WO2003064377A1 - 4,5-substituted-2-formylaminobenzamides and processes for their production and conversion - Google Patents

Abstract

4,5-Substituted-2-formylaminobenzamides of the general formula (1) can be produced by reacting a compound of the general formula (6) with formic acid in an organic solvent, and can be further converted into 6,7-substituted-quinazolin-4-ones of the general formula (7) through cyclization in the presence of a base: (1) (6) (7) wherein R1 and R2 are each hydrogen, alkyl which may have a substituent, cycloalkyl, alkenyl, aralkyl, aryl, or acyl, and the substituent is alkyl, cycloalkyl, alkenyl, aryl, acyl, alkoxycarbonyl, halogeno, or the like.

Description

 Specification

4,5-Substituted-2-formylaminobenzamide compounds, their production and their conversion

 The present invention relates to a 4,5-substituted-2-formylaminonovenzamide compound useful as a synthetic intermediate for pharmaceuticals, a method for industrially and efficiently producing the compound, and a method for industrially and efficiently producing the compound. , 7-substituted-quinazolin-4-ones. Background art

 A conventional method for producing 4,5-substituted-2-formylamino novenzamide is disclosed in Acta Chim. Acad. Sci. Hung., 94, 233 (1977). A method of reacting aminovenzamide with acetic acid-formic acid mixed anhydride in a methylene chloride solvent under reflux to obtain 4,5-methylenedioxy-2-formylaminobenzenamide in a yield of 72%. Is disclosed.

 However, acetic acid-formic acid mixed anhydride used as a formylating agent in the above-mentioned conventional method is extremely unstable with respect to moisture, and this method is disadvantageous as an industrial production method.

 Also, the above-mentioned document discloses a method of converting 4,5-methylenedioxy-2-formylaminobenzamide to a 4,5-methylenedioxyquinazolin-4-one by heating it at a high temperature of 245 to 250 ° C. Is described. However, this method requires the above high temperature of 245 to 250 ° C., and therefore, it was difficult to carry out this method as an industrial conversion method.

In addition, two non-cyclized amino acids at the 4th and 5th positions of formylaminovensamide 4,5-Substituted-2-formylaminobenzamide compounds having an alkoxy group have not been known, and thus no industrially effective production method and conversion method have been known. Disclosure of the invention

 The present invention provides a 4,5-substituted-2-formylaminobenzamide compound having a substituted or unsubstituted hydrocarbonoxy group at the 4 and 5 positions, a method for industrially and efficiently producing the compound, and It is intended to provide a method for converting a compound into a ring.

 The 4,5-substituted-2-formylaminobenzamide compound of the present invention has the following general formula (1):

[However, in the above formula (1), R ¹ and R ² each independently represent a hydrogen atom, and an unsubstituted alkynole having at least one substituent, a cycloanolequinole, an anorekeninole, Represents a member selected from the group consisting of an aranoquinone, an arynole, and an asinole group, wherein the substituent is an alkyl, cycloalkyl, alkenyl, heterocyclic alkenyl, aryl, acryl, alkoxycarbonyl, aryloxycanoleboninole Selected from alkyl, cyano, hydroxy, alkoxy, aryloxy, mercapto, thioalkoxy, and thioaryloxy groups, and halogen atom.)

It is represented by In the general formula (1), which represents the 4,5-substituted-2-formylaminobenzamide compound of the present invention, R ¹ and R ² each independently represent a methyl, ethyl, or 2-methoxyl group. The 4,5-substituted-2-formylaminobenzamide compound of the present invention is preferably selected from the following formula (2):

によ り表される、 4， 5 -ジメ トキシ -2-ホルミルアミ ノベンズアミ ド 化合物を包含する。

And a 5,5-dimethoxy-2-formylaminobenzamide compound represented by

 The 4,5-substituted-2-formylaminobenzamide compound of the present invention has the following formula (3):

によ り表される、 5-ェ トキシ- 4-メ トキシ -2-ホルミノレアミ ノベンズ ァミ ドを包含する。

And 5-ethoxy-4-methoxy-2-forminoleaminobenzamide.

