 mole of l-(l,2-benzisothiazol-3-yl)piperazine hydrochloride, 1 mole of 5-(2-chloroethyl)-6-chlorooxindole, 3.3 mole of Sodium carbonate, water 7.5 times based on oxindole weight and 1 % of dispersing agent Morwet. All the reactants are charged in to the flask and refluxed under nitrogen, under stirring for 12-l6hr. After the completion of the reaction, the reaction mass is cooled to room temperature and the resulting mass is filtered. It is slurred in IPA and then in water and isolated by filtration. The solid is dried at 95-100°C and is purified as per the procedure given in example 5. Yield: 93 %; Purity: 99.3% EXAMPLE 3 2.2 moles of l-(l,2-benzisothiazol-3-yl)piperazine hydrochloride , 1 mol of 5-(2-chloroethyl)-6-chlorooxindole, 2.2 mo! of Sodium hydroxide, water 20 times based on oxindole weight and 1 % of dispersing agent Morwet. All the reactants are charged in to the flask and refluxed under nitrogen, under stirring for 12-l6hr. After the completion of the reaction, the reaction mass is cooled to room temperature and the resulting mass is filtered. It is slurried in IPA and then in water and isolated by filtration. The solid is dried at 95-100°C and purified as per the procedure given in example 5. Yield: 90%; Purity: 98% EXAMPLE 4 2 moles of l-(l,2-benzisothiazol-3-yl)piperazine, 1 mole of 5-(2-chloroethyl)-6-chlorooxindole in water (20 times based on benzisothiazole) and in the presence of dispersing agent. All the reactants are charged in to the flask and refluxed under nitrogen, under stirring for 12-l6hr. After the completion of the reaction, the reaction mass is cooled to room temperature and the resulting mass is filtered. It is slurried in IPA and then in water and isolated by filtration. The solid is dried at 95-100°C and is purified as per the procedure given in example 5. Yield: 90-92%, purity 98 % EXAMPLE 5 Purification of ziprasidone: Ziprasidone free base (50 g) is taken in the thimble and subjected to soxhlet extraction using THF (200 ml) as solvent. Pure compound is obtained after 6-10 extractions depending on the purity of the product. The product remaining in the thimble is of purity 99 % min. The resulting product is isolated and dried at 90 to 100 deg C. Recovery of the product is 95-97%. Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. It should be emphasized that the above-described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the principles of the invention. Accordingly, it is to be understood that the drawings and descriptions herein are proffered by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
PATENTS RULES, 2006
PROVISIONAL SPECIFICATION
(SECTION 10; RULE 13)
"AN IMPROVED PROCESS FOR THE PREPARATION AND PURIFICATION OF ZIPRASIDONE"
ALKEM LABORATORIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE. OFFICE AT ALKEM HOUSE, DEVASHISH, ADJACENT TO MATULYA CENTRE, S.B.MARG, LOWER PAREL, MUMBAI - 400013, MAHARASHTRA, INDIA
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation and purification of ziprasidone.
BACKGROUND OF THE INVENTION
Ziprasidone is an antipsychotic agent with the following chemical name: 5-[2-[4-(l, 2- benzisothiazol-3-yl)-l-pi perazinyl] ethyl]-6- chloro-l,3-dihydro-2 H -indol-2-one of formula (I)

o> — J*, i "VoN H

(1)

Ziprasidone is disclosed in U.S. Patent no. 4,831,031 and 5,312,925 (assigned to Pfizer). Ziprasidone inhibits synaptic reuptake of serotonin and norepinephrine. No appreciable affinity was exhibited for other receptor/binding sites tested, including the cholinergic muscarinic receptor. The mechanism of action of ziprasidone, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that this drug's efficacy in schizophrenia is mediated through a combination of dopamine type 2 (D 2) and serotonin type 2 (5HT 2) antagonism. Ziprasidone's antagonism of histamine H receptors may explain the somnolence observed with this drug.
US 5,312,925 (Pfizer Inc.) describes a process for the synthesis of monohydrate of 5-(2- (4-(l,2-benzisothiazol-3-yl)piperazinyl)ethyl)-G-chloro-l,3-dihydro-2H-indol-2-one hydrochloride and its characterization based on IR, XRD and moisture content,. The '925 patent also discloses that the he mi hydrate may be obtained by the process described in Example 10 of US Patent No. 4,831,031

