JP2006036758A - Process for producing iminoquinazolinone derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a novel and economical process for producing an iminoquinazolinone derivative useful as an active ingredient for medicines and agrochemicals. <P>SOLUTION: An aniline derivative represented by formula (II) is reacted with a halogenated formic ester to obtain a phenylcarbamic ester. The phenylcarbamic ester is reacted with a halogenating agent in the presence of a free-radical initiator to obtain a halomethylphenylcarbamic ester. The halomethylphenylcarbamic ester is reacted with hydrazine to obtain an aminoquinazoline derivative. The aminoquinazoline derivative is reacted with an aldehyde to produce an iminoquinazolinone derivative represented by formula (I). By the process, an iminoquinazolinone derivative useful as a starting material or active ingredient for medicines and agrochemicals can be efficiently provided at a low cost. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a novel method for producing iminoquinazolinones useful as raw materials or active ingredients for pharmaceuticals and agricultural chemicals.

  It is known that iminoquinazolinones related to the present invention can be produced by using a corresponding halomethylphenylcarbamic acid ester as a starting material, and reacting with an aldehyde after a cyclization reaction with hydrazine (for example, Patent Document 1). reference). Further, it is known that halomethylphenylcarbamic acid esters can be produced by halogenating phenylcarbamic acid esters (see, for example, Patent Document 2).

JP 2001-342186 A Japanese Patent Laid-Open No. 10-298156

  When the production of the iminoquinazolinones related to the present invention is carried out by a known method, it is necessary to use expensive halomethylphenylcarbamic acid esters as starting materials, and economical efficiency using industrially readily available and inexpensive starting materials. There has been a demand for a method for producing iminoquinazolinones excellent in the above-mentioned.

  As a result of diligent studies to solve the above-mentioned problems, the present inventors have developed a series of production methods characterized in that, in the production of iminoquinazolinones, industrially easily available and inexpensive anilines are used as starting materials. The headline and the present invention were completed.

（式中、Ｒは同一又は異なっても良く、ハロゲン原子、シアノ基、ニトロ基、C₁-C₆アル
キル基、C₁-C₆アルキルカルボニル基、カルボキシル基、C₁-C₆アルコキシカルボニル基、ハロC₁-C₆アルキル基又はハロ C₁-C₆アルコキシ基を示し、ｎは０〜４の整数を示す。）
で表されるアニリン類と一般式（III）

ＸＣＯ₂Ｒ¹ （III）

（式中、Ｘは塩素原子、臭素原子又はヨウ素原子を示し、Ｒ¹はC₁-C₆アルキル基又はフェニル基を示す。）で表されるハロゲン化ギ酸エステル類とを反応させ、一般式（IV）

（式中、Ｒ、Ｒ¹及びｎは前記に同じ。）で表されるフェニルカルバミン酸エステル類と
し、 That is, the present invention provides the following general formula (II)

(In the formula, R may be the same or different, and is a halogen atom, cyano group, nitro group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkylcarbonyl group, carboxyl group, C ₁ -C ₆ alkoxycarbonyl group. A halo C ₁ -C ₆ alkyl group or a halo C ₁ -C ₆ alkoxy group, and n represents an integer of 0 to 4.)
And the general formula (III)

XCO ₂ R ¹ (III)

(Wherein, X represents a chlorine atom, a bromine atom or an iodine atom, and R ¹ represents a C ₁ -C ₆ alkyl group or a phenyl group). (IV)

(Wherein R, R ¹ and n are the same as defined above),

（式中、Ｙは塩素原子、臭素原子又はヨウ素原子を示し、Ｒ、Ｒ¹及びｎは前記に同じ。
）で表されるハロメチルフェニルカルバミン酸エステル類とし、該ハロメチルフェニルカルバミン酸エステル類を単離し又は単離せずしてヒドラジンと反応させ、一般式（VI）

（式中、Ｒ及びｎは前記に同じ。）で表されるアミノキナゾリノン類とし、 The phenylcarbamic acid esters are isolated or not isolated and reacted with a halogenating agent in the presence of a radical initiator,

