TW201431860A - Method for production of 1,2-dihydroquinoline synthetic intermediate - Google Patents

Abstract

Provided is a method for production of a compound represented by formula (2), or a salt thereof, which is characterized in enabling a compound represented by formula (1) or a salt thereof to react with 2, 2-dialkoxy propane or isopropenyl alkyl ether in the presence of (A) acid selected from the group consisting of p-toluene sulfonic acid, p- toluene sulfonic acid pyridinium, hydrobromic acid and pyridine hydrobromide and/or (B) base selected from the group consisting of pyridine and N, N-dimethylaniline, and (C) water. The method of this invention is suitable for the industrial production of a synthetic intermediate for dihydroquinoline derivative having glucocorticoid receptor binding activity.

Description

Method for producing 1,2-dihydroquinoline synthesis intermediate

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

The compound represented by the formula (2) or a salt thereof is known as a synthetic intermediate which can be used as, for example, a 1,2-dihydroquinoline derivative having a glucocorticoid receptor-binding activity (Patent Document 1). A method of synthesizing the compound represented by the above formula (2) or a salt thereof, and Patent Document 1 describes a synthesis method using the following reaction: 8-amino-3-hydroxybenzo[c]benzopyran (chromene) The 6-ketone is used as a raw material, and iodine and acetone are used to form a 1,2-dihydroquinoline skeleton. In the post-treatment of the method, it is necessary to carry out the purification step of the column chromatography (hereinafter also referred to as column purification), so that there are still problems in industrial production. Therefore, after the above reaction, the phenolic hydroxyl group of the compound represented by the formula (2) or a salt thereof is subjected to p-methoxybenzylation or benzyloxymethylation without performing column purification. The compound represented by the formula (3) or a salt thereof is produced. However, since iodine remains in the reaction system, a side reaction occurs, so that it is difficult to efficiently produce the compound represented by the formula (3) or a salt thereof.

[In the formula (3), R ⁰ represents p-methoxybenzyl or benzyloxymethyl. ]

[Previous Technical Literature]

[Patent Literature]

[Patent Document 1] International Publication No. 2008/059865

SUMMARY OF THE INVENTION An object of the present invention is to find a novel production method suitable for industrially producing a synthetic intermediate of a 1,2-dihydroquinoline derivative having a glucocorticoid receptor-binding activity.

In view of such facts, the inventors have intensively studied and found that by using an 8-amino-benzo[c]benzopyran-6-one derivative having a hydroxyl group in a specific acid and/or base, In the presence of water, it is reacted with 2,2-dialkoxypropane or isopropenyl alkyl ether, and the synthetic intermediate of the 1,2-dihydroquinoline derivative can be obtained without using iodine (2). A compound or a salt thereof. Further, after the reaction, the phenolic hydroxyl group of the compound represented by the formula (2) or a salt thereof can be subjected to p-methoxybenzylation or benzyloxymethylation without the need for column purification. The column is purified to efficiently obtain a compound represented by the formula (3) or a salt thereof.

Meanwhile, it has also been found that the compound represented by the formula (2) or a salt thereof can be obtained from the compound represented by the formula (4) or a salt thereof.

Further, it has been found that by treating the compound represented by the formula (5) or a salt thereof with p-toluenesulfonic acid, hydrochloric acid or bromic acid, p-toluenesulfonate and a salt of the compound represented by the formula (1) excellent in filterability can be obtained. The present invention has been accomplished by acid or bromate.

That is, the present invention is as described below.

[1] A method for producing a compound represented by the formula (2) or a salt thereof, Characterized by the compound represented by the formula (1) or a salt thereof (A) an acid selected from the group consisting of p-toluenesulfonic acid, pyridinium p-toluenesulfonate, hydrogen bromide and pyridine hydrobromide and/or (B) selected from the group consisting of pyridine and N, The base in the group formed by N-dimethylaniline and (C) water are reacted with 2,2-dialkoxypropane or isopropenyl alkyl ether.

[2] A method for producing a compound represented by the formula (3) or a salt thereof, [wherein, R ⁰ represents p-methoxybenzyl or benzyloxymethyl. The compound represented by the formula (2) or a salt thereof is obtained by the method of the above [1], and then the compound represented by the formula (2) or a salt thereof is selected from the group consisting of an acid and a base. In the presence of at least one of them, it is reacted with a compound represented by the formula (a) R ⁰ X or a salt thereof. Wherein R ⁰ represents p-methoxybenzyl or benzyloxymethyl, and X represents a leaving group. ]

[3] The method for producing the compound represented by the formula (2) or a salt thereof, the compound represented by the formula (1) of the above formula (1) or a salt thereof, is a reaction method according to the above [1] or [2] The compound represented by the formula (4) or a salt thereof formed in the middle of the reaction is carried out.

[4] The production method of the above [1] to [3], wherein the compound represented by the formula (1) or a salt thereof is a compound represented by the formula (5) or a salt thereof and p-toluenesulfonic acid, hydrochloric acid or bromine Manufactured by acid reaction.

[5] The production method of the compound of the above formula (1), wherein the salt of the compound represented by the formula (1) is a p-toluenesulfonate, a hydrochloride or a bromate of the compound represented by the formula (1). .

[6] A method for producing a compound represented by the formula (7) or a salt thereof, [wherein, R ¹ represents a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a lower alkylcarbonyl group, a carboxyl group, an amine group, a nitro group or a cyano group; and p represents an integer of 0 to 4. ], which is a compound represented by the formula (6) or a salt thereof [wherein, R ¹ represents a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a lower alkylcarbonyl group, a carboxyl group, an amine group, a nitro group or a cyano group; and p represents an integer of 0 to 4. (A) an acid selected from the group consisting of p-toluenesulfonic acid, pyridinium p-toluenesulfonate, hydrogen bromide and pyridine hydrobromide and/or (B) selected from the group consisting of pyridine and N The reaction with a 2,2-dialkoxypropane or an isopropenylalkyl ether in the presence of a base in the group formed by N-dimethylaniline and (C) water.

[7] The production method according to the above [1] to [6] wherein the 2,2-dialkoxypropane is 2,2-dimethoxypropane.

[8] The production method according to the above [1] to [6] wherein the isopropenylalkyl ether is isopropenylmethyl ether.

