KR100504522B1 - Process for producing 1,4-benzodioxane derivatives - Google Patents

Abstract

The present invention provides a 1,4-, comprising reacting a diol compound (2) with a carbonizing agent to produce a carbonate compound (3), removing the protecting group, and then cyclizing it by heating or treating with a base or a fluoride salt. A method for producing a benzodioxane derivative (1).

Description

Method for producing 1,4-benzodioxane derivatives {PROCESS FOR PRODUCING 1,4-BENZODIOXANE DERIVATIVES}

The present invention relates to a process for the preparation of 1,4-benzodioxane derivatives useful as intermediates of circulatory drugs and psychoneurotic drugs which are α and β-adrenergic antagonists.

1,4-benzodioxane derivatives are used as intermediates for the preparation of psychiatric neuropathic drugs with circulatory drugs and α- and β-adrenergic antagonist activity, and the preparation of several kinds thereof is known. For example, a method of reacting a catechol derivative with glycidyl tosylate in the presence of sodium hydride (Japanese Patent Publication No. 6-9613 (1994)) or reacting a catechol derivative with epichlorohydrin in the presence of pyridine The method (J. Org. Chem. 46, 3846 (1981)) is known. In addition, the catechol derivative is reacted with glycerol 1-tosylate acetonide, the acetonide as a protecting group is removed, two tosyl groups are introduced thereon, 1,4-benzodi is separated and cyclized. Methods of preparing the oxane backbone are also known (J. Chem. Soc., Chem. Commun., 921 (1976)).

Among the above methods, the method involving the use of glycidyl tosylate is not only costly due to the cost of its compound, but also reduces the epoxy group and decreases the yield in deprotection by hydrolysis. In methods involving the use of epichlorohydrin, excess epichlorohydrin and dichloropropanediol as by-products should be removed by evaporation with xylene and the hydrochloric acid and acetic acid used are removed by evaporation with ethanol. That process is cumbersome because it must be. In addition, the reaction is carried out under reflux of piperidine or hydrochloric acid. Thus, compounds having substituents labile to acids or bases cannot be used. When using optically active epichlorohydrin, racemization occurs and an optically pure product cannot be obtained. In a method involving the reaction of glycerol 1-tosylate acetonide with a catechol derivative, the yield of the ditosylated product is not more than 55% since the obtained ditosylated product must be separated after tosylation. This method has many disadvantages in industrial scale applications. Improved methods have been required.

In view of the above, the present inventors have worked hard to find out an improved method for preparing 1,4-benzodioxane derivatives. As a result, after carbonizing the phenoxypropanediol compound, the obtained product is heated or treated with a base to cyclize, so that the desired 1,4-benzodioxane derivative can be preferably obtained on an industrial scale. Figured out.

The present invention relates to a method for producing a 1,4-benzodioxane derivative represented by the following general formula (1), wherein the diol compound represented by the following general formula (2) is reacted with a carbonating agent to the following general formula (3) It is characterized by preparing the carbonate compound shown, removing the protecting group of the carbonate compound to produce a phenol derivative represented by the following formula (4), and then cyclizing the phenol derivative by heat treatment or treatment with a base or a fluoride salt.

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

In the above formulas (1) to (4), R ¹ is a protecting group of hydroxy, R ² , R ³ , R ⁴ and R ⁵ are the same or different, hydrogen, halogen, hydroxy, nitro, cyano, fort Mill, hydroxycarbonyl, alkoxycarbonyloxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms Haloalkyl having, N, N-dialkylamino having alkyl having 1 to 4 carbon atoms, alkylcarbonyl having 1 to 4 carbon atoms in the alkyl moiety, alkoxycar having 1 to 4 carbon atoms in the alkyl moiety Carbonyl, or phenyl, which may be substituted with one or more alkyl having 1 to 4 carbon atoms, and two adjacent groups of R ² , R ³ , R ^4, and R ⁵ may constitute methylenedioxy, or the group is Benzene ring by the bonded carbon atom And R ² and OR ¹ may constitute methylenedioxy, isopropylidenedioxy, cyclohexylidenedioxy or diphenylmethylenedioxy.

Best way to carry out the invention

The present invention is described in detail according to the following scheme.

R ¹ , R ² , R ³ , R ⁴ and R ⁵ in the above formula are as defined above.

First, the carbonate compound (3) is obtained by reacting the diol compound (2) with a carbonizing agent.

Examples of carbonizing agents are: dimethyl carbonate, diethyl carbonate, dipropyl carbonate, diallyl carbonate, allyl methyl carbonate, diphenyl carbonate, bis (4-nitrophenyl) carbonate, ethylene carbonate and the like, methyl chloro Formate, ethyl chloroformate, 1-chloroethyl chloroformate, 2-chloroethyl chloroformate, 2-bromoethyl chloroformate, 2,2,2-trichloroethyl chloroformate, 1,2, 2,2-tetrachloroethyl chloroformate, propyl chloroformate, isopropyl chloroformate, butyl chloroformate, 4-chlorobutyl chloroformate, isobutyl chloroformate, hexyl chloroformate, octyl chloroformate Chlorocarboxylic acid esters, such as vinyl chloroformate, allyl chloroformate, N, N´- Carbonate esters having a heterocycle as a eliminator, phosgene, and oligomers thereof, such as trichloromethyl chloroformate, bis-trichloromethyl carbonate, and the like, such as vonyldiimidazole, N, N'-disuccinimidyl carbonate, and the like .

The reaction is carried out in or without solvent. Examples of solvents are as follows: bipolar aprotic solvents such as N, N-dimethylformamide, dimethyl sulfoxide, sulfolane, hexamethylphosphoramide, tetrahydrofuran, dioxane, t-butyl methyl ether, Ethers such as diethyl ether, chlorinated compounds such as methylene chloride, chloroform, dichloroethane and the like, aromatic hydrocarbons such as benzene, toluene and the like, nitrile and water such as acetonitrile, butyronitrile and the like.

