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【结 构 式】 
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【分子编号】42574 【品名】[2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide 【CA登记号】 |
【 分 子 式 】C33H51O3PSi2 【 分 子 量 】582.910902 【元素组成】C 68% H 8.82% O 8.23% P 5.31% Si 9.64% |
合成路线1
该中间体在本合成路线中的序号：(XIV)Synthesis of phosphine oxide (XIV): Epoxidation of l-carvone (I) with H2O2 and LiOH in methanol gives the epoxide (II), which is reduced with L-Selectride in THF to yield the alcohol (III). Oxidation of the isopropenyl group of (III) with OsO4, KIO4, MCPBA and HOAc affords the acetate (IV), which is hydrolyzed to the diol (V) with MeONa in methanol. Protection of the two OH groups of (V) with TBDMS-Cl and imidazole provides the bis-silyl ether (VI), which is oxidized with periodic acid in ethyl ether to give the aldehyde (VII). Compound (VII) is submitted to a Wittig condensation with CBr4, PPh3 and Zn in dichloromethane to yield the dibromovinyl compound (VIII), which is converted into the acetylenic vinyl triflate (X) by treatment with LDA in THF followed by the triflic imide (IX). Cyclization of triflate (X) by means of Pd(OAc)2 and PPh3, followed by carbonylation with CO in methanol provides the methyl ester (XI) as a 2:1 mixture of the Z- and E-isomers. Photoisomerization of this mixture (XIa-b) under the Hoffman-La Roche conditions (presence of 9-fluorenone) gives the Z-isomer (XII) in a high yield. Reduction of ester (XII) with DIBAL in toluene provides the primary alcohol (XIII), which is finally converted into the phosphine oxide (XIV) by known methods.
| 【1】 Mourino, A.; et al.; Efficient and versatile synthesis of A-ring precursors of 1alpha,25-dihydroxyvitamin D3 and analogues. Application to the synthesis of Lythgoe-Roche phosphine oxide. Tetrahedron Lett 1997, 38, 26, 4713. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIa),(XII) | 52149 | methyl 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)acetate | C22H42O4Si2 | 详情 | 详情 | |
| (XIb) | 52150 | methyl 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)acetate | C22H42O4Si2 | 详情 | 详情 | |
| (I) | 13386 | (5R)-5-Isopropenyl-2-methyl-2-cyclohexen-1-one; L-(-)-Carvone | 6485-40-1 | C10H14O | 详情 | 详情 |
| (II) | 52141 | (1R,4R,6R)-4-isopropenyl-1-methyl-7-oxabicyclo[4.1.0]heptan-2-one | C10H14O2 | 详情 | 详情 | |
| (III) | 52142 | (1R,2S,4S,6R)-4-isopropenyl-1-methyl-7-oxabicyclo[4.1.0]heptan-2-ol | C10H16O2 | 详情 | 详情 | |
| (IV) | 52143 | (1R,3S,5S,6S)-5-hydroxy-6-methyl-7-oxabicyclo[4.1.0]hept-3-yl acetate | C9H14O4 | 详情 | 详情 | |
| (V) | 52144 | (1S,2S,4S,6R)-1-methyl-7-oxabicyclo[4.1.0]heptane-2,4-diol | C7H12O3 | 详情 | 详情 | |
| (VI) | 52145 | tert-butyl[((1R,2S,4R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-7-oxabicyclo[4.1.0]hept-2-yl)oxy]dimethylsilane; tert-butyl(dimethyl)silyl (1R,2S,4R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-7-oxabicyclo[4.1.0]hept-2-yl ether | C19H40O3Si2 | 详情 | 详情 | |
| (VII) | 52146 | (3S,5S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-6-oxoheptanal | C19H40O4Si2 | 详情 | 详情 | |
| (VIII) | 52147 | (3S,5R)-8,8-dibromo-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-7-octen-2-one | C20H40Br2O3Si2 | 详情 | 详情 | |
| (IX) | 34685 | N-(5-chloro-2-pyridinyl)(trifluoro)-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 145100-51-2 | C7H3ClF6N2O4S2 | 详情 | 详情 |
| (X) | 52148 | (2S,4R)-2,4-bis[[tert-butyl(dimethyl)silyl]oxy]-1-methylene-6-heptynyl trifluoromethanesulfonate | C21H39F3O5SSi2 | 详情 | 详情 | |
| (XIII) | 47614 | 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)-1-ethanol | C21H42O3Si2 | 详情 | 详情 | |
| (XIV) | 42574 | [2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide | C33H51O3PSi2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)Synthesis of ketone (XXIV): Reaction of the known diol (XV) obtained by degradation of vitamin D2 with TsOH in pyridine gives, regioselectively, the monotosylate (XVI), which is protected at the secondary OH group by silylation with TBDMS-Cl and imidazole to yield the silyl ether (XVII). Oxidation of the tosyloxy group of (XVII) with O2 and t-BuOK in DMSO/t-BuOH affords ketone (XVIII), which is reduced with K and i-PrOH providing alcohol (XIX). Condensation of compound (XIX) with ethyl prop-ynoate (XX) by means of NMM in benzene gives the alkoxyacrylate (XXI), which is reduced with H2 over Pd/C in EtOH to yield the alkoxypropionate (XXII). Deprotection of the OH group of (XXII) with HF in acetonitrile affords alcohol (XXIII), which is oxidized with pyridinium dichromate (PDC) in CH2Cl2 providing ketone (XXIV). Wittig-Horner condensation of ketone (XXIV) with phosphine oxide (XIV) by means of BuLi in THF yields the corresponding adduct (XXV), which is submitted to a Grignard reaction with MeLi in THF to give the protected maxacalcitol precursor (XXVI). Finally, this compound is desilylated by means of TBAF in THF.