[9] A compound and a salt thereof, which are selected from p-toluenesulfonate of ‧8-amino-3-hydroxybenzo[c]benzopyran-6-one, ‧8-(1,1 - dimethyl-3-oxobutylbutylamino)-3-hydroxybenzo[c]benzopyran-6-one, ‧8-amino-3-(4-methoxybenzyl Oxy)benzo[c]benzopyran-6-one, ‧8-Amino-3-benzyloxymethoxybenzo[c]benzopyran-6-one, ‧8-(1,1-dimethyl-3-oxobutylbutylamine 3-(4-methoxybenzyloxy)benzo[c]benzopyran-6-one, ‧8-(1,1-dimethyl-3-oxobutyl Amino)-3-benzyloxymethoxybenzo[c]benzopyran-6-one, ‧2-(2,4-dimethoxyphenyl)-5-aminobenzoic acid Methyl ester, methyl ‧6-(2,4-methoxy)-2,2,4-trimethyl-1,2-dihydroquinolin-5-carboxylate, ‧6-bromo-2,2 ,4-trimethyl-1,2-dihydroquinolin-5-carboxylic acid, ‧6-bromo-2,2,4-trimethyl-1,2-dihydroquinolin-5-carboxylic acid Ester, methyl ‧ 2-bromo-5-(1,1-dimethyl-3-oxobutylbutylamino)benzoate.

According to the present invention, by reacting an 8-amino-benzo[c]benzopyran-6-one derivative having a hydroxyl group with 2,2-dioxane in the presence of an acid and/or a base, and water The compound represented by the formula (2) or a salt thereof can be obtained by reacting oxypropane or isopropenyl alkyl ether without using iodine to obtain a synthetic intermediate of the 1,2-dihydroquinoline derivative. At the same time, after the reaction, the phenolic hydroxyl group of the compound represented by the formula (2) or the salt thereof is subjected to p-methoxybenzylation or benzyloxymethylation without the column purification. The compound represented by the formula (3) or a salt thereof can be efficiently obtained by purifying the column. Meanwhile, the compound represented by the formula (2) or a salt thereof can be obtained from the compound represented by the formula (4) or a salt thereof. Further, by treating the compound represented by the formula (5) or a salt thereof with p-toluenesulfonic acid, hydrochloric acid or bromic acid, p-toluenesulfonate and hydrochloric acid of the compound represented by the formula (1) excellent in filterability can be obtained. Salt or bromate.

The definitions of atoms, radicals, rings, and the like used in the present specification are described in detail below. At the same time, when the definition of the following words is used in the definition of another word, it can also be used in the preferred range and the particularly good range of each definition.

The "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The "lower alkyl group" means a linear or branched alkyl group having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, and particularly preferably 1 to 4 carbon atoms. Specific examples thereof 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, second butyl group, and third group. Butyl, isopentyl and the like.

The "lower alkoxy group" means a group in which a hydrogen atom of a hydroxyl group is substituted with a lower alkyl group. Specific examples thereof include a methoxy group, an ethoxy group, a n-propoxy group, a n-butoxy group, a n-pentyloxy group, a n-hexyloxy group, a n-heptyloxy group, a n-octyloxy group, an isopropoxy group, and an isobutyl group. An oxy group, a second butoxy group, a third butoxy group or an isopentyloxy group.

The "lower alkylcarbonyl group" means a group in which a hydrogen atom of a formazan group is substituted with a lower alkyl group. Specific examples thereof include a methylcarbonyl group, an ethylcarbonyl group, a n-propylcarbonyl group, a n-butylcarbonyl group, a n-pentylcarbonyl group, a n-hexylcarbonyl group, an isopropylcarbonyl group, an isobutylcarbonyl group, a second butylcarbonyl group, and a Tributylcarbonyl or isopentylcarbonyl and the like.

The "amino group" may, for example, be an -NH ₂ group or an amine group substituted with 1 or 2 lower alkyl groups.

"Dissociation group" means a substituent which can be detached by a reaction. Specific examples thereof include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a lower alkyl sulfonate such as a methanesulfonyloxy group, a chloromethylphosphoniumoxy group or a trifluoromethanesulfonyloxy group. An arylsulfonyloxy group such as a mercaptooxy group, a phenylsulfonyloxy group or a p-toluenesulfonyloxy group; a cyano group, a nitro group, a trichloroacetonitrile imine ester or the like.

Raw materials, reagents, and other combinations described in the present specification used in the present invention It can also form acids or bases and "salts". Specific examples thereof include inorganic acids and salts such as hydrochloric acid, hydrogen bromide acid, bromic acid, hydrogen iodide acid, nitric acid, sulfuric acid, and phosphoric acid, carbonic acid, acetic acid, fumaric acid, maleic acid, and succinic acid. , citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, hydroxyethylsulfonate Acid, lactobionic acid, oleic acid, palmitic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, sulfuric acid Organic acids and salts such as dialkyl ester, methyl sulfate, naphthalenesulfonic acid and sulfosalicylic acid; quaternary ammonium salts such as methyl bromide and methyl iodide; halogen ions and salts such as bromide, chloride and iodide; Alkali metals and salts such as lithium, sodium and potassium, alkaline earth metals and salts such as calcium and magnesium, metal salts such as copper, iron and zinc, ammonium and salts, tri-ethylenediamine, 2-aminoethanol, 2,2 -iminobis(ethanol), 1-desoxy-1-(methylamino)-2-D-sorbitol, 2-amino-2-(hydroxymethyl)-1,3-propanediol, Procaine, N,N-dimethylaniline or N,N-bis(benzene An organic amine such as a methyl group)-1,2-ethanediamine and a salt, a pyridine and a salt.

The raw materials, reagents, and other compounds described in the present specification used in the present invention may be in the form of a hydrate or a solvate.

When a geometric isomer or an optical isomer is present in the starting materials, reagents, and other compounds described in the present specification, the isomers are also included in the scope of the present invention.

When a raw material, a reagent, and other compounds described in the present specification have proton tautomerism, the tautomer thereof is also included in the scope of the present invention.

The raw materials, reagents, other compounds described in the specification, and the hydrates or solvates thereof may also be crystals in the present invention, and crystals are present in the crystals. In the case of polymorphs and crystalline polymorphs (crystalline polymorphs), such crystalline polymorphs and crystalline polymorphs (crystalline polymorphs) are also included in the present invention. Here, the crystal polymorphism (crystal polymorph) refers to a condition and a state in which production, crystallization, storage, and the like can be performed by such crystallography (and, in this state, a state in which formulation is also included), and crystallization is performed. The shape of the crystal in each stage of the change and its overall process.

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 by the following steps 1 (synthesis route 1-1) and step 2 (synthesis route 1-2).

<Step 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. Further, the compound represented by the formula (5) or a salt thereof can be obtained according to the description in the International Publication No. 2012/108455.

With respect to the compound represented by the formula (5) or a salt thereof, p-toluenesulfonic acid, hydrochloric acid or bromic acid may be used in an amount of 0.1 or more, and preferably 1 to 6 is used, and 3 to 4 is used. good.

