Synthesis and in vitro activity of a new carbapenem, RS-533.

Miyadera, Tetsuo; Sugimura, Yukio; Hashimoto, Toshihiko; Takano, Teruo; Iino, Kimio; Shibata, Tomoyuki; Sugawara, Shichiro

doi:10.7164/antibiotics.36.1034

Cited by 80 publications

(14 citation statements)

References 13 publications

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“…The mixture was concentrated under reduced pressure and then extracted with EtOAc (30 ml). The combined organic layer separated was washed with 10 ml of brine, dried over anhydrous MgSO 4 , filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/n-hexaneϭ1 : 4) gave 0.65 g (41%) of 4a and 0.68 g (44%) of 4b as yellow oil …”

Section: Ethyl 3(r)-hydroxy-3-[1-(1(s)-a A-methylbenzyl)-aziridin-2(smentioning

confidence: 99%

Syntheses of 1.BETA.-Methylcarbapenems Bearing 5-Methyl-4-hydroxypyrrolidinone.

Pyun

Kim

Jung

et al. 2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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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.

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Section: Ethyl 3(r)-hydroxy-3-[1-(1(s)-a A-methylbenzyl)-aziridin-2(smentioning

confidence: 99%

Syntheses of 1.BETA.-Methylcarbapenems Bearing 5-Methyl-4-hydroxypyrrolidinone.

Pyun

Kim

Jung

et al. 2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Carbapenems are well recognized to have broad antibacterial activities, and most of the carbapenem compounds have been developed for parenteral use such as imipenem [1], panipenem [2], meropenem [3], biapenem [4,5], ertapenem [6] and doripenem [7]. The development of oral carbapenems is now expected in the clinical realm because oral administration is advantageous for patients.…”

Section: Introductionmentioning

confidence: 99%

Syntheses and Pharmacokinetic Studies of Prodrug Esters for the Development of Oral Carbapenem, L-084

et al. 2006

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“…The attention of both academic and industrial scientists has been attracted to the development of a new carbapenem for clinical use. Since imipenem 1) was launched in 1987 by Merck Co., five additional compounds, panipenem, 2) meropenem, 3) biapenem, 4) ertapenem 5) and doripenem, 6) are now on the market. However, all these were developed for parenteral use, and the development of carbapenems for oral use has been expected for a long time.…”

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confidence: 99%

A Practical and Facile Synthesis of Azetidine Derivatives for Oral Carbapenem, L-084

Isoda¹,

Yamamura²,

Tamai³

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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An orally active carbapenem L-084, which exhibits high bioavailability in humans, has a 1-(1,3-thiazolin-2-yl)azetidin-3-ylthio moiety at the C-2 position of the 1b b-methylcarbapenem skeleton. We established a practical and cost-effective synthesis of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine (1) for further scale-up production of L-084. This synthesis method entails an industry-oriented reaction of azetidine ring-closure to yield N-benzyl-3-hydroxyazetidine (16), which is eventually converted to 1 via key intermediates, Bunte salts 19 and 20.

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Synthesis and in vitro activity of a new carbapenem, RS-533.

Cited by 80 publications

References 13 publications

Syntheses of 1.BETA.-Methylcarbapenems Bearing 5-Methyl-4-hydroxypyrrolidinone.

Syntheses of 1.BETA.-Methylcarbapenems Bearing 5-Methyl-4-hydroxypyrrolidinone.

Syntheses and Pharmacokinetic Studies of Prodrug Esters for the Development of Oral Carbapenem, L-084

A Practical and Facile Synthesis of Azetidine Derivatives for Oral Carbapenem, L-084

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