The reaction is carried out smoothly by removing the obtained alcohol or absorbing it into molecular sieves or the like. During the reaction, if hydrochloric acid occurs on the kind of carbonizing agent used, the reaction is carried out in the presence of a base. By doing so, not only the reaction mixture is neutralized, but also the reaction is carried out smoothly.

Examples of bases are as follows: trialkylamines having 1 to 6 carbon atoms, such as trimethylamine, triethylamine, ethyldiisopropylamine, and the like, N, N-dimethylaniline, N, N-diethylaniline, and the like. Organic bases containing nitrogen atoms, such as tertiary amines, pyridine, picoline, lutidine, etc., substituted with a group selected from alkyl and phenyl having 1 to 4 carbon atoms, such as sodium methoxide, sodium ethoxide, and the like, Inorganic bases such as alkali metal or alkaline earth metal salts, alkali metal hydrides, alkali metal or alkaline earth metals, hydrogen carbonates or carbonates of lower alcohols having 1 to 4 carbon atoms. Examples of inorganic bases are as follows: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate and the like.

In the case of using a carbonizing agent which does not generate hydrochloric acid during the reaction, for example dimethyl carbonate or diethyl carbonate, the reaction is carried out smoothly in the presence of a catalytic amount of the following substances: trimethylamine, triethylamine, ethyldiisopropyl Tertiary substituted with a group selected from phenyl having 1 to 6 carbon atoms, such as amines, alkyl having 1 to 4 carbon atoms, and phenyl, such as N, N-dimethylaniline, N, N-diethylaniline, and the like Alkali metal or alkaline earth metal salts of lower alkanols having 1 to 4 carbon atoms, such as amines, pyridine, picoline, rutidine and the like, organic bases containing nitrogen atoms, sodium methoxide, sodium ethoxide and the like, hydrogenated alkali Inorganic bases such as metals, alkali metal hydroxides or alkaline earth metals, hydrogen carbonates, carbonates and the like.

Next, removal of the protecting group which is R <^1> of carbonate compound (3) is performed.

The protecting group R ¹ is not limited unless he affects the reaction.

When the protecting group is benzyl, allyl or benzyloxycarbonyl, the protected compound is hydrogen gas or in the presence of palladium-carbon or Raney nickel in an organic solvent such as methanol, ethanol, ethyl acetate or the like or mixtures thereof with water or Catalytic hydrogenation is carried out by using ammonium formate to remove the protecting groups.

If the protecting group is o-nitrobenzyl, the protected compound is removed by application to radiation in an organic solvent such as methanol or ethanol. When the protecting group is t-butyldimethylsilyl, it is deprotected using fluoride salts such as sodium fluoride, potassium fluoride, tetrabutylammonium fluoride and the like in an organic solvent such as dimethylformamide, tetrahydrofuran or a mixture thereof with water.

When the protecting group consisting of R ² and OR ¹ is methylenedioxy, isopropylidenedioxy, cyclohexylidenedioxy or diphenylmethylenedioxy, the protected compound is subjected to acidic conditions normally used when removing such protecting groups. Usually deprotected.

So-called clad by heating or treating in the presence of a Lewis acid where R ¹ is allyl and one or both of R ² and R ⁴ are hydrogen (one or both of the 3 and 5 positions on the benzene ring are hydrogen) now the case of applying the potential response (Claisen-rearrangement reaction), the removal of benzene and the potential of the R ¹ to 3 or 5 position on the ring of R ¹ occur simultaneously.

The heat treatment is carried out in or without solvent. Examples of solvents are as follows: aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, bipolar aprotic solvents such as N, N-dimethylformamide, dimethyl sulfoxide, sulfolane, hexamethylphosphoramide, and the like. Ketones such as diisobutyl ketone, dipropyl ketone, methyl pentyl ketone, butyl methyl ketone, acetone, ethyl methyl ketone, methyl propyl ketone, diethyl ketone, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, dibutyl Ethers such as ether, dioxane, tetrahydrofuran, t-butyl methyl ether, diethyl ether and the like, chlorinated compounds such as methylene chloride, chloroform, dichloroethane and the like, nitriles such as acetonitrile, butyronitrile and the like. This reaction is carried out at a pressure of 0 to 250 ° C., preferably 20 to 200 ° C., atmospheric pressure or lower. The translocation of R ¹ first occurs at position 3, and over time the amount of phenol derivative transposed at position 5 increases.

In the case of the Klaisen translocation reaction in the presence of Lewis acids, examples of Lewis acids are as follows: boron compounds such as boron trichloride, boron trifluoride, boron tribromide and the like, and acetic acid or ethers and mixtures thereof, triethylaluminum , Organoaluminum compounds such as chlorodiethylaluminum, chlorodiisobutylaluminum, dichloroethylaluminum, aluminum (III) chloride and the like, Grignard reagents such as phenylmagnesium bromide, antimony chloride (v), stannic chloride ( Tin compounds such as IV), zinc (II) compounds such as zinc (II) chloride, zinc bromide (II) and the like, titanium (IV) compounds such as titanium (IV) tetrachloride, silver (I) trifluoroborate, silver Mercury (II) compounds such as silver (I) salts such as trifluoroacetate, mercury (II) trifluoroacetate, etc. water. Of the Lewis acids, chlorodiethyl aluminum is particularly preferred. The amount of Lewis acid is 0.3 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to carbonate compound (3). Examples of solvents used in this reaction are as follows: chlorinated compounds such as methylene chloride, chloroform, carbon tetrachloride, chlorobenzene and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like, saturated hydrocarbons such as hexane, heptane, decahydronaphthalene and the like Ethers such as diethyl ether and the like. Methylene chloride is preferred. The reaction temperature is -78 to 120 ° C, preferably room temperature to 42 ° C.

The phenol derivative (4) prepared above is cyclized by heat treatment or treatment with a base or fluoride salt to produce a 1,4-benzodioxane derivative (1).

