KR100780538B1 - Process for the preparation of chiral 2-hydroxymethyl-1,4-benzodioxane compound - Google Patents

Abstract

A method for preparing a methyl-1,4-benzodioxane compound is provided to obtain a chiral 1,4-benzodioxane compound with high optical purity of at least 99% by reducing side reactions. A method for preparing a methyl-1,4-benzodioxane compound comprises the steps of: (a) reacting an epoxide compound represented by the formula(2), in the presence of a tertiary organic amine or an ammonium salt thereof, with a catechol compound represented by the formula(3) to be subject to an epoxide ring opening reaction to obtain a ring opened product; and (b) treating the ring opened product with an inorganic base to be subject to a cyclization reaction to obtain a desired 2-hydroxymethyl-1,4,-benzodioxane compound represented by the formula(1), wherein * is a chiral center; each R1, R2, R3, and R4 is independently H, halogen, nitro, cyano, formyl, C1-4 alkyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, C1-4 alkylcarbonyloxy, C1-4 haloalkyl, N,N-di-(C1-4)alkylamino, (C1-4)alkylcarbonyl, (C1-4)alkoxycarbonyloxy, C6-10 aromatic hydrocarbon, C6-10 aromatic hydrocarbon substituted with halogen, C6-10 aromatic hydrocarbon substituted with C1-4 alkyl or two of the R1, R2, R3, and R4 adjacent to each other forms methylene deoxy or benzene ring; and X is a leaving group such as halogen and sulfonate.

Description

Process for preparing chiral 2-hydroxymethyl-1,4-benzodioxane compound {PROCESS FOR THE PREPARATION OF CHIRAL 2-HYDROXYMETHYL-1,4-BENZODIOXANE COMPOUND}

The present invention relates to a method for producing a 1,4-benzodioxane compound. More specifically, the present invention relates to a method for preparing a chiral 2-hydroxymethyl-1,4-benzodioxane compound.

1,4-benzodioxane or a derivative thereof is useful as an intermediate of psychoneuroplastic drugs, which are α- and β-adrenergic antagonists, and 2-hydroxymethyl-1,4-benzodioxane is particularly useful for the synthesis of doxazosin. . Doxazosin is a compound used as a therapeutic agent for hypertension (US Pat. No. 4,188,390), which is usually marketed in the form of (±) -doxazosin mesylate salt (Pfizer, trade name Kadura).

Doxazosin has one chiral center and can exist as (R) -isomer or (S) -isomer. Among them, it is known that the (S) -isomer has less side effects such as lethargy and dizziness than the racemate and the (R) -isomer and is more effective in treating hypertension (US Pat. No. 5,510,352). Such (S) -doxazosin can be easily obtained using (R) -2-hydroxymethyl-1,4-benzodioxane as a starting material. Specifically, (R) -2-hydroxy methyl-1,4-benzodioxane is oxidized to synthesize (S) -1,4-benzodioxane-2-carboxylic acid, and the obtained compound is combined with piperazine. The reaction is carried out to synthesize (S) -N- (1,4-benzodioxane) -2-carbonyl) piperazine. Thereafter, the reaction can be carried out with 4-amino-2-chloro-6,7-dimethoxyquinazoline to synthesize (S) -doxazosin or an acid addition salt thereof. If necessary, (S) -doxazosin or acid addition salts thereof can be reacted with methanesulfonic acid to synthesize (S) -doxazosin mesylate salt.

Such chiral medicines should be prepared with high optical purity in order to enhance the efficacy. In order to prepare high optical purity pharmaceuticals, it is essential to prepare high purity of 2-hydroxymethyl-1,4-benzodioxane or a derivative thereof used as starting materials. The following methods are known as methods for producing racemates or chiral bodies of 1,4-benzodioxane compounds.

