Catalytic hydrogenation of 4-nitroacetanilide (I) afforded aniline (II), which was condensed with N,N-dimethylformamide azine to produce the triazolyl derivative (III). Acid hydrolysis of the acetamido group gave rise to amine (IV). Then, diazotization, followed by stannous chloride reduction of the diazonium salt, furnished the intermediate hydrazine (V).

5-Bromovaleryl chloride (VI) was reduced to aldehyde (VII) by means of lithium tri-tert-butoxyaluminumhydride at -78 C and subsequently converted into the dimethyl acetal (VIII) with H2SO4 in methanol (1). Alkylation of 4-hydroxypiperidine (IX) with bromoacetal (VIII) gave adduct (X). This was subjected to Fisher indolization with the hydrazine (V), yielding indole (XI). The piperidine hydroxyl group was then oxidized to the corresponding ketone (XII) using sulfur trioxide-pyridine complex in DMSO.

The chiral amino alcohol (XIV) was obtained by reduction of (R)-(4-fluorophenyl)glycine (XIII) with LiAlH4. Finally, reductive condensation of amino alcohol (XIII) with piperidinone (XII) provided the title compound.

Hydrogenation of p-nitroacetanilide (I) over Pd/C afforded p-aminoacetanilide (II), which was converted to triazolylacetanilide (III) upon treatment with N,N-dimethylformamide azine and p-toluenesulfonic acid. Acid hydrolysis of the acetamide (III) provided triazolylaniline (IV). Subsequent diazotization of (IV), followed by SnCl2 reduction of the diazonium salt furnished hydrazine (V). Fischer indole synthesis employing (V) and dihydropyran (VI) gave rise to the indolylpropanol (VII), which was converted to the intermediate mesylate (VIII) using CH3SO2Cl and Et3N.

An alternative procedure for the synthesis of indolylpropanol (VII) is depicted as follows: alkylation of 2-trimethylsilyl-1,3-dithiane (IX) with bromide (X) employing n-butyllithium in cold THF afforded (XI). Subsequent hydrolysis of the thioacetal group of (XI) by means of HgO/HgCl2 provided acylsilane (XII). Iodoaniline (XIII) was prepared by iodination of p-triazolylaniline (IV) with iodine monochloride. Condensation of iodoaniline (XIII) with acylsilane (XII) in the presence of Pd(OAc)2 produced the silylated indole (XIV). Then acid treatment of (XIV) removed both silyl groups to give (VII).

4-(Aminomethyl)-1-benzyl-4-hydroxypiperidine (XV) was protected as the tert-butyl carbamate (XVI) and the benzyl group was subsequently cleaved by transfer hydrogenolysis employing ammonium formate and Pd/C yielding (XVII). Condensation of piperidine (XVII) with mesylate (VIII) in the presence of K2CO3 in boiling isopropanol furnished adduct (XVIII). After deprotection of the Boc group of (XVIII) with trifluoroacetic acid, reductive alkylation of the resulting amine (XIX) with benzaldehyde in the presence of NaBH3CN provided the N-benzyl amine (XX). Finally, a further reductive alkylation of (XX) with formaldehyde and NaBH3CN yielded the title compound.

An alternative process consisted in the palladium-catalyzed condensation of iodoaniline (VIII) with the acyl silane (XV), to produce the 2-silyl indole (XVI). Then, acid desilylation of (XVI), followed by treatment with oxalic acid yielded the title compound.

An alternative procedure for the synthesis of indolylpropanol (VII) is depicted as follows: alkylation of 2-trimethylsilyl-1,3-dithiane (IX) with bromide (X) employing n-butyllithium in cold THF afforded (XI). Subsequent hydrolysis of the thioacetal group of (XI) by means of HgO/HgCl2 provided acylsilane (XII). Iodoaniline (XIII) was prepared by iodination of p-triazolylaniline (IV) with iodine monochloride. Condensation of iodoaniline (XIII) with acylsilane (XII) in the presence of Pd(OAc)2 produced the silylated indole (XIV). Then acid treatment of (XIV) removed both silyl groups to give (VII).

In an alternative method, the title compound was obtained by desilylation of the 2-silylindole precursor (XXI).

Hydrogenation of p-nitroacetanilide (I) over Pd/C afforded p-aminoacetanilide (II), which was converted to triazolylacetanilide (III) upon treatment with N,N-dimethylformamide azine and p-toluenesulfonic acid. Acid hydrolysis of the acetamide (III) provided triazolylaniline (IV). Subsequent diazotization of (IV), followed by SnCl2 reduction of the diazonium salt furnished hydrazine (V). Fischer indole synthesis employing (V) and dihydropyran (VI) gave rise to the indolylpropanol (VII), which was converted to the intermediate mesylate (VIII) using CH3SO2Cl and Et3N.

4-(Aminomethyl)-1-benzyl-4-hydroxypiperidine (XV) was protected as the tert-butyl carbamate (XVI) and the benzyl group was subsequently cleaved by transfer hydrogenolysis employing ammonium formate and Pd/C yielding (XVII). Condensation of piperidine (XVII) with mesylate (VIII) in the presence of K2CO3 in boiling isopropanol furnished adduct (XVIII). After deprotection of the Boc group of (XVIII) with trifluoroacetic acid, reductive alkylation of the resulting amine (XIX) with benzaldehyde in the presence of NaBH3CN provided the N-benzyl amine (XX). Finally, a further reductive alkylation of (XX) with formaldehyde and NaBH3CN yielded the title compound.