WO2008016199A1

WO2008016199A1 - Process for the preparation of chiral 2-hydroxymethyl-1,4-benzodioxane compound

Info

Publication number: WO2008016199A1
Application number: PCT/KR2006/003458
Authority: WO
Inventors: Jin Auh; Duk Kwon Won; Byung Hyun Moon; O Zoon Kwon; Chang Woo Jong; Kyung Yong Jin; Long Guo Quan; Hyun Bin Kang; Seong-Jin Kim
Original assignee: Ahn-Gook Pharmaceutical Co., Ltd.; Rstech Corporation
Priority date: 2006-08-02
Filing date: 2006-08-31
Publication date: 2008-02-07
Also published as: CN101501016A; CN101501016B; KR100780538B1

Abstract

The present invention relates to a process for the preparation of chiral 2-hydroxymethyl-l,4-benzodioxane compound. The method in accordance with the present invention comprises the steps of reacting chiral epihalohydrin or chiral glycidyl sulfonate with catechol or its derivative in a presence of a tertiary organic amine or its ammonium salt to carry out an ring opening reaction of the epoxide compound and treating the ring-opened product with an inorganic base to carry out a cyclization reaction of the ring-opened product to prepare the targeted 2-hydroxymethyl-l,4-benzodioxane. The method of the present invention provides the chiral 2-hydroxymethyl-l,4-benzodioxane compound in high optical purity and with improved yield due to reduced side reactions.

Description

PROCESS FOR THE PREPARATION OF CHIRAL 2-HYDROXYMETHYL-l,4-BENZODIOXANE COMPOUND

Technical Field

[1] The present invention relates to a process for the preparation of a 1,4-benzodioxane compound. More particularly, the present invention relates to a process for the preparation of a chiral 2-hydroxymethyl- 1,4-benzodioxane compound. Background Art

[2] 1,4-Benzodioxane and its derivatives are useful intermediates for the synthesis of α- or β- adrenoceptor antagonist, a psychoneurotic drug. Especially, 2-hydroxymethyl- 1,4-benzodioxane is useful in the synthesis of doxazosin. Doxazosin is a compound useful for the treatment of hypertension (U.S. Patent No. 4,188,390), which is typically sold in a form of (±)-doxazosin mesylate (Pfizer, trademark name "Cardular").

[3] Doxazosin has one chiral center and can be present in either (R)-isomer or (S

)-isomer. Of the two stereoisomers, the (S)-isomer is known to be more effective in the treatment of hypertension compared with the racemate or the (R)-isomer, because of fewer side effects such as lethargy, dizziness, etc. (U.S. Patent No. 5,510,352). (S )-Doxazosin can be easily prepared from (R) -2-hydroxymethyl- 1,4-benzodioxane as the starting material. Specifically, (R) -2-hydroxymethyl- 1,4-benzodioxane is oxidized to provide (S)-l,4-benzodioxane-2-carboxylic acid, which is reacted with piperazine to provide (S)-/V-((l,4-benzodioxane)-2-carbonyl)piperazine. Thereafter, the obtained product is reacted with 4-amino-2-chloro-6,7-dimethoxyquinazoline to obtain (S )-doxazosin or its acid additive salt. If necessary, (S)-doxazosin or its acid additive salt may be reacted with methanesulfonic acid to prepare (S)-doxazosin mesylate.

[4] Such a chiral drug needs to be prepared in high optical purity to exhibit superior efficacy. In order to produce a drug with high optical purity, the starting material 2-hydroxymethyl- 1,4-benzodioxane or its derivative has to be prepared in high purity. The following methods were known for preparing racemic or chiral 1,4-benzodioxane compound.

