The reaction of o-chlorophenylacetic acid (I) with SOCl2 gives the corresponding acyl chloride (II), which is condensed with 2-(methylamino) ethanol (III) yielding o-chloro-N-methyl-N-(2-hydroxyethyl)phenylacetamide (IV). The reduction of (IV) with diborane in THF affords N-methyl-N-(2-hydroxyethyl)-2-(2-chlorophenyl)ethylamine (V), which by reaction with PCl5 in CHCl3 is con-verted into N-methyl-N-(2-chloroethyl)-2-(2-chlorophenyl)ethylamine (VI). Finally, this compound is cyclized by means of anhydrous AlCl3-NH4Cl at 175 C.
A new synthesis of 13C- or 14C-labeled SKF-86466 has been described: The Friedel Craft's condensation of labeled benzene (I) with oxalyl chloride by means of AlCl3 in CS2 yields benzoic acid (II), which is chlorinated by means of cupric chloride and thallium (III) trifluoroacetate in trifluoroacetic acid to give 2-chlorobenzoic acid (III). The reduction of (III) by means of borane/THF complex in THF affords 2-chlorobenzyl alcohol (IV), which is treated with hot concentrated HCl to afford 2-chlorobenzyl chloride (V). The Grignard condensation of (V) with N-methyloxazolidine (VI) by means of Mg in ether gives N-[2-(2-chlorophenyl)ethyl]-N-methyl-2-hydroxyethylamine (VII), which is finally cyclized by treatment with PCl5 in hot trichlorobenzene followed by addition of AlCl3 and heating at 215-25 C.
By condensation of styrene oxide (I) with 3,4-dimethoxyphenylethylamine (II) at 100 C to give N-(beta-hydroxy-beta-phenyl)ethyl-2-(3',4'-dimethoxyphenyl)ehtylamine (III), which is cyclized with H2SO4 to 1-phenyl-7,8-dimethoxy-2,3,4,5-tetrahydro-3,1-benzazepine (IV). This product is finally methylated with a refluxing mixture of formaldehyde and formic acid.
The bromination of labeled acetophenone (I) with Br2 and AlCl3 gives phenacyl bromide (II), which is condensed with N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylamine (III), yielding the 2-aminoacetophenone (IV). The reduction of (IV) with NaBH4 affords the secondary alcohol (V), which is finally cyclized by means of H2SO4 and trifluoroacetic acid to provide the target 3-benzazepine.
The condensation of 2-chloro-3,4-dimethoxyphenylethylamine (I) with 4-methoxystyrene oxide (II) in refluxing THF gives the hydroxy phenylethylamine (III). The yield of this reaction is only 19%. In a better sequence (I) is heated with methyl 4-methoxymandelate (IV) to give the mandelamide (V), which is then reduced without purification by B2H6 in THF to give (III). The latter is cyclized by treatment with trifluoroacetic acid - sulfuric acid yielding 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-(1H)-3-benzazepine (VI). Finally, this compound is demethylated by treatment with BBr3 in methylene chloride and treated with methanesulfonic acid.
The bromination of 4-methoxystyrene (I) with Br2 gives the alpha,beta-dibromo derivative (II), which by selective debromination with potassium tert-butoxide yields the tert-butyl ether (III). The condensation of (III) with 2-(2-chloro-3,4-dimethoxyphenyl)ethylamine (IV) affords the secondary amine (V), which is deprotected with H2SO4 to provide the substituted ethanolamine (VI). The cyclization of (VI) by means of Ms-OH and trifluoroacetic acid gives the 3-benzazepine (VII), which is finally demethylated with BBr3 and treated with methanesulfonic acid to afford the target mesylate.
The bromination of labeled 4'-methoxyacetophenone (I) with CuBr2 gives 4'-methoxyphenacyl bromide (II), which is reduced with NaBH4, yielding the carbinol (III). The protection of (III) with DHP affords the tetrahydropyranyl ether (IV), which is condensed with 2-(2-chloro-3,4-dimethoxyphenyl)ethylamine (V) and acidified to provide the aminoalcohol (VI). The cyclization of (VI) with MsOH and trifluoroacetic acid furnishes labeled 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (VII), which is finally demethylated with BBr3 and MsOH.
The optical resolution of the racemic 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (I) (+)- or (-)-dibenzoyltartaric acid gives the corresponding (R)-isomer (II), which is N-demethylated by means of BrCN to yield 6-chloro-7,8-dimethoxy-1(R)-(4-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (III). Finally, this compound is fully demethylated by treatment with BBr3. The optical resolution can also be performed by treatment of racemic (III) with (+)- or (-)-dibenzoyltartaric acid.
The optical resolution of the racemic 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (I) (+)- or (-)-dibenzoyltartaric acid gives the corresponding (S)-isomer (II), which is N-demethylated by means of BrCN to yield 6-chloro-7,8-dimethoxy-1(S)-(4-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (III). Finally, this compound is fully demethylated by treatment with BBr3. The optical resolution can also be performed by treatment of racemic (III) with (+)- or (-)-dibenzoyltartaric acid.
The condensation of labeled 2-(3-chlorphenyl)acetic acid (I) with N-methylethanolamine (II) by means of SOCl2 gives the corresponding amide (III), which is reduced with BH3, yielding the tertiary amine (IV). The reaction of (IV) with PCl3 affords the chloroethylamine (V), which is finally cyclized by means of AlCl3 to provide the target benzazepine.
The condensation of 3,4-dimethoxyphenethylamine (I) with styrene oxide (II) by heating at 100 C gives N-[2-(3,4-dimethoxyphenyl)ethyl]-2-phenyl-2-hydroxyethylamine (III), which can be cyclized with H2SO4 in refluxing trifluoroacetic acid yielding 2,3,4,5-tetrahydro-7,8-dimethoxy-1-phenyl-1H-3-benzazepine (IV). Finally, intermediate (IV) is demethylated with refluxing 48% HBr (III) can also by cyclized and demethylated simultaneously by refluxing with 48% HBr.
The bromination of labeled acetophenone (I) with Br2 and AlCl3 gives the phenacyl bromide (II), which is reduced with NaBH4, yielding 2-bromo-1-phenylethanol (III). The condensation of (III) with N-benzyl-N-[2-(3,4-dimethoxyphenyl)ethyl]amine (IV) affords the tertiary amine (V), which is debenzylated by hydrogenolysis with H2 over Pd/C to provide the substituted ethanolamine (VI). Finally, this compound is cyclized and demethylated by treatment with 48% HBr to provide the target benzazepine.
The optical resolution of the racemic 7,8-dimethoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (I) (+)- or (-)-dibenzoyltartaric acid gives the corresponding (S)-isomer (II), which is N-demethylated by means of CN-Br to yield 7,8-dimethoxy-1(S)-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (III). Finally, this compound is fully demethylated by treatment with MsOH and methionine. An earlier alternative route to demethylation of (III) involves its conversion to the N-benzyl derivative (V) with benzyl bromide (IV), followed by demethylation with BBr3, yielding (VI), and final debenzylation with H2 over Pd/C.
The optical resolution of the racemic 7,8-dimethoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (I) (+)- or (-)-dibenzoyltartaric acid gives the corresponding (R)-isomer (II), which is N-demethylated by means of CN-Br to yield 7,8-dimethoxy-1(R)-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (III). Finally, this compound is fully demethylated by treatment with Ms-OH and methionine. An earlier alternative route to demethylation of (III) involves its conversion to the N-benzyl derivative (V) with benzyl bromide (IV), followed by demethylation with BBr3, yielding (VI), and final debenzylation with H2 over Pd/C.