Study On The Asymmetric Synthesis Of Chiral Sulfoxide And Applied To The Synthesis Of Sulfoxide Drugs

Catalytic asymmetric oxidation of thioether was generally a simple and effective method in the synthesis of chiral sulfoxide compounds. The enantioselectivity in the catalytic asymmetric oxidative reaction of methyl p-tolyl sulfide and methyl 4-nitrophenyI sulfide was studied in our research using the following 20 chiral ligands: (2R,3R)-dimethyl tartrate, (2R,3R)-diethyl tartrate, (2R,3R)-diisopropyl tartrate, (2R,3R)-dibenzyl tartrate, (2R,3R)-N,N'-diphenyl tartramide, (2R,3R)-N,N'-dibenzyl tartramide, (2R.3R)-N,N'-di-m-tolyl tartramide, (2R,3R)-N,N'-di-p-tolyl tartramide, R-(+)-2,2'-dihydroxy-1,1'-binaphthyl, S-(-)-2,2'-dihydroxy-1,1 '-binaphthyl, R-(-)-6,6'-dibromo-2,2'-dihydroxy-1,1 '-binaphthyl, S-(+)-6,6'-dibromo-2,2'-dihydroxy-1,1 '-binaphthyl, R-(+)-2,2'-diamino-1,1 '-binaphthyl, S-(-)-2,2'-diamino-1,1 '-binaphthyl, R-(+)-2,2'-bis(methylamino)-1,1'-binaphthyl, S-(-)-2,2'-bis(methylamino)-1,1 '-binaphthyl, R-(+)-2,2'-bis(methanesulfonylamino)-1,1 '-binaphthyl, S-(-)-2,2'-bis(methanesulfonylamino)-1,1'-binaphthyl, R-(-)-2,2'-bis[((2-hydroxyphenyl)methylene)amino]-l,l'-binaphthyl, S-(+)-2,2'-bis[((2-hydroxyphenyl)methylene)amino]-1,1'- binaphthyl.Various asymmetric oxidation system were made up of the above chiral ligands, oxidants and different organic transition metal compounds and studied on the asymmetric oxidation of thioether, it is found that all the following 5 oxidation system showed good enantioselectivity in the catalytic asymmetric oxidation of methyl p-tolyl sulfide: Ti(O-iPr)₄-[(2R,3R)-diisopropyl tartrate]-H₂O-TBHP-4aMS (oxidation system I ), Ti(O-iPr)₄-[R-(+)-2,2'-dihydroxy-1,1'-binaphthyl]-H₂O-TBHP (oxidation system II ), Ti(O-iPr)₄-[S-(-)-2,2'-dihydroxy-1,1'-binaphthyl]-H₂O-TBHP (oxidation system III ), Ti(O-iPr)₄-[R-(-)-6,6'-dibromo-2,2'-dihydroxy-1,1'-binaphthyl]-H₂O-TBHP (system IV ), Ti(O-iPr)₄-[S-(+)-6,6'-dibromo-2,2'-dihydroxy-1,1'-binaphthyl]-H₂O-TBHP (system V ), methyl p-tolyl sulfide can be oxidation to corresponding methyl p-tolyl sulfoxide by these systems with e.e. value up to 77%, meanwhile, Ti(O-iPr)₄-(2R,3R)-diisopropyl tartrate-H₂O-TBHP-4a MS (oxidation system I) can also be used in the catalytic asymmetric oxidation of methyl 4-nitrophenyl sulfide to corresponding methyl 4-nitrophenyl sulfoxide with e.e. value up to 61%.The above asymmetric oxidation systems were applied in the synthesis of 2 chiral sulfoxide drugs, Modafinil and Omeprazole, when Ti(O-iPr)₄-[S-(+)-6,6'-dibromo-2,2' -dihydroxy-1,1'-binaphthyl]-H₂O-TBHP (system V ) was used in the oxidation of pro-thioether of Modafinil, Modafinil was achieved with yield of 80ï¼…and e. e. value of 46ï¼…, but no satisfactory results achieved in the asymmetric oxidation of pro-thioether of Omeprazole to Omeprazole, the chemical yield and e. e. value were only 35ï¼…and 9.2ï¼…correspondingly.Meanwhile, a new oxidation method for the synthesis of racemic Omeprazole was found with steady chemical yield between 82～92ï¼…, this method was more simple and effective than the present ways and could be hopefully applied in the industrial preparation of Omeprazole.20 optically active chiral ligands were prepared through chemical synthesis and resolution, new synthetic way to racemic 2, 2'-diamino-1, 1'-binaphthyl was found, which was more convenient and with higher yield than the present reference methods. This new method fits large-scale preparation of 2, 2'-diamino-1, 1'-binaphthyl.