CYPROHEPTADINE HYDROCHLORIDE CAS NO.969-33-5

Product Name:    CYPROHEPTADINE HYDROCHLORIDE
Synonyms:    CYPROHEPTADINE HYDROCHLORIDE(GRP B SL NO.1124);Cycloheptadine Hydrochloride;1-methyl-4-(5-dibenzo(a,e)cycloheptatrienylidene)piperidinehydrochloride;4-(5-dibenzo(a,e)cycloheptatrienylidene)piperidinehydrochloride;4-(5h-dibenzo(a,d)cyclohepten-5-ylidene)-1-methyl-piperidinhydrochloride;cyproheptadienehydrochloride;nuran;4-(5H-DIBENZO[A,D]CYCLOHEPTEN-5-YLIDINE)-METHYLPIPERIDINE HYDROCHLORIDE
CAS:    969-33-5         
MF:    C21H22ClN
MW:    323.86         
EINECS:    213-535-1        
Product Categories:    Serotonin receptor;Active Pharmaceutical Ingredients
Mol File:    969-33-5.mol         
         

CYPROHEPTADINE HYDROCHLORIDE Chemical Properties
Melting point     254-256.5 °C(Solv: ethanol (64-17-5); ethyl ether (60-29-7))
storage temp.     Inert atmosphere,Room Temperature
solubility     ethanol: soluble
color     Crystals from EtOH/Et2O
Safety Information
Hazard Codes     Xn
Risk Statements     22-36/37/38
Safety Statements     26-36
RIDADR     UN 2811 6.1/PG 3
WGK Germany     3
RTECS     TM7050000
HazardClass     6.1(b)
PackingGroup     III
Toxicity    LD50 orl-rat: 295 mg/kg DRUGAY 6,340,82
MSDS Information
Provider    Language
SigmaAldrich    English
CYPROHEPTADINE HYDROCHLORIDE Usage And Synthesis
Originator    Periactin,Merck Sharp and Dohme,US,1961
Uses    Cyproheptadine hydrochloride is an antihistamine in which antiserotonin activity has been demonstrated both in vivo and in vitro. As yet, however, there is no evidence that this action contributes to clinical therapeutic effects. Anticholinergic and sedative effects are observed. Cyproheptadine may be more effective than other H1 blockers in the management of cold urticaria.
Uses    Antipruritic;5-HT antagonist
Definition    ChEBI: The hydrochloride salt of cyproheptadine. Note that the drug named cyproheptadine hydrochloride generally refers to cyproheptadine hydrochloride sesquihydrate.
Manufacturing Process    (A) Preparation of 1-Methyl-4-Piperidyl-Magnesium Chloride: Magnesium turnings (5.45 g, 0.22 g-atom) were placed in a 500 ml 3-necked flask provided with a condenser, Hershberg stirrer and dropping funnel and protected with a drying tube. An atmosphere of dry nitrogen was maintained in the apparatus throughout the reaction. The magnesium was covered with 20 ml of dry tetrahydrofuran. A crystal of iodine and 1.2 g of ethyl bromide were added and after the reaction had subsided (formation of ethylmagnesium bromide) a solution of 29.4 g (0.22 mol) of 4-chloro-1-methyl-piperidine in dry tetrahydrofuran (total volume, 103 ml) was added dropwise at such a rate that gentle reflux was maintained.
The solution of 4-chloro-1-methylpiperidine in tetrahydrofuran was dried over calcium hydride at ice-bath temperature prior to use. When the addition of the halide was complete the reaction mixture was refluxed with stirring for one hour. In some subsequent experiments this period of refluxing was omitted with no deleterious result.
The solution of 4-chloro-1-methylpiperidine in tetrahydrofuran was dried over calcium hydride at ice-bath temperature prior to use. When the addition of the halide was complete the reaction mixture was refluxed with stirring for one hour. In some subsequent experiments this period of refluxing was omitted with no deleterious result.
The solvent was evaporated from the combined benzene extracts to give 33.4 g of a clear light brown resin. Crystallization from an alcohol-water mixture gave 19.5 g of 1-methyl-4-(5-hydroxy-5-dibenzo[a,e]cycloheptatrienyl)- piperidine, MP 156° to 157°C. Two recrystallizations from alcohol-water mixtures followed by two recrystallizations from benzene-hexane mixtures gave analytically pure product, MP 166.7° to 167.7°C.
(C) Preparation of 1-Methyl-4-(5-Dibenzo[a,e]Cycloheptatrienylidene)- Piperidine Hydrochloride: 1-Methyl-4-(5-hydroxy-5-dibenzo[a,e] cycloheptatrienyl)-piperidine (3.05 g, 0.01 mol) was dissolved in glacial acetic acid, 15 ml. The solution was saturated with dry hydrogen chloride with external cooling. A white solid separated. Acetic anhydride (3.07 g, 0.03 mol) was added and the mixture heated on the steam bath for one hour. The solid dissolved in the first 5 minutes of the heating period. 
The reaction mixture was poured into 25 ml of water and the mixture made strongly basic with 10N sodium hydroxide solution. The mixture was extracted 3 times with 50 ml portions of benzene, the combined extracts washed with water and concentrated to a volume of approximately 50 ml. The solution was saturated with dry hydrogen chloride and the white crystalline product collected and dried. The yield of product, MP 251.6° to 252.6°C (dec.) was 2.5 g. Recrystallization from a mixture of absolute alcohol and absolute ether gave a product, MP 252.6° to 253.6°C. A sample was analyzed after drying for 7 hours at 110°C over phosphorus pentoxide in vacuo. 
(D) Preparation of 1-Methyl-4-(5-Dibenzo[a,e]Cycloheptatrienylidene)- Piperidine: The hydrochloride salt, 4.3 g, was suspended in 100 ml of warm water and the mixture made strongly alkaline by the addition of 15 ml of 5% sodium hydroxide. The mixture was extracted with four 50 ml portions of benzene and the extracts dried over sodium sulfate. Evaporation of the benzene on the steam-bath at reduced pressure left 3.7 g (97%) of the base,MP 110.3° to 111.3°C. Recrystallization from a mixture of alcohol and water gave product, MP 112.3° to 113.3°C.
Brand name    Periactin (Merck).
Therapeutic Function    Antipruritic, Antihistaminic, Appetite stimulant
General Description    Cyproheptadinehydrochloride, 4-(5H-dibenzo-[a,d]-cyclohepten-5-ylidine)-1-methylpiperidine hydrochloride sesquihydrate(Periactin), is slightly soluble in water and sparingly solublein alcohol.
Cyproheptadine possesses both antihistamine and antiserotoninactivity and is used as an antipruritic agent. It isindicated for the treatment of hypersensitivity reactions,perennial, and seasonal allergic rhinitis; vasomotor rhinitis;allergic conjunctivitis, uncomplicated allergic skin manifestationsof urticaria and angioedema; amelioration of allergicreactions to blood or plasma; and cold urticaria. It is alsoused off-label for nightmares associated with posttraumaticstress disorder (PTSD), prevention of migraine, suppressionof vascular headaches, and appetite stimulation. Sedation isthe most prominent side effect, and this is usually brief, disappearingafter 3 or 4 days of treatment.
Biological Activity    Non-selective 5HT 2 antagonist, migraine prophylactic.
Safety Profile    Poison by ingestion and intraperitoneal routes. Human systemic effects by ingestion: jaundice, liver function tests impaired, gastrointestinal effects. An experimental teratogen. Experimental reproductive effects. Human mutation data reported. Whenheated