Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Patent
1998-08-07
2000-09-19
McKane, Joseph K.
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
558423, C07C25500
Patent
active
061214809
DESCRIPTION:
BRIEF SUMMARY
This invention concerns a method for producing unsymmetrically substituted biphenylcarbonitriles.
Some angiotensin II inhibitors contain a biphenyl residue as part of the molecule. The synthesis of these pharmaceutically active substances requires the use of unsymmetrically substituted biphenyls as starting materials or intermediates from which the final synthesis of the target molecule can be carried out. There is therefore a requirement for a simple and reliable method for the synthesis of unsymmetrically substituted biphenyls, which can be meaningfully incorporated into an economical overall process. This requires in particular a high selectivity and high yield. A special significance in this connection attaches to biphenyl derivatives bearing a cyano function.
Unsymmetrically substituted biphenyl- and biaryl-compounds are also suitable for use as liquid crystal compounds and as a part of electro-optical components, in particular for use in non-linear optics.
Methods which have been suggested for the synthesis of unsymmetrically substituted cyanobiphenyls include the reaction of organo-boron, zinc or tin compounds with bromobenzonitriles [J.Organometallic Chem. 390(1990)389-3981]. The palladium-catalysed coupling of an aryl Grignard compound with an iodo-substituted benzonitrile has also been described. A method for the synthesis of 4'-methylbiphenyl-2-carbonitrile has been disclosed [EP 566468 A] in which a halobenzonitrile is treated with 4-methylphenyl-magnesium halide in the presence of a manganese salt as catalyst. These methods suggest that the very low yields observed under palladium catalysis are open to considerable improvement. For example, the authors of EP 566468 A saw a yield of only 1% on the reaction of 2.2 equivalents of 4-methylphenylmagnesium bromide with 2-bromobenzonitrile in the presence of catalytic amounts of tetrakis (triphenylphosphine)-palladium over 6 hours at 65.degree. C. In this investigation the reactants were mixed together all at once.
On theoretical grounds, it would be expected that the coupling of an aryl Grignard compound with a haloaryl compound with electron-withdrawing functionality would produce the desired biaryl coupling-product in high selectivity and with high yield [see J.Organometallic Chem. 390(1990)389-398, especially Table 1 on page 391]. In the present state of the art, this requires that on addition of the Grignard reagent the carbon-halogen bond of the aryl halide with which the Grignard reagent reacts is considerably more reactive than any other electron-accepting groups which may be present in the substrate molecule. These considerations in practice exclude the use of bromobenzonitrile as a coupling partner, if high selectivity and high yield are to be achieved.
The present invention comprises a simple to carry out method for the synthesis of unsymmetrically substituted cyanobiphenyl and cyanobiaryl compounds in high selectivity and with high yield. A further object of the invention is to make possible a general method for obtaining compounds incorporating a biphenyl or biaryl structure. In particular, a highly selective, simple and economical synthesis of the unsymmetrically substituted cyanobiphenyl compounds would make possible a simple synthesis of such target molecules as angiotensin II inhibitors.
We have now found that by slow addition (i.e. addition over a relatively long time scale) of a solution of an aryl Grignard compound to a reaction medium containing a bromobenzonitrile and a suitable palladium complex catalyst coupling takes place with as the main reaction the formation of biphenylcarbonitrile. The main reaction resulting when the reactants are mixed all at once, i.e. the addition of the Grignard compound to the nitrile function, is by this means almost entirely suppressed. The formation of imines (and after hydrolysis, benzophenones) is not observed to any significant extent.
The high selectivity arising from this method, which leads almost exclusively to the desired biphenylcarbonitrile, is surprising on the basis of current knowle
REFERENCES:
patent: 4956507 (1990-09-01), Matson et al.
patent: 5288895 (1994-02-01), Bouisset et al.
Minato, A., et al, "Selective Mono-alkylation and Arylation of Dihalides by Palladium-Catalyzed Cross-Coupling with the Gringnard and Organozinc Reagents", (21), 847, 1980.
Chemical Abstracts, vol. 125, No. 9, Aug. 26, 1996 p. 1136 col. 2 and N.A. Bumagin et al., ZH. Org. Khim., vol. 31, No. 11 1995 pp. 1650-1656.
Kohler Bernd
Langer Manfred
Mosandl Thomas
Great Lakes Chemical Konstanz GmbH
McKane Joseph K.
Murray Joseph
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