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【结 构 式】 
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【分子编号】12542 【品名】(1S,3R,8S,9S,10R,13R,14S,17R)-10,13-Dimethyl-17-[(1R)-6,6,6-trifluoro-5-hydroxy-1-methyl-5-(trifluoromethyl)hexyl]-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-1,3-diol 【CA登记号】 |
【 分 子 式 】C27H40F6O3 【 分 子 量 】526.6032192 【元素组成】C 61.58% H 7.66% F 21.65% O 9.11% |
合成路线1
该中间体在本合成路线中的序号：(VIII)Falecalcitriol can be obtained by several different ways: 1) The reaction of 24-(tosyloxy)chol-5-en-3beta-ol tetrahydropyranyl ether (I) with LiBr gives the corresponding 24-bromo derivative (II), which is treated with activated Mg (to yield the Grignard reagent) and hexafluoroacetone affording 26,26,26,27,27,27-hexafluoro-3beta-(tetrahydropyranyloxy)cholest-5-en-25-ol (III). The hydrolysis of (III) with p-toluenesulfonic acid gives the diol (V), which is oxidized with dichlorodicyanobenzoquinone (DDQ) in hot dioxane yielding the hexafluoro-25-hydroxycholest-1,4,6-trien-3-one (VI). The epoxidation of (VI) with H2O2 and NaOH in methanol/THF affords the 1alpha,2alpha-epoxide (VII), which is reduced with Li in liquid ammonia to give the hexafluorocholest-5-en-1alpha,3beta,25-triol (VIII). The acetylation of (VIII) with acetic anhydride and dimethylaminopyridine (DMAP) yields the corresponding triacetate (IX), which is treated with N-bromosuccinimide (NBS) and collidine (2,4,6-trimethylpyridine) to afford the hexafluoro-1alpha,3beta,25-triacetoxycholest-5,7-diene (X). The U.V. irradiation of (X) with a medium pressure mercury lamp in benzene/ethanol gives the triacetylated vitamin D3 derivative (XI), which is finally deacetylated with KOH in methanol/THF. 2) An alternative synthesis of the intermediate 26,26,26,27,27,27-hexafluoro-3beta-(tetrahydropyranyloxy)cholest-5-en-25-ol (III) is the reaction of the previously obtained bromo derivative (II) with sodium benzenesulfinate in DMF yielding the sulfone (IV), which is then condensed with hexafluoroacetone by means of lithium diisopropylamide (LDA) in THF.
| 【1】 Kobayashi, Y.; Taguchi, T.; Kanuma, N.; Synthesis of 26,26,26,27,27,27-hexafluoro-25-hydroxyvitamin D3. J Chem Soc Chem Commun 1980, 459-460. |
| 【2】 Graul, A.; Castaner, J.; Falecalcitriol. Drugs Fut 1997, 22, 5, 473. |
| 【3】 Kobayashi, Y.; Taguchi, T.; Mitsuhashi, S.; Eguchi, T.; Ohshima, E.; Ikekawa, N.; Studies on organic fluorine compounds. XXXIX. Studies on steroids. LXXIX. Synthesis of 1alpha,25-dihydroxy-26,26,26,27,27,27-hexafluorovitamin D3. Chem Pharm Bull 1982, 30, 12, 4297-4303. |
| 【4】 DeLuca, H.F.; Tanaka, Y.; Ikekawa, M.; Kobayashi, Y. (Wisconsin Alumni Research Foundation); 26,26,26,27,27,27-Hexafluoro-1alpha,25-dihydroxycholecalciferol and process for preparing the same. JP 1994025280; US 4358406 . |
| 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) | 12535 | (4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentyl 4-methylbenzenesulfonate | C37H56O5S | 详情 | 详情 | |
| (II) | 12536 | [(3S,8S,9S,10R,13R,14S,17R)-17-[(1R)-4-Bromo-1-methylbutyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl]methyl tetrahydro-2H-pyran-2-yl ether | C30H49BrO2 | 详情 | 详情 | |
| (III) | 12537 | (6R)-6-[(3S,8S,9S,10R,13R,14S,17R)-10,13-Dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1,1,1-trifluoro-2-(trifluoromethyl)-2-heptanol | C33H50F6O3 | 详情 | 详情 | |
