JPH11189580A - Production of benzyl bromide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain in an industrially advantageous way the subject high-purity compound useful as an intermediate for manufacturing compounds having plant disease injury control efficacy by reacting a specified methylphenylacetic acid derivative with bromine in the presence of an alkali metal salt and recrystallizing the resultant reaction product in an aliphatic hydrocarbon solution. SOLUTION: This compound of formula II is obtained by reacting (A) a methylphenylacetic acid derivative of formula I (R1 is ethyl or isopropyl) [e.g. (E)-α-methoxyimino-o-tolylacetic acid ethyl ester], (B) preferably in the presence of an alkali metal salt such as carbonate (e.g. sodium carbonate) with (C) bromine preferably at rates of 1.5-5.0 mol component B and 0.9-1.2 mol component C per mol component A, preferably at 80-95 deg.C and usually for 0.5-10 h and recrystallizing the resultant reaction product preferably in (D) an aliphatic hydrocarbon solution such as n-hexane preferably using 4-6 g component D per g component A.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a benzyl bromide derivative.

[0002]

2. Description of the Related Art General formula 3

Embedded image [Wherein, R ₂ and R ₃ are the same or different and are each a hydrogen atom, a C1-C6 alkyl group, a halogen atom, a C1-C6
An alkoxy group, a C1-C6 haloalkyl group or a C1-
Represents a C6 haloalkoxy group, or R ₂ and R ₃
And represents a methylenedioxy group which may be substituted by a fluorine atom. Z represents a CH group or a nitrogen atom. That the dithiocarbonimide derivative represented by the formula (1) has an excellent plant disease controlling effect, is described in JP-A-8-73424.

Embedded image A process for producing the dithiocarbonimide derivative using a benzyl bromide derivative represented by the following formula as an intermediate is disclosed. JP-A-63-30463, JP-A-03-246268
No. 5 in the official gazette

Embedded image A method for producing a benzyl bromide derivative represented by the formula 4 by reacting a 2-methylphenylacetic acid derivative represented by the formula with N-bromosuccinimide (NBS) is described, and JP-A-03-52871 describes the method. A method is described in which a 2-methylphenylacetic acid derivative shown below is reacted with bromine under irradiation of a mercury lamp to produce a benzyl bromide derivative represented by the formula (4). However, the bromination reaction using NBS is not industrially practical, and the reaction with bromine under irradiation of a mercury lamp requires an industrial-scale photoreaction equipment. It is desired to develop an industrially advantageous production method for producing a benzyl bromide derivative.

[0003]

Means for Solving the Problems In view of the above situation, the present inventors have conducted intensive studies on a method for producing a benzyl bromide derivative from a 2-methylphenylacetic acid derivative. As a result, 2-methylphenyl represented by the following general formula 6 is obtained. After reacting the acetic acid derivative with bromine in the presence of an alkali metal salt,
By recrystallizing the reaction product in an aliphatic hydrocarbon solution, it has been found that the benzyl bromide derivative represented by the general formula 7 can be obtained efficiently and with high purity, and the present invention has been accomplished. That is, the present invention provides a compound represented by the general formula:

Embedded image [In the formula, R ₁ represents an ethyl group or an isopropyl group. Is reacted with bromine in the presence of an alkali metal salt, and then the reaction product is recrystallized in an aliphatic hydrocarbon solution.

Embedded image [Wherein, R ₁ represents the same meaning as described above. And a method for producing the benzyl bromide derivative represented by the formula:

[0004]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. Examples of the alkali metal salt used in the production method of the present invention include sodium carbonate, magnesium carbonate, potassium carbonate, calcium carbonate, sodium hydrogencarbonate, carbonates such as potassium hydrogencarbonate, sodium phosphate, and the like.
Phosphates such as potassium phosphate, and sodium acetate,
Carboxylates such as potassium acetate are mentioned, and it is preferable to use sodium salts. The reaction is usually performed in an inert solvent, and examples of the solvent include halogenated aromatic hydrocarbon solvents such as chlorobenzene and dichlorobenzene, and halogenated aliphatic hydrocarbon solvents such as chloroform and dichloroethane. The reaction temperature is usually in the range of 50 to 110 ° C, preferably in the range of 75 to 100 ° C, more preferably in the range of 80 to 95 ° C. The reaction time is usually 0.5 to 10 hours. The amount of the reagent to be subjected to the reaction is preferably 1.5 to 1.5 mol per mol of the 2-methylphenylacetic acid derivative represented by the general formula (6).
5.0 moles and the amount of bromine is 0.7-1.5 moles, preferably 0.9-1.2 moles. Further, from the reaction product, 2-
When the methylphenylacetic acid derivative is recovered and reused, the amount of bromine should be 0.4 to 0.8 mol per 1 mol of the 2-methylphenylacetic acid derivative represented by the general formula (6). Is desirable. Bromine can be used as it is or after dilution with a solvent, but it is preferable to react the bromine by heating and vaporizing it. As the alkali metal salt, it is possible to use a commercially available product as it is,
It is preferable to use the alkali metal salt by grinding it immediately before the reaction. Although the reaction proceeds without the addition of a radical initiator, it is preferable to perform the reaction by adding a radical initiator.
Examples of such a radical initiator include benzoyl peroxide, azobis isobutyronitrile, and azobis (cyclohexanecarbonitrile). The amount of the radical initiator to be subjected to the reaction is 0.005 to 1 mol of the 2-methylphenylacetic acid derivative represented by the general formula (6).
The ratio is 0.2 mol, preferably 0.01 to 0.1 mol. After completion of the reaction, the reaction solution is obtained by filtering off the alkali metal salt, washing the organic layer with water or dilute hydrochloric acid water, concentrating the organic layer, adding an aliphatic hydrocarbon to the residue, and recrystallizing the residue. And a high-purity target product can be obtained.
As the solvent used for recrystallization, normal hexane, normal heptane, normal octane, cyclohexane,
Examples thereof include aliphatic hydrocarbons such as cyclooctane, petroleum ether and mixtures thereof, and one or more selected from C5 to C12 saturated aliphatic hydrocarbons are preferable. From the viewpoint of industrial production, normal One or more selected from the group consisting of hexane, normal heptane and normal octane is more preferred. The amount of the solvent used for the recrystallization is 1 to 20 g, preferably 4 to 6 g, based on 1 g of the 2-methylphenylacetic acid derivative represented by the general formula 6 used in the reaction. The heating temperature at the time of recrystallization is in the range of 40 ° C. to the boiling point of the solvent used, preferably in the range of 50 ° C. to 90 ° C. The cooling temperature at the time of performing recrystallization is in the range of -20 ° C to 20 ° C, preferably -5 ° C to 10 ° C.
° C, and the cooling rate is 0.01 ° C / min to 1.0 ° C.
/ Min, preferably in the range of 0.1 ° C / min to 0.6 ° C / min.

[0005] The 2-methylphenylacetic acid derivative represented by the general formula (6) is, for example, represented by the following scheme:

Embedded image [Wherein, R ₁ has the same meaning as described above. ]. In the formula, 2-methylbenzoyl formate is, for example, Tetrahedron Lett
ers Vol. 21 (1980), p. 3539, S
yynetic CommunicationVo
l. 11 (1981), page 943, and the like.

[0006]

EXAMPLES The present invention will be described in more detail with reference to production examples, but the present invention is not limited to these examples.

Production Example 1 6.36 g of sodium carbonate pulverized by a centrifugal pulverizer (60
mmol), 5.53 g (25 mmol) of ethyl (E) -α-methoxyimino-O-tolylacetate and 15.00 g of chlorobenzene were heated to 85 ° C. with vigorous stirring. To this mixture was added a solution of 0.61 g of azobis (cyclohexanecarbonitrile) in 6.00 g of chlorobenzene and 4.80 g (30 mmol) of bromine in 2.0 ml of chlorobenzene.
0 g solution was co-injected and dropped over 1 hour. After completion of the dropwise addition, the reaction solution was kept at 86 to 88 ° C. for 2 hours, and then cooled to room temperature. 50 ml of water was added to the reaction solution, and the mixture was separated. The organic layer was washed twice with 25 ml of water, and the solvent was distilled off under reduced pressure to obtain 6.77 g of a crude product. The crude product was analyzed using a gas chromatography analyzer (GC), and as a result, the target product (E) -α-methoxyimino-2-
The content of ethyl (bromomethyl) phenylacetate is 75.
4%, the starting material and (E) -α-methoxyimino-
The contents of ethyl 2- (dibromomethyl) phenylacetate [hereinafter abbreviated as dibromide] were 4.5% and 13.7% (% indicates an area percentage). The crude product 6.04
25.00 g of normal hexane is added to the resulting mixture at 73 to 75 ° C.
To obtain a uniform solution. This solution was cooled to 3 to 5 ° C. over 3.5 hours, kept at the same temperature for 1 hour, and aged. The precipitated crystals were collected by suction filtration, washed twice with 12.00 g of cold normal hexane, and dried to obtain 3.87 g of ethyl (E) -α-methoxyimino-2- (bromomethyl) phenylacetate. The purified product was also analyzed by GC. As a result, the content of the target product was 95.8%, and the contents of the raw material and dibromide were 0.6% and 2.3%, respectively. Melting point 80.0-81.0 ° C 1H-NMR (CDCl3 / TMS, 300MHz, δ (ppm)) 1.33 (3H, t, J = 7Hz),
4.05 (3H, s), 4.34 (2H, s), 4.35 (2H, q, J = 7Hz), 7.15 (1H,
(dd, J = 8,1Hz), 7.20-7.40 (3H, m)

