Asymmetric Mannich Reaction Of 4-Nitroisoxazole With β,γ-Alkynyl-α-Imino Ester Catalyzed By Chiral Quaternary Phosphonium Salt;Improved Synthesis Of Coagulation Factor Ⅺa Inhibitor BMS-962212 Intermediate

This thesis mainly consists of two parts,with the first part focusing on the asymmetric Mannich reaction of 4-nitroisoxazole with β,γ-alkynyl-α-imino ester catalyzed by chiral quaternary phosphonium salt and the second part focusing on an improved synthesis of the key intermediate of coagulation factor Ⅺa inhibitor BMS-962212.On the one hand,structural moiety containing a propargylated chiral quaternary carbon can be found in some bio-active natural products and pharmaceuticals,the other hand compounds bearing an isoxazole moiety are of great value to medicinal chemistry research.Thus,the construction of chiral compounds containing the above two structural moieties is of great significance to both synthetic chemistry and medicinal chemistry.To that end,a series of bifunctional quaternary phosphonium salt phase transfer catalysts were employed to promote the asymmetric Mannich reaction of nitroisoxazole compounds with β,γ-alkynyl-α-imino esters.Consequently an array of compounds containing both a propargylated quaternary carbon and a nitroisoxazole moiety was obtained.Initially with model substrates the reaction conditions were optimized by screening various catalysts,bases,temperatures and solvents.Next,the scope of the substrates was explored,and it was found that the reaction has a good generality of substrates,affording adducts in moderate to good yields and with good to excellent enantioselectivity.The absolute configuration of an adduct was determined by single crystal diffraction,and hence a postulated transition state was proposed to account for the chiral induction.Moreover,chiral adducts prepared from this reaction were subjected to further derivatization,which proved no harm to the chiral purity of the derivatives.According to the literature,factor Ⅺa inhibitors are able to reduce the formation of thrombus without affecting normal hemostasis,and have great applications in clinical studies.(E)-3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylic acid is a key intermediate in the synthesis of factor Ⅺa inhibitor BMS-962212.However the reported synthetic route for preparing this intermediate suffered from low yield,high cost and poor reproducibility for the key step of tetrazole formation.Toward finding a better synthesis of the key intermediate,the readily available 3-fluoro-4-chloroaniline was chosen as starting material.In the literature,the acrylate moiety was installed by a Heck reaction with expensive Pd catalysts,which was cleverly avoided by a two-step operation in our hand: aldehyde formation and subsequent chain elongation via HWE reaction.In the key reaction for the tetrazole formation,TMSN3 and water were used to generate hydrazoic acid in-situ to react with the isonitrile.As compared with the method reported in the literature,the advantages are obvious: mild reaction conditions,high yield and good reproducibility.The new route reported in this thesis makes the synthesis of key intermediates of BMS-962212 cost efficient and easily reproducible.