JPH07309851A - Production of benzooxazinon derivative - Google Patents

Abstract

PURPOSE:To simply obtain the subject compound useful as a medicine (raw material) in good yield by subjecting a carboxylic acid (derivative) to acylation reaction with a 2-aminobenzoic acid derivative in the presence of a specific condensing agent and successively subjecting the reaction product to cyclization reaction. CONSTITUTION:(A) A carboxylic acid or its reactive derivative is subjected to acylation reaction with (C) a 2-aminobenzoic acid derivative such as a compound of formula I (R<1> is H, a halogen, an alkyl, etc.; R<2> is R<1>, OH, carboxyl, etc.) in the presence of (B) a halogenated carbonic acid monoalkyl ester, an acyl halide, 1,1'-carbonyldiimidazole, an aliphatic sulfonyl halide, an aromatic sulfonyl halide, a diphenyl phosphoric acid halide or a compound of the formula, Me2N<+>=CHX.X (X is Br or C1; Me is CH3) and successively (without isolating the product) subjected to cyclization reaction in the presence of a condensing agent B to provide the objective compound such as a compound of formula II (R is an ormanic srouo derived from the component A).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an improved process for producing benzoxazinone derivatives.

[0002]

BACKGROUND ART Conventionally, as a method for producing a compound having a benzoxazinone skeleton, the following (A), (B), (C)
As shown in the reaction formula of (1), a method of ring-closing (1) 2- (acylamino) benzoic acid with acetic anhydride or thionyl chloride by heating under reflux for several hours [reaction formula (A)] [Journal of Organic Chemistry (J. Org. Chem) Vol. 42, P. 12-
18, 1977], (2) A method of ring-closing reaction of 2- (acylamino) benzoic acid or its ester derivative in a concentrated sulfuric acid solution [Reaction formula (B)] [Synthesis (SYNT).
HESIS), P. 383-386, 1988],
(3) Method of reacting aminobenzoic acid derivative with an excess amount of halogenated carbonic acid monoalkyl ester [reaction formula (C)] [Journal of Medicinal Chemistry (J. Med. Chem), 33, p. 464-4
79, 1990] and the like are reported. However, the method (A) requires heating under reflux to proceed the reaction, and the method (B) requires the use of concentrated sulfuric acid,
Further, in the method (C), when the alkyl part of the halogenated carbonic acid monoalkyl ester is a complex derivative, the production of the halogenated carbonic acid monoalkyl ester itself is complicated, and expensive reaction raw materials are not effectively used. In addition, none of the methods is not suitable as an industrial production method because high yield cannot be expected.

[0003]

[Chemical 6]

Further, as a modification of the method (A), a carboxylic acid derivative is reacted with, for example, N-hydroxysuccinimide in the presence of a dehydrating condensing agent such as N, N-dicyclohexylcarbodiimide (DCC) to form an N-hydroxysuccinimide ester. And then reacted with 2-aminobenzoic acid to isolate the resulting 2-acylaminobenzoic acid,
After purification, the isolated and purified compound is again cyclized by dehydration condensation reaction using DCC, and the reaction product is isolated and purified by column chromatography to obtain a benzoxazinone derivative. (JP-A-5
No. 148249). Since this method uses DCC in the preparation of the active ester derivative of the above-mentioned carboxylic acid, it is isolated and purified by column chromatography to remove the dicyclohexylurea formed after the reaction with 2-aminobenzoic acid, and then In addition, this compound
The dehydration cyclization reaction using C, column chromatography, and the extremely complicated treatment operation of isolating and purifying the target compound are required and the DC to be used.
Since C is a substance that is not desirable for the safety and health of workers, it is not suitable as an industrial production method.

[0005]

DISCLOSURE OF THE INVENTION As a result of intensive studies on the method for producing a benzoxazinone derivative, the present inventors have found that 2-aminobenzoic acid was reacted with a reactive derivative of carboxylic acid or a carboxylic acid in the presence of a specific condensing agent. Reaction and acylation 2
By producing a-(acylamino) benzoic acid derivative and subjecting it to a ring closure reaction in the presence of the above-mentioned condensing agent without isolation / purification, the desired benzoic acid can be obtained under extremely efficient and mild conditions. It has been found that an oxazinone derivative is obtained. The present invention is based on such findings.

The present invention provides a method for producing a benzoxazinone derivative shown in the following (1) to (7). (1) Reactive derivative of carboxylic acid or carboxylic acid, which is a halogenated carbonic acid monoalkyl ester, acyl halide, 1,1′-carbonyldiimidazole, aliphatic sulfonyl halide or aromatic sulfonyl halide, diphenylphosphoric acid halide or Me ₂ N ⁺ = CHX
· X ^- (wherein X is, Br, represents a Cl) in the presence of a condensing agent selected from reacted with 2-aminobenzoic acid derivatives,
Next, a method for producing a benzoxazinone derivative, which comprises performing a ring-closing reaction in the presence of a condensing agent selected from the above condensing agents.

(2) Reactive derivative of carboxylic acid or carboxylic acid is halogenated carbonic acid monoalkyl ester, acyl halide, 1,1'-carbonyldiimidazole, aliphatic sulfonyl halide, aromatic sulfonyl halide, diphenylphosphoric acid Halide or Me ₂ N ⁺ = C
HX · X ⁻ (wherein X represents Br or Cl) is reacted with a 2-aminobenzoic acid derivative in the presence of a condensing agent to give a 2- (acylamino) benzoic acid derivative. Without isolating the-(acylamino) benzoic acid derivative, a halogenated carbonic acid monoalkyl ester, an acyl halide, 1,1'-carbonyldiimidazole, an aliphatic sulfonyl halide, an aromatic sulfonyl halide, a diphenylphosphoric acid halide or Me ₂
A method for producing a benzoxazinone derivative, which comprises performing a ring-closing reaction in the presence of a condensing agent selected from N ⁺ = CHX · X ⁻ (wherein X represents Br or Cl).

(3) A reactive derivative of carboxylic acid or carboxylic acid, and a general formula

[Chemical 7] [In the formula, R ¹ represents a hydrogen atom, a halogen atom, an alkyl group or an alkoxy group, and R ² is a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group, an alkoxy group, an alkoxycarbonyl group, a carboxyl group, a nitro group or a nitrile. Base,
Alkylthio group, acyl group, acyloxy group or -NR
³ R ⁴ (wherein R ³ and R ⁴ are the same or different and each represents a hydrogen atom, an alkyl group, an acyl group or an amino protecting group, and R ³ and R ⁴ are substituted together with an adjacent nitrogen atom). Optionally formed heterocycle)
A 2-aminobenzoic acid derivative represented by

[Chemical 8] (In the formula, R ¹ and R ² have the same meanings as described above, and R means an organic residue.) 2- (acylamino)
A general formula characterized by being a benzoic acid derivative and subjecting this compound to a ring closure reaction without isolation.

