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【结 构 式】 
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【分子编号】49460 【品名】Dimethyl benzylidenemalonate 【CA登记号】 |
【 分 子 式 】C12H12O4 【 分 子 量 】220.22488 【元素组成】C 65.45% H 5.49% O 29.06% |
合成路线1
该中间体在本合成路线中的序号：(III)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：(VIII)Alternatively, the condensation of dimethyl malonate (VI) with benzaldehyde (VII) by means of piperidine in refluxing toluene gives dimethyl benzylidenemalonate (VIII), which is reduced with H2 over Pd/C in toluene to yield the corresponding benzyl derivative (IX). The hydrolysis of (IX) with NaOH in water affords the benzylmalonic acid (X). Alternatively, intermediate (X) can also be obtained starting from diethyl malonate (XI), which is condensed with with benzaldehyde (VII) by means of piperidine in refluxing toluene to give diethyl benzylidenemalonate (XII). Reduction of (XII) with H2 over Pd/C in toluene yields the corresponding benzyl derivative (XIII), which is then hydrolized with NaOH in water. The monodecarboxylation of (X) and its condensation with paraformaldehyde and diethylamine in refluxing ethyl acetate provides 2-benzylacrylic acid (XIV), which is condensed with thioacetic acid (V) by heating at 70 C to afford 2-(acetylsulfanylmethyl)-3-phenylpropionic acid (XV). Finally, this compound is condensed with N-tosylglycine benzyl ester (XVI) by means of HOBt, DCC and TEA in THF.
| 【1】 Roques, B.; Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Amino acid derivs. and their therapeutic application. EP 0038758 . |
| 【2】 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 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 12893 | Ethanethioic S-acid | C2H4OS | 详情 | 详情 | |
| (VI) | 19373 | dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
| (VII) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (VIII) | 49460 | Dimethyl benzylidenemalonate | C12H12O4 | 详情 | 详情 | |
| (IX) | 49461 | dimethyl 2-benzylmalonate | C12H14O4 | 详情 | 详情 | |
| (X) | 37280 | 2-benzylmalonic acid | 616-75-1 | C10H10O4 | 详情 | 详情 |
| (XI) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (XII) | 37482 | diethyl 2-benzylidenemalonate | 5292-53-5 | C14H16O4 | 详情 | 详情 |
| (XIII) | 20208 | diethyl 2-benzylmalonate | 607-81-8 | C14H18O4 | 详情 | 详情 |
| (XIV) | 37279 | 2-benzylacrylic acid | C10H10O2 | 详情 | 详情 | |
| (XV) | 55230 | 3-(acetylsulfanyl)-2-benzylpropanoic acid | C12H14O3S | 详情 | 详情 | |
| (XVI) | 55228 | N-p-Tosylglycine benzyl ester | C16H17NO4S | 详情 | 详情 |