The solvent to be used in this step is not particularly limited as long as it does not inhibit the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene, and xylene; dichloromethane, chloroform, and the like. Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, cyclopentyl methyl ether, methyl-tert-butyl ether, two Ethers such as alkane, dimethoxyethane, diethylene glycol dimethyl ether; lower alkyl carboxylic acids such as ethyl acetate and isopropyl acetate; formamide, N,N-dimethylformamidine Amidoxime such as amine, N,N-dimethylacetamide, N-methyl-2-tetrahydropyrrolidone, hexamethylphosphoric acid triamide, etc.; anthraquinones such as dimethyl hydrazine and cyclobutyl hydrazine; a lower alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol or tert-butanol; water; or a mixed solvent of such solvents, and preferably a lower alcohol and water, Ethanol and water are better.

Although the reaction temperature may vary depending on the starting compound and the reaction reagent, it may be carried out at 0 ° C to 100 ° C, preferably 0 ° C to 50 ° C.

The reaction time may vary depending on the reaction temperature, the starting compound, the reaction reagent or the solvent to be used, but it is usually from 1 minute to 48 hours, and preferably from 15 hours to 24 hours.

After the reaction is completed, the reaction solution is allowed to cool, and a solvent such as water, ammonia water or methanol is added thereto while stirring under ice cooling, and the precipitated solid is filtered or subjected to an extraction operation, and toluene, ethyl acetate or the like is added to the residue obtained after concentration. After the solvent which can be recrystallized, the precipitated solid is filtered and dried to obtain the objective compound. Further, after the precipitated solid is filtered, it is preferably washed with toluene, ethyl acetate, water or the like.

When necessary, the obtained objective compound can be purified by a general method such as recrystallization, reprecipitation, or the like.

At the same time, the compound of interest can be obtained by forming p-toluenesulfonate, hydrochloride or bromate.

<Step 2>

Step 2 is a production step of producing a compound represented by the formula (2) and a salt thereof, wherein the compound represented by the formula (1) and a salt thereof are selected from (A) selected from the group consisting of p-toluenesulfonic acid and pyridinium p-toluenesulfonate. An acid in the group formed by hydrogen bromide and pyridine hydrobromide and/or (B) a base selected from the group consisting of pyridine and N,N-dimethylaniline, and (C) In the presence of water, it is reacted with 2,2-dialkoxypropane or isopropenyl alkyl ether. In the graph of <Step 2>, R ² represents a lower alkyl group, and a methyl group is preferred.

The acid (A) used in this step is preferably p-toluenesulfonic acid or pyridinium p-toluenesulfonate, and more preferably p-toluenesulfonic acid.

With respect to the compound represented by the formula (1) or a salt thereof, 0.10 equivalent or more of the acid (A) may be used in this step, preferably from 0.5 to 2.0 equivalents, more preferably from 0.90 to 1.10 equivalents.

The base (B) used in this step is preferably pyridine.

With respect to the compound represented by the formula (1) or a salt thereof, 0.10 equivalent or more of the base (B) may be used in this step, preferably from 0.5 to 2.0 equivalents, more preferably from 0.90 to 1.10 equivalents.

In this step, (A) and (B) can also be used. In this case, it is preferred to use a combination of p-toluenesulfonic acid as (A) and pyridine as (B).

At the same time, (A) or (B) can also be used. When using (A), use p-toluenesulfonic acid Pyridinium is preferred.

Meanwhile, with respect to the compound represented by the formula (1) or a salt thereof, 5 equivalents or more of water (C) may be used in this step, preferably 10 to 30 equivalents, and more preferably 15 to 25 equivalents.

Meanwhile, examples of the 2,2-dialkoxypropane used in this step include, for example, 2,2-dimethoxypropane, 2,2-diethoxypropane, and the like, with respect to the formula (1). The compound or a salt thereof may be used in an amount of 10 equivalents or more, preferably 30 to 100 equivalents, more preferably 50 to 60 equivalents.

In addition, the isopropenyl alkyl ether used in this step may, for example, be isopropenylmethyl ether or isopropenylethyl ether, and may be used in combination with the compound represented by the formula (1) or a salt thereof. It is more than the equivalent and is preferably from 30 to 100 equivalents, more preferably from 50 to 60 equivalents.

The solvent to be used in this step is not particularly limited as long as it does not inhibit the reaction, and is a solvent which dissolves the starting material to some extent, and examples thereof include aromatic hydrocarbons such as benzene, toluene, and xylene; dichloromethane and chloroform. , halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, cyclopentyl methyl ether, methyl-tert-butyl ether ,two Ethers such as alkane, dimethoxyethane, diethylene glycol dimethyl ether; lower alkyl carboxylic acids such as ethyl acetate and isopropyl acetate; formamide, N,N-dimethylformamidine Amidoxime such as amine, N,N-dimethylacetamide, N-methyl-2-tetrahydropyrrolidone, hexamethylphosphoric acid triamide, etc.; anthraquinones such as dimethyl hydrazine and cyclobutyl hydrazine; a lower alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol or tert-butanol; water; or a mixed solvent of such solvents, preferably lower alcohols and aromatic hydrocarbons; And methanol and toluene are better.

Although the reaction temperature may vary depending on the starting compound and the reaction reagent, It can be carried out at 0 ° C to 150 ° C, preferably at 25 ° C to 130 ° C, and more preferably at 40 ° C to 110 ° C.

Although the reaction time may vary depending on the reaction temperature, the starting compound, the reaction reagent or the type of solvent to be used, it is usually from 12 hours to 96 hours, and preferably from 24 hours to 84 hours.

After the reaction is completed, the reaction solution is allowed to cool, and while stirring under ice cooling, a solvent such as water, ammonia water or methanol is added, and the precipitated solid is filtered or concentrated, and extracted, and toluene and n-hexane are added to the residue obtained after concentration. After the recrystallizable solvent such as n-heptane, the precipitated solid is filtered and dried to obtain the desired compound. Further, after the precipitated solid is filtered, it is preferably washed with toluene, n-hexane, n-heptane, water or the like.

When necessary, the obtained objective compound can be purified by a general method such as recrystallization, reprecipitation, or the like.

Manufacturing method 2

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

In other words, the compound represented by the formula (1) or a salt thereof is reacted with 2,2-dialkoxypropane or isopropenyl alkyl ether according to the production method of the <Step 2> of the above Production Method 1. 2) A compound or a salt thereof. The compound represented by the formula (2) or a salt thereof can be obtained without column column purification. Further, the 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, and a compound represented by the formula (a) R ⁰ X or a salt thereof The reaction is carried out to produce a compound represented by the formula (3) or a salt thereof. The compound represented by the formula (3) or a salt thereof can be obtained without column column purification. In the formulae (a) and (3), R ⁰ represents a p-methoxybenzyl group or a benzyloxymethyl group.