| 【1】 Vidal, B.; Fall, Y.; Mourino, A.; Gonzalez, V.; Stereoselective synthesis of 22-oxacalcitriol (OCT) and analogues modified at C25. Tetrahedron Lett 2002, 43, 3, 427. |
| 【2】 Fall, Y.; A new approach to the synthesis of the 25-hydroxy-22-oxa-vitamin D3 side chain. Tetrahedron Lett 1997, 38, 27, 4909. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 42574 | [2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide | C33H51O3PSi2 | 详情 | 详情 | |
| (XV) | 52151 | (1R,3aR,4S,7aR)-1-[(1S)-2-hydroxy-1-methylethyl]-7a-methyloctahydro-1H-inden-4-ol | C13H24O2 | 详情 | 详情 | |
| (XVI) | 52152 | (2S)-2-[(1R,3aR,4S,7aR)-4-hydroxy-7a-methyloctahydro-1H-inden-1-yl]propyl 4-methylbenzenesulfonate | C20H30O4S | 详情 | 详情 | |
| (XVII) | 52153 | (2S)-2-((1R,3aR,4S,7aR)-4-[[tert-butyl(dimethyl)silyl]oxy]-7a-methyloctahydro-1H-inden-1-yl)propyl 4-methylbenzenesulfonate | C26H44O4SSi | 详情 | 详情 | |
| (XVIII) | 52154 | 1-((1S,3aR,4S,7aS)-4-[[tert-butyl(dimethyl)silyl]oxy]-7a-methyloctahydro-1H-inden-1-yl)-1-ethanone | C18H34O2Si | 详情 | 详情 | |
| (XIX) | 52155 | (1S)-1-((1S,3aR,4S,7aR)-4-[[tert-butyl(dimethyl)silyl]oxy]-7a-methyloctahydro-1H-inden-1-yl)-1-ethanol | C18H36O2Si | 详情 | 详情 | |
| (XX) | 35333 | ethyl propiolate | 623-47-2 | C5H6O2 | 详情 | 详情 |
| (XXI) | 52156 | ethyl (E)-3-[[(1S)-1-((1S,3aR,4S,7aR)-4-[[tert-butyl(dimethyl)silyl]oxy]-7a-methyloctahydro-1H-inden-1-yl)ethyl]oxy]-2-propenoate | C23H42O4Si | 详情 | 详情 | |
| (XXII) | 52157 | ethyl 3-[[(1S)-1-((1S,3aR,4S,7aR)-4-[[tert-butyl(dimethyl)silyl]oxy]-7a-methyloctahydro-1H-inden-1-yl)ethyl]oxy]propanoate | C23H44O4Si | 详情 | 详情 | |
| (XXIII) | 52158 | ethyl 3-([(1S)-1-[(1S,3aR,4S,7aS)-4-hydroxy-7a-methyloctahydro-1H-inden-1-yl]ethyl]oxy)propanoate | C17H30O4 | 详情 | 详情 | |
| (XXIV) | 52159 | ethyl 3-([(1S)-1-[(1S,3aR,7aR)-7a-methyl-4-oxooctahydro-1H-inden-1-yl]ethyl]oxy)propanoate | C17H28O4 | 详情 | 详情 | |
| (XXV) | 52160 | ethyl 3-[((1S)-1-[(1S,3aS,7aS)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]ethyl)oxy]propanoate | C38H68O5Si2 | 详情 | 详情 | |
| (XXVI) | 11724 | 4-[((1S)-1-[(1S,3aS,7aS)-4-[(E)-2-((3S,5R)-3,5-Bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]ethyl)oxy]-2-methyl-2-butanol | C38H70O4Si2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)1-Ethylideneperhydroindan-4-ol (I) reacts with Me2AlCl and paraformaldehyde via an ene process to give the homoallylic diol (II), the primary hydroxyl group of which is tosylated by means of TsCl and DMAP and the secondary hydroxyl group silylated by means of TESOTf and lutidine to yield (III). Conversion of (III) into the corresponding nitrile by means of KCN in DMSO, followed by reduction with DIBALH in toluene, affords the aldehyde (IV) (1), which is further reduced in THF by treatment with DIBALH in hexanes to yield (V). The hydroxy silyl ether (V) is then converted into the iodo derivative (VI) by treatment with PPh3, imidazole and I2 in dichloromethane. The iodo silyl ether (VI) reacts with t-BuSH in the presence of DBU in benzene to afford sulfide (VII), which is then oxidized and deprotected with oxone to provide the hydroxy sulfone (VIII). Oxidation of (VIII) with pyridinium dichromate (PDC) in CH2Cl2 gives the keto sulfone (IX), which reacts with the phosphine oxide derivative (X) in THF in the presence of PhLi. Finally, the protecting silyl ether moiety is removed by means of Bu4NF in THF.
