JPH09194461A - Production of 3-(aminomethyl)-6-chloropyridine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently obtain 3-(aminomethyl)-6-chloropyridine which is useful as a precursor of important starting substances for agrochemicals by using a compound readily available from 3-(aminomethyl)pyridines as a starting substance. SOLUTION: An organic base of the formula: R'R"R'''N [R', R" and R''' are each a lower alkyl, an aromatic group or they together form a (substituted) pyridine] and an electrophilic reagent having at least one chlorine atom are allowed to act on a 3-(substituted aminomethyl)pyridine 1-oxide of formula I (R<1> is an alkyl, an aryl, aralkyl, an alkoxy; R<2> is H, a lower alkyl; R<3> is H, a lower alkyl, a halogen), the reaction mixture is treated with water in combination with an acid to give 3-(aminomethyl)-6-chloropyridine. The organic base is preferably trimethylamine and the electrophilic reagent is preferably phosgene.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to substituted aminomethylpyridines useful as a precursor for producing important raw materials in the production of agricultural chemicals.

[0002]

[Prior art]

 General formula [II]

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(Wherein R ² represents a hydrogen atom or a lower alkyl group, and R ³ represents a hydrogen atom, a lower alkyl group or a halogen atom), 3- (aminomethyl) -6-chloropyridines are Since it is an important raw material for the production of pesticides and pesticides, various production methods have been proposed.

For example, (1) a method in which 6-chloro-3- (chloromethyl) pyridine is used as a raw material and chlorine on the methyl group of this is converted to an amino group (EP391205, E).
P302389, EP366085, EP37627
9, JP5286936), or (2) using 6-chloro-3-cyanopyridine as a precursor to reduce the cyano group thereof to an aminomethyl group (DE422215).
2, WO9213840) is known.

However, the method of substituting chlorine on a methyl group with an amino group in the method (1) produces a by-product such as a dimer, so that there is no industrially satisfactory method.
Further, as a method for producing 6-chloro-3- (chloromethyl) pyridine as a raw material, chlorination of 6-chloro-3-methylpyridine produced by the method described in EP556683 etc. (DE3630046, DE40)
16175), reduction of 6-chloro-3- (trichloromethyl) pyridine (EP512463, JP5320).
132), or a method of deriving from 6-chloronicotinic acid (EP569974, EP256990, US4).
576629, EP 42530) is generally known. However, in any of the methods, it is difficult to stop the reaction by the desired monosubstitution of chlorine on the methyl group, and there is a problem in the selectivity of this reaction. In the method, the raw materials are expensive and the reduction step is costly. There was a problem such as.

In the method (2), there is a problem that chlorine is eliminated and dimer and the like are by-produced in the cyano group reduction step of 6-chloro-3-cyanopyridine, and the 6-position of 3-cyanopyridine is also produced in the production of raw materials. There was a problem that 6-chloro-3-cyanopyridine could not be obtained efficiently because a positional isomer was generated during chlorination. That is, in all of the known methods, the amino group-building reaction on the methyl group at the 3-position is carried out after chlorination at the 6-position. Had the drawback that

[0007]

The present inventors have proposed the general formula [I
I]

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As a result of earnest search for an industrially advantageous production method of 3- (aminomethyl) -6-chloropyridines represented by the formula (wherein R ² and R ³ have the same meanings as described above), Three
General formula [I] easily available from-(aminomethyl) pyridines

[0009]

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(Wherein R ¹ is an alkyl group, an aryl group,
An aralkyl group or an alkoxy group represented by R ² and R ³ has the same meanings as described above, and 3- (substituted aminomethyl) pyridine 1-oxide represented by the general formula [II] can be efficiently used.

[0011]

[Chemical 6]

The present invention has been completed by finding that 3- (aminomethyl) -6-chloropyridines represented by the formula (wherein R ² and R ³ have the same meanings as described above) can be obtained. That is, the present invention provides a compound represented by the general formula [I]:

[0013]

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(Wherein R ¹ is an alkyl group, an aryl group,
An aralkyl group or an alkoxy group, R ² represents a hydrogen atom, a lower alkyl group, and R ³ represents a hydrogen atom, a lower alkyl group, or a halogen atom), and the 3- (substituted aminomethyl) pyridine 1-oxide is an organic base. The general formula [II] is characterized by treating with an electrophilic reagent and then treating with acid together with water.

[0015]

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A process for producing 3- (aminomethyl) -6-chloropyridines represented by the formula (wherein R ² and R ³ have the same meanings as described above).

