phenazocine Chemical Properties

pka

pKa 8.50(50% aq EtOH) (Uncertain)

Safety Information

DEA Controlled Substances

CSCN: 9715
CSA SCH: Schedule II
NARC: Yes

phenazocine Usage And Synthesis

Originator

Phenazocine, SmithKline French (GSK)

Uses

Phenazocine is an opioid analgesic drug related to Pentazocine (P274300) and has a similar profile of effects. The use of Phenazocine results in analgesia and euphoria and in some cases dysphoria and hallucinations at high doses, most likely due to action at κ-opioid and σ receptors. Phenazocine is a much more potent analgesic than morphine with about 4 times the potency and very little side effects making it a better treatment option for biliary or pancreatic pain. Controlled Substance.

Manufacturing Process

25.0 g 3,4-lutidine methyl iodide in 60 ml of dry ethyl ether is stirred while 400 ml of a 0.3958 N ethereal solution of p-methoxybenzylmagnesium chloride is added at room temperature. The mixture is stirred for 30 minutes and then decomposed with a solution of 100 ml of water containing 25 g of ammonium chloride and 10 ml of concentrated ammonium hydroxide. The layers are separated. The organic layer is extracted with a solution of 75 ml of water and 17 ml of concentrated hydrochloric acid. The extracts are neutralized and taken into ether. The volatiles are evaporated to leave a light yellow oil, the dehydro base.
The oily residue is then hydrogenated at 17 p.s.i. of hydrogen with 5% palladium-on-barium sulfate in 100 ml of 2 N hydrochloric acid for six hours. The reaction mixture is filtered, made alkaline and taken through ether to give the tetrahydro base as a clear oil.
The oily tetrahydro base (about 10.0 g) in 150 ml of 48% hydrobromic acid is heated at 135°C for 24 hours, and then quenched in an ice Treating with baseand taking through chloroform gives a brown residue of the isomeric mixture of 2'-hydroxy-2,5,9-trimethyl-6,7-benzmorphan.
This residue is triturated with ether, cooled and the resulting slurry filtered. The solid product is dissolved in a minimum of dry ethanol and made acid with ethereal hydrogen chloride. The cooled mixture is filtered to give the hydrochloride salt of the N-methyl-iso-benzmorphan, MP: 279-282°C, after recrystallization from ethanol. The base melts at 215°C.
The ethereal filtrate is evaporated. A residue is neutralized to give the crude normal N-methyl-benzmorphan isomer, MP: 229-230°C. The hydrochloride salt of this isomer is formed, MP: 196-198°C, as a hydrate. A mixture of 10.0 g of the N-methyl-iso-benzmorphan isolated above in 15 ml of acetic anhydride is heated on the steam bath for about an hour, then quenched in an ice slurry. The mixture is then neutraliized and taken through ether to give the O-acetate derivative, iso-2'-acetoxy-2,5,9-trimethyl-6,7-benzomorphan. The crude acetate (9.5 g) is reacted with 5.0 g of cyanogen bromide in 100 ml of chloroform at reflux for several hours. The volatiles are removed in vacuo to leave a residue, which is refluxed in 150 ml of dilute hydrochloric acid for 24 hours. The mixture is cooled, neutralized and taken through chloroform to give the desired base with two methyl groups as a viscous syrup which crystallized slowly, MP: 173-175°C from methanol. The base, 6.5 g, is reacted with 5.0 g of phenylacetyl chloride in the presence of an excess of sodium carbonate in water. The mixture is stirred for several hours, diluted with water and taken into ether to give the N-phenacetylated compound. This compound in ether (250 ml) is reacted with an excess of 1.5 M ethereal lithium aluminum hydride at reflux overnight. The reaction mixture is evaporated to dryness, after quenching carefully with water and hydrobromic acid, to give the crude 2'-hydroxy-5,9-dimethyl-2-phenethyl-6,7-benzomorphan hydrobromide salt which is optionally recrystallized from ethanol, MP: 272273°C. The hydrobromide salt in the normal series melts at 170-173°C. The base is isolated by neutralizing of the hydrobromide salt in an ether alkali mixture, with following separating and evaporating the organic solvent.

brand name

Prinadol(SmithKline Beecham).

Therapeutic Function

Narcotic analgesic

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