The condensation of 4-methoxybenzylmagnesium chloride (I) with 3,4-dimethylpyridine methiodide (II) gives N,3,4-trimethyl-2-(p-methoxybenzyl)-1,2-dihydropyridine (III), which by partial reduction with NaBH4 in methanol is converted into the corresponding 1,2,5,6-tetrahydro derivative (IV). The cyclization of (IV) by refluxing with AlBr3 in CS2 yields 2,5,9-trimethyl-2'-hydroxy-7-benzomorphane (V), which is acetylated with acetic anhydride to the acetoxy compound (VI) and treated with BrCN in refluxing CHCl3 to afford the N-cyano compound (VII). This compound is refluxed with 6% HCl yielding 5,9-dimethyl-2'-hydroxy-6,7-benzomorphane (VIII) , which is condensed with 4-(p-fluorophenyl)-4,4-ethylenedioxy-1-chlorobutane (XVI) by means of NaHCO3 in DMF at 140 C to afford the corresponding N-alkyl derivative (IX). Finally, this compound is hydrolyzed by refluxing with diluted aqueous HCl.

The condensation of (VIII) with 3-(p-fluorobenzoyl)propionic acid (A) by means of ethyl chloroformate (B) and triethylamine in CHCl3 gives the corresponding N,O-diacyl derivative (X), which is then reduced with LiAlH4 in refluxing THF yielding 5,9-dimethyl-2-[4''-(p-fluorophenyl)4''-hydroxy-1''-butyl]-2'-hydroxy-5,9-dimethyl-6,7-benzomorphane (XI). Finally, this compound is oxidized with Jones reagent (H2CrO4 in H2SO4).

The condensation of 3,4-dimethylpyridine (XV) with 4-(p-fluorophenyl)-4,4-ethylenedioxy-1-chlorobutane (XVI) gives the corresponding pyridinium salt (XVII), which by reaction with p-methoxybenzylmagnesium chloride (I) in ether yields the dihydropyridine (XVIII). The reduction of (XVIII) with NaBH4 in methanol affords the tetrahydropyridine (XIX), which is finally cyclized by refluxing with AlBr3 in CS2; this reaction can also be performed by heating (XIX) with 48% aqueous HBr at 130 C.

The condensation of 4-methoxybenzylmagnesium chloride (I) with 3,4-dimethylpyridine methiodide (II) gives N,3,4-trimethyl-2-(p-methoxybenzyl)-1,2-dihydropyridine (III), which by partial reduction with NaBH4 in methanol is converted into the corresponding 1,2,5,6-tetrahydro derivative (IV). The cyclization of (IV) by refluxing with AlBr3 in CS2 yields 2,5,9-trimethyl-2'-hydroxy-7-benzomorphane (V), which is acetylated with acetic anhydride to the acetoxy compound (VI) and treated with BrCN in refluxing CHCl3 to afford the N-cyano compound (VII). This compound is refluxed with 6% HCl yielding 5,9-dimethyl-2'-hydroxy-6,7-benzomorphane (VIII) , which is condensed with 4-(p-fluorophenyl)-4,4-ethylenedioxy-1-chlorobutane (XVI) by means of NaHCO3 in DMF at 140 C to afford the corresponding N-alkyl derivative (IX). Finally, this compound is hydrolyzed by refluxing with diluted aqueous HCl.

The condensation of (VIII) with 3-(p-fluorobenzoyl)propionic acid (A) by means of ethyl chloroformate (B) and triethylamine in CHCl3 gives the corresponding N,O-diacyl derivative (X), which is then reduced with LiAlH4 in refluxing THF yielding 5,9-dimethyl-2-[4''-(p-fluorophenyl)4''-hydroxy-1''-butyl]-2'-hydroxy-5,9-dimethyl-6,7-benzomorphane (XI). Finally, this compound is oxidized with Jones reagent (H2CrO4 in H2SO4).

The nitration of 2,5,9-trimethyl-6,7-benzomorphane (XII) gives the 2'-nitro derivative (XIII), which by hydrogenation is converted into the corresponding 2'-amino compound (XIV). Finally, this compound is diazotized and converted into the hydroxy compound (V), already obtained.

