JP2009286717A - Method for producing benzoxazinone compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a benzoxazinone compound. <P>SOLUTION: The method for producing a benzoxazinone compound represented by formula (4) (wherein R<SP>1</SP>and R<SP>2</SP>are each hydrogen, a hydroxy group, a 1-3C alkyl group, a 1-3C alkoxy group, a 1-3C acyl group, a 1-3C acyloxy group, a 1-3C alkoxycarbonyl group, a halogen, a nitro group or a carboxy group, and X is a halogen) comprises reacting an anthranilic acid derivative with an aromatic dicarboxylic acid dihalogenide in an inert gas stream in an organic solvent to produce an amide compound and thereafter reacting the amide compound with a dehydrating agent. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a bisbenzoxazinone compound.

Bisbenzoxazinone compounds are conventionally known as synthetic intermediates for various pharmaceutical compounds and are also known as ultraviolet absorbers.
Various methods have been proposed so far for producing bisbenzoxazinone compounds. For example, JP-A-58-194854 (Patent Document 1) proposes a method of reacting an alkaline aqueous solution of anthranilic acid with an organic solvent solution of a dicarboxylic acid dihalogen compound. In this method, anthranilic acid as a raw material and a dicarboxylic acid dihalogen compound are reacted in a mixed solvent of water and an organic solvent to isolate an amide as an intermediate, and then reacted with a dehydrating agent such as acetic anhydride. To obtain a bisbenzoxazinone compound. This method has a high product yield and is easy to operate. However, since water is used as the reaction solvent, it takes a very long time to dry the amide compound as an intermediate. In order to supplement the hydrogen halide produced by the reaction, an alkali metal compound such as sodium hydroxide or sodium carbonate is used. As a result, the obtained bisbenzoxazinone compound contains an alkali metal salt, which becomes an impurity, and if it is contained in a thermoplastic resin as an ultraviolet absorber, the resin may be easily hydrolyzed.

Japanese Patent Application Laid-Open No. 61-291575 (Patent Document 2) discloses an anthranilic acid and a dicarboxylic acid dihalide in order to supplement hydrogen chloride produced by the reaction in a mixed solvent of water and acetone. There has been proposed a method in which the reaction is carried out in the presence of such an alkali metal and then phosphorus pentoxide is reacted in an N, N-dimethylformamide solvent to cause dehydration and cyclization. This method can also obtain a bisbenzoxazinone compound with high yield and high purity. However, this also tends to leave alkali metal salts and the like.
Further, JP-A-2003-155468 (Patent Document 3) reacts anthranilic acid and dicarboxylic acid dihalide in a mixed solvent of water and acetone in the presence of an alkali metal such as sodium carbonate, and then toluene. There has been proposed a method for reducing the acid value and chloride ion concentration by reacting acetic anhydride in a solvent to perform dehydration and cyclization and then washing with an aqueous sodium hydroxide solution. However, this also leaves an alkali metal salt such as sodium chloride in the bisbenzoxazinone compound that is hardly soluble in the solvent and an alkali metal compound used for washing.

In any of the proposals in Patent Documents 1 to 3, since an alkali metal compound such as sodium carbonate or sodium hydroxide is used as a dehydrohalogenating agent, sodium chloride or the like is added to the target bisbenzoxazinone compound. Contains trace amounts of alkali metal halides. When a bisbenzoxazinone compound is added to a resin as an ultraviolet absorber, it has been a problem that the durability of the resin, particularly the heat-and-moisture resistance, is significantly reduced by the remaining alkali metal.
JP 58-194854 A Japanese Patent Laid-Open No. 61-291575 JP 2003-155468 A

  Accordingly, an object of the present invention is to provide a method for producing a bisbenzoxazinone compound from an anthranilic acid derivative without using an alkali metal compound such as sodium hydroxide or sodium carbonate as a dehydrohalogenating agent. .