In the formula (a), X is a leaving group, and any substituent which can be removed by the reaction may be, for example, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, or a methanesulfonyloxy group. An arylsulfonyl group such as a lower alkylsulfonyloxy group, a phenylsulfonyloxy group or a p-toluenesulfonyloxy group such as a chloromethylmethyleneoxy group or a trifluoromethanesulfonyloxy group; A oxy group, a cyano group, a nitro group, a trichloroethylene imidate, a carbonyl dioxyphenyl group, etc., preferably a halogen atom, and more preferably a chlorine atom.

With respect to the compound represented by the formula (2) or a salt thereof, the compound represented by the formula (a) or a salt thereof can be used in an amount of 1 equivalent or more, preferably 1 to 2 equivalents, more preferably 1.2 to 1.5 equivalents.

The acid used in this step may, for example, be an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrogen bromide or hydrofluoric acid; trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid or p-toluene; An organic acid such as a sulfonic acid or an aminosulfonic acid; a Lewis acid such as boron tribromide, boron trichloride, boron trifluoride or aluminum chloride; and the like.

With respect to the compound represented by the formula (2) or a salt thereof, one equivalent or more of an acid may be used in this step, preferably from 1 to 5 equivalents, more preferably from 2 to 3 equivalents.

The base to be used in this step may, for example, be an alkali metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate or lithium carbonate; or an alkali metal hydrogencarbonate such as sodium hydrogencarbonate, potassium hydrogencarbonate or lithium hydrogencarbonate; Alkali metal hydroxides such as sodium, potassium hydroxide, barium hydroxide, lithium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride; alkali metal fluorides such as sodium fluoride and potassium fluoride Inorganic bases; alkali metal alcohols such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium butoxide or lithium methoxide Salts; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrole Pyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethyl Aniline, N,N-diethylaniline, 1,5-diazacyclo[4.3.0]non-5-ene (DBN), 1,4-diazacyclo[2.2.2]octane (DABCO) , 1,8-diazaheterocycle [5.4.0]undec-7-ene (DBU), N,N,N',N',N",N"-trimethylammonium phosphate (HMPA) And other organic bases, and alkali metal carbonates are preferred, and potassium carbonate is more preferred.

With respect to the compound represented by the formula (2) or a salt thereof, 1 equivalent or more of a base may be used in this step, preferably 1 to 5 equivalents, and more preferably 2 to 3 equivalents.

The solvent to be used in this step is not particularly limited as long as it does not inhibit the reaction, and is a solvent which dissolves the starting material to some extent, and examples thereof include aromatic hydrocarbons such as benzene, toluene, and xylene; dichloromethane and chloroform. , halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, cyclopentyl methyl ether, methyl-tert-butyl ether ,two Ethers such as alkane, dimethoxyethane, diethylene glycol dimethyl ether; lower alkyl carboxylic acids such as ethyl acetate and isopropyl acetate; formamide, N,N-dimethylformamidine Amidoxime such as amine, N,N-dimethylacetamide, N-methyl-2-tetrahydropyrrolidone, hexamethylphosphoric acid triamide, etc.; anthraquinones such as dimethyl hydrazine and cyclobutyl hydrazine; a lower alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol or tert-butanol; water; or a mixed solvent of such solvents, preferably with amidoxime and water, N,N-dimethylformamide is preferred with water.

Although the reaction temperature may vary depending on the starting compound and the reaction reagent, it may be carried out at 0 ° C to 100 ° C, preferably 0 ° C to 50 ° C.

Although the reaction time may vary depending on the reaction temperature, the starting compound, the reaction reagent or the type of solvent to be used, it is usually from 1 hour to 48 hours, and is from 2 hours to 5 hours. Time is better.

After the reaction is completed, the reaction solution is allowed to cool, and while stirring under ice cooling, a solvent such as water, ammonia water or methanol is added, and the precipitated solid is filtered or subjected to an extraction operation, and toluene, ethyl acetate or the like is added to the residue obtained after concentration. The solvent which can be recrystallized, the precipitated solid is filtered, and after drying, the objective compound can be obtained. Further, after the precipitated solid is filtered, it is preferably washed with toluene, ethyl acetate, water or the like.

When necessary, the obtained objective compound can be purified by a general method such as recrystallization, reprecipitation, or the like.

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.

In other words, the compound represented by the formula (1) or a salt thereof is reacted with 2,2-dialkoxypropane or isopropenyl alkyl ether according to the production method of the <Step 2> of the above Production Method 1 to obtain a formula ( And a salt of the compound represented by the formula (4) or a salt thereof, and a 2,2-dialkoxypropane, which can be obtained by the production method according to the <Step 2> of the above Production Method 1 The compound represented by the formula (2) or a salt thereof is produced by reacting with isopropenylalkyl 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.

In other words, the compound represented by the formula (1) or a salt thereof is reacted with a 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. A compound represented by the formula (8) or a salt thereof. Next, the obtained compound represented by the formula (8) or a salt thereof can be reacted with 2,2-dialkoxypropane or isopropenyl alkyl ether using the production method according to <Step 2> of the above Production Method 1. A compound represented by the formula (3) or a salt thereof is produced. In addition, the reaction of the compound represented by the formula (8) or a salt thereof to produce the compound represented by the formula (3) or a salt thereof can be carried out by a compound represented by the formula (4b) produced in the middle of the reaction or a salt thereof. In the formulae (a), (8), (3), and (4b), R ⁰ represents a p-methoxybenzyl group or a benzyloxymethyl group.

Manufacturing method 5

The compound (2a) can also be produced according to the following synthesis route 5.

In other words, the boric acid (b) corresponding to the halide (9a) is reacted in a solvent such as DMF with a base such as sodium carbonate or a catalyst such as bis(triphenylphosphine)palladium(II) dichloride. The compound (10a) is available. The obtained compound (10a) is contact-reduced under a hydrogen atmosphere to obtain a compound (11a), followed by a production method according to <Step 2> of the above Production Method 1, to give a compound (11a) and 2,2-dialkoxy The compound (12a) is obtained by reacting a propane or an isopropenyl alkyl ether. Then, the obtained compound (12a) can be ring-closed to produce a compound (2a).

