JP2001002644A - Production of 4-phenoxypyridine compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a 4-phenoxypyridine compound useful as an intermediate for pharmaceuticals in high yield without necessitating troublesome operations by using a compound easily available on industrial scale as a starting raw material and reacting the compound to enable smooth reaction. SOLUTION: (A) An acid salt (preferably hydrochloric acid salt) of a 1-(pyridyl)pyridinium salt optionally having substituents is made to react with (B) an inorganic base (preferably hydroxide of alkali or alkaline earth metal, etc.), and (C) a phenolic compound to obtain (D) the objective 4-phenoxypyridine compound. For example, 4-phenoxypyridine compound of formula III is produced as the component D by carrying out the above reaction using a halogenic acid salt of a 1-(pyridyl)pyridinium salt of formula I (R is an alkyl; X-is a halogen ion; (m) is an integer of 1-4) as the component A and a phenol of formula II (Y is an alkyl or the like; (n) is 0-5) as the component C. The amounts of the components C and B are preferably 1-20 mol and 1-5 equivalent based on 1 mol of the component A.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing 4-phenoxypyridines. 4-phenoxypyridines are compounds useful as pharmaceutical intermediates.

[0002]

2. Description of the Related Art As a method for producing 4-phenoxypyridines, for example, an acid salt of a 1- (pyridyl) pyridinium salt which may have a substituent (hereinafter, simply referred to as an acid salt of a 1- (pyridyl) pyridinium salt) is used. ) Is reacted with an alkali metal phenoxide.
-Phenoxypyridines have been obtained [Agricu
italal and Biological Che
history, 34 (1), 68 (1970), Che
Mische Berichte, 64, 1049 (1
931) etc.]. For example, 1- (4-pyridyl) pyridinium chloride hydrochloride is mixed with a well-dried mixture of potassium phenoxide and phenol, and then heated to carry out a reaction to obtain 4-phenoxypyridine.

[0003]

SUMMARY OF THE INVENTION The above-mentioned conventional method has the following problems.
The alkali metal phenoxide to be reacted with the acid salt of a (pyridyl) pyridinium salt is very easy to absorb moisture, and its anhydride is difficult to obtain industrially. Therefore, in order to produce 4-phenoxypyridines by the above-mentioned conventional method, it is necessary to produce an alkali metal phenoxide in advance, and the alkali metal phenoxide is often used for the reaction with the acid salt of 1- (pyridyl) pyridinium salt. Complicated operations are required such as drying. An object of the present invention is to provide a method for producing 4-phenoxypyridines that uses a compound that is relatively easily available industrially as a starting material and does not require complicated operations.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve the above problems. As a result, 1-
It has been found that when an acid salt of a (pyridyl) pyridinium salt, an inorganic base, and a phenol are used as starting materials, they can easily react to produce 4-phenoxypyridines in a high yield, thereby completing the present invention. Was.

That is, the present invention relates to a method for producing 4-phenoxypyridines, which comprises reacting an acid salt of 1- (pyridyl) pyridinium salt with an inorganic base and a phenol.

The present invention does not require a step of producing an alkali metal phenoxide which is required before producing 4-phenoxypyridines in the conventional method, and a good yield can be obtained even when an aqueous solution thereof is used as the inorganic base in the present invention. Thus, a complicated operation such as drying of the starting material is not required since 4-phenoxypyridine is obtained. The present invention is an industrially useful method capable of producing 4-phenoxypyridines easily and in good yield.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
As the acid salt of 1- (pyridyl) pyridinium salt used in the present invention, for example, the following general formula (1):

[0008]

Embedded image (Wherein, R represents an alkyl group bonded to the α-position and / or β-position of the pyridine nucleus, X ⁻ represents a halogen ion, and m represents 0 to 4).
Represents an integer. A)-(pyridyl) pyridinium salt represented by the formula (1), and a salt composed of an inorganic acid or an organic acid, preferably a halogenated salt (hydrochloride) of the 1- (pyridyl) pyridinium salt represented by the above formula (1) , Hydrobromide and the like), particularly preferably hydrochloride.

The alkyl group represented by R in the above formula includes a linear or branched alkyl group having 1 to 3 carbon atoms, and is preferably a methyl group or an ethyl group. m
Is an integer of 2 or more, the plurality of alkyl groups represented by R may be the same or different.

[0010] The present invention includes a 1
Any acid salt of-(pyridyl) pyridinium salt can be used. An example of the method for producing the acid salt of 1- (pyridyl) pyridinium salt may be represented by the following formula:

[0011]

Embedded image (Wherein R and m are the same as those described above) can be easily produced by a method of reacting a pyridine with a halogen in the presence of sulfur (JP-A-57-108069). When the acid salt of 1- (pyridyl) pyridinium salt is produced by the method, the reaction solution containing the acid salt of 1- (pyridyl) pyridinium salt after the reaction can be directly used in the present invention.

The phenols used in the present invention include:
For example, general formula (2):

[0013]

Embedded image (Wherein, Y represents an alkyl group, an aryl group, a halogen atom or a nitro group, and n represents an integer of 0 to 5). Examples of the alkyl group represented by Y in the formula include a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms, preferably a methyl group or ethyl. Examples include a phenyl group and a naphthyl group which may have one or two or more alkyl groups selected from a methyl group and an ethyl group to be bonded, preferably a phenyl group, and the halogen atom represented by Y is preferably chlorine. Is an atom. When n is an integer of 2 or more, a plurality of substituents represented by Y may be the same or different.

