合成路线1

The condensation of 7-methoxy-3,4-dihydro-1(2H)-naphthalenone (I) with tetramethylene dibromide (A) by means of NaH in benzene gives 3,4-dihydro-7-methoxy-2,2-tetramethylene-1(2H)-naphthalenone (II), b.p.(0.05) = 120-3 C, which is treated with acetonitrile and butyllithium in THF yielding 1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2,2-tetramethylene-1-naphthaleneacetonitrile (III), m.p. 140-2 C. This compound is reduced with LiAlH4 in THF to afford hydro-2,2-tetramethylene-1-naphthol (IV), m.p 178-80 C, and isomerized to 4a-(2-aminoethyl)-1,2,3,4,4a,9-hexahydro-6-methoxy-phenantrene (V), m.p. 187 C. This amine is cyclized by reaction with bromine in CHCl3 giving 3-methoxy-9a-bromonrhasybanan hydrobromide (VI), m.p. 207.0-8.5 C (decomp.), and isomerized with dehydrobromination by treatment with NaHCO3 in DMF affording 3-methoxy-DELTA(8,14)-morphinan (VII), m.p. 180-4 C. The acetylation of (VII) with trifluoroacetic anhydride (B) yields 3-methoxy-N-trifluoroacetyl-DELTA(8,14)-morphinan (VIII), m.p. 94-6 C, which is epoxidized with m-chloroperbenzoic acid in methylene chloride giving 8,14-epoxy-3-methoxy-N-trifluoroacetylmorphinan (IX), m.p. 102-5 C. The deacetylation of (IX) with NaSH4 in ethanol gives 8,14-epoxy-3-methoxymorphinan (X), oily product that is treated with LiAlH4 in THF to open the epoxide ring and yield 14-hydroxy-3-methoxymorphinan (XI) (HCl salt, m.p. 243-4 C (decomp.)). The condensation of (Xl) with cyclobutylcarbonyl chloride (C) by means of pyridine in CH2Cl2 affords N-cyclobutylcarbonyl-14-hydroxy-3-methoxymorphinan (XII), m.p. 183-5 C, which is reduced with LiAlH4 in refluxing THF giving N-cyclobutylmethyl-14-hydroxy-3-methoxymorphinan (XIII) (HCl salt, mp. 248-50 C (decomp.)). Finally, (XIII) is demethylated by treatment with refluxing 48% HBr.