Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-03-13
1999-04-27
Lambkin, Deborah C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
548486, C07D20952
Patent
active
058980750
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to a process for the separation of the enantiomers enhancement of an enantiomeric excess (ee) of one enantiomer in a mixture.
BACKGROUND OF THE INVENTION
manufacture of pharmaceutical entities. In particular, it can be used to prepare carbocyclic nucleosides which differ from the natural ribosyl nucleosides in having oxygen replaced by a methylene. Various carboxylic nucleosides have been demonstrated to possess useful therapeutic activity, for instance as antivirals and cardiac vasodilators. For the therapeutic purpose, it is preferred that the agents are obtained in single-enantiomer form, and this is conveniently accomplished by the use of the single enantiomers of the bicyclic lactam or derivatives thereof.
Various processes for obtaining the enantiomers of the bicyclic lactam are known. EP-A-0424064 discloses biocatalytic hydrolysis with enzymes that have a preference for one or other isomer, so that after the biotransformation of racemic lactam there are obtained one enantiomer as the untransformed lactam and the other enantiomer as ring-opened amino-acid. More recently, resolution of the bicyclic lactam through lipase-mediated resolution of the N-hydroxymethyl derivative has been reported by Nakano et al, Tetrahedron Asymmetry, 5: 1155-56 (1994).
SUMMARY OF THE INVENTION
The present invention is based on the discovery that, while procedures as described above offer effective means to obtain the single enantiomers of the bicyclic lactam, a simpler more economic procedure is available, since the enantiomers can be separated directly and efficiently by a direct crystallisation technique. We have found to our surprise that, in the case enantiomer showed much lower solubility than the racemate in ethereal solvents. Direct enantiomer separation, without the need for resolving agents, has been achieved by seeding a supersaturated solution of the racemate with a single enantiomer, under controlled conditions. The separation may also be achieved for any derivative thereof which exhibits the same effect, e.g. carrying one or more substituents in the carbocyclic ring, or a N-substituent, e.g. N-acyl or another cleavable moiety.
Without wishing to be bound by theory, it seems that racemic lactam exists as a conglomerate of its enantiomers rather than the more common case where racemates crystallise in space groups containing both enantiomeric forms. Evidence for the presence of a conglomerate is that, when racemate is mixed with the single enantiomer in any proportion, at no point is the melting point depressed below that of the racemate (racemate m.p. 54.degree. C.; enantiomer m.p. 98.degree. C.). Further, differential calorimetric studies on the racemate showed a peak characteristic of a conglomerate.
Accordingly, a supersaturated solution of the lactam may be entrained by seeding with crystals of the single enantiomer to grow larger crystals having an excess of the isomer seeded, and leaving the opposite isomer enriched in the mother liquors. In order to make such an entrainment crystallisation procedure useful for the production of single-enantiomer lactam it is desirable that the optically-enriched lactam obtained can be raised in enantiomeric purity through recrystallisation. Nonetheless the overall procedure is a resolution leaving an issue of utilisation of the wrong enantiomer. If it could be racemized or the configuration inverted, then all material could in principle be directed to the required isomer.
According to a second aspect of the invention, it has been discovered that recrystallisation of optically-enriched lactam will give crystals of higher enantiomeric excess (ee). This means that methods that initially produce the lactam of low ee could become commercially useful. Such methods include entrainment of the racemate with seed crystals of the single enantiomer, as described above, or a method of asymmetric synthesis that produces material of unsatisfactory ee. Even a low initial ee of the lactam will provide, after a suitable number of cryst
REFERENCES:
patent: 5102890 (1992-04-01), Bourzat et al.
Nakano et al., "A Facile Lipase-Catalyzed Resolution of 7, (1994), pp. 1155-1156.
Handa et al., "The Enantioselective Synthesis; of an Important Intermediate to the Antiviral, (-)-Carbovir", J. Chem. Soc. Perkin Trans., (1994), pp. 1885-1886.
Adger Brian Michael
McCague Raymond
Potter Gerard Andrew
Taylor Stephen John Clifford
Chirotech Technology Limited
Lambkin Deborah C.
Oswecki Jane C.
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