Racecadotril, Acetorphan, Hidrasec, Tiorfan, -Drug Synthesis Database

【结构式】

【药物名称】Racecadotril, Acetorphan, Hidrasec, Tiorfan

【化学名称】N-[2(R,S)-(Acetylthiomethyl)-3-phenylpropionyl]glycine benzyl ester
　　　　　　N-[3-(Acetylmercapto)-2(R,S)-benzylpropanoyl]glycine benzyl ester

【CA登记号】81110-73-8

【分子式】C₂₁H₂₃NO₄S

【分子量】385.48576

【开发单位】Bioprojet (Originator), GlaxoSmithKline (Licensee)

【药理作用】Antidiarrheal Agents, Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems, GASTROINTESTINAL DRUGS, Enkephalinase Inhibitors

合成路线1 合成路线2

合成路线1

The reaction of 2-benzylacrylic acid (I) with SOCl2 in hot toluene gives the acyl chloride (II), which is condensed with N-tosylglycine benzyl ester (III) by means of TEA in toluene to yield the corresponding amide (IV). Finally, this compound is condensed with thioacetic acid by heating at 80 C to afford the target acylthio compound.

参考文献中间体

【1】 Schwartz, J.-C.; Lecomte, J.-M.; Duhamel, P.; Duhamel, L.; Danvy, D.; Plaquevent, J.-C.; Monteil, T.; Piettre, S. (Societe Civile Bioprojet); Process for synthesizing N-(mercaptoacyl)amino acid derivs. from alpha-substd. acrylic acids. FR 2816309; US 2002055645 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	37279	2-benzylacrylic acid	C₁₀H₁₀O₂	详情	详情
(II)	55227	2-benzylacryloyl chloride	C₁₀H₉ClO	详情	详情
(III)	55228	N-p-Tosylglycine benzyl ester	C₁₆H₁₇NO₄S	详情	详情
(IV)	55229	benzyl 2-[(2-benzylacryloyl)amino]acetate	C₁₉H₁₉NO₃	详情	详情
(V)	12893	Ethanethioic S-acid	C₂H₄OS	详情	详情

合成路线2

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

【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