Synthesis Of Tasquinimod And Obeticholic Acid

The thesis consists of two parts, the synthesis of new angiogenesis inhibitors Tasquinimod and Farnesoid X Receptor (FXR) agonist Obeticholic Acid.The first part is the synthesis of Tasquinimod. Tasquinimod is a novel oral anti-prostate cancer drug which was developed by Ipsen and Active Biotech. At present, Phase III clinical trial of Tasquinimod is finished. During the process of synthesizing Tasquinimod, a suitable synthetic route was selected through comparing different methods. Tasquinimod was synthesized from 2,6-difluorobenzonitrile (1) by nucleophilic substitution, hydrolyzation, cyclization, decarboxylation and cyclization, and amidation with an overall yield of 50.8%. Firstly, 2-methoxy-6-(methylamino)benzonitrile (2) was purified through salifying with concentrated hydrochloric acid to obtain product with high purity (99%). Secondly, the reaction condition of hydrolyzation was optimized, the yield was increased from 60% to 71.7%. Thirdly, several malonic esters and alkalis were screened for the synthesis of key intermediate ethyl 4-hydroxy-5-methoxy-1-methyl-2-oxo-1,2-dihydroqui-noline-3-carboxylate (5). We used diethyl malonate and sodium ethoxide to achieve the highest yield, and we effectively reduced the side reaction by removing generated ethanol through vacuum distillation. We successfully increased the overall yield of intermediate 5 from 48% to 53.8%. Indicated by LC-MS, qualified final product with high purity was obtained. Finally, The impurities above were synthesized and was confirmed by 1H-NMR and MS. Tasquinimod obtained was confirmed by MS、1H-NMR、 13C-NMR, and its purity was 99.9%.The second part is the synthesis of Obeticholic Acid. Obeticholic Acid is an oral FXR agonist, developed by Intercept for the treatment of primary biliary cirrhosis (PBC) patients who has no ability to tolerate UDCA or inadequately responses to UDCA. Now Phase Ⅲ clinical trial is finished.Obeticholic Acid owns fast track designation in the US and orphan drug designation in the US and Europe for the treatment of PBC. Obeticholic Acid may has became a preferred new method of the treating PBC over the next 20 years. In this paper, Obeticholic Acid was synthesized from chenodeoxycholic acid(CDCA) which was much cheaper via 6 steps with an overall yield of 27%, including oxidation, esterification, enolization, aldol condensation, hydrogenation-reduction and carbonyl reduction. In the oxidation step, NBS was used as oxidant instead of sodium hypochlorite to simplify the experimental operation and improve the reaction yield. In the next transformation, also known as esterification, we found that using the cheap, easily preserved K2CO3 as catalyst could achieve a higher yield then Cs2CO3. Through reducing benzyl bromide to 3 equivalent we could purify the final product by recrystallization without column chromatography. The structure of Obeticholic Acid prepared was confirmed by MS,1H-NMR,13C-NMR, and DEPT and the purity was 99.87%. Furthermore, two isomers were synthesized to lay the foundation of quality control of final product which were confirmed by MS, 1H-NMR and 13C-NMR.