JPH0987251A - Production of mono-and di-cyanopyridine n-oxide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To oxidize only pyridine nitrogen and produce mono-or di- cyanopyridine without hydrolyzing cyano group by reacting mono-cyanopyridine with hydrogen peroxide or a peracid in the presence of an oxy acid and a metallic oxide in an aqueous solvent. SOLUTION: A mono-cyanopyridine of formula I (cyano group is bonded to the 2-, 3-or 4-position of the pyridine ring) (e.g. 2-cyanopyridine) is reacted with a peracid selected from performic acid, peracetic acid, perbenzoic acid and perterephthalic acid in an aqueous solvent in the presence of an oxy acid (e.g. nitric acid or chromic acid) and a metallic oxide (e.g. Mo2 O3 or V2 O5 ) to afford the objective compound of formula II. The oxy acid and the metallic oxide are respectively used in an amount of preferably 0.01-0.1mol based of compound of formula I and the hydrogen peroxide or the peracid is used in an amount of perferably 1-3mol based on the compound of formula I. Furthermore, the reaction is preferably carried out at 40-70 deg.C usually for 10-20hr.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to mono- or di-
Cyanopyridine to mono- or di-cyanopyridine-
It relates to a method for producing N-oxide.

[0002]

2. Description of the Related Art Pyridine-N-oxide compounds are produced by oxidizing pyridine compounds with hydrogen peroxide or peracid. For example, in “Pharmaceutical Journal” Vol. 72, No. 11, pp. 1474-1477 (1952), picolinic acid or ethyl picolinate is oxidized with hydrogen peroxide or perphthalic acid to give picolinic acid-N-oxide or A method for producing ethyl picolinate-N-oxide is disclosed in JP-A-48-80570. Pyridinecarboxylic acid or pyridinedicarboxylic acid is oxidized with hydrogen peroxide in the presence of sodium tungstate to obtain pyridinecarboxylic acid. -N
-Oxides or pyridinedicarboxylic acid-N-oxides are described.

When a reactive substituent is present on the pyridine ring during the oxidation with hydrogen peroxide or peracid, it is known that this substituent will also be changed to a different substituent when it reacts. Has been.

For example, JP-A-48-67282 describes a method for producing 6-methylpicolinic acid-N-oxide by reacting 6-methylpicolinaldehyde with hydrogen peroxide in the presence of sodium tungstate. Has been done. In this case, the aldehyde group present on the pyridine ring is also converted to a carboxylic acid by the reaction.

Further, JP-A-59-144760 describes a method for producing pyridinecarboxylic acid amide 1-oxide by reacting pyridinecarbonitrile with hydrogen peroxide in the presence of a metal oxide. In this case, the cyano group is converted to a carboxylic acid amide by being hydrolyzed.

Further, in Japanese Patent Publication No. 63-2262, there is 3
-Cyanopyridine N-oxide is described as being able to be quantitatively produced by reacting 3-cyanopyridine with hydrogen peroxide, but any hydrolysis of the cyano group that is easily expected from the above is not described. There is no description as to whether the target compound was obtained by suppressing it under the conditions.

[0007]

Therefore, when a pyridine compound having a cyano group as a substituent on the pyridine ring is oxidized with hydrogen peroxide or a peracid, the pyridine compound-N can be obtained without hydrolyzing the cyano group. -If oxide can be produced, a compound extremely useful as an intermediate raw material for chemical synthesis can be obtained,
The development of such a method has just been called for.

[0008]

In order to solve the above problems, the present inventors have earnestly studied, and as a result, cyanopyridine having one cyano group on the pyridine ring, or two cyano groups on the pyridine ring were found. The present invention has been completed by elucidating a method for producing N-oxide by oxidizing the dicyanopyridine possessed without changing the cyano group.

That is, the present invention provides the following structural formula (1)

Embedded image (In the formula, the cyano group is 2-, 3-, or 4- of the pyridine ring.
A mono-cyanopyridine represented by the formula (1) in the presence of an oxyacid and a metal oxide in an aqueous solvent, or hydrogen peroxide, or formic acid, peracetic acid, perbenzoic acid, and By reacting with a peracid selected from perphthalic acid, the following general formula (2)

[Chemical 6] (In the formula, the position of the cyano group is as described above.) The present invention relates to a method for producing a cyanopyridine-N-oxide.

Furthermore, the present invention provides the following structural formula (3):

[Chemical 7] (In the formula, the two cyano groups are 2,3-positions of the pyridine ring,
2,4-position, 2,5-position, 2,6-position, 3,4-position, or 3,5-position) The indicated di-cyanopyridine is Hydrogen peroxide, or formic acid, in the presence of oxyacids and metal oxides,
By reacting with a peracid selected from peracetic acid, perbenzoic acid, and perphthalic acid, the following general formula (4)

Embedded image (In the formula, the positions of two cyano groups are as described above.) The present invention also relates to a method for producing a dicyanopyridine-N-oxide.