Manufacturing method 6

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

That is, the compound (13a) can be obtained by reacting the compound (13a) with 2,2-dialkoxypropane or isopropenyl alkyl ether according to the production method of <Step 2> of the above Production Method 1. The carboxyl group of the obtained compound (14a) is subjected to methyl esterification to obtain a compound (15a), the boric acid (b) corresponding to the obtained compound (15a) is used in a solvent such as DMF, and a base such as sodium carbonate and dichloro The compound (12a) can be obtained by reacting in the presence of a catalyst such as bis(triphenylphosphine)palladium (II). The obtained compound (12a) can be produced by ring closure Compound (2a). Meanwhile, the compound (15a) can also be obtained by reacting the compound (16a) with 2,2-dialkoxypropane or isopropenyl alkyl ether according to the production method of <Step 2> of the above Production Method 1.

Manufacturing method 7

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

In other words, the compound represented by the formula (6) or a salt thereof can be produced by reacting the compound represented by the formula (6) with 2,2-dialkoxypropane or isopropenyl alkyl ether according to the production method of the <Step 2> of the above Production Method 1.

In the formulae (6) and (7), R ¹ may, for example, be a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a lower alkylcarbonyl group, a carboxyl group, an amine group, a nitro group or a cyano group. good. p may be an integer of 0 to 4, preferably 1 to 2.

The production example of the present invention is shown below. Further, the examples are intended to provide a more complete understanding of the invention and are not intended to limit the scope of the invention.

[Manufacturing example]

<Production of <8-Amino-3-hydroxybenzo[c]benzopyran-6-one p-toluenesulfonate (1a)>

8-Acetylamine-3-hydroxy-6H-benzo[c]benzopyran-6-one (5a) (60.0 g, 223 mmol, International Publication 2012/108455 booklet) and ethanol (900 mL), The mixture of water (120 mL) was stirred at room temperature, 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 liquid was stirred at an internal temperature of 0 to 5 ° C for 1 hour, 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%).

Manufacture of <8-hydroxy-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-aza--5-one (2a) 1>

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 rt. Benzo[c]benzopyran-6-one p-toluenesulfonate (1a) (3.51 g, 8.79 mmol) was stirred at an external temperature of 105 ° C for 72 hours under pressure. After cooling and concentrating the reaction mixture, tetrahydrofuran (17.5 mL), ethyl acetate (24.5 mL) and water (21.0 mL) were added to the residue. And extract. The aqueous layer was extracted with ethyl acetate (24.5 mL), and the organic layer was combined, washed twice with water (21.0 mL), and washed with 4% aqueous sodium hydrogen carbonate (21.0 mL). The concentrated residue was purified by a silica gel column chromatography (ethyl acetate-hexane) to give the title compound (1.30 g, yield 48%).

<8-(4-Methoxybenzyloxy)-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azacyclo-5-one (3a) Manufacturing 1>

8-Amino-3-hydroxybenzo[c]benzopyran-6-one (1b) (5.00 g, 22.0 mmol), 2,2-dimethoxypropane (135.0 mL, 1102 mmol), pyridine (1.77 mL, 22.0 mmol) and a mixture of 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 mixture was stirred at an external temperature of 105 ° C under pressure. 66 hours and 10 minutes. The reaction mixture was cooled, cooled and concentrated, and ethyl acetate-tetrahydrofuran (3:2, 100.0 mL) and saturated aqueous sodium hydrogen carbonate (50.0 mL) were added to the residue to extract. The aqueous layer was extracted twice with ethyl acetate-tetrahydrofuran (3:2, 50.0 mL). The organic layer was collected and washed three times with saturated aqueous sodium hydrogen carbonate (50.0 mL). N,N-dimethylformamide (60.0 mL) was added to the concentrated residue, and the mixture was concentrated several times to remove pyridine. N,N-dimethylformamide was added to make 60.0 mL of a concentrated residue, and potassium carbonate (7.61 g, 55.1 mmol) and water (3.00 mL) were added, and stirred at room temperature. 4-Methoxybenzyl chloride (3.9 mL, 28.6 mmol) was added to the mixture, and the mixture was stirred at 40 ° C for 3 hours and 25 minutes. The reaction solution was stirred with ice cold, water (300.0 mL) was added, and the mixture was stirred for 1 hour and 15 minutes, filtered, and washed with water (100.0 mL). The mixture of the crude labeled compound and ethyl acetate (300.0 mL) was stirred at 85 ° C, filtered, and the filtrate was concentrated. Toluene (46.0 mL) and ethyl acetate (12.0 mL) were added to the residue, and the mixture was stirred at an external temperature of 85 ° C for 1 hour. The reaction mixture was stirred at 0 ° C for 18 hours and 50 minutes. After filtered, washed with toluene (15.0 mL), and dried under reduced pressure at 50 ° C to give the title compound (4.10 g, yield 44%).

<8-(4-Methoxybenzyloxy)-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azacyclo-5-one (3a) Manufacturing 2>

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-hydroxyl was added. Benzo[c]benzopyran-6-one p-toluenesulfonate (1a) (50.00 g, 125.2 mmol) was stirred at an internal temperature of 90.5 to 98.5 ° C for 72 hours under pressure. The reaction solution was cooled and cooled, and concentrated under reduced pressure. ethyl acetate (313 g), THF ( 222 g), and water (300 g) were added to the residue. The organic layer was washed twice with water (300 g) and 4% aqueous sodium hydrogencarbonate (300 g), and then evaporated to THF (2,2 g) and washed with 4% aqueous sodium hydrogencarbonate (302 g). N,N-dimethylformamide (327.30 g) was added to the organic layer, and concentrated under reduced pressure. After concentration, N,N-dimethylformamide was added to make the concentrated residue 327.05 g, and potassium carbonate (42.51 g, 307.59 mmol) and water (14.70 g) were added and 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 to 41 ° C for 4 hours. The reaction liquid was cooled to room temperature, and ethyl acetate (232 g), tetrahydrofuran (686 g), and 28% aqueous ammonia (705 g) were added and stirred, and the layers were separated. Ethyl acetate (310 g) was added to the aqueous layer to separate the layers. The whole organic layer was collected, washed once with 5% aqueous sodium chloride (786 g), washed twice with 5% brine (393 g), and washed once with water (400 g). Add toluene (213g) for The mixture was concentrated under reduced pressure three times. Toluene (221.34 g) and ethyl acetate (35.4 g) were added to the residue. The mixture was stirred at an internal temperature of 84 to 90 ° C for 31 minutes, and then stirred at an internal temperature of 1 to 10 ° C for 18 hours to precipitate. Solid filtration. 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 obtain a labeled compound (19.41 g, yield 36.3%).