First, a catechol derivative is reacted with racemic epihalohydrin in the presence of an inorganic strong base (sodium hydride, sodium butoxide, lithium amide) to undergo an epoxide ring-opening reaction and a subsequent ring-forming reaction, in-situ. ), A method of simultaneously performing (US Patent No. 4595767), a method of reacting a catechol derivative with chiral glycidyl nosylate in the presence of a fluorine salt or a fluorinated salt and an alkali / alkaline metal salt (JP-A-2001) -316385) are known. Since the former method uses a strong base, the selectivity is inferior, and racemization reaction proceeds during the reaction. Thus, although it may be useful for the preparation of racemates, it is difficult to produce chiral 1,4-benzodioxane compounds in high optical purity. The latter method is economical because it requires the use of expensive reagents such as cesium fluoride. In particular, when applied to mass production, waste containing fluorine adversely affects the environment and causes problems such as an increase in treatment costs.

It is known to selectively protect one of the two hydroxy groups present in the catechol and then to prepare 1,4-benzodioxane or derivatives thereof. For example, in the presence of potassium carbonate and a catalytic amount of tetrabutylammoniumhydrosulfonate, a mono-protected catechol derivative is reacted with a chiral glycidyl derivative or a chiral solketal derivative, followed by deprotection and cyclization to perform chiral A method for preparing 1,4-benzodioxane derivatives has been reported (US Pat. No. 5,999,909; Tetrahedron Lett. 1988, vol 29, p3671). However, the optical purity of the chiral glycidyl derivatives and chiral solketal derivatives are expensive compounds and the final product, the chiral 1,4-benzodioxane derivative, is lowered to 98% or less. Do.

In addition, the benzyl protected catechol derivatives in the presence of sodium hydride are reacted with chiral 3-halo-1,2-propanediol, followed by the formation of a carbonate compound using dimethyl carbonate, followed by debenzylation with a Pd / C catalyst. , A method for producing a 1,4-benzodioxane derivative by cyclization in the presence of sodium hydroxide has been reported (Korean Patent No. 504,522). Catechol derivatives protected in a similar manner. After reacting with chiral 3-halo-1,2-propanediol in the presence of sodium hydride, the obtained compound is reacted with a benzenesulfonyl chloride derivative and undergoes a cyclization reaction using sodium hydride to yield 1,4-benzodi. A method for preparing an oxane derivative has been reported (European Patent No. 1,553,095). However, since these methods use protected catechol derivatives, the protection and deprotection reactions must be carried out. Therefore, the reaction step is long. In addition, the use of expensive chiral 3-chloro-1,2-propanediol is inferior in economics.

As another alternative, there is an enzymatic method for selectively separating (S) -1,4-benzodioxane derivatives with racemic 1,4-benzodioxane derivatives in a vinyl acetate solvent using a lipase catalyst (Tetrahedron: Asymmetry , 1993, vol 4, p 339). This manufacturing method can obtain (S) -1,4-benzodioxane derivative with high optical purity of 99% ee or more, but it is inferior in industrial applicability due to low yield.

In addition, the salicylic aldehyde derivative or 2-hydroxy acetophenone derivative is reacted with epihalohydrin, followed by a Bayer-Villiger reaction using meta-chloroperbenzoic acid, and potassium hydroxide or alkali carbonate. There is a method of synthesizing 1,4-benzodioxane derivative by cyclization with a metal (Bioorg. Med. Chem. Lett. 2001, vol 11, p2783; European Patent No. 520,674; and European Patent 498,770). However, the use of expensive meta-chloroperbenzoic acid affords 1,4-benzodioxane having low economical efficiency and low optical purity of 93% ee or less.

It is an object of the present invention to provide a method for more economically preparing a chiral 1,4-benzodioxane compound having a high optical purity of 99% or more. According to the present invention, there is provided a method in which the chirality of the starting material is maintained and the desired 1,4-benzodioxane compound can be applied to industrial production with high optical purity of 99% ee or more.