The mono-cyanopyridine starting material for the process of the present invention includes 2-cyanopyridine, 3-cyanopyridine, and 4-cyanopyridine, and dicyanopyridine includes 2,3-dicyanopyridine, 2 , 4-dicyanopyridine, 2,5-dicyanopyridine, 2,6-dicyanopyridine, 3,4-dicyanopyridine, or 3,
5-dicyanopyridine may be mentioned.

The oxyacids used in the method of the present invention include nitric acid, sulfuric acid, phosphoric acid, chromic acid and antimonic acid. These oxy acids may be used alone or in combination of two or more of them. These oxy acids are used in an amount in the range of 0.001 to 10 mol, preferably in the range of 0.05 to 1 mol, and most preferably in the range of 0.01 to 0.0, based on the mono- or dicyanopyridine compound. It is in the range of 1 mol.

The metal oxide used in the method of the present invention includes molybdenum, tungsten, vanadine, titanium, selenium,
And oxides of tellurium, and compounds selected from hydrates and salts thereof.

Specific examples of these compounds include Mo₂
O_Three, MoO₂, Mo₂O_Three, MoO_ThreeAnd its hydrates
Form H₂MoO_Four; WO₂, WO_ThreeAnd its hydrate form
State H ₂WO_FourVO, V₂0_Three, VO₂, V₂O_FiveAnd that
H in the form of hydrate₂V_FourO₁₁TiO₂And its hydration
H in the form of things₂TiO_Three, H_FourTiO_Four, SeO₂, SeO_Three
And H in the form of its hydrate₂SeO_Three, H₂SeO_Four, T
eO₂, TeO_ThreeAnd H in the form of its hydrate₂TeO_Three,
H₆TeO₆Etc., and their sodium salts, Kariu
Examples of the salt include calcium salt and calcium salt.

These metal compounds are mono- or di-
It is used in an amount in the range of 0.001 to 10 mols, preferably in the range of 0.05 to 1 mol, and most preferably in the range of 0.01 to 0.1 mol, based on the cyanopyridine compound.

The hydrogen peroxide used in the method of the present invention may be industrially available at a concentration of 25 to 40%, but may be at a higher concentration or at a lower concentration. However, any compound that can oxidize pyridine nitrogen can be used, and the amount of the hydrogen peroxide used is 0.8 to 5 mol, preferably 1 to 1 mol, per mol of the pyridine compound.
The amount is in the range of 3 mol.

The formic acid, peracetic acid, perbenzoic acid, and perphthalic acid used in the method of the present invention can be obtained by adding an excess amount of hydrogen peroxide to formic acid, acetic acid, benzoic acid, or phthalic anhydride in a high concentration of, for example, 98%. The hydrogen peroxide is reacted and the obtained peracid is used as a separated product, or in the reaction site in formic acid, acetic acid, benzoic acid, or phthalic anhydride,
40% hydrogen peroxide was added and reacted to give a corresponding peracid, which was used as it was for the oxidation of the pyridine compound.

The amount of these peracids used is in the range of 0.8 to 5 mol, preferably 1 to 3 mol per mol of the pyridine compound as the peracid, but this amount is not always known exactly. Therefore, the amount may be in the range of 1 to 10 mol, preferably 1 to 3 mol, based on 1 mol of the pyridine compound, in terms of the amount of hydrogen peroxide used first.

The oxyacids used in the method of the present invention function as stabilizers for hydrogen peroxide and peracids, and the presence of the oxyacids prevents the hydrogen peroxide and peracids from self-decomposing, and the pyridine compound It will be used for the oxidation of pyridine nitrogen.

The method of the present invention can be carried out by dissolving a pyridine compound in an aqueous solvent, adding necessary oxyacid and metal oxide thereto, and reacting with hydrogen peroxide or peracid. The reaction is usually at room temperature to 90 ° C., preferably 3
It progresses rapidly at a temperature of 0 to 80 ° C., more preferably 40 to 70 ° C., for 30 minutes to 40 hours, usually 10 to 40 hours.
It takes 20 hours to complete the reaction.

After the reaction, the reaction solution is cooled to precipitate a reaction product, which is separated by a separation operation such as filtration and, if necessary, subjected to a purification step such as washing and recrystallization to obtain the desired pyridine-N-oxide. . The mother liquor separated by the separation operation is used as it is as the next reaction solvent,
The target pyridine-N-oxide can be obtained in a high yield of 7% or more.

