71-68-1

(-)-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [35S]GTPγS binding, forskolin-induced cAMP accumulation assay, and MOR-mediated β-arrestin recruitment assays). "Body"and "tail"interactions with opioid receptors (a subset of Portoghese's message-address theory) were used for molecular modeling and simulations, where the "address"can be considered the "body"of the hydromorphone molecule and the "message"delivered by the substituent (tail) on the aromatic ring of the N-phenethyl moiety. One compound, N-p-chlorophenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro- 1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 2i), was found to have nanomolar binding affinity at MOR and DOR. It was a potent partial agonist at MOR and a full potent agonist at DOR with a δ/μ potency ratio of 1.2 in the ([35S]GTPγS) assay. Bifunctional opioids that interact with MOR and DOR, the latter as agonists or antagonists, have been reported to have fewer sideeffects than MOR agonists. The p-chlorophenethyl compound 2i was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound 2i did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO2), respiration was depressed in squirrel monkeys.

There is provided a novel process for the preparation of a compound of formula (I), wherein R1 is as described in the description, by demethylation of a corresponding O-methyl derivative.

The invention aims to overcome the defects in the prior art, and provides a new refinement method of hydromorphone acid salt. The method comprises the following steps: a. adding hydromorphone and dilute acid into a reaction kettle, and dissolving by stirring at 30-60 DEG C; cooling to 15--5 DEG C, stirring to precipitate abundant solid, adding alcohol and ether, and stirring to crystallize for 0.5-3 hours; filtering, washing until the pH value of the filtrate is 6-7, and drying in a drying oven to obtain a hydromorphone acid salt crude product; b. adding purified water into a refinement decolorization tank, heating to 30-60 DEG C, adding the hydromorphone acid salt crude product, stirring until the hydromorphone acid salt crude product is completely dissolved, adding medicinal carbon, adding dilute acid, and decolorizing at the constant temperature of 30-60 DEG C for 10-30 minutes; filtering, washing the filter cake with purified water, merging the washing liquid and filtrate, distilling under reduced pressure, refrigerating at 5+/-5 DEG C to crystallize for more than 8 hours; and filtering, washing the filter cake with 95% ethanol, drying in a drying oven to obtain the hydromorphone acid salt.

Dihydromorphone was prepared from morphine in high yield, excellent purity, and low residual metal content. The key steps used palladium on porous glass and a modified Oppenauer oxidation, or Wilkinson's catalyst. Georg Thieme Verlag Stuttgart ? New York.

The present invention provides processes for the preparation of saturated ketone morphinan compounds by catalytic isomerization. In particular, the invention provides processes for the conversion of a morphinan comprising an allyl alcohol ring moiety into a morphinan comprising a saturated ketone ring moiety by an isomerization reaction catalyzed by an allyl-transition metal catalyst.

A method of preparation of 4,5α-epoxy-6-oxomorphinan derivatives of formula (I), wherein R1 is hydrogen, methyl, or ethyl and R2 is hydrogen, methyl, cyclobutylmethyl or benzyl, in which compounds of formula (II), wherein R1 and R2 are as defined with respect to compounds (I), are isomerized into compounds of formula (I) in the presence of a mixed catalyst containing at least two elements from the group of platinum metals. The method provides the product in high yield and with low contents of impurities.