WO2014098046A1

WO2014098046A1 - Method for producing 1,2-dihydroquinoline synthetic intermediate

Info

Publication number: WO2014098046A1
Application number: PCT/JP2013/083666
Authority: WO
Inventors: 敦嗣大野; 一弘工藤; 健勝平
Original assignee: 参天製薬株式会社; 協和発酵バイオ株式会社
Priority date: 2012-12-20
Filing date: 2013-12-16
Publication date: 2014-06-26
Also published as: JP2014139161A; TW201431860A

Abstract

A method for producing a compound represented by formula (2) or a salt thereof, characterized in that a compound represented by formula (1) or a salt thereof is reacted with 2,2-dialkoxypropane or isopropenyl alkyl ether in the presence of (A) an acid selected from the group consisting of p-toluenesulfonic acid, pyridinium-p-toluenesulfonate, hydrobromic acid, and pyridine hydrobromide, and/or (B) a base selected from the group consisting of pyridine and N,N-dimethylaniline, and (C) water. This production method is suited to the industrial production of a synthetic intermediate of a 1,2-dihydroquinoline derivative having glucocorticoid receptor-binding activity.

Description

Process for producing 1,2-dihydroquinoline synthesis intermediate

The present invention relates to a method for producing a synthetic intermediate of a 1,2-dihydroquinoline derivative having glucocorticoid receptor binding activity.

Formula (2)

Or a salt thereof is known to be useful as, for example, a synthetic intermediate of a 1,2-dihydroquinoline derivative having glucocorticoid receptor binding activity (Patent Document 1). As a method for synthesizing the compound represented by the above formula (2) or a salt thereof, Patent Document 1 uses 8-amino-3-hydroxybenzo [c] chromen-6-one as a raw material and iodine and acetone. Thus, a synthesis method using a reaction for forming a 1,2-dihydroquinoline skeleton is described. Since the post-treatment of the method required a purification step by column chromatography (hereinafter also referred to as column purification), there was a problem in industrial production. Therefore, after the above reaction, the compound represented by the formula (2) or a salt thereof is p-methoxybenzylated or benzyloxymethylated without performing column purification to give the formula (3)

[In the formula (3), R ⁰ represents a p-methoxybenzyl group or a benzyloxymethyl group. ]
However, since iodine remains in the reaction system, a side reaction occurs, and the compound represented by formula (3) or a salt thereof is efficiently produced. It was difficult to do.

International Publication 2008/059865 Pamphlet

An object of the present invention is to find a new production method suitable for industrial production of a synthetic intermediate of a 1,2-dihydroquinoline derivative having glucocorticoid receptor binding activity.

As a result of intensive studies in view of such circumstances, the present inventor obtained an 8-amino-benzo [c] chromen-6-one derivative having a hydroxy group in the presence of a specific acid and / or base and water in the presence of 2,2 -By reacting with a dialkoxypropane or isopropenyl alkyl ether, a compound represented by the formula (2) which is a synthetic intermediate of a 1,2-dihydroquinoline derivative or a salt thereof can be obtained without using iodine. I found out. Further, after the reaction, the compound represented by the formula (2) or a salt thereof is p-methoxybenzylated or benzyloxymethylated without performing column purification to give the compound represented by the formula (3). It was found that the obtained compound or a salt thereof can be efficiently obtained without column purification.
Moreover, it discovered that the compound or its salt represented by Formula (2) was obtained from the compound or its salt represented by Formula (4).
Further, by treating the compound represented by the formula (5) or a salt thereof with p-toluenesulfonic acid, hydrochloric acid or bromic acid, p-toluenesulfone of the compound represented by the formula (1) having good filterability The present invention was completed by finding that it can be obtained as an acid salt, a hydrochloride or a bromate.
That is, the present invention is as follows.

[1] Formula (1)

Or a salt thereof,
(A) an acid selected from the group consisting of p-toluenesulfonic acid, pyridinium p-toluenesulfonate, hydrobromic acid and pyridine hydrobromide and / or (B) from pyridine and N, N-dimethylaniline A base selected from the group consisting of: (C) in the presence of water;
Reacting with 2,2-dialkoxypropane or isopropenyl alkyl ether,
Formula (2)

Or a salt thereof.

[2] By the method [1] above,
A compound represented by the formula (2) or a salt thereof is obtained, and then the compound represented by the formula (2) or a salt thereof is represented by the formula in the presence of at least one selected from the group consisting of an acid and a base. (A) R ⁰ X
[Wherein R ⁰ represents a p-methoxybenzyl group or a benzyloxymethyl group, and X represents a leaving group. ]
Characterized by reacting with a compound represented by the formula:
Formula (3)

[Wherein R ⁰ represents a p-methoxybenzyl group or a benzyloxymethyl group. ]
Or a salt thereof.

[3] The reaction for producing the compound represented by formula (2) or the salt thereof from the compound represented by formula (1) of the above [1] or a salt thereof is represented by the formula (4) generated during the reaction. The production method of [1] or [2], which is carried out through a compound or a salt thereof.
Formula (4)

[4] A compound represented by the formula (1) or a salt thereof,
Formula (5)

The method of [1] to [3] above, wherein the compound represented by the formula or a salt thereof is reacted with p-toluenesulfonic acid, hydrochloric acid or bromic acid.

[5] The salt of the above-mentioned [1] to [4], wherein the salt of the compound represented by the formula (1) is p-toluenesulfonate, hydrochloride or bromate of the compound represented by the formula (1) Production method.
[6] Formula (6)

[Wherein R ¹ represents a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylcarbonyl group, a carboxyl group, an amino group, a nitro group, or a cyano group; p represents an integer of 0 to 4 . ]
Or a salt thereof,
(A) an acid selected from the group consisting of p-toluenesulfonic acid, pyridinium p-toluenesulfonate, hydrobromic acid and pyridine hydrobromide and / or (B) from pyridine and N, N-dimethylaniline A base selected from the group consisting of: (C) in the presence of water;
Reacting with 2,2-dialkoxypropane or isopropenyl alkyl ether,
Formula (7)

[Wherein R ¹ represents a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylcarbonyl group, a carboxyl group, an amino group, a nitro group, or a cyano group; p represents an integer of 0 to 4 . ]
Or a salt thereof.

[7] The production method of the above [1] to [6], wherein the 2,2-dialkoxypropane is 2,2-dimethoxypropane.
[8] The production method of the above [1] to [6], wherein the isopropenyl alkyl ether is isopropenyl methyl ether.
[9]-p-toluenesulfonate of 8-amino-3-hydroxybenzo [c] chromen-6-one,
8- (1,1-dimethyl-3-oxobutylamino) -3-hydroxybenzo [c] chromen-6-one,
8-amino-3- (4-methoxybenzyloxy) benzo [c] chromen-6-one,
8-amino-3-benzyloxymethoxybenzo [c] chromen-6-one,
8- (1,1-dimethyl-3-oxobutylamino) -3- (4-methoxybenzyloxy) benzo [c] chromen-6-one,
8- (1,1-dimethyl-3-oxobutylamino) -3-benzyloxymethoxybenzo [c] chromen-6-one,
-Methyl 2- (2,4-dimethoxyphenyl) -5-aminobenzoate,
6- (2,4-methoxy) -2,2,4-trimethyl-1,2-dihydroquinoline-5-carboxylate methyl,
6-bromo-2,2,4-trimethyl-1,2-dihydroquinoline-5-carboxylic acid,
-Methyl 6-bromo-2,2,4-trimethyl-1,2-dihydroquinoline-5-carboxylate,
A compound selected from methyl 2-bromo-5- (1,1-dimethyl-3-oxobutylamino) benzoate or a salt thereof.