According to a preferred embodiment of the present invention, a) epoxide ring-opening reaction is carried out by reacting an epoxide compound having formula (2) below with a catechol compound having formula (3) in the presence of a tertiary organic amine or an ammonium salt thereof. To obtain a ring-opening product from the reaction mixture, and b) treating the ring-opening product with an inorganic base to carry out a cyclization reaction, and from the obtained reaction mixture, the desired 2-hydroxy of formula (1) There is provided a process for the preparation of 2-hydroxymethyl-1,4-benzodioxane compound of Formula 1, comprising obtaining a methyl-1,4-benzodioxane compound:

Formula 1

Formula 2

Formula 3

In Chemical Formulas 1 to 3, * denotes a chiral center, and R ₁ , R ₂ , R _3, and R ₄ independently of each other, hydrogen, halogen, nitro, cyano, formyl, (C ₁ -C ₄ ) Alkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkylcarbonyloxy, (C ₁ -C ₄ ) haloalkyl, N, N-di - (C ₁ - C ₄₎ alkylamino, (C ₁ -C ₄₎ alkylcarbonyl, (C ₁ -C ₄₎ alkoxycarbonyloxy, C ₆ -C ₁₀ aromatic hydrocarbon group, a halogen atom-substituted C ₆ -C ₁₀ aromatic hydrocarbon, C ₆ -C ₁₀ aromatic hydrocarbon substituted by (C ₁ -C ₄ ) alkyl, or two adjacent groups of R ₁ , R ₂ , R ₃ and R ₄ combine with each other to form a methylenedioxy group or a benzene ring Where X represents a leaving group.

According to a more preferred embodiment of the present invention, 2-hydroxymethyl-1,4-benzodi, characterized in that the ring-opening product of step a) is applied to the next step of cyclization reaction in crude form. A method for producing an oxane compound is provided.

According to another preferred embodiment of the present invention, the ring-opening product is characterized in that having the formula (4), there is provided a method for preparing a 2-hydroxymethyl-1,4-benzodioxane compound:

Formula 4

In Chemical Formula 4, * means chiral center, and R ₁ , R ₂ , R ₃ , R ₄ and X are as defined above.

According to another preferred embodiment of the present invention, the epoxide compound of the formula (2) is epihalohydrin or glycidylsulfonate, the method for preparing 2-hydroxymethyl-1,4-benzodioxane Is provided. Examples of epihalohydrin are chiral epifluorohydrin, chiral epichlorohydrin, chiral epibromohydrin or chiral epiiohydrin, and examples of glycidylsulfonate include chiral glycidylmethanesulfonate, Chiral glycidyl-p-toluenesulfonate, chiral glycidyl-m-nitrobenzenesulfonate, chiral glycidyl-p-nitrobenzene sulfonate, chiral glycidyltrifluoromethanesulfonate or chiral glycidyl Benzene sulfonate. Most preferably, it is chiral epichlorohydrin.

According to another preferred embodiment of the invention, the tertiary organic amine is an aliphatic amine represented by R ₁ R ₂ R ₃ N (wherein R ₁ , R ₂ and R ₃ are independently of each other C ₁ -C Of an alkyl group of ₆ , an alkenyl group of C ₂ -C ₁₆ , or a benzyl group) or a heteroaromatic organic amine of C ₄ -C ₁₀ of the 2-hydroxymethyl-1,4-benzodioxane compound. A manufacturing method is provided. Specific examples include trimethylamine, triethylamine, tripropylamine, dimethylethylamine, tributylamine, N-methylpyrrolidine, N-methylpiperidine, diisopropylethylamine, triphenylamine, pyridine, pyrrole Or lutidine. Most preferably pyridine.

According to another preferred embodiment of the invention, step a) is carried out in an organic solvent which is not mixed with water, and step b) is carried out in 2-hydroxymethyl-1, which is carried out in an organic solvent which is mixed with water, Provided is a method for preparing a 4-benzodioxane compound. Preferably, the organic solvent of step a) is ethyl acetate, and the organic solvent of step b) is C ₁ -C ₄ alcohol.

The present invention relates to a method for preparing a chiral 1,4-benzodioxane compound, the method comprising:

a) carrying out an epoxide ring opening reaction by reacting a chiral epoxide compound having the formula (2) with a catechol compound having the formula (3) in the presence of a tertiary organic amine or an ammonium salt thereof and performing ring opening from the reaction mixture. Obtaining a equivalent; And

b) subjecting the obtained ring-opening product to an inorganic base to carry out a cyclization reaction, and from the obtained reaction mixture, obtaining the desired chiral 2-hydroxymethyl-1,4-benzodioxane compound of the formula (1); Include.