[Chemical 9] (In the formula, R ¹ , R ² and R have the same meanings as described above.)
A method for producing a benzoxazinone derivative represented by:

[0009] (4) above wherein R, ^-NR 8 ^{R 9} (wherein ^{R 8} and ^{R 9} are the same or different and each is a hydrogen atom, an alkyl group means an acyl group, or an amino protecting group, and ^{R 8} R ⁹ may form a hetero ring together with the adjacent nitrogen atom, and the hetero ring may have a substituent), an alkoxy group, a hydroxyl group, a halogen atom, a nitro group, an alkoxycarbonyl. Substituted with one or more substituents selected from a group, a carboxyl group, a nitrile group, an alkylthio group, an alkylthioalkyl group, an acyl group, an acyloxy group, an optionally substituted aryl group or an optionally substituted heteroaryl Optionally substituted alkyl or alkenyl groups; or general formula

[Chemical 10] [Wherein R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a linear or branched alkyl group, or R ⁵ and R 6
⁶ represents a cycloalkyl group or an alkylthioalkyl group which may be combined together, and A is-(CH ₂ )
_m - (m is 1 to 4 _{integer), - * CH 2 -O -} , - *
_{O-CH 2 -, - *} CONH-CH 2 -, * = CH-,
- * CH = CH- or _{^{- * NR 10 - (CH 2}} ) n -
(N is an integer of 1 to 2, R ¹⁰ is hydrogen, lower alkyl or lower acyl, and * represents a binding site on the R ⁷ side)
And R ⁷ is R ¹¹ R ¹² CH— (wherein R ¹¹ ,
R ¹² is the same or different and means a hydrogen atom, an optionally substituted aryl or an optionally substituted heteroaryl), R ¹³ R ¹⁴ N— (here, R ¹³ , R
¹⁴ means the same or different and each represents a hydrogen atom, an optionally substituted aryl or an optionally substituted heteroaryl), an optionally substituted adamantyl, an optionally substituted 9H-xanthene-9- Represents an optionally substituted 5H-dibenzo [a, d] cyclohepten-5-yl, an optionally substituted 9-fluorenyl, or an optionally substituted 9-fluorene]
The method for producing a benzoxazinone derivative according to (3) above.

(5) R is a general formula

[Chemical 11] [Wherein R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a linear or branched alkyl group, or R ⁵ and R 6
⁶ represents a cycloalkyl group or an alkylthioalkyl group which may be combined together, R ⁷ is an optionally substituted adamantyl, diphenylmethyl, diphenylamino, pyridylbenzyl, dipyridylmethyl, 9-fluorenyl, or 9 -Represents fluorene, A
_{Is, - (CH 2) m -} (m is 1 to 4 integer), - * C
_{H 2 -O -, - * O} -CH 2 -, - * CONH-CH 2
-, * = CH-,-* CH = CH- or-* NR < ¹⁰ >-
_{(CH 2)} n - (n is 1 or 2 an ^{integer, R 10} is hydrogen,
A lower alkyl or a lower acyl is represented, and * represents a binding site on the R ⁷ side)].

(6) The method for producing a benzoxazinone derivative according to any one of (1) to (5) above, wherein the condensing agent is a halogenated carbonic acid monoalkyl ester or diphenyloxyphosphoric acid chloride. (7) The method for producing a benzoxazinone derivative according to any one of (1) to (5) above, wherein the condensing agent is an acyl halide.

The present invention will be described in detail below. In the above general formula, R is an organic group that does not adversely influence the reaction in the acylation reaction and ring closure reaction in the production method of the present invention.

Specific examples of R include --NR ⁸ R
⁹ (wherein R ⁸ and R ⁹ are the same or different and each represents a hydrogen atom, an alkyl group, an acyl group or an amino-protecting group, and R ⁸ R ⁹ is taken together with an adjacent nitrogen atom to form a heterocycle. This heterocycle may have a substituent), an alkoxy group, a hydroxyl group, a halogen atom, a nitro group, an alkoxycarbonyl group, a carboxyl group, a nitrile group, an alkylthio group, an alkylthioalkyl group, an acyl group. , An acyloxy group, an optionally substituted aryl group, or an optionally substituted heteroaryl, an alkyl group or an alkenyl group each optionally substituted with one or more substituents; or a general formula

[Chemical 12] [Wherein R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a linear or branched alkyl group, or R ⁵ and R 6
⁶ represents a cycloalkyl group or an alkylthioalkyl group which may be combined together, and A is-(CH ₂ )
_m - (m is 1 to 4 _{integer), - * CH 2 -O -} , - *
_{O-CH 2 -, - *} CONH-CH 2 -, * = CH-,
- * CH = CH- or _{^{- * NR 10 - (CH 2}} ) n -
(N is an integer of 1 to 2, R ¹⁰ is hydrogen, lower alkyl or lower acyl, and * represents a binding site on the R ⁷ side)
And R ⁷ is R ¹¹ R ¹² CH— (wherein R ¹¹ and R ¹² are the same or different and represent a hydrogen atom, an optionally substituted aryl or an optionally substituted heteroaryl). , R ¹³ R ¹⁴ N- (where R
¹³ and R ¹⁴ are the same or different and each represents a hydrogen atom, an optionally substituted aryl or an optionally substituted heteroaryl), an optionally substituted adamantyl and an optionally substituted 9H-xanthene. -9-yl, optionally substituted 5H-dibenzo [a, d] cyclohepten-5-yl, optionally substituted 9-fluorenyl, or optionally substituted 9-fluorene] N-acylaminoalkyl group and the like can be mentioned.

The alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms, and is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-.
A butyl, tert-butyl, pentyl or isopentyl group etc. can be mentioned. Preferred is a linear or branched alkyl group having 1 to 4 carbon atoms. Examples of the substituent of the alkyl group include a hydroxyl group, a nitro group, a carboxyl group and an amino group.

Examples of the alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and pentyloxy groups. The halogen atom is fluorine, chlorine, bromine or iodine.

Examples of the alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, sec-butoxycarbonyl and tert-butoxycarbonyl groups.

The alkylthioalkyl group is a thioalkyl group having a linear or branched alkyl group,
For example, (methylthio) methyl, 2- (methylthio) ethyl, (ethylthio) methyl, 2- (ethylthio) ethyl, 1- (ethylthio) ethyl or (isopropylthio) methyl group can be mentioned.

