1) The condensation of 4-(triphenylmethyl)-2-(p-toluenesulfonyloxymethyl)morpholine (I) with 4-hydroxy-1 indanone (II) through the corresponding potassium salt in hot DMF gives 2-(1-oxoindan-4-yloxymethyl)-4-(triphenylmethyl)morpholine (III), which is reduced with LiAlH4 in THF to 2-(1-hydroxyindan-4-yloxymethyl)-4-(triphenylmethyl)morpholine (IV). Finally, this compound is dehydrated and deprotected with HCl in refluxing ethanol.
2) Treatment of 1-[inden-7(or4)-yloxyl-2,3-epoxypropane (V) with excess 2-aminoethyl hydrogen sulfate (VI) and aqueous NaOH gives (+)-2-[[inden-7(or4)-yloxylmethyl]morpholine (VII). The 4-indenyl isomer (VIII) and the 7-indenyl isomer (indeloxazine) can be separated by fractional crystallization.
3) The reaction of 2-(2-benzyloxyphenyl)ethanol (I) with triphenylphosphine and N-bromosuccinimide in benzene gives 2-(2-benzyloxyphenyl)ethyl bromide (II), which upon treatment with potassium [14C]cyanide (II) in dimethylformamide affords 3-(2-benzyloxyphenyl)-[1-14C]propionitrile (IV), which is hydrogenated with H2 over Pd/C in methanol to give 3-(2-hydroxyphenyl)[1-14C]propionitrile (V). Nitrile (V) is treated with hydrogen chloride in ethanol to give 3,4-dihydro[2-14C]coumarin (VIII) through the acid (VI) and the ester (VII). The reaction of compound (VIII) with sodium chloride- aluminum chloride complex gives 4 hydroxy-1-[1-14C]indanone (IX), which is acetylated with acetic anhydride in anhydrous 1,2-dichloromethane and triethylamine giving the acetate (X) in order to obtain pure (IX) after alkaline hydrolysis. Compound (IX) is treated with 2-bromomethyl-4 triphenyl-methylmorpholine (XI) in the presence of anhydrous K2CO3 to dimethylformamide to give 2-[(1-oxo[1-14C]indan-4-yloxy)methyl]-4-triphenylmethylmorpholine (XII), which is reduced with NaBH4 giving 2-[(1-hydroxy[1-14C]indan-4yloxy)methyl]-4-triphenylmethylmorpholine (XIII). Compound (XIII) is treated with an excess of HCl in ethanol to give (rac)-2-[[[3-14C]inden-7-yloxy]methyl]morpholine hydrochloride (indeloxazine hydrochloride) without formation of the corresponding 4-isomer.
The reaction of 2-(p-toluenesulfonyloxymethyl)-4-triphenylmethylmorpholine (I) with the potassium salt of 4-hydroxy-1-indanone (II) in DMSO at 100 C gives 2-(1-oxoindan-4-yloxymethyl)-4-triphenylmethylmorpholine (III), which is hydrolyzed with trifluoroacetic acid yielding 2-(1-oxoindan-4-yloxymethyl)morpholine (IV). The reduction of (IV) with LiAlH4-THF affords 2-(1-hydroxyindan-4-yloxymethyl)morpholine (V), which is finally dehydrated by treatment with p-toluenesulfonic acid in refluxing toluene.
The Friedel Crafts condensation of fumaryl chloride (I) with bromobenzene (II) gives 1,2-bis(4-bromobenzoyl)ethylene (III), which is reduced with Zn and Ac-OH to yield 1,4-bis(4-bromophenyl)butane-1,4-dione (IV). The cyclization of (IV) in refluxing Ac2O affords 2,5-bis(4-bromophenyl)furan (V) which is treated with CNCu in refluxing quinoline to provide 2,5-bis(4-cyanophenyl)furan (VI). The reaction of (VI) with HCl in ethanol gives the bis imidate (VII), which is finally treated with ammonia in ethanol to yield the target bis benzamidine.