Synthesis Of20-formyl-vitamin D Analogues Intermediate And Its Derivatives

As common drugs, vitamin D analogues have been widely used in the clinical treatment of various diseases, such as Tacalcitol, Calcipotriol, Seocalcitol, Calcitriol, Maxacalcitol, etc. There was a common "intermediate"—1(S),3(R)-Bis-(tert-butyldimethylsilyloxy)-20(S)-formyl-9,10-secopregna-5(E),7(E),10(19)-triene in the synthesis process of those analogues. In this paper, we analyzed several preparation methods of the "intermediate", and developed a suitable route considering industrial cost, green chemistry, atom economy, safety and other factors. The route was first found by Calverley in1987, but it involved several chiral center formation and configuration transformation which increased the difficulty of synthesis. The original conditions were not suitable for the amplification of production. Based on this, we studied the preparation technology deeply and thoroughly to make it more suitable for industrialization.Using3(R)-(tert-butyldi-methylsilyloxy)-9,10-seco-ergosta-5(E),7(E),10(19),22(E)-tetraene as starting material, the "intermediate" was prepared through5steps including1a-hydroxylation, hydroxyl protection, SO2cycloaddition, ozonization and deprotection of SO2. Also, we deeply studied the reaction mechanisms, side reactions and influence factors of each step to find the best process conditions through single factor experiments.Based on the "intermediate", we studied its protection and deprotection, epimerization methods. Besides, we prepared1(S),3(R)-Bis-(tert-butyldimethylsilyloxy)-20(S)-22-Br-9,10-seco-ergosta-5(E),7(E),10(19)-triene through4steps including ozonization, deprotection of SO2, tosylation reaction and bromination using1(S),3(R)-Bis-(tert-butyldimethylsilyloxy)-9,10-seco-ergosta-5,7(E),10(19),22(E)-tetraene-6(S)-SO2-adducts as starting material which laid a foundation for the synthesis of Vitamin D Grignard reagent.