[5] The compound was prepared by reacting a catechol derivative with racemic epi- halohydrin in the presence of an inorganic strong base (sodium hydride, sodium butoxide or lithium amide) to result in in-situ epoxide ring opening and cyclization (U.S. Patent No. 4,595,767), or by reacting a catechol derivative with chiral glycidyl nosylate in the presence of a fluoride salt or in combination with a salt of an alkali/ alkaline earth metal (Japanese Laid-Open Patent No. 2001-316385). The former has low selective due to the use of a strong base and racemization occurs during the reaction. Accordingly, while the method is useful for the preparation of racemates, it is not adequate for the preparation of the chiral 1,4-benzodioxane compound in high optical purity. The latter suffers from low price competitiveness because expensive reagent such as cesium fluoride has to be used. Especially, when applied to mass production, the fluorine-containing wastes are deleterious to the environment and increase the treatment cost.

[6] 1,4-benzodioxane or its derivatives was known to be prepared after selectively protection of one of two hydroxyl groups of the catechol. For example, there was reported a method of preparing a chiral 1,4-benzodioxane derivative, comprising reacting a mono-protected catechol derivative with a chiral glycidyl derivative or a chiral solketal derivative in the presence of potassium carbonate and a catalytic amount of tetrabutylammonium hydrosulfonate, followed by deprotection and cyclization (U.S. Patent No. 5,948,909; Tetrahedron Lett. 1988, vol. 29, p3671). However, the chiral glycidyl derivative and the chiral solketal derivative are expensive compounds and the final product, chiral 1,4-benzodioxane derivative, has an optical purity of no more than 98%, which is not sufficient to be used as an intermediate for the preparation of chiral drugs.

[7] There was reported a method of preparing a 1,4-benzodioxane derivative, comprising reacting a catechol derivative protected with benzyl with a chiral 3-halo-l,2-propanediol in the presence of sodium hydride, followed by the reaction with dimethyl carbonate to provide a carbonate compound, removing the benzyl group using a Pd/C catalyst and performing cyclization in the presence of sodium hydroxide (Korean Patent No. 504,522 d). As an similar method, there was also reported a process of preparing a 1,4-benzodioxane derivative, comprising reacting a protected catechol derivative with a chiral 3-halo-l,2-propanediol in the presence of sodium hydride, reacting the obtained compound with a benzenesulfonyl chloride derivative and performing cyclization using sodium hydride (European Patent No. 1,553,095). But, these methods require the protected catechol as a starting material, so protection and deprotection reaction are essentially required. As thus, the reaction procedures become complicated. Further, they are uneconomical due to the use of an expensive chiral 3-chloro-l,2-propanediol.

[8] Alternative was an enzymatic method that selectively separates the (S

)- 1,4-benzodioxane derivative from racemic 1,4-benzodioxane by a lipase catalyst in vinyl acetate as a solvent (Tetrahedron: Asymmetry, 1993, vol. 4, p339). The method provides the (S)- 1,4-benzodioxane derivative in high optical purity of 99%ee or more. However, the method was industrially inapplicable due to low productivity.

[9] Besides, there was known a method of preparing the 1,4-benzodioxane derivative, comprising reacting a salicylaldehyde derivative or a 2-hydroxy acetophenone derivative with epihalohydrin, performing Baeyer-Villiger reaction using m - chloroperoxybenzoic acid and performing cyclization using potassium hydroxide or alkali metal carbonate (Bioorg. Med. Chem. Lett. 2001, vol. 11, p. 2783; European Patent No. 520,674; and European Patent No. 498,770). However, the method is uneconomical because expensive m-chloroperoxybenzoic acid is used and the resultant 1,4-benzodioxane has a low optical purity of no more than 93%ee. Disclosure of Invention Technical Problem

[10] An object of the present invention is to provide a process for the preparation of a chiral 1,4-benzodioxane compound having a high optical purity of 99% or more in an economic manner. According to the present invention, there is provided a process for preparing the 1,4-benzodioxane compound, wherein the chirality of the starting material is retained and the targeted 1,4-benzodioxane compound is prepared in an optical purity of 99%ee or more. Technical Solution