| 【1】 Posner, G.H.; Wang, Q.; Han, G.; et al.; Conceptually new sulfone analogues of the hormone 1alpha,25-dihydroxyvitamin D3: Synthesis and preliminary biological evaluation. J Med Chem 1999, 42, 18, 3425. |
| 【2】 Posner, G.H.; et al.; Noncalcemic, antiproliferative, transcriptionally active, 24-fluorinated hybrid analogues of the hormone 1alpha,25-dihydroxyvitamin D3. Synthesis and preliminary biological evaluation. J Med Chem 1998, 41, 16, 3008. |
| 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) | 42566 | (3aR,4S,7aS)-1-[(Z)ethylidene]-7a-methyloctahydro-1H-inden-4-ol | C12H20O | 详情 | 详情 | |
| (II) | 38682 | (3aS,7S,7aR)-3-[(1S)-2-hydroxy-1-methylethyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol | C13H22O2 | 详情 | 详情 | |
| (III) | 42567 | (2S)-2-[(3aS,7S,7aR)-3a-methyl-7-[(triethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]propyl 4-methylbenzenesulfonate | C26H42O4SSi | 详情 | 详情 | |
| (IV) | 42568 | (3R)-3-[(3aS,7S,7aR)-3a-methyl-7-[(triethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]butanal | C20H36O2Si | 详情 | 详情 | |
| (V) | 42569 | (3R)-3-[(3aS,7S,7aR)-3a-methyl-7-[(triethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]-1-butanol | C20H38O2Si | 详情 | 详情 | |
| (VI) | 42570 | ([(3aS,7S,7aR)-3-[(1R)-3-iodo-1-methylpropyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl]oxy)(triethyl)silane; (3aS,7S,7aR)-3-[(1R)-3-iodo-1-methylpropyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl triethylsilyl ether | C20H37IOSi | 详情 | 详情 | |
| (VII) | 42571 | (3aS,7S,7aR)-3-[(1R)-3-(tert-butylsulfanyl)-1-methylpropyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl triethylsilyl ether; ([(3aS,7S,7aR)-3-[(1R)-3-(tert-butylsulfanyl)-1-methylpropyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl]oxy)(triethyl)silane | C24H46OSSi | 详情 | 详情 | |
| (VIII) | 42572 | (3aS,7S,7aR)-3-[(1R)-3-(tert-butylsulfonyl)-1-methylpropyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol | C18H32O3S | 详情 | 详情 | |
| (IX) | 42573 | (3aR,7aS)-1-[(1R)-3-(tert-butylsulfonyl)-1-methylpropyl]-7a-methyl-3,3a,5,6,7,7a-hexahydro-4H-inden-4-one | C18H30O3S | 详情 | 详情 | |
| (X) | 42574 | [2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide | C33H51O3PSi2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXXa),(X)The silylation of the acetonide (XVIII) with Tms-Cl and LDA in THF gives dienolate (XIX), which is enantioselectively condensed with acrolein (XX) by means of Carreira's Ti catalyst in ethyl ether to yield the chiral allyl alcohol (XXI). The reaction of (XXI), N,O-dimethylhydroxylamine (XXII) and Me2AlCl affords the amide (XXIII), which is selectively reduced with Me4NBH(OAc)3 in HOAc/acetonitrile to provide the dihydroxyamide (XXIV). The silylation of the OH groups of (XXIV) with Tbdms-Cl and imidazole gives the disilylated compound (XXV), which is submitted to a Grignard reaction with vinylmagnesium bromide (XXVI) in THF to yield the vinyl ketone (XXVII). The Michael addition reaction with Ph2P(O)-Li and simultaneous triflation with (XXVIII) in THF affords the enol triflate (XXIX), which is cyclized by means of Pd(OAc)2, PPh3 and TEA in THF to provide the phosphorane (XXXa-b) as an inseparable mixture of the (Z)- and (E)-isomers. Finally, this mixture is submitted to photochemical isomerization with a medium-pressure UV mercury lamp in the presence of 9-fluorenone, furnishing the target intermediate, the (Z)-isomer (X) with a 95 % yield.
