Resolution of amines

Details Resolution of amines Resolution of amines

2000-04-10

2001-02-13

Ramsuer, Robert W. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06187930

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a new procedure for the optical resolution of a mixture that comprises 2-[phenyl(1-methyl-1 H-pyrazole-5-yl) methoxy]-N,N-dimethylethanamine into its enantiomers.
BACKGROUND OF THE INVENTION
The compound 2-[phenyl(1-methyl-1 H-pyrazole-5-yl) methoxy]-N,N-dimethylethanamine (which can also be given the name 5-[&agr;-(2-dimethylaminoethoxy)benzyl]-1-methyl-1 H-pyrazole or 5-{[N,N-dimethylaminoethoxy)phenyl]methyl}-1-methyl-1 H-pyrazole), of formula I
is a compound described in the European patent EP 289 380 which has analgesic properties.
The two enantiomers of the compound of formula I have been synthesised and their properties as analgesics evaluated [J. A. Hueso, J. Berrocal, B. Gutiérrez, A. J. Farré and J. Frigola,
Biorg. Med. Chem. Lett.
1993, 3, 269]. It was found that the dextrorotatory enantiomer was the most active.
The enantiomers of the compound of formula I are obtained by O-alkylation of the corresponding enantiomers of [phenyl-hydroxy-(1-methyl-1 H-pyrazole-5-yl]methane, of formula II
The dextrorotatory enantiomer of the compound of formula (II), hereinafter (+) -II, has been obtained from the synthesis of enantiomerically pure compounds (EPC) with very poor yield. The starting compound is (−)-ethyl madelate allowing an absolute configuration (R) to be assigned to the enantiomer (+)-II.
The enantiomers of the compound of formula (II) have also been obtained from laborious processes of separation of the diastereoisomeric esters formed by the reaction of (+)-II with (+)-O-acetylmandelic acid by column chromatography or by fractionated crystallisation. The yields obtained were 25% for the enantiomer (+)-II and 22% for the levorotatory enantiomer of the compound of formula (II), hereinafter (−)-II [J. A: Hueso, J. Berrocal, B. Gutiérrez, A. J. Farré and J. Frigola,
Bioorg. Med. Chem. Lett.
1993, 3, 269].
The methods for resolving racemic mixtures are very abundant and have been extensively described [for a monograph on the properties of racemates and their resolution see: Jacques, Collet, Wilen, “Enantiomers Racemates and Resolutions”, Wiley: New York, 1981; for reviews see: Wilen,
Top. Stereochem.,
1971, 6, 107; Boyle,
Q. Rev. Chem. Soc.,
1971, 25; Buss, Vermeulen,
Industrial. Eng. Chem.,
1968, 60, 12 ].
A pair of the enantiomers can be resolved by different methods. The most commonly employed is that of separation thereof by fractionated crystallisation. If the racemic compound contains an amine group in its structure it is possible to form diastereoisomeric salts with an optically active acid. Tartaric acid and its derivatives, such as dibenzoyltartaric, ditoluyltartaric, o-nitrotartaric acid and others, malic acids, mandelic acid and its derivatives, 2-phenoxypropionic acid, quinic acid and canphorsulphonic acid and its derivatives, among others, are the most commonly used. Once the diastereoisomeric salts are obtained and separated, the enantiomeric amines can be easily liberated and the chiral acid recovered. This simple and economical method has been widely utilised on industrial scales.
The object of the present invention consists of providing a commercially useful procedure suitable for obtaining the two enantiomers of the compound of formula I separately with a high yield and suitable enantiomeric purity.


REFERENCES:
patent: 0787715 (1997-08-01), None
patent: 9720817 (1997-06-01), None
Jacques, J., et al., “Enantiomers, Racemates and Resolutions”,Krieger Publishing Companypp 259-261, 387-388 (1991).
Hueso-Rodriguez, J.A., et al., “Preparation of the enantiomers of the analgesic E-3710”Bioorganic&Medicinal Chemistry Letters, vol. 3. No. 2, pp 269-272 (1993).

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