JP2000212120A - Production of intermediate for agrochemical or medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially advantageously produce a compound useful as an intermediate for agrochemicals and medicines while suppressing the production of byproducts by brominating a specific compound with bromine by using a specified radical initiator in a mixed solvent of water with an organic solvent. SOLUTION: A compound of formula I A is a group of formulas II to IV [R1 and R2 are each a (substituted) alkyl, an allyl, a propagyl or an aralkyl]} is brominated with bromine in a mixed solvent of water with an organic solvent (preferably a halogenated hydrocarbon such as chlorobenzene) by using a radical initiator having the temperature of 10-hr half-life not higher than the boiling point of the bromine [e.g. 2,2-azobis(4-methoxy-2,4-dimethylvaleronitrile) and 2,2-azobis(2,4-dimethylvaleronitrile)], preferably of 1-3 mol (based on the reactant) to provide the objective compound of formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a compound represented by the general formula (II), which is useful as an agricultural chemical and a pharmaceutical intermediate.

[0002]

2. Description of the Related Art Several methods have been known for producing a compound represented by the general formula (II), for example, methyl 2- (2-bromomethylphenyl) -3-methoxyacrylate. EP-203606 describes a production method in which a compound corresponding to the general formula (I) is brominated with N-bromosuccinimide using azobisisobutyronitrile (hereinafter abbreviated as AIBN) as an initiator.

[0003] EP-278595 discloses that benzoyl peroxide (hereinafter abbreviated as BPO) is used as an initiator and N-
A process for brominating a compound corresponding to the general formula (I) with bromosuccinimide or with bromine using AIBN and a tungsten lamp is described. Also,
WO 94/05620 describes a non-aqueous production method in which a compound corresponding to the general formula (I) is brominated with bromine under irradiation with light using a deoxidizer polymer as a catalyst.

On the other hand, as radical initiators used for radical halogenation using bromine and the like, organic peroxides such as BPO and azo compounds such as AIBN have been known. Organic peroxides are generally unstable to impact, and the danger of fire and explosion is considered a problem.Azo compounds are relatively stable physically and chemically, and the reaction operation, In addition to safe handling during transportation and storage, it is easy to control because it is accurately decomposed in the primary reaction without self-induced decomposition as seen in general peroxides. .

[0005] Among azo compounds, particularly, compounds having excellent performance such as reaction selectivity have recently been developed. For example, JP-A-8-127562 discloses that 4'-methyl-2-cyanobiphenyl is converted to 2,2'-azobis (4-
It is described that when bromination is performed with bromine using methoxy-2,4-dimethylvaleronitrile) as an initiator, the reaction proceeds even at a relatively low temperature, and a monobromo compound can be selectively synthesized.

[0006]

However, in the above-mentioned production method, N-bromosuccinimide is very expensive and is not industrially preferable. In addition, when inexpensive bromine is used, an industrially unfavorable photoreaction or A
When a bromination reaction is performed using IBN or BPO as a radical initiator, the reaction temperature must be higher than the boiling point of bromine,
It was disadvantageous in terms of safety and bromination efficiency, and side reactions such as dibromide proceeded, and the yield tended to decrease.
Further, 2,2'-azobis (4-methoxy-), a radical initiator at which the reaction proceeds selectively at a relatively low temperature.
Even when 2,4-dimethylvaleronitrile) is used, since the reaction activity is high, hydrogen bromide generated as the reaction proceeds causes a side reaction to be added to the double bond of acrylic acid. There was a problem that the rate decreased.

Accordingly, the present invention provides a method for industrially producing a compound represented by the general formula (II), which is a useful intermediate of agricultural chemicals or pharmaceuticals, safely and efficiently using bromine as an inexpensive raw material. The purpose is to provide.

[0008]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, as a radical initiator, a 10-hour half-life temperature at which radical decomposition occurs at a lower temperature than that of AIBN or the like is caused by the temperature of bromine. A method for producing a 2-bromomethyl compound inexpensively, easily controlled, and safely and efficiently by using a radical initiator having a boiling point or lower and further halogenating the benzyl position using bromine in a mixed solvent of an organic solvent and water. And completed the present invention.

