JPH09291080A - Production of dioxoquinazoline compounds - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently obtain a dioxoquinazoline compound useful as an intermediate for medicines for treating diabetic complications, etc., by reacting a corresponding amide-substituted anthranylamide compound with phosgene. SOLUTION: An amide-substituted anthranylamide compound of formula I (R1 , R2 are each independently H, a halogen, nitro, a lower alkyl or aralkyl which may be substituted by a halogen, an alkoxy, etc.; X is a lower alkyl or aralkyl which may be substituted by a halogen, etc.), is reacted with (B) phosgene to obtain (C) a dioxoquinazoline compound of formula II. The reaction is preferably carried out in the presence of a base (preferably an organic base) in an organic solvent (preferably a cyclic ether compound). The component B is preferably used in an amount of 0.9-1.1 mole times that of the component A.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing dioxoquinazolines, and more particularly to a method for producing dioxoquinazolines by reacting a corresponding amide-substituted anthranilamide with phosgene.

[0002]

BACKGROUND OF THE INVENTION Dioxoquinazolines are useful as intermediates for anti-inflammatory agents, therapeutic agents for diabetic complications and the like. As a method for producing them, anthranilamides and carbonyldiimidazole are used. It is also known to produce by reacting (for example,
JP-A-62-97476). However, the above method has an industrial difficulty in that the starting material, carbonyldiimidazole, is expensive.

[0003]

Means for Solving the Problems In order to solve such a problem, the inventors of the present invention have conducted extensive studies on a method of using inexpensive phosgene instead of carbonyldiimidazole, and as a result, have found that the amide group has a substituent. Non-amino-substituted anthranilamides give a desired product by reacting with phosgene, even though phosgene acts on them. In addition to the above findings, it was found that the target product can be obtained more efficiently by allowing phosgene to act in the presence of a base, and the present invention was completed by further various studies.

That is, the present invention is of the formula (I)

(In the formula, R _{1 and} R ₂ are each independently a hydrogen atom, a halogen atom, a nitro group, a lower alkyl group which may be substituted with a halogen atom, or a halogen atom which may be substituted. Aralkyl group, alkoxy group which may be substituted with halogen atom, alkoxycarbonyl group which may be substituted with halogen atom, or YNR
₃ R ₄ (Y represents a mere bond, a lower alkylene group or a carbonyl group. R ₃ and R ₄ are each independently a lower alkyl group or N, R ₃ and R ₄ together include another hetero atom. 5 heterocyclic ring or 6-membered heterocyclic ring, which, when containing other heteroatoms, may also have a substituent). X is a lower alkyl group which may be substituted with a halogen atom, an aralkyl group which may be substituted with a halogen atom, or ZCO
₂ R ₅ (Z represents a lower alkylene group, and R ₅ represents a lower alkyl group or an aralkyl group). A amide-substituted anthranilamide represented by the formula (II) characterized by reacting phosgene

[0006] (In the formula, R ₁ and R ₂ have the same meanings as described above.)
The present invention provides an industrially excellent method for producing dioxoquinazolines.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. The substituents R ₁ and R ₂ of the amide-substituted anthranilamide (I) in the present invention are each independently a hydrogen atom,
Halogen atom, nitro group, lower alkyl group which may be substituted by halogen atom, aralkyl group which may be substituted by halogen atom, alkoxy group which may be substituted by halogen atom, halogen atom is substituted Alkoxycarbonyl group or YNR ₃ R
₄ (Y represents a simple bond, a lower alkylene group or a carbonyl group. R ₃ and R ₄ each independently represent a lower alkyl group or N, R ₃ and R ₄ together contain another hetero atom. Represents a 5-membered heterocycle or a 6-membered heterocycle, and when other heteroatoms are included, the heteroatoms may have a substituent). X is a lower alkyl group which may be substituted with a halogen atom, an aralkyl group which may be substituted with a halogen atom, or ZCO ₂ R
₅ (Z represents a lower alkylene group, and R ₅ represents a lower alkyl group or an aralkyl group).

