JP2007261982A - Method for producing quinazolin-2,4-dione derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an efficient and industrially practical method for producing a quinazolin-2,4-dione derivative important as a medicinal raw material or the like from an anthranilic acid derivative and urea. <P>SOLUTION: The objective quinazoline-2,4-dione derivative can be produced in high yield by carrying out the reaction under a condition in which at least an organic carboxylic acid is present as a catalyst. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

（式中、Ｒ_１、Ｒ_２、Ｒ_３およびＲ_４は、相互に独立して水素原子、ハロゲン基、ニトロ基、Ｃ１〜Ｃ６のアルキル基、またはＣ１〜Ｃ６のアルコキシ基を示す。また、Ｘは、水酸基、アミノ基、またはＣ１〜Ｃ６のアルコキシ基を示す。）

（式中、Ｒ_１、Ｒ_２、Ｒ_３およびＲ_４は、相互に独立して水素原子、ハロゲン基、ニトロ基、Ｃ１〜Ｃ６のアルキル基、またはＣ１〜Ｃ６のアルコキシ基を示す。） In the present invention, when an anthranilic acid derivative represented by the general formula (1) is reacted with urea to synthesize a quinazoline-2,4-dione derivative represented by the general formula (2), at least an organic carboxylic acid is used as a catalyst. The present invention relates to a method for producing a quinazoline-2,4-dione derivative represented by the general formula (2). The quinazoline-2,4-dione derivative represented by the general formula (2) is an important substance as an intermediate material for pharmaceuticals.

(Wherein R ₁ , R ₂ , R ₃ and R ₄ each independently represent a hydrogen atom, a halogen group, a nitro group, a C1-C6 alkyl group, or a C1-C6 alkoxy group. X represents a hydroxyl group, an amino group, or a C1-C6 alkoxy group.)

(In the formula, R ₁ , R ₂ , R ₃ and R ₄ each independently represent a hydrogen atom, a halogen group, a nitro group, a C1-C6 alkyl group, or a C1-C6 alkoxy group.)

As a conventional method for producing a quinazoline-2,4-dione derivative, for example, the following methods are known.
1) A method of synthesizing a 2,4-quinazolinedione derivative by heating an anthranilic acid derivative and urea in the presence of an alcohol to cyclize it (for example, see Patent Documents 1 and 2). 2) A reaction of anthranilic acid with an isocyanate. A method of obtaining a 2,4-dihydroxyquinazoline derivative by cyclizing the obtained phenylurea derivative (see, for example, Patent Document 3), 3) reacting anthranilic acid amide with carbon monoxide and sulfur, and inserting a carbonyl group 2. A method for obtaining a 2,4-dihydroxyquinazoline derivative (for example, see Non-Patent Document 1), 4) a method for reacting aminobenzonitriles and carbon dioxide in a solvent in the presence of a bicyclic amidine (for example, see Patent Document 4) ), 5) A method for producing a 2,4-dioxoquinazoline derivative by reacting anthranilic acid amides with a carbonate ester ( Eg to a patent document 5, 6 reference) and the like.

However, in the methods of Patent Documents 1 and 2, the reaction temperature is 180 to 250 ° C., the reaction time is 3 to 10 hours, and it is necessary to react at a high temperature for a long time. There is a need to. The method of Patent Document 3 is a two-step process in which a phenylurea derivative is once synthesized and then closed, and there is a problem in that a toxic isocyanate must be used. Further, the method of Non-Patent Document 1 has a problem that toxic carbon monoxide must be used. In the method of Patent Document 4, it is necessary to use an expensive bicyclic amidine although it is a catalytic amount in producing a quinazoline-2,4-dione derivative, and at a relatively low reaction temperature of 80 ° C., It is necessary to react for a long time, and there is room for further improvement industrially. The methods of Patent Documents 5 and 6 use a relatively expensive carbonate as a raw material, and are not economical. As described above, any of the conventional methods is not satisfactory because there is room for further improvement on an industrial scale.
Japanese Patent Laid-Open No. 50-140471 JP 50-157384 A JP-A-8-59630 JP 2003-160569 A JP 2000-1479 A JP 11-292855 A Toshiyuki Miyata, Takumi Mizuno, Yoshio Nagahama, Ikuzo Nishiguchi, and Tsuneaki Hirashima, Heteroatom Chem., 2,473 (1991)

  The object of the present invention is to solve the above-mentioned problems in the prior art and efficiently convert a quinazoline-2,4-dione derivative represented by the general formula (2) from an anthranilic acid derivative represented by the general formula (1) and urea. It is to provide a method for industrial production.

