Morphinans 4-hydroxy

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.]... 

D,L-3-Hydroxy-N-methyl-morphinan Phenyl trimethyl ammonium chloride D-Tartaric acid... 

The methylation of 51.4 parts by weight of D,L-3-hydroxy-N-methyl-morphinan is carried out with a methylating solution obtained from 51.5 parts by weight of phenyl-trimethyl-ammonium-chloride. The D,L-3-methoxy-N-methyl-morphinan is isolated in the form of its hydrobromide, which melts with 1 mol of water at 92°-94°C, without water at 239°-240°C. The base isolated from the aqueous solution by means of sodium carbonate melts at 81°-83 C. 

Hydroxy-morphinane, 12. Mitteilung. Die Konfiguration der Morphinane, by H. Corrodi, J. Hellerbach, A. Ziist, E. Hardegger, and O. Schnider, Helv. Chim. Acta, 42 (1959) 212-217. 

The Delft synthesis makes use of an acid-catalyzed ring closure - in fact an intramolecular aromatic alkylation - of a l-(3,5-dihydroxy-4-methoxybenzyl) isoquinoline derivative that is prepared starting from (natural) gallic acid. One of the hydroxyl groups is removed via a Pd/ C hydrogenation of the benzyl ether. Other catalytic steps play an important role some steps were improved recently [27]. The crucial step in the Rice synthesis makes use of a l-(2-bromo-5-hydroxy-4-methoxybenzyl)isoquinoline derivative that is also cyclized in an acid-catalyzed ring closure to the morphinan skeleton, followed by catalytic removal of the bromo substituent (Scheme 5.8). 

Dromoran (Sometimes called Methorphinan or 3-Hydroxy-N-Methyl-Morphinan)... 

Hellerbach, J., Grussner, A., Schnider, O. (-)-3-Hydroxy-N-allyl-morphinan und verwandte Verbindungen, Helv. Chim. Acta 1956, 39, 429-440. 

Chemical Name Morphinan-6-one, 4,5a-epoxy-14-hydroxy-3-methoxy-17-methyl- hydrochloride... 

Modifications to the C-ring of the morphinan structure can produce compounds with increased activity, as well as changes in the receptor selectivity profiles [18]. Most pronounced is oxidation of the 6-hydroxy to the 6-keto derivative. With the 7,8-olefin in place, the activity is reduced when compared to morphine. However, reduction of the 7,8-olefin produces compounds with increased activity. Combining the 7,8-dihydro and 6-keto modifications to the morphinan skeleton produces compounds with greatly increased activities (10-fold) over morphine. 

O-Desmethylibogaine (= 12-Hydroxy-ibogamine)] (indole) [Dihydroakuammine] (indolomonoterpene) Dihydrocodeine (morphinan isoquinoline) d.v-8,10-Di-A-Propyllobelidiol hydrochloride dehydrate (piperidine)... 

Hydroxy-N-methylmorphinan was also found to bind to opioid receptors), but its analgesic activity in the MW assay was of doubtful significance. Related morphinan-6-ones were synthesized via 3-methoxyphenylethyl-amide(76,77) (e.g., Scheme 3.10). Resolution at the 2-benzyltetrahydroiso-quinoline stage afforded (-)-2-hydroxy-N-methylmorphinan-6-one (75a) and the corresponding methyl ether (75b). Neither compound exhibited significant MHP activity,(50) with the ether being only about i x morphine. The (+)-enantiomorphs were prepared in a similar manner.<50)... 

Several 4-hydroxymorphinan-6-ones bearing a 14-OH function have been made from oxymorphone (108).(1O9) Here there is a marked contrast in the qualitative action observed relative to the actions seen in the 3,14-dihydroxy-morphinans. Whereas, in the latter, high antagonist activities with little agonism occurred, 4-methoxy-14-hydroxy-N-methylmorphinan-6-one (109b), for example, was 6x as potent as morphine in the MHP antinociceptive assay. This activity is 4 x that of the corresponding 3-OH analog. 

Belleau and a Bristol Laboratories group developed a novel morphinan synthesis which leads to 14-hydroxy derivatives.(62) The procedure rests upon rearrangement of the spirane 13 and may be adapted to provide either 14-/3-or 14-a-hydroxy (iso) diastereoisomers (see 13 and p. 110). Out of this work... 

