Study On The Synthesis And Process Of D-threo-P-methylsulfonylphenylserine Ethyl Ester

D-threo-p-methylsulfonylphenylserine ethyl ester is abbreviated as"D-ethyl ester",which is an important intermediate for synthesis of florfenicol,and has important economic value.In this thesis,the aim of our studies is developing an industrial route of synthesizing D-ethyl ester,and we have designed a new synthesis route through analyzing the existing industrial synthesis routes.Finally,we optimized the synthetic process in order to meets the requirements of industrial production.The new synthetic route used p-methylsulfonylbenzoic acid as raw materials,and Acyl chloride compound 4-?methylsulfonyl?benzoyl chloride 3 was obtained through chlorination reaction of raw materials and SOCl₂,the reaction yield was more than 99%.Then,three synthesis routes were designed for synthesizing the key intermediate ethyl3-?4-?methylsulfonyl?phenyl?-3-oxopropanoate 6,by comparing and analyzing three reaction routes,one step synthesis method of using coupound 3 and ethyl acetoacetate as raw materials,CaO as the chelating agent,ethanol as the lysing agent to synthesize compound 6 was determined,the reaction yield was 95%with 97%of the purity.In the process of synthesizing 6,a new method for?-acylation of?-dicarbonyl compounds with DES?choline chloride/zinc chloride?as catalyst was proposed.It made the reaction more green and efficient.Next,the oximation reaction was carried out using compound6 and sodium nitrite as raw materials,acetic acid as the solvent to synthesize 2-oxime-2-?4-?methylsulfonyl?benzoyl?ethyl acetate 7 with the yield of 95%,and the purity was more than 98%.Finally,a chiral compound p-methylsulfonylphenylserine ethyl ester 8was obtained through reduction reaction of compound 7 using the Raney nickel as a catalyst under the action of hydrogen at 0.5MPa for 2h.The reaction yield was above 76%and the purity was 94%.Next,methyl?2S,3S?-2-amino-3-hydroxy-3-?4-?methylsulfonyl?phenyl?propanoate 9and methyl?2R,3R?-2-amino-3-hydroxy-3-?4-?methylsulfonyl?phenyl?propanoate 10were successfully separated through using D-tartaric acid as the resolving reagent to resolve the erythro racemic compound 8.The yield was up to 48%with the purity above98%?ee value>98%?.Then,the compound 10 was racemized by using 5-nitrosalicylic aldehyde as the catalyst,and the compound D-threo-p-methylsulfonylphenylserine ethyl ester 1 could obtain through using D-tartaric acid to induce crystallization,the yield of the reaction was 93%,the purity was up to 98%?ee value>98%?.Finally,the above compounds were analyzed and characterized by HPLC,LC-MS and ¹H NMR.