[11] According to a preferred embodiment of the present invention, there is provided a process for the preparation of 2-hydroxymethyl- 1,4-benzodioxane compound having formula 1, which comprises the steps of: a) reacting an epoxide compound of formula 2 with a catechol compound of formula 3 in a presence of a tertiary organic amine or its ammonium salt to carry out a ring opening reaction of the epoxide compound, followed by collecting a ring-opened product from a reaction mixture; and b) treating the ring-opened product with an inorganic base to carry out a cyclization reaction of the ring-opened product, followed by recovering the targeted product 2-hydroxymethyl- 1,4-benzodioxane of formula 1 from a reaction mixture:

[12] Formula 1

[13]

[14] Formula 2

[15]

[16] Formula 3 [17]

[18] wherein, * represents a chiral center, R , R , R and R are each independently hydrogen, halogen, nitro, cyano, formyl, (C -C ) alkyl, (C -C ) alkoxy, (C -C ) alkoxycarbonyl, (C -C ) alkylcarbonyloxy, (C -C ) haloalkyl, N,N-di-(C -C )

1 4 1 4 1 4 alkylamino, (C -C ) alkylcarbonyl, (C -C ) alkoxycarbonyloxy, C -C aromatic hydrocarbon, C -C aromatic hydrocarbon substituted with halogen, or C -C aromatic

6 10 ^{J to} 6 10 hydrocarbon substituted with (C -C ) alkyl, or two neighboring substituents of R , R ,

1 4 1 2

R and R taken together form a methylenedioxy group or a benzene ring, and X

3 4 represents a leaving group.

[19] According to more preferred embodiment of the present invention, there is provided a process for the preparation of 2-hydroxymethyl-l,4-benzodioxane compound, wherein the ring-opened product of the step a) is collected as a crude product and subjected to the next cyclization reaction.

[20] According to another preferred embodiment of the present invention, there is provided a process for the preparation of 2-hydroxymethyl-l,4-benzodioxane compound, wherein the ring-opened product has formula 4:

[21] Formula 4 [22]

[23] wherein, * represents a chiral center and R , R , R , R and X are the same as defined in the above. [24] According to further another preferred embodiment of the present invention, there is provided a process for the preparation of 2-hydroxymethyl-l,4-benzodioxane compound, wherein the epoxide compound of formula 2 is epihalohydrin or glycidyl sulfonate. Examples of the epihalohydrin include chiral epifluorohydrin, chiral epichlorohydrin, chiral epibromohydrin and chiral epiiodohydrin and examples of the glycidyl sulfonate includes chiral glycidylmethanesulfonate, chiral glycidyl-/? - toluenesulfonate, chiral glycidyl-m-nitrobenzenesulfonate, chiral glycidyl-/? - nitrobenzenesulfonate, chiral glycidyltrifluoromethanesulfonate and chiral glycidyl- benzenesulfonate. Most preferable is chiral epichlorohydrin.

[25] According to still further another preferred embodiment of the present invention, there is provided a process for the preparation of 2-hydroxymethyl-l,4-benzodioxane compound, wherein the tertiary organic amine is an aliphatic amine represented by R i R

R N (wherein R , R and R are each independently C -C alkyl, C -C alkenyl or

2 3 1 2 3 ^{r ■7} 1 6 -⁷ 2 16 ^J benzyl) or a C -C heteroaromatic organic amine. As a specific example, trimethylamine, triethylamine, tripropylamine, dimethylethylamine, tributylamine, N - methylpyrrolidine, JV-methylpiperidine, diisopropylethylamine, triphenylamine, pyridine, pyrrole or lutidine can be mentioned. Most preferable is pyridine. [26] According to yet another preferred embodiment of the present invention, there is provided a process for the preparation of 2-hydroxymethyl-l,4-benzodioxane compound, wherein the step a) is performed in a water-immiscible organic solvent and the step b) is performed in a water-miscible organic solvent. Preferably, the organic solvent of the step a) is ethyl acetate and the organic solvent of the step b) is C -C alcohol.

