JP2001316385A - Method for producing 1,4-benzodioxane derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To solve the industrial problem that the yield of 2-hydroxymethyl-1,4- benzodioxanes of products is low, and position isomers of which the separation is difficult by a general method such as recrystallization and distillation because chemical and physical properties resemble, are required to be separated. SOLUTION: This method for producing the 1,4-benzodioxane derivative represented by formula (1) is characterized in that a catechol derivative of formula (2) is reacted with a glycidyl derivative of formula (3) in an organic solvent in the presence of a salt of fluorine. (wherein, R1, R2 and R3 are each a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a cyano group, a formyl group, a hydroxycarbonyl group, an alkoxycarbonyloxy group, a saturated or unsaturated alkyl group, an amide group or the like; and X is a halogen atom or a sulfonyloxy group).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a 1,4-benzodioxane derivative which is useful as a pharmaceutical intermediate such as a drug for treating cardiovascular diseases and a drug for treating neuropsychiatric disorders having α and β adrenergic antagonism.

[0002]

2. Description of the Related Art 1,4-benzodioxane derivatives are known as α
And β-adrenergic antagonists, and is used as a synthetic intermediate such as a therapeutic drug for circulatory diseases and a psychiatric drug. Most of the conventional methods are very complicated, such as isolating intermediates and replacing the reaction solvent in each step during the multi-step reaction of 3 to 5 from the starting materials. on the other hand,
As a one-step method, for example, a method of reacting catechol with glycidyl tosylate in the presence of potassium carbonate (Tetrahedron Letters, 29, 3671, 1988), a reaction of catechol with glycidyl tosylate in the presence of sodium hydride (J. Med. Chem., 32, 1402, 198
9), a method of reacting a catechol derivative with epichlorohydrin in the presence of a base (J. Med. Chem., 30, 49, 1)
987), a method of reacting a catechol derivative with glycidyl 3-nitrobenzenesulfonate in the presence of a base (JP-A-10-45746), and the like.

[0003]

The above-mentioned method of reacting catechol or a derivative thereof with glycidyl tosylate or epichlorohydrin in the presence of a base such as potassium carbonate or sodium hydride is a method of reacting 2-hydroxymethyl The yield of -1,4-benzodioxane is low (21-75%), and the above-mentioned catechol derivative and glycidyl 3-nitrobenzenesulfonate are reacted in the presence of a base in a single step. Although benzodioxane derivatives are obtained, regioselectivity problems arise depending on the position of substituents of the catechol derivative, and regioisomers must be separated. These isomers have similar chemical and physical properties and are difficult to separate by common methods such as recrystallization and distillation. These methods have many industrial problems, and the development of better methods is required.

[0004]

Means for Solving the Problems In view of the above-mentioned drawbacks, the present inventors have conducted intensive studies to find an improved method for synthesizing a 1,4-benzodioxane derivative. As a result, a catechol derivative and a glycidyl derivative were dissolved in an organic solvent. The present inventors have found that when the reaction is carried out in the presence of a fluorine salt, the desired 1,4-benzodioxane derivative can be synthesized in one step with high yield and high regioselectivity, and thus completed the present invention. The present invention relates to a catechol derivative represented by the following formula (2) and a catechol derivative represented by the following formula (3):
A novel method for producing a 1,4-benzodioxane derivative represented by the following formula (1), characterized by reacting a glycidyl derivative represented by the following formula with an organic solvent in the presence of a fluorine salt:

[0005]

