JP4391503B2 - Diene compound and method for producing the same - Google Patents

Description

The present invention relates to an intermediate useful for producing 2-chloro-5-cyanopyridine, a process for producing the intermediate, and a process for producing 2-chloro-5-cyanopyridine from the intermediate .

  As a production method of 2-chloro-5-cyanopyridine, a method of chlorinating 5-cyanopyridine (see JP-A-5-43549), a method of chlorinating 5-cyanopyridine-1-oxide (chemical fur) Chemical Pharmaceutical Bulletin, 36, 2244 (1988) and JP-A-6-306049, and a method for chlorinating 2-hydroxy-5-cyanopyridine (JP-A-8-53418) And JP-A-6-319575).

  However, in the method of chlorinating the above 5-cyanopyridine or 5-cyanopyridine-1-oxide, the 3-position, 4-position or 6-position is chlorinated in addition to the desired 2-chloro-5-cyanopyridine. As a result, there was a problem that the reaction product became a mixture of isomers, and the separation of the isomers was necessary to obtain the target product. In the method of chlorinating 2-hydroxy-5-cyanopyridine, 2-hydroxy-5-cyanopyridine as a raw material is produced by microbial conversion, and the production efficiency of this process is low. Therefore, these methods cannot be said to be industrially advantageous production methods of 2-chloro-5-cyanopyridine. Therefore, an object of the present invention is to produce 2-chloro-5-cyanopyridine in a high yield from readily available raw materials.

According to the present invention, the above object is
[1] General formula ( I-1 )

(Wherein represents R 1 ^'is an aryl group which may optionally be substitution)
In shown is 5-cyano-2 Suruhonirupiriji down,
[2] 3-butenenitrile and formate are represented by the general formula (V)

(Wherein R ³ represents an alkyl group, and M represents an alkali metal atom)
In the presence of an alkali metal alcoholate [hereinafter abbreviated as alkali metal alcoholate (V)].

(Wherein M is as defined above)
2-alkalineformyl-3-butenenitrile [hereinafter abbreviated as 2-alkaliformyl-3-butenenitrile (IV)], and the obtained 2-alkaliformyl-3-butenenitrile (IV) was obtained. By reacting an acylating agent, alkylating agent, aralkylating agent or silylating agent, the compound represented by the general formula (II)

(Wherein R ² represents an acyl group, an alkyl group, an optionally substituted aralkyl group or a silyl group)
A diene compound represented by the formula [hereinafter abbreviated as diene compound (II)], and then the obtained diene compound (II) and the general formula (III)

(Wherein R ¹ represents an alkyl group, a cycloalkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group)
And a sulfonylcyanide represented by general formula (I), which is reacted with sulfonylcyanide (hereinafter abbreviated as sulfonylcyanide (III) ).

( Wherein R ¹ is as defined above.)
A process for producing 5-cyano-2-sulfonylpyridine [hereinafter abbreviated as 5-cyano-2-sulfonylpyridine (I) ] ,
[3] A process for producing 5-cyano-2-sulfonylpyridine (I), which comprises reacting a diene compound (II) and a sulfonylcyanide (III),
[4] General formula (II-1)

(Wherein R ⁴ represents an alkyl group, a cycloalkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group)
A diene compound represented by:
[5] A process for producing a diene compound (II) comprising reacting 2-alkaliformyl-3-butenenitrile (IV) with an acylating agent, alkylating agent, aralkylating agent or silylating agent,
[6] 2-alkaliformyl-3-butenenitrile (IV),
[7] A process for producing 2-alkaliformyl-3-butenenitrile (IV), comprising reacting 3-butenenitrile with a formate in the presence of an alkali metal alcoholate (V), and
[8] It is achieved by providing a process for producing 2-chloro-5-cyanopyridine, which comprises reacting 5-cyano-2-sulfonylpyridine (I) with a chlorinating agent under radical generating conditions. .

According to the present invention, 2-chloro-5-cyanopyridine can be produced in high yield from readily available raw materials.

In the above general formula, the alkyl group represented by R ¹ may be either linear or branched, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, A pentyl group, a hexyl group, an octyl group, a decyl group, etc. are mentioned. Examples of the cycloalkyl group represented by R ¹ include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, and a cyclooctyl group. The aryl group represented by R ¹ and R ^{1 ',} for example, a phenyl group, Ru naphthyl group and the like. Examples of the aralkyl group represented by R ¹ include a benzyl group and a phenethyl group. These aryl groups and aralkyl groups are alkyl groups such as methyl group, ethyl group, propyl group, tert-butyl group; alkoxy groups such as methoxy group, ethoxy group, propoxy group; fluorine atom, chlorine atom, bromine atom, etc. It may have a substituent such as halogen atom; cyano group; nitro group.

