JP4698991B2 - Pyridylmethylcarbamic acid ester compound, method for producing the same, and method for producing pyridylmethylamine compounds - Google Patents

Description

  The present invention relates to a pyridylmethylcarbamic acid ester compound useful as an intermediate for producing agricultural chemicals and pharmaceuticals, and a method for easily and efficiently producing a pyridylmethylcarbamic acid ester compound and a pyridylmethylamine compound.

  Pyridylmethylcarbamic acid ester compounds such as 2-chloro-5-pyridylmethylcarbamic acid ester are useful as production intermediates for pyridylmethylamine compounds such as (2-chloro-5-pyridyl) methylamine, which are raw materials for agricultural chemicals. (Patent Documents 1 and 2).

  Conventionally, as a method for producing a pyridylmethylcarbamate compound, a production method in which 3- (chloromethyl) pyridine is reacted with a carbamate in the presence of sodium hydride and potassium iodide or sodium iodide is known. (Patent Documents 3 and 4). However, this method has a very low yield of the desired 3-pyridylmethylcarbamic acid ester compound, and is impractical.

JP-A-9-132565 JP-A-9-194461 EP06060925A1 publication WO02 / 083143

  The present invention has been made in view of such problems of the prior art, and a method for producing a pyridylmethylcarbamate compound and a pyridylmethylamine compound simply and in good yield, and a novel pyridylmethylcarbamate compound It is an issue to provide.

  In order to solve the above problems, the present inventors produce a 2-chloro-5-pyridylmethylcarbamic acid ester compound by reacting a pyridylmethylisocyanate compound such as 2-chloro-5-pyridylmethylisocyanate with an alcohol. Devised a method. If the pyridylmethylcarbamic acid ester compound can be produced easily and with a good yield, it is considered that the pyridylmethylamine compound can be produced easily and with a good yield as a result.

  However, in the above reaction, when a normal alcohol such as methyl alcohol, ethyl alcohol, isopropyl alcohol or the like is used, the produced pyridylmethylcarbamic acid ester compound further reacts with a pyridylmethylisocyanate compound or an alcohol to achieve the target. It was found that the pyridylmethylcarbamic acid ester compound could not be obtained with good yield.

Thus, as a result of intensive studies, the present inventors have used an alkoxy alcohol compound represented by the following formula (III) as an alcohol to be reacted with an isocyanate compound represented by the following formula (II). It was found that the pyridylmethylcarbamic acid ester compound represented by the above can be obtained in good yield, and the present invention has been completed.
Thus, according to the first invention, the formula (I)

(In the formula, X represents a hydrogen atom or a halogen atom, and R ^{1 to} R ⁴ each independently represents a hydrogen atom, an optionally substituted alkyl group having 1 to 20 carbon atoms, or a substituent. R ⁵ represents an optionally substituted aryl group, and R ⁵ represents an optionally substituted alkyl group having 1 to 20 carbon atoms or an optionally substituted aryl group. Pyridylmethylcarbamate compounds are provided.
According to the second invention, the compound of formula (II)

(Wherein X represents a hydrogen atom or a halogen atom) and the formula (III)

(In the formula, R ^{1 to} R ⁴ each independently represent a hydrogen atom, an optionally substituted alkyl group having 1 to 20 carbon atoms, or an optionally substituted aryl group. , R ⁵ represents an optionally substituted alkyl group having 1 to 20 carbon atoms, or an aryl group optionally having substituent (s)). Characteristic formula (I)

(Wherein, X and R ^{1 to} R ⁵ represent the same meaning as described above), and a method for producing a pyridylmethylcarbamic acid ester compound is provided.
According to a third aspect of the present invention, the compound of formula (IV)

(In the formula, X represents a hydrogen atom or a halogen atom, and L may have a halogen atom, an alkylsulfonyloxy group having 1 to 20 carbon atoms, a haloalkylsulfonyloxy group having 1 to 20 carbon atoms, or a substituent. Represents a good phenylsulfonyloxy group.) By reacting a pyridine compound represented by formula (II) with cyanate.

(Wherein X represents the same meaning as described above), an isocyanate compound represented by the formula (II), and a formula (III)

(In the formula, R ^{1 to} R ⁴ each independently represent a hydrogen atom, an optionally substituted alkyl group having 1 to 20 carbon atoms, or an optionally substituted aryl group. , R ⁵ represents an optionally substituted alkyl group having 1 to 20 carbon atoms or an optionally substituted aryl group.) And a step of reacting with an alkoxy alcohol compound represented by Having the formula (I)

(Wherein, X and R ^{1 to} R ⁵ represent the same meaning as described above), and a method for producing a pyridylmethylcarbamic acid ester compound is provided.
In the production method of the third aspect of the present invention, it is preferable to react the pyridine compound represented by the formula (IV) and cyanate in the presence of a phase transfer catalyst.
According to a fourth aspect of the present invention, the compound of formula (IV)

(In the formula, X represents a hydrogen atom or a halogen atom, and L may have a halogen atom, an alkylsulfonyloxy group having 1 to 20 carbon atoms, a haloalkylsulfonyloxy group having 1 to 20 carbon atoms, or a substituent. A pyridine compound represented by the formula (III)

(In the formula, R ^{1 to} R ⁴ each independently represent a hydrogen atom, an optionally substituted alkyl group having 1 to 20 carbon atoms, or an optionally substituted aryl group. , R ⁵ represents an optionally substituted alkyl group having 1 to 20 carbon atoms, or an aryl group optionally having substituent (s)). Formula (I)

