Synthesis Of 1?-Hydroxyprovitamin D₃ And 25-hydroxyvitamin D₃

As semi-active metabolites of vitamin D₃,both 1?-OH-VD₃ and25-OH-VD₃ own higher physiological activities than parent vitamin D₃.1?-OH-VD₃ can be clinically used as a treatment for some diseases such as osteoporosis,nephrosis,hyperthyroidism etc.25-OH-VD₃,the main form of VD₃ in the blood circulation,is widely used in many areas such as medicine,health products,food,feed and so on.In this thesis,some plausible synthetic routes of 25-OH-VD₃ as well as1?-hydroxyprovitamin D₃?1?-hydroxy-7-dehydrocholesterol?,the potoprecusor of 1?-OH-VD₃,were designed,experimentally verified and optimized.The first chapter comprehensively introduced the pharmacological activity of vitamin D₃ and its wide application in the treatment of rickets,cancer,diabetes,nephrosis,and some immune system diseases.The second chapter reviewed the known methods of synthesizing1?-hydroxy-7-dehydrocholesterol,and made an specific introduction from the following three aspects:synthesis of 1?-hydroxycholesterol,introduction of double bond in C-7 position of ring B and preparation of1?-hydroxy-7-dehydrocholesterol through enol acetylation of cholest-1,4,6-triene-3-one.The third chapter introduced the pharmacological activity of25-OH-VD₃ and presented the synthetical methods of 25-OH-VD₃ from three aspects:total-chemical synthesis,semi-chemical synthesis and biological synthesis.In the fourth chapter,the synthetic strategies of1?-hydroxy-7-dehydrocholesterol were designed and the feasibility of synthesizing the key intermediate cholesta-1,4,6-trien-3-one was verified by experimental.Cholesta-1,4,6-trien-3-one could be obtained from cholesterol employing the following four routes:1)DDQ-mediated dehydrogenation,2)Oppenauer oxidation-DDQ dehydrogenation,3)oxidation-bromination-dehydrobromination,4)bromination-oxidation-bromination-dehydrobromination.Experimental results showed that all of these four routes were feasible and could give the desired product.The highest yield was obtained when employing the third method and it also avoided the disadvantages of massive use of DDQ.In the fifth chapter,the feasibility of the designed synthetic route of1?-hydroxy-7-dehydrocholesterol from cholesta-1,4,6-trien-3-one was investigated.Initially,the intermediate ester containing 1,2-double bond was obtained through enol acetylation,reduction,D-A reaction and acetylation of cholesta-1,4,6-trien-3-one.Three methods were designed to introduce C-1 hydroxyl group:1)acid additon-reduction,2)halohydoxylation-reduction,and 3)epoxidation-reduction.The results showed that through silyl protection,epoxidation,desilylation and reduction,the target product could be obtained from cholesta-1,4,6-trien-3-one with 38%yield.Method?1?could not give the target product because of the elimination of 3-hydroxyl group under acidic condition.Method?2?provided a new way to synthesize the similar derivatives,including 1?-hydroxy-7-dehydrocholesterol and2?-hydroxy-7-dehydrocholesterol,with yield of 49%and 37%respectively.The designed methods for preparation of 25-hydroxy-7-dehydrocholesterol were verified through experiments in the sixth chapter.Starting from 7-dehydrodesmosterol,25-hydroxyl-7-dehydrocholesterol was obtained through the following two methods:1)halohydroxylation-reduction,2)acid additon-reduction.The results indicated that both of the two methods were feasible and the products were obtained with a yield of 72%and 73%after optimization of the synthetic process.However,the route for preparation of 25-hydroxy-7-dehydrocholesterol using 7-dehydrocholesterol as the starting material through 25-SP³C-H activated reaction was not successful.Finally,25-hydroxy-7-dehydrocholesterol was converted to 25-OH-VD₃via the photoisomerization with 64%yield.In summary,a preferred route for preparation of1?-hydroxy-7-dehydrocholesterol from cholesterol,25-hydroxyvitamin D₃ from 7-dehydrodesmosterol was proposed after analysis of experimental data.1?-OH-7-DHC and 25-OH-VD₃ was obtained with a yield of 27%and 47%respectively,which was higher than those in previous reported.