Process Development For The Synthesis Of Intermediates Of Darunavir

Darunavir,an HIV(Human Immunodeficiency Virus)protease inhibitor,is used in the clinical treatment of AIDS to interrupt the replication process of HIV and improve the symptoms of autoimmune disease by specifically binding to the active site of HIV protease.(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol is a key intermediate of HIV protease inhibitors with lower toxicity and better drug resistance.The reported routes of(3R,3aS,6aR)-hexahydro-furo[2,3-b]furan-3-ol have many problems,such as high production costs,low yield of product,difficulties in the purification of intermediates.Therefore,the study on the synthesis of the intermediate is of great significance for the production of darunavir.In this paper,L-ascorbic acid was selected as the chiral substrate by analyzing the existing literature.(3R,3aS,6aR)-hexahydro-furo[2,3-b]furan-3-ol was synthesized in eight steps with Knoevenagel reaction,Michael addition reaction,Nef reaction and Krapcho dealkoxycarbonylation reaction as the key steps.Subsequently,the selected key steps were studied in detail,and a better process was obtained.The influence of catalyst on the Knoevenagel reaction was explored,and it was found that the by-product could be effectively inhibited when pyridine was used.The final yield could reach 80.3% with fewer catalyst and shorter reaction time.The effect of the ester groups on the yield and diastereoselectivity in Michael addition reaction was investigated,and1,3-Dimethyl-2-[[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methylene]propanedioate was determined as the better substrate with 93.5% yield and 96.6% de.Considering the instability of the product of Michael addition reaction,Methyl(3R,3aS,4S,6aR)-hexahydro-4-methoxy-2-oxofuro[3,4-b]furan-3-carboxylate was directly synthesized by one-pot method from1,3-Dimethyl-2-[[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methylene]propanedioate with55.0% yield,which was higher than the 48% yield reported in the literature.Two reaction routes had been studied for the synthesis of(3aS,4S,6aR)-4-Methoxy-tetrahydro-furo[3,4-b]furan-2(3H)-one.By studying the two-step reaction route of decarboxylation and esterification,the optimized yield could reach 63.7%.In Krapcho dealkoxycarbonylation reaction route,the lactone removed carboxyl group without ring opening,which effectively avoided the polymerization reaction of the intermediates and the yieid could reach 82.2%.The yield was higher than the 52% yield reported in the literature.By studying the mechanism of the reduction reaction and intramolecular cyclization reaction,the optimized yield could reach 81.1% with lower cost and milder reaction conditions.In this paper,a synthetic process route with higher reaction yield,lower cost,milder reaction conditions and simpler operations for(3R,3aS,6aR)-hexahydro-furo[2,3-b]furan-3-ol was developed,which had a good application prospect.