CN111807975A - Preparation method of hydrochloric acid dopol butylamine intermediate compound - Google Patents
Preparation method of hydrochloric acid dopol butylamine intermediate compound Download PDFInfo
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- CN111807975A CN111807975A CN202010853350.8A CN202010853350A CN111807975A CN 111807975 A CN111807975 A CN 111807975A CN 202010853350 A CN202010853350 A CN 202010853350A CN 111807975 A CN111807975 A CN 111807975A
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- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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Abstract
The invention discloses a preparation method of a hydrochloric acid dopol butylamine intermediate compound. The invention adopts 3, 4-dimethoxy phenethylamine and 4- (4-methoxyphenyl) -2-butanone as initial raw materials, acetic acid as a catalyst and cyclohexane as a reflux water diversion agent, the condensation product is obtained by reflux water diversion, potassium borohydride is adopted for further hydrogenation reduction, and hydrochloric acid is salified to obtain a dopamine hydrochloride intermediate crude product. Isopropanol is adopted for reflux dissolution, inorganic salt generated in the intermediate preparation process is removed by hot filtration, and the dopamine-butylamine hydrochloride intermediate is obtained by refining. The method avoids high-pressure catalytic hydrogenation operation in the prior art, greatly reduces potential safety hazards, avoids using expensive metal catalysts, and reduces production cost; the use of some highly toxic and genotoxic agents is avoided.
Description
Technical Field
The invention belongs to the technical field of medical chemistry, and particularly relates to a preparation method of a hydrochloric acid dopol butamine intermediate compound.
Background
With the progress of the development of modern society, the dietary life of people is greatly improved, and then a plurality of 'happiness troubles' are followed, and the incidence rate of cardiovascular diseases is increased year by year. The heart disease is more likely to be younger due to the accelerated pace of life and the pressure of daily life. Both heart failure and myocardial infarction are cardiovascular diseases with high incidence, and the market demand of cardiogenic shock drugs caused by cardiovascular diseases is increasing year by year. Dobutamine hydrochloride is an important anti-shock drug. Dobutamine hydrochloride mainly acts as stimulation of beta-adrenergic receptors, and has the effects of enhancing cardiac contraction, increasing heart rate, increasing blood pressure and dilating blood vessels. Dobutamine produces less heart rate increase and peripheral vasodilation. Has better market prospect when being used as short-term treatment medicine.
Dobutamine hydrochloride, compound patent US3987200, was filed in 1972 by Lilly corporation. Currently, the synthesis of dobutamine hydrochloride mainly uses 3, 4-dimethoxy phenethylamine and 4- (4-methoxyphenyl) -2-butanone as starting raw materials, and the intermediate N- (3, 4-dimethoxy phenethyl) -4- (4-methoxyphenyl) butane-2-amine hydrochloride (compound V) is obtained after condensation, hydrogenation and salt formation reactions, and the compound V is demethylated and refined to obtain the dobutamine hydrochloride. Wherein the compound V is one of the most important intermediates of dobutamine hydrochloride, and the dobutamine hydrochloride can be obtained after demethylation and hydrochloric acid salification.
In patent US3987200, a method for preparing compound V from 3, 4-dimethoxyphenethylamine and 4- (4-methoxyphenyl) -2-butanone as raw materials is reported, in example 1 of the patent, 3, 4-dimethoxyphenethylamine and 4- (4-methoxyphenyl) -2-butanone are directly condensed, reduced and acidified by adopting a palladium-carbon high-pressure hydrogenation method to obtain compound V; in the embodiment 2, p-toluenesulfonic acid is used as a catalyst, toluene is used as a reflux solvent, 3, 4-dimethoxyphenethylamine and 4- (4-methoxyphenyl) -2-butanone are condensed to obtain a compound III, and the compound III is subjected to hydrogenation reduction by palladium-carbon and salified to obtain a compound V. Both methods involve high-pressure hydrogenation reaction, expensive palladium-carbon noble metal catalysts are needed, the material cost is high, and the potential safety hazard in the high-pressure hydrogenation operation process is serious.
