JPH0475231B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing pyridine derivatives useful as synthetic intermediates for pharmaceuticals, agricultural chemicals, and others. Specifically, the present invention relates to a method for producing a pyridine derivative having a halogen and a cyano group on a pyridine ring by reacting a compound having a halogen and a substituted sulfonyl group on the pyridine ring with an alkali cyanide.

Generally, when a compound having a halogen and a sulfonyl group on the benzene ring is reacted with a nucleophile such as amines, CH ₃ O, CH ₃ S, CN, etc., a substitution reaction with the nucleophile occurs on the halogen side. It is known that 1
It has been confirmed that when a nucleophilic agent such as a primary amine or a secondary amine is reacted, a substitution reaction occurs on the halogen side. The present inventors reacted a compound having a halogen and a substituted sulfonyl group on the pyridine ring using CN as a nucleophile, and surprisingly, no substitution occurred on the halogen side.
It was discovered that substitution of a sulfonyl group with a cyano group occurs selectively and with good yield, and the present invention was completed.

In this way, the reactive site on the pyridine ring differs depending on the type of nucleophile, and even if a group that easily leaves, such as a halogen, exists on the ring, only another leaving group can selectively react. Moreover, such substitution with good yield has not been observed in benzene rings, which is completely unexpected.

The present invention is based on the general formula or [In the formula, R ¹ and R ² represent an alkyl group, an aralkyl group, an aryl group, or an alkyl-substituted aryl group, and X ¹ to X ⁴ and Y ¹ to ^{Y 4} each represent hydrogen, an alkyl group, an aryl group, or an alkoxy group, aryloxy group, thioalkoxy group, thioaryloxy group, amino group, or halogen, and X ¹ to
At least one of X ⁴ and at least one of Y ¹ to Y ⁴ represent halogen. ] 2-
(or 6-) or 4-substituted sulfonyl-halopyridine derivative and an alkali cyanide are reacted, or [In the formula, X ¹ to X ⁴ and Y ¹ to ^{Y 4} are the same as above. ] This is a novel method for producing a 2-(or 6-) or 4-cyano-halopyridine derivative.

According to the present invention, even if a easily substituted group such as a halogen is attached to the pyridine ring, the sulfonyl group can be selectively and efficiently substituted with a cyano group without replacing the halogen. ,
Pyridine derivatives having both halogen and cyano groups on the pyridine ring can be produced extremely easily and with good yield.

In the 2-(or 6-) or 4-substituted sulfonyl-halopyridine derivatives represented by the general formula [] or [] used in the present invention, R ¹ or R ² is, for example, a methyl group or an ethyl group. , isopropyl group, alkyl group such as n-butyl group, benzyl group,
Aralkyl groups such as phenethyl group and phenylpropyl group, aryl groups such as phenyl group and naphthyl group,
Examples include alkyl-substituted aryl groups substituted with methyl groups, ethyl groups, and the like. Moreover, as X ¹ to X ⁴ and Y ¹ to ^{Y 4} , for example, hydrogen or a methyl group,
Alkyl groups such as ethyl and propyl groups, aryl groups such as phenyl and naphthyl groups, alkoxy groups such as methoxy and ethoxy groups, aryloxy groups such as phenoxy groups, thioalkoxy groups such as thiomethoxy and thioethoxy groups, thiophenoxy thioaryloxy groups such as _NH2 groups, N-monoalkylamino groups such as N-methylamino groups, N-ethylamino groups, N,N-dimethylamino groups, N,N
- N,N-dialkylamino groups such as diethylamino groups, N-arylamino groups such as N-phenylamino groups, N,N such as N,N-diphenylamino groups
-Diarylamino group, N-alkyl-N'-arylamino group such as N-methyl-N'-phenylamino group, halogen such as chlorine, bromine, iodine, etc., and any of these may be used, but X ¹ ～
At least one of X ⁴ and at least one of Y ¹ to ^{Y 4} are halogens.

The alkali cyanide used in the present invention includes:
Examples include sodium cyanide, potassium cyanide, etc., and the amount used is 2-(or 6-) or 4-
For substituted sulfonyl-halopyridine derivatives,
Usually 1 to 2 times the mole is sufficient.

The reaction is usually carried out at a temperature of 20 to 70°C, preferably 50 to 60°C.

In addition, the reaction time varies depending on the temperature conditions, but
For example, if carried out at around 60℃, it will take 8 to 15 hours.
When carried out at room temperature, the time is 120 to 180 hours.

