合成路线1

By condensation of 5-methoxyindole (I) with 4-piperidone (II) in acetic acid at 100 C, followed by neutralization with succinic acid (A).

合成路线2

A new synthesis of roxindole has been described: The condensation of 5-methoxyindole (I) with succinic anhydride (II) by means of methylmagnesium bromide in hot anisole gives the 4-oxobutyric acid derivative (III), which is condensed with the 4-phenyltetrahydropyridine (IV) by means of EDC and DIPEA in DMF yielding the butanedione (V). The reduction of (V) with LiAlH4 in refluxing THF affords intermediate (VI), which is finally demethylated with DIBAH in refluxing toluene.

合成路线3

The title compound has been prepared by two related procedures. Treatment of N-carbobenzoxy-D-proline (I) with oxalyl chloride provided the corresponding acid chloride (II). This was condensed with 5-methoxyindolyl magnesium bromide, generated from 5-methoxyindole (III) and ethylmagnesium bromide, to afford the indolyl ketone (IV). Reduction of both keto and carbamate groups of (IV) by means of LiAlH4 in refluxing THF then furnished the target compound.

合成路线4

Alternatively, 5-methoxyindole (III) was N-silylated employing tert-butyldimethylsilyl chloride and n-BuLi, and the resulting silyl derivative (V) was brominated with N-bromosuccinimide at -78 C to afford the 3-bromoindole (VI). After lithium-bromine exchange in (VI) with n-BuLi at -78 C, the 3-lithio compound was condensed with N-methyl-D-proline methyl ester (VII) to give the indolyl ketone (VIII). The ketone function of (VIII) was finally reduced employing LiAlH4 in boiling THF.

合成路线5

Tetrahydropyridine (II), obtained by NaBH4 reduction of the 1-benzylpyridinium salt (I), was condensed with 5-methoxyindole (III) in refluxing 50% AcOH to produce, through a biomimetic sequence, the aminoethyl carbazole compound (IV). Catalytic debenzylation of (IV) led to the primary amine (V), which was converted to the oxalic acid mono-amide (VI) upon heating with diethyl oxalate. Cyclization of amide (VI) in the presence of POCl3 under Vilsmeier conditions furnished the pyridocarbazole tetracyclic system (VII). Dehydrogenation of (VII) over Pd/C in boiling diphenyl ether led to a mixture of the desired aromatized compound (VIII) and the decarbethoxylated byproduct (IX), which were separated by column chromatography. N-Methylation of the pyrrole ring of (VIII) to give (X) was performed by using dimethyl carbonate in DMF in the presence of K2CO3 and crown ether. Reaction of ester (X) with 2-(dimethylamino)ethylamine (XI) at 115 C gave amide (XII). Finally, the desired 9-hydroxy derivative was obtained by methyl ether cleavage in (XII) employing boron tribromide. Alternatively, the title compound was obtained by demethylation of ether (X) and subsequent reaction with 2-(dimethylamino)ethylamine (XI).

合成路线6

The cyclization of 5-methoxy-1H-indole (I) with hexane-2,6-dione (II) by means of BF3 ethearate in refluxing dioxane gives 6-methoxy-1,4-dimethylcarbazole (III), which is formylated with N-methylformanilide (IV) and POCl3 in hot o-dichlorobenzene yielding the 3-formyl derivative (V). The condensation of (V) with 2-aminoacetaldehyde diethylacetal (VI) by heating at 100 C affords the expected imino derivative (VII), which is cyclized by acid (HCl) hydrolysis of the acetal group and cyclization of the resulting aldehyde by means of NaOH in water to the 9-methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole (VIII). The oxidation of (VIII) with m-chloroperbenzoic acid (MCPBA) in acetone gives the correponding N-oxide (IX), which is treated with BBr3 in dichloromethane yielding 9-hydroxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole (X). Finally, this compound is treated with 1-bromo-3-methoxy-2-propanone in DMF to afford the desired quaternary salt.

合成路线7

The hydrogenation of 5-methoxy-1H-indole (I) by means of NaCNBH3 in acetic acid gives 5-methoxyindoline (II), which is benzoylated with benzonitrile (III) by means of BCl3/AlCl3 in dichloroethane yielding 7-benzoyl-5-methoxyindoline (IV). The cyclization of (IV) with glycine ethyl ester (V) in pyridine affords the pyrrolo[1,4]benzodiazepine (VI), which is treated with amyl nitrite in toluene/THF to provide the oxime (VII). The reduction of (VII) with H2 over Ru/C in methanol gives the racemic amine (VIII), which is submitted to optical resolution with di-p-toluoyl-D-tartaric acid yielding the corresponding (R)-isomer (IX). Finally, this compound is condensed with 1H-indole-2-carboxylic acid (X) by means of TOTU and DIEA in dichloromethane.

合成路线8

The reaction of 5-methoxyindol (I) with 4-fluorobenzyl chloride in DMF gives 5-methoxy-1-(4-fluorobenzyl)indol (II). This compound is acylated with oxalyl chloride, yielding 5-methoxy-[1-(4-fluorobenzyl)indol-3-yl]glyoxylic acid chloride (III), which is transformed with 4-amino-3,5-dichloropyridine into the corresponding amide (IV). The reaction of (IV) with borontribromide in toluene cleaves the methoxy group, yielding AWD 12-281.

合成路线9

Protection of 5-methoxyindole (I) with benzenesulfonyl chloride (II) in the presence of NaH affords the N-sulfonyl indole (III). Acylation of the 2-lithio derivative of (III) with benzoyl chloride (IV) gives rise to ketone (V). Finally, removal of the phenylsulfonyl protecting group of (V) is achieved by either basic hydrolysis or by treatment with tetrabutylammonium fluoride.

合成路线10

合成路线11