| (IV) | 12538 | 2-([(3S,8S,9S,10R,13R,14S,17R)-10,13-Dimethyl-17-[(1R)-1-methyl-4-(phenylsulfonyl)butyl]-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl]methoxy)tetrahydro-2H-pyran; (4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-Dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentyl phenyl sulfone | C36H54O4S | 详情 | 详情 | |
| (V) | 12539 | (3S,8S,9S,10R,13R,14S,17R)-10,13-Dimethyl-17-[(1R)-6,6,6-trifluoro-5-hydroxy-1-methyl-5-(trifluoromethyl)hexyl]-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol | C27H40F6O2 | 详情 | 详情 | |
| (VI) | 12540 | (8S,9S,10S,13R,14S,17R)-10,13-Dimethyl-17-[(1R)-6,6,6-trifluoro-5-hydroxy-1-methyl-5-(trifluoromethyl)hexyl]-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-3-one | C27H34F6O2 | 详情 | 详情 | |
| (VII) | 12541 | (2aR,3aR,3bR,3cS,5aR,6R,8aS,8bS)-3b,5a-Dimethyl-6-[(1R)-6,6,6-trifluoro-5-hydroxy-1-methyl-5-(trifluoromethyl)hexyl]-2a,3a,3b,3c,4,5,5a,6,7,8,8a,8b-dodecahydro-2H-cyclopenta[7,8]phenanthro[3,4-b]oxiren-2-one | C27H34F6O3 | 详情 | 详情 | |
| (VIII) | 12542 | (1S,3R,8S,9S,10R,13R,14S,17R)-10,13-Dimethyl-17-[(1R)-6,6,6-trifluoro-5-hydroxy-1-methyl-5-(trifluoromethyl)hexyl]-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-1,3-diol | C27H40F6O3 | 详情 | 详情 | |
| (IX) | 12543 | (1S,3R,8S,9S,10R,13R,14S,17R)-1-(acetoxy)-17-[(1R)-5-(acetoxy)-6,6,6-trifluoro-1-methyl-5-(trifluoromethyl)hexyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C33H46F6O6 | 详情 | 详情 | |
| (X) | 12544 | (1S,3R,9S,10R,13R,14R,17R)-1-(acetoxy)-17-[(1R)-5-(acetoxy)-6,6,6-trifluoro-1-methyl-5-(trifluoromethyl)hexyl]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C33H44F6O6 | 详情 | 详情 | |
| (XI) | 12545 | (1R,5S)-3-((Z)-2-[(1R,3aR,7aR)-1-[(1R)-5-(acetoxy)-6,6,6-trifluoro-1-methyl-5-(trifluoromethyl)hexyl]-7a-methyloctahydro-4H-inden-4-ylidene]ethylidene)-5-(acetoxy)-4-methylenecyclohexyl acetate | C33H44F6O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)3) An alterantive synthesis of the intermediate 26,26,26,27,27,27-hexafluorocholest-5-en-1alpha,3beta,25-triol (VIII) is as follows: The oxidative dehydrogenation of 3beta-hydroxy-5-cholene-24-oic acid methyl ester (XII) with dichlorodicyanobenzoquinone (DDQ) in refluxing dioxane gives 3-oxochola-1,4,6-triene-24-oic acid methyl ester (XIII), which is selectively epoxidized with 30% H2O2 and NaOH in methanol yielding the 1alpha,2alpha-epoxide (XIV). The reductive cleavage of (XIV) with lithium in liquid NH3, followed by hydrolysis with water affords the unsaturated triol (XV), which by selective protection with trityl chloride in pyridine, followed by acetylation with acetic anhydride and dimethylaminopyridine (DMAP) and elimination of the trityl group with p-toluenesulfonic acid, gives 1alpha,3beta-diacetoxy-5-cholen-24-ol (XVI). The reaction of (XVI) with tosyl chloride-pyridine and then with LiBr in DMF yields the 24-bromo derivative (XVII), which is treated with sodium phenylsulfinate in hot DMF affording the sulfone (XVIII). Hydrolysis of the acetoxy groups of (XVIII) with KOH in methanol, followed by silylation of the resulting diol with trimethylsilyl chloride and triethylamine in pyridine gives the silylated sulfone (XIX), which is then condensed with hexafluoroacetone by means of lithium diisopropylamide in THF yielding the sulfonated adduct (XX). Finally, this compound is desilylated to the previously reported triol (VIII) with HCl in methanol.
