JPH09132565A - 3-(substituted aminomethyl)-6-chloropyridine and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a chloropyridine compound useful as a precursor for producing an agrochemical, especially an insecticide. SOLUTION: This 3-(substituted aminomethyl)-6-chloropyridine is shown by formula I (R<1> is an alkyl, an aryl, an aralkyl or an alkoxy; R<2> is H, an alkyl, etc.) such as 3-benzylaminomethyl)-6-chloropyridine. The compound of formula I is obtained by treating a 3-(substituted aminomethyl)pyridine 1-oxide with 2-6mol equivalent organic base of the formula, R'R"R"'N (R', R" and R"' are each pyridine which may contain an alkyl, an aromatic group or a substituent group) and an equimolar to 5mol electrophilic reagent containing at least one chlorine atom preferably at -20 deg.C to a room temperature for 1-6 hours and further reacting the treated substance with hydrogen chloride.

Description

Detailed Description of the Invention

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to substituted aminomethylpyridines useful as a production precursor of important raw materials in the production of agricultural chemicals.

2. Description of the Related Art General formula [II]

[Chemical 6] Since 3- (aminomethyl) -6-chloropyridines represented by the formula (wherein R ² 'represents a hydrogen atom or a lower alkyl group) is an important raw material for the production of pesticides, various production methods are proposed. Has been done. 6-chloro-3- (chloromethyl)
Many methods for obtaining 3- (aminomethyl) -6-chloropyridines using pyridine as a raw material have been reported (EP4
25030, EP391205, EP302389, E
P366085, EP376279, JP528693
6). However, this method has a problem that by-products such as dimers are generated in the reaction of substituting chlorine on a methyl group with an amino group. In addition, the raw material 6-chloro-3-
There is also a problem with the method for producing (chloromethyl) pyridine. The production method of the raw material pyridine is (1) EP 55668.
The method of chlorinating the methyl group of 6-chloro-3-methylpyridine produced by the method described in No. 3, etc. (D
E3630046, DE 4016175), (2) 6-
A method for reducing chloro-3- (trichloromethyl) pyridine (EP512463, JP5320132),
(3) Method of obtaining 3- (polychloromethyl) pyridine derived from nicotinic acid or β-picoline through rearrangement / hydrolysis / chlorination steps (EP 373464, JP221)
2475, EP2292262), or (4) a method using 6-hydroxynicotinic acid, 6-chloronicotinic acid and its ester as a starting material (EP56994).
However, in the method (1), the selectivity and yield of chlorination to the methyl group at the 3-position of the pyridine ring are insufficient, and (2) is trichloromethyl. The reduction yield of the group to a monochloromethyl group was unsatisfactory, and (3) and (4) had a large number of steps and a low overall yield, so that any of the production methods had low practicability. 6
-Chloro-3-cyanopyridine as a precursor to reduce the cyano group to an aminomethyl group (DE42
22152, WO9213840) are also known. However, in this method, there is a problem that chlorine is eliminated and dimers are by-produced in the cyano group reduction step, and also in the production of the raw material, a positional isomer is produced during 6-position chlorination of 3-cyanopyridine. There was a problem that chloro-3-cyanopyridine could not be obtained efficiently. As described above, various methods for producing 3- (aminomethyl) -6-chloropyridines represented by the general formula [II] have been proposed, but an industrial production method has not been established yet.

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

Embedded image (In the formula, R ² 'has the same meaning as described above)
We have eagerly searched for an advantageous intermediate for industrially producing (aminomethyl) -6-chloropyridines. as a result,
General formula [III] available from 3- (aminomethyl) pyridines

Embedded image (In the formula, R ¹ represents an alkyl group, an aryl group or an alkoxy group, R ² represents a hydrogen atom, a lower alkyl group or a carbonyl group bonded to R ¹ when it is an aryl group.)
From 3- (substituted aminomethyl) pyridine 1-oxide represented by the general formula [I] and [I ′]

Embedded image (In the formula, R ¹ , R ² and R ² 'have the same meanings as described above.)
3- (substituted aminomethyl) -6-chloropyridine represented by the following formula can be derived, and the compound represented by the general formula [I ′] can be efficiently converted to the compound represented by the general formula [II]. And completed the present invention. That is, the present invention is 3- (substituted aminomethyl) -6-chloropyridine represented by the general formulas [I] and [I ′] and a method for producing the same.

