- A key intermediate for the preparation of ziprasidone
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The present invention relates to a ziprasidone key intermediate preparation method, wherein benzo[d]isothiazole-3-ol (or one) is adopted as a raw material, and reacts with a substituted sulfonyl chloride or anhydride under an alkaline condition to obtain benzo[d]isothiazole-3-substituted sulfonate, and the benzo[d]isothiazole-3-substituted sulfonate reacts with piperazine to prepare the ziprasidone key intermediate 3-(1-piperazinyl)-1,2-benzoisothiazole. The method of the present invention has characteristics of simple operation, easily available raw materials, less byproducts, simple post-treatment, less industrial three-waste and the like, and is especially suitable for industrial production.
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- Purification method and preparation method for ziprasidone mesilate
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The invention discloses a purification method for ziprasidone mesilate. The purification method comprises the following steps: (1) taking a ziprasidone mesilate crude product, heating for dissolving the ziprasidone mesilate crude product into a mixed solvent formed by tetrahydrofuran and water, and adding carbon for decoloration, and separating out solids, wherein the volume ratio of tetrahydrofuran to water is 15 to (1-5); and (2) washing and drying the solids so as to obtain a ziprasidone mesilate pure product. The purification method is simple and safe to operate and relatively high in yield and purity, does not have special requirements on equipment and can meet the requirements on large-scale industrial production, the industrial production efficiency is improved, the materials are greatly saved, and the industrial production cost is lowered. The invention further discloses a preparation method of high-purity ziprasidone mesilate by virtue of the purification method.
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Paragraph 0033-0051
(2018/07/30)
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- A SHORT PROCESS FOR THE PREPARATION OF ZIPRASIDONE AND INTERMEDIATES THEREOF
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A process for the preparation of oxindole derivative (Ziprasidone hydrochloride) of formula (I) comprising reacting compound of formula (II) with metal or metal compound mineral acid to give compound of formula (III) in a single step which is converted into compound of formula IV which is a key intermediate for the preparation of compound of compound of formula (I).
- -
-
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- Process for the Preparation of Ziprasidone
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The present invention relates to a process for preparing Ziprasidone of formula I, or a pharmaceutically acceptable salt or a solvate or a hydrate thereof; comprising the steps of reacting 1-(1,2-benzisothiazol-3-yl) piperazine of formula II or its salt: with 5-(2-haloethyl)-6-chloro-oxindole of formula III: wherein X is leaving groups like fluoro, chloro, bromo, iodo or sulphonyl; in the presence of a dispersing agent and a base in a solvent to form ziprasidone of formula I; and optionally converting the ziprasidone formed into a pharmaceutically acceptable acid addition salts of ziprasidone; or a solvate or a hydrate thereof.
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Page/Page column 5
(2011/01/12)
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- PROCESS FOR PURIFICATION OF ZIPRASIDONE
-
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.
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Page/Page column 3-4
(2011/07/30)
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- PROCESS FOR PREPARING ZIPRASIDONE
-
The present invention relates to improved process for preparing Ziprasidone an its acid addition salts thereof. The invention particularly provides a method f purifying Ziprasidone base thereby providing substantially pure Ziprasidone and i acid addition salts, hydrates, solvates etc.
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Page/Page column 9
(2010/07/09)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF ZIPRASIDONE
-
The present invention relates to a process for preparing Ziprasidone of formula (I), or a pharmaceutically acceptable salt or a solvate or a hydrate thereof; comprising the steps of reacting 1-(1,2-benzisothiazol-3-yl) piperazine of formula (II) or its salt with 5-(2-haloethyl)-6-chloro-oxindole of formula (III) wherein X is leaving groups like fiuoro, chloro, bromo, iodo or sulphonyl; in the presence of a dispersing agent and a base in a solvent to form ziprasidone of formula I; and optionally converting the ziprasidone formed into a pharmaceutically acceptable acid addition salts of ziprasidone; or a solvate or a hydrate thereof.