According to the present invention, an 8-amino-benzo [c] chromen-6-one derivative having a hydroxy group is reacted with 2,2-dialkoxypropane or isopropenyl alkyl ether in the presence of an acid and / or base and water. Thus, a compound represented by the formula (2) or a salt thereof, which is a synthetic intermediate of a 1,2-dihydroquinoline derivative, can be obtained without using iodine. In addition, after the reaction, the compound represented by the formula (2) or a salt thereof is p-methoxybenzylated or benzyloxymethylated without performing column purification to obtain a compound represented by the formula (3). Or a salt thereof can be efficiently obtained without column purification. Moreover, the compound represented by Formula (2) or its salt can be obtained from the compound represented by Formula (4) or its salt. Further, by treating the compound represented by the formula (5) or a salt thereof with p-toluenesulfonic acid, hydrochloric acid or bromic acid, p-toluenesulfone of the compound represented by the formula (1) having good filterability It can be obtained as an acid salt, hydrochloride or bromate.

The definitions of atoms, groups, rings and the like used in this specification will be described in detail below. Moreover, when the definition of the following words is applied mutatis mutandis to the definition of another wording, it can apply mutatis mutandis also to the preferable range and especially preferable range of each definition.
“Halogen atom” refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
The “lower alkyl group” refers to a straight or branched alkyl group having 1 to 8, preferably 1 to 6, and particularly preferably 1 to 4 carbon atoms. Specific examples include methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, isopropyl group, isobutyl group, sec-butyl group. , Tert-butyl group, isopentyl group and the like.

The “lower alkoxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkyl group. Specific examples include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexyloxy, n-heptyloxy, n-octyloxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy or isopentoxy group Etc.
The “lower alkylcarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with a lower alkyl group. Specific examples include methylcarbonyl group, ethylcarbonyl group, n-propylcarbonyl group, n-butylcarbonyl group, n-pentylcarbonyl group, n-hexylcarbonyl group, isopropylcarbonyl group, isobutylcarbonyl group, sec-butylcarbonyl group, Examples thereof include a tert-butylcarbonyl group and an isopentylcarbonyl group.
Examples of the “amino group” include —NH ₂ group, an amino group substituted with 1 or 2 lower alkyl groups, and the like.

“Leaving group” refers to a substituent that is eliminated by a reaction. Specific examples include halogen atoms such as fluorine atom, chlorine atom, bromine atom, iodine atom, lower alkylsulfonyloxy group such as methanesulfonyloxy group, chloromethylsulfoxyoxy group, trifluoromethanesulfonyloxy group, benzenesulfonyloxy group, Arylsulfonyloxy groups such as p-toluenesulfonyloxy group, cyano group, nitro group, trichloroacetimidate and the like can be mentioned.
The raw materials, reagents, and other compounds described in the present specification used in the present invention may form “salts” with acids or bases. Specific examples include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, bromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid , Adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearin Acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, salts with organic acids such as sulfosalicylic acid, methyl bromide Quaternary ammonium salts such as methyl iodide, bromine ion, chlorine ion, iodine ion Salt with gen ion, salt with alkali metal such as lithium, sodium, potassium, salt with alkaline earth metal such as calcium, magnesium, metal salt with copper, iron, zinc, salt with ammonia, triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- (hydroxymethyl) -1,3-propanediol, procaine , Salts with organic amines such as N, N-dimethylaniline or N, N-bis (phenylmethyl) -1,2-ethanediamine, and salts with pyridine.

The raw materials, reagents, and other compounds described in the present specification used in the present invention may be in the form of hydrates or solvates.
When geometrical isomers or optical isomers exist in the raw materials, reagents, and other compounds described in the present specification, such isomers are also included in the scope of the present invention.
When proton tautomerism exists in the raw materials, reagents and other compounds described in the present specification used in the present invention, such tautomers are also included in the present invention.
The raw materials, reagents, other compounds described in the present specification, hydrates or solvates thereof used in the present invention may be crystals, and crystal polymorphs and crystal polymorph groups (crystal polymorphs) are included in the crystals. When the system is present, the crystal polymorphs and crystal polymorph groups (crystal polymorph systems) are also included in the present invention. Here, the crystal polymorph group (crystal polymorph system) refers to various crystal forms depending on the conditions and states of production, crystallization, storage, etc. of these crystals (including the formulated state in this state). It means the crystal form and the whole process at each stage when changing.

Hereinafter, the production method of the present invention will be described.
Manufacturing method 1
The compound represented by the formula (2) or a salt thereof can be produced according to the following Step 1 (Synthesis route 1-1) and Step 2 (Synthesis route 1-2).
<Step 1>

Synthesis route 1-1

Step 1 is a step of producing a compound represented by the formula (1) or a salt thereof by reacting a compound represented by the formula (5) or a salt thereof with p-toluenesulfonic acid, hydrochloric acid or bromic acid. is there. In addition, the compound represented by Formula (5) or its salt can be obtained according to description of the international publication 2012/108455 pamphlet.
p-Toluenesulfonic acid, hydrochloric acid or bromic acid is 0.1 equivalent or more, preferably 1 to 6 equivalents, more preferably 3 to 4 equivalents, relative to the compound represented by the formula (5) or a salt thereof. Used.

The solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aromatic hydrocarbons such as benzene, toluene, xylene; dichloromethane, chloroform, Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, cyclopentyl methyl ether, methyl-tert-butyl ether, dioxane, dimethoxyethane, diethylene glycol dimethyl ether Ters; lower alkyl carboxylic acid esters such as ethyl acetate and isopropyl acetate; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, Amides such as oxamethyl phosphorotriamide; Sulfoxides such as dimethyl sulfoxide and sulfolane; Lower alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol and tert-butanol; Water; or a mixed solvent thereof Preferred are lower alcohols and water, and more preferred are ethanol and water.

While the reaction temperature varies depending on the raw material compound and the reaction reagent, it is carried out at 0 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
While the reaction time varies depending on the reaction temperature, raw material compound, reaction reagent or the type of solvent used, it is generally 1 min to 48 hr, preferably 15 hr to 24 hr.
After completion of the reaction, the target compound is allowed to cool, and while stirring under ice cooling, a solvent such as water, aqueous ammonia or methanol is added, and the precipitated solid is filtered or extracted. It can be obtained by adding a recrystallizable solvent such as toluene or ethyl acetate to the residue obtained after concentration and filtering and drying the precipitated solid. In addition, after filtering the depositing solid, it is preferable to wash | clean with toluene, ethyl acetate, water, etc.
If necessary, the obtained target compound can be purified by a conventional method such as recrystallization and reprecipitation.
The target compound can also be obtained as p-toluenesulfonate, hydrochloride or bromate.

