Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Patent
1997-07-07
1998-07-28
Ramsuer, Robert W.
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
C07C25300
Patent
active
057864985
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP96/00236 filed on Jan. 20, 1996.
Phenylacetonitriles which have various substituents on the phenyl group and have a basic side chain have found use as effective pharmaceutical agents. Thus, of the phenylacetonitriles of the formula II with basic substituents described in DE 11 54 810, verapamil (II, R=H) and gallopamil (II, R=OCH.sub.3) are of proven use in the treatment of coronary heart disease and high blood pressure. ##STR2##
EP 0 271 013 describes phenylacetonitriles which have an aliphatic side chain in place of the dimethoxyphenylethyl radical on the nitrogen as agents for cardiovascular and asthmatic disorders.
The substituted phenylacetonitriles have a chiral carbon atom so that, in the absence of other centers of chirality, they form two enantiomers (optical antipodes). Conventional chemical syntheses starting from achiral substances produce the two enantiomers in equal amounts so that a racemate results.
It is known of verapamil and gallopamil that there are distinct quantitative differences between the enantiomers in their pharmacodynamics and -kinetics (M. Raschack, Naunyn-Schmiedeberg's Arch. Pharmacol. 294 (1976) 285; M. Eichelbaum et al., Br. J. Clin. Pharmacol. 17 (1984) 453). Thus, the levorotatory enantiomer is a much more effective coronary dilator whereas the dextrorotatory antipode has been used to break resistance in malaria and tumor therapy.
The preparation of optically active phenylacetonitriles is therefore of great importance.
However, this preparation is very difficult: when chiral catalysts are used in the synthesis of verapamil, the maximum enantiomeric excess which could be achieved was only 10%, ie. a 55:45 ratio of enantiomers (H. Brunner and H. Zintl, Monatsh. Chemie 122 (1991) 841-848). The enantiomeric excesses provided by other chiral catalysts are also completely inadequate.
The stereospecific synthesis of the enantiomers of verapamil and gallopamil described by L. J. Theodore and W. L. Nelson (J. Org. Chem. 52 (1987) 1309-1315) starts from the stereoisomeric lactic acids and cannot be carried out on the industrial scale because of the large number of reaction stages and complicated chemical modifications of functionalities.
Methods of racemate resolution have been published relatively frequently. There is a special case in WO 92/07821, where resolution of a racemate of the phenylacetonitrile moiety takes place by linkage to optically active .beta.-methylaminotetralin, which becomes part of the agent, and fractional crystallization of the diastereomers: ##STR3##
More widely applicable is the intermediate formation of diastereomeric salts which can be fractionated by crystallization or chromatography, and liberation of the required optically active product from the salt.
The difficulty of racemate resolution is evident from the fact that it was for a long time not possible to resolve the final product itself, ie. the agent or one of its basic precursors via which the syntheses normally take place, on the contrary there was racemate resolution of the carboxy derivatives III or IV, whose conversion into the required product verapamil requires additional synthetic steps, with chiral bases. ##STR4##
Brucine is used to resolve III (DE 2059 985), which is disadvantageous because of the extreme toxicity and high price of brucine. Although IV can be resolved with cinchonidine, it must be modified at two functionalities in order to obtain the desired product, which is difficult to carry out industrially (H. Ramuz, Helv. Chim. Acta 58 (1975) 2050-2060).
The chiral precursors V and VI used in Examples 6 and 7 in EP 0271 013 were prepared by the method described in DE 2059 985. ##STR5##
Only later were processes described for resolving the racemate of verapamil free base. (R)- or (S)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate is used as resolving acid in DE-A 3 723 684, but the preparation of this is extremely elaborate and it is not available in industrial quantities. DE-A 4 203 547 uses one to two equivalents of O,O'-dibenzoyl- or O,O'-di-p-t
REFERENCES:
patent: 5457224 (1995-10-01), Ehrmann et al.
Helvetica Chimica Acta, vol. 58, 7 (1975), 2050-2060.
J. Org. Chem, (1987), 52, 1309-1315.
Monatsheft fur Chem. 122, 841-848 (1991).
Karl Ulrich
Seitz Werner
BASF - Aktiengesellschaft
Murray Joseph
Ramsuer Robert W.
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