The second pharmaceutical factory in Shanghai reported that 3, 4-dimethoxyphenethylamine and 4- (4-methoxyphenyl) -2-butanone are used as raw materials, benzene is refluxed and dehydrated under the catalysis of p-toluenesulfonic acid to obtain a compound III, potassium borohydride is adopted for reduction, ether is adopted for extraction, and ether hydrochloric acid solution is adopted for salification to obtain a compound V. Although the method uses less expensive palladium-carbon catalyst, the used catalyst p-toluenesulfonic acid is easy to react with alcohols to generate genotoxic impurity p-toluenesulfonic acid ester, the benzene toxicity is very high, the two materials of p-toluenesulfonic acid and benzene need to be independently set up very strict control limits in the production of raw material medicines, the difficulty of process impurity removal is invisibly increased, and the product quality risk is increased. In addition, the method of ether extraction is adopted to remove inorganic salts, organic matters are difficult to be completely extracted, the ether flash point is low, and the danger coefficient is large in the using process.
Disclosure of Invention
The invention provides a preparation method of a dobutamine hydrochloride intermediate compound for solving the existing problems, the method avoids the use of a high-toxicity or warning structure reagent and the operation with higher risk coefficient, all the used solvents are conventional reagents, the toxicity is lower, the solvent is convenient to recover, and a method for effectively removing electrodeless salt is provided in the post-treatment process.
The technical scheme adopted by the invention for solving the technical problems is as follows: a preparation method of a hydrochloric acid dopol butamine intermediate compound is provided, which comprises the following steps:
the method comprises the following specific steps:
(1) condensation reaction: taking a compound I and a compound II as initial raw materials, adding the compound I, the compound II, a water diversion agent and a catalyst into a reactor, stirring and heating to reflux, and carrying out reflux water diversion until no water is separated out to obtain a condensation product (a compound III);
(2) reduction reaction: removing the water separating agent by normal pressure distillation, adding a solvent and a reducing agent, stirring, heating and reacting to obtain a compound IV;
(3) salt forming reaction: dripping hydrochloric acid into the reaction solution of the compound IV to form salt, cooling and crystallizing, filtering and drying to obtain a crude product of the compound V;
(4) and (3) hot filtering to remove salt: heating and dissolving the crude product of the compound V in a solvent, carrying out heat filtration to remove salt, cooling and crystallizing to obtain a crude product of the compound V after salt removal;
(5) refining: and (4) dissolving the crude salt-removed compound V obtained in the step (4) in a solvent, cooling, crystallizing and drying to obtain the high-purity and high-content compound V.
Further preferably, the catalyst used in the condensation reaction in step (1) is one of formic acid, acetic acid and propionic acid, preferably acetic acid. Formic acid or acetic acid or propionic acid is used as a catalyst, so that the introduction of toxic impurities of the p-toluenesulfonic acid group is avoided.
Further preferably, the molar ratio of the compound I to the compound II in the step (1) is 1.3:1-1:1.3, preferably 1:1.05, the compound II is cheaper than the compound I, the compound II is slightly excessive, the compound I can be fully reacted, the material cost can be reduced, in addition, the compound II is excessive, and the generated byproducts are relatively more.
Further preferably, the molar ratio of the catalyst to the compound I in the step (1) is 0.01:1-0.3:1, preferably 0.01:1, so that the catalytic effect can be ensured, and the phenomenon that the catalyst is salified with the compound I to influence the yield due to overhigh dosage can be prevented.
Further preferably, the refluxing and water-dividing solvent in the step (1) is cyclohexane, the temperature for refluxing and water-dividing the cyclohexane is 80-85 ℃, the reaction time is 2-12h, preferably 6-8h, and the complete water-dividing can be ensured. Cyclohexane is used as a reflux water-separating solvent to carry out condensation reaction, so that the use of high-toxicity compounds of toluene and benzene is avoided, and simultaneously, the energy consumption can be reduced to a certain extent due to the lower azeotropic point of the cyclohexane/water.
Preferably, the reducing agent used in the hydrogenation reduction reaction in the step (2) is one of lithium borohydride, sodium borohydride and potassium borohydride, preferably potassium borohydride, and the reaction of potassium borohydride and the alcohol solvent is mild, so that the potential safety hazard in the reaction process is reduced.
It is further preferable that the molar ratio of the reducing agent and the compound I in the step (2) is 0.25:1 to 1:1, preferably 0.5:1, and the reduction reaction is sufficiently performed with a small amount of the catalyst.
