Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1999-01-21
2000-08-01
Davis, Zinna Northington
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C07D26702
Patent
active
060968842
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a method of producing 2,4'-dipyridyl derivatives, a method of separating 2,4'-dipyridyl derivatives, and methods of producing benzoxazepine derivatives and their salts. More specifically, it relates to a method of producing 2,4'-dipyridyl derivatives by a cross coupling reaction of halopyridines, a method of separating a 2,4'-dipyridyl derivative from a dipyridyl derivative isomer mixture containing the 2,4'-dipyridyl derivative, and methods of producing benzoxazepine derivatives and their salts using the above methods.
BACKGROUND ART
Various reports have been made up to now on methods for synthesis of 2,4'-dipyridyl, but all of these methods of synthesis involve problems. None of the methods of synthesis are satisfactory.
For example, in the condensation reaction of 4-cyanopyridine and acetylene disclosed in the specification of U.S. Pat. No. 4,196,287, there is the danger of explosion since a high pressure acetylene gas is used, and therefore, special equipment is required, and the method is not generally accepted.
Further, in the Ullmann-like reaction of 2-halopyridine and 4-halopyridine (Khim. Geol. Nauk., vol. 5, p. 114, 1970), 2,2'-dipyridyl and 4,4'-dipyridyl are produced, in addition to the desired 2,4'-dipyridyl, and therefore, the yield is poor.
Further, cross coupling reactions between a halopyridine and various pyridine metal reagents (see Grignard reagent: Synthesis, vol. 7, p. 564, 1986; tin reagents: T. L., vol. 33, no. 16, p. 2199, 1992; borane reagent: Chem. Pharm. Bull., vol. 33, no. 11, p. 4755, 1985) using a palladium catalyst has been reported in numerous conditions, but isomers such as 2,2'-dipyridyl and 4,4'-dipyridyl are produced in large amounts in addition to the desired 2,4'-dipyridyl, and therefore, the yield is poor and the purification is very tedious.
Further, as another method, the reaction with an N-ethoxycarbonyl pyridinium salt (see J. Chin. Chem. Soc. (Taipei), vol. 36, no. 6, p. 609, 1989) was reported, but the yield is extremely poor and in the improved method (see Heterocycle, vol. 31, no. 4, p. 637, 1990), the number of reaction steps is tremendously increased, and therefore, this method is not practical.
There have been other methods reported in literature, but the synthetic routes are long and the yields of all of the processes are low (for example, see T.L., vol. 25, no. 35, p. 3887, 1994 and Pol. J. Chem., vol. 53, no. 4, p. 893, 1979).
As explained above, all of the reported methods of 2,4'-dipyridyl up to now have been poor in yield or have not been easy in operation and were not industrially satisfactory. Further, the simple removal method of the isomers, i.e., 2,2'-dipyridyl or 4,4'-dipyridyl, which were sometimes produced has not been studied at all.
DISCLOSURE OF INVENTION
The object of the present invention is to provide a method of producing 2,4'-dipyridyl derivatives which is good in yield, easy in operation, and industrially satisfactory and a simple method for separating the 2,4'-dipyridyl derivatives from a mixture of dipyridyl derivative isomers.
Another object of the present invention is to provide an industrially satisfactory method of producing benzoxazepine derivatives and the salts thereof, using the above method.
The present inventors engaged in intensive studies in consideration of the above situation with the intent of establishing a method for the industrial production of 2,4'-dipyridyl derivatives and easy separation and refinement of its isomers as a result found that with a coupling reaction between a 2-halopyridine derivative of the formula (I): ##STR1## wherein X represents a halogen atom and R.sup.3 and R.sup.4 independently represents a hydrogen atom, a halogen atom, or a C.sub.1 -C.sub.4 lower alkyl group and 4-halopyridine is carried out using a nickel complex catalyst, a 2,4'-dipyridyl derivative is simply obtained with a good yield and, further due to the difference in chelating abilities among dipyridyl isomers, the process of separation and purification of the desired 2,4'-
REFERENCES:
Takao Sakamoto et al., Preparation of .pi.-Deficient Heteroarylzinc Halides by Oxidative Addition of Active Zinc and Its Palladium-Catalyzed Reaction, (1993), Tetrahedron vol. 49, No. 43, pp. 9713-9720.
A Novel Synthesid of 4-Aryl- and 4-Heteroarylpyridines via Diethyl(4-pyridy)borane, (1985), Minoru Ishijura et al, Chem. Pharm. Bull., vol. 33, No. 11, pp. 4755-4763.
Synthese von unsymmetrischen and symmetrischen Dihydroxybipyridinen, (1992), Echehard V. Dehmlow et al., Liebigs Ann. Chem., pp. 953-959.
Kamei Katsuhide
Tatsuoka Toshio
Davis Zinna Northington
Robinson Binta
Suntory Limited
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