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【结 构 式】 
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【分子编号】11800 【品名】1,3,5-Cyclohexanetriol; cis,cis-1,3,5-Cyclohexanetriol dihydrate 【CA登记号】50409-12-6 |
【 分 子 式 】C6H12O3 【 分 子 量 】132.15948 【元素组成】C 54.53% H 9.15% O 36.32% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of cyclohexane-1,3,5-triol (I) with trimethyl orthobenzoate (II) by means of BF3/Et2O gives the cyclic orthoester (III), which is partially reduced with borane in THF to yield the alcohol (IV). Oxidation with Dess-Martin periodinane affords cyclohexanone (V), which is enantioselectively deprotonated with the chiral lithium (S,S')-alpha,alpha'-dimethyldibenzylamide (VI) in the presence of Tms-Cl in THF to provide the chiral silylated enol ether (VII). Ozonolysis of the double bond of (VII) gives the 6-oxohexanoic acid (VIII), which is reduced with NaBH4 to the corresponding hydroxyacid (IX). The methylation of (IX) with methyl iodide and K2CO3 yields the hydroxyester (X), which is oxidized with oxalyl chloride in DMSO to afford the oxoester (XI). The Wittig condensation of (XI) with decyltriphenylphosphonium bromide (XII) by means of BuLi in THF provides the unsaturated hexadecenoic ester (XIII), which is finally reduced, deprotected and cyclized by treatment with H2 over Pd/C in acetic acid to furnish the target (4S,6S)-4-hydroxy-6-undecyltetrahydrofuran-2-one (XIV). The conversion of (XIV) into tetrahydrolipstatin has already been described in scheme 11082304a.
| 【1】 Ono, S.; Endo, K.; Honda, T.; Construction of an enatiomerically pure 6-substituted 3,5-syn-dihydroxyhexanoic acid system by an enatioselective deprotonation strategy: Formal synthesis of an antiobesity agent, (-)-tetrahydrolipstatin. Chem Pharm Bull 2000, 48, 10, 1545. |
| 【2】 Ghosh, A.K.; Liu, C.; A stereoselective synthesis of (-)-tetrahydrolipstatin. Chem Commun (London) 1999, 1743. |
| 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) | 11800 | 1,3,5-Cyclohexanetriol; cis,cis-1,3,5-Cyclohexanetriol dihydrate | 50409-12-6 | C6H12O3 | 详情 | 详情 |
| (II) | 38531 | dimethoxy(phenyl)methyl methyl ether; 1-(trimethoxymethyl)benzene | 707-07-3 | C10H14O3 | 详情 | 详情 |
| (III) | 49608 | 3-phenyl-2,4,10-trioxatricyclo[3.3.1.1(3,7)]decane | C13H14O3 | 详情 | 详情 | |
| (IV) | 49609 | (1R,5S)-3-phenyl-2,4-dioxabicyclo[3.3.1]nonan-7-ol | C13H16O3 | 详情 | 详情 | |
| (V) | 49610 | (1R,5S)-3-phenyl-2,4-dioxabicyclo[3.3.1]nonan-7-one | C13H14O3 | 详情 | 详情 | |
| (VI) | 49611 | C16H18LiN | 详情 | 详情 | ||
| (VII) | 49612 | trimethyl[[(1S,3S,5R)-3-phenyl-2,4-dioxabicyclo[3.3.1]non-6-en-7-yl]oxy]silane; (1S,3S,5R)-3-phenyl-2,4-dioxabicyclo[3.3.1]non-6-en-7-yl trimethylsilyl ether | C16H22O3Si | 详情 | 详情 | |
| (VIII) | 49613 | 2-[(2S,4S,6R)-6-formyl-2-phenyl-1,3-dioxan-4-yl]acetic acid | C13H14O5 | 详情 | 详情 | |
| (IX) | 49614 | 2-[(2S,4S,6R)-6-(hydroxymethyl)-2-phenyl-1,3-dioxan-4-yl]acetic acid | C13H16O5 | 详情 | 详情 | |
| (X) | 49615 | methyl 2-[(2S,4S,6R)-6-(hydroxymethyl)-2-phenyl-1,3-dioxan-4-yl]acetate | C14H18O5 | 详情 | 详情 | |
| (XI) | 49616 | methyl 2-[(2S,4S,6R)-6-formyl-2-phenyl-1,3-dioxan-4-yl]acetate | C14H16O5 | 详情 | 详情 | |
| (XII) | 49618 | n-Decyl triphenylphosphonium bromide | 32339-43-8 | C28H36BrP | 详情 | 详情 |
| (XIII) | 49617 | methyl 2-[(2S,4S,6R)-2-phenyl-6-[(E)-1-undecenyl]-1,3-dioxan-4-yl]acetate | C24H36O4 | 详情 | 详情 | |
