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Preparation method of dobutamine hydrochloride intermediate compound

A technology for dobutamine hydrochloride and compound, applied in the field of medicinal chemistry, can solve the problems of high risk factor, low flash point of ether, high toxicity of benzene, etc., so as to reduce operational safety hazards, improve purity, yield, and safety risks low effect

Inactive Publication Date: 2020-10-23
QIANFOSHAN HOSPITAL OF SHANDONG +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this method does not use expensive palladium carbon catalyst, the catalyst p-toluenesulfonic acid used is easy to react with alcohols to generate genotoxic impurity p-toluenesulfonate, and benzene is very toxic, p-toluenesulfonic acid, benzene In the production of raw materials, the two materials need to set very strict control limits separately, which virtually increases the difficulty of removing impurities in the process and increases the risk of product quality
In addition, it is difficult to completely extract the organic matter by using ether extraction to remove inorganic salts, and the flash point of ether is low, so the risk factor is relatively high during use

Method used

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  • Preparation method of dobutamine hydrochloride intermediate compound
  • Preparation method of dobutamine hydrochloride intermediate compound
  • Preparation method of dobutamine hydrochloride intermediate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] A preparation method of dobutamine hydrochloride intermediate (compound V),

[0031]

[0032] 1. Add 203g of 3,4-dimethoxyphenethylamine, 210g of 4-(4-methoxyphenyl)-2-butanone, 0.7g of acetic acid, and 1.2L of cyclohexane into a 3L reactor, and stir to raise the temperature 80-85°C to reflux, reflux for water separation reaction, heat preservation and reflux reaction for 6 hours, and no more water will come out at this time;

[0033] 2. Evaporate cyclohexane under normal pressure, recover it, and then cool down to room temperature, add 2.0L of absolute ethanol, 30.2g of potassium borohydride, stir and raise the temperature to 60-70°C, keep stirring and react for 2-3h, Stop heat preservation and cool down to below 40°C;

[0034] 3. Under the condition of stirring, add 0.2L of concentrated hydrochloric acid dropwise, cool down to 20-30°C, stir and keep warm for crystallization for 2-3h, filter, and dry the filter cake in a blast oven at 50-60°C to obtain 362g of filt...

Embodiment 2

[0038] A preparation method of dobutamine hydrochloride intermediate (compound V),

[0039]

[0040]1. Add 223g of 3,4-dimethoxyphenethylamine, 200g of 4-(4-methoxyphenyl)-2-butanone, 6.7g of acetic acid, and 1.2L of cyclohexane into a 3L reactor, and stir to raise the temperature 80-85°C to reflux, reflux for water separation reaction, heat preservation and reflux reaction for 6 hours, and no more water will come out at this time;

[0041] 2. Evaporate the cyclohexane under normal pressure, and then cool down to room temperature, add 2.0L of absolute ethanol, 30.2g of potassium borohydride, stir and react at room temperature for 10h, stop the heat preservation, and cool down to room temperature;

[0042] 3. Under the condition of stirring, add 0.2L of concentrated hydrochloric acid dropwise, cool down to 20-30°C, keep warm, stir and crystallize for 3 hours, filter, and dry the filter cake in a blast oven at 50-60°C to obtain 353g of filter cake;

[0043] 4. Add the above-...

Embodiment 3

[0046] A preparation method of dobutamine hydrochloride intermediate (compound V),

[0047]

[0048] 1. Add 203g of 3,4-dimethoxyphenethylamine, 260g of 4-(4-methoxyphenyl)-2-butanone, 0.7g of acetic acid, and 1.5L of cyclohexane into a 3L reactor, and stir to raise the temperature 80-85°C to reflux, reflux for water separation reaction, heat preservation and reflux reaction for 6 hours, and no more water will come out at this time;

[0049] 2. Evaporate the cyclohexane under normal pressure, and then cool down to room temperature, add 3.0L of isopropanol, add 21.2g of sodium borohydride in portions, stir and heat up to 60-70°C, keep warm for 2 hours, stop keeping warm , cooled to room temperature;

[0050] 3. Under the condition of stirring, add 0.2L of concentrated hydrochloric acid dropwise, cool down to 20-30°C, stir and keep warm for crystallization for 3 hours, filter, and dry the filter cake in a blast oven at 50-60°C to obtain 349g of filter cake;

[0051] 4. Add ...

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Abstract

The invention discloses a preparation method of a dobutamine hydrochloride intermediate compound. According to the method, 3, 4-dimethoxyphenylethylamine and 4-(4-methoxyphenyl)-2-butanone are adoptedas the starting materials, acetic acid is adopted as a catalyst, cyclohexane is adopted as a reflux water diversion agent, reflux water diversion is performed to obtain a condensation product, potassium borohydride is adopted for further hydrogenation reduction, and hydrochloric acid salification is performed to obtain a crude product of a dobutamine hydrochloride intermediate. Isopropanol is adopted for refluxing and dissolving, an inorganic salt generated in the preparation process of the intermediate is removed through filtering while the solution is hot, and refining is conducted to obtain the dopamine hydrochloride intermediate. According to the method, high-pressure catalytic hydrogenation operation in the prior art is avoided, potential safety hazards are greatly reduced, meanwhile, an expensive metal catalyst is prevented from being used, and the production cost is reduced; and the use of some high-toxicity reagents and genotoxic reagents is avoided.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular to a preparation method of a dobutamine hydrochloride intermediate compound. Background technique [0002] With the progress of the development of modern society, people's dietary life has been greatly improved, followed by some "happy troubles", and the incidence of cardiovascular diseases is increasing year by year. The accelerated pace of life and the pressure of daily life make the incidence of cardiovascular diseases tend to be younger. Both heart failure and myocardial infarction are cardiovascular diseases with high incidence, and the market demand for cardiogenic shock drugs caused by cardiovascular diseases is increasing year by year. Dobutamine hydrochloride is an important anti-shock drug. The main function of dobutamine hydrochloride is to stimulate β-adrenergic receptors, which can enhance cardiac contraction, increase heart rate, increase blood pressure a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/10C07C213/08C07C213/02C07C217/48C07C249/02C07C251/16
CPCC07C213/10C07C213/08C07C213/02C07C249/02
Inventor 梁英郭恒邓义蒙蒋东洋李广乾刘发文
Owner QIANFOSHAN HOSPITAL OF SHANDONG
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