(2S)-2-(acetylsulfanyl)-3-phenylpropionic acid -Drug Synthesis Database

【结构式】

【分子编号】22493

【品名】(2S)-2-(acetylsulfanyl)-3-phenylpropionic acid

【CA登记号】

【分子式】C₁₁H₁₂O₃S

【分子量】224.28048

【元素组成】C 58.91% H 5.39% O 21.4% S 14.3%

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：(VII)

1) The condensation of S-acetyl-N-(benzyloxycarbonyl)-L-homocysteine (I) with 6-hydroxy-L-norleucine methyl ester (II) by means of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (WSC) and hydroxybenzotriazole (HOBT) in dichloromethane gives the corresponding dipeptide (III), which is oxidized with oxalyl chloride in dichloromethane, yielding the aldehyde (IV). The cyclization of (IV) by means of sodium methoxide and trifluoroacetic acid affords the perhydro-pyridothiazepinone (V), which is deprotected with trimethylsilyl iodide (TMS-I) in dichloromethane to give (VI) with a free amino group (1). The acylation of (VI) with 2(S)-(acetylsulfanyl)-3-phenylpropionic acid (VII) by means of (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) in dichloromethane yields the corresponding amide (VIII), which is finally deprotected with NaOH in methanol and treated with HCl. 2) The intermediates S-acetyl-N-(benzyloxycarbonyl)-L-homocysteine (I) and 6-hydroxy-L-norleucine (II) have been obtained as follows: 2a) The protection of 3-aminotetrahydrothiophen-2-one (IX) with N-(benzyloxycarbonyloxy)succinimide gives the expected carbamate (X), which is treated first with KOH and then with acetic anhydride, yielding S-acetyl-N-(benzyloxycarbonyl)-DL-homocysteine (XI). Finally, this compound is submitted to optical resolution with (S)-alpha-methylbenzylamine to afford intermediate (I). 2b) The alkylation of acetamidomalonic acid diethyl ester (XII) with 4-acetoxybutyl bromide (XIII) by means of NaH in DMF gives the alkylated ester (XIV), which by a decarboxylative saponification yields 6-acetoxy-DL-norleucine (XV). Optical resolution of (XV) by means of porcine kidney acylase/LiOH in water affords pure 6-hydroxy-L-norleucine (XVI), which is finally esterified with methanol/HCl to intermediate (II).

参考文献中间体

合成目标

【1】 Robl, J.A.; Sun, C.-Q.; Stevenson, J.; et al.; Dual metalloprotease inhibitors: Mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase. J Med Chem 1997, 40, 11, 1570.
【2】 Graul, A.; Castañer, J.; Leeson, P.; Omapatrilat. Drugs Fut 1999, 24, 3, 269.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	10039	(1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine	3886-69-9	C₈H₁₁N	详情	详情
(I)	22487	(2S)-4-(acetylsulfanyl)-2-[[(benzyloxy)carbonyl]amino]butyric acid		C₁₄H₁₇NO₅S	详情	详情
(II)	22488	methyl (2S)-2-amino-6-hydroxyhexanoate		C₇H₁₅NO₃	详情	详情
(III)	22489	methyl (2S)-2-[((2S)-4-(acetylsulfanyl)-2-[[(benzyloxy)carbonyl]amino]butanoyl)amino]-6-hydroxyhexanoate		C₂₁H₃₀N₂O₇S	详情	详情
(IV)	22490	methyl (2S)-2-[((2S)-4-(acetylsulfanyl)-2-[[(benzyloxy)carbonyl]amino]butanoyl)amino]-6-oxohexanoate		C₂₁H₂₈N₂O₇S	详情	详情
(V)	22491	methyl (4S,7S,10aS)-4-[[(benzyloxy)carbonyl]amino]-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate		C₁₉H₂₄N₂O₅S	详情	详情
(VI)	22492	methyl (4S,7S,10aS)-4-amino-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate		C₁₁H₁₈N₂O₃S	详情	详情
(VII)	22493	(2S)-2-(acetylsulfanyl)-3-phenylpropionic acid		C₁₁H₁₂O₃S	详情	详情
(VIII)	22494	methyl (4S,7S,10aS)-4-[[(2S)-2-(acetylsulfanyl)-3-phenylpropanoyl]amino]-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate		C₂₂H₂₈N₂O₅S₂	详情	详情
(IX)	22495	3-aminodihydro-2(3H)-thiophenone	10593-85-8	C₄H₇NOS	详情	详情
(X)	22496	benzyl 2-oxotetrahydro-3-thiophenylcarbamate		C₁₂H₁₃NO₃S	详情	详情
(XI)	22497	acetyl-N-[(benzyloxy)carbonyl]homocysteine		C₁₄H₁₇NO₅S	详情	详情
(XII)	16710	Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate	1068-90-2	C₉H₁₅NO₅	详情	详情
(XIII)	22499	4-bromobutyl acetate		C₆H₁₁BrO₂	详情	详情
(XIV)	22500	diethyl 2-(acetamido)-2-[4-(acetoxy)butyl]malonate		C₁₅H₂₅NO₇	详情	详情
(XV)	22501	6-(acetoxy)norleucine		C₈H₁₅NO₄	详情	详情
(XVI)	22502	(2S)-2-amino-6-hydroxyhexanoic acid	6033-32-5	C₆H₁₃NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIII)

Removal of phthaloyl protecting group of (VIII) provided amine (IX), which was protected as the tert-butyl carbamate (X) with Boc2O. Alkylation at the lactam nitrogen atom of (X) was then achieved employing LiN(SiMe3)2 and ethyl bromoacetate to afford (XI), which was deprotected under acidic conditions to furnish amine (XII). Alternatively, amine (IX) could be protected using a N-trityl group. Coupling of amine (XII) with 2-(acetylthio)benzenepropanoic acid (XIII) using either BOP or EDC as the condensing reagents produced amide (XIV). Finally, both ethyl ester and acetyl thioester of (XIV) were hydrolyzed with NaOH to yield the title compound.

参考文献中间体

合成目标

【1】 Robl, J.A.; Sulsky, R.; Sieber-McMaster, E.; Ryono DE; Cimarusti MP; Simpkins LM; Karanewsky, D.S.; Chao, S.; Asaad, M.M.; Seymour, A.A.; Fox, M.E.; Smith, P.L.; Trippodo, N.C.; Vasopeptidase inhibitors: Incorporation of geminal and spirocyclic substituted azepinones in mercaptoacyl dipeptides. J Med Chem 1999, 42, 2, 305.
【2】 Karanewsky, D.S.; Barrish, J.C.; Petrillo, E.W. Jr.; Robl, J.A.; Ryono, D.E. (Bristol-Myers Squibb Co.); Dual action inhibitors. EP 0599444; US 5552397 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VIII)	26847	2-[(3S)-7,7-dimethyl-2-oxoazepanyl]-1H-isoindole-1,3(2H)-dione	C₁₆H₁₈N₂O₃	详情	详情
(IX)	26848	(3S)-3-amino-7,7-dimethyl-2-azepanone	C₈H₁₆N₂O	详情	详情
(X)	26849	tert-butyl (3S)-7,7-dimethyl-2-oxoazepanylcarbamate	C₁₃H₂₄N₂O₃	详情	详情
(XI)	26850	methyl 2-[(6S)-6-[(tert-butoxycarbonyl)amino]-2,2-dimethyl-7-oxoazepanyl]acetate	C₁₆H₂₈N₂O₅	详情	详情
(XII)	26851	methyl 2-[(6S)-6-amino-2,2-dimethyl-7-oxoazepanyl]acetate	C₁₁H₂₀N₂O₃	详情	详情
(XIII)	22493	(2S)-2-(acetylsulfanyl)-3-phenylpropionic acid	C₁₁H₁₂O₃S	详情	详情
(XIV)	26852	methyl 2-((6S)-6-[[(2S)-2-(acetylsulfanyl)-3-phenylpropanoyl]amino]-2,2-dimethyl-7-oxoazepanyl)acetate	C₂₂H₃₀N₂O₅S	详情	详情

Extended Information