Study On Synthesis And Crystallization Process Of Key Intermediates Of Efinaconazole

Efinaconazole is the first topical triazole antifungal drug,which is used in the loc-al treatment of onychomycosis.It has the characteristics of good curative effect,low toxicity,high cure rate,high safety,etc.Among them,(2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol(TM1)is the key chiral intermediate of Efinacona-zole,and also the key intermediate of known triazole antifungal drugs such as Ravuc-onazole and Fluconazole.Therefore,it is of great significance to study the synthesis process of the key intermediate chiral diol of Efinaconazole.First,this thesis optimizes the reaction conditions on the basis of the existing synthetic route,and then improves the existing synthetic route by changing the hydroxyl protecting group to obtain a new synthetic route,and calculates the total yield of the two routes selected in this th-esis,purity and e.e.were compared,and the crystallization conditions of B2 and B5 in the new synthetic route were studied at the same time.(1)R-methyl lactate is used as the starting material,and firstly undergo the amine transesterification reaction with morpholine,and then the alcohol hydroxyl group is protected by dihydropyran,and then subjected to Grignard reaction and epoxidation reaction,epoxy ring-opening reaction and deprotection reaction to obtain the methanesulfonate of chiral diol TM1 with a purity of 98.6%,86.8%ee,and a total yield of 38.8%.The morpholine used in this route is prone to generate an irregular five-membered ring due to the intramolecular space induction effect,so the reaction requires a higher temperature.At the same time,the high-temperature rotary steaming in the post-processing causes the product to racemize about13.2%,and 86.8%ee;Using phosphorous acid with lower acidity to catalyze the hydroxyl protection reaction of dihydropyran,the purity of A2 is 97.3%;The Grignard reaction is carried out at-20°C,but the product A3 needs to be purified by column chromatography,resulting in a 25.1% reduction in yield.At the same time,due to the asymmetry of the tetrahydropyran group,the use of it will result in a mixture of diastereomeric products,which will also seriously affect the purity and yield of the product;Oxysulfur ylides are used to generate epoxides,and then the intermediate A5 is obtained by basic ring opening of1,2,4-triazole;Finally,after screening,methanesulfonic acid was used to cleave the hydroxyl protecting group,and the product TM1 was separated and purified by salt formation,with a purity of 98.6%.(2)R-methyl lactate is used as the starting material,first pyrrolidine is used instead of morpholine,and then react with benzyl chloride,and obtain solid B2 by solvation and crystallization purification,and then subjected to Grignard reaction,epoxidation reaction,the epoxy ring-opening reaction and deprotection reaction gave the key intermediate chiral diol TM1,with a purity of 97.4%,99.6%ee,and the total yield reaches 49.0%.The pyrrolidine used in this route is more reactive than morpholine.Because the N atom contained in the pyrrolidine structure has strong nucleophilicity activity.At room temperature,adding a catalytic amount of sodium hydride can reduce the reaction time to 4.5 h,yielding intermediate B1 with a purity of 98.8%.The reaction conditions are mild,and the racemization of the product TM1 caused by high temperature is avoided.The product B2 obtained by reacting B1 with benzyl chloride can be eluted and crystallized to obtain a high-purity solid,which is convenient for purification.The use of benzyl group as a protecting group also prevents the asymmetry of the tetrahydropyran group leads to the existence of a mixture of diastereomers;The Grignard reaction product B3 can participate in the next step of epoxidation without purification by column chromatography,avoiding product loss;After epoxidation and epoxy ring-opening reaction,intermediate B5 was obtained.At the same time,the crystallization process of B5 was studied,and the crystal form was prismatic and a white solid with a purity of 99.1% was obtained;At 60°C,0.4 MPa,use10%Pd/C catalyzed the hydrogenolysis of B5 to debenzylate to obtain the key intermediate chiral diol TM1,with a purity of 97.4% and 99.6%ee.In this thesis,the intermediates of Efinaconazole were confirmed and characterized by nuclear magnetism,high performance liquid chromatography,and liquid chromatog-raphy-mass spectrometry.