Advantageous Effects

[27] According to the method of the present invention, the optical purity of the starting material is retained throughout the reactions, thereby producing the 2-hydroxymethyl-l,4-benzodioxane compound of formula 1 in high optical purity of 99%ee or more. Further, the ring-opened intermediate can be subjected to the cy- clization reaction as a crude product such that the overall yield can be improved. Mode for the Invention

[28] The present invention relates to a process for the preparation of

2-hydroxymethyl-l,4-benzodioxane compound having formula 1, which comprises the steps of:

[29] a) reacting an epoxide compound of formula 2 with a catechol compound of formula 3 in a presence of a tertiary organic amine or its ammonium salt to carry out a ring opening reaction of the epoxide compound, followed by collecting a ring-opened product from a reaction mixture; and

[30] b) treating the ring-opened product with an inorganic base to carry out a cyclization reaction of the ring-opened product, followed by recovering the targeted product 2-hydroxymethyl-l,4-benzodioxane of formula 1 from a reaction mixture:

[31] Formula 1

[32]

[34]

O

X

[35] Formula 3 [36]

[37] wherein, * represents a chiral center, R , R , R and R are each independently hydrogen, halogen, nitro, cyano, formyl, (C -C ) alkyl, (C -C ) alkoxy, (C -C ) alkoxycarbonyl, (C -C ) alkylcarbonyloxy, (C -C ) haloalkyl, N,N-di-(C -C ) alkylamino, (C -C ) alkylcarbonyl, (C -C ) alkoxycarbonyloxy, C -C aromatic hydrocarbon, C -C aromatic hydrocarbon substituted with halogen, or C -C aromatic

6 10 ^{J &} 6 10 hydrocarbon substituted with (C -C ) alkyl, or two neighboring substituents of R , R , R and R taken together form a methylenedioxy group or a benzene ring, and X represents a leaving group, preferably halogen or sulfonate represented by

, wherein R is C -C alkyl group, C -C aryl group or C -C aryl group substituted

5 1 10 6 10 6 10 with nitro group, methyl group, ethyl group, fluoro group or chloro group.

[38] In accordance with the present invention, the ring opening reaction of the epoxide compound of formula 2 by the catechol compound of formula 3 in the presence of a tertiary organic amine or its an ammonium salt and the cyclization reaction of the ring- opened product by an inorganic base are carried out sequentially .

[39] Preferred examples of the epoxide compound of formula 2 are chiral epihalohydrin and chiral glycidyl sulfonate. As a chiral epihalohydrin, chiral epifluorohydrin, chiral epichlorohydrin, chiral epibromohydrin or chiral epiiodohydrin can be used. And, as a chiral glycidyl sulfonate, chiral glycidylmethanesulfonate, chiral glycidyl-/? - toluenesulfonate, chiral glycidyl-m-nitrobenzenesulfonate, chiral glycidyl-/? - nitrobenzenesulfonate, chiral glycidyltrifluoromethanesulfonate or chiral glycidylben- zenesulfonate can be used. Most preferable is chiral epichlorohydrin. A preferred example of the catechol compound of formula 3 is catechol, in which all the sub- stituents R , R , R and R are hydrogen.

