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【结 构 式】 
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【分子编号】17435 【品名】2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline 【CA登记号】 |
【 分 子 式 】C18H13FIN 【 分 子 量 】389.2108332 【元素组成】C 55.55% H 3.37% F 4.88% I 32.61% N 3.6% |
合成路线1
该中间体在本合成路线中的序号：(XXI)2) Lactone form: The regioselective opening of (R)-2-(tert-butyldimethylsilylethynyl)oxirane (XIV) with KCN in ethanol gives 3(S)-hydroxy-5-(tert-butyldimethylsilyl)-4-pentynenitrile (XV), which is condensed with tert-butyl bromoacetate (XVI) by means of Zn in refluxing THF to afford the 5(S)-hydroxyketoester (XVII). The controlled reduction of (XVII) with NaBH4/diethylmethoxyborane yields the 3(R),5(S)-dihydroxy ester (XVIII), which is deprotected with 2,2-dimethoxypropane and p-toluenesulfonic acid in THF/methanol to the protected heptynoic ester (XIX). The desilylation of (XIX) with tetrabutylammonium fluoride (TBAF) in THF affords the protected heptynoic ester (XX), which is condensed with 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (XXI, see Scheme 5) to give the protected NK-104 tert-butyl ester (XXII). Finally, this compound is treated with trifluoroacetic acid in dichloromethane.
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859. |
| 【2】 Minami, T.; Hiyama, T.; Takahashi, K.; Ohara, Y.; Synthesis of an artificial HMG-CoA reductase inhibitor NK-104 via a hydrosilylation-cross-coupling reaction. Bull Chem Soc Jpn 1995, 68, 5, 2649-56. |
| 【3】 Takahashi, K.; Minami, T.; Ohara, Y.; Hiyama, T.; A new synthesis of HMG-CoA reductase inhibitor NK-104 through hydrosilylation-cross coupling reaction. Tetrahedron Lett 1993, 34, 51, 8263-6. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 17428 | tert-butyl(dimethyl)[2-[(2R)oxiranyl]ethynyl]silane | C10H18OSi | 详情 | 详情 | |
| (XV) | 17429 | (3S)-5-[tert-butyl(dimethyl)silyl]-3-hydroxy-4-pentynenitrile | C11H19NOSi | 详情 | 详情 | |
| (XVI) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (XVII) | 17431 | tert-butyl (5S)-7-[tert-butyl(dimethyl)silyl]-5-hydroxy-3-oxo-6-heptynoate | C17H30O4Si | 详情 | 详情 | |
| (XVIII) | 17432 | tert-butyl (3R,5S)-7-[tert-butyl(dimethyl)silyl]-3,5-dihydroxy-6-heptynoate | C17H32O4Si | 详情 | 详情 | |
| (XIX) | 17433 | tert-butyl 2-((4R,6S)-6-[2-[tert-butyl(dimethyl)silyl]ethynyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate | C20H36O4Si | 详情 | 详情 | |
| (XX) | 17434 | tert-butyl 2-[(4R,6S)-6-ethynyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate | C14H22O4 | 详情 | 详情 | |
| (XXI) | 17435 | 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline | C18H13FIN | 详情 | 详情 | |
| (XXII) | 17436 | tert-butyl 2-((4R,6S)-6-[(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate | C32H36FNO4 | 详情 | 详情 | |
| (XLIV) | 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：(XXI)3) The condensation of 3-(trimethylsilyl)propynal (XXIII) with the dialkaline salt of ethylacetoacetate (XXIV) in THF gives 5-hydroxy-3-oxo-7-(trimethylsilyl)-6-heptynoic acid ethyl ester (XXV), which is reduced with NaBH4/diethylmethoxyborane to the racemic 3,5-dihydroxy-7-(trimethylsilyl)-6-heptynoic acid ethyl ester (XXVI). The protection and desilylation of (XXVI) with 2,2-dimethoxypropane and p-toluenesulfonic acid yields the protected heptynoic ester (XXVII), which is saponified to the corresponding acid (XXVIII) with NaOH. The optical resolution of the racemic acid (XXVIII) by treatment with 1(R)-(1-naphthyl)ethylamine (XXIX) and crystallization of the diastereomeric salts affords the protected (3R,5S)-isomer (XXX), which is esterified with ethyl iodide and DBU to the corresponding ester (XXXI). The condensation of (XXXI) with 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (XXI, see Scheme 5) by means of disiamylborane, NaOEt and PdCl2 in acetonitrile gives the protected (3R,5S)-NK-104 ethyl ester (XXXII).