(Wherein, X and R ^{1 to} R ⁵ represent the same meaning as described above), and a method for producing a pyridylmethylcarbamic acid ester compound is provided.
In the fourth production method of the present invention, the pyridine compound represented by the formula (IV) is reacted with a cyanate salt and the alkoxy alcohol compound represented by the formula (III) in the presence of a phase transfer catalyst. Is preferred.
According to a fifth aspect of the present invention, there is provided a formula (I)

(In the formula, X represents a hydrogen atom or a halogen atom, and R ^{1 to} R ⁴ each independently represents a hydrogen atom, an optionally substituted alkyl group having 1 to 20 carbon atoms, or a substituent. R ⁵ represents an optionally substituted aryl group, and R ⁵ represents an optionally substituted alkyl group having 1 to 20 carbon atoms or an optionally substituted aryl group. Having a step of hydrolyzing the pyridylmethylcarbamic acid ester compound to be represented by the formula (V)

(Wherein X represents the same meaning as described above). A method for producing a pyridylmethylamine compound is provided.
According to a sixth aspect of the present invention, the compound of formula (IV)

(In the formula, X represents a hydrogen atom or a halogen atom, and L may have a halogen atom, an alkylsulfonyloxy group having 1 to 20 carbon atoms, a haloalkylsulfonyloxy group having 1 to 20 carbon atoms, or a substituent. A pyridine compound represented by the formula (III)

(In the formula, R ^{1 to} R ⁴ each independently represent a hydrogen atom, an optionally substituted alkyl group having 1 to 20 carbon atoms, or an optionally substituted aryl group. , R ⁵ represents an optionally substituted alkyl group having 1 to 20 carbon atoms, or an aryl group optionally having substituent (s)). Formula (I)

(Wherein, X, R ^{1 to} R ⁵ represent the same meaning as described above), and a step (I) for obtaining a pyridylmethylcarbamate compound represented by the formula (I) is obtained. Hydrolyzing step (II), having the formula (V)

(Wherein X represents the same meaning as described above). A method for producing a pyridylmethylamine compound is provided.
In the production method of the sixth aspect of the present invention, it is preferable to carry out the reaction of step (I) in the presence of a phase transfer catalyst.

According to the present invention, there is provided a pyridylmethylcarbamic acid ester compound represented by the above formula (I), which is useful as an intermediate for producing agricultural chemicals and pharmaceuticals.
According to the production method of the present invention, the pyridylmethylcarbamic acid ester compound represented by the formula (I) and the pyridylmethylamine compound represented by the formula (V) can be produced simply and with a high yield.

Hereinafter, the present invention will be described in detail.
1) Pyridylmethylcarbamate compound represented by the formula (I) The first present invention is a pyridylmethylcarbamate compound represented by the formula (I) (hereinafter sometimes referred to as “ester compound (I)”). It is.

In the formula (I), X represents a hydrogen atom; or a halogen atom such as a fluorine atom, a chlorine atom, or a bromine atom. Of these, a halogen atom is preferable, and a chlorine atom is particularly preferable.
R ^{1 to} R ⁴ each independently represent a hydrogen atom, an optionally substituted alkyl group having 1 to 20 carbon atoms, or an optionally substituted aryl group.
Examples of the alkyl group having 1 to 20 carbon atoms that may have a substituent include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, and an isobutyl group. , Tert-butyl group and the like.
Examples of the aryl group of the aryl group that may have a substituent include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.

  Examples of the substituent of the alkyl group having 1 to 20 carbon atoms which may have the substituent include nitro group; cyano group; halogen atom such as fluorine atom, chlorine atom and bromine atom; methoxy group, ethoxy group, n An alkoxy group such as a propoxy group or an isopropoxy group; an alkylthio group such as a methylthio group or an ethylthio group; an alkylsulfonyl group such as a methylsulfonyl group or an ethylsulfonyl group; an alkoxycarbonyl group such as a methoxycarbonyl group or an ethoxycarbonyl group; a phenyl group , A phenyl group optionally having a substituent such as a 4-chlorophenyl group and a 2-methylphenyl group; Moreover, as a substituent of the said aryl group, alkyl groups, such as a methyl group and an ethyl group, etc. other than what was listed as a substituent of the said C1-C20 alkyl group, etc. are mentioned. The substitution position of these substituents is not particularly limited, and two or more identical or different substituents may be bonded.

Among these, as R < ¹ > -R < ⁴ >, the C1-C20 alkyl group which may have a hydrogen atom or a substituent is preferable, and a hydrogen atom or a methyl group is more preferable.

R ⁵ represents an alkyl group having 1 to 20 carbon atoms which may have a substituent, or an aryl group which may have a substituent. Specific examples of the alkyl group having 1 to 20 carbon atoms which may have a substituent and the aryl group which may have a substituent include the substituents of R ^{1 to} R ^4. The thing similar to what was illustrated as a C1-C20 alkyl group and the aryl group which may have a substituent is mentioned. Among these, R ^5, is preferably an alkyl group having 1 to 20 carbon atoms that may have a substituent, more preferably an alkyl group having 1 to 4 carbon atoms.

