Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-01-03
1998-10-06
Berch, Mark L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D20508, C07F 718
Patent
active
058178066
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to an improved process for the preparation of cyclohexane derivatives useful in the preparation of antibacterial agents.
European Patent Application, publication No. 0416953A2 describes a novel class of tricyclic antibacterial agents. A particularly preferred compound described and claimed therein is the compound (A) ##STR3## and salts thereof.
A key intermediate in the synthesis of compound (A) is the cyclohexane derivative (I). ##STR4## wherein R.sub.1 is a hydroxyl protecting group such as trialkylsilyl group e.g. t-bulydimethylsilyl.
The present invention provides a process for preparing the compounds of formula (I) in good yield and a high degree of enantiomeric purity.
Thus the present invention provides a process for the preparation of compounds of formula (I) ##STR5## wherein R.sub.1 is a hydroxyl protecting group which comprises reacting of the azetidinone (II) wherein R.sub.1 is a hydroxyl protecting group. ##STR6## with the homochiral (2S)-2-methoxycyclohexanone (III) or the complex thereof formed with one molecule of stannic chloride ##STR7## in an aprotic solvent and in the presence of a sterically hindered amine and a Lewis Acid.
Examples of suitable aprotic solvents for use in the reaction include halohydrocarbons such as dichloromethane, chlorobenzene or fluorobenzene. Other aprotic solvents that may be used in the reaction include aromatic hydrocarbons such as toluene, esters such as ethyl acetate or isopropyl acetate, or ethers such as 1-2 dimethoxyethane.
Suitable sterically hindered amines include tertiary amines and heterocyclic amines in which one or both of the carbon atoms attached to the nitrogen atom therein are substituted by one or two C.sub.1-4 straight or branched chain alkyl groups.
Examples of suitable sterically hindered tertiary amines include tri C.sub.1-6 straight or branched alkylamines (e.g. triethylamine, diisopropylethylamine, tri-isopropylamine or tri-isobutylamine), or tertiary aralkylamines (e.g. dibenzylethylamine, dibenzylmethylamine or N,N-dimethylbenzylamine).
Examples of suitable sterically hindered heterocyclic amines include .alpha.substituted pyrrolidines or piperidines e.g. 2,5-dimethylpyrrolidine, 2,6-dimethylpiperidine, 2,2,6,6-tetramethylpiperidine or .alpha.substituted aromatic heterocyclic amines such as 2,6-diterbutylpyridine or 2,6-dimethylpyridine.
Particularly convenient sterically hindered amines for use in the reaction include diisopropylethylamine, tri-isopropylamine, tri-isobutylamine, or 2,6-dimethylpyridine and more especially diisopropylethylamine.
Examples of suitable Lewes acids for use in the reaction include stannic chloride and stannic bromide. A particularly convenient Lewis acid for use in the reaction is stannic chloride.
Conveniently the reaction is carried out at a temperature within the range -30.degree. to 20.degree. e.g. -20.degree. to 10.degree. and more particularly -10.degree. to 50.degree.
In a preferred embodiment of this process the azetidinone (II) is added to a mixture of the compound (III) with the Lewis acid, optionally containing a small amount of the sterically hindered amine followed by addition of the sterically hindered amine.
The hydroxyl protecting group R.sub.1, is preferably a trialkylsilyl group such as a tri(C.sub.1-4)alkyl silyl group. Examples of suitable trialkylsilyl groups include trimethylsilyl and t-butyidimethylsilyl.
In a preferred embodiment of the invention the reaction is preferably carried out with an azetidinone of formula (II) wherein R.sub.1 is a t-butyldimethylsilyl group.
The (2S)-2-methoxycyclohexanone (III) may be prepared by oxidation of (1S,2S)-2-methoxycyclohexanol using conventional procedures. Thus for example the oxidation may be carried out using oxalyl chloride and dimethylsulphoxide, pyridine/sulphur trioxide, sodium hypochlorite, N-bromacetamide 1,3-dibromo-5,5-dimethyl-hydantoin or Jones reagent (CrO.sub.3 /H.sub.2 SO.sub.4). The reaction is conveniently carried out in a solvent, the choice of which will depend upon the oxidants to be used. Thus
Rossi Tino
Thomas John Russel
Zarantonello Paola
Berch Mark L.
Glaxo Wellcome SpA
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