Here, examples of the halogen atom include chlorine, bromine, fluorine and the like. Examples of the lower alkyl group which may be substituted with a halogen atom include, for example, methyl, ethyl, propyl, i-propyl, butyl, i-
Butyl, t-butyl, pentyl, i-pentyl, lower alkyl groups such as hexyl, monohalo lower alkyl groups such as chloromethyl, bromomethyl, chloropropyl, 1,2-dichloroethyl, 1,2-dibromoethyl, 2,2 -Dihalo lower alkyl groups such as dichloroethyl, and trihalo lower alkyl groups such as trifluoromethyl. Examples of the aralkyl group which may be substituted with a halogen atom include, for example, benzyl, phenylethyl, 4-chlorobenzyl, 2,4-dichlorobenzyl, 2,4-dibromobenzyl and the like.

Alkoxy groups which may be substituted with halogen atoms include, for example, methoxy, ethoxy,
Propoxy, i-propoxy, butoxy, i-butoxy, t-
Butoxy, pentyloxy, i-pentyloxy, lower alkoxy groups such as hexyloxy, chloromethoxy, bromomethoxy, 1-, 2-chloroethoxy, 1-, 2-, 3-chloropropoxy, dichloromethoxy, sibromomethoxy, 1,
Lower alkoxy groups substituted by halogen atoms such as 2-dichloroethoxy, 2,2-dichloroethoxy, trifluoromethoxy and the like can be mentioned. Examples of the alkoxycarbonyl group which may be substituted with a halogen atom include a carbonyl group having an alkoxy group which may be substituted with the same halogen atom as described above.

Further, examples of the lower alkylene group in YNR ₃ R ₄ include methylene, dimethylene, trimethylene, tetramethylene and the like. Examples of the lower alkyl group of R ₃ and R ₄ in NR ₃ R ₄ are the same as above. The lower alkyl group of is mentioned, and specific examples in this case include dimethylamino, diethylamino, dipropylamino, dibutylamino and the like. NR ₃ R ₄
Specific examples of the case where N, R ₃ and R ₄ together represent a 5-membered heterocycle or 6-membered heterocycle which may together contain other heteroatoms are, for example, pyrrolyl, 2H, 4H-pyrrolyl , Pyrrolidino, pyrazolyl, piperidino, morpholino, imidazolyl and the like. When the other heteroatom is N, N may have a substituent. Examples of the substituent include a lower alkyl group which may be substituted with the same halogen atom as described above, an aralkyl group which may be substituted with the same halogen atom as described above, and a lower alkoxy group which is substituted. Examples thereof include a phenylcarbonyl group which may be substituted with an aralkyl group or a lower alkoxy group.

Examples of the lower alkyl group which may be substituted with a halogen atom in X and the aralkyl group which may be substituted with a halogen atom are, for example, R ₁ and
The same as R ₂ can be mentioned. Examples of Z include linear and branched lower alkylenes such as methylene, methylmethylene, dimethylene, 2-methyldimethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene. Preferred are methylene and methylmethylene. Examples of R ₅ include lower alkyl groups and aralkyl groups similar to the above R ₁ and R ₂ .

Representative compounds of the anthranilamides (I) are, for example, N-methyl-2-aminobenzamide, N-ethyl-2-aminobenzamide and N-benzyl-2-.
Aminobenzamide, N- (2-aminobenzoyl) methyl aminoacetate, N- (2-aminobenzoyl) ethyl aminoacetate, N- (2-aminobenzoyl) benzylaminoacetate, N-
(2-amino-4-chlorobenzoyl) ethyl aminoacetate,
N- (2-amino-5-chlorobenzoyl) ethyl acetate, N- (2-amino-6-chlorobenzoyl) ethyl amino acetate, N- (2-amino-4,5-dichlorobenzoyl) ethyl acetate, N- (2-amino-3,5-dichlorobenzoyl)
Ethyl aminoacetate, N- (2-amino-4-bromobenzoyl) ethylaminoacetate, N- (2-amino-5-bromobenzoyl) ethylaminoacetate, N- (2-amino-4-fluorobenzoyl) aminoacetic acid Ethyl, ethyl N- (2-amino-5-fluorobenzoyl) aminoacetate,

