JP2002145868A - Method for producing quinazoline derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for industrially advantageously producing a 1-alkoxycarbonylmethyl-2,4 (1H, 3H) quinazolinedione derivative in a high yield under an inexpensive and mild condition not requiring a reagent having high toxicity and irritation and without requiring a long-time reaction. SOLUTION: This method for producing a 1-alkoxycarbonylmethyl-2,4 (1H, 3H) quinazolinedione derivative represented by general formula (III) (R1, R2 and R5 are each as shown in the specification) is characterized in that a 2- alkoxycarbonylmethylaminobenzoic acid derivative represented by general formula (I) is reacted with a halogenating agent to give a 2- alkoxycarbonylmethylaminobenzoic acid halide derivative represented by general formula (II) and the obtained 2-alkoxycarbonylmethylaminobenzoic acid halide derivative is reacted with chlorosulfonyl isocyanate in the presence of a base and then treated with water.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a 1-alkoxycarbonylmethyl-2,4 (1H, 3H) quinazolinedione derivative. 1 obtained by the present invention
-Alkoxycarbonylmethyl-2,4 (1H, 3H)
Quinazolinedione derivatives are useful as synthetic intermediates of 3-dihalobenzyl-2,4-quinazolinedione derivatives useful as aldose reductase inhibitors (WO97).
/ 24335).

[0002]

2. Description of the Related Art Conventionally, as a method for producing a 1-alkoxycarbonylmethyl-2,4 (1H, 3H) quinazolinedione derivative, an N- (2-carbamoylphenyl) aminoacetic acid derivative is converted to N, N'-carbonyldiimidazole. (See JP-A-62-96476), a method of reacting an N- (2-carbamoylphenyl) aminoacetic acid derivative with pyridines and phosgene (see JP-A-9-268180). Quinazolinedione derivative obtained from 1,4-chloroanthranilic acid, followed by selectively reacting the obtained silylquinazoline derivative with ethyl bromoacetate at the 1-position to desilylate (JP-A-64-25767) 2)
A method of reacting an alkoxycarbonylmethylaminobenzoic acid derivative with a cyanate and hydrogen chloride in the presence of an inert solvent (see JP-A-11-511441);
A method is known in which a 2-carboxymethylaminobenzoic acid derivative is reacted with cyanic acid or a salt thereof or urea and then esterified (see WO 97/24335).

[0003]

However, in the above method, N, N'-carbonyldiimidazole is expensive and difficult to obtain. In the above method, highly toxic phosgene is used. The above method using expensive silylating agent and highly irritating ethyl bromoacetate uses strongly corrosive hydrogen chloride. The above method requires a long time to complete the esterification reaction. In either method, 1-alkoxycarbonylmethyl-2,4 (1H,
This is not an industrially advantageous method for producing 3H) quinazolinedione derivatives.

[0004] An object of the present invention is to provide a method which is inexpensive, has a mild condition that does not require highly toxic or irritating reagents, and does not require a long-time reaction.
-Alkoxycarbonylmethyl-2,4 (1H, 3H)
An object of the present invention is to provide a method capable of producing a quinazolinedione derivative.

[0005]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that the above object can be achieved by using chlorosulfonyl isocyanate, and have completed the present invention. That is, the present invention provides a compound represented by the general formula (I):

[0006]

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[Wherein R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, a nitro group, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent An aralkyl group which may have a substituent,
An alkoxyl group which may have a substituent, a cycloalkyloxy group which may have a substituent, an alkoxycarbonyl group which may have a substituent, or a compound represented by the formula -YN
R ³ R ⁴ (wherein, Y represents an alkylene group or a carbonyl group, and R ³ and R ⁴ each independently represent an alkyl group or a cycloalkyl group, or together with a nitrogen atom to which they are bonded, To form a 5- or 6-membered heterocyclic ring which may further contain a heteroatom, and when the heteroatom is a nitrogen atom, it may have a substituent on the nitrogen atom.) R ⁵ represents an alkyl group optionally having a substituent, a cycloalkyl group optionally having a substituent, an aryl group optionally having a substituent or a substituent Represents an aralkyl group which may be substituted. A 2-alkoxycarbonylmethylaminobenzoic acid derivative (hereinafter sometimes referred to as a 2-alkoxycarbonylmethylaminobenzoic acid derivative (I)) represented by the general formula (II)

[0008]

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(Wherein R ¹ , R ² and R ⁵ are as defined above, and X represents a halogen atom.) 2-alkoxycarbonylmethylaminobenzoic acid halide derivative represented by the following formula: 2-alkoxycarbonylmethylaminobenzoic acid halide derivative (II)], and the resulting 2-alkoxycarbonylmethylaminobenzoic acid halide derivative was added in the presence of a base.
General formula (III) characterized by reacting with chlorosulfonyl isocyanate and then treating with water

[0010]

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(Wherein R ¹ , R ² and R ⁵ are as defined above), a 1-alkoxycarbonylmethyl-2,4 (1H, 3H) quinazolinedione derivative [hereinafter referred to as 1 -Alkoxycarbonylmethyl-2,
4 (1H, 3H) quinazolinedione derivative (III) in some cases].

