Improved Synthesis Intermediate Of Saxagliptin And Synthesis Characterization Of Pioglitazon Rosiglitazone Derivative

Saxagliptin(Sax) is a powerful selective dipeptidyl peptidase-IV(DPP-IV)inhibitor,which can specifically inhibit DPP-IV,thus prolonging endogenous glucagon-like peptide-1(GLP-1)and glucose-dependent insulin-releasing peptide,GIP)can promote the secretion of insulin(INS),protect the α and β cells of islet of Langerhans,and play a sustained and safe hypoglycemic effect.The main method of its preparation is the semi synthetic method proposed by the original research plant Bristol Myers Squibb Company,which is to synthesize the key intermediate3-hydroxy-α-oxoadamantane-1-aceticaid(HOAA)by chemical method first,and then to obtain Sax by enzymatic ammoniation.However,due to the highly symmetrical structure and good stability of adamantane ring,its oxidation reaction is very difficult to take place,and it needs very intense oxidation conditions to introduce hydroxyl.At the same time,due to the great hydrophobicity and poor solubility of adamantane ring,the reaction is often incomplete,which is manifested as low yield.Based on the above two reasons,the total yield of synthesis is limited,the synthesis difficulty of HOAA is increased,and it is not conducive to the amplification of Sax.Therefore,it is of great significance to improve the synthesis process of HOAA and explore an efficient,economic and green route suitable forlarge-scale industrial scale-up production,so as to promote the pharmaceutical research of sax and related adamantane derivatives.This paper reviews the existing methods of HOAA synthesis,comprehensively analyzes and evaluates the relevant routes,according to its advantages and disadvantages,combined with the previous research results of our research group,proposes a new method of preparing HOAA by esterification activation and re hydroxylation,that is,by acylation,condensation,decarboxylation,oxidation,esterification,hydroxylation,hydrolysis,seven steps of synthesis of HOAA,and processes each step The total yield of HOAA was 80%.The core of the process improvement lies in esterification and then hydroxylation.Through esterification of α-oxoadamantane-1-aceticaid,introduction of hydrocarbon groups and hyperconjugation,on the one hand,the electronic cloud density of adamantane ring as a whole is enhanced,making the oxidation more smooth,sealing the carboxyl group,protecting the unstable structure of α-oxoadamantane-1-aceticaid,avoiding decarboxylation into 1-adamantane carboxylic acid under severe oxidation,and improving the yield.Thiazolidinediones(TZDs)is a classic insulin sensitizer,which was once regarded as a star drug on the market.However,due to serious adverse reactions,potential cardiovascular risks and bladder cancer risks,it has been warned and restricted by the European Medicines Agency(EMA),the Food and Drug Administration(FMA)of the United States and China food and Drug Administration(CFDA).Although it has gradually lifted the ban in recent years,the safety of TZDs has been a problem,which limits the use of TZDs,and makes researchers’ research on TZDs less.However,the unique mechanism of TZDs resistance to IR,whether itis the International Diabetes Federation(IDF),American Diabetes Association(ADA),or Chinese Diabetes Society(CDS)and treatment guidelines,has not changed the recognition of its efficacy,the recommended position of TZDs in diabetes treatment has not changed,and TZDs is still the most powerful class of drugs found to protect β cell function,In the past two decades,the advantages and disadvantages of TZDs have been widely and comprehensively evaluated and discussed.Over time,TZDs not only proved their efficacy in improving insulin resistance,reducing plasma fatty acid level and lipid toxicity,but also in improving blood glucose and lipid metabolism in many aspects.We also found anti-inflammatory,anti breast cancer,improvement of mental illness(Alzheimer’s disease),diabetic nephropathy,anti non-alcoholic fatty liver,polycystic ovary syndrome and other hypoglycemic effects.Therefore,the development of new TZDs to overcome its unnecessary side effects can undoubtedly create great possibilities.In this paper,pioglitazone(PGZ),which has less adverse reactions reported in TZDs,was selected as the mother.Based on the previous experience of the research group,in order to reduce the adverse reactions and enhance the pharmacological activity of TZDs,11 new compounds were synthesized by derivative modification.The results of IR,NMR and MS showed that the structure of 11 compounds was correct,which laid a foundation for the screening of new drugs of TZDs.