  As a result of intensive studies to solve the above problems, the present inventors have reacted the reaction of the anthranilic acid derivative (1) and the aromatic dicarboxylic acid dihalide (2) represented by the following reaction formula. The reaction proceeds smoothly by removing the hydrogen halide (HX in the formula) generated in the reaction by introducing an inert gas such as nitrogen into the reaction solution or reaction vessel in an organic solvent that is not involved. The intermediate amide compound (3) was obtained in high yield, and then the obtained amide compound was reacted with a dehydrating agent, and it was found that a highly pure bisbenzoxazinone compound (4) could be produced. Completed the invention.

(R ¹ , R ² and X are the same as those in the above formulas (1) to (4).)
That is, the present invention reacts an anthranilic acid derivative represented by the following formula (1) with an aromatic dicarboxylic acid dihalide represented by the following formula (2) in an organic solvent under an inert gas stream, After producing the amide compound represented by the formula (3),

(However, R ¹ and R ² are each independently a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, an acyl group having 1 to 3 carbon atoms, or 1 to 3 carbon atoms. An acyloxy group, an alkoxycarbonyl group having 1 to 3 carbon atoms, a halogen atom, a nitro group, or a carboxyl group, and X represents a halogen atom.)
The following formula (4) comprising reacting the obtained amide compound represented by formula (3) with a dehydrating agent

(However, R ¹ and R ² are the same as those in the formulas (1) to (3).)
The manufacturing method of the bisbenzoxazinone compound represented by these.

  Moreover, this invention includes the bisbenzoxazinone compound represented by Formula (4) obtained by the said manufacturing method.

  According to the production method of the present invention, as shown in the above reaction formula, an alkali metal such as sodium hydroxide or sodium carbonate is used to remove hydrogen halide by-produced when producing the amide compound (3). Since no compound is used, the resulting bisbenzoxazinone compound has high purity without substantially containing an alkali metal salt. Therefore, even if the obtained bisbenzoxazinone compound is used as an ultraviolet absorber for a resin, the action of promoting the hydrolysis of the resin by alkali metal hardly occurs. Moreover, according to this invention, a bisbenzoxazinone compound can be manufactured with a high yield.

<Method for producing bisbenzoxazinone compound>
The production method of the present invention comprises Step 1 for obtaining an amide compound (3) and Step 2 for dehydrating and cyclizing the amide compound to obtain a bisbenzoxazinone compound (4).

<Process 1>
Step 1 is a step of obtaining an amide compound (3) by reacting an anthranilic acid derivative (1) and an aromatic dicarboxylic acid dihalide (2) in an organic solvent under an inert gas stream.
(Anthranilic acid derivative)
An anthranilic acid derivative is represented by the following formula (1).

In the formula, R ¹ is a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, an acyl group having 1 to 3 carbon atoms, an acyloxy group having 1 to 3 carbon atoms, or a carbon number. 1-3 alkoxycarbonyl group, a halogen atom, a nitro group, and a carboxyl group are represented.

Examples of the alkyl group having 1 to 3 carbon atoms include a methyl group, an ethyl group, and a propyl group. Examples of the alkoxy group having 1 to 3 carbon atoms include a methoxy group, an ethoxy group, and a propoxy group. Examples of the acyl group having 1 to 3 carbon atoms (R—CO—) include an acetyl group and an acryloyl group. Examples of the acyloxy group having 1 to 3 carbon atoms (R—CO—O—) include those in which R is a methyl group or an ethyl group. Examples of the alkoxycarbonyl group having 1 to 3 carbon atoms (—CO—OR) include those in which R is a methyl group or an ethyl group. Examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. More preferably, R ¹ is a hydrogen atom. Specifically, anthranilic acid is mentioned.

(Aromatic dicarboxylic acid dihalide)
The aromatic dicarboxylic acid dihalide is represented by the following formula (2).