によ り表される、 4， 5-ジエ トキシ- 2-ホルミルァミ ノべンズアミ ド 化合物を包含する。 The 4,5-substituted-2-formylaminobenzamide compound of the present invention has the following formula (4):

And 4,5-diethoxy-2-formylaminobenzamide compounds.

 The 4,5-substituted-2-formylaminobenzamide compound of the present invention has the following formula (5):

And 4,5-bis (2-methoxetoxy) -2-formylaminobenzamide compounds.

 The method for producing the 4,5-substituted-2-formylaminobenzamide compound of the present invention is represented by the following general formula (1):

[However, in the above formula (1), R ¹ and R ² are each independently of each other. Represents a hydrogen atom and one member selected from an unsubstituted and at least one substituent selected from the group consisting of anolequinole, cycloalkyl, alkenyl, aralkyl, aryl, and acyl; and the substituent is an alkyl group. , Cycloalkyl, alkenyl, heterocyclic alkenyl, aryl, acynore, anorecoxycanololeponyl, arixoxycanolebonyl, alkyl halide, cyano, hydroxy, alkoxy, arylioxy, mercapto, Selected from thioalkoxy, thioaryloxy, and halogen atoms.)

In order to produce a compound represented by the following general formula (6):

[Wherein, in the above formula (6), R ¹ and R ² are as defined above], and a 4,5-substituted-2-aminobenzamide compound represented by the following formula: The reaction is performed in an organic solvent. In the method for producing a 4,5-substituted-2-formylaminobenzamide compound of the present invention, R ¹ and R ^{2 in the} general formulas (1) and (6) are each independently methyl or ethyl. , And a 2-methoxyl group.

In the method for producing a 4,5-substituted-2-formylaminobenzamide compound of the present invention, the reaction between the 4,5-substituted-2-aminobenzamide of the general formula (6) and formic acid is 10 to 10%. Preferably, the reaction is carried out at a temperature of 50 ° C. In the process for producing a 4,5-substituted-2-formylaminobenzamide compound according to the present invention, the 4,5-substituted-2-amide of the general formula (6) is preferably used. Novenzamide and The organic solvent used in the reaction with formic acid is-a tritol compound, an ether compound, a ketone compound, a halogenated aliphatic hydrocarbon compound, an aromatic hydrocarbon compound, a haegenated aromatic hydrocarbon compound, Preferably, the compound is selected from a compound, a sulfoxide compound, and a urea compound.

 The method for converting a 4,5-substituted-2_formylaminobenzamide compound of the present invention comprises a 4,5-substituted-2-formylaminonovenzamide represented by the general formula (1) of the present invention. The compound is subjected to a cyclization reaction in the presence of a basic substance to obtain a compound represented by the following general formula (7):

[However, in the above formula (7), R ¹ and R ² are as defined above]

Which is converted to a 6,7-substituted-quinazolin-4-one compound represented by the following formula:

 In the method for converting a 4,5-substituted-2-formylaminobenzamide compound according to the present invention, the basic substance may be an alkali metal hydroxide, an alkaline earth metal hydroxide, or an alkali metal carbonate. And alkali metal bicarbonates, and alkali metal alkoxides. In the method for converting a 4,5-substituted-2-formylaminobenzamide compound according to the present invention, it is preferable that the cyclization reaction is performed in a liquid reaction medium.

In the method for converting a 4,5-substituted-2-formylaminobenzamide compound according to the present invention, the cyclization reaction is carried out at a temperature of 0 to 100 ° C. Is preferred. BEST MODE FOR CARRYING OUT THE INVENTION

 The 4,5-substituted-2-formylaminobenzamide compounds of the general formula (1) of the present invention are the same as the 4,5-substituted-2-aminobenzamides substituted by the general formula (6). And formic acid in an organic solvent.

(1) In the above formulas (1) and (6), R ¹ and R ² each independently represent a hydrogen atom and an unsubstituted and at least one alkynole and cycloanolequinolene having a substituent. , Anoleckeninole, aralkynole, aryl, and an acyl group, wherein the substituent is an alkyl, cycloalkyl, alkenyl, heterocyclic alkenyl, aryl, ashinole, anorecoxycanololepo Selected from the group consisting of alkylene, halogenated alkyl, cyano, hydroxy, anorecoxy, aryloxy, menolecapto, thioalkoxy, and thioaryloxy groups, and halogen atom. . The alkyl group preferably has 1 to 10 carbon atoms

More preferably, it is selected from, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group and the like. These groups include various isomers.