BEST MODE FOR CARRYING OUT THE INVENTION R ¹ , R ² and R ² 'will be specifically described. R ¹ is an alkyl group, an aryl group, an aralkyl group or an alkoxy group. R ¹ is a general formula [I]
Any substance can be used as long as it is stable during the oxidation reaction and the quaternary ammonium chloride reaction at the 6-position of pyridine in the production of the raw material compound and the acylamino group is hydrolyzed in the presence of an acid. , A linear alkyl group,
As the branched or cyclic C1 to C18 alkyl group or aryl group, a phenyl group or a condensed ring type aromatic group such as naphthalene or anthracene can be used, and further, a lower alkyl group such as methyl or ethyl, or methoxy group. Those substituted with a lower alkoxy group such as ethoxy, or a halogen atom such as fluorine or chlorine can also be used. As the aralkyl group, any combination of the above-mentioned alkyl group and aryl group is possible, and the alkoxy group is a lower alkoxy group such as methoxy, ethoxy or i-propoxy,
A benzyloxy group and the like are exemplified. R ² is a hydrogen atom or a lower alkyl group such as methyl or ethyl, or a carbonyl group bonded to the ortho position when R ¹ is an aryl group. R ² 'is a hydrogen atom or a lower alkyl group such as methyl and ethyl. Examples of the organic base represented by the general formula [V] include tertiary amines such as trimethylamine, triethylamine, N, N-dimethyl-aniline, pyridine and N, N-dimethyl-4-aminopyridine, or lower alkyls such as methyl and ethyl. Examples thereof include pyridine which may be substituted with a group. Electrophilic reagents include chlorides such as phosgene, thionyl chloride, sulfuryl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus chlorides such as (diethylamido) phosphonic acid dichloride, and methanesulfonic acid chloride and toluenesulfonic acid chloride. Sulfonic acid chlorides,
Examples thereof include acid chlorides such as acetyl chloride and benzoic acid chloride, and chloroformates such as methyl chloroformate and isopropyl chloroformate. The compounds [I] and [I ′] of the present invention can be synthesized by the following method.

Embedded image Step A The compound represented by the general formula [IV] is prepared by reacting the compound represented by the general formula [III] with the organic base represented by the general formula [V] and an electrophilic reagent.
(Wherein R ¹ , R ² and R ′ R ″ R ″ ′ N have the same meanings as described above), an ammonium salt represented by the formula is formed. Step B The ammonium salt [IV] obtained in the step A is reacted with hydrogen chloride under atmospheric pressure or pressure to form 3- (substituted aminomethyl) -6-chloropyridine represented by the general formulas [I] and [I ′]. To get 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, THF, diethyl ether and other ether-based compounds, and acetone , A ketone-based inert solvent such as MEK, or a mixed solvent thereof, or a mixed solvent obtained by adding a hydrocarbon-based solvent such as hexane or toluene to these inert solvents. The base represented by the general formula [V] is used in an amount of 2 to 6 moles equivalent to the compound represented by the general formula [III], and the electrophilic reagent is equimolar to 5 to the compound represented by the general formula [III]. 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. The step B can be performed continuously from the step A because the solvent of the step A can be used and there is no need to isolate and purify the compound [IV].
The reaction uses 3 to 20 equivalents of hydrogen chloride, preferably 5 to 10 equivalents, and atmospheric pressure to 20 kgf / cm ^2, preferably atmospheric pressure to 1.
It is carried out at room temperature to 120 ° C., preferably at 40 to 80 ° C. for 3 to 20 hours under a pressure of 0 kgf / cm ² . The 3- (substituted aminomethyl) -6-chloropyridine represented by the general formula [I ′] thus obtained is capable of hydrolyzing an acylamino group, and therefore has the general formula [II]

Embedded image Can be derived to 3- (aminomethyl) -6-chloropyridines. That is, by diluting the compound represented by the general formula [I ′] with an aqueous solution of an acid or a mixed solution of this and a lower alcohol solvent such as methanol, and treating at room temperature to the boiling point of the solvent, preferably at 85 to 95 ° C. A compound represented by the general formula [II] is obtained. Examples of the acid include hydrochloric acid and sulfuric acid. The suitable acid concentration is 6 to 12 N for hydrochloric acid and 50 to 80% for sulfuric acid. Further, they can be used even if they are mixed. The 3- (substituted aminomethyl) pyridine 1-oxide represented by the general formula [III] as a raw material can be produced from 3- (aminomethyl) pyridines [VI], for example, as follows.

