Calcipotriene, Calcipotriol, BMS-181161, MC-903, Psorcutan, Divonex, Dovonex, Daivonex

卡泊三醇 卡泊三醇 Chemical Name: 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
CAS No. 112828-00-9, 112965-21-6 (no stereoch. at C24)
项目整合开发状态: Launched-1991
项目研究机构: Leo (Originator), Bristol-Myers Squibb (Licensee), CSL (Licensee), Fujisawa (Licensee), Schering AG (Licensee), Teikoku Seiyaku (Licensee), Warner Chilcott (Comarketer)
合成路线: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).

合成路线: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.