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【结 构 式】 
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【分子编号】11804 【品名】allyl (3R,5S)-3,5-bis[[tert-butyl(diphenyl)silyl]oxy]-6-hydroxyhexanoate 【CA登记号】 |
【 分 子 式 】C41H52O5Si2 【 分 子 量 】681.03188 【元素组成】C 72.31% H 7.7% O 11.75% Si 8.25% |
合成路线1
该中间体在本合成路线中的序号：(XIX)The condensation of 3-(4-fluorophenyl)-2-(hydroxymethyl)-1-isopropyl-1H-indole (IX) with trimethyl phosphite by means of oxalyl chloride in toluene gives 3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-ylmethylphosphonic acid dimethyl ester (X), which is condensed with erythro-3,5-di(tert-butyldiphenylsilyloxy)-6-oxohexanoic acid allyl ester (XI) by means of butyllithium in THF yielding erythro-3,5-di(tert-butyldiphenylsilyloxy)-7-[3-(4-fluorophenyl)-1H-indol-2-yl]-6(E)-heptenoic acid allyl ester (XII). The hydrolysis of (XII) by means of triphenylphosphine and palladium tetrakis triphenylphosphine in acetic acid affords the corresponding silylated free acid (XIII), which is finally deprotected with tetrabutylammonium fluoride in THF - acetic acid, and treated with NaOH. (racemic). The allyl ester (XI) is obtained as follows: The hydrogenation of fluoroglucinol (XIV) with H2 over W4 Raney Nickel in ethanol gives, after crystallization, cis-1,3,5-trihydroxycyclohexane (XV), which is treated with tert-butyldiphenylsilyl chloride and imidazole in DMF to afford the bis-silylated compound (XVI). The oxidation of (XVI) with pyridinium chlorochromate in dichloromethane gives the protected cyclohexanone (XVII), which is oxidized again with m-chloroperbenzoic acid in dichloromethane yielding cis-4,6-bis(tert-butyldiphenylsilyloxy hexahydrooxepin-2-one (XVIII). The hydrolysis of (XVIII) with trifluoroacetic acid and refluxing allyl alcohol affords erythro-3,5-bis(tert-butyldiphenylsilyloxy)-6-hydroxyhexanoic acid allyl ester (XIX), which is finally oxidized with pyridinium chlorochromate in dichloromethane to give the desired oxo-ester (XI).
| 【1】 Kathawala, F. (Novartis AG); Analogs of mevalolactone and derivs. thereof, processes for their production, pharmaceutical compsns. containing them and their use as pharmaceuticals. JP 1991047167; US 4739073; WO 8402131 . |
| 【2】 Kapa, P.K. (Novartis AG); 6-Substituted-4-hydroxy-tetrahydropyran-2-ones. US 4571428 . |
| 【3】 Chen, K.-M.; Hardtmann, G.E.; Lee, G.T.; Linder, J.; Wattanasin, S. (Novartis AG; Novartis Deutschland GmbH); Preparation of olefinic cpds. EP 0244364 . |
| 【4】 Castaner, J.; Prous, J.; Fluvastatin Sodium. Drugs Fut 1991, 16, 9, 804. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 11794 | [3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]methanol | C18H18FNO | 详情 | 详情 | |
| (X) | 11795 | dimethyl [3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]methylphosphonate | C20H23FNO3P | 详情 | 详情 | |
| (XI) | 11796 | allyl (3R,5S)-3,5-bis[[tert-butyl(diphenyl)silyl]oxy]-6-oxohexanoate | C41H50O5Si2 | 详情 | 详情 | |
| (XII) | 11797 | allyl (3R,5S,6E)-3,5-bis[[tert-butyl(diphenyl)silyl]oxy]-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-6-heptenoate | C59H66FNO4Si2 | 详情 | 详情 | |
| (XIII) | 11798 | (3R,5S,6E)-3,5-Bis[[tert-butyl(diphenyl)silyl]oxy]-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-6-heptenoic acid | C56H62FNO4Si2 | 详情 | 详情 | |
| (XIV) | 11799 | 1,3,5-Benzenetriol; Fluoroglucinol | 108-73-6 | C6H6O3 | 详情 | 详情 |
| (XV) | 11800 | 1,3,5-Cyclohexanetriol; cis,cis-1,3,5-Cyclohexanetriol dihydrate | 50409-12-6 | C6H12O3 | 详情 | 详情 |
| (XVI) | 11801 | (3R,5S)-3,5-Bis[[tert-butyl(diphenyl)silyl]oxy]cyclohexanol | C38H48O3Si2 | 详情 | 详情 | |
| (XVII) | 11802 | (3R,5S)-3,5-Bis[[tert-butyl(diphenyl)silyl]oxy]cyclohexanone | C38H46O3Si2 | 详情 | 详情 | |
| (XVIII) | 11803 | (4R,6S)-4,6-Bis[[tert-butyl(diphenyl)silyl]oxy]-2-oxepanone | C38H46O4Si2 | 详情 | 详情 | |