In the formula, X represents a halogen atom. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a chlorine atom is preferable. R ² is a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, an acyl group having 1 to 3 carbon atoms, an acyloxy group having 1 to 3 carbon atoms, or 1 to 3 carbon atoms. Represents an alkoxycarbonyl group, a halogen atom, a nitro group, or a carboxyl group. These specific examples are the same as those in the formula (1). More preferably, R ² is a hydrogen atom. Specific examples include terephthalic acid dichloride.
In the above reaction, compound (3) is obtained by reacting 2 moles of anthranilic acid derivative with 1 mole of aromatic dicarboxylic acid dihalide, but 1 mole of anthranilic acid derivative with respect to 1 mole of aromatic dicarboxylic acid dihalide. In order to suppress the formation of the by-product represented by the following formula (5) which has reacted, it is preferable to use an anthranilic acid derivative slightly in excess of the stoichiometric amount. That is, the amount of the aromatic dicarboxylic acid dihalide used for the reaction is preferably 0.43 to 0.5 mol, more preferably 0.47 to 0.5 mol, relative to 1 mol of the anthranilic acid derivative.

(Wherein R ¹ , R ² and X are the same as those in the above formulas (1) to (4)).

(Organic solvent)
The organic solvent is a solvent in which the starting anthranilic acid derivative (1) and the aromatic dicarboxylic acid dihalide (2) are soluble and do not participate in the reaction. Specifically, ketones such as acetone, methyl isobutyl ketone (MIBK) and cyclohexanone, aromatic hydrocarbons such as toluene and xylene, ethers such as tetrahydrofuran and dioxane, 1,2-dichloroethane, 1,1,1- Halogenated hydrocarbons such as trichloroethane and chlorobenzene are preferred. Of these, ketones are particularly preferred from the viewpoints of solubility of raw materials and ease of reaction.
The amount of the organic solvent used for the reaction is not particularly limited, but is preferably 350 to 3500 parts by weight, more preferably 800 to 1200 parts by weight with respect to 100 parts by weight of the anthranilic acid derivative.

(Inert gas)
The present invention is characterized in that an inert gas is introduced into the reaction system, the reaction proceeds under an inert gas stream, and hydrogen halide is removed.
Examples of the inert gas used in the present invention include nitrogen and argon, and nitrogen is particularly preferable. The amount of the inert gas used for the reaction is preferably 1 to 50 L / hour with respect to 1 mol of the anthranilic acid derivative. If the amount exceeds this amount, the amount of transpiration due to the inert gas stream becomes large. Is extremely slow. More preferably, it is 5-10L / hour. Note that the inert gas may be blown into an organic solvent or may be blown into the gas phase of the reaction vessel.
The reaction apparatus may be anything that has an inert gas introduction section, a gas outlet section, and a reflux apparatus and can stir a normal slurry-like reaction liquid. However, a facility for removing hydrogen halide contained in the aerated inert gas is necessary. The reaction temperature is preferably from room temperature to 140 ° C, and the tendency to color at higher temperatures is increased, more preferably from 50 to 90 ° C. Moreover, although reaction time changes with the flow volume and reaction temperature of an inert gas, it is preferable to set it as 0.5 to 20 hours, More preferably, it is 8 to 12 hours. The amide compound represented by the formula (3) can be used in the next step without any particular purification.

(Amide compound)
In step 1, an amide compound represented by the following formula (3) is obtained as crystals.

In the formula, R ¹ and R ² are the same as those in the formulas (1) to (3).

<Process 2>
In step 2, the amide compound represented by formula (3) obtained in step 1 is reacted with a dehydrating agent and cyclized to form the following formula (4).

Is a step of obtaining a bisbenzoxazinone compound represented by the formula: In the formula, R ¹ and R ² are the same as those in the formulas (1) to (3). More preferably, R ¹ and R ² are hydrogen atoms. Specifically, 2,2′-phenylenebis (3,1-benzoxazin-4-one) can be mentioned.

