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【结 构 式】 
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【分子编号】17466 【品名】Fluorobenzene 【CA登记号】462-06-6 |
【 分 子 式 】C6H5F 【 分 子 量 】96.1041032 【元素组成】C 74.99% H 5.24% F 19.77% |
合成路线1
该中间体在本合成路线中的序号：(A)The reaction of 2-thiophenecarbonyl chloride (I) with fluorobenzene (A) by means of AlCl3 gives (4-fluorophenyl)(2-thienyl)ketone (II), which is then condensed with diethyl methylmalonate (B) by means of NaH in benzene-HMPA to yield diethyl 2-methyl-2-[4-(2-thienylcarbonyl)phenyl]malonate (III); this product is finally hydrolyzed and partially decarboxylated with refluxing aqueous NaOH.
| 【1】 Van Daele, P.G.H.; et al.; Synthesis of alpha-methyl-4-(2-thienylcarbonyl)benzene acetic acid, suprofen and derivatives. Arzneim-Forsch Drug Res 1975, 25, 10, 1495-1501. |
| 【2】 Castaner, J.; Chatterjee, S.S.; Suprofen. Drugs Fut 1976, 1, 3, 148. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 17466 | Fluorobenzene | 462-06-6 | C6H5F | 详情 | 详情 |
| (B) | 30310 | diethyl 2-methylmalonate | 609-08-5 | C8H14O4 | 详情 | 详情 |
| (I) | 14103 | 2-Thiophenecarbonyl chloride | 5271-67-0 | C5H3ClOS | 详情 | 详情 |
| (II) | 34018 | (4-fluorophenyl)(2-thienyl)methanone | 579-49-7 | C11H7FOS | 详情 | 详情 |
| (III) | 34019 | diethyl 2-methyl-2-[4-(2-thienylcarbonyl)phenyl]malonate | C19H20O5S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)2) The reaction of fluorobenzene (VI) with N-acetylsulfanilyl chloride (VII) in the presence of anhydrous aluminum chloride gives the desired acetamide in one step.
| 【1】 Durr, F.E.; Lang, S.A. Jr.; Shang Wang, B.; Ruszala-Mallon, V.; Lin, Y.-i.; Fields, T.L.; CL-259,763. Drugs Fut 1987, 12, 5, 431. |
合成路线3
该中间体在本合成路线中的序号：(I)A synthesis of [14C]-labeled fluvastatin has been described: The acylation of fluorobenzene (I) with [14C]-bromoacetyl chloride (II) by means of AlCl3 gives the expected phenacyl bromide (III), which is condensed with N-isopropylaniline (IV) in hot ethanol yielding the tertiary amine (V). The cyclization of (V) by means of anhydrous ZnCl2 in refluxing ethanol affords the indole (VI), which is alkylated with 3-(N-methyl-N-phenylamino)acroleine (VII) by means of POCl3 in refluxing acetonitrile giving 3-[3-(4-fluorophenyl)-1-isopropylindol-2-yl]acroleine (VIII). The reductocondensation of (VIII) with tert-butyl acetoacetate (IX) by means of NaH and BuLi in THF yields 7-[3-(4-fluorophenyl)-1-isopropylindol-2-yl)-5-hydroxy-3-oxo-6-heptenoic acid tert-butyl ester (X), which is further reduced with NaBH4 and diethyl(methoxy)borane in THF to the dihydroxy compound (XI) as a mixture of the two syn-enantiomers (XI). Finally, this compound is hydrolyzed with NaOH in methanol to the expected sodium salt.