In the above general formula, examples of the acyl group represented by R ² include aliphatic acyl groups such as acetyl group, propanoyl group, butanoyl group, and pivaloyl group; aromatic acyl groups such as benzoyl group. Examples of the silyl group represented by R ² include a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilyl group, and a tert-butyldiphenylsilyl group. Examples of the alkyl group represented by R ² and the optionally substituted aralkyl group include the same groups as those represented by R ¹ .

In the above general formula, examples of the alkyl group represented by R ³ include the same groups as those represented by R ¹ . Examples of the alkali metal atom represented by M include sodium and potassium.

In the above general formula, the alkyl group represented by R ⁴ is, as the cycloalkyl group, an optionally substituted aryl group and an optionally substituted aralkyl group include the same groups as R ¹ represents.

  Hereafter, the manufacturing method of this invention is demonstrated in detail for every process.

Step 1 [Step of obtaining 2-alkaliformyl-3-butenenitrile (IV) by reacting 3-butenenitrile with a formate in the presence of an alkali metal alcoholate (V)]

Examples of the formate used in this step include formic acid alkyl esters such as methyl formate, ethyl formate, and propyl formate. As the alkali metal alcoholate (V), sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, sodium propylate methoxide, potassium c Mupuropirato, sodium butyrate, potassium butylate, and the like.

  The amount of 3-butenenitrile used as a raw material is preferably in the range of 0.1 to 100 mol and more preferably in the range of 1 to 10 mol with respect to 1 mol of the alkali metal alcoholate (V). Moreover, the range of 0.1-100 mol is preferable with respect to alkali metal alcoholate (V), and, as for the usage-amount of formic ester, the range of 1-10 mol is more preferable.

  Such a reaction can be carried out in the presence or absence of a solvent. The solvent is not particularly limited as long as it does not participate in the reaction. For example, hydrocarbons such as hexane, heptane, benzene and toluene; ethers such as tetrahydrofuran and dioxane are used. The amount of the solvent used is preferably in the range of 0.1 to 300 times by weight, more preferably in the range of 1 to 100 times by weight with respect to 3-butenenitrile.

  The reaction temperature is preferably in the range of -20 to 200 ° C, more preferably in the range of 0 to 120 ° C. The reaction can be carried out under normal pressure, reduced pressure or increased pressure.

  The reaction can be performed either batchwise or continuously. Since the target product is obtained in the form of a slurry after completion of the reaction, it can be easily obtained by appropriately adopting operations such as filtration, washing and drying.

  Step 2 [Step of obtaining diene compound (II) by reacting 2-alkaliformyl-3-butenenitrile (IV) with an acylating agent, alkylating agent, aralkylating agent or silylating agent]

  Examples of the acylating agent include acid chlorides such as acetyl chloride and benzoyl chloride; and acid anhydrides such as acetic anhydride. Examples of the alkylating agent include alkyl halides such as methyl chloride, ethyl chloride, propyl chloride, butyl chloride, methyl bromide and methyl iodide; sulfonic acid alkyl esters such as methyl trifluoromethanesulfonate and methyl toluenesulfonate; sulfuric acid Examples include dimethyl and the like. Examples of the aralkylating agent include halogenated aralkyls such as benzyl chloride, benzyl bromide, and benzyl iodide; sulfonic acid aralkyl esters such as benzyl trifluoromethanesulfonate and benzyltoluenesulfonate. Examples of the silylating agent include silyl halides such as trimethylsilyl chloride and tert-butyldimethylsilyl chloride. The amount of the acylating agent, alkylating agent, aralkylating agent or silylating agent used is preferably in the range of 0.1 to 100 mol with respect to 1 mol of 2-alkaliformyl-3-butenenitrile (IV). The range of 1-10 mol is more preferable.

  Such a reaction can be carried out in the presence or absence of a solvent. The solvent is not particularly limited as long as it does not participate in the reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chlorobenzene and the like. Hydrocarbons such as benzene, toluene, xylene, cumene, heptane and octane; ethers such as diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane and dimethoxyethane; ketones such as acetone and methyl ethyl ketone; ethyl acetate and butyl acetate Ester; Nitriles such as acetonitrile and propionitrile; Amides such as dimethylformamide; Dimethyl sulfoxide and the like are used. The amount of the solvent used is preferably in the range of 0.1 to 300 times by weight, more preferably in the range of 1 to 100 times by weight with respect to 2-alkaliformyl-3-butenenitrile (IV).

  The reaction temperature is preferably in the range of -20 to 200 ° C, more preferably in the range of 0 to 100 ° C. The reaction can be carried out under normal pressure, reduced pressure or increased pressure.

  The reaction can be performed either batchwise or continuously. After completion of the reaction, the target product is easily isolated and purified by a conventional method. For example, a crude product is obtained by concentrating the reaction mixture to dryness, and the resulting crude product is distilled, column chromatography or recrystallized.

