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