[40] The epoxide ring opening reaction is carried out in the presence of a tertiary organic amine or an ammonium salt thereof. An aliphatic amine represented by R R R N (wherein R , R and R are each independently C -C alkyl, C -C alkenyl or benzyl) or a C -C heteroaromatic organic amine can be used. As a specific example, trimethylamine, triethylamine, tripropylamine, dimethylethylamine, tributylamine, N - methylpyrrolidine, JV-methylpiperidine, diisopropylethylamine, triphenylamine, pyridine, pyrrole or lutidine can be mentioned. The organic amine may be used in a form of an ammonium salt. Examples of the ammonium salt include benzyltrimethy- lammonium chloride, diallyldimethylammonium chloride, benzyltrimethylammonium bromide, n-octyltrimethylammonium bromide, stearyltrimethylammonium bromide, cetyldimethylethylammonium bromide, tetra-n-butylammonium iodide, β- methylcholine iodide, tetra-n-butylammonium hydrogen sulfate and phenyltrimethy- lammonium hydroxide. Test results on various organic amines and their ammonium salts showed that pyridine is the most preferable. The tertiary organic amine or an ammonium salt thereof is preferable used in a range of 0.01-1.00 equivalent based on the epoxide compound of formula 2. More preferably, it is used in a range of 0.1-0.2 equivalent.

[41] The epoxide ring opening reaction is performed in an organic solvent. The choice of the adequate organic solvent is well known to a person of ordinary skill to which the present invention pertains. Organic solvent such as alcohol, tetrahydrofuran, dioxane, acetone, JV,./V-dimethylformaldehyde, dimethyl sulfoxide, aromatic hydrocarbon, ether, ester, C -C halogenated hydrocarbon, etc. may be used. Preferable is a water- immiscible organic solvent. Particularly preferable is ethyl acetate. The organic solvent is used in 0.5-10 times, preferably 1.5 times, based on the volume of the epoxide compound of formula 2. The epoxide ring opening reaction is carried out at 0-80⁰C, preferably at 20-45⁰C.

[42] From the ring opening reaction, the ring-opened product represented by formula 4 is preferably obtained. The product may also be present in a form of epoxide.

[43] Formula 4

[44]

[45] wherein, * represents a chiral center and R , R , R , R and X are the same as defined in the above.

[46] After the epoxide ring opening reaction, the cyclization reaction is carried out. The cyclization is performed in the presence of an inorganic base. As a base used in the cyclization reaction, alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal hydride, alkali metal alkoxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, alkali metal phosphate and alkaline earth metal phosphate can be mentioned. Specifically, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, sodium methoxide, sodium ethoxide, sodium ?-butoxide, potassium ?-butoxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, 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. Preferable is sodium hydroxide. The base is added as dissolved in water.

[47] As an organic solvent used in the cyclization reaction of the step b), a water- miscible organic solvent such as C -C alcohol such as methanol, ethanol, propanol, isopropanol or butanol, tetrahydrofuran, acetonitrile, JV,./V-dimethylformamide and dimethyl sulfoxide may be used. Preferable is methanol or ethanol. Most preferable is methanol. The solvent is used in 1/20-10 equivalents, preferably 1/10-1 equivalent, based on the base solution.

[48] The present invention will be more fully illustrated referring to the following examples, but it should not be construed that the scope of the present invention is limited thereto.

[49] EXAMPLES

[50] Example 1

[51] 10 g (0.1081 mole, 1.0 eq) of (R)-epichlorohydrin was dissolved into 18 mL of ethyl acetate, and 21.436 g (0.1946 mole, 1.8 eq) of catechol was added thereto. 1.74 mL (0.0216 mole, 0.2 eq) of pyridine was added to the solution and the reaction solut ion was stirred at 4O⁰C for 2 days. To the reaction mixture, 2 M sulfuric acid solution was added to adjust the pH to 4-5. After washing with water, the solvent was removed under reduced pressure. The resultant crude product was dissolved into 23 mL of methanol and 233 niL (0.2594 mole, 2.4 eq) of 2 M NaOH was added dropwise to the solution at O⁰C for 1.5 hours. After stirring for 2.5 hours, the reaction mixture was extracted with methylene chloride. After successive washing with 2 M aqueous NaOH solution and water, the extract was dried with magnesium sulfate and filtered. The solvent was removed from the mother liquor under reduced pressure. 12.124 g (68%, 99.4%ee) of (R)-2-hydroxymethyl-l,4-benzodioxane was obtained.