The condensation of 3,4-dimethylpyridine (XV) with 4-(p-fluorophenyl)-4,4-ethylenedioxy-1-chlorobutane (XVI) gives the corresponding pyridinium salt (XVII), which by reaction with p-methoxybenzylmagnesium chloride (I) in ether yields the dihydropyridine (XVIII). The reduction of (XVIII) with NaBH4 in methanol affords the tetrahydropyridine (XIX), which is finally cyclized by refluxing with AlBr3 in CS2; this reaction can also be performed by heating (XIX) with 48% aqueous HBr at 130 C.

The condensation of 4-methoxybenzylmagnesium chloride (I) with 3,4-dimethylpyridine methiodide (II) gives N,3,4-trimethyl-2-(p-methoxybenzyl)-1,2-dihydropyridine (III), which by partial reduction with NaBH4 in methanol is converted into the corresponding 1,2,5,6-tetrahydro derivative (IV). The cyclization of (IV) by refluxing with AlBr3 in CS2 yields 2,5,9-trimethyl-2'-hydroxy-7-benzomorphane (V), which is acetylated with acetic anhydride to the acetoxy compound (VI) and treated with BrCN in refluxing CHCl3 to afford the N-cyano compound (VII). This compound is refluxed with 6% HCl yielding 5,9-dimethyl-2'-hydroxy-6,7-benzomorphane (VIII) , which is condensed with 4-(p-fluorophenyl)-4,4-ethylenedioxy-1-chlorobutane (XVI) by means of NaHCO3 in DMF at 140 C to afford the corresponding N-alkyl derivative (IX). Finally, this compound is hydrolyzed by refluxing with diluted aqueous HCl.

The condensation of 4-methoxybenzylmagnesium chloride (I) with 3,4-dimethylpyridine methiodide (II) gives N,3,4-trimethyl-2-(p-methoxybenzyl)-1,2-dihydropyridine (III), which by partial reduction with NaBH4 in methanol is converted into the corresponding 1,2,5,6-tetrahydro derivative (IV). The cyclization of (IV) by refluxing with AlBr3 in CS2 yields 2,5,9-trimethyl-2'-hydroxy-7-benzomorphane (V), which is acetylated with acetic anhydride to the acetoxy compound (VI) and treated with BrCN in refluxing CHCl3 to afford the N-cyano compound (VII). This compound is refluxed with 6% HCl yielding 5,9-dimethyl-2'-hydroxy-6,7-benzomorphane (VIII) , which is condensed with 4-(p-fluorophenyl)-4,4-ethylenedioxy-1-chlorobutane (XVI) by means of NaHCO3 in DMF at 140 C to afford the corresponding N-alkyl derivative (IX). Finally, this compound is hydrolyzed by refluxing with diluted aqueous HCl.

The condensation of 4-methoxybenzylmagnesium chloride (I) with 3,4-dimethylpyridine methiodide (II) gives N,3,4-trimethyl-2-(p-methoxybenzyl)-1,2-dihydropyridine (III), which by partial reduction with NaBH4 in methanol is converted into the corresponding 1,2,5,6-tetrahydro derivative (IV). The cyclization of (IV) by refluxing with AlBr3 in CS2 yields 2,5,9-trimethyl-2'-hydroxy-7-benzomorphane (V), which is acetylated with acetic anhydride to the acetoxy compound (VI) and treated with BrCN in refluxing CHCl3 to afford the N-cyano compound (VII). This compound is refluxed with 6% HCl yielding 5,9-dimethyl-2'-hydroxy-6,7-benzomorphane (VIII) , which is condensed with 4-(p-fluorophenyl)-4,4-ethylenedioxy-1-chlorobutane (XVI) by means of NaHCO3 in DMF at 140 C to afford the corresponding N-alkyl derivative (IX). Finally, this compound is hydrolyzed by refluxing with diluted aqueous HCl.

The nitration of 2,5,9-trimethyl-6,7-benzomorphane (XII) gives the 2'-nitro derivative (XIII), which by hydrogenation is converted into the corresponding 2'-amino compound (XIV). Finally, this compound is diazotized and converted into the hydroxy compound (V), already obtained.