A kind of preparation method of terbutaline sulfate

A technology of terbutaline sulfate and concentrated sulfuric acid, which is applied in the field of medicine and chemical industry, can solve the problems of increased post-processing cost and environmental protection pressure of mixed solvents, high market price of raw materials, poor purification effect, etc., to avoid high energy consumption operating conditions The use of water, avoiding the introduction of water and inorganic salts, and reducing the effect of environmental protection pressure

Active Publication Date: 2020-04-07
SHIJIAZHUANG NO 4 PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantages are that the raw materials are sold at a high price; hydrolyzed polyphenols are easily oxidized under alkaline conditions; the amount of solvent used in the refining process is large, the purification effect is poor, and the indicators such as impurity content and residue on ignition are difficult to meet the quality standards.
[0012] Both CN201710080371.9 and CN200810189857.7 disclose the method for preparing terbutaline sulfate from terbutaline, respectively using ethanol solution and water-saturated esters as solvents, adjusting the pH to 4-6 with sulfuric acid, and the pH value of the process is Difficult to control, and the use of mixed solvents increases post-processing costs and environmental pressure
[0013] The content of terbutaline sulfate sulfate and the control of its residue on ignition are difficult points for its preparation. The reported processes all control the content of sulfate radicals by adjusting the pH of terbutaline sulfate aqueous solution. The acid-base adjustment process introduces a large amount of inorganic salts. Because terbutaline sulfate has good water solubility and is easy to oxidize itself, the post-treatment is relatively cumbersome. At present, after the solvent is evaporated to dryness, methanol is refluxed to cool down and crystallize. High temperature conditions can easily cause the oxidation of the target substance, resulting in The yield and purity of butaline are not ideal

Method used

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  • A kind of preparation method of terbutaline sulfate
  • A kind of preparation method of terbutaline sulfate
  • A kind of preparation method of terbutaline sulfate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043]Add 1.18kg of the compound of formula I to 13.8L of glacial acetic acid and 59g of palladium carbon, replace with nitrogen 6 times, hydrogen 6 times, and stir at 60°C under normal pressure for 5 hours in the dark. Cool down to 10-15°C, suction filter under nitrogen atmosphere, place the suction filtrate in a reaction flask, add acetic acid solution of concentrated sulfuric acid equivalent to 0.5eq of the compound of formula I (mass volume concentration is 5%) under nitrogen protection, stir for 15min, Transfer to a distillation flask, replace with nitrogen, distill under reduced pressure, concentrate, cool down to room temperature, add 650ml of methanol, stir and crystallize under nitrogen atmosphere for 30min, drop to 10-15℃ for 1.5h, suction filter to obtain a white crystalline solid 645g, yield 98.4%, purity 99.87%.

Embodiment 2

[0045] Add 1.19 kg of the compound of formula II to 17.8 L of glacial acetic acid and 119 g of Ni, replace with nitrogen 6 times and hydrogen 6 times, and stir at 50°C under normal pressure for 4 hours in the dark. Cool down to 10-15°C, suction filter under a nitrogen atmosphere, place the suction filtrate in a reaction flask, add an acetic acid solution of concentrated sulfuric acid equivalent to 0.505 eq of the compound of formula I (mass volume concentration: 8%) under nitrogen protection, and stir for 20 minutes. Transfer to a distillation flask, replace with nitrogen, distill under reduced pressure, concentrate, cool down to room temperature, add methanol, stir and crystallize under a nitrogen atmosphere for 30 minutes, drop to 10-15°C for 2 hours, and filter with suction to obtain 652 g of a white crystalline solid. Yield 99.1%, purity 99.83%.

Embodiment 3

[0047] Add 1.18kg formula I compound to 11.8L glacial acetic acid and 59g Pd(OH) 2 , 6 times of nitrogen replacement, 6 times of hydrogen replacement, stirring at 40° C. under normal pressure in the dark for 5 h. Cool down to 10-15°C, suction filter under nitrogen atmosphere, place the suction filtrate in a reaction flask, add acetic acid solution of concentrated sulfuric acid equivalent to 0.495eq of the compound of formula I (mass volume concentration is 5%) under nitrogen protection, and stir for 15min. Transfer to a distillation flask, replace with nitrogen, distill under reduced pressure, concentrate, cool down to room temperature, add 1300ml of methanol, stir and crystallize under nitrogen atmosphere for 30min, drop to 10-15°C for 1.5h, and suction filter to obtain a white crystalline solid 642g, yield 98.0%, purity 99.0%.

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Abstract

The invention relates to a preparation method of terbutaline sulfate, which comprises the following steps: dissolving a compound of formula I or formula II into a solvent A, adding a metal catalyst for catalytic hydrogenation, so as to obtain 5-[2-[(1,1-dimethylethyl)amido]-1-ethoxyl]-1,3-resorcinol; after the reaction is finished, filtering, collecting filter liquor, adding a certain amount of concentrated sulfuric acid in the filter liquor, after stirring is stopped, recycling the solvent A, adding a solvent B into a residue, stirring to separate out a white crystal substance, performing suction filtration, thus obtaining the terbutaline sulfate. According to the method provided by the invention, the treating difficulty after the reaction is greatly reduced, the introduction of water and inorganic salt is avoided, and the product content is high; furthermore, the stability of the terbutaline sulfate is obviously improved by distilling the product under acidic conditions, the catalyst and the reaction solvents are recyclable, so that the environmental protection pressure is greatly reduced.

Description

technical field [0001] The invention relates to a preparation method of terbutaline sulfate, which specifically belongs to the field of medicine and chemical industry. Background technique [0002] 5-[2-[(1,1-Dimethylethyl)amino]-1-hydroxyethyl]-1,3-resorcinol sulfate (2:1) (terbutaline sulfate) CAS It is 23031-32-5, the molecular formula is (C 12 h 19 NO 3 ) 2 ·H 2 SO 4 , the structural formula is as follows: [0003] [0004] Terbutaline sulfate is a short-acting β2-receptor agonist COPD drug developed by AstraZeneca, and it is a clinically recommended drug for mild and moderate COPD patients. Compared with other marketed short-acting β2-receptor agonist terbutaline sulfate inhalation, it has lower dose-dependent side effects. [0005] The patent of terbutaline sulfate compound (SE335359) was applied by Swedish Draco Company on October 19, 1966, and there is no Chinese patent of the same family. This patent uses 3,5-dibenzyloxyacetophenone as the starting mater...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C213/08C07C213/00C07C215/60
CPCC07C213/00C07C213/08C07C215/60
Inventor 李坤赵学斌王海荣
Owner SHIJIAZHUANG NO 4 PHARMA
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