When carrying out this reaction, the higher the reaction temperature, the shorter the time required for the reaction (for example, if the reaction is carried out at 100°C, the reaction will be completed in less than an hour), but the temperature As the becomes higher,
Not only substitution of the sulfonyl group by CN but also substitution of the halogen occurs, which is not very preferable because by-products are produced.

Pyridyl sulfones having substituents used in the present invention can generally be easily obtained as follows.

For example, 2-chloro-6-methylsulfonylpyridine can be obtained as follows.

That is, 2,6-dichloropyridine and methyl mercaptan are mixed in an organic solvent such as benzene,
The reaction is carried out by heating and stirring in the presence of a phase transfer catalyst such as tetra-n-butyl-ammonium bromide. After the reaction, the organic layer is separated, washed with water, dried, and then the solvent is distilled off to quantitatively obtain 2-chloro-6-methylsulfenylpyridine. Next, by oxidizing this with an oxidizing agent such as hydrogen peroxide, the desired 2-chloro-6-methylsulfonylpyridine can be obtained quantitatively.

The present invention can be easily implemented, for example, as follows.

For example, 1 to 2 equivalents of alkali cyanide are added to 1 equivalent of a halogen-substituted pyridylsulfone derivative, an organic solvent such as N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, acetonitrile, etc. Stir. Keep the reaction solution at about 60°C and continue stirring for 10-12 hours. After the reaction is completed, the solvent is distilled off under reduced pressure if necessary, the residue is washed with water, and then extracted several times with an organic solvent such as chloroform. The target pyridine derivative is obtained by combining the extracts and distilling off the solvent under reduced pressure if necessary.

Solvents used in the present invention include formamide, N,N-dimethylformamide (DMF), N,N-dimethylacetamide, dimethylsulfoxide (DMSO), hexamethylphosphoramide (HMPA), acetonitrile, etc. Solvents that dissolve alkali are preferred, but other organic solvents such as methanol, ethanol,
Alcohols such as n-propanol and t-butanol, diethyl ether, tetrahydrofuran,
Ethers such as anisole, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, dioxane, benzene, toluene,
Low solubility of alkali cyanides such as aromatic hydrocarbons such as xylene, ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, esters such as methyl acetate and ethyl acetate, and halogenated hydrocarbons such as chloroform and dichloromethane. A solvent can also be used in combination with a phase transfer catalyst such as a quaternary ammonium salt or a crown ether.

In the present invention, when forming a C-C bond on a pyridine ring, instead of using halogen, which is generally considered to be easily substituted, the C-C bond can be easily formed by a reaction accompanying the cleavage of the C-S bond. It is characterized by being able to form a It is extremely wide-ranging, and its contribution to the industry is extremely large.

Reference examples and examples are listed below, but the present invention is not limited thereto.

Reference example 1 2,6-dichloropyridine 50g (0.338mole)
and methyl mercaptan (15% aqueous solution) 237g
(0.507 mole) was dissolved in 150 ml of benzene, 3 g (0.0093 mole) of tetra-n-butylammonium bromide was added thereto, and the mixture was refluxed for 6 hours with vigorous stirring. After the reaction is completed, the organic layer is separated, washed thoroughly with water, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. By distilling the residue under reduced pressure, a colorless and transparent 2-
Chlor-6-methylsulfenylpyridine 52.9g
(yield 98%).

bp: 105-107℃/14mmHg IR (neat): ν=2940, 1570, 1415, 1160, 795
cm ^-1 .

NMR (CCl ₄ ): δ=2.47 (s, CH ₃ , 3H), 6.60
~7.37ppm (m, pyrH, 3H).

Elemental analysis: C ₆ H ₆ NSCl Actual value (%): C45.2; H3.8; N9.0 Calculated value (%): C45.1; H3.8; N8.8 Reference example 2 2-chlor-6 -Methylsulfenylpyridine
Dissolve 50g (0.313mole) in 300ml of acetic acid,
110 ml of H ₂ O ₂ (30%) aqueous solution, cooled to 15 °C
(0.971 mole) was added dropwise, the temperature was returned to room temperature, and the mixture was stirred overnight. After the reaction is completed, cool the mixture, carefully add saturated aqueous ammonia to make it slightly alkaline, and then extract with dichloromethane. The extracted layer was thoroughly washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from methanol to obtain 56 g of 2-chloro-6-methylsulfonylpyridine (yield 93%).

mp: 108.5~109.0℃ IR (KBr): ν=3030, 2940, 1570, 1420,
1310 (−SO ₂ ), 1150 (−SO ₂ ), 965, 800,
750 cm ^-1 .

