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
Department of Process Research, Merck Research Laboratories, Post Office Box 2000, Rahway, New Jersey 07065, USA.
J Org Chem. 2005 Sep 16;70(19):7479-87. doi: 10.1021/jo0501442.
[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.
[反应：见正文] 已开发出一种用于大规模生产新型碳青霉烯抗生素[4R,5S,6S]-3-[[(3S,5S)-5-[[(3-羧基苯基)氨基]羰基]-3-吡咯烷基]硫基]-6-[(1R)-1-羟乙基]-4-甲基-7-氧代-1-氮杂双环[3.2.0]庚-2-烯-2-羧酸单钠盐（厄他培南钠，1）的实用合成方法。该合成的特点是新颖地使用1,1,3,3-四甲基胍作为碱，用于由反式-4-羟基-L-脯氨酸衍生的硫醇与作为烯醇磷酸酯活化的碳青霉烯核的低温反应。使用钯-炭催化剂进行对硝基苄酯的氢解，两步的总收率为90%。在氢解中使用碳酸氢盐是保护吡咯烷胺作为氨基甲酸钠的关键，这提高了反应性能和产物稳定性。这一发现使得大规模生产加工成为可能。提供了形成氨基甲酸钠的实验证据。一种用于同时纯化和浓缩含水产物流的非常简便的方法依赖于离子对萃取以去除水溶性的1,1,3,3-四甲基胍。然后结晶得到产物单钠盐形式的总收率为59 - 64%。