（式中、Ｒ_１、Ｒ_２、Ｒ_３およびＲ_４は、相互に独立して水素原子、ハロゲン基、ニトロ基、Ｃ１〜Ｃ６のアルキル基、またはＣ１〜Ｃ６のアルコキシ基を示す。また、Ｘは、水酸基、アミノ基、またはＣ１〜Ｃ６のアルコキシ基を示す。）

（式中、Ｒ_１、Ｒ_２、Ｒ_３およびＲ_４は、相互に独立して水素原子、ハロゲン基、ニトロ基、Ｃ１〜Ｃ６のアルキル基、またはＣ１〜Ｃ６のアルコキシ基を示す。）
２）有機カルボン酸と共に、塩基類、有機カルボン酸塩の何れか一種以上を触媒として用いる、１）に記載の一般式（２）で示されるキナゾリン−２，４−ジオン誘導体の製造方法。
３）有機カルボン酸が、ギ酸、酢酸の何れか一種以上である、１）または２）に記載の一般式（２）で示されるキナゾリン−２，４−ジオン誘導体の製造方法。
４）塩基類が、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸水素ナトリウム、炭酸水素カリウム、炭酸水素セシウム、ナトリウムメトキシド、ナトリウムエトキシド、カリウムエトキシド、メチルアミン、エチルアミン、プロピルアミン、ブチルアミン、ジメチルアミン、ジエチルアミン、ジプロピルアミン、エチレンジアミン、プロパンジアミン、トリメチルアミン、トリエチルアミンの何れか一種以上である、２）に記載の一般式（２）で示されるキナゾリン−２，４−ジオン誘導体の製造方法。
５）有機カルボン酸塩が、ギ酸ナトリウム塩、ギ酸カリウム塩、ギ酸アンモニウム塩、酢酸ナトリウム塩、酢酸カリウム塩、酢酸アンモニウム塩の何れか一種以上である、２）に記載の一般式（２）で示されるキナゾリン−２，４−ジオン誘導体の製造方法。 In order to solve the above-mentioned problems, the present inventors have obtained a quinazoline-2,4-dione derivative represented by the general formula (2) from the anthranilic acid derivative represented by the general formula (1) and urea in a high yield and is economical. As a result of intensive studies on an industrially practicable method that can be produced in the following, quinazoline-2,4 represented by the general formula (2) at a relatively low temperature in a short time by reacting at least with an organic carboxylic acid as a catalyst. -A dione derivative can be produced in a high yield, and by reacting under conditions in which a base, an organic carboxylate salt, or both of them are present in addition to the organic carboxylic acid, the general formula ( It was found that the quinazoline-2,4-dione derivative represented by 2) can be produced, and the present invention has been completed.
That is, in the present invention, an anthranilic acid derivative represented by the general formula (1) is reacted with urea under the conditions in which at least an organic carboxylic acid is present as a catalyst, as shown in the following 1) to 5). It relates to a method for producing a quinazoline-2,4-dione derivative represented by 2).
1) When an anthranilic acid derivative represented by the general formula (1) is reacted with urea to synthesize a quinazoline-2,4-dione derivative represented by the general formula (2), at least an organic carboxylic acid is used as a catalyst. A method for producing a quinazoline-2,4-dione derivative represented by the general formula (2), which is characterized.

