JP2012162464A - Method for producing n-[4-(6,7-difluoro-2,4-dioxo-1,4-dihydro-2h-quinazoline-3-yl)-phenyl]-acetamide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for efficiently producing high-purity N-[4-(6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)-phenyl]-acetamide used as an important precursor for production of pharmaceutical intermediates.SOLUTION: In the method for producing N-[4-(6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)-phenyl]-acetamide, N-[4-(6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)-phenyl]-acetamide is obtained by reacting 2-amino-4,5-difluorobenzoic acid methyl ester with a phenyl chloroformate compound at a predetermined molar ratio, and then, reacting the resultant phenoxy carbonyl amine compound with N-acetyl 1,4-phenylene diamine in a solvent in the presence of a base without performing an isolating process.

Description

  The present invention relates to N- [4- (6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) used as an important production precursor for pharmaceutical intermediates. It relates to a process for producing -phenyl] -acetamide.

Of N- [4- (6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -phenyl] -acetamide, an important production precursor for pharmaceutical intermediates As manufacturing methods, the following methods are conventionally known.
(1) Methyl 2-amino-4,5-difluorobenzoate and phosgene are reacted to form isocyanate or carbamoyl chloride, and then reacted with phenylenediamine in which one amino group is protected, and then cyclized in the presence of a base. A method of obtaining a target product by performing a chemical reaction.
(2) 1 mol of 2-amino-4,5-difluorobenzoate is reacted with 1.2 mol of 4-nitrophenyl chloroformate as a phenyl chloroformate in a solvent, and isolated by crystallization and filtration. Then, after reacting with one of the amino groups protected phenylenediamine, a method of obtaining a target product by carrying out a cyclization reaction in the presence of a base (Patent Document 1) and the like can be mentioned.

International Publication No. 07/056167 pamphlet

  However, according to the production method of (1) above, extremely toxic phosgene is used as a reaction reagent, and handling thereof requires strict care. It was not an advantageous manufacturing method in production.

In addition, according to the production method of (2) above, 4,5-difluoro-2- (4-) obtained by reacting methyl 2-amino-4,5-difluorobenzoate with 4-nitrophenyl chloroformate is allowed to react. To isolate nitro-phenoxycarbonylamino) -methyl benzoate, a complicated isolation operation such as filtration was required.
In general, by-products have similar physicochemical properties to target products and are often difficult to separate and purify. In particular, in order to obtain high-purity target products required as precursors for the production of pharmaceutical intermediates. It is necessary to perform the isolation operation as described above.

In particular, in the production method of the above (2), since 1 mol of methyl 2-amino-4,5-difluorobenzoate is reacted with 1.2 mol of 4-nitrophenyl chloroformate, Even after the completion of the reaction, unreacted 4-nitrophenyl chloroformate is present in the reaction system, and in order to prevent the formation of by-products that can be generated in the reaction of the next step, the above isolation operation should be omitted. Was difficult. Therefore, the production method (2) has a long production process until the desired product is obtained, and is not an advantageous production method in industrial production.
For this reason, the method of manufacturing a target compound efficiently and with high purity was calculated | required.

  The present invention relates to N- [4- (6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-useful as an important precursor for the production of pharmaceutical intermediates. An object of the present invention is to provide a method for producing phenyl] -acetamide efficiently and with high purity.

  As a result of intensive studies to solve the above problems, the present inventors have used a predetermined molar ratio in the reaction of methyl 2-amino-4,5-difluorobenzoate and phenyl chloroformate. N- [4- (6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -phenyl] -acetamide without isolation of the phenoxycarbonylamine compound It discovered that it could manufacture efficiently and highly purified.