Synthesis route 1-2
In step 2, the compound represented by the formula (1) or a salt thereof is selected from the group consisting of (A) p-toluenesulfonic acid, pyridinium p-toluenesulfonate, hydrobromic acid and pyridine hydrobromide. And (B) a base selected from the group consisting of pyridine and N, N-dimethylaniline, and (C) a reaction with 2,2-dialkoxypropane or isopropenyl alkyl ether in the presence of water. This is a process for producing a compound represented by formula (2) or a salt thereof. In the figure of <Step 2>, R ² represents a lower alkyl group, preferably a methyl group.

The acid (A) used in this step is preferably p-toluenesulfonic acid or pyridinium p-toluenesulfonate, and more preferably p-toluenesulfonic acid.
The acid (A) used in this step is 0.10 equivalents or more, preferably 0.5 to 2.0 equivalents, more preferably 0.00 equivalents, relative to the compound represented by the formula (1) or a salt thereof. 90 to 1.10 equivalents are used.
The base (B) used in this step is preferably pyridine.
The acid (B) used in this step is 0.10 equivalents or more, preferably 0.5 to 2.0 equivalents, more preferably 0.8 equivalents, relative to the compound represented by the formula (1) or a salt thereof. 90 to 1.10 equivalents are used.
In this step, (A) and (B) may be used. In such a case, a combination using p-toluenesulfonic acid as (A) and pyridine as (B) is preferable.
Further, (A) or (B) may be used. When (A) is used, it is preferable to use pyridinium p-toluenesulfonate.

The water (C) used in this step is used in an amount of 5 equivalents or more, preferably 10 to 30 equivalents, more preferably 15 to 25 equivalents, relative to the compound represented by the formula (1) or a salt thereof. It is done.
Examples of the 2,2-dialkoxypropane used in this step include 2,2-dimethoxypropane and 2,2-diethoxypropane. The compound represented by the formula (1) or its It is used in an amount of 10 equivalents or more, preferably 30-100 equivalents, more preferably 50-60 equivalents, relative to the salt.
Examples of the isopropenyl alkyl ether used in this step include isopropenyl methyl ether and isopropenyl ethyl ether. The compound represented by the formula (1) or a salt thereof is 10 equivalents or more. The amount is preferably 30 to 100 equivalents, more preferably 50 to 60 equivalents.

The solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aromatic hydrocarbons such as benzene, toluene, xylene; dichloromethane, chloroform, Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, cyclopentyl methyl ether, methyl-tert-butyl ether, dioxane, dimethoxyethane, diethylene glycol dimethyl ether Lower alkyl carboxylic acid esters such as ethyl acetate and isopropyl acetate; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, Amides such as samethyl phosphorotriamide; Sulfoxides such as dimethyl sulfoxide and sulfolane; Lower alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol and tert-butanol; Water; or a mixed solvent thereof Preferred are lower alcohols and aromatic hydrocarbons, and more preferred are methanol and toluene.

While the reaction temperature varies depending on the raw material compound and the reaction reagent, it is carried out at 0 ° C. to 150 ° C., preferably 25 ° C. to 130 ° C., more preferably 40 ° C. to 110 ° C.
While the reaction time varies depending on the reaction temperature, raw material compound, reaction reagent or the type of solvent used, it is generally 12 to 96 hours, preferably 24 to 84 hours.
After completion of the reaction, the target compound is allowed to cool, and while stirring under ice-cooling, a solvent such as water, aqueous ammonia or methanol is added, and the precipitated solid is filtered or concentrated / extracted. The residue obtained after the concentration can be obtained by adding a recrystallizable solvent such as toluene, n-hexane or n-heptane and filtering and drying the precipitated solid. The precipitated solid is preferably filtered and then washed with toluene, n-hexane, n-heptane, water or the like.
If necessary, the obtained target compound can be purified by a conventional method such as recrystallization and reprecipitation.

Manufacturing method 2
The compound represented by the formula (3) or a salt thereof can be produced according to the following synthesis route 2.

Synthesis route 2
That is, the compound represented by the formula (1) or a salt thereof is reacted with 2,2-dialkoxypropane or isopropenyl alkyl ether by using the production method according to <Step 2> of the production method 1 above. 2) or a salt thereof is obtained. The compound represented by the formula (2) or a salt thereof can be obtained without performing column purification. The obtained compound represented by the formula (2) or a salt thereof in the presence of at least one selected from the group consisting of an acid and a base, or a compound represented by the formula (a) R ⁰ X or a salt thereof By reacting with a salt, the compound represented by the formula (3) or a salt thereof can be produced. The compound represented by the formula (3) or a salt thereof can be obtained without performing column purification. In the formulas (a) and (3), R ⁰ represents a p-methoxybenzyl group or a benzyloxymethyl group.

In the formula (a), X represents a leaving group, and any substituent can be used as long as it is eliminated by reaction. For example, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, methane Lower alkylsulfonyloxy groups such as sulfonyloxy group, chloromethylsulfoxyoxy group, trifluoromethanesulfonyloxy group, arylsulfonyloxy groups such as benzenesulfonyloxy group, p-toluenesulfonyloxy group, cyano group, nitro group, trichloroacetate Examples thereof include imidate and carbonyldioxyphenyl, preferably a halogen atom, more preferably a chlorine atom.
The compound represented by the formula (a) or a salt thereof is 1 equivalent or more, preferably 1 to 2 equivalents, more preferably 1.2 to 1.5 equivalents, relative to the compound represented by the formula (2) or a salt thereof. Used.

Examples of the acid used in this step include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrogen bromide, and hydrofluoric acid; trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- Examples thereof include organic acids such as toluenesulfonic acid and aminosulfonic acid; Lewis acids such as boron tribromide, boron trichloride, boron trifluoride and aluminum chloride.
The acid used in this step is used in an amount of 1 equivalent or more, preferably 1 to 5 equivalents, more preferably 2 to 3 equivalents, relative to the compound represented by the formula (2) or a salt thereof.

Examples of the base used in this step include alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate; Alkali metal hydroxides such as sodium, potassium hydroxide, barium hydroxide, and lithium hydroxide; Alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride; such as sodium fluoride and potassium fluoride Inorganic bases such as alkali metal fluorides; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium methoxide; N-methylmorpholine, triethylamine, tri Propyl Min, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4 -Methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2 .2] Octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), N, N, N ′, N ′, N ″, N ″ -hexamethylphosphorus Organic bases such as acid triamide (HMPA) can be mentioned, preferably alkali metal carbonates, and more preferably potassium carbonate.

The base used in this step is used in an amount of 1 equivalent or more, preferably 1 to 5 equivalents, more preferably 2 to 3 equivalents, relative to the compound represented by the formula (2) or a salt thereof.
The solvent used in this step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aromatic hydrocarbons such as benzene, toluene, xylene; dichloromethane, chloroform, Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, cyclopentyl methyl ether, methyl-tert-butyl ether, dioxane, dimethoxyethane, diethylene glycol dimethyl ether Lower alkyl carboxylic acid esters such as ethyl acetate and isopropyl acetate; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, Amides such as samethyl phosphorotriamide; Sulfoxides such as dimethyl sulfoxide and sulfolane; Lower alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol and tert-butanol; Water; or a mixed solvent thereof Preferred are amides and water, and more preferred are N, N-dimethylformamide and water.

