【结 构 式】 |
【分子编号】12425 【品名】(1S)-3-((Z)-2-[(1R,3aR,7aR)-7a-Methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]ethylidene)-4-methylenecyclohexanol 【CA登记号】50-14-6 |
【 分 子 式 】C28H44O 【 分 子 量 】396.65676 【元素组成】C 84.79% H 11.18% O 4.03% |
合成路线1
该中间体在本合成路线中的序号:(I)The reaction of vitamin D2 (I) with refluxing liquid SO2 gives a mixture of the 6(R)- and 6(S)-SO2-adducts (II), which by treatment with tert-butyl-dimethylsilyl chloride (TBDMSCI) and imidazole in DMF yields the corresponding mixture of silylated adducts (III). The reaction of the mixture (III) with NaHCO3 in ethanol affords the silylated 5(E)-vitamin D2 (IV), which by oxidation with SeO2 and N-methylmorpholine N-oxide in refluxing methanol-dichloromethane is converted into a mixture of silylated 1(S)- and 1(R)-hydroxy-5(E)-vitamin D2 (V). The silylation of (V) as before, followed by crystallization in ethyl ether-ethanol gives the 1(S)-isomer of the fully silylated compound (VI), which is treated with refluxing SO2 as before to yield the mixture of the 6(R)- and 6(S)-SO2-adducts (VII). The ozonolysis of the mixture (VII) in dichloromethane-methanol at -65 C affords the corresponding mixture of the 6(R)- and 6(S)-SO2-aldehydic adducts (VIII).
【1】 Calverley, M.J.; Synthesis of MC 903, a biologically active vitamin D metabolite analogue. Tetrahedron 1987, 43, 20, 4609-19. |
【2】 Binderup, E.; CALCIPOTRIOL. Drugs Fut 1990, 15, 1, 15. |
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) | 12425 | (1S)-3-((Z)-2-[(1R,3aR,7aR)-7a-Methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]ethylidene)-4-methylenecyclohexanol | 50-14-6 | C28H44O | 详情 | 详情 |
(II) | 12426 | (6S)-1-([(1R,3aR,7aR)-7a-Methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]methyl)-6-hydroxy-1,3,4,5,6,7-hexahydro-2H-2-benzothiophene-2,2-dione | C28H44O3S | 详情 | 详情 | |
(III) | 12427 | (6S)-1-([(1R,3aR,7aR)-7a-Methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]methyl)-6-[[tert-butyl(dimethyl)silyl]oxy]-1,3,4,5,6,7-hexahydro-2H-2-benzothiophene-2,2-dione | C34H58O3SSi | 详情 | 详情 | |
(IV) | 12428 | (1S)-3-((E)-2-[(1R,3aR,7aR)-7a-Methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]ethylidene)-4-methylenecyclohexyl tert-butyl(dimethyl)silyl ether; [[(1S)-3-((E)-2-[(1R,3aR,7aR)-7a-Methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]ethylidene)-4-methylenecyclohexyl]oxy](tert-butyl)dimethylsilane | C34H58OSi | 详情 | 详情 | |
(V) | 12429 | (5R)-3-((E)-2-[(1R,3aR,7aR)-7a-Methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]ethylidene)-5-[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexanol | C34H58O2Si | 详情 | 详情 | |
(VI) | 12430 | [((1R,5S)-3-((E)-2-[(1R,3aR,7aR)-7a-Methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]ethylidene)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylenecyclohexyl)oxy](tert-butyl)dimethylsilane | 111594-58-2 | C40H72O2Si2 | 详情 | 详情 |
(VII) | 12431 | (4S,6R)-1-([(1R,3aR,7aR)-7a-Methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]methyl)-4,6-bis[[tert-butyl(dimethyl)silyl]oxy]octahydro-2H-2-benzothiophene-2,2-dione | C40H74O4SSi2 | 详情 | 详情 | |
(VIII) | 12432 | (2S)-2-[(1R,3aR,7aR)-4-[(E)-((4S,6R)-4,6-bis[[tert-Butyl(dimethyl)silyl]oxy]-2,2-dioxooctahydro-1H-2-benzothiophen-1-yl)methylidene]-7a-methyloctahydro-1H-inden-1-yl]propanal | C34H62O5SSi2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(XXIII)The silylation of vitamin D2 (XXIII) with TBDMS-Cl and imidazole in dichloromethane gives the silyl ether (XXIV), which is cyclized with N-sulfinyl-p-toluenesulfonamide yielding the Diels-Alder adduct (XXV). The oxidation of (XXV) with SeO2 and N-methylmorpholine-oxide in ethanol affords the trans-1alpha-hydroxy-3-O-(tert-butyldimethylsilyl)vitamin D2 (XXVI), which is irradiated with UV light in benzene containing anthracene yielding 1alpha-hydroxy-3-O-(tert-butyldimethylsilyl)vitamin D2 (XXVII). Finally, this compound is desilylated with TBAF in THF. The cyclization of the silyl ether (XXIV) can also be performed with Ts-N=Se=N-Ts yielding the corresponding adduct (XXVIII), which is oxidized with SeO2 as before to afford the trans-1alpha-hydroxy-3-O-(tert-butyldimethylsilyl) vitamin D2 (XXVI) already reported.