and their characterization by IR, XRD and moisture content. It also discloses the IR, XRD and moisture content of anhydrous Ziprasidone hydrochloride. According to the invention in the '925 patent, water content having 3.97, 2.55 and 0.37 % were used for the IR and XRD study of Ziprasidone hydrochloride monohydrate, hemihydrate and anhydrous. In this invention, the monohydrate of Ziprasidone hydrochloride was prepared by reacting anhydrous 5- (2-(4-l,2-benzisothiazol-3-yl)piperazinyl)ethyl)-6-chloro-l,3-dihydro-2H-indol-2-one with aqueous hydrochloric acid. The temperature range of the reaction was maintained between 60 to 65 °C and aqueous hydrochloride used for salt formation was around 0.7 M. Depending on the reaction temperature and other conditions, the reaction times were set around 3 to 24 hours. The final product thus obtained was dried carefully monitored conditions to make certain that water content was from about 3.8 % to about 4.5 % to obtain the stable monohydrate.
US Patent No. 6,150,366, discloses a manufacturing process of ziprasidone
hydrochloride monohydrate, which states: 1) dissolving ziprasidone free base
in a solvent comprising THF and water, in a volume ratio of about 22-35 unit
volumes of THF to about 1.5-8 volumes of water; 2) heating the solution
resulting from step (1); 3) adding HC1 to the solution resulting from step (2);
and 4) cooling the solution resulting from step (3) and crystals were collected
by filtration and drying. j
US 5,206,366 and US 5,338,846 describe a process for preparing ziprasidone by reacting 1-(1, 2-benzisothiazol-3-yl) piperazine with 5-(2-chloroethyl)-6-chloro-oxindole in water with a neutralizing agent such as sodium carbonate under reflux.
J. Med. Chem. 1996, 39, 143-148 discloses preparation of ziprasidone 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.
Some salts of ziprasidone, and in particular, its hydrochloride salt is a potent commercial antipsychotic agent useful in the treatment of various disorders, including schizophrenia and anxiety diseases. Ziprasidone hydrochloride is

currently marketed under the proprietary name of Geodon. Other salts of ziprasidone are also reported to be effective for the treatment of the same type of diseases.
Some of the processes described in the aforementioned patents necessitate the use of ion-exchange catalyst (i.e. sodium iodide) and/or phase transfer catalysts (for example tetra butyl ammonium bromide or tetra butyl phosphoriium bromide) in order for the coupling reaction producing ziprasidone to take place. For example, U.S. Patent No. 4,831, 031 indicates that arylpiperazinyl-ethyl (or butyl)-heterocydic compounds may be prepared by reacting piperazines of the formula II with compounds of the formula III as follows:

Ar—N

Nli+hai(t>>li,)'/- \ K

ii

in

Wherein Hal is fluoro, chioro, bromo or iodo; and Ar is naphthyl optionally substituted by fluoro, chioro, tritluoromethyl, methoxy, cyano or nitro; quinolyl; isoquinolyl; 6-hydroxy-8-quinolyl; benzoisothiazolyl or an oxide or dioxide thereof, each optionally substituted by fluoro, chioro, trifluoromethyl, methoxy, cyano, or nitro; benzothiazolyl; benzothiadiazolyl; benzotriazolyl; benzoxazolyl; benzoxazolonyl; indolyl; indanyl optionally substituted by one or two fluoro; 3-indazolyl optionally substituted by 1-trifluoromethylphenyl; or phthalazinyl; n is 1 or 2; and X and Y together with the phenyl to which they are attached form quinolyl; 2-hydroxyquinolyl; benzothiazolyl; 2-aminobenzothiazolyl; benzoisothiazolyl; indazolyl; 3-hydroxyindazolyl; indolyl; spiro[cyclopentane-l,3'-indolinyl]; oxindolyl; optionally substituted by one to three of (Ci-O,) alkyl, or one of chioro, fluoro or phenyl, said phenyl optionally substituted by one chioro or fluoro; benzoxazolyl; 2-aminobenzoxazolyl; benzoxazolonyl; 2-aminobenzoxazoimyl; benzol hiazolony I; bonzoimidazolonyl; or benzotriazolyl. According to the '031 patent the coupling reaction is

