JPH11292855A - Process for producing 6,7-disubstituted-2,4-dioxoquinazoline - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a 6,7-disubstituted-2,4 from a 4,5-disubstituted anthranilamide without a complicated operation.
It is an object of the present invention to provide an industrially suitable method for producing 6,7-disubstituted-2,4-dioxoquinazoline, which is capable of producing dioxoquinazoline with high yield and high selectivity. The object of the present invention is solved by a method for producing 6,7-disubstituted-2,4-dioxoquinazoline, which comprises reacting a 4,5-disubstituted anthranilamide with a carbonate ester. You.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing 6,7-disubstituted-2,4-dioxoquinazoline from 4,5-disubstituted anthranilamide with high yield and high selectivity. 6,7-Disubstituted-2,4-dioxoquinazoline is a compound useful as a raw material for synthesis of pharmaceuticals and agricultural chemicals.

[0002]

2. Description of the Related Art Conventionally, as a method for obtaining 6,7-disubstituted-2,4-dioxoquinazoline from 4,5-disubstituted anthranilamide, 2-ureido is disclosed in J. Chem. Soc., 1948 , 1759. -4,5-Dimethoxybenzoic acid treated with sodium hydroxide to give 6,7-disubstituted-
A method for synthesizing 2,4-dioxoquinazoline is disclosed, but this method has a problem that the yield is extremely low. JP-A-59-73558 discloses that 2-ureido-4,5-dimethoxybenzoic acid amide derived from dimethoxyanthranilamido is treated with sodium hydroxide to give
Methods for obtaining 7-dimethoxy-2,4-dioxoquinazoline have been described. However, this method is a two-stage reaction, which is disadvantageous due to low productivity industrially, and is not effective as an industrial production method because of using highly toxic potassium cyanate.

[0003]

The object of the present invention is to provide a method for preparing 6,7-disubstituted-2,4-dioxo compounds from 4,5-disubstituted anthranilamides without requiring complicated operations. An object of the present invention is to provide an industrially suitable method for producing 6,7-disubstituted-2,4-dioxoquinazoline which can produce quinazoline with high yield and high selectivity.

[0004]

The object of the present invention is to provide a compound of the general formula (1)

[0005]

Embedded image

(Wherein R ¹ and R ² may be the same or different and each represents a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms,
It represents either an aryl group having 6 to 20 carbon atoms or an acyl group having 2 to 20 carbon atoms. R ¹ and R ² may be linked to form a ring. ) -Represented 4,5-disubstituted anthranilamides of the general formula (2)

[0007]

Embedded image (Wherein, R ³ and R ⁴ may be the same or different and represent an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, or an aryl group having 6 to 20 carbon atoms). General formula (3), characterized by reacting with the carbonate ester shown

[0008]

Embedded image (Wherein R ¹ and R ² may be the same or different and each represent a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, ~
It represents either an aryl group having 20 or an acyl group having 2 to 20 carbon atoms. R ¹ and R ² may be linked to form a ring. ), The method for producing a 6,7-disubstituted-2,4-dioxoquinazoline.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The starting 4,5-disubstituted anthranilamide used in the reaction of the present invention is represented by the above general formula (1). In the general formula (1), R ¹ and R ² may be the same or different, and represent a hydrogen atom,
An unsubstituted or substituted alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an aryl group having 6 to 20 carbon atoms, or an acyl group having 2 to 20 carbon atoms. R ¹ and R ² may be linked to form a ring.

The alkyl group having 1 to 8 carbon atoms includes, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl Group, n-hexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and the like.

Examples of the alkenyl group having 2 to 8 carbon atoms include a vinyl group, an allyl group, an i-propenyl group, a cyclopropenyl group, a cyclobutenyl group and a cyclopentenyl group.

Examples of the aryl group having 6 to 20 carbon atoms include a phenyl group, a tolyl group, a xylyl group, a biphenyl group, a naphthyl group, an anthryl group and a phenanthryl group.

Examples of the acyl group having 2 to 20 carbon atoms include an acetyl group, a propionyl group, a pivaloyl group, a cyclohexylcarbonyl group, a benzoyl group, a naphthoyl group and a toluoyl group.