로 표시되는 술포네이트기이고, 여기서, R₅는 C₁-C₁₀ 알킬기; C₆-C₁₀ 아릴기; 또는 니트로기, 메틸기, 에틸기, 플루오로기 또는 클로로기로 치환된 C₆-C₁₀ 아릴기를 의미한다. In Chemical Formulas 1 to 3, * denotes a chiral center, and R ₁ , R ₂ , R _3, and R ₄ independently of each other, hydrogen, halogen, nitro, cyano, formyl, (C ₁ -C ₄ ) Alkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkylcarbonyloxy, (C ₁ -C ₄ ) haloalkyl, N, N-di -(C ₁ -C ₄ ) alkylamino, (C ₁ -C ₄ ) alkylcarbonyl, (C ₁ -C ₄ ) alkoxycarbonyloxy, C ₆ -C ₁₀ aromatic hydrocarbons, C ₆ -C substituted with halogen atoms ₁₀ aromatic hydrocarbon, C ₆ -C ₁₀ aromatic hydrocarbon substituted by (C ₁ -C ₄ ) alkyl, or two adjacent groups of R ₁ , R ₂ , R ₃ and R ₄ combine with each other to form a methylenedioxy group or a benzene ring X may represent a leaving group, preferably a halogen group or

Is a sulfonate group represented by: wherein R ₅ is a C ₁ -C ₁₀ alkyl group; C ₆ -C ₁₀ aryl group; Or a C ₆ -C ₁₀ aryl group substituted with a nitro group, methyl group, ethyl group, fluoro group or chloro group.

In the present invention, the ring-opening reaction of the epoxide compound having the formula (2) with the catechol compound of the formula (3) and the ring-opening reaction of the ring-opening product with an inorganic base in the presence of a tertiary organic amine or an ammonium salt thereof This is done sequentially.

The epoxide compound of Formula 2 is preferably an optically active substance. Preferred examples of the epoxide compound having the formula (2) are chiral epihalohydrin or chiral glycidylsulfonate. As chiral epihalohydrin, chiral epifluorohydrin, chiral epichlorohydrin, chiral epibromohydrin or chiral epiiodhydrin can be used. As chiral glycidylsulfonate, chiral glycidylmethanesulfonate, chiral glycidyl-p-toluenesulfonate, chiral glycidyl-m-nitrobenzenesulfonate, chiral glycidyl-p-nitrobenzene sulfonate Chiral glycidyltrifluoromethanesulfonate or chiral glycidyl benzene sulfonate can be used. Most preferably, it is chiral epichlorohydrin. Preferred examples of the catechol compound of formula (3) are catechols in which the substituents R ₁ , R ₂ , R ₃ and R ₄ are all hydrogen.

The epoxide ring-opening reaction is carried out in the presence of a tertiary organic amine or an ammonium salt thereof. The tertiary organic amine is an aliphatic amine represented by R ₁ R ₂ R ₃ N (wherein R ₁ , R ₂ and R ₃ are independently of each other an alkyl group of C ₁ -C ₆ and an alkenyl group of C ₂ -C ₁₆₎ . Or a benzyl group) or a C ₄ -C ₁₀ heteroaromatic organic amine can be used. Specific examples include trimethylamine, triethylamine, tripropylamine, tributylamine, dimethylethylamine, N-methylpyrrolidine, N-methylpiperidine, diisopropylethylamine, triphenylamine, pyridine, pyrrole , Rutidine and the like can be mentioned. The organic amine may be used in the form of an ammonium salt. Examples of ammonium salts are benzyltrimethylammonium chloride, diallyldimethylammonium chloride, benzyltrimethylammonium bromide, n-octyltrimethylammonium bromide, stearyl trimethylammonium bromide, cetyldimethyldimethylammonium bromide, tetra n-butylammonium iodide, iodide β-methyl Choline, hydrogen sulfate tetra-n-butylammonium, phenyl trimethylammonium hydroxide, etc. are mentioned. Pyridine was most preferred as a result of tests on various organic amines and ammonium salts thereof. The tertiary organic amine or its ammonium salt may be used within the range of 0.01 to 1.00 equivalent, based on the epoxide compound of the formula (2). More preferably, it is 0.1-0.2 equivalent.

