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AssigneeBristol-Myers Company
InventorsDonald E. Horning, Leeson R. Morris, James L. Douglas
Estimating the term…
There is described the stereoselective total synthesis of novel .DELTA..sup.2,3 -1,4-morpholine-2-carboxylic acids possessing a fused .beta.-lactam ring in the 1,6-position and carrying a substituent cis to carbon 5 in the 7-position of the fused ring system represented by the general formula ##STR1## wherein X is amino, azido or acylamido and Z represents optionally substituted C.sub.1 -C.sub.6 alkyl, aryl, aralkyl or heterocyclic. Also included in the invention are compounds of formula I in which the carboxyl group at the 2-position is protected as by an easily cleavable ester group and salts of both the free acids and carboxyl-protected compounds of formula I. The compounds of formula I are potent antibacterial agents or are of use as intermediates in the preparation of such antibacterial agents.
A compound having the formula ##STR190## wherein R" is hydrogen or an easily cleavable ester carboxyl-protecting group selected from the group consisting of benzhydryl, benzyl, p-nitrobenzyl, trichloroethyl, trimethylsilyl, phenacyl, acetonyl, (lower)alkyl, triphenylmethyl, methoxymethyl, indanyl, phthalidyl, pivaloyloxymethyl and acetoxymethyl and Z represents a radical of the formula
Dependencies are inferred from the claim text.
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Not condensed with other rings: five-membered rings
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents
With one oxygen atom directly attached in position 2, e.g. beta-lactams: with a nitrogen atom directly attached in position 3
With substituted hydrocarbon radicals attached to ring carbon atoms: radicals substituted by carbon atoms having three bonds to hetero atoms with…
Term ended 27 Dec 1994 (estimated)
USPTO file history isn’t available for this patent, so only indexed dates are shown.
1. Field of the Invention
The chemical processes of the present invention produce novel antibacterial agents of the .beta.-lactam type containing a hitherto unknown nucleus and useful intermediates for their synthesis.
2. Description of the Prior Art
To a solution of p-nitrobenzyl 7.beta.-azido-3-methylsulfonyloxymethyl-.DELTA..sup.3 O-2-isocephem-4-carboxylate (4.53 g., 10 mmole) and triethylamine (1.4 ml., 10 mmole) in 90 ml. of methylene chloride was added 10 mmole of 1-methyltetrazole thiol. The solution was stirred at 24.degree. C. for 16 hours, then washed with 5% HCl and water (100 ml. each), dried and the solvent evaporated in vacuo to give the product as a yellow oil. Upon recrystallization from ethyl acetate, the title product was obtained in 78% yield; m.p. 150.degree.-152.degree. C. The NMR was consistent with the proposed structure.
The procedure of Example 1 is repeated except that the 1-methyltetrazole thiol used therein is replaced by 10 mmole of 2-methylthiadiazole thiol. The title product was isolated as a yellow oil in 95% yield. The NMR and IR spectra of the product were in agreement with the proposed structure.
A solution of p-nitrobenzyl 7.beta.-azido-3-methylsulfonyloxymethyl-.DELTA..sup.3 -O-2-isocephem-4-carboxylate (1.36 g., 3.0 mmoles) and triethylamine (0.38 ml., 3.0 mmoles) in 50 ml. of dichloromethane was treated with 2-methyl-1,3,4-oxadiazole-5-thiol (0.35 g., 3.0 mmoles). The reaction mixture was stirred at room temperature for 48 hours and then washed with 10% HCl, water and brine. The solution was dried over sodium sulfate and evaporated in vacuo giving crude product. The crude product was purified by dry-column chromatography on silica gel (60 g., Activity III) eluting with 15% ethyl acetate in ether. There was obtained 1.0 g. of pure title product in 70% yield. The NMR spectrum was in agreement with the proposed structure.