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【结 构 式】

【分子编号】37482

【品名】diethyl 2-benzylidenemalonate

【CA登记号】5292-53-5

【 分 子 式 】C14H16O4

【 分 子 量 】248.27864

【元素组成】C 67.73% H 6.5% O 25.78%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(II)

The reaction of 2-aminothiophenol (I) with diethyl benzylidenemalonate (II) by heating at 90 C gives diethyl 2-(2-aminophenylthio)-2-phenylethane-1,1-dicarboxylate (III), which is cyclized by heating at 180 C with triethylamine hydrochloride yielding 2,3-dihydro-3-ethoxycarbonyl-2-phenyl-1,5-benzothiazepin-4(5H)-one (IV). The reduction of (IV) with LiAlH4 in THF affords 2,3-dihydro-3-hydroxymethyl-2-phenyl-1,5-benzothiazepin-4(5H)-one (V), which by reaction with SOCl2 in refluxing benzene is converted into 2,3-dihydro-3-chloromethyl-2-phenyl-1,5-benzothiazepin-4(5H)-one (VII). Finally, this compound is treated with N-methylpiperazine at reflux temperature, and acidified with HCl. An alternative way is the reaction of (V) with methanesulfonyl chloride in pyridine affording 2,3-dihydro-3-methanesulfonyloxymethyl-2-phenyl-1,5-benzothiazepin-4(5H)-one (VI), which is then treated with N-methylpiperazine and HCl as before.

1 Izumi, K.; et al.; FR 2416890 .
2 Hillier, K.; Castaner, J.; BTM-1042. Drugs Fut 1981, 6, 9, 534.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(I) 25182 2-aminobenzenethiol 137-07-5 C6H7NS 详情 详情
(II) 37482 diethyl 2-benzylidenemalonate 5292-53-5 C14H16O4 详情 详情
(III) 37483 diethyl 2-[[(2-aminophenyl)sulfanyl](phenyl)methyl]malonate C20H23NO4S 详情 详情
(IV) 37484 ethyl (2R,3R)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-3-carboxylate C18H17NO3S 详情 详情
(V) 37485 (2R,3S)-3-(hydroxymethyl)-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C16H15NO2S 详情 详情
(VI) 37486 (2R,3S)-3-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C19H21NO2S2 详情 详情
(VII) 37487 (2R,3S)-3-(chloromethyl)-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C16H14ClNOS 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XII)

Alternatively, the condensation of dimethyl malonate (VI) with benzaldehyde (VII) by means of piperidine in refluxing toluene gives dimethyl benzylidenemalonate (VIII), which is reduced with H2 over Pd/C in toluene to yield the corresponding benzyl derivative (IX). The hydrolysis of (IX) with NaOH in water affords the benzylmalonic acid (X). Alternatively, intermediate (X) can also be obtained starting from diethyl malonate (XI), which is condensed with with benzaldehyde (VII) by means of piperidine in refluxing toluene to give diethyl benzylidenemalonate (XII). Reduction of (XII) with H2 over Pd/C in toluene yields the corresponding benzyl derivative (XIII), which is then hydrolized with NaOH in water. The monodecarboxylation of (X) and its condensation with paraformaldehyde and diethylamine in refluxing ethyl acetate provides 2-benzylacrylic acid (XIV), which is condensed with thioacetic acid (V) by heating at 70 C to afford 2-(acetylsulfanylmethyl)-3-phenylpropionic acid (XV). Finally, this compound is condensed with N-tosylglycine benzyl ester (XVI) by means of HOBt, DCC and TEA in THF.

1 Roques, B.; Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Amino acid derivs. and their therapeutic application. EP 0038758 .
2 Lecomte, J.-M.; Duhamel, P.; Danvy, D.; Schwartz, J.-C.; Duhamel, L.; Monteil, T. (Societe Civile Bioprojet); Process for the synthesis of alpha-substd. acrylic acids and their application. EP 0729936 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 12893 Ethanethioic S-acid C2H4OS 详情 详情
(VI) 19373 dimethyl malonate;Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(VII) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(VIII) 49460 Dimethyl benzylidenemalonate C12H12O4 详情 详情
(IX) 49461 dimethyl 2-benzylmalonate C12H14O4 详情 详情
(X) 37280 2-benzylmalonic acid 616-75-1 C10H10O4 详情 详情
(XI) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(XII) 37482 diethyl 2-benzylidenemalonate 5292-53-5 C14H16O4 详情 详情
(XIII) 20208 diethyl 2-benzylmalonate 607-81-8 C14H18O4 详情 详情
(XIV) 37279 2-benzylacrylic acid C10H10O2 详情 详情
(XV) 55230 3-(acetylsulfanyl)-2-benzylpropanoic acid C12H14O3S 详情 详情
(XVI) 55228 N-p-Tosylglycine benzyl ester C16H17NO4S 详情 详情
Extended Information