Examples of the dehydrating agent include acetic anhydride, phosphorus pentoxide, sulfur trioxide and the like, and acetic anhydride is preferable from the viewpoint of ease of handling. The dehydrating agent is required to be at least 2 equivalents, preferably 5 equivalents or more, more preferably 20 equivalents or more, per 1 equivalent of the amide compound represented by the formula (3). It can also be used as a solvent as a preferred embodiment.
The reaction apparatus should just be a thing which has a recirculation | reflux apparatus and can stir the reaction liquid of a slurry state. However, some of the acid gas generated during the reaction comes out at the exhaust port, and equipment to remove it is necessary. Moreover, although reaction temperature changes with boiling points of the solvent to be used, it is preferable to set it as 80 degreeC or more, More preferably, it is 120-140 degreeC. Moreover, it is preferable to wash with water in order to remove acidic components by-produced during the dehydration reaction. The reaction time varies depending on the equivalent and type of the dehydrating agent, but is preferably 1 to 24 hours, and more preferably 8 to 16 hours.

  Examples are given below to make the configuration and effects of the present invention more specific, but the present invention is not limited to these Examples. Evaluation in Examples was performed by the following method.

(1) Measurement of HPLC purity It was performed on Hitachi L6200 system under the following conditions Column: ODS-3 4.6 mm × 250 mm manufactured by GL Science
Column temperature: 45 ° C
Eluent: 0.02M phosphoric acid aqueous solution / acetonitrile = 7/3
Flow rate: 1 ml / min
Measurement wavelength: 346 nm

(2) Measurement of melting point Using MPA100 manufactured by SRS, the melting point was measured by the method described in JIS K0064.
operation:
A hard glass capillary with an inner diameter of 0.8 to 1.2 mm, a wall thickness of 0.2 to 0.3 mm, and a length of 150 mm and closed at one end is tightly filled to a height of about 3 mm. Secure to the measuring device. Heating starts at a temperature about 10 ° C. lower than the expected melting point, and the temperature is increased at a rate of 2 ° C./min. The contraction point is when the sample shrinks and a gap is clearly formed between the inner wall of the capillary and the end point of melting is when the solid sample remaining in the liquid is completely liquefied by further heating. The same operation is performed for the three samples, and the average value of the measured values is set as the shrinkage point and the melting end point, respectively, and the temperature range from the shrinkage point to the melting end point is set as the melting range.

Example 1 Production of 2,2′-phenylenebis (3,1-benzoxazin-4-one) (Step 1: Amidation)
In a 500 ml four-necked flask equipped with a thermometer, a stirrer, a reflux condenser, a dropping funnel, a nitrogen gas inlet, and a gas outlet connected to a hydrogen halide removing facility, 25 g of anthranilic acid was converted to methyl isobutyl ketone (MIBK). ) Dissolved in 150 g. Next, the temperature of the solution was set in the range of 55 to 60 ° C., and 18 g of terephthalic acid dichloride dissolved in 72 g of MIBK was added dropwise over 30 minutes. Then, it was made to react at 80-85 degreeC for 12 hours, flowing nitrogen at 15 ml / min to the gaseous-phase part of a reaction flask. After the reaction, the temperature of the solution was cooled to 30 ° C. or lower, filtered, and the obtained crystal was washed with MIBK.

(Process 2: Dehydration)
A 500 ml four-necked flask equipped with a thermometer, a stirrer, a reflux condenser, a dropping funnel, a reflux outlet and a gas outlet connected to an acid gas removing facility was charged with 300 g of the obtained crystals and acetic anhydride for 1 hour. The mixture was heated to reflux for 12 hours while distilling about 10 g of the reflux solution. The temperature gradually increased and eventually exceeded 130 ° C. Thereafter, the mixture was cooled to 30 ° C. or lower and filtered.
This crystal and 120 g of methanol were placed in a 500 ml four-necked flask equipped with a thermometer, a stirrer, a reflux condenser, a dropping funnel, and a gas outlet connected to an acid gas removal facility, and stirred at a temperature of 50 to 60 ° C. for 30 minutes. Washed. To this, 120 g of ion-exchanged water was added dropwise, cooled to 30 ° C. or lower, filtered, and the resulting crystals were washed with methanol. The obtained crystals were dried at 60 ° C. to obtain 29 g of 2,2′-phenylenebis (3,1-benzoxazin-4-one) as slightly yellow crystals.
Table 1 shows the yield, melting point, and HPLC purity.

