Synthesis Of Moxifloxacin Chiral Intermediate

Moxifloxacin is a broad-spectrum antimicrobial agent developed Bayer Corporation.Due to its excellent antibacterial activity,wide antibacterial spectrum and few adverse reactions,moxifloxacin is widely used in respiratory tract infection,specific bacterial infection and other fields which has a broad application prospects.The moxifloxacin 7-position substituent,(S,S)-2,8-diazabicyclo [4.3.0] nonane,is an important structure that influence its efficacy and is an important intermediate in the synthesis.In this paper,a series of studies were carried out on the synthesis of this intermediate.An efficient synthetic route for moxifloxacin chiral intermediate via dehydration(yield 84.2%),catalytic hydrogenation(yield 95.4%),resolution(yield 38.4%),reduction reaction(yield 93.2%),and hydrogen transfer catalytic hydrogenation(yield 90.5%)was established.The undesired enantiomer was recycled by racemization and resolution,resulting in an increase in overall yield(total yield 39.0%).In the study,6-benzyl-5H-pyrrolo [3,4-b] pyridine-5,7(6H)-dione was synthesized by one-pot method.This method combined dehydration reaction,acylation reaction and cyclization reaction into one step,which simplified the operation,increased efficiency and reduced the pollution of the environment.Tetrahydrofuran was chosen as the solvent for catalytic hydrogenation which made the yield higher than others,and 3.5 MPa hydrogen atmosphere can achieve high enough yield,which made the process safer.Isopropyl alcohol-water system was used in resolution,with the optimization of solvent and temperature,a higher ee value and yield can be gained in single resolution.In the process of reducing the carbonyl group,we compared the commonly used reduction reagents such as sodium borohydride,Red-Al and lithium aluminum hydride,lithium aluminium hydride performed better with a higher yield.In debenzylation process,hydrogen transfer catalytic hydrogenation method instead of catalytic hydrogenation which need high temperature and high pressure was used avoiding the use of high pressure equipment.The method of racemization and resolution for recovery of undesired enantiomer was used in our work.The racemination process is carried out in two steps by oxidation and reduction.Manganese dioxide was used as oxidant,and the yield was up to 97.0%.In this way,the overall yield increased from 26.0% to 39.0%.