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula, R ¹ , R ²
Examples of the halogen atom represented by X and X include a chlorine atom, a bromine atom, an iodine atom, and a fluorine atom.

The alkyl group represented by R ¹ , R ² and R ⁵ is preferably a linear or branched alkyl group having 1 to 8 carbon atoms, such as a methyl group, an ethyl group, a propyl group and an isopropyl group. , Butyl group, isobutyl group,
sec-butyl group, tert-butyl group, pentyl group,
An isopentyl group, a neopentyl group, a hexyl group, a heptyl group, an octyl group, and the like are exemplified. As the cycloalkyl group, a cycloalkyl group having 3 to 6 carbon atoms is preferable.
For example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like can be mentioned. As the alkylene part of the aralkyl group, for example, a linear or branched alkylene group having 1 to 4 carbon atoms is preferable, and as the aryl part, for example, a phenyl group, a naphthyl group, a tolyl group, and the like are preferable. For example, a benzyl group, a phenylethyl group and the like can be mentioned.

The alkoxyl group represented by R ¹ and R ² is preferably a straight-chain or branched-chain alkoxyl group having 1 to 8 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy and butoxy. Group, hexyloxy group, octyloxy group, and the like. As the cycloalkyloxy group, a cycloalkyloxy group having 3 to 6 carbon atoms is preferable, for example, a cyclopentyloxy group, a cyclohexyloxy group, and the like, and an alkoxycarbonyl group Is preferably a linear or branched alkoxycarbonyl group having 1 to 8 carbon atoms, for example, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group,
Butoxycarbonyl group, hexyloxycarbonyl group,
An octyloxycarbonyl group;

The aryl group represented by R ⁵ includes, for example, a phenyl group, a naphthyl group and a tolyl group.

These alkyl groups, cycloalkyl groups,
The aralkyl group, the alkoxyl group, the cycloalkyloxy group, the alkoxycarbonyl group and the aryl group may each have a substituent, and such a substituent may be
Examples thereof include a halogen atom such as a chlorine atom, a bromine atom, an iodine atom and a fluorine atom; an alkoxyl group having 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group; a nitro group.

The alkylene group represented by Y has 1 carbon atom.
Preferred are straight-chain or branched-chain alkylene groups of 4 to 4, for example, a methylene group, an ethylene group, a trimethylene group,
And a tetramethylene group.

An alkyl group represented by R ³ and R ⁴ ,
Examples of the cycloalkyl group include the same alkyl groups and cycloalkyl groups represented by R ¹ and R ² , respectively. Examples of the group represented by the formula —NR ³ R ⁴ include a dimethylamino group, a diethylamino group, and a diamino group. Propylamino group,
And a dibutylamino group.

R ³ and R ⁴ are formed together with the nitrogen atom to which they are bonded, and may further contain a hetero atom.
Examples of the hetero atom in the 6-membered heterocyclic ring or the 6-membered heterocyclic ring include a nitrogen atom, an oxygen atom, a sulfur atom and the like.
Examples of the membered heterocycle include a pyrrolyl group, a 2H, 4H-pyrrolyl group, a pyrrolidino group, a pyrazolyl group, a piperidino group, a morpholino group, and an imidazolyl group.
When the above hetero atom is a nitrogen atom, the hetero atom may have a substituent on the nitrogen atom, and examples of such a substituent include an alkyl group which may have a substituent (having 1 to 1 carbon atoms).
Preferred are straight-chain or branched-chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and te.
Examples thereof include an rt-butyl group, a pentyl group, an isopentyl group, a neopentyl group, and a hexyl group. Examples of the substituent which these alkyl groups may have include, for example, a chlorine atom, a bromine atom, an iodine atom, and a fluorine atom. Halogen atoms such as methoxy group, ethoxy group, propoxy group, butoxy group and the like; alkoxyl groups having 1 to 4 carbon atoms; nitro groups and the like; aralkyl groups (the alkylene portion is a straight chain having 1 to 4 carbon atoms) Alternatively, a branched alkylene group is preferable, and the aryl portion is preferably a phenyl group, a naphthyl group, a tolyl group, and the like, for example, a benzyl group and the like); and a phenylcarbonyl group.