<Production of <8-Amino-3-hydroxybenzo[c]benzopyran-6-one (1b)>

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

Production of <8-(1,1-dimethyl-3-oxobutylbutylamino)-3-hydroxybenzo[c]benzopyran-6-one (4a) >

8-Amino-3-hydroxybenzo[c]benzopyran-6-one (1b) (5.00 g, 22.0 mmol), 2,2-dimethoxypropane (135 mL, 1100 mmol), pyridine ( A mixture of 1.76 mL, 21.9 mmol) and water (7.90 mL, 440 mmol) was stirred at room temperature, p-toluenesulfonic acid monohydrate (4.15 g, 21.8 mmol) was added, and 1-methyl- 2-Tetrahydropyrrolidone (125 mL) was stirred and dissolved, and stirred for 66 hours and 40 minutes. The reaction solution was concentrated, and ethyl acetate (1000 mL) and saturated double water (500 mL) were added to extract. After extracting the aqueous layer twice with ethyl acetate (500 mL), the organic layer was collected and washed three times with water (500 mL). The organic layer was concentrated, chloroform was added to the residue, and the filtrate was concentrated. The residue was purified with EtOAc (EtOAc) elute

Manufacture of <8-hydroxy-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-aza--5-one (2a) 2>

8-(1,1-Dimethyl-3-oxobutylamino)-3-hydroxybenzo[c]benzopyran-6-one (4a) (0.76 g, 2.34 mmol), A mixture of 2,2-dimethoxypropane (16.0 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 was added. (0.45 g, 2.36 mmol), and stirred at an external temperature of 105 ° C for 61.5 hours under pressure. The reaction solution was cooled and cooled, and ethyl acetate (5.50 mL), tetrahydrofuran (4.00 mL), and water (4.50 mL) were added to extract. The organic layer was washed with water (4.50 mL), and then aqueous layer was evaporated, ethyl acetate (5. 5 mL), and the organic layer was collected and washed with 4% aqueous sodium hydrogencarbonate (4.50 mL). After drying, the organic layer was concentrated. The residue was purified by silica gel chromatography (ethyl acetate-hexane) to give the title compound (0.37 g, yield: 51.2%).

<Production of <8-Amino-3-(4-methoxybenzyloxy)benzo[c]benzopyran-6-one (8a)>

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

<Production of <8-Amino-3-benzyloxymethoxybenzo[c]benzopyran-6-one (8b)>

A mixture of 8-amino-3-hydroxybenzo[c]benzopyran-6-one (1b) (2.00 g, 8.80 mmol) and anhydrous dimethylformamide (40.0 mL) was cooled Stir in cold ice. When the internal temperature was 0.4 ° C, 60% sodium hydride (0.42 g, 10.5 mmol) was added, and further benzyl chloromethyl ether (1.45 ml, 10.5 mmol) was added, and the external temperature was returned to room temperature, and stirred for 2 hours. 8 minutes. The reaction solution was allowed to stand to cool, then stirred under ice-cooling, and water (80.0 mL) was stirred for 1 hour, and then the precipitated solid was filtered. The filtrate was washed with water (30.0 mL) and dried at 50 °C. A mixed liquid of the obtained product (3.24 g) and methanol (64.0 mL) was heated under reflux and stirred for 1 hour. The mixture was allowed to cool, and then stirred under ice cooling for 1 hour and 5 minutes, and then filtered. The filtrate was washed with methanol (5.00 mL), and then dried at 50 &lt;0&gt;C to give the title compound (2.59 g, yield: 85%).

<8-(4-Methoxybenzyloxy)-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azacyclo-5-one (3a) Manufacturing 3>

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

<8-(1,1-Dimethyl-3-oxobutylbutylamino)-3-(4-methoxybenzyloxy)benzo[c]benzopyran-6-one (4b-1) Manufacturing>

8-Amino-3-(4-methoxybenzyloxy)benzo[c]benzopyran-6-one (8a) (2.51 g, 7.23 mmol), 2,2-dimethyl A mixture of oxypropane (49.0 mL, 400 mmol), pyridine (0.58 mL, 7.22 mmol) and water (7.90 mL, 144 mmol) was stirred at room temperature and p-toluenesulfonic acid monohydrate (1.37 g, 7.20 mmol) was added. The mixture was dissolved in 1-methyl-2-tetrahydropyrrolidone (35 mL) and stirred for 71 hours and 4 minutes. The reaction solution was concentrated, and ethyl acetate (50.0 mL) and water (100 mL) After extracting the aqueous layer with ethyl acetate (50.0 mL), the organic layer was combined, and ethyl acetate (100 mL) and water (100 mL) were added to the mixture, and ethyl acetate (100 mL) and tetrahydrofuran (20 mL) were added to the organic layer. Water (100 mL) was extracted, and ethyl acetate (100 mL) and water (100 mL) were added to the organic layer to extract. 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 concentrated residue, and the solid was filtered, and the filtrate was concentrated. Adding chloroform to the filtered solid, dissolving and concentrating, and crystallizing the precipitate After filtration, the filtrate was concentrated. Chloroform was added to the concentrated residue, dissolved and concentrated, and the precipitated crystals were filtered, and the filtrate was concentrated. Each of the concentrated residue was purified by a silica gel column chromatography (ethyl acetate-hexane), and the fractions were combined to obtain a labeled compound (1.17 g, yield 37%).

<8-(4-Methoxybenzyloxy)-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azacyclo-5-one (3a) Manufacturing 4>

8-(1,1-Dimethyl-3-oxobutylbutylamino)-3-(4-methoxybenzyloxy)benzo[c]benzopyran-6-one (4b-1) (1.12g, 2.51mmol), a mixture of 1-methyl-2-tetrahydropyrrolidone (10.0mL) and pyridine (0.20mL, 2.49mmol), stirred at room temperature, added p-toluene The acid monohydrate (0.47 g, 2.47 mmol) was stirred at an external temperature of 50 ° C for 20 hours and 20 minutes. The reaction solution was cooled and cooled, and ethyl acetate (55.0 mL) and water (55.0 mL) were added for extraction. After extracting the aqueous layer with ethyl acetate (10.0 mL), the organic layer was combined, then added to tetrahydrofuran (30.0 mL), and washed twice with water (55.0 mL) to 4% sodium bicarbonate water The solution (55.0 mL) was washed twice and the organic layer was concentrated. Chloroform (22.0 mL) was added to the residue, and the solid was filtered, washed with chloroform (10.0 mL), and the filtrate was concentrated. The concentrated residue was purified by a cerium chloride gel column chromatography (chloroform), and then purified by a silica gel column chromatography (ethyl acetate-hexane) to give a crude compound (0.018 g). ). Toluene-n-heptane (0.36 mL) was added to the residue, and the solid was filtered and washed with toluene-n-heptane (0.54mL) to give the title compound (0.010 g, yield: 0.95%).