The epoxide ring-opening reaction is carried out under an organic solvent. Selection of organic solvents will be apparent to those of ordinary skill in the art. Organic solvents such as alcohols, tetrahydrofuran, dioxane, acetone, N, N-dimethylformaldehyde, dimethylsulfoxide, aromatic hydrocarbons, ethers, esters, C ₁ -C ₄ halogenated hydrocarbons and the like can be widely employed. Preferably, it is an organic solvent which is not mixed with water. Especially preferably, it is ethyl acetate. The organic solvent is used 0.5 to 10 times based on the volume of the epoxide compound of formula (2). Preferably it is 1.5 times. The epoxide ring-opening reaction is carried out in the range of 0 to 80 ℃, preferably 20 to 45 ℃.

By the ring-opening reaction, preferably, a ring-opening product having the formula (4) is obtained. Sometimes they may be in the form of epoxides.

In Chemical Formula 4, * means a chiral center, and the definitions of R ₁ , R ₂ , R ₃ , R _4, and X are as described above.

Following the epoxide ring-opening reaction, a cyclization reaction is performed. The cyclization reaction is carried out in the presence of an inorganic base. Examples of bases that can be used in the cyclization reaction include alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal hydrides, alkali metal alkoxide salts, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, alkaline earth metal bicarbonates, alkali metal phosphates and alkalis. Earth metal phosphates. Specifically, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, carbonate Magnesium, calcium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, cesium phosphate, magnesium phosphate and calcium phosphate may be used. Preferably, sodium hydroxide. They are added in the dissolved state.

The organic solvent used in step b), which is a cyclization reaction, may be a C ₁ -C ₄ alcohol such as methanol, ethanol, propanol, isopropanol, butanol, etc., tetrahydrofuran, acetonitrile, N, N-dimethylformamide or dimethylsulfoxide. It is a solvent that can be mixed with water such as seeds. Preferably, it is methanol or ethanol. Most preferably, methanol. The amount of the solvent used is 1/20 to 10 times the base solution, preferably 1/10 to 1 times.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are presented for the understanding of the present invention, and the scope of the present invention is not limited to these examples.

Example

Example 1

10 g (0.1081 mole, 1.0 eq) of (R) -epichlorohydrin was dissolved in 18 ml of ethyl acetate, and then 21.436 g (0.1946 mole, 1.8 eq) of catechol was added. To this, 1.74 ml (0.0216 mole, 0.2 eq) of pyridine was added and stirred at 40 ° C. for 2 days. 2M sulfuric acid was added to the reaction mixture to adjust the pH to 4-5. After washing with water, the solvent was removed under reduced pressure. The resulting crude product was dissolved in 23 ml of methanol, 233 ml (0.2594 mole, 2.4 eq) of 2M NaOH at 0 ° C. was added dropwise for 1.5 hours, followed by stirring for 2.5 hours. The reaction was terminated and extracted with methylene chloride, and washed sequentially with 2M aqueous NaOH solution and water. After drying over magnesium sulfate, the solvent was filtered off and the mother liquor was removed under reduced pressure to obtain 12.124 g (68%, 99.4% ee) of (R) -2-hydroxymethyl-1,4-benzodioxane.

The optical purity (% ee) of 2-hydroxymethyl-1,4-benzodioxane was calculated from the area ratio using a high performance liquid chromatography method. Knauer's Eurocel OD (0.46 cm) 25 cm) was used, and a mixture of n-hexane and isopropanol 90:10 (v / v) was flowed at 1.0 ml / min. Spectra were obtained at 254 nm, and (R) was detected at 7.51 min and (S) was at 8.07 min.

Example 2

10 g (0.1081 mole, 1.0 eq) of (R) -epichlorohydrin was dissolved in 18 ml of acetone, followed by addition of 21.436 g (0.1946 mole, 1.8 eq) of catechol. To this, 1.74 ml (0.0216 mole, 0.2 eq) of pyridine was added and stirred at 40 ° C. for 2 days. The reaction mixture was removed solvent under reduced pressure. The resulting crude product was dissolved in 23 ml of methanol, 233 ml (0.2594 mole, 2.4 eq) of 2M NaOH at 0 ° C. was added dropwise for 1.5 hours, followed by stirring for 2.5 hours. The reaction was terminated and extracted with methylene chloride, and washed sequentially with 2M aqueous NaOH solution and water. After drying over magnesium sulfate, the mixture was filtered and the mother liquor was removed under reduced pressure to synthesize 11.045 g (61%, 99.2% ee) of (R) -2-hydroxymethyl-1,4-benzodioxane.