| 【1】 Anné, S.; et al.; Enantioselective syntheses of key A-ring precursors of 1alpha,25-dihydroxyvitamin D3 and analogues. Synlett 1999, 9, 1435. |
| 【2】 Hiyamizu, H.; et al.; A concise enantioselective synthesis of a key A-ring synthon for 1alpha-hydroxyvitamin D3 compounds. Org Lett 2001, 3, 3, 473. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXa),(X) | 42574 | [2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide | C33H51O3PSi2 | 详情 | 详情 | |
| (XXXb) | 53658 | (E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide; (E)-[2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane | n/a | C33H51O3PSi2 | 详情 | 详情 |
| (XVIII) | 13327 | 2,2,6-Trimethyl-4H-1,3-dioxin-4-one；2,2,6-trimethyl-1,3-dioxin-4-one；2,2,6-trimethyl-m-Dioxin-4-one;3-(1-hydroxy-1-methylethoxy)-d-lactone Crotonicacid | 5394-63-8 | C7H10O3 | 详情 | 详情 |
| (XIX) | 53651 | [(2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl)oxy](trimethyl)silane; 2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl trimethylsilyl ether | n/a | C10H18O3Si | 详情 | 详情 |
| (XX) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (XXI) | 53652 | 6-[(2S)-2-hydroxy-3-butenyl]-2,2-dimethyl-4H-1,3-dioxin-4-one | n/a | C10H14O4 | 详情 | 详情 |
| (XXII) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (XXIII) | 53653 | (5S)-5-hydroxy-N-methoxy-N-methyl-3-oxo-6-heptenamide | n/a | C9H15NO4 | 详情 | 详情 |
| (XXIV) | 53654 | (3S,5S)-3,5-dihydroxy-N-methoxy-N-methyl-6-heptenamide | n/a | C9H17NO4 | 详情 | 详情 |
| (XXV) | 53655 | (3S,5S)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-N-methoxy-N-methyl-6-heptenamide | n/a | C21H45NO4Si2 | 详情 | 详情 |
| (XXVI) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (XXVII) | 53626 | (4S)-3,3-diethyl-4-{4-[(4-methyl-1-piperazinyl)carbonyl]phenoxy}-2-azetidinone | n/a | C19H27N3O3 | 详情 | 详情 |
| (XXVIII) | 34685 | N-(5-chloro-2-pyridinyl)(trifluoro)-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 145100-51-2 | C7H3ClF6N2O4S2 | 详情 | 详情 |
| (XXIX) | 53657 | (3S,5S)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-1-[(E)-2-(diphenylphosphoryl)ethylidene]-6-heptenyl trifluoromethanesulfonate | n/a | C34H52F3O6PSSi2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)Oxidation of hydroxylated diene (I) with m-CPBA followed by acetylation provides epoxide (II), which is then converted to the corresponding hydroxy derivative (III) by means of SeO2 and PyO in dioxane followed by isomer separation. Treatment of compound (III) with t-butyldimethylsilyl chloride and imidazole in DMF yields the 5,7-bis-protected derivative (IV), which reacts in THF with tungsten hexachloride (WCl6) and BuLi in hexane/THF to furnish compound (V). Hydrolysis of acetate (V) with NaOH in MeOH provides alcohol (VI), which is then converted into the corresponding chloro derivative (VII) by treatment with N-chlorosuccinimide (NCS) and dimethylsulfide (Me2S) in CH2Cl2. Treatment of compound (VII) with potassium diphenylphosphide (PPh2K) in THF and aqueous H2O2 in CH2Cl2 gives diphenylphosphine oxide (VIII), which is condensed in THF with hexahydro indenone derivative (IX) by means of n-BuLi in hexane to afford compound (X). Finally, derivative (X) is deprotected by treatment with tetrabutyl ammonium fluoride in THF to yield the desired product.