 The cycloalkyl group preferably has 3 to 10 carbon atoms, and more preferably, for example, a cyclopropyl group, a cyclopentinole group, a cyclopentinole group, a cyclohexyl / re group , Cycloheptyl group, cyclooctyl group and the like.

 The alkenyl group preferably has 2 to 10 carbon atoms, and is more preferably selected from, for example, a butyl group, an aryl group, a propinole group, a butageninole group, and the like. Each of these groups includes various isomers.

 The aralkyl group preferably has 7 to 20 carbon atoms, and is more preferably selected from, for example, a benzyl group, a phenethyl group, a phenylpropyl group and the like. These groups each include various isomers.

 The aryl group preferably has 6 to 20 carbon atoms, and is more preferably selected from, for example, a ferr group, a P-trinole group, a naphthyl group, an anthranyl group and the like. Each of these groups includes various isomers.

 The acetyl group preferably has 2 to 20 carbon atoms, and more preferably, for example, acetyl, propionyl, acryloyl, piperoyl, cyclohexylcarbonyl, benzoyl Group, naphthyl group, toluoyl group and the like. Each of these groups includes various isomers.

The above alkyl group, cycloalkyl group, alkenyl group, aralkyl The aryl group, aryl group and acyl group may have a substituent. Examples of the substituent include a substituent bonded via a carbon atom, a substituent bonded via an oxygen atom, a substituent bonded via a sulfur atom, and a halogen atom. Can be

Examples of the substituent bonded through the carbon atom include an alkyl group, preferably: an alkyl group having 10 to 10 carbon atoms, such as a methyl group, an ethyl group, a propyl group, a butyl group, Pentyl group, hexyl group and the like; cycloalkyl group, preferably cycloalkyl group having 3 to 10 carbon atoms, for example, cyclopropyl group, cyclobutyl group, cyclopentinole group, cyclohexylene group, An alkenyl group, preferably an alkenyl group having 2 to 10 carbon atoms, for example, a vinyl group, an aryl group, a propenyl group, a cyclopropenyl group, a cyclobutenyl group, A pentenyl group, etc .; a heterocyclic alkenyl group, preferably a pyrrolidyl group, a pyrrolyl group, a furyl group, a cyenyl group, etc .; an aryl group, preferably Is an aryl group having 6 to 20 carbon atoms, for example, phenyl, tolyl, xylyl, biphenyl, naphthyl, anthryl, phenanthryl, etc .; Or an acyl group having 1 to 20 carbon atoms, such as formyl group, acetyl group, propionyl group, acryloyl group, piperoyl group, cyclohexylcarbinole group, benzoyl group, naphthyl group, Carboxyl group; alkoxycarbonyl group, for example, alkoxycarbonyl group having 2 to 10 carbon atoms, for example, methoxycanolebonyl group, ethoxycanoleponinole group, etc .; Preferably, an aryloxycarbonyl group having 7 to 20 carbon atoms, such as a phenoxycarbonyl group ; Nono halogenated alkyl group preferably C port Gen of Al Kill group having 1 to 10 carbon atoms, such as Application Benefits Furuoromechiru group; and include Shiano group Can be Each of these groups includes various isomers. The substituent bonded via the oxygen atom is a hydroxyl group; an alkoxy group, preferably an alkoxy group having 1 to 10 carbon atoms, for example, a methoxy group, an ethoxy group, a propoxy group, a butoxy group, Pentyloxy group, hexyloxy group, heptyloxy group, benzyloxy group and the like; aryloxy group, preferably an aryloxy group having 6 to 20 carbon atoms, for example, phenoxy group, tolyloxy group, naphthyloxy group and the like. Each of these groups includes various isomers.

