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【结 构 式】 
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【分子编号】11724 【品名】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 【CA登记号】 |
【 分 子 式 】C38H70O4Si2 【 分 子 量 】647.1424 【元素组成】C 70.53% H 10.9% O 9.89% Si 8.68% |
合成路线1
该中间体在本合成路线中的序号：(XII)1) The microbiological oxidation of 3beta-hydroxyandrost-5-en-17-one (I) gives 1alpha,3beta-dihydroxyandrost-5-en-17-one (II), which is silylated with tert-butyldimethylsilyl (TBS) chloride and imidazole to the bis(silyloxy) compound (III). The dehydrogenation of (III) by bromination with N-bromosuccinimide (NBS) and dehydrobromination with 2,4,6-trimethylpyridine (TMPyr) yields 1alpha,3beta-bis(tert-butyldimethylsilyloxy)androsta-5,7-dien-17-one (IV). The Wittig condensation of (IV) with ethyltriphenylphosphonium bromide (V) by means of NaH in DMS gives the corresponding ethylidene derivative (VI), which is treated first with 9-borabicyclo[3.3.1]nonane (9-BBN) and then with H2O2 and NaOH in THF yielding a mixture of the 20(S)- and 20(R)-isomers of 1alpha,3beta-bis(tert-butyldimethylsilyloxy)pregna-5,7-dien-20-ol that was separated by preparative TLC. The 20(S)-isomer (VII) was condensed with 1-bromo-3-butene (VIII) by means of NaH in refluxing xylene affording 20(S)-(3-butenyloxy)-1alpha,3beta-bis(tert-butyldimethylsilyloxy)pregna-5,7-diene (IX), which is oxidized with O2 gas in DMF/water catalyzed by Cu2Cl2 and PdCl2 to give the corresponding 3-oxobutoxy derivative (X). The Grignard alkylation of (X) with methylmagnesium bromide in THF afforded the 20(S)-(3-hydroxy-3-methylbutoxy) derivative (XI), which was submitted to UV irradiation with a 200 W high-pressure mercury lamp in ethanol yielding the silylated 22-oxavitamin D3 derivative (XII). Finally, this compound is desilylated by a treatment with tetrabutylammonium fluoride (TBAF) in THF. 2) The addition of ethyl acrylate (XIII) to the previously reported pregna-5,7-dien-20(S)-ol (VII) by means of tetrabutylammonium hydroxide/NaOH in water/toluene gives the 2-(ethoxycarbonyl)ethoxy derivative (XIV), which by alkylation of the carbonyl function with methyllithium yields the 3-hydroxy-3-methylbutoxy derivative (XI), already obtained. 3) The addition of N,N-dimethylacrylamide (XV) to the previously reported pregna-5,7-dien-20(S)-ol (VII) by means of NaH gives the corresponding propionamide derivative (XVI), which by a Grignard alkylation with methylmagnesium bromide and CeCl3 is converted into the 3-hydroxy-3-methylbutoxy derivative (XI), already obtained.
| 【1】 Murayama, E.; Miyamoto, K.; Kubodera, N.; Mori, T.; Matsunaga, I.; Synthetic studies of vitamin D3 analogues. VIII. Synthesis of 22-oxavitamin D3 analogues. Chem Pharm Bull 1986, 34, 10, 4410-3. |
| 【2】 Kubodera, N.; Watanabe, H.; Kawanishi, T.; Matsumoto, M.; Synthetic studies of vitamin D analogues. XI. Synthesis and differentiation-inducing activity of 1alpha,25-dihydroxy-22-oxavitamin D3 analogues. Chem Pharm Bull 1992, 40, 6, 1494-9. |
| 【3】 Leeson, P.A.; Martel, A.M.; Castaner, J.; 22-Oxacalcitriol. Drugs Fut 1996, 21, 12, 1229. |
| 【4】 Kubodera, N.; Miyamoto, K.; Ochi, K.; Matsunaga, I.; Murayama, E. (Chugai Pharmaceutical Co. Ltd.); Novel vitamin D derivs. and process for producing the same. EP 0184112; JP 1986267548; JP 1986267550 . |
| 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) | 11713 | Dehydroepiandrosterone;prasterone；(3S,8R,9S,10R,13S,14S)-3-Hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | 53-43-0 | C19H28O2 | 详情 | 详情 |
| (II) | 11714 | (1S,3R,8R,9S,10R,13S,14S)-1,3-Dihydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C19H28O3 | 详情 | 详情 | |
| (III) | 11715 | (1S,8R,9S,10R,13S,14S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C31H56O3Si2 | 详情 | 详情 | |
| (IV) | 11716 | (1S,3R,9S,10R,13S,14S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-1,2,3,4,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one | C31H54O3Si2 | 详情 | 详情 | |
| (V) | 11717 | Ethyl(triphenyl)phosphonium bromide; (Ethyl)triphenylphosphonium bromide | 1530-32-1 | C20H20BrP | 详情 | 详情 |
| (VI) | 11718 | tert-Butyl(dimethyl)silyl (1S,3R,9S,10R,13S,14S)-1-[[tert-butyl(dimethyl)silyl]oxy]-17-[(E)ethylidene]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl ether; tert-Butyl([(1S,3R,9S,10R,13S,14S)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-[(E)ethylidene]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-1-yl]oxy)dimethylsilane | C33H58O2Si2 | 详情 | 详情 | |
| (VII) | 11719 | (1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)-1-ethanol | C33H60O3Si2 | 详情 | 详情 | |
| (VIII) | 11720 | 4-Bromo-1-butene | 5162-44-7 | C4H7Br | 详情 | 详情 |
| (IX) | 11721 | (1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl 3-butenyl ether; [((1S,3R,9S,10R,13S,14S,17S)-17-[(1S)-1-(3-Butenyloxy)ethyl]-3-[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-1-yl)oxy](tert-butyl)dimethylsilane | C37H66O3Si2 | 详情 | 详情 | |
| (X) | 11722 | 4-[[(1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]-2-butanone | C37H66O4Si2 | 详情 | 详情 | |
| (XI) | 11723 | 4-[[(1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]-2-methyl-2-butanol | C38H70O4Si2 | 详情 | 详情 | |
| (XII) | 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 | |
| (XIII) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (XIV) | 11726 | ethyl 3-[[(1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]propanoate | C38H68O5Si2 | 详情 | 详情 | |
| (XV) | 11727 | N,N-Dimethylacrylamide; N,N-Dimethyl-2-propenamide | 2680-03-7 | C5H9NO | 详情 | 详情 |
| (XVI) | 11728 | 3-[[(1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]-N,N-dimethylpropanamide | C38H69NO4Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXVI)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 |