【1】 Guo, L.; Moriarty, R.M.; Penmasta, R.A. (Lunar Corp.); Synthesis of 1alpha-hydroxy vitamin D. WO 9602501 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XXIII) | 12425 | (1S)-3-((Z)-2-[(1R,3aR,7aR)-7a-Methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]ethylidene)-4-methylenecyclohexanol | 50-14-6 | C28H44O | 详情 | 详情 |
(XXIV) | 34603 | [[(1S)-3-((Z)-2-[(1R,3aR,7aR)-7a-methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]ethylidene)-4-methylenecyclohexyl]oxy](tert-butyl)dimethylsilane; (1S)-3-((Z)-2-[(1R,3aR,7aR)-7a-methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]ethylidene)-4-methylenecyclohexyl tert-butyl(dimethyl)silyl ether | C34H58OSi | 详情 | 详情 | |
(XXV) | 34600 | (5S)-4-([(1R,3aR,7aR)-7a-methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]methyl)-5-[[tert-butyl(dimethyl)silyl]methyl]-3-[(4-methylphenyl)sulfonyl]-3,4,5,6,7,8-hexahydro-2lambda(4),3-benzothiazin-2(1H)-one | C42H67NO3S2Si | 详情 | 详情 | |
(XXVI) | 34601 | (1S,5R)-3-((E)-2-[(1R,3aR,7aR)-7a-methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]ethylidene)-5-[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexanol | C34H58O2Si | 详情 | 详情 | |
(XXVII) | 34604 | (1S,5R)-3-((Z)-2-[(1R,3aR,7aR)-7a-methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]ethylidene)-5-[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexanol | C34H58O2Si | 详情 | 详情 | |
(XXVIII) | 34599 | N-[(5S)-4-([(1R,3aR,7aR)-7a-methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]methyl)-5-[[tert-butyl(dimethyl)silyl]methyl]-3-[(4-methylphenyl)sulfonyl]-3,4,5,6,7,8-hexahydro-2lambda(4),3-benzoselenazin-2(1H)-ylidene]-4-met | C49H74N2O4S2SeSi | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(XXIII)By allylic oxidation of vitamin D2 (XXIII) with SeO2 and tert-butyl hydroperoxide in pyridine followed by purification by TLC over silicagel. The allylic oxidation of trans-vitamin D2 (XXIX) with SeO2, tert-butyl hydroperoxide and octahydroacridine in dichloromethane gives the trans-1alpha-hydroxyvitamin D2 (XXX), which is isomerized to the target compound by irradiation with UV light with anthracene as photosensitizer.
【1】 Schnoes, H.K.; Paaren, H.E.; DeLuca, H.F.; Hamer, D.E. (Wisconsin Alumni Research Foundation); Process for preparing 1-hydroxylated vitamin D cpds. from 5,6-trans-vitamin D cpds.. US 4265822 . |
【2】 DeLuca, H.F.; Hamer, D.E.; Paaren, H.E.; Schnoes, H.K. (Wisconsin Alumni Research Foundation); Process for preparing 1alpha-hydroxylated cpds.. US 4202829 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XXIII) | 12425 | (1S)-3-((Z)-2-[(1R,3aR,7aR)-7a-Methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]ethylidene)-4-methylenecyclohexanol | 50-14-6 | C28H44O | 详情 | 详情 |
(XXIX) | 34605 | (1S)-3-((E)-2-[(1R,3aR,7aR)-7a-methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]ethylidene)-4-methylenecyclohexanol | C28H44O | 详情 | 详情 | |
(XXX) | 34602 | (1R,3S)-5-((E)-2-[(1R,3aR,7aR)-7a-methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]ethylidene)-4-methylene-1,3-cyclohexanediol | C28H44O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(XXIII)
【1】 Andrews DR, Barton DHR, et aL. 1986.A direct, regio- and stereoselective lα-rhydroxylation of (5E-calciferol derivatives.J Org Chem, 51: 1635~1637 |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XXIII) | 12425 | (1S)-3-((Z)-2-[(1R,3aR,7aR)-7a-Methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]ethylidene)-4-methylenecyclohexanol | 50-14-6 | C28H44O | 详情 | 详情 |
(XXVI) | 34601 | (1S,5R)-3-((E)-2-[(1R,3aR,7aR)-7a-methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]ethylidene)-5-[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexanol | C34H58O2Si | 详情 | 详情 | |
(XXVII) | 34604 | (1S,5R)-3-((Z)-2-[(1R,3aR,7aR)-7a-methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]ethylidene)-5-[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexanol | C34H58O2Si | 详情 | 详情 | |
(XXIX) | 34605 | (1S)-3-((E)-2-[(1R,3aR,7aR)-7a-methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]ethylidene)-4-methylenecyclohexanol | C28H44O | 详情 | 详情 | |
(XXXI) | 12428 | (1S)-3-((E)-2-[(1R,3aR,7aR)-7a-Methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]ethylidene)-4-methylenecyclohexyl tert-butyl(dimethyl)silyl ether; [[(1S)-3-((E)-2-[(1R,3aR,7aR)-7a-Methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]octahydro-4H-inden-4-ylidene]ethylidene)-4-methylenecyclohexyl]oxy](tert-butyl)dimethylsilane | C34H58OSi | 详情 | 详情 |