で表される２−アミノ−４，５−ジフルオロ安息香酸メチル１モルに対して、式（２）：

（式中、Ｒは水素原子、ハロゲン原子、またはニトロ基を示す。）で表されるクロロギ酸フェニル化合物を０．９〜１．１モル反応させる工程１、および
工程１にて得られる式（３）：

（式中、Ｒは式（２）におけるＲと同じ基を示す。）で表されるフェノキシカルボニルアミン化合物を単離することなく、式（４）：

で表されるＮ−アセチル １，４−フェニレンジアミンと溶媒中で塩基存在下にて反応させる工程２を含む、式（５）：

で表されるＮ−［４−（６，７−ジフルオロ−２，４−ジオキソ−１，４−ジヒドロ−２Ｈ−キナゾリン−３−イル）−フェニル］−アセトアミドの製造方法を提供する。 That is, the present invention
Formula (1):

With respect to 1 mol of methyl 2-amino-4,5-difluorobenzoate represented by the formula (2):

(Wherein R represents a hydrogen atom, a halogen atom, or a nitro group), 0.9 to 1.1 mol of a phenyl chloroformate compound represented by formula (1), and the formula (1) obtained in step 1 3):

(Wherein R represents the same group as R in formula (2)), without isolating the phenoxycarbonylamine compound represented by formula (4):

Comprising a step 2 of reacting N-acetyl 1,4-phenylenediamine represented by the above in a solvent in the presence of a base:

A method for producing N- [4- (6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -phenyl] -acetamide represented by the formula:

Moreover, this invention provides the said manufacturing method whose chloroformate phenyl compound is 0.98-1.04 mol with respect to 1 mol of methyl 2-amino-4,5-difluorobenzoates.
Furthermore, the present invention provides the above production method, wherein an organic base is used in the step 2 described above.

  According to the present invention, N- [4- (6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl, useful as a precursor for the production of various pharmaceutical intermediates. ) -Phenyl] -acetamide can be produced efficiently and with high purity.

The present invention relates to N-acetyl 1,4-phenylenediamine and a solvent without isolating a phenoxycarbonylamine compound obtained by reacting methyl 2-amino-4,5-difluorobenzoate with phenyl chloroformate. -[4- (6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -phenyl] -acetamide obtained by reacting in the presence of a base It relates to a method of manufacturing.
The present invention is described in detail below.

In the production method according to the present invention, first, Step 1 in which methyl 2-amino-4,5-difluorobenzoate and phenyl chloroformate are mixed and reacted is performed.
The methyl 2-amino-4,5-difluorobenzoate used in the present invention may be obtained by any method, but according to the method described in US 2002/077486, it can be produced relatively easily. it can.

式（２）中、Ｒは水素原子、ハロゲン原子、またはニトロ基を示す。これらの中でも、水素原子およびニトロ基が好適に用いられる。
ハロゲン原子としては、例えば、塩素原子、臭素原子等を挙げることができる。これらの中でも塩素原子が好適に用いられる。 Moreover, the chloroformate phenyl compound used for this invention is represented by following formula (2).

In formula (2), R represents a hydrogen atom, a halogen atom, or a nitro group. Among these, a hydrogen atom and a nitro group are preferably used.
As a halogen atom, a chlorine atom, a bromine atom, etc. can be mentioned, for example. Among these, a chlorine atom is preferably used.

Specific examples of the phenyl chloroformate compound represented by the formula (2) used in the present invention include, for example, phenyl chloroformate, 4-chlorophenyl chloroformate, 4-bromophenyl chloroformate, 4-nitrophenyl chloroformate, chloroformate Acid 3-nitrophenyl and the like can be mentioned. Among these, phenyl chloroformate and 4-nitrophenyl chloroformate are preferably used because they are easily available.
A commercially available thing may be used for the said phenyl chloroformate compound, and what was obtained by the various well-known methods may be used.

  The amount of phenyl chloroformate used in the reaction of methyl 2-amino-4,5-difluorobenzoate and phenyl chloroformate in Step 1 is 1 mol of methyl 2-amino-4,5-difluorobenzoate. 0.9 to 1.1 mol. Preferably, it is 0.98 to 1.04 mol, and more preferably 1.01 to 1.02 mol.