That is, the present invention provides a compound represented by the general formula (I):

Embedded image [Where A is the following formula

Embedded image (Wherein R ₁ and R ₂ may be the same or different and represent an optionally substituted alkyl group, allyl group, propargyl group or aralkyl group). Represents a group of species. A compound represented by the general formula (II), characterized in that the compound represented by the formula (II) is brominated with bromine in a mixed solvent of water and an organic solvent using a radical initiator having a 10-hour half-life temperature not higher than the boiling point of bromine.

Embedded image (Wherein, A, R ₁ and R ₂ represent the same groups as described above).

The radical initiator is 2,2'-azobis (4-methoxy-2,4-dimethylvaleronitrile)
And 2,2′-azobis (2,4-dimethylvaleronitrile), and a method for producing a compound represented by the general formula (II), which is at least one member selected from the group consisting of:

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION In the substituent A of the compound represented by the formula (I), R ₁ and R ₂ may be the same or different, and may be an optionally substituted alkyl group, allyl group or propargyl group. Alternatively, it represents an aralkyl group.
Specific examples include a methyl group, an ethyl group, an isopropyl group, an allyl group, a propargyl group, a methoxymethyl group, a chloroethyl group, a benzyl group, and a p-chlorobenzyl group.

The organic solvent used in this reaction is not limited as long as it does not participate in the radical reaction. In particular, a solvent that is immiscible with water is preferable, and specific examples thereof include aromatic hydrocarbons such as benzene and toluene; Aliphatic hydrocarbons such as octane, or chlorobenzene, halogenated hydrocarbon compounds such as chlorophorom and the like can be exemplified,
Halogenated hydrocarbons are particularly preferred. Water is preferably used in an amount of 10 to 50% by volume, particularly 20 to 40% by volume, based on the organic solvent.

As the radical initiator used in the present reaction, a radical initiator having a 10-hour half-life temperature equal to or lower than the boiling point of bromine is used. This means an initiator capable of efficiently decomposing below the boiling point of bromine to generate a radical species, and specifically, 2,2′-azobis (4-methoxy-
2,4-dimethylvaleronitrile) or 2,2′-
Azobis (2,4-dimethylvaleronitrile) can be exemplified. These initiators can be used alone or in an appropriate mixture. Further, it can be used in an amount of 0.1 to 10 mol%, preferably 1 to 3 mol%, based on the reaction substrate.

In the reaction of the present invention, for example, the compound represented by the general formula (I) is dissolved in an organic solvent, and water is further added.
After heating to near the reaction temperature, add a radical initiator,
It is performed by a method of dropping bromine or a solution in which bromine and a radical initiator are well mixed. The reaction temperature may be any temperature that is not higher than the boiling point of bromine and is not lower than the temperature at which the radical initiator exhibits a 10-hour half-life, and is particularly preferably a temperature obtained by adding 10 to 40 ° C to the 10-hour half-life temperature. It is preferable to use 1 to 1.5 equivalents, particularly 1 to 1.3 equivalents, of bromine with respect to the reaction substrate.

The reaction can be carried out while controlling the pH of hydrogen bromide generated during the reaction with an aqueous alkali solution.
Examples of the alkali used include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate. Can be used, but an alkali metal hydroxide is particularly preferred. Further, the pH is in the range of 0 to 8, particularly pH 0.
It is preferable to carry out in the range of ~ 3.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.

[0017]

EXAMPLE 1 40 ml of water was added to 131.12 g of a chlorobenzene solution of 15.7% by weight of methyl 2- (2-methylphenyl) -3-methoxyacrylate at room temperature, and the mixture was heated with good stirring. . When the internal temperature reaches 50 ° C., the radical initiator 2,2 ′
After adding 0.31 g of -azobis (4-methoxy-2,4-dimethylvaleronitrile), the temperature was raised to 55 ° C,
A solution prepared by dissolving 19.98 g of bromine and 0.62 g of 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile) in 40 ml of chlorobenzene was heated to an internal temperature of 55-5.
While maintaining the temperature at 8 ° C., the mixture was dropped continuously appropriately. This drop took 75 minutes. After stirring and aging at this temperature for 30 minutes, the mixture was cooled to 25 ° C and separated. The separated organic layer was washed with 40 ml of 5% by weight aqueous sodium bicarbonate and 40 ml of water, separated, and then dried over magnesium sulfate. The magnesium sulfate was separated by filtration, and the insoluble material was thoroughly washed with 20 ml of chlorobenzene to obtain 191.57 g of 2- (2-bromomethylphenyl)-.
A chlorobenzene solution of methyl 3-methoxyacrylate was obtained. As a result of quantitative analysis of this solution by high performance liquid chromatography, it was found that methyl 2- (2-bromomethylphenyl) -3-methoxyacrylate contained 11.80% by weight.
(79.3% yield)

