Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-04-11
1997-09-02
Dees, Jose G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
549 1, 549 9, 549 23, 549200, 549355, 549404, 549439, 548483, 546160, 564302, 540476, 540594, C07D33366, C07D30782, C07D31158, C07D20988
Patent
active
056633688
DESCRIPTION:
BRIEF SUMMARY
This invention relates to novel diastereoisomeric acid addition salts of homochiral hydroxylamines, to processes for obtaining such, to processes for the conversion thereof to the corresponding homochiral hydroxylamines, to certain novel homochiral hydroxylamines and to processes for using these as intermediates.
Substituted hydroxylamines having an organic radical which has a chiral center will exist as a racemic mixture of the (+)- and (-)-enantiomers. For certain uses, such as a drug per se or as an intermediate in preparation thereof, it is increasingly important for regulatory purposes to be able to provide a single enantiomer, rather than the racemate. Accordingly, processes for obtaining such are being actively investigated.
In general, classical resolution techniques have taken advantage of the presence in the molecule of a functional group which may be used as a handle for the formation of a covalent or ionic bond. Thus, the racemic mixture may be reacted with a homochiral reagent to give a mixture of diastereoisomeric adducts which may then be separated by conventional techniques such as chromatography or fractional crystallization. The initial adduct forming reaction is then reversed on each of the isolated diastereoisomers, to yield the individual enantiomers. By way of example, a hydroxyl group in the compound of interest may be used to form an ester with a homochiral acid. Alternatively, if a suitable group is present in the compound of interest, ionic acid/base addition salts may be formed. Thus, a racemic amine may be treated with a homochiral acid (or vice versa) to form a pair of diastereoisomeric acid addition salts. More recently, use has been made of high performance liquid chromatography (hplc) in which the stationary phase is homochiral, thereby forming diastereoisomeric interactions in situ as the racemic material is eluted through the column.
In the past, it has been suggested that certain homochiral hydroxylamines may be obtained from homochiral precursors, for instance the corresponding homochiral amine or alcohol or via the intermediacy of diastereoisomeric adducts formed with, for instance, the N-chlorocarbonyl derivative of a homochiral oxazolidinone. See for example, PCT application no. WO 91/14774, (SmithKline Beecham) and the references cited therein.
We have now found that homochiral hydroxylamines may be obtained by a more direct process which does not involve the intermediacy of a covalently bonded diastereoisomeric adduct but instead takes advantage of the ability of a hydroxylamine to form acid addition salts. In particular, the combination of a racemic hydroxylamine and a homochiral organic acid will lead to the formation of a pair of diastereoisomeric acid addition salts. While such an approach has previously been used for amines, it has not yet, as far as we are aware, been applied to a hydroxylamine.
Accordingly, the present invention provides a diastereoisomeric acid addition salt of the formula (II): R* is an organic radical which contains a chiral carbon to which the NHOZ is attached, and Z is hydrogen or a hydroxyl protecting group; and HA* is a homochiral organic acid.
The asterisk * is used herein to denote chirality.
It will be appreciated that each of the homochiral hydroxylamines of formula (I) and the homochiral organic acid HA* may be either the (+)- or the (-)-enantiomer. It will be further appreciated that each diastereoisomeric salt of formula (II) may be one of four possible combinations viz. the (+)(+), (+)(-), (-)(+) and (-)(-) [(hydroxylamine)(acid)] combinations. This invention covers all such possibilities.
Suitable homochiral hydroxylamines of the formula (I) include homochiral organic radicals R* which contain a chiral carbon (C*) to which the hydroxylamine group NHOZ is attached and Z is as defined in relation to formula (I).
Examples of suitable such homochiral organic radicals (R*) of formula (I) include compounds of the formula (A): ##STR1## in which one of R.sub.2 and R.sub.3 is hydrogen; and the other is the chiral carbon (C*) to which t
REFERENCES:
patent: 1390260 (1921-09-01), Sulzberger
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patent: 3163677 (1964-12-01), Hoffman et al.
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patent: 5264577 (1993-11-01), Beylin et al.
Berge et al., J. Pharm. Sci., vol. 66, No. 1, pp. 1-19, (1977).
Flisak Joseph R.
Ross Stephen Torey
Cebulak Mary C.
Dees Jos,e G.
Dinner Dara L.
Lentz Edward T.
SmithKline Beecham Corporation
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