 Examples of the substituent bonded via the sulfur atom include a mercapto group; a thioalkoxy group, preferably a thioalkoxy group containing 1 to 10 carbon atoms, for example, a thiomethoxy group and a thioethoxy group. A thioaryloxy group, preferably a thioaryloxy group having 6 to 20 carbon atoms, such as a thioenoxyl group, a thiotoluyloxyl group, a thionaphthyloxyl group or the like; It is. Each of these groups includes various isomers.

 The halogen atom for the substituent is selected from a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

 The amount of formic acid used in the formylation reaction in the method of the present invention is preferably 1 to 50 mol, more preferably 2 to 50 mol of the 4,5-substituted-2-aminobenzamide compound. ~ 30mol. The formic acid may be used in the form of an aqueous solution.

The formylation reaction of the method of the present invention is performed in the presence of an organic solvent. The organic solvent used in the method of the present invention is not particularly limited as long as it does not inhibit the reaction. Examples thereof include nitrile compounds such as acetonitrile and propionitrile; tetrahydrofuran; 1,4-Zoki Ether compounds such as sun; ketone conjugates such as acetone and methylethylketone; and haguchi-genated aliphatic hydrocarbon compounds such as dichloromethane, black mouth form, carbon tetrachloride, and dichloroethane. Aromatic hydrocarbons such as benzene, toluene and xylene; halogenated aromatic hydrocarbons such as benzene and dichlorobenzene; Ν, Ν-dimethylformamide, ,, Ν-dimethylacetamide, Ν Amide compounds such as -methylpyrrolidone; sulfoxide compounds such as dimethylsulfoxide; and urea compounds such as Ν, Ν'-dimethylimidazolidinone. Preferably, nitrile compounds, ether compounds, ketone compounds, halogenated aliphatic hydrocarbon compounds, and aromatic hydrocarbon compounds are used, and more preferably, nitrile compounds, ether compounds, and ketone compounds are used. It is more preferable to use a nitrile compound. These compounds for organic solvents may be used alone or in combination of two or more.

 The amount of the organic solvent to be used can be appropriately set in consideration of the uniformity of the reaction solution, the stirring property, and the like.In general, the amount of the organic solvent is based on the raw material 4,5-substituted-2-aminobenzamide compound lg. It is preferable to use 1 to 30 g, and more preferably 1 to 15 g.

 In the formylation reaction in the method of the present invention, for example, a raw material 4,5_-substituted-2-aminobenzamide compound, formic acid and an organic solvent are mixed and reacted in an inert gas atmosphere. And so on. The reaction temperature at that time is preferably 10 to 50 ° C, more preferably 10 to 30 ° C, and the reaction pressure is not particularly limited.

After completion of the reaction, the 4,5-substituted-2-formylaminobenzamide compound, which is the target product, can be obtained by a simple method such as filtration, concentration, distillation, recrystallization, or column chromatography. Separated and refined. The 4,5-substituted-2-formylaminobenzamide compound represented by the general formula (1) of the present invention is a compound of the following formula (2). Nsamide, 5-ethoxy-4-methoxy-2-formylaminobenzenamide of formula (3), 4,5-diethoxy-2-formylaminobenzamide of formula (4), chemical formula Includes 4,5-bis (2-methoxyethoxy)--formylaminobenzamide in (5).

上記化学式（2)〜（5)の化合物を包含する一般式（1)の 4， 5-置換 -2 - ホルミルアミ ノベンズァミ ド化合物は、 本発明方法によ り、 工業的 に効率よく環化して一般式（7)：

The 4,5-substituted-2-formylaminobenzamide compounds of the general formula (1) including the compounds of the above chemical formulas (2) to (5) can be industrially efficiently cyclized by the method of the present invention to obtain general cyclized compounds. Equation (7):

(Wherein, R ¹ and R ² are the same as defined above)

Can be converted to the 6,7-substituted-quinazolin-4-one represented by The compound of the general formula (7) is useful as an intermediate for synthesizing pharmaceuticals such as inflammation inhibitors and stake cancer drugs. (For example, W096 / 28430, Japanese Patent Publication No. 11-503412)

 The cyclization of the 4,5-substituted-2-formylaminobenzamide compound of the general formula (1) is carried out in the presence of a base as follows.

