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【结 构 式】 
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【分子编号】17472 【品名】[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methanol 【CA登记号】 |
【 分 子 式 】C19H16FNO 【 分 子 量 】293.3405832 【元素组成】C 77.8% H 5.5% F 6.48% N 4.77% O 5.45% |
合成路线1
该中间体在本合成路线中的序号：(LIX)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 |
合成路线2
该中间体在本合成路线中的序号：(LIX)8) Open form: The silylation of (S,S)-tartaric acid diisopropyl ester (LXI) with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole in DMF gives the bissilylated compound (LXII), which is condensed with the disodium salt of tert-butyl acetoacetate (LXIII) in THF, yielding (S,S)-7-(tert-butoxycarbonyl)-2,3-bis (tert-butyldimethylsilyloxy)-4,6-dioxoheptanoic acid isopropyl ester (LXIV). The selective reduction of (LXIV) with DIBAL in THF affords the monohydroxylated compound (LXV), which is further reduced with diethylmethoxyborane in THF to the dihydroxylated compound (LXVI). The protection of the OH groups of (LXVI) with 2,2-dimethoxypropane and p-toluenesulfonic acid gives the 1,3-dioxane derivative (LXVII), which is desilylated with TBAF in THF to the gem-diol (LXVIII). Oxidation of the diol (LXVIII) with sodium metaperiodate in water/ethyl ether affords the aldehyde (LXIX), which is then condensed with 2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-ylmethyl(diphenyl)phosphine oxide (LXX) by means of lithium 2,2,6,6-tetramethylpiperidine (TMPip-Li) or butyllithium in THF, giving the protected tert-butyl ester (XXII). Finally, this compound is deprotected and hydrolyzed with trifluoroacetic acid in dichloromethane. 9) The phosphine oxide (LXX) has been obtained as follows: 2-Cyclopropyl-4-(4-fluorophenyl)-3-(hydroxy-methyl)quinoline (LIX, Scheme 5) was treated with PBr3, yielding the corresponding bromomethyl derivative (LXXI), which was then treated with diphenyl(ethoxy)phosphorane in refluxing toluene.
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859. |
| 【2】 Hiyama, T.; Takahashi, K.; Minami, T.; Synthesis of artificial HMG-CoA reductase inhibitors based on the olefination strategy. Bull Chem Soc Jpn 1995, 68, 1, 364-72. |
| 【3】 Yanagawa, E.; Minami, T.; Obara, Y.; Kaiyama, T. (Nissan Chemical Industry, Ltd.; Sagami Chemical Research Center); Condensed pyridines mevalonolactone intermediates and their preparation method. JP 1993310700 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (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 | |
| (LIX) | 17472 | [2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methanol | C19H16FNO | 详情 | 详情 | |
| (LXI) | 17474 | diisopropyl (2S,3S)-2,3-dihydroxybutanedioate | C10H18O6 | 详情 | 详情 | |
| (LXII) | 17475 | diisopropyl (2S,3S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxybutanedioate | C16H32O6Si | 详情 | 详情 | |
| (LXIII) | 17476 | disodium (1E)-1-(tert-butoxy)-1,3-butadiene-1,3-diolate | C8H12Na2O3 | 详情 | 详情 | |
| (LXIV) | 17477 | 8-(tert-butyl) 1-isopropyl (2S,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-hydroxy-4,6-dioxooctanedioate | C21H38O8Si | 详情 | 详情 | |
| (LXV) | 17478 | 8-(tert-butyl) 1-isopropyl (2S,3S,6R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dihydroxy-4-oxooctanedioate | C21H40O8Si | 详情 | 详情 | |
| (LXVI) | 17479 | 8-(tert-butyl) 1-isopropyl (2S,3R,4S,6R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4,6-trihydroxyoctanedioate | C21H42O8Si | 详情 | 详情 | |
| (LXVII) | 17480 | isopropyl (2S,3S)-3-[(4S,6R)-6-[2-(tert-butoxy)-2-oxoethyl]-2,2-dimethyl-1,3-dioxan-4-yl]-3-[[tert-butyl(dimethyl)silyl]oxy]-2-hydroxypropanoate | C24H46O8Si | 详情 | 详情 | |
| (LXVIII) | 17481 | isopropyl (2S,3S)-3-[(4S,6R)-6-[2-(tert-butoxy)-2-oxoethyl]-2,2-dimethyl-1,3-dioxan-4-yl]-2,3-dihydroxypropanoate | C18H32O8 | 详情 | 详情 | |
| (LXIX) | 17482 | tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate | C13H22O5 | 详情 | 详情 | |
| (LXX) | 17483 | [2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methyl(diphenyl)phosphine oxide; 2-cyclopropyl-3-[(diphenylphosphoryl)methyl]-4-(4-fluorophenyl)quinoline | C31H25FNOP | 详情 | 详情 | |
| (LXXI) | 17484 | 3-(bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)quinoline | C19H15BrFN | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)A systematic chiral synthesis of NK-104 and its enantiomer (X) has been reported: The oxidation of the already known 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-methanol (I) with DMSO, P2O5 and triethylamine gives the corresponding aldehyde (II), which is condensed with diethyl cyanomethylphosphonate by means of NaOH in toluene yielding the propenenitrile (III). The reduction of (III) with DIBAL affords the unsaturated aldehyde (IV), which is condensed with ethyl acetoacetate by means of NaH and n-BuLi to provide the 3-oxo-5-hydroxy-6-heptenoic acid ethyl ester derivative (V). The highly syn stereoselective reduction of (V) by means of diethylmethoxyborane and NaBH4 yields the desired syn racemic mixture of erythro-beta,delta-dihydroxyesters (VII), which is submitted to optical resolution with chiral (+)-alpha-methylbenzylamine [(+)-MBA] to obtain NK-104 free acid (VIII), which is finally treated with NaOH and CaCl2. The enantiomer of NK-104 has been obtained by optical resolution of the racemic mixture (VII) with (-)-alpha-methylbenzylamine to obtain the enantiomeric free acid (IX), which is treated with NaOH and CaCl2 as before.
