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【结 构 式】 
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【分子编号】30302 【品名】[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 【CA登记号】 |
【 分 子 式 】C32H51O3PSi2 【 分 子 量 】570.899902 【元素组成】C 67.32% H 9% O 8.41% P 5.43% Si 9.84% |
合成路线1
该中间体在本合成路线中的序号：(IX)The epoxidation of the chiral cyclohexenone (I) with H2O2 and NaOH in methanol gives the epoxide (II), which is condensed with triethyl phosphonoacetate (III) by means of NaH in THF to yield the cyclohexylidene acetate (IV). The regioselective opening of the epoxide ring of (V) by means of formic acid, Pd2(dba)3 and Bu3P in chloroform affords the cyclohexanol derivative (V), which is silylated by means of Tbdms-Cl and imidazole to provide the fully silylated compound (VI). The reduction of the ester group of (VI) by means of DIBAL in toluene gives the primary alcohol (VII) (1), which is treated with NCS and Me2S in dichloromethane to yield the chloride compound (VIII). The reaction of (VIII) with lithium diphenylphosphide, followed by oxidation with H2O2 affords the phosphine oxide (IX), which is condensed with the known synthon (X) by means of BuLi in THF to provide the silylated precursor (XI). Finally, this compound is desilylated by means of TBAF in THF to afford the target 1-alpha,25-dihydroxy-19-nor-vitamin D3.
| 【1】 Hanazawa, T.; et al.; Efficient and practical synthesis of the A-ring precursor of 19-nor-1alpha,25-dihydroxyvitamin D3 and its (3C- or 2H-labeled derivative. Org Lett 2001, 3, 14, 2205. |
| 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) | 57138 | (5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclohexen-1-one | C12H22O2Si | 详情 | 详情 | |
| (II) | 57139 | (1S,4S,6S)-4-{[tert-butyl(dimethyl)silyl]oxy}-7-oxabicyclo[4.1.0]heptan-2-one | C12H22O3Si | 详情 | 详情 | |
| (III) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (IV) | 57148 | ethyl 2-((1R,4R,6S)-4-{[tert-butyl(dimethyl)silyl]oxy}-7-oxabicyclo[4.1.0]hept-2-ylidene)acetate | C16H28O4Si | 详情 | 详情 | |
| (V) | 57149 | ethyl 2-((3R,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxycyclohexylidene)acetate | C16H30O4Si | 详情 | 详情 | |
| (VI) | 49047 | ethyl 2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)acetate | C22H44O4Si2 | 详情 | 详情 | |
| (VII) | 49048 | 2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)-1-ethanol | C20H42O3Si2 | 详情 | 详情 | |
| (VIII) | 57150 | tert-butyl(dimethyl)silyl (1R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-(2-chloroethylidene)cyclohexyl ether; tert-butyl{[(1R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-(2-chloroethylidene)cyclohexyl]oxy}dimethylsilane | C20H41ClO2Si2 | 详情 | 详情 | |
| (IX) | 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 | |
| (X) | 47151 | ethyl 4-[[4-(benzyloxy)-2-hydroxy-3,6-dimethylbenzoyl]oxy]-2-hydroxy-3,6-dimethylbenzoate | C27H28O7 | 详情 | 详情 | |
| (XI) | 57147 | [((1R,5R)-3-[2-((1R,7aR)-1-{(1R)-1,5-dimethyl-5-[(trimethylsilyl)oxy]hexyl}-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene]-5-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)oxy](tert-butyl)dimethylsilane; (5R)-5-{(1R,7aR)-4-[(E)-2-((3R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}cyclohexylidene)ethylidene]-7a-methyloctahydro-4H-inden-1-yl}-1,1-dimethylhexyl trimethylsilyl ether | C41H80O3Si3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Condensation of the lithium anion of alkyne (I) with hexafluoroacetone provided the tertiary alcohol (II). Subsequent deprotection of the silyl ether of (II) with tetrabutylammonium fluoride yielded alcohol (III), which was oxidized to ketone (IV) by means of pyridinium chlorochromate. Wittig condensation of (IV) with the ylide resulting from phosphine (V) and BuLi produced diene (VI). Finally, both silyl ethers of (VI) were cleaved with tetrabutylammonium fluoride to furnish the title compound.
