S-[(2R)-3-chloro-2-methyl-3-oxopropyl] benzenecarbothioate -Drug Synthesis Database

【结构式】

【分子编号】41584

【品名】S-[(2R)-3-chloro-2-methyl-3-oxopropyl] benzenecarbothioate

【CA登记号】

【分子式】C₁₁H₁₁ClO₂S

【分子量】242.72584

【元素组成】C 54.43% H 4.57% Cl 14.61% O 13.18% S 13.21%

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：(VI)

The protected hydroxyproline tosylate (I) was condensed with the sodium derivative of thiophenol (II) to produce thioether (III). After saponification of the methyl ester function of (III), the N-benzyloxycarbonyl group of (IV) was removed by means of HBr in refluxing HOAc, yielding cis-4-(phenylthio)-L-proline (V). Acylation of (V) with (S)-3-(benzoylthio)-2-methylpropionyl chloride (VI) afforded zofenopril (VII), which was finally converted to the corresponding calcium salt by treatment with calcium oxide in EtOH/H2O. The intermediate (S)-3-(benzoylthio)-2-methylpropionyl chloride (VI) was obtained by enzymatic resolution of racemic 3-(benzoylthio)-2-methylpropionic acid (VIII) with Pseudomonas fluorescens (Amano lipase P-30) to yield (S)-3-(benzoylthio)-2-methylpropionic acid (IX), which was activated with oxalyl chloride to afford the chiral acyl chloride (VI).

参考文献中间体

合成目标

【1】 Ondetti, M.A.; Krapcho, J. (Bristol-Myers Squibb Co.); Mercaptoacyl derivs. of substd. prolines. US 4316906 .
【2】 Giachetti, A.; Giorgi, R.; Mannucci, C.; Falezza, A. (Menarini Industrie Farma Riunite Srl); A process for the preparation of zofenopril calcium salt. EP 1102745; JP 2002522417; WO 0007984 .
【3】 Patel, R.N.; Howell, J.M.; Szarka, L.J. (Bristol-Myers Squibb Co.); Enzymatic resolution process hydrolyzing thio-ester. US 5128263 .
【4】 Powell, J.R.; Cushman, D.W.; Krapcho, J.; Turk, C.; DeForrest, J.M.; Spitzmiller, E.R.; Karanewsky, D.S.; Duggan, M.; Rovnyak, G.; Schwartz, J.; et al.; Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines. J Med Chem 1988, 31, 6, 1148.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	55623	1-benzyl 2-methyl (2S,4R)-4-{[(4-methylphenyl)sulfonyl]oxy}-1,2-pyrrolidinedicarboxylate		C₂₁H₂₃NO₇S	详情	详情
(II)	12951	Benzenethiol; Phenylmercaptan; Phenylhydrosulfide	108-98-5	C₆H₆S	详情	详情
(III)	55624	1-benzyl 2-methyl (2S,4S)-4-(phenylsulfanyl)-1,2-pyrrolidinedicarboxylate		C₂₀H₂₁NO₄S	详情	详情
(IV)	55625	(2S,4S)-1-[(benzyloxy)carbonyl]-4-(phenylsulfanyl)-2-pyrrolidinecarboxylic acid		C₁₉H₁₉NO₄S	详情	详情
(V)	55626	(2S,4S)-4-(phenylsulfanyl)-2-pyrrolidinecarboxylic acid		C₁₁H₁₃NO₂S	详情	详情
(VI)	41584	S-[(2R)-3-chloro-2-methyl-3-oxopropyl] benzenecarbothioate		C₁₁H₁₁ClO₂S	详情	详情
(VII)	55627	(2S,4S)-1-[(2S)-3-(benzoylsulfanyl)-2-methylpropanoyl]-4-(phenylsulfanyl)-2-pyrrolidinecarboxylic acid		C₂₂H₂₃NO₄S₂	详情	详情
(VIII)	55628	3-(benzoylsulfanyl)-2-methylpropanoic acid		C₁₁H₁₂O₃S	详情	详情
(IX)	35379	(2S)-3-(benzoylsulfanyl)-2-methylpropionic acid		C₁₁H₁₂O₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

(S)-3-Benzoylthio-2-methylpropionic acid (VI) was activated as the acid chloride (VII) by treatment with SOCl2 or optionally converted to the active ester (VIII) upon condensation with p-nitrophenol in the presence of DCC. Coupling of aminoacid (V) with either acid chloride (VII) under Schotten-Baumann conditions or with p-nitrophenyl ester (VIII) in the presence of Et3N gave rise to the corresponding amide (IX). The benzoyl thioester of (IX) was finally cleaved employing aqueous ammonia to afford the title thiol.

参考文献中间体

合成目标

【1】 Miyake, Y.; Horiuchi, M.; Mita, S.; Tsuji, F.; Involvement of leukotriene B4 in murine dermatitis models. Biochem Pharmacol 1998, 55, 297.
【2】 Kawashima, Y.; Horiuchi, M. (Santen Pharmaceutical Co., Ltd.); Novel amino acid derivs. having N,N-dialkylaminophenyl group. EP 0870762; JP 1996301840; WO 9627585 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(V)	41582	(2R)-2-amino-3-[[4-(dimethylamino)benzyl]sulfanyl]propionic acid	C₁₂H₁₈N₂O₂S	详情	详情
(VI)	35379	(2S)-3-(benzoylsulfanyl)-2-methylpropionic acid	C₁₁H₁₂O₃S	详情	详情
(VII)	41584	S-[(2R)-3-chloro-2-methyl-3-oxopropyl] benzenecarbothioate	C₁₁H₁₁ClO₂S	详情	详情
(VIII)	35380	4-nitrophenyl (2S)-3-(benzoylsulfanyl)-2-methylpropanoate	C₁₇H₁₅NO₅S	详情	详情
(IX)	41583	(2R)-2-[[(2S)-3-(benzoylsulfanyl)-2-methylpropanoyl]amino]-3-[[4-(dimethylamino)benzyl]sulfanyl]propionic acid	C₂₃H₂₈N₂O₄S₂	详情	详情

Extended Information