摘要
优化了头孢托罗活性硫酯-(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-三苯甲氧亚胺基硫代乙酸(S-2-苯并噻唑)酯(2)的合成工艺。以3-氨基-5-乙酰胺基异噁唑(3)为原料,与特戊酰基异硫氰酸酯经重排反应,制得N-乙酰基-2-(5-特戊酰胺基-1,2,4-噻二唑-3-基)乙酰胺(5),收率为72%;采用亚硝酸异丙酯对中间体5进行肟化、然后与三苯基氯甲烷进行醚化制得(Z)-N-乙酰基-2-(5-特戊酰胺基-1,2,4-噻二唑-3-基)-2-三苯甲氧亚胺基乙酰胺(7a),收率为78%;7a经碱性水解,制得(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-三苯甲氧亚胺基乙酸(8),收率为65%;,在乙腈与甲苯的混合溶剂中,8与亚磷酸三乙酯、二苯并噻唑二硫醚混合反应,制得活性硫酯2,路线的总收率达24%。该合成工艺具有反应条件温和,操作简便,易于分离等优点,因而有较好的工业化应用前景。
An improved synthesis technology of （Z）-S-benzo[d]thiazol-2-yl-2-（5-amino-l,2,4-thiadiazol-3-yl）-2- （（tri-tyloxy）imino） ethanethioate （2）, which is a key intermediate of ceftobiprole （I）, was studied. The starting material N-（3-aminoisoxazol-5-yl）acetamide （3） was converted into the corresponding N-（3-（2-acetamido-2- oxoethyl）-1,2,4-thiadiazol-5-yl）pivalamide （5） with 72% yield through the skeletal rearrangement with pivaloyl isothiocyanate, followed by reaction with isopropyl nitrite and triphenylchloromethane in succession to afford （Z）-N-（3-（2-acetamido-2-oxo-l-（（trityloxy）imino）ethyl）-1,2,4-thiadiazo1-5-yl） pival-amide （7a） with 78% yield. The hydrolysis of compound 7a under basic conditions could afford （Z）-2-（5-amino-l,2,4-thiadiazol-3-yl）- 2-（（trityloxy）imino）acetic acid （8） with 65% yield, followed by reaction with 1,2-bis（benzo[d]thiazol-2-yl） disulfane promoted by triethyl phosphate in the mixture of acetonitrile and toluene to give the title compound 2 with total yield of 24% from 3. The present procedure has advantages of mild reaction condition, convenient operation and easy separation, thus it can be expected to have a promising application for the industry.
出处
《高校化学工程学报》
EI
CAS
CSCD
北大核心
2014年第6期1322-1327,共6页
Journal of Chemical Engineering of Chinese Universities
基金
国家自然科学基金(21076194
21276238)