(Wherein R ₁ , R ₂ , R ₃ and R ₄ each independently represent a hydrogen atom, a halogen group, a nitro group, a C1-C6 alkyl group, or a C1-C6 alkoxy group. X represents a hydroxyl group, an amino group, or a C1-C6 alkoxy group.)

(In the formula, R ₁ , R ₂ , R ₃ and R ₄ each independently represent a hydrogen atom, a halogen group, a nitro group, a C1-C6 alkyl group, or a C1-C6 alkoxy group.)
2) A method for producing a quinazoline-2,4-dione derivative represented by the general formula (2) according to 1), wherein any one or more of bases and organic carboxylates are used as a catalyst together with an organic carboxylic acid.
3) The method for producing a quinazoline-2,4-dione derivative represented by the general formula (2) according to 1) or 2), wherein the organic carboxylic acid is at least one of formic acid and acetic acid.
4) Bases are lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, sodium methoxide, sodium ethoxide, potassium ethoxide, methylamine, ethylamine, propylamine, Production of quinazoline-2,4-dione derivative represented by the general formula (2) according to 2), which is at least one of butylamine, dimethylamine, diethylamine, dipropylamine, ethylenediamine, propanediamine, trimethylamine and triethylamine Method.
5) The organic carboxylate is at least one of sodium formate, potassium formate, ammonium formate, sodium acetate, potassium acetate, and ammonium acetate. Process for the production of the quinazoline-2,4-dione derivative shown.

  According to the present invention, a quinazoline-2,4-dione derivative represented by the general formula (2) useful as an intermediate raw material for pharmaceuticals is efficiently produced from an anthranilic acid derivative represented by the general formula (1) and urea. It becomes possible.

Hereinafter, the production method of the quinazoline-2,4-dione derivative represented by the general formula (2) of the present invention will be described in detail. The raw material anthranilic acid derivative used in the present invention is represented by the general formula (1). In the general formula, R ₁ , R ₂ , R ₃ and R ₄ each independently represent a hydrogen atom, a halogen group, a nitro group, a C1-C6 alkyl group, or a C1-C6 alkoxy group. X represents a hydroxyl group, an amino group, or a C1-C6 alkoxy group.

The C1-C6 alkyl group is a C1-C6 alkyl group and represents a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group. These groups include various isomers. A C1-C6 alkoxy group is a C1-C6 alkoxy group, and shows a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentoxyl group, or a hexyloxy group. These groups also include various isomers. The halogen group represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and R ₁ , R ₂ , R _3, and R ₄ may be the same type of halogen atom or different types of halogen atoms. May be.

  The anthranilic acid derivative represented by the general formula (1) is a known compound or can be prepared from a known compound using a known method, for example, by catalytic hydrogenation of the corresponding nitrobenzoic acid. Such nitrobenzoic acid can be produced by, for example, International Publication No. 03/064399 or a similar method.

  Commercially available urea can be used for the present invention. As for the amount used, it is preferable to use 0.8-30 moles of urea, more preferably 0.8-20 moles of urea, per mole of anthranilic acid derivative represented by the general formula (2). It is desirable to use When the amount of urea is less than 0.8-fold mol, there is a disadvantage that the reaction rate is lowered due to a substrate shortage. On the other hand, there is no particular upper limit, but if it exceeds 30 moles, it is uneconomical that only a large amount of urea needs to be recovered after the reaction.

（式中、Ｒ_１、Ｒ_２、Ｒ_３およびＲ_４は、相互に独立して水素原子、ハロゲン基、ニトロ基、Ｃ１〜Ｃ６のアルキル基、またはＣ１〜Ｃ６のアルコキシ基を示す。また、Ｘは、水酸基、アミノ基、Ｃ１〜Ｃ６のアルコキシ基を示す。）
本反応は無触媒でも進行するが反応速度は著しく遅く、本発明のごとく、少なくとも有機カルボン酸を触媒として使用することにより反応速度を高めることが可能となる。 Here, this reaction in which the anthranilic acid derivative represented by the general formula (1) and urea are reacted with the quinazoline-2,4-dione derivative represented by the general formula (2) is represented by the formula (3).