  Preferable specific examples of the ester compound (I) include [(pyridin-3-yl) methyl] carbamic acid (2′-methoxyethyl), [(pyridin-3-yl) methyl] carbamic acid (2′-ethoxyethyl). ), [(2-chloropyridin-5-yl) methyl] carbamic acid (2′-methoxyethyl), [(2-chloropyridin-5-yl) methyl] carbamic acid (2′-ethoxyethyl), [( 2-chloropyridin-5-yl) methyl] carbamic acid (2′-propoxyethyl), [(2-chloropyridin-5-yl) methyl] carbamic acid (2′-butoxyethyl), [(2-chloropyridine) -5-yl) methyl] carbamic acid (2'-methoxy-1'-methylethyl), [(2-chloropyridin-5-yl) methyl] carbamic acid (2'-ethyl) Xyl-1′-methylethyl), [(2-chloropyridin-5-yl) methyl] carbamic acid (2′-propoxy-1′-methylethyl), [(2-chloropyridin-5-yl) methyl] And carbamic acid (2′-butoxy-1′-methylethyl).

  The ester compound (I) of the present invention is useful as an intermediate for the production of pyridylmethylamine compounds such as [(2-chloropyridin-5-yl) methyl] amine.

2) Production method of ester compound (I) The ester compound (I) of the present invention comprises an isocyanate compound represented by the formula (II) (hereinafter sometimes referred to as “isocyanate compound (II)”) and the formula (II). It can be produced by reacting with an alkoxy alcohol compound represented by III) (hereinafter sometimes referred to as “alcohol compound (III)”).

(1) Isocyanate compound (II)
The isocyanate compound (II) is a compound represented by the formula (II).
In the formula (II), X represents the same meaning as described above.

  The isocyanate compound (II) can be produced by reacting a pyridine compound represented by the formula (IV) (hereinafter sometimes referred to as “pyridine compound (IV)”) with a cyanate.

(Pyridine compound (IV))
In the formula (IV), X represents the same meaning as described above.
L represents a halogen atom, an alkylsulfonyloxy group having 1 to 20 carbon atoms, a haloalkylsulfonyloxy group having 1 to 20 carbon atoms, or a phenylsulfonyloxy group which may have a substituent.
Examples of the halogen atom for L include a fluorine atom, a chlorine atom, and a bromine atom.
Examples of the alkylsulfonyloxy group having 1 to 20 carbon atoms include a methylsulfonyloxy group, an ethylsulfonyloxy group, and an n-propylsulfonyloxy group.
Examples of the haloalkylsulfonyloxy group having 1 to 20 carbon atoms include a trifluoromethylsulfonyloxy group.

Examples of the substituent of the phenylsulfonyloxy group which may have a substituent include halogen atoms such as fluorine atom, chlorine atom and bromine atom; alkyl groups such as methyl group and ethyl group; methoxy group and ethoxy group Alkoxy groups such as haloalkyl groups such as trifluoromethyl groups, nitro groups, and the like. The phenylsulfonyloxy group may have two or more substituents which are the same or different at any position on the benzene ring.
Specific examples of the phenylsulfonyloxy group which may have a substituent include a phenylsulfonyloxy group and a 4-methylphenylsulfonyloxy group.

  Examples of the pyridine compound (IV) include a method of halogenating 2-halogeno-5-methylpyridine (JP-A-5-230024), 2-halogeno-5-hydroxymethylpyridine and an alkylsulfonyl halide compound or arylsulfonyl. It can be produced by a method in which a halide compound is reacted in the presence of a base.

  Specific examples of the pyridine compound (IV) include 3- (fluoromethyl) pyridine, 3- (chloromethyl) pyridine, 3- (bromomethyl) pyridine, [(pyridin-3-yl) methyl] methylsulfonate, [(pyridine -3-yl) methyl] ethyl sulfonate, [(pyridin-3-yl) methyl] n-propyl sulfonate, [(pyridin-3-yl) methyl] phenyl sulfonate, 2-fluoro-5- (fluoromethyl) pyridine, 5-chloromethyl-2-fluoropyridine, 5-bromomethyl-2-fluoropyridine, [(2-fluoropyridin-5-yl) methyl] methylsulfonate, [(2-fluoropyridin-5-yl) methyl] ethylsulfonate , (2-fluoropyridin-5-yl) n-propyl sulfonate, [( -Fluoropyridin-5-yl) methyl] phenylsulfonate, 2-chloro-5- (fluoromethyl) pyridine, 2-chloro-5- (chloromethyl) pyridine, 5-bromomethyl-2-chloropyridine, [(2- Chloropyridin-5-yl) methyl] methylsulfonate, [(2-chloropyridin-5-yl) methyl] ethylsulfonate, [(2-chloropyridin-5-yl) methyl] n-propylsulfonate, [(2- Chloropyridin-5-yl) methyl] phenylsulfonate, 2-bromo-5- (fluoromethyl) pyridine, 2-bromo-5- (chloromethyl) pyridine, 2-bromo-5- (bromomethyl) pyridine, [(2 -Bromopyridin-5-yl) methyl] methylsulfonate, [(2-bromopyridin-5-yl) Chill] ethyl sulfonate, [(2-bromopyridin-5-yl) methyl] n- propyl sulfonate, and a [(2-bromo-yl) methyl] phenyl sulfonates.

  Among these, as the pyridine compound (IV), a compound in which L is a halogen atom is preferable, a compound in which L is a chlorine atom is more preferable, and 2-chloro-5- (chloromethyl) pyridine is particularly preferable.

(Cyanate)
The cyanate used is not particularly limited, and examples thereof include alkali metal salts such as sodium cyanate and potassium cyanate; alkaline earth metal salts such as magnesium cyanate and calcium cyanate;

  A commercially available cyanate can be used as it is, but a cyanate produced by a method of oxidizing cyanide with an oxidizing agent such as manganese (IV) oxide or lead (IV) oxide can also be used. .