Wherein Y represents a chlorine atom, a bromine atom or an iodine atom, and R, R ¹ and n are the same as above.
A halomethylphenylcarbamic acid ester represented by the following general formula (VI), and the halomethylphenylcarbamic acid ester is reacted with hydrazine with or without isolation:

(Wherein R and n are the same as defined above), and aminoquinazolinones represented by

（式中、Ｒ、Ｒ²及びｎは前記に同じ。）で表されるイミノキナゾリノン類の製造方法に
関するものである。 The aminoquinazolinones are isolated or not isolated and are represented by the general formula (VII)

R ² CHO (VII)

(In the formula, R ² may be the same or different and is a halogen atom, a cyano group, a nitro group, a C ₁ -C ₆ alkyl group, a halo C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ alkoxy group. Or a substituted phenyl group having one or more substituents selected from halo C ₁ -C ₆ alkoxy groups, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-furyl group, 3-furyl group, A general formula (I), which is reacted with an aldehyde represented by 2-thienyl group or 3-thienyl group.
)

(Wherein R, R ² and n are the same as above), and relates to a method for producing iminoquinazolinones.

  According to the present invention, desired iminoquinazolinones can be produced and supplied simply and inexpensively.

The present invention will be described in detail below.
In the definition of iminoquinazolinones represented by the general formula (I) of the present invention, “halogen atom” refers to a chlorine atom, bromine atom, iodine atom or fluorine atom, and “C ₁ -C ₆ alkyl” refers to For example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-
A straight-chain or branched alkyl group having 1 to 6 carbon atoms such as butyl, t-butyl, n-pentyl, n-hexyl and the like, and “halo C ₁ -C ₆ alkyl” means, for example, trifluoro Same as methyl group, pentafluoroethyl group, 1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl group, 2,2,2-trifluoro-1- (trifluoromethyl) ethyl group Or a linear or branched alkyl group having 1 to 6 carbon atoms substituted with one or more halogen atoms which may be different.

（式中、Ｙ、Ｒ、Ｒ¹、Ｒ²及びｎは前記に同じ。）
即ち、一般式（II）で表されるアニリン類と一般式（III）で表されるハロゲン化ギ酸
エステル類とを塩基の存在下、不活性溶媒の存在下又は不存在下に反応させることにより、一般式（IV）で表されるフェニルカルバミン酸エステル類とし、該フェニルカルバミン酸エステル類を単離し又は単離せずして、不活性溶媒中、ラジカル開始剤の存在下にハロゲン化剤と反応させることにより、一般式（V）で表されるハロメチルフェニルカルバミ
ン酸エステル類とし、該ハロメチルフェニルカルバミン酸エステル類を単離し又は単離せずして、不活性溶媒の存在下又は不存在下にヒドラジンと反応させることにより、一般式（VI）で表されるアミノキナゾリン類とし、該アミノキナゾリン類を単離し又は単離せずして、不活性溶媒の存在下又は不存在下に一般式（VII）で表されるアルデヒド類と反応
させることにより、一般式（I）で表されるイミノキナゾリノン類を製造することができ
る。 A method for producing the substituted iminoquinazolinones of the present invention is schematically represented as follows.

(In the formula, Y, R, R ¹ , R ² and n are the same as above.)
That is, by reacting the anilines represented by the general formula (II) and the halogenated formate esters represented by the general formula (III) in the presence of a base, in the presence or absence of an inert solvent. A phenylcarbamic acid ester represented by the general formula (IV), and the phenylcarbamic acid ester is reacted with a halogenating agent in the presence of a radical initiator in an inert solvent with or without isolation. To produce halomethylphenylcarbamic acid esters represented by the general formula (V), with or without isolating the halomethylphenylcarbamic acid esters in the presence or absence of an inert solvent. Is reacted with hydrazine to give aminoquinazolines represented by the general formula (VI), and the aminoquinazolines are isolated or not isolated in the presence or absence of an inert solvent. The iminoquinazolinones represented by the general formula (I) can be produced by reacting with aldehydes represented by the general formula (VII) below.

