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【结 构 式】

【药物名称】Fasidotril, Alatriopril, Aladotril, BP1.137

【化学名称】(-)-(S)-N-[2-(Acetylthiomethyl)-3-(3,4-methylenedioxyphenyl)propanoyl]-(S)-alanine benzyl ester

【CA登记号】135038-57-2

【 分 子 式 】C23H25NO6S

【 分 子 量 】443.5228

【开发单位】Bioprojet (Originator), Lilly (Licensee)

【药理作用】CARDIOVASCULAR DRUGS, Heart Failure Therapy, Hypertension, Treatment of, Angiotensin-I Converting Enzyme (ACE) Inhibitors, Neprilysin Inhibitors

合成路线1

Condensation of piperonyl chloride (I) with diethyl malonate (II) by means of Na in anhydrous refluxing EtOH (NaOEt) provides 2-[3,4-(methylenedioxy)benzyl]malonic acid diethyl ester (III), which is converted into the monoethyl ester (IV) by saponification with KOH in EtOH. Treatment of (IV) with diethylamine in paraformaldehyde/H2O affords acrylic ester (V), which is then subjected to saponification with NaOH in acetone/H2O to provide [3,4-(methylenedioxy)benzyl]-2-propenoic acid (VI). Alternatively, derivative (VI) can also be obtained by following this route: treatment of piperonal (VII) with diethyl malonate (II) in refluxing toluene in the presence of piperidine and acetic acid provides diethyl piperonylidene malonate (VIII), which is then hydrogenated over Pd/C to furnish diethyl piperonylmalonate (IX). Saponification of the ethyl ester moiety of (IX) by refluxing with NaOH in H2O affords piperonylmalonic acid (X), which is finally converted into intermediate (VI) by decarboxylation by treatment with diethylamine in refluxing paraformaldehyde. Reaction of (VI) with thioacetic acid at 70 C affords a racemic mixture of propionic acid derivatives (XI), which is resolved by first formation of a chiral salt (either by reaction with (R)-alpha-methylbenzylamine or by reaction with (+)-ephedrine in ether), recrystallization of the corresponding diastereomer and finally liberation of the 2-(S)-(acetylthiomethyl)-3-[3,4-(methylenedioxy)benzyl]propionic acid [(S)-(XII)] by hydrolysis with HCl in H2O/CH2Cl2. Finally, fasidotril is obtained by condensation of (S)-(XII) with benzyl alaninate (XIII) by means of HOBt and DCC in THF/CHCl3 in the presence of Et3N.

1 Plaquevent, J.-C.; Danvy, D.; Monteil, T.; Greciet, H.; Duhamel, L.; Duhamel, P.; Gros, C.; Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Amino acid derivs., method for their preparation and their therapeutic application. EP 0419327; FR 2652087; WO 9104246 .
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
(III),(IX) 49496 diethyl 2-(1,3-benzodioxol-5-ylmethyl)malonate C15H18O6 详情 详情
(S)-(XII) 49501 (2S)-3-(acetylsulfanyl)-2-(1,3-benzodioxol-5-ylmethyl)propionic acid C13H14O5S 详情 详情
(I) 28617 5-(chloromethyl)-1,3-benzodioxole C8H7ClO2 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(IV) 49497 2-(1,3-benzodioxol-5-ylmethyl)-3-ethoxy-3-oxopropionic acid C13H14O6 详情 详情
(V) 38469 ethyl (E)-3-(1,3-benzodioxol-5-yl)-2-propenoate C12H12O4 详情 详情
(VI) 11634 (E)-3-(1,3-Benzodioxol-5-yl)-2-propenoic acid; 3,4-(Methylenedioxy)cinnamic acid 2373-80-0 C10H8O4 详情 详情
(VII) 10127 1,3-Benzodioxole-5-carbaldehyde; Heliotropine 120-57-0 C8H6O3 详情 详情
(VIII) 49499 diethyl 2-(1,3-benzodioxol-5-ylmethylene)malonate C15H16O6 详情 详情
(X) 49500 2-(1,3-benzodioxol-5-ylmethyl)malonic acid C11H10O6 详情 详情
(XI) 49498 3-(acetylsulfanyl)-2-(1,3-benzodioxol-5-ylmethyl)propionic acid C13H14O5S 详情 详情
(XIII) 10143 benzyl (2S)-2-aminopropanoate C10H13NO2 详情 详情
Extended Information