The alkyl group having 1 to 8 carbon atoms, the alkenyl group having 2 to 8 carbon atoms, the aryl group having 6 to 20 carbon atoms and the acyl group having 2 to 20 carbon atoms may have a substituent. good. As the substituent, a halogen atom, a substituent formed through a carbon atom, a substituent formed through an oxygen atom,
At least one selected from a substituent formed through a nitrogen atom and a substituent formed through a sulfur atom is exemplified.

[0015] Examples of the halogen atom include fluorine, chlorine, bromine and iodine.

The substituents formed through the carbon atom include a methyl group, an ethyl group, an n-propyl group, an n-butyl group,
alkyl groups such as s-butyl group, t-butyl group, n-pentyl group, n-hexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and cycloheptyl group; vinyl group, allyl group, i-propenyl Alkenyl groups such as a group, cyclopropenyl group, cyclobutenyl group and cyclopentenyl group; heterocyclic alkenyl groups such as a pyrrolidinyl group, a pyrrolyl group, a furyl group and a thienyl group; a phenyl group, a tolyl group, a xylyl group, a biphenyl group and a naphthyl group Aryl groups such as, anthryl group and phenanthryl group;
Acyl groups such as formyl group, acetyl group, propionyl group, pivaloyl group, cyclohexylcarbonyl group, benzoyl group, naphthoyl group and toluoyl group (which may be acetalized); carboxyl group; methoxycarbonyl group and ethoxycarbonyl group An alkoxycarbonyl group; an aryloxycarbonyl group such as a phenoxycarbonyl group; a halogenated alkyl group such as a trifluoromethyl group; and a cyano group.

Examples of the substituent formed through the oxygen atom include a hydroxy group; a methoxy group, an ethoxy group, a propoxy group, an i-propoxy group, a butoxy group, an i-butoxy group, and an s-group.
Butoxy group, t-butoxy group, pentyloxy group, hexyloxy group, i-pentyloxy group, alkoxy group such as benzyloxy group; phenoxy group, p-toluyloxy group,
And an aryloxy group such as a 2-naphthyloxy group.

Examples of the substituent formed through the nitrogen atom include primary amino groups such as methylamino group, ethylamino group, n-butylamino group, cyclohexylamino group, phenylamino group and 2-naphthylamino group; Secondary amino groups such as dimethylamino group, diethylamino group, di-n-butylamino group, methylethylamino group, methyl n-butylamino group, diphenylamino group; morpholino group, piperidino group, piperazinyl group, pyrazolidinyl group, pyrrolidino A heterocyclic amino group such as a group or an indolinyl group; an imino group.

The substituents formed through the sulfur atom include a mercapto group; a thiomethoxy group, a thioethoxy group,
A thioalkoxy group such as a thiopropoxy group; and a thioaryloxy group such as a thiophenoxy group, a thio-p-toluyloxy group, and a thio-2-naphthyloxy group.

The 4,5-disubstituted anthranilamide used in the reaction of the present invention includes, for example, 4,5-dimethoxyanthranilamido, 4,5-diethoxyanthranilamido, 5-ethoxy-4-methoxyanthranilamido , 4,5
-Methylenedioxyanthranilamido, 4-methoxy-5-
(3-morpholinopropoxy) anthranilamido, 4,
5-bis (2-methoxyethoxy) anthranilamide and the like. These 4,5-disubstituted anthranilamides
It can be synthesized from the corresponding 4,5-disubstituted anthranilic acid according to Japanese Patent Publication No. 46-10543.

The carbonate used in the reaction of the present invention includes, for example, di-n-propyl carbonate, di-i-propyl carbonate, di-n-butyl carbonate, i-butyl carbonate, di-t-butyl carbonate, di-n-carbonate -Pentyl, di-i-pentyl carbonate, di-n-hexyl carbonate, di-i-hexyl carbonate, di-n-heptyl carbonate, di-carbonate
Carbonic esters such as i-heptyl, isobutylphenyl carbonate, methylphenyl carbonate, isobutylmethyl carbonate, diphenyl carbonate and the like can be mentioned. The amount of the carbonate used is
It is preferably 1 to 10 moles, more preferably 1 to 5 moles, per 1 mole of the raw material 4,5-disubstituted anthranilamide.