Production Example 2 6.36 g of sodium carbonate pulverized by a centrifugal pulverizer (60
mmol), 5.88 g (25 mmol) of (E) -α-methoxyimino-o-tolyl acetate isopropyl, and 15.00 g of chlorobenzene were stirred vigorously for 85 minutes.
Heated to ° C. To the mixture was added 0.61 g of azobis (cyclohexanecarbonitrile) and 6.00 g of chlorobenzene.
While dripping the solution, the mixture was heated at 90 to 100 ° C., and 4.80 g (30 mmol) of vaporized gaseous bromine was blown in with a nitrogen stream for 1 hour. After the completion of blowing, add 8
The temperature was kept at 6 to 88 ° C for 2 hours, and then cooled to room temperature. 50 ml of water was added to the reaction solution, and the mixture was separated.
After washing twice with ml, the solvent was distilled off under reduced pressure to obtain 7.13 g of a crude product. The crude product was analyzed by GC, and as a result, the desired product (E) -α-methoxyimino-2 was obtained.
The content of isopropyl- (bromomethyl) phenylacetate was 76.3%, and the content of the raw material and dibromide was 4.8% and 13.5%, and the crude product was 6.53.
25.00 g of normal hexane is added to the resulting mixture at 73 to 75 ° C.
To obtain a uniform solution. This solution was cooled to 3 to 5 ° C. over 3.5 hours, kept at the same temperature for 1 hour, and aged. The precipitated crystals were collected by suction filtration, washed twice with 10.00 g of cold normal hexane, and dried to obtain 4.00 g of (E) -α-methoxyimino-2- (bromomethyl) phenylacetate isopropyl. The purified product was also analyzed by GC. As a result, the content of the target product was 96.4%, and the contents of the raw material and the dibromo compound were 0.9% and 3.2, respectively.
%Met. Melting point 76.0-77.0 ° C 1H-NMR (CDCl3 / TMS, 300MHz, δ (ppm)) 1.30 (6H, d, J = 5Hz),
4.04 (3H, s), 4.34 (2H, s), 5.18 (1H, sept, J = 5Hz), 7.14
(1H, m), 7.15 to 7.35 (3H, m)

Comparative Example 1 12.72 g of sodium carbonate (1
20 mmol), 10.36 g (50 mmol) of methyl (E) -α-methoxyimino-o-tolylacetate, and 29.94 g of chlorobenzene were mixed with vigorous stirring for 85 minutes.
Heated to ° C. 9.59 g (60 mmol) of gaseous bromine heated and vaporized to 90 to 100 ° C. was blown into the mixture over 1 hour in a nitrogen stream. After the completion of blowing, add 8
The mixture was kept at 6-88 ° C for 2 hours, and then cooled to room temperature. 100 ml of water was added to the reaction solution, and the mixture was separated.
After washing twice with 0 ml, the solvent was distilled off under reduced pressure to obtain 13.21 g of a crude product. As a result of analysis by GC, the content of methyl (E) -α-methoxyimino-2- (bromomethyl) phenylacetate as the target substance was 79.5%,
The content of the raw material and dibromide is 5.1% and 13.
7%. (% Indicates area percentage) 25.00 g of normal hexane was added to 6.00 g of the crude product.
And heated to 73 to 75 ° C. to form a uniform solution. The solution was cooled to 3-5 ° C. over 3.5 hours and
Incubation for a period of time, aging, and purification by recrystallization was attempted.
No crystals of (E) -α-methoxyimino-2- (bromomethyl) phenylacetate were precipitated.

