Preparation Of Aldosterone By C-20 Hydroxyl-oriented [1,5]-hydrogen Migration Iodization Under Light Conditions

Steroids are widely distributed in animals and plants and have broad-spectrum biological activities.They have been applied in many fields of pharmaceutical chemistry.For example,this paper relates to the two steroidal compounds.aldosterone,which has pharmacological activities such as regulating water and salt metabolism and maintaining electrolyte balance.2-methoxyestradiol?2ME?,which can inhibit cell proliferation,induce cell apoptosis,and inhibit angiogenesis.The first part of this paper is to explore the preparation of aldosterone by[1,5]-hydrogen transfer,and the second part is to optimize the synthesis process of 2ME.Part ?:Using hydrocortisone as raw material,a new idea of C?sp³?-H bond functional group is adopted in this paper,preparation of aldosterone by C-20hydroxyl-oriented[1,5]-hydrogen migration iodization under light conditions.AcOI is used as iodine positive ion source,C-18 angle methyl hydrogen undergoes iodination under light,and then aldosterone was prepared by converting C-18 iodine into aldehyde group.Compared with D.H.R.Barton's method of esterifying C-11hydroxyl nitrite,which produces[1,5]-hydrogen migration nitrosation reaction of C-18 angle methyl hydrogen under light,and then aldosterone was prepared by converting C-18 nitrosation into aldehyde group,This method has better selectivity and simpler operation.In this paper,we try two strategies:strategy 1,referring to the method of D.H.R.Barton et al,using the C-11 hydroxyl group as the guiding group.strategy 2,creatively using the hydroxyl group reduced by C-20 carbonyl as the guiding group.Finally,50 g of iodide product A6 was successfully synthesized by using hydroxyl group reduced by C-20 carbonyl group as the guiding group.The yield of iodization mediated by C-11 hydroxyl group was 25%,The C-20 hydroxyl-mediated iodization reaction was highly selective and the yield was 83.1%.Subsequently,we successfully hydroxylated C-18 iodin by Dess-Martin oxidation and AgOAc hydrolysis;C-18hydroxyaldehyde was successfully alkylated by NaBH₄ reduction and Swern oxidation,and aldosterone A11 was prepared by LiOH hydrolysis.Overall,aldosterone was successfully synthesized from hydrocortisone in 10 steps with a total yield of 3.1%,using highly selective iodization mediated by C-20 hydroxyl group as an innovative point.Part ?:In this paper,on the basis of P.Narasimha Rao two-step synthesis of2ME,the process was optimized,the method was optimized.The method of recrystallization and purification of 2-bromoestradiol was improved.After succinimide was removed by washing,4-bromoestradiol was removed by ethanol recrystallization,and mother liquor was directly put into the next reaction.The method of recrystallization and purification of 2ME was successfully explored.Activated carbon in ethyl acetate was decolorized and recrystallized with chloroform to produce 2ME white powder.At the same time,a large number of screening conditions have been carried out,such as:the replacement of brominated reagent2,4,4,6-tetrabromo-2,5-cyclohexanedione with NBS,which facilitated post-treatment;the concentration of methoxy reagent NaOMe was changed from 2M to 5M,which improved the conversion rate.In general,2ME was prepared from estradiol in 19.5%yield and 90.2%purity by recrystallization after two steps of bromination and methoxylation.