上記環化反応において使用される塩基と しては、 例えば、 水酸化 リ チウム、 水酸化ナ ト リ ウム、 水酸化力 リ ウム等のアルカ リ金属水 酸化物 ； 水酸化カルシウム、 水酸化マグネシウム等のアル力 リ 土類 金属水酸化物 ； 炭酸リ チウム、 炭酸ナ ト リ ウム、 炭酸カ リ ウム、 炭 酸セシウム等のアルカ リ金属炭酸塩 ； 炭酸水素ナ ト リ ウム、 炭酸水 素カ リ ウム、 炭酸水素セシゥム等のアルカ リ金属炭酸水素塩 ； ナ ト リ ウムメ トキシ ド、 ナ ト リ ウムエ トキシ ド、 カ リ ウムエ トキシ ド、 力 リ ゥム t-ブトキシ ド等のアル力 リ金属アルコキシ ドが挙げられる が、 好ましく はアルカ リ金属水酸化物が用いられ、 更に好ましく は 水酸化ナ ト リ ウムが使用される。 なお、 上記の塩基は、 単独に用い られてもよ く 、 又はその二種以上を混合して使用してもよい。

Examples of the base used in the cyclization reaction include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and lithium hydroxide; calcium hydroxide, magnesium hydroxide and the like. Alkali metal hydroxides; Alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate; sodium hydrogen carbonate, hydrogen carbonate Alkali metal bicarbonates, such as cesium bicarbonate; sodium methoxide, sodium ethoxide, potassium ethoxide, lithium metal alkoxides such as potassium t-butoxide Preferably, an alkali metal hydroxide is used, and more preferably, sodium hydroxide is used. The above bases may be used alone or in combination of two or more.

 The amount of the base to be used in the above cyclization reaction is preferably 1 to 20 mol, more preferably 2 to 10 mol, per 1 mol of the compound of the general formula (1).

The cyclization reaction of the compound of the general formula (1) is preferably performed in the presence of a solvent. The solvent used in this case is not particularly limited as long as it does not inhibit the reaction. For example, the solvent used for the cyclization reaction may be water; acetonitrile, propionitrile, etc. Nitril compounds; ether compounds such as tetrahydrofuran and 1,4-dioxane; ketone compounds such as acetone and methylethylketone; dichloromethane, chloroforme, carbon tetrachloride, dichloroethane Halogenated aliphatic hydrocarbon compounds such as benzene; toluene, xylene and the like; aromatic hydrocarbon compounds such as chlorobenzene and dichlorobenzene; and halogenated aromatic hydrocarbon compounds such as chlorobenzene and dichlorobenzene; N, N-dimethylformamid Amide compounds such as N, N-dimethylacetamide and N-methylpyrrolidone; sulfoxide compounds such as dimethylsulfoxide; N, N, -diamine Horst Midazori can and Mochiiruko urea compounds such Gino down, preferably water, two preparative Lil compounds, er Ter compounds, ketone compounds, halogenated aliphatic hydrocarbon compounds, and aromatic hydrocarbon compounds are used, more preferably water, nitrile compounds, ether compounds, and ketone compounds, and particularly preferably, Water and / or nitrile compounds are used. These solvents may be used alone or in combination of two or more. 'The amount of the solvent to be used may be appropriately determined depending on the uniformity of the reaction solution, the stirring property, and the like. Preferably it is 1 to 20 ml.

 The cyclization reaction of the compound of the general formula (1) is preferably performed by a method such as mixing and reacting the compound of the general formula (1) with a base and a solvent in an inert gas atmosphere. Will be The reaction temperature at that time is preferably from 0 to 100 ° C, more preferably from 0 to 50 ° C, and the reaction pressure is not particularly limited.

 After completion of the reaction, the 6,7-substituted quinazolin-4-one compound of the general formula (7), which is the final product of the above cyclization reaction, is subjected to, for example, filtration, extraction, concentration, distillation, recrystallization, and column chromatography. It can be isolated and purified by a general method such as chromatography. Example

 The present invention will be specifically described by the following examples.

