合成路线1

The esterification of indomethacin (I) with paracetamol (II) in the presence of DCC is performed in pyridine to afford apyramide, which is recrystallized in isopropanol.

合成路线2

Friedel-Crafts acetylation of acetaminophen (I) using acetyl chloride and AlCl3 gave acetophenone (II). Subsequent condensation of (II) with N-(tert-butoxycarbonyl)-4-piperidone (III) in the presence of pyrrolidine provided the spirochroman-2,4'-piperidine (IV), from which the diamine (V) was obtained by acid hydrolysis. The piperidine amino group of (VI) was then alkylated with 1-(2-bromoethyl)naphthalene (VI) to afford (VII). Finally, condensation of the remaining amino group of (VII) with the sulfonyl chloride (VIII) furnished the title sulfonamide.

合成路线3

The cyclocondensation of triphenylphosphite (I) with 4-(benzyloxycarbonyl-L-prolylamino)butyraldehyde (II) in hot acetic acid gives the pyrrolidinylphosphonate (III), which is deprotected by hydrogenation with H2 over Pd/C in methanol. The intermediates (I) and (II) have been obtained as follows: Phosphite (I): The acylation of 4-aminophenol (IV) with acetic acid and isobutyl chloroformate in DMF gives N-(4-hydroxyphenyl)acetamide (V), which is allowed to react with PCl3 and triethylamine in DMF yielding phosphite (I). 4-(Benzyloxycarbonyl-L-prolylamino)butyraldehyde (II): The condensation of N-(benzyloxycarbonyl)-L-proline (VI) with 4-aminobutyraldehyde diethylacetal (VII) by means of isobutyl chloroformate and triethylamine in chloroform gives 4-[N-(benzyloxycarbonyl)-L-prolylamino]butyraldehyde diethylacetal (VIII), which is hydrolyzed to the target aldehyde (II) with HCl in THF.

合成路线4

The esterification of paracetamol (I) with 4-bromobutyric acid (II) by means of DCC and DMAP in DMF gives the corresponding ester (III), which is finally treated with AgNO3 in hot acetonitrile to yield the target nitrate ester.

合成路线5

Alkylation of 4-hydroxyacetanilide (I) with n-propyl bromide provided 4-propoxyacetanilide (II). Aromatic nitration of (II) with fuming nitric acid in the presence of acetic anhydride afforded the nitro acetanilide (III), which was further hydrolyzed to the nitro aniline (IV) under basic conditions. Subsequent catalytic hydrogenation of the nitro group of (IV) furnished the phenylenediamine (V). Cyanocarbamate (VI), generated from cyanamide and methyl chloroformate, was then condensed with 4-propoxy-1,2-phenylenediamine (V) in hot pyridine to provide the title benzimidazolyl carbamate.

合成路线6

The acetylation of 4-acetamidophenol (I) with acetyl chloride in refluxing benzene gives 4-acetoxyacetanilide (II), which by a Fries reaction with AlCl3 at 170 C is converted into 2-hydroxy-5-acetamidoacetophenone (III). (1,2) The reaction of (III) with epichlorohydrin (IV) by means of sodium ethoxide in refluxing ethanol affords 1-(2-acetyl-4-acetamidophenoxy)-2,3-epoxypropane (V), which is finally treated with isopropylamine (VI) in refluxing ethanol. (1-3)

合成路线7

合成路线8

合成路线9