Synthesis Of Isavuconazonium Sulfate

Isavuconazonium sulfate,a new generation of triazole antifungal drugs,is indicated for the treatment of invasive fungal disease.This is a water-soluble prodrug,which is convenient for the preparation of injection.Also,the oral bioavailability is improved and the half-life is prolonged.Clinical trials have proved that Isavuconazonium sulfate has non-inferior effect to Voriconazole for the treatment of invasive fungal disease.What'more,Isavuconazonium sulfate is more safe than Voriconazole.In this paper,the synthesis of Isavuconazonium sulfate was investigated.Methyl?R?-lactate was used as the starting material to prepare?R?-1-?2,5-diflu orophenyl?-2-??tetrahydro-2H-pyran-2-yl?oxy?propan-1-one by morpholinamidation,THPprotection and Grignard reaction.The second chiral centers were introd-uced by asymmetric epoxidation.After opening the epoxide and cleaving the THP gro up,?2R,3R?-2-?2,5-difluorophenyl?-1-?1H-1,2,4-triazol-1-yl?butane-2,3-diol methanesu lfonatewas obtained as a solid form.Further operations such asring formation,ring opening with TMSCN,thioamidation,and condesationwith 4'-cyano-2-bromoaceto phenone gaveIsavuconazole withan overall yield of 16.0%.In addition,2-chloro nicotinic acid underwentesterification,amination and reduction to give 2-methylam ino-3-pyridinemethanol.The latter was reacted with 1-chloroethylchloroformate an d Boc-sarcosine to give N-methyl-N-?3-[??N-tertbutyloxycarboxy-N-methylaminom ethyl?acetoxy?methyl]pyridinyl-2?carbamic?1-chloroethyl?ester?3?.Isazaconazole was reacted with 3,followed by cleaving the Boc group and salt formationto give I savuconazonium chloride hydrochloride.Although the synthetic route is known fromliterature,the physicochemical constants ofvarious intermediates have not been reported,and several intermediates have been purified by column chromatography in the literature.In this paper,the reactionsof each step were studied in depth and the reaction conditions were optimized.Purification by columnchromatographyabout all intermediateswas eliminated and the physicochemical constants of each intermediate were determined to establish quality control methods;Grignard reaction conditions were optimizedto allow the reaction to be effectively initiated at room temperature andeliminate the potential danger owing to temperature out of control duringpreparation;The three steps of reaction to prepare M6from M3 was completed by“one-pot method”.M6forms a salt with methanesulfonic acid,which not only allows the formation of an oily M6as a solid,but also effectively removes theisomer to achieve the purpose of purification;M8 was prepared by the reaction of M7 and trimethylsilyl cyanide with n-butylammonium fluoride,the reaction condition is mild and efficient.This method has not been reported in the literature;The reducing reagent for tert-butyl 2-?methylamino?nicotinate was changed from LiAlH₄ in the literature to NaBH₄/ZnCl₂,and the latter two improvements havebeen applied for Chinese patents.