  The amount of cyanate used is usually 1 mol to 10 mol, preferably 1 mol to 5 mol, per 1 mol of pyridine compound (IV).

(Reaction of pyridine compound (IV) with cyanate)
The reaction of the pyridine compound (IV) and cyanate is usually performed in an organic solvent. The organic solvent to be used is not particularly limited as long as it is inert to the reaction. Nonpolar solvents such as aliphatic hydrocarbon solvents, alicyclic hydrocarbon solvents, aromatic hydrocarbon solvents; ketone solvents Any of polar solvents such as ether solvents can be used.

  As the aliphatic hydrocarbon solvent, n-pentane, n-hexane, n-heptane, n-octane, etc. are used, and as the alicyclic hydrocarbon solvent, cyclopentane, cyclohexane, etc. are used as the aromatic hydrocarbon solvent. Benzene, toluene, xylene, chlorobenzene, etc., ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, cyclohexanone, etc., ether solvents such as diethyl ether, tetrahydrofuran, dioxane 1,2-dimethoxyethane and the like can be exemplified. These solvents can be used alone or in combination of two or more. Among these, the use of a nonpolar solvent is preferred, and the use of an aromatic hydrocarbon solvent is more preferred because the target product can be obtained with good yield and the handleability is excellent.

  The reaction temperature is usually in the temperature range from room temperature to the boiling point of the solvent used, preferably 100 to 120 ° C. The reaction time is usually several minutes to several days, preferably 1 to 24 hours. The completion of the reaction can be confirmed, for example, by sampling the reaction solution and using a known analysis means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.

In the present invention, the pyridine compound (IV) and cyanate are preferably reacted in the presence of a phase transfer catalyst.
By reacting the pyridine compound (IV) and cyanate in the presence of a phase transfer catalyst, the reactivity of these compounds is increased, and the isocyanate compound (II) can be obtained in a high yield.

  The phase transfer catalyst used in the present invention is not particularly limited. For example, a quaternary ammonium salt; a quaternary phosphonium salt such as a phosphonium salt such as tetrabutylphosphonium chloride, tetrabutylphosphonium bromide, benzyltrimethylphosphonium chloride, and benzyltrimethylphosphonium bromide. Macrocyclic polyethers such as 12-crown-4, 18-crown-6, and benzo-18-crown-6; Among these, the use of a quaternary ammonium salt is preferable because the target product can be obtained with higher yield.

  Specific examples of the quaternary ammonium salt include chlorides such as tetramethylammonium chloride, tetraethylammonium chloride, tetra-n-propylammonium chloride, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, benzyltripropylammonium chloride; tetramethylammonium bromide Bromides such as tetraethylammonium bromide, tetran-propylammonium bromide, benzyltriethylammonium bromide, benzyltriethylammonium bromide, benzyltripropylammonium bromide; tetramethylammonium iodide, tetraethylammonium iodide, tetra n-propylammonium iodide, Benji Trimethylammonium iodide, benzyltriethylammonium iodide, iodide and benzyl tripropyl ammonium iodide; and the like.

  The amount of the phase transfer catalyst used is usually 0.005 to 0.5 mol, preferably 0.01 to 0.25 mol, per 1 mol of pyridine compound (IV). By using the phase transfer catalyst within this range, the isocyanate compound (II) can be obtained in a high yield.

  In the present invention, the isocyanate compound (II) obtained as described above can be used as it is in the next reaction without isolation.

(2) Alcohol compound (III)
The alcohol compound (III) is a compound represented by the formula (III).
In said formula (III), R < ¹ > -R < ⁵ > represents the same meaning as the above.
As the alcohol compound (III), a commercially available one can be used as it is. For example, a compound produced by a method of reacting a halogenated alcohol such as ethylene chlorohydrin with sodium alkoxide is used. It can also be used.

  Preferred specific examples of the alcohol compound (III) include 2-methoxyethanol, 2-ethoxyethanol, 2-propoxyethanol, 2-butoxyethanol, 2-methoxy-1-methylethanol, 2-ethoxy-1-methylethanol, 1-methyl-2-propoxyethanol, 2-butoxy-1-methylethanol, 1-ethyl-2-methoxyethanol, 2-methoxy-1-ethylethanol, 1-ethyl-2-propoxyethanol, 2-butoxy-1 -Ethylethanol etc. are mentioned.

  The usage-amount of alcohol compound (III) is 1-10 mol normally with respect to 1 mol of isocyanate compounds (II), Preferably it is 1-5 mol. Moreover, when using alcohol compound (III) as a reaction solvent, it is 1-100 mol normally with respect to 1 mol of isocyanate compounds (II).

(3) Reaction method Reaction of isocyanate compound (II) and alcohol compound (III) is normally performed in an organic solvent. When the alcohol compound (III) to be used is a liquid, it can be used as a reaction solvent.

  The organic solvent to be used is not particularly limited as long as it is inert to the reaction, and examples thereof include those listed as organic solvents used for the reaction of pyridine compound (IV) and cyanate. Among these, the use of a nonpolar solvent is preferable and the use of an aromatic hydrocarbon solvent is more preferable because the target product can be obtained with good yield and the handleability is excellent.

  The reaction temperature is usually in the temperature range from room temperature to the boiling point of the solvent used, preferably in the temperature range from 40 ° C. to the boiling point of the solvent. The reaction time is usually several minutes to several days, preferably 1 to 24 hours. The completion of the reaction can be confirmed, for example, by sampling the reaction solution and using a known analysis means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.