  The reaction in Step 1 is performed, for example, in the presence of a solvent. Examples of the solvent include aliphatic hydrocarbons such as pentane, hexane, cyclohexane, and heptane; aromatics such as benzene, toluene, xylene, and chlorobenzene. Group hydrocarbons; ethers such as diethyl ether, tetrahydrofuran and dioxane; and esters such as methyl acetate, ethyl acetate and butyl acetate. Among these, aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene, among which chlorobenzene is preferably used from the viewpoint of reactivity and the like.

  The amount of the solvent used is not particularly limited, but is preferably 500 to 2000 parts by weight, preferably 800 to 1200 parts by weight, based on 100 parts by weight of methyl 2-amino-4,5-difluorobenzoate. If the amount of solvent used is less than 500 parts by weight, stirring may be difficult. Moreover, when the usage-amount of a solvent exceeds 2000 weight part, there exists a possibility that volumetric efficiency may deteriorate.

  The reaction temperature of the said process 1 is 65-80 degreeC, for example. If it is less than 65 degreeC, there exists a possibility that reaction may require a long time, and when it exceeds 80 degreeC, a side reaction will occur and there exists a possibility that a yield may fall as a result. The reaction time varies depending on the reaction temperature, but is usually 1 to 7 hours.

式中、Ｒは式（２）におけるＲと同じ基を示す。
前記フェノキシカルボニルアミン化合物は、単離することなく、引き続き次工程２を行う。なお、所望により反応液から溶媒を留去した後に、引き続き次工程２を行うことができる。
工程１および次工程２の反応は、フェノキシ基のフェニル環が置換されていなくても進行する。工程１および次工程２の反応を阻害しない限り、前記フェニル環は置換されていてもよい。そのようなＲとしては、ハロゲン原子またはニトロ基が挙げられる。 The phenoxycarbonylamine compound thus obtained is represented by the formula (3).

In formula, R shows the same group as R in Formula (2).
The phenoxycarbonylamine compound is then subjected to the next step 2 without isolation. In addition, after distilling a solvent off from a reaction liquid if desired, the following process 2 can be performed continuously.
The reaction of step 1 and next step 2 proceeds even if the phenyl ring of the phenoxy group is not substituted. As long as the reaction of the step 1 and the next step 2 is not inhibited, the phenyl ring may be substituted. Such R includes a halogen atom or a nitro group.

  In the next step 2, the phenoxycarbonylamine compound obtained in the reaction of the above step 1 is reacted with phenylenediamine in which one amino group is protected in the presence of a base in a solvent, and 2- [3 -(4-Acetylamino-phenyl) -ureido] -4,5-difluoro-methyl benzoate via N- [4- (6,7-difluoro-2,4-dioxo-1,4-dihydro- 2H-quinazolin-3-yl) -phenyl] -acetamide is obtained.

  As the phenylenediamine protected on one amino group according to the present invention, for example, phenylenediamine protected on one amino group with a benzyl group, an acetyl group, a t-butoxycarbonyl group or the like can be used. N-acetyl 1,4-phenylenediamine, in which one amino group is protected with an acetyl group, is preferable because of its superiority. As the N-acetyl 1,4-phenylenediamine, commercially available products may be used, and those obtained by various known methods may be used.

  In the reaction of Step 2, the solvents used are aliphatic hydrocarbons such as pentane, hexane, cyclohexane and heptane; aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene; diethyl ether, tetrahydrofuran and dioxane. And ethers such as methyl acetate, ethyl acetate, and butyl acetate. Among these, ethers such as diethyl ether, tetrahydrofuran, and dioxane, and aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene are preferably used from the viewpoint of reactivity and the like. Of these, ethers, particularly dioxane, are preferably used.

  The amount of the solvent used is not particularly limited, but is 500 to 3000 parts by weight and 1200 to 1800 parts by weight with respect to 100 parts by weight of methyl 2-amino-4,5-difluorobenzoate used in Step 1. It is more preferable.