Example 1 (Synthesis of 4,5-dimethoxy-2-formylaminobenzamide—)

In a 10-ml flask equipped with a stirrer and thermometer, under an argon atmosphere, 0.30 g (l.53 mmol) of 4,5-dimethoxy-2-aminobenzamide and 2 ml of acetonitrile were placed. The mixture was cooled to 5 ° C with stirring. 1.05 g (22.92 mmol) of formic acid was added to the obtained solution at 5 ° C. After the addition, the temperature of the reaction mixture was raised to 25 ° C., and the benzamide compound and formic acid were reacted for 48 hours. After completion of the reaction, the precipitated crystals were collected by filtration, washed with acetonitril, and dried under reduced pressure to give colorless crystals as 4,5-dimethoxy-2-formylaminobenz. 246 mg of the amide were obtained. On the other hand, the mixture of the filtrate and the crystal washing solution was cooled, and the precipitated crystals were filtered, washed with acetonitrile, and dried under reduced pressure to give colorless crystals of 4,5-dimethoxy-2. -27 mg of formylamino benzamide were obtained. The obtained crystals of 4,5-dimethoxy-2-formylaminobenzamide were 273 mg in total (isolation yield: 80%).

 4,5-Dimethoxy-2-formylaminobenzamide is a novel compound identified by the following physical data.

Melting point 231 ~ 233 ° C

Elemental analysis: 53.31% carbon, 5.45% hydrogen, 12.49% nitrogen

, δ (ppm) ) ； 3.784(3H， s)、 3.794(3H，s)、 7.362( lH，s)、 7.571(lH，brs)、 8.165 ( 1H， br s )、 8.270(lH，s)、 8·412〜8·4 17(lH，m)、 11.797(lH,s) (Theoretical value (CH NsOa); carbon 53.57%, hydrogen 5.39%, nitrogen 12.49%)

, δ (ppm)); 3.784 (3H, s), 3.794 (3H, s), 7.362 (lH, s), 7.571 (lH, brs), 8.165 (1H, brs), 8.270 (lH, s), 8412 to 8417 (lH, m), 11.797 (lH, s)

^{13 C-NMR (DMSO-d} 6, δ (ppm)); 55.857 (CH 3 0_), 55.949 (CH 3 0-), 1 04.179, 110.874, 111.658, 134.125, 143.544, 151.227, 160.128 (- NHC (= 0) H), 170.138 (-C (= 0) NH 2)

 FAB-MS; 225 (MH +)

Examples 2 to 4

In each of Examples 2 to 4, a 4,5-substituted-2-formylaminobenzamide compound was produced in the same manner as in Example 1. However, as the starting compound, a compound having R ¹ and R ² shown in Table 1 in the general formula (1) was used. Table 1 shows the results. table 1.

[Note] _{Me - CH 3 - Et- h 3} H 2 one noted, the reaction product obtained in Example 2 4, are novel compounds which are identified by the following physical properties.

 5-ethoxy-4-methoxy-2-formylaminobenzamide (Example 2)

Melting point: 200 203 ° C

Elemental analysis; carbon 55.26%, hydrogen 5.96%, nitrogen 11.77%

(Theoretical value ₍₍₁₁ 11 ₁₄ ^ 0 _4); carbon 55.46%, hydrogen 5.92%, 11.76% nitrogen) - negation _{R (MS0_d 6, δ (ppm} )); 1.327 (3H, t, J = 6.84Hz), 3.786 (3Hs), 4.048 (2HqJ = 6.84Hz) 7.361 (lH, s), 7548 (1Hbrs) 8.139 (1H, brs), 8.271 (lH, s), 8.411 8.415 (lH, m ), 11.807 (lH, s)

^{13 C-NMR (DMS0-d} 6, δ (ppm)); 14.618 (CH 3 -) 55.321 (CH 3 0 -), 64 .158 (- CH 2 0 -), 104.243 110.846 112.877 134.171 142.722 1 51.485 160.119 ( - NHC (= 0) H) , 170.138 (-C (= 0) NH 2)

 FAB-MS; 238 (M +)