Next, a production example of a 2-methylphenylacetic acid derivative represented by the general formula (6) will be described. Reference Production Example 1 (1) 19.2 g of ethyl 2-methylbenzoylformate
To a solution of (0.1 mol) in 100 ml of ethanol was added 7.6 g (0.11 mol) of hydroxylamine hydrochloride, and the mixture was refluxed for 5 hours. Then, as a post-processing operation,
The solvent was distilled off under reduced pressure to obtain a solid. Hexane was added to this solid, and the solid was crushed and collected by filtration to obtain 14.1 g (yield: 68%) of ethyl (E) -α-hydroxyimino-O-tolylacetate. Further, the filtrate was concentrated, ethanol and a catalytic amount of thionyl chloride were added to the residue, and the mixture was heated under reflux for 5 hours, and the same post-treatment operation as described above was carried out. I got something. Melting point 88.0
-89.0 ° C 1H-NMR (CDCl3 / TMS, 300 MHz, δ (ppm)) 1.25 (3H, t, J = 8 Hz),
2.21 (3H, s), 4.28 (2H, q, J = 8Hz), 7.15 (1H, dd, J = 8,1H
z), 7.20 to 7.40 (3H, m), 10.25 (1H, brs) In the same manner, using a solution of 20.6 g (0.1 mol) of isopropyl 2-methylbenzoylformate in isopropanol, (E) -α-hydroxy 14.9 g (yield 68%) of isopropyl imino-O-tolyl acetate was obtained. Melting point 7
7.0-78.0 ° C 1H-NMR (CDCl3 / TMS, 300MHz, δ (ppm)) 1.27 (6H, d, J = 6Hz),
2.23 (3H, s), 5.16 (1H, sept, J = 6Hz), 7.15 (1H, dd, J = 8,1H
z), 7.2 to 7.4 (3H, m), 9.78 (1H, brs) (2) A solution of 10.0 g (48 mmol) of ethyl (E) -α-hydroxyimino-O-tolylacetate in 50 ml of THF under ice-cooling was added with 60 ml % Sodium hydride 2.2 g (53 mm
ol) and stirred for 30 minutes. 6.7 g (53 mmol) of dimethylsulfuric acid was added dropwise to this solution, followed by stirring at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution, and the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated.
(E) -α-methoxyimino-O-tolyl ethyl acetate 1
0.4 g (98% yield) was obtained. 1H-NMR (CDCl3 / TMS, 300MHz, δ (ppm)) 1.33 (3H, t, J = 8Hz),
2.19 (3H, s), 4.04 (3H, s), 4.33 (2H, q, J = 8Hz), 7.12 (1H,
(dd, J = 8.1 Hz), 7.15 to 7.40 (3H, m) By the same operation, from 10.0 g (46 mmol) of (E) -α-hydroxyimino-O-tolyl isopropyl acetate
10.1 g (75% yield) of (E) -α-methoxyimino-O-tolyl isopropyl acetate was obtained. 1H-NMR (CDCl3 / TMS, 300 MHz, δ (ppm)) 1.28 (6H, d, J = 6 Hz),
2.19 (3H, s), 4.02 (3H, s), 5.17 (1H, sept, J = 6Hz), 7.0
9 (1H, dd, J = 8,1Hz), 7.15 to 7.35 (3H, m) Next, ethyl (E) -α-methoxyimino-2- (bromomethyl) phenylacetate or (E) -α-methoxyimino An example of the production of a dithiocarbonimide derivative described in JP-A-8-73424 using isopropyl 2- (bromomethyl) phenylacetate is shown.

Reference Production Example 2 (1) 6.0 g of ethyl (E) -α-methoxyimino-2- (bromomethyl) phenylacetate (content: 95.8%;
19 mmol), a mixture of 4.05 g (19 mmol) of methyl 4-ethylphenyldithiocarbamate, 0.33 g (1 mmol) of tetra-n-butylammonium bromide and 20 ml of toluene was vigorously stirred. 2.50ml (20mmo
l) was added dropwise at an internal temperature of 10 ° C or lower. After completion of the dropwise addition, the reaction solution was further stirred at 20 ° C. for 2 hours. Water 20
Then, anhydrous magnesium sulfate was added to the organic layer, followed by drying. After filtration of the anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain an oil. A small amount of ethanol was added to the oil, and the mixture was solidified under ice-cooling. The obtained solid was crushed and collected by filtration to give S- [2-((E) -α-methoxyimino-α-ethoxycarbonyl) methyl. 6.63 g (81% yield) of phenylmethyl-S-methyl-N- (4-ethylphenyl) dithiocarbonimide was obtained. Melting point 69.0-70.0 ° C 1H-NMR (CDCl3 / TMS, 300MHz, δ (ppm)) 1.21 (3H, t, J = 6Hz),
1.28 (3H, t, J = 6Hz), 2.42 (3H, s), 2.61 (2H, q, J = 6Hz), 4.
02 (3H, s), 4.21 (2H, s), 4.25 (2H, q, J = 6Hz), 6.78 (2H, d,
J = 8 Hz), 7.0 to 7.6 (6H, m) (2) S- [2-((E) -α-methoxyimino-α-ethoxycarbonyl) methyl] phenylmethyl-S- obtained in the above (1). 5.0 g (12 mmol) of methyl-N- (4-ethylphenyl) dithiocarboximide was diluted with 25 ml of ethanol, and 4.6% aqueous solution of methylamine 4.6.
5 g (60 mmol) was added, and the mixture was stirred at room temperature for 7 hours.
After completion of the reaction, water was added, methylamine and ethanol were distilled off under reduced pressure, toluene was added to the residue, and liquid separation was performed. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a solid. Diisopropyl ether was added to this solid, and the solid was crushed and collected by filtration.
-[(E) -α-methoxyimino-α- (N-methylcarbamoyl)] methyl} phenylmethyl-S-methyl-
N- (4-ethylphenyl) dithiocarbonimide 4.
58 g (92% yield) were obtained.

