Preparation method of high-purity injection-grade terbutaline sulfate

A technology of terbutaline sulfate and sulfuric acid, which is applied in the preparation of organic compounds, carbon-based compounds, chemical instruments and methods, etc., can solve the problems of high-risk reagent environmental pollution risk and high cost, and achieve low cost, mild reaction, The effect of simple process

Inactive Publication Date: 2019-02-05
HAINAN LEVTEC PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The present invention solves the technical problems of high-risk reagents, high risk of environmental pollution, and high cost in the preparation method of terbutaline sulfate, and provides easy-to-obtain raw materials for the synthesis route, mild reaction, simple process, low cost, and high yield. Can be used for industrial production

Method used

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  • Preparation method of high-purity injection-grade terbutaline sulfate
  • Preparation method of high-purity injection-grade terbutaline sulfate
  • Preparation method of high-purity injection-grade terbutaline sulfate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Measure THF 10L, add EtOH 10L, stir and mix, add TB-01 1.66kg, cool to 0-10°C, add THF solution of TBATB (THF 8.8L, add TBATB 3.7kg, dissolve). 0 ~ 20 ℃ reaction 2h. Evaporate the solvent under reduced pressure, add 4L of ethanol and continue to replace the reaction solvent once under reduced pressure until the volume reaches 5L, add 10L of ethanol, stir and beat for 5h; drain, transfer the filter cake to a vacuum drying oven, and vacuum dry at 40°C for 10 hours to obtain White or off-white solid (TB-02) 1.69kg.

[0019] Add 5L of water to the reactor, stir, add TB-02, add 2.4kg of SM1, add 4.4L of ACN, heat to 60-90°C, count for 5 hours, stop heating, adjust the pH of the HBr solution to 1.0, add 10L of water, and stir Cool to 10-20°C, filter under reduced pressure, pump dry, stir and beat the filter cake with a mixed solvent of 8L of toluene and 8L of water for 4h; Vacuum dry at 45°C (vacuum degree is -0.085~-0.1Mpa) for 4 hours. Obtained TB-031.58kg.

[0020] Tak...

Embodiment 2

[0023] Measure THF 10L, add MeOH 10L, stir and mix, add TB-01 1.66kg, cool to 0-10°C, add THF solution of TBATB (THF9.2L, add TBATB 2.8kg, dissolve). 0 ~ 20 ℃ reaction 2h. Evaporate the solvent under reduced pressure, add 4L of ethanol and continue to replace the reaction solvent once under reduced pressure, until the volume is 4L, add 8L of ethanol, stir and beat for 4h; drain, transfer the filter cake to a vacuum drying oven, and vacuum dry at 40°C for 10 hours to obtain White or off-white solid (TB-02) 1.57kg

[0024] Add 4L of water to the reaction kettle, stir, add TB-02, add SM1 2.7kg, add ACN 4.1L, heat to 50-90°C, time for 4 hours, stop heating, adjust the pH of HBr solution to 0.9, add 10L of water, stir and cool to 10-20°C, filter under reduced pressure, pump dry, stir and beat the filter cake with a mixed solvent of 8L of toluene and 8L of water for 4h; Dry in vacuum at 45°C (vacuum degree is -0.085~-0.1Mpa) for 4 hours. Obtained TB-031.46kg.

[0025] Take THF 8...

Embodiment 3

[0028]Measure THF 10L, add MeOH 8L, stir and mix, add TB-01 1.66kg, cool to 0-10°C, add THF solution of TBATB (THF 9L, add TBATB 2.9kg, dissolve). 0 ~ 20 ℃ reaction 2h. Evaporate the solvent under reduced pressure, add 4L of ethanol and continue to replace the reaction solvent once under reduced pressure until the volume reaches 5L, add 10L of ethanol, stir and beat for 5h; drain, transfer the filter cake to a vacuum drying oven, and vacuum dry at 40°C for 10 hours to obtain White or off-white solid (TB-02) 1.71kg.

[0029] Add 5L of water to the reactor, stir, add TB-02, add 2.4kg of SM1, add 4.4L of ACN, heat to 60-90°C, count for 5 hours, stop heating, adjust the pH of the HBr solution to 1.0, add 10L of water, and stir Cool to 10-20°C, filter under reduced pressure, pump dry, stir and beat the filter cake with a mixed solvent of 8L of toluene and 8L of water for 4h; Vacuum dry at 45°C (vacuum degree is -0.085~-0.1Mpa) for 4 hours. Obtained TB-031.57kg.

[0030] Take TH...

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Abstract

The invention provides a preparation method of high-purity injection-grade terbutaline sulfate. The preparation method is characterized in that 3,5-dibenzyloxyacetophenone is adopted as a raw material, a bromination reaction, a substitution reaction, carbonyl reduction and hydrogenation reduction are conducted, salifying with sulfuric acid is conducted, and the terbutaline sulfate is obtained. A synthetic route is shown in the description.

Description

technical field [0001] The invention relates to a preparation method of high-purity injection-grade terbutaline sulfate, which belongs to the field of chemical drug synthesis. Background technique [0002] Terbutaline sulfate is a drug mainly used in the treatment of bronchial asthma, asthmatic tracheitis and bronchospasm of chronic obstructive pulmonary disease. The drug is highly selective for β2 receptors, has few cardiac side effects, and is suitable for patients with high blood pressure. Patients with cardiovascular diseases such as coronary heart disease can also use it. The product is soluble in water, slightly soluble in methanol, almost insoluble in chloroform. [0003] At present, there are few reports on the relevant literature of the synthetic route of terbutaline sulfate: [0004] Chinese Journal of Pharmaceutical Industry, 1990, 30 (1): 4-6 and the patent route reported by U.S. Patent US3937838 are complex, and dangerous chemicals methyllithium and selenium ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/60C07C213/08C07C221/00C07C225/06C07C45/63C07C49/84
CPCC07C45/63C07C213/08C07C221/00C07C49/84C07C225/06C07C217/70C07C215/60
Inventor 翁贤坤庞京团龙娇
Owner HAINAN LEVTEC PHARMA
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