Synthesis method of levorotatory albuterol hydrochloride

A technology for levsalbutamol and salbutamol, which is applied in the field of synthesis of levalbuterol hydrochloride, can solve the problems of difficulty in extracting salbutamol, difficult industrialized production, low optical purity and the like, and achieves the effects of cheap raw materials, stable finished products, and easy availability of raw materials

Inactive Publication Date: 2007-03-14
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The third is the technology disclosed in U.S. Patent No. 6,365,756. The dihydroxyl group of racemic albuterol is protected and the albuterol is prepared by splitting. The optical purity is relatively low.
[0006] The amount of solvent needed for the above method is large, the process is loaded down with trivial details, it is difficult to extract albuterol from water, and it is not easy for industrialized production

Method used

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  • Synthesis method of levorotatory albuterol hydrochloride
  • Synthesis method of levorotatory albuterol hydrochloride
  • Synthesis method of levorotatory albuterol hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0030] Preparation of 2-(N-tert-butylamino)-1-(2,2-dimethyl-4H-benzo[1,3]dioxo-6-yl)ethanol (I):

[0031] Add racemic albuterol (38g, 0.16mol) into acetone (400ml, 5.4mol) under nitrogen protection, cool with ice salt, add boron trifluoride ether (43ml, 0.35mol) dropwise, after the addition is complete, react at 0°C for 1h, and The mixture was poured into 390 g of 10% sodium hydroxide solution with a weight concentration of 0° C., stirred, the excess acetone was evaporated to dryness under reduced pressure, extracted with ethyl acetate (150 ml×3), the combined organic phases were washed with saturated brine , dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 38 g of light yellow solid (I), yield: 85%, which was directly used in the next reaction without purification.

Embodiment 2

[0033] Preparation of 2-(N-tert-butylamino)-1-(2,2-dimethyl-4H-benzo[1,3]dioxo-6-yl)ethanol (I):

[0034] Add racemic albuterol (38g, 0.16mol) into acetone (800ml, 11mol) under nitrogen protection, cool with ice salt, add boron trifluoride diethyl ether (59ml, 0.48mol) dropwise, after the addition is complete, react at -10°C for 2h. The mixture was poured into 535 g of 10% sodium hydroxide solution with a weight concentration of 0° C., stirred, the excess acetone was evaporated to dryness under reduced pressure, extracted with ethyl acetate (150ml×3), the combined organic phases were washed with saturated brine , dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 42 g of light yellow solid (I), yield: 94%, which was directly used in the next reaction without purification.

Embodiment 3

[0036] (1) R-2-(N-tert-butylamino)-1-(2,2-dimethyl-4H-benzo[1,3]dioxo-6-yl)ethanol. The preparation of D-(+)-dibenzoyl tartrate (II):

[0037] Methanol (135ml), was added to the mixture of compound (I) (17g, 0.061mol) and D-(+)-dibenzoyl tartaric acid (11.8g, 0.033mol), heated to reflux for 30min, gradually cooled to room temperature within 30min , stirred at 5°C for 1h, filtered, washed the solid with ethyl acetate (20ml), and dried to give 9.2g of white solid (II), yield: 65% (for single isomer), 88.8% ee

[0038] (2) R-2-(N-tert-butylamino)-1-(2,2-dimethyl-4H-benzo[1,3]dioxo-6-yl)ethanol. Recrystallization of D-(+)-dibenzoyl tartrate (II)

[0039] The solid (II) (9.2g, 0.02mol) obtained in Example 3.1 was added to methanol (135ml), heated to reflux for 2h, gradually cooled to room temperature, stirred at 2°C for 1h, filtered, and the solid was washed with ethyl acetate (20ml) , dried to obtain a white solid (II), repeat the above operation twice to obtain a white solid (...

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Abstract

The process of preparing levosalbutamol hydrochloride with racemoid salbutamol as material includes the following steps: dewatering racemoid salbutamol in acetone to obtain compound I, resolving compound I with optically pure organic acid A in solvent of water consolute fatty alcohol to obtain compound II, dissociating compound II under the action of alkali to obtain compound III, deprotecting compound III in HCl solution to form salt, and refining to obtain levosalbutamol hydrochloride. The process of the present invention has facile material, simple operation and short reaction period, and is simple and suitable for industrial production.

Description

technical field [0001] The invention relates to a synthetic method of levalbuterol hydrochloride. Background technique [0002] Wheezing is one of the common symptoms of respiratory diseases, especially in bronchial asthma and wheezing bronchitis. It is the result of bronchospasm and increased secretions caused by bronchial mucosal inflammation and small airway obstruction caused by mucosal edema. The pathogenesis of asthma is mostly related to type I allergy. Beta-receptor function is low during asthma. [0003] Levosalbutamol hydrochloride, its chemical name is: (R)-α 1 -[[(1,1-Dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol hydrochloride. [0004] Salbutamol is a very effective adrenergic β-receptor agonist, which has high selectivity for β-1 and β-2 receptors, and is currently widely used in the treatment of asthma. Such β-receptor agonists have less toxic and side effects than other β-receptor agonists. Pharmacological studies have shown that levalbuter...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/60C07C213/10C07D319/08
Inventor 袁哲东刘相奎潘红娟王强
Owner SHANGHAI INST OF PHARMA IND CO LTD
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