Manufacture of <8-benzyloxymethoxy-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azacyclo-5-one (3b) 1>

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

<8-(1,1-Dimethyl-3-oxobutylbutylamino)-3-benzyloxymethoxybenzo[c]benzopyran-6-one (4c) Manufacturing >

8-Amino-3-benzyloxymethoxybenzo[c]benzopyran-6-one (8b) (1.50 g, 4.32 mmol), 2,2-dimethoxypropane ( 36.0 mL, 294 mmol), a mixture of pyridine (0.43 mL, 5.35 mmol) and water (1.94 mL, 108 mmol) was stirred at room temperature, and p-toluenesulfonic acid monohydrate (1.03 g, 5.41 mmol) was added and suspended. The solution was dissolved in 1-methyl-2-tetrahydropyrrolidone (10.0 mL) and stirred for 67 hours and 12 minutes. Concentrate the reaction solution The mixture was extracted with ethyl acetate (30.0 mL) and water (60.0 mL). After extracting the aqueous layer with ethyl acetate (30.0 mL), the organic layer was combined, and ethyl acetate (30.0 mL) and water (60.0 mL) were added to extract, and the organic layer was washed three times with water (60.0 mL). The organic layer was concentrated, and the residue was purified to silica gel chromatography eluting

Manufacture of <8-benzyloxymethoxy-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azacyclo-5-one (3b) 2>

8-(1,1-Dimethyl-3-oxobutylbutylamino)-3-benzyloxymethoxybenzo[c]benzopyran-6-one (4c) ( 0.79 g, 1.77 mmol), a mixture of 1-methyl-2-tetrahydropyrrolidone (16.0 mL) and pyridine (0.15 mL, 1.87 mmol) was stirred at room temperature, and p-toluenesulfonic acid monohydrate (0.36) was added. g, 1.89 mmol), stirred at an external temperature of 50 ° C for 23 hours and 53 minutes. The reaction solution was cooled and cooled, and ethyl acetate (40.0 mL) and water (40.0 mL) were added to extract. After extracting the aqueous layer with ethyl acetate (8.0 mL), the organic layer was combined, washed twice with water (40.0 mL), and washed twice with 4% aqueous sodium bicarbonate (40.0 mL). The organic layer was concentrated. Chloroform (16.0 mL) was added to the residue, and 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 give the title compound (0.0092 g, yield: 1.15%).

Production of <2-(2,4-dimethoxyphenyl)-5-aminobenzoic acid methyl ester (11a) >

Methyl 2-(2,4-dimethoxyphenyl)-5-nitrobenzoate (4.00 g, 12.6 mmol, International Publication No. 2008/059865), N,N-dimethylformamidine A mixture of an amine (46.0 mL), methanol (12.0 mL) and 10% palladium carbon (52.1%) (0.19 g) was stirred at room temperature, and stirred under a condition of 3.0 kgf/cm ² of hydrogen for 4 hours and 25 minutes. The reaction solution was filtered over Celite, and washed with methanol and water (100.0 mL). Ethyl acetate (200.0 mL) and water (100.0 mL) were added to the filtrate for extraction. The aqueous layer was extracted twice with ethyl acetate (100.0 mL), and the organic layer was combined and washed twice with 5% aqueous sodium chloride (200.0 mL). The concentrated residue was purified twice with a silica gel column chromatography (chloroform-methanol) to give the title compound (2.60 g, yield 72%).

Manufacture of <6-(2,4-methoxy)-2,2,4-trimethyl-1,2-dihydroquinolin-5-carboxylic acid methyl ester (12a) >

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

<6-Bromo-2,2,4-trimethyl-1,2-dihydroquinolin-5-carboxylic acid (14a) and 6-bromo-2,2,4-trimethyl-1,2- Manufacture of isomer mixtures of dihydroquinoline-7-carboxylic acid >

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 of 466 mmol) was stirred at room temperature, and 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 residue was purified by EtOAc (EtOAc) eluting with EtOAc (EtOAc) , a mixture of labeled isomers (1.26 g, yield 18%) was obtained.

<Manufacture of <6-bromo-2,2,4-trimethyl-1,2-dihydroquinolin-5-carboxylic acid (14a)>

6-Bromo-2,2,4-trimethyl-1,2-dihydroquinolin-5-carboxylic acid (14a) and 6-bromo-2,2,4-trimethyl-1,2- A mixture of the isomer mixture of dihydroquinoline-7-carboxylic acid (1.00 g, 3.38 mmol) and a low water solvent methanol (80.0 mL) was stirred at an external temperature of 4 ° C, and sulphur chloride (2.30 mL, 31.7) was added. Methyl) was stirred for 73 hours and 10 minutes. The reaction solution was concentrated, and ethyl acetate (80.0 mL) and 4% aqueous sodium hydrogen carbonate (180.0 mL) was added to extract. After extracting the aqueous layer with ethyl acetate (50.0 mL), the organic layer was combined, washed twice with 4% aqueous sodium hydrogen carbonate (100.0 mL), and the organic layer was concentrated to give an isomer compound. The aqueous layer was combined, and concentrated hydrochloric acid (14.7 mL) was added, and ethyl acetate (400.0 mL) was evaporated. After repeating the above operation three times, a labeled compound (0.26 g, yield 25%) was obtained.

<Manufacture of <6-bromo-2,2,4-trimethyl-1,2-dihydroquinolin-5-carboxylic acid methyl ester (15a)>

Mixture of 6-bromo-2,2,4-trimethyl-1,2-dihydroquinolin-5-carboxylic acid (14a) (0.24 g, 0.81 mmol) with low water solvent methanol (20.0 mL) The solution was stirred with ice cold, sulphur chloride (18.6 mL, 257 mmol). The reaction mixture was cooled and cooled and concentrated. ethyl acetate (20.0 mL) and 4% aqueous sodium hydrogencarbonate (20.0 mL) was added to extract and the organic layer was concentrated. The residue was purified by silica gel chromatography (ethyl acetate-hexane) to give the title compound (0.021 g, yield 8.6%).

<6-Bromo-2,2,4-trimethyl-1,2-dihydroquinolin-5-carboxylic acid methyl ester (15a) and 6-bromo Manufacture of an isomer mixture of -2,2,4-trimethyl-1,2-dihydroquinoline-7-carboxylic acid methyl ester >

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 ( The mixture of 6.30 mL, 350 mmol) was stirred at room temperature, and 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. The reaction solution was cooled, cooled and concentrated, and ethyl acetate (80.0 mL) and water (80.0 mL) were added for extraction. The organic layer was washed with water (80.0 mL) and washed with 4% aqueous sodium hydrogen carbonate (80.0 mL). The concentrated residue was purified by a cerium oxide gel column chromatography (ethyl acetate-hexane) three times, and then purified twice with a cerium oxide gel column chromatography (chloroform) to obtain a labeled isomer. Bulk mixture (1.50 g, yield 28%).

