JP2000327660A - Preparation of acetylpyridines - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare the subject compound useful for raw compound of medicine in an industrially advantageous method by reacting pyridine ethanol-1-oxides and an acid anhydride. SOLUTION: The subject compound (preferably a compound of formula II, concretely, 2-acetylpyridine, etc.), is obtained by reacting pyridine ethanol-1- oxides [preferably a compound of formula I (R is an alkyl, aryl or alkoxy; n is 0-4), concretely, e.g. 2-pyridine ethanol-1-oxide, etc.], and an acid anhydride (e.g. an aliphatic carboxylic acid anhydride, aromatic carboxylic acid anhydride, heterocyclic carboxylic acid anhydride, etc.). The reaction is carried out, preferably in the presence of a base normally at 50-150 deg.C, preferably 90-130 deg.C, using 1-10 mole, preferably 2-5 mole of the acid anhydride per 1 mole of pyridine ethanol-1-oxides.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing acetylpyridines useful as a starting compound for medicines.

[0002]

2. Description of the Related Art Various methods are known as methods for producing acetylpyridines. For example, pyridinecarboxylic acid or its ester is converted to acetic acid in the presence of
A method of producing acetylpyridine by performing a gas phase contact reaction under a high temperature condition of 20 ° C. (Japanese Patent Laid-Open No. 2-73031, etc.). Must (pyridyl)
-1,2-ethanediol is reacted with an alkyl chloroformate or phosgene, and the resulting reaction product is heated to produce acetylpyridine (JP-B-48-5593). Are reacted with Grignard with methylmagnesium bromide,
A method for producing acetylpyridine by hydrolyzing the obtained reaction product [Liebigs. Ann. Chem. ,
7, 1351 (1976)], (pyridyl) -1,
A method for producing acetylpyridine by reacting 2-ethanediol with acetic anhydride to produce a monoacetylated product, dehydrating the monoacetylated product, and then hydrolyzing to produce acetylpyridine [Bul
l. Chem. Soc. Jpn. , 45, 1924 (1
972)], a method for producing acetylpyridine by reacting methyl picolinate with trimethylaluminum [J. Org. Chem. , 63, 10063 (199
8)] are known.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a method for producing acetylpyridines by a novel reaction using a raw material completely different from the conventional method.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies in order to develop a novel method for producing acetylpyridines. As a result, when a pyridineethanol-1-oxide is reacted with an acid anhydride, an acetylpyridine can be easily produced, and a novel production method different from the conventional reaction has been found, and the present invention has been completed. Was. That is, the present invention relates to a method for producing acetylpyridines, which comprises reacting pyridineethanol-1-oxides with an acid anhydride. According to the present invention, it is not necessary to use a high reaction temperature as in the conventional method, and it is not necessary to use a substance derived from a compound having a strong skin irritating property as in the conventional method. Acetyl pyridines can be produced without using a conventional method and an organometallic compound which requires special handling or requires special equipment, so that the method of the present invention is a method useful as an industrial production method. is there.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
The pyridineethanol-1-oxides used in the present invention are compounds having at least a 2-hydroxyethyl group bonded to a carbon atom of a pyridine nucleus and an oxygen atom bonded to a nitrogen atom of a pyridine nucleus. 1):

[0006]

Embedded image (In the formula, R represents an alkyl group, an aryl group or an alkoxy group, and n represents an integer of 0 to 4. When n is 2 or more, a plurality of substituents R may be the same or different. .)). Preferred are pyridineethanol-1-oxides of the general formula (1) having a 2-hydroxyethyl group at the 2- or 4-position of the pyridine nucleus.

The alkyl group represented by R in the formula (1) is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, more preferably a methyl group, Ethyl group, n-propyl group, isopropyl group, n
A linear or branched alkyl group having 1 to 4 carbon atoms, such as -butyl group, isobutyl group, sec-butyl group and the like. The aryl group represented by R is preferably a phenyl group which may have at least one substituent selected from the group consisting of a methyl group, an ethyl group, a methoxy group, an ethoxy group and a chlorine atom on the aromatic ring. And examples thereof include a phenyl group, a methylphenyl group, a methoxyphenyl group, and a chlorophenyl group. The alkoxy group represented by R in the formula is preferably a linear or branched alkoxy group having 1 to 6 carbon atoms, and more preferably a methoxy group, an ethoxy group, an n-propoxy group, or an isopropoxy group. A straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms such as a group, an n-butyloxy group, an isobutyroxy group, a sec-butyroxy group.

Specific examples of pyridineethanol-1-oxides include, for example, 2-pyridineethanol-1-oxide
Oxide, 3-pyridineethanol-1-oxide, 4
-Pyridineethanol-1-oxide, 6-methyl-2
-Pyridineethanol-1-oxide, 5-ethyl-2
-Pyridineethanol-1-oxide, 6-methoxy-
2-pyridineethanol-1-oxide, 5-phenyl-2-pyridineethanol-1-oxide and the like.

The acid anhydride used in the present invention is an aliphatic carboxylic acid anhydride, an aromatic carboxylic acid anhydride, a heterocyclic carboxylic acid anhydride, preferably an aliphatic carboxylic acid anhydride. Acetic acid, propionic anhydride, butyric anhydride and the like can be mentioned.

