Synthetic method for terbutaline sulfate

A technology of terbutaline sulfate and synthetic method, which is applied in the field of medicine, can solve the problems of large environmental pollution, long steps, and low yield, and achieve the effects of small environmental pollution, short steps, and low cost

Inactive Publication Date: 2018-09-07
CHENGDU BRILLIANT PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The purpose of the present invention is to provide a kind of terbutaline sulfate in order to solve the technical problems of using high-risk and highly toxic reagents, long steps, low yield and great environmental pollution in the synthesis process of terbutaline sulfate existing in the prior art. The preparation method of taline

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  • Synthetic method for terbutaline sulfate

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Experimental program
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Effect test

Embodiment 1

[0041] A kind of synthetic method of terbutaline sulfate, see appendix figure 1 The shown reaction step diagram specifically includes:

[0042] (1) Synthesis of 3,5-dibenzyloxyacetophenone

[0043] 20.0g (0.13mol) of 3,5-dihydroxyacetophenone was dissolved in 150g N,N-dimethylformamide (DMF), and 90.5g potassium carbonate (0.65mol) was added while stirring slowly, and 77.8 mL benzyl chloride (0.68mol) was reacted at 80-90°C for 3-4 hours. Then cool down and filter to remove the solid, rinse the filter cake with a small amount of N,N-dimethylformamide solvent, pour the filtrate into ice water, and precipitate a white solid, wash and dry to obtain a white solid, namely 3,5-dibenzyloxy Acetophenone 44.8g (0.11mol), the molar yield is 85%.

[0044] 1 H NMR (300MHz, CDCl 3 ): δ=2.55(3H,d), 5.07(4H,t), 6.81(1H,m), 7.20(2H,m), 7.38(6H,d), 7.47(4H,d)

[0045] (2) Synthesis of 1-(3,5-bis(benzyloxy)phenyl)-2-ethoxy-2-hydroxyethanone

[0046] Dissolve 50.0 g (0.15 mol) of 3,5-dibenz...

Embodiment 2

[0055] A kind of synthetic method of terbutaline sulfate, see appendix figure 1 The shown reaction step diagram specifically includes:

[0056] (1) Synthesis of 3,5-dibenzyloxyacetophenone

[0057] 100.0g (0.66mol) of 3,5-dihydroxyacetophenone was dissolved in 700g dimethyl sulfoxide (DMSO), and 212.5g triethylamine (2.1mol) was added under stirring, and 282.2g benzyl bromide (1.65 mol) at 70-80°C for 3-4 hours. Then cool down and filter to remove the solid, rinse the filter cake with a small amount of solvent, pour the filtrate into ice water, and precipitate a white solid, wash and dry to obtain a white solid, namely 189.5g (0.57mol) of 3,5-dibenzyloxyacetophenone , 87% molar yield.

[0058] 1 H NMR (300MHz, CDCl 3 ): δ=2.55(3H,d), 5.07(4H,t), 6.81(1H,m), 7.20(2H,m), 7.38(6H,d), 7.47(4H,d)

[0059] (2) Synthesis of 1-(3,5-bis(benzyloxy)phenyl)-2-ethoxy-2-hydroxyethanone

[0060] Dissolve 80g (0.24mol) of 3,5-dibenzyloxyacetophenone in 450g DMSO, add 76.1g refined iodi...

Embodiment 3

[0069] A kind of synthetic method of terbutaline sulfate, see appendix figure 1 The shown reaction step diagram specifically includes:

[0070] (1) Synthesis of 3,5-dibenzyloxyacetophenone

[0071] 20.0g (0.13mol) of 3,5-dihydroxyacetophenone was dissolved in 160g of N,N-dimethylacetamide, 55g of sodium carbonate (0.52mol) was added while stirring slowly, and 38.9mL of benzyl chloride ( 0.34mol) at 60-70°C for 3-4 hours. Then cool down and filter to remove the solid, rinse the filter cake with a small amount of solvent, pour the filtrate into ice water, and precipitate a white solid, wash and dry to obtain a white solid, namely 40.7g (0.1mol) of 3,5-dibenzyloxyacetophenone , the molar yield was 82%.

[0072] (2) Synthesis of 1-(3,5-bis(benzyloxy)phenyl)-2-ethoxy-2-hydroxyethanone

[0073] Dissolve 60.0g (0.18mol) of 3,5-dibenzyloxyacetophenone in 400g DMSO, add 180ml of 50% hydroiodic acid (0.9mol) at 40-50°C, and then raise the temperature to 70-80°C for reaction After 3...

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Abstract

The invention provides a synthetic method for terbutaline sulfate. The method comprises the following specific synthetic route: using 3,5-dihydroxyacetophenone as a raw material, performing benzyl protection, performing oxidization, performing esterification, performing reductive amination, performing debenzylation, and finally performing salt formation with sulfuric acid to obtain the terbutalinesulfate. The preparation method for the terbutaline sulfate provided by the invention has the following beneficial effects: 1, dimethyl sulfoxide (DMSO) is adopted to replace highly-toxic product selenium dioxide, a highly-dangerous reagent is avoided from being used, and the method is safe and high-efficiency; 2, the method does not have a bromination process, and has less pollution to the environment; and 3, the method is easy to operate, has mild reaction conditions, short steps and low costs, and is more suitable for industrialized production.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a synthetic method of terbutaline sulfate. Background technique [0002] Terbutaline Sulfate, also known as hydroxyalbutaline and terbutaline, is an adrenergic agonist that can selectively stimulate β2 receptors to relax bronchial smooth muscle and inhibit endogenous spasm-induced The release of substances and the edema caused by endogenous mediators can improve the clearance ability of bronchial mucociliary epithelium. Terbutaline sulfate was first developed by AstraZeneca Pharmaceutical Co., Ltd., and it was produced and marketed abroad in 1988. Clinically, it is mainly used for the treatment of bronchospasm in bronchial asthma, asthmatic bronchitis and chronic obstructive pulmonary disease. At present, the processes for synthesizing terbutaline sulfate at home and abroad all have long routes, and the production involves highly toxic raw materials, which are not suitable for...

Claims

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Application Information

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IPC IPC(8): C07C213/00C07C215/60
CPCC07C45/64C07C213/00C07C213/02C07C215/60C07C49/84C07C217/70
Inventor 刘洋郭守雷张海军
Owner CHENGDU BRILLIANT PHARMA CO LTD
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