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【结 构 式】 
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【分子编号】17460 【品名】1-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-[(2R)oxiranyl]ethyl phenyl sulfide; 2-cyclopropyl-4-(4-fluorophenyl)-3-[2-[(2R)oxiranyl]-1-(phenylsulfanyl)ethyl]quinoline 【CA登记号】 |
【 分 子 式 】C28H24FNOS 【 分 子 量 】441.5691032 【元素组成】C 76.16% H 5.48% F 4.3% N 3.17% O 3.62% S 7.26% |
合成路线1
该中间体在本合成路线中的序号：(IL)4) Lactone form: The condensation of 2(S)-(chloromethyl)oxirane (XXXIII) with trimethylsilylacetylene (XXXIV) by means of butyllithium and BF3 ethearate in THF gives 5-chloro-4(S)-hydroxy-1-(trimethylsilyl)-1-pentyne (XXXV), which is cyclized with KOH in THF to the chiral epoxide (XXXVI). The condensation of (XXXVI) with 2-cyclopropyl-4-(4-fluorophenyl)-3-(phenylsulfanylmethyl)quinoline (XXXVII, see Scheme 5) by means of butyllithium in THF affords the silylated heptynol (XXXVIII), which is desilylated with K2CO3 in methanol to the terminal acetylene (XXXIX). The carboxylation of (XXXIX) with CO by means of PdCl2/CuCl2 in methanol yields the heptynoic acid ester (XL), which is selectively reduced with H2 over the Lindlar catalyst in methanol to the cis-heptenoic ester (XLI). The cyclization of (XLI) with PPTS in refluxing toluene affords the (S)-unsaturated lactone (XLII), which is oxidized with m-chloroperbenzoic acid to the corresponding sulfinyl derivative (XLIII).
| 【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 |
|---|---|---|---|---|---|---|
| (IL) | 17460 | 1-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-[(2R)oxiranyl]ethyl phenyl sulfide; 2-cyclopropyl-4-(4-fluorophenyl)-3-[2-[(2R)oxiranyl]-1-(phenylsulfanyl)ethyl]quinoline | C28H24FNOS | 详情 | 详情 | |
| (XXXIII) | 13917 | (S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin | 67843-74-7 | C3H5ClO | 详情 | 详情 |
| (XXXIV) | 23897 | ethynyl(trimethyl)silane；trimethylsilyl acetylene | 1066-54-2 | C5H10Si | 详情 | 详情 |
| (XXXV) | 17449 | (2S)-1-chloro-5-(trimethylsilyl)-4-pentyn-2-ol | C8H15ClOSi | 详情 | 详情 | |
| (XXXVI) | 17450 | trimethyl[3-[(2S)oxiranyl]-1-propynyl]silane | C8H14OSi | 详情 | 详情 | |
| (XXXVII) | 17451 | [2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methyl phenyl sulfide; 2-cyclopropyl-4-(4-fluorophenyl)-3-[(phenylsulfanyl)methyl]quinoline | C25H20FNS | 详情 | 详情 | |
| (XXXVIII) | 17452 | (3S)-1-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-1-(phenylsulfanyl)-6-(trimethylsilyl)-5-hexyn-3-ol | C33H34FNOSSi | 详情 | 详情 | |
| (XXXIX) | 17453 | (3S)-1-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-1-(phenylsulfanyl)-5-hexyn-3-ol | C30H26FNOS | 详情 | 详情 | |
| (XL) | 17454 | methyl (5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-5-hydroxy-7-(phenylsulfanyl)-2-heptynoate | C32H28FNO3S | 详情 | 详情 | |
| (XLI) | 17455 | methyl (Z,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-5-hydroxy-7-(phenylsulfanyl)-2-heptenoate | C32H30FNO3S | 详情 | 详情 | |
| (XLII) | 17456 | (6S)-6-[2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-(phenylsulfanyl)ethyl]-5,6-dihydro-2H-pyran-2-one | C31H26FNO2S | 详情 | 详情 | |
| (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 | |
| (XLVII) | 38067 | (2R)-2-(Chloromethyl)oxirane; (R)-Epichlorohydrin | 51594-55-9 | C3H5ClO | 详情 | 详情 |
| (XLVIII) | 17459 | (2R)-1-chloro-4-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-4-(phenylsulfanyl)-2-butanol | C28H25ClFNOS | 详情 | 详情 | |
| (L) | 17461 | ethynyllithium | C2HLi | 详情 | 详情 |