【结 构 式】 |
【分子编号】49480 【品名】2-benzyl-3-hydroxypropionic acid 【CA登记号】 |
【 分 子 式 】C10H12O3 【 分 子 量 】180.20348 【元素组成】C 66.65% H 6.71% O 26.64% |
合成路线1
该中间体在本合成路线中的序号:(XXI)Alternatively, ecadotril can be obtained by an analogous route: Treatment of the already reported methyl beta-hydroxy-alpha-methylene-benzenepropionate (XVI) with sulfuric acid and acetic anhydride provides 2-benzylidene-3-acetoxypropionate methyl ester (XIXa-b), which is then subjected to hydrolysis with NaOH in MeOH/H2O to give carboxylic acid (XXa-b). Hydrogenation of (XXa-b) over Pd/C in MeOH/H2O in the presence of Et3N yields racemic 3-hydroxy-2-benzylpropionic acid (XXI), from which isomer (S)-(XXIII) is isolated by formation of a diastereomeric salt with (1R,2S)-(+)-cis-1-amino-2-indanol (XXII) in 2-propanol at 70 C followed by crystallization and decomposition of the salt with HCl. Coupling of compound (S)-(XXIII) with benzyl glycinate (XIV) by means of Et3N, HOBt and DCC in THF gives N-(3-hydroxy-2(S)-benzylpropionyl)-glycine benzyl ester (XXIV), which is then converted into the corresponding methanesulfonyloxy derivative (XXV) by reaction with methanesulfonyl chloride in toluene in the presence of pyridine followed by treatment with HCl. Finally, treatment of (XXV) with LiBr in refluxing acetone provides N-(3-bromo-2(S)-benzylpropionyl)glycine benzyl ester (XXVI), which is converted into ecadotril by reaction with potassium thioacetate in methyl isobutyl ether at 50 C.
【1】 Izawa, K.; Hamada, T.; Suzuki, T. (Ajinomoto Co., Inc.); Method for producing an optically active phenylpropionic acid deriv.. EP 0937710 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XXa) | 49473 | (Z)-2-(hydroxymethyl)-3-phenyl-2-propenoic acid | C10H10O3 | 详情 | 详情 | |
(XIXa) | 49474 | methyl (Z)-2-[(acetoxy)methyl]-3-phenyl-2-propenoate | C13H14O4 | 详情 | 详情 | |
(XIXb) | 49475 | methyl (E)-2-[(acetoxy)methyl]-3-phenyl-2-propenoate | C13H14O4 | 详情 | 详情 | |
(XXb) | 49476 | (E)-2-(hydroxymethyl)-3-phenyl-2-propenoic acid | C10H10O3 | 详情 | 详情 | |
(S)-(XXIII) | 49481 | (2S)-2-benzyl-3-hydroxypropionic acid | C10H12O3 | 详情 | 详情 | |
(XIV) | 13601 | benzyl 2-aminoacetate; Glycine benzyl ester hydrochloride | 1738-68-7 | C9H11NO2 | 详情 | 详情 |
(XVI) | 49470 | methyl 2-[hydroxy(phenyl)methyl]acrylate | C11H12O3 | 详情 | 详情 | |
(XXI) | 49480 | 2-benzyl-3-hydroxypropionic acid | C10H12O3 | 详情 | 详情 | |
(XXII) | 27559 | (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol | C9H11NO | 详情 | 详情 | |
(XXIV) | 49477 | benzyl 2-[[(2S)-2-benzyl-3-hydroxypropanoyl]amino]acetate | C19H21NO4 | 详情 | 详情 | |
(XXV) | 49478 | benzyl 2-([(2S)-2-benzyl-3-[(methylsulfonyl)oxy]propanoyl]amino)acetate | C20H23NO6S | 详情 | 详情 | |
(XXVI) | 49479 | benzyl 2-[[(2S)-2-benzyl-3-bromopropanoyl]amino]acetate | C19H20BrNO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(IX)
【1】 Li L, Tian QS, Wei WT, et al. 2003. Process for preparation of alvimopan and intermediates. 发明专利申请公开说明书, CN 1827598(Tianjiu Taipu Medicine Science and Technology Development Co, Ltd, Peop Rep China) |
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) | 16618 | (3R,4R)-4-(3-isopropoxyphenyl)-1,3,4-trimethylhexahydropyridine; isopropyl 3-[(3R,4R)-1,3,4-trimethylhexahydro-4-pyridinyl]phenyl ether | C17H27NO | 详情 | 详情 | |
(II) | 67026 | (3R,4R)-phenyl 4-(3-isopropoxyphenyl)-3,4-dimethylpiperidine-1-carboxylate | C23H29NO3 | 详情 | 详情 | |
(III) | 16620 | 3-[(3R,4R)-3,4-dimethylhexahydro-4-pyridinyl]phenol | 119193-19-0 | C13H19NO | 详情 | 详情 |
(IV) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
(V) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
(VI) | 49470 | methyl 2-[hydroxy(phenyl)methyl]acrylate | C11H12O3 | 详情 | 详情 | |
(VII) | 49475 | methyl (E)-2-[(acetoxy)methyl]-3-phenyl-2-propenoate | C13H14O4 | 详情 | 详情 | |
(VIII) | 49476 | (E)-2-(hydroxymethyl)-3-phenyl-2-propenoic acid | C10H10O3 | 详情 | 详情 | |
(IX) | 49480 | 2-benzyl-3-hydroxypropionic acid | C10H12O3 | 详情 | 详情 | |
(X) | 49481 | (2S)-2-benzyl-3-hydroxypropionic acid | C10H12O3 | 详情 | 详情 | |
(XI) | 13601 | benzyl 2-aminoacetate; Glycine benzyl ester hydrochloride | 1738-68-7 | C9H11NO2 | 详情 | 详情 |
(XII) | 49477 | benzyl 2-[[(2S)-2-benzyl-3-hydroxypropanoyl]amino]acetate | C19H21NO4 | 详情 | 详情 | |
(XIII) | 49478 | benzyl 2-([(2S)-2-benzyl-3-[(methylsulfonyl)oxy]propanoyl]amino)acetate | C20H23NO6S | 详情 | 详情 | |
(XIV) | 49479 | benzyl 2-[[(2S)-2-benzyl-3-bromopropanoyl]amino]acetate | C19H20BrNO3 | 详情 | 详情 | |
(XV) | 67027 | benzyl 2-(2-benzyl-3-(4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl)propanamido)acetate | C32H38N2O4 | 详情 | 详情 |