Ziprasidone hydrochloride monohydrate

Ziprasidone hydrochloride monohydrate Basic information
Product Name:Ziprasidone hydrochloride monohydrate
Synonyms:Ziprasidone (hydrochloride hydrate);5-(2-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)-6-chloroindolin-2-one hydrochloride hyd;Ziprasidone for system suitability 2;Ziprasidone for system suitability 1;ZIPRASIDONE HCL;ZIPRASIDONE HYDROCHLORIDE;ZIPRASIDONE HYDROCHLORIDE MONOHYDRATE;5-[2-[4-(1,2-BENZISOTHIAZOL-3YL)-1-PIPERAZINYL]ETHYL]-6-CHLORO-1,3-DIHYDRO-2H-INDOL-2-ONE, HYDROCHLORIDE MONOHYDRATE
CAS:138982-67-9
MF:C21H24Cl2N4O2S
MW:467.41
EINECS:
Product Categories:Other APIs;APIs;Intermediates & Fine Chemicals;Pharmaceuticals;Heterocycles;Pfizer compounds;Sulfur & Selenium Compounds;138982-67-9
Mol File:138982-67-9.mol
Ziprasidone hydrochloride monohydrate Structure
Ziprasidone hydrochloride monohydrate Chemical Properties
Melting point 300°C
storage temp. 2-8°C
solubility DMSO: >10mg/mL
form solid
color Light Orange
Merck 14,10171
BCS Class2?
CAS DataBase Reference138982-67-9(CAS DataBase Reference)
Safety Information
Safety Statements 24/25
RIDADR UN1230 - class 3 - PG 2 - Methanol, solution
WGK Germany 3
RTECS NM3241200
HS Code 38220010
MSDS Information
Ziprasidone hydrochloride monohydrate Usage And Synthesis
Chemical PropertiesPale Tan Powder
OriginatorGeodon,Pfizer,USA
UsesCombined serotonin (5HT2) and dopamine (D2) receptor antagonist. Used as an antipsychotic.
Usesantipsychotic;Dopamine D2/serotonin 5-HT2 antagonist
UsesZiprasidone Hydrochloride is the hydrochloride salt of a benzisothiazolylpiperazine analog structurally related to the atypical antipsychotic drug tiospirone that antagonizes both central serotonin 5-HT2A (Ki = 0.42 nM) and dopamine D2 (Ki = 4.8 nM) receptors. It is also a potent agonist at 5-HT1A receptors (Ki = 3.4 nM), increasing cortical dopamine release which may offset negative effects associated with dopamine D2 antagonism, and an inverse agonist at 5-HT1B and 5-HT1D receptors (pKis = 8.8 and 8.6, respectively).[Cayman Chemical]
DefinitionChEBI: The hydrochloride hydrate salt of ziprasidone.
Manufacturing ProcessPreparation of 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro- 1,3-dihydro-2H-indol-2-one
A 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-one
To 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 Ziprasidone 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.
Brand nameGeodon (Pfizer).
Therapeutic FunctionH-Indol-2-one, 5-(2-(4-(1,2-benzisothiazol-3-yl)-1- piperazinyl)ethyl)-6-chloro-1,3-dihydro-, monohydrochloride monohydrate
Biological ActivityAtypical antipsychotic that displays combined serotonin and dopamine receptor antagonism. Displays high affinity at 5-HT 2A receptors with a 5-HT 2A /D 2 affinity ratio greater than any other clinically available atypical antipsychotics (pK i values are 9.38, 8.88, 8.69, 8.47, 8.32, 8.14, 7.98, 7.49, 7.33 and 6.28 for 5-HT 2A , 5-HT 2C , 5-HT 1D , 5-HT 1A , D 2 , D 3 , α 1 , D 4 , H 1 and D 1 receptors respectively).
Biochem/physiol ActionsZiprasidone is an atypical antipsychotic; FDA approved for the treatment of schizophrenia.
Biochem/physiol ActionsZiprasidone (CP-88059) hydrochloride monohydrate is an orally active combined 5-HT and dopamine receptor antagonist. Ziprasidone hydrochloride monohydrate has affinities for Rat D2 (Ki=4.8 nM), 5-HT2A (Ki=0.42 nM) and 5-HT1A (Ki=3.4 nM).
in vitroZiprasidone hydrochloride monohydrate (0-500 nM, 150 seconds) blocks wild-type hERG current.
in vivoZiprasidone hydrochloride monohydrate (oral gavage; 20 mg/kg; once daily; 7 weeks) results in weight loss, low level physical activity, high resting energy expenditure and greater capacity for thermogenesis when subjected to cold.
storageRoom temperature
Ziprasidone hydrochloride monohydrate Preparation Products And Raw materials
Raw materialsIsopropyl alcohol-->Piperazine-->Indole-->Serotonin hydrochloride-->p-Terphenyl-->3-(1-Piperazinyl)-1,2-benzisothiazole-->6-Chloro-5-(2-chloroethyl)oxindole
Ziprasidone HCl Ziprasidone hydrochloride monohydrate 1-(2-PHENYLETHYL)PIPERAZINE 4-[2-(4-methylpiperazin-1-yl)ethyl]aniline 1,2-Benzisothiazol-3-amine etisazole 6-Chloro-5-methylindoline 6-CHLORO-2,3-DIHYDRO-1H-INDOLE HYDROCHLORIDE N-[4-(2-aminoethyl)phenyl]acetamide Ziprasidone 6-CHLORO-2,3-DIHYDRO-1H-INDOLE 3-Piperazinobenzisothiazole hydrochloride Ziprasidone mesilate 1,2-BENZISOTHIAZOLE 4-(2-DIMETHYLAMINO-ETHYL)-ANILINE DIHYDROCHLORIDE Thiazole 1H-INDOLE,5-ETHYL-2,3-DIHYDRO- 6-Chlorooxindole

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