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Page/Page column 13-14
(2009/10/22)
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- Polymorphic forms of ziprasidone sulphates
-
The present invention relates to novel polymorphic forms of Ziprasidone sulfates, as well as to a process for their preparation and pharmaceutical formulations containing it. The present polymorphic forms of Ziprasidone sulfates are characterized by small average particle sizes and high solubility bestowing the compounds an improved bioavailability.
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Page/Page column 12
(2008/06/13)
-
- Process for the preparation of ziprasidone
-
The present invention relates to an improved method for the preparation of ziprasidone comprising the steps of mixing 5-(2-chloroethyl)-6-chloro-1,3-dihydroindole-2(2H)-one with either a free base or salt form of 3-(1-piperazinyl)-1,2-benzoisothiazole in the presence of a base and an organic solvent characterized in that the organic solvent is a polar aprotic solvent or a mixture of polar aprotic solvents and that the reaction requires the addition of 0,1-0,8 Equivalents of an halide salt, preferably 0,3-0,6 Equivalents, more preferably 0,4-0,5 Equivalents.
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Page/Page column 1; 3; 5
(2008/12/07)
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- A process for the preparation of ziprasidone
-
A process for the preparation of ziprasidone and a novel intermediate useful in its preparation. The process comprises the reduction of a compound (III) to give a compound (V) which is then reduced to compound (II). This is reacted with compound (IV) to give the desired compound.
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Page/Page column 5
(2008/06/13)
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- Process for the preparation of ziprasidone
-
A process for the preparation of ziprasidone and a novel intermediate useful in its preparation. The process comprises the reduction of a compound (III) to give a compound (V) which is then reduced to compound (II). This is reacted with compound (IV) to give the desired compound.
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Page/Page column 3
(2008/06/13)
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- NOVEL PROCESS FOR PRODUCTION OF 5-{2-[4-(1,2-BENZISOTHIAZOL-3-YL)-1-PIPERAZINYL]-ETHYL}-6-CHLORO-1,3-DIHYDRO-2H-INDOL-2-ONE (ZIPRASIDONE)
-
The present invention provides a novel, industrially easily realisable and economically preferable process for production of pure 5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-ethyl}-6-chloro-1,3-dihydro-2H-indol-2-one i.e., ziprasidone hydrochloride shown in the reaction scheme (II), (III), (IV), (V) and (VI). According to the invention the intermediate compound 5-(2-bromoethyl)-6-chloro-1,3-dihydro-2H-indol-2-one of Formula (III) is produced from 5-(2-bromoacethyl)-6-chloro-1,3-dihydro-2H-indole-2-one of Formula (IV). The highly pure ziprasidone base of Formula (II) is obtained in the reaction of 3-piperazinyl-1,2-benzisothiazol of Formula (VI) with 5-(2-bromoethyl)-6-chloro-1,3-dihydro-2H-indol-2-one of Formula (III) in an organic solvent or organic solvent mixture.
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Page/Page column 7
(2008/06/13)
-
- Ziprasidone process
-
A process for preparing ziprasidone having low levels of keto ziprasidone and hydroxy ziprasidone impurities.
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Page/Page column 7
(2008/06/13)
-
- A NOVEL METHOD FOR THE PREPARATION OF ARYL PIPERAZINYL-HETEROCYCLIC COMPOUNDS
-
A novel method for preparing a compound of formula (I), which comprises of coupling the piperazine derivative of formula (II), with alkyl halide containing compound of the formula (III), by heating in solvent free conditions or, optionally, in a minimum quantity of non-aqueous suspending liquid, in presence of a catalyst and a neutralizing agent to neutralize the hydrohalic acid.
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Page/Page column 6
(2008/06/13)
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- PROCESS FOR ZIPRASIDONE USING NOVEL INTERMEDIATES
-
The present invention relates to a novel process for the preparation of high purity ziprasidone and pharmaceutically acceptable acid addition salts of ziprasidone; and solvates and hydrates thereof using novel intermediates and a purification method for ziprasidone and pharmaceutically acceptable acid addition salts of ziprasidone; and solvates and hydrates thereof. Thus, 1-(1,2-benzisothiazol-3-yl)piperazine is silylated with trimethylsilylchloride in methylene chloride in the presence of triethylamine and the solvent is distilled off to obtain silylated 1-(1,2-benzisothiazol-3-yl)piperazine. The silylated compound is reacted with 5-(2-chloroethyl)-6-chloro-oxindole in the presence of sodium carbonate to obtain ziprasidone.