[52] The optical purity (%ee) of 2-hydroxymethyl-l,4-benzodioxane was measured by high performance liquid chromatography. Knauer's Eurocel OD column (0.46 cm x 25 cm) was used and 90:10 (v/v) n-hexane/isopropanol mixed solvent was flown at a rate of 1.0 mL/min. HPLC spectrum was obtained at 254 nm. The (R)-isomer was detected at 7.51 minutes and the (S)-isomer was detected at 8.07 minutes.

[53] Example 2

[54] 10 g (0.1081 mole, 1.0 eq) of (R)-epichlorohydrin was dissolved into 18 mL of acetone and 21.436 g (0.1946 mole, 1.8 eq) of catechol was added thereto. 1.74 mL (0.0216 mole, 0.2 eq) of pyridine was added to the solution and the reaction solution was stirred at 4O⁰C for 2 days. The solvent was removed from the reaction mixture under reduced pressure. The resultant crude product was dissolved into 23 mL of methanol and 233 mL (0.2594 mole, 2.4 eq) of 2 M NaOH was added dropwise at O⁰C for 1.5 hours. After stirring for 2.5 hours, the reaction mixture was extracted with methylene chloride. After successive washing with 2 M aqueous NaOH solution and water, the extract was dried with magnesium sulfate and filtered. The solvent was removed from the mother liquor under reduced pressure. 11.045 g (61%, 99.2%ee) of ( /?)-2-hydroxymethyl-l,4-benzodioxane was obtained.

[55] Example 3

[56] 10 g (0.1081 mole, 1.0 eq) of (R)-epichlorohydrin was dissolved into 18 mL of ethyl acetate and 21.436 g (0.1946 mole, 1.8 eq) of catechol was added thereto. 0.87 mL (0.0108 mole, 0.10 eq) of pyridine was added to the solution and the reaction solution was stirred at 4O⁰C for 3 days. 2 M 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 resultant crude product was dissolved into 23 mL of methanol and 233 mL (0.2594 mole, 2.4 eq) of 2 m NaOH was added dropwise at O⁰C for 1.5 hours. After stirring for 2.5 hours, the reaction mixture was extracted with methylene chloride. After washing with 2 M aqueous NaOH solution and water, the extract was dried with magnesium sulfate and filtered. The solvent was removed from the mother liquor under reduced pressure. 9.551 g (53 %, 99.3 %ee) of (R )-2-hydroxymethyl-l,4-benzodioxane was obtained.

[57] Example 4

[58] 10 g (0.1081 mole, 1.0 eq) of (R)-epichlorohydrin was dissolved into 18 mL of ethyl acetate and 21.436 g (0.1946 mole, 1.8 eq) of catechol was added thereto. 0.87 rnL (0.0108 mole, 0.10 eq) of pyridine was added to the solution and the reaction solution was stirred at room temperature for 4.5 days. 2 M 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 resultant crude product was dissolved into 23 mL of methanol and 233 mL (0.2594 mole, 2.4 eq) of 2 M NaOH was added dropwise at O⁰C for 1.5 hours. After stirring for 2.5 hours, the reaction mixture was extracted with methylene chloride. After successive washing with 2 M aqueous NaOH solution and water, the extract was dried with magnesium sulfate and filtered. The solvent was removed from the mother liquor under reduced pressure. 9.542 g (53%, 99.4%ee) of (R )-2-hydroxymethyl-l,4-benzodioxane was obtained.