In the reaction of the present invention, a basic catalyst may be present in the reaction solution to improve the reaction rate.
Examples of the basic catalyst include an inorganic base and an organic base. Examples of the inorganic base include lithium carbonate,
Alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and cesium hydrogen carbonate; alkali metal hydrogen such as lithium hydride, sodium hydride and potassium hydride And alkali metal hydroxides or alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide. Examples of organic bases include sodium methoxide and sodium ethoxide. And alkali metal alkoxides such as potassium ethoxide and potassium t-butoxide. Among them, particularly preferred are alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium ethoxide and potassium t-butoxide.

The amount of the catalyst to be used is preferably 1 / 10,000 to 1 mol of the 4,5-disubstituted anthranilamide as the raw material.
It is 1/2 mole, more preferably 1/10000 to 1/5. These catalysts may be used alone or in combination of two or more.

The reaction of the present invention is preferably performed in a solvent. Solvents used include aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, dimethylimidazolidinone, N-methylpyrrolidone; n-butanol, n-pen Alcohol solvents such as tanol, ethylene glycol and phenol; ether solvents such as diglyme, and preferably N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, dimethylimidazolidinone, N-methyl It is an aprotic polar solvent such as pyrrolidone.

The amount of the solvent used is preferably 1 to 100 ml, more preferably 1 to 50 ml, based on 1 g of the raw material of the 4,5-disubstituted anthranilamide. These solvents may be used alone or in combination of two or more.

In the reaction of the present invention, the 4,5-disubstituted anthranilamide and the carbonate are preferably brought into contact in a liquid phase. For example, in an inert gas atmosphere, the 4,5-disubstituted anthranilamide, carbonate It is carried out under normal pressure or under pressure by a method such as mixing an ester, a solvent and a catalyst, and stirring with heating. The reaction temperature at that time is preferably 50 to 250
° C, more preferably 100-200 ° C. The obtained product is separated and purified by a general method such as recrystallization.

[0027]

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

Example 1 In a glass autoclave having an inner volume of 300 ml, 1 g (5.10 mmol) of 4,5-dimethoxyanthranilamide and diphenyl carbonate were added.
After adding 2.19 g (10.20 mmol), 5 ml of dimethylimidazolidinone and 7 mg (0.05 mmol) of potassium carbonate, the temperature was raised to 110 ° C. under a nitrogen atmosphere. Subsequently, after stirring at the same temperature for 2.5 hours, the reaction solution was cooled to 0 ° C. The precipitated crystals were filtered, washed with methanol, and then dried under reduced pressure.
1.08 g of 7-dimethoxy-2,4-dioxoquinazoline (95% yield)
I got

Example 2 The procedure of Example 1 was repeated, except that potassium carbonate was not used, the reaction temperature was changed to 150 ° C., and the reaction time was changed to 6 hours. As a result, 1.07 g (94% yield) of 6,7-dimethoxy-2,4-dioxoquinazoline was obtained.

Reference Example 1 Synthesis of 4,5-diethoxyanthranilic amide According to Japanese Patent Publication No. 46-10543, it was synthesized from the corresponding 4,5-disubstituted anthranilic acid. Physical properties were measured by ¹ H-NMR (CDC
l ₃ ); 1.381 ppm (3H, t, J = 6.83 Hz), 1.456 ppm (3H, t, J = 6.84 Hz)
Hz), 3.991 ppm (2H, q, J = 6.83 Hz), 4.055 ppm (2H, q, J = 6.84
Hz), 5.568 ppm (4H, brs), 6.162 ppm (1H, s), 6.911 ppm (1
H, s): MS (M ⁺ );

REFERENCE EXAMPLE 2 Synthesis of 5-ethoxy-4-methoxyanthranilamide The same procedure as in Reference Example 1 was carried out from the corresponding 4,5-disubstituted anthranilic acid. Physical properties are ¹ H-NMR (CDCl ₃ ); 1.403 ppm (3H,
t, J = 6.83Hz), 3.846ppm (3H, s), 3.996ppm (2H, q, J = 6.83H
z), 5.574 ppm (4H, brs), 6.176 ppm (1H, s), 6.899 ppm (1H,
s): MS (M ⁺ );