Embedded image Step C 3- (aminomethyl) pyridines [VI] with an acid halide,
The acid anhydride or ester is reacted to give 3- (substituted aminomethyl) pyridine [VII]. Step D [VII] is oxidized to give 3- (substituted aminomethyl) pyridine.
1-oxide [III]. Step C is performed according to the method described below. (1) General formula R ¹ COX [VIII] (wherein R ¹ has the same meaning as described above, and X represents a halogen atom) or general formula (R ¹ CO) ₂ O [IX] (wherein R ^{1 1} represents the same meaning as described above), and an acid halide, haloformic acid ester, or acid anhydride represented by the formula: Compound 1 represented by the general formula [VI] is used.
Mol and 1 to 1.1 mol of the compound represented by the general formula [VIII] or the general formula [IX] in methylene chloride, chloroform,
-10 to 40 ° C in the presence of an organic base such as triethylamine in an amount of 1 to 1.5 mol in an organic solvent such as toluene or xylene.
React with. Further, an aqueous solution of an inorganic base such as sodium hydroxide is used in place of the organic base, and if necessary, in the presence of a phase transfer catalyst such as a quaternary ammonium salt, the temperature is from room temperature to 50 ° C
It can also be produced by carrying out a two-phase reaction at the temperature of. (2) Use of esters represented by the general formula R ¹ 'COOY [X] (wherein R ¹ ' represents an alkyl group, an aryl group or an aralkyl group, and Y represents a lower alkyl group): general formula 1 mol of the compound represented by [VI] and 1.5 to 5.0 mol of the ester represented by the general formula [X] in the presence of an acid catalyst such as hydrogen chloride or sulfuric acid, the same solvent as (1) The reaction is carried out at room temperature to the boiling point of the solvent used. Step D is [VI
I]] to give 3- (substituted aminomethyl) pyridine 1-
Lower alcohols, water, and acetic acid can be used as the solvent in the step of forming oxide [III], and 1 to 2 equivalents of hydrogen peroxide, peracetic acid, metachloroperbenzoic acid, or the like are used as the oxidizing agent, and the solvent can be used at room temperature. React at temperatures up to boiling point. At this time, good results can be obtained even if tungstate is used as the catalyst.
The compound represented by the general formula [III] thus obtained can be used as a raw material for the next step without isolation.

[Examples] Examples and reference examples will be described in detail. Example 1 (Compound 1) 3- (Benzamidomethyl) -6
-Synthesis of chloropyridine

Embedded image 3- (Benzamidomethyl) pyridine 1-oxide (10.0 g, 0.044 mol) and trimethylamine (12.3 g, 0.21 mol) in chloroform solution (150 ml) was stirred at -5 ° C with phosgene (1).
6.0 g, 0.16 mol) was bubbled in over 1 hour. The reaction mixture was warmed to room temperature and further stirred for 2 hours, and then phosgene was removed at 40 ° C./450 torr (distillate 80 ml). Next, hydrogen chloride gas (2
2.4 g, 0.61 mol) was introduced and the mixture was stirred in an autoclave at 80 to 85 ° C. and 1.8 to 2.3 kgf / cm ^2.
For 5 hours. After cooling to room temperature, the reaction mixture was poured into water, extracted and separated, and the aqueous layer was further extracted with chloroform. The organic layers were combined and dried over magnesium sulfate, and the solvent was distilled off to obtain 9.2 g of crystals of 3- (benzamidomethyl) -6-chloropyridine (yield 85%). Melting point: 124 to 126 ° C. Example 2 (Compound 2) 3- (phthalimidomethyl) -6
-Synthesis of chloropyridine