Embedded image

In the above formulas (1) and (2), R ¹ , R ² , R
³ is a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a formyl group, a hydroxycarbonyl group,
An alkoxy moiety having 1 to 4 carbon atoms, an alkoxycarbonyloxy group having 1 to 4 carbon atoms, a saturated or unsaturated alkyl group having 1 to 4 carbon atoms, and an unsubstituted or substituted phenyl group having 1 to 4 carbon atoms; An alkyl group, a saturated or unsaturated alkoxy group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms substituted by an unsubstituted or alkyl group substituted with an alkyl group having 1 to 4 carbon atoms, A haloalkyl group, an alkyl moiety having 1 to 4 carbon atoms, an N, N-dialkylamino group, an alkyl moiety having 1 to 4 carbon atoms, an alkylcarbonyl group having 1 to 4 carbon atoms, and an alkyl moiety having 1 to 4 carbon atoms. A mono- or dialkylcarbamoyl group having 1 to 4 carbon atoms, an acylamide group having 1 to 5 carbon atoms, or an alkoxycarbonyl having an alkyl portion having 1 to 4 carbon atoms. Ku denotes an atom or a group selected from phenyl group substituted with protected amino group, and an unsubstituted or alkyl group having 1 to 4 carbon atoms in the aralkyl group,
Or means R ^1, R ² and methylenedioxy group or a cyclic amido group any two are bonded on carbon adjacent together of R ^3, or any of R ^1, R ² and R ³ In the above formula (3), X means a halogen atom or a sulfonyloxy group, wherein two are a phenyl group bonded on adjacent carbons.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail.

A catechol derivative represented by the above formula (2) and a glycidyl derivative represented by the above formula (3) are reacted in an organic solvent in the presence of a fluorine salt to give 1,1 represented by the above formula (1). A 4-benzodioxane derivative can be produced.

Specific examples of the catechol derivative (2) include catechol, 3-chlorocatechol, 4-chlorocatechol, 3-bromocatechol, 4-bromocatechol, 3-iodocatechol, 4-iodocatechol,
3-nitrocatechol, 4-nitrocatechol, 3-cyanocatechol, 4-cyanocatechol, 3-formylcatechol, 4-formylcatechol, 3-methylcatechol, 4-methylcatechol, 3-butylcatechol, 3-benzylcatechol, 4-benzylcatechol, 3-allylcatechol, 4-allylcatechol,
3,5-dimethylcatechol, 3-butyl-5-methylcatechol, 3-methoxycatechol, 4-methoxycatechol, 3-butoxycatechol, 3-allyloxycatechol, 4-allyloxycatechol, 3-benzyloxycatechol, -Benzyloxycatechol,
3-chloromethylcatechol, 4-chloromethylcatechol, 3-bromomethylcatechol, 4-bromomethylcatechol, 3- (1-chlorobutyl) catechol,
-(3-bromobutyl) catechol, 3-dimethylaminocatechol, 4-dimethylaminocatechol, 3-dibutylaminocatechol, 4-dibutylaminocatechol, 3-acetylcatechol, 4-acetylcatechol, 3-ethylcarbonylcatechol, 4- Butylcarbonylcatechol, 3-methoxycarbonylcatechol, 4-ethoxycarbonylcatechol, 3-ethoxymethoxycatechol, 3-phenylcatechol, 4
-Phenylcatechol, 3- (4-methylphenyl) catechol, 4- (4-methylphenyl) catechol,
1,2-dihydroxynaphthalene, 2,3-dihydroxynaphthalene, 3,4-methylenedioxycatechol,
4,5-methylenedioxycatechol, 3-benzyloxycarbonylaminocatechol, 4- (N-methylcarbamoyl) catechol, 4,5-dihydroxy-2,
3-dihydro-2-oxindole, 5,6-hydroxy-1,2,3,4-tetrahydro-2-oxyquinoline and the like.

The substituent X of the glycidyl derivative represented by the formula (3) is a halogen atom or a sulfonate group. Examples of the halogen atom include a chlorine atom, a bromine atom and an iodine atom, and preferably a chlorine atom and a bromine atom.
Preferred as the sulfonate group are an unsubstituted or substituted alkyl sulfonate group having 1 to 10 carbon atoms such as a methanesulfonate group and a trifluoromethanesulfonate group, or a benzenesulfonate group, a p-toluenesulfonate group, m —An unsubstituted or substituted aromatic sulfonate group such as a nitrobenzene sulfonate group.

