合成路线1

The reaction of ethyl iminodiacetate (I) with 2-ethoxycarbonylacetyl chloride (II) by means ot triethylamine in refluxing methylene chloride gives ethyl N-(2-ethoxycarbonylacetyl)iminodiacetate (III), which is cyclized by means of sodium ethoxide in refluxing ethanol yielding ethyl 4-hydroxy-3-(ethoxycarbonyl)-DELTA3-pyrrolin-2-one-1-acetate (IV). The isomerization of (IV) with water in refluxing acetonitrile affords ethyl pyrrolidine-2,4-dione-1-acetate (V), which is reduced with NaBH4 in dimethoxyethane to ethyl 4-hydroxypyrrolidine-2-one-1-acetate (VI). Finally, this compound is treated with ammonia in methanol.

合成路线2

The reductive cleavage of 4-phenylazo-3-methyl-5-methylaminopyrazole (I) with H2 over RaNi in ethanol gives 4-amino-3-methyl-5-methylaminopyrazole (II), which is acylated with ethoxycarbonylacetyl chloride (III) in toluene yielding 4-(ethoxycarbonylacetylamino)-3-methyl-5-methylaminopyrazole (IV). The cyclization of (IV) by means of sodium ethoxide in ethanol affords 4,8-dihydro-3,8-dimethylpyrazolo[3,4b][1,4]diazepine-5,7(1H,6H) dione (V), which is finally phenylated by a treatment with powdered Cu and potassium acetate in refluxing bromobenzene

合成路线3

The condensation of 2-methoxyphenol (I) with 2-bromoethanal dimethylacetal (II) by means of K2CO3 in hot DMF gives 2-(2-methoxyphenoxy)ethanal dimethylacetal (III), which is hydrolyzed to the corresponding free aldehyde (IV) with 2N H2SO4 in methanol. The cyclization of (IV) with cysteamine (V) by means of potassium acetate in water affords 2-(2-methoxyphenoxymethyl)thiazolidine (VI), which is finally condensed with ethoxymalonyl chloride (VII) by means of KHCO3 in ethyl acetate.

合成路线4

Tetrahydrofuranone (XIII): The Grignard condensation of isobutyraldehyde (I) with vinylmagnesium bromide (II) in THF gives the magnesium alcoholate (III), which is condensed with ethyl malonyl chloride (IV) in the same solvent, yielding the mixed ester (V). Treatment of (V) with Ti(OEt)4 at 190 C affords 6-methyl-4(E)-heptenoic acid methyl ester (VI), which by reaction with (R,R)-(-)-pseudoephedrine (VII), oxalyl chloride and DMF in benzene gives the amide (VIII). The regiocontrolled addition of 4-fluorobenzyl chloride (IX) to the chiral amide (VIII) by means of BuLi and LiCl in THF yields the 2(S)-(4-fluorobenzyl)heptanamide (X), which by reaction with NBS in THF/water/acetic acid at 0 C, followed by reflux for 45 min, affords 5(S)-[1(R)-bromo-2-methylpropyl]-3(R)-(4-fluorobenzyl)tetrahydrofuran-2-one (XI). The reaction of (XI) with NaN3 in DMF gives the corresponding azide (XII), which is reduced with H2 over Pd/C, and the resulting amine is protected with tert-butoxycarbonyl anhydride to obtain the desired tetrahydrofuranone (XIII).

合成路线5

2-Cyanophenol (I) was condensed with 2-bromo-4'-methoxyacetophenone (II) in the presence of K2CO3 in acetone to give aminobenzofuran (III). This was acylated with trifluoroacetic anhydride, and the resulting trifluoroacetamide (IV) was alkylated with 2,5-dimethoxybenzyl chloride (V) under phase-transfer conditions to afford monobenzylated compound (VI). The benzofuro[3,2-b]pyridine nucleus was formed by acylation of the secondary amine group of (VI) with ethyl malonyl chloride (VII) to give (VIII) followed by an intramolecular Knoevenagel condensation over silica gel in refluxing CH2Cl2 to give (IX). Alkaline hydrolysis of the ester function of (IX) then provided the corresponding carboxylic acid.

合成路线6

Reaction of 2-amino-6-chlorobenzoic acid (I) with phosgene and NaHCO3 in dioxane gives 5-chloroisatoic anhydride (II), which is methylated by means of iodomethane and NaH in DMF to yield 5-chloro-1-methylisatoic anhydride (III). Finally, anhydride (III) is condensed with the malonic monoamide (IV) by means of NaH in hot dimethylacetamide. Alternatively, condensation of anhydride (III) with ethoxy malonyl chloride (V) by means of NaOMe and triethylamine in dichloromethane affords 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3- carboxylic acid ethyl ester (VI), which is finally condensed with N-ethylaniline (VII) in refluxing toluene. Alternatively, ester (VI) is hydrolyzed by means of concentrated HCl in hot Ac2O to give the carboxylic acid (VIII), which is finally condensed with N-ethylaniline (VII) by means of SOCl2 and TEA in dichloromethane

合成路线7

合成路线8

Chlorination of 2-chloro-5-nitrobenzenesulfonic acid (XIV) with SOCl2 in refluxing DMF gives the sulfonyl chloride (XV), which is converted to the corresponding sulfonamide (XVI) by treatment with NH4OH in toluene/THF. Amination of the chloro sulfonamide (XVI) with (NH4)2CO3 and NH4OH in the presence of CuSO4 at 118 °C leads to 2-amino-5-nitrobenzenesulfonamide (XVII). Alternatively, chlorination of 2-amino-5-nitrobenzenesulfonic acid (XVIII) using POCl3 in sulfolane at 110-120 °C provides the corresponding sulfonyl chloride (XIX), which is treated with NH4OH to yield sulfonamide (XVII). Reduction of the nitro moiety of compound (XVII) with H2 over Pd/C in the presence of MsOH in EtOH/H2O at 55 °C affords 2,5-diaminobenzenesulfonamide mesylate (XX), which can also be obtained by chloride substitution in 2-chloro-5-nitrobenzenesulfonamide (XVI) with benzylamine by means of Et3N in acetonitrile at 92 °C, followed by hydrogenolysis of the resulting 2-(benzylamino)-5-nitrobenzenesulfonamide (XXI) over Pd/C in the presence of MsOH in THF/EtOH/H2O. Selective N-sulfonylation of diamine (XX) with methanesulfonyl chloride (XXII) and pyridine in CH2Cl2 or acetonitrile gives rise to 2-amino-5-(methylsulfonamido)benzenesulfonamide (XXIII), which is then condensed with either methyl malonyl chloride (XXIV) in THF or ethyl malonyl chloride (XXV) in DMF/Et2O or DMA , yielding amides (XXVI) or (XXVII). Finally, carbamoyl sulfonamides (XXVI) and (XXVII) are cyclized and simultaneously hydrolyzed by treatment with NaOH (XII) .