Embedded image 3- (phthalimidomethyl) pyridine 1-oxide (12.7 g, 50 mmol) and trimethylamine (1
1.8 g, 0.20 mol of methylene chloride (250 m
Phosgene (16 g, 0.16 mol) was bubbled into the solution dissolved in 1) with stirring at −20 ° C. in 0.5 hours. The reaction mixture was warmed to room temperature and stirred for 2 hours, and then the solvent was distilled off. The residue was again converted into methylene chloride (2
Diluted with hydrogen chloride gas (8g, 0.22mo)
l) was introduced and stirred in an autoclave at 55 to 65 ° C.,
The reaction was performed at 2.3 to 2.6 kgf / cm ² for 7 hours. After cooling to room temperature, the reaction mixture was poured into water for extraction and separation, and the aqueous layer was repeatedly extracted with chloroform. The organic layers were combined and dried over magnesium sulfate, and the solvent was distilled off to give 3- (phthalimidomethyl) -6-chloropyridine crystals 11.3 g.
(83% yield). Example 3 (Compound 3) 3- (acetamidomethyl) -6
-Synthesis of chloropyridine

Embedded image 3- (acetamidomethyl) pyridine 1-oxide (8.3 g, 50 mol) and trimethylamine (16
g, 0.27 mol) was dissolved in methylene chloride (150 ml). Phosgene (16 g, 0.16 mol) was bubbled into this solution for 1 hour with stirring at -10 ° C.
The reaction mixture was warmed to room temperature and stirred for 2 hours, and then the solvent was distilled off. The residue was diluted with 1,2-dichloroethane (300 ml) and hydrogen chloride gas (12.6 g,
0.35 mol) and introduced into the autoclave with stirring 9
The reaction was carried out at 0 to 100 ° C. and 2.0 to 2.4 kgf / cm ² for 5 hours. After cooling to room temperature, the reaction mixture was concentrated, poured into water and adjusted to pH 12, and then extracted and separated with methylene chloride. The aqueous layer was repeatedly extracted with methylene chloride. The organic layers were combined and dried over magnesium sulfate, and the solvent was distilled off to obtain 4.4 g (yield 49%) of crystals of 3- (acetamidomethyl) -6-chloropyridine. ¹ H-NMR (CDCl ₃ ): δ 8.27 (br, 1
H), 7.62 (dd, J = 7.92 and 2.4)
8 Hz, 1H), 7.28 (d, J = 7.92 H
z, 1H), 6.29 (brs, 1H), 4.40.
(D, J = 5.94 Hz, 2H), 2.03 (s, 3
H). Examples 4 to 16 (Compounds 4 to 16) The following compounds 4 to 16 were synthesized in the same manner as in Example 1. The results are shown in Table 1.

[Table 1] Example 17 Synthesis of 3- (aminomethyl) -6-chloropyridine

Embedded image 5.0 g (20 mmol) of 3- (benzamidomethyl) -6-chloropyridine (Compound 1) was added to 9N hydrochloric acid 100
It was dissolved in ml and kept at 95 ° C. for 10 hours with stirring. The mixture was cooled to room temperature and extracted three times with 50 ml of chloroform to recover benzoic acid (95%). Chloroform (50 ml) was added to the aqueous layer to adjust the pH to 13, and the layers were separated. The aqueous layer was further extracted with chloroform. The chloroform layers were combined and dried over magnesium sulfate, the solvent was distilled off, and 2.7 g of crystals of 3- (aminomethyl) -6-chloropyridine (yield 95
%). Examples 18-28 Compounds 4-16 were treated as in Example 17. The results are shown in Table-2.

