合成路线:Acetylation of 5-aminosalicylic acid (I) with acetic anhydride in hot acetic acid gives 5-acetaminosalicylic acid (II),which is methylated with dimethyl sulfate and K2CO3 in refluxing acetone yielding methyl 2-methoxy-5-acetaminobenzoate (III).Nitration of (III) with HNO3 in acetic acid affords methyl 2-methoxy-4-nitro-5-acetaminobenzoate (IV),which is deacetylated with H2SO4 in refluxing methanol to give methyl 2-methoxy-4-nitro-5-aminobenzoate (V).The diazotation of (V) with NaNO2-HCl,followed by reaction with sodium ethylmercaptide,oxidation with H2O2 and hydrolysis with NaOH in ethanol yields 2-methoxy-4-nitro-5-(ethylsulfonyl)benzoic acid (VI),which is condensed with N-ethyl-2-aminomethylpyrrolidine (VII) by means of ethyl chloroformate and triethylamine in dioxane affording 2-methoxy-4-nitro-N-[(1-ethyl-2-pyrrolidinyl) methyl]-5-(ethylsulfonyl)benzamide (VIII).Finally,this compound is reduced with H2 over Raney-Ni in ethanol.
合成路线:Acetylation of 5-aminosalicylic acid (I) with acetic anhydride in hot acetic acid gives 5-acetaminosalicylic acid (II),which is methylated with dimethyl sulfate and K2CO3 in refluxing acetone yielding methyl 2-methoxy-5-acetaminobenzoate (III).Nitration of (III) with HNO3 in acetic acid affords methyl 2-methoxy-4-nitro-5-acetaminobenzoate (IV),which is deacetylated with H2SO4 in refluxing methanol to give methyl 2-methoxy-4-nitro-5-aminobenzoate (V).The diazotation of (V) with NaNO2-HCl,followed by reaction with sodium ethylmercaptide,oxidation with H2O2 and hydrolysis with NaOH in ethanol yields 2-methoxy-4-nitro-5-(ethylsulfonyl)benzoic acid (VI).The reaction of (VI) with refluxing SOCl2 gives the corresponding acyl chloride (IX),which is then condensed with (VII) in butannne yielding (VIII).Finally,this compound is reduced with H2 over Raney-Ni in ethanol.
合成路线:Alkylation of 2-methoxy-4-amino-5-mercaptobenzoic acid (X) with diethyl sulfate acid Na2CO3 gives 2-methoxy-4-amino-5-ethylthiobenzoic acid (XI),which is oxidized with H2O2 in acetic acid yielding 2-methoxy-4-amino-5-(ethylsulfonyl)benzoic acid (XII).Finally,this compound is condensed with (VII) by means of ethyl chloroformate.
合成路线:Treatment of thiourea (I) with iodomethane provided S-methylthiouronium iodide (II).This was further condensed with N-methylpiperazine (III) to afford the intermediate piperazine-1-carboxamidine (IV)
合成路线:Regioselective lithiation of 1,2,4-trichlorobenzene (V) with n-BuLi at -60 C,followed by quenching of the resultant organolithium compound (VI) with N,N-dimethylformamide yielded 2,3,5-trichlorobenzaldehyde (VII) (1),which was then reduced with NaBH4 to provide alcohol (VIII).Bromination of (VIII) using PBr3 afforded compound (IX),whose bromide atom was displaced with KCN to give the trichlorophenylacetonitrile (X).Claisen condensation of (X) with ethyl formate in the presence of NaOEt furnished the oxo nitrile sodium enolate (XI),which was subsequently O-alkylated with iodomethane yielding the methoxy acrylonitrile (XII).Finally,cyclization of (XII) with the piperazine-1-carboxamidine (IV) in EtOH gave rise to the target pyrimidine derivative
参考文献标题:Process of preparing 2,3,5-trihalobenzaldehyde
文献作者:Patel,R.; Packham,T.W.; Germain,A.L.; Barras,J.R.; Milne,D.J.(GlaxoSmithKline plc)
参考来源:WO 9507877
产品链接: CAS No. 130800-90-7››