(Wherein R ₁ , R ₂ , R ₃ and R ₄ each independently represent a hydrogen atom, a halogen group, a nitro group, a C1-C6 alkyl group, or a C1-C6 alkoxy group. X represents a hydroxyl group, an amino group, or a C1-C6 alkoxy group.)
Although this reaction proceeds even without a catalyst, the reaction rate is remarkably slow. As in the present invention, the reaction rate can be increased by using at least an organic carboxylic acid as a catalyst.

  For example, formic acid and acetic acid are used as the organic carboxylic acid to be used. In addition, you may use these organic carboxylic acid individually or in mixture of 2 or more. Regarding the amount of the organic carboxylic acid used, the ammonia generated in the reaction process of the formula (3) is trapped to produce a necessary amount of the organic carboxylate having higher catalytic activity than the organic carboxylic acid, that is, the reaction It is necessary for the liquid to contain an organic carboxylic acid in an amount of 0.1-fold mol or more, preferably 0.5-fold mol or more based on 1 mol of the anthranilic acid derivative represented by the general formula (1). When the amount of the organic carboxylic acid is less than 0.1 times mole, the effect of promoting the reaction by the organic carboxylate cannot be obtained. On the other hand, although there is no particular upper limit, it is preferably 20 times mol or less, more preferably 10 times mol or less. Even if it exceeds 20 times mole, there is no remarkable effect and it becomes wasteful and uneconomical.

  Bases used as catalysts include inorganic base ammonia, alkali metal carbonate lithium carbonate, sodium carbonate, potassium carbonate, or cesium carbonate, alkali metal bicarbonate sodium bicarbonate, potassium bicarbonate, or bicarbonate. Cesium, etc., alkali metal alkoxides such as sodium methoxide, sodium ethoxide, or potassium ethoxide, organic amines such as methylamine, ethylamine, propylamine, butylamine, dimethylamine, diethylamine, dipropylamine, ethylenediamine, propanediamine, trimethylamine, Or a triethylamine etc. can be illustrated. Among them, inorganic bases such as ammonia, sodium carbonate, potassium carbonate, organic amines propylamine, diethylamine, or ethylenediamine are preferable. In addition, you may use these bases individually or in mixture of 2 or more types. The amount of the bases used is 0.1 times moles or more, preferably 0.2 times moles or more of the bases per mole of the anthranilic acid derivative represented by the general formula (1) in the reaction solution. It is desirable to add so as to. When the base is present in an amount of 0.1-fold mol or more, it is possible to further increase the reaction rate until the organic carboxylate ammonium salt trapped with ammonia generated in the reaction process of the formula (3) is formed. On the other hand, although there is no particular upper limit, it is preferably 5 times mol or less, more preferably 3 times mol or less. Even if it exceeds 5 times mol, there is no remarkable effect and it is wasteful and uneconomical.

  Examples of the organic carboxylate used as the catalyst include sodium formate, potassium formate, ammonium formate, sodium acetate, potassium acetate, ammonium acetate, ethylenediamine acetate, and the like. In addition, you may use these organic carboxylate individually or in mixture of 2 or more types. The organic carboxylate is used in an amount of 0.1-fold mol or more, preferably 0.2-fold mol or more, of 1 mol of anthranilic acid derivative represented by the formula (1) in the reaction solution. It is desirable to add so that the salt is present. By allowing the organic carboxylate to be present in an amount of 0.1-fold mol or more, it is possible to further increase the reaction rate until the organic carboxylate ammonium salt is formed as in the case of using bases in addition to the organic carboxylic acid. Become. On the other hand, although there is no particular upper limit, it is preferably 5 times mol or less, more preferably 3 times mol or less. Even if it exceeds 5 times mol, there is no remarkable effect and it is wasteful and uneconomical.