Example 3

10 g (0.1081 mole, 1.0 eq) of (R) -epichlorohydrin was dissolved in 18 ml of ethyl acetate, and then 21.436 g (0.1946 mole, 1.8 eq) of catechol was added. To this, 0.87 ml (0.0108 mole, 0.10 eq) of pyridine was added and stirred at 40 ° C. for 3 days. 2M sulfuric acid was added to the reaction mixture to adjust the pH to 4-5. After washing with water, the solvent was removed under reduced pressure. The resulting crude product was dissolved in 23 ml of methanol, 233 ml (0.2594 mole, 2.4 eq) of 2M NaOH at 0 ° C. was added dropwise for 1.5 hours, followed by stirring for 2.5 hours. The reaction was terminated and extracted with methylene chloride, and washed sequentially with 2M aqueous NaOH solution and water. After drying over magnesium sulfate, the solution was filtered and the mother liquor was removed under reduced pressure to synthesize 9.551 g (53%, 99.3% ee) of (R) -2-hydroxymethyl-1,4-benzodioxane.

Example 4

10 g (0.1081 mole, 1.0 eq) of (R) -epichlorohydrin was dissolved in 18 ml of ethyl acetate, and then 21.436 g (0.1946 mole, 1.8 eq) of catechol was added. To this, 0.87 ml (0.0108 mole, 0.10 eq) of pyridine was added and stirred at room temperature for 4.5 days. 2M sulfuric acid was added to the reaction mixture to adjust the pH to 4-5. After washing with water, the solvent was removed under reduced pressure. The obtained crude product was dissolved in 23 ml of methanol, 233 ml (0.2594 mole, 2.4 eq) of 2M NaOH at 0 ° C. was added dropwise for 1.5 hours, followed by stirring for 2.5 hours. The reaction was terminated and extracted with methylene chloride, and washed sequentially with 2M aqueous NaOH solution and water. After drying over magnesium sulfate, the solution was filtered and the mother liquor was removed under reduced pressure to synthesize 9.542 g (53%, 99.4% ee) of (R) -2-hydroxymethyl-1,4-benzodioxane.

Example 5

10 g (0.1081 mole, 1.0 eq) of (R) -epichlorohydrin was dissolved in 18 ml of ethyl acetate, and then 21.436 g (0.1946 mole, 1.8 eq) of catechol was added. To this was added 3.01 ml (0.0216 mole, 0.2 eq) of triethylamine and stirred at 40 ° C. for 3 days. 2M sulfuric acid was added to the reaction mixture to adjust the pH to 4-5. After washing with water, the solvent was removed under reduced pressure. The obtained crude product was dissolved in 23 ml of methanol, 233 ml (0.2594 mole, 2.4 eq) of 2M NaOH at 0 ° C. was added dropwise for 1.5 hours, followed by stirring for 2.5 hours. The reaction was terminated and extracted with methylene chloride, and washed sequentially with 2M aqueous NaOH solution and water. After drying over magnesium sulfate, the mixture was filtered and the mother liquor was removed under reduced pressure to synthesize 9.873 g (55%, 99.4% ee) of (R) -2-hydroxymethyl-1,4-benzodioxane.

Example 6

10 g (0.1081 mole, 1.0 eq) of (R) -epichlorohydrin was dissolved in 18 ml of ethyl acetate, and then 21.436 g (0.1946 mole, 1.8 eq) of catechol was added. To this, 1.15 ml (0.0108 mole, 0.1 eq) of triethylamine was added and stirred at 40 ° C. for 4.5 days. 2M sulfuric acid was added to the reaction mixture to adjust the pH to 4-5. After washing with water, the solvent was removed under reduced pressure. The obtained crude product was dissolved in 23 ml of methanol, 233 ml (0.2594 mole, 2.4 eq) of 2M NaOH at 0 ° C. was added dropwise for 1.5 hours, followed by stirring for 2.5 hours. The reaction was terminated and extracted with methylene chloride, and washed sequentially with 2M aqueous NaOH solution and water. After drying over magnesium sulfate, the mixture was filtered and the mother liquor was removed under reduced pressure to synthesize 6.138 g (34%, 99.2% ee) of (R) -2-hydroxymethyl-1,4-benzodioxane.