  In the reaction of Step 2, examples of the base used include inorganic bases such as sodium methylate and organic bases such as triethylamine. Among these, the phenols by-produced from the phenoxycarbonylamine compound during the reaction in Step 2 are not sodium salts that are insoluble in the reaction solvent, and are easily dissolved in the solvent without washing with a large amount of water (repulp washing). It is preferable to use an organic base because it can be removed as a filtrate.

Examples of the organic base used include trialkylamines such as trimethylamine, triethylamine, tributylamine, and diisopropylethylamine; dialkylarylamines such as dimethylaniline; heteroaromatic amines such as 2-methyl-5-ethylpyridine and pyridine; Can be mentioned. Among these, trialkylamine is preferable, and triethylamine and tributylamine are more preferable.
The amount of the base used is preferably 0.01 to 0.5 mol, based on 1 mol of methyl 2-amino-4,5-difluorobenzoate used in Step 1, and is 0.05 to 0. It is more preferable to add 1 mol.

  It is preferable that the reaction temperature of the said process 2 is 50-120 degreeC, for example.

  Moreover, although reaction time changes with reaction temperature, it is 0.1 to 24 hours normally.

  The reaction solution thus obtained contained N- [4- (6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -phenyl]-which is the target product. Along with acetamide, methyl 2- [3- (4-acetylamino-phenyl) -ureido] -4,5-difluoro-benzoate prior to cyclization of the desired product may be included.

The methyl 2- [3- (4-acetylamino-phenyl) -ureido] -4,5-difluoro-benzoate before cyclization is subsequently subjected to a cyclization reaction, and the target product N- [4- ( 6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -phenyl] -acetamide can be obtained.
As the cyclization reaction, a method of cyclization by heating the reaction solution obtained in step 2 again, or adding a base as necessary after raising the temperature, or the like is used.

In the cyclization reaction, examples of the base to be added include inorganic bases such as sodium methylate and organic bases such as triethylamine. Among these, it is preferable to add an organic base.
The amount of the base used is preferably 0 to 0.5 mol with respect to methyl 2-amino-4,5-difluorobenzoate used in Step 1.
Moreover, 90-120 degreeC of the temperature of a cyclization reaction is preferable, for example. The reaction time varies depending on the reaction temperature, but is usually 6 to 18 hours.
After completion of the reaction, the mixture is cooled, and the precipitated crystals are filtered and dried to give N- [4- (6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazoline- 3-yl) -phenyl] -acetamide can be obtained.

EXAMPLES The present invention will be specifically described below with reference to examples and comparative examples, but the present invention is not limited to these examples.
The purity was measured according to the following method, and was determined as the area% of the chromatographic peak.
Apparatus: Shimadzu LC10A system Column: Water Xtera RP18 3.5 μm 4.6 mm I.D. D. × 150mm
・ Detection wavelength: 254 nm
-Column temperature: 40 ° C
・ Injection volume: 1 μl
-Mobile phase: acetonitrile / water (0.5 wt% phosphoric acid added) = 50/50
-Mobile phase flow rate: 1.0 ml / min

Example 1
In a 3 L four-necked flask equipped with a stirrer, a condenser, a thermometer and a dropping funnel, 93.5 g (0.50 mol) of methyl 2-amino-4,5-difluorobenzoate and 4-nitrophenyl chloroformate 103.8 g (0.51 mol) and 1000 g of chlorobenzene were charged, and the temperature was raised to 75 ° C. Thereafter, the mixture was stirred at the same temperature for 6 hours, and after completion of the reaction, the solvent was distilled off. The purity of methyl 4,5-difluoro-2- (4-nitro-phenoxycarbonylamino) -benzoate in the reaction solution was 98.5 area% by HPLC (high performance liquid chromatography).