  In the present invention, the ester compound (I) can also be obtained all at once by reacting the pyridine compound (IV) with the cyanate salt and the alcohol compound (III). That is, by stirring a mixture of a pyridine compound (IV), a cyanate salt and an alcohol compound (III) at a predetermined temperature, an isocyanate compound (II) is produced in the reaction system, which is further added to the alcohol compound (III). To obtain the target ester compound (I).

  The usage-amount of alcohol compound (III) is 1-10 mol normally with respect to 1 mol of pyridine compounds (IV), Preferably it is 1-5 mol. Moreover, when using alcohol compound (III) as a reaction solvent, it is 1-100 mol normally with respect to 1 mol of pyridine compounds (IV). The solvent used, the reaction temperature, the reaction time, the reaction completion confirmation method, etc. are the same as described above.

  Furthermore, in this case, the reaction is preferably performed in the presence of a phase transfer catalyst. Examples of the phase transfer catalyst to be used include those listed as the phase transfer catalysts that can be used when the pyridine compound (IV) and cyanate are reacted to obtain the isocyanate compound (II).

After completion of the reaction, the target ester compound (I) can be isolated by a usual post-treatment operation.
The structure of the resulting ester compound (I) can be confirmed by known analytical means such as ¹ H-NMR, ¹³ C-NMR, IR spectrum, mass spectrum, and elemental analysis.

3) Method for producing pyridylmethylamine compound represented by formula (V) The amine compound (V) of the present invention is prepared by reacting a pyridine compound (IV) with a cyanate salt and an alkoxy alcohol compound (III). It can be produced by the step (I) for obtaining the compound (I) and the step (II) for hydrolyzing the ester compound (I) obtained.

Step (I)
Step (I) is a step of obtaining ester compound (I) by reacting pyridine compound (IV) with cyanate and alkoxy alcohol compound (III). Step (I) can be carried out in the same manner as in the method for producing ester compound (I).

  In the present invention, after completion of the reaction in the step (I), the ester compound (I) is isolated from the reaction solution, and the isolated ester compound (I) can be used in the next step (II). Without isolating the ester compound (I) from the reaction solution obtained in I), it can also be subjected to the reaction of the next step (II) in the form of a solution.

Step (II)
Step (II) is a step of obtaining an amine compound (V) by hydrolyzing the ester compound (I).
Hydrolysis of the ester compound (I) can usually be carried out in an acidic or basic aqueous solution, but it is preferably carried out in an acidic aqueous solution from the viewpoint of obtaining the desired product in good yield.

The acid to be used is not particularly limited, and examples thereof include inorganic acids such as sulfuric acid, hydrochloric acid and phosphoric acid; carboxylic acids such as acetic acid and trifluoroacetic acid; sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid and trifluoromethanesulfonic acid; Is mentioned.
The usage-amount of an acid is 1-100 mol normally with respect to 1 mol of ester compound (I), Preferably it is 1-20 mol.

The hydrolysis temperature is usually from 0 ° C. to reflux temperature, preferably from 40 ° C. to reflux temperature. The reaction time is usually 1 hour to several days, preferably 10 to 24 hours.
The completion of the reaction can be confirmed, for example, by sampling the reaction solution and using a known analysis means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.

  After completion of the reaction, a usual post-treatment operation is performed, and the target amine compound (V) can be isolated by a known purification means such as a distillation method or column chromatography.

The structure of the resulting amine compound (V) can be confirmed by known analytical means such as ¹ H-NMR spectrum, ¹³ C-NMR spectrum, IR spectrum, mass spectrum, and elemental analysis.

According to the present invention, the amine compound (V) can be produced easily and with good yield.
The amine compound (V) obtained by the production method of the present invention is useful as an intermediate for producing an active ingredient of a pesticide / pharmaceutical production intermediate, for example, an active ingredient of a chloronicotyl pesticide such as imidacloprid, nitenpyram, and acetamiprid. .

Next, an Example is given and this invention is demonstrated further in detail. However, the present invention is not limited to the following examples.
The reaction product was analyzed using high performance liquid chromatography (HPLC, LC-10A type, manufactured by Shimadzu Corporation).

Example 1 Production of [(2-chloropyridin-5-yl) methyl] carbamic acid (2'-methoxyethyl) (I-1)

  To a mixture of 0.49 g (6 mmol) of potassium cyanate and 2-methoxyethanol (5 ml), 0.12 g (0.5 mmol) of benzyltriethylammonium chloride and 2-chloro-5- (chloromethyl) pyridine (IV-1) 0.81 g (5 mmol) was sequentially added at room temperature, and then heated at 95 to 100 ° C. for 7 hours. The reaction solution was returned to room temperature and concentrated under reduced pressure, and ethyl acetate and water were added to the resulting mixture to separate the organic layer. The organic layer was washed 3 times with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was further concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (developing solvent; ethyl acetate: n-hexane = 1: 1) to obtain [(2-chloropyridin-5-yl) methyl. ] 0.72 g of carbamic acid (2'-methoxyethyl) (I-1) was obtained as an oil (yield 59%).

