122883-93-6

Basic information

• Product Name: Ziprasidone
• Synonyms: 5-[2-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one hydrochloride;5-[2-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]ethyl]-6-chloro-1,3-dihydroindol-2-one hydrochloride;5-[2-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]ethyl]-6-chloro-oxindole hydrochloride;5-(2-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)-6-chloroindolin-2-one hydrochloride;2H-Indol-2-one,5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-,hydrochloride (1:1)
• CAS NO: 122883-93-6
• Molecular Formula: C₂₁H₂₁ClN₄OS
• Molecular Weight: 412.943
• EINECS: 1312995-182-4
• Product Categories: Ziprasidone;Geodon, Zeldox
• Mol File: 122883-93-6.mol

Chemical Properties

• Melting Point: >300 °C
• Boiling Point: 554.8 °C at 760 mmHg
• Flash Point: 289.3 °C
• Appearance: /
• CAS DataBase Reference: Ziprasidone(CAS DataBase Reference)
• NIST Chemistry Reference: Ziprasidone(122883-93-6)
• EPA Substance Registry System: Ziprasidone(122883-93-6)

Safety Data

• Hazardous Substances Data: 122883-93-6(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Ziprasidone is used as an atypical antipsychotic medication for the treatment of schizophrenia and bipolar disorder. Its complex binding profile for serotonin and dopamine receptors results in high antipsychotic efficacy with low extrapyramidal side effects and antidepressive action with low propensity for weight gain.
Used in Acute Agitation Treatment:
The intramuscular injection form of Ziprasidone is used for the treatment of acute agitation in patients with schizophrenia and agitated psychoses. An intramuscular formulation of ziprasidone has been demonstrated to be superior to haloperidol, a conventional neuroleptic, for the short-term treatment of agitation in acutely psychotic patients.
Used in Forensic Drug Analysis:
Ziprasidone is also used as a Certified Spiking Solution, applicable to use in forensic drug analysis or calibrator preparation by LC/MS or GC/MS.

Originator

Pfizer (US)

Manufacturing Process

Preparation of 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro- 1,3-dihydro-2H-indol-2-oneA 20-gallon glass lined tank, under a nitrogen atmosphere, was charged with 33.5 liters of water and 9.4 kilograms (kg) of sodium carbonate (dense, 89.1 moles, 3.4 eq.). The resulting mixture was stirred to give a solution. To the solution 6.4 kg of 2-chloroethyl-6-chloro-oxindole (27.8 moles, 1.06 eq.) was charged, followed by 6.7 kg of 3-piperazinyl-1,2-benzisothiazole hydrochloride (26.2 moles, 1.0 eq.). This was stirred and heated to reflux (100°C). After 11 hours the reaction was sampled for high pressure liquid chromatography (HPLC) assay. The reflux was continued for another 2 hours then the reaction was cooled to 25°C and the slurry stirred for 1 hour. The product was observed and found to be essentially free from lumps and gummy matter. The product was collected by filtration. A 14 liter water was added to the tank and cooled to 12°C and then used to wash the product. The cake was pulled as dry as possible, and the product was returned to the tank along with 40 liters of isopropyl alcohol (IPO). This was cooled and then stirred for 2 hours and the product was collected by filtration. The cake was washed with 13.4 liters of fresh IPO, then dried under vacuum at 30° to 40°C. After drying, 17.3 kg of the title compound was obtained. This was in excess of the theoretical weight yield due to some residual carbonate in the crude product.Recrystallization of 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6- chloro-1,3-dihydro-2H-indol-2-oneTo a clean and dry 100-gallon glass lined tank was charged 9.0 kg of the material obtained above and 86 gallons of tetrahydrofuran (THF). The slurry was heated to reflux and held for 1 hour. The hazy solution was then filtered through a 14" sparkler precoated with filter aid and backed with a Fulflo filter to a clean, dry, and "spec free" glass-lined tank on a lower level. The batch was concentrated by vacuum distillation. Another 8.3 kg of the material obtained in above was dissolved in 83 gallons of THF in the upper tank. This was filtered to the lower tank. The tank lines and sparkler were rinsed with 10 gallons of THF. The batch was concentrated to about 22 gallons, then cooled to 5°C and stirred for 1 hour. The product was collected by filtration. Then 20 gallons of fresh IPO were cooled in the tank and used to rinse the product cake. The product was collected and dried under vacuum at 45°C; yielding 9.05 kg of product (83.8% yield for the coupling and recrystallization. The product matched the spectra of a standard NMR and showed the correct retention time by HPLC with 99.7% assay. Another way for preparation of 5-(2-(4-(1,2-benzisothiazol-3-yl)-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2-H- indol-2-one.A clean and dry 20-gallon glass lined tank was charged with 19 L of water and 4.44 kg of sodium carbonate, after the carbonate had dissolved 4.29 kg (17.5 moles) of 5-(2-chloroethyl)-6-chloro-oxindole and 3.62 kg (16.5 moles) of 1- (1,2-benzisothiazol-3-yl)piperazine were added. The aqueous slurry was heated to reflux and the temperature maintained for 14 hours. When the reaction was complete the solution was cooled to 20°C and filtered. The wet product was reslurried in 23 L of isopropyl alcohol at room temperature for 2 hours. The product was collected by filtration on 2 large Buchner funnels, each was washed with 3.4 L of fresh isopropyl alcohol. The product was vacuum dried at 30° to 40°C. until no isopropyl alcohol remained, giving 5.89 kg (86.4% yield) of the desired free base which matched a standard sample by high performance liquid chromatography (HPLC).A clean and dry 20-gallon reactor was charged with 17.4 gallons of deionized water and 4.44 L of concentrated hydrochloric acid, to give a 0.77 M solution. To the solution was added 4.44 kg of the anhydrous 5-(2-(4-(1,2- benzisothiazol-yl)-1-piperazinyl)-ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one free base. The slurry was warmed to 65°C and held for 18 hours. The slurry was cooled to room temperature. The product was filtered and washed with 2x5-gallon portions of deionized water, and then air dried at 50°C for 30 hours. The dried product contained 4.4% water and the x-ray diffraction method confirmed that the desired product was obtained.