While the reaction temperature varies depending on the raw material compound and the reaction reagent, it is carried out at 0 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
While the reaction time varies depending on the reaction temperature, raw material compound, reaction reagent or the type of solvent used, it is generally 1 hour to 48 hours, preferably 2 hours to 5 hours.
After completion of the reaction, the target compound is allowed to cool, and while stirring under ice cooling, a solvent such as water, aqueous ammonia or methanol is added, and the precipitated solid is filtered or extracted. It can be obtained by adding a recrystallizable solvent such as toluene or ethyl acetate to the residue obtained after concentration and filtering and drying the precipitated solid. In addition, after filtering the depositing solid, it is preferable to wash | clean with toluene, ethyl acetate, water, etc.
If necessary, the obtained target compound can be purified by a conventional method such as recrystallization and reprecipitation.

Manufacturing method 3
The compound represented by the formula (2) or a salt thereof can also be produced according to the following synthesis route 3.

Synthesis route 3

That is, the compound represented by the formula (1) or a salt thereof is reacted with 2,2-dialkoxypropane or isopropenyl alkyl ether by using the production method according to <Step 2> of the production method 1 above. 4) or a salt thereof, and a compound represented by formula (4) or a salt thereof obtained by using a production method according to <Step 2> of production method 1 above. A compound represented by the formula (2) or a salt thereof can be produced by reacting with 2-dialkoxypropane or isopropenyl alkyl ether.

Manufacturing method 4
The compound represented by the formula (3) or a salt thereof can also be produced according to the following synthesis route 4.

Synthesis route 4

That is, the compound represented by the formula (1) or a salt thereof is reacted with the compound represented by the formula (a) R ⁰ X or a salt thereof in the presence of at least one selected from the group consisting of an acid and a base. Thus, a compound represented by the formula (8) or a salt thereof is obtained. Next, the obtained compound represented by the formula (8) or a salt thereof is reacted with 2,2-dialkoxypropane or isopropenyl alkyl ether using the production method according to <Step 2> of the production method 1 above. Thus, the compound represented by the formula (3) or a salt thereof can be produced. In addition, the reaction for producing the compound represented by the formula (3) or the salt thereof from the compound represented by the formula (8) or a salt thereof is generated in the course of the reaction (4b)

It may be carried out via a compound represented by the formula: In the formulas (a), (8), (3) and (4b), R ⁰ represents a p-methoxybenzyl group or a benzyloxymethyl group.

Manufacturing method 5
Compound (2a) can also be produced according to the following synthesis route 5.

Synthesis route 5

That is, by reacting the halide (9a) and the corresponding boronic acid (b) with a base such as sodium carbonate in the presence of a catalyst such as bis (triphenylphosphine) palladium (II) dichloride in a solvent such as DMF, Compound (10a) is obtained. The obtained compound (10a) is catalytically reduced in a hydrogen atmosphere to obtain the compound (11a), and then the compound (11a) is converted into 2,2-- using the production method according to <Step 2> of the above production method 1. Reaction with dialkoxypropane or isopropenyl alkyl ether gives compound (12a). And the compound (2a) can be manufactured by ring-closing the compound (12a) obtained.

Manufacturing method 6
Compound (2a) can also be produced according to the following synthesis route 6.

Synthesis route 6

That is, the compound (13a) is reacted with 2,2-dialkoxypropane or isopropenyl alkyl ether using the production method according to <Step 2> of the production method 1 to obtain the compound (14a). The carboxyl group of the obtained compound (14a) is methyl esterified to obtain the compound (15a), and the resulting compound (15a) and the corresponding boronic acid (b) are mixed with a base such as sodium carbonate in a solvent such as DMF. Compound (12a) is obtained by reacting in the presence of a catalyst such as bis (triphenylphosphine) palladium (II) dichloride. The resulting compound (12a) can be cyclized to produce compound (2a). Compound (15a) can also be obtained by reacting compound (16a) with 2,2-dialkoxypropane or isopropenyl alkyl ether using the production method according to <Step 2> of production method 1 above. .

Manufacturing method 7
The compound represented by the compound (7) or a salt thereof can be produced according to the following synthesis route 7.

Synthesis route 7

That is, it is produced by reacting the compound represented by the formula (6) or a salt thereof with 2,2-dialkoxypropane or isopropenyl alkyl ether by using a production method according to <Step 2> of Production Method 1 above. be able to.
In Formula (6) and Formula (7), R ¹ can include a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylcarbonyl group, a carboxyl group, an amino group, a nitro group, or a cyano group. , Preferably a hydrogen atom. p may be an integer of 0 to 4, preferably 1 to 2.
Below, the manufacture example of this invention is shown. In addition, these illustrations are for understanding this invention better, and do not limit the scope of the present invention.

[Production example]
<Production of 8-amino-3-hydroxybenzo [c] chromen-6-one p-toluenesulfonate (1a)>

A mixture of 8-acetamido-3-hydroxy-6H-benzo [c] chromen-6-one (5a) (60.0 g, 223 mmol, WO 2012/108455 pamphlet), ethanol (900 ml) and water (120 ml) at room temperature Then, p-toluenesulfonic acid monohydrate (127 g, 669 mmol) was added, and the mixture was stirred at an internal temperature of 79 to 81 ° C. for 17 hours. Further, p-toluenesulfonic acid monohydrate (42.3 g, 223 mmol) was added, and the mixture was stirred at an internal temperature of 79 to 81 ° C. for 5 hours. The reaction solution was stirred for 1 hour at an internal temperature of 0 to 5 ° C., and the crystals were separated by filtration, washed with ethanol (300 ml) and dried under reduced pressure at 50 ° C. to give the title compound (77.1 g, yield 86.5%). Obtained.

A mixture of 2,2-dimethoxypropane (59.0 ml, 482 mmol), pyridine (0.70 ml, 8.71 mmol) and water (3.20 ml, 178 mmol) was stirred at room temperature, and 8-amino-3-hydroxybenzo [C] Chromen-6-one p-toluenesulfonate (1a) (3.51 g, 8.79 mmol) was added, and the mixture was stirred at an external temperature of 105 ° C. for 72 hours under pressure resistance. The reaction solution was allowed to cool and cooled, concentrated, and the residue was extracted with tetrahydrofuran (17.5 mL), ethyl acetate (24.5 mL), and water (21.0 mL). The aqueous layer was extracted with ethyl acetate (24.5 ml), and the organic layers were combined, washed twice with water (21.0 ml), washed with 4% aqueous sodium hydrogen carbonate solution (21.0 ml), and the organic layer was concentrated. . The concentrated residue was purified several times by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (1.30 g, yield 48%).

