Precise Preparation of a High-Purity Key Intermediate of Tazobactam

• Published in: Organic process research & development 2020-12, Vol.24 (12), p.2898-2905
• Main Authors: Zhou, Yanan, Wu, Chengjun, Ma, Hongzhi, Chen, Jianchao, Sun, Tiemin
• Format: Article
• Language: English
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.0c00407

In situ IR was used to precisely prepare high-purity diphenylmethyl 6α-bromopenicillanate 8, a key intermediate of tazobactam. 8 was obtained when 6α-bromopenicillanic acid 2 reacted with diphenyldiazomethane (DDM). 2 is unstable and must therefore react immediately with DDM upon preparation. DDM is also unstable. As DDM decomposes rapidly upon preparation, the DDM content cannot be precisely determined using high-performance liquid chromatography (HPLC) or gas chromatography (GC). Therefore, good yield and purity are difficult to obtain, resulting in large batch-to-batch variations (yield 69.3–82.8%, purity 89.8–98.4%) for 8. The developed preparation method for 8 involved the use of in situ IR to monitor the reaction process and achieved good results (82.7–83.1% yield and 97.3–98.5% purity). This method was also used to prepare the key intermediate for the synthesis of cephalosporin derivatives, which have high industrial value.