The ring closure reaction is carried out by heat treatment in the presence or absence of a solvent. Examples of solvents are as follows: dipolar aprotic solvents such as N, N-dimethylformamide, dimethyl sulfoxide, sulfolane, hexamethylphosphoramide, diisobutyl ketone, dipropyl ketone, methyl pentyl ketone, Ketones such as butyl methyl ketone, acetone, ethyl methyl ketone, methyl propyl ketone, diethyl ketone and the like, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, dibutyl ether, dioxane, tetrahydrofuran, t-butyl methyl ether Ethers such as diethyl ether, chlorinated compounds such as methylene chloride, chloroform, dichloroethane and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like, nitriles such as acetonitrile, butyronitrile and the like. This reaction is carried out at a pressure of 0 to 250 ° C, preferably 30 to 200 ° C, atmospheric pressure or lower.

The ring closure reaction is also carried out by treatment with a base in the presence or absence of a solvent. Examples of solvents are as follows: dipolar aprotic solvents such as N, N-dimethylformamide, dimethyl sulfoxide, sulfolane, hexamethylphosphoramide, diisobutyl ketone, dipropyl ketone, methyl pentyl ketone, Ketones such as butyl methyl ketone, acetone, ethyl methyl ketone, methyl propyl ketone, diethyl ketone, etc., diethylene glycol dimethyl ether, diethylene glycol diethyl ether (diglyme), dibutyl ether, dioxane, tetrahydrofuran, t Ethers such as butyl methyl ether, diethyl ether and the like, chlorinated compounds such as methylene chloride, chloroform, dichloroethane and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like, nitriles such as acetonitrile, butyronitrile and the like.

Examples of bases are as follows: trialkylamines such as trimethylamine, triethylamine, ethyldiisopropylamine, trioctylamine and the like, 1 to 4, such as N, N-dimethylaniline, N, N-diethylaniline, and the like. From 1 to 4 carbon atoms, such as organic bases containing nitrogen atoms, sodium methoxide, sodium ethoxide, etc., such as tertiary amines substituted with alkyl and phenyl having 3 carbon atoms, pyridine, picoline, lutidine, etc. Inorganic bases having lower alcohols such as alkali metal or alkaline earth metal salts, alkali metal hydrides, alkali metal hydroxides or alkaline earth metals, hydrogen carbonates, carbonates and the like. Examples of inorganic bases are sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate and the like. Among these, hydrogenated alkali metals and trialkylamines are preferable. The amount of base is 0.005 to 10 mol, preferably 0.01 to 5 mol, relative to compound (4). Reaction temperature is -50-250 degreeC, Preferably it is 0-150 degreeC.

The ring closure reaction of the phenol compound (4) can also be carried out by treatment with fluoride salts.

Fluoride salts are preferably alkali metal salts and alkaline metal salts, which are used alone or in mixtures. They are also used with support agents. Examples of fluoride salts are sodium fluoride, potassium fluoride, cesium fluoride, magnesium fluoride and calcium fluoride. Potassium fluoride, cesium fluoride and mixtures thereof are preferably used. Examples of support agents are celite, alumina, silica gel, molecular sieves and variations thereof. This reaction is carried out in the presence or absence of a solvent. Examples of solvents are as follows: bipolar aprotic solvents such as N, N-dimethylformamide, dimethyl sulfoxide, sulfolane, hexamethylphosphoramide, tetrahydrofuran, dioxane, t-butyl methyl ether, Ethers such as diethyl ether, chlorinated compounds such as methylene chloride, chloroform, dichloroethane and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like, nitriles such as acetonitrile, butyronitrile and the like, ethyl acetate, butyl acetate and the like. The amount of fluoride salt is 0.005 to 10 mol, preferably 0.01 to 5 mol, relative to compound (4). This reaction is carried out at 0 to 250 ° C, preferably 30 to 150 ° C.

As mentioned above, when the so-called Kreisen dislocation reaction is carried out by heating a carbonate compound (3) in which R ¹ is allyl and one or both of R ² and R ⁴ are hydrogen, or in the presence of a Lewis acid , R ¹ removal and dislocation occur simultaneously to form phenol derivative (4). In the case of heat treatment, by further heating the obtained phenol derivative, it is simultaneously cyclized to prepare a 1,4-benzodioxane derivative.

The reaction is carried out in the presence or absence of a solvent. Examples of solvents are as follows: dipolar aprotic solvents such as N, N-dimethylformamide, dimethyl sulfoxide, sulfolane, hexamethylphosphoramide, diisobutyl ketone, dipropyl ketone, methyl pentyl ketone, Ketones such as butyl methyl ketone, acetone, ethyl methyl ketone, methyl propyl ketone, diethyl ketone and the like, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, dibutyl ether, dioxane, tetrahydrofuran, t-butyl methyl ether Ethers such as diethyl ether, chlorinated compounds such as methylene chloride, chloroform, dichloroethane and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like, nitriles such as acetonitrile, butyronitrile and the like. The reaction proceeds by heating without a catalyst, but in the presence of a basic catalyst the reaction proceeds smoothly without side reactions.

As the base, trialkylamines such as trimethylamine, triethylamine, ethyldiisopropylamine, trioctylamine and the like, and 1 to 4 carbon atoms, such as N, N-dimethylaniline, N, N-diethylaniline, and the like One or more bases selected from tertiary amines substituted with groups selected from alkyl and phenyl having: Also alkali metal hydrides, alkali metal hydroxides or alkaline earth metals, or alkali metal or alkaline earth metal salts of lower alkanols having 1 to 4 carbon atoms (e.g. sodium hydride, sodium hydroxide, potassium hydroxide, sodium methoxide, or Sodium ethoxide) can be used. Among these, trialkylamine is particularly preferable. The amount of base is from 0.005 to 10 mol, preferably from 0.01 to 5 mol, relative to the carbonate compound (3). Reaction temperature is -50-250 degreeC, Preferably it is 0-200 degreeC.

