Research On The Synthesis Route Of Vitamin D Derivatives

Falecalcitriol can be used for the treatment of hyperparathyroidism in patients with renal dialysis,osteoporosis,and psoriasis,and its effect is better than calcitriol and other vitamin D analogs.And does not produce persistent hypercalcemia and hyperphosphatemia.However,there are few reports on the synthesis route of falecalcitriol.Therefore,this research group has developed a new synthetic route for falecalcitriol,that is,intermediate A and the fluorinated fragment undergo Wittig reaction,reduction reaction,light isomerization,and deprotection to synthesize falecalcitriol.Compared with the 18 steps reported in the literature,the 16 steps reaction of this route is relatively simple,and the yield of this experiment is quite considerable.In this thesis,vitamin D₂ is used as a raw material,and intermediate A is finally formed after eight steps of reaction.After that,in the process of splicing fragments B,C,D and benzaldehyde,determine the method of feeding in the order of fragment B（C,D）and benzaldehyde,and optimize the proportion.The ratio is 1:2.5:2,making the yields43.30%,46.15%,and 36.14%,respectively.Through optimization of conditions,the splicing yield of intermediate A and fragments C was 30.67%.The splicing product of intermediate A and fragments C was reduced to obtain the target product with a yield of40.11%.By improving the reaction conditions,the process route for the synthesis of intermediate A was finally determined.（1）In the protection of conjugated double bonds of vitamin D₂,liquid SO₂ should be added first,then vitamin D₂ should be added,and the yield of compound 49should be 98.90%in about 25 minutes of reaction at（-11±2）℃.（2）Using anhydrous CH₂Cl₂ as a solvent,the hydroxyl protection of Compound 49 was performed at 20℃,so that the yield of Compound 50 reached97.82%.（3）When the SO₂ group of compound 50 is removed,a molar ratio of 1:4.57 of substrate:NaHCO₃ is used in this experiment,and the reaction is performed at 82℃for 2.6 hours,so that the yield of compound 51 is 98.83%.（4）When allylic oxidation of compound 51 is performed,the molar ratio of compound 3:selenium dioxide:NMO is optimized to 0.9:1:4.5,and the NMO is dehydrated for 2 hours to obtain the yield of compound 52.It is 67.97%,which is 13.97%higher than the literature^[150].（5）When compound 53 is protected by a conjugated double bond,anhydrous diethyl ether is used as a reaction solvent,so that the yield of compound 54 is 98.10%.Through the improvement of the intermediate A synthesis process,the final yield was 28.88%higher than that in the literature^[164],which was 56.14%.