Preparation method of terbutaline

A technology of terbutaline and chemical equation, applied in the field of preparation of terbutaline, can solve the problems such as that the antioxidant problem cannot be well solved, will not be significantly improved, and the purity of terbutaline is low. , to reduce environmental pressure, reduce polarity, and achieve the effect of high purity

Active Publication Date: 2020-11-20
南京恒道医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the reported process, due to the good water solubility of terbutaline sulfate and its own easy oxidation, the post-treatment is relatively cumbersome. At present, after the solvent is evaporated to dryness, the terbutaline sulfate is refluxed with methanol to cool down and crystallize. High temperature conditions are very likely to cause terbutaline Oxidation of butaline, resulting in lower purity of terbutaline
If the antioxidant problem is not well resolved, the quality of the final product of terbutaline will not be significantly improved

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1: a kind of preparation method of terbutaline

[0031] Including the following steps:

[0032] S1. Add 10 kg of compound I (65.72 mol) and 30 L of dichloromethane into the reactor, stir and dissolve, add 8.55 kg of propionic anhydride (65.72 mol), control the reaction temperature and stir at 10°C for 10 h;

[0033] S2. After the reaction is completed, add 10% diisopropylethylamine aqueous solution to the system, stir and wash thoroughly, collect the dichloromethane phase, and distill under reduced pressure to obtain 18.44 kg of yellow oil compound II (96% yield);

[0034] S3. Add 18.44kg compound II (63.08mol) and 35L ethyl acetate, 4.61kg tert-butylamine (63.08mol), 2.52kg sodium hydroxide (63.08mol) and sodium thiosulfate (63.08mol) in the reactor, control reaction The temperature was stirred and reacted at 10°C for 8h;

[0035] S4. After the reaction is completed, add purified water to the system to wash the reaction solution, collect the ethyl acetate ...

Embodiment 2

[0038] Embodiment 2: a kind of preparation method of terbutaline

[0039] Including the following steps:

[0040] S1. Add 10kg of compound I (65.72mol) and 30L of dichloromethane into the reactor, stir and dissolve, add 51.98kg of butyric anhydride (65.72mol), control the reaction temperature at 25°C and stir for 6h;

[0041] S2. After the reaction is completed, add 20% 1-methylpiperidine aqueous solution to the system, stir and wash thoroughly, collect the dichloromethane phase, and distill under reduced pressure to obtain 18.64 kg of yellow oil compound II (97% yield);

[0042] S3. Add 18.64kg compound II (63.76mol) and 35L ethyl acetate, 46.64kg tert-butylamine (637.6mol), 7.65kg sodium hydroxide (191.28mol) and antioxidant BHT (255.04mol) in the reactor to control the reaction Stir the reaction at 40°C for 4.5h;

[0043]S4. After the reaction is completed, add purified water to the system to wash the reaction solution, collect the ethyl acetate phase, and distill under r...

Embodiment 3

[0044] Embodiment 3: a kind of preparation method of terbutaline

[0045] S1. Add 10kg of compound I (65.72mol) and 30L of dichloromethane into the reactor, stir and dissolve, add 122.40kg of valeric anhydride (657.2mol), control the reaction temperature at 40°C and stir for 1h;

[0046] S2. After the reaction is completed, add 30% 4-methylmorpholine aqueous solution to the system, stir and wash thoroughly, collect the dichloromethane phase, and distill under reduced pressure to obtain 17.67kg (yield 92%) of yellow oil compound II;

[0047] S3. Add 17.67kg compound II (60.46mol) and 35L ethyl acetate, 88.44kg tert-butylamine (1209.25mol), 12.09kg sodium hydroxide (302.3mol) and antioxidant BHA (483.68mol) in the reactor to control the reaction Stir the reaction at 70°C for 1 h;

[0048] S4. After the reaction, add purified water to the system to wash the reaction solution, collect the ethyl acetate phase, and distill under reduced pressure to obtain 12.40 kg of terbutaline fi...

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PUM

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Abstract

The invention belongs to the field of pharmacy, and particularly relates to a preparation method of terbutaline. The method comprises: S1, adding a compound I and dichloromethane into a reaction kettle, stirring and dissolving, and then adding anhydride, S2, after the reaction is finished, adding dilute alkaline water into the system, fully stirring and washing, collecting a dichloromethane phase,and carrying out reduced pressure distillation to obtain a yellow oily matter, namely a compound II, S3, adding the compound II, ethyl acetate, tert-butylamine, sodium hydroxide and an oxidation protective agent into the reaction kettle, and S4, after the reaction in the step S3 is finished, adding purified water into the system to wash the reaction solution in the step S3, collecting an ethyl acetate phase, and carrying out reduced pressure distillation on the ethyl acetate phase to obtain terbutaline. According to the technical scheme provided by the invention, the post-reaction treatment difficulty is reduced, so that an intermediate compound is easily separated from a reaction system, meanwhile, side reactions such as epoxy bond hydrolysis are avoided, and the stability and yield of the final product terbutaline are improved.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a preparation method of terbutaline. Background technique [0002] Terbutaline is a short-acting β2-receptor agonist COPD drug developed by AstraZeneca, and it is a clinically recommended drug for patients with mild and moderate COPD. Compared with other marketed short-acting β2-receptor agonist terbutaline sulfate inhalation, it has lower dose-dependent side effects. Terbutaline first used 3,5-dibenzyloxyacetophenone as the starting raw material to obtain 2-(N-benzyl tert-butylamino)-1-(3,5-dibenzyl Oxyphenyl) ethanone sulfate. After debenzylation by hydrogenation reduction, terbutaline was prepared, dissolved in water, adjusted to pH 5.5 with alkali, evaporated to dryness, and purified by crystallization of a large amount of methanol. Acid-base adjustment and pH control to control the sulfate content lead to the introduction of a large amount of salt, and the solubility o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/04C07C213/00C07C213/10C07C215/30C07D301/00C07D303/16
CPCC07C213/04C07C213/00C07C213/10C07D301/00C07D303/16C07C215/30
Inventor 陶义华穆加兵黄迎春凌岫泉
Owner 南京恒道医药科技股份有限公司
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