General formula (II) → General formula (IV)
Examples of the halogenated formate represented by the general formula (III) include methyl chloroformate, ethyl chloroformate, phenyl chloroformate, methyl bromoformate, and ethyl bromate. The amount of the aniline represented by the general formula (II) can be used in an amount from 0.5 equivalent to an excess amount, preferably about 1 equivalent to 3 equivalents, more preferably 1 equivalent.
Equivalent to about 1.5 equivalents.
Examples of the base used in this reaction include inorganic bases such as sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, potassium carbonate and potassium hydroxide, and organic bases such as triethylamine, diethylaniline and pyridine. May be used alone or in admixture of two or more. These bases may be used as they are or as an aqueous solution. The amount of the base used is about 1 equivalent to 10 equivalents, preferably about 1 equivalent to 3 equivalents, more preferably about 1 equivalent to 2 equivalents with respect to the anilines represented by the general formula (II). is there.

The inert solvent used in this reaction is not particularly limited as long as it does not significantly inhibit the progress of this reaction, and is not limited, but ether solvents such as dioxane, tetrahydrofuran (THF), tertiary butyl methyl ether, dimethyl Amide solvents such as formamide (DMF), dimethylacetamide (DMAC) and N-methylpyrrolidone, aromatic solvents such as toluene, xylene and chlorobenzene, ester solvents such as ethyl acetate and butyl acetate, ketones such as methyl ethyl ketone and cyclohexanone System solvents, halogenated hydrocarbon solvents such as chloroform and dichloromethane, water and the like can be used. These solvents can be used alone or in admixture of two or more.

  The reaction temperature for this reaction can be carried out in the range of 0 ° C. to the boiling point of the solvent, preferably about 10 ° C. to about 200 ° C., more preferably about 10 ° C. to about 100 ° C. The reaction time is not constant depending on the reaction scale and reaction temperature, but may be appropriately selected within the range of 1 minute to 24 hours. After completion of the reaction, it may be isolated from the reaction system containing the target product according to a conventional method, and the target product can be produced by purification by recrystallization, column chromatography or the like, if necessary. Moreover, by refine | purifying by operation, such as concentration, extraction, washing | cleaning, and liquid separation as needed, it can use for the next process, without isolating.

General formula (IV) → General formula (V)
Examples of the halogenating agent used in this reaction include chlorine, bromine, iodine, sulfuryl chloride, sulfuryl bromide, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, 1 , 3-dibromo-5,5-dimethylhydantoin, 1,3-diiodo-5,5-dimethylhydantoin and the like. The amount of the halogenating agent to be used is generally about 0.5 equivalent to 3 equivalents, preferably 0.8 equivalents to 1.5 equivalents, relative to the phenylcarbamic acid ester represented by the general formula (IV). is there.

  As radical initiators used in this reaction, 2,2′-azobisisobutyronitrile (AIBN), 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile) (AMVN), 2 Azobis compounds such as 2,2′-azobis (2,4-dimethylvaleronitrile) (ADVN), peracid radical initiators such as benzoyl peroxide, and light. The amount of radical initiators other than light can be used in an amount of usually about 0.002 equivalents to 2 equivalents, preferably 0.01 equivalents, relative to the phenylcarbamic acid esters represented by the general formula (IV). About 0.05 equivalent. These radical initiators can be used alone or in admixture of two or more.

The inert solvent used in this reaction is not particularly limited as long as it does not significantly inhibit the progress of this reaction. For example, halogenated hydrocarbon solvents such as methylene chloride, chloroform and dichloroethane, and halogenated aromatics such as chlorobenzene and fluorobenzene. Family solvents can be used. These solvents can be used alone or in admixture of two or more.
The reaction temperature for this reaction can be carried out in the range of 0 ° C. to the boiling point of the solvent, preferably about 20 ° C. to about 200 ° C., more preferably about 20 ° C. to about 70 ° C. The reaction time is not constant depending on the reaction scale and reaction temperature, but may be appropriately selected within the range of 1 minute to 24 hours. After completion of the reaction, it may be isolated from the reaction system containing the target product according to a conventional method, and the target product can be produced by purification by recrystallization, column chromatography or the like, if necessary. Moreover, it can be used for the next step without isolation by purification by concentration, extraction, washing, liquid separation, etc., if necessary.

