合成路线1

The reaction of 3-hydroxypyridine (I) with (S)-glycidol 3-nitrobenzenesulfonate (II) by means of sodium hexamethyldisylazide in DMSO gives 2(S)-(3-pyridyloxymethyl)oxirane (III), which is condensed with 2-(4-nitrophenyl)ethylamine (IV) by means of triethylamine in refluxing methanol yielding the chiral isopropanol (V). The protection of the secondary amino group of (V) with tert-butoxycarbonyl anhydride affords the carbamate (VI), which is submitted to reduction at the nitro group with H2 over palladium hydroxide in ethyl acetate providing the aniline derivative (VII). The acylation of (VII) with 4-iodobenzenesulfonyl chloride (VIII) and pyridine in dichloromethane affords the sulfonamide (IX), which is finally deprotected with 6N HCl in methanol.

合成路线2

The reaction of 2-acetamido-5-hydroxypyridine (I) with (S)-glycidol 3-nitrobenzenesulfonate (II) by means of NaOH in DMF gives 2(S)-(6-acetamido-3-pyridyloxymethyl)oxirane (III), which is condensed with 2-(4-nitrophenyl)ethylamine (IV) by means of triethylamine in refluxing methanol yielding the chiral isopropanol (V). The protection of the secondary amino group of (V) with tert-butoxycarbonyl anhydride affords the carbamate (VI), which is submitted to reduction at the nitro group with H2 over Pd/C in ethyl acetate providing the aniline derivative (VII). The acylation of (VII) with 4-iodobenzenesulfonyl chloride (VIII) and pyridine in dichloromethane affords the sulfonamide (IX), which is finally deprotected with 2N HCl in refluxing methanol.

合成路线3

Alternatively, reaction of 6-chloronicotinic acid (XIII) with methyllithium-lithium bromide complex gave methyl ketone (XIV). This was brominated by means of dibromobarbituric acid (XV) to produce bromoketone (XVI). Asymmetric reduction of (XVI) with (-)-B-chlorodiisopinocampheylborane provided the (R)-bromohydrin (XVII), which was converted to epoxide (XVIII) with NaOH in aqueous THF. Epoxide (XVIII) opening with 4-nitrophenethylamine (XIX) produced amino alcohol (XX), which by further protection with Boc2O gave carbamate (XXI). Concomitant dechlorination and nitro group reduction in (XXI) by hydrogenation using Raney Nickel as catalyst provided amine (XI). This was finally converted to the target compound by means of sulfonylation and deprotection as above.

合成路线4

3-Acetylpyridine (I) was converted to the hydrochloride salt and then chlorinated with N-chlorosuccinimide to afford (chloroacetyl)pyridine (II). Asymmetric reduction of (II) by means of (-)-B-chlorodiisopinocampheylborane in THF produced the (R)-alcohol (III), which was cyclized to oxirane (IV) upon heating with K2CO3 in acetone. Epoxide (IV) opening with 4-aminophenethyl amine (V) in boiling MeOH gave aminoalcohol (VI). Then, selective protection of the aliphatic amine of (VI) as the tert-butyl carbamate yielded the target intermediate (VII). In a similar procedure, 2-chloro-5-acetylpyridine (VIII) was brominated employing dibromobarbituric acid in THF to afford bromide (IX), which was enantioselectively reduced to the (R)-alcohol (X). After cyclization of (X) to epoxide (XI), its opening with 4-nitrophenethyl amine (XII) yielded aminoalcohol (XIII). This was protected as the N-Boc derivative (XIV) and then, hydrogenation of the nitro group of (XIV) with concomitant halogen hydrogenolysis in the presence of Raney Nickel provided an alternative access to intermediate (VII).