Compound (3), wherein R ¹ is allyl, is subjected to a rearrangement reaction, and the displaced product is also subjected to a ring-closure reaction to prepare target compound (1), wherein R ² or R ⁴ is allyl. This reaction is shown schematically as follows.

Wherein R ¹¹ is allyl and R ²¹ , R ²² , R ⁴¹ , and R ⁴² are the same or different and hydrogen, halogen, hydroxyl, nitro, cyano, formyl, hydroxycarbonyl, alkyl moiety Alkoxycarbonyloxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, haloalkyl having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms N, N-dialkylamino having carbon atoms, alkylcarbonyl having 1 to 4 carbon atoms in the alkyl moiety, alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety, or 1 to 4 carbon atoms Phenyl which may be substituted with one or more alkyls, provided that one or both of R ²¹ and R ⁴¹ are hydrogen and one or both of R ²² and R ⁴² are allyl. And R ³ and R ⁵ are the same as defined above.

The diol compound (2) used as starting material in the present invention is prepared by the method shown in the following scheme.

Wherein R ¹ , R ² , R ³ , and R ⁵ are the same as defined above and X is hydrogen.

The diol compound (2) is used to prepare the catechol derivative (5) in the presence of a base in a solvent, 3-halogeno-1,2-propanediol, preferably 3-chloro-1,2-propanediol or 3-bromo- Prepared by reacting with 1,2-propanediol.

Examples of solvents are as follows: bipolar aprotic solvents such as N, N-dimethylformamide, dimethyl sulfoxide, sulfolane, hexamethylphosphoramide, tetrahydrofuran, dioxane, t-butyl methyl ether, Ethers such as diethyl ether, chlorinated compounds such as methylene chloride, chloroform, dichloroethane and the like, aromatic hydrocarbons such as benzene, toluene, xylene, nitrile such as acetonitrile, butyronitrile, acetone, ethyl methyl ketone, diisopropyl Ketones such as ketones and the like, methanol, ethanol, isopropanol, t-butanol and the like, and water.

Examples of bases are as follows: trialkylamines such as trimethylamine, triethylamine, ethyldiisopropylamine, trioctylamine, and the like, and alkali or alkaline earth metal salts of alkanols having 1 to 4 carbon atoms. Inorganic bases (eg, sodium methoxide, sodium ethoxide, magnesium ethoxide, magnesium ethoxide), alkali metal hydrides, alkali metal hydroxides or alkaline earth metals, alkali metal carbonates or alkali metals or carbonates and the like. Examples of inorganic bases are as follows: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate and the like. Preferred examples are alkali metal hydroxides such as: sodium hydride, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate and the like. The amount of base is 1 to 5 mol, preferably 1.1 to 3 mol, relative to the catechol derivative (5). The amount of 3-halogeno-1,2-propanediol is 1 to 5 mol, preferably 1.1 to 3 mol relative to the catechol derivative. Reaction temperature is -50-250 degreeC, Preferably it is 0-150 degreeC.

The diol compound (2), which is the starting material of the present invention, can also be prepared by known methods, that is, by reacting a catechol derivative (5) with glycidol. However, glycidol is unstable and easily polymerized. In contrast, 3-halogeno-1,2-propanediol is stable and inexpensive. Therefore, as defined above, methods involving the use of these compounds are industrially advantageous.

According to the invention, the 1,4-dibenzodioxane derivative (1) having optical activity can be obtained by using the diol compound (2) having optical activity. Such optically active diol compounds are prepared, for example, by reacting a catechol derivative (5) with optically active 3-halogeno-1,2-propanediol (6) under the conditions mentioned above. . When 3-halogeno-1,2-propanediol having high optical purity is used as a starting material, racemization does not occur remarkably during the reaction, and thus 1,4-benzodioxane derivative having high optical purity (1 ) Can be obtained. For example, 3-halo having high optical purity (greater than 98% ee) by the method described in Japanese Patent Publication (2) 4-73998 (1992) or 4-73999 (1992) developed by the applicant. Geno-1,2-propanediol is obtained. According to the process of the invention, (S) -1,4-benzodioxane derivative (1) is obtained from (R) -3-halogeno-1,2-propanediol and (R) -1,4- The benzodioxane derivative (1) is obtained from (S) -3-halogeno-1,2-propanediol.

The invention is described in detail in the following examples, but the invention is not limited to the examples.

Example 1

Sodium hydride (2.4 g, 0.06 mol) was added to the oil to wash the 60% dispersant with n-hexane and anhydrous N, N-dimethylformamide (18 ml) was added thereto. Over 15 minutes under ice cooling, 2-benzyloxy-3-methylphenol (6.39 g, 0.03 mol) in anhydrous N, N-dimethylformamide (10 ml) is added dropwise to the obtained suspension. After the end of the gas evolution, over 15 minutes at the same temperature, dropwise addition of 3-chloro-1,2-propanediol (3.98 g, 0.036 mol) in anhydrous N, N-dimethylformamide (5 ml) to the solution. . The solution is then stirred at 60 ° C. for two hours. After the reaction is completed, water is added thereto and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the crude product as a pale yellow oil. The crude product was purified by column chromatography to yield 8.28 g of diol compound (2-1) (R ¹ is benzyl, R ² is methyl and R ³ , R ⁴ and R ⁵ are H) as a colorless oil. : Yield 96%.

¹ H-NMR (CDCl ₃ ): δ 7.48-7.30 (m, 5H), 6.99-6.78 (m, 3H), 4.96 (s, 2H), 4.10-3.97 (m, 3H), 3.78-3.64 (m , 2H), 2.34 (s, 3H)

Diol compound (2-1) (2.16 g, 7.5 mmol) is dissolved in dimethyl carbonate (30 ml) and sodium hydroxide (23 mg, 0.6 mmol) is added to the solution. The mixture is heated at 60 ° C. for 30 minutes under nitrogen gas. Then, reaction temperature is raised to 90 degreeC and methanol is evaporated. After the reaction is completed, the remaining dimethyl carbonate is concentrated in vacuo, to which tetrahydrofuran (20 ml) is added. The insoluble material is filtered off and the filtrate is condensed to afford the crude product as a pale yellow solid (2.38 g). In addition, the crude product is recrystallized to give 2.16 g of carbonate compound (3-1) (R ¹ is benzyl, R ² is methyl and R ³ , R ⁴ and R ⁵ are H) as white crystals: yield 92.4%, mp 90-95.1 ° C.