Example 2 Production of 2,2′-phenylenebis (3,1-benzoxazin-4-one) (Step 1: Amidation)
In a 500 ml four-necked flask equipped with a thermometer, a stirrer, a reflux condenser, a dropping funnel, a nitrogen gas inlet, and a gas outlet connected to a hydrogen halide removing facility, 25 g of anthranilic acid was converted to methyl isobutyl ketone (MIBK). ) Dissolved in 150 g. Next, the temperature of the solution was set in the range of 55 to 60 ° C., and 18 g of terephthalic acid dichloride dissolved in 72 g of MIBK was added dropwise over 30 minutes. Thereafter, the reaction was completed by maintaining the temperature in the range of 80 to 85 ° C. for 12 hours while flowing nitrogen at a rate of 15 ml / min through the gas phase of the reaction flask.

(Process 2: Dehydration)
150 g of acetic anhydride was added to the reaction solution, and the mixture was heated to reflux for 24 hours while distilling the reflux solution at a rate of about 10 to 20 g per hour. On the way, 100 g of acetic anhydride was added twice. The temperature gradually increased and eventually exceeded 130 ° C. Then, it cooled to 30 degrees C or less, and filtered. This crystal and 120 g of methanol were placed in a 500 ml four-necked flask equipped with a thermometer, a stirrer, a reflux condenser, a dropping funnel, and a gas outlet connected to an acid gas removal facility, and stirred at a temperature of 50 to 60 ° C. for 30 minutes. Washed. To this, 120 g of ion-exchanged water was added dropwise, cooled to 30 ° C. or lower, filtered, and the crystals were washed with methanol. The obtained crystals were dried at 60 ° C. for 15 hours to obtain 28.5 g of slightly yellow crystal 2,2′-phenylenebis (3,1-benzoxazin-4-one).
Table 1 shows the yield, melting point, and HPLC purity.

<Comparative Example 1> Production of 2,2'-phenylenebis (3,1-benzoxazin-4-one) without carrying out inert gas flow Step 1: carried out except that nitrogen was not bubbled during the reaction in amidation Performed as in Example 1. Table 1 shows the yield, melting point, and HPLC purity.

  The production method of the present invention can be used for the production of bisbenzoxazinone compounds as pharmaceuticals and ultraviolet absorbers.

Claims (7)

An anthranilic acid derivative represented by the following formula (1) and an aromatic dicarboxylic acid dihalide represented by the following formula (2) are reacted in an organic solvent under an inert gas stream, and the following formula (3): After producing the represented amide compound,

(However, R ¹ and R ² are each independently a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, an acyl group having 1 to 3 carbon atoms, or 1 to 3 carbon atoms. An acyloxy group, an alkoxycarbonyl group having 1 to 3 carbon atoms, a halogen atom, a nitro group, or a carboxyl group, and X represents a halogen atom.)
The following formula (4) comprising reacting the obtained amide compound represented by formula (3) with a dehydrating agent

(However, R ¹ and R ² are the same as those in the formulas (1) to (3).)
The manufacturing method of the bisbenzoxazinone compound represented by these. The method according to claim 1, wherein the organic solvent is at least one selected from the group consisting of ketones, aromatic hydrocarbons, halogenated hydrocarbons, and ethers. The production method according to claim 1, wherein the inert gas is nitrogen. The process according to claim 1, wherein the dehydrating agent is acetic anhydride. The production method according to claim 1, wherein R ^{1 in} formula (1) to formula (4) is a hydrogen atom, R ² is a hydrogen atom, and X is a chlorine atom. The bisbenzoxazinone compound represented by Formula (4) obtained by the manufacturing method of Claims 1-5. The bisbenzoxazinone compound according to claim 6, wherein R ^{1 in the} formula (4) is a hydrogen atom and R ² is a hydrogen atom.