Specific examples of the glycidyl derivative (3) include epichlorohydrin, epibromohydrin, glycidylmethanesulfonate, glycidyltrifluoromethanesulfonate, glycidylethanesulfonate, glycidylpropanesulfonate, and glycidylbutanesulfonate. Nate, glycidylphenylmethanesulfonate, glycidyl p-trifluoromethylbenzenesulfonate,
Glycidylbenzenesulfonate, glycidyl p-toluenesulfonate, glycidyl 2,4,6-triisopropylbenzenesulfonate, glycidyl p-tert
-Butylbenzenesulfonate, glycidyl p-chlorobenzenesulfonate, glycidyl p-bromobenzenesulfonate, glycidyl p-iodobenzenesulfonate, glycidyl 2,4,5-trichlorobenzenesulfonate, glycidyl o-nitrobenzenesulfonate, glycidylm -Nitrobenzenesulfonate, glycidyl p-nitrobenzenesulfonate, glycidyl 2,4-dinitrobenzenesulfonate, glycidyl p
-Methoxybenzenesulfonate, glycidyl 4-chloro-3-nitrobenzenesulfonate, glycidyl 1-
Examples thereof include naphthalene sulfonate and glycidyl 2-naphthalene sulfonate. Of these, glycidyl m-nitrobenzenesulfonate, glycidyl p-toluenesulfonate and epichlorohydrin are particularly preferably used.

The amount of the catechol derivative (2) to be used is 0.5-3 equivalents, preferably 0.8-1.2 equivalents, to the glycidyl derivative (3). It is safe to use more than 3 equivalents, but it is not economical. On the other hand, if the used amount is less than 0.5 equivalent, excess unreacted glycidyl derivative remains in the reaction solution, which is not economical.

The fluorine salt used in this reaction includes:
A quaternary ammonium salt of fluorine, an alkali metal salt of fluorine or an alkaline earth metal salt of fluorine is preferable, and an alkali metal salt of fluorine or an alkaline earth metal salt of fluorine is more preferable. A mixture of two or more types may be used. Further, the target compound can be obtained in the same manner by using the compound supported on a suitable carrier.

Examples of the quaternary ammonium salt of fluorine include tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride, tetraoctylammonium fluoride and benzyltrimethylammonium fluoride. Examples thereof include sodium fluoride, potassium fluoride and cesium fluoride, and examples of the alkaline earth metal salt of fluorine include magnesium fluoride and calcium fluoride. Examples of the carrier that can be used include celite, alumina, silica gel, molecular sieves, and modified products thereof.

The amount of the fluorine salt used is preferably 0.5 to 6 equivalents, more preferably 0.9 to 6 equivalents, to the glycidyl derivative (3). If the amount is less than 0.5 equivalent, the reaction is not completed, and if it exceeds 6 equivalents, stirring becomes difficult, which is not preferable. When an alkali metal or alkaline earth metal bicarbonate or carbonate is used in combination with a fluorine salt as an acid trapping agent described below, the amount of the fluorine salt used is 0.1 to 0.1% based on the glycidyl derivative (3). It can be reduced to 02 equivalents. Although the reaction proceeds even if the amount is less than 0.02 equivalent, the reaction time becomes long and is not practical.

The solvent used in this reaction is N, N
Aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, sulfolane, hexamethylphosphoramide, butyl acetate, ester solvents such as butyl acetate, tetrahydrofuran, 1,4-dioxane, 1,2
Dimethoxyethane, tert-butyl methyl ether,
Ether solvents such as diethyl ether, aromatic hydrocarbon solvents such as benzene, toluene and xylene, ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitrile solvents such as acetonitrile and butyronitrile, and mixed solvents thereof Is mentioned. Preferably, tetrahydrofuran, tert-butyl methyl ether, acetonitrile, more preferably N, N-dimethylformamide, dimethylsulfoxide.

This reaction proceeds without a catalyst, but N, N-dimethylaminopyridine, cesium iodide, potassium bromide, sodium bromide, magnesium bromide, calcium bromide, potassium iodide, sodium iodide, iodide Magnesium, halides of alkali metals or alkaline earth metals such as calcium iodide, quaternary ammonium salts such as tetrabutylammonium fluoride, tetrabutylammonium chloride and trimethylbenzylammonium bromide, and crown ethers such as 18-crown-6 The addition accelerates the reaction. The amount used is 0.1 to 50 mol% based on the catechol derivative (2).