8-amino-3-hydroxybenzo [c] chromen-6-one (1b) (5.00 g, 22.0 mmol), 2,2-dimethoxypropane (135.0 ml, 1102 mmol) and pyridine (1.77 ml, 22 0.0 mmol) and water (7.90 ml, 438 mmol) were stirred at room temperature, p-toluenesulfonic acid monohydrate (4.19 g, 22.0 mmol) was added, and the external temperature was 105 ° C. under pressure resistance. For 66 hours and 10 minutes. The reaction mixture was allowed to cool and cooled, concentrated, and the residue was extracted with ethyl acetate-tetrahydrofuran (3: 2, 100.0 mL) and saturated aqueous sodium hydrogen carbonate (50.0 mL). The aqueous layer was extracted twice with ethyl acetate-tetrahydrofuran (3: 2, 50.0 mL), and the organic layers were combined, washed three times with a saturated aqueous sodium hydrogen carbonate solution (50.0 mL), and the organic layer was concentrated. N, N-dimethylformamide (60.0 mL) was added to the concentrated residue and concentrated several times to remove pyridine. N, N-dimethylformamide was added so that the concentration residue was 60.0 mL, potassium carbonate (7.61 g, 55.1 mmol) and water (3.00 mL) were added, and the mixture was stirred at room temperature. 4-Methoxybenzyl chloride (3.90 mL, 28.6 mmol) was added to the mixture, and the mixture was stirred at an external temperature of 40 ° C. for 3 hours and 25 minutes. The reaction solution was stirred under ice-cooling, water (300.0 mL) was added, the mixture was stirred for 1 hour and 15 minutes, filtered, and washed with water (100.0 mL). A mixture of the crude title compound and ethyl acetate (300.0 mL) was stirred at an external temperature of 85 ° C., filtered, and the filtrate was concentrated. Toluene (46.0 mL) and ethyl acetate (12.0 mL) were added to the concentrated residue, and the mixture was stirred at an external temperature of 85% for 1 hour. The reaction solution was stirred at 0 ° C. for 18 hours and 50 minutes, filtered, washed with toluene (15.0 mL), and dried under reduced pressure at 50 ° C. to obtain the title compound (4.10 g, yield 44%).

A mixture of 2,2-dimethoxypropane (717.28 g, 6887 mmol), pyridine (9.90 g, 125.2 mmol) and water (45.12 g, 2504 mmol) was stirred at room temperature, and 8-amino-3-hydroxybenzo [C] Chromen-6-one p-toluenesulfonate (1a) (50.00 g, 125.2 mmol) was added, and the mixture was stirred at an internal temperature of 90.5 to 98.5 ° C. for 72 hours under pressure resistance. The reaction mixture was allowed to cool and cooled, concentrated under reduced pressure, and ethyl acetate (313 g), tetrahydrofuran (222 g), and water (300 g) were added to the residue to separate the layers. The organic layer was washed twice with water (300 g), 4% aqueous sodium hydrogen carbonate solution (300 g), tetrahydrofuran (222 g) was added, and the mixture was washed with 4% aqueous sodium hydrogen carbonate solution (302 g). N, N-dimethylformamide (327.30 g) was added to the organic layer, and the mixture was concentrated under reduced pressure. After concentration, N, N-dimethylformamide was added so that the residue was 327.05 g, potassium carbonate (42.51 g, 307.59 mmol) and water (14.70 g) were added, and the mixture was stirred at room temperature. 4-Methoxybenzyl chloride (25.07 g, 160.08 mmol) was added to the mixture, and the mixture was stirred at an internal temperature of 40-41 ° C. for 4 hours. The reaction mixture was cooled to room temperature, ethyl acetate (232 g), tetrahydrofuran (686 g), 28% aqueous ammonia (705 g) were added, and the mixture was stirred and separated. Ethyl acetate (310 g) was added to the aqueous layer and the layers were separated. All the organic layers were combined, washed once with 5% brine (786 g), washed twice with 5% brine (393 g), washed once with water (400 g), and the organic layer was concentrated under reduced pressure. Toluene (213 g) was added and concentrated under reduced pressure three times. Toluene (221.34 g) and ethyl acetate (35.4 g) were added to the concentrated residue, and the mixture was stirred at an internal temperature of 84 to 90 ° C. for 31 minutes. The mixture was stirred at ˜10 ° C. for 18 hours, and the precipitated solid was filtered. The obtained mixture of wet crystals and toluene (128 g) was stirred at an internal temperature of 85 ° C. for 1 hour and 13 minutes, and then cooled. After stirring at an internal temperature of 1 to 10 ° C. for 2 hours and 59 minutes, the mixture was filtered, washed with toluene (20 g) three times, and dried under reduced pressure at 50 ° C. for 2 hours and 15 minutes to give the title compound (19.41 g, yield 36.3). %).

A mixture of 8-amino-3-hydroxybenzo [c] chromen-6-one p-toluenesulfonate (1a) (8.02 g, 20.1 mmol) and methanol (40.0 ml) was stirred with ice cooling. . When the internal temperature reached 3 ° C., sodium hydrogen carbonate (2.02 g, 24.0 mmol) was added and the external temperature was returned to room temperature and stirred for 2 hours. The solid in the reaction solution was filtered, washed with water (30.0 mL), and dried at 50 ° C. to obtain the title compound (4.58 g, yield 100%).

8-Amino-3-hydroxybenzo [c] chromen-6-one (1b) (5.00 g, 22.0 mmol), 2,2-dimethoxypropane (135 ml, 1100 mmol) and pyridine (1.76 ml, 21.9 mmol) ) And water (7.90 ml, 440 mmol) were stirred at room temperature, p-toluenesulfonic acid monohydrate (4.15 g, 21.8 mmol) was added, and 1-methyl-2 was added to the suspension. -Pyrrolidone (125 ml) was added and dissolved by stirring, and the mixture was stirred for 66 hours and 40 minutes. The reaction solution was concentrated and extracted by adding ethyl acetate (1000 mL) and saturated multistory water (500 mL). The aqueous layer was extracted twice with ethyl acetate (500 ml), and the organic layers were combined and washed three times with water (500 ml). The organic layer was concentrated, chloroform was added to the residue, the filtrate was concentrated after filtration. The concentrated residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (2.66 g, yield 37%).

8- (1,1-Dimethyl-3-oxobutylamino) -3-hydroxybenzo [c] chromen-6-one (4a) (0.76 g, 2.34 mmol) and 2,2-dimethoxypropane (16. A mixture of 0 ml, 131 mmol), pyridine (0.19 ml, 2.36 mmol) and water (0.84 ml, 46.6 mmol) was stirred at room temperature, and p-toluenesulfonic acid monohydrate (0.45 g, 2 .36 mmol) was added, and the mixture was stirred at an external temperature of 105 ° C. for 61.5 hours under pressure resistance. The reaction mixture was allowed to cool and cooled, and extracted by adding ethyl acetate (5.50 mL), tetrahydrofuran (4.00 mL), and water (4.50 mL). The organic layer was washed with water (4.50 ml), and the aqueous layer was collected and extracted with ethyl acetate (5.50 ml). The organic layer was collected, washed with 4% aqueous sodium hydrogen carbonate solution (4.50 ml), and anhydrous. After drying with magnesium sulfate, the organic layer was concentrated. The concentrated residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (0.37 g, yield 51.2%).

A mixture of 8-amino-3-hydroxybenzo [c] chromen-6-one (1b) (2.00 g, 8.80 mmol) and anhydrous dimethylformamide (40.0 ml) was stirred with cooling at an external temperature and ice cooling. When the internal temperature reached 4 ° C., 60% sodium hydride (0.42 g, 10.5 mmol) and 4-methoxybenzyl chloride (1.40 ml, 10.3 mmol) were added, and the external temperature was returned to room temperature for 14 hours 55 Stir for minutes. The reaction mixture was allowed to cool and then stirred under ice-cooling, water (40.0 mL) was added and the mixture was stirred for 43 min, and the precipitated solid was filtered. The filtered product was further washed with water (20.0 mL) and dried at 65 ° C. to obtain the title compound (2.87 g, yield 94%).