generally conducted in a polar solvent, such as a lower alcohol, dimethylformamide or methylisobutylketone, and in the presence of a weak base and that, preferably, the reaction is in the further presence of a catalytic amount of sodium iodide, and a neutralizing agent for hydrochloride such as sodium carbonate.
Another process uses potentially explosive gases such as hydrogen in the presence of catalysts, for example zinc, palladium on carbon, followed by acid treatment to carry out a reduction and cyclization of an intermediate, in order to obtain ziprasidone. Other processes utilize very large volumes of solvents such as tetrahydrofuran to accomplish the clarification and purification of crude ziprasidone (nearly 40 times the amount of crude ziprasidone, i.e. 40 volumes), thus severely limiting the utility of the process for large-scale manufacturing purposes.
In some instances, the ziprasidone obtained in those manners was purified by column chromatography, thus making the process impractical for large-scale preparations. Purification of ziprasidone base is revealed in various solvents. The solubility of ziprasidone free base is poor in most of the organic solvents. Normally huge volumes of solvents are used for purification. United Sates Patent Application No. 2005/0049295A1 uses 18.75 times of methanol and G.25 volumes of chloroform. PCTApplication No. WO03/099198 uses 20 times by volume THF for the purification of 1PA wet free base. PCT Application No. WO03/070246 uses 52 times by volumes for the purification. The above references indicate the need for suitable purification procedure for the manufacture of pure ziprasidone free base.
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 thereof in high purity and yield.
The present invention provides a process for the preparation and purification of ziprasidone in high yields and purity, suitable for large-scale

manufacturing, which helps to overcome some of the deficiencies of the prior art.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation and purification of 5-[2-[4-(l, 2- benzisothiazol-3-yl)-l-piperazinyl] ethyl]-6- chloro-1, 3-dihydro-2 H -indol-2-one, also known as ziprasidone, of formula I.
DETAILED DESCRIPTION OF THE INVENTION
This present invention provides a process for the preparation and purification of 5-[2-[4-(l, 2- benzisothiazol-3-yl)-l-piperazinyl] ethyl]-6- chloro-1, 3-dihydro-2 H -indol-2-one, also known as ziprasidone, of formula I.
Surprisingly, we have found that by using a dispersing agent in the prior art process, we were able to produce pharmaceutical grade ziprasidone in an efficient manner with a yield and purity higher than the prior art processes.
The purpose of using dispersing agent under nitrogen atmosphere, in the reaction is to overcome the problem of sticky mass that is generated during the reaction. This sticky mass is not easily soluble in water and may cause problems in the reaction during manufacture. Additionally the use of a dispersing agent results in pharmaceutical grade ziprasidone in an efficient manner with a yield and purity higher than the prior art processes.
The compounds that can be used as dispersing agent are for example polymers of the arylsulphonate type, in particvilar the alkaline polynaphthalene sulphonates obtained by condensation of (alkyl) aryl sulphonate derivatives with formaldehyde, lignosulphonates (for example: sodium lignosulfonate and calcium lignosulphate), the polyphenol sulphonates, the salts of polyacrylic acids, the sails of lignosulphonic acids (for example: the sodium salt of polymerized lignosuiphonic acids of the Kraft type), the salts of sulphonic phenol acids or sulphonic naphthalenes, the phosphoric esters of alcohols or of

