Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-12-13
2002-12-03
Morris, Patricia L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S258000
Reexamination Certificate
active
06489483
ABSTRACT:
TECHNICAL FIELD
This invention provides a process for producing a 2-pyridylpyridine derivative, an important intermediate for producing medicines, agricultural chemicals, catalyst ligands, organic electroluminescence elements, charge transfer materials, electrophotographic photo-sensitive materials and dyes, in a high yield and with a high purity in a sequential manner at a low production cost, which process can be conducted on an industiral scale.
BACKGROUND ART
As reactions for synthesizing 2-pyridylpyridine derivatives, there have conventionally been known Ullmann reaction between 2-bromopyridine and 4-chloropyridine in nitrobenzene (Khim. Geol. Nauk., 114 (1970)), a reaction utilizinga cobalt catalyst (Synthesis, 600 (1975); Chem. Pharm. Bull., 33, 4755 (1985)), a coupling reaction between an alkyltin derivative and a halogenated pyridine in the presence of a Pd catalyst (Tetrahedron Lett., 33, 2199 (1992)), and a coupling reaction of halogenated pyridine derivatives with each other (W09852922). These reactions, however, involve many problems. For example, they require extremely expensive catalysts or reagents, require a special treatment for metal-containing waste liquor, and require difficult separation of by-products produced therefrom, thus not being said to be industrially advantageous techniques.
In addition, there have been proposed a cross-coupling reaction utilizing Grignard reaction (Japanese Patent Laid-Open No. 3169/1989; Tetrahedron Lett., 28, 5845 (1987) and synthesis by Wurtz reaction of halogenated pyridine derivatives with each other in the presence of Li metal under irradiation with ultrasonic waves (Tetrahedron Lett., 30, 3567 (1989); Synthesis, 564 (1986)). However, these reactions require exclusive equipment, and involve many problems for production on a large scale.
Recently, it has been reported to form a pyridine ring via pyridinium ion by iodinating an acetylpyridine derivative (Synthesis., 815 (1999)). This technique causes environmental problems since it involves halogenation and, in case where iodine used in the iodination remains, by-products are produced in the subsequent step. Thus, a purification step must be provided before the step after the iodination, which is not advantageous for synthesis on a large scale.
The present invention provides a process for producing a 2-pyridylpyridine derivative usable as an intermediate for medicines or agricultural chemicals, which does not require expensive special catalysts and special equipment, which does not cause environmental problems, and which can be conducted on an industrial scale and, more particularly, provides a process for producing a 2-pyridylpyridine derivative with a high positional specificity and a high purity in a high yield, which enables to produce the 2-pyridylpyridine derivative in a sequential manner at a low production cost.
DISCLOSURE OF THE INVENTION
The objects of the invention can be attained by the following processes. That is:
(1) a process for producing a 2-pyridylpyridine derivative, which comprises reacting an acetyl-substituted pyridine derivative with a 3-aminoacrolein, then reacting the reaction product with ammonia or an ammonium salt;
(2) a process for producing a 2-pyridylpyridine derivative as described in (1) above, wherein the acetyl-substituted pyridine derivative is a compound represented by the following general formula (I):
wherein R1 and R2 each independently represent a hydrogen atom, a halogen atom, an alkyl group, a heterocyclic group or an aryl group or, when taken together, R1 and R2 may form a ring, R3 represents an acetyl group, and n represents an integer of 1 to 3;
(3) a process for producing a 2-pyridylpyridine derivative as described in (1) above, wherein the ammonium salt is ammonium chloride, ammonium acetate or ammonium formate;
(4) a process for producing a 2-pyridylpyridine derivative as described in (1) above, wherein amount of the ammonia or the ammonium salt to be used is 1 to 30 mols per mol of the acetyl-substituted pyridine derivative;
(5) a process for producing a 2-pyridylpyridine derivative as described in (1) above, wherein the acetyl-substituted pyridine derivative and the 3-aminoacrolein are reacted with each other in the presence of a base;
(6) a process for producing a 2-pyridylpyridine derivative as described in (5) above, wherein amount of the base to be used is 0.1 to 10 mols per mol of the acetyl-substituted pyridine derivative;
(7) a process for producing a 2-pyridylpyridine derivative as described in (1) above, wherein an acid catalyst is used in the reaction between the reaction product of the acetyl-substituted pyridine with the 3-aminoacrolein and ammonia or the ammonium salt;
(8) a process for producing a 2-pyridylpyridine derivative as described in (7) above, wherein the acid is formic acid, ac acid or propionic acid; and
(9) a process for producing a 2-pyridylpyridine derivative as described in (1) above, wherein a solvent is used in the reaction between the acetyl-substituted pyridine derivative and the 3-aminoacrolein.
The invention is described in more detail below.
In order to describe the invention in more detail, one embodiment of the process of the invention is shown below which, however, does not limit the invention in any way.
In the invention, the acetyl-substituted pyridine derivative is exemplified by the compounds represented by the following general formula (I). The 3-aminoacrolein is exemplified by those 3-aminoacroleins which are represented by the following general formula (II) or (III). However, these are not to be construed to limit the scope of the invention.
In the above general formula (I), R1 and R2 each independently represents a hydrogen atom, a halogen atom, an alkyl group, a heterocyclic group or an aryl group or, when taken together, R1 and R2 may form a ring, R3 represents an acetyl group, and n represents an integer of 1 to 3. In the above embodiment of the process of the invention, n=1.
In the above formula (II) or (III), R4 and R5 each independently represent an alkyl group or, when taken together, R4 and R5 may form a ring, and R6 represents a hydrogen atom, a halogen atom or an alkyl group.
In the above general formulae (I) to (III), the alkyl group includes amethyl group, an ethyl group and a propyl group, with methyl group being preferred. The aryl group includes aphenyl group. The heterocyclic group includes a pyridyl group and a pyrazyl group, with pyridyl group being preferred. The halogen atom includes a fluorine atom, a chlorine atom and a bromine atom, with fluorine atom and chlorine atom being preferred. The ring formed by R1 and R2 includes a benzene ring and a cyclohexane ring, with benzene ring being preferred.
The ring formed by R4 and R5 includes a piperidine ring, a pyrrolidine ring and a morpholine ring, with morpholine ring being preferred.
As the acetyl-substituted pyridine derivatives to be used in the invention, there are specifically illustrated following compounds (IV-1) to (IV-6) including those represented by the above general formula (I). In the following formulae, R7 represents an acetyl group.
These acetyl-substituted pyridine derivatives may be obtained from, for example, easily available compounds wherein R7 represents a cyano group, by reacting them with a Grignard reagent (MeMgI) prepared from methyl iodide according to the process described in Org. Syntheses., Coll. Vol. III, 26(1965), then hydrolyzing the product to thereby convert R7 to acetyl group.
In the invention, no reaction solvents may be used throughout the all steps but, if necessary, there may be used any of polar or non-polar organic solvents such as aromatic solvents, e.g., benzene, toluene, xylene, chlorobenzene and dichlorobenzene; polar solvents, e.g., pyridine, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone; ester solvents, e.g., methyl acetate, ethyl acetate and butyl acetate; and alcohols, e.g., methanol, ethanol, isopropyl alcohol, butanol and t-butanol. Preferred solvents are ether solvents such as diethyl ether, diisopropyl ether
Suda Hirokazu
Umihara Ken
Morris Patricia L.
Sankio Chemical Co., Ltd.
Sughrue & Mion, PLLC
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