| 【1】 Jones, L.; Tang, Y.S.; Sunay, U.B.; Synthesis of carbon-14 labeled fluvastatin (Lescol(R)). J Label Compd Radiopharm 1998, 41, 1, 1. |
| 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) | 17466 | Fluorobenzene | 462-06-6 | C6H5F | 详情 | 详情 |
| (II) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
| (II) | 45080 | 2-bromoacetyl chloride | C2H2BrClO | 详情 | 详情 | |
| (III) | 27904 | 2-bromo-1-(4-fluorophenyl)-1-ethanone | 403-29-2 | C8H6BrFO | 详情 | 详情 |
| (III) | 45081 | 2-bromo-1-(4-fluorophenyl)-1-ethanone | C8H6BrFO | 详情 | 详情 | |
| (IV) | 27905 | N-isopropyl-N-phenylamine | 768-52-5 | C9H13N | 详情 | 详情 |
| (V) | 11787 | 1-(4-Fluorophenyl)-2-(isopropylanilino)-1-ethanone | C17H18FNO | 详情 | 详情 | |
| (V) | 45082 | 1-(4-fluorophenyl)-2-(isopropylanilino)-1-ethanone | C17H18FNO | 详情 | 详情 | |
| (VI) | 11788 | 3-(4-Fluorophenyl)-1-isopropyl-1H-indole | 93957-49-4 | C17H16FN | 详情 | 详情 |
| (VI) | 45083 | 3-(4-fluorophenyl)-1-isopropyl-1H-indole | C17H16FN | 详情 | 详情 | |
| (VII) | 27906 | (E)-3-(methylanilino)-2-propenal | C10H11NO | 详情 | 详情 | |
| (VIII) | 11790 | (E)-3-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-2-propenal | C20H18FNO | 详情 | 详情 | |
| (VIII) | 45084 | (E)-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-2-propenal | C20H18FNO | 详情 | 详情 | |
| (IX) | 27907 | Acetoacetic acid tert-butyl ester;3-Oxo-butanoic acid 1,1-dimethylethyl estertert-butyl 3-oxobutanoate | 1694-31-1 | C8H14O3 | 详情 | 详情 |
| (X) | 27908 | tert-butyl (E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo-6-heptenoate | C28H32FNO4 | 详情 | 详情 | |
| (X) | 45085 | tert-butyl (E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo-6-heptenoate | C28H32FNO4 | 详情 | 详情 | |
| (XI) | 27909 | tert-butyl (3R,5S,6E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoate | C28H34FNO4 | 详情 | 详情 | |
| (XI) | 45086 | tert-butyl (3R,5S,6E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoate | C28H34FNO4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The Friedel-Crafts condensation of fluorobenzene (I) with chloroacetyl chloride (II) by means of AlCl3 gives the phenacyl chloride (III), which is cyclized with N-isopropylaniline (IV) by means of ZnCl2 to yield 3-(4-fluorophenyl)-1-isopropyl-1H-indole (V). The condensation of (V) with 3-(N-methyl-N-phenylamino)acrolein (VI) by means of POCl3 in acetonitrile affords 3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]acrolein (VII), which is further condensed with tert-butyl acetoacetate (VIII) by means of BuLi and NaH in THF to provide 7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo-6(E)-heptenoic acid tert-butyl ester (IX). The reduction of the ketonic group of (IX) with NaBH4 catalyzed by Et2B-OMe as chelating agent gives the diol (X) with a syn configuration. Finally, the tert-butyl ester group of (X) is hydrolyzed with NaOH in ethanol/water to afford the target fluvastatin sodium.
| 【1】 Repic, O.; et al.; The story of Lescol: From research to production. Org Process Res Dev 2001, 5, 5, 519. |
| 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) | 17466 | Fluorobenzene | 462-06-6 | C6H5F | 详情 | 详情 |
| (II) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (III) | 11786 | 2-Chloro-1-(4-fluorophenyl)-1-ethanone; 2-Chloro-4'-fluoroacetophenone | 456-04-2 | C8H6ClFO | 详情 | 详情 |
| (IV) | 27905 | N-isopropyl-N-phenylamine | 768-52-5 | C9H13N | 详情 | 详情 |
| (V) | 11788 | 3-(4-Fluorophenyl)-1-isopropyl-1H-indole | 93957-49-4 | C17H16FN | 详情 | 详情 |
| (VI) | 27906 | (E)-3-(methylanilino)-2-propenal | C10H11NO | 详情 | 详情 | |
| (VII) | 11790 | (E)-3-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-2-propenal | C20H18FNO | 详情 | 详情 | |
| (VIII) | 27907 | Acetoacetic acid tert-butyl ester;3-Oxo-butanoic acid 1,1-dimethylethyl estertert-butyl 3-oxobutanoate | 1694-31-1 | C8H14O3 | 详情 | 详情 |
| (IX) | 27908 | tert-butyl (E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo-6-heptenoate | C28H32FNO4 | 详情 | 详情 | |
| (X) | 27909 | tert-butyl (3R,5S,6E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoate | C28H34FNO4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(LIII)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6
该中间体在本合成路线中的序号：(III)The reaction of 3-bromo-5-iodobenzoic acid (I) with SOCl2 gives the corresponding acyl chloride (II), which by a Friedel-Crafts condensation with fluorobenzene (II) by means of AlCl3 in refluxing dichloromethane yields the benzophenone (IV). The condensation of (IV) with ethyl acrylate (V) by means of palladium acetate and triethylamine in refluxing acetonitrile affords the cinnamic acid derivative (VI), which is condensed with N-vinylphthalimide (VII) by means of palladium acetate and diisopropylamine in refluxing xylene to provide the unsaturated adduct (VIII). The reduction of the carbonyl group of (VIII) with triethylsilane and TFA gives the diphenylmethane derivative (IX), which is hydrogenated with H2 over Pd/C in ethyl acetate to yield the saturated diphenylmethane derivative (X). Elimination of the phthalimido group of (X) with hydrazine affords (XI) with a primary amino group. that is sulfonated with 4-chlorophenylsulfonyl chloride (XII) and triethylamine in THF to provide the sulfonamide (XIII). Finally, the ester group of (XIII) is hydrolyzed with aqueous NaOH.
