Study On The Synthesis Of A Novel Angiotensin Converting Enzyme Inhibitor 221s(2,9)

Hypertension is one of the most common diseases of cardiovascular and cerebrovascular diseases, and also a major risk factor for a series of complications such as cerebral vascular accident, hypertension, heart failure and renal failure. As a first-line antihypertensive drug in the treatment of hypertension, angiotensin converting enzyme inhibitors can regulate blood pressure by acting on renin angiotensin aldosterone system, kallikrein kinin system and etc. 221s(2,9) is a novel angiotensin converting enzyme inhibitor, which is based on Combined Chinese Medicine Molecular Chemistry strategy. (S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 1-((S)-2-((R)-3-(3,4-dihydroxyphenyl)-2-hydroxypropanamido)propanoyl)pyrrolidine-2-carbo xylate is its chemical name. Pre-experimental in vivo and in vitro activity tests have showed that the compound possesses an equivalent antihypertensive activity compared to captopril.In this paper, we design a new synthetic route of 221s(2,9), subsequently optimize and enlarge its production process. Boc-Pro-Borneol ester as well as Boc-Ala-Pro-Borneol ester and DSS-Ala-Pro-borneol ester are synthesized through acyl chloride esterification method and mixed acid anhydride method, respectively. Compared to early synthetic routes, not only the total yield is increased from less than 10% to 63%, but labor intensity and cost of production are also reduced, meanwhile, also lays the foundation for the possible industrial production of 221s(2,9). This paper is divided into three chapters and the main research contents are as follows:(1) Using mid infrared online process analysis, full band scanning of synthesis process of precursor Boc-Pro-Borneol ester of key intermediate is carried out. Based on the principal component analysis results, the data point table collected in the process of the reaction process is analyzed using MCR-ALS, which results in the concentration versus time curve of one pot synthesis of reactant, intermediate and product of Boc-Pro-Borneol ester. Thus provides a reference for further optimization of the synthesis of Boc-Pro-Borneol ester. Further optimizations not only avoid the formation of prolyl cyclic dipeptide, but also avoid Vilsmeier reagent's reaction with D-Borneol to generate D-Borneol formic acid ester. Thereby, the yield of the ester bond is improved by 20% and the reaction time is shortened by 88%, and the intermediate is not required column purification. In addition, through a series of optimization on the synthesis of H2N-Ala-Pro-Borneol ester and DSS-Ala-Pro-Borneol ester, optimum carboxyl activating agent, polypeptide condensing agent as well as reaction temperature are preferably obtained. Thus, the yield of the synthesized amide bond is increased by 50% and the reaction time is reduced by 94%.(2) Based on the new synthetic route of 221s(2,9), the realization of kg-grade productions of Boc-Pro-Borneol ester, Pro-Borneol ester and Boc-Ala-Pro-Borneol ester as well as 100 g level production of H2N-Ala-Pro-Borneol ester are achieved. The structure of partial intermediates and final product are identified by 1HNMR,13CNMR and MS, which are proved to be correct. And the further HPLC determination of final product shows that its chemical purity is no less than 95%.