Examples of the alkylthio group include methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, pentylthio and isopentylthio groups.

Examples of the acyloxy group include acetoxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, isobutylcarbonyloxy or sec-butylcarbonyloxy group, and benzoyloxy group.

Examples of the acyl group include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl group, and benzoyl group.

The R ³ R ⁴ N-group is, for example, an amino group, a dimethylamino group, or an isopropylamino group, and examples of the heterocycle formed by R ³ and R ⁴ together with the adjacent nitrogen atom. Can be a piperidino group.

The R ⁸ R ⁹ N-group is, for example, an amino group, a dimethylamino group, or an isopropylamino group, and examples of the heterocycle formed by R ⁸ and R ⁹ together with the adjacent nitrogen atom. Examples thereof include a piperidino group and the like.

The aryl which may be substituted as the substituent of the alkyl group in R or the substituent in R ¹¹ and R ¹² is, for example, an alkyl group, an alkoxy group or an aryl group substituted with a halogen atom. And more specifically, a methyl group, a methoxy group,
Examples thereof include a benzyl group which may be substituted with a chlorine atom or a nitro group.

The heteroaryl which may be substituted for the alkyl group in R or for R ¹¹ and R ¹² includes, for example, a heteroaryl group substituted with an alkyl group, a halogen atom or an alkoxy group. And more specifically, a 2-, 3-, or 4-pyridyl group and the like can be mentioned.

An optionally substituted aryl as a substituent for R ¹³ and R ¹⁴ is, for example, an alkyl group,
Examples thereof include an aryl group substituted with an alkoxy group or a halogen atom, and more specific examples include a methyl group, a methoxy group, a phenyl group optionally substituted with a chlorine atom or a nitro group, and the like. .

Examples of the optionally substituted heteroaryl for R ¹³ and R ¹⁴ include a heteroaryl group substituted with an alkyl group, a halogen atom, or an alkoxy group, and more specifically, 2- , 3- or 4
-Pyridyl group etc. can be mentioned.

Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. Examples of the alkenyl group include allyl, 1-propenyl, butenyl, 3-methyl-
2-butenyl, a hexenyl group, etc. can be mentioned.

Specific examples of the R group include the substituent R ⁷ -A.
^{-CONH-C (-R 5) (} - R 6) - but may be mentioned as specific examples thereof, mention may be made for example such substituents described below. (1) 1-[(9-fluorenylmethoxycarbonyl) amino] ethyl, (2) 1-[(9-fluorenylmethoxycarbonyl) amino] -2-methylpropyl, (3) 1-[(9 -Fluorenylmethoxycarbonyl) amino] -1-methylethyl, (4) 1-{[[N-acetyl-N- (9-fluorenyl)] carbonyl] amino} methyl, (5) 1-[(fluorene- Δ ^9.α -acetyl) amino] ethyl (6) 1-[(fluorene-Δ ^9.α -acetyl) amino] -2-methylpropyl (7) 1-[(9-fluorenyloxyacetyl) amino] -1-Methylethyl (8) 1-[(9-fluorenyloxyacetyl) amino] -1-methylpropyl (9) 1-[(9-fluorenylmethoxycarbonyl) amino] -1-si Rohexylmethyl (10) 1-[(9-fluorenylmethoxycarbonyl) amino] -1-methylbutyl (11) 1-{[(2- (9-fluorenyl) acryloyl] amino} -2-methylpropyl (12 ) 1-[(9-fluorenyloxyacetyl)
Amino] -1-cyclopropyl (13) 1-[(9-fluorenyloxyacetyl)
Amino] -2-methylpropyl (14) 1-[(1-adamantylmethoxycarbonyl) amino] -1-methylethyl

(15) 1-{[9- (2,7-bis (dimethylamino) fluorenyl]] amino} ethyl (18) 1-[(9-fluorenyloxymethylcarbonyl) amino] -1- ( Methylthio) methyl (19) 1-{[(2,2-diphenylethoxy) carbonyl] amino} -2-methylpropyl (20) 1-{[(diphenylmethoxy) acetyl]
Amino} -2-methylpropyl (21) 2-methyl-1-{[[[(+)-α- (2-
Pyridyl) benzyloxy] acetyl] amino} propyl (22) 1-{[[di- (2-pyridyl) methoxy]]
Acetyl] amino} -2-methylpropyl (23) 1-[(4,4-diphenylbutyryl) amino] -2-methylpropyl (24) 1-{[[bis (4-fluorophenyl) methoxy] acetyl] Amino} -2-methylpropyl (25) [(4,4-diphenyl-2-butenoyl)
Amino] methyl (26) 1-[(3,3-diphenylpropionyl)
Amino] -2-methylpropyl (27) 1-[(N, N-diphenylglycyl) amino] -2-methylpropyl (28) 1-{[3- (N, N-diphenylamino)
Propionyl] amino} -2-methylpropyl (29) 1-[(N, N-diphenylglycyl) amino] -2-methylpropyl (30) 1-methylethyl (31) 2-methoxyethyl (32) tert- Butoxycarbonylaminomethyl (33) 3-ethoxy-3-oxopropyl (34) vinyl and the like can be mentioned.

Examples of the optionally substituted heteroaryl include 2-, 3- or 4-pyridyl.

In the production method of the present invention, the functional groups such as carboxyl group, hydroxyl group and amino group present in the above-mentioned substituent R or R ² are protected with a protecting group by a conventional method used in ordinary peptide synthesis. It is used as it is. As the protecting group, those that can be easily removed after the reaction are preferably used after the reaction.

As the protective group for the carboxyl group, an alkyl group such as methyl group and ethyl group; unsubstituted or methyl,
Examples thereof include a benzyl group substituted with a methoxy group, a nitro group and the like. As the hydroxyl-protecting group, a methyl group,
An alkyl group such as an ethyl group; a benzyl group which is unsubstituted or substituted with a methyl, methoxy, nitro group or the like can be mentioned.

The protecting group for the amino group is an unsubstituted benzyloxycarbonyl group; or a methyl group on the aromatic ring,
Benzyloxycarbonyl group substituted with methoxy group, chlorine atom, nitro group, etc .; alkoxycarbonyl group such as trichloroethoxycarbonyl group, tert-butoxycarbonyl group; formyl group, trifluoroacetyl group, phthalyl group, tosyl group or benzyl group Etc. can be mentioned. The reactive derivative of carboxylic acid is an active ester,
Examples thereof include acid halides, acid azides, acid anhydrides, mixed acid anhydrides, and imidazole amides.