| 【1】 Kobayashi, Y.; Taguchi, T.; Mitsuhashi, S.; Eguchi, T.; Ohshima, E.; Ikekawa, N.; Studies on organic fluorine compounds. XXXIX. Studies on steroids. LXXIX. Synthesis of 1alpha,25-dihydroxy-26,26,26,27,27,27-hexafluorovitamin D3. Chem Pharm Bull 1982, 30, 12, 4297-4303. |
| 【2】 Graul, A.; Castaner, J.; Falecalcitriol. Drugs Fut 1997, 22, 5, 473. |
| 【3】 Hata, G.; Mutoh, M.; Hashimoto, H. (Toray Industries, Inc.); Novel platinum(II) complex and drug for treating malignant tumor. EP 0457921; JP 1991500696; US 5302587; WO 9109041 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 12542 | (1S,3R,8S,9S,10R,13R,14S,17R)-10,13-Dimethyl-17-[(1R)-6,6,6-trifluoro-5-hydroxy-1-methyl-5-(trifluoromethyl)hexyl]-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-1,3-diol | C27H40F6O3 | 详情 | 详情 | |
| (XII) | 12546 | methyl (4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoate; 3beta-Hydroxichol-5-en-24-oic acid methyl ester | 20231-57-6 | C25H40O3 | 详情 | 详情 |
| (XIII) | 12547 | methyl (4R)-4-[(8S,9S,10S,13R,14S,17R)-10,13-dimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl]pentanoate | C25H34O3 | 详情 | 详情 | |
| (XIV) | 12548 | methyl (4R)-4-[(2aR,3aR,3bR,3cS,5aR,6R,8aS,8bS)-3b,5a-dimethyl-2-oxo-2a,3a,3b,3c,4,5,5a,6,7,8,8a,8b-dodecahydro-2H-cyclopenta[7,8]phenanthro[3,4-b]oxiren-6-yl]pentanoate | C25H34O4 | 详情 | 详情 | |
| (XV) | 12549 | (1S,3R,8S,9S,10R,13R,14S,17R)-17-[(1R)-4-Hydroxy-1-methylbutyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-1,3-diol | C24H40O3 | 详情 | 详情 | |
| (XVI) | 12550 | (1S,3R,8S,9S,10R,13R,14S,17R)-1-(acetoxy)-17-[(1R)-4-hydroxy-1-methylbutyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C28H44O5 | 详情 | 详情 | |
| (XVII) | 12551 | (1S,3R,8S,9S,10R,13R,14S,17R)-1-(acetoxy)-17-[(1R)-4-bromo-1-methylbutyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C28H43BrO4 | 详情 | 详情 | |
| (XVIII) | 12552 | (1S,3R,8S,9S,10R,13R,14S,17R)-1-(acetoxy)-10,13-dimethyl-17-[(1R)-1-methyl-4-(phenylsulfonyl)butyl]-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C34H48O6S | 详情 | 详情 | |
| (XIX) | 12553 | (4R)-4-[(1S,3S,8S,9S,10S,13R,14S,17R)-10,13-Dimethyl-1,3-bis[(trimethylsilyl)methyl]-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentyl phenyl sulfone; ([(1S,3S,8S,9S,10S,13R,14S,17R)-10,13-Dimethyl-17-[(1R)-1-methyl-4-(phenylsulfonyl)butyl]-3-[(trimethylsilyl)methyl]-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-1-yl]methyl)(trimethyl)silane | C38H64O2SSi2 | 详情 | 详情 | |
| (XX) | 12554 | (6R)-6-[(1S,3S,8S,9S,10S,13R,14S,17R)-10,13-Dimethyl-1,3-bis[(trimethylsilyl)methyl]-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1,1,1-trifluoro-3-(phenylsulfonyl)-2-(trifluoromethyl)-2-heptanol | C41H64F6O3SSi2 | 详情 | 详情 |