Reference Production Example 3 (1) 5.0 g of isopropyl (E) -α-methoxyimino-2- (bromomethyl) phenylacetate (content: 96.0%)
4%, 15 mmol), methyl 4-ethylphenyldithiocarbamate 3.25 g (15 mmol), anhydrous potassium carbonate 4.20 g (30 mmol), 2-propanol 2
5 ml of the mixture was stirred at 50 ° C. for 4 hours. The insolubles were filtered through celite, washed with 2-propanol, and the filtrate was concentrated under reduced pressure to obtain an oil. Toluene and water were added to the oily material, and the mixture was separated. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. After the anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off under reduced pressure to obtain an oil. Ethanol was added to this oil, and the mixture was solidified by cooling with ice water.
The obtained solid is crushed and collected by filtration to give S- [2-((E)
-Α-methoxyimino-α-isopropyloxycarbonyl) methyl] phenylmethyl-S-methyl-N- (4
5.53 g of -ethylphenyl) dithiocarbonimide
(87% yield). Melting point 85.0-86.0 ° C.1H-NMR (CDCl3 / TMS, 300 MHz, δ (ppm)) 1.21 (3H, t, J = 6 Hz),
1.25 (6H, d, J = 6Hz), 2.42 (3H, s), 2.61 (2H, q, J = 6Hz), 4.
02 (3H, s), 4.22 (2H, s), 5.12 (1H, sept, J = 6Hz), 6.79 (2H
(H, d, J = 8 Hz), 7.0 to 7.6 (6H, m) (2) S- [2-((E) -α-methoxyimino-α-isopropyloxycarbonyl) methyl] obtained in the above (1) Phenylmethyl-S-methyl-N- (4-ethylphenyl) dithiocarbonimide 5.0 g (11 mmol)
l) with 20 ml of ethanol and 5 ml of chlorobenzene
, And 4.26 g of a 40% aqueous methylamine solution (55
mmol) and stirred at room temperature overnight. After the reaction,
Water was added, methylamine and the solvent were distilled off under reduced pressure, toluene was added to the residue, and the mixture was separated. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain an oil. This oily substance was separated and purified by silica gel column chromatography, and 1.40 g of raw material (yield 28)
%) And S- {2-[(E) -α-methoxyimino-α-
(N-methylcarbamoyl)] 2.96 g (yield 65%) of methyl @ phenylmethyl-S-methyl-N- (4-ethylphenyl) dithiocarboximide was obtained.

[0013]

According to the method of the present invention, the benzyl bromide derivative represented by the general formula (7) can be produced industrially advantageously and with high purity.

Claims (4)

[Claims] 1. A compound represented by the general formula: [In the formula, R ₁ represents an ethyl group or an isopropyl group. A) reacting the 2-methylphenylacetic acid derivative with bromine in the presence of an alkali metal salt, and recrystallizing the reaction product in an aliphatic hydrocarbon solution. [Wherein, R ₁ represents the same meaning as described above. ] The method for producing a benzyl bromide derivative represented by the formula: 2. The method according to claim 1, wherein the alkali metal salt is a carbonate, phosphate or carboxylate. 3. The method according to claim 1, wherein the aliphatic hydrocarbon is at least one selected from C5 to C12 saturated aliphatic hydrocarbons. 4. The process according to claim 1, wherein the aliphatic hydrocarbon is at least one selected from the group consisting of normal hexane, normal heptane and normal octane.