| (XIX) | 11804 | allyl (3R,5S)-3,5-bis[[tert-butyl(diphenyl)silyl]oxy]-6-hydroxyhexanoate | C41H52O5Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXIX)3) The esterification of L-malic acid (XX) with methanol and acetyl chloride gives the dimethyl ester (XXI), which is reduced with borane-dimethyl sulfide in THF yielding 3(S),4-dihydroxybutyric acid methyl ester (XXII). Partial protection of (XXII) with trityl chloride in pyridine affords 3(S)-hydroxy-4-(trityloxy) butyric acid methyl ester (XXIII), which is hydrolyzed with NaOH to the corresponding free acid (XXIV). The condensation of (XXIV) with succinic acid monoallyl ester, magnesium salt (XXV) by means of the carbonyl diimidazole (DCI) in THF gives 5(S)-hydroxy-3-oxo-6-(trityloxy)hexanoic acid allyl ester (XXVI), which is reduced with triethylborane and NaBH4 in THF and treated with H2O2 at -70 C to afford 3(R),5(S)-6-(trityloxy)hexanoic acid allyl ester (XXVII). The protection of the hydroxyl groups of (XXVII) with tert-butyldiphenylsilyl chloride and imidazole in DMF gives the fully protected ester (XXVIII), which is treated with trifluoroacetic acid in dichloromethane yielding erythro-3(R),5(S)-bis(tert-butyldiphenylsilyloxy)-6-hydroxyhexanoic acid allyl ester (XXIX). The oxidation of (XXIX) with pyridinium chlorochromate in dichloromethane affords the oxo-ester (XXX), which is condensed with phosphonate (X), as in method 2 above, to give ester (XXXI). The hydrolysis of (XXXI) with triphenylphosphine and palladium tetrakis triphenylphosphine as before yields the protected acid (XXXII), which is finally deprotected with tetrabutylammonium fluoride, also as before. [3(R),5(S)-erythro-isomer].
| 【1】 Kathawala, F. (Novartis AG); Analogs of mevalolactone and derivs. thereof, processes for their production, pharmaceutical compsns. containing them and their use as pharmaceuticals. JP 1991047167; US 4739073; WO 8402131 . |
| 【2】 Chen, K.-M.; Hardtmann, G.E.; Lee, G.T.; Linder, J.; Wattanasin, S. (Novartis AG; Novartis Deutschland GmbH); Preparation of olefinic cpds. EP 0244364 . |
| 【3】 Kapa, P.K. (Novartis AG); 6-Substituted-4-hydroxy-tetrahydropyran-2-ones. US 4571428 . |
| 【4】 Castaner, J.; Prous, J.; Fluvastatin Sodium. Drugs Fut 1991, 16, 9, 804. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 11795 | dimethyl [3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]methylphosphonate | C20H23FNO3P | 详情 | 详情 | |
| (XX) | 11058 | (S)-(+)-Hydroxysuccinic acid; (S)-(+)-Malic acid; (S)-(+)-2-Hydroxybutanedioic acid; L-(-)-Apple acid | 97-67-6 | C4H6O5 | 详情 | 详情 |
| (XXI) | 11806 | dimethyl (2S)-2-hydroxybutanedioate | 617-55-0 | C6H10O5 | 详情 | 详情 |
| (XXII) | 11807 | methyl (3S)-3,4-dihydroxybutanoate | C5H10O4 | 详情 | 详情 | |
| (XXIII) | 11808 | methyl (3R)-3-hydroxy-5,5,5-triphenylpentanoate | C24H24O3 | 详情 | 详情 | |
| (XXIV) | 11809 | (3R)-3-Hydroxy-5,5,5-triphenylpentanoic acid | C23H22O3 | 详情 | 详情 | |
| (XXV) | 11810 | magnesium di[3-(allyloxy)-3-oxopropanoate] | C12H14MgO8 | 详情 | 详情 | |
| (XXVI) | 11811 | allyl (5S)-5-hydroxy-3-oxo-6-(trityloxy)hexanoate | C28H28O5 | 详情 | 详情 | |
| (XXVII) | 11812 | allyl (3R,5S)-3,5-dihydroxy-6-(trityloxy)hexanoate | C28H30O5 | 详情 | 详情 | |
| (XXVIII) | 11813 | allyl (3R,5S)-3,5-bis[[tert-butyl(diphenyl)silyl]oxy]-6-(trityloxy)hexanoate | C60H66O5Si2 | 详情 | 详情 | |
| (XXIX) | 11804 | allyl (3R,5S)-3,5-bis[[tert-butyl(diphenyl)silyl]oxy]-6-hydroxyhexanoate | C41H52O5Si2 | 详情 | 详情 | |
| (XXX) | 11815 | allyl (3R,5R)-3,5-bis[[tert-butyl(diphenyl)silyl]oxy]-6-oxohexanoate | C41H50O5Si2 | 详情 | 详情 | |
| (XXXI) | 11797 | allyl (3R,5S,6E)-3,5-bis[[tert-butyl(diphenyl)silyl]oxy]-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-6-heptenoate | C59H66FNO4Si2 | 详情 | 详情 | |
| (XXXII) | 11798 | (3R,5S,6E)-3,5-Bis[[tert-butyl(diphenyl)silyl]oxy]-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-6-heptenoic acid | C56H62FNO4Si2 | 详情 | 详情 |