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【结 构 式】 
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【分子编号】17462 【品名】(6S)-6-[(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl]-5,6-dihydro-2H-pyran-2-one 【CA登记号】 |
【 分 子 式 】C25H20FNO2 【 分 子 量 】385.4377432 【元素组成】C 77.9% H 5.23% F 4.93% N 3.63% O 8.3% |
合成路线1
该中间体在本合成路线中的序号：(XLIV)Elimination of thiophenol from (XLIII) by means of CaCO3 in refluxing toluene gives the unsaturated lactone (XLIV) with the (E)-vinylene bond. The alpha,beta-epoxidation of the unsaturated lactone (XLIV) with H2O2 and NaOH in methanol/dichloromethane affords the monoepoxy lactone (XLV) regioselectively, which is finally submitted to a regioselective ring opening with diphenyl diselenide and NaBH4 in THF.
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859. |
| 【2】 Kamikubo, T.; Takano, S.; Sugihara, T.; Suzuki, M.; Ogasawara, K.; Enantioconvergent synthesis of a promising HMG-CoA reductase inhibitor NK-104 from both enantiomers of epichlorohydrin. Tetrahedron Asymmetry 1993, 4, 2, 201-4. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XLIII) | 17457 | (6S)-6-[2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-(phenylsulfinyl)ethyl]-5,6-dihydro-2H-pyran-2-one | C31H26FNO3S | 详情 | 详情 | |
| (XLIV) | 17462 | (6S)-6-[(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl]-5,6-dihydro-2H-pyran-2-one | C25H20FNO2 | 详情 | 详情 | |
| (XLV) | 17463 | (1R,4S,6R)-4-[(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl]-3,7-dioxabicyclo[4.1.0]heptan-2-one | C25H20FNO3 | 详情 | 详情 | |
| (XLVI) | 64696 | (4R,6S)-6-{(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl}-4-hydroxytetrahydro-2H-pyran-2-one | C25H22FNO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Isonipecotic acid (I) was protected with benzyl chloroformate and the resultant 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (II) was subsequently converted to the corresponding acid chloride (III) by treatment with SOCl2. Coupling of acid chloride (III) with 4-(tert-butoxycarbonylamino)piperidine (IV) afforded the piperidinyl amide (V), which was further reduced with BH3 to the piperidinylmethyl piperidine (VI). Aminopiperidine (VII), obtained by acidic cleavage of the N-Boc group of (VI), was then coupled with 4-amino-5-chloro-2-methoxybenzoic acid (VIII) to provide amide (IX). Deprotection of the N-benzyloxycarbonyl group was carried out by means of methanesulfonic acid in the presence of anisole to give (X). Acylation of piperidine (X) with the protected aminoacid (XI) yielded amide (XII). Then, selective reduction of the aliphatic amide function, followed by deprotection of the amino group provided the title compound.
| 【1】 Harada, H.; et al.; Novel N-[1-(1-substituted 4-piperidinylmethyl)-4-piperidinyl]benzamides as potent colonic prokinetic agents. Bioorg Med Chem Lett 2002, 12, 6, 967. |
| 【2】 Kato, S.; Yoshida, N.; Harada, H.; Toyotomi, Y.; Morikage, S. (Dainippon Pharmaceutical Co., Ltd.); Benzamido derivs. and medicinal compsns. containing the same. JP 1999001472 . |
| 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) | 17462 | (6S)-6-[(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl]-5,6-dihydro-2H-pyran-2-one | C25H20FNO2 | 详情 | 详情 | |
| (II) | 56082 | Z-Isonipecotic acid | 10314-98-4 | C14H17NO4 | 详情 | 详情 |
| (III) | 35165 | benzyl 4-(chlorocarbonyl)-1-piperidinecarboxylate | C14H16ClNO3 | 详情 | 详情 | |
| (IV) | 41601 | tert-butyl 4-piperidinylcarbamate; 4-tert-Boc-aminopiperidine | 73874-95-0 | C10H20N2O2 | 详情 | 详情 |
| (V) | 56548 | benzyl 4-({4-[(tert-butoxycarbonyl)amino]-1-piperidinyl}carbonyl)-1-piperidinecarboxylate | C24H35N3O5 | 详情 | 详情 | |
| (VI) | 56549 | benzyl 4-({4-[(tert-butoxycarbonyl)amino]-1-piperidinyl}methyl)-1-piperidinecarboxylate | C24H37N3O4 | 详情 | 详情 | |
| (VII) | 56550 | benzyl 4-[(4-amino-1-piperidinyl)methyl]-1-piperidinecarboxylate | C19H29N3O2 | 详情 | 详情 | |
| (VIII) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
| (IX) | 56551 | benzyl 4-({4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidinyl}methyl)-1-piperidinecarboxylate | C27H35ClN4O4 | 详情 | 详情 | |
| (X) | 56552 | 4-amino-5-chloro-2-methoxy-N-[1-(4-piperidinylmethyl)-4-piperidinyl]benzamide | C19H29ClN4O2 | 详情 | 详情 | |
| (XI) | 56553 | N-Carbobenzoxy-4-amino-n-butyric acid; N-Carbobenzoxy-gamma-aminobutyric acid | 5105-78-2 | C12H15NO4 | 详情 | 详情 |
| (XII) | 56554 | benzyl 4-[4-({4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidinyl}methyl)-1-piperidinyl]-4-oxobutylcarbamate | C31H42ClN5O5 | 详情 | 详情 |