Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1992-07-21
1994-07-05
Lee, Mary C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
5483171, 5483205, 5483211, C07D41704, C07D23374
Patent
active
053268784
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a method for the resolution of chiral hydrantoins of general formula I: ##STR2## in which
R.sub.1 is a lower alkyl radical having 1 to 5 carbon atoms with linear or branched chain;
R.sub.2 is a phenyl radical, possibly mono-, di- or tri-substituted by lower alkyl or alkoxy radicals or halogen atoms, which are identical or different, or a heteroaryl radical containing a ring of 5 to 7 members in which the only heteroatom is the nitrogen, oxygen or sulfur, or else an aralkyl radical, the alkyl part of which comprises one or two carbon atoms and the aryl cycle is a phenyl group, possibly mono, di- or tri-substituted by lower alkyl or alkoxy radicals or identical or different halogen atoms.
It is known that the resolution of chiral molecules conventionally makes use of the formation of diastereoisomeric salts the differences in solubility of which permit the separation of one or them, which is then decomposed to lead to the selected enantiomer.
It is also known that these methods use optically active resolution agents which are frequently toxic or unstable and which are offered on the market on an industrial scale in a form of very relative purity and/or costly form and that, furthermore, frequently only a single enantiomeric form of the resolution agent is proposed.
The importance of chiral hydantoin enantiomers is also known, particularly the enantiomers of hydantoins of formula I. Thus, the racemic hydantoin (I) in which R.sub.1 is an ethyl radical and R.sub.2 a phenyl radical has been used for its anti-convulsant properties in the treatment of epilepsy under the name "phenytoin" or else "Nirvanol" (DCI). Its analog, which is N-methylated in 3 position of the hydantoin ring, has the same properties and has been used under the name of "mephenytoin". Now, among other writers, Kuepfer et al (J. Pharmacol. Exp. Ther. 221 (3), 590-7, 1982 and 230 (1) 28-33, 1984) have noted in man, in the case o these two compounds, differences in bioavailability and metabolism which can be used for improving the treatment of convulsive attacks.
Furthermore, the chiral hydantoins (I), which are easily prepared from the corresponding R.sub.1 --CO--R.sub.2 carbonyl derivatives by the Bucherer-Berg reaction, are intermediaries of choice for the preparation of acid amino enantiomers of general formula II: ##STR3## in which R.sub.1 and R.sub.2 have the meanings previously indicated for the hydantoins (I).
Some of these enantiomers exhibit interesting anti-hypertensive properties, such as, in particular, "methyldopa" (DCI) which is the levorotatory enantiomer of the amino acid in which R.sub.1 is a methyl radical and R.sub.2 a 3,4-dihydroxybenzyl radical. Other optically active amino acids are intermediates of choice for the preparation of therapeutically active compounds.
Thus the enantiomers and the racemic of the amino acid in which R.sub.1 is a methyl radical and R.sub.2 a 3,4-dichlorobenzyl radical lead, after reduction by metallic or organo metallic hydrides, to amino alcohols, some of which, N-substituted, described in Document FR-A-86 01 295, have analgesic properties and are active on the central nervous system.
The optically active amino acids in which R.sub.1 is an ethyl radical and R.sub.2 is a phenyl radical or a thienyl radical also permit, after their reduction in amino alcohols, the obtaining of amino esters or amino ethers which are active on the gastrointestinal tract, like some of the compounds described in FR-A-2 643 369 and EP-A-0 297 782.
In order to effect the resolution of the chiral hydantoins (I), various methods have been proposed. Thus, methods of preferred crystallization have been proposed which require a crystal seeding with an enantiomeric form previously obtained and which are generally of poor yield. Chromatographic techniques on chiral support have also been proposed, they being little adapted to industry and being particularly expensive. Finally, various methods have been proposed which are based on the formation of diastereoisomeric salts with enantiomers of differe
REFERENCES:
patent: 4634713 (1987-01-01), Werner et al.
Bouaziz Roger
Coquerel Gerard
Depernet Dominique
Petit Marie N.
Haley Jacqueline
Jouveinal SA
Lee Mary C.
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