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【结 构 式】 
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【分子编号】21589 【品名】ethyl 3-cyano-3-[3-(cyclopentyloxy)-4-methoxyphenyl]propanoate 【CA登记号】 |
【 分 子 式 】C18H23NO4 【 分 子 量 】317.38496 【元素组成】C 68.12% H 7.3% N 4.41% O 20.16% |
合成路线1
该中间体在本合成路线中的序号：(VI)This compound can be obtained by three related ways: 1) The condensation of 3-cyclopentyloxy-4-methoxybenzaldehyde (I) with diethyl malonate (II) by means of piperidine in refluxing acetic acid gives diethyl 3-cyclopentyloxy-4-methoxybenzylidenemalonate (III), which is treated with nitromethane and tetramethylguanidine (TMG) yielding diethyl 2-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-nitroethyl]malonate (IV). The reductocyclization of (IV) with H2 over Raney Ni in hot methanol gives ethyl 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylat (V). Finally, this compound is hydrolyzed and decarboxylated. 2) The reaction of malonate (III) with KCN in ethanol at 60 C gives ethyl 3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)propionate (VI), which is reduced with H2 over PtO2 in acetic acid yielding ethyl 4-amino-3-(3-cyclopentyloxy-4-methoxyphenyl)butanoate (VII). Finally, this compound is hydrolyzed and cyclized. 3) The reaction of malonate (III) with KNC in refluxing ethanol gives 3-cyano-3-(3-cyclopentyloxy-4-methoxy)propanoic acid (VIII), which is reduced with H2 over PtO2 as before yielding 4-amino-3-(3-cyclopentyloxy-4-methoxyphenyl)butanoic acid (IX). Finally, this compound is cyclized.
| 【1】 Huth, A.; Schmiechen, R.; Kehr, W.; Palenschat, D.; Paschelke, G.; Wachtel, H. (Schering AG); 4-(Polyalkoxyphenyl)-2-pyrrolidones (II).. BE 846335; ES 451518; FR 2324299; GB 1563398; US 4153713 . |
| 【2】 Crossland, J.; Prous, J.; Castaner, J.; ROLIPRAM < Rec INN; USAN >. Drugs Fut 1988, 13, 1, 38. |
| 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) | 16510 | 3-(cyclopentyloxy)-4-methoxybenzaldehyde | C13H16O3 | 详情 | 详情 | |
| (II) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (III) | 21586 | diethyl 2-[3-(cyclopentyloxy)-4-methoxybenzylidene]malonate | C20H26O6 | 详情 | 详情 | |
| (IV) | 21587 | diethyl 2-[1-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-nitroethyl]malonate | C21H29NO8 | 详情 | 详情 | |
| (V) | 21588 | ethyl 4-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-oxo-3-pyrrolidinecarboxylate | C19H25NO5 | 详情 | 详情 | |
| (VI) | 21589 | ethyl 3-cyano-3-[3-(cyclopentyloxy)-4-methoxyphenyl]propanoate | C18H23NO4 | 详情 | 详情 | |
| (VII) | 21590 | ethyl 4-amino-3-[3-(cyclopentyloxy)-4-methoxyphenyl]butanoate | C18H27NO4 | 详情 | 详情 | |
| (VIII) | 21591 | 3-cyano-3-[3-(cyclopentyloxy)-4-methoxyphenyl]propionic acid | C16H19NO4 | 详情 | 详情 | |
| (IX) | 21592 | 4-amino-3-[3-(cyclopentyloxy)-4-methoxyphenyl]butyric acid | C16H23NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)N-Boc-O-benzyltyrosine (I) was converted to the aminoalcohol derivative (III) via conversion to the mixed anhydride (II) with isobutyl chloroformate and subsequent reduction with NaBH4. Acid cleavage of the N-Boc protecting group of (III) gave the free amine (IV), which was acylated with oleoyl chloride (V) to afford amide (VI). Phosphitylation of (VI) with N,N-diisopropyl di-tert-butyl phosphoroamidite in the presence of tetrazole, followed by oxidation of the intermediate phosphite with hydrogen peroxide, furnished the phosphate (VII). The tert-butyl phosphate ester groups of (VII) were finally cleaved by treatment with trifluoroacetic acid.
| 【1】 Santos, W.L.; et al.; Structure-activity relationships of lysophosphatidic acid: Synthesis and analysis of EDG receptor agonists and antagonists. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 272. |
| 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) | 30396 | (2S)-3-[4-(benzyloxy)phenyl]-2-[(tert-butoxycarbonyl)amino]propionic acid | 54784-43-9 | C21H25NO5 | 详情 | 详情 |
| (II) | 51294 | C26H33NO7 | 详情 | 详情 | ||
| (III) | 21589 | ethyl 3-cyano-3-[3-(cyclopentyloxy)-4-methoxyphenyl]propanoate | C18H23NO4 | 详情 | 详情 | |
| (IV) | 51290 | (2S)-2-amino-3-[4-(benzyloxy)phenyl]-1-propanol | C16H19NO2 | 详情 | 详情 | |
| (V) | 51291 | (Z)-9-hexadecenoyl chloride | C16H29ClO | 详情 | 详情 | |
| (VI) | 51292 | (Z)-N-[(1S)-1-[4-(benzyloxy)benzyl]-2-hydroxyethyl]-9-hexadecenamide | C32H47NO3 | 详情 | 详情 | |
| (VII) | 51293 | (2S)-3-[4-(benzyloxy)phenyl]-2-[(Z)-9-hexadecenoylamino]propyl di(tert-butyl) phosphate | C40H64NO6P | 详情 | 详情 |