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【结 构 式】 
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【分子编号】27909 【品名】tert-butyl (3R,5S,6E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoate 【CA登记号】 |
【 分 子 式 】C28H34FNO4 【 分 子 量 】467.5807032 【元素组成】C 71.93% H 7.33% F 4.06% N 3% O 13.69% |
合成路线1
该中间体在本合成路线中的序号：(XI)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2
该中间体在本合成路线中的序号：(X)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 |