Process for preparing penem esters

Details Process for preparing penem esters Process for preparing penem esters

1992-09-21

1994-11-01

Rizzo, Nicholas

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

540350, C07D49900

Patent

active

053609042

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a novel process for preparing penem esters starting from a suitable oxalic acid derivative and an appropriate azetidinone.
It is known that the penems are useful as antibacterial agents as described and claimed in e.g. U.S. Pat. No. 4,482,565.
The penems may be prepared by means of many processes as for example those shown in GB-A-2144743 or in GB A-2111496. The known methods of preparation require long syntheses and the use of expensive protecting groups and reagents; for example, the preparation of the intermediate acetoxymethyl oxalic acid requires a multistep synthesis starting from an expensive oxalyl chloride; moreover the preparation of the azetidinones is characterized by low yields and poor purity of the desired intermediates.
We have found a new method to obtain penem esters under very mild conditions, with high stereoselectively, high yields and an easy workup and a new method for the preparation of acetoxymethyl oxalic acid starting from an unexpensive reagent with an easy procedure.
According to the present invention, there is provided a process for preparing a compound of the formula (I): ##STR4## wherein R.sub.1 is a hydrogen atom or a hydroxy protecting group and R.sub.2 is a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group, the process comprising the following steps: ##STR5## wherein R.sub.1 is as defined above and Z is a C.sub.1 -C.sub.10 alkyl or an aryl group, with a compound of the formula (III): ##STR6## wherein R.sub.1 is as defined above and M is hydrogen atom or a cation, to obtain an azetidinone of the formula IV): ##STR7## wherein R.sub.1 and R.sub.2 are as defined above, b) condensing the azetidinone of the formula (IV) as defined above with an acetoxymethyl oxalic acid derivative of the formula (V): ##STR8## wherein X is a halogen atom or a --OCOOR.sub.3 group wherein R.sub.3 is a C.sub.1 -C.sub.10 alkyl group, ##STR9## wherein R.sub.1 and R.sub.2 are as defined above, and c) cyclizing and optionally removing the protecting groups of the compounds of the formula (VI) as defined above.
The configuration of the compounds of the formula (I) is 5R, 6S, 1R; the configuration of the compounds of formula (IV) is 1R, 3S, 4R.
The hydroxy protecting group R.sub.1 may be, for example, t-butyldimethylsilyl, p-nitrobenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, trimethylsilyl, benzyl, p-bromophenacyl, triphenylmethyl or pyranyl group, preferably t-butyldimethylsilyl, p-nitrobenzyloxycarbonyl, trimethylsilyl or pyranyl groups, in particular t-butyldimethylsilyl or trimethylsilyl group.
When R.sub.2 is a C.sub.1 -C.sub.6 alkyl group, it is preferably methyl or ethyl group; most preferably R.sub.2 represents a hydrogen atom.
When Z is a C.sub.1 -C.sub.10 alkyl, it is preferably methyl, ethyl or propyl group; when Z is an aryl group, it is preferably phenyl unsubstituted or substituted by an electron withdrawing group such as a nitro, a methoxy group, or a halogen atom, such as, e.g. bromine, chlorine or iodine. The cation M preferably represents an alkali or an alkaline-earth metal, in particular sodium or potassium, or an ammonium or an alkylammonium group.
When X is a --OCOOR.sub.3 group, R.sub.3 is preferably a C.sub.1 -C.sub.6 alkyl group, in particular methyl, ethyl, propyl or butyl group.
In particular the reaction between the compounds of the formula (II) and the compounds of the formula (III) in step (a) may be carried out, e.g., in a solid-liquid phase or in a homogeneous phase, in an anhydrous organic solvent, at a temperature of from 20.degree. to 100.degree. C. for a period of from a few minutes to a few days, optionally operating in presence of a quaternary ammonium or phosphonium salt or of trialkylsilyl iodide.
Preferably the anhydrous organic solvents may be, e.g., toluene, xylene, methylenechloride, chloroform, diethyl-ether, dioxane, tetrahydrofurane, acetonitrile, acetone, dimethylformamide; in particular toluene, dioxane and tetrahydrofurane are the preferred ones. The reaction is preferably carried out at from, e.g., about 25.degree. to a

REFERENCES:
patent: 5153315 (1992-10-01), Hungerbuhler et al.
Tetrahedron Letters, vol. 34, No. 21, pp. 3491-3492, "The Total Synthesis of Ritipenems. Construction of Penem Thiazoline Ring by Incorporation of Two 2C Units of Glycolic Acid", Walter Cabri, et al. (Mar. 26, 1993).

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