[0022]

EXAMPLES Next, the present invention will be described in more detail by way of examples, but it should be understood that the examples described here are for explaining the present invention and are not intended to limit the present invention. Don't

[0023]

Example 1 3-Cyanopyridine (50.0 g), 95% sulfuric acid (1.5 g) and molybdenum trioxide (1.0 g) were added to water (41.6 g), and the temperature was raised to 70 ° C. with stirring.
% Hydrogen peroxide solution (58.3 g) was added dropwise over 30 minutes, and the reaction was carried out at 70 ° C. for 20 hours after the addition. After completion of the reaction, the reaction solution was cooled to 0 ° C., and the precipitated crystals were separated by filtration and dried to obtain 48.9 g of 3-cyanopyridine N-oxide crystals. Yield 84.8% The result of high performance liquid chromatography analysis of the obtained crystal showed that it consisted of 3-cyanopyridine N-oxide 99% and nicotinic acid amide N-oxide 1%.

[0024]

[Comparative Example 1] 3-Cyanopyridine (50.0 g) and molybdenum trioxide (1.0 g) were added to water (41.6 g), and the mixture was stirred while stirring.
After heating to 0 ° C, add 35% hydrogen peroxide solution 58.
3 g was added dropwise over 30 minutes, and the reaction was performed at 70 ° C. for 20 hours after the addition. After completion of the reaction, the reaction solution was cooled to 0 ° C., and the precipitated crystals were separated by filtration and dried to obtain 45.0 g of 3-cyanopyridine N-oxide crystals. Yield 78.1% The results of high performance liquid chromatography analysis of the obtained crystals showed that 3-cyanopyridine N-oxide 77%, nicotinamide N-oxide 22%, 3-cyanopyridine 1%.
It turned out to consist of.

[0025]

[Example 2] 3-cyanopyridine (50.0 g), 95% sulfuric acid (0.8 g) and molybdenum trioxide (1.0 g) were added to the mother liquor (44.4 g) of Example 1, and the temperature was raised to 70 ° C with stirring. 35% hydrogen peroxide solution (55.0 g) was added dropwise over 30 minutes, and the reaction was carried out at 70 ° C. for 20 hours after the addition. After the reaction was completed, the reaction solution was cooled to 0 ° C. and the precipitated crystals were filtered off.
Dry crystals of 3-cyanopyridine N-oxide 56.
2 g was obtained. Yield 97.5% The result of high performance liquid chromatography analysis of the obtained crystal revealed that it consisted of 3-cyanopyridine N-oxide 96% and nicotinic acid amide N-oxide 4%.

[0026]

[Comparative Example 2] 50.0 g of 3-cyanopyridine and 1.0 g of molybdenum trioxide were added to 44.4 g of the mother liquor of Comparative Example 1, the temperature was raised to 70 ° C with stirring, and then 35% hydrogen peroxide solution was added thereto. 55.0 g was added dropwise over 30 minutes, and after the addition 70
The reaction was carried out at 0 ° C for 20 hours. After the reaction is completed, the reaction solution is cooled to 0 ° C.
After cooling to room temperature, the precipitated crystals were separated by filtration and dried to obtain 50.2 g of 3-cyanopyridine N-oxide crystals. Yield 87.0
% The results of high performance liquid chromatography analysis of the obtained crystals showed that 3-cyanopyridine N-oxide 71%, nicotinic acid amide N-oxide 26%, 3-cyanopyridine 3%
It turned out to consist of.

[0027]

Example 3 4-Cyanopyridine (50.0 g), 95% sulfuric acid (1.5 g) and molybdenum trioxide (1.0 g) were added to water (41.6 g), and the temperature was raised to 70 ° C. with stirring.
% Hydrogen peroxide solution (58.3 g) was added dropwise over 30 minutes, and the reaction was carried out at 70 ° C. for 20 hours after the addition. After completion of the reaction, the reaction solution was cooled to 0 ° C., and the precipitated crystals were separated by filtration and dried to obtain 49.2 g of 4-cyanopyridine N-oxide crystals. Yield 85.3% The result of high performance liquid chromatography analysis of the obtained crystal showed that it consisted of 4-cyanopyridine N-oxide 99% and isonicotinic acid amide N-oxide 1%.

[0028]

[Comparative Example 3] 4-cyanopyridine (50.0 g) and molybdenum trioxide (1.0 g) were added to water (41.6 g), and the mixture was stirred with stirring.
After heating to 0 ° C, add 35% hydrogen peroxide solution 58.
3 g was added dropwise over 30 minutes, and the reaction was performed at 70 ° C. for 20 hours after the addition. After completion of the reaction, the reaction solution was cooled to 0 ° C., and the precipitated crystals were separated by filtration and dried to obtain 45.4 g of 4-cyanopyridine N-oxide crystals. Yield 78.7% The result of high performance liquid chromatography analysis of the obtained crystal showed that it was composed of 78% of 4-cyanopyridine N-oxide, 21% of isonicotinic acid amide N-oxide, and 1% of 4-cyanopyridine. Do you get it.