| 【1】 Waite, D.C.; Mason, C.P.; A scalable synthesis of the thromboxane receptor antagonist 3-(3-[2-(4-chlorobenzenesulfonamido)ethyl]-5-(4-fluorobenzyl)phenyl]propionic acid via a regioselective heck cross-coupling strategy. Org Process Res Dev 1998, 2, 2, 116. |
| 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) | 32745 | 3-bromo-5-iodobenzoic acid | 188815-32-9 | C7H4BrIO2 | 详情 | 详情 |
| (II) | 32746 | 3-bromo-5-iodobenzoyl chloride | C7H3BrClIO | 详情 | 详情 | |
| (III) | 17466 | Fluorobenzene | 462-06-6 | C6H5F | 详情 | 详情 |
| (IV) | 32747 | (3-bromo-5-iodophenyl)(4-fluorophenyl)methanone | C13H7BrFIO | 详情 | 详情 | |
| (V) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (VI) | 32748 | ethyl (E)-3-[3-bromo-5-(4-fluorobenzoyl)phenyl]-2-propenoate | C18H14BrFO3 | 详情 | 详情 | |
| (VII) | 32749 | 2-vinyl-1H-isoindole-1,3(2H)-dione | 3485-84-5 | C10H7NO2 | 详情 | 详情 |
| (VIII) | 32750 | ethyl (E)-3-[3-[(E)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethenyl]-5-(4-fluorobenzoyl)phenyl]-2-propenoate | C28H20FNO5 | 详情 | 详情 | |
| (IX) | 32751 | ethyl (E)-3-[3-[(E)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethenyl]-5-(4-fluorobenzyl)phenyl]-2-propenoate | C28H22FNO4 | 详情 | 详情 | |
| (X) | 32752 | ethyl 3-[3-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(4-fluorobenzyl)phenyl]propanoate | C28H26FNO4 | 详情 | 详情 | |
| (XI) | 27001 | ethyl 3-[3-(2-aminoethyl)-5-(4-fluorobenzyl)phenyl]propanoate | C20H24FNO2 | 详情 | 详情 | |
| (XII) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (XIII) | 27002 | ethyl 3-[3-(2-[[(4-chlorophenyl)sulfonyl]amino]ethyl)-5-(4-fluorobenzyl)phenyl]propanoate | C26H27ClFNO4S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)The Friedel Krafts reaction of fluorobenzene (I) and 3-nitro-4-chlorobenzoyl chloride (II) by means of AlCl3 gives 3-nitro-4-chloro-4’-fluorobenzophenone (III), which by reaction with NH3 in ethylenglycol at 130 C yields 3-nitro-4-amino-4’-fluorobenzophenone (IV). The reduction of (IV) with H2 over Pd/C in methanol affords 3,4-diamino-4’-fluorobenzophenone (V), which is finally cyclized with S-methylthiourea (VI) and methyl chloroformate by means of NaOH in water
| 【1】 Tan, K.; Duquette, M.; Liu, J.H.; Dong, Y.; Zhang, R.; Joachimiak, A.; Lawler, J.; Wang, J.H.; Crystal structure of the TSP-1 type 1 repeats: A novel layered fold and its biological implication. Arzneim-Forsch Drug Res 1978, 28, 4, 586. |
| 【2】 Van Gelder, J.L.H.; et al. (Janssen Pharmaceutica NV); BE 752089; DE 2029637; FR 2052988; GB 1307306; US 3657267; ZA 7004191 . |
| 【3】 Castaner, J.; Bogan, J.A.; Flubendazole.. Drugs Fut 1978, 3, 10, 739. |
| 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) | 17466 | Fluorobenzene | 462-06-6 | C6H5F | 详情 | 详情 |
| (II) | 14486 | 4-Chloro-3-nitrobenzoylchloride; 4-chloro-3-nitrobenzoyl chloride | 38818-50-7 | C7H3Cl2NO3 | 详情 | 详情 |
| (III) | 60714 | (4-chloro-3-nitrophenyl)(4-fluorophenyl)methanone | C13H7ClFNO3 | 详情 | 详情 | |
| (IV) | 60715 | (4-amino-3-nitrophenyl)(4-fluorophenyl)methanone | C13H9FN2O3 | 详情 | 详情 | |
| (V) | 60716 | (3,4-diaminophenyl)(4-fluorophenyl)methanone | C13H11FN2O | 详情 | 详情 | |
| (VI) | 10272 | [[Amino(imino)methyl]sulfanyl]methane | 2986-19-8 | C2H6N2S | 详情 | 详情 |