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【结 构 式】 
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【药物名称】Pitavastatin calcium, Itavastatin calcium, Nisvastatin, NKS-104, NK-104, Livalo 【化学名称】(3R,5S)-7-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid calcium salt (2:1) 【CA登记号】147526-32-7, 147511-69-1 (free acid), 141750-63-2 (lactone), 192565-91-6 (monoK salt) 【 分 子 式 】C50H46CaF2N2O8 【 分 子 量 】881.00952 |
【开发单位】Nissan Chemical (Originator), Kowa (Licensee), Novartis (Licensee), Recordati (Licensee), Sankyo (Licensee) 【药理作用】Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, APOA1 Expression Enhancers, HMG-CoA Reductase Inhibitors, SPP1 (Osteopontin) Expression Inhibitors |
合成路线1
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
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3
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4
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 |
合成路线5
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6
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7
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8
10) Lactone form: The reduction of 7-phenyl-3,5-dioxo-6(E)-heptenoic acid methyl ester (LXXII) with diethylmethoxyborane and NaBH4 in THF/methanol gives the (3R*,5S*,6E)-dihydroxy ester (LXXIII), which by reaction with acetone dimethylacetal and p-toluenesulfonic acid yields the acetonide (LXXIV). The ozonolysis of (LXXIV) with O3 and dimethylsulfide in methanol affords the aldehyde (LXXV), which is condensed with 2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-ylmethylphosphonic acid diethyl ester (LXXVI) by means of butyllithium to give the acetonide of the methyl ester (LXXVII). Finally, this compound is treated with trifluoroacetic acid to yield the lactone (XLVI). The phosphonate (LXXVI) has been obtained by reaction of the bromomethyl derivative (LXXI) with triethylphosphite (8).
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859. |
| 【2】 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 |
|---|---|---|---|---|---|---|
| (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 | |
| (LXXI) | 17484 | 3-(bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)quinoline | C19H15BrFN | 详情 | 详情 | |
| (LXXII) | 17485 | methyl (E)-3,5-dioxo-7-phenyl-6-heptenoate | C14H14O4 | 详情 | 详情 | |
| (LXXIII) | 17486 | methyl (3R,5S,6E)-3,5-dihydroxy-7-phenyl-6-heptenoate | C14H18O4 | 详情 | 详情 | |
| (LXXIV) | 17487 | methyl 2-[(4R,6S)-2,2-dimethyl-6-[(E)-2-phenylethenyl]-1,3-dioxan-4-yl]acetate | C17H22O4 | 详情 | 详情 | |
| (LXXV) | 17488 | methyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate | C10H16O5 | 详情 | 详情 | |
| (LXXVI) | 17489 | diethyl [2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methylphosphonate | C23H25FNO3P | 详情 | 详情 | |
| (LXXVII) | 64695 | methyl 2-((4R,6S)-6-{(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl}-2,2-dimethyl-1,3-dioxan-4-yl)acetate | C29H30FNO4 | 详情 | 详情 |
合成路线9
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10
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 |