N- (2-amino-4,5-dimethoxybenzoyl) ethyl aminoacetate, N- (2-amino-5-methylbenzoyl) ethyl aminoacetate, N- (2-amino-5-ethylbenzoyl) amino Ethyl acetate, N- (2-amino-5-nitrobenzoyl) ethyl amino acetate, N- (2-amino-5-dimethylaminobenzoyl) ethyl amino acetate, N- (2-amino
-5- (1-pyrrolidinyl) benzoyl) ethyl aminoacetate,
N- (2-amino-5-trifluoromethylbenzoyl) ethyl acetate, N- (2-amino-5-imidazolylbenzoyl) ethyl acetate, N- (2-amino-5-benzylbenzoyl) ethyl acetate, Examples thereof include N- (2-amino-5-ethoxycarbonylbenzoyl) aminoethyl acetate and N- (2-amino-6-piperazinylbenzoyl) aminoethyl acetate.

The present invention is characterized by reacting such an amide-substituted anthranilamide (I) with phosgene, and the reaction is usually carried out by adding phosgene to a mixture of the solvent and the amide-substituted anthranilamide (I). It is implemented by introducing. Phosgene may be introduced in the gas state or in the liquid state under pressure. It is also possible to introduce phosgene dissolved in an organic solvent. Phosgene is an amide-substituted anthranilamide (I),
It is usually introduced in an amount of about 0.9 to 1.1 mole times, preferably about 0.9 to 1.0 mole times. If the amount exceeds 1.1 mole times, the yield tends to decrease rapidly, so it is preferable not to exceed 1.1 mole times. The introduction port of phosgene may be in either the gas phase part or the liquid phase part, but in the latter case, the reaction product may precipitate and block the introduction port, so this should be taken into consideration. .

The solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include cyclic ethers such as tetrahydrofuran and dioxane, glymes such as ethylene glycol dimethyl ether and diethylene glycol dimethyl ether, benzene, toluene, xylene and the like. Hydrocarbons, dichloromethane, chloroform, carbon tetrachloride,
Organic solvents such as halogenated hydrocarbons such as 1,2-dichloroethane, monochlorobenzene and dichlorobenzene can be mentioned. Of these, cyclic ethers, especially tetrahydrofuran, are preferably used. The solvent is usually used in an amount of about 0.5 to 40 times by weight, preferably about 1 to 20 times by weight, based on the amide-substituted anthranilamide (I). The reaction temperature is generally about -10 to 60 ° C, preferably about 0 to 30 ° C.

[0016] The reaction is preferably carried out in the presence of a base, which can improve the yield of the desired product. Examples of such a base include tertiary amines such as alkylamines such as triethylamine, tripropylamine and tributylamine which are organic bases, and alkylarylamines such as dimethylaniline and diethylaniline. Of these, triethylamine is preferably used. When a base is used, it is usually 1.8 with respect to the amide-substituted anthranilamide (I).
It is used in an amount of about 5 to 5 mol times, preferably about 2 to 2.5 mol times.

Thus, the desired dioxoquinazolines (II) are produced, but when taking them out from the reaction mixture, it is usual to first remove the residual phosgene. Examples of such detoxification methods include a method of adding a base. When the base is used in an amount of 2 times or more the mole of phosgene, water, an aqueous solution of an acid or the like may be added. The dioxoquinazolines (II) can be taken out from the reaction mixture after being removed by removing a part or all of the organic solvent and then applying a separating means such as filtration. The obtained dioxoquinazolines (II) can be further purified if necessary.

[0018]

INDUSTRIAL APPLICABILITY According to the present invention, dioxoquinazolines (II) can be industrially advantageously produced by reacting amide-substituted anthranilamides (I) with phosgene.