Specific examples of the specific condensing agent in the production method of the present invention include ethyl chlorocarbonate and 1-chlorocarbonate.
Halogenated carbonic acid monoalkyl esters such as methylpropyl, isobutyl chlorocarbonate and trichloromethyl chlorocarbonate; acyl halides such as acetyl chloride, propionyl chloride or pivaloyl chloride, methanesulfonyl chloride, benzenesulfonyl chloride, 2,4,4.
Aliphatic or aromatic sulfonyl halides such as 6-triisopropylbenzenesulfonyl chloride; diphenylphosphoric acid chloride, 1,1′-carbonylimidazole or Meyer's reagent represented by Me ₂ N ⁺ = CHCl · Cl ⁻ be able to. Preference is given to halogenated monoalkyl carbonate.

Next, the manufacturing method of the present invention will be described in detail. The method for producing the benzoxazinone derivative of the present invention can be represented by the following reaction formula.

[0036]

[Chemical 13] (In the formula, R ¹ , R ² and R are as defined above)

The production method of the present invention will be described in detail by dividing it into the N-acylation reaction in the first stage and the ring-closing reaction in the second stage according to the above reaction formula.

In the N-acylation reaction in the first stage of the production method of the present invention, the carboxylic acid (formula I) is treated with a halogenated carbonic acid monoalkyl ester, an acyl halide, 1,1'-carbonyldiimidazole, an aliphatic sulfonyl halide, Alternatively, N, N-dimethylformamide (DMF), tetrahydrofuran (THF), 1 in the presence of a condensing agent (II) selected from aromatic sulfonyl halides, diphenylphosphoric acid halides or Me ₂ N ⁺ ═CHX · X ^−. , 4-
In a solvent such as dioxane, 1,2-dimethoxyethane, methylene chloride, chloroform, acetone, acetonitrile or ethyl acetate, if necessary, an organic base such as trimethylamine, triethylamine, N-methylmorpholine, dimethylaminopyridine, pyridine or lutidine may be used. In coexistence,

[Chemical 14] (Wherein R ¹ and R ² have the same meanings as described above)
By reacting with an aminobenzoic acid derivative to give a compound of general formula (IV)

[Chemical 15] (Wherein R ¹ , R ² and R have the same meanings as described above), and 2-acylaminobenzoic acid is produced.

The amount of the condensing agent used is, for example, in the case of a halogenated carbonic acid ester, at least an equimolar amount or more based on the number of moles of the carboxylic acid (I), and it is usually preferable to use an equimolar amount. is there.

The amount of the organic base used is preferably at least equimolar, and more preferably equimolar to the amount of the carboxylic acid (I) used.

In carrying out the N-acylation reaction in the first step, the carboxylic acid (I) and the condensing agent (II) are mixed with an organic base, if desired, at low temperature, and then the 2-aminobenzoic acid (III) is added. In a preferred embodiment, it is reacted with The temperature at which the condensing agent (II) is added to the carboxylic acid (I) is selected according to the type of compound used, the type of solvent, the type of organic base, etc., but it is usually between -20 ° C and room temperature, and is suitable. Between 0 ° C. and room temperature.

The reaction temperature of the carboxylic acid (I) and the 2-aminobenzoic acid (III) is selected in various ranges depending on the kind of compound used, kind of solvent, kind of basic substance, etc. Not -20 ℃ to 100 ℃
And preferably between 0 ° C and 50 ° C.

The reaction time varies depending on the type of compound used, the reaction temperature, the type of basic substance, the type of solvent and other conditions, but it is usually in the range of several minutes to about 20 hours,
Generally, if the reaction product is stable, the higher the reaction temperature, the shorter the reaction time.

Next, the latter-stage ring closure reaction will be described. The 2-acylaminobenzoic acid (IV) obtained by the above method is reacted in the presence of a substance selected from the above-mentioned condensing agents (II) in an organic solvent in the presence of a base without isolation and purification. According to the general formula (V)

[Chemical 16] A benzoxazinone derivative represented by the formula (wherein R ¹ , R ² and R are as defined above) can be obtained.

A condensing agent that can be used in the above ring closure reaction,
As the base and the solvent, those which are the same as or different from those used in the preceding acylation reaction can be appropriately used.
Preferably, the condensing agent, basic substance and solvent used in the preceding stage are used.

The reaction temperature range of the above reaction is appropriately selected depending on the conditions such as the type of compound used, the type of solvent, the type of basic substance, etc., but is not specified, but it is usually from -20 ° C to 50 ° C. Between ℃.

The reaction time varies depending on the type of compound used, reaction temperature, type of basic substance, type of solvent and other conditions, but it is usually in the range of several minutes to about 72 hours,
Generally, if the reaction product is stable, higher reaction temperature can shorten the reaction time.

The amount of the condensing agent used in the ring-closing reaction is preferably an equimolar amount with respect to 2-acylaminobenzoic acid (IV).
The amount of compound (IV) produced in the reaction system can be quantified by a conventional method such as HPLC.

The amount of the base used in the ring-closing reaction is at least an equimolar amount, more preferably the equimolar amount, with respect to the amount of the condensing agent used in the ring-closing reaction.

The above reaction product can be separated and purified by a known appropriate means such as solvent extraction or recrystallization.

An inert solvent is used as the extraction solvent,
Chloroform, dichloromethane, dichloroethane, ethyl acetate or a mixture thereof is preferred.

As the solvent used for recrystallization, ethers such as isopropyl ether, alkyl halides such as chloroform and dichloromethane, esters such as methyl acetate and ethyl acetate, alkanes such as n-hexane, and mixtures thereof are used. Can be mentioned.

Compound (I) and compound (III) used in the production method of the present invention may have an asymmetric carbon atom in the molecular skeleton, and are stereoisomers such as enantiomers and diastereomers. Since the body may exist, the scope of the present invention also includes these isomers and a mixture thereof.

Suitable examples of the compounds which can be produced by the method of the present invention are shown in the table below. In the table, Me represents a methyl group, Et represents an ethyl group, t-Bu represents a tert-butyl group, 4-F-phenyl represents a 4-fluorophenyl group, and a substitution site of R ¹ in the benzoxazinone skeleton. Is at the 5-position and the substitution site for R ² is at the 7-position.

[0055]

[Chemical 17]

[0056]

[Table 1]

[0057]

[Table 2]

[0058]

[Table 3]

[0059]

[Chemical 18]

[0060]

[Table 4]

The method of the present invention will be described in detail by the following examples. In the description of Examples, FAB-MS shows a fast atom bombardment mass spectrometry spectrum, and EI-MS shows an electron bombardment ionization mass spectrometry spectrum.