The ¹ H-NMR data of the obtained [(2-chloropyridin-5-yl) methyl] carbamic acid (2′-methoxyethyl) (I-1) is shown below.
¹ H-NMR (CDCl ₃ , δ ppm); 3.37 (s, 3H), 3.58 (t, 2H), 4.27 (t, 2H), 4.35 (d, 2H), 5.75 (Brs, 1H), 7.28 (d, 1H), 7.63 (dd, 1H), 8.31 (brs, 1H)

(Comparative Example 1) Production of isopropyl (VI) [(2-chloropyridin-5-yl) methyl] carbamate

  To a mixture of 0.97 g (12 mmol) of potassium cyanate and 2-propanol (10 ml), 0.23 g (1 mmol) of benzyltriethylammonium chloride and 1.62 g of 2-chloro-5- (chloromethyl) pyridine (IV-1) (10 mmol) was sequentially added at room temperature, and the whole was heated at 95-100 ° C. for 14 hours. Workup and separation / purification were carried out in the same manner as in Example 1 to obtain 0.11 g of isopropyl [VI (2-chloropyridin-5-yl) methyl] carbamate (VI) (yield 4.8%).

¹ H-NMR data of the obtained [(2-chloropyridin-5-yl) methyl] carbamate isopropyl (VI) is shown below.
¹ H-NMR (CDCl ₃ , δ ppm); 1.23 (d, 6H), 4.34 (bs, 2H), 4.93 (m, 1H), 5.26 (bs, 1H), 7.30 (D, 1H), 7.63 (d, 1H), 8.31 (s, 1H)

Example 2 Production of [(2-chloropyridin-5-yl) methyl] carbamic acid (2'-ethoxyethyl) (I-2)

  To a mixture of 0.49 g (7.5 mmol) of sodium cyanate and toluene (5 ml), 60 mg (0.25 mmol) of benzyltriethylammonium chloride, 0.75 ml (7.8 mmol) of 2-ethoxyethanol and 2-chloro-5- 0.81 g (5 mmol) of (chloromethyl) pyridine (IV-1) was sequentially added at room temperature, and then heated at 95 to 100 ° C. for 7 hours. The reaction solution was washed with water three times, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 1.26 g of [(2-chloropyridin-5-yl) methyl] carbamic acid (2′-ethoxyethyl) (I-2) having a purity of 81.4% (HPLC) as an oily substance. (Yield 79%).

The ¹ H-NMR data of the obtained [(2-chloropyridin-5-yl) methyl] carbamic acid (2′-ethoxyethyl) (I-2) is shown below.
¹ H-NMR data (CDCl ₃ , δ ppm); 1.20 (t, 3H), 3.53 (q, 2H), 3.65 (t, 2H), 4.27 (t, 2H), 4. 35 (d, 2H), 5.45 (brs, 1H), 7.28 (d, 1H), 7.63 (dd, 1H), 8.31 (brs, 1H)

(Example 3) Method for producing [(2-chloropyridin-5-yl) methyl] carbamic acid (2'-methoxy-1'-methylethyl) (I-3)

  [(2-Chloropyridin-5-yl) methyl] carbamic acid (2′-methoxy-1) was obtained in the same manner as in Example 2 except that 1-methoxy-2-propanol was used instead of 2-ethoxyethanol. '-Methylethyl) (I-3) 1.58g was obtained (yield 61%).

¹ H-NMR data of the obtained [(2-chloropyridin-5-yl) methyl] carbamic acid (2′-methoxy-1′-methylethyl) (I-3) are shown below.
¹ H-NMR data (CDCl ₃ , δ ppm); 1.26 (d, 3H), 3.37 (s, 3H), 3.43, (bs, 2H), 4.35 (d, 2H), 5 .19 (bs, IH), 7.28 (d, 1H), 7.63 (dd, 1H), 8.31 (brs, 1H)

(Comparative Example 2) Production of isopropyl (VI) [(2-chloropyridin-5-yl) methyl] carbamate

  To a mixture of sodium cyanate 0.49 g (7.5 mmol) and toluene (5 ml), benzyltriethylammonium chloride 60 mg (0.25 mmol), 2-propanol 0.5 ml (6.4 mmol) and 2-chloro-5- ( Chloromethyl) pyridine (IV-1) 0.81 g (5 mmol) was sequentially added at room temperature, and then heated at 95 to 100 ° C. for 7 hours. As a result of analysis by HPLC (HPLC area percentage method), it was confirmed that isopropyl (VI) carbamate (VI) was obtained in a yield of 4.0%.

Example 4 Production of (2-chloropyridin-5-yl) methylamine (V-1)

  5 ml of 9N hydrochloric acid was added to 1.29 g (5 mmol) of [(2-chloropyridin-5-yl) methyl] carbamic acid (2′-methoxy-1′-methylethyl) (I-3) at 100 to 105 ° C. Heated for 16 hours. After adding chloroform to the reaction solution, the aqueous layer was separated and made alkaline by adding 28% sodium hydroxide. Extraction with chloroform and concentration yielded 0.59 g of (2-chloropyridin-5-yl) methylamine (V-1) as a white solid (yield 83%).

