title: Practical synthesis of the new carbapenem antibiotic ertapenem sodium.
abstract: [reaction: see text] 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.
authors.affiliation: Department of Process Research, Merck Research Laboratories, Post Office Box 2000, Rahway, New Jersey 07065, USA. mike_williams@merck.com
authors.forename: J Michael
authors.initials: JM
authors.lastname: Williams
authors.forename: Karel M J
authors.initials: KM
authors.lastname: Brands
authors.forename: Renato T
authors.initials: RT
authors.lastname: Skerlj
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Jobson
authors.forename: George
authors.initials: G
authors.lastname: Marchesini
authors.forename: Karen M
authors.initials: KM
authors.lastname: Conrad
authors.forename: Brenda
authors.initials: B
authors.lastname: Pipik
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Savary
authors.forename: Fuh-Rong
authors.initials: FR
authors.lastname: Tsay
authors.forename: Peter G
authors.initials: PG
authors.lastname: Houghton
authors.forename: D Richard
authors.initials: DR
authors.lastname: Sidler
authors.forename: Ulf-H
authors.initials: UH
authors.lastname: Dolling
authors.forename: Lisa M
authors.initials: LM
authors.lastname: DiMichele
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Novak
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis*; D000077727:Ertapenem; D047090:beta-Lactams / Q000138:chemical synthesis*
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D000077727:Ertapenem