Reference Example 1 N- (9-fluorene-Δ ^9.α -acetyl) -L-valine a) Methyl 9-fluorene-Δ ^9. A toluene suspension (400 ml) of ^α -acetate 9-fluorenone (20 g) and methyl (triphenylphosphoranidene) acetate (63.1 g) was heated under reflux for 139 hours. The reaction mixture was concentrated and the resulting residue was purified by silica gel chromatography to give yellow crystals of methyl 9-fluorene-
Δ ^{9. α} -Acetate (24 g) was obtained.

B) 9-fluorene-Δ ^{9. α-} Methyl acetate 9-fluorenone-Δ ^{9. α} -acetate (1
1N sodium hydroxide (130 ml) was added dropwise to a methanol suspension solution (600 ml) of 1.8 g) under ice cooling, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated, water was added, and the mixture was washed with ether. Concentrated hydrochloric acid (about 3
5%) was used to adjust the liquidity of the aqueous layer to pH 1.
The deposited precipitate was filtered and washed with water until it became neutral. The precipitate was recrystallized from ethyl acetate to give 9-fluorene-Δ ^{9. α} -Acetic acid (10.2 g) was obtained.

C) N- (9-fluorene-Δ ^9.α -acetyl) -L-valine methyl ester 9-fluorene-Δ ^{9. To a} methylene chloride solution of ^α -acetic acid and L-valine methyl ester hydrochloride, triethylamine and 1-hydroxytriazole were sequentially added under ice cooling, and water-soluble carbodiimide hydrochloride was added. 0 at 0 ° C.
After stirring for 5 hours, the mixture was stirred at room temperature for 20 hours. The reaction mixture was washed successively with 5% hydrochloric acid, saturated sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is purified by silica gel column chromatography,
N- (9-fluorene-Δ ^9.α -acetyl) -L-valine methyl ester was obtained.

D) N- (9-fluorene-Δ ^9.α -acetyl) -L-valine N- (9-fluorene-Δ ^9.α -acetyl) -L-valine methyl ester in ethanol solution was ice-cooled. Below,
1N sodium hydroxide was added dropwise. The reaction solution was concentrated, the residue was dissolved in water and extracted with ether. The liquidity of the water layer,
The pH was adjusted to 3 to 4 with hydrochloric acid, and the precipitated substance was collected by filtration. The deposited material was washed with ice cold water. This substance was recrystallized using a mixed solution of methyl acetate-methanol to obtain N- (9-fluorene- ^Δ9.α -acetyl) -L-valine.

[0066]

【Example】

Example 1 2- {1-[(9-fluorenyloxyacetyl) amino] -1-methylethyl} -5-methyl-4H-3,1
-Benzoxazin-4-one 2-[(9-fluorenyloxyacetyl) amino]-
2-Methylpropionic acid (50.0 g) was added to DMF (25
0 ml). Add triethylamine (2
(3.6 ml) was added dropwise at 3 to 7 ° C over 3 minutes. When the temperature of the reaction solution returned to 3 ° C, ethyl chlorocarbonate (16.1 ml) was added dropwise between 3 to 8 ° C over 5 minutes, and the mixture was stirred at 3 ° C for 20 minutes. A solution of 2-amino-6-methylbenzoic acid (23.3 g) and triethylamine (21.5 ml) in DMF (80 ml) was added to the reaction solution,
The solution was added dropwise at a temperature of 1 to 5 ° C over 10 minutes. Add this reaction mixture to 5
After stirring at 0 ° C for 12 hours, the mixture was ice-cooled to 3 ° C. After ice cooling,
Triethylamine (23.6 ml) was added dropwise at 3 ° C. over 1 minute, and then ethyl chlorocarbonate (16.1 ml) was added to 3 to 3.
It was added dropwise at 10 ° C. over 10 minutes. This reaction solution was added at 3 ° C for 6
After stirring for an hour, saturated aqueous sodium chloride solution (500 m
It was poured into a mixture of l) and water (500 ml). Next, ethyl acetate (1 liter) and methylene chloride (800
(ml) and extracted with a mixed solvent with ethyl acetate (1 liter). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate (800 ml). The precipitated crystals were collected by filtration and dried under reduced pressure at 50 ° C. for 15 hours to give 2- {1-[(9-fluorenyloxyacetyl) amino] -1-methylethyl} -5-methyl-4H.
47.3 g of -3,1-benzoxazin-4-one was obtained as white needle crystals. mp: 162.1-162.8 ° C FAB-MS (m / z): 441 (MH ⁺ ) ¹ HNMR (CDCl ₃ , δ value): 1.78 (6H,
s), 2.80 (3H, s), 3.75 (2H, s),
5.77 (1H, s), 7.3-7.45 (6H,
m), 7.6-7.7 (5H, m), 7.90 (1H,
brs)

Example 2 2- {1-[(9-fluorenyloxyacetyl) amino] -1-methylethyl} -5-methyl-4H-3,1
-Benzoxazin-4-one In the method of Example 1, 2-[(9-fluorenyloxyacetyl) amino] -2-methylpropionic acid (5
0.0 g) was dissolved in) DMF (250 ml). Triethylamine (23.6 ml) was added dropwise to this solution at 3 to 7 ° C over 3 minutes. When the temperature of the reaction solution returned to 3 ° C., ethyl chlorocarbonate (16.1 ml) was added to 3-
The mixture was added dropwise between 8 ° C over 5 minutes, and stirred at 3 ° C for 20 minutes.
2-amino-6-methylbenzoic acid (2
A solution of 3.3 g) and triethylamine (21.5 ml) in DMF (80 ml) was added dropwise at a temperature of 1 to 5 ° C over 10 minutes. The reaction was stirred at 2 ° C for 72 hours. Thereafter, the same treatment as in Example 1 was carried out to obtain 40 g of the compound described in Example 1.