¹ H-NMR (CDCl ₃ ): δ 7.47-7.30 (m, 5H), 6.99-6.77 (m, 3H), 5.01-4.88 (m, 3H), 4.51 (t, 2H), 4.28 (dd, 1H ), 4.12 (dd, 1H), 2.22 (s, 3H)

Compound (3-1) (1.00 g, 3.2 mmol) is dissolved in methanol (30 ml) and the solution is subjected to a hydrogenation reaction under hydrogen in the presence of 200 mg of Pd-C (10 w / w%) at room temperature. . After the reaction is complete, Pd-C is filtered off and the filtrate is condensed in vacuo to yield the crude product as a white solid (715 mg). The crude product is recrystallized to give 689 mg of phenol derivative (4-1) (R ² is methyl and R ³ , R ⁴ and R ⁵ are H) as white crystals: yield 96.1%.

¹ H-NMR (d ₆ -DMSO): δ 8.43 (br-s, 1 H), 6.82-6.63 (m, 3 H), 5.16-5.13 (m, 1 H), 4.66-4.88 (m, 2H), 4.26 -4.16 (m, 2H), 2.14 (s, 3H)

Sodium hydride (101 mg, 2.31 mmol) was added to the oil, and the 60% dispersant was washed with n-hexane, to which anhydrous dimethylformamide (3 ml) was added. To the obtained dispersant was added dropwise the above product (4-1) (462.8 mg, 2.1 mmol) dissolved in 5 ml of dimethylformamide over 20 minutes under ice-cooling and nitrogen gas. After the release of the gas, the reaction mixture is stirred at 50 ° C. for 6 hours. After the reaction is completed, water is added to the reaction mixture and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the crude product (380 mg) as a pale yellow oil. The crude product was subjected to column chromatography to give 358 mg of 2-hydroxymethyl-8-methyl-1,4-benzodioxane (1-1) (R ² is methyl and R ³ , R ⁴ and R ⁵ are H) as a colorless oil: yield 94.7%.

¹ H-NMR (CDCl ₃ ): δ6.68 (s, 3H), 4.51-3.68 (m, 5H), 2.60-2.21 (br-s, 1H), 2.20 (s, 3H)

Example 2

2-Benzyloxy-3-fluorophenol was used instead of 2-benzyloxy-3-methylphenol and optically active (R) -3-chloro-1,2-propanediol as the diol compound (optical purity: 99.4 (S) -2-hydroxymethyl-8-fluoro-1,4-benzodioxane (1-2) (R ² is F in the same manner as in Example 1 except that% ee) was used. And R ³ , R ⁴ and R ⁵ are H). 71% yield. The optical purity of this product is 99.3% ee as measured by chiral column OD (Daisel Chemical Industries Ltd.).

Example 3

In the same manner as in Example 2, except that 2-benzyloxy-3-methoxyphenol was used instead of 2-benzyloxy-3-fluorophenol, (S) -2-hydroxymethyl-8-meth Obtain oxy-1,4-benzodioxane (1-3) (R ² is CH ₃ O and R ³ , R ⁴ and R ⁵ are H): yield 83%. The optical purity of this product is 98.9% ee as measured by chiral column OD (Daisel Chemical Industries Ltd.).

Example 4

(S) -2-hydroxymethyl-5-nitro in the same manner as in Example 2 except for using 2-benzyloxy-6-nitrophenol instead of 2-benzyloxy-3-fluorophenol -1,4-benzodioxane (1-4) (R ⁵ is NO ₂ , R ² , R ³ and R ⁴ is H): yield 77%. The optical purity of this product is 98.9% ee as measured by chiral column OD (Daisel Chemical Industries Ltd.).

Example 5

In the same manner as in Example 2 except for using 2-benzyloxy-5-ethoxycarbonylphenol instead of 2-benzyloxy-3-fluorophenol, (S) -2-hydroxymethyl- 6-ethoxycarbonyl-1,4-benzodioxane (1-5) (R ⁴ is EtOCO, R ² , R ³ and R ⁵ is H): yield 65%. The optical purity of this product is 98.9% ee as measured by chiral column OD (Daisel Chemical Industries Ltd.).

Example 6

(S) -2-hydroxymethyl-8-methyl in the same manner as in Example 2 except for using 2-benzyloxy-3-methylphenol instead of 2-benzyloxy-3-fluorophenol Obtain -1,4-benzodioxane (1-6) (R ² is CH ₃ and R ³ , R ⁴ and R ⁵ are H): yield 81%. The optical purity of this product is 98.9% ee as measured by chiral column OD (Daisel Chemical Industries Ltd.).

Example 7

2-allyloxyphenol (6.78 g) was used instead of 2-benzyloxy-3-methylphenol, and the optically active (R) -3-chloro-1,2-propanediol as the diol compound (optical purity: 99.4% According to the method described in Example 1 except using ee), (S) -carbonate compound (3-2) (R ¹ is allyl and R ²¹ , R ³ and R ⁴¹ are H) Obtained: Yield 89.3%, mp 76.3-79.7 ° C.