Further preferably, the solvent used in the hydrogenation reduction reaction in step (2) is one of anhydrous methanol, anhydrous ethanol and isopropanol, and is preferably anhydrous ethanol; the hydrogenation reduction reaction temperature is 20-80 ℃, the reaction time is 1-12h, the preferable reaction temperature is 60-70 ℃, the reaction time is 2-3h, the reaction rate is moderate at the temperature, and the reaction time is relatively short.
Further preferably, the solvent used for desalting the crude compound V in step (4) and step (5) is one of methanol, anhydrous ethanol and isopropanol, preferably isopropanol. One of methanol, absolute ethyl alcohol or isopropanol is selected for removing salt through heat filtration, so that inorganic salt can be conveniently and thoroughly removed, and the content of the product is ensured. The three alcohols have the smallest solubility of the compound V in isopropanol, and the isopropanol is preferably used as a desalting and refining solvent, so that higher yield can be ensured.
Further preferably, the mass ratio of the solvent in the step (4) to the crude compound V in the step (5) is 8:1-20:1, preferably 12:1, so that the solvent consumption is reduced while the convenience of dissolution and filtration is ensured.
Compared with the prior art, the invention has the following beneficial effects:
1. the method provided by the invention avoids the high-pressure catalytic hydrogenation reaction condition in the prior art, avoids the use of a highly toxic reagent such as p-toluenesulfonic acid, toluene or benzene, uses a conventional reagent acetic acid as a catalyst, uses cyclohexane as a reflux water-separating agent to carry out condensation reaction, and prepares an intermediate by potassium borohydride hydrogenation reduction. Provides a method for carrying out hot filtration and desalination by adopting conventional alcohols, improves the purity and yield of the product, and reduces the potential safety hazard in the production process.
2. The preparation method of the dobutamine hydrochloride intermediate is simple and convenient to operate, low in safety risk, capable of obtaining the intermediate compound with high purity and high content, and more suitable for industrial large-scale production.
Drawings
FIG. 1: HPLC detection spectrogram of the dobutamine hydrochloride intermediate obtained in the first example.
Detailed Description
The present application will be described in further detail with reference to examples. It is to be understood that the specific embodiments described herein are merely illustrative of the relevant invention and not restrictive of the invention.
Example one
A preparation method of dobutamine hydrochloride intermediate (compound V),
1. adding 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, stirring, heating to 80-85 ℃ to reflux, carrying out reflux water diversion reaction, carrying out heat preservation and reflux reaction for 6h, and then no water is separated out;
2. steaming cyclohexane under normal pressure, recovering, cooling to room temperature after steaming, adding 2.0L of anhydrous ethanol and 30.2g of potassium borohydride, stirring and heating to 60-70 ℃, keeping the temperature and stirring for reaction for 2-3h, stopping keeping the temperature, and cooling to below 40 ℃;
3. dropwise adding 0.2L of concentrated hydrochloric acid under the stirring condition, cooling to 20-30 ℃, stirring, preserving heat, crystallizing for 2-3h, filtering, and drying a filter cake in a forced air oven at 50-60 ℃ to obtain 362g of the filter cake;
4. adding the dried filter cake into a 10L reactor, adding 5.4L isopropanol, stirring and heating to reflux, filtering while hot after heat preservation and stirring for 0.5h to another clean 10L reactor, stirring and cooling for crystallization, cooling to 20-30 ℃, preserving heat and stirring for crystallization for 1h, filtering, and carrying out forced air drying at 50-60 ℃ to obtain 298g of solid;
5. and adding the dried solid into a 5L reactor, adding 4.5L of isopropanol, stirring, heating to dissolve, cooling to 20-30 ℃, carrying out heat preservation and crystallization for 1h, filtering, and carrying out forced air drying on a filter cake at 50-60 ℃ to obtain 283g of a compound V with the purity of 99.94% and the preparation molar yield of a dobutamine hydrochloride intermediate (compound V) of 66.5%.