[0019]

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

Example 1 Under a nitrogen atmosphere, 442 g of tetrahydrofuran, 44 g of N- (2-aminobenzoyl) ethyl aminoacetate and 40 g of triethylamine were placed in a 1000 ml flask equipped with a condenser (-20 ° C.), and the mixture was cooled to 5%.
After cooling to 0 ° C., phosgene was introduced into the gas phase portion at a flow rate of 0.5 g / min for 40 minutes, and the reaction was continued by stirring at the same temperature for 90 minutes. Then, after adding 265 g of water, concentration under reduced pressure, filtration,
By drying, the target product 2- (2,4-dioxo-1,2,3,4
-Tetrahydroquinazolin-3-yl) ethyl acetate (50 g) was obtained. When this product was analyzed by high performance liquid chromatography, the purity was 96%. When the filtrate was analyzed, the raw material conversion rate was 100%, and the target product formation rate was calculated to be 98%.

Example 2 In Example 1, phosgene was introduced at a flow rate of 0.2 g / min for 120 minutes without using triethylamine, and the mixture was continuously stirred for 105 minutes. Then, a mixture of 51 g of triethylamine and 100 g of tetrahydrofuran was added to 0. The reaction and post-treatment were carried out in accordance with Example 1 except that the mixture was added at -5 ° C over 30 minutes and the temperature was raised to 25 ° C and stirring was continued for 30 minutes at the same temperature. The raw material conversion rate was 92%, and the target product formation rate was 77%.

Example 3 The reaction and post-treatment were carried out in the same manner as in Example 1 except that the amount of triethylamine was 65 g and the introduction time of phosgene was 60 minutes. The raw material conversion rate was 100%, and the target product formation rate was 19%.

Example 4 The reaction and post-treatment were carried out in the same manner as in Example 1 except that triethylamine was not used. The raw material conversion rate was 86%, and the target product formation rate was 40%.

Comparative Example 1 Same as Example 1 except that ethyl N- (2-carbamoyl-5-chlorophenyl) aminoacetate was used instead of ethyl N- (2-aminobenzoyl) aminoacetate in Example 4. It was carried out. The raw material conversion rate is 78.5%, and the target product 2- (7
The production rate of -chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl) ethyl acetate was 2.2%.

Claims (7)

[Claims] (1) Formula (I) (In the formula, R _{1 and} R ₂ are each independently a hydrogen atom, a halogen atom, a nitro group, a lower alkyl group which may be substituted with a halogen atom, an aralkyl group which may be substituted with a halogen atom, An alkoxy group which may be substituted with a halogen atom, an alkoxycarbonyl group which may be substituted with a halogen atom or YNR ₃ R ₄ (Y represents a simple bond, a lower alkylene group or a carbonyl group.
R ₃ and R ₄ are each independently a lower alkyl group or N, R ₃ ,
R ₄ together represents a 5-membered heterocycle or a 6-membered heterocycle, which may also contain other heteroatoms. When it contains another hetero atom, the hetero atom may have a substituent. ). X is a lower alkyl group which may be substituted with a halogen atom, an aralkyl group which may be substituted with a halogen atom, or ZCO ₂ R ₅ (Z is a lower alkylene group, R ₅ is a lower alkyl group or Represents an aralkyl group. A amide-substituted anthranilamide represented by the formula (II) characterized by reacting with phosgene (In the formula, R ₁ and R ₂ have the same meanings as described above.)
A method for producing a dioxoquinazoline represented by: 2. The method according to claim 1, which is carried out in the presence of an organic solvent. 3. The method according to claim 2, wherein the organic solvent is at least one selected from cyclic ethers, glymes, hydrocarbons and halogenated hydrocarbons. 4. The method according to claim 2, wherein the organic solvent is a cyclic ether. 5. The production method according to claim 1, which is carried out in the presence of a base. 6. The production method according to claim 5, wherein the base is an organic base. 7. The method according to claim 1, wherein phosgene is used in an amount of 0.9 to 1.1 mole times that of the amide-substituted anthranilamide (I).