¹ H-NMR (CDCl ₃ ): δ 7.02-6.87 (m, 4H), 6.06 (2q, 1H), 5.41 and 5.28 (m, 2H), 5.03-4.95 (m, 1H), 4.66-4.53 (m , 4H), 4.28-4.15 (m, 1H)

The (S) -compound (3-2) (2.5 g, 0.01 mol) is dissolved in diglyme (5 ml). Trioctylamine (3.58 g, 0.01 mol) is added thereto and the reaction is carried out in an autoclave at 185 ° C. After the reaction is complete, diglyme and trioctylamine are removed in vacuo to yield the crude product (2.15 g) as a brown oil. The crude product was purified by column chromatography to give 1.75 g of (S) -2-hydroxymethyl-8-allyl-1,4-benzodioxane (1-7) (R ²² is allyl, R ³ , R ⁴² And R ⁵ is H) is obtained as a colorless oil: yield: 85%. The optical purity of this product is 98.5% ee as measured by chiral column OD (Daisel Chemical Industries Ltd.).

¹ H-NMR (CDCl ₃ ): δ6.73 (s, 3H), 6.03-5.88 (m, 1H), 5.05 and 5.03 (m, 2H), 4.24-4.16 (m, 2H), 4.07-4.00 (m , 1H), 3.78 (m, 2H), 3.36-3.32 (m, 2H), 2.70 (br-s, 1H)

(S) -Compound (3-2) (1 g, 0.004 mol) is added to diisobutyl ketone (10 ml). The reaction is carried out at 180 ° C. in an autoclave. After the reaction was completed, the reaction mixture was ice-cooled, the obtained crystals were filtered and dried in vacuo to give 0.876 g of (S) -phenol derivative (4-2) (R ²² is allyl, R ³ , R ⁴² and R ⁵ is H) as light yellow crystals: yield 87.6%, mp 150.9-155.1 ° C.

¹ H-NMR (DMSO-d ₆ ): δ8.50 (br-s, 1H), 6.86-6.82 (m, 1H), 6.76-6.01 (m, 2H), 6.70 (2q, 1H), 5.15-4.97 (m, 3H), 4.54 (ddd, 2H), 4.23 (m, 2H), 3.33 (m, 2H)

(S) -Compound (3-2) (990 mg, 4.0 mmol) is dissolved in methylene chloride (10 ml). Diethyl aluminum chloride (7 ml, 8.8 mol in 15% hexanes) is added thereto and the solution is stirred at 42 ° C. for 1 hour. After completion of the reaction, diluted hydrochloric acid is added to the reaction mixture, the mixture is extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the crude product (955 mg). The crude product was purified by column chromatography to give 793 mg of (S) -compound (4-2), where R ² is allyl and R ³ , R ⁴ and R ⁵ are H: yield 80%.

The (S) -compound (4-2) (500 mg, 2 mmol) was dissolved in anhydrous dimethylformamide (5 ml), CsF (6.1 mg, 0.04 mmol) was added thereto under nitrogen gas, and the mixture was Stir for 3 hours. After the reaction is complete, water is added to the reaction mixture, the mixture is extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the crude product (432 mg) as a pale yellow oil. The crude product was purified by column chromatography to give 397 mg of (S) -2-hydroxymethyl-8-allyl-1,4-benzodioxane (1-7) (R ² is allyl, R ³ , R ⁴ And R ⁵ is H) as a colorless oil: yield 96.4%. The optical purity of this product is 98.9% ee as measured by chiral column OD (Daisel Chemical Industries Ltd.).

According to the process of the present invention, the 1,4-benzodioxane derivative (1) can be obtained in good yield using readily available and inexpensive starting materials, and the optically active target compound is also in high optical purity. Can be obtained. The 1,4-benzodioxane derivative (1) is useful as an intermediate of drugs such as circulatory drugs and psychoneuropathy drugs which are α and β-adrenergic antagonists.

Claims (35)

