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【结 构 式】 
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【药物名称】Ecadotril, Sinorphan, (S)-Acetorphan, S-049, BP-1.02, Bay-y-7432 【化学名称】N-[2(S)-(Acetylthiomethyl)-3-phenylpropionyl]glycine benzyl ester 【CA登记号】112573-73-6 【 分 子 式 】C21H23NO4S 【 分 子 量 】385.48576 |
【开发单位】Bioprojet (Originator), Bayer (Licensee) 【药理作用】CARDIOVASCULAR DRUGS, Diuretics, Heart Failure Therapy, RENAL-UROLOGIC DRUGS, Neprilysin Inhibitors |
合成路线1
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
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 |