Process Design For Annual Output Of 100 Tons Of(4r,6r)-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetic Acid Tert-butyl Ester

Atorvastatin calcium is an effective lipid regulating drug,the market demand for this drug is large.(4R,6R)-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester(TBIN)is an important choral intermediate for the synthesis of atorvastatin calcium.The conventional synthesis method of the TBIN was chemical synthesis.Our laboratory had established a reasonable route which combined biological and chemical technology for the synthesis of TBIN and there is a compelling advantage to chemical synthesis.It is of great significance to research the industrialization of this synthesis route,inorder to promote technology transform and bring economic value for the industry.The main topic of this paper is to establish TBIN synthesis route which is combined biological and chemical technology and suitable in the industrialization production.A(3R,5R)-6-cyano-3,5-dihydroxy-hexanoic acid tert-butyl ester synthesis route which suited for the industrial production was established,this route was finished enlarging test of 1.5 t reaction vessel.The finalized industrialization technology:reaction vessel was 1.5 t,loading volume was 1 t,t-butyl(R)-6-cyano-5-hydroxy-3-carbonylhexanoate 0.3 t,glucose 0.3 t,enzymes 15 kg(dry cell weight),pH 6.5?7.0,temperature 30?,mixing speed 100 rpm,reaction time 1 Oh.Under this condition,the conversion of substrate could be as high as 100%and the d.e.value could over 99.5%.The phenomenon of emulsification appeared in the process of organic extraction in(3R,5R)-6-cyano-3,5-dihydroxy-hexanoic acid tert-butyl ester bioconversion mixture was studied.The(3R,5R)-6-cyano-3,5-dihydroxy-hexanoic acid tert-butyl ester extraction process was established and enlarging test was finished.The finalized industrialization technology:extraction agent was ethyl acetate,phase ratio was 1:1,extraction stage was 3,operated in room temperature,time for every extraction was 0.5 h.In this process,the recovery of(3R,5R)-6-cyano-3,5-dihydroxy-hexanoic acid tert-butyl ester could over 95%.The optimum technological conditions for producing TBIN was obtained.TBIN crude product extraction methods and the technology of TBIN recrystallization were studied and the optimum technological condition was determined finally.Also the kinetic of TBIN crystallization was studied too.IR,NMR,MS were used to characterize the property of the prepared TBIN and the final purity of prepared TBIN could over 99.5%.An annual output of 100 tons TBIN process route was designed based on results from laboratory and enlarging test.According to product cost calculation,annual output of 100 tons TBIN could get 8.357 million yuan profit To be sure,this process was suitable for industrial production.