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Page/Page column 15
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF ZIPRASIDONE (5-[2-[4-(1,2-BENZISOTHIAZOL-3-Y1)-1-PIPERAZINY1]ETHY1]-6-CHLORO-1,3-DIHYDRO-2H-INDOL-2-ONE)
-
The present invention provides a new and useful process for preparing 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one (ziprasidone) and methods for its purification. The process comprises the steps of: (i) mixing 6-chloro-5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one with either a free base or salt form of 3-(1-piperazinyl)-1,2-benzoisothiazole, in the presence of an alkaline compound and a high-boiling polar organic solvent or mixture of high boiling polar organic solvents, (ii) heating the mixture and stirring for a sufficient amount of time to obtain ziprasidone formation, (iii) cooling the mixture, adding it to water and filtering off the product, (iv) adding water to the product and stirring the suspension, and (v) isolating crude ziprasidone.
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Page/Page column 7
(2008/06/13)
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- PROCESS FOR PREPARING ZIPRASIDONE
-
The present invention concerns a process for the preparation of 5-(2-(4-(1,2- 5 benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one of the formula (I), or a pharmaceutically acceptable acid addition salt, solvate, hydrates or clathrate thereof, said process comprising reacting a compound of formula (II) wherein X is a halogen atom, with a compound of formula (III), said compound of formula (III) being the free base or an addition salt with an organic or inorganic acid, wherein said process is characterized in that said compounds according to formulas (II) and (III) are reacted in the presence of a neutralizing agent, and are reacted in a solvent comprising acetonitrile.
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Page/Page column 16-17
(2008/06/13)
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- PROCESS FOR THE PURIFICATION OF ZIPRASIDONE
-
Process for the purification of ziprasidone. The present invention concerns a process for the purification of 5- [2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6- chloro-1,3-dihydro-2H-indol-2-one of the formula (I) from a composition comprising said compound, wherein said compound is reacted with maleic acid or acetic acid to obtain an acid addition salt of the following formula (II), wherein R is formula (IV), or formula (V).
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Page/Page column 6; 7
(2008/06/13)
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- Methods and compositions for the treatment of neuroleptic and related disorders using ziprasidone metabolites
-
The invention relates to novel methods using, and pharmaceutical compositions comprising, ziprasidone metabolites. The methods and compositions of the invention are suitable for the treatment of neuroleptic and related disorders. The invention further encompasses methods of preparing ziprasidone sulfoxide and ziprasidone sulfone.
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Page/Page column 7
(2008/06/13)
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- POLYMORPHIC FORM B2 OF ZIPRASIDONE BASE
-
Provided is a crystalline form of ziprasidone base and processes for its preparation.
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Page/Page column 17-18
(2008/06/13)
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- PROCESSES FOR PREPARATION OF ZIPRASIDONE
-
Provided are processes for preparing ziprasidone from CEI and BIPT.
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Page/Page column 17-18
(2010/02/11)
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- PROCESS FOR THE PREPARATION OF ZIPRASIDONE
-
The invention relates to processes for the preparation of substantially pure ziprasidone. The invention also relates to the preparation of acid addition salts of ziprasidone. More particularly, it relates to the preparation of substantially pure hydrochloride salt of ziprasidone. The invention also relates to pharmaceutical compositions that include the substantially pure ziprasidone or ziprasidone hydrochloride and use of said compositions for treating schizophrenia.
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Page/Page column 11; 15-16
(2008/06/13)
-
- Process for the preparation of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1piperazinyl) ethyl)-6-chloro-1, 3-dihydro-2h-indol-2-one hydrochloride (ziprasidone hydrochloride) and its intermediate
-
The present invention relates to improved processes for the preparation of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl) ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one and its hydrochloride, which is known as Ziprasidone hydrochloride of Formula (I) and 5-(2-Chloro acetyl)-6-chloro oxindole of Formula (IV), which is an intermediate for the preparation of 5-(2-chloro ethyl)-6-chloro oxindole of Formula (V). Ziprasidone hydrochloride of Formula (I) of the present invention is depicted by the following structure.