Example 3 2- (2-methoxyethyl) -5-methyl-4H-3,
1-benzoxazin-4-one 3-methoxypropionic acid (1.00 g) in DMF solution (20 ml) under ice cooling, triethylamine (1.48 m
l) and ethyl chlorocarbonate (1.00 ml) were added dropwise.
Stir for 0 minutes. Under cooling with ice, 2-amino-6-methylbenzoic acid (1.45 g) and triethylamine (1.34 m)
A DMF mixed solution (5 ml) of 1) was added dropwise, and after stirring for 4.5 hours, the mixture was further stirred at room temperature for 17 hours. The reaction mixture was ice-cooled, and triethylamine (1.48 ml) and ethyl chlorocarbonate (1.00 ml) were sequentially added dropwise. After stirring for 1.5 hours, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed successively with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. Residue n
-Crystallized from hexane, 2- (2-methoxyethyl)
-5-Methyl-4H-3,1-benzoxazine-4-
1.24 g of on crystals were obtained as white crystals. mp: 81.6-82.7 ° C FAB-MS (m / z): 220 (MH ⁺ ), 188,
160 ¹ HNMR (CDCl ₃ , δ value): 2.79 (3H,
s), 2.93 (2H, t, J = 6.6Hz), 3.3.
9 (3H, s), 3.85 (2H, t, J = 6.6H
z), 7.27 (1H, d, J = 8.1 Hz), 7.4
0 (1H, d, J = 8.1Hz), 7.62 (1H,
t, J = 8.1 Hz)

Example 4 2-{[N- (tert-butoxycarbonyl) amino] methyl} -5-methyl-4H-3,1-benzoxazin-4-one N- (tert-butoxycarbonyl) glycine (1 ．
(00 g) in DMF solution (10 ml) under ice-cooling, triethylamine (0.87 ml) and ethyl chlorocarbonate (0.5
(9 ml) was added dropwise, and the mixture was stirred for 15 minutes. 2-amino-6
-Methylbenzoic acid (0.86 g) and triethylamine (0.79 ml) in DMF solution (8 ml) were added dropwise, and the mixture was stirred under ice cooling for 30 minutes and then at room temperature for 17 hours. The reaction mixture was ice-cooled and then triethylamine (0.79
ml) and ethyl chlorocarbonate (0.54 ml) were added dropwise,
Stir for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed successively with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was crystallized using a mixed solution of ethyl acetate-n-hexane to give 2-{[N- (tert-butoxycarbonyl).
Amino] methyl} -5-methyl-4H-3,1-benzoxazin-4-one was obtained as white crystals (770 mg). mp: 126.9-128.0 ° C FAB-MS (m / z): 291 (MH ⁺ ), 235.
191, 160 ¹ HNMR (CDCl ₃ , δ value): 1.49 (9H,
s), 2.79 (3H, s), 4.27 (2H, d, J
= 5.0 Hz), 5.33 (1H, brs), 7.30
(1H, d, J = 7.8Hz), 7.42 (1H, d,
J = 7.8 Hz), 7.64 (1H, t, J = 7.8H
z)

Example 5 2-{(S) -1-[(fluorene- ^Δ9.α -acetyl) amino] -2-methylpropyl} -5-methyl-4
H-3,1-benzoxazin-4-one By the same method as in Example 4, N- (fluorene-Δ
^9. By reacting ^α -acetyl) -L-valine with 2-amino-6-methylbenzoic acid and treating in the same manner as in Example 4, 2-{(S) -1-[(fluorene-Δ
^{9. α} -Acetyl) amino] -2-methylpropyl}-
Pale yellow crystals of 5-methyl-4H-3,1-benzoxazin-4-one were obtained. mp: 196.0-197.0 ° C. FAB-MS (m / z): 437 (MH ⁺ ), 205 ¹ HNMR (CDCl ₃ , δ value): 1.05 (3H,
d, J = 6.9 Hz), 1.11 (3H, d, J = 6.
9Hz), 2.44 (1H, m), 2.79 (3H,
s), 5.09 (1H, dd, J = 8.8, 5.5H)
z), 6.69 (1H, d, J = 8.8Hz), 6.8
5 (1H, s), 7.18 to 7.42 (6H, m),
7.61-7.70 (4H, m), 8.71 (1H,
d, J = 7.7 Hz)

Example 6 5-Methyl-2-vinyl-4H-3,1-benzoxazinon-4-one In the same manner as described in Example 4, 3-chloropropionic acid and 2-amino-6 were used. By reacting with -methylbenzoic acid and treating in the same manner as in Example 4, 5-methyl-2-vinyl-4H-3,1-benzoxazinone-4-one was obtained as white crystals. In this reaction, dehydrochlorination results in a vinyl group at the 2-position. mp: 92.7-93.1 ° C FAB-MS (m / z): 188 (MH ⁺ ) ¹ HNMR (CDCl ₃ , δ value): 2.80 (3H,
s), 5.91 (1H, dd, J = 10.2, 1.5H
z), 6.40 (1H, dd, J = 17.4, 10.2)
Hz), 6.56 (1H, dd, J = 17.4, 1.5
Hz), 7.28 (1H, d, J = 7.8 Hz), 7.
42 (1H, d, J = 7.8 Hz), 7.63 (1H,
t, J = 7.8 Hz)

In the following Examples 7 to 11, the case where different activators were used is shown. The results are shown in Table 5 in comparison with Example 1. Example 7 2- {1-[(9-fluorenyloxyacetyl) amino] -1-methylethyl} -5-methyl-4H-3,1
-Benzoxazin-4-one 2-[(9-fluorenyloxyacetyl) amino]-
2-Methylpropionic acid (1.0 g) was added to DMF (10 m).
l) and dissolved in triethylamine (0.37
g) was added and cooled to -10 ° C. Pivaloyl chloride (0.39 g) was added dropwise to the reaction solution at -10 ° C, and the mixture was reacted for 1 hour under ice cooling. 2-amino-6-
A solution of methylbenzoic acid (0.4 g) and triethylamine (0.37 g) in DMF (2 ml) was added dropwise under ice cooling, and the mixture was reacted at room temperature for 1 hour and at 40 ° C. for 15 hours. After triethylamine (1.56 g) was added dropwise to this reaction solution,
Pivaloyl chloride (1.5 g) was added under ice cooling. Then, the same treatment as in Example 1 was carried out to obtain a compound (0.87 g) obtained by the production method of Example 1.

Example 8 2- {1-[(9-fluorenyloxyacetyl) amino] -1-methylethyl} -5-methyl-4H-3,1
-Benzoxazin-4-one 2-[(9-fluorenyloxyacetyl) amino]-
2-Methylpropionic acid (1.0 g) was added to DMF (10 m).
It was dissolved in 1). Triethylamine (0.4
7 g) was added dropwise at -10 ° C. Next, ethyl chlorocarbonate (0.37 g) was added dropwise at -10 ° C, and the mixture was stirred at room temperature for 1 hour. 2-amino-6-methylbenzoic acid (0.4 g) and triethylamine (0.37 g) were added to the above reaction solution.
DMF (2 ml) solution was added at room temperature, and at 40 ° C, 1
The reaction was carried out for 5 hours. Triethylamine (1.3
7 g) was added, and the mixture was ice-cooled. Mesyl chloride (1.53 g) was added dropwise under ice cooling. Thereafter, the same treatment as in Example 1 was carried out to obtain the compound (81
1 mg) was obtained.