Example 2 To 131.11 g of a chlorobenzene solution of 15.7% by weight of methyl 2- (2-methylphenyl) -3-methoxyacrylate was added 40 ml of water at room temperature, followed by heating with good stirring. When the internal temperature reaches 50 ° C., the radical initiator 2,2 ′
After adding 0.31 g of -azobis (4-methoxy-2,4-dimethylvaleronitrile), the temperature was raised to 55 ° C,
A solution obtained by dissolving 19.98 g of bromine and 0.62 g of 2,2'-azobis (4-methoxy-2,4-dimethylvaleronitrile) in 30 ml of chlorobenzene and a 25% aqueous sodium hydroxide solution were heated to an internal temperature of 55 to 56 ° C. And pH 2-3
While maintaining the above conditions. This drop took 66 minutes. After stirring and aging at 55 ° C. for 30 minutes, the mixture was cooled and separated. The separated organic layer was washed with 40 ml of 5% by weight aqueous sodium bicarbonate and 40 ml of water, separated, and then dried over magnesium sulfate. The magnesium sulfate was filtered off and 192.87 g of
A chlorobenzene solution of methyl 2- (2-bromomethylphenyl) -3-methoxyacrylate was obtained. As a result of quantitative analysis of this solution by high performance liquid chromatography, methyl 2- (2-bromomethylphenyl) -3-methoxyacrylate was 1
The content was 0.63% by weight. (Yield 71.9%)

EXAMPLE 3 131.11 g of a 15.7% by weight solution of methyl 2- (2-methylphenyl) -3-methoxyacrylate in chlorobenzene
After adding 10 ml of water at room temperature, the mixture was heated with good stirring. When the internal temperature reaches 50 ° C., the radical initiator 2,
After adding 0.31 g of 2′-azobis (4-methoxy-2,4-dimethylvaleronitrile), the temperature was raised to 55 ° C., and 19.98 g of bromine and 2,2′-azobis (4-methoxy-2) were added. , 4-dimethylvaleronitrile) in a solution of 0.62 g in 30 ml of chlorobenzene and 8.33%
The internal temperature of the aqueous sodium hydroxide solution is adjusted to 55-59 ° C.
While keeping the H5 to 8, it was dropped simultaneously. 6 for this dripping
It took five minutes. After stirring and aging at 55 to 57 ° C for 30 minutes, the mixture was cooled and separated. The separated organic layer was washed with 40 ml of 5% by weight aqueous sodium bicarbonate and 40 ml of water, separated, and then dried over magnesium sulfate. The magnesium sulfate was filtered off, and 19
1.83 g of a chlorobenzene solution of methyl 2- (2-bromomethylphenyl) -3-methoxyacrylate was obtained. As a result of quantitative analysis of this solution by high performance liquid chromatography, methyl 2- (2-bromomethylphenyl) -3-methoxyacrylate was contained at 9.06% by weight. (Yield 60.
(1%)

Example 5 To 131.35 g of a chlorobenzene solution of 15.7% by weight of methyl 2- (2-methylphenyl) -3-methoxyacrylate was added 40 ml of water at room temperature, and then a radical initiator 2,2 'was obtained.
0.93 g of -azobis (4-methoxy-2,4-dimethylvaleronitrile) was added, and the mixture was heated with good stirring. When the internal temperature reaches 55 ° C., a solution obtained by mixing 19.98 g of bromine in 40 ml of chlorobenzene is heated to 55 to 5 ° C.
While maintaining the temperature at 7 ° C., the mixture was dropped continuously. This dripping required 60 minutes. After stirring and aging at this temperature for 30 minutes, the mixture was cooled to 25 ° C and separated. The separated organic layer was washed with 40 ml of 5% by weight sodium bicarbonate water and 40 ml of water, separated, and then dehydrated with magnesium sulfate. The magnesium sulfate was filtered off, washed with 20 ml of chlorobenzene,
A solution of 1.03 g of methyl 2- (2-bromomethylphenyl) -3-methoxyacrylate in chlorobenzene was obtained. As a result of quantitative analysis of this solution by high performance liquid chromatography, it was found that methyl 2- (2-bromomethylphenyl) -3-methoxyacrylate contained 9.76% by weight. (Yield 68.
8%)

