Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-09
2003-09-23
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06624308
ABSTRACT:
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 4,41-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):
wherein X represents a halogen atom and R
3
and R
4
independently represents a hydrogen atom, a halogen atom, or a C
1
-C
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′-dipyridyl derivative from the byproduct 2,2′-dipyridyl derivative and 4,4′-dipyridyl, can be effected by using copper sulfate to insolubilize the by-products as copper salts, whereby the present invention has been completed.
In the present invention, in the above general formula (I), when X is C1, R
3
and R
4
are preferably F as halogen atoms and are preferably methyl groups and ethyl groups as the lower alkyl groups. In the most preferable combination of R
3
and R
4
, R
3
and R
4
are the same and are hydrogen atoms. According to the present invention, by using a 2-halopyridine derivative and 4-halopyridine as the starting materials, using the nickel complex catalyst used for homoaryl coupling (J. Organomet., Chem., 1971, vol. 28, p. 287), and performing a coupling reaction in the presence of zinc and a tetraalkylammonium halide salt, a 2,4′-dipyridyl derivative can be obtained with a good yield in a single step.
Further, depending on the reaction conditions, in addition to the 2,4′-dipyridyl derivative, small amounts of 2,2′-dipyridyl derivative or 4,4′-dipyridyl may be produced as by-products. The separation of only the 2,4′-dipyridyl derivative from the mixture of these dipyridyl isomers can be achieved as follows. Due to the difference in the chelating ability among dipyridyl isomers, it has been found that, by dissolving the mixture of the dipyridyl derivative isomers in an organic solvent, followed by adding a dilute copper sulfate solution, then stirring, the 2,2′-dipyridyl derivative and 4,4′-dipyridyl formed copper salts and precipitated as insolubles. By filtering out these insolubles using Celite etc., it is possible to obtain just the desired 2,4′-dipyridyl derivative in the organic solvent layer. By condensing this organic layer under reduced pressure, only the pure 2,4′-dipyridyl derivative can be obtained.
Further, according to this method, benzoxazepine derivatives and its salts can be industrially advantageously obtained.
BEST MODE FOR CARRYING OUT THE INVENTION
I. Method of Production of 2,4′-Dipyridyl Derivatives
The 2-halopyridine derivative capable of being used in the method of production of a 2,4′-dipyridyl derivative by a coupling reaction of the present invention is a 2-bromopyridine derivative or a 2-chloropyridine derivative. The 4-halopyridine is 4-bromopyridine or 4-chloropyridine. These may be added to the reaction mixture as free amines or pyridinium salts, or added after being neutralized by an amine in an organic solvent.
The molar ratio of the 2-halopyridine derivative and the 4-halopyridine is preferably 4:1 to 1:4, more preferably 1:1. Even if the amount of 2-halopyridine is present in excess, the 2,4′-dipyridyl derivative is preferentially produced (see Examples 1 and 2).
The nickel complex catalyst used in the coupling reaction is, for example, bis(triphenylphosphine) nickel (II) dihalides, such as NiCl
2
(PPh
3
)
2
, NiBr
2
(PPh
3
)
2
, NiI
2
(PPh
3
)
2
, NiCl
2
[Ph
2
P(CH
2
)
2
PPh
2
], NiCl
2
[Ph
2
P(CH
2
)
3
PPh
2
], or Ni (PPh
3
)
4
, Ni(1,5-cyclooctadiene)
2
(Ph indicates phenyl group), preferably NiCl
2
(PPh
3
)
2
, NiBr
2
(PPh
3
)
2
, NiCl
2
[Ph
2
P(CH
2
)
2
PPh
2
], or Ni (PPh
3
)
4
, most preferably NiCl
2
(PPh
3
)
2
or NiBr
2
(PPh
3
)
2
is used in an amount of preferably 10 to 50 mol %, more preferably 30 mol %, based upon the 2-halopyridine derivative and 4-halopyridine.
When the catalyst is bivalent nickel, the reaction proceeds well in the copresence of zinc.
The zinc used in the reaction is used in an amount-of preferably 1 to 4 equivalents, more preferably 1.5 equivalents, of the 2-halopyridine derivative and 4-halopyridine. The alkyl group constituting the tetraalkylammonium halide, is preferably a lower alkyl group, more preferably a methyl group, ethyl group, n-propyl group, or n-butyl group, most prefer
Kamei Katsuhide
Tatsuoka Toshio
Daiichi Suntory Pharma Co., Ltd.
Robinson Binta
Rotman Alan L.
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