Examples of the inorganic base used in the present invention include hydroxides, carbonates and hydrogen carbonates of alkali metals or alkaline earth metals. In the present invention, one or more of these may be used. it can. The inorganic base can be used as an aqueous solution, and the reaction can be performed without any problem even if water is present in the reaction system.

The use ratio of the phenol to the 1- (pyridyl) pyridinium salt is usually 1 to 20 mol, preferably 2 to 6 mol, per 1 mol of the 1- (pyridyl) pyridinium salt. is there. If the amount of the phenol used is less than the above range, the yield tends to decrease, which is not preferable.Moreover, even if the phenol is used more than the above range, the improvement in the yield according to the amount used is not recognized, so the more No need to use.

The use ratio of the inorganic base to the 1- (pyridyl) pyridinium salt is usually 1 to 5 equivalents, preferably 1 to 2 mol, per mol of the 1- (pyridyl) pyridinium salt. Is equivalent. If the amount of the phenol used is less than the above range, the yield tends to decrease, which is not preferable.Moreover, even if the phenol is used more than the above range, the improvement in the yield according to the amount used is not recognized, so the more It is not necessary to use it, and the above range is sufficient.

According to the present invention, the acid salt of 1- (pyridyl) pyridinium salt, phenol and inorganic base are simply mixed with stirring to react easily to form 4-phenoxypyridine. . The reaction temperature is usually 50 to 1
80 ° C, preferably 100 to 120 ° C. If the reaction temperature is lower than the above range, the yield may be lowered, which is not preferable. The reaction may be carried out under reduced pressure, normal pressure or increased pressure.

According to the present invention, the reaction temperature may be difficult to control due to heat generated by the reaction. Therefore, when the acid salt of 1- (pyridyl) pyridinium salt, phenol and inorganic base are mixed and reacted. The reaction is preferably carried out while adding an acid salt of a 1- (pyridyl) pyridinium salt and / or an inorganic base. That is, a method of reacting a mixture of an acid salt of a 1- (pyridyl) pyridinium salt and a phenol while adding an inorganic base, while adding an acid salt of a 1- (pyridyl) pyridinium salt to a mixture of a phenol and an inorganic base Reaction method, or 1-
It is preferred to carry out the reaction by adding the acid salt of the (pyridyl) pyridinium salt and the inorganic base while separately adding them.

When mixing and reacting while adding an acid salt of 1- (pyridyl) pyridinium salt and / or an inorganic base, the reaction is usually carried out in 1 to 3 hours, and after the completion of the addition, aging is continued for 5 to 6 hours. It is better to do.

Since pyridines are by-produced by the reaction, the reaction may be carried out while distilling the pyridines out of the reaction system.

When the reaction is carried out as described above, 4-phenoxypyridines are produced in good yield. For example, 1-
When an acid salt of a 1- (pyridyl) pyridinium salt represented by the above general formula (1) is used as an acid salt of a (pyridyl) pyridinium salt and a phenol represented by the above general formula (2) is used as a phenol, (3):

[0022]

Embedded image (Wherein, R, m and n are the same as above) to produce 4-phenoxypyridines.

After completion of the reaction, neutralization, extraction,
By combining unit operations such as filtration and distillation, 4-phenoxypyridines can be isolated.

[0024]

EXAMPLES Next, the present invention will be described specifically with reference to examples, but the present invention is not limited to the following examples. Example 1 25 g (0.106 mol) of phenol, 1.83 g (0.0458 mol) of sodium hydroxide and 10 g (0.00 mol) of 1- (4-pyridyl) pyridinium chloride hydrochloride
(436 mol) was stirred and reacted at 180 ° C. for 6 hours. During the reaction, pyridine and water generated by the reaction were distilled out of the reaction system and maintained at the above temperature. After the reaction was completed, the reaction solution was cooled to room temperature and analyzed by high performance liquid chromatography. As a result, the yield of 4-phenoxypyridine was 51.7% [based on the hydrochloride of 1- (4-pyridyl) pyridinium chloride]. there were.

Example 2 1000 g (12.8 mol) of pyridine and 15 g of sulfur
To the mixture (0.5 mol), 149 g (4.20 mol) of chlorine gas was blown in for 2 hours through an inlet tube under stirring and reflux, and the reaction was further continued under reflux for 1 hour while stirring. . Thus, 430 g (1.88 mol) of 1- (4-pyridyl) pyridinium chloride hydrochloride
Was obtained. 535 g of phenol (5.69) was added to the resulting reaction solution containing 1- (4-pyridyl) pyridinium chloride hydrochloride under stirring at 100 to 120 ° C.
Mol), and the resulting mixture is then treated at the same temperature with 48%
The reaction was carried out while 158 g of an aqueous sodium hydroxide solution (1.89 mol of sodium hydroxide) was added dropwise over 2 hours.
After the addition of the aqueous sodium hydroxide solution is completed,
Stirring was continued for an hour to complete the reaction. The obtained reaction solution was cooled to room temperature, and 2,000 g of water and 1000 g of toluene
Was added, and 50 g of activated carbon was further added and mixed, followed by filtration. A 48% aqueous sodium hydroxide solution 4 was added to the obtained filtrate.
24 g was added, and the aqueous layer and the organic layer were separated. The resulting organic layer was distilled to give 4-phenoxypyridine 171.
4 g [1.00 mol, yield 53.3%: based on 1- (4-pyridyl) pyridinium chloride hydrochloride] was obtained.

Claims (1)

[Claims] 1. A process for producing 4-phenoxypyridines, which comprises reacting an acid salt of a 1- (pyridyl) pyridinium salt which may have a substituent with an inorganic base and a phenol.