[Table 2] Reference Example 1 Synthesis of 3- (benzamidomethyl) pyridine

Embedded image 3-pyridinemethanamine (108 g, 1.0 mol)
28% caustic soda solution (2
00 g) and toluene (300 ml) were added, and benzoic acid chloride (180 g, 1.28 mol) was added dropwise with stirring at 0 ° C. for 2 hours, and the stirring was continued for another 3 hours. Then, the reaction suspension solution was filtered, and the obtained crystals were washed with cold water. The crystals were dried to obtain 208 g of 3- (benzamidomethyl) pyridine (yield 98%). Reference Example 2 3- (benzamidomethyl) pyridine 1-
Oxide synthesis

Embedded image 3- (benzamidomethyl) pyridine (205 g, 0.
95 mol) and sodium tungstate (1 g) were dissolved in glacial acetic acid (500 ml), and 30% hydrogen peroxide solution (150 g) was added dropwise at 95 ° C under stirring for 1 hour. After reacting at 105 ° C for 1 hour, the mixture was cooled to room temperature and hypo was added until the iodine-starch reaction became negative. The reaction solution was concentrated, methylene chloride (3.5 L) and water (2 L) were added, the pH was adjusted to 13 with a 28% aqueous sodium hydroxide solution, and the mixture was extracted and separated. Repeat the extraction of the aqueous layer and dry the organic layers together with magnesium sulfate,
The solvent was distilled off to give 3- (benzamidomethyl) pyridine 1.
190 g (yield 88%) of crystals of -oxide were obtained. Melting point: 112 to 113 ° C Reference Example 3 3- (benzamidomethyl) pyridine 1-
Oxide synthesis

Embedded image 3- (benzamidomethyl) pyridine (5.0 g, 2
3.5 mmol), sodium tungstate (0.3 g)
And 35% hydrochloric acid (0.13 g) were suspended in water (7.5 ml). To this suspension solution, 30% hydrogen peroxide solution (3.2 g) was added dropwise under reflux and stirring for 15 minutes, the reaction was continued for 4 hours, then cooled to room temperature, and hypo was added until the iodine-starch reaction became negative. When this reaction solution was analyzed by HPLC, the production rate of 3- (benzamidomethyl) pyridine 1-oxide was 97%. Reference Example 4 3- (acetamidomethyl) pyridine 1-
Oxide synthesis

Embedded image 3-pyridinemethanamine (50 g, 0.46 mol)
And triethylamine (46.8 g, 0.46 mol) in methylene chloride solution (250 ml) were mixed with acetic acid chloride (3
A solution of 6.3 g, 0.46 mol) in chloroform (10
(0 ml) was added dropwise with stirring at 0 to 10 ° C over 1.5 hours, and the stirring was continued for another hour. After that, water (200 m) was added to the reaction solution.
1) was added, and the mixture was extracted and separated with ethyl acetate (600 ml). The aqueous layer was extracted with isobutanol (500 ml × 2), the organic layers were combined, and 1200 ml of the solvent was distilled off. The precipitated crystals were filtered, the mother liquor and the washed ethyl acetate were combined, dried over magnesium sulfate, and the solvent was distilled off.
70 g (yield 99%) of crystals of-(acetamidomethyl) pyridine were obtained. Then this crystal (35g, 0.23m
ol) and sodium tungstate (0.5 g) were dissolved in glacial acetic acid (60 ml), and 30% aqueous hydrogen peroxide (48 g) was added dropwise at 100 ° C. over 3 hours with stirring. After reacting at the same temperature for 3 hours, the mixture was cooled to room temperature and hypo was added until the iodine-starch reaction became negative. Toluene was added to this reaction solution, and the mixture was azeotropically dehydrated and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl ₃ / MeOH = 9/1) and 16 g of 3- (benzamidomethyl) pyridine 1-oxide (yield 42% ) Got. ¹ H-NMR (DMSO): δ 8.45 (brs, 1
H), 8.11 (brs, 2H), 7.35 (dd, J
= 7.91 and 7.91 Hz, 1H), 7.2
2 (d, J = 7.91 Hz, 1H), 4.22 (d,
J = 5.94 Hz, 2H), 1.89 (s, 3H). Reference Examples 5 to 14 The following compounds 19 to 28 were synthesized in the same manner as in Reference Example 3.
The results are shown in Table-3.