General formula (V) → General formula (VI)
Examples of hydrazine used in this reaction include anhydrous hydrazine, hydrazine hydrate, hydrazine hydrochloride, hydrazine sulfate, etc., and anhydrous hydrazine and hydrazine hydrate should be used as they are or diluted with an inert solvent such as water. Can do. Further, salts such as hydrazine hydrochloride and hydrazine sulfate may be used as free hydrazine by adding organic bases such as triethylamine and inorganic bases such as sodium carbonate, sodium hydrogen carbonate, sodium hydroxide and potassium hydroxide. . The amount of hydrazine to be used can generally be about 1 equivalent to 10 equivalents, preferably 1 equivalent to 5 equivalents, relative to the halomethylphenylcarbamic acid ester represented by the general formula (V).
The solvent used in this reaction is not particularly limited as long as it does not significantly inhibit the progress of this reaction. However, ether solvents such as dioxane, tetrahydrofuran (THF), and tertiary butyl methyl ether, dimethylformamide ( DMF), amide solvents such as dimethylacetamide (DMAC) and N-methylpyrrolidone, aromatic solvents such as toluene, xylene, chlorobenzene and fluorobenzene, ester solvents such as ethyl acetate and butyl acetate, methyl ethyl ketone and cyclohexanone Ketone solvents, halogenated hydrocarbon solvents such as chloroform and dichloromethane, alcohol solvents such as methanol, ethanol, propanol, 2-propanol and butanol, water and the like can be used. These solvents can be used alone or in admixture of two or more.

  The reaction temperature for this reaction can be carried out in the range of room temperature to the boiling point of the solvent, but is preferably between about 20 ° C and about 200 ° C, more preferably between about 20 ° C and 100 ° C. The reaction time is not constant depending on the reaction scale and reaction temperature, but may be appropriately selected within the range of 1 minute to 24 hours. After completion of the reaction, it may be isolated from the reaction system containing the target product according to a conventional method, and the target product can be produced by purification by recrystallization, column chromatography or the like, if necessary. Or it can use for the next process, without isolating by refine | purifying by concentration, extraction, washing | cleaning, liquid separation, etc. as needed.

General formula (VI) → General formula (I)
The amount of the aldehyde represented by the general formula (VII) used in this reaction can be 0.5 to 10 equivalents relative to the aminoquinazolinones represented by the general formula (VI). Is 0.8 to 3 equivalents.
The solvent used in this reaction is not particularly limited as long as it does not significantly inhibit the progress of this reaction, but alcohol solvents such as methanol, ethanol, 2-propanol, propanol, butanol, dioxane, tetrahydrofuran (THF) ), Ether solvents such as tertiary butyl methyl ether, amide solvents such as dimethylformamide (DMF), dimethylacetamide (DMAC), N-methylpyrrolidone, aromatic solvents such as toluene, xylene, chlorobenzene, fluorobenzene, Ester solvents such as ethyl acetate and butyl acetate, ketone solvents such as methyl ethyl ketone and cyclohexanone, halogenated hydrocarbon solvents such as chloroform and dichloromethane, water and the like can be used. These solvents can be used alone or in admixture of two or more.

