Lexacalcitol, KH-1060

来沙骨化醇Chemical Name: 20(R)-(4-Ethyl-4-hydroxyhexyloxy)-1(S),3(R)-dihydroxy-9,10-secopregna-5(Z),7(E),10(19)-triene
CAS No. 131875-08-6
项目整合开发状态: Phase II
项目研究机构: Leo (Originator)
合成路线:Lexacalcitol can be obtained by two related ways:1) The decarboxylative oxidation of 1(S),3(R)-bis(tert-butyldimethylsilyloxy)-20(S)-formyl-9,10-secopregna-5(E),7(E),10(19)-triene (I) by bubbling air and catalyzed by cupric acetate and 1,4-diazabicyclo[2.2.2]octane in DMF gives compound (II) with a keto group at C20.The reduction of (II) with NaBH4 in THF/methanol yields the corresponding alcohol (III) as the 20(R)-isomer,which is condensed with 6-bromo-3-ethyl-3-(trimethylsilyloxy)hexane (IV) by means of potassium tert-butoxide in THF,affording 1(S),3(R)-bis(tert-butyldimethylsilyloxy)-20(R)-[4-ethyl-4-(trimethylsilyloxy)hexyl]-9,10-secopregna-5(E),7(E),10(19)-triene (V).Isomerization of (V) by irradiation with a UV lamp with anthracene as photosensitizer in dichloromethane gives the corresponding 5(Z),7(E),10(19)-isomer (VI),which is finally deprotected with HF in ethyl acetate/acetonitrile/water.2) The condensation of alcohol (III) with 6-bromo-3-ethyl-3-(tetrahydropyran-2-yloxy)hexane (VII) with potassium tert-butoxide as before gives 1(S),3(R)-bis(tert-butyldimethylsilyloxy)-20(R)-[4-ethyl-4-(tetrahydropyran-2-yloxy)hexyl]-9,10-secopregna-5(E),7(E),10(19)-triene (VIII),which is isomerized with UV light and anthracene as before,affording the corresponding 5(Z),7(E),10(19)-isomer (IX).Finally,this compound is also deprotected with HF in the same mixture of solvents.