Next, the total amount of methyl 4,5-difluoro-2- (4-nitro-phenoxycarbonylamino) -benzoate obtained, 1600 g of dioxane, and 75.09 g of N-acetyl 1,4-phenylenediamine (0.5 Mol) was added, and 5.0 g (0.05 mol) of triethylamine was added, followed by heating to 65 ° C. and stirring for 1 hour at the same temperature.
Subsequently, the temperature of the reaction solution was raised to 100 ° C., 15.1 g (0.15 mol) of triethylamine was added, and the mixture was stirred at the same temperature for 7 hours. After completion of the reaction, the reaction solution was cooled to 20-30 ° C., and the precipitated product was filtered and dried to give N- [4- (6,7-difluoro-2,4-dioxo-1,4- This gave 152.4 g (0.46 mol) of dihydro-2H-quinazolin-3-yl) -phenyl] -acetamide. The purity of the obtained N- [4- (6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -phenyl] -acetamide is HPLC (high performance liquid chromatography). The yield was 92% based on methyl 2-amino-4,5-difluorobenzoate.

Example 2
In a 3 L four-necked flask equipped with a stirrer, a condenser, a thermometer and a dropping funnel, 93.5 g (0.50 mol) of methyl 2-amino-4,5-difluorobenzoate and 4-nitrophenyl chloroformate 98.76 g (0.49 mol) and 1000 g of chlorobenzene were charged, and the temperature was raised to 75 ° C. Thereafter, the mixture was stirred at the same temperature for 6 hours, and after completion of the reaction, the solvent was distilled off. The purity of methyl 4,5-difluoro-2- (4-nitro-phenoxycarbonylamino) -benzoate in the reaction solution was 97.5 area% by HPLC (high performance liquid chromatography).

Next, the total amount of methyl 4,5-difluoro-2- (4-nitro-phenoxycarbonylamino) -benzoate obtained, 1600 g of dioxane, and 75.09 g of N-acetyl 1,4-phenylenediamine (0.5 Mol) was added, and 5.0 g (0.05 mol) of triethylamine was added, followed by heating to 65 ° C. and stirring for 1 hour at the same temperature.
Subsequently, the temperature of the reaction solution was raised to 100 ° C., 15.1 g (0.15 mol) of triethylamine was added, and the mixture was stirred at the same temperature for 7 hours. After completion of the reaction, the reaction solution was cooled to 20-30 ° C., and the precipitated product was filtered and dried to give N- [4- (6,7-difluoro-2,4-dioxo-1,4- 145.76 g (0.44 mol) of dihydro-2H-quinazolin-3-yl) -phenyl] -acetamide were obtained. The purity of the obtained N- [4- (6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -phenyl] -acetamide is HPLC (high performance liquid chromatography). The yield was 88% based on methyl 2-amino-4,5-difluorobenzoate.

Example 3
In a 3 L four-necked flask equipped with a stirrer, a condenser, a thermometer and a dropping funnel, 93.5 g (0.50 mol) of methyl 2-amino-4,5-difluorobenzoate and 4-nitrophenyl chloroformate 104.8 g (0.52 mol) and 1000 g of chlorobenzene were charged, and the temperature was raised to 75 ° C. Thereafter, the mixture was stirred at the same temperature for 6 hours, and after completion of the reaction, the solvent was distilled off. The purity of methyl 4,5-difluoro-2- (4-nitro-phenoxycarbonylamino) -benzoate in the reaction solution was 97.8 area% by HPLC (high performance liquid chromatography).

Next, the total amount of methyl 4,5-difluoro-2- (4-nitro-phenoxycarbonylamino) -benzoate obtained, 1600 g of dioxane, and 75.09 g of N-acetyl 1,4-phenylenediamine (0.5 Mol) was added, and 5.0 g (0.05 mol) of triethylamine was added, followed by heating to 65 ° C. and stirring for 1 hour at the same temperature.
Subsequently, the temperature of the reaction solution was raised to 100 ° C., 15.1 g (0.15 mol) of triethylamine was added, and the mixture was stirred at the same temperature for 7 hours. After completion of the reaction, the reaction solution was cooled to 20-30 ° C., and the precipitated product was filtered and dried to give N- [4- (6,7-difluoro-2,4-dioxo-1,4- 144.09 g (0.435 mol) of dihydro-2H-quinazolin-3-yl) -phenyl] -acetamide were obtained. The purity of the obtained N- [4- (6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -phenyl] -acetamide is HPLC (high performance liquid chromatography). 99.8 area%, and the yield was 87% based on methyl 2-amino-4,5-difluorobenzoate.

