Synthesis Of Plazomicin And Key Intermediates Of Venetoclax

This paper contains two parts.The first part of this paper is the synthesis of aminoglycoside antibiotics Plazomicin.The second part is the synthesis of three key fragments for preparing Venetoclax.The first part is the synthesis of Plazomicin.Plazomicin,a new semi-synthetic aminoglycoside antibiotic,was developed by Ibis Therapeutics and Achaogen Inc to treat bacterial urinary tract infection and pyelonephritis.Achaogen Inc announced that phase III clinical trial of plazomicin was completed.With analyzing literatures’ routes,Plazomicin was synthesized as follow steps: isolation of Sisomicin Sulfate(1);selective N-protection at 6’ position with 4-nitrobenzyloxycarbonyl(PNZ),2’ and 3 position with tert-Butoxycarbonyl(Boc),1 position with Fluorenylmethoxycarbonyl(Fmoc),3"position with Boc;then deprotection of Fmoc,and amide condensation,deprotection of PNZ;followed with reductive amination,deprotection of benzoyl(Bz)and Boc to get plazomicin(1)with an overall yield of about 3.8%(based on 2).The structure of plazomicin prepared by this process was confirmed by 1H NMR,13 C NMR,MS and so on.The yield of compound 4 was increased to 83.5% by the improvement of working up,and the purity of 5a was also improved by screening the best reaction conditions as described in the paper.Microwave reaction and cyanide were removed as well,intermediate 9a and 10 in the process are new compounds.The optimized process of plazomicin is easy to operate in a mild condition which provides basic research for industrialization.The second part of this paper is the synthesis of three key fragments for preparing Venetoclax.Venetoclax,a selective Bcl-2 protein inhibitor,was developed by Abbvie and Genentech Inc to treat chronic lymphocytic leukemia and was approved by the FDA on April 11/2016.Based on literatures,three key fragments of Venetoclax were synthesized.Part A(compound 32)was prepared from 5-bromo-7-azaindole(28)by protection with tert-Butyldimethylsilyl(TBS),conversion from bromine to hydroxyl and nucleophilic substitution.Part B(compound 44)was prepared from 3,3-dimethylcyclohexanone(45)via Vilsmerier reaction,Suzuki coupling reaction,reductive amination and deprotection of Boc.Part C(compound 51)was prepared from 4-chloro-3-nitrobenzenesulfonamide(49)by nucleophilic substitution.All of the intermediates prepared by this process were confirmed by 1H NMR,13 C NMR and MS.Chemical purity of the intermediates detected by HPLC were above 99%.We designed a new synthetic route of compound 32 by using difference protection group and got an new important intermediate 30 a,which was a white solid and easy to purify.We also optimized the reaction condition of following steps: the solvent of Suzuki coupling reaction,the amount of reducing agent in reductive amination reaction and the method of Boc deprotection.We prepared three key intermediates of Venetoclax and it could be basic research work for synthesizing Venetoclax.