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Preparation method of levosalbutamol hydrochloride

A technology of levosalbutamol hydrochloride and potassium carbonate, which is applied in the field of preparation of levosalbutamol hydrochloride, can solve the problems of low yield, heavy metals, pollution, etc., and achieve the effect of good yield, low equipment requirements and simple operation

Pending Publication Date: 2022-04-29
广州博济生物医药科技园有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The technical problem to be solved by the present invention is to overcome the low yield of the existing method for synthesizing levosalbutamol hydrochloride, the catalyst used is expensive and has heavy metal pollution, and it is necessary to combine the defects and deficiencies of column chromatography purification which is not conducive to industrial scale-up, and provide a low-cost , high yield, mild conditions, environmental protection, simple operation, low equipment requirements, suitable for the preparation of levosalbutamol hydrochloride for industrialized large-scale production

Method used

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  • Preparation method of levosalbutamol hydrochloride
  • Preparation method of levosalbutamol hydrochloride
  • Preparation method of levosalbutamol hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Synthesis of Example 1 Compound B (5-(2-bromoacetyl)-2-hydroxybenzyl alcohol)

[0053]

[0054] (1) Weigh 200.53g of compound A (5-(2-bromoacetyl)-2-hydroxybenzaldehyde), add 2.0L tetrahydrofuran and stir to dissolve, cool down to 15°C; weigh 263.51g sodium triacetoxyborohydride , added to the reaction system in batches, the temperature is controlled at 20±5°C, the feeding time is 120min, and the reaction is 60min at 20°C;

[0055] (2) HPLC and TLC monitor until the reaction is complete, add 2.0L of purified water, quench at room temperature for 60min, concentrate below 40°C to remove most of the tetrahydrofuran, add 1.6L of ethyl acetate to stir and extract, let stand to separate layers, and then use 0.4 Extract with L ethyl acetate once, combine the organic phases, wash once with 1.0L purified water; add an appropriate amount of anhydrous sodium sulfate to remove water;

[0056] (3) Filter, wash the filter residue with a small amount of ethyl acetate, collect the ...

Embodiment 2

[0058] Synthesis of Example 2 Compound C (6-bromoacetyl-2,2-dimethyl-4H-benzo[1,3]dioxin)

[0059]

[0060] (1) Weigh 150.06g compound B (5-(2-bromoacetyl)-2-hydroxybenzyl alcohol), add 1.5L dichloromethane, stir and disperse at room temperature, add 1.16g p-toluenesulfonic acid monohydrate; weigh 128.87g of 2,2-dimethoxypropane was added dropwise into the reaction system, and reacted at room temperature for 2h;

[0061] (2) Monitor by HPLC and TLC until the reaction is complete, add 0.75L of purified water, adjust the pH to 7-8 with saturated potassium bicarbonate solution, leave to separate layers, collect the lower organic phase, and wash the organic phase with 0.75L of purified water for 1 times; add anhydrous sodium sulfate to the organic phase to remove water;

[0062] (3) Filtrate, wash the filter residue with a small amount of dichloromethane, and concentrate under reduced pressure to obtain 174.01 g of oil, which is compound C (6-bromoacetyl-2,2-dimethyl-4H-benzo[...

Embodiment 3

[0064] Example 3 Synthesis of compound D (6-(2-bromo-1-(S)-ethanol)-2,2-dimethyl-4H-benzo[1,3]dioxin)

[0065]

[0066] (1) Weigh 9.21g of (1R,2S)-(+)-cis-1-amino-2-indanol, add 1.5L of anhydrous tetrahydrofuran, replace the nitrogen, cool down to 5±5°C, under the protection of nitrogen, Slowly add 150.31g of N,N-diethylaniline borane (DEANB) dropwise, after the addition is complete, keep warm at 5±5°C for 30min;

[0067] (2) Compound C (6-bromoacetyl-2,2-dimethyl-4H-benzo[1,3]dioxin) was dissolved by adding 1.5L of anhydrous tetrahydrofuran and stirring, under nitrogen protection, dropwise Into the reaction system of (1) above, the dropwise addition time is 180min, and the temperature is maintained at 5±5°C; the dropwise addition is completed, and the reaction is 30min;

[0068] (3) HPLC and TLC monitor until the compound C (6-bromoacetyl-2,2-dimethyl-4H-benzo[1,3]dioxin) is consumed, and the intermediate compound D is generated;

[0069] (4) 200ml of acetone was added d...

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Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of levosalbutamol hydrochloride. According to the method, 5-(2-bromoacetyl)-2-hydroxybenzaldehyde is taken as a starting material, and levosalbutamol hydrochloride is prepared through aldehyde group reduction, propylidene protection, carbonyl group asymmetric reduction, epoxidation, amination, chiral resolution and purification and deprotection salification in sequence. According to the whole method, reaction is carried out under mild conditions, expensive or easily-polluted reagents are not needed, and the purity of 99% or above can be achieved without combination with column chromatography purification; and the synthesis route is simple to operate, low in equipment requirement, relatively good in yield and very suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis. More specifically, it relates to a preparation method of levosalbutamol hydrochloride. Background technique [0002] Salbutamol is a selective β2 receptor agonist, which can effectively inhibit the release of allergenic substances such as histamine and prevent bronchospasm. It is suitable for bronchial asthma, asthmatic bronchitis, bronchospasm, emphysema and other diseases. The drug of choice for asthma attacks has already become one of the top ten best-selling single drugs in the world. Levosalbutamol hydrochloride is a single optical isomer of salbutamol, and its drug effect is 80 times that of dexalbuterol. The side effects are reduced and the curative effect is further improved. Levosalbutamol hydrochloride only needs 1 / 4 of the dose of the racemate to produce the same curative effect. At 1 / 2 dose, its effect is better than that of the racemate. Therefore, levalbuterol is expec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/00C07C215/60C07D319/08C07D407/04C07C45/64C07C49/82
CPCC07C213/00C07D319/08C07D407/04C07C45/64C07B2200/07C07C49/82C07C215/60
Inventor 马仁强王廷春张海龙苏建伟
Owner 广州博济生物医药科技园有限公司
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