No abstract

Carbapenems are the most potent b-lactam antibiotics, which have a broad spectrum of antibacterial activity against both gram-positive and gram-negative organisms.1,2) The introduction of the 1b-methyl moiety to the carbapenem skeleton resulted in increased stability of carbapenems against dehydropeptidase-1 (DHP-1). For parenteral use, imipenem, 3) panipenem, 4) and meropenem 5) have been launched on the market, and several compounds are currently under clinical evaluation.Our attention was focused on the synthesis of 5-methyl-4-hydroxypyrrolidinone which could be used as the synthon of a-hydroxy-b-amino acid. Furthermore, we synthesized four enantio pure isomers of a 1b-methylcarbapenem derivative at the C-2 side chain, which were modified from R-83201, 6) and evaluated them for antibacterial activities and other biological properties. We prepared the 5-methyl-4-mercaptopyrrolidinones from enantiomerically pure aziridine ester. 7) In this paper, we describe the synthesis of the 1b-methylcarbapenems (1a-d) and optically active 5-methyl-4-hydroxypyrrolidinones (5a-d).The C-2 substituted derivatives of 1b-methylcarbapenem were synthesized through the general procedure shown in Chart 1. Treatment of the PNB-protected carbapenem enolphosphate 8 8) with freshly prepared thiols 7a-d in the presence of DIPEA in CH 3 CN at 0-5°C afforded the PNB-protected 1b-methylcarbapenems 9a-d, respectively (Chart 1). Deprotection of the 4-nitrobenzyl group was accomplished by catalytic hydrogenation using 10% palladium on charcoal in tetrahydrofuran (THF), EtOH, and morphorinopropanesulfonate (MOPS). The resulting carbapenem derivatives 1a-d were purified by reverse-phase column chromatography and subsequent lyophilization. Optically active 5-methyl-4-mercaptopyrrolidinones 7a-d were prepared from enantiomerically pure aziridine ester 2, respectively, as shown in Chart 2.b-Keto esters 3 9) of aziridine were obtained from aziridine ester 2 with the lithium enolate from ethyl acetate and LiH-MDS in THF. Reduction of the b-keto ester 3 with NaBH 4 in the presence of NH 4 Cl resulted in a diastereomeric mixture of hydroxy aziridines 4 (approximately R/Sϭ1/1 to 2/1), which were readily separable by flash chromatography. We did not optimize reduction conditions to obtain high stereoselectivity. 5-Methyl-4-hydroxypyrrolidinones 5a-d were prepared from the aziridine propionates 4a-d through regioselective reductive cleavage by catalytic hydrogenation in A new series of 1b b-methylcarbapenems 1a-d bearing 5-methyl-4-mercaptopyrrolidinone rings has been prepared and evaluated for in vitro antibacterial activity and pharmacokinetic parameters. Most compounds showed excellent antibacterial activity and high stability to dehydropeptidase-1. We have synthesized optically active 5-methyl-4-hydroxypyrrolidinones from enantiomerically pure aziridine esters.

KRK-701P is a broad-spectrum antibiotic with methicillin-resistant antibacterial activity. The objective of this preformulation study was to determine the physicochemical properties of KRK-701P. The n-octanol-to-water partition coefficients of KRK-701P were 0.448 at pH 4 and 2.546 at pH 8. One crystal form and one amorphous form of KRK-701P were isolated by recrystallization and characterized by differential scanning calorimetry, powder X-ray diffractometry and thermogravimetric analysis. After storage for 1 month at 0% RH (silica gel, 20 °C), 52% RH (saturated solution of Na2Cr2O7.2H2O/20 °C) and 95% RH (saturated solution of Na2HPO4/20 °C), the two forms were not transformed.