 4,5-Jetoxy-2-formylaminobenzamide (Example 3) Melting point: 172 175 ° C

Elemental analysis; carbon 56.88%, hydrogen 6.48%, nitrogen 11.07%

δ (ppm)) ； 1.303〜： 1.372(6H m)、 4·012 4.078 (4H，m)、 7.361(lH，s)、 7.534(lH，brs)、 8.127(1H， brs )、 8.255(1H, s)、 8.396〜8· 399(lH，m)、 11.780(lH,s) (Theoretical value _{(C 12 H 16 N 2 0} 4); carbon 57.13%, hydrogen 6.39%, 11.10% nitrogen)

δ (ppm)); 1.303-: 1.372 (6H m), 4.012 4.078 (4H, m), 7.361 (lH, s), 7.534 (lH, brs), 8.127 (1H, brs), 8.255 (1H, s), 8.396 to 8399 (lH, m), 11.780 (lH, s) )

_{^{13 C-NMR (DMS0- d 6}} , δ (ppm)); 14.396 (CH 3 -), 14.636 (CH 3 -), 63. 715 (- CH 2 0-), 64.278 (-CH 2 0-), 105.222, 110.846, 113.422, 134. 180 , 142.786, 150.839, 160.100 (- NHCO0) H), 170.101 (- C (= 0) NH 2)

 FAB-MS; 252 (M +)

 4,5-bis (2-methoxyethoxy) -2_formylamino benzoamide (Example 4)

- negation _{R (DMS0- d 6, δ (} ppm)); 3.327 (6H, s), 3.650~3 · 707 (4H, m), 4.098~4.156 (4H, m), 7.409 (lH, s), 7.554 (1H, brs), 8.144 (lH, brs), 8.270 (lH, s), 8410 ~ 8.415 (1H, m), 11.758 (lH, s)

^{13 C-NMR (DMS0-d} 6, δ (ppm)); 58.145 (CH 3 0-), 58.194 (CH 3 0-), 6 7.812 (MeO - CH 2 -), 68.414 (Me0- CH 2 _) _{, 70.004 (- CH 2 0 -} ), 70.334 (-CH 2 0 -), 105-814, 111.394, 114.114, 134-322, 142.893, 150.921, 160.168 (-NHC (= 0) H), 170.033 (-C (= 0) NH ₂ )

 FAB-MS; 312 (M +)

Example 5 (Conversion to 6,7-dimethoxy-3H_quinazolin-4-one)

In a flask having an internal volume of 10 ml equipped with a stirrer and a thermometer, 100 mg (0.45 mmol) of 4,5-dimethoxy-2-formylamino novenzamide and pH were synthesized in the same manner as in Example 1 in an argon atmosphere. 0.5 ml of an aqueous sodium hydroxide solution adjusted to 13.5 was added, and the mixture was reacted at 25 ° C for 30 minutes. After the completion of the reaction, the pH was adjusted to 7.6 by adding 20 ml of water and 0.5 mol / liter hydrochloric acid to the reaction mixture. Crystals precipitated from this mixture were collected by filtration. On the other hand, the filtrate was extracted with 100 ml of ethyl acetate, the organic layer was separated, and concentrated under reduced pressure to precipitate crystals. The obtained crystals are combined and dried under reduced pressure to give colorless crystals. 86.2 mg of 7-dimethoxy-3H-quinazolin-4-one was obtained (isolation yield: 93%)

).

Examples 6 to 8

In each of Examples 6 to 8, the same conversion operation as in Example 5 was performed. However, 4,5-substituted-2-formylaminobenzamide having R ¹ and R ² shown in FIG. 2 in the general formula (1) was used as a starting compound for the conversion reaction. FIG. 2 shows the yield of the conversion product.

Table 2.

産業上の利用可能性

Industrial applicability

 The 4,5-substituted-2-formylaminobenzamide compounds of the general formula (1) according to the present invention are useful as intermediates of various medicines, and the method of the present invention relates to the compound of the general formula (6) The present invention makes it possible to industrially and efficiently produce a compound of the general formula (1) from a 5-substituted-2-aminobenzamide compound and formic acid by a simple process. The compound of the general formula (1) is cyclized in the presence of a base to give a 6,7-substituted-quinazoline-4 compound of the general formula (7), which is useful as a pharmaceutical intermediate. It can be converted to a compound.