| 【1】 Yanagihara, K.; Iwasaki, H.; Yanagawa, Y.; Yazaki, Y.; Suzuki, M.; Kanda, H.; Matsumoto, H.; Ohara, Y.; Sakoda, R.; First systematic chiral syntheses of two pairs of enantiomers with 3,5-dihydroxyheptenoic acid chain, associated with a potent synthetic statin NK-104. Bioorg Med Chem Lett 1999, 9, 20, 2977. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10045 | Diethyl cyanomethylphosphonate | 2537-48-6 | C6H12NO3P | 详情 | 详情 | |
| (IX),(X) | 39670 | (3S,5R,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid | C25H24FNO4 | 详情 | 详情 | |
| (I) | 17472 | [2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methanol | C19H16FNO | 详情 | 详情 | |
| (II) | 17425 | 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarbaldehyde | 121660-37-5 | C19H14FNO | 详情 | 详情 |
| (III) | 39665 | (E)-3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-propenenitrile | C21H15FN2 | 详情 | 详情 | |
| (IV) | 39666 | (E)-3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-propenal | C21H16FNO | 详情 | 详情 | |
| (V) | 39667 | ethyl (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-5-hydroxy-3-oxo-6-heptenoate | C27H26FNO4 | 详情 | 详情 | |
| (VI) | 39668 | ethyl (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoate | C27H28FNO4 | 详情 | 详情 | |
| (VII) | 39669 | (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid | C25H24FNO4 | 详情 | 详情 | |
| (VIII) | 39671 | (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid | C25H24FNO4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)A synthesis of pitavastatin has been reported: Cyclization of 2-amino-4'-fluorobenzophenone (I) with 3-cyclopropyl-3-oxopropionic acid methyl ester (II) by means of H2SO4 in refluxing acetic acid or methanesulfonic acid in refluxing benzene gives 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxylic acid methyl ester (III), which is reduced with DIBAL in toluene to yield the carbinol (IV). Oxidation of compound (IV) with PCC and AcONa in dichloromethane affords carbaldehyde (V), which is condensed with tributylstannane (VI) by means of BuLi in THF to provide the enol ether (VII). Hydrolysis of (VII) by means of TsOH in THF/water gives the unsaturated carbaldehyde (VIII), which is condensed with acetoacetic ester (IX) by means of NaH and BuLi in THF to yield the 5-hydroxy-3-oxoheptenoic ester derivative (X). Stereoselective reduction of the oxo group of (X) by means of diethylmethoxyborane and NaBH4 in THF/methanol gives the racemic syn-dihydroxy compound (XI) in a syn/anti ratio of 98:2. Finally, compound (XI) is hydrolyzed with NaOH in aqueous ethanol to yield racemic pitavastatin sodium. Alternatively, the unsaturated carbaldehyde (VIII) can also be obtained by reaction of carbaldehyde (V) with phosphonate (XII) by means of NaOH in toluene/water to give the unsaturated nitrile (XIII), which is finally reduced with DIBAL in toluene to afford the target carbaldehyde (VIII).
| 【1】 Fujikawa, Y.; Suzuki, M.; Iwasaki, H.; Kitahara, M.; Sakashita, M.; Sakoda, R.; Synthesis and biological evaluations of quinolone-based HMG-CoA reductase inhibitors. Bioorg Med Chem 2001, 9, 10, 2727. |
| 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) | 17467 | (2-aminophenyl)(4-fluorophenyl)methanone | C13H10FNO | 详情 | 详情 | |
| (II) | 51482 | Methyl 3-cyclopropyl-3-oxopropanoate | 32249-35-7 | C7H10O3 | 详情 | 详情 |
| (III) | 51483 | methyl 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarboxylate | C20H16FNO2 | 详情 | 详情 | |
| (IV) | 17472 | [2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methanol | C19H16FNO | 详情 | 详情 | |
| (V) | 17425 | 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarbaldehyde | 121660-37-5 | C19H14FNO | 详情 | 详情 |
| (VI) | 51484 | ethyl (E)-2-(tributylstannyl)ethenyl ether; tributyl[(E)-2-ethoxyethenyl]stannane | C16H34OSn | 详情 | 详情 | |
| (VII) | 51485 | (E)-1-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3-ethoxy-2-propen-1-ol | C23H22FNO2 | 详情 | 详情 | |
| (VIII) | 39666 | (E)-3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-propenal | C21H16FNO | 详情 | 详情 | |
| (IX) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (X) | 39667 | ethyl (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-5-hydroxy-3-oxo-6-heptenoate | C27H26FNO4 | 详情 | 详情 | |
| (XI) | 51486 | ethyl (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoate | C27H28FNO4 | 详情 | 详情 | |
| (XII) | 10045 | Diethyl cyanomethylphosphonate | 2537-48-6 | C6H12NO3P | 详情 | 详情 |
| (XIII) | 39665 | (E)-3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-propenenitrile | C21H15FN2 | 详情 | 详情 |