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【结 构 式】 
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【药物名称】Falecalcitriol, Flocalcitriol, Hexafluorocalcitriol, DSC-103, Ro-23-4194, ST-630, Fulstan, Horner 【化学名称】(+)-1alpha,25-Dihydroxy-26,26,26,27,27,27-hexafluorovitamin D3 【CA登记号】83805-11-2 【 分 子 式 】C27H38F6O3 【 分 子 量 】524.59251 |
【开发单位】Wisconsin Alumni Research Foundation (Originator), Kissei (Marketer), Sumitomo Pharmaceuticals (Licensee), Taisho (Licensee), Tetrionics (Bulk Supplier) 【药理作用】Bone Diseases, Treatment of, ENDOCRINE DRUGS, METABOLIC DRUGS, Thyroid Disease Therapy, Treatment of Hyperparathyroidism, Treatment of Osteoporosis, Vitamin D Analogs |
合成路线1
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
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 |
合成路线3
The Grignard condensation of carbaldehyde (I) with methylmagnesium bromide in ethyl ether gives the secondary alcohol (II), which is oxidized with TPAP and NMO in dichloromethane to yield the methyl ketone (III). The aldol reaction of (III) with hexafluoroacetone (IV) by means of LiHMDS in THF affords the hexafluorohydroxy ketone (V), which is reduced with NaBH4 in THF/methanol to provide the diol (VI). The selective acetylation of the secondary OH group of (VI) with Ac2O and pyridine gives the monoacetate (VII), which is treated with Mom-Cl and DIEA in order to protect its tertiary OH group, yielding (VIII). The deacetylation of (VIII) with KOH in methanol affords the secondary alcohol (IX), which is treated with CS2, NaH and Me-I to provide the thionocarbonate (X). The reduction of (X) with Bu3SnH in refluxing toluene gives the protected intermediate (XI), which is finally deprotected by reaction with methanesulfonic acid in methanol to yield the target vitamin D3 derivative.
| 【1】 Ikeda, M.; et al.; Synthesis and biological evaluations of A-ring isomers of 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3. Bioorg Med Chem 2000, 8, 8, 2157. |
| 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) | 25263 | (3R)-3-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]butanal | C35H62O3Si2 | 详情 | 详情 | |
| (II) | 55446 | (4R)-4-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}-2-pentanol | C36H66O3Si2 | 详情 | 详情 | |
| (III) | 55447 | (4R)-4-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}-2-pentanone | C36H64O3Si2 | 详情 | 详情 | |
| (IV) | 44260 | 1,1,1,3,3,3-hexafluoroacetone | 684-16-2 | C3F6O | 详情 | 详情 |
| (V) | 55448 | (6R)-6-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}-1,1,1-trifluoro-2-hydroxy-2-(trifluoromethyl)-4-heptanone | C39H64F6O4Si2 | 详情 | 详情 | |
| (VI) | 55449 | (6R)-6-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}-1,1,1-trifluoro-2-(trifluoromethyl)-2,4-heptanediol | C39H66F6O4Si2 | 详情 | 详情 | |
| (VII) | 55450 | 1-((2R)-2-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}propyl)-4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butyl acetate | C41H68F6O5Si2 | 详情 | 详情 | |
| (VIII) | 55451 | 1-((2R)-2-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}propyl)-4,4,4-trifluoro-3-(methoxymethoxy)-3-(trifluoromethyl)butyl acetate | C43H72F6O6Si2 | 详情 | 详情 | |
| (IX) | 55452 | (6R)-6-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}-1,1,1-trifluoro-2-(methoxymethoxy)-2-(trifluoromethyl)-4-heptanol | C41H70F6O5Si2 | 详情 | 详情 | |
| (X) | 55453 | O-[1-((2R)-2-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}propyl)-4,4,4-trifluoro-3-(methoxymethoxy)-3-(trifluoromethyl)butyl] S-methyl carbonodithioa | C43H72F6O5S2Si2 | 详情 | 详情 | |
| (XI) | 55454 | (1R,5S)-3-((Z)-2-{(1R,3aR,7aR)-7a-methyl-1-[(1R)-6,6,6-trifluoro-5-(methoxymethoxy)-1-methyl-5-(trifluoromethyl)hexyl]octahydro-4H-inden-4-ylidene}ethylidene)-5-{[tert-butyl(dimethyl)silyl]oxy}-4-methylenecyclohexyl tert-butyl(dimethyl)silyl ether; [((1R,5S)-3-((Z)-2-{(1R,3aR,7aR)-7a-methyl-1-[(1R)-6,6,6-trifluoro-5-(methoxymethoxy)-1-methyl-5-(trifluoromethyl)hexyl]octahydro-4H-inden-4-ylidene}ethylidene)-5-{[tert-butyl(dimethyl)silyl]oxy}-4-methylenecyclohexyl)oxy](tert-butyl)dimethylsilane | C41H70F6O4Si2 | 详情 | 详情 |