According to the present invention, pyridineethanol-1
Reacting the -oxides with the acid anhydride to produce acetylpyridines in which the 2-hydroxyethyl group of pyridineethanol-1-oxides has been converted to an acetyl group.
For example, when the pyridineethanol-1-oxides represented by the general formula (1) are reacted with an acid anhydride, the general formula (2):

[0011]

Embedded image (Wherein R and n are the same as those described above), and from the pyridineethanol-1-oxides mentioned as the specific examples, 2-acetylpyridine, 3-acetylpyridine, 4-Acetylpyridine, 2-acetyl-6-methylpyridine, 2-acetyl-5-ethylpyridine, 2-acetyl-6-methoxypyridine, 2-acetyl-5-phenylpyridine are obtained.

To practice the present invention, it is only necessary to mix the pyridineethanol-1-oxides with the acid anhydride at the desired reaction temperature, which reacts readily to form the corresponding acetylpyridines. The reaction can be performed using a batch reactor or a continuous reactor.

The amount of the acid anhydride used in the reaction of the present invention is usually 1 to 10 mol, preferably 2 to 5 mol, per 1 mol of pyridineethanol-1-oxide.
If the amount of the acid anhydride used is less than the above range, the yield of the target acetylpyridines decreases. If the amount of the acid anhydride used is larger than the above range, no particular effect is brought about in the reaction, and problems such as troublesome recovery treatment operation of the acid anhydride after completion of the reaction occur.

[0014] The reaction temperature is usually 50 to 150 ° C, preferably 90 to 130 ° C. If the reaction temperature is lower than the above range, the reaction rate tends to be low and the yield of the target acetylpyridines tends to decrease, which is not preferable. If the reaction temperature is higher than the above range, side reactions such as decomposition of acetylpyridines may occur.

A solvent may be used in the reaction of the present invention.
Examples of the solvent include organic carboxylic acids such as acetic acid and propionic acid, and aromatic hydrocarbons such as toluene and xylene. When a solvent is used, the amount of the solvent is usually 1 to 1 part by weight of pyridineethanol-1-oxides.
10 to 10 parts by weight, preferably 2 to 5 parts by weight.

When the reaction of the present invention is carried out in the presence of a base, the yield is improved. Examples of the base used include alkali metal acetates such as sodium acetate and potassium acetate, and tertiary amines such as triethylamine, tripropylamine and tributylamine. The amount of base used is
For 1 mol of pyridineethanol-1-oxides,
Usually, it is 0.05-5 mol, preferably 0.1-2 mol. If the amount of the base is less than the above range, there is no effect of improving the yield of the target acetylpyridines. Although more bases can be used than the above range, the use of more bases has no particular effect.

As a method for isolating acetylpyridines from the reaction solution after completion of the reaction, a method of extracting with an appropriate solvent, a method of distilling the reaction solution, a method of isolating by column chromatography, and the like can be mentioned.

[0018]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the invention is limited thereto. Example 1 17.98 g (0.18 mol) of acetic anhydride and acetic acid 10.
After mixing 00 g with stirring, the temperature was raised to 110 ° C.
To the obtained mixture, 10.00 g (0.07 mol) of 2-pyridineethanol-1-oxide was added to 10.02 g of acetic acid.
Was dissolved dropwise over 20 minutes. Next, the temperature was maintained at 110 to 120 ° C., and the reaction was carried out with stirring for 4 hours. As a result of analyzing the reaction solution after the reaction by high performance liquid chromatography, the yield of 2-acetylpyridine was 29.
6%.

Example 2 8.34 g (0.08 mol) of acetic anhydride and 4.70 of acetic acid
g was mixed with stirring and then heated to 110 ° C. To the resulting mixture, a solution of 4.70 g (0.03 mol) of 4-pyridineethanol-1-oxide dissolved in 4.73 g of acetic acid was added dropwise over 20 minutes.
The reaction was maintained under stirring at 20 ° C. for 4 hours. As a result of analyzing the reaction solution after the reaction by high performance liquid chromatography, the yield of 4-acetylpyridine was 29.9%.

EXAMPLE 3 14.26 g (0.14 mol) of acetic anhydride and acetic acid 10.
After mixing with stirring, the temperature was raised to 110 ° C.
To the resulting mixture, a solution of 10.00 g (0.06 mol) of 5-ethyl-2-pyridineethanol-1-oxide dissolved in 10.02 g of acetic acid was added dropwise over 20 minutes. The reaction was carried out with stirring at 4 ° C. for 4 hours. As a result of analyzing the reaction solution after the reaction by high performance liquid chromatography, the yield of 2-acetyl-5-ethylpyridine was 30.1%.

Example 4 The procedure of Example 3 was repeated, except that 14.26 g (0.14 mol) of acetic anhydride and 10.03 g of acetic acid were mixed with stirring. 1
Example 3 was repeated except that 0.03 g and 4.70 g (0.06 mol) of sodium acetate were mixed with stirring. As a result, the yield of 2-acetyl-5-ethylpyridine was 31.6%.

Claims (4)

[Claims] 1. A process for producing acetylpyridines, comprising reacting pyridineethanol-1-oxides with an acid anhydride. 2. General formula (1): (In the formula, R represents an alkyl group, an aryl group or an alkoxy group, and n represents an integer of 0 to 4. When n is 2 or more, a plurality of substituents R may be the same or different. Wherein pyridineethanol-1-oxides represented by the following general formula (2) are reacted with an acid anhydride: (Wherein, R and n are the same as described above). 3. The method according to claim 1, wherein the reaction is performed in the presence of a base. 4. The method according to claim 1, wherein the reaction is carried out at 50 to 150 ° C.
4. The method according to 2 or 3.