Claims

SB request 1. The following general formula (1)

[However, in the above formula (1), R ¹ and R ² each independently represent a hydrogen atom, and an unsubstituted and at least one alkynole, cycloanolequinole, anorekeninole having at least one substituent, Represents a member selected from the group consisting of aryl, alkynole, and acylole, wherein the substituent is alkyl, cycloalkyl, alkenyl, heterocyclic alkenyl, aryl, isyl, alkoxy canola, and aryl. Selected from the group consisting of hydroxycanolepoxy, halogenide lanolequinole, cyano, hydroxy, alkoxy, aryl, carboxy, mercapto, thioalkoxy, and thioallyloxy, as well as halogen atom. A 4,5-substituted-2-formylaminobenzamide compound represented by 2. In the general formula (1), R ¹ and R ² are each independently selected from methyl, ethyl, and 2-methoxyl groups. Substituted 2-formyl novenamide compounds 3. The following equation (2): (2)

The 4,5-substituted'-2-formylaminobenzamide compound according to claim 1, which is represented by the following formula:  4. Equation (3) below:

The 4,5-substituted-2-formylamino benzobenamide compound according to claim 1, which is represented by the following formula:  5. The following equation (4):

The 4,5-substituted-2-formylamino benzobenamide compound according to claim 1, which is represented by the following formula: 6. The following equation (5):

The 4,5-substituted-2_formylamino benzobenz compound according to claim 1, which is represented by the following formula:  7. The following general formula (1):

[However, in the above formula (1), R ¹ and R ² each independently represent a hydrogen atom and alkyl, cycloalkyl, alkenyl, aralkyl, unsubstituted and having at least one substituent. And a member selected from the group consisting of alkyl, cycloalkyl, alkenyl, heterocyclic alkenyl, aryl, acyl, and anorecoxycanololeponic acid. Selected from the group consisting of phenol, halogenated anolequinole, cyano, hydroxy, anorecoxy, aryloxy, menolecapto, thioalkoxy, and thioaryloxy groups, and halogen atom.) In order to produce a compound represented by the following general formula (6):

[Wherein, in the above formula (6), R ¹ and R ² are as defined above], and a formic acid and a 4,5-substituted-2-aminobenzamide compound in an organic solvent A method for producing a 4,5_substituted-2-formylaminobenzamide compound, characterized in that the reaction is carried out in the following manner. 8. The method according to claim 7, wherein, in the general formulas (1) and (6), R ¹ and R ² are each independently selected from a methyl, an ethyl, and a 2-methoxethyl group. Method for producing 4,5-substituted-2-formylaminobenzamide compound.  9. The reaction between the 4,5-substituted-2-aminobenzamide of the general formula (6) and formic acid at a temperature of 10 to 50 ° C. A method for producing a 5-substituted-2-formylaminobenzamide compound.  10. The organic solvent used for the reaction between the 4,5-substituted-2-aminobenzamide of the general formula (6) and formic acid is a nitrile compound, an ether compound, a ketone compound, 9. The method according to claim 7, wherein the compound is selected from the group consisting of a genated aliphatic hydrocarbon compound, an aromatic hydrocarbon compound, a halogenated aromatic hydrocarbon compound, an amide compound, a sulfoxide compound, and a urea compound. Method for producing substituted 2-formylamino novenzamide compound 11. The 4,5_-substituted-2-formylaminonovenzamide compound represented by the general formula (1) according to any one of claims 1 to 6 is a basic substance. In a cyclization reaction in the presence of a compound represented by the following general formula (7)

[In the formula (7), R ¹ and R ² are as defined above.] A method for converting a 4,5-substituted-2-formylaminobenzamide compound, represented by the formula:, to a 6,7-substituted-quinazolin-4-one compound.  12. The basic substance is selected from an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, and an alkali metal alkoxide. A method for converting a 4,5-substituted-2-formylaminobenzamide compound described in item 11 of the scope.  13. The method for converting a 4,5-substituted-2-formylaminobenzamide compound according to claim 11, wherein the cyclization reaction is performed in a liquid reaction medium.  14. The method for converting a 4,5-substituted-2-formylaminobenzamide compound according to claim 11, wherein the cyclization reaction is performed at a temperature of 0 to 100 ° C.