Therapeutic Function

H-Indol-2-one, 5-(2-(4-(1,2-benzisothiazol-3-yl)-1- piperazinyl)ethyl)-6-chloro-1,3-dihydro-, monohydrochloride monohydrate

Upstream product

• 2634-33-5 1,2-benzisothiazol-3-one 
• 147124-32-1 dimethyl (4-chloro-2-nitrophenyl)malonate 
• 89-61-2 2,5-dichloronitrobenzene 
• 87691-87-0 3-(1-piperazinyl)-1,2-benzisothiazole 
• 133070-64-1 3-(piperazin-1-yl)-1,2-benzisothiazole hydrochloride 
• 118289-55-7 6-chloro-5-(2-chloroethyl)-2-oxindole 
• 884305-06-0 6-chloro-5-(2-chloro-1-hydroxyethyl) indolin-2-one 
• 118307-04-3 6-chloro-5-(2-chloroacetyl) indolin-2-one 
• 87691-88-1 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride 
• 155167-98-9 7-bromo-3-piperazinyl-1,2-benzisothiazole 
• 155167-97-8 3,7-dibromo-1,2-benzisothiazole 
• 56341-37-8 6-chloro-2-oxindole 
• 160384-45-2 methyl (5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-4-chloro-2-nitrophenyl)-cyanoacetate 
• 160384-39-4 5-Chloro-4-(2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl)-2-(bis-(methoxycarbonyl)methyl)-nitrobenzene 

Downstream Products

• 1028903-39-0 5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-ethyl}-6-chloro-1,3-dihydro-2H-indol-2-one hydrobromide monohydrate 
• 188797-80-0 Ziprasidone sulfoxide 
• 195244-32-7 Dihydroziprasidone 

Relevant articles and documents

A key intermediate for the preparation of ziprasidone

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.

Purification method and preparation method for ziprasidone mesilate

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.

A SHORT PROCESS FOR THE PREPARATION OF ZIPRASIDONE AND INTERMEDIATES THEREOF

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).

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.

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 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.

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.

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.

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.

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.

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.