Continuous Flow Synthesis Of Candesartan Intermediate

Candesartan named 2-ethoxy-1-[[2'-?1h-tetrazolidinyl-5?-4-]]methylbenzimi-dazole-7-carboxylic acid,is an antagonist of angiotension II receptor.It can antagonize the vasoconstriction of angiotension II by binding with AT1 receptor of vascular smooth muscle.It is a good antihypertensive drug with high bioavailability,few adverse reactions and long acting time.In this paper,the key intermediate of candesartan,2-[?2'-cyanobenzyl-4-yl?methyl]amino]-3-aminobenzoic acid methyl ester,was synthesized by flow methods.The first chapter introduces the characteristics and advantages of microreactor technology in chemical synthesis,as well as the applications of continuous microreactation technology in drug synthesis in recent years.The synthetic route of Candesartan was reviewed,and the route of synthesis of candesartan intermediate from phthalimide by Hofmann degradation,nitrification,rearrangement,nitrification,condensation and reduction reaction was researched.This route has obvious exothermic effect and long reaction time.The continuous flow reaction technology is proposed to solve the problems of high safety hazard,long reaction time and low yield in traditional process.In the second chapter,the process improvement of the intermediate methyl anthranilate was introduced by the continuous flow reaction.The process is divided into two parts:the synthesis of isocyanate by phthalimide and sodium hypochlorite,and the synthesis of methyl anthranilate by isocyanate and water.The continuous flow synthesis of isocyanate was studied,optimize the process route.The ratio of phthalimide and sodium hypochlorite was investigated that the molar flow ratio of phthalimide and sodium hypochlorite was 1:1.15.The reaction temperature and residence time was investigated.The investigation confirmed that the preferred residence time t₁was 10 s,and the preferred reaction temperature T₁was-5 ^oC.Continuous flow reaction technology was used to prepare methyl anthranilate.The investigation confirmed that the preferred residence time t₂was 90 s,and the preferred reaction temperature T₂was 70^oC,at this time,the total yield is 94.1%and the process capacity is 1031.7 g/h.In the third chapter,the research process of preparation of methyl 2-?nitroamino?benzoate by continuous flow nitration is introduced.The reaction temperature,residence time and molar ratio of materials was investigated.The investigation confirmed that the preferred residence time was 30 s,and the preferred reaction temperature was 20 ^oC,and the molar ratio of fuming nitric acid:Acetic anhydride:meradimate=4.0:1.8:1.0;the yield is 87.2%and the process capacity is 844.8 g/h.In chapter four,methyl 3-nitro-2-aminobenzoate was synthesized from methyl n-nitrobenzoate by concentrated sulfuric acid rearrangement.The solvent,reaction temperature and sulfuric acid concentration were studied.Acetone was selected.The investigation confirmed that the reaction temperature is 5 ^oC,and sulfuric acid concentration is 90%;the the product yield is 76.4%;the selectivity is 91.0%.In chapter five,the research process of preparation of methyl 3-nitro-2-?nitroamino?benzoate by continuous flow nitration is introduced.The reaction temperature,residence time and molar ratio of materials was investigated.The investigation confirmed that the preferred residence time was 30 s,and the preferred reaction temperature was 25^oC,and the molar ratio of fuming nitric acid:Acetic anhydride:meradimate=6.0:1.8:1.0,the yield is 80.1%.In chapter six,candesartan intermediate 2-[?2'-cyanobenzyl-4-yl?methyl]amino]-3-aminobenzoic acid methyl ester was synthesized from methyl 3-nitro-2-?nitroamino?benzoate.Finally,a new process for the production of candesartan intermediate by combining microreactor with reactor was determined.