<2-Bromo-5-(1,1-dimethyl-3-oxobutylbutylamino)benzoic acid methyl ester (17) Manufacturing >

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 ( The mixture of 6.30 mL, 350 mmol) was stirred at room temperature, and p-toluenesulfonic acid monohydrate (3.31 g, 17.4 mmol) was added and stirred for 71 hours and 18 minutes. The reaction solution was concentrated, and ethyl acetate (80.0 mL) and water (80.0 mL) were added to extract. After the aqueous layer was extracted twice with ethyl acetate, the organic layer was combined, washed with 4% aqueous sodium hydrogen carbonate (80.0 mL), and the organic layer was concentrated. The concentrated residue was purified 3 times with EtOAc (EtOAc-hexane) to afford titled compound ( 1.29 g, yield 23%).

<Manufacture of <6-bromo-2,2,4-trimethyl-1,2-dihydroquinolin-5-carboxylic acid methyl ester (15a)>

Methyl 2-bromo-5-(1,1-dimethyl-3-oxobutylbutyl)benzoate (17) (1.00 g, 3.05 mmol), methanol in low water (10.0 mL) , pyridine (0.25mL, 3.11 The mixture of 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 solution was allowed to cool at room temperature and concentrated, and then ethyl acetate (15.0 mL) and water (10.0 mL) were added to extract. The organic layer was extracted with a 4% aqueous sodium hydrogen sulfate solution (10.0 mL), and evaporated. The concentrated residue was purified by silica gel chromatography (ethyl acetate-hexane) to give the title compound (0.0095 g, yield 1.00%).

<Manufacture of <2,2,4-trimethyl-1,2-dihydroquinoline (7a)>

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) After stirring, 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 residue was evaporated to mjjjjjjjj

[Possibility of application in industry]

According to the present invention, it is possible to industrially produce a synthetic intermediate of a 1,2-dihydroquinoline derivative having a glucocorticoid receptor-binding activity. At the same time, these intermediates can be used for the prevention or treatment of diseases related to glucocorticoid receptors, and can be used for inflammatory diseases such as diabetes, obesity and other metabolic abnormal diseases, enteritis, chronic obstructive pulmonary diseases, and rheumatoid joints. Autoimmune diseases such as inflammation and collagen diseases, asthma, atopic dermatitis, allergic rhinitis and other allergic diseases, psychosis, Alzheimer's disease, drug use disorders and other central nervous system diseases, hypertension, hypercalcemia Prevention, treatment of cardiovascular diseases such as hyperinsulinemia, hyperinsulinemia, and hyperlipidemia, and dynamic balance-related diseases caused by abnormal balance of nerves, immunity, and endocrine, and glaucoma.

Claims (9)

A method for producing a compound represented by the formula (2) or a salt thereof, Characterized by the compound represented by the formula (1) or a salt thereof (A) an acid selected from the group consisting of p-toluenesulfonic acid, pyridinium p-toluenesulfonate, hydrogen bromide and pyridine hydrobromide and/or (B) selected from the group consisting of pyridine and N, The base in the group formed by N-dimethylaniline and (C) water are reacted with 2,2-dialkoxypropane or isopropenyl alkyl ether. A method for producing a compound represented by the formula (3) or a salt thereof, [In the formula (3), R ⁰ represents p-methoxybenzyl or benzyloxymethyl], which is characterized by the method of the first aspect of the patent application, wherein the formula (2) is obtained. a compound or a salt thereof, and then a 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, and a compound represented by the formula (a) R ⁰ X or Its salt reaction [wherein, R ⁰ represents p-methoxybenzyl or benzyloxymethyl, and X represents a cleavable group]. The production method according to the first or second aspect of the invention, wherein the compound represented by the formula (1) described in the first aspect of the patent application or the salt thereof is used for producing a compound represented by the formula (2) or a salt thereof. The compound represented by the formula (4) or a salt thereof formed in the middle of the reaction is carried out. The production method according to any one of the above aspects, wherein the compound represented by the formula (1) or a salt thereof is a compound represented by the formula (5) or a salt thereof and p-toluenesulfonic acid, Manufactured by the reaction of hydrochloric acid or bromic acid. The production method according to any one of claims 1 to 4, wherein the salt of the compound represented by the formula (1) is a p-toluenesulfonate or a hydrochloride of the compound represented by the formula (1) or Bromate. A method for producing a compound represented by the formula (7) or a salt thereof, Wherein R ¹ represents a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a lower alkylcarbonyl group, a carboxyl group, an amine group, a nitro group or a cyano group; p represents an integer of 0 to 4, wherein The compound represented by (6) or a salt thereof is [wherein, R ¹ represents a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a lower alkylcarbonyl group, a carboxyl group, an amine group, a nitro group or a cyano group; p represents an integer of 0 to 4] (A) is selected from the group consisting of The acid in the group formed by p-toluenesulfonic acid, pyridinium p-toluenesulfonate, hydrogen bromide and pyridine hydrobromide and/or (B) is selected from the group consisting of pyridine and N,N-dimethyl The reaction with a 2,2-dialkoxypropane or an isopropenylalkyl ether in the presence of a base in the group formed by aniline and (C) water. The production method according to any one of claims 1 to 6, wherein the 2,2-dialkoxypropane is 2,2-dimethoxypropane. The production method according to any one of claims 1 to 6, wherein the isopropenylalkyl ether is isopropenylmethyl ether. a compound and a salt thereof selected from p-toluenesulfonate of ‧8-amino-3-hydroxybenzo[c]benzopyran-6-one, ‧8-(1,1-dimethyl 3-yloxybutylamino)-3-hydroxybenzo[c]benzopyran-6-one, ‧8-Amino-3-(4-methoxybenzyloxy)benzo[c]benzopyran-6-one, ‧8-amino-3-benzyloxymethoxy Benzo[c]benzopyran-6-one, ‧8-(1,1-dimethyl-3-oxobutylbutylamino)-3-(4-methoxybenzyloxy) Benzo[c]benzopyran-6-one, ‧8-(1,1-dimethyl-3-oxobutylbutylamino)-3-benzyloxymethoxybenzo [c] benzopyran-6-one, methyl ‧2-(2,4-dimethoxyphenyl)-5-aminobenzoate, ‧6-(2,4-methoxy)- Methyl 2,2,4-trimethyl-1,2-dihydroquinolin-5-carboxylate, ‧6-bromo-2,2,4-trimethyl-1,2-dihydroquinoline 5-carboxylic acid, methyl ‧6-bromo-2,2,4-trimethyl-1,2-dihydroquinolin-5-carboxylate, ‧2-bromo-5-(1,1-dimethyl Methyl-3-oxobutylbutylamino)benzoate.