Example 4
In a 3 L four-necked flask equipped with a stirrer, a condenser, a thermometer and a dropping funnel, 93.5 g (0.50 mol) of methyl 2-amino-4,5-difluorobenzoate and 4-nitrophenyl chloroformate 90.7 g (0.45 mol) and 1000 g of chlorobenzene were charged, and the temperature was raised to 75 ° C. Thereafter, the mixture was stirred at the same temperature for 6 hours, and after completion of the reaction, the solvent was distilled off. The purity of methyl 4,5-difluoro-2- (4-nitro-phenoxycarbonylamino) -benzoate in the reaction solution was 91.3 area% by HPLC (high performance liquid chromatography).

Next, the total amount of methyl 4,5-difluoro-2- (4-nitro-phenoxycarbonylamino) -benzoate obtained, 1600 g of dioxane, and 75.09 g of N-acetyl 1,4-phenylenediamine (0.5 Mol) was added, and 5.0 g (0.05 mol) of triethylamine was added, followed by heating to 65 ° C. and stirring for 1 hour at the same temperature.
Subsequently, the temperature of the reaction solution was raised to 100 ° C., 15.1 g (0.15 mol) of triethylamine was added, and the mixture was stirred at the same temperature for 7 hours. After completion of the reaction, the reaction solution was cooled to 20-30 ° C., and the precipitated product was filtered and dried to give N- [4- (6,7-difluoro-2,4-dioxo-1,4- Dihydro-2H-quinazolin-3-yl) -phenyl] -acetamide 135.8 g (0.41 mol) was obtained. The purity of the obtained N- [4- (6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -phenyl] -acetamide is HPLC (high performance liquid chromatography). The yield was 82% based on methyl 2-amino-4,5-difluorobenzoate.

Example 5
In a 3 L four-necked flask equipped with a stirrer, a condenser, a thermometer and a dropping funnel, 93.5 g (0.50 mol) of methyl 2-amino-4,5-difluorobenzoate and 4-nitrophenyl chloroformate 110.9 g (0.55 mol) and 1000 g of chlorobenzene were charged, and the temperature was raised to 75 ° C. Thereafter, the mixture was stirred at the same temperature for 6 hours, and after completion of the reaction, the solvent was distilled off. The purity of methyl 4,5-difluoro-2- (4-nitro-phenoxycarbonylamino) -benzoate in the reaction solution was 95.2 area% by HPLC (high performance liquid chromatography).

  Next, the total amount of methyl 4,5-difluoro-2- (4-nitro-phenoxycarbonylamino) -benzoate obtained, 1600 g of dioxane, and 75.09 g of N-acetyl 1,4-phenylenediamine (0.5 Mol) was added, and 25.3 g (0.25 mol) of triethylamine was added, followed by heating to 100 ° C. and stirring at the same temperature for 7 hours. After completion of the reaction, the reaction solution was cooled to 20-30 ° C., and the precipitated product was filtered and dried to give N- [4- (6,7-difluoro-2,4-dioxo-1,4- 142.4 g (0.43 mol) of dihydro-2H-quinazolin-3-yl) -phenyl] -acetamide were obtained. The purity of the obtained N- [4- (6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -phenyl] -acetamide is HPLC (high performance liquid chromatography). The yield was 86% based on methyl 2-amino-4,5-difluorobenzoate.