| 【1】 Kiegiel, J.; et al.; Chemical conversion of vitamin D3 to its 1,25-dihydroxy metabolite. Tetrahedron Lett 1991, 32, 43, 6057. |
| 【2】 Batcho, A.D.; Hennessy, B.M.; Uskokovic, M.R. (F. Hoffmann-La Roche AG); Vitamin D3 analogs. WO 0104089 . |
| 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) | 47609 | 2-((5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)-1-ethanol | C15H28O2Si | 详情 | 详情 | |
| (II) | 47610 | ((2R,3S,7S)-7-[[tert-butyl(dimethyl)silyl]oxy]-4-methylene-1-oxaspiro[2.5]oct-2-yl)methyl acetate | C17H30O4Si | 详情 | 详情 | |
| (III) | 47611 | ((2R,3S,5S,7S)-7-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4-methylene-1-oxaspiro[2.5]oct-2-yl)methyl acetate | C17H30O5Si | 详情 | 详情 | |
| (IV) | 47612 | ((2R,3S,5S,7S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methylene-1-oxaspiro[2.5]oct-2-yl)methyl acetate | C23H44O5Si2 | 详情 | 详情 | |
| (V) | 47613 | 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl acetate | C23H44O4Si2 | 详情 | 详情 | |
| (VI) | 47614 | 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)-1-ethanol | C21H42O3Si2 | 详情 | 详情 | |
| (VII) | 47615 | tert-butyl(dimethyl)silyl (1R,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-[(E)-2-chloroethylidene]-4-methylenecyclohexyl ether; tert-butyl([(1R,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-[(E)-2-chloroethylidene]-4-methylenecyclohexyl]oxy)dimethylsilane | C21H41ClO2Si2 | 详情 | 详情 | |
| (VIII) | 42574 | [2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide | C33H51O3PSi2 | 详情 | 详情 | |
| (IX) | 47616 | (3aR,7aS)-1-[(1R)-1,5-dimethyl-5-[(trimethylsilyl)oxy]hexyl]-7a-methyl-3,3a,5,6,7,7a-hexahydro-4H-inden-4-one | C21H38O2Si | 详情 | 详情 | |
| (X) | 47617 | C41H78O4Si3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XIV)The intermediate phosphine oxide (XIV) has been obtained as follows: The epoxidation of l-carvone (I) with H2O2 and LiOH in methanol gives the epoxide (II), which is reduced with L-Selectride in THF to yield the alcohol (III). The oxidation of the isopropenyl group of (III) with OsO4, KIO4, MCPBA and HOAc affords the acetate (IV), which is hydrolyzed to the diol (V) with NaOMe in methanol. The protection of the two OH groups of (V) with Tbdms-Cl and imidazole provides the bis-silyl ether (VI), which is oxidized with periodic acid in ethyl ether to give the ketoaldehyde (VII). The aldehyde group of (VII) is subjected to a Wittig condensation with CBr4, PPh3 and Zn in dichloromethane to yield the dibromovinyl compound (VIII), which by treatment with LDA and the triflic imide (IX) in THF affords the acetylenic vinyl triflate (X). The cyclization of (X) by means of Pd(OAc)2 and PPH3, followed by carbonylation in methanol, provides the methyl ester (XI) as a 2:1 mixture of the (Z)- and (E)-isomers. The photoisomerization of this mixture under the Hoffmann-La Roche conditions (presence of 9-fluorenone) gives a high yield of the (Z)-isomer (XII), which is reduced with DIBAL in toluene to give the primary alcohol (XIII). Finally, this compound is converted into the target phosphine oxide (XIV) is performed by known methods.
