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【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%

与该中间体有关的原料药合成路线共 4 条

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
Extended Information