The reaction temperature may be in the range of −50 ° C. to the boiling point of the solvent used, but preferably 0 ° C. to 100 ° C. The reaction time is not constant depending on the reaction scale and reaction temperature, but may be appropriately selected within the range of 1 minute to 24 hours. After the reaction, the target compound of the general formula (I) can be isolated by crystallization from the reaction mixture, followed by filtration and washing. The target compound is represented by the general formula (I). Iminoquinazolinones are obtained. Although the quality may be sufficient as it is, it can be purified by means of washing or recrystallization using the reaction solvent if necessary.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.
Example 1. Production of 3- (3-pyridylmethylideneamino) -3,4-dihydro-6-pentafluoroethyl-2 (1H) quinazolinone (example in which each intermediate was produced without isolation)
To a mixture of 4.80 g (21.3 mmol) of 2-methyl-4-pentafluoroethylaniline, 2.52 g (30.0 mmol) of sodium bicarbonate, 8 ml of tetrahydrofuran and 2 ml of water, 2.35 g of methyl chloroformate at room temperature ( 27.8 mmol) was added dropwise over 3 hours with stirring. After further stirring at room temperature for 1 hour, 26 ml of ethyl acetate and 10 ml of water were added to separate the layers. To the organic layer, 50 ml of chlorobenzene was added and heated under normal pressure, and about 35 ml of a mixture of ethyl acetate and chlorobenzene was distilled off. The obtained solution of methyl 2-methyl-4-pentafluoroethylphenylcarbamate was cooled to room temperature, and then 0.27 g of 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile) was added to the solution ( 0.88 mmol) was added. At 40 ° C., 3.40 g (25.2 mmol) of sulfuryl chloride was added dropwise with stirring. After completion of the addition, the mixture was further stirred at 40 ° C. for 1 hour. A solution prepared by dissolving 0.7 g of sodium hydrogen carbonate in 12.6 ml of water was added at room temperature, followed by liquid separation. The organic layer was concentrated under reduced pressure, and about 15 ml of chlorobenzene was distilled off to obtain a solution of methyl 2-chloromethyl-4-pentafluoroethylphenylcarbamate. The obtained solution of methyl 2-chloromethyl-4-pentafluoroethylphenylcarbamate was added dropwise at 80 ° C. with stirring to a solution prepared from 3.12 g (62.4 mmol) of hydrazine hydrate and 5 ml of 2-propanol. did. The mixture was further stirred at 80 ° C. for 1 hour, washed with 12 ml of warm water, and separated to obtain a solution of 3-amino-3,4-dihydro-6-pentafluoroethyl-2 (1H) -quinazolinone. To the resulting solution of 3-amino-3,4-dihydro-6-pentafluoroethyl-2 (1H) -quinazolinone was added 1 ml of 2-propanol, followed by 6.45 g (60.2 mmol) of nicotinaldehyde at 50 ° C. ) Was added dropwise with stirring. After further stirring at 50 ° C. for 5 hours, the precipitated crystals were collected by filtration. The obtained crystals were washed sequentially with 20 ml of water and 20 ml of chlorobenzene, dried at 50 ° C., and the desired product 3- (3-pyridylmethylideneamino) -3,4-dihydro-6-pentafluoroethyl-2. (1H) 5.92 g of quinazolinone was obtained.
Yield: 75%
Physical property: Melting point 298-300 ° C

Example 2 Production of 3- (3-pyridylmethylideneamino) -3,4-dihydro-6-trifluoromethoxy-2 (1H) quinazolinone (example in which each intermediate was produced without isolation)
To a mixture of 5.10 g (26.7 mmol) of 2-methyl-4-trifluoromethoxyaniline, 3.31 g (39.4 mmol) of sodium bicarbonate, 10 ml of tetrahydrofuran and 4 ml of water, 3.00 g of methyl chloroformate at room temperature ( 31.7 mmol) was added dropwise over 3 hours with stirring. After further stirring at room temperature for 1 hour, 40 ml of ethyl acetate and 20 ml of water were added to separate the layers. 70 ml of chlorobenzene was added to the organic layer and heated under normal pressure, and about 50 ml of a mixture of ethyl acetate and chlorobenzene was distilled off. The obtained methyl 2-methyl-4-trifluoromethoxyphenylcarbamate solution was cooled to room temperature, and 0.22 g of 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile) was added to the solution ( 0.91 mmol) was added. At 40 ° C., 3.25 g (24.1 mmol) of sulfuryl chloride was added dropwise with stirring. After completion of the addition, the mixture was further stirred at 40 ° C. for 1 hour. A solution prepared by dissolving 1.1 g of sodium hydrogen carbonate in 14.3 ml of water was added at room temperature, followed by liquid separation. The organic layer was concentrated under reduced pressure, and about 15 ml of chlorobenzene was distilled off to obtain a solution of methyl 2-chloromethyl-4-trifluoromethoxyphenylcarbamate. The resulting solution of methyl 2-chloromethyl-4-trifluoromethoxyphenylcarbamate was added dropwise to a solution prepared from 3.51 g (70.2 mmol) of hydrazine hydrate and 6 ml of 2-propanol while stirring at 80 ° C. did. The mixture was further stirred at 80 ° C. for 1 hour, washed with 15 ml of warm water, and separated to obtain a solution of 3-amino-3,4-dihydro-6-trifluoromethoxy-2 (1H) -quinazolinone. To the obtained solution of 3-amino-3,4-dihydro-6-trifluoromethoxy-2 (1H) -quinazolinone was added 1 ml of 2-propanol, followed by 7.12 g (66.5 mmol) of nicotinaldehyde at 50 ° C. ) Was added dropwise with stirring. After further stirring at 50 ° C. for 5 hours, the precipitated crystals were collected by filtration. The obtained crystals were washed successively with 30 ml of water and 20 ml of chlorobenzene, dried at 50 ° C., and the desired product 3- (3-pyridylmethylideneamino) -3,4-dihydro-6-trifluoromethoxy-2. (1H) 6.81 g of quinazolinone was obtained.
Yield: 76%
Physical property: melting point 264-266 ° C.

Example 3 Preparation of methyl 2-methyl-4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] phenylcarbamate 2-methyl-4- [1,2,2,2-tetrafluoro -1- (Trifluoromethyl) ethyl] aniline 275.0 g (1.00 mol), sodium hydrogen carbonate 101.0 g (1.20 mol), tetrahydrofuran 300 ml and water 300 ml in a mixture at 10 ° C. with cooling Methyl 104.0 g (1.10 mol) was added dropwise over 1 hour with stirring. After completion of dropping, the mixture was further stirred at room temperature for 3 hours. The organic layer was separated and the aqueous layer was extracted with 300 ml of ethyl acetate. The organic layers were combined, washed with saturated brine, and concentrated under reduced pressure. The obtained white crystals were washed with 200 ml of n-hexane to obtain 303.2 g of the desired product.
Yield: 91%
Physical property: Melting point 68-70 ° C

Example 4 Preparation of methyl 2-chloromethyl-4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] phenylcarbamate 2-methyl-4- [1,2,2,2-tetra 20.0 g (60.0 mmol) of methyl fluoro-1- (trifluoromethyl) ethyl] phenylcarbamate was dissolved in 100 ml of chlorobenzene and heated to 35 ° C. After adding 0.7 g (2.3 mmol) of 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile) and stirring for 5 minutes, 9.7 g (71.9 mmol) of sulfuryl chloride was stirred. The solution was added dropwise over 1 hour. After completion of dropping, the mixture was further stirred at 35 ° C. for 1 hour. The reaction solution was washed with 100 ml of water, and then washed twice with 100 ml of saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The concentrated residue was recrystallized with a mixed solvent of ethyl acetate / n-hexane to obtain 17.9 g of the desired product.
Yield: 81%
Physical property: Melting point 89 ° C

Embodiment 5 FIG. Production of 3-amino-3,4-dihydro-6- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] -2 (1H) quinazoline 291.5 g of hydrous hydrazine (5. 83 mol) was added to 400 ml of 2-propanol and the temperature was raised to 80 ° C. Next, a solution of 613.7 g (1.67 mol) of methyl 2-chloromethyl-4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] phenylcarbamate in 1200 ml of chlorobenzene was stirred. The solution was added dropwise over 4 hours. After completion of the dropwise addition, the mixture was further stirred at 80 ° C. for 1 hour, and 1200 ml of water was added. The mixture was further stirred for 30 minutes at 80 ° C. and then separated. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. 500 ml of n-hexane was added to the residue and the precipitated crystals were collected by filtration to obtain 530.6 g of the desired product as an amorphous solid.
Yield: 96%
Physical properties: ¹ H-NMR (400 MHz, solvent DMSO-d6, δ value)
4.5 (s, 2H), 4.7 (s, 2H), 6.9 (d, 1H),
7.4 (m, 2H), 9.7 (s, 1H)

Example 6 3- (3-Pyridylmethylideneamino) -3,4-dihydro-6- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] -2 (1H) quinazolinone 3- 50.0 g (151 mmol) of amino-3,4-dihydro-6- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] -2 (1H) quinazoline was dissolved in 500 ml of tetrahydrofuran. Then, 19.4 g (181 mmol) of nicotinaldehyde was added dropwise at 40 ° C. over 1 hour with stirring. After completion of dropping, the mixture was further stirred at 50 ° C. for 3 hours and cooled to room temperature. The precipitated crystals were collected by filtration and washed with 50 ml of tetrahydrofuran to obtain 61.5 g of the desired product.
Yield: 96.9%
Physical property: Melting point> 300 ° C

Example 7 Preparation of 3-phenylmethylideneamino-3,4-dihydro-6- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] -2 (1H) quinazolinone 3-amino-3, 2-dihydro-6- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] -2 (1H) quinazolinone 20.0 g (60.4 mmol) was dissolved in 100 ml of tetrahydrofuran, The benzaldehyde 7.6g (71.7 mmol) was dripped at 1 degreeC over 1 hour at 40 degreeC. After completion of dropping, the mixture was further stirred at 50 ° C. for 3 hours and cooled to room temperature. The solvent was distilled off under reduced pressure, and the residue was washed with n-hexane to obtain 20.7 g of the desired product.
Yield: 94%
Physical properties: ¹ H-NMR (400 MHz, solvent DMSO-d6, δ value)
5.2 (s, 2H), 7.1 (d, 1H), 7.4 (m, 4H),
7.5 (m, 2H), 7.6 (m, 2H), 7.9 (s, 1H)

Example 8 FIG. Production of 3- (3-pyridylmethylideneamino) -3,4-dihydro-6- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] -2 (1H) quinazolinone (each Example of production without isolation of intermediate)
2.79 g (21.0 mmol) 2-methyl-4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] aniline, 2.20 g (26.2 mmol) sodium bicarbonate Then, 2.46 g (26.0 mmol) of methyl chloroformate was added dropwise to a mixture of 8 ml of ethyl acetate and 2 ml of water at room temperature over 3 hours with stirring. After further stirring at room temperature for 1 hour, 6 ml of ethyl acetate and 10 ml of water were added to separate the layers. 30 ml of chlorobenzene was added to the organic layer and heated under normal pressure, and about 20 ml of a mixture of ethyl acetate and chlorobenzene was distilled off. The obtained solution of methyl 2-methyl-4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] phenylcarbamate was cooled to room temperature, and 2,2′- 0.25 g (0.81 mmol) of azobis (4-methoxy-2,4-dimethylvaleronitrile) was added. Sulfuryl chloride (3.18 g, 23.6 mmol) was added dropwise at 40 ° C. with stirring, and the mixture was further stirred at 40 ° C. for 1 hour after the completion of the addition. A solution prepared by dissolving 0.6 g of sodium hydrogen carbonate in 11.6 ml of water was added at room temperature, followed by liquid separation. The organic layer was concentrated under reduced pressure, and about 10 ml of chlorobenzene was distilled off to obtain methyl 2-chloromethyl-4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] phenylcarbamate. A solution was obtained. The resulting solution of methyl 2-chloromethyl-4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] phenylcarbamate was added to 2.92 g (58.4 mmol) of hydrazine hydrate. And added dropwise to a solution prepared from 4 ml of 2-propanol at 80 ° C. with stirring. The mixture was further stirred at 80 ° C. for 1 hour, washed with 12 ml of warm water, and separated to give 3-amino-3,4-dihydro-6- [1,2,2,2-tetrafluoro-1- (trifluoromethyl). A solution of ethyl] -2 (1H) -quinazolinone was obtained. To the obtained 3-amino-3,4-dihydro-6- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] -2 (1H) -quinazolinone solution, 2-propanol ( 1 ml) was added, followed by dropwise addition of 2.09 g (19.5 mmol) of nicotinaldehyde with stirring at 50 ° C. After further stirring at 50 ° C. for 5 hours, the precipitated crystals were collected by filtration, washed successively with 20 ml of water and 20 ml of chlorobenzene, dried at 50 ° C., and the desired product 3- (3-pyridylmethylideneamino)- 6.55 g of 3,4-dihydro-6- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] -2 (1H) quinazolinone was obtained.
Yield: 78%
Physical property: Melting point> 300 ° C