A mixture of 8-amino-3-hydroxybenzo [c] chromen-6-one (1b) (2.00 g, 8.80 mmol) and anhydrous dimethylformamide (40.0 ml) was stirred with cooling at an external temperature and ice cooling. When the internal temperature reached 0.4 ° C., 60% sodium hydride (0.42 g, 10.5 mmol) and benzyl chloromethyl ether (1.45 ml, 10.5 mmol) were added, and the external temperature was returned to room temperature for 2 hours. Stir for 8 minutes. The reaction solution was allowed to cool and then stirred under ice-cooling. Water (80.0 mL) was added and stirred for 1 hour, and then the precipitated solid was filtered. The filtered product was further washed with water (30.0 mL) and dried at 50 ° C. A mixture of the obtained product (3.24 g) and methanol (64.0 ml) was heated to reflux and stirred for 1 hour. The mixture was allowed to cool, stirred for 1 hour and 5 minutes under ice cooling, and filtered. The filtered product was further washed with methanol (5.00 mL) and dried at 50 ° C. to obtain the title compound (2.59 g, yield 85%).

8-Amino-3- (4-methoxybenzyloxy) benzo [c] chromen-6-one (8a) (0.83 g, 2.39 mmol), 2,2-dimethoxypropane (16.0 ml, 131 mmol) and pyridine (0.19 ml, 2.36 mmol) and water (0.86 ml, 47.7 mmol) were stirred at room temperature, p-toluenesulfonic acid monohydrate (0.45 g, 2.37 mmol) was added, The mixture was stirred at an external temperature of 75 ° C. for 141 hours and 35 minutes under pressure resistance. The reaction solution was allowed to cool and cooled and concentrated, and the residue was extracted with ethyl acetate (10.0 mL), tetrahydrofuran (14.0 mL), and water (12.0 mL). The aqueous layer was extracted with ethyl acetate (10.0 ml), the organic layers were combined, washed with 4% aqueous sodium hydrogen carbonate solution (12.0 ml), and the organic layer was concentrated. The concentrated residue was purified by silica gel column chromatography (chloroform) to obtain the crude title compound (0.32 g). Toluene (3.20 mL) and n-heptane (3.20 mL) were added to the crude product, stirred at an external temperature of 80 ° C. for 40 minutes, cooled at an external temperature of 4 ° C. for 18 hours and 20 minutes, filtered, toluene and n-heptane. Was washed with a mixed solvent (1: 2, 6.00 mL) to obtain the title compound (0.24 g, yield 20%).

8-amino-3- (4-methoxybenzyloxy) benzo [c] chromen-6-one (8a) (2.51 g, 7.23 mmol), 2,2-dimethoxypropane (49.0 ml, 400 mmol) and pyridine (0.58 ml, 7.22 mmol) and water (7.90 ml, 144 mmol) were stirred at room temperature, and p-toluenesulfonic acid monohydrate (1.37 g, 7.20 mmol) was added. 1-Methyl-2-pyrrolidone (35 ml) was added to the suspension to dissolve it, and the mixture was stirred for 71 hours and 4 minutes. The reaction mixture was concentrated and extracted by adding ethyl acetate (50.0 mL) and water (100 mL). The aqueous layer was extracted with ethyl acetate (50.0 ml), and the organic layers were combined. After extraction by adding ethyl acetate (100 ml) and water (100 ml), the organic layer was mixed with ethyl acetate (100 ml), tetrahydrofuran (20 ml), water ( 100 ml) and extracted, and the organic layer was extracted with ethyl acetate (100 ml) and water (100 ml). The organic layer was concentrated, tetrahydrofuran was added to the residue, the solid was filtered, and the filtrate was concentrated. Ethyl acetate was added to the concentration residue, the solid was filtered, and the filtrate was concentrated. Chloroform was added to the filtered solid for dissolution and concentration, and the precipitated crystals were filtered, and then the filtrate was concentrated. Chloroform was added to the concentration residue and dissolved and concentrated, the precipitated crystals were filtered, and the filtrate was concentrated. Each concentrated residue was purified by silica gel column chromatography (ethyl acetate-hexane), and the fractions were combined to obtain the title compound (1.17 g, yield 37%).

8- (1,1-Dimethyl-3-oxobutylamino) -3- (4-methoxybenzyloxy) benzo [c] chromen-6-one (4b-1) (1.12 g, 2.51 mmol) and 1 -Methyl-2-pyrrolidone (10.0 ml) and pyridine (0.20 ml, 2.49 mmol) were stirred at room temperature, and p-toluenesulfonic acid monohydrate (0.47 g, 2.47 mmol) was added. In addition, the mixture was stirred at an external temperature of 50 ° C. for 20 hours and 20 minutes. The reaction solution was allowed to cool and cooled, and extracted by adding ethyl acetate (55.0 mL) and water (55.0 mL). The aqueous layer was extracted with ethyl acetate (10.0 ml), and the organic layer was collected. Tetrahydrofuran (30.0 ml) was added, washed twice with water (55.0 ml), and 4% aqueous sodium hydrogen carbonate solution (55.0 ml). And the organic layer was concentrated. Chloroform (22.0 mL) was added to the concentration residue, the solid was filtered, washed with chloroform (10.0 mL), and the filtrate was concentrated. The concentrated residue was purified by silica gel column chromatography (chloroform) and subsequently purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the crude title compound (0.018 g). Toluene-normal heptane (0.36 ml) was added to the crude product, and the solid was filtered and washed with toluene-normal heptane (0.54 ml) to obtain the title compound (0.010 g, yield 0.95%). .

8-amino-3-benzyloxymethoxybenzo [c] chromen-6-one (8b) (1.00 g, 2.88 mmol), 2,2-dimethoxypropane (19.4 ml, 158 mmol) and pyridine (0.23 ml) 2.86 mmol) and water (1.04 ml, 57.7 mmol) were stirred at room temperature, p-toluenesulfonic acid monohydrate (0.55 g, 2.89 mmol) was added, The mixture was stirred at an external temperature of 75 ° C. for 138 hours and 44 minutes. The reaction mixture was allowed to cool and cooled, and concentrated, and the residue was extracted with ethyl acetate (14.0 mL), tetrahydrofuran (10.0 mL), and water (12.0 mL). The aqueous layer was extracted with ethyl acetate (10.0 ml), the organic layers were combined, washed with 4% aqueous sodium hydrogen carbonate solution (12.0 ml), and the organic layer was concentrated. The concentrated residue was purified twice by silica gel column chromatography (chloroform) to obtain the crude title compound (0.43 g). Toluene (2.10 mL) and n-heptane (4.20 mL) were added to the crude product, stirred at an external temperature of 80 ° C. for 30 minutes, cooled at an external temperature of 4 ° C. for 19 hours, filtered, and mixed with toluene and n-heptane. Washing with the solvent (1: 2, 4.00 mL) gave the title compound (0.17 g, 14% yield).