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-
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- POLYMORPHIC FORMS OF ZIPRASIDONE AND ITS HYDROCHLORIDE
-
The present invention is related to crystalline forms of ziprasidone and its hydrochloride salt and an amorphous form of ziprasidone hydrochloride and the process for the preparation thereof. The crystalline forms and amorphous form of the invention are suitable for pharmaceutical purposes in the treatment of psychosis. The processes of the invention are simple, non-hazardous and commercially suitable.
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-
- A PROCESS FOR THE PREPARATION OF OXINDOLE DERIVATIVES
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A process for the preparation of oxindole derivative of formula (I) comprising reacting compound of formula (II) with dialkyl malonate, COOR1-COOR1, in the presence of a mild base to give compound of formula (III); and wherein R is selected from hydrogen, linear, branched or cyclic alkyl, aryl, substituted aryl, heteroaryl, haloalkyl like CF3, alkoxy, haloalkoxy, thioalkyl and halogen.; R1 is selected from linear, branched and cyclic alkyl (C1 to C4 groups); and X is selected from chloro, bromo, fluoro and iodo groups;further converting compound of formula (III) to compound of formula (I).
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-
-
- Fast atom bombardment-promoted reductive ring opening of 1,2-benzisothiazoles
-
Fast atom bombardment mass spectral examination of molecules containing a 1,2-benzisothiazole ring, using a thiol reducing agent matrix, promotes reductive ring opening of the benzisothiazole ring, giving an [M+H]+ two daltons higher than expected. Measurements using a non-reducing matrix produce the expected [M+H]+. This is a general phenomenon, observed with a number of molecules containing the benzisothiazole ring. The ring-opened structure has been confirmed by chemical synthesis and observed in metabolic studies.
- Sharp, Thomas R.,Lambert, John F.,Walinsky, Stanley W.
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p. 2117 - 2120
(2007/10/03)
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- Combination treatment for anxiety, depression, obsessive compulsive disorder and psychosis
-
The present invention relates to a method of treating depression, obsessive compulsive disorder and psychosis in a mammal, including a human, by administering to the mammal an atypical antipsychotic in combination with an antidepressant agent with improvement in efficiency. It also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier, an atypical antipsychotic, and an SRI.
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- METHOD OF SELECTING A SALT FOR MAKING AN INCLUSION COMPLEX
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A method of locating one or more salts of a compound, said salts having a solubility in a cyclodextrin equal to or greater than a desired target solubility, comprising obtaining a series of salts of said compound, measuring the equilibrium solubility of each salt in said series in said cyclodextrin, and comparing each measured solubility with said target solubility.
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- Inclusion complexes of aryl-heterocyclic salts
-
Compositions of matter comprising a pharmaceutically acceptable salt of an aryl-heterocyclic compound, such as ziprasidone, in a cyclodextrin. Preferred cyclodextrins are SBECD and HPBCD. The composition can comprise a dry mixture, a dry inclusion complex or an aqueous solution. The salt/cyclodextrin inclusion complex preferably provides an amount of ziprasidone of at least 2.5 mgA/ml when the complex is dissolved in water at 40% w/v. A variety of ziprasidone salts are preferred, including the mesylate, esylate, besylate, tartrate, napsylate, and tosylate.
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-
- Processes for producing isothiazole derivatives
-
A method for producing a 1,2-benzisothiazole characterized by treating a 2-(alkylthio)benzaldehyde oxime with a halogen compound; a method for producing a 3-halo-1,2-benzisothiazole characterized by treating a 1,2-benzisothiazole with a halogenating agent; and a method for producing a 1-(1,2-benzisothiazol-3-yl)piperazine characterized by reacting the obtained 3-halo-1,2-benzisothiazoles with a piperazine. By the method of the present invention, 1,2-benzisothiazoles and 3-halo-1,2-benzisothiazoles, which are useful as intermediates for pharmaceutical compositions such as psychotropic agents, and 1-(1,2-benzisothiazole-3-yl)piperazines synthesized therefrom can be obtained in a high yield without using expensive starting materials by shorter and simpler process than conventional methods.