Example two
A preparation method of dobutamine hydrochloride intermediate (compound V),
1. adding 223g of 3, 4-dimethoxy phenethylamine, 200g of 4- (4-methoxyphenyl) -2-butanone, 6.7g of acetic acid and 1.2L of cyclohexane into a 3L reactor, stirring, heating to 80-85 ℃ to reflux, carrying out reflux water diversion reaction, carrying out heat preservation and reflux reaction for 6h, and then no water is separated out;
2. steaming cyclohexane under normal pressure, cooling to room temperature after completely steaming, adding 2.0L of absolute ethyl alcohol and 30.2g of potassium borohydride, stirring at room temperature for reaction for 10h, stopping heat preservation, and cooling to room temperature;
3. dropwise adding 0.2L of concentrated hydrochloric acid under the stirring condition, cooling to 20-30 ℃, preserving heat, stirring, crystallizing for 3h, filtering, and drying a filter cake in a forced air oven at 50-60 ℃ to obtain 353g of the filter cake;
4. adding the dried filter cake into a 5L reactor, adding 2.8L of absolute ethyl alcohol, stirring and heating to reflux, keeping the temperature and stirring for 0.5h, filtering to another clean 5L reactor while the filter cake is hot, stirring and cooling for crystallization, cooling to 0-10 ℃, keeping the temperature and stirring for crystallization for 1h, filtering, and carrying out forced air drying at 50-60 ℃ to obtain 286g of solid;
5. adding the dried solid into a 5L reactor, adding 2.3L of absolute ethyl alcohol, stirring and heating to dissolve, cooling to 0-10 ℃, preserving heat, stirring and crystallizing for 1h, filtering, and carrying out forced air drying on a filter cake at 50-60 ℃ to obtain 257g of a compound V with the purity of 99.99%, wherein the preparation molar yield of the dobutamine hydrochloride intermediate (compound V) is 60.4%.
EXAMPLE III
A preparation method of dobutamine hydrochloride intermediate (compound V),
1. adding 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, stirring, heating to 80-85 ℃ to reflux, carrying out reflux water diversion reaction, carrying out heat preservation and reflux reaction for 6h, and then no water is separated out;
2. steaming cyclohexane under normal pressure, cooling to room temperature after steaming, adding 3.0L of isopropanol, adding 21.2g of sodium borohydride in portions, stirring and heating to 60-70 ℃, keeping the temperature for reaction for 2h, stopping keeping the temperature, and cooling to room temperature;
3. dropwise adding 0.2L of concentrated hydrochloric acid under the stirring condition, cooling to 20-30 ℃, stirring, preserving heat, crystallizing for 3h, filtering, and drying a filter cake in a forced air oven at 50-60 ℃ to obtain 349g of the filter cake;
4. adding the dried filter cake into a 10L reactor, adding 5.2L isopropanol, stirring and heating to reflux, filtering while hot after heat preservation and stirring for 0.5h to another clean 10L reactor, stirring and cooling for crystallization, cooling to 20-30 ℃, preserving heat and stirring for crystallization for 1h, filtering, and carrying out forced air drying at 50-60 ℃ to obtain 290g of solid;
5. and adding the dried solid into a 5L reactor, adding 4.4L of isopropanol, stirring, heating to dissolve, cooling to 20-30 ℃, carrying out heat preservation and crystallization for 2h, filtering, and carrying out forced air drying on a filter cake at 50-60 ℃ to obtain 278g of a compound V with the purity of 99.8% and the preparation molar yield of the dobutamine hydrochloride intermediate (compound V) of 65.3%.
Other technical features than those described in the specification are known to those skilled in the art, and are not described herein in detail in order to highlight the innovative features of the present invention. Therefore, the scope of the invention should not be limited by the above description, but should be determined by the following claims and their equivalents.
Claims (10)
1. A preparation method of dobutamine hydrochloride intermediate (compound V),
the method comprises the following specific steps:
(1) condensation reaction: taking a compound I and a compound II as initial raw materials, adding a catalyst and a water separating agent, and carrying out condensation reaction under the reflux condition to obtain a compound III;
(2) reduction reaction: carrying out reduction reaction on the compound III and a reducing agent in a solvent to obtain a compound IV;
(3) salt forming reaction: dripping hydrochloric acid into the reaction solution of the compound IV to form salt, cooling and crystallizing, and drying to obtain a crude product of the compound V;
(4) and (3) hot filtering to remove salt: heating the crude product of the compound V, dissolving the crude product in a solvent, carrying out heat filtration to remove salt, cooling and crystallizing to obtain a crude product of the compound V after the salt is removed;
(5) refining: and (4) heating the crude product of the desalted compound V obtained in the step (4), dissolving the crude product in a solvent, cooling, crystallizing, and drying to obtain the compound V with high purity and high content.