Reference Example 3 Synthesis of 4-methoxy-5- (3-morpholinopropoxy) anthranilamido Synthesized from the corresponding 4,5-disubstituted anthranilic acid in the same manner as in Reference Example 1. Physical property values are ¹ H-NMR (CDCl ₃ ); 1.91 to 2.04 ppm
(2H, m), 2.45 to 2.55 ppm (6H, m), 3.72 ppm (4H, t, J = 4.4H
z), 3.83ppm (3H, s), 3.98ppm (2H, t, J = 6.6Hz), 4.18ppm
(2H, s), 6.23 ppm (1H, s), 6.85 ppm (1H, s): MS (M ⁺ ); 309
Met.

Reference Example 4 Synthesis of 4,5-bis (2-methoxyethoxy) anthranilamido
Success  The corresponding 4,5-disubstituted anthranilic acid as in Reference Example 1
Synthesized. Physical property values are¹H-NMR (CDCl_Three); 3.437 ppm (3H,
s), 3.439ppm (3H, s), 3.690ppm (2H, t, J = 4.40Hz), 3.770
ppm (2H, t, J = 4.40Hz), 4.078ppm (2H, t, J = 4.40Hz), 4.121
ppm (2H, t, J = 4.40Hz), 5.633ppm (4H, brs), 6.175ppm (1H,
s), 7.029 ppm (1H, s): MS (M⁺); 284.

Examples 3 to 8 The same procedures as in Example 1 were carried out except that the starting materials, 4,5-disubstituted anthranilamide, the amount of carbonate, the amount of potassium carbonate, the reaction temperature and the reaction time were changed. Operation. Table 1 shows the results. The physical properties of the target compounds obtained from the starting compounds 5 and 6 are shown below. 7-methoxy-6- (3-morpholinopropoxy) -2,4-dioxoquinazoline (raw material: compound 5) ¹ H-NMR (DMSO-d6); 1.861 ppm (2H, tt, J = 6.83, 6.35 Hz) ), 2.34
2ppm (4H, m), 2.396ppm (2H, t, J = 6.83Hz), 3.559ppm (4H, t, J
= 4.40Hz), 3.814ppm (3H, s), 3.995ppm (2H, t, J = 6.35Hz), 6.
662ppm (1H, s), 7.247ppm (1H, s), 10.892ppm (1H, brs), 1
1.071 ppm (1H, brs): MS (MH ⁺ ); 336 6,7-bis (2-methoxyethoxy) -2,4-dioxoquinazoline (raw material: compound 6) ¹ H-NMR (DMSO-d6); 3.302 (3H, s), 3.318 (3H, s), 3.644 (2H,
t, J = 4.39Hz), 3.694 (2H, t, J = 4.39Hz), 4.088 (2H, t, J = 4.39
Hz), 4.124 (2H, t, J = 4.39Hz), 6.674 (1H, s), 7.278 (1H, s), 1
0.888 (1H, brs), 11.074 (1H, brs): MS (M ⁺ ); 310

[0035]

【table 1】

[0036]

Industrial Applicability According to the present invention, 6,7-disubstituted-2,4-dioxoquinazoline can be selected from 4,5-disubstituted anthranilamide in a high yield and a high selectivity without requiring complicated operations. Industrially suitable 6,7-disubstituted-2,4
-A method for producing dioxoquinazoline can be provided.

Claims (2)

[Claims] 1. A compound of the general formula (1) (Wherein R ¹ and R ² may be the same or different and each represent a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, ~
It represents either an aryl group having 20 or an acyl group having 2 to 20 carbon atoms. R ¹ and R ² may be linked to form a ring. 4,5-disubstituted anthranilamide represented by the general formula (2): (Wherein, R ³ and R ⁴ may be the same or different and represent an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, or an aryl group having 6 to 20 carbon atoms). A compound represented by the following general formula (3): (Wherein R ¹ and R ² may be the same or different and each represent a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, ~
It represents either an aryl group having 20 or an acyl group having 2 to 20 carbon atoms. R ¹ and R ² may be linked to form a ring. ), A method for producing 6,7-disubstituted-2,4-dioxoquinazoline. 2. The method for producing 6,7-disubstituted-2,4-dioxoquinazoline according to claim 1, wherein a basic catalyst is used.