  As described above, when a base or an organic carboxylate is used as a catalyst together with an organic carboxylic acid from the beginning, the reaction rate is accelerated as compared with the case where the organic carboxylic acid is used alone. The reason is that, as shown in the above formula (3), ammonia is generated as a by-product in this reaction, but when an organic carboxylic acid is used alone as a catalyst, no active reaction occurs in the initial reaction stage. This is because the reaction proceeds only vigorously until the organic carboxylate produced from the generated ammonia and organic carboxylic acid has accumulated to some extent. That is, when a base or an organic carboxylate is used as a catalyst together with an organic carboxylic acid from the beginning, the reaction rate is accelerated compared to the case where the organic carboxylic acid is used alone, and the reaction can be completed in a shorter time.

When a base is used in addition to the organic carboxylic acid, it is preferable to combine acetic acid as the organic carboxylic acid, and ammonia, sodium carbonate, or potassium carbonate as the base, and particularly preferably a combination of acetic acid, sodium carbonate, and potassium carbonate. This is the case. The quantitative relationship of the combination is such that the ratio of sodium carbonate or potassium carbonate to acetic acid is in the range of 0.05 to 1 mole.
In addition to organic carboxylic acid, when organic carboxylate is used in combination, acetic acid is preferable as organic carboxylic acid, and when ammonium acetate, sodium acetate, potassium acetate is combined as organic carboxylate, it is particularly preferable. Is the combination of acetic acid and ammonium acetate. As a quantitative relationship of the combination, the ratio of ammonium acetate to acetic acid is in the range of 0.05 to 1 times mol.

  If the solvent used in the present invention is inert to the present reaction, it is sufficient that the solvent is in an amount sufficient to always stir the reaction mixture. Further, urea or organic carboxylic acid such as formic acid, acetic acid, propionic acid, butanoic acid, pentanoic acid, and hexanoic acid may be used as a solvent. Examples of the solvent that can be used include the following. That is, alcohols such as methanol or ethanol, esters such as methyl acetate or ethyl acetate, lactones such as butyrolactone, cyclic ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide or dimethylacetamide, N- Examples include lactams such as methyl pyrrolidone, and ketones such as acetone, methyl isobutyl ketone, and cyclohexanone. Particularly preferably, urea or acetic acid is used.

  The reaction of the present invention is performed by, for example, a method of mixing and stirring the anthranilic acid derivative represented by the general formula (1), urea, organic carboxylic acid and catalyst in an inert gas atmosphere. The reaction temperature in that case is 120-200 degreeC, Preferably it is 135-180 degreeC more than melting | fusing point (135 degreeC) of urea, Reaction time is 0.5 to 10 hours, Preferably it is 1 to 5 hours. The reaction pressure is higher than the self-generated pressure and the reaction is carried out in the liquid phase.

  The reaction mixture containing the quinazoline-2,4-dione derivative obtained by the reaction of the present invention is cooled, for example, hot water is added to this after completion of the reaction, and the precipitated crystals are filtered. The obtained filter cake is washed with the solvent used, etc., and then treated by drying it in vacuo at a moderate temperature. If further purification is required, it is purified by a general method such as recrystallization or distillation.

Hereinafter, the present invention will be described more specifically with reference to examples and comparative examples. However, the present invention is not limited by these examples.
Example 1
Synthesis of 6,7-dimethoxyquinazoline-2,4-dione In an autoclave made of sus316 having an internal volume of 25 mL equipped with a stirrer, a thermometer and a pressure gauge, 0.84 g of methyl 4,5-dimethoxyanthranilate was added in a nitrogen atmosphere. 4 mmol), 3.60 g (60 mmol) of urea, and 1.44 g (24 mmol) of acetic acid were added and reacted at 150 ° C. for 2 hours. After completion of the reaction, 20 g of hot water was added, the reaction solution was cooled to room temperature, the precipitated crystals were filtered, washed with acetic acid, and dried in vacuo at 70 ° C. for 2 hours. The obtained crystal weight was 0.81 g. As a result of analyzing the components by high performance liquid chromatography, the yield of 6,7-dimethoxyquinazoline-2,4-dione was 91.8%. The results are shown in Table 1.