[Table 3] Reference Example 15 Synthesis of 3-((N-methylbenzamido) methyl) pyridine 1-oxide

Embedded image 6- (chloromethyl) pyridine hydrochloride (5.00 g, 3
0.5 mmol) in ethanol (35 ml) at 0-5 ° C. with stirring at 40% methylamine aqueous solution (28.4 g,
(366 mmol) was added dropwise over 1 hour and then refluxed for 3 hours, and the solvent was distilled off. 28% caustic soda solution (20m
l) and THF (50 ml) were added for extraction. After separation, the aqueous layer was repeatedly extracted with THF, and the organic layers were combined, dried over magnesium sulfate, and the solvent was distilled off to obtain 3- (methylaminomethyl) pyridine (3.60 g, yield 96.8%). . Then this pyridine (3.40 g, 27.8 mm
Ol) to a methylene chloride solution (55 ml), triethylamine (2.81 g, 27.8 mmol) was added, and a methylene chloride solution (10 ml) of benzoic acid chloride (3.91 g, 27.8 mmol) was added thereto at 0 ° C. under stirring. The mixture was added dropwise over 0.5 hour and stirring was continued for another hour. Then, the reaction solution was poured into water (50 ml), stirred for 1 hour, and then separated.
The aqueous layer was repeatedly extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, and the solvent was distilled off to give 3-((N
6.13 g (yield 97.5%) of white crystals of -methylbenzamido) methyl) pyridine were obtained. Next, this crystal (6.00 g, 26.5 mmol) and sodium tungstate (0.05 g) were dissolved in acetic acid (12.5 ml) and stirred at 90 to 100 ° C. for 30% hydrogen peroxide solution (3.6 g).
Was added dropwise over 1 hour. After refluxing for 1 hour, the mixture was cooled to room temperature and hypo was added until the iodine-starch reaction became negative. After distilling off the solvent, methylene chloride (50 ml) and 10% aqueous sodium hydroxide solution (30 ml) were added for extraction. After separation, the aqueous layer was repeatedly extracted and the organic layers were combined and dried over magnesium sulfate, and the solvent was distilled off to give 3-((N-methylbenzamide)).
Methyl) pyridine 1-oxide 6.21 g (yield 9
6.7%) was obtained. ¹ H-NMR (CDCl ₃ ): δ 8.3 to 8.2
(M, 2H), 7.4 to 7.2 (m, 7H), 4.69
(Brs, 2H), 2.98 (brs, 3H). Reference Example 16 3- (phthalimidomethyl) pyridine 1
-Synthesis of oxide

Embedded image 3-Pyridinemethanamine (45.0 g, 0.42mo
4.2 g of triethylamine and phthalic anhydride (61.6 g, 0.42 mo) in a toluene solution (700 ml) of 1).
l) was added and the mixture was azeotropically dehydrated for 3 hours with stirring, and the solvent was distilled off
85.0 g (yield 98.9%) of crystals of (phthalimidomethyl) pyridine were obtained. Next, the crystals were mixed with glacial acetic acid (240
ml) and refluxed with 30% hydrogen peroxide water (41 ml) for 3 hours. Then, the mixture was cooled to room temperature and hypo was added until the iodine-starch reaction became negative. This reaction solution was poured into water, extracted with chloroform and separated, and the aqueous layer was repeatedly extracted with chloroform. The organic layers are combined, dried over magnesium sulfate, and the solvent is distilled off to give 3- (phthalimidomethyl).
80.0 g of crystals of pyridine 1-oxide (yield 88
%). ¹ H-NMR (CDCl ₃ ): δ 8.27 (br, 1
H), 7.62 (dd, J = 7.92 and 2.4)
8 Hz, 1H), 7.28 (d, J = 7.92 H
z, 1H), 6.29 (brs, 1H), 4.40.
(D, J = 5.94 Hz, 2H), 2.03 (s, 3
H). Example 29 Synthesis of 3- (aminomethyl) -6-chloropyridine

