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【结 构 式】 
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【药物名称】Calcipotriene, Calcipotriol, BMS-181161, MC-903, Psorcutan, Divonex, Dovonex, Daivonex 【化学名称】20(R)-[3'(S)-Cyclopropyl-3'-hydroxyprop-1'(E)-enyl]-1(S),3(R)-dihydroxy-9,10-secopregna-5(Z),7(E),10(19)-triene 【CA登记号】112828-00-9, 112965-21-6 (no stereoch. at C24) 【 分 子 式 】C27H40O3 【 分 子 量 】412.61805 |
【开发单位】Leo (Originator), Bristol-Myers Squibb (Licensee), CSL (Licensee), Fujisawa (Licensee), Schering AG (Licensee), Teikoku Seiyaku (Licensee), Galen (Comarketer) 【药理作用】Antipsoriatics, DERMATOLOGIC DRUGS, Vitamin D Analogs |
合成路线1
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
The treatment with NaHCO3 of the corresponding mixture of the 6(R)- and 6(S)-SO2-aldehydic adducts (VIII) gives a mixture of the 20(R) and 20(S) epimeric aldehydes (IX). The Wittig condensation of the aldehyde mixture (IX) with cyclopropylcarbonylmethylenetriphenylphosphorane (X) [prepared from acetylcyclopropane (XI) by bromination to bromoacetylcyclopropane (XII), reaction with triphenylphosphine (XIII) to the phosphonium salt (XIV) and treatment with NaOH] in DMSO at 105 C, followed by chromatographic separation yields the epimeric 20(R)-enone (XV). The reduction of (XV) with NaBH4 and CeCl3 in THF-methanol, followed by chromatographic purification affords the epimeric 3'(R)-allylic alcohol (XVI), which is isomerized by irradiation with UV-light from a TQ 718Z2 Hanau lamp in toluene in the presence of anthracene to give the corresponding 5(Z)-derivative (XVII). Finally, this compound is deprotected by a treatment with tetrabutylammonium fluoride in THF at 60 C.
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (IX) | 12433 | 2-[(1R,3aS,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-Butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]propanal | C34H60O3Si2 | 详情 | 详情 | |
| (X) | 12434 | 1-cyclopropyl-2-(triphenylphosphoranylidene)-1-ethanone | C23H21OP | 详情 | 详情 | |
| (XI) | 12435 | Acetylcyclopropane; 1-Cyclopropyl-1-ethanone; Cyclopropylmethylketone | 765-43-5 | C5H8O | 详情 | 详情 |
| (XII) | 12436 | 2-Bromo-1-cyclopropyl-1-ethanone | 69267-75-0 | C5H7BrO | 详情 | 详情 |
| (XIII) | 12437 | Triphenylphosphine; Triphenyl phosphine | 603-35-0 | C18H15P | 详情 | 详情 |
| (XIV) | 12438 | (2-Cyclopropyl-2-oxoethyl)(triphenyl)phosphonium bromide | 112849-15-7 | C23H22BrOP | 详情 | 详情 |
| (XV) | 12439 | (E,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]-1-cyclopropyl-2-penten-1-one | C39H66O3Si2 | 详情 | 详情 | |
| (XVI) | 12440 | (1S,2E,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]-1-cyclopropyl-2-penten-1-ol | C39H68O3Si2 | 详情 | 详情 | |
| (XVII) | 12441 | (1S,2E,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]-1-cyclopropyl-2-penten-1-ol | C39H68O3Si2 | 详情 | 详情 |