8-amino-3-benzyloxymethoxybenzo [c] chromen-6-one (8b) (1.50 g, 4.32 mmol), 2,2-dimethoxypropane (36.0 ml, 294 mmol) and pyridine (0.43 ml) 5.35 mmol) and water (1.94 ml, 108 mmol) were stirred at room temperature, p-toluenesulfonic acid monohydrate (1.03 g, 5.41 mmol) was added, and -Methyl-2-pyrrolidone (10.0 ml) was added and dissolved, and the mixture was stirred for 67 hours and 12 minutes. The reaction mixture was concentrated and extracted by adding ethyl acetate (30.0 mL) and water (60.0 mL). The aqueous layer was extracted with ethyl acetate (30.0 ml), and the organic layers were combined. After extraction by adding ethyl acetate (30.0 ml) and water (60.0 ml), the organic layer was washed with water (60.0 ml) three times. Washed. The organic layer was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (0.78 g, yield 33%).

8- (1,1-Dimethyl-3-oxobutylamino) -3-benzyloxymethoxybenzo [c] chromen-6-one (4c) (0.79 g, 1.77 mmol) and 1-methyl-2-pyrrolidone (16.0 ml) and pyridine (0.15 ml, 1.87 mmol) were stirred at room temperature, p-toluenesulfonic acid monohydrate (0.36 g, 1.89 mmol) was added, and the external temperature was 50 ° C. For 23 hours 53 minutes. The reaction solution was allowed to cool and cooled, and extracted by adding ethyl acetate (40.0 mL) and water (40.0 mL). The aqueous layer was extracted with ethyl acetate (8.0 ml), and the organic layers were combined, washed twice with water (40.0 ml), washed twice with 4% aqueous sodium bicarbonate (40.0 ml), and the organic layer Was concentrated. Chloroform (16.0 mL) was added to the concentration residue, the solid was filtered, washed with chloroform (5.0 mL), and the filtrate was concentrated. The concentrated residue was purified by silica gel column chromatography (chloroform) to obtain the title compound (0.0092 g, yield 1.15%).

Methyl 2- (2,4-dimethoxyphenyl) -5-nitrobenzoate (4.00 g, 12.6 mmol, WO 2008/059865 pamphlet), N, N-dimethylformamide (46.0 ml) and methanol (12 0.0 ml) and 10% palladium carbon (moisture 52.1%) (0.19 g) were stirred at room temperature, and hydrogen gas was stirred for 4 hours and 25 minutes under 3.0 kgf / cm ² conditions. The reaction mixture was filtered through celite and washed with methanol and water (100.0 mL). The filtrate was extracted with ethyl acetate (200.0 mL) and water (100.0 mL). The aqueous layer was extracted twice with ethyl acetate (100.0 mL), the organic layers were combined, washed 6 times with 5% aqueous sodium chloride solution (200.0 ml), the organic layer was dried over anhydrous magnesium sulfate and concentrated. The concentrated residue was purified twice by silica gel column chromatography (chloroform-methanol) to obtain the title compound (2.60 g, yield 72%).

Methyl 2- (2,4-dimethoxyphenyl) -5-aminobenzoate (11a) (2.64 g, 9.19 mmol), 2,2-dimethoxypropane (60.0 ml, 490 mmol) and pyridine (0.73 ml, 9.08 mmol) and water (3.20 ml, 178 mmol) were stirred at room temperature, p-toluenesulfonic acid monohydrate (1.72 g, 9.04 mmol) was added, and the external temperature was 105 ° C. for 72 hours. Stir. Insoluble matters in the reaction solution were removed by filtration, and the filtrate was concentrated. The concentrated residue was extracted with ethyl acetate (26.0 mL) and water (26.0 mL). The aqueous layer was extracted twice with ethyl acetate (13.0 mL), the organic layers were combined, washed twice with 4% aqueous sodium chloride solution (50.0 ml), and the organic layer was dried over anhydrous magnesium sulfate and concentrated. The concentrated residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (0.27 g, yield 8.1%).

<6-Bromo-2,2,4-trimethyl-1,2-dihydroquinoline-5-carboxylic acid (14a) and 6-bromo-2,2,4-trimethyl-1,2-dihydroquinoline-7-carvone Production of acid isomer mixture>

5-amino-2-bromobenzoic acid (13a) (5.00 g, 23.1 mmol), 2,2-dimethoxypropane (156 ml, 1273 mmol), pyridine (1.86 ml, 23.1 mmol) and water (8.40 ml) The mixture was stirred at room temperature, p-toluenesulfonic acid monohydrate (4.40 g, 23.1 mmol) was added, and the mixture was stirred at an external temperature of 100 ° C. for 48 hours. The reaction mixture was concentrated, and the concentrated residue was purified three times by silica gel column chromatography (ethyl acetate-hexane), and then purified twice by silica gel column chromatography (chloroform-methanol) to give the title isomer mixture (1. 26 g, yield 18%).

6-Bromo-2,2,4-trimethyl-1,2-dihydroquinoline-5-carboxylic acid (14a) and 6-bromo-2,2,4-trimethyl-1,2-dihydroquinoline-7-carboxylic acid A mixture of isomers (1.00 g, 3.38 mmol) and low-moisture solvent methanol (80.0 ml) was stirred at an external temperature of 4 ° C., thionyl chloride (2.30 mL, 31.7 mmol) was added for 73 hours. Stir for 10 minutes. The reaction mixture was concentrated and extracted by adding ethyl acetate (80.0 mL) and 4% aqueous sodium hydrogen carbonate solution (180.0 mL). The aqueous layer was extracted with ethyl acetate (50.0 ml), the organic layers were combined, washed twice with 4% aqueous sodium hydrogen carbonate solution (100.0 ml), and the organic layer was concentrated to obtain an isomer compound. The aqueous layer was collected, concentrated hydrochloric acid (14.7 mL) was added, extracted with ethyl acetate (400.0 mL), and concentrated to obtain the title compound (0.56 g) in which the isomer remained. The above operation was repeated three times to obtain the title compound (0.26 g, yield 25%).

A mixture of 6-bromo-2,2,4-trimethyl-1,2-dihydroquinoline-5-carboxylic acid (14a) (0.24 g, 0.81 mmol) and low moisture solvent methanol (20.0 ml) was ice-cooled. And thionyl chloride (18.6 mL, 257 mmol) was added and stirred at reflux for 42 hours and 50 minutes. The reaction mixture was allowed to cool and cooled, concentrated, extracted by adding ethyl acetate (20.0 mL) and 4% aqueous sodium hydrogen carbonate solution (20.0 mL), and the organic layer was concentrated. The concentrated residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (0.021 g, yield 8.6%).

Methyl 2-bromo-5-aminobenzoate (16a) (4.00 g, 17.4 mmol), 2,2-dimethoxypropane (120 ml, 979 mmol), pyridine (1.40 ml, 17.4 mmol) and water (6. 30 ml, 350 mmol) was stirred at room temperature, p-toluenesulfonic acid monohydrate (3.32 g, 17.5 mmol) was added, and the mixture was stirred at an external temperature of 105 ° C. for 65 hours and 30 minutes under pressure resistance. The reaction solution was allowed to cool and concentrated, and extracted by adding ethyl acetate (80.0 mL) and water (80.0 mL). The organic layer was washed with water (80.0 mL), washed with 4% aqueous sodium hydrogen carbonate solution (80.0 ml), and the organic layer was concentrated. The concentrated residue was purified three times by silica gel column chromatography (ethyl acetate-hexane) and then purified twice by silica gel column chromatography (chloroform) to obtain the title isomer mixture (1.50 g, yield 28%). Obtained.