Embedded image 3-Pyridinemethanamine (10.8g, 0.10mo
1) and an aqueous solution (50 ml) of caustic soda (5.2 g) and toluene (40 ml) were mixed with benzoic acid chloride (14.1 g, 0.10 mol) under stirring at 0-10 ° C.
The mixture was added dropwise over 1 hour, and stirring was continued for another hour. The precipitated crystals were separated by filtration and washed with cold water (20 ml). The obtained crystals [3- (benzamidomethyl) pyridine] and sodium tungstate (0.3 g) were suspended in water (30 ml),
30% at 95-100 ° C in this solution while adjusting to pH4
Hydrogen peroxide solution (14.7 g) was added dropwise over 1 hour. After refluxing for 5 hours, the mixture was cooled to room temperature and hypo was added until the iodine-starch reaction became negative. After adjusting the pH of this reaction solution to 9, the solvent (60 g) was distilled off and azeotropic dehydration was carried out while adding ethyl acetate. A solution of 3- (benzamidomethyl) pyridine 1-oxide thus obtained in ethyl acetate (2
Acetonitrile solution (100 ml) of trimethylamine (20.0 g) was added to (00 ml), and then phosgene (20.0 g) was bubbled in for 1 hour while stirring at -5 ° C. The reaction mixture was warmed to room temperature and stirred for a further 2 hours, then 23 ° C / 60 torr to 57 ° C / 55 torr.
And phosgene and acetonitrile were distilled off (distillate ~ 20
0 ml). The reaction mixture volume was adjusted to 300 ml with ethyl acetate, and then hydrogen chloride gas (22.4 g, 0.61 mol)
In an autoclave with stirring at 70-80 ° C for 2k
The reaction was carried out at gf / cm ² for 5 hours. After cooling to room temperature, the reaction mixture was poured into water for extraction and liquid separation, and the aqueous layer was repeatedly extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, and the solvent was distilled off to give 3- (benzamidomethyl) -6.
20.8 g of crystals of chloropyridine were obtained. The crystals were suspended in 500 ml of 9N hydrochloric acid and kept at 95 ° C. for 10 hours with stirring. The mixture was cooled to room temperature and extracted three times with 300 ml of chloroform to recover benzoic acid (85%). Chloroform (500 ml) was added to the aqueous layer to adjust the pH to 13, and the layers were separated. The aqueous layer was further extracted with chloroform. The chloroform layers were combined, dried over magnesium sulfate, and the solvent was distilled off to obtain 10.9 g (yield: 76%) of 3- (aminomethyl) -6-chloropyridine crystals. Example 30 Synthesis of 3- (aminomethyl) -6-chloropyridine

Embedded image 3-Pyridinemethanamine (10.8g, 0.10mo
l) was reacted in the same manner as in Example 29, and the volume of the reaction mixture solution after the phosgene was distilled off was adjusted to 400 ml with ethyl acetate. Hydrogen chloride gas (40 g, 1.1 m
was blown at 60 ° C. with stirring for reaction for 10 hours. After cooling to room temperature, the reaction mixture was poured into water for extraction and liquid separation, and the aqueous layer was repeatedly extracted with ethyl acetate. The organic layers are combined, dried over magnesium sulfate, and evaporated to remove the solvent.
Crystal of (benzamidomethyl) -6-chloropyridine 2
0.4 g was obtained. The crystals were suspended in 500 ml of 9N hydrochloric acid and kept at 95 ° C. for 10 hours with stirring. The mixture was cooled to room temperature and extracted three times with 300 ml of chloroform to recover benzoic acid (83%). 100ml of water layer at 50 ℃ / 20mmHg
Concentrated. Add 500 ml of chloroform to pH 1
After separating the mixture into 3, the aqueous layer was further extracted with chloroform repeatedly. The chloroform layers were combined, dried over magnesium sulfate, and the solvent was distilled off to give 3- (aminomethyl) -6.
10.4 g (yield 73%) of crystals of chloropyridine were obtained. Example 31 Synthesis of 3- (aminomethyl) -6-chloropyridine from 3- (pivaloylaminomethyl) pyridine 1-oxide

