Process for the preparation of 14-hydroxymorphinan derivatives
AssigneeBristol-Myers Company
InventorsIvo Monkovic, Carol Bachand, Henry Wong
Life of this patent
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Abstract
N-substituted-14-hydroxy-3-substituted-morphinan derivatives have been found to possess potent narcotic agonist or antagonist activity. In particular, the compound N-Cyclobutylmethyl-3,14-dihydroxymorphinan has been found to possess potent agonist/antagonist activity as a non-narcotic analgesic. A new and efficient total synthesis of these compounds is described herein from the starting material 2-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline.
Claims3
The process for the preparation of compounds having the formulas ##STR32## wherein R.sup.2 is H or (lower)alkyl and R is cyclobutyl or cyclopropyl;
- which process consists of the consecutive steps of
- A. treating the compound having the formula ##STR33## in which R is cyclopropyl or cyclobutyl and R.sup.2 is (lower)alkyl with borane in a ratio of about one mole of compound VI to 1 to 1.5 moles of borane in the presence of an acid selected from the group consisting of phosphoric, orthophosphoric, pyrophosphoric and polyphosphoric, boron trifluoride etherate and mixtures thereof to produce the compound having the formula ##STR34## in which R and R.sup.2 are as described above;
- and B. cleaving the R.sup.2 O-ether function of compound LV by treatment with an agent selected from the group consisting of NaSC.sub.2 H.sub.5, hydrobromic acid, boron tribromide and pyridine hydrochloride to produce the compound having the formula ##STR35## in which R is cyclopropyl or cyclobutyl.
The process for the preparation of the compound having the formula ##STR40## in which R.sup.2 is H or CH.sub.3 ;
- which process comprises the consecutive steps of
- A. treating the compound having the formula ##STR41## with borane in a molar ratio of about 1 mole of borane to about 1 mole of compound VIb in the presence of a large excess of anhydrous phosphoric acid with the aid of heat in the range of about +40.degree. C. to about +50.degree. C. until the cyclization is essentially complete to produce the compound having the formula ##STR42## and B. cleaving the ether function of compound LVb by treatment with an agent selected from the group consisting of NaSC.sub.2 H.sub.5, hydrobromic acid, boron tribromide or pyridine hydrochloride to produce the compound having the formula ##STR43##
Dependencies are inferred from the claim text.