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- 3-Benzisothiazolylpiperazine derivatives as potential atypical antipsychotic agents
-
A series of substituted phenethyl derivatives of 3- benzisothiazolylpiperazine incorporating potent D2 and 5-HT(2A) antagonist activity was investigated as an approach to a novel atypical antipsychotic agent. The in vitro profile of 8e from this series is a combination of D2 receptor affinity comparable to the typical antipsychotic agent haloperidol and a 5-HT(2A)/D2 ratio comparable to the atypical agent clozapine. In vivo 8e possesses activity consistent with an efficacious antipsychotic agent with less tendency to induce extrapyramidal side effects in man.
- Howard, Harry R.,Lowe III, John A.,Seeger, Thomas F.,Seymour, Patricia A.,Zorn, Stevin H.,Maloney, Patrick R.,Ewing, Frank E.,Newman, Michael E.,Schmidt, Anne W.,Furman, Jerome S.,Robinson, Gwendolyn L.,Jackson, Elisa,Johnson, Celeste,Morrone, Jean
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p. 143 - 148
(2007/10/03)
-
- A novel synthesis of the antipsychotic agent ziprasidone
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A new synthesis of the antipsychotic ziprasidone from 2,5-dichloro-4-nitrotoluene 3 is presented. The nitro group in 3 was used to activate the orthochlorine for displacement and the methyl group for enamine formation and introduction of the piperazinyl moiety.
- Urban, Frank J.,Breitenbach, Ralph,Gonyaw, Dianne
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p. 1629 - 1638
(2007/10/03)
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- Synthesis of 3H- and 14C-labelled CP-88,059: A potent atypical antipsychotic agent
-
The syntheses of 3H- and 14C-labelled CP-88,059 [i.e., 5-(2-(4-(1,2-benzisothiazol-3-yl)piperazinyl)ethyl)-6-chloro-1, 3-dihydro-2H-indol-2-one] are described. CP-88,059 (5b) is a combined D2/5-HT2 antagonist currently undergoing clinical evaluation as an antipsychotic agent with reduced potential for induction of EPS in schizophrenic patients. Displacement of bromine from the 7-position of the benzisothiazole moiety, by reductive dehydrogenation with tritium gas and Pd/BaSO4 catalysis, provided 3H-CP-88,059 (5c). Incorporation of 14C into the ethylene portion of the molecule was achieved via the Friedel-Crafts acylation of 6-chlorooxindole with [2-14C]-chloroacetyl chloride, followed by triethylsilane reduction of the aryl carbonyl and coupling with N-(1,2-benzisothiazol-3-yl)piperazine in refluxing aqueous Na2CO3.
- Howard,Shenk,Smolarek,Marx,Windels,Roth
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p. 117 - 125
(2007/10/02)
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- Processes and intermediates for the preparation of 5-[2-(4-(benzoisothiazol-3-yl)-piperazin-1-yl)ethyl]-6-chloro-1,3-dihydro-indol-2-one
-
A process for preparing the compound of the formula STR1 which comprises treating a compound of the formula STR2 wherein R2 is hydrogen, CN or CO2 R1 and R1 is hydrogen or (C1 -C6)alkyl with a reducing agent with the proviso that when R2 is CN or CO2 R1 and R1 is (C1 -C6)alkyl the product of the reduction is heated with an acid. Compounds of formula II wherein R2 is CN or CO2 R1 and R1 is (C1 -C6)alkyl or R2 is hydrogen and R1 is (C1 -C6)alkyl or hydrogen. The compound of formula VII R1 is (C1 -C6)alkyl. The compound of formula III. The compound of formula I is useful in the treatment of psychotic disorders.
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- Monohydrate of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one-hydrochloride
-
The monohydrate of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indole-2-one hydrochloride has advantageous stability for formulation as a neuroleptic agent.
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