Morphinans hydrogenation

Somewhat more effective catalysts are obtained by replacing BINAP with TolBINAP, which is 2,2 -bis(di-p-tolylphosphino)-l,l -binaphthyl.4 The presently preferred catalysts are complexes of Ru(OCOCF3)2 with (R)- or (S)-TolBINAP, obtained by treatment of Ru(OAc)2TolBINAP with 2 equiv. of trifluoroacetic acid. Such catalysts promote hydrogenation of typical enamides in 98% ee and 98% yield. This reaction can be used to provide asymmetric synthesis of isoquinoline alkaloids as well as of morphinans used as substitutes for morphine. 

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). 

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

Other 3-substituted morphinans were isolated during attempts to prepare 3-hydroxymorphinans by sequential nitration, hydrogenation to the amine, and diazotization of the unsubstituted precursor/381 A mixture of 2- and 3-nitromorphinans was isolated, but no biological data were reported. 

In a manner similar to that outlined previously, dihydrothebaine (80) gave on reaction with Me2CuLi the morphinan-6-one enol ether (81), which, on mild acid hydrolysis, yielded the 7a-methylmorphinan-6-one (82a) (B/C cis). The same product was obtained from 79 by first, acid hydrolysis of the enol-ether to a 3 1 mixture of B/C cis (morphinan) and B/C trans (isomor-phinan) isomers, followed by catalytic hydrogenation of the appropriate isomer to a mixture of 82a and 82b. 

Other five-membered C-ring morphinans (129c) have been isolated from the photolysis or catalytic hydrogenation (Pd-C), under various conditions, of 14-methyl-C-nordihydrocodeinone (129b) derived from cyclocodeinone (129a) (p. 48). Biological data were not reported.0 47 ... 

A wide variety of substituents are tolerated. The group R can be alkyl, halogen, alkoxy, -amido, azi-domethyl, ester, aryl, aryloxy and aryloyl, and at least one ortho substituent is permissible with no loss in yield. TTie aromatic ring can also be 2-naphthyl, 9,10-dihydro-2-phenanthryl, 3-pyridyl, thiophen-2-yl or pyrrol-3-yl. The group R can be hydrogen, yl, acyl or acetic acid. Beyond Ae antiinflammatory targets, successful reaction substrates include the methyl ketones of a binaphthyl crown ether, a morphinane and a polyaromatic hydrocarbon. The preparation of ibuprofen methyl ester (38) is shown in equation (37) as a typical example. ... 

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],... 

Fig. 12 Our previous superimposition of U-50488H (arylacetamide) on TRK-820 (morphinan) [16]. TRK-820 is shown in green, and U-50488H is shown in white. Sphere colors indicate the following properties (see Sect. 4.3) hydrophobic (HP, white) aromatic (AR, green) hydrogen-bond donors (HD, blue) hydrogen-bond acceptors (HA, red) and hydrogen-bond donors/acceptor (DA, violet). Large and small spheres represent radii of 1 and 0.5 A, respectively. The TRK-820 and U-50488H spheres are represented by dotted and solid spheres, respectively. Only matched spheres are indicated...

Dihydromorphine. <5a,6a) 4,5-Epoxy-l7-merhyf-morphinan-3t6-diol CpHjjNOjl mol wt 287.35. C 71.05%, H 7.37%, N 4.87%. O 16.70%. Prepd by hydrogenation of morphine Or opium by demethylation of tetrahydrothe-baine from dihydrocodeine. Ref Small Lutz, Chemistry of the Opium Alkaloids. Suppt. No. 103, Public Health Repons, Washington (1932) Eddy Reid X Pharmacol 52, 468 (1934) K. W. Bentley The Chemistry of the Morphine Alkaloids (Oxford, 1954). 

Hydrocodone, 4,5-Epoxy-3-methoxy- 17-methvt-morphinan-6-one dihydrocodeinone Bekadid Dicodid. C,H31NOj mol wt 299.36. C 72.21%, H 7-07%, N 4.68%, O [6,03%. Prepn by hydrogenation of codeinone Mannich, Lowenheim, Arch. Pharm. 258, 295 (1920) by oxidation of dihydrocodeine, Ger. pat. 415,097 (1925 to E. Merck), Frdl. 15, 1518 (1925-1927) by catalytic rearrangement of codeine Ger. pet. 623,821. Industrial prepn from dihydrocodeine Pfister. Tishler, U.S. pal, 2,715,626 (1955 to Merck Co-)-Toxicity data Eddy, Reid, J. Pharmacol. Exp. Ther. 52,468 (1934). Review Small. Lutz. "Chemistry of the Opium Alkaloids, Suppl. No. 103, Public Health Reports, Washington (1932). 

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