Isomerisation process

Details Isomerisation process Isomerisation process

1998-03-27

2000-02-15

Berch, Mark L.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

540302, C07D20508

Patent

active

060254874

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a process for obtaining an intermediate useful in the preparation of antibacterial agents.
European Patent Application EP0416953 describes a novel class of tricyclic antibacterial agents and the process for their preparation. A particularly preferred compound described and claimed therein is the compound of formula (A) ##STR3## and salts thereof.
A key intermediate in the synthesis of compound of formula (A) is the azetidinone derivative of formula (I) ##STR4## wherein R is a hydroxyl protecting group.
The process described therein for preparing the compound of formula (I) gives the compounds as a mixture of isomers from which it is separated. One of the other isomers that may be obtained by the general process described for preparation of compound of formula (I) is the compound of formula (II) ##STR5## wherein R is a hydroxyl protecting group.
We have now found that it is possible to obtain a compound of formula (I) by isomerisation of the corresponding compounds of formula (II) in good yield without the need to use a chiral cyclohexanone derivative.
Thus the present invention provides a process for the preparation of a compound of formula (I) wherein R is a hydroxyl protecting group, ##STR6## which comprises isomerisation of a compound of formula (II) wherein R is a hydroxyl protecting group by reaction in an aprotic solvent with a base in the presence of Lewis acid and a compound of formula (III). ##STR7## wherein R.sub.1 and R.sub.2 each independently represent cyano, COR.sub.5 or CO.sub.2 R.sub.6 or R.sub.1 and R.sub.2 together with the carbon atom to which they are attached form a C.dbd.O group; optionally substituted phenyl or phenylalkyl group; phenylalkyl group; optionally substituted phenyl group.
The term alkyl as a group or part of a group when used herein refers to a straight or branched chain alkyl group containing from 1 to 4 carbon atoms. examples of such groups include methyl, propyl, isopropyl, n-butyl, isobutyl, secondary butyl or tertiary butyl.
The term cycloalkyl refers to a C.sub.3-7 cycloalkyl group.
The term substituted phenyl or phenylalkyl refers to a group in which the phenyl moiety is substituted by 1 to 3 groups selected from halogen, alkyl, amino, alkylamino, dialkylamino, nitro, cyano.
Preferred compounds of formula (III) are those wherein R.sub.1 and R.sub.2 each independently represent cyano, C.sub.1-4 alkoxycarbonyl eg. ethoxycarbonyl, methoxycarbonyl or t-butoxycarbonyl groups or those wherein R.sub.1 and R.sub.2 together with the carbon atom to which they are attached form a C.dbd.O group and R.sub.3 and R.sub.4 each independently represent hydrogen, phenyl or methyl group. Examples of such compounds include diethyl malonate, malononitrile, ethyl cyanoacetate, diethyl dimethylmalonate, diethyl methylmalonate di t-butylmalonate, benzaldehyde, benzophenene or t-butyl acetate.
Examples of suitable base for use in the reaction include sterically hindered organic bases for example lithium amides such as lithium diisopropyl amide, lithium bis(trimethylsilyl)amide or lithium tetramethyl piperidide.
Particularly convenient compounds of formula (III) are diethyl malonate, ethyl cyanoacetate or diethyl dimethyl malonate, di ter-butyl malonate or benzaldehyde of which diethyl malonate is particularly preferred.
Examples of suitable Lewis acid for use in the reaction include zinc salts such as zinc chloride or zinc bromide.
A particularly convenient Lewis acid for use in the reaction is zinc bromide.
The reaction is carried out in an aprotic solvent such as an ether e.g. tetrahydrofuran, a hydrocarbon such as hexane, cyclohexane or halohydrocarbon e.g chlorobenzene or mixtures thereof and preferably at a temperature within the range -78.degree. to 10.degree..
The process of the invention may be carried out using a mixture of compound (II) and compound (I).
The hydroxyl protecting group R is preferably a trialkylsilyl group such as tri(C.sub.l-4)alkylsilyl group. Examples of suitable trialkylsilyl groups include trimethylsilyl and t-butyldimethylsily

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