Comparative Example 1 80 ml of water was added to 262.0 g of a chlorobenzene solution of 18.06% by weight of methyl 2- (2-methylphenyl) -3-methoxyacrylate at room temperature, and 0.33 g of AIBN was added. Heat with good stirring. When the internal temperature reached 85 ° C., a solution in which 40.0 g of bromine was mixed with 100 ml of chlorobenzene was added dropwise over 9 minutes. At this time, the internal temperature is 9
The temperature rose to 8.5 ° C. and began to reflux. After stirring and aging under reflux for 30 minutes, the mixture was cooled to 30 ° C. and separated. The separated organic layer was washed with 40 ml of water, separated, and then dried over magnesium sulfate. The magnesium sulfate was filtered off and 41
A chlorobenzene solution of 7.10 g of methyl 2- (2-bromomethylphenyl) -3-methoxyacrylate was obtained. As a result of quantitative analysis of this solution by high performance liquid chromatography, it was found that methyl 2- (2-bromomethylphenyl) -3-methoxyacrylate contained 8.89% by weight. (Yield 65.0%)

COMPARATIVE EXAMPLE 2 131.35 g of a 15.7 wt% methyl 2- (2-methylphenyl) -3-methoxyacrylate solution in chlorobenzene was heated with good stirring, the internal temperature was 50 ° C., and the radical initiator was heated. After adding 0.31 g of 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile), the internal temperature was reduced to 5%.
When the temperature reaches 5 ° C., 19.98 g of bromine and 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile)
A solution prepared by mixing 0.62 g in 40 ml of chlorobenzene was added dropwise appropriately continuously while maintaining the internal temperature at 55 to 56 ° C. This dripping required 65 minutes. After stirring and aging at this temperature for 30 minutes, the mixture was cooled to 25 ° C., and 40 ml of water was added to separate the layers. The separated organic layer was treated with 5% by weight aqueous sodium bicarbonate 40.
The mixture was washed with 40 ml of water and 40 ml of water, separated, and then dehydrated with magnesium sulfate. The magnesium sulfate was separated by filtration and washed with 20 ml of chlorobenzene to obtain 203.36 g of a chlorobenzene solution of methyl 2- (2-bromomethylphenyl) -3-methoxyacrylate. As a result of quantitative analysis of this solution by high performance liquid chromatography, 2- (2-bromomethylphenyl) -3-
The content of methyl methoxyacrylate was 0.48% by weight. (3.4% yield)

[0023]

As described above, according to the production method of the present invention, the general formula (I) useful as an intermediate for agricultural chemicals and pharmaceuticals
The compound represented by I) can be industrially efficiently produced by suppressing by-products.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification FI FI Theme Court 参考 (Reference) C07C 271/28 C07C 271/28 (72) Inventor Yutaka Ishii 950 Nakazawa-mura, Nakago-mura, Niigata Prefecture Nippon Soda Nihonso (72) Inventor Yukiyuki Iiyoshi Yukiyuki Iiyoshi Nakazawa-mura, Niigata Pref. 950

Claims (2)

[Claims] 1. A compound of the general formula (I) [Wherein A is the following formula: (Wherein R ₁ and R ₂ may be the same or different and represent an optionally substituted alkyl group, allyl group, propargyl group or aralkyl group). Represents a group of species. A compound represented by the general formula (II), characterized in that the compound represented by the formula (II) is brominated with bromine in a mixed solvent of water and an organic solvent using a radical initiator having a 10-hour half-life temperature not higher than the boiling point of bromine. Embedded image (Wherein, A, R ₁ and R ₂ represent the same groups as described above). 2. The method according to claim 1, wherein the radical initiator is 2,2'-azobis (4
-Methoxy-2,4-dimethylvaleronitrile) and at least one selected from the group consisting of 2,2'-azobis (2,4-dimethylvaleronitrile). A method for producing a compound represented by the formula (II).