NMR (CDCl ₃ ): δ=3.25 (s, CH ₃ , 3H),
7.34-8.04ppm (m, 3H, pyrH).

Elemental analysis: C ₆ H ₆ NO ₂ SCl Actual value (%): C37.65; H3.14; N7.29 Calculated value (%): C37.60; H3.15; N7.30 Example 1 2-chlor -6-methylsulfonylpyridine 10
g (0.052mole) and NaCN5.12g (0.104mole)
into a reaction container, add 100ml of DMF to it, and add 60ml of DMF.
Stir well at ℃. After stirring for 12 hours, the solvent was distilled off under reduced pressure. Water is added to the residue, extracted three times with chloroform, and chloroform is distilled off from the extract to obtain 5.50 g (yield: 76%) of the desired 2-chloro-6-cyanopyridine.

mp85-88℃ (lit, 86-88℃) Example 2 In Example 1, instead of 10 g of 2-chloro-6-methylsulfonylpyridine, 2-chloro-6-
Ethylsulfonylpyridine 10g (0.0486mole)
2 in exactly the same manner as in Example 1 except for using
-chloro-6-cyanopyridine 5.53g (yield 82
%).

Example 3 In Example 1, 10 g of 2-n-butylsulfonyl-6-chloropyridine was used instead of 10 g of 2-chloro-6-methylsulfonylpyridine.
2-chloro-6-cyanopyridine
Obtain 4.33 g (73% yield).

Example 4 In Example 1, instead of 10 g of 2-chloro-6-methylsulfonylpyridine, 3-chloro-6-
3-3-
Chlor-6-cyanopyridine 5.78g (yield 80%)
get.

mp82-84℃ (lit.83-84℃) Example 5 In Example 1, 4-chloro-2-
4-4-
Chlor-2-cyanopyridine 5.69g (yield 79%)
get.

mp85-86℃ (lit.85-86℃) Example 6 2-chloro-6-methylsulfonylpyridine 10
In place of g, 15 g (0.059 mole) of 2-chloro-6-phenylsulfonylpyridine was used, and
Instead of NaCN5.12g, KCN7.70g (0.118mole)
The reaction and treatment were carried out in the same manner as in Example 1, except that 7.79 g (yield: 72%) of 2-chloro-6-cyanopyridine was obtained.

Example 7 2-chloro-6-methylsulfonylpyridine 10
Example 1
The reaction and treatment were carried out in the same manner as above to obtain 5.74 g (yield 74%) of 2-chloro-6-cyanopyridine.

Example 8 2-chloro-6-methylsulfonylpyridine 10
3,5-dibromo-2-methylsulfonylpyridine (0.0318 mole) was used in place of 2-cyano-3,
4.99 g (60%) of 5-dibromopyridine are obtained.

mp117~118℃ (lit.117~117.5℃) Example 9 2-chloro-6-methylsulfonylpyridine 10
g (0.052mole) and NaCN5.12g (0.104mole)
was placed in a reaction vessel, 100 ml of DMF was added thereto, and the mixture was stirred and reacted at room temperature for 162 hours. After the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted three times with chloroform. By distilling off chloroform from the extract, 6.80 g (yield 94%) of the desired 2-chloro-6-cyanopyridine is obtained.

Claims (1)

[Claims] 1. General formula or [In the formula, R ¹ and R ² represent an alkyl group, an aralkyl group, an aryl group, or an alkyl-substituted aryl group, and X ¹ to X ⁴ and Y ¹ to ^{Y 4} each represent hydrogen, an alkyl group, an aryl group, or an alkoxy group, an aryloxy group, a thioalkoxy group, a thioaryloxy group, an optionally substituted amino group, or a halogen, and at least one of X ¹ to X ⁴
and at least one of Y ¹ to ^{Y 4} represents a halogen. The general formula is characterized by reacting a 2-(or 6-) or 4-substituted sulfonyl-halopyridine derivative represented by ] with an alkali cyanide. or [In the formula, X ¹ to X ⁴ and Y ¹ to ^{Y 4} are the same as above. ]
A method for producing a 2-(or 6-) or 4-cyano-halopyridine derivative represented by