Practical Synthesis of the New Carbapenem Antibiotic Ertapenem Sodium

• Published in: Journal of organic chemistry Vol. 70; no. 19; pp. 7479 - 7487
• Main Authors: Williams, J. Michael, Brands, Karel M. J, Skerlj, Renato T, Jobson, Ronald B, Marchesini, George, Conrad, Karen M, Pipik, Brenda, Savary, Kimberly A, Tsay, Fuh-Rong, Houghton, Peter G, Sidler, D. Richard, Dolling, Ulf-H, DiMichele, Lisa M, Novak, Thomas J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 16.09.2005; Amer Chemical Soc
• Subjects: Anti-Bacterial Agents - chemical synthesis; beta-Lactams - chemical synthesis; Chemistry; Chemistry, Organic; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Organic chemistry; Physical Sciences; Preparations and properties; Science & Technology; DEHYDROPEPTIDASE-I; ONE-POT SYNTHESIS; AMINO-ACIDS; N-FORMIMIDOYL THIENAMYCIN; NUCLEAR MAGNETIC-RESONANCE; LONG-ACTING CARBAPENEM; CARBAMATE FORMATION; CARBON-DIOXIDE; 6-AMINOPENICILLANIC ACID; AQUEOUS-SOLUTION; Antibiotic; Carbapenem derivatives; Thiol; Hydrogenolysis; Nitrogen heterocycle; Sodium compound; Chemical synthesis; Organic carbamate; Ertapenem; Pyrrolidine derivatives; Organic sulfide
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo0501442

A practical synthesis for the large-scale production of the new carbapenem antibiotic, [4R,5S,6S]-3-[[(3S,5S)-5-[[(3-Carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium salt (ertapenem sodium, 1), has been developed. The synthesis features the novel use of 1,1,3,3-tetramethylguanidine as base for the low-temperature reaction of a thiol, derived from trans-4-hydroxy-l-proline, with the carbapenem nucleus activated as the enol phosphate. Hydrogenolysis of a p-nitrobenzyl ester is effected using a palladium on carbon catalyst to give an overall yield for the two steps of 90%. The use of bicarbonate in the hydrogenolysis was key in providing protection of the pyrrolidine amine as the sodium carbamate improving both the performance of the reaction and the stability of the product. This discovery made processing at manufacturing scale possible. Experimental evidence for the formation of the sodium carbamate is provided. A remarkably expedient process for the simultaneous purification and concentration of the aqueous product stream relies on ion-pairing extraction for the removal of the water-soluble 1,1,3,3-tetramethylguanidine. Crystallization then affords 59−64% overall yield of the monosodium salt form of the product.