合成路线1

The condensation of 4-hydroxybenzyl alcohol (I) with 2-isopropoxyethanol (II) by heating at 150 C gives the corresponding benzyl ether (III), which is condensed with epichlorohydrin (IV) to yield the adduct (V). Finally, this compound is treated with isopropylamine in ethanol.

合成路线2

This compound has been obtained by two related ways: 1) The reaction of phenol (I) with formaldehyde gives 4-(hydroxymethyl)phenol (II), which is treated with NaCN in hot DMF to yield 2-(4-hydroxyphenyl)acetonitrile (III). The hydrolysis of (III) in refluxing ethanol/water, catalyzed by a Pt catalyst affords the corresponding acetamide (IV), which is condensed with an excess of hot epichlorohydrin (V) by means of piperidine gives 2-[4-(2-oxiranylmethoxy)phenyl]acetamide (VI). Finally, the oxirane ring of (VI) is opened with isopropylamine in methanol. 2)The condensation of acetonitrile (III) with epichlorohydrin (V) as before gives the 2-[4-(2-oxiranylmethoxy)phenyl]acetonitrile (VIII), which is treated with isopropylamine (VII) in methanol yielding 2-[4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl]acetonitrile (IX). Finally, this compound is hydrolyzed with refluxing ethanol/water catalyzed by a Pt catalyst as before to afford the target acetamide.

合成路线3

Alkylation of 4-hydroxybenzaldehyde (I) with chloro derivative (II) by means of K2CO3 in DMF at reflux affords benzaldehyde derivative (III), which is reduced with NaBH4 in MeOH to provide the benzylic alcohol (IV) --alternatively, alcohol (IV) can be obtained by reaction of 4-hydroxybenzyl alcohol (V) with chloro derivative (II) by means of NaOH and benzyltriethylammonium bromide in toluene--. Alcohol (V) is treated with HCl in THF and then chlorinated with SOCl2 to furnish hydrochloride salt (VI), which is condensed with the indole derivative (VII) – produced by condensation of the bromo ketone (VIII) and 4-benzyloxyaniline hydrochloride (IX) either refluxing by with DMF or with Et3N in refluxing DMF – by means of NaH in DMF to give the N-alkylated indole (X). Finally, the O-benzyl protecting groups of (X) are removed by transfer hydrogenolysis using cyclohexadiene and Pd/C.

合成路线4

The reaction of 4-hydroxybenzyl alcohol (V) with ethyl 2-bromoacetate (XI) by means of K2CO3 gives the phenoxyacetate (XII), which is then treated with SOCl2 in THF to obtain the benzyl chloride (XIII). Reaction of (XIII) with the indole derivative (VII) by means of NaH in DMF yields the adduct (XIV), whose ester group is reduced with LiAlH4 in THF to afford the 2-hydroxyethoxy compound (XV). Treatment of (XV) with CBr4 and PPh3 in THF provides the 2-bromoethoxy compound (XVI), which is converted into compound (XVIIII) by reaction with hexamethyleneimine (homopiperidine) (XVII) in THF. Finally, compound (XVIII) is debenzylated by hydrogenation with either H2 over Pd/C in ethanol/THF or with cyclohexadiene and Pd/C in THF/EtOH.

合成路线5

Alkylation of p-hydroxybenzaldehyde (I) with 1-(2-chloroethyl)piperidine (II) afforded 4-(2-piperidinylethoxy)benzaldehyde (III). Aldehyde function reduction using NaBH4 provided the benzylic alcohol (IV). Alternatively, alcohol (IV) can be obtained by reaction of 4-hydroxybenzyl alcohol (A) with 1-(2-chloroethyl)piperidine hydrochloride (II) by means of NaOH and benzyl triethylammonium bromide in toluene.The hydrochloride salt of (IV) was then treated with SOCl2 to furnish chloride (V).

合成路线6

The intermediate 2-[4-(chloromethyl)phenoxy]acetic acid ethyl ester (IV) has been obtained as follows: The reaction of 4-hydroxybenzyl alcohol (I) with ethyl 2-bromoacetate (II) by means of K2CO3 gives the phenoxyacetate (III), which is then treated with SOCl2 in THF to obtain the desired intermediate (IV). The cyclization of 4-(benzyloxy)aniline (V) with 2-bromo-1-[4-(benzyloxy)phenyl]-1-propanone (VI) by means of TEA in DMF gives 5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indole (VII), which is alkylated with the intermediate (IV) by means of NaH in DMF to yield the adduct (VIII). The reduction of the ester group of (VIII) with LiAlH4 in THF affords the 2-hydroxyethoxy compound (IX), which is treated with CBr4 and PPh3 in THF to provide the 2-bromoethoxy compound (X). The reaction of (X) with piperidine in THF gives the piperidinoethoxy compound (XI), which is finally debenzylated by hydrogenation with H2 over Pd/C in ethanol/THF to afford the target indole derivative.

合成路线7

By condensation of substituted nicotinamide (VI) with the carbazolyoxymethyl-oxirane (XII) in hot methanol/water. The intermediates the nicotinamide (VI) and the oxirane (XII) have been obtained as follows: 1.- Nicotinamide (VI): The reaction of 4-hydroxybenzyl alcohol (I) with 2-nitropropane (II) by means of potassium tert-butoxide in hot diglyme gives 4-(2-methyl-2-nitropropyl)phenol (III), which is reduced to the corresponding amino derivative (IV) with H2 over Pd/C in methanol/ethanol/acetic acid. Finally, this compound is condensed with 6-chloronicotinamide (V) by means of K2CO3 in dimethylacetamide/isooctane. 2.- Oxirane (XII): The reaction of phenylhydrazine (VII) with cyclohexane-1,3-dione (VIII) by means of NaHCO3 in isopropanol/water gives the monohydrazone (IX), which is cyclized with hotpolyphosphoric acid yielding the 4-hydroxycarbazole (X). Finally, this compound is condensed with the glycidyl 3-nitrophenylsulfonate (XI) by means of K2CO3 in refluxing acetone.

合成路线8

The condensation of 4-hydroxybenzyl alcohol (I) with nitrocyclopentane (II) by means of TBAF at 130 C gives 4-(1-nitrocyclopentylmethyl)phenol (III), which is reduced to the corresponding amine (IV) with hydrogen over Raney-Ni in methanol. The protection of the NH2 group of (IV) with di-tert-butyl dicarbonate affords the carbamate (V), which is condensed with the phosphinic ester (VI) by means of NaH in DMF giving the substituted phosphinate (VII). The elimination of the carbamate group of (VII) with TFA in dichloromethane yields the cyclopenatylamine (VIII), which is condensed with the chiral oxirane (IX) in refluxing methanol affording the substituted aminopropanol (X). Elimination of the benzyl protecting group of (X) gives the intermediate phosphinic ester (XI) that is finally hydrolyzed with LiOH in methanol.

合成路线9