Although the details of the reaction mechanism of the present invention are not known, the reaction proceeds under almost neutral conditions, and it is assumed that the generated acid is trapped by a metal salt of fluorine. In fact,
Addition of a weak base such as an alkali metal or alkaline earth metal bicarbonate or carbonate as an acid trapping agent accelerates the reaction and reduces the amount of fluorine metal salt used. Therefore, in the present invention, the addition of an alkali metal or alkaline earth metal bicarbonate or carbonate such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate and barium carbonate as an acid trapping agent is not possible. It is valid.
The amount of these used is not particularly limited, but is usually 0.1 to 10 equivalents, and preferably about 1 to 3 equivalents, based on the catechol derivative (2).

In the present invention, the reaction temperature is from -50 ° C to the boiling point of the solvent, and particularly preferably from -10 ° C to 100 ° C. If the temperature is too low, the reaction progresses extremely slowly,
If it is too high, the raw materials and products are decomposed, and the yield decreases. Further, when an optically active substance is used as a glycidyl derivative as a raw material, if the temperature exceeds 100 ° C., racemization proceeds, which is not preferable.

After the completion of the reaction, the post-treatment is carried out after filtering the insolubles.
The method is very simple, for example, a method in which water is added and the desired substance is extracted with an organic solvent, or the insoluble matter is filtered, and then the solvent is distilled off as it is and subjected to distillation, recrystallization or purification by column chromatography. Therefore, unlike the conventional case, the excess of a strong base is carefully reacted with water or dilute hydrochloric acid, and no complicated processing such as neutralization and extraction is required.

In the reaction of the catechol derivative (2) with the glycidyl derivative (3), two types of structural isomers represented by the following formulas (1) and (4) may be obtained. These isomers have similar chemical and physical properties and are difficult to separate by common methods such as recrystallization and distillation. But,
According to the method of the present invention, R ¹ has an alkoxy moiety having 1 carbon atom.
Alkoxycarbonyloxy group having 1 to 4 carbon atoms, a saturated or unsaturated alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with an unsubstituted or alkyl group having 1 to 4 carbon atoms, A saturated or unsaturated alkoxy group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms substituted with an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, and an alkyl moiety An N, N-dialkylamino group having 1 to 4 carbon atoms, an alkylcarbonyl group having 1 to 4 carbon atoms in the alkyl portion, an alkoxycarbonyl group having 1 to 4 carbon atoms in the alkyl portion, and a monoalkyl group having 1 to 4 carbon atoms in the alkyl portion. Or a dialkylcarbamoyl group, an acylamide group having 1 to 5 carbon atoms, and an alkyl moiety protected with an alkoxycarbonyl or aralkyl group having 1 to 4 carbon atoms. Amino group, and unsubstituted or whether it is substituted with atoms or groups selected from phenyl group with an alkyl group having 1 to 4 carbon atoms, or bonds on carbon R ^1, R ² are adjacent together If the 3-position of the catechol derivative is substituted with a bulky substituent such as a methylenedioxy group or a cyclic amide group, or a phenyl group in which R ¹ and R ² are bonded on adjacent carbons, a high selection is obtained. The 1,4-benzodioxane derivative of the formula (1) is preferentially obtained due to the nature.

[0022]

Embedded image

In the method of the present invention, by using the optically active glycidyl derivative (3), the optically active 1,4-benzodioxane derivative (1) can be produced. When a glycidyl derivative (3) having a high optical purity is used as a raw material, a remarkable racemization reaction does not occur during the reaction, and a 1,4-benzodioxane derivative (1) having a high optical purity can be produced. High optical purity (98% e
e or more) glycidyl derivative (3) is disclosed in, for example, Patent No. 2894134 and WO97 / 26
254 can be obtained. Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited to these Examples.