| (XIV) | 49598 | (4S,6S)-4-hydroxy-6-undecyltetrahydro-2H-pyran-2-one | C16H30O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)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3
该中间体在本合成路线中的序号：(I)The reaction of cis,cis-cyclohexane-1,3,5-triol (I) with Ac2O and pyridine gives the triacetate (II), which is monodeacylated by means of porcine liver esterase at pH 7 to yield the diacetate (III). The silylation of the OH group of (III) with Tbdms-Cl , TEA and DMAP in dichloromethane affords the silyl ether (IV), which is submitted to desymmetrization by enzymatic hydrolysis with porcine liver esterase to provide the chiral cyclohexanol derivative (V). The oxidation of (V) by means of PCC in dichloromethane gives the chiral cyclohexanone (VI), which is finally treated with DBU in dichloromethane to yield the intermediate 5(S)-(Tbdms-O)-2-cyclohexenone (VII).
| 【1】 Kalkote, U.R.; et al.; Simple, efficient chemoenzymatic synthesis of (S)-5-(tert-butyldimethylsilyloxy)-2-cyclohexenone and enantiomeric ketone intermediates of 19-Nor-1alpha,25-dihydroxyvitamin D3. J Org Chem 2001, 66, 24, 8277. |
| 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) | 11800 | 1,3,5-Cyclohexanetriol; cis,cis-1,3,5-Cyclohexanetriol dihydrate | 50409-12-6 | C6H12O3 | 详情 | 详情 |
| (II) | 49040 | 3,5-bis(acetoxy)cyclohexyl acetate | C12H18O6 | 详情 | 详情 | |
| (III) | 57152 | (1R,3S)-3-(acetyloxy)-5-hydroxycyclohexyl acetate | C10H16O5 | 详情 | 详情 | |
| (IV) | 57153 | (1R,3S)-3-(acetyloxy)-5-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl acetate | C16H30O5Si | 详情 | 详情 | |
| (V) | 57154 | (1S,3R,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxycyclohexyl acetate | C14H28O4Si | 详情 | 详情 | |
| (VI) | 57155 | (1R,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-oxocyclohexyl acetate | C14H26O4Si | 详情 | 详情 | |
| (VII) | 57138 | (5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclohexen-1-one | C12H22O2Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XI)The hydrogenation of 1,3,5-trihydroxybenzene (X) with H2 over Raney-Ni gives a mixture of the cis-triol (XI) and the trans-triol (XII), which is submitted to a thermal isomerization to obtain a trans-enriched mixture. The acetylation of (XI) + (XII) with acetic anhydride and pyridine affords the mixture of triacetates (XIII) + (XIV), which is submitted to a selective deacetylation by means of Lipase OF (isolated from Candida rugosa) to provide the enantiomerically pure diacetate (XV). The oxidation of (XV) with NaOCl and tempo in dichloromethane/water gives the chiral ketone (XVI), which is condensed with ethyl 2-(trimethylsilyl)acetate (XVII) by means of LDA in THF to yield the cyclohexylideneacetate (XVIII). The deacetylation of (XVIII) by means of K2CO3 in methanol/water affords the chiral dihydroxy compound (XIX), which is protected with Tbdms-Cl and imidazole to provide the bis-silyl ether (XX). The reduction of the ester group of (XX) with Red-Al in toluene furnishes the allyl alcohol (XXI), which is treated with TsCl and n-BuLi to obtain the tosylate (XXII). The reaction of (XXII) with diphenylphosphine and BuLi in THF gives the phosphinoxide (XXIII), which is condensed with the intermediate aldehyde (IX) by means of BuLi in THF to yield the silylated precursor (XXIV). Finally, this compound is desilylated by means of TBAF in THF.