Step 3 [Step of obtaining 5-cyano-2-sulfonylpyridine (I) by reacting diene compound (II) with sulfonylcyanide (III)]

Examples of the sulfonylcyanide (III) include alkanesulfonylcyanides such as methanesulfonylcyanide and propanesulfonylcyanide; cycloalkanesulfonylcyanides such as cyclohexanesulfonylcyanide and cyclooctanesulfonylcyanide; benzenesulfonylcyanide, p- Examples include arylsulfonyl cyanides such as toluenesulfonyl cyanide and p-chlorobenzenesulfonyl cyanide; aralkylsulfonyl cyanides such as phenylmethanesulfonyl cyanide and the like. The sulfonylcyanide (III) can be obtained from the corresponding sodium sulfinate according to the method described in Organic Synthesis, 57, 88 (1977). The amount of sulfonylcyanide (III) used is preferably in the range of 0.01 to 100 mol, more preferably in the range of 0.1 to 10 mol, per 1 mol of diene compound (II).

  Such a reaction can be carried out in the presence or absence of a solvent. The solvent is not particularly limited as long as it does not participate in the reaction. For example, those listed as the solvent used in Step 2 are similarly used. The amount of the solvent used is preferably in the range of 0.1 to 300 times by weight and more preferably in the range of 0.1 to 30 times by weight with respect to the sulfonylcyanide (III).

  The reaction temperature is preferably in the range of -20 ° C to 200 ° C, more preferably in the range of 50 ° C to 200 ° C.

  The reaction can be carried out in the presence or absence of a polymerization inhibitor. Polymerization inhibitors include 4-methoxyphenol, phenol such as 2,6-ditert-butyl-4-methylphenol; hydroxyamines such as N, N-dimethylhydroxyamine; hydroquinones such as hydroquinone and ditert-butylhydroquinone. Naphthols such as 1-naphthol and 2-naphthol; catechols such as catechol and p-tert-butylcatechol; amines such as phenothiazine, diphenylamine, 4-acetoxy-2,2,6,6-tetramethylpiperidine and the like are used. The The amount of the polymerization inhibitor used is preferably in the range of 10 ppm to 2000 ppm by weight of the diene compound (II), and more preferably in the range of 100 ppm to 500 ppm.

  The reaction can be performed either batchwise or continuously. After completion of the reaction, the target product is easily isolated and purified by a conventional method. For example, a crude product is obtained by concentrating the reaction mixture to dryness, and the resulting crude product is distilled, column chromatography or recrystallized.

Step 4 [Step of obtaining 2-chloro-5-cyanopyridine by reacting 5-cyano-2-sulfonylpyridine (I) with a chlorinating agent under radical generating conditions]

  The chlorinating agent may be any as long as it generates chlorine radicals under radical generating conditions, but chlorine or sulfuryl chloride is preferred from the viewpoint of reaction efficiency and cost. The chlorinating agent is preferably added continuously or sequentially during the reaction.

  In order to generate chlorine radicals, radical initiators can be used. Examples of the radical initiator include nitriles such as 2,2′-azobis (isobutyronitrile) and 1,1′-azobis (cyclohexanecarbonitrile); peroxides such as benzoyl peroxide and acetyl peroxide. . The radical initiator can be added continuously or sequentially before or during the reaction. The amount of the radical initiator added is preferably in the range of 0.001 to 3.0 molar equivalents, and more preferably in the range of 0.05 to 1.0 molar equivalents. Also, chlorine radicals can be generated by light irradiation.

The reaction can be carried out in the presence or absence of a solvent , but is preferably carried out in the presence of a solvent. The solvent is not particularly limited as long as it does not participate in the reaction. For example, acetonitrile, acetic acid, carbon disulfide, tetrachloroethane, carbon tetrachloride, chlorobenzene and the like are used.

  The reaction is preferably carried out at 20 ° C. to the solvent reflux temperature, more preferably 60 ° C. to 100 ° C.

  Isolation and purification of the product from the reaction mixture can be carried out by a conventional method. For example, a crude product is obtained by concentrating the reaction mixture to dryness, and the resulting crude product is distilled, column chromatography or recrystallized.

  Hereinafter, the present invention will be described specifically by way of examples. The present invention is not limited to these examples.

Example 1 Synthesis of 2-sodioformyl-3-butenenitrile In a reactor equipped with a stirrer, distillation apparatus, dropping funnel, thermometer, 10.02 g (52.0 mmol) of 28% sodium methylate methanol solution and 27. 60 g was added and methanol was distilled off azeotropically. The obtained slurry was ice-cooled, 13.70 g of heptane, 3.20 g (53.3 mmol) of methyl formate and 3.60 g (53.7 mmol) of 3-butenenitrile were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was washed with methyl formate and dried to obtain 3.84 g (32.8 mmol, yield 63.1%) of 2-sodioformyl-3-butenenitrile having the following physical properties. It was.

