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【结 构 式】

【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
      1(S),24(S)-Dihydroxy-22,23:26,27-tetradehydrovitamin D3

【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
Extended Information