The cytochrome P450 responsible for the oxidation of (S)-N-methylcoclaurine to (S)-3 -hydroxy-N-methylcocluarine has been overexpressed in opium poppy plants, and morphinan alkaloid production in the latex is increased subsequently to 4.5 times the level in wild-type plants (58). Additionally, suppression of this enzyme resulted in a decrease in morphinan alkaloids to 16% of the wild-type level. Notably, analysis of a variety of biosynthetic gene transcript levels in these experiments supports the hypothesis that this P450 enzyme plays a regulatory role in the biosynthesis of benzylisoquinoline alkaloids. Collectively, these studies highlight that the complex metabolic networks found in plants are not redirected easily or predictably in all cases. 

Methyl-6-hydroxy-2-pyrone, 156 Methylides, 434-435 Methyl isobutyl ketone, 275, 276 Methyl jasmonate, 261, 262 Methyl linolenate, 293 Methyllithium, 3 N-Methyl-14a-morphinan, 68 N-Methylmorpholine N-oxide, 16, 141, 291-292... 

Schnider and Grtissner in the same way prepared 3- and 2- (or 4) hydroxy-N-methylmorphinane, obtained the same compounds from N-methylmorphinane by way of the nitro and amino compounds, and also synthesized the 3-hydroxy-derivative from [liv] by nitration, reduction, diazotization, c., followed by cyclization [25]. They have more recently resolved [lxxih] and prepared 3-hydroxy-N-allyl-morphinane [26], Schnider and Hellerbach [27] prepared an isomer of [lxxiii] and also synthesized dZ-tetrahydrodesoxycodeine [lxxv] by the cyclization of [lxxvi], in which reaction a small amount of 2 3-dihy-droxy-N-methylmorphinane [lxxvii], isomeric with dZ-tetrahydrodes-oxymorphine, was also obtained. Both [lxxhi] and [lxxvii] exhibit marked analgesic properties to about the same extent, whilst the 2- (or 4) hydroxy-compound is much less active [25, 27]. 

Because of the low reactivity of the tertiary alcohol, alkylation of the 014-hydroxyl with alkyl halides such as propyl or isoamyl halides was unsuccessful [Schmidhammer H, unpublished observations]. Therefore, allylic halides were employed to introduce 14-O-alkenyl substituents using similar conditions as described above [ 43—461. Catalytic hydrogenation afforded the corresponding 14-O-alkyl derivatives [43 -5]. Thus, 14-hydroxy-5-methylcodeinone (20) was treated with 3,3-dimethylallyl bromide in DMF in the presence of NaH to give compound 21, which underwent catalytic hydrogenation to yield 14-O-isoamyl-substituted morphinan 24 (Scheme 5) [43]. Similarly 14-phenylpropoxymorphinans 25 and 26 were prepared from 14-hydroxycodeinone (3) and 21, respectively, via intermediates 22 and 23, which were obtained by alkenylation using cinnamyl bromide (Scheme 5) [44, 45],... 

Scheme 8 Reaction of 4-hydroxy morphinan 25 with stable sulfur ylide. Reagents and conditions (a) trimethylsulfoxonium iodide, NaH, THF, 55 °C to rt, 58%...

To investigate the source of the unexpected cyclization, we combined a precursor 28 that did not have a 4-hydroxy group with the same stable ylide. This produced compound 29 with an oxabicyclo[2.2.1]heptane skeleton via the epoxide 30. Alternatively, the morphinan methyl ether 28 could also react with the stable sulfur ylide derived from trimethylsulfoxonium iodide at room temperature. The definitive intermediate, 6a-epoxide 30, was isolated, and then treated with NaH in DMF at 80 °C to produce the objective bicyclic compound 29 (Scheme 9). 

The levo isomers of 3-hydroxy-7V-methyl-morphinan and of methadone are demethylated by rat hver 2-3 times more rapidly than the corresponding dextro antipodes. The S(+)-enantiomer of hexobarbital (Figure 26.4) is metabohzed almost twice as rapidly as the R(-)-enantiomer by allylic hydroxylation and, in the dog, the dextrorotatory isomer of 5-ethyl-5-phenyl-hydantoin affords 10 times more para-hydroxy-metabolite than the levorotatory isomer. ° Hydroxylation takes place alpha to a carbonyl in the dextrorotary enantiomer of glutethimide whereas the levorotamer is hydroxylated on the methylene group of the ethyl side chain. Numerous other examples are found in the literature. ... 

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