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859. |
| 【2】 Iwasaki, H.; Miyachi, N.; Yanagawa, Y.; Ohara, Y.; Hiyama, T.; A novel synthetic method of HMG-CoA reductase inhibitor NK-104 via a hydroboration-cross-coupling sequence. Tetrahedron Lett 1993, 34, 51, 8267-70. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 17435 | 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline | C18H13FIN | 详情 | 详情 | |
| (XXIII) | 17437 | 2-butynal | C4H4O | 详情 | 详情 | |
| (XXIV) | 17438 | lithium sodium (1E)-1-ethoxy-1,3-butadiene-1,3-diolate | C6H8LiNaO3 | 详情 | 详情 | |
| (XXV) | 17439 | ethyl 5-hydroxy-3-oxo-7-(trimethylsilyl)-6-heptynoate | C12H20O4Si | 详情 | 详情 | |
| (XXVI) | 17440 | ethyl 3,5-dihydroxy-7-(trimethylsilyl)-6-heptynoate | C12H22O4Si | 详情 | 详情 | |
| (XXVII) | 17441 | ethyl 2-(6-ethynyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate | C12H18O4 | 详情 | 详情 | |
| (XXVIII) | 17442 | 2-(6-ethynyl-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid | C10H14O4 | 详情 | 详情 | |
| (XXIX) | 17443 | (1R)-1-(1-naphthyl)ethylamine; (1R)-1-(1-naphthyl)-1-ethanamine | 3886-70-2 | C12H13N | 详情 | 详情 |
| (XXX) | 17444 | 2-[(4R,6S)-6-ethynyl-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid | C10H14O4 | 详情 | 详情 | |
| (XXXI) | 17445 | ethyl 2-[(4R,6S)-6-ethynyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate | C12H18O4 | 详情 | 详情 | |
| (XXXII) | 17446 | ethyl 2-((4R,6S)-6-[(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate | C30H32FNO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXI)6) Synthesis of the quinoline (XXI): Anthranilic acid (LI) is tolylated with tosyl chloride and treated with PCl5 in 1,2-dichloroethane to give the corresponding acyl chloride (LII), which is submitted to a Friedel Crafts condensation with fluorobenzene (LIII)/AlCl3 yielding 2-amino-4'-fluorobenzophenone (LIV). The cyclization of (LIV) with ethyl 2-(cyclopropylcarbonyl)acetate (LV) [obtained by condensation of cyclopropyl methyl ketone (LVI) and diethyl carbonate (LVII) with H2SO4] by means of p-toluenesulfonic acid yields 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carboxylic acid ethyl ester (LVIII), which is submitted to a decarboxylative iodination with I2 and acetyl peroxide to afford 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (XXI). 7) Synthesis of the quinoline (XXXVII): The reduction of the quinolinecarboxylate (LVIII) with LiAlH4 in THF gives the corresponding methanol derivative (LIX), which is then treated with diphenyl disulfide (LX) and tri-butylphosphine in pyridine to afford 2-cyclopropyl-4-(4-fluorophenyl)-3-(phenylsulfanylmethyl)quinoline (XXXVII).
| 【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. |
| 【3】 Iwasaki, H.; Miyachi, N.; Yanagawa, Y.; Ohara, Y.; Hiyama, T.; A novel synthetic method of HMG-CoA reductase inhibitor NK-104 via a hydroboration-cross-coupling sequence. Tetrahedron Lett 1993, 34, 51, 8267-70. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 17435 | 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline | C18H13FIN | 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 | |
| (LI) | 11661 | 2-Aminobenzoic acid;Anthranilic acid; o-Aminobenzoic acid | 118-92-3 | C7H7NO2 | 详情 | 详情 |
| (LII) | 17465 | 2-aminobenzoyl chloride | C7H6ClNO | 详情 | 详情 | |
| (LIII) | 17466 | Fluorobenzene | 462-06-6 | C6H5F | 详情 | 详情 |
| (LIV) | 17467 | (2-aminophenyl)(4-fluorophenyl)methanone | C13H10FNO | 详情 | 详情 | |
| (LV) | 15949 | 3-Cyclopropyl-3-oxo-propionic acid ethyl ester; ethyl 3-cyclopropyl-3-oxopropanoate | 24922-02-9 | C8H12O3 | 详情 | 详情 |
| (LVI) | 12435 | Acetylcyclopropane; 1-Cyclopropyl-1-ethanone; Cyclopropylmethylketone | 765-43-5 | C5H8O | 详情 | 详情 |
| (LVII) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (LVIII) | 17471 | ethyl 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarboxylate | C21H18FNO2 | 详情 | 详情 | |
| (LIX) | 17472 | [2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methanol | C19H16FNO | 详情 | 详情 | |
| (LX) | 17473 | diphenyl disulfide; 1-(phenyldisulfanyl)benzene; diphenyldisulfide | 882-33-7 | C12H10S2 | 详情 | 详情 |