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【结 构 式】 
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【分子编号】11634 【品名】(E)-3-(1,3-Benzodioxol-5-yl)-2-propenoic acid; 3,4-(Methylenedioxy)cinnamic acid 【CA登记号】2373-80-0 |
【 分 子 式 】C10H8O4 【 分 子 量 】192.17112 【元素组成】C 62.5% H 4.2% O 33.3% |
合成路线1
该中间体在本合成路线中的序号：(I)3,4-Methylenedioxycinnamic acid (I) is transformed into the corresponding acid chloride (II) by treatment with oxalyl chloride in benzene. The acid chloride is then converted without purification into antiepilepsirine by treatment with piperidine in benzene.
| 【1】 Ruyun, J.; ANTIEPILEPSIRINE. Drugs Fut 1990, 15, 4, 331. |
| 【2】 Pei, Y.; Li, J.; Cai, Z.; Zhang, B.; Ku, B.; Pharmacological study of tablettae antiepilepticae I. Its effect on the CNS. Nat Med J China 1978, 58, 4, 216-9. |
| 【3】 Wang, S.; Li, R.; Liu, W.; et al.; Structure-anticonvulsant activity relationships of some cinnamamides of substituted aromatic ring. Acta Pharm Sin 1986, 21, 7, 542-5. |
合成路线2
该中间体在本合成路线中的序号：(VI)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 |
合成路线3
该中间体在本合成路线中的序号：(VII)Treatment of 3,4-(methylenedioxy)cinnamic (VII) with SOCl2 and then with EtOH provided ethyl ester (VIII). Subsequent conjugate addition of the chiral amine (IX) to ester (VIII) in the presence of BuLi gave amino ester (X). Cleavage of benzyl and alpha-methylbenzyl protecting groups of (X) was then achieved by catalytic hydrogenolysis over Pd/C. The resulting primary amine (XI) was acylated with 4-nitrophenyl chloroformate (XII) to produce carbamate (XIII), which was condensed with amine (VI) to generate urea (XIV). Finally, basic hydrolysis of the ethyl ester of (XIV) furnished the title carboxylic acid.
| 【1】 Scott, I.L.; et al.; Novel N,N-disubstituted amides that are highly potent VLA-4 antagonists. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 284. |
| 【2】 Raju, B.G.; Scott, I.L.; Biediger, R.J.; Market, R.V.; Grabbe, V.O.; Kassir, J.M.; Kogan, T.P.; Lin, S. (Texas Biotechnology Corp.); N,N-Disubstd. amides that inhibit the binding of integrins to their receptors. US 6096773; WO 9952493; WO 9952898 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 38468 | (2S)-2-amino-N,N-bis(2-thienylmethyl)hexanamide | C16H22N2OS2 | 详情 | 详情 | |
| (VII) | 11634 | (E)-3-(1,3-Benzodioxol-5-yl)-2-propenoic acid; 3,4-(Methylenedioxy)cinnamic acid | 2373-80-0 | C10H8O4 | 详情 | 详情 |
| (VIII) | 38469 | ethyl (E)-3-(1,3-benzodioxol-5-yl)-2-propenoate | C12H12O4 | 详情 | 详情 | |
| (IX) | 38470 | (1S)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1S)-1-phenylethyl]amine | 38235-77-7 | C15H17N | 详情 | 详情 |
| (X) | 38471 | ethyl (3S)-3-(1,3-benzodioxol-5-yl)-3-[benzyl[(1S)-1-phenylethyl]amino]propanoate | C27H29NO4 | 详情 | 详情 | |
| (XI) | 38472 | ethyl (3S)-3-amino-3-(1,3-benzodioxol-5-yl)propanoate | C12H15NO4 | 详情 | 详情 | |
| (XII) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (XIII) | 38473 | ethyl (3S)-3-(1,3-benzodioxol-5-yl)-3-[[(4-nitrophenoxy)carbonyl]amino]propanoate | C19H18N2O8 | 详情 | 详情 | |
| (XIV) | 38474 | ethyl (3S)-3-(1,3-benzodioxol-5-yl)-3-([[((1S)-1-[[bis(2-thienylmethyl)amino]carbonyl]pentyl)amino]carbonyl]amino)propanoate | C29H35N3O6S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Treatment of 3,4-methylenedioxycinnamic acid (I) with thionyl chloride and pyridine gives the benzothiophene-2-carbonyl chloride (II), which is reacted with methanol in toluene to produce the methyl ester (III). Cleavage of the methylenedioxy group of (III) with BBr3 affords the dihydroxy derivative (IV), which upon alkylation with 4-(phenylsulfanyl)benzyl chloride (V) yields the diether derivative (VI). The ester function of (VI) is then reduced by LiAlH4 to the primary alcohol (VII), which is further oxidized to aldehyde (VIII) by means of MnO2 in toluene. Substitution of the chlorine atom of (VIII) with 4-chlorophenol (IX) in the presence of NaH furnishes the chlorophenyl ether (X).
| 【1】 De Nanteuil, G.; Lila-Ambroise, C.; Rupin, A.; Vallez, M.-O.; Verbeuren, T.J.; New fibrinolytic agents: Benzothiophene derivatives as inhibitors of the t-PA-PAI-1 complex formation. Bioorg Med Chem Lett 2003, 13, 10, 1705. |
| 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) | 11634 | (E)-3-(1,3-Benzodioxol-5-yl)-2-propenoic acid; 3,4-(Methylenedioxy)cinnamic acid | 2373-80-0 | C10H8O4 | 详情 | 详情 |
| (II) | 64848 | 7-chlorothieno[2,3-f][1,3]benzodioxole-6-carbonyl chloride | C10H4Cl2O3S | 详情 | 详情 | |
| (III) | 64849 | methyl 7-chlorothieno[2,3-f][1,3]benzodioxole-6-carboxylate | C11H7ClO4S | 详情 | 详情 | |
| (IV) | 64850 | methyl 3-chloro-5,6-dihydroxy-1-benzothiophene-2-carboxylate | C10H7ClO4S | 详情 | 详情 | |
| (V) | 31094 | 1-(chloromethyl)-4-(phenylsulfanyl)benzene; 4-(chloromethyl)phenyl phenyl sulfide | C13H11ClS | 详情 | 详情 | |
| (VI) | 64851 | methyl 3-chloro-5,6-bis{[4-(phenylsulfanyl)benzyl]oxy}-1-benzothiophene-2-carboxylate | C36H27ClO4S3 | 详情 | 详情 | |
| (VII) | 64852 | (3-chloro-5,6-bis{[4-(phenylsulfanyl)benzyl]oxy}-1-benzothiophen-2-yl)methanol | C35H27ClO3S3 | 详情 | 详情 | |
| (VIII) | 64853 | 3-chloro-5,6-bis{[4-(phenylsulfanyl)benzyl]oxy}-1-benzothiophene-2-carbaldehyde | C35H25ClO3S3 | 详情 | 详情 | |
| (IX) | 35543 | 4-chlorophenol | 106-48-9 | C6H5ClO | 详情 | 详情 |
| (X) | 64854 | 3-(4-chlorophenoxy)-5,6-bis{[4-(phenylsulfanyl)benzyl]oxy}-1-benzothiophene-2-carbaldehyde | C41H29ClO4S3 | 详情 | 详情 |