The ¹ H-NMR data of the obtained (2-chloropyridin-5-yl) methylamine (V-1) is shown below.
¹ H-NMR (CDCl ₃ , δ ppm); 1.46 (bs, 2H), 3.94 (s, 2H), 7.30 (d, 1H), 7.68 (d, 1H), 8.34 (S, 1H)

Claims (9)

Formula (I)

(In the formula, X represents a hydrogen atom or a halogen atom,
R ^{1 to} R ⁴ are each independently a hydrogen atom; a nitro group, a cyano group, a halogen atom, an alkoxy group, an alkylthio group, an alkylsulfonyl group, an alkoxycarbonyl group, a phenyl group, a 4-chlorophenyl group, and a 2-methylphenyl group. An alkyl group having 1 to 20 carbon atoms which may have a substituent selected from : or an alkyl group, a nitro group, a cyano group, a halogen atom, an alkoxy group, an alkylthio group, an alkylsulfonyl group, an alkoxycarbonyl group, phenyl An aryl group optionally having a substituent selected from a group, a 4-chlorophenyl group and a 2-methylphenyl group;
R ⁵ has a substituent selected from a nitro group, a cyano group, a halogen atom, an alkoxy group, an alkylthio group, an alkylsulfonyl group, an alkoxycarbonyl group, a phenyl group, a 4-chlorophenyl group, and a 2-methylphenyl group. Or an alkyl group, nitro group, cyano group, halogen atom, alkoxy group, alkylthio group, alkylsulfonyl group, alkoxycarbonyl group, phenyl group, 4-chlorophenyl group and 2-methyl. Represents an aryl group which may have a substituent selected from a phenyl group ; )
A pyridylmethylcarbamate compound represented by the formula: Formula (II)

(In the formula, X represents a hydrogen atom or a halogen atom.)
An isocyanate compound represented by formula (III)

Wherein R ^{1 to} R ⁴ are each independently a hydrogen atom; a nitro group, a cyano group, a halogen atom, an alkoxy group, an alkylthio group, an alkylsulfonyl group, an alkoxycarbonyl group, a phenyl group, a 4-chlorophenyl group, and 2 An alkyl group having 1 to 20 carbon atoms which may have a substituent selected from a methylphenyl group ; or an alkyl group, a nitro group, a cyano group, a halogen atom, an alkoxy group, an alkylthio group, an alkylsulfonyl group, an alkoxy group An aryl group optionally having a substituent selected from a carbonyl group, a phenyl group, a 4-chlorophenyl group and a 2-methylphenyl group;
R ⁵ has a substituent selected from a nitro group, a cyano group, a halogen atom, an alkoxy group, an alkylthio group, an alkylsulfonyl group, an alkoxycarbonyl group, a phenyl group, a 4-chlorophenyl group, and a 2-methylphenyl group. Or an alkyl group, nitro group, cyano group, halogen atom, alkoxy group, alkylthio group, alkylsulfonyl group, alkoxycarbonyl group, phenyl group, 4-chlorophenyl group and 2-methyl. Represents an aryl group which may have a substituent selected from a phenyl group ; )
Wherein the compound is reacted with an alkoxy alcohol compound represented by formula (I):

(Wherein X and R ^{1 to} R ⁵ represent the same meaning as described above.)
The manufacturing method of the pyridylmethyl carbamate ester compound shown by these. Formula (IV)

(In the formula, X represents a hydrogen atom or a halogen atom, L represents a halogen atom, an alkylsulfonyloxy group having 1 to 20 carbon atoms; a haloalkylsulfonyloxy group having 1 to 20 carbon atoms ; or a halogen atom, an alkyl group, or alkoxy. A phenylsulfonyloxy group which may have a substituent selected from a group, a haloalkyl group and a nitro group;
By reacting a pyridine compound represented by the formula (II) with cyanate.

(In the formula, X represents the same meaning as described above.)
A process for obtaining an isocyanate compound represented by formula (II), an isocyanate compound represented by formula (II), and formula (III)

Wherein R ^{1 to} R ⁴ are each independently a hydrogen atom; a nitro group, a cyano group, a halogen atom, an alkoxy group, an alkylthio group, an alkylsulfonyl group, an alkoxycarbonyl group, a phenyl group, a 4-chlorophenyl group, and 2 An alkyl group having 1 to 20 carbon atoms which may have a substituent selected from a methylphenyl group ; or an alkyl group, a nitro group, a cyano group, a halogen atom, an alkoxy group, an alkylthio group, an alkylsulfonyl group, an alkoxy group An aryl group optionally having a substituent selected from a carbonyl group, a phenyl group, a 4-chlorophenyl group and a 2-methylphenyl group;
R ⁵ has a substituent selected from a nitro group, a cyano group, a halogen atom, an alkoxy group, an alkylthio group, an alkylsulfonyl group, an alkoxycarbonyl group, a phenyl group, a 4-chlorophenyl group, and a 2-methylphenyl group. Or an alkyl group, nitro group, cyano group, halogen atom, alkoxy group, alkylthio group, alkylsulfonyl group, alkoxycarbonyl group, phenyl group, 4-chlorophenyl group and 2-methyl. Represents an aryl group which may have a substituent selected from a phenyl group ; )
Having the step of reacting with an alkoxy alcohol compound represented by formula (I)

(Wherein X and R ^{1 to} R ⁵ represent the same meaning as described above.)
The manufacturing method of the pyridylmethyl carbamate ester compound shown by these.   The method for producing a pyridylmethylcarbamic acid ester compound according to claim 3, wherein the pyridine compound represented by the formula (IV) and cyanate are reacted in the presence of a phase transfer catalyst. Formula (IV)

(Wherein X represents a hydrogen atom or a halogen atom, L represents a halogen atom; an alkylsulfonyloxy group having 1 to 20 carbon atoms; a haloalkylsulfonyloxy group having 1 to 20 carbon atoms ; or a halogen atom, an alkyl group, alkoxy A phenylsulfonyloxy group which may have a substituent selected from a group, a haloalkyl group and a nitro group;
A pyridine compound represented by formula (III)