Example 7

10 g (0.1081 mole, 1.0 eq) of (R) -epichlorohydrin was dissolved in 18 ml of ethyl acetate, and then 21.436 g (0.1946 mole, 1.8 eq) of catechol was added. To this, 6.008 g (0.0216 mole, 0.2 eq) of tetrabutylammonium chloride was added and stirred at 40 ° C. for 3 days. The reaction mixture was removed under reduced pressure. The obtained crude product was dissolved in 23 ml of methanol, 233 ml (0.2594 mole, 2.4 eq) of 2M NaOH at 0 ° C. was added dropwise for 1.5 hours, followed by stirring for 2.5 hours. The reaction was terminated and extracted with methylene chloride, and washed sequentially with 2M aqueous NaOH solution and water. After drying over magnesium sulfate, the solution was filtered and the mother liquor was removed under reduced pressure to synthesize 7.954 g (44%, 99.2% ee) of (R) -2-hydroxymethyl-1,4-benzodioxane.

Example 8

200 g (2.1617 mole, 1.0 eq) of (R) -epichlorohydrin was dissolved in 18 ml of ethyl acetate, and then 428.72 g (3.8911 mole, 1.8 eq) of catechol was added. To this, 34.97 ml (0.4323 mole, 0.2 eq) of pyridine was added and stirred at 40 ° C. for 2 days. 2M sulfuric acid was added to the reaction mixture to adjust the pH to 4-5. After washing with water, the solvent was removed under reduced pressure. The obtained crude product was dissolved in 23 ml of methanol, 4320 ml of 2M NaOH (8.6468 mole, 4.0 eq) was added dropwise at 0 ° C. for 1.5 hours, followed by stirring for 2.5 hours. The reaction was terminated and extracted with methylene chloride and washed sequentially with 2M aqueous NaOH solution and water. After drying over magnesium sulfate, the mixture was filtered and the mother liquor was removed under reduced pressure to synthesize 223.35 g (62%, 99.4% ee) of (R) -2-hydroxymethyl-1,4-benzodioxane.

According to the present invention, a 2-hydroxymethyl-1,4-benzodioxane compound having the formula (1) is obtained while maintaining the optical purity of the starting material. Thus, a target compound having a high optical purity of 99% ee or higher is produced. In addition, the intermediate produced as the ring-opening product can be applied directly to the cyclization reaction as a crude product. This contributes to the improvement of yield.

Claims (16)

a) epoxide ring opening reaction is carried out by reacting an epoxide compound having the formula (2) below with a catechol compound having the formula (3), in the presence of a tertiary organic amine or an ammonium salt thereof, Obtaining water, and b) subjecting the ring-opening product to an inorganic base to perform a cyclization reaction, and from the obtained reaction mixture, obtaining the desired 2-hydroxymethyl-1,4-benzodioxane compound of the formula (1). Method for producing a 2-hydroxymethyl-1,4-benzodioxane compound of the formula (I): Formula 1

Formula 2

Formula 3

In Chemical Formulas 1 to 3, * denotes a chiral center, and R ₁ , R ₂ , R _3, and R ₄ independently of each other, hydrogen, halogen, nitro, cyano, formyl, (C ₁ -C ₄ ) Alkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkylcarbonyloxy, (C ₁ -C ₄ ) haloalkyl, N, N-di -(C ₁ -C ₄ ) alkylamino, (C ₁ -C ₄ ) alkylcarbonyl, (C ₁ -C ₄ ) alkoxycarbonyloxy, C ₆ -C ₁₀ aromatic hydrocarbons, C ₆ -C substituted with halogen atoms ₁₀ aromatic hydrocarbon, C ₆ -C ₁₀ aromatic hydrocarbon substituted by (C ₁ -C ₄ ) alkyl, or two adjacent groups of R ₁ , R ₂ , R ₃ and R ₄ combine with each other to form a methylenedioxy group or a benzene ring X can be taken as a leaving group, and a halogen group or a sulfonate group is meant. The preparation of 2-hydroxymethyl-1,4-benzodioxane according to claim 1, wherein the ring-opening product of step a) is subjected to the cyclization reaction of the next step in a crude form. Way. The method for preparing 2-hydroxymethyl-1,4-benzodioxane according to claim 1, wherein the ring-opening product has the following Chemical Formula 4. Formula 4