| 【1】 Baggiolini, B.J.; Shiuey, S.-J.; Uskokovic, M.R. (F. Hoffmann-La Roche AG); Vitamin D3 fluorinated analogs. US 5451574; US 5753638 . |
| 【2】 Uskokovic, M.R.; Baggiolini, E.G.; Shiuey, S.-J. (F. Hoffmann-La Roche AG); Vitamin D3 fluorinated analogs. EP 0580968 . |
| 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) | 30298 | ([(3aS,7S,7aR)-3a-methyl-3-[(1R)-1-methyl-3-butynyl]-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl]oxy)(tert-butyl)dimethylsilane; (3aS,7S,7aR)-3a-methyl-3-[(1R)-1-methyl-3-butynyl]-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl tert-butyl(dimethyl)silyl ether | C21H36OSi | 详情 | 详情 | |
| (II) | 30299 | (6R)-6-((3aS,7S,7aR)-7-[[tert-butyl(dimethyl)silyl]oxy]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl)-1,1,1-trifluoro-2-(trifluoromethyl)-3-heptyn-2-ol | C24H36F6O2Si | 详情 | 详情 | |
| (III) | 30300 | (3aS,7S,7aR)-3a-methyl-3-[(1R)-6,6,6-trifluoro-5-hydroxy-1-methyl-5-(trifluoromethyl)-3-hexynyl]-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol | C18H22F6O2 | 详情 | 详情 | |
| (IV) | 30301 | (3aR,7aS)-7a-methyl-1-[(1R)-6,6,6-trifluoro-5-hydroxy-1,5-dimethyl-3-hexynyl]-3,3a,5,6,7,7a-hexahydro-4H-inden-4-one | C18H23F3O2 | 详情 | 详情 | |
| (V) | 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 | |
| (VI) | 30303 | (6R)-6-[(3aS,7aS)-7-[(E)-2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)ethylidene]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]-1,1,1-trifluoro-2-(trifluoromethyl)-3-heptyn-2-ol | C38H60F6O3Si2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXIII)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 |
合成路线4
该中间体在本合成路线中的序号：(XVIII)The condensation of aldehyde (XVII) with the chiral phosphinoxide (XVIII) by means of BuLi in THF gives the silylated precursor (XIX), which is finally treated with TBAF in THF.
| 【1】 Mohr, P.; Barbier, P.; Pirson, W.; Muller, M.; Bauer, F. (F. Hoffmann-La Roche AG); Cyclohexanediole derivs.. EP 1056716; WO 9943646 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 49063 | (Z)-10,10,10-trifluoro-5,5-dimethyl-9-(trifluoromethyl)-9-[(trimethylsilyl)oxy]-7-decenal | C16H26F6O2Si | 详情 | 详情 | |
| (XVIII) | 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 | |
| (XIX) | 49064 | [[(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](trimethyl)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 trimethylsilyl ether | C36H66F6O3Si3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(X)The dimethylaluminium chloride-catalyzed addition of formaldehyde to the isopropenyl derivative (I) produced the homoallylic alcohol (II). The cyclopropane ring was then constructed over (II) by the Simmons-Smith procedure using diiodomethane and diethylzinc. The resulting cyclopropylethyl alcohol (III) was oxidized to aldehyde (IV) with pyridinium chlorochromate in CH2Cl2, and subsequent addition of diethyl azomethylphosphonate generated the terminal acetylene (V). The lithium acetylide of (V) was then added to hexafluoroacetone (VI), producing the propargylic alcohol (VII). Cleavage of the silyl protecting group with fluorosilicic acid liberated the secondary alcohol (VIII), which was further oxidized to ketone (IX) employing pyridinium dichromate. Condensation of this ketone (IX) with the ylide resulting from phosphine oxide (X) and n-butyllithium at low temperature produced the silylated cholecalciferol analogue (XI). Finally, desilylation with tetrabutylammonium fluoride gave the title compound.