Comparative Example 1
Synthesis of 6,7-dimethoxyquinazoline-2,4-dione The reaction was performed in the same manner as in Example 1 except that acetic acid was not added. The obtained crystal weight was 0.73 g. As a result of analyzing the components by high performance liquid chromatography, the yield of quinazoline-2,4-dione was 15.6%. The results are shown in Table 1.

Examples 2-5
Synthesis of 6,7-dimethoxyquinazoline-2,4-dione In Example 1, the reaction was conducted in the same manner as in Example 1 except that 2.8 mmol of bases or organic carboxylate was added in addition to acetic acid. It was. The results are shown in Table 1.

Example 6
In an autoclave made of sus316 having a volume of 25 mL equipped with a quinazoline-2,4-dione synthesis stirrer, a thermometer and a pressure gauge, 0.55 g (4 mmol) of anthranilic acid, 2.40 g (40 mmol) of urea, under a nitrogen atmosphere, Acetic acid 0.90 g (15 mmol) and ammonium acetate 0.15 g (2.0 mmol) were added and reacted at 150 ° C. for 4 hours. After completion of the reaction, 20 g of hot water was added, the reaction solution was cooled to room temperature, the crystals were filtered, the crystals were washed with acetic acid and vacuum dried at 70 ° C. for 2 hours. The obtained crystal weight was 0.52 g. As a result of analyzing the components by high performance liquid chromatography, the yield of quinazoline-2,4-dione was 79.7%. The results are shown in Table 2.

Comparative Example 2
Synthesis of quinazoline-2,4-dione In Example 6, the reaction was carried out in the same manner as in Example 6 except that acetic acid and ammonium acetate were not added. The obtained crystal weight was 0.40 g. As a result of analyzing the components by high performance liquid chromatography, the yield of quinazoline-2,4-dione was 61.2%. The results are shown in Table 2.

Examples 7-11
Synthesis of quinazoline-2,4-dione In Example 6, the reaction was carried out in the same manner as in Example 6 except that the type of base used as the catalyst was changed and that no base was added. The results are shown in Table 2.

Examples 12-20
In Example 6, the reaction was performed in the same manner as in Example 6 except that the anthranilic acid derivative was replaced with an anthranilic acid derivative. The results are shown in Table 3.

Claims (5)

When an anthranilic acid derivative represented by the general formula (1) is reacted with urea to synthesize a quinazoline-2,4-dione derivative represented by the general formula (2), at least an organic carboxylic acid is used as a catalyst. A process for producing a quinazoline-2,4-dione derivative represented by the general formula (2).

(Wherein R ₁ , R ₂ , R ₃ and R ₄ each independently represent a hydrogen atom, a halogen group, a nitro group, a C1-C6 alkyl group, or a C1-C6 alkoxy group. X represents a hydroxyl group, an amino group, or a C1-C6 alkoxy group.)

(In the formula, R ₁ , R ₂ , R ₃ and R ₄ each independently represent a hydrogen atom, a halogen group, a nitro group, a C1-C6 alkyl group, or a C1-C6 alkoxy group.)   The manufacturing method of the quinazoline-2,4-dione derivative | guide_body shown by General formula (2) of Claim 1 using any one or more of bases and organic carboxylate as a catalyst with organic carboxylic acid.   The method for producing a quinazoline-2,4-dione derivative represented by the general formula (2) according to claim 1 or 2, wherein the organic carboxylic acid is at least one of formic acid and acetic acid.   Bases are lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, sodium methoxide, sodium ethoxide, potassium ethoxide, methylamine, ethylamine, propylamine, butylamine, The method for producing a quinazoline-2,4-dione derivative represented by the general formula (2) according to claim 2, which is at least one of dimethylamine, diethylamine, dipropylamine, ethylenediamine, propanediamine, trimethylamine, and triethylamine .   The organic carboxylate is represented by the general formula (2) according to claim 2, wherein the organic carboxylate is at least one of sodium formate, potassium formate, ammonium formate, sodium acetate, potassium acetate, and ammonium acetate. For producing a quinazoline-2,4-dione derivative.