合成路线5

3-Acetylpyridine (I) was chlorinated employing N-chlorosuccinimide, and the resulting chloroketone (II) was enantioselectively reduced with (-)-B-chlorodiisopinocampheylborane (DIP-Cl) to furnish the chiral chlorohydrin (III). Intramolecular cyclization of (III) in the presence of K2CO3 in refluxing acetone produced (R)-(3-pyridyl)oxirane (IV). Further ring opening with 4-aminophenethylamine (V) gave rise to diaminoalcohol (VI), which was selectively proteced with Boc2O at the aliphatic amino group, yielding carbamate (VII). In a related alternative procedure, 2-chloro-5-acetylpyridine (VIII) was brominated to (IX) by means of dibromobarbituric acid (DBBA), followed by reduction of bromoketone (IX) with (-)-DIP-Cl. The resulting (R)-bromohydrin (X) was converted to epoxide (XI) by treatment with NaOH, and subsequent ring opening with 4-nitrophenethylamine (XII) provided aminoalcohol (XIII). Protection of the amino group of (XIII) with Boc2O afforded carbamate (XIV). Further reduction of the nitro group of (XIV) with simultaneous hydrogenolysis of the halogen atom furnished the target intermediate (VII).

合成路线6

4-Nitrophenethylamine (I) was acylated with propionyl chloride and the resulting amide (II) was reduced to amine (III) with borane-dimethyl sulfide complex in refluxing THF. Amine (III) was then protected as the tert-butyl carbamate (IV) using Boc2O in THF. Subsequent catalytic hydrogenation of the nitro group of (IV) over Pd/C furnished aniline (V), which was coupled with 4-(trifluoromethoxy)benzenesulfonyl chloride (VI) to yield sulfonamide (VII). The Boc protecting group of (VII) was finally removed by treatment with trifluoroacetic acid.

合成路线7

Oxidation of aldehyde (I) with AgNO3 in EtOH/H2O in the presence of KOH provides carboxylic acid (II), which is then converted into acid chloride (III) by means of (COCl)2 in CH2Cl2 and catalytic DMF. Treatment of (III) with trimethylsilyl diazomethane (TMSCH2N2) in Et2O followed by HCl(g) in Et2O furnishes chloro derivative (IV), which is then enantioselectively reduced by means of (-)-Dip-Cl to afford alcohol (V). Treatment of (V) with NaOH in THF/H2O induces formation of epoxy derivative (VI), which is then condensed with amine (VII) to yield compound (VIII). N-Protection of (VIII) by reaction with Boc2O in CH2Cl2, followed by reduction of the nitro moiety by hydrogenation over Pd(OH)2 in MeOH, gives amine (IX). Amine (IX) is converted into sulfonamide (XI) by reaction with sulfonyl chloride (X) in CH2Cl2 in the presence of pyridine. Finally, the Boc group of (XI) is removed by means of TFA in CH2Cl2 to furnish the desired product.

合成路线8

Reaction of 6-chloronicotinic acid (I) with methyllithium lithium bromide complex gives methyl ketone (II), which is treated with dibromobarbituric acid (III) in refluxing THF to afford bromoketone (IV). Asymmetric reduction of (IV) with (-)-DIP-chloride [(-)-B-chlorodiisopinocampheylborane] provides bromohydrin (V), which is converted into epoxide (VI) by treatment with NaOH in THF/H2O. Opening of the epoxide moiety of (VI) with p-nitrophenethylamine hydrochloride (VII) in MeOH in the presence of Et3N followed by N-protection with Boc2O in THF yields ethanolamine (VIII), which is then hydrogenated over Ni-Raney in EtOH/NaOH to furnish dechlorinated aniline (IX). Condensation of (IX) with 1,1-bis(methylsulfanyl)-2-nitroethylene (X) in isopropanol gives compound (XI), which is then subjected to reaction with aniline (XII) in isopropanol to afford nitroethylenediamine (XIII). Finally, the desired product is obtained by Boc removal of (XIII) by treatment with TFA in CH2Cl2.

合成路线9

Alkylation of 1-napthol (I) with 1,2-dibromoethane provides the (naphthyloxy)ethyl bromide (II), which is condensed with p-nitrophenethylamine (III) to afford the secondary amine (IV). After acetylation of amine (IV) to produce acetamide (V), the nitro group of (V) is reduced by means of iron and HCl, yielding aniline (VI). Finally, acylation of the amino group of (VI) with methanesulfonyl chloride furnishes the target sulfonamide.

合成路线10