Examples 9 and 10 2- {1-[(9-fluorenyloxyacetyl) amino] -1-methylethyl} -5-methyl-4H-3,1
-Benzoxazin-4-one 2-[(9-fluorenyloxyacetyl) amino]-
2-Methylpropionic acid (1.0 g) was added to DMF (10 m).
It was dissolved in 1). Triethylamine (0.4
7 g) was added dropwise at -10 ° C. Next, ethyl chlorocarbonate (0.37 g) was added dropwise at -10 ° C, and the mixture was stirred at room temperature for 1 hour. 2-amino-6-methylbenzoic acid (0.4 g) and triethylamine (0.37 g) were added to the above reaction solution.
DMF (2 ml) solution was added at room temperature, and at 40 ° C., 1
The reaction was carried out for 5 hours. The reaction solution was treated in the same manner as in Example 8 except that the mesyl chloride in Example 8 was replaced by the activators (Examples 9 and 10) shown in the following table, to give the process of Example 1. The compound obtained in (1) was obtained.

Example 11 2- {1-[(9-fluorenyloxyacetyl) amino] -1-methylethyl} -5-methyl-4H-3,1
-Benzoxazin-4-one 2-[(9-fluorenyloxyacetyl) amino]-
2-Methylpropionic acid (1.0 g) was added to DMF (10 m).
It was dissolved in 1), cooled to 0 ° C. and 0.5 g of 1,1′-carbonyldiimidazole was added. To the above reaction solution,
A solution of amino-6-methylbenzoic acid (0.46 g) and triethylamine (0.37 g) in DMF (1 ml) was added, and the mixture was reacted at 0 ° C for 44 hours. This reaction solution was treated in the same manner as in Example 8 except that chlorocarbonic acid ethyl ester was used in place of mesylate chloride in Example 8, to obtain 0.79 g of the compound obtained by the production method of Example 1.

In Table 5, EtOCOCl is ethyl chlorocarbonate, (Me) ₃ CCO Cl is pivaloyl chloride, MSCl is mesylate chloride, and (Ph
O) ₂ -P (═O) Cl means diphenyloxyphosphoric acid chloride, and Me ₂ N ⁺ = CHCl · Cl ⁻ means virus-Meier reagent.

[0077]

[Table 5]

Example 12 5-Methyl-2- (1-methylethyl) -4H-3,1
TH of -benzoxazin-4-one 2-amino-6-methylbenzoic acid (1.00 g)
Triethylamine (1.84 ml) was added to the F solution (15 ml) under ice cooling, and then isobutyryl chloride (1.39 ml) was added dropwise. After stirring for 45 minutes, triethylamine (1.01 ml) and ethyl chlorocarbonate (0.69 ml) were added dropwise under ice cooling, and the mixture was stirred for 1 hour. The reaction mixture was treated in the same manner as in Example 4 to give 5-methyl-2- (1-
Methylethyl) -4H-3,1-benzoxazine-4
-One was obtained as white crystals (1.25 g). mp: 76.0 to 76.8 ° C FAB-MS (m / z): 204 (MH ⁺ ) ¹ HNMR (CDCl ₃ , δ value): 1.36 (6H,
d, J = 6.9 Hz), 2.79 (3H, s), 2.9
0 (1H, septet, J = 6.9 Hz), 7.26
(1H, d, J = 7.8Hz), 7.40 (1H, d,
J = 7.8Hg), 7.61 (1H, t, J = 7.8H
z)

Example 13 2- (3-Ethoxy-3-oxopropyl) -5-methyl-4H-3,1-benzoxazin-4-one 2-amino-6-methylbenzoic acid (1.00 g) TH
To the F solution (20 ml) under ice cooling, triethylamine (1.94 ml) and ethylsuccinyl chloride (1.
(04 ml) was sequentially added dropwise and the mixture was stirred for 1 hour. Triethylamine (1.01 ml) and ethyl chlorocarbonate (0.69 ml) were successively added dropwise under ice cooling, and the mixture was stirred for 2.5 hours.
The reaction mixture was treated in the same manner as in Example 4, and the residue was crystallized from n-hexane to give 2- (3-ethoxy-3-oxopropyl) -5-methyl-4H-3,1-benzoxazine-
4-one was obtained as pale yellow crystals (1.10 g). mp: 51.0-52.3 ° C FAB-MS (m / z): 262 (MH ⁺ ), 216.
188,160 ¹ H NMR (CDCl ₃ , δ value): 1.26 (3 H,
t, J = 7.0 Hz), 2.78 (3H, s), 2.8
2 (2H, t, J = 7.0Hz), 3.00 (2H,
t, J = 7.0 Hz), 4.18 (2H, q, J = 7.
0 Hz), 7.27 (1H, d, J = 8.0 Hz),
7.36 (1H, d, J = 8.0 Hz), 7.61 (1
H, t, J = 8.0 Hz)

Example 14 2-{(S) -1-[(9-fluorenylmethoxycarbonyl) amino] -2methylpropyl} -5-methyl-
4H-3,1-benzoxazin-4-one N- (9-fluorenylmethoxycarbonyl) -L-valine and 2-amino-6-methylbenzoic acid were prepared according to Example 4
2-{(S) -1-
[(9-Fluorenylmethoxycarbonyl) amino]-
2-Methylpropyl} -5-methyl-4H-3,1-benzoxazin-4-one was obtained as a white powder. The results of instrumental analysis were the same as those obtained in Example 12.

[0081]

As is apparent from the detailed description above,
In the production method according to the present invention, a carboxylic acid is a halogenated carbonic acid monoalkyl ester, an acyl halide, 1,1′-carbonyldiimidazole, an aliphatic sulfonyl halide or an aromatic sulfonyl halide, a diphenylphosphoric acid halide, or Me ₂ N ⁺ = CHX · X ⁻ (where X is
(Representing Br and Cl) and a 2-aminobenzoic acid derivative are reacted with each other, and then the reaction product of this reaction is subjected to a ring closure reaction without isolation and purification, whereby the benzoxazinone derivative is easily and easily collected. It can be manufactured efficiently. Such a method of the present invention is a method in which the number of steps is halved as compared with the conventional method, the reaction proceeds in a high yield, and the treatment such as isolation and purification is extremely easy. It is extremely useful as an industrial production method of a benzoxazinone derivative useful as a raw material.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Kazuhide Hayakawa 1-1 No. 1 Murasaki-cho, Takatsuki-shi, Osaka Inside the Pharmaceutical Research Institute, Japan Tobacco Inc. (72) Inventor Kazuya Omiyama 1 Murasaki-cho, Takatsuki-shi, Osaka No. 1 Japan Tobacco Industry Co., Ltd. Pharmaceutical Research Institute (72) Inventor Koji Kobayashi 1-1 Murasakicho, Takatsuki City, Osaka Prefecture Japan Tobacco Industry Co., Ltd. Pharmaceutical Research Institute