N MR (270 MHz, CDCl ₃ ) δ: 8.19 (s, 1H), 6.19 (dd, 1H), 4.26 (d, 1H), 4.07 (d, 1H)

Example 2 Synthesis of 1-acetoxy-2-cyano-1,3-butadiene A reactor equipped with a stirrer, a thermometer, and a dropping funnel was charged with 8.26 g (0.105 mol) of acetyl chloride and 100 ml of toluene, and iced. Chilled. 2-Sodioformyl-3-butenenitrile (8.42 g, 0.0576 mol) was added over 30 minutes and the mixture was stirred for 1 hour. The reaction mixture was filtered, and the filtrate was washed with water and 5% aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was distilled under reduced pressure, and 5.94 g (0.0436) of 1-acetoxy-2-cyano-1,3-butadiene having the following physical properties was obtained as a fraction having a boiling point of 65 to 67 ° C. (3 mmHg). Mol, yield of 75.3% based on 2-sodioformyl-3-butenenitrile).

N MR (270 MHz, CDCl ₃ ) δ: 7.87 (s, 1H), 6.24 (dd, 1H), 5.69 (d, 1H), 5.40 (d, 1H)

Reference Example 1 Synthesis of 2-benzenesulfonyl-5-cyanopyridine Toluene was placed in a reactor equipped with a stirrer, reflux condenser, thermometer, and dropping funnel and heated to 100 ° C. After a mixture of 68.5 g (0.500 mol) of 1-acetoxy-2-cyano-1,3-butadiene and 60.0 g (0.359 mol) of benzenesulfonylcyanide was added dropwise over 1 hour, 2 at 100 ° C. Stir for hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the resulting residue was recrystallized from toluene to give 64.0 g (0.262 mol, benzenesulfonyl) 2-benzenesulfonyl-5-cyanopyridine having the following physical properties. Yield 73.0% based on cyanide).

N MR (270 MHz, CDCl ₃ ) δ: 8.89 (d, 1H, J = 2.2 Hz), 8.33 (d, 1H, J = 8.1 Hz), 8.22 (dd, 1H, J = 2.2 Hz, 8.1 Hz), 8.04-8.08 (m, 2H), 7.54-7.68 (m, 3H)

Reference Example 2 Synthesis of 2 -chloro-5-cyanopyridine To a reactor equipped with a stirrer, a reflux condenser, a thermometer, and a gas introduction tube, 1.00 g (4.10 mmol) of 2-benzenesulfonyl-5-cyanopyridine And 10 ml of acetonitrile were added and heated to 80 ° C. While adding 6.0 mg (0.037 mmol) of 2,2′-azobisisobutyronitrile every 30 minutes, chlorine (4.0 ml / min) was introduced into the reaction solution for 3 hours. After cooling, nitrogen was blown into the reaction solution to remove excess chlorine, and the mixture was concentrated under reduced pressure. The obtained residue was recrystallized to obtain 0.510 g (3.68 mmol, yield 89.8%) of 2-chloro-5-cyanopyridine. This was consistent with the standard in NMR analysis.

  2-Chloro-5-cyanopyridine obtained by the present invention is useful as a starting material for various pyridine compounds important in the fields of medicine and agricultural chemicals. 2-Chloro-5-cyanopyridine can be easily converted to 2-chloro-5-aminomethylpyridine by a general reduction reaction such as catalytic hydrogen reduction. 2-Chloro-5-aminomethylpyridine is useful as an intermediate for the synthesis of N-cyanoacetamidine derivatives useful as insecticides (see JP-A-5-178834).

Claims (4)

Formula (II-1)

(Wherein R ⁴ represents an alkyl group having 1 to 10 carbon atoms or a phenyl group )
A diene compound represented by: Formula (IV)

(In the formula, M represents an alkali metal atom)
A general formula (II) characterized in that an acylating agent, an alkylating agent, an aralkylating agent or a silylating agent is reacted with 2-alkaliformyl-3-butenenitrile represented by the formula (II)

(Wherein R ² represents an acyl group, an alkyl group, an optionally substituted aralkyl group or a silyl group)
The manufacturing method of the diene compound shown by these. Formula (IV)

(In the formula, M represents an alkali metal atom)
2-alkaliformyl-3-butenenitrile represented by the formula: 3-Butenenitrile and formate are represented by the general formula (V)

(Wherein R ³ represents an alkyl group, and M represents an alkali metal atom)
The reaction is carried out in the presence of an alkali metal alcoholate represented by the general formula (IV)

(Wherein M is as defined above)
The manufacturing method of 2-alkaliformyl-3-butenenitrile shown by these.