[59] Example 5

[60] 10 g (0.1081 mole, 1.0 eq) of (R)-epichlorohydrin was dissolved into 18 mL of ethyl acetate and 21.436 g (0.1946 mole, 1.8 eq) of catechol was added thereto. 3.01 mL (0.0216 mole, 0.2 eq) of triethylamine was added to the solution and the reaction solution was stirred at 4O⁰C for 3 days. 2 M 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 resultant crude product was dissolved into 23 mL of methanol and 233 mL (0.2594 mole, 2.4 eq) of 2 M NaOH was added dropwise at O⁰C for 1.5 hours. After stirring for 2.5 hours, the reaction mixture was extracted with methylene chloride. After washing with 2 M aqueous NaOH solution and water, the extract was dried with magnesium sulfate and filtered. The solvent was removed from the mother liquor under reduced pressure. 9.873 g (55%, 99.4%ee) of (R )-2-hydroxymethyl-l,4-benzodioxane was obtained.

[61] Example 6

[62] 10 g (0.1081 mole, 1.0 eq) of (R)-epichlorohydrin was dissolved into 18 mL of ethyl acetate and 21.436 g (0.1946 mole, 1.8 eq) of catechol was added thereto. 1.15 mL (0.0108 mole, 0.1 eq) of triethylamine was added to the solution and the reaction solution was stirred at 4O⁰C for 4.5 days. 2 M 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 resultant crude product was dissolved into 23 mL of methanol and 233 mL (0.2594 mole, 2.4 eq) of 2 M NaOH was added dropwise at O⁰C for 1.5 hours. After stirring for 2.5 hours, the reaction mixture was extracted with methylene chloride. After washing with 2 M aqueous NaOH solution and water, the extract was dried with magnesium sulfate and filtered. The solvent was removed from the mother liquor under reduced pressure. 6.138 g (34%, 99.2%ee) of (R )-2-hydroxymethyl-l,4-benzodioxane was obtained.

[63] Example 7 [64] 10 g (0.1081 mole, 1.0 eq) of (R)-epichlorohydrin was dissolved into 18 niL of ethyl acetate and 21.436 g (0.1946 mole, 1.8 eq) of catechol was added thereto. 6.008 g (0.0216 mole, 0.2 eq) of tetrabutylammonium chloride was added to the solution and the reaction solution was stirred at 4O⁰C for 3 days. The solvent was removed from the reaction mixture under reduced pressure. The resultant crude product was dissolved into 23 mL of methanol and 233 mL (0.2594 mole, 2.4 eq) of 2 M NaOH was added dropwise at O⁰C for 1.5 hours. After stirring for 2.5 hours, the reaction mixture was extracted with methylene chloride. After washing with 2 M aqueous NaOH solution and water, the extract was dried with magnesium sulfate and filtered. The solvent was removed from the mother liquor under reduced pressure. 7.954 g (44%, 99.2%ee) of (R )-2-hydroxymethyl-l,4-benzodioxane was obtained.

[65] Example 8

[66] 200 g (2.1617 mole, 1.0 eq) of (R)-epichlorohydrin was dissolved into 18 mL of ethyl acetate and 428.72 g (3.8911 mole, 1.8 eq) of catechol was added thereto. 34.97 mL (0.4323 mole, 0.2 eq) of pyridine was added to the solution and the reaction solution was stirred at 4O⁰C for 2 days. 2 M 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 resultant crude product was dissolved into 23 mL of methanol and 4320 mL (8.6468 mole, 4.0 eq) of 2 M NaOH was added dropwise at O⁰C for 1.5 hours. After stirring for 2.5 hours, the reaction mixture was extracted with methylene chloride. After washing with 2 M aqueous NaOH solution and water, the extract was dried with magnesium sulfate and filtered. The solvent was removed from the mother liquor under reduced pressure. 223.35 g (62%, 99.4%ee) of (R )-2-hydroxymethyl-l,4-benzodioxane was obtained.