In the present invention, R ¹ and R ² are both a hydrogen atom, a combination of a hydrogen atom and a halogen atom (particularly a chlorine atom, a fluorine atom, a bromine atom), a hydrogen atom and a nitro group. Are preferable, and both are preferably a hydrogen atom, or a combination of a hydrogen atom and a chlorine atom is particularly preferable. Also, R ⁵
Preferred are a methyl group, an ethyl group, a propyl group, and an isopropyl group, and a methyl group and an ethyl group are particularly preferred.

The halogenating agent used in the present invention includes, for example, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, dichlorotriphenylphosphorane, dibromotriphenylphosphorane and the like, of which thionyl chloride is preferred. The amount of the halogenating agent to be used is preferably in the range of 0.5 to 10 mol, more preferably 1.0 to 5.0 mol, per 1 mol of the 2-alkoxycarbonylmethylaminobenzoic acid derivative (I).

The amount of the chlorosulfonyl isocyanate used is preferably in the range of 0.5 to 10 mol, and more preferably in the range of 1.0 to 5.0 mol, per 1 mol of the 2-alkoxycarbonylmethylaminobenzoic acid derivative (I). More preferred.

As the base, an organic base or an inorganic base is used. Examples of the organic base include tertiary amines such as trimethylamine, triethylamine, tripropylamine and tributylamine; pyridine, picoline,
Examples thereof include pyridines such as lutidine. Examples of the inorganic base include a carbonate such as sodium carbonate and potassium carbonate; and a hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate. Among these, trimethylamine, triethylamine, tripropylamine and tributylamine are preferred. The amount of base used is 2
-The range is preferably 0.5 to 10 mol, more preferably 1.0 to 5.0 mol, per 1 mol of the alkoxycarbonylmethylaminobenzoic acid derivative (I).

In the present invention, water may be used alone, but is preferably used as an acidic, neutral or basic aqueous solution. Examples of the acidic aqueous solution include an aqueous solution of an acid such as hydrochloric acid, sulfuric acid, and phosphoric acid. Examples of the neutral aqueous solution include an aqueous solution of a neutral salt such as sodium chloride, potassium chloride, and sodium sulfate. Examples of the basic aqueous solution include aqueous solutions of bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium sulfite, sodium hydrogen sulfite, and potassium hydrogen phosphate. The above bases can be used alone or in combination of two or more. When using two or more types,
Preferred combinations include, for example, a combination of a sulfite such as sodium sulfite or sodium hydrogen sulfite and a hydroxide such as sodium hydroxide or potassium hydroxide.

The amount of water used is 0.5 to 2 with respect to the 2-alkoxycarbonylmethylaminobenzoic acid derivative (I).
A range of 0 times by weight is preferable, and a range of 1 to 10 times by weight is more preferable. When an acidic aqueous solution is used, the amount of the acid used is preferably 0.5 to 20 mol, more preferably 1.0 to 10 mol, per 1 mol of the 2-alkoxycarbonylmethylaminobenzoic acid derivative (I). preferable. When a neutral aqueous solution is used, the amount of the neutral salt used is 2-alkoxycarbonylmethylaminobenzoic acid derivative (I)
The range of 0.05 to 10 mol is preferably based on 1 mol,
The range of 0.1 to 5.0 mol is more preferable. When a basic aqueous solution is used, the amount of the base used is preferably in the range of 0.05 to 20 mol, and more preferably 0.1 to 20 mol, per 1 mol of the 2-alkoxycarbonylmethylaminobenzoic acid derivative (I).
A range of from 10 to 10 mol is more preferred.

The reaction in the present invention can be carried out in the presence or absence of a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction. For example, hydrocarbons such as hexane, heptane, cyclohexane, benzene, toluene and xylene; diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, 1,2- Ethers such as diethoxyethane and diethylene glycol dimethyl ether; and halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, and dichlorobenzene. Although the amount of the solvent to be used is not particularly limited, it is usually preferably in the range of 1 to 200 times by weight based on the 2-alkoxycarbonylmethylaminobenzoic acid derivative (I).