Embodiment 1 FIG. Catechol under nitrogen atmosphere 11.
01 g (100 mmol) was dissolved in 50 ml of dimethylformamide (DMF), 30.38 g (200 mmol) of CsF was added, and the mixture was stirred at room temperature for 1 hour. Next, the internal temperature was set to 80 ° C., and 25.92 g of (R) -glycidyl m-nitrobenzenesulfonate of 99.3% ee (100
mmol) and stirred at the same temperature. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. After the ethyl acetate layer was dried over magnesium sulfate, it was concentrated to dryness under reduced pressure. As a result of analyzing the optical purity of the residue by high performance liquid chromatography, it was 99.2% ee. The residue is purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the desired (S) -2-hydroxymethyl-1,4.
-Benzodioxane 16.00g (Yield 96.3%, optical purity
99.2% ee) was obtained as colorless needle crystals.

Embodiment 2 FIG. Catechol under nitrogen atmosphere 11.
00g (100 mmol) was dissolved in 50 ml of DMF, and 3.05 g of CsF was dissolved.
(20 mmol) and 17.97 g (130 mmol) of potassium carbonate were added, and the mixture was stirred at room temperature for 1 hour. Next, the internal temperature was set to 80 ° C and 99.
25% (100 mmol) of (R) -glycidyl m-nitrobenzenesulfonate with 3% ee was added, and the mixture was stirred at the same temperature. After completion of the reaction, the inorganic substance was filtered, water was added, and the mixture was extracted with ethyl acetate. After the ethyl acetate layer was dried over magnesium sulfate, it was concentrated to dryness under reduced pressure. The optical purity of the residue was analyzed by high performance liquid chromatography and found to be 99.1% ee. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 15.85 g of the desired (S) -2-hydroxymethyl-1,4-benzodioxane (yield 95.4%, optical yield). Purity 99.1% ee) was obtained as colorless needles.

Embodiment 3 FIG. Catechol 1.1 under nitrogen atmosphere
0 g (10 mmol) was dissolved in DMSO 20 ml, and CsF 3.04 g
(20 mmol) was added and stirred at room temperature for 1 hour. Next, the internal temperature was adjusted to 80 ° C., and 2.59 g (10 mmol) of (R) -glycidyl m-nitrobenzenesulfonate with 99.3% ee was added, followed by stirring at the same temperature. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. After drying the ethyl acetate layer with magnesium sulfate,
It was concentrated to dryness under reduced pressure. As a result of analyzing the optical purity of the residue by high performance liquid chromatography, it was 98.8% ee.
The residue is purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the desired product.
(S) -2-hydroxymethyl-1,4-benzodioxane
1.53 g (yield 92.1%, optical purity 98.8% ee) was obtained as colorless needle crystals.

Embodiment 4 FIG. Under a nitrogen atmosphere, 12.41 g (100 mmol) of 3-methylcatechol was dissolved in 50 ml of DMF, and C
30.38 g (200 mmol) of sF was added, and the mixture was stirred at room temperature for 1 hour. Next, the internal temperature was set to 80 ° C., and 25.92 g (100 mmol) of (R) -glycidyl m-nitrobenzenesulfonate having 99.3% ee.
Was added and stirred at the same temperature. After the reaction, add water and
Extracted with ethyl acetate. After the ethyl acetate layer was dried over magnesium sulfate, it was concentrated to dryness under reduced pressure. The residue was analyzed by high performance liquid chromatography to find (S) -2-hydroxymethyl-8-methyl-1,4-benzodioxane and (S) -2-hydroxymethyl-5-methyl-1,4
-The formation ratio of benzodioxane was 93: 7. The residue is purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to give the desired (S)-
16.21 g of 2-hydroxymethyl-8-methyl-1,4-benzodioxane (yield 90.0%, optical purity 99.2% ee)
Was obtained as a colorless oil.

Embodiment 5 FIG. Under a nitrogen atmosphere, 15.01 g (100 mmol) of 3-allylcatechol was dissolved in 50 ml of DMF, and C
30.38 g (200 mmol) of sF was added, and the mixture was stirred at room temperature for 1 hour. Next, the internal temperature was set to 80 ° C., and 25.92 g of (R) -glycidyl m-nitrobenzenesulfonate of 99.3% ee (100 mm
ol) and stirred at the same temperature. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. After the ethyl acetate layer was dried over magnesium sulfate, it was concentrated to dryness under reduced pressure. ¹ H
As a result of analysis by -NMR, (S) -2-hydroxymethyl-8-allyl-1,4-benzodioxane and (S) -2-hydroxymethyl-5-allyl-1,4-
The production ratio of benzodioxane was 95: 5. The residue is purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the desired (S) -2-
18.10 g of hydroxymethyl-8-allyl-1,4-benzodioxane (yield 87.8%, optical purity 99.2% ee) was obtained as a colorless oil.

Comparative Example 1 (Example using potassium carbonate) Under nitrogen atmosphere, 1.10 g (10 mmol) of catechol was added to DMF 1
Dissolve in 5 ml, add potassium carbonate 1.38 g (10 mmol),
Stirred at room temperature for 1 hour. Next, the internal temperature was set to 60 ° C, and 99.3% e
2.59 g (10 mmol) of (R) -glycidyl m-nitrobenzenesulfonate from e was added and stirred at the same temperature. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and then concentrated to dryness under reduced pressure to obtain 2.26 g of crude (S) -2-hydroxymethyl-1,4-benzodioxane. As a result of analyzing the optical purity by high performance liquid chromatography, it was 96.3% ee. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 1.28 g of the desired (S) -2-hydroxymethyl-1,4-benzodioxane (77.0% yield). Obtained as colorless needle crystals.

Comparative Example 2 (Example of use of sodium hydride) Under a nitrogen atmosphere, 3.88 g of sodium hydride (63.7% in oi)
l, 103 mmol) was washed with hexane and charged with 10.31 g (93.6 mmol) of catechol in 50 ml of DMF.
Was added to the solution cooled to 0 ° C., and the mixture was stirred at the same temperature for 1 hour. Next, 24.29 g (93.7 mmol) of (R) -glycidyl m-nitrobenzenesulfonate having 99.3% ee was added to DMF.
A solution dissolved in 30 ml was added dropwise over 1 hour, and then 45
Stirred at ° C. After completion of the reaction, ice water was added, the mixture was neutralized with 0.1N hydrochloric acid, extracted with ethyl acetate, and washed with saturated saline.
The ethyl acetate layer was dried over magnesium sulfate, concentrated to dryness under reduced pressure, and crude (S) -2-hydroxymethyl-1,4
-16.8 g of benzodioxane were obtained. This optical purity was analyzed by high performance liquid chromatography, and as a result, 93.6% ee
Met. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give
10.8 g (yield 69.4%) of the desired (S) -2-hydroxymethyl-1,4-benzodioxane was obtained as colorless needle crystals.

Comparative Example 3 (Example of use of sodium hydride) 0.780 g (63.7% in oi) of sodium hydride under a nitrogen atmosphere
l, 20.6 mmol) was washed with hexane and charged with 2.33 g (18.8 mmol) of 3-methylcatechol in DM.
The solution dissolved in 50 ml of F was cooled to 0 ° C and added.
Stirred for hours. Next, 99.3% ee of (R) -glycidyl
A solution of 4.87 g (18.8 mmol) of m-nitrobenzenesulfonate in 10 ml of DMF was added dropwise over 1 hour, and then stirred at 45 ° C. After the reaction, add ice water and add 0.1N
After neutralization with hydrochloric acid, the mixture was extracted with ethyl acetate and washed with saturated saline. After the ethyl acetate layer was dried over magnesium sulfate, it was concentrated to dryness under reduced pressure. The residue was analyzed by high performance liquid chromatography and found to be (S) -2-hydroxymethyl-
8-methyl-1,4-benzodioxane and (S) -2-
The production ratio of hydroxymethyl-5-methyl-1,4-benzodioxane was 65:35. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to give 1.55 g of the desired (S) -2-hydroxymethyl-8-methyl-1,4-benzodioxane.
(Yield 45.8%, optical purity 94.2% ee) was obtained as a colorless oil.

Comparative Example 4 (Example of use of sodium hydride) Under a nitrogen atmosphere, 129 mg of sodium hydride (63.7% in oi)
l, 3.4 mmol) was washed with hexane and charged with 3-allylcatechol 465.6 mg (3.1 mmol) in D
The solution dissolved in 5 ml of MF was cooled to 0 ° C and added.
Stir for 1 hour. Next, 99.3% ee of (R) -glycidyl
A solution of 803 mg (3.1 mmol) of m-nitrobenzenesulfonate dissolved in 2 ml of DMF was added dropwise over 1 hour, and then stirred at 50 ° C. After the reaction, add ice water and add 0.1N
After neutralization with hydrochloric acid, the mixture was extracted with ethyl acetate and washed with saturated saline. After the ethyl acetate layer was dried over magnesium sulfate, it was concentrated to dryness under reduced pressure. The residue was analyzed by ¹ H-NMR and found to be (S) -2-hydroxymethyl-8-allyl-1,
The formation ratio of 4-benzodioxane and (S) -2-hydroxymethyl-5-allyl-1,4-benzodioxane is 5
It was 5:45. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the desired (S) -2-hydroxymethyl-8-allyl-1,4-benzodioxane (201 mg, yield 31.4). %,
Optical purity 92.4% ee) was obtained as a colorless oil.

[0033]

According to the process for producing a 1,4-benzodioxane derivative in one step of the present invention, the desired product can be obtained in a high yield by a simple operation using easily available and inexpensive starting materials. An active target can also be obtained with high optical purity.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Daisuke Fukumoto, Inventor Daiso Fukumoto 1-10-8, Edobori, Nishi-ku, Osaka, Osaka (72) Inventor Hiroshi Yoshimoto 1-10-8, Edobori, Nishi-ku, Osaka, Osaka Daiso Co., Ltd. F term (reference) 4C022 LA02

Claims (5)

[Claims] [Claim 1] The following formula (2) A catechol derivative represented by the following formula (3): Wherein the glycidyl derivative is reacted in an organic solvent in the presence of a fluorine salt. A method for producing a 1,4-benzodioxane derivative represented by the formula:
However, in the above formulas (1) and (2), R ¹ , R ² and R ³ each represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group,
A cyano group, a formyl group, a hydroxycarbonyl group, an alkoxycarbonyloxy group having 1 to 4 carbon atoms in an alkoxy moiety, a saturated or unsaturated alkyl group having 1 to 4 carbon atoms, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms C1-C4 alkyl group substituted with phenyl group, C1
A saturated or unsaturated alkoxy group having 1 to 4 carbon atoms, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, An N, N-dialkylamino group having 1 to 4 carbon atoms, an alkylcarbonyl group having 1 to 4 carbon atoms in the alkyl portion, an alkoxycarbonyl group having 1 to 4 carbon atoms in the alkyl portion, a mono- or monoalkyl having 1 to 4 carbon atoms in the alkyl portion. A dialkylcarbamoyl group, an acylamide group having 1 to 5 carbon atoms, an amino group in which the alkyl portion is protected by an alkoxycarbonyl or aralkyl group having 1 to 4 carbon atoms, and phenyl unsubstituted or substituted by an alkyl group having 1 to 4 carbon atoms Means an atom or group selected from the group, or any ^{two of} R ¹ , R ² and R ³ are bonded together on an adjacent carbon A methylenedioxy group or a cyclic amide group, or a phenyl group in which any ^{two of} R ¹ , R ² and R ³ are bonded to adjacent carbons, and X in the above formula (3) Represents a halogen atom or a sulfonyloxy group. 2. The method according to claim 1, wherein when the reaction is carried out in the presence of a fluorine salt, the alkali metal or alkaline earth metal bicarbonate or carbonate is reacted in the presence of the fluorine salt. -Method for producing benzodioxane derivatives. 3. The method according to claim 1, wherein
A method for producing an optically active 1,4-benzodioxane derivative by using an optically active substance as the glycidyl derivative represented by the formula (3). 4. The production of a 1,4-benzodioxane derivative according to claim 1, wherein the glycidyl derivative represented by the formula (3) is glycidyl m-nitrobenzenesulfonate or glycidyl p-nitrobenzenesulfonate. Law. 5. The method for producing a 1,4-benzodioxane derivative according to claim 1, wherein the fluorine salt is potassium fluoride, cesium fluoride or a mixture thereof.