| 【1】 Mourino, A.; et al.; Efficient and versatile synthesis of A-ring precursors of 1alpha,25-dihydroxyvitamin D3 and analogues. Application to the synthesis of Lythgoe-Roche phosphine oxide. Tetrahedron Lett 1997, 38, 26, 4713. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIa),(XII) | 52149 | methyl 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)acetate | C22H42O4Si2 | 详情 | 详情 | |
| (XIb) | 52150 | methyl 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)acetate | C22H42O4Si2 | 详情 | 详情 | |
| (I) | 13386 | (5R)-5-Isopropenyl-2-methyl-2-cyclohexen-1-one; L-(-)-Carvone | 6485-40-1 | C10H14O | 详情 | 详情 |
| (II) | 52141 | (1R,4R,6R)-4-isopropenyl-1-methyl-7-oxabicyclo[4.1.0]heptan-2-one | C10H14O2 | 详情 | 详情 | |
| (III) | 52550 | 1-methyl-4-(1-methylethenyl)-7-oxabicyclo[4.1.0]heptan-2-ol | C10H16O2 | 详情 | 详情 | |
| (IV) | 52143 | (1R,3S,5S,6S)-5-hydroxy-6-methyl-7-oxabicyclo[4.1.0]hept-3-yl acetate | C9H14O4 | 详情 | 详情 | |
| (V) | 52144 | (1S,2S,4S,6R)-1-methyl-7-oxabicyclo[4.1.0]heptane-2,4-diol | C7H12O3 | 详情 | 详情 | |
| (VI) | 52145 | tert-butyl[((1R,2S,4R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-7-oxabicyclo[4.1.0]hept-2-yl)oxy]dimethylsilane; tert-butyl(dimethyl)silyl (1R,2S,4R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-7-oxabicyclo[4.1.0]hept-2-yl ether | C19H40O3Si2 | 详情 | 详情 | |
| (VII) | 52146 | (3S,5S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-6-oxoheptanal | C19H40O4Si2 | 详情 | 详情 | |
| (VIII) | 52147 | (3S,5R)-8,8-dibromo-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-7-octen-2-one | C20H40Br2O3Si2 | 详情 | 详情 | |
| (IX) | 34685 | N-(5-chloro-2-pyridinyl)(trifluoro)-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 145100-51-2 | C7H3ClF6N2O4S2 | 详情 | 详情 |
| (X) | 52148 | (2S,4R)-2,4-bis[[tert-butyl(dimethyl)silyl]oxy]-1-methylene-6-heptynyl trifluoromethanesulfonate | C21H39F3O5SSi2 | 详情 | 详情 | |
| (XIII) | 47614 | 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)-1-ethanol | C21H42O3Si2 | 详情 | 详情 | |
| (XIV) | 42574 | [2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide | C33H51O3PSi2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XIV)The intermediate phosphonate (XXI) has been obtained as follows: The reaction of tert-butyl mercaptan (XV) with allyl bromide (XVI) by means of NaOH in ethanol gives the sulfide (XVII), which is oxidized with Oxone in methanol/water to yield the sulfone (XVIII). The bromination of (XVIII) with Br2 in CCl4 followed by dehydrobromination with TEA affords the bromosulfone (XIX), which is finally condensed with tributyl phosphite (XX) by heating at 130 C to provide the target intermediate phosphonate (XXI). The silylation of the known diol (XXII) (obtained by degradation of vitamin D2) with Tes-OTf and lutidine gives the bis silyl ether (XXIII), which is submitted to a Swern oxidation ((COCl)2), yielding the carbaldehyde (XXIV). The Wadsworth-Emmons condensation of aldehyde (XXIV) with the intermediate phosphonate (XXI) by means of tBu-OLi affords the diinsaturated sulfone (XXV), which is desilylated with HF in THF to provide the alcohol (XXVI). The oxidation of (XXVI) with TPAP and NMO furnishes the ketone (XXVII), which is submitted to a Wittig-Horner condensation with the intermediate phosphine oxide (XIV) by means of PhLi, giving the silylated precursor (XXVIII). Finally, this compound is desilylated with HF in ethanol to afford the target vitamin D3 analogue.
