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Method for preparing l-betaxolol hydrochloride

A technology of betaxolol hydrochloride and molar ratio, which is applied in the preparation of organic compounds, chemical instruments and methods, and the preparation of amino hydroxyl compounds, can solve the problems of high cost, high energy consumption, and difficult product separation, and achieve easy separation , the effect of high yield

Active Publication Date: 2010-03-10
GUANGZHOU BOJI MEDICINE SERVICES
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] This method mainly has the following problems: the first step reaction uses the irritating benzyl chloride as the protecting group of the phenolic hydroxyl group, and the molar amount is twice that of p-hydroxyphenylethyl alcohol, which causes waste of raw materials and environmental pollution; the raw material used in the second step reaction Sodium tert-butoxide and chloromethylcyclopropane are expensive, unstable, high cost, and wasteful; the third step is to remove the benzyl protecting group and use Pd / C high-pressure catalytic hydrogenation, which brings difficulties to large-scale production; the fourth step The reaction of intermediate 4 and R-epichlorohydrin was heated at 60°C for 8 hours to make the chiral center racemize, so the chiral purity of the final product L-betaxolol hydrochloride was greatly reduced
At the same time, the final salt-forming step requires freezing and crystallization, which not only requires high energy consumption, but also makes product separation difficult

Method used

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  • Method for preparing l-betaxolol hydrochloride
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  • Method for preparing l-betaxolol hydrochloride

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0045] a) Preparation of compound 1 1-p-toluenesulfonyl-2-p-hydroxyphenylethane.

[0046] According to the method described in literature synthesis 2003, 4, 509-512, 1-p-toluenesulfonyl-2-p-hydroxyphenylethane was prepared.

[0047] Dissolve p-hydroxyphenethyl alcohol (6.90g, 50.0mmol) in 10.0ml of pyridine, then add a mixture of p-toluenesulfonyl chloride (10.03g, 52.5mmol) and 10.0ml of pyridine, and stir at -10°C for 25min. Stirred at 0°C for 2h, and reacted at 10°C for 12h. After the reaction, add 125ml of ice water and stir for 1h, then extract with diethyl ether (2×75ml), wash the ether layer with 1% HCl (2×50ml), wash with anhydrous Na 2 SO 4 After drying, filtration and concentration, 14.6 g of compound 1, 1-p-toluenesulfonyl-2-p-hydroxyphenylethane was obtained, with a yield of 95%.

[0048] b) Preparation of compound 2(2S)-3-(4-p-toluenesulfonyloxyethylphenoxy)-1,2-propylene oxide.

[0049] Compound 1 (29.2g, 0.1mol) was dissolved in 50ml of ethanol, and then 11....

Embodiment 2

[0058] Embodiment 2 prepares compound 2

[0059] Compound 1 (29.2g, 0.1mol) and 40 grams of 20% NaOH solution were dissolved in 120ml of water at 5-15°C, then 11.3 grams of R-epichlorohydrin and 3 grams of benzyltriethylammonium chloride were added, and then The reaction was carried out at this temperature for 35 hours. Use TLC (developing agent ethyl acetate: methanol = 2: 1) to detect, after the reaction is completed, filter, after the filtrate is concentrated under reduced pressure (temperature 30-35 ° C, pressure 5-20mmHg) to remove the solvent, add 120ml of dichloromethane to dissolve , washed with 50ml of water, the organic layer was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure (temperature 20-50°C, pressure 20-100mmHg) to remove the solvent to obtain intermediate 2, (2S)-3-(4- 33.5 grams of p-toluenesulfonyloxyethylphenoxy)-1,2-propylene oxide, the yield is 86.2%,

Embodiment 3

[0060] Embodiment 3 prepares compound 2

[0061] Compound 1 (29.2g, 0.1mol) was dissolved in 50ml of acetone, and then 11.3 grams of R-epichlorohydrin and 20 grams of anhydrous K 2 CO 3 , React at 30-35°C for 25 hours. Use TLC (developing agent ethyl acetate: methanol = 2: 1) to detect, after the reaction is completed, filter, after the filtrate is concentrated under reduced pressure (temperature 30-35 ° C, pressure 5-20mmHg) to remove the solvent, add 120ml of dichloromethane to dissolve , washed with 50ml of water, the organic layer was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure (temperature 20-50°C, pressure 20-100mmHg) to remove the solvent to obtain intermediate 2, (2S)-3-(4- 27.2 g of p-toluenesulfonyloxyethylphenoxy)-1,2-propylene oxide, the yield was 78.2%.

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Abstract

The invention provides a method for preparing l-betaxolol hydrochloride, which takes p-hydroxy phenylethanol as starting material and obtains the pure l-betaxolol hydrochloride by selectively esterfying alcoholichydroxyl, etherifying phenolichydroxyl, carrying out amination on isopropamide and finally etherifying cyclopropylmethanol to lead HCl to be salified. The invention also provides an important intermediate compound 2-(2S)-3-(4-p-toluene sulfonyloxy ethyl phenoxy)-1,2-propylene oxide which is used for preparing the l-betaxolol hydrochloride, and a preparation method thereof. The invention avoids using bromotoluene cyclopropane which is higher in price, unstable and very irritant; the final products are easy to separate from each other and purify; and the obtained product has higher chemical purity (99.0-100.0%) and optical purity (99.0-100.0%) as well as high yield (total yield is 62%), and is suitable for industrialized production.

Description

technical field [0001] The invention relates to medicine preparation, in particular to a preparation method of L-betaxolol hydrochloride. Background technique [0002] The L-betaxolol hydrochloride developed by Alcon Company was launched in the United States in February 2000 under the trade name "Betaxon". The drug is mainly used to treat chronic open-angle glaucoma or to reduce intraocular pressure in patients with ocular hypertension. In recent years, the incidence of glaucoma has increased. According to the statistics of the World Health Organization, there are currently about 67 million glaucoma patients worldwide, and about 4.5 million people have lost vision due to glaucoma. At present, the clinical treatment of glaucoma is mainly based on surgery and drug therapy. However, surgery only temporarily lowers eye pressure and, for some types of glaucoma, only relieves symptoms and eventually leads to blindness. Drugs for the treatment of glaucoma mainly include parasymp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C217/34C07C213/04C07D303/24
CPCC07C213/04C07D303/24C07D303/34
Inventor 黄庆云黄庆国娄美仙
Owner GUANGZHOU BOJI MEDICINE SERVICES
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