polyethoxylated phenols, the esters of fatty acids and of polyols, derivatives with a sulphates, sulphonafces and phosphates function of the preceding compounds.
Suitable for use as dispersants are, for example, modified sodium lignosulfonates, such as Borresperse Na.RTM., Ufoxane 3A.RTM and Ultrazine Na.RTM. (Borregard), Craft sodium lignosulfonates, such as Reax 88 B.RTM. (Westvaco) or naphthaline-formaldehyde condensates, such as Dispersing Agent SI.RTM. (Clariant GmbH), Morwet D425. (Witco Corporation) and Galoryl DT 201. RTM (CFPI).
Preferred dispersants are sodium salts of alkylnaphthylsulfonic acid/formaldehyde condensates and sodium lignosulfonate which are commercially available, for example, under the trade names Morwet D425 and having the structure below:.

/

SO-.iSa

\J^™r
Wherein n ranges from 2 to 9,
Therefore based on the object of discovering that the dispersing agents particularly Morwet D425 was found to give a product with lesser impurities, an efficient, high-yield and being a significantly cheaper raw material, it becomes an excellent source for the production of 5-[2-[4-(l,2- benzisothiazol-3-yl)-l-pi perazinyl] ethyl]-6- chloro-l,3-dihydro-2 H -indol-2-one. The invention accordingly provides, in a first aspect, use of dispersing agent such as Morwet D425 in the prior art process in presence of a base such as for example sodium hydroxide or sodium carbonate.

The invention accordingly provides, in another aspect, use of dispersing agent such as Morwet D425 in the prior art process in absence of any base.
In an embodiment of the present invention, piperazine benzisothiazole hydrochloride, 5-(2-chloroefchyl)-6-chlorooxindole, Sodium hydroxide in which water is added 20 times based on oxindole weight and 1 % of dispersing agent Morwet D425 is mixed. All these reactants are charged in to the flask and refluxed under nitrogen, under stirring for 12-16hr. After the completion of the reaction, the reaction mass is then cooled to room temperature and the resulting mass is filtered. It is slurried in IPA and then in water and isolated by filtration. The solid is dried at 95-100°C
As previously stated, this invention provides improvement in processes known to those skilled in the art, for normally, huge volumes of solvents are used for purification in the various patent applications for the purification. Therefore this invention is particularly applicable to the commercially significant process of purifying the Ziprasidone that may otherwise severely limit the utility of the process for large-scale manufacturing purposes. The improved purification process of the instant invention provides increased efficiency through improved and suitable purification procedure for the manufacture of pure ziprasidone free base by the soxhlet extraction using tetrahydrofuran as solvent. Pure compound is obtained after G-10 extractions depending on the purity of the product.
The following example illustrates the [(reparation of ziprasidone and is not to be construed as limiting the scope of the invention in any manner.
EXAMPLE 1
1 mole of l-(l,2-bonzisothiazol-;5-yI)pipera/.ine hydrochloride, 1 mole of 5-(2-ehloroethyI)-(5-chlorooxindole, ',).'.) mole of Sodium carbonate, water 5.2 times based on oxindole weight, and 1 % of dispersing agent Morwet. All the

