Cyclopropylmethyl morphinans

Naltrexone hydrochloride dihydrate (l-7V-cyclopropylmethyl-7,8-dihydro-14-hydroxy-morphinan-6-one hydrochloride) [16676-29-2] M 413.9, m 274-276°, [a] -173° (c 1, H2O), pKEst(i) 6 (N-cyclopropylmethyl), pKEst(i) (phenolic OH). This narcotic antagonist has been purified by recrystn from MeOH and dried air. The free base has m 168-170° after recrystn from Me2CO. [Cone et al. J Pharm Sci 64 618 7975 Gold et al. Med Res Rev 2 211 7952.]... 

Chemical Name Morphinan-3,14-diol, 17-(cyclopropylmethyl)-4,5-epoxy-6-methylene-, (5alpha)-... 

Preparation of 17-(cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-4,5a-epoxy-5 -nitropyrido[21,31 6,7]morphinan... 

Schmidhammer H, Burkard WP, Eggstein-Aeppli L, Smith CFC (1989) Synthesis and biological evaluation of 14-alkoxymorphinans. 2. (-)-N-(cyclopropylmethyl)-4, 14-dimethoxy-morphinan-6-one, a selective p opioid receptor antagonist. J Med Chem 32 418—421... 

The 17-substituent of morphinans is believed to influence its agonistic or antagonistic activity towards the opioid receptor [5]. For example, 17-methyl morphinans, morphine, and oxymorphone are agonists. On the other hand, 17-aflyl and 17-cyclopropylmethyl (CPM) morphinans, naloxone and naltrexone (1) are antagonists [5]. Therefore, a dealkylation, especially demethylation reaction of 17-substituents has been widely used to synthesize morphinan derivatives that possess various 17-substituents [27-33]. However, the reaction with chloroformates has only been applied to 14-H-morphinans. Therefore, we were interested in the 17-dealkylation reaction in 14-OH-morphinans, like naltrexone (1). In the course of the study, we found a novel reaction that cleaved the C16-N17 bond in a naltrexone derivative 35 that produced oxazolidinone 36, which lacked a D-ring (Scheme 15). 

The benzomorphans thus far studied were all racemic. In view of the diverse pharmacological properties of the cycloalkylmethyl derivatives it was desirable that the compounds be resolved to ascertain wherein each action resided. Fortunately, for comparison with the morphine and morphinan nuclei we had available from Gates (8) the corresponding cyclopropylmethyl derivatives, 13 and 14. Table IV compares the analgesic antagonist activity of a group of cyclopropylmethyl derivatives with the resolved optically active dimethylallylbenzomorphan, 9. 

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