Comparative Example 1
In a 3 L four-necked flask equipped with a stirrer, a condenser, a thermometer and a dropping funnel, 93.5 g (0.50 mol) of methyl 2-amino-4,5-difluorobenzoate and 4-nitrophenyl chloroformate 120.9 g (0.60 mol) and 1000 g of chlorobenzene were charged, and the temperature was raised to 75 ° C. Thereafter, the mixture was stirred at the same temperature for 6 hours, and after completion of the reaction, the solvent was distilled off. The purity of methyl 4,5-difluoro-2- (4-nitro-phenoxycarbonylamino) -benzoate in the reaction solution was 91.5 area% by HPLC (high performance liquid chromatography).

Next, the total amount of methyl 4,5-difluoro-2- (4-nitro-phenoxycarbonylamino) -benzoate obtained, 1600 g of dioxane, and 75.09 g of N-acetyl 1,4-phenylenediamine (0.5 Next, 5.0 g (0.05 mol) of triethylamine was added, and then the temperature was raised to 65 ° C., followed by stirring at the same temperature for 1 hour.
Subsequently, the temperature of the reaction solution was raised to 100 ° C., 15.1 g (0.15 mol) of triethylamine was added, and the mixture was stirred at the same temperature for 7 hours. After completion of the reaction, the reaction solution was cooled to 20-30 ° C., and the precipitated product was filtered and dried to give N- [4- (6,7-difluoro-2,4-dioxo-1,4- 105.0 g (0.317 mol) of dihydro-2H-quinazolin-3-yl) -phenyl] -acetamide were obtained. The purity of the obtained N- [4- (6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -phenyl] -acetamide is HPLC (high performance liquid chromatography). The yield was 63% based on methyl 2-amino-4,5-difluorobenzoate.

  The final product obtained in Comparative Example 1, N- [4- (6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -phenyl] -acetamide, , Produced by an excess of phenyl chloroformate after reaction between methyl 2-amino-4,5-difluorobenzoate and phenyl chloroformate and N-acetyl 1,4-phenylenediamine used in the next step By-product, N- {4- [3-acetylamino-phenyl) -ureido] -phenyl} -acetamide and the like were confirmed by HPLC (high performance liquid chromatography) to be about 17 area%. In addition to the by-products and unreacted compounds used in each reaction step, it was confirmed that a plurality of by-products having unknown structures were present in HPLC (high performance liquid chromatography) by about 5 area%. . Therefore, N- [4- (6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -phenyl] -acetamide obtained in Comparative Example 1 is It is not preferred for use as an important production precursor of the body. On the other hand, in Examples 1 to 5, the presence of such a by-product of unknown structure was not confirmed, and the production method of the present application was N- [as an important production precursor of a pharmaceutical intermediate. 4- (6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -phenyl] -acetamide can be produced with high purity, and the conventional N- [4- For the production method of (6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -phenyl] -acetamide (for example, the production method described in Patent Document 1) Was found to be a production method capable of exhibiting a very advantageous effect in industrial production, in which an isolation step such as filtration can be omitted.

Claims (3)

Formula (1):

With respect to 1 mol of methyl 2-amino-4,5-difluorobenzoate represented by the formula (2):

(Wherein R represents a hydrogen atom, a halogen atom, or a nitro group), 0.9 to 1.1 mol of a phenyl chloroformate compound represented by formula (1), and the formula (1) obtained in step 1 3):

(Wherein R represents the same group as R in formula (2)), without isolating the phenoxycarbonylamine compound represented by formula (4):

Comprising a step 2 of reacting N-acetyl 1,4-phenylenediamine represented by the above in a solvent in the presence of a base:

A method for producing N- [4- (6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -phenyl] -acetamide represented by the formula:
  The production method according to claim 1, wherein the amount of the phenyl chloroformate compound relative to 1 mol of methyl 2-amino-4,5-difluorobenzoate is 0.98 to 1.04 mol.   The manufacturing method of Claim 1 or 2 whose base in process 2 is an organic base.