[0029]

Example 4 2-cyanopyridine (50.0 g), 85% phosphoric acid (1.0 g), vanadium pentoxide (1.0 g) and water (41.6 g)
In addition to the above, the temperature was raised to 60 ° C with stirring, and then 3
58.3 g of 5% hydrogen peroxide solution was added dropwise over 30 minutes,
After the dropping, the reaction was carried out at 60 ° C. for 20 hours. After completion of the reaction, the reaction solution was cooled to 0 ° C., and the precipitated crystals were separated by filtration and dried to give 2-
49.0 g of crystals of cyanopyridine N-oxide were obtained.
Yield 85.0% The result of high performance liquid chromatography analysis of the obtained crystal showed that it consisted of 2-cyanopyridine N-oxide 97% and picolinic acid amide N-oxide 3%.

[0030]

Example 5 4-cyanopyridine (50.0 g), 60% nitric acid (1.0 g), tungsten trioxide (1.0 g) and water (41.6 g)
In addition to the above, the temperature was raised to 60 ° C with stirring, and then 3
58.2 g of 5% hydrogen peroxide solution was added dropwise over 30 minutes,
After the dropping, the reaction was carried out at 60 ° C. for 20 hours. After completion of the reaction, the reaction solution was cooled to 0 ° C., and the precipitated crystals were separated by filtration and dried to give 4-
49.3 g of crystals of cyanopyridine N-oxide were obtained.
Yield 85.5% The result of high performance liquid chromatography analysis of the obtained crystal showed that it consisted of 4-cyanopyridine N-oxide 96% and isonicotinic acid amide N-oxide 4%.

[0031]

Example 6 2,3-Dicyanopyridine 55.0 g and 95
% Sulfuric acid 1.5 g and molybdenum trioxide 1.0 g in water 41.6
In addition to g, the temperature was raised to 70 ° C. with stirring, 58.3 g of 35% hydrogen peroxide solution was added dropwise over 30 minutes, and the reaction was carried out at 70 ° C. for 20 hours after the dropping. After the reaction was completed, the reaction solution was cooled to 0 ° C., and the precipitated crystals were separated by filtration and dried to obtain 2,3-dicyanopyridine N-oxide crystals 50.1
g was obtained. Yield 89.2% The result of high performance liquid chromatographic analysis of the obtained crystal was 2,3-dicyanopyridine N-oxide 99%, 2
-Cyanonicotinic acid amide was found to consist of 1% N-oxide.

[0032]

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to oxidize only the pyridine nitrogen to form mono- and dicyano-pyridine oxides without hydrolyzing the cyano groups of the mono- and dicyano-pyridine compounds.

Claims (4)

[Claims] 1. The following structural formula (1): (In the formula, the cyano group is 2-, 3-, or 4- of the pyridine ring.
A mono-cyanopyridine represented by the formula (1) in the presence of an oxyacid and a metal oxide in an aqueous solvent, or hydrogen peroxide, or formic acid, peracetic acid, perbenzoic acid, and By reacting with a peracid selected from perphthalic acid, the following general formula (2) (In the formula, the position of the cyano group is as described above.) A method for producing a cyanopyridine-N-oxide. 2. The oxyacid is an acid selected from nitric acid, sulfuric acid, phosphoric acid, chromic acid and antimonic acid, and the metal oxides are oxides of molybdenum, tungsten, vanadine, titanium, selenium and tellurium, and oxides thereof. The method according to claim 1, which is a compound selected from a hydrate and a salt thereof. 3. The following structural formula (3): (In the formula, the two cyano groups are 2,3-positions of the pyridine ring,
2,4-position, 2,5-position, 2,6-position, 3,4-position, or 3,5-position) The indicated di-cyanopyridine is Hydrogen peroxide, or formic acid, in the presence of oxyacids and metal oxides,
By reacting with a peracid selected from peracetic acid, perbenzoic acid, and perphthalic acid, the following general formula (4): (In the formula, the positions of two cyano groups are as described above.) A method for producing a dicyanopyridine-N-oxide. 4. The oxyacid is an acid selected from nitric acid, sulfuric acid, phosphoric acid, chromic acid and antimonic acid, and the metal oxides are oxides of molybdenum, tungsten, vanadine, titanium, selenium and tellurium, and their oxides. The method according to claim 3, which is a compound selected from hydrates and salts thereof.