reactants are charged in to the flask and refluxed under nitrogen, under stirring for 12-16hr. After the completion of the reaction, the reaction mass is cooled to room temperature and the resulting mass is filtered. It is slurred in IPA and then in water and isolated by filtration. The solid is dried at 95-100°C and purified as per the procedure given in example 5.
Yield: 90 %; Purity: 100.30%
EXAMPLE 2
1 mole of l-(l,2-benzisothiazol-3-yl)piperazine hydrochloride, 1 mole of 5-(2-chloroethyl)-6-chlorooxindole, 3.3 mole of Sodium carbonate, water 7.5 times based on oxindole weight and 1 % of dispersing agent Morwet. All the reactants are charged in to the flask and refluxed under nitrogen, under stirring for 12-l6hr. After the completion of the reaction, the reaction mass is cooled to room temperature and the resulting mass is filtered. It is slurred in IPA and then in water and isolated by filtration. The solid is dried at 95-100°C and is purified as per the procedure given in example 5.
Yield: 93 %; Purity: 99.3%
EXAMPLE 3
2.2 moles of l-(l,2-benzisothiazol-3-yl)piperazine hydrochloride , 1 mol of 5-(2-chloroethyl)-6-chlorooxindole, 2.2 mo! of Sodium hydroxide, water 20 times based on oxindole weight and 1 % of dispersing agent Morwet. All the reactants are charged in to the flask and refluxed under nitrogen, under stirring for 12-l6hr. After the completion of the reaction, the reaction mass is cooled to room temperature and the resulting mass is filtered. It is slurried in IPA and then in water and isolated by filtration. The solid is dried at 95-100°C and purified as per the procedure given in example 5.
Yield: 90%; Purity: 98%

EXAMPLE 4
2 moles of l-(l,2-benzisothiazol-3-yl)piperazine, 1 mole of 5-(2-chloroethyl)-6-chlorooxindole in water (20 times based on benzisothiazole) and in the presence of dispersing agent. All the reactants are charged in to the flask and refluxed under nitrogen, under stirring for 12-l6hr. After the completion of the reaction, the reaction mass is cooled to room temperature and the resulting mass is filtered. It is slurried in IPA and then in water and isolated by filtration. The solid is dried at 95-100°C and is purified as per the procedure given in example 5.
Yield: 90-92%, purity 98 %
EXAMPLE 5
Purification of ziprasidone:
Ziprasidone free base (50 g) is taken in the thimble and subjected to soxhlet extraction using THF (200 ml) as solvent. Pure compound is obtained after 6-10 extractions depending on the purity of the product. The product remaining in the thimble is of purity 99 % min. The resulting product is isolated and dried at 90 to 100 deg C. Recovery of the product is 95-97%.
Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. It should be emphasized that the above-described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the

principles of the invention. Accordingly, it is to be understood that the drawings and descriptions herein are proffered by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.

Documents:

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Patent Number

271004

Indian Patent Application Number

499/MUM/2008

PG Journal Number

05/2016

Publication Date

29-Jan-2016

Grant Date

29-Jan-2016

Date of Filing

11-Mar-2008

Name of Patentee

ALKEM LABORATORIES LTD.

Applicant Address

DEVASHISH, ALKEM HOUSE, SENAPATI BAPAT MARG, LOWER PAREL, MUMBAI

Inventors:

#	Inventor's Name	Inventor's Address
1	SHASHIPRABHA	#422/423, ANUGRAHA, 3RD FLOOR 10TH MAIN, RAMAIAH ENCLAVE T DASARAHALLI, BANGALORE-560073.
2	SHRIDHARA K	#422/423, ANUGRAHA, 3RD FLOOR 10TH MAIN, RAMAIAH ENCLAVE T DASARAHALLI, BANGALORE-560073.
3	DEBKIRON MUKHERJEE	C/O LALITHAMMA #377, 6TH MAIN NAGENRDA BLOCK, BSK 3RD STAGE, BANGALORE-560050.
4	PADMASHREE BENDRAJE	C/O BHARATHI RATHOD #57/1003, 1 N BLOCK, 1 A MAIN,RAJAJINAGAR, BANGALORE-560010.
5	K SUNDARRAJA RAO	#14 AMR, MIG ROW HOUSES, NANDINI LAYOUT BANGALORE-560096.
6	K NAGARAJAN	#4A, ATISHI, ROSE GARDEN ROAD, 15TH MAIN, J.P.NAGAR 5TH PHASE, BANGALORE-560078.

PCT International Classification Number

C07D417/12; A61K31/428; A61P25/18

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA