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【结 构 式】

【分子编号】22487

【品名】(2S)-4-(acetylsulfanyl)-2-[[(benzyloxy)carbonyl]amino]butyric acid

【CA登记号】

【 分 子 式 】C14H17NO5S

【 分 子 量 】311.35872

【元素组成】C 54.01% H 5.5% N 4.5% O 25.69% S 10.3%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(I)

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).

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
Extended Information