JP2003212862A - Method for producing quinazolin-4-one derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a simple and industrially preferred method for producing quinozolin-4-one derivative, by which the quinozolin-4-one derivative represented by general formula (2) (R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>and R<SP>4</SP>are each a group not participating in the reaction, provided that R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>and R<SP>4</SP>may be bound to each other to form a ring) can be produced from an anthranilic acid derivative ammonium salt represented by general formula (1) in a high yield under mild conditions. <P>SOLUTION: This industrially preferred method for producing the quinozolin-4-one derivative is characterized by reacting the anthranilic acid derivative ammonium salt with a formic acid derivative. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a quinazolin-4-one derivative from an anthranilic acid derivative. The quinazolin-4-one derivative is a compound useful as a synthetic intermediate or a raw material for medicines and agricultural chemicals.

[0002]

2. Description of the Related Art Conventionally, the following methods have been known as a method for producing a quinazolin-4-one derivative from an anthranilic acid derivative. EP 1029853 discloses a method for producing 6-iodoquinazolin-4-one by reacting 5-iodoanthranilic acid and formamidine acetate in ethanol for 20 hours. However, with this method,
There is a problem that the reaction time is long and expensive formamidine acetate must be used in excess. Che
m.Pharm.Bull., 46 , 1926 (1998) discloses a method for producing quinazolin-4-one by reacting anthranilic acid with formamide. However, this method has a problem that teratogenic formamide must be used in excess. As described above, each of the methods has various problems and is not effective as an industrial method for producing a quinazolin-4-one derivative.

[0003]

The object of the present invention is to solve the above-mentioned problems and to obtain a high yield of a quinazolin-4-one derivative from an ammonium salt of an anthranilic acid derivative by a simple method under mild conditions. The process for producing an industrially suitable quinazolin-4-one derivative that can be produced at a high rate is provided.

[0004]

The object of the present invention is to solve the problems of the general formula (1) in the presence of ammonia.

[0005]

[Chemical 4]

(Where R is¹, R^Two, R^ThreeAnd R^FourIs the same
It may be one or different and may have a substituent.
Group which does not participate in the reaction. In addition, R¹, R^Two, R
^ThreeAnd R ^FourMay combine with each other to form a ring.
Yes. ) Ammonium of anthranilic acid derivative
General, characterized by reacting a salt with a formic acid derivative
Formula (2)

[0007]

[Chemical 5]

This can be solved by a method for producing a quinazolin-4-one derivative represented by the formula (wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above).

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The ammonium salt of an anthranilic acid derivative used in the present invention has the above-mentioned general formula (1).
Indicated by. In the general formula (1), R ¹ , R ² ,
R ³ and R ⁴ may be the same or different and may have a substituent and are groups that do not participate in the reaction. Specifically, for example, a hydrogen atom, an alkyl group, a cycloalkyl group , An aralkyl group, an aryl group, a halogen atom, a hydroxyl group, an alkoxyl group, an alkylthio group, a nitro group, a cyano group, a carbonyl group or an amino group (excluding R ¹ ). In addition, R ¹ , R ² , R ³ and R ⁴ may be bonded to each other to form a ring.

Examples of the alkyl group include methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group and decyl group. In addition, these groups include various isomers.

Examples of the cycloalkyl group include:
Examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and a cyclooctyl group.

Examples of the aralkyl group include a benzyl group, a phenethyl group and a phenylpropyl group. In addition, these groups include various isomers.

Examples of the aryl group include a phenyl group, a p-tolyl group, a naphthyl group and an anthranyl group. In addition, these groups include various isomers.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Examples of the alkoxyl group include a methoxyl group, an ethoxyl group and a propoxyl group. In addition, these groups include various isomers.

Examples of the alkylthio group include a methylthio group, an ethylthio group and a propylthio group. In addition, these groups include various isomers.

The above alkyl group, cycloalkyl group, aralkyl group, aryl group, alkoxyl group, alkylthio group or amino group (excluding R ¹ ) may have a substituent. As the substituent, a substituent formed via a carbon atom, a substituent formed via an oxygen atom, a substituent formed via a nitrogen atom, a substituent formed via a sulfur atom,
A halogen atom etc. are mentioned.

Examples of the substituent formed via the carbon atom include alkyl groups such as methyl group, ethyl group, propyl group, butyl group, pentyl group and hexyl group; cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group. Group, cycloalkyl group such as cyclobutyl group; alkenyl group such as vinyl group, allyl group, propenyl group, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group; heterocyclic group such as pyrrolidyl group, pyrrolyl group, furyl group and thienyl group Alkenyl group; phenyl group, tolyl group, xylyl group, biphenyl group, naphthyl group, anthryl group, aryl group such as phenanthryl group; formyl group,
Acetyl group, propionyl group, acryloyl group, pivaloyl group, cyclohexylcarbonyl group, benzoyl group,
Acyl group such as naphthoyl group and toluoyl group (may be acetalized); carboxyl group; alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group; aryloxycarbonyl group such as phenoxycarbonyl group; trifluoromethyl group etc. And a cyano group. In addition, these groups are
Including various isomers.

Examples of the substituent formed via the oxygen atom include a hydroxyl group; a methoxyl group, an ethoxyl group, a propoxyl group, a butoxyl group, a pentyloxyl group, a hexyloxyl group, a heptyloxyl group and a benzyloxyl group. Alkoxyl group; phenoxyl group,
Examples thereof include aryloxyl groups such as a toluyloxyl group and a naphthyloxyl group. In addition, these groups include various isomers.

Examples of the substituent formed through the nitrogen atom include primary amino groups such as methylamino group, ethylamino group, butylamino group, cyclohexylamino group, phenylamino group and naphthylamino group; dimethylamino. Groups, diethylamino groups, dibutylamino groups, methylethylamino groups, methylbutylamino groups, diphenylamino groups and other secondary amino groups; morpholino groups, piperidino groups,
Heterocyclic amino groups such as piperazinyl group, pyrazolidinyl group, pyrrolidino group and indolyl group; and imino groups. In addition, these groups include various isomers.

Examples of the substituent formed through the sulfur atom include a mercapto group; a thioalkoxyl group such as a thiomethoxyl group, a thioethoxyl group and a thiopropoxyl group; a thiophenoxyl group, a thiotoluyloxyl group, a thionaphthyl group. Examples thereof include thioaryloxyl groups such as oxyl groups. In addition, these groups include various isomers.

The halogen atom is a fluorine atom,
Examples thereof include chlorine atom, bromine atom and iodine atom.

The ammonium salt of the anthranilic acid derivative is obtained by adding an excess amount of ammonia gas, liquid ammonia, aqueous ammonia or an organic solvent solution of ammonia (for example, ammonia methanol solution, ammonia dioxane solution, etc.) to the anthranilic acid derivative. It is a compound that can be easily obtained by contact (described in Reference Examples 1 to 4 below).

Examples of the formic acid derivative used in the reaction of the present invention include formic acid; formic acid esters such as methyl formate and ethyl formate; orthoformate esters such as methyl orthoformate and ethyl orthoformate, and the like. Formic acid ester and orthoformate ester are used, more preferably orthoformate ester, particularly preferably methyl orthoformate and ethyl orthoformate are used.

The amount of the formic acid derivative used is preferably 1. mol per 1 mol of the ammonium salt of the anthranilic acid derivative.
The amount is 0 to 10 mol, more preferably 1.1 to 3.0 mol.

The reaction of the present invention is carried out in the presence or absence of a solvent. The solvent used is not particularly limited as long as it does not inhibit the reaction, and examples thereof include alcohols such as methanol, ethanol, isopropyl alcohol, n-butyl alcohol and t-butyl alcohol; N, N-
Amides such as dimethylformamide and N-methylpyrrolidone; ureas such as N, N'-dimethylimidazolidinone; sulfoxides such as dimethylsulfoxide; aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene; methylene chloride , Halogenated aliphatic hydrocarbons such as chloroform and dichloroethane; nitriles such as acetonitrile and propionitrile; ethers such as diethyl ether, tetrahydrofuran and dioxane.
Alcohols and nitriles are preferably used, and more preferably methanol, ethanol and acetonitrile are used. You may use these solvent individually or in mixture of 2 or more types.

The amount of the solvent used is appropriately adjusted depending on the homogeneity and agitation property of the reaction solution, but is preferably 0 to 50 g, more preferably 0 to 20 g, particularly preferably 0 to 20 g, per 1 g of the ammonium salt of the anthranilic acid derivative. It is preferably 0 to 5 g.

The reaction of the present invention is carried out by, for example, a method of mixing an ammonium salt of an anthranilic acid derivative, a formic acid derivative and a solvent and stirring the mixture. The reaction temperature in that case is preferably 40 to 200 ° C, more preferably 50 to 150.
The reaction pressure is not particularly limited.

The final product, the quinazolin-4-one derivative, is isolated and purified after the reaction by a general method such as concentration, distillation, recrystallization, column chromatography and the like.

[0030]

EXAMPLES Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited to these.

Reference Example 1 (Synthesis of ammonium anthranilate) 5.0 g (36.5 mmol) of anthranilic acid and 20 ml (156 mmol) of a 15% by mass ammonia methanol solution were placed in a glass container having an inner volume of 50 ml equipped with a stirrer and a thermometer. In addition, the mixture was reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 5.0 g of ammonium anthranilate as a white solid.
(Isolated yield: 94%). The physical properties of ammonium anthranilate are as follows.

Melting point (sublimation): 145 to 146 ° C. ¹ H-NMR (DMSO-d ₆ , δ (ppm)); 6.37 to 6.43 (1 H, m), 6.56 (1
H, dd, J = 1.2,8.1Hz), 6.95 (6H, brs), 6.98 ~ 7.04 (1H,
m), 7.69 to 7.72 (1H, dd, J = 1.8,7.8Hz)

Example 1 (Synthesis of quinazolin-4-one) 280 mg of ammonium anthranilate synthesized in the same manner as in Reference Example 1 (1.
8 mmol), methyl orthoformate 400 mg (3.6 mmol) and methanol 1.5 ml were added, and the mixture was reacted at 120 ° C. for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and analyzed by high performance liquid chromatography (absolute quantitative method).
214 mg of 4-one was produced (reaction yield: 81%).

Reference Example 2 (Synthesis of ammonium 4-chloroanthranilate) In a glass container having an inner volume of 50 ml equipped with a stirrer and a thermometer, 5.0 g (29.1 mmol) of 4-chloroanthranilic acid and 15 mass% ammonia methanol A solution (20 ml, 156 mmol) was added, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain 5.0 g of ammonium 4-chloroanthranilate as a white solid (isolated yield: 95%). Ammonium 4-chloroanthranilate is a novel compound having the following physical properties.

Melting point (sublimation); 232 to 233 ° C. ¹ H-NMR (DMSO-d ₆ , δ (ppm)); 6.43 (1H, dd, J = 2.4,8.4H)
z), 6.69 (1H, d, J = 2.4Hz), 7.0 (3H, brs), 7.69 (1H, d, J =
8.4Hz), 11.0 (3H, brs)

Example 2 (Synthesis of 7-chloroquinazolin-4-one) Ammonium 4-chloroanthranilate synthesized in the same manner as in Reference Example 2 in a stainless steel pressure vessel having an internal volume of 2 ml.
340 mg (1.8 mmol), methyl orthoformate 400 mg (3.6 mmol) and methanol 1.5 ml were added and reacted at 120 ° C. for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and analyzed by high performance liquid chromatography (absolute quantification method) to find that 176 mg of 7-chloroquinazolin-4-one was produced (reaction yield: 54%).

Reference Example 3 (Synthesis of ammonium 5-chloroanthranilate) 5.0 g (29.1 mmol) of 5-chloroanthranilic acid and 15% by mass ammonia methanol were placed in a glass container having an internal volume of 50 ml equipped with a stirrer and a thermometer. A solution (20 ml, 156 mmol) was added, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain 5.0 g of ammonium 5-chloroanthranilate as a pale yellow solid (isolated yield: 95%). In addition, ammonium 5-chloroanthranilate is a novel compound having the following physical properties.

Melting point (sublimation): 161-162 ° C. ¹ H-NMR (DMSO-d ₆ , δ (ppm)); 6.57 (1 H, d, J = 8.4 Hz), 6.99
(1H, dd, J = 2.7,8.4Hz), 7.0 (3H, brs), 7.65 (1H, d, 2.7H
z), 11.0 (3H, brs)

Example 3 (Synthesis of 6-chloroquinazolin-4-one) Ammonium 5-chloroanthranilate synthesized in the same manner as in Reference Example 3 was placed in a stainless steel pressure vessel having an internal volume of 2 ml.
340 mg (1.8 mmol), methyl orthoformate 400 mg (3.6 mmol) and methanol 1.5 ml were added and reacted at 120 ° C. for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature and analyzed by high performance liquid chromatography (absolute quantitative method). As a result, 307 mg of 6-chloroquinazolin-4-one was produced (reaction yield: 94%).

Example 4 (Synthesis of 6-chloroquinazolin-4-one) Ammonium 5-chloroanthranilate synthesized in the same manner as in Reference Example 3 was placed in a pressure-resistant stainless steel container having an internal volume of 2 ml.
340 mg (1.8 mmol), methyl orthoformate 400 mg (3.6 mmol) and acetonitrile 1.5 ml were added, and the mixture was reacted at 120 ° C. for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, and the reaction mixture was analyzed by high performance liquid chromatography (absolute quantitative method) to find that 6-chloroquinazolin-4-one (303 mg) was formed
(Reaction yield: 93%).

Reference Example 4 (Synthesis of ammonium 5-iodoanthranilate) In a glass container having an inner volume of 200 ml equipped with a stirrer and a thermometer, 10.0 g (38 mmol) of 5-iodoanthranilic acid and a 15% by mass ammonia methanol solution were prepared. Add 100 ml (780 mmol),
The reaction was carried out at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain 9.0 g of ammonium 5-iodoanthranilate as a light red solid (isolated yield: 85%). In addition, ammonium 5-iodoanthranilate is a novel compound having the following physical properties.

Melting point (decomposition): 160 ° C. ¹ H-NMR (DMSO-d ₆ , δ (ppm)); 6.45 (1 H, d, J = 8.7 Hz), 6.5
(3H, brs), 7.25 (1H, dd, J = 2.4,8.7Hz), 7.96 (1H, d, J = 2.4
Hz), 11.0 (3H, brs)

Example 5 (Synthesis of 6-iodoquinazolin-4-one) Ammonium 5-iodoanthranilate synthesized in the same manner as in Reference Example 4 was placed in a stainless steel pressure vessel having an internal volume of 2 ml.
530 mg (1.9 mmol), methyl orthoformate 403 mg (3.8 mmol) and methanol 1.5 ml were added and reacted at 120 ° C. for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature and analyzed by high performance liquid chromatography (absolute quantitative method) to find that 402 mg of 6-iodoquinazolin-4-one was produced (reaction yield: 77%).

Example 6 (Synthesis of 6-iodoquinazolin-4-one) In a glass container having an inner volume of 2 ml equipped with a reflux condenser, 530 mg of ammonium 5-iodoanthranilate synthesized in the same manner as in Reference Example 4 (1.9 mmol), methyl orthoformate 403 mg (3.
8 mmol) and 1.5 ml of n-butyl alcohol, and add 2 at 120 ° C.
Reacted for hours. After completion of the reaction, the reaction solution was cooled to room temperature and analyzed by high performance liquid chromatography (absolute quantification method). As a result, 350 mg of 6-iodoquinazolin-4-one was produced (reaction yield: 67%).

[0045]

INDUSTRIAL APPLICABILITY According to the present invention, an industrially suitable quinazolin-4-one capable of producing a quinazolin-4-one derivative in high yield from an ammonium salt of an anthranilic acid derivative by a simple method under mild conditions. A method for producing a derivative can be provided.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Takashi Harada             5 Ube, 1978, Kogushi, Obu, Ube City, Yamaguchi Prefecture             Usan Laboratory, Kosan Co., Ltd. (72) Inventor Hiroyuki Oda             5 Ube, 1978, Kogushi, Obu, Ube City, Yamaguchi Prefecture             Usan Laboratory, Kosan Co., Ltd.

Claims (3)

[Claims] 1. A general formula (1) [Chemical 1] (In the formula, R¹, R^Two, R^ThreeAnd R^FourAre the same or different
May be present or may have a substituent, participates in the reaction
Indicates a group that does not. In addition, R¹, R^Two, R^ThreeAnd R ^FourIs
They may be bonded to each other to form a ring. )
Ammonium salt of anthranilic acid derivative and formic acid derivative
A general formula (2) characterized by reacting [Chemical 2] (In the formula, R¹, R^Two, R^ThreeAnd R^FourIs as defined above
It ) The manufacturing method of the quinazolin-4-one derivative shown by these. 2. The method for producing a quinazolin-4-one derivative according to claim 1, wherein the formic acid derivative is an orthoformate ester. 3. A general formula (2): (In the formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above, except for the case where all of R ¹ , R ² , R ³ and R ⁴ are hydrogen atoms.). Ammonium salt of anthranilic acid derivative.