diethyl 2-benzylidenemalonate -Drug Synthesis Database

【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 合成路线2

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.

参考文献中间体

合成目标

【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.

参考文献中间体

合成目标

【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