| 【1】 Posner, G.H.; et al.; A non-calcemic sulfone version of the vitamin D3 analogue seocalcitol (EB 1089): Chemical synthesis, biological evaluation and potency enhancement of the anticancer drug adriamycin. Bioorg Med Chem 2001, 9, 9, 2365. |
| 【2】 Fall, Y.; A new approach to the synthesis of the 25-hydroxy-22-oxa-vitamin D3 side chain. Tetrahedron Lett 1997, 38, 27, 4909. |
| 【3】 Lee, J.K.; Crawford, K.R.; Wang, Q.; Posner, G.H.; Han, G. (Johns Hopkins University); Non-calcemic, antiproliferative, transcriptionally active sulfur-containing analogs of 1alpha,25-dihydroxyvitamin D3. US 6380408; WO 0059513 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 42574 | [2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide | C33H51O3PSi2 | 详情 | 详情 | |
| (XV) | 52551 | tert-Butyl mercaptan; 2-Methyl-2-propanethiol | 75-66-1 | C4H10S | 详情 | 详情 |
| (XVI) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XVII) | 52552 | 1,1-dimethylethyl 2-propenyl sulfide; 3-[(1,1-dimethylethyl)sulfanyl]-1-propene | C7H14S | 详情 | 详情 | |
| (XVIII) | 52553 | (1,1-dimethylethyl)(dioxo)2-propenyl-lambda~6~-sulfane; 1,1-dimethylethyl 2-propenyl sulfone | C7H14O2S | 详情 | 详情 | |
| (XIX) | 52554 | (3-bromo-1-propenyl)(1,1-dimethylethyl)dioxo-lambda~6~-sulfane; 3-bromo-1-propenyl 1,1-dimethylethyl sulfone | C7H13BrO2S | 详情 | 详情 | |
| (XX) | 52555 | Tri-n-butylphosphite; Tributyl phosphite; Phosphorous acid Tri-N-butyl ester | 102-85-2 | C12H27O3P | 详情 | 详情 |
| (XXI) | 52556 | dibutyl 3-[(1,1-dimethylethyl)sulfonyl]-2-propenylphosphonate | C15H31O5PS | 详情 | 详情 | |
| (XXII) | 52151 | (1R,3aR,4S,7aR)-1-[(1S)-2-hydroxy-1-methylethyl]-7a-methyloctahydro-1H-inden-4-ol | C13H24O2 | 详情 | 详情 | |
| (XXIII) | 52557 | 7a-methyl-1-{1-methyl-2-[(triethylsilyl)oxy]ethyl}octahydro-1H-inden-4-yl triethylsilyl ether; [(7a-methyl-1-{1-methyl-2-[(triethylsilyl)oxy]ethyl}octahydro-1H-inden-4-yl)oxy](triethyl)silane | C25H52O2Si2 | 详情 | 详情 | |
| (XXIV) | 52558 | 2-{7a-methyl-4-[(triethylsilyl)oxy]octahydro-1H-inden-1-yl}propanal | C19H36O2Si | 详情 | 详情 | |
| (XXV) | 52559 | [(1-{5-[(1,1-dimethylethyl)sulfonyl]-1-methyl-2,4-pentadienyl}-7a-methyloctahydro-1H-inden-4-yl)oxy](triethyl)silane; 5-{7a-methyl-4-[(triethylsilyl)oxy]octahydro-1H-inden-1-yl}-1,3-hexadienyl 1,1-dimethylethyl sulfone | C26H48O3SSi | 详情 | 详情 | |
| (XXVI) | 52560 | 1-{5-[(1,1-dimethylethyl)sulfonyl]-1-methyl-2,4-pentadienyl}-7a-methyloctahydro-1H-inden-4-ol | C20H34O3S | 详情 | 详情 | |
| (XXVII) | 52561 | 1-{5-[(1,1-dimethylethyl)sulfonyl]-1-methyl-2,4-pentadienyl}-7a-methyloctahydro-4H-inden-4-one | C20H32O3S | 详情 | 详情 | |
| (XXVIII) | 52562 | (1,1-dimethylethyl)({3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-[2-(1-{5-[(1,1-dimethylethyl)sulfonyl]-1-methyl-2,4-pentadienyl}-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene]-4-methylidenecyclohexyl}oxy)dimethylsilane; 5-{4-[2-(3,5-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-methylidenecyclohexylidene)ethylidene]-7a-methyloctahydro-4H-inden-1-yl}-1,3-hexadienyl 1,1-dimethylethyl sulfone | C41H72O4SSi2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VI)Alkylation of the lithium enolate of pinacolone (II) with alkyl iodide (I) affords ketone (III). After desilylation of (III) by means of tetrabutylammonium fluoride, the resultant alcohol (IV) is oxidized to the corresponding ketone (V) employing N-methylmorpholine-N-oxide in the presence of a catalytic amount of tetrapropylammonium perruthenate. Wadsworth-Emmons condensation of ketone (V) with the racemic phosphine oxide (VI) provides a diastereomeric mixture of diene adducts (VII). After conversion of (VII) to the corresponding oxime, the desired isomer (VIII) is isolated by column chromatography. Finally, desilylation of (VIII) by means of tetrabutylammonium fluoride provides the title compound.