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION R ¹ , R ² and R ³ will be specifically described. R ¹ is an alkyl group, an aryl group, an aralkyl group or an alkoxy group, and is stable during the oxidation reaction in producing the starting compound represented by the general formula [I] and the quaternary ammonium chloride reaction at the 6-position of pyridine. Any substance can be used as long as it forms an acylamino group which is hydrolyzed in the acid treatment step in the presence of water of the present invention.
As the alkyl group, straight-chain, branched, or cyclic C1 to C1
As the alkyl group or aryl group of 8, a phenyl group or a condensed ring type aromatic group such as naphthalene or anthracene can be used. Alternatively, those substituted with a halogen atom such as fluorine and chlorine can also be used. The aralkyl group may be any combination of the above-mentioned alkyl group and aryl group, and examples of the alkoxy group include lower alkoxy groups such as methoxy, ethoxy and i-propoxy, and a benzyloxy group. R ² is a hydrogen atom or a lower alkyl group such as methyl or ethyl. R ³ is a hydrogen atom, a lower alkyl group such as methyl or ethyl, or a halogen atom.

Examples of the base represented by the general formula [III] include tertiary amines such as trimethylamine and triethylamine,
Examples thereof include tertiary amines such as N, N-dimethylaniline and N, N-dimethyl-4-aminopyridine, and pyridine which may be substituted with a lower alkyl group such as methyl and ethyl.

Examples of electrophilic reagents include chlorides such as phosgene, thionyl chloride and sulfuryl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus chlorides such as (diethylamido) phosphonic acid dichloride, methanesulfonic acid chloride and toluenesulfonic acid chloride. Sulfonic acid chlorides, such as
Examples thereof include acid chlorides such as acetyl chloride and benzoic acid chloride, and chloroformates such as methyl chloroformate and isopropyl chloroformate. The acid is hydrochloric acid or a mixture of hydrochloric acid and sulfuric acid. The reaction scheme of the present invention is as follows.

[0020]

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Step A To the mixed solution of the compound represented by the general formula [I] and the base represented by the general formula [III], an electrophilic reagent is added to prepare a compound represented by the general formula [IV] (wherein R ¹ , R ² and R ³
And R′R ″ R ′ ″ N have the same meaning as described above) to form an ammonium salt. Step B When the ammonium salt [IV] obtained in Step A is treated with hydrochloric acid or a mixture of hydrochloric acid and sulfuric acid in the presence of water, 3- (aminomethyl) -6-chloropyridines represented by the general formula [II] are obtained. obtain. As the solvent in the step A, methylene chloride, chloroform, carbon tetrachloride, chlorobenzene and other chlorine-based compounds, acetonitrile, benzonitrile and other nitrile-based compounds, ethyl acetate, methyl acetate and other ester-based compounds, and TH
Inert solvents such as ethers such as F and diethyl ether, ketones such as acetone and MEK, or mixed solvents thereof, or mixed solvents obtained by adding hydrocarbon solvents such as hexane and toluene to these inert solvents Etc. can be used. The base represented by the general formula [III] is used in an amount of 2 to 6 molar equivalents for the compound represented by the general formula [I], and the electrophilic agent is equimolar to 5 to the compound represented by the general formula [I].
Use molar equivalents. The reaction is carried out at -40 ° C to the boiling point of the solvent, preferably -20 ° C to room temperature, for 1 to 6 hours.

As the solvent used in the acid treatment in the step B, water or a mixed solvent obtained by adding a lower alcohol solvent such as methanol or ethanol to water can be used. The compound represented by the general formula [IV] is obtained by diluting the compound represented by the general formula [IV] with the above solvent and treating at room temperature to the boiling point of the solvent, preferably at 60 to 100 ° C. for 3 to 20 hours. To be The concentration of acid is preferably 6 to 12 N in the case of hydrochloric acid, and 6 to 12 in the case of using hydrochloric acid and sulfuric acid as a mixture.
A mixture of 12N hydrochloric acid and concentrated sulfuric acid in an amount of 5 to 50% (V / V) can be used.

[0023]

EXAMPLES Examples will be described in detail. Example 1 3- (Heptanamidomethyl) pyridine 1
Synthesis of 3- (aminomethyl) -6-chloropyridine from -oxide:

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3- (heptanamidomethyl) pyridine
Phosgene (9 ml) was stirred in chloroform solution (100 ml) of 1-oxide (10.4 g, 0.05 mol) and trimethylamine (8 g, 0.13 mol) at -5 ° C.
g, 0.09 mol) was bubbled in over 1 hour. The reaction mixture was warmed to room temperature and stirred for a further 2 hours, then 40
Concentrated to dryness at ° C / 450 torr. Then, concentrated hydrochloric acid (150 ml) was added to the dried solid, and the mixture was reacted at 60 to 70 ° C for 3 hours and further at 90 to 100 ° C for 5 hours. After cooling to room temperature and extracting the reaction mixture with chloroform to recover heptanoic acid (97%), the aqueous layer having a pH of 14 was repeatedly extracted with chloroform. As a result of HPLC analysis, 5.8 g (yield 81%) of 3- (aminomethyl) -6-chloropyridine was confirmed in this chloroform solution.