A method for producing a 1,4-benzodioxane derivative represented by the following general formula (1), wherein the phenol derivative represented by the following general formula (4) is cyclized by treatment with a base or a fluoride salt at -50 to 250 ° C. How to: (In the formulas (1) and (4), R ² , R ³ , R ⁴ and R ⁵ are the same or different and hydrogen, halogen, hydroxy, nitro, cyano, formyl, hydroxycarbonyl, alkyl. Alkoxycarbonyloxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, haloalkyl having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms N, N-dialkylamino having 4 carbon atoms, alkylcarbonyl having 1 to 4 carbon atoms in the alkyl moiety, alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety, or 1 to 4 carbons Phenyl which may be substituted with one or more alkyls having atoms, and two adjacent groups of R ² , R ³ , R ⁴ and R ⁵ may constitute methylenedioxy, or a benzene ring by a carbon atom to which said group is bound Can be configured). As a method for producing a 1,4-benzodioxane derivative represented by the following formula (1), a carbonate compound represented by the following formula (3) is prepared by reacting a diol compound represented by the formula (2) with a carbonizing agent, And removing the protecting group of the obtained carbonate compound to prepare a phenol derivative represented by the following formula (4), and then cyclizing the obtained phenol derivative by treating with a base or a fluoride salt at -50 to 250 ° C. Way: (In the above formulas (1) to (4), R ¹ is a protecting group of hydroxy, R ² , R ³ , R ⁴ and R ⁵ are the same or different, hydrogen, halogen, hydroxy, nitro, cyano, Formyl, hydroxycarbonyl, alkoxycarbonyloxy where the alkyl moiety has 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, 1 to 4 carbon atoms Haloalkyl with N, N-dialkylamino with alkyl having 1 to 4 carbon atoms, alkylcarbonyl with 1 to 4 carbon atoms in the alkyl moiety, alkoxy having 1 to 4 carbon atoms in the alkyl moiety Carbonyl, or phenyl, which may be substituted with one or more alkyl having 1 to 4 carbon atoms, and two adjacent groups of R ² , R ³ , R ⁴ and R ⁵ may constitute methylenedioxy, or To the benzene ring by a carbon atom And R ² and OR ¹ may constitute methylenedioxy, isopropylidenedioxy, cyclohexylidenedioxy or diphenylmethylenedioxy). The process for producing a 1,4-benzodioxane derivative (1) according to claim 2, wherein the optically active form is used as the diol compound (2) to produce an optically active 1,4-benzodioxane derivative. The method for producing a 1,4-benzodioxane derivative (1) according to claim 2 or 3, wherein the carbonizing agent is a carbonate ester, a phosgene or a phosgene oligomer. The process for producing the 1,4-benzodioxane derivative (1) according to claim 2 or 3, wherein R ¹ , which is a protecting group, is benzyl, allyl or benzyloxycarbonyl. The process for producing a 1,4-benzodioxane derivative (1) according to claim 5, wherein the removal of R ¹ which is a protecting group on the carbonate compound (3) is carried out by catalytic hydrogenation. The process for producing a 1,4-benzodioxane derivative (1) according to claim 1 or 2, wherein the phenol derivative (4) is cyclized by treatment with a base. The process for producing a 1,4-benzodioxane derivative (1) according to claim 7, wherein the base is a hydrogenated alkali metal or trialkylamine. The process for producing a 1,4-benzodioxane derivative (1) according to claim 1 or 2, wherein the phenol derivative (4) is cyclized by treating with a fluoride salt. The method for producing a 1,4-benzodioxane derivative (1) according to claim 9, wherein the fluoride salt is an alkali metal fluoride or alkaline earth metal fluoride. The method for producing a 1,4-benzodioxane derivative (1) according to claim 10, wherein the alkali metal fluoride is potassium fluoride, cesium fluoride or a mixture thereof. A method for producing a 1,4-benzodioxane derivative represented by the following general formula (1a), wherein the carbonate compound represented by the following general formula (3a) is heated or treated in the presence of a Lewis acid to the 3 or 5 position on the benzene ring. A method for producing a phenol derivative represented by the following formula (4a) by applying to an allyl group potential reaction, and then cyclizing the obtained phenol derivative by treating with a base or a fluoride salt at -50 to 250 ° C. : (In the formulas (1a), (3a) and (4a), R ¹¹ is allyl, R ²¹ , R ²² , R ³ , R ⁴¹ , R ⁴² and R ⁵ are the same or different, and hydrogen, halogen, hydroxide Roxy, nitro, cyano, formyl, hydroxycarbonyl, alkoxycarbonyloxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms , Haloalkyl having 1 to 4 carbon atoms, N, N-dialkylamino alkyl having 1 to 4 carbon atoms, alkylcarbonyl having 1 to 4 carbon atoms, alkyl portion having 1 to 4 carbon atoms Alkoxycarbonyl having 4 carbon atoms, or phenyl which may be substituted with one or more alkyl having 1 to 4 carbon atoms, provided that one or both of R ²¹ and R ⁴¹ are hydrogen and R ²² and R ⁴² Either or both are allyl). 13. The 1,4-benzodioxane derivative according to claim 12, which is subjected to a potential reaction of an allyl group to the 3 or 5 position on the benzene ring by heating the carbonate compound (3a), and further cyclizing the product obtained by further heating ( The manufacturing method of 1a). The process for producing the 1,4-benzodioxane derivative (1a) according to claim 13, wherein the rearrangement reaction and the ring closure reaction are performed by heating under a base. The process for producing the 1,4-benzodioxane derivative (1a) according to claim 14, wherein the base is trialkylamine. The base of claim 2 or 3, wherein the diol compound (2) is a 3-halogeno-1,2-propanediol and a base in which the catechol derivative represented by the following general formula (5) is represented by the following general formula (6): Process for preparing 1,4-benzodioxane derivative (1) prepared by reacting under: (Wherein X is a halogen). The process for producing a 1,4-benzodioxane derivative (1) according to claim 16, wherein the base is a base selected from the group of alkali metal or alkaline earth metal alkoxides, hydrides, hydroxides, hydrogen carbonates and carbonates. 