Claims

[1] A process for the preparation of 2-hydroxymethyl-l,4-benzodioxane compound having formula 1, which comprises the steps of: a) reacting an epoxide compound of formula 2 with a catechol compound of formula 3 in a presence of a tertiary organic amine or its ammonium salt to carry out a ring opening reaction of the epoxide compound, followed by collecting a ring-opened product from a reaction mixture; and b) treating the ring-opened product with an inorganic base to carry out a cy- clization reaction of the ring-opened product, followed by recovering the targeted product 2-hydroxymethyl-l,4-benzodioxane of formula 1 from a reaction mixture:

Formula 1

wherein, * represents a chiral center, R , R , R and R are each independently hydrogen, halogen, nitro, cyano, formyl, (C -C ) alkyl, (C -C ) alkoxy, (C -C ) alkoxycarbonyl, (C -C ) alkylcarbonyloxy, (C -C ) haloalkyl, N,N-di-(C -C )

1 4 1 4 1 4 alkylamino, (C -C ) alkylcarbonyl, (C -C ) alkoxycarbonyloxy, C -C aromatic hydrocarbon, C -C aromatic hydrocarbon substituted with halogen, or C -C aromatic hydrocarbon substituted with (C -C ) alkyl, or two neighboring sub- stituents of R , R , R and R taken together form a methylenedioxy group or a benzene ring, and X represents a leaving group.

[2] The process as set forth in claim 1, wherein the ring-opened product of the step a) is collected as a crude product and subjected to the next cyclization reaction. [3] The process as set forth in claim 1, wherein the ring-opened product has formula 4: Formula 4

wherein, * represents a chiral center and R , R , R , R and X are the same as

1 2 3 4 defined in claim 1.

[4] The process as set forth in claim 1, wherein the epoxide compound of formula 2 is epihalohydrin or glycidyl sulfonate.

[5] The process as set forth in claim 4, wherein the epihalohydrin is selected from the group consisting of chiral epifluorohydrin, chiral epichlorohydrin, chiral epi- bromohydrin and chiral epiiodohydrin, and the glycidyl sulfonate is selected from the group consisting of chiral glycidylmethanesulfonate, chiral glycidyl-/? - toluenesulfonate, chiral glycidyl-m-nitrobenzenesulfonate, chiral glycidyl-/? - nitrobenzenesulfonate, chiral glycidyltrifluoromethanesulfonate and chiral gly- cidylbenzenesulfonate.

[6] The process as set forth in claim 4, wherein the epihalohydrin is chiral epichlorohydrin.

[7] The process as set forth in claim 1, wherein all of R , R , R and R are hydrogen.

[8] The process as set forth in claim 1, wherein the tertiary organic amine is an aliphatic amine represented by R R R N (wherein R , R and R are each inder pendently ^J C \ -C f, alky ^J l, C 2 -C 16 alkeny ^J l or benzy ^J l) or a C 4 -C 10 heteroaromatic organic amine.

[9] The process as set forth in claim 8, wherein the tertiary organic amine is trimethylamine, triethylamine, tripropylamine, dimethylethylamine, trib- utylamine, JV-methylpyrrolidine, JV-methylpiperidine, diisopropylethylamine, triphenylamine, pyridine, pyrrole or lutidine.

[10] The process as set forth in claim 9, wherein the tertiary organic amine is pyridine.

[H] The process as set forth in claim 1, wherein the epoxide compound of formula 2 is an optically active compound.

[12] The process as set forth in claim 1, wherein X is halogen or sulfonate represented by

, wherein R is C -C alkyl, C -C aryl or C -C aryl substituted with nitro,

5 1 10 6 10 6 10 methyl, ethyl, fluoro or chloro.

[13] The process as set forth in claim 1, wherein the inorganic base of step b) is alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal hydride, alkali metal alkoxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, alkali metal phosphate or alkaline earth metal phosphate.

[14] The process as set forth in claim 13, wherein the inorganic base is sodium hydroxide.

[15] The process as set forth in claim 1, wherein the step a) is performed in a water- immiscible organic solvent and the step b) is performed in a water-miscible organic solvent.

[16] The process as set forth in claim 15, wherein the organic solvent of the step a) is ethyl acetate and the organic solvent of the step b) is C -C alcohol.