Synthesis And Crystallization Process Of Avibactam Key Intermediates

In recently years,various antibiotics have been developed to treat infections.Because antibiotic resistance of bacteria caused of beta-lactamases,drugs that inhibit beta-lactamases have gradually developed.In resisting bacterial resistance,Avibactam has injected new vitality into the field of antibiotics by inhibiting beta-lactamase extensively and long-term.The antibacterial and bactericidal of Avibactam compound preparation are excellent.?2R,5S?-5-?benzyloxyamino?-piperidine-2-carboxylic acid benzyl ester oxalate salt is a key intermediate of Avibactam.Its synthesis not only has great economic and social significance for the synthesis of Avibactam and the wide application of Avibactam,but also has important research significance and application value.However,the synthesis process of the key intermediate is complex and difficult to be industrialized,which hinders the wide application of Avibactam in the medical field.Therefore,a production route beneficial to industrialization was designed,excellent reaction conditions were explored through experiments,and the products were crystallized to obtain the key intermediate of Avibactam with excellent yield and purity.This paper develops a synthetic route that is beneficial to industrial production.In order to avoid the problem of high cost and difficult separation caused by multiple chiral raw materials,then the low price,easy to obtain,and one chiral L-pyroglutamic acid is used as a starting material.It was synthesized by six steps of carboxyl protection,amino protection,ring opening,one-pot chlorination and condensation,cyclization and reduction.The overall yield was 73%by optimizing the reactions.In order to improve the selectivity of the protecting group,the benzyl group?-Bn?was selected as the carboxyl protective group,the ratio of the material was1:1.2,the reaction temperature is optimized to be 65?and the pH value is optimized to be 8.5.The tert-butyloxycarbonyl?-Boc?protected amino group,the catalyst is4-dimethylaminopyridine?DMAP?,the material ratio is optimized to be 1:1.25,the reaction temperature is optimized to be 25?.Ring opening reaction:the sulfur ylide?Me₃SOI and t-BuOK?was used to extent the carbon chain under low temperature nitrogen,the ratio of material is optimized to be 1:1.20,the reaction temperature is optimized to be-15?,and the reaction time is optimized to be 4.0 h.One-pot chlorination and condensation:benzoxyamine hydrochloride?BnONH₂·HCl?was used for one-step chlorination and benzyloxyamino reaction,the ratio of materials is optimized to be 1:1.10.Cyclization reaction:in order to avoid the problems of high cost and difficult post-treatment caused by heavy metal catalyst catalytic cyclization,methanesulfonic acid?MeSO₃H?is used to selectively remove the protecting group on the amino nitrogen,and the ratio of materials is optimized to be 1:3.0.The weak base potassium bicarbonate?KHCO₃?is subjected to catalytic cyclization with a reaction temperature of 45?.Reduction reaction:sodium triacetoxyborohydride?NaBH?OOCCH₂CH₃?₃?carbon-nitrogen double bond is used for reduction,the ratio of materials is optimized to be 1:1.20,and the obtained reduction product is subjected to salt formation and crystallization by oxalic acid?HOOCCOOH?,The ratio of materials is optimized to be 1:1.10,the reaction temperature is optimized to be 0?,and the reaction time is optimized to be 6.0-6.5 h,the oxalate solids of the key intermediates of a Avibactam are obtained.Through the improvement of the process route and the optimization of the reaction conditions,the route is more suitable for industrial production,and also laid the foundation for the industrialization of Avibactam.The intermediate N-L-tert-butoxycarbonyl pyroglutamic acid benzyl ester?K₂?and?2R,5S?-5-?benzyloxyamino?-piperidine-2-carboxylic acid benzyl ester oxalate salt?K₆?different solubility in different solvents,these two kinds of intermediate impurities removed using the cooling crystallization to achieve the purification purposes for the two intermediates.For K₂crystallization,cyclohexane is selected as solvent,the dosage of decolorizing agent was 0.15eq.,the decolorization time was 15 min,the stirring rate was 60 r/min,when the holding time is1.5 h,the purity of K₂ product reach 99.8%after crystallization.For K₆ crystallization,mixed solvent of methanol?MeOH?and isopropanol?IPA?was optimized,the dosage of decolorizer was 0.12 eq.,decolorization time was 40 min,agitation rate was 90 r/min,the product with good crystal form to attain a good purity?over 99.6%?and the vaule of enantiomeric excess also exceed 99.0%.