Methyl 2-bromo-5-aminobenzoate (16a) (4.00 g, 17.4 mmol), 2,2-dimethoxypropane (120 ml, 979 mmol), pyridine (1.40 ml, 17.4 mmol) and water (6. 30 ml, 350 mmol) was stirred at room temperature, p-toluenesulfonic acid monohydrate (3.31 g, 17.4 mmol) was added, and the mixture was stirred for 71 hours and 18 minutes. The reaction mixture was concentrated and extracted by adding ethyl acetate (80.0 mL) and water (80.0 mL). The aqueous layer was extracted twice with ethyl acetate (80.0 ml), the organic layers were combined, washed with 4% aqueous sodium hydrogen carbonate solution (80.0 ml), and the organic layer was concentrated. The concentrated residue was purified by silica gel column chromatography (ethyl acetate-hexane) three times to obtain the title compound (1.29 g, yield 23%).

Methyl 2-bromo-5- (1,1-dimethyl-3-oxobutylamino) benzoate (17) (1.00 g, 3.05 mmol), low moisture solvent methanol (10.0 ml) and pyridine (0.25 ml) 3.11 mmol) was stirred at room temperature, p-toluenesulfonic acid monohydrate (0.57 g, 3.00 mmol) was added, and the mixture was stirred at an external temperature of 50 ° C. for 17 hours and 15 minutes. The reaction mixture was allowed to cool to room temperature, concentrated, and extracted with ethyl acetate (15.0 mL) and water (10.0 mL). The organic layer was extracted with 4% aqueous sodium hydrogen carbonate solution (10.0 ml), and then the organic layer was concentrated. The concentrated residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (0.0095 g, yield 1.00%).

A mixture of aniline (6a) (0.980 mL, 10.7 mmol), 2,2-dimethoxypropane (66 ml, 537 mmol), pyridine (0.860 ml, 10.7 mmol) and water (3.90 ml, 216 mmol) was brought to room temperature. Then, p-toluenesulfonic acid monohydrate (2.04 g, 10.7 mmol) was added, and the mixture was stirred at an external temperature of 50 ° C. for 22 hours. The reaction mixture was concentrated, and the concentrated residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (1.18 g, yield 63.2%).

According to the present invention, a synthetic intermediate of a 1,2-dihydroquinoline derivative having glucocorticoid receptor binding activity can be produced industrially and is useful.
In addition, these are diseases involving glucocorticoid receptors, that is, metabolic disorders such as diabetes and obesity, inflammatory diseases such as enteritis and chronic obstructive pulmonary disease, rheumatoid arthritis, autoimmune diseases such as collagen disease, asthma, Allergic diseases such as atopic dermatitis and allergic rhinitis, central nervous system diseases such as psychosis, Alzheimer, drug use disorders, cardiovascular diseases such as hypertension, hypercalcemia, hyperinsulinemia, hyperlipidemia It is useful for the prevention or treatment of homeostasis-related diseases and glaucoma that cause abnormal balance of nerve, immunity and endocrine.

Claims

Formula (1)

Or a salt thereof,
(A) an acid selected from the group consisting of p-toluenesulfonic acid, pyridinium p-toluenesulfonate, hydrobromic acid and pyridine hydrobromide and / or (B) from pyridine and N, N-dimethylaniline A base selected from the group consisting of: (C) in the presence of water;
Reacting with 2,2-dialkoxypropane or isopropenyl alkyl ether,
Formula (2)

Or a salt thereof.
According to the method of claim 1,
A compound represented by formula (2) or a salt thereof is obtained, and then the compound represented by formula (2) or a salt thereof is represented by the formula in the presence of at least one selected from the group consisting of an acid and a base. (A) R 0 X
[Wherein R 0 represents a p-methoxybenzyl group or a benzyloxymethyl group, and X represents a leaving group. ]
Characterized by reacting with a compound represented by the formula:
Formula (3)

[In the formula (3), R 0 represents a p-methoxybenzyl group or a benzyloxymethyl group. ]
Or a salt thereof.
A compound represented by the formula (4) produced in the course of the reaction for producing a compound represented by the formula (2) or a salt thereof from the compound represented by the formula (1) or a salt thereof according to claim 1 Or the manufacturing method of Claim 1 or 2 performed via the salt.
Formula (4)
The compound represented by the formula (1) or a salt thereof is
Formula (5)

The production method according to any one of claims 1 to 3, wherein the compound represented by the formula or a salt thereof is produced by reacting with a p-toluenesulfonic acid, hydrochloric acid or bromic acid.
The production according to any one of claims 1 to 4, wherein the salt of the compound represented by the formula (1) is p-toluenesulfonate, hydrochloride or bromate of the compound represented by the formula (1). Method.
Formula (6)

[Wherein R 1 represents a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylcarbonyl group, a carboxyl group, an amino group, a nitro group, or a cyano group; p represents an integer of 0 to 4 . ]
Or a salt thereof,
(A) an acid selected from the group consisting of p-toluenesulfonic acid, pyridinium p-toluenesulfonate, hydrobromic acid and pyridine hydrobromide and / or (B) from pyridine and N, N-dimethylaniline A base selected from the group consisting of: (C) in the presence of water;
Reacting with 2,2-dialkoxypropane or isopropenyl alkyl ether,
Formula (7)

[Wherein R 1 represents a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylcarbonyl group, a carboxyl group, an amino group, a nitro group, or a cyano group; p represents an integer of 0 to 4 . ]
A method for producing a compound represented by the formula:
The production method according to any one of claims 1 to 6, wherein the 2,2-dialkoxypropane is 2,2-dimethoxypropane.
The method according to any one of claims 1 to 6, wherein the isopropenyl alkyl ether is isopropenyl methyl ether.
-P-toluenesulfonate of 8-amino-3-hydroxybenzo [c] chromen-6-one,
8- (1,1-dimethyl-3-oxobutylamino) -3-hydroxybenzo [c] chromen-6-one,
8-amino-3- (4-methoxybenzyloxy) benzo [c] chromen-6-one,
8-amino-3-benzyloxymethoxybenzo [c] chromen-6-one,
8- (1,1-dimethyl-3-oxobutylamino) -3- (4-methoxybenzyloxy) benzo [c] chromen-6-one,
8- (1,1-dimethyl-3-oxobutylamino) -3-benzyloxymethoxybenzo [c] chromen-6-one,
-Methyl 2- (2,4-dimethoxyphenyl) -5-aminobenzoate,
6- (2,4-methoxy) -2,2,4-trimethyl-1,2-dihydroquinoline-5-carboxylate methyl,
6-bromo-2,2,4-trimethyl-1,2-dihydroquinoline-5-carboxylic acid,
-Methyl 6-bromo-2,2,4-trimethyl-1,2-dihydroquinoline-5-carboxylate,
A compound selected from methyl 2-bromo-5- (1,1-dimethyl-3-oxobutylamino) benzoate or a salt thereof.