The iminoquinazolinones represented by the general formula (I) that can be produced by the production method of the present invention are useful as intermediates for synthesizing insecticides described in JP-A-2001-342186, and acetylate the 1-position of the quinazolinone ring. After that, the insecticide described in JP-A-2001-342186 can be produced by reducing imine.
Reference Example 1 Of 1-acetyl-3- (3-pyridylmethylamino) -3,4-dihydro-6- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] -2 (1H) quinazolinone Preparation 3- (3-pyridylmethylideneamino) -3,4-dihydro-6- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] -2 (1H) quinazolinone 10.5 g (25.0 mmol), 1.4 g (35.0 mmol) of sodium hydride and 60 ml of dimethylacetamide were added and stirred at room temperature for 2 hours. Acetic anhydride (3.6 g, 35.0 mmol) was added dropwise at room temperature, and the mixture was further stirred for 2 hours. 0.75 g (12.5 mmol) of acetic acid was added dropwise at room temperature, and the mixture was further stirred for 10 minutes. After 2.3 g (24.0 mmol) of concentrated sulfuric acid was added dropwise at room temperature, the mixture was further stirred for 10 minutes. Next, 0.23 g (0.06 mmol) of 5% -Pd carbon and 0.04 g (0.24 mmol) of potassium iodide were added, and the mixture was stirred at room temperature under normal pressure hydrogen for 4 hours. The obtained reaction solution was poured into 64 ml of a 7% -sodium hydrogen carbonate aqueous solution and the precipitated crystals were filtered, and the obtained crystals were washed with 50 ml of n-heptane to give 1-acetyl-3- (3-pyridylmethylamino). 9.9 g of -3,4-dihydro-6- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] -2 (1H) quinazolinone was obtained.
Yield: 94%
Physical properties: melting point 138-139 ° C.

Claims (2)

Formula (II)

(In the formula, R may be the same or different, and is a halogen atom, cyano group, nitro group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkylcarbonyl group, carboxyl group, C ₁ -C ₆ alkoxycarbonyl group. A halo C ₁ -C ₆ alkyl group or a halo C ₁ -C ₆ alkoxy group, and n represents an integer of 0 to 4.)
And the general formula (III)

XCO ₂ R ¹ (III)

(Wherein, X represents a chlorine atom, a bromine atom or an iodine atom, and R ¹ represents a C ₁ -C ₆ alkyl group or a phenyl group). (IV)

(Wherein R, R ¹ and n are the same as defined above), and the phenylcarbamic acid ester is isolated or not isolated and halogenated in the presence of a radical initiator. Reaction with an agent, general formula (V)

Wherein Y represents a chlorine atom, a bromine atom or an iodine atom, and R, R ¹ and n are the same as above.
And the halomethylphenylcarbamic acid ester is isolated or reacted with hydrazine without isolation to produce a compound of the general formula (VI)

(Wherein R and n are the same as defined above), and the aminoquinazolinones represented by the general formula (VII) are isolated or not isolated.

R ² CHO (VII)

(In the formula, R ² may be the same or different and is a halogen atom, a cyano group, a nitro group, a C ₁ -C ₆ alkyl group, a halo C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ alkoxy group. Or a substituted phenyl group having one or more substituents selected from halo C ₁ -C ₆ alkoxy groups, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-furyl group, 3-furyl group, 2-thienyl group or 3-
Represents a thienyl group; ) Which is reacted with an aldehyde represented by the general formula (I
)

(Wherein R, R ² and n are the same as defined above), a process for producing iminoquinazolinones. R may be the same or different and each represents a halogen atom, a C ₁ -C ₆ alkyl group, a halo C ₁ -C ₆ alkyl group or a halo C ₁ -C ₆ alkoxy group, and R ² is a phenyl group, the same or different One or more substituents selected from a halogen atom, a C ₁ -C ₆ alkyl group, a halo C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group or a halo C ₁ -C ₆ alkoxy group The manufacturing method of Claim 1 which shows the substituted phenyl group which has, 2-pyridyl group, 3-pyridyl group, or 4-pyridyl group.