Example 2 Synthesis of 3-((aminomethyl) -6-chloropyridine from 3- (pivaloylaminomethyl) pyridine 1-oxide:

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3- (Pivaloylaminomethyl) pyridine 1-oxide (20.8 g, 0.1 mol) in chloroform (110 ml) was added with trimethylamine (15.
9 g, 0.27 mol) was added, phosgene (13.4 g, 0.135 mol) was blown in for 30 minutes while stirring at -5 ° C, and the stirring was continued for another 2 hours. Then, the reaction solution was concentrated and dried under reduced pressure. Solidified Next, 9N hydrochloric acid (3
00 ml) was added and the mixture was heated at 90 to 95 ° C for 12 hours. After cooling to room temperature and extracting the reaction mixture with chloroform to recover pivalic acid (78%), 50% aqueous sodium hydroxide solution was added to adjust the pH of the solution to 13.5. Chloroform (100 ml) was added to this solution for liquid separation, and the aqueous layer was further extracted with chloroform repeatedly. The chloroform layers were combined and dried over magnesium sulfate. As a result of HPLC analysis, 3- (aminomethyl) -6-chloropyridine 1 was found in this solution.
It contained 0.3 g (0.072 mol, 72% yield).

Example 3 3- (benzamidomethyl) pyridine 1-oxide to 3- (aminomethyl) -6-
Synthesis of chloropyridine:

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3- (benzamidomethyl) pyridine 1
-Oxide (6.9 g, 0.03 mol) and trimethylamine (6 g, 0.10 mol) in chloroform (100 ml) were stirred at -5 ° C with phosgene (7).
g, 0.07 mol) was bubbled in over 1 hour. The reaction mixture was warmed to room temperature and stirred for a further 2 hours, then 40
Concentrated to dryness at ° C / 450 torr. Then, concentrated hydrochloric acid (120 ml) was added to the dried product, and the mixture was reacted at 80 to 100 ° C for 15 hours. After cooling to room temperature, the reaction mixture was extracted with chloroform to recover benzoic acid (95%). By HPLC analysis, 3.2 g (yield 75%) of 3- (aminomethyl) -6-chloropyridine was confirmed in the aqueous layer.

Example 4 Synthesis of 3- (aminomethyl) -6-chloropyridine from 3- (i-propoxycarbonylaminomethyl) pyridine 1-oxide:

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3- (i-propoxycarbonylaminomethyl) pyridine 1-oxide (42.0 g, 0.2 m)
ol) in chloroform (250 ml), trimethylamine (29.6 g, 0.5 mol) was added, and phosgene (24.0 g, 0.24 mol) was added with stirring at -5 ° C.
Was blown in one hour. Then, concentrate the reaction solution
Dry to dryness, add 160 ml of 35% hydrochloric acid, and add at 90-95 ° C for 8
Heated for hours. After cooling to room temperature, 28% caustic soda aqueous solution (220 ml) was added to adjust the pH of the solution to 13.5. Chloroform (150 ml) was added to this solution for liquid separation, and the aqueous layer was further extracted with chloroform repeatedly. The chloroform layers were combined and dried over magnesium sulfate. H
As a result of PLC analysis, 3- (aminomethyl) was found in this solution.
21.3 g (0.15 mol, yield 75%) of -6-chloropyridine was contained.

[0031]

In the production method of the present invention, the chlorination of the 6-position of pyridine is carried out in the final step (simultaneous with the hydrolysis for deprotecting the amino group). It is an industrially excellent manufacturing method that does not occur.

Claims (5)

[Claims] 1. A compound of the general formula [I] (In the formula, R ¹ represents an alkyl group, an aryl group, an aralkyl group or an alkoxy group, R ² represents a hydrogen atom, a lower alkyl group and R ³ represents a hydrogen atom, a lower alkyl group or a halogen atom). (Substituted aminomethyl) pyridine 1-oxide is represented by the general formula [III] R′R ″ R ′ ″ N [III] (wherein R ′, R ″ and R ″ ′ are the same or different and are lower Represents an alkyl group or an aromatic group, or R '
R ″ R ″ ′ N together represents a pyridine which may have a substituent) and an electrophilic reagent having at least one chlorine atom, and then water And a general formula [II] characterized by treatment with an acid together with (In the formula, R ² and R ³ have the same meanings as described above.) A method for producing 3- (aminomethyl) -6-chloropyridines. 2. The production method according to claim 1, wherein R ³ is a hydrogen atom. 3. The method according to claim 1, wherein R ² is a hydrogen atom. 4. The base represented by the general formula [III] is trimethylamine, triethylamine, N, N-dimethylaniline, N, N-dimethyl-4-aminopyridine, or pyridine, and the electrophilic reagent is phosgene or chloride. Chlorides such as thionyl and sulfuryl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus chlorides such as (diethylamido) phosphonic acid dichloride, sulfonic acid chlorides such as methanesulfonic acid chloride and toluenesulfonic acid chloride,
4. The method according to claim 1, which is an acid chloride such as acetyl chloride or benzoic acid chloride, or a chloroformate such as methyl chloroformate or isopropyl chloroformate. 5. The method according to claim 1, wherein the organic base is trimethylamine and the electrophilic reagent is phosgene.