| 【1】 Posner, G.H.; Kensler, T.W.; Dolan, P.; Peleg, S.; Halford, B.A.; Conceptually new low-calcemic oxime analogues of the hormone 1alpha,25-dihydroxyvitamin D3: Synthesis and biological testing. J Med Chem 2002, 45, 8, 1723. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIa) | 57668 | (7R)-7-{(3aS,7aS)-7-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl}-2,2-dimethyl-3-octanone | C41H72O3Si2 | 详情 | 详情 | |
| (VIIb) | 57669 | (7R)-7-{(3aS,7aS)-7-[(E)-2-((3R,5S)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl}-2,2-dimethyl-3-octanone | C41H72O3Si2 | 详情 | 详情 | |
| (I) | 42570 | ([(3aS,7S,7aR)-3-[(1R)-3-iodo-1-methylpropyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl]oxy)(triethyl)silane; (3aS,7S,7aR)-3-[(1R)-3-iodo-1-methylpropyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl triethylsilyl ether | C20H37IOSi | 详情 | 详情 | |
| (II) | 10128 | 3,3-Dimethyl-2-butanone; Pinacolin | 75-97-8 | C6H12O | 详情 | 详情 |
| (III) | 57651 | (7R)-7-{(3aS,7S,7aR)-3a-methyl-7-[(triethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl}-2,2-dimethyl-3-octanone | C26H48O2Si | 详情 | 详情 | |
| (IV) | 57666 | (7R)-7-[(3aS,7S,7aR)-7-hydroxy-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]-2,2-dimethyl-3-octanone | C20H34O2 | 详情 | 详情 | |
| (V) | 57667 | (3aR,7aS)-7a-methyl-1-[(1R)-1,6,6-trimethyl-5-oxoheptyl]-3,3a,5,6,7,7a-hexahydro-4H-inden-4-one | C20H32O2 | 详情 | 详情 | |
| (VI) | 42574 | [2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide | C33H51O3PSi2 | 详情 | 详情 | |
| (VIII) | 57670 | (7R)-7-{(3aS,7aS)-7-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl}-2,2-dimethyl-3-octanone oxime | C41H73NO3Si2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(VII)Alkylation of the lithium enolate of pinacolone (II) with alkyl iodide (I) affords ketone (III), which is then condensed with O-methyl hydroxylamine to produce oxime (IV). After desilylation of (IV) by means of tetrabutylammonium fluoride, the resultant alcohol (V) is oxidized to the corresponding ketone (VI), employing N-methylmorpholine-N-oxide in the presence of a catalytic amount of tetrapropylammonium perruthenate. Wadsworth-Emmons condensation of ketone (VI) with the racemic phosphine oxide (VII) provides a diastereomeric mixture of diene adducts (VIII). After desilylation of (VIII) by means of tetrabutylammonium fluoride, the resultant mixture of diol isomers is separated by column chromatography to furnish the title compound.
| 【1】 Posner, G.H.; Kensler, T.W.; Dolan, P.; Peleg, S.; Halford, B.A.; Conceptually new low-calcemic oxime analogues of the hormone 1alpha,25-dihydroxyvitamin D3: Synthesis and biological testing. J Med Chem 2002, 45, 8, 1723. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIIa) | 57655 | (7R)-7-{(3aS,7aS)-7-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl}-2,2-dimethyl-3-octanone O-methyloxime | C42H75NO3Si2 | 详情 | 详情 | |
| (VIIIb) | 57656 | (7R)-7-{(3aS,7aS)-7-[(E)-2-((3S,5S)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl}-2,2-dimethyl-3-octanone O-methyloxime | C42H75NO3Si2 | 详情 | 详情 | |
| (I) | 42570 | ([(3aS,7S,7aR)-3-[(1R)-3-iodo-1-methylpropyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl]oxy)(triethyl)silane; (3aS,7S,7aR)-3-[(1R)-3-iodo-1-methylpropyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl triethylsilyl ether | C20H37IOSi | 详情 | 详情 | |
| (II) | 10128 | 3,3-Dimethyl-2-butanone; Pinacolin | 75-97-8 | C6H12O | 详情 | 详情 |
| (III) | 57651 | (7R)-7-{(3aS,7S,7aR)-3a-methyl-7-[(triethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl}-2,2-dimethyl-3-octanone | C26H48O2Si | 详情 | 详情 | |
| (IV) | 57652 | (7R)-7-{(3aS,7S,7aR)-3a-methyl-7-[(triethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl}-2,2-dimethyl-3-octanone O-methyloxime | C27H51NO2Si | 详情 | 详情 | |
| (V) | 57653 | (7R)-7-[(3aS,7S,7aR)-7-hydroxy-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]-2,2-dimethyl-3-octanone O-methyloxime | C21H37NO2 | 详情 | 详情 | |
| (VI) | 57654 | (3aR,7aS)-1-[(1R)-5-(methoxyimino)-1,6,6-trimethylheptyl]-7a-methyl-3,3a,5,6,7,7a-hexahydro-4H-inden-4-one | C21H35NO2 | 详情 | 详情 | |
| (VII) | 42574 | [2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide | C33H51O3PSi2 | 详情 | 详情 |