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【结 构 式】 
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【分子编号】17425 【品名】2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarbaldehyde 【CA登记号】121660-37-5 |
【 分 子 式 】C19H14FNO 【 分 子 量 】291.3247032 【元素组成】C 78.33% H 4.84% F 6.52% N 4.81% O 5.49% |
合成路线1
该中间体在本合成路线中的序号：(XI)1NK-104 in its open and lactone forms has been synthesized by several different ways: 1) Lactone form: The reaction of 1(R),7,7-trimethylbicyclo[2.2.1]heptan-2-one (I) with 1-naphthylmagnesium bromide (II) gives the tertiary alcohol (III), which by reaction with SOCl2 and then with NaHCO3 yields 2-(1-naphthyl)-1(R),7,7-trimethylbicyclo[2.2.1]heptene (IV). Hydroboration of (IV) with BH3 followed by oxidation with H2O2 affords 4(S),7,7-trimethyl-3exo-(1-naphthyl)bicyclo[2.2.1]heptan-2exo-ol (V), which is submitted to transesterification with methyl acetoacetate (VI) and dimethyl-aminopyridine (DMAP) to give the corresponding ester (VII). The condensation of (VII) with N-methoxy-N-methyl-3-[2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl]-2(E)-propenamide (VIII) by means of NaH yields the corresponding chiral 3,5-dioxoheptenoic acid ester (IX), which is selectively reduced first with diisobutylaluminum hy-dride acid (DIBAL) and then with diethylmethoxyborane and sodium borohydride affording the 3(R),5(S)-dihydroxyheptenoic ester (X). Finally, this compound is saponified with NaOH and treated with acetic acid/sodium acetate. The intermediate amide (VIII) is obtained by condensation of 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde (XI) with N-methoxy-N-methylacetamide (XII) by means of butyllithium to the hydroxy propionamide (XIII), which is then dehydrated with methanesulfonyl chloride and triethylamine in the usual way).
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859. |
| 【2】 Guntor, B.; Kaiyama, T.; Arai, K.; Minami, T.; Suzuki, M.; Kobara, Y.; Sakota, R. (Nissan Chemical Industry, Ltd.; Sagami Chemical Research Center); Optically active ß,*-diketo acid esters and their reduced forms. JP 1994025092 . |
| 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) | 17415 | (1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one | 464-49-3 | C10H16O | 详情 | 详情 |
| (II) | 17416 | bromo(1-naphthyl)magnesium | C10H7BrMg | 详情 | 详情 | |
| (III) | 17417 | (1R,2S,4R)-1,7,7-trimethyl-2-(1-naphthyl)bicyclo[2.2.1]heptan-2-ol | C20H24O | 详情 | 详情 | |
| (IV) | 17418 | 1-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl]naphthalene | C20H22 | 详情 | 详情 | |
| (V) | 17419 | (1S,2R,3R,4S)-4,7,7-trimethyl-3-(1-naphthyl)bicyclo[2.2.1]heptan-2-ol | C20H24O | 详情 | 详情 | |
| (VI) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (VII) | 17421 | (1S,2R,3R,4S)-4,7,7-trimethyl-3-(1-naphthyl)bicyclo[2.2.1]hept-2-yl 3-oxobutanoate | C24H28O3 | 详情 | 详情 | |
| (VIII) | 17422 | (E)-3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-N-methoxy-N-methyl-2-propenamide | C23H21FN2O2 | 详情 | 详情 | |
| (IX) | 17423 | (1S,2R,3R,4S)-4,7,7-trimethyl-3-(1-naphthyl)bicyclo[2.2.1]hept-2-yl (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dioxo-6-heptenoate | C45H42FNO4 | 详情 | 详情 | |
| (X) | 17424 | (1S,2R,3R,4S)-4,7,7-trimethyl-3-(1-naphthyl)bicyclo[2.2.1]hept-2-yl (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoate | C45H46FNO4 | 详情 | 详情 | |
| (XI) | 17425 | 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarbaldehyde | 121660-37-5 | C19H14FNO | 详情 | 详情 |
| (XII) | 17426 | N-methoxy-N-methylacetamide | 78191-00-1 | C4H9NO2 | 详情 | 详情 |
| (XIII) | 17427 | 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3-hydroxy-N-methoxy-N-methylpropanamide | C23H23FN2O3 | 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：(II)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3
该中间体在本合成路线中的序号：(V)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 |