CN104860833A - Purification method of dobutamine hydrochloride - Google Patents
Purification method of dobutamine hydrochloride Download PDFInfo
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- CN104860833A CN104860833A CN201510216051.2A CN201510216051A CN104860833A CN 104860833 A CN104860833 A CN 104860833A CN 201510216051 A CN201510216051 A CN 201510216051A CN 104860833 A CN104860833 A CN 104860833A
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- dobutamine hydrochloride
- purification process
- hydrochloride usp
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- dobutamine
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Abstract
The invention discloses a purification method of dobutamine hydrochloride. The purification method comprises the following steps that (1) a dobutamine hydrochloride crude product and methyl alcohol are mixed, heated and stirred, and then solvent A is added, wherein the solvent A is one or more of water, ethyl alcohol and acetone; (2) natural cooling is conducted to enable the temperature to range from 10 DEG C to 30 DEG C, crystallization is conducted for 10-14 hours at the temperature ranging from 1 DEG C to 5 DEG C, filtration under the reduced pressure is conducted, and vacuum drying is conducted. According to the purification method, the price of the solvent is quite low, the toxicity is low, and the environmental pollution is little; the heating temperature is low, and is smaller than or equal to 60 DEG C, the energy consumption is low, corrosive gas cannot be generated, and the purification method is applicable to industrial production; the whole technological process is simple, the purity of the prepared dobutamine hydrochloride is more than 99%, and the yield is high.
Description
Technical field
The present invention relates to chemicals preparation field, be specifically related to a kind of purification process of Dobutamine Hydrochloride USP.
Background technology
Dobutamine Hydrochloride USP, chemical name: 4-[2-[[1-methyl-3-(4-hydroxyphenyl) propyl group] is amino] ethyl]-1,2-dihydroxy-benzene hydrochloride, English Dobutamine Hydrochloride by name, molecular formula is C
18h
23nO
3hCl is Dopamine HCL homologue, is a selectivity heart β1-receptor stimulant, clinical be used for the treatment of organic heart disease myocardial contraction decline cause heart failure, cardiogenic shock caused by myocardial infarction and postoperative ypotension.
In prior art, Dobutamine Hydrochloride USP preparation method is (patent US5073648A): with 3,4-dimethoxy-phenylethylamine is raw material, under tosic acid effect, imine structure is condensed into to anisole butanone, N-(3 is generated again with the reduction of palladium hydrocarbonize, 4-Dimethoxyphenethyl)-4-(4-p-methoxy-phenyl) butane-2-amine, then slough the methyl on three methoxyl groups with 48% Hydrogen bromide, finally obtain Dobutamine Hydrochloride USP with hydrochloric acid displaces Hydrogen bromide.
The Dobutamine Hydrochloride USP crude product that this method obtains, main containing following impurity: N-(3,4-Dimethoxyphenethyl)-4-(4-p-methoxy-phenyl) butane-2-amine only sloughs the by product of a methyl and two methyl, phenolic hydroxyl group is oxidized to the impurity of sub-quinone or quinone, and variously reacts the impurity left over above.Character and the Dobutamine Hydrochloride USP of these impurity are similar, are difficult to be separated, and have a strong impact on the quality of Dobutamine Hydrochloride USP.
Shionogi company of Japan (patent US5073648A) discloses a kind of purification process of Dobutamine Hydrochloride USP, Dobutamine Hydrochloride USP crude product is put into a certain amount of hydrochloric acid (4N), heating makes it all dissolve, naturally cooling is placed and is spent the night at ambient temperature, crystallization, solid after filtration is dried, and can obtain the Dobutamine Hydrochloride USP that purity is 98.3%, yield 84%.The shortcoming of this method is, highly acid hydrochloric acid life-time service is high to equipment requirements, and hydrochloric acid easily evaporate in air after heating, corrosion surrounding devices and to environment.
Summary of the invention
Technical problem solved by the invention is that the purification process purity in order to overcome Dobutamine Hydrochloride USP in prior art is not high, the defect of the easy contaminate environment of solvent and etching apparatus, and provides a kind of purification process of Dobutamine Hydrochloride USP.Purification process solvent price of the present invention is very cheap, and toxicity is low, and environmental pollution is little; Heating temperature is not high yet, is no more than 60 DEG C, consumes energy low, can not produce corrosive gases, is applicable to suitability for industrialized production; Whole technical process is simple, and the purity of obtained Dobutamine Hydrochloride USP is all more than 99%, and yield is higher.
The present invention solves the problems of the technologies described above by the following technical programs:
The invention provides a kind of purification process of Dobutamine Hydrochloride USP, it comprises the steps:
(1) by Dobutamine Hydrochloride USP crude product and methanol mixed, heated and stirred, then add solvent orange 2 A, described solvent orange 2 A is one or