The present invention can be carried out, for example, as follows. First, a solvent is mixed with the 2-alkoxycarbonylmethylaminobenzoic acid derivative (I) as necessary,
2-alkoxycarbonylmethylaminobenzoic acid halide derivative (II) by the action of a halogenating agent
Get. The obtained 2-alkoxycarbonylmethylaminobenzoic acid halide derivative (II) is reacted without addition of chlorosulfonyl isocyanate and a base without isolation from the reaction mixture, and then treated with an acidic, neutral or basic aqueous solution. Then, 1-alkoxycarbonylmethyl-2,4 (1H, 3H) quinazolinedione derivative (III) is obtained.

The reaction temperature varies depending on the type of the solvent used, but is usually preferably in the range of 0 ° C. to the reflux temperature of the reaction system. The reaction can be carried out under any of normal pressure, pressurized and reduced pressure conditions. The reaction time varies depending on the reaction temperature, but is usually preferably in the range of 30 minutes to 24 hours. The reaction time can be adjusted by appropriately adjusting the reaction temperature.

After completion of the reaction, the 1-alkoxycarbonylmethyl-2,4 (1H, 3H) quinazolinedione derivative (III) is isolated and purified from the reaction mixture by, for example, returning the reaction mixture to room temperature and then removing the solvent. Is distilled off, and the residue is subjected to recrystallization, column chromatography and the like. 1-alkoxycarbonylmethyl-2,4 (1H, 3H) quinazolinedione derivative (II
When I) is precipitated in the reaction mixture, the reaction can be carried out by cooling the reaction mixture, adding a poor solvent as needed, and filtering the mixture.

The 2-alkoxycarbonylmethylaminobenzoic acid derivative (I) used as a raw material in the present invention
Can be easily and inexpensively synthesized by, for example, reacting a 2-chlorobenzoic acid derivative with glycine and then reacting it with an alcohol in the presence of an acid catalyst.
No. 51440).

[0031]

EXAMPLES The present invention will be described below in detail with reference to examples, but the present invention is not limited to these examples.

Example 1 To 6.44 g (25.0 mmol) of 2-ethoxycarbonylmethylamino-4-chlorobenzoic acid was added 60 ml of toluene.
L at 20 ° C. and 2.98 g of thionyl chloride (25 mm
ol), and heated at 70-80 ° C. for 2 hours. The reaction mixture was cooled to 5 ° C. or lower, 3.54 g (25.0 mmol) of chlorosulfonyl isocyanate was added dropwise over 30 minutes, and the mixture was stirred at 20 ° C. for 1 hour. The reaction mixture was cooled again to below 5 ° C. and triethylamine 2.53 g
(25 mmol) was added dropwise over 30 minutes, followed by stirring at 20 ° C. for 2 hours. To this reaction mixture, 6.74 g of a 2.4% by weight aqueous solution of sodium sulfite was added so that the internal temperature would be 30 ° C. or lower, and the mixture was neutralized with a 30% by weight aqueous solution of sodium hydroxide. The precipitated product was collected by filtration, washed with water and acetone, and then dried to give 1-ethoxycarbonylmethyl-2,4 (1H, 3H) quinazolinedione 4.2.
1 g (59.6% yield) was obtained.

[0033]

According to the present invention, the 1-alkoxycarbonylmethyl-2,4 (1H, 3H) quinazolinedione derivative (III) can be prepared at a low cost under mild conditions which do not require highly toxic or irritating reagents. , And can be produced industrially and advantageously with a high yield without requiring a long-time reaction.

Claims (1)

[Claims] 1. A compound of the general formula (I) [Wherein, R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, a nitro group, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent,
Aralkyl group which may have a substituent, alkoxyl group which may have a substituent, cycloalkyloxy group which may have a substituent, alkoxycarbonyl group which may have a substituent or formula -YNR ³ R ^4, (in the formula, Y represents an alkylene group or a carbonyl group, R ³
And R ⁴ each independently represent an alkyl group or a cycloalkyl group, or together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic ring which may further contain a heteroatom. When formed, when the hetero atom is a nitrogen atom, it may have a substituent on the nitrogen atom. And R ⁵ is an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent or a substituent. Represents an aralkyl group which may have By reacting a 2-alkoxycarbonylmethylaminobenzoic acid derivative represented by the formula (II) with a halogenating agent. (Wherein R ¹ , R ² and R ⁵ are as defined above, and X represents a halogen atom.) 2-alkoxycarbonylmethylaminobenzoic acid halide derivative represented by the following formula: General formula (III) characterized in that chlorosulfonyl isocyanate is allowed to act on an alkoxycarbonylmethylaminobenzoic acid halide derivative in the presence of a base and then treated with water. (Wherein R ¹ , R ² and R ⁵ are as defined above).
A method for producing a 2,4 (1H, 3H) quinazolinedione derivative.