| 【1】 Uskokovic, M.R.; Manchand, P.S. (F. Hoffmann-La Roche AG); 1,3-Dihydroxy-20,20-dialkyl-vitamin D3 analogs. EP 1015423; WO 9912894 . |
| 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) | 44255 | (1R,3aR,4S,7aR)-1-isopropenyl-7a-methyloctahydro-1H-inden-4-yl tert-butyl(dimethyl)silyl ether; [[(1R,3aR,4S,7aR)-1-isopropenyl-7a-methyloctahydro-1H-inden-4-yl]oxy](tert-butyl)dimethylsilane | C19H36OSi | 详情 | 详情 | |
| (II) | 44256 | 3-((1R,3aR,4S,7aR)-4-[[tert-butyl(dimethyl)silyl]oxy]-7a-methyloctahydro-1H-inden-1-yl)-3-buten-1-ol | C20H38O2Si | 详情 | 详情 | |
| (III) | 44257 | 2-[1-((1R,3aR,4S,7aR)-4-[[tert-butyl(dimethyl)silyl]oxy]-7a-methyloctahydro-1H-inden-1-yl)cyclopropyl]-1-ethanol | C21H40O2Si | 详情 | 详情 | |
| (IV) | 44258 | 2-[1-((1R,3aR,4S,7aR)-4-[[tert-butyl(dimethyl)silyl]oxy]-7a-methyloctahydro-1H-inden-1-yl)cyclopropyl]acetaldehyde | C21H38O2Si | 详情 | 详情 | |
| (V) | 44259 | ([(1R,3aR,4S,7aR)-7a-methyl-1-[1-(2-propynyl)cyclopropyl]octahydro-1H-inden-4-yl]oxy)(tert-butyl)dimethylsilane; (1R,3aR,4S,7aR)-7a-methyl-1-[1-(2-propynyl)cyclopropyl]octahydro-1H-inden-4-yl tert-butyl(dimethyl)silyl ether | C22H38OSi | 详情 | 详情 | |
| (VI) | 44260 | 1,1,1,3,3,3-hexafluoroacetone | 684-16-2 | C3F6O | 详情 | 详情 |
| (VII) | 44261 | 5-[1-((1R,3aR,4S,7aR)-4-[[tert-butyl(dimethyl)silyl]oxy]-7a-methyloctahydro-1H-inden-1-yl)cyclopropyl]-1,1,1-trifluoro-2-(trifluoromethyl)-3-pentyn-2-ol | C25H38F6O2Si | 详情 | 详情 | |
| (VIII) | 44262 | (1R,3aR,4S,7aR)-7a-methyl-1-[1-[5,5,5-trifluoro-4-hydroxy-4-(trifluoromethyl)-2-pentynyl]cyclopropyl]octahydro-1H-inden-4-ol | C19H24F6O2 | 详情 | 详情 | |
| (IX) | 44263 | (1R,3aR,7aR)-7a-methyl-1-[1-[5,5,5-trifluoro-4-hydroxy-4-(trifluoromethyl)-2-pentynyl]cyclopropyl]octahydro-4H-inden-4-one | C19H22F6O2 | 详情 | 详情 | |
| (X) | 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 | |
| (XI) | 44264 | 5-(1-[(1R,3aS,7aR)-4-[(E)-2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]cyclopropyl)-1,1,1-trifluoro-2-(trifluoromethyl)-3-pentyn-2-ol | C39H62F6O3Si2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)Reduction of the triple bond of compound (I) with LiAlH4 in the presence of NaOMe furnished the E-olefin (II). The secondary alcohol group of (II) was then oxidized to the corresponding ketone (III) by means of pyridinium dichromate in the presence of pyridinium p-toluenesulfonate. Condensation of this ketone with the ylide resulting from phosphine oxide (IV) and n-BuLi produced the silylated cholecalciferol analogue (V). The silyl protecting groups of (V) were finally removed by treatment with tetrabutylammonium fluoride.
| 【1】 Doran, T.I.; Hennessy, B.M.; McLane, J.A.; Pizzolato, G.; Sedarati, F.; Uskokovic, M.R. (F. Hoffmann-La Roche AG); Vitamin D3 analogs. EP 0654467; JP 1995188159; US 5428029 . |
| 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) | 30300 | (3aS,7S,7aR)-3a-methyl-3-[(1R)-6,6,6-trifluoro-5-hydroxy-1-methyl-5-(trifluoromethyl)-3-hexynyl]-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol | C18H22F6O2 | 详情 | 详情 | |
| (II) | 44265 | (3aS,7S,7aR)-3a-methyl-3-[(1R,3E)-6,6,6-trifluoro-5-hydroxy-1-methyl-5-(trifluoromethyl)-3-hexenyl]-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol | C18H24F6O2 | 详情 | 详情 | |
| (III) | 44266 | (3aR,7aS)-7a-methyl-1-[(1R,3E)-6,6,6-trifluoro-5-hydroxy-1-methyl-5-(trifluoromethyl)-3-hexenyl]-3,3a,5,6,7,7a-hexahydro-4H-inden-4-one | C18H22F6O2 | 详情 | 详情 | |
| (IV) | 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 | |
| (V) | 44267 | (1R,5R)-3-[2-((3aS,7aS)-7a-methyl-1-[(1R,3E)-6,6,6-trifluoro-1-methyl-5-(trifluoromethyl)-5-[(trimethylsilyl)oxy]-3-hexenyl]-3,3a,5,6,7,7a-hexahydro-4H-inden-4-ylidene)ethylidene]-5-[[tert-butyl(dimethyl)silyl]oxy]cyclohexyl tert-butyl(dimethyl)sily; [((1R,5R)-3-[2-((3aS,7aS)-7a-methyl-1-[(1R,3E)-6,6,6-trifluoro-1-methyl-5-(trifluoromethyl)-5-[(trimethylsilyl)oxy]-3-hexenyl]-3,3a,5,6,7,7a-hexahydro-4H-inden-4-ylidene)ethylidene]-5-[[tert-butyl(dimethyl)silyl]oxy]cyclohexyl)oxy](tert-butyl)dimeth | C41H70F6O3Si3 | 详情 | 详情 |