Embedded image 3- (pivaloylamino) pyridine 1-oxide (2
0.8g, 0.1mol) of chloroform solution (110
ml) to trimethylamine (15.9g, 0.27mo)
1) was added and phosgene (13.4 was added with stirring at -5 ° C).
g, 0.135 mol) was bubbled in over 30 minutes. Then, this reaction solution was transferred to an autoclave, hydrogen chloride gas (40.2 g, 1.1 mol) was introduced, and the mixture was stirred at 60 ° C.
After reacting at (5 kgf / cm ² ) for 5 hours, it was cooled to room temperature. The reaction solution was washed with water and the organic layer was further washed with water at pH 2, and then the organic layer was concentrated and dried to obtain crystals of 3- (bivaloylaminomethyl) -6-chloropyridine (Compound 13) (20. 8 g, yield 92%). This crystal is 9N
It was dissolved in hydrochloric acid (300 ml) and heated at 90 to 95% for 9 hours. Cool to room temperature, add 50% caustic soda solution,
The pH of the solution was 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, the solvent was distilled off, and 12.6 g (0.08) of crystals of 3- (aminomethyl) -6-chloropyridine were obtained.
8 mol) yield 88% was obtained. Example 32 Synthesis of 3- (aminomethyl) -6-chloropyridine from 3- (i-propoxycarbonylaminomethyl) pyridine 1-oxide

Embedded image 3- (i-Propoxycarbonylaminomethyl) pyridine 1-oxide (42.0 g, 0.2 mol) in chloroform solution (250 ml) was added with trimethylamine (2
9.6 g, 0.5 mol) was added, and phosgene (24.0 g, 0.24 mol) was bubbled in over 1 hour while stirring at -5 ° C. Then, the reaction solution was transferred to an autoclave, hydrogen chloride gas (67.0 g, 1.8 mol) was introduced, and the reaction was carried out at 50 ° C. (5 kgf / cm ² ) for 5 hours with stirring, and then cooled to room temperature. When the reaction solution was analyzed by HPLC, 36.6 g of 3- (i-propoxycarbonylaminomethyl) -6-chloropyridine (Compound 25) was obtained.
(80% yield) and 4.3 g (15% yield) of 3- (aminomethyl) -6-chloropyridine were included. 35% Hydrochloric acid (200 ml) was added to this reaction solution for extraction and liquid separation, and the obtained hydrochloric acid aqueous solution was heated at 90 to 95 ° C. for 3.5 hours. After cooling to room temperature, a 28% aqueous sodium hydroxide solution 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. When this solution was analyzed by HPLC, it contained 25.7 g (0.18 mol, yield 90%) of 3- (aminomethyl) -6-chloropyridine.

INDUSTRIAL APPLICABILITY The compound of the present invention represented by the general formula [I] can be converted into a compound represented by the general formula [IX] which is useful as an insecticide according to the following reaction formula.

Embedded image Further, according to the following reaction formula, the compound represented by the general formula [IX] can be synthesized by shortening the process without passing through the compound represented by the general formula [II]. The compounds described are very useful intermediates.

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Front Page Continuation (72) Inventor Kazuhiro Hatanaka 300 Mukaihoncho, Takaoka City, Toyama Prefecture Inside the Takaoka Factory of Nippon Soda Co., Ltd.

Claims (3)

[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, and R ² represents a hydrogen atom, a lower alkyl group or a carbonyl group bonded to this when R ¹ is an aryl group.) 3- (substituted aminomethyl)-
6-chloropyridine. 2. A compound represented by the general formula [III]: (In the formula, R ¹ and R ² have the same meanings as described above), the 3- (substituted aminomethyl) pyridine 1-oxide represented by the general formula [V] R ′ R ″ R ″ ′ N [V (Wherein R ′, R ″ and R ′ ″ are the same or different and represent a lower alkyl group or an aromatic group, or
R ″ R ″ ′ N together represents pyridine which may have a substituent) and at least 1
A compound of the general formula [I] characterized by reacting an electrophilic reagent having one chlorine atom and further reacting with hydrogen chloride. (In the formula, R ¹ and R ² have the same meanings as described above.) A method for producing 3- (substituted aminomethyl) -6-chloropyridine. 3. A compound represented by the general formula [I ′]: (In the formula, R ¹ has the same meaning as described above, and R ² 'represents a hydrogen atom or an alkyl group) and 3- (substituted aminomethyl) -6-chloropyridine represented by the following formula: General formula [II] characterized by processing (In the formula, R ² 'has the same meaning as described above)
A method for producing (aminomethyl) -6-chloropyridines.