Claims (7)

[Claims] 1. A reactive derivative of a carboxylic acid or a carboxylic acid, which is a halogenated carbonic acid monoalkyl ester, an acyl halide, 1,1′-carbonyldiimidazole, an aliphatic sulfonyl halide or an aromatic sulfonyl halide, and diphenyl. Phosphoric acid halide or Me ₂ N ⁺ = C
HX · X ⁻ (wherein X represents Br or Cl) is reacted with a 2-aminobenzoic acid derivative in the presence of a condensing agent, and then a ring-closing reaction is performed in the presence of a condensing agent selected from the above condensing agents. And a method for producing a benzoxazinone derivative. 2. A reactive derivative of a carboxylic acid or a carboxylic acid is a halogenated carbonic acid monoalkyl ester, an acyl halide, 1,1′-carbonyldiimidazole, an aliphatic sulfonyl halide, an aromatic sulfonyl halide, or a diphenylphosphoric acid halide. Or Me ₂ N ⁺ = CHX
· X ^- (wherein X is, Br, represents a Cl) by reaction with 2-aminobenzoic acid derivative in the presence of a condensing agent selected from 2- (acylamino) benzoic acid derivatives and without, the 2- Without isolating the (acylamino) benzoic acid derivative, a halogenated carbonic acid monoalkyl ester, an acyl halide, 1,1′-carbonyldiimidazole,
Aliphatic sulfonyl halide, aromatic sulfonyl halide, diphenylphosphoric acid halide or Me ₂ N ⁺ =
A method for producing a benzoxazinone derivative, which comprises performing a ring-closing reaction in the presence of a condensing agent selected from CHX · X ⁻ (wherein X represents Br or Cl). 3. A reactive derivative of a carboxylic acid or a carboxylic acid, and a compound of the general formula: [In the formula, R ¹ represents a hydrogen atom, a halogen atom, an alkyl group or an alkoxy group, and R ² represents a hydrogen atom, a hydroxyl group,
Halogen atom, alkyl group, alkoxy group, alkoxycarbonyl group, carboxyl group, nitro group, nitrile group, alkylthio group, acyl group, acyloxy group or-
NR ³ R ⁴ (wherein R ³ and R ⁴ are the same or different and each represents a hydrogen atom, an alkyl group, an acyl group or an amino-protecting group, and R ³ and R ⁴ are taken together with an adjacent nitrogen atom). (Which may form a heterocyclic ring which may be substituted)], and is reacted with a 2-aminobenzoic acid derivative represented by the following general formula: (In the formula, R ¹ and R ² have the same meanings as described above, and R means an organic residue.) 2- (acylamino)
A general formula characterized in that the compound is converted into a benzoic acid derivative and the compound is subjected to a ring closure reaction without isolation. (In the formula, R ¹ , R ² and R have the same meanings as described above.)
The method for producing the benzoxazinone derivative according to claim 1 or 2, wherein Wherein said R is, ^-NR 8 ^{R 9} (wherein ^{R 8} and ^{R 9} are the same or different and each means a hydrogen atom, an alkyl group, an acyl group or an amino protecting group, ^{R 8} and R
⁹ may form a hetero ring together with the adjacent nitrogen atom, and this hetero ring may have a substituent), an alkoxy group, a hydroxyl group, a halogen atom, a nitro group, an alkoxycarbonyl group. , A carboxyl group, a nitrile group, an alkylthio group, an alkylthioalkyl group, an acyl group, an acyloxy group, an optionally substituted aryl group, or an optionally substituted heteroaryl, each of which is substituted with one or more substituents. Optionally an alkyl group or an alkenyl group; or a general formula: [Wherein R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a linear or branched alkyl group, or R ⁵ and R 6
⁶ represents a cycloalkyl group or an alkylthioalkyl group which may be combined together, and A is-(CH ₂ )
_m - (m is 1 to 4 _{integer), - * CH 2 -O -} , - *
_{O-CH 2 -, - *} CONH-CH 2 -, * = CH-,
- * CH = CH- or _{^{- * NR 10 - (CH 2}} ) n -
(N is an integer of 1 to 2, R ¹⁰ is hydrogen, lower alkyl or lower acyl, and * represents a binding site on the R ⁷ side)
And R ⁷ is R ¹¹ R ¹² CH— (wherein R ¹¹ ,
R ¹² is the same or different and means a hydrogen atom, an optionally substituted aryl or an optionally substituted heteroaryl), R ¹³ R ¹⁴ N— (wherein R ¹³ , R
¹⁴ are the same or different and each represents a hydrogen atom, an optionally substituted aryl or an optionally substituted heteroaryl), an optionally substituted adamantyl, an optionally substituted 9H-xanthene-9- Represents an optionally substituted 5H-dibenzo [a, d] cyclohepten-5-yl, an optionally substituted 9-fluorenyl, or an optionally substituted 9-fluorene]
The method for producing a benzoxazinone derivative according to claim 3, wherein 5. The above R is represented by the general formula: [Wherein R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a linear or branched alkyl group, or R ⁵ and R 6
⁶ represents a cycloalkyl group or an alkylthioalkyl group which may be combined together, R ⁷ is an optionally substituted adamantyl, diphenylmethyl, diphenylamino, pyridylbenzyl, dipyridylmethyl, 9-fluorenyl, or 9 -Represents fluorene, A
_{Is, - (CH 2) m -} (m is 1 to 4 integer), - * C
_{H 2 -O -, - * O} -CH 2 -, - * CONH-CH 2
-, * = CH-,-* CH = CH- or-* NR < ¹⁰ >-
_{(CH 2)} n - (n is 1 or 2 an ^{integer, R 10} is hydrogen,
The method for producing a benzoxazinone derivative according to claim 3, wherein lower alkyl or lower acyl is represented, and * represents a binding site on the R ⁷ side). 6. The method for producing a benzoxazinone derivative according to claim 1, wherein the condensing agent is a halogenated carbonic acid monoalkyl ester or diphenyloxyphosphoric acid chloride. 7. The method for producing a benzoxazinone derivative according to claim 1, wherein the condensing agent is an acyl halide.