17. The process for producing an optically active 1,4-benzodioxane derivative (1) according to claim 16, wherein the 3-halogeno-1,2-propanediol (6) is in an optically active form. A method for producing a phenol derivative represented by the following general formula (4a), wherein the carbonate compound represented by the following general formula (3a) is heated to 0 to 250 ° C to be applied to the rearrangement reaction of allyl groups to the 3 or 5 position on the benzene ring. Method characterized by: (In the formulas (4a) and (3a), R ¹¹ is allyl, R ²¹ , R ²² , R ³ , R ⁴¹ , R ⁴² and R ⁵ are the same or different, hydrogen, halogen, hydroxy, nitro, Cyano, formyl, hydroxycarbonyl, alkoxycarbonyloxy where the alkyl moiety has 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, 1 to 4 Haloalkyl having 3 carbon atoms, N, N-dialkylamino alkyl having 1 to 4 carbon atoms, alkylcarbonyl having 1 to 4 carbon atoms in the alkyl moiety, 1 to 4 carbon atoms in the alkyl moiety Alkoxycarbonyl having 1 or phenyl which may be substituted with one or more alkyl having 1 to 4 carbon atoms, provided that one or both of R ²¹ and R ⁴¹ are hydrogen and one or two of R ²² and R ⁴² All are informed). A method for producing a phenol derivative represented by the following general formula (4a), wherein the carbonate compound represented by the following general formula (3a) is treated at -78 to 120 ° C in the presence of a Lewis acid to the 3 or 5 position on the benzene ring Method for applying to the potential reaction of: (In the formulas (4a) and (3a), R ¹¹ is allyl, R ²¹ , R ²² , R ³ , R ⁴¹ , R ⁴² and R ⁵ are the same or different, hydrogen, halogen, hydroxy, nitro, Cyano, formyl, hydroxycarbonyl, alkoxycarbonyloxy where the alkyl moiety has 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, 1 to 4 Haloalkyl having 3 carbon atoms, N, N-dialkylamino alkyl having 1 to 4 carbon atoms, alkylcarbonyl having 1 to 4 carbon atoms in the alkyl moiety, 1 to 4 carbon atoms in the alkyl moiety Alkoxycarbonyl having 1 or phenyl which may be substituted with one or more alkyl having 1 to 4 carbon atoms, provided that one or both of R ²¹ and R ⁴¹ are hydrogen and one or two of R ²² and R ⁴² All are informed). The method for producing an optically active 1,4-benzodioxane derivative (1) according to claim 1, wherein the phenol derivative (4) is in an optically active form. A method for producing a 1,4-benzodioxane derivative represented by the following general formula (1), wherein the phenol derivative represented by the following general formula (4) is cyclized by heat treatment at 0 to 250 ° C: (In the formulas (1) and (4), R ² , R ³ , R ⁴ and R ⁵ are the same or different and hydrogen, halogen, hydroxy, nitro, cyano, formyl, hydroxycarbonyl, alkyl. Alkoxycarbonyloxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, haloalkyl having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms N, N-dialkylamino having 4 carbon atoms, alkylcarbonyl having 1 to 4 carbon atoms in the alkyl moiety, alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety, or 1 to 4 carbons Phenyl which may be substituted with one or more alkyls having atoms, and two adjacent groups of R ² , R ³ , R ⁴ and R ⁵ may constitute methylenedioxy, or a benzene ring by a carbon atom to which said group is bound Can be configured). The method for producing an optically active 1,4-benzodioxane derivative (1) according to claim 22, wherein the phenol derivative (4) is in an optically active form. As a method for producing a 1,4-benzodioxane derivative represented by the following formula (1), a carbonate compound represented by the following formula (3) is prepared by reacting a diol compound represented by the formula (2) with a carbonizing agent, A method for producing a phenol derivative represented by the following formula (4) by removing the protecting group of the obtained carbonate compound, and then cyclizing the obtained phenol derivative by heat treatment at 0 to 250 ° C. (In the above formulas (1) to (4), R ¹ is a protecting group of hydroxy, R ² , R ³ , R ⁴ and R ⁵ are the same or different, hydrogen, halogen, hydroxy, nitro, cyano, Formyl, hydroxycarbonyl, alkoxycarbonyloxy where the alkyl moiety has 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, 1 to 4 carbon atoms Haloalkyl with N, N-dialkylamino with alkyl having 1 to 4 carbon atoms, alkylcarbonyl with 1 to 4 carbon atoms in the alkyl moiety, alkoxy having 1 to 4 carbon atoms in the alkyl moiety Carbonyl, or phenyl, which may be substituted with one or more alkyl having 1 to 4 carbon atoms, and two adjacent groups of R ² , R ³ , R ⁴ and R ⁵ may constitute methylenedioxy, or To the benzene ring by a carbon atom And R ² and OR ¹ may constitute methylenedioxy, isopropylidenedioxy, cyclohexylidenedioxy or diphenylmethylenedioxy). 25. The process for producing a 1,4-benzodioxane derivative (1) according to claim 24, wherein an optically active form is used as the diol compound (2) to produce an optically active 1,4-benzodioxane derivative. 26. The process for producing a 1,4-benzodioxane derivative (1) according to claim 24 or 25, wherein the carbonizing agent is a carbonate ester, phosgene or phosgene oligomer. 26. The process for producing the 1,4-benzodioxane derivative (1) according to claim 24 or 25, wherein R ¹ , which is a protecting group, is benzyl, allyl or benzyloxycarbonyl. 28. The process for producing a 1,4-benzodioxane derivative (1) according to claim 27, wherein the removal of R ¹ which is a protecting group on the carbonate compound (3) is carried out by catalytic hydrogenation. 26. The base of claim 24 or 25, wherein the diol compound (2) is a 3-halogeno-1,2-propanediol and a base in which the catechol derivative represented by the following formula (5) is represented by the following formula (6): Process for preparing 1,4-benzodioxane derivative (1) prepared by reacting under: (Wherein X is a halogen). 30. The method for producing a 1,4-benzodioxane derivative (1) according to claim 29, wherein the base is a base selected from the group of alkali metal or alkaline earth metal alkoxides, hydrides, hydroxides, hydrogen carbonates and carbonates. 30. The process for producing an optically active 1,4-benzodioxane derivative (1) according to claim 29, wherein the 3-halogeno-1,2-propanediol (6) is in an optically active form. A method for producing a 1,4-benzodioxane derivative represented by the following general formula (1a), wherein the carbonate compound represented by the following general formula (3a) is heated or treated in the presence of a Lewis acid to the 3 or 5 position on the benzene ring. A method for producing a phenol derivative represented by the following general formula (4a) by applying to a potential reaction of an allyl group, and then cyclizing the obtained phenol derivative by heat treatment at 0 to 250 ° C . : (In the formulas (1a), (3a) and (4a), R ¹¹ is allyl, R ²¹ , R ²² , R ³ , R ⁴¹ , R ⁴² and R ⁵ are the same or different, and hydrogen, halogen, hydroxide Roxy, nitro, cyano, formyl, hydroxycarbonyl, alkoxycarbonyloxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms , Haloalkyl having 1 to 4 carbon atoms, N, N-dialkylamino alkyl having 1 to 4 carbon atoms, alkylcarbonyl having 1 to 4 carbon atoms, alkyl portion having 1 to 4 carbon atoms Alkoxycarbonyl having 4 carbon atoms, or phenyl which may be substituted with one or more alkyl having 1 to 4 carbon atoms, provided that one or both of R ²¹ and R ⁴¹ are hydrogen and R ²² and R ⁴² Either or both are allyl). 33. The 1,4-benzodioxane derivative according to claim 32, which is subjected to a potential reaction of an allyl group to the 3 or 5 position on the benzene ring by heating the carbonate compound (3a), and further cyclizing the product obtained by further heating ( The manufacturing method of 1a). The process for producing the 1,4-benzodioxane derivative (1a) according to claim 33, wherein the rearrangement reaction and the ring closure reaction are performed by heating under a base. 35. The process for producing the 1,4-benzodioxane derivative (1a) according to claim 34, wherein the base is trialkylamine.