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【结 构 式】

【分子编号】49470

【品名】methyl 2-[hydroxy(phenyl)methyl]acrylate

【CA登记号】

【 分 子 式 】C11H12O3

【 分 子 量 】192.21448

【元素组成】C 68.74% H 6.29% O 24.97%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(XVI)

Reaction of benzaldehyde (I) with dimethyl malonate (II) in refluxing toluene in the presence of piperidine and HOAc provides dimethyl benzylidene malonate (III), which is then hydrogenated over Pd/C to afford dimethyl benzyl malonate (IV). Reduction of (IV) with LiAlH4 in refluxing THF furnishes 2-benzyl-1,3-propanediol (V), which is then subjected to reaction with vinyl acetate (VI) by means of Novozym 435 enzyme to yield diacetate (VII). Enantioselective removal of one acetyl group from (VII) by treatment with Pseudomonas fluorescens Lipase in acetone/phosphate buffer (pH = 7) at 30 C gives 3-acetoxy-2(S)-benzyl-propanol (S)-(VIII), which is then oxidized by means of Jones reagent in acetone/isopropanol to provide carboxylic acid (R)-(IX). The hydrolysis of (IX) with LiOH in THF/H2O gives 2(R)-benzyl-3-hydroxypropanoic acid (R)-(X). Alternatively, intermediate (X) can also be synthesized as follows: Condensation of benzaldehyde (I) with methyl acrylate (XV) by means of diaza-1,4-bicyclo[2.2.2.]octane affords methyl beta-hydroxy-alpha-methylene-benzenepropanoate (XVI), which is then subjected to hydrolysis with KOH in MeOH/H2O to yield carboxylic acid (XVII). Treatment of (XVII) with p-toluenesulfonic acid in refluxing HOAc gives (E)-2-(acetoxymethyl)-3-phenylpropionic acid (XVIII), which is finally converted into (X) by enantioselective hydrogenation in the presence of S-Binap and ruthenium catalyst [CodRu(all)2]. Derivative (R)-(X) is then converted into 3-(acetylsulfanyl)-2(S)-benzylpropionic acid (XI) by means of a Mitsunobu reaction with thioacetic acid, diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (PPh3). Compound (XI) is then subjected to optical purification by formation and isolation of the corresponding salt with (-)-ephedrine and subsequent hydrolysis with HCl to furnish enantiomerically pure (S)-(XII). Finally, carboxylic acid (S)-(XII) is converted into ecadotril by its coupling with benzyl glycinate (XIV), either by means of Et3N, DCC and HOBt in CHCl3, or by first reaction with thionyl chloride to give acid chloride (S)-(XIII) and subsequent coupling with glycinate (XIV) by means of Et3N in CH2Cl2.

1 Monteil, T.; et al.; New asymmetric synthesis of dexecadotril and ecadotril starting from a single precursor. Synth Commun 2001, 31, 2, 211.
2 Duhamel, P.; Duhamel, L.; Danvy, D.; Plaquevent, J.-C.; Giros, B.; Gros, C.; Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Enantiomeric derivs. of amino acids, process for their preparation and their pharmaceutical applications. EP 0318377; FR 2623498; JP 1990000161; JP 1996059606; US 5296509; US 5331008 .
3 Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Novel pharmaceutical compsns. for the treatment of functional colophaties and their process of obtention. EP 0501870; JP 1993105627 .
4 Schwartz, J.-C.; Danvy, D.; Lecomte, J.-M.; Duhamel, P.; Duhamel, L.; Monteil, T. (Societe Civile Bioprojet); Method for the asymmetrical synthesis of S-acylated derivs. of 2-mercaptomethyl 3-phenyl propanoic acid, and use thereof for synthesising N-(mercaptoacyl)amino acid derivs.. WO 9729086 .
5 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 .
6 Henry, J.C.; Genet, J.P.; Dellis, P.; Vidal, V.; Binay, P. (Fournier Industrie et Santé); Preparation of S- and R-isomers of 2-mercaptomethyl-3-aryl propanoic acid by asymmetric reduction of an aryl propenoic acid. FR 2772027 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(S)-(VIII) 49464 (2S)-2-benzyl-3-hydroxypropyl acetate C12H16O3 详情 详情
(R)-(IX) 49465 (2R)-3-(acetoxy)-2-benzylpropionic acid C12H14O4 详情 详情
(R)-(X) 49466 (2R)-2-benzyl-3-hydroxypropionic acid C10H12O3 详情 详情
(XI),(S)-(XII) 49467 (2S)-3-(acetylsulfanyl)-2-benzylpropionic acid C12H14O3S 详情 详情
(I) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(II) 19373 dimethyl malonate;Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(III) 49460 Dimethyl benzylidenemalonate C12H12O4 详情 详情
(IV) 49461 dimethyl 2-benzylmalonate C12H14O4 详情 详情
(V) 49462 2-Benzylpropane-1,3-diol C10H14O2 详情 详情
(VI) 24543 vinyl acetate 108-05-4 C4H6O2 详情 详情
(VII) 49463 3-(acetoxy)-2-benzylpropyl acetate C14H18O4 详情 详情
(XIII) 49468 S-[(2R)-2-benzyl-3-chloro-3-oxopropyl] ethanethioate C12H13ClO2S 详情 详情
(XIV) 49469 1-amino-3-phenylacetone C9H11NO 详情 详情
(XV) 14156 methyl acrylate 96-33-3 C4H6O2 详情 详情
(XVI) 49470 methyl 2-[hydroxy(phenyl)methyl]acrylate C11H12O3 详情 详情
(XVII) 49471 2-[hydroxy(phenyl)methyl]acrylic acid C10H10O3 详情 详情
(XVIII) 49472 (E)-2-[(acetoxy)methyl]-3-phenyl-2-propenoic acid C12H12O4 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XVI)

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3

该中间体在本合成路线中的序号:(VI)

 

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
Extended Information