2. The method of claim 1, wherein: the catalyst used in the condensation reaction in the step (1) is one of formic acid, acetic acid and propionic acid.
3. The method of claim 2, wherein: the molar ratio of the catalyst to the compound I is 0.01:1-0.3: 1.
4. The method of claim 1, wherein: the molar ratio of the compound I to the compound II in the step (1) is 1.3:1-1: 1.3.
5. The method of claim 1, wherein: the refluxing and water-dividing solvent in the step (1) is cyclohexane, the temperature for refluxing and water-dividing the cyclohexane is 80-85 ℃, and the reaction time is 2-12 h.
6. The method of claim 1, wherein: and (3) the reducing agent used in the hydrogenation reduction reaction in the step (2) is one of lithium borohydride, sodium borohydride and potassium borohydride.
7. The method of claim 6, wherein: the molar ratio of the reducing agent to the compound I is 0.25:1-1: 1.
8. The method of claim 1, wherein: the temperature of the hydrogenation reduction reaction in the step (2) is 20-80 ℃, and the reaction time is 1-12 h; the solvent used in the hydrogenation reduction reaction is one of anhydrous methanol, anhydrous ethanol and isopropanol.
9. The method of claim 1, wherein: the solvent used in the step (4) of hot filtering and salt removal and the step (5) of refining is one of methanol, absolute ethyl alcohol and isopropanol.
10. The method of claim 9, wherein: the mass ratio of the solvent in the step (4) to the crude compound VI in the step (5) is 8:1-20: 1.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114524734A (en) * | 2021-12-27 | 2022-05-24 | 嘉实（湖南）医药科技有限公司 | Preparation method of novel dobutamine hydrochloride |
| CN115322109A (en) * | 2022-08-26 | 2022-11-11 | 安徽恒星制药有限公司 | Preparation method of dobutamine hydrochloride suitable for industrial production |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3987200A (en) * | 1972-04-12 | 1976-10-19 | Eli Lilly And Company | Method for increasing cardiac contractility |
| CN101121670A (en) * | 2007-09-11 | 2008-02-13 | 上海紫源制药有限公司 | Method for preparing 3,4-dimethoxy-N-[3-(4-methoxyphenyl)-1-methyl-n-propyl]-beta-phenylethylamine hydrochloride |
| CN109851511A (en) * | 2017-11-30 | 2019-06-07 | 浙江普利药业有限公司 | A kind of synthetic method of dobutamine hydrochloride |
-
2020
- 2020-08-23 CN CN202010853350.8A patent/CN111807975A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3987200A (en) * | 1972-04-12 | 1976-10-19 | Eli Lilly And Company | Method for increasing cardiac contractility |
| CN101121670A (en) * | 2007-09-11 | 2008-02-13 | 上海紫源制药有限公司 | Method for preparing 3,4-dimethoxy-N-[3-(4-methoxyphenyl)-1-methyl-n-propyl]-beta-phenylethylamine hydrochloride |
| CN109851511A (en) * | 2017-11-30 | 2019-06-07 | 浙江普利药业有限公司 | A kind of synthetic method of dobutamine hydrochloride |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114524734A (en) * | 2021-12-27 | 2022-05-24 | 嘉实（湖南）医药科技有限公司 | Preparation method of novel dobutamine hydrochloride |
| CN114524734B (en) * | 2021-12-27 | 2024-04-26 | 嘉实（湖南）医药科技有限公司 | Preparation method of dobutamine hydrochloride |
| CN115322109A (en) * | 2022-08-26 | 2022-11-11 | 安徽恒星制药有限公司 | Preparation method of dobutamine hydrochloride suitable for industrial production |
| CN115322109B (en) * | 2022-08-26 | 2024-02-27 | 安徽恒星制药有限公司 | Preparation method of dobutamine hydrochloride suitable for industrial production |
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Application publication date: 20201023 |