| 【1】 Wirz, B.; Hilpert, H.; Novel versatile approach to an enantiopure 19-nor, des-C,D vitamin D-3 derivative. Tetrahedron 2001, 57, 4, 681. |
| 【2】 Hilpert, H.; Wirz, B. (F. Hoffmann-La Roche AG); New process for the preparation of retiferol derivs.. EP 1094060 . |
| 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) | 49038 | (Z)-10,10,10-trifluoro-5,5-dimethyl-9-[(triethylsilyl)oxy]-9-(trifluoromethyl)-7-decenal | C19H32F6O2Si | 详情 | 详情 | |
| (X) | 11799 | 1,3,5-Benzenetriol; Fluoroglucinol | 108-73-6 | C6H6O3 | 详情 | 详情 |
| (XI) | 11800 | 1,3,5-Cyclohexanetriol; cis,cis-1,3,5-Cyclohexanetriol dihydrate | 50409-12-6 | C6H12O3 | 详情 | 详情 |
| (XII) | 49039 | 1,3,5-cyclohexanetriol | C6H12O3 | 详情 | 详情 | |
| (XIII) | 49040 | 3,5-bis(acetoxy)cyclohexyl acetate | C12H18O6 | 详情 | 详情 | |
| (XIV) | 49041 | 3,5-bis(acetoxy)cyclohexyl acetate | C12H18O6 | 详情 | 详情 | |
| (XV) | 49042 | (1R,3R)-3-(acetoxy)-5-hydroxycyclohexyl acetate | C10H16O5 | 详情 | 详情 | |
| (XVI) | 49043 | (1S,3S)-3-(acetoxy)-5-oxocyclohexyl acetate | C10H14O5 | 详情 | 详情 | |
| (XVII) | 49044 | ethyl 2-(trimethylsilyl)acetate | C7H16O2Si | 详情 | 详情 | |
| (XVIII) | 49045 | ethyl 2-[(3R,5R)-3,5-bis(acetoxy)cyclohexylidene]acetate | C14H20O6 | 详情 | 详情 | |
| (XIX) | 49046 | ethyl 2-[(3R,5R)-3,5-dihydroxycyclohexylidene]acetate | C10H16O4 | 详情 | 详情 | |
| (XX) | 49047 | ethyl 2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)acetate | C22H44O4Si2 | 详情 | 详情 | |
| (XXI) | 49048 | 2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)-1-ethanol | C20H42O3Si2 | 详情 | 详情 | |
| (XXII) | 49049 | 2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)ethyl 4-methylbenzenesulfonate | C27H48O5SSi2 | 详情 | 详情 | |
| (XXIII) | 30302 | [2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)ethyl(diphenyl)phosphine oxide | C32H51O3PSi2 | 详情 | 详情 | |
| (XXIV) | 49050 | [[(2Z,9E)-11-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)-5,5-dimethyl-1,1-bis(trifluoromethyl)-2,9-undecadienyl]oxy](triethyl)silane; (2Z,9E)-11-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)-5,5-dimethyl-1,1-bis(trifluoromethyl)-2,9-undecadienyl triethylsilyl ether | C39H72F6O3Si3 | 详情 | 详情 |