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Method for preparing levalbuterol

A technology of levosalbuterol and isopropanol, which is applied in the field of preparation of compound levosalbutamol, can solve the problems of low synthesis efficiency, high price, inconvenient large-scale production, etc., and achieve the effect of simple preparation process

Inactive Publication Date: 2015-02-18
XINXIANG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] However, the problem in these known synthetic methods is that the synthetic efficiency is relatively low, especially the chemical resolution method, the actual synthetic efficiency is lower than 50%; in addition, in these synthetic methods, the raw materials used, such as manual Sexual acids or chiral catalysts are expensive and not convenient for large-scale production

Method used

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  • Method for preparing levalbuterol
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  • Method for preparing levalbuterol

Examples

Experimental program
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Effect test

Embodiment 1

[0035] Example 1: Synthesis of chiral amphiphilic block copolymer MPEO-b-PGTQ with quinine in the side chain

[0036] (1) Vacuum degas the reaction flask three times, add 0.36g (0.015mol) of sodium hydride after elution of mineral oil and 20g (0.01mol) of dry methoxy-terminated polyethylene glycol (MPEO) under nitrogen protection , heated in an oil bath to 100°C, stirred until sodium hydride was dissolved in molten MPEO, and reacted for 1 hour ([NaH] / [OH]=1.5:1), the syringe was purged with nitrogen three times, and allyl glycidyl ether (AGE ) into the reaction bottle, and reacted for 24 hours under the protection of nitrogen at 100°C. After the reaction, the reaction mixture was cooled to room temperature. Dissolve the crude product in a certain amount of dichloromethane, add silica gel, and remove the dichloromethane by rotary evaporation to obtain silica gel powder with polymer adsorbed, which is transferred to a silica gel column, and the PAGE homopolymer is first eluted w...

Embodiment 2

[0040] Embodiment 2: the synthesis of (chloroacetyl) salicylaldehyde

[0041]

[0042] Add 20g (0.15mol) of anhydrous aluminum trichloride to a 250mL three-necked flask, add 15mL of dichloromethane dropwise while stirring, raise the temperature to 50°C, and add dropwise 10mL of a dichloromethane solution of 6.61g (0.042mol) of chloroacetyl chloride , stirred for 30min. 3.66g (0.03mol) of salicylaldehyde was dissolved in 10mL of dichloromethane, dropped into the reactant at 40°C, and refluxed for 12h. The reaction solution was slowly poured into 120 g of crushed ice, 15 mL of water and 30 mL of dichloromethane under stirring. Adjust the pH to 2, stir for 20 min, separate the organic layer, wash the aqueous layer with dichloromethane (30mI×3), combine the dichloromethane layers, wash with water (20mL×2), wash with saturated brine (50mL), anhydrous sulfuric acid Sodium dry. Concentrate to obtain a purple-black oil, which is washed with 40 mL of dichloromethane to obtain a d...

Embodiment 3

[0044] Embodiment 3: [[(1,1-dimethylethyl) amino] acetyl] the synthesis of salicylaldehyde hydrochloride

[0045]

[0046] Suspend 2.43g (0.01mol) of the compound (chloroacetyl) salicylaldehyde in 10mL of isopropanol, add 3.15mL (0.03mol) of tert-butylamine dropwise in an ice-water bath, and stir the reaction at 40°C for 2h. A mixture of 2.55 mL of concentrated hydrochloric acid and 2.55 mL of isopropanol was slowly added dropwise, and the reaction was stirred at room temperature for 10 h. Filter, dry the filter cake to obtain the crude product, wash with a little isopropanol, and dry to obtain the light yellow solid compound [[(1,1-dimethylethyl) amino] acetyl] salicylaldehyde hydrochloride, 2.3g, Yield 85%, mp 232--234°C.

[0047] 1 H NMR (DMSO-d 6 ): 1.15-1.36 (S, 9H), 4.70 (S, 1H), 7.10 (d, 1H), 8.11-8.31 (t, 2H), 10.30 (s, 1H).

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Abstract

The invention discloses a new way for synthesizing levalbuterol. A chirally amphiphilic block copolymer is used as a chiral catalyst in asymmetric synthesis of the levalbuterol. The method comprises the steps of reacting salicylaldehyde with aluminium chloride anhydrous and chloroacetyl chloride in dichloromethane to obtain (chloracetyl) salicylaldehyde; reacting the (chloracetyl) salicylaldehyde with tert-butylamine in isopropanol to obtain a compound (4) ((1,1-dimethyl ethyl) amino) acetyl) salicylaldehyde hydrochloride; dissolving the ((1,1-dimethyl ethyl) amino) acetyl) salicylaldehyde hydrochloride in mixed solution of potassium hydroxide (or sodium hydroxide) and isopropanol to prepare the levalbuterol by chiral catalyst. The synthesizing method has simple preparation process, is easy to control, has high target product yield and ee value, and meets the green and environment-friendly requirements.

Description

technical field [0001] The invention relates to the field of preparation of optical isomers of medicinal compounds, in particular to a preparation method of levosalbutamol, a compound capable of treating asthma. Background technique [0002] Asthma is a common disease that seriously endangers people's health. In recent years, with the continuous deepening of the understanding of the pathogenesis of bronchial asthma, important progress has been made in the drug treatment and research of asthma. beta 2 Receptor agonists are divided into 4 categories according to the speed of onset of action and duration of action: ①slow onset and short duration of action, such as albuterol tablets and terbutaline tablets; ②rapid onset of action and duration of action Short, such as albuterol aerosol and terbutaline aerosol; ③ slow onset of action, long duration of action, such as salmeterol inhalation; ④ rapid onset of action, long duration of action, such as formoste Luo (form oterol) inha...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C215/60C07C213/00C07C213/02B01J31/06C07B53/00C08G65/26C08G65/48C08G65/00
Inventor 刘冰周勇姜玉钦姚文慧苗长庆
Owner XINXIANG UNIV
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