Wherein R ^{1 to} R ⁴ are each independently a hydrogen atom; a nitro group, a cyano group, a halogen atom, an alkoxy group, an alkylthio group, an alkylsulfonyl group, an alkoxycarbonyl group, a phenyl group, a 4-chlorophenyl group, and 2 An alkyl group having 1 to 20 carbon atoms which may have a substituent selected from a methylphenyl group ; or an alkyl group, a nitro group, a cyano group, a halogen atom, an alkoxy group, an alkylthio group, an alkylsulfonyl group, an alkoxy group An aryl group optionally having a substituent selected from a carbonyl group, a phenyl group, a 4-chlorophenyl group and a 2-methylphenyl group;
R ⁵ has a substituent selected from a nitro group, a cyano group, a halogen atom, an alkoxy group, an alkylthio group, an alkylsulfonyl group, an alkoxycarbonyl group, a phenyl group, a 4-chlorophenyl group, and a 2-methylphenyl group. Or an alkyl group, nitro group, cyano group, halogen atom, alkoxy group, alkylthio group, alkylsulfonyl group, alkoxycarbonyl group, phenyl group, 4-chlorophenyl group and 2-methyl. Represents an aryl group which may have a substituent selected from a phenyl group ; )
Wherein the compound is reacted with an alkoxy alcohol compound represented by formula (I):

(Wherein X and R ^{1 to} R ⁵ represent the same meaning as described above.)
The manufacturing method of the pyridylmethyl carbamate ester compound shown by these.   The pyridyl according to claim 5, wherein the pyridine compound represented by the formula (IV) is reacted with a cyanate salt and the alkoxy alcohol compound represented by the formula (III) in the presence of a phase transfer catalyst. A method for producing a methylcarbamic acid ester compound. Formula (I)

(In the formula, X represents a hydrogen atom or a halogen atom, and R ^{1 to} R ⁴ are each independently a hydrogen atom; a nitro group, a cyano group, a halogen atom, an alkoxy group, an alkylthio group, an alkylsulfonyl group, an alkoxycarbonyl group. An alkyl group having 1 to 20 carbon atoms which may have a substituent selected from phenyl group, 4-chlorophenyl group and 2-methylphenyl group; or alkyl group, nitro group, cyano group, halogen atom, alkoxy An aryl group which may have a substituent selected from a group, an alkylthio group, an alkylsulfonyl group, an alkoxycarbonyl group, a phenyl group, a 4-chlorophenyl group and a 2-methylphenyl group;
R ⁵ has a substituent selected from a nitro group, a cyano group, a halogen atom, an alkoxy group, an alkylthio group, an alkylsulfonyl group, an alkoxycarbonyl group, a phenyl group, a 4-chlorophenyl group, and a 2-methylphenyl group. Or an alkyl group, nitro group, cyano group, halogen atom, alkoxy group, alkylthio group, alkylsulfonyl group, alkoxycarbonyl group, phenyl group, 4-chlorophenyl group and 2-methyl. Represents an aryl group which may have a substituent selected from a phenyl group ; )
The method comprises hydrolyzing a pyridylmethylcarbamate compound represented by formula (V):

(In the formula, X represents the same meaning as described above.)
The manufacturing method of the pyridylmethylamine compound shown by these. Formula (IV)

(In the formula, X represents a hydrogen atom or a halogen atom, L is a halogen atom; an alkylsulfonyloxy group having 1 to 20 carbon atoms; a haloalkylsulfonyloxy group having 1 to 20 carbon atoms ; or a halogen atom, an alkyl group, Represents a phenylsulfonyloxy group which may have a substituent selected from an alkoxy group, a haloalkyl group and a nitro group .)
A pyridine compound represented by formula (III)

Wherein R ^{1 to} R ⁴ are each independently a hydrogen atom; a nitro group, a cyano group, a halogen atom, an alkoxy group, an alkylthio group, an alkylsulfonyl group, an alkoxycarbonyl group, a phenyl group, a 4-chlorophenyl group, and 2 An alkyl group having 1 to 20 carbon atoms which may have a substituent selected from a methylphenyl group ; or an alkyl group, a nitro group, a cyano group, a halogen atom, an alkoxy group, an alkylthio group, an alkylsulfonyl group, an alkoxy group An aryl group optionally having a substituent selected from a carbonyl group, a phenyl group, a 4-chlorophenyl group and a 2-methylphenyl group;
R ⁵ has a substituent selected from a nitro group, a cyano group, a halogen atom, an alkoxy group, an alkylthio group, an alkylsulfonyl group, an alkoxycarbonyl group, a phenyl group, a 4-chlorophenyl group, and a 2-methylphenyl group. Or an alkyl group, nitro group, cyano group, halogen atom, alkoxy group, alkylthio group, alkylsulfonyl group, alkoxycarbonyl group, phenyl group, 4-chlorophenyl group and 2-methyl. Represents an aryl group which may have a substituent selected from a phenyl group ; )
By reacting with an alkoxy alcohol compound represented by formula (I)

(Wherein X and R ^{1 to} R ⁵ represent the same meaning as described above.)
And a step (I) of obtaining a pyridylmethylcarbamate compound represented by formula (I) and a step (II) of hydrolyzing the pyridylmethylcarbamate compound represented by formula (I).

(In the formula, X represents the same meaning as described above.)
The manufacturing method of the pyridylmethylamine compound shown by these.   The method for producing a pyridylmethylamine compound according to claim 8, wherein the reaction in the step (I) is carried out in the presence of a phase transfer catalyst.