Improvement in the synthesis of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(Z)-methoxyiminoacetic acid 2-benzothiazolyl thioester

Abstract

2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(Z)-methoxyiminoacetic acid 2-benzothiazolyl thioester(III), an important intermediate of the fourth generation cephalosporins, was efficiently synthesized by reacting 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(Z)-methoxyiminoacetic acid (I) with 2,2′-dibenzothiazole disulfide (II) in the presence of triphenylphosphine. Effects of reaction time, temperature, solvents, catalysts and feeding molar ratio on the yield and quality of products were investigated, and an improved procedure suitable for industrial production was established. Using 1,2-dichloroethane as solvent, triphenylphosphine as reducer, and triethylamine as catalyst, n(I) : n(II) : n(triphenylphosphine) = 1.0 : 1.0 : 1.0, the product was obtained at room temperature in 98.1% yield. The purity of the product without further purification is 98.7% determined by HPLC method. This procedure could be a suitable alternative to the traditional processes because of its easy handling, high yield and low cost.

References

1. Zhang Z P Progressin research of antibacterial agentsChineseJournal of Antibiotics 2002 27(2)6779(in Chinese)
2. Jiang J Liu B Q Guo H Y The fourth generation cephalosporin-cefozopran hydrochlorideWorld Notes on Antibiotics 2006 27(2)6168(in Chinese)
3. Yu T Zhang K L Wang H Zhao Y F Gong P Synthesis of cefozopran hydrochlorideChinese Journal of Medicinal Chemistry 2006 16(2)9192(in Chinese)
4. Fu D C Di R Li B Review on the new development of cephalosporin antibioticsJournal of Hebei Normal University (Natural ScienceEdition) 2006 30(6)693697(in Chinese)
5. Xia C C Cheng D P Yu W B Yan J Z Study and synthesisof the forth generation cephalosporinAppliedChemical Industry 2005 34(3)137140(in Chinese)
6. Yoshizawa H Kubota T Itani H Ishitobi H Miwa H Nishitani Y Newbroad-spectrum parenteral cephalosporins exhibiting potent activityagainst both methicillin-resistant staphylococcus aureus (MRSA) andpseudomonas aeruginosa. Part 2: Synthesis and structure-activity relationshipsin the S-3578 series.Bioorganic & MedicinalChemistry 2004 12(15)42114219
7. Malcolm P Anti-MRSA β-lactams in developmentCurrent Opinion in Pharmacology 2006 6(5)480485
8. Carlet J Conclusion:fourth-generation cephalosporins: new hopes and new duties. ClinicalMicrobiology and Infection 1999 5(Suppl.1)3536
9. Bertrand G Jose M R Philippe M β-Lactams againstmethicillin-resistant staphylococcus aureusCurrent Opinion in Pharmacology 2005 5(5)479489
10. Wang M X Guideto the development of novel products of national chemical pharmaceuticalsand drugs. 2002 versionBeijingState Economy & Trade Commission 2002 155(in Chinese)
11. Liu J J Studyon the development and current production status of the cephalosporinsChinese Journal of Antibiotics 2006 31(2)100106(in Chinese)
12. Furlenmeier A Hubschwerlen C N Hofheinz W Isenring H P Process forthe preparation of 1-sulfo-2-oxoazetidine derivativesEP 0 096 297
13. Kishimoto S Tomimatsu K Miyake A Yoshimura Y Cephemcompounds, their production and useEP 0249 170
14. Gerd A Newprocess for producing cephalosporin antibiotics, and novel intermediatesfor use in such process and their productionUS 4 767 852
15. Furlenmeier A Hofheinz W Hubschwerlen C N Isenring H P Process forthe manufacture of 1-sulpho-2-oxoazetidine carboxylic acid intermediatesvia catalytic ester cleavageUS 4 652 651
16. Li A J Zhou X Q Liu D Z An improved procedure for the preparation of 2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetic acid s-benzthiazolyl thioesterFine Chemicals 2005 22(10)792794(in Chinese)
17. Xie J X Applicationof infrared spectra in organic and medicinal chemistryBeijingScience Press 1987 205(in Chinese)
18. Cheng Q F Wang Q F Xu X Y Gao J Preparation ofZ-2-(2-aminothiazol-4-yl)- 2-methoxyimino acetyl chloride hydrochlorideJournal of Chemical Engineering of Chinese Universities 2006 20(1)100103(in Chinese)
19. Cheng N L Handbookof solvents. 2nd edition. BeijingChemical Industry Press 1994 (in Chinese)