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

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

technical field

[0001] The present invention relates to a method for preparing chiral 1,4-benzodioxane compound. More specifically, the present invention relates to a process for the preparation of chiral 2-hydroxymethyl-1,4-benzodioxane compounds. Background technique

[0002] 1,4-Benzodioxane and its derivatives are useful intermediates in the synthesis of alpha- or beta-adrenoceptor antagonists, a drug for psychoneuropathy. In particular, 2-hydroxymethyl-1,4-benzodioxane is a useful intermediate for the synthesis of doxazosin. Doxazosin is a compound used in the treatment of hypertension (US Patent No. 4,188,390), which is generally sold as (±)doxazosin mesylate (Pfizer under the trade name "Cardular").

[0003] Doxazosin has one chiral center and may exist as (R) isomer or (S) isomer. Of these two isomers, the (S) isomer is known to be more effective in treating hypertension than the racemic or (R) isomer due to its fewer side effects such as drowsiness , dizziness, ...

Examples

example 1

[0054] 10 g (0.1081 mol, 1.0 equivalent) of (R)-epichlorohydrin was dissolved in 18 ml of ethyl acetate, and 21.436 g (0.1946 mol, 1.8 equivalent) of catechol were added thereto. To this solution was added 1.74 ml (0.0216 mol, 0.2 equivalent) of pyridine, and stirred at 40° C. for 2 days. 2M sulfuric acid solution 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 23ml of methanol, and 233ml (0.2594mol, 2.4eq) of 2M NaOH was added dropwise at 0°C for 1.5 hours. After stirring for 2.5 hours, the reaction mixture was extracted with dichloromethane. The extract was washed successively with 2M aqueous NaOH solution and water, dried over anhydrous magnesium sulfate and filtered. The solvent was removed from the mother liquor under reduced pressure to yield 12.124 g (68%, 99.4% ee) of (R)-2-hydroxymethyl-1,4-benzodioxane.

[0055] The optical purity (%ee)...

example 2

[0057]10 g (0.1081 mol, 1.0 equivalent) of (R)-epichlorohydrin was dissolved in 18 ml of acetone, and 21.436 g (0.1946 mol, 1.8 equivalent) of catechol were added thereto. To this solution was added 1.74 ml (0.0216 mol, 0.2 equivalent) of pyridine, and stirred at 40° C. for 2 days. The solvent was removed under reduced pressure. The obtained crude product was dissolved in 23ml of methanol, and 233ml (0.2594mol, 2.4eq) of 2M NaOH was added dropwise at 0°C for 1.5 hours. After stirring for 2.5 hours, the reaction mixture was extracted with dichloromethane. The extract was washed successively with 2M aqueous NaOH solution and water, dried over anhydrous magnesium sulfate and filtered. The solvent was removed from the mother liquor under reduced pressure to afford 11.045 g (61%, 99.2% ee) of (R)-2-hydroxymethyl-1,4-benzodioxane.

example 3

[0059] 10 g (0.1081 mol, 1.0 equivalent) of (R)-epichlorohydrin was dissolved in 18 ml of ethyl acetate, and 21.436 g (0.1946 mol, 1.8 equivalent) of catechol were added thereto. To this solution was added 0.87 ml (0.0108 mol, 0.1 equivalent) of pyridine, and stirred at 40° C. for 3 days. 2M sulfuric acid solution 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 23ml of methanol, and 233ml (0.2594mol, 2.4eq) of 2M NaOH was added dropwise at 0°C for 1.5 hours. After stirring for 2.5 hours, the reaction mixture was extracted with dichloromethane. The extract was washed successively with 2M aqueous NaOH solution and water, dried over anhydrous magnesium sulfate and filtered. The solvent was removed from the mother liquor under reduced pressure to afford 9.551 g (53%, 99.3% ee) of (R)-2-hydroxymethyl-1,4-benzodioxane.

technical field

[0001] The present invention relates to a method for preparing chiral 1,4-benzodioxane compound. More specifically, the present invention relates to a process for the preparation of chiral 2-hydroxymethyl-1,4-benzodioxane compounds. Background technique

[0002] 1,4-Benzodioxane and its derivatives are useful intermediates in the synthesis of alpha- or beta-adrenoceptor antagonists, a drug for psychoneuropathy. In particular, 2-hydroxymethyl-1,4-benzodioxane is a useful intermediate for the synthesis of doxazosin. Doxazosin is a compound used in the treatment of hypertension (US Patent No. 4,188,390), which is generally sold as (±)doxazosin mesylate (Pfizer under the trade name "Cardular").

[0003] Doxazosin has one chiral center and may exist as (R) isomer or (S) isomer. Of these two isomers, the (S) isomer is known to be more effective in treating hypertension than the racemic or (R) isomer due to its fewer side effects such as drowsiness , dizziness, ...

Examples

example 1

[0054] 10 g (0.1081 mol, 1.0 equivalent) of (R)-epichlorohydrin was dissolved in 18 ml of ethyl acetate, and 21.436 g (0.1946 mol, 1.8 equivalent) of catechol were added thereto. To this solution was added 1.74 ml (0.0216 mol, 0.2 equivalent) of pyridine, and stirred at 40° C. for 2 days. 2M sulfuric acid solution 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 23ml of methanol, and 233ml (0.2594mol, 2.4eq) of 2M NaOH was added dropwise at 0°C for 1.5 hours. After stirring for 2.5 hours, the reaction mixture was extracted with dichloromethane. The extract was washed successively with 2M aqueous NaOH solution and water, dried over anhydrous magnesium sulfate and filtered. The solvent was removed from the mother liquor under reduced pressure to yield 12.124 g (68%, 99.4% ee) of (R)-2-hydroxymethyl-1,4-benzodioxane.

[0055] The optical purity (%ee)...

example 2

[0057]10 g (0.1081 mol, 1.0 equivalent) of (R)-epichlorohydrin was dissolved in 18 ml of acetone, and 21.436 g (0.1946 mol, 1.8 equivalent) of catechol were added thereto. To this solution was added 1.74 ml (0.0216 mol, 0.2 equivalent) of pyridine, and stirred at 40° C. for 2 days. The solvent was removed under reduced pressure. The obtained crude product was dissolved in 23ml of methanol, and 233ml (0.2594mol, 2.4eq) of 2M NaOH was added dropwise at 0°C for 1.5 hours. After stirring for 2.5 hours, the reaction mixture was extracted with dichloromethane. The extract was washed successively with 2M aqueous NaOH solution and water, dried over anhydrous magnesium sulfate and filtered. The solvent was removed from the mother liquor under reduced pressure to afford 11.045 g (61%, 99.2% ee) of (R)-2-hydroxymethyl-1,4-benzodioxane.

example 3

[0059] 10 g (0.1081 mol, 1.0 equivalent) of (R)-epichlorohydrin was dissolved in 18 ml of ethyl acetate, and 21.436 g (0.1946 mol, 1.8 equivalent) of catechol were added thereto. To this solution was added 0.87 ml (0.0108 mol, 0.1 equivalent) of pyridine, and stirred at 40° C. for 3 days. 2M sulfuric acid solution 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 23ml of methanol, and 233ml (0.2594mol, 2.4eq) of 2M NaOH was added dropwise at 0°C for 1.5 hours. After stirring for 2.5 hours, the reaction mixture was extracted with dichloromethane. The extract was washed successively with 2M aqueous NaOH solution and water, dried over anhydrous magnesium sulfate and filtered. The solvent was removed from the mother liquor under reduced pressure to afford 9.551 g (53%, 99.3% ee) of (R)-2-hydroxymethyl-1,4-benzodioxane.

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