In Chemical Formula 4, * means chiral center, and the definitions of R ₁ , R ₂ , R ₃ , R _4, and X are as defined in claim 1. The method of claim 1, wherein the epoxide compound of Formula 2 is epihalohydrin or glycidylsulfonate. The method according to claim 4, wherein the epihalohydrin is selected from the group consisting of chiral epifluorohydrin, chiral epichlorohydrin, chiral epibromohydrin and chiral epiiodhydrin, and the glycidyl sulfo Nate is chiral glycidyl methanesulfonate, chiral glycidyl-p-toluenesulfonate, chiral glycidyl-m-nitrobenzenesulfonate, chiral glycidyl-p-nitrobenzene sulfonate, chiral glycidyl triple A process for producing a 2-hydroxymethyl-1,4-benzodioxane compound, characterized in that it is selected from the group consisting of rocromethanesulfonate and chiral glycidyl benzene sulfonate. The method for producing 2-hydroxymethyl-1,4-benzodioxane compound according to claim 4, wherein the epihalohydrin is chiral epichlorohydrin. The method for producing 2-hydroxymethyl-1,4-benzodioxane compound according to claim 1, wherein R ₁ , R ₂ , R ₃ and R ₄ are all hydrogen. The tertiary organic amine of claim 1, wherein the tertiary organic amine is an aliphatic amine represented by R ₁ R ₂ R ₃ N, wherein R ₁ , R _2, and R ₃ are each independently of the C ₁ -C ₆ alkyl group, C ₂ -C ₁₆ alkenyl group, or benzyl group) or C ₄ -C ₁₀ heteroaromatic organic amine, characterized in that the method for producing a 2-hydroxymethyl-1,4-benzodioxane compound. The method of claim 8, wherein the tertiary organic amine is trimethylamine, triethylamine, tripropylamine, dimethylethylamine, tributylamine, N-methylpyrrolidine, N-methylpiperidine, diisopropylethyl A method for producing a 2-hydroxymethyl-1,4-benzodioxane compound, characterized in that it is an amine, triphenylamine, pyridine, pyrrole or lutidine. 10. The process for producing 2-hydroxymethyl-1,4-benzodioxane compound according to claim 9, wherein the tertiary organic amine is pyridine. According to claim 1, wherein the epoxide compound having the formula (2) is characterized in that the optically active, a method for producing a 2-hydroxymethyl-1,4-benzodioxane compound. The method of claim 1, wherein X is

Is a sulfonate group represented by: wherein R ₅ is a C ₁ -C ₁₀ alkyl group; C ₆ -C ₁₀ aryl group; Or a C ₆ -C ₁₀ aryl group substituted with a nitro group, methyl group, ethyl group, fluoro group, or chloro group. The inorganic base used in step b) is an alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal hydride, alkali metal alkoxide salt, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, alkali It is a metal phosphate or alkaline-earth metal phosphate, The manufacturing method of the 2-hydroxymethyl- 1, 4- benzo dioxane compound. The method for producing the 2-hydroxymethyl-1,4-benzodioxane compound according to claim 13, wherein the inorganic base is sodium hydroxide. The method of claim 1, wherein step a) is performed in an organic solvent which is not mixed with water, and step b) is performed in an organic solvent which is mixed with water, 2-hydroxymethyl-1, Method for producing 4-benzodioxane compound. The method of claim 15, wherein the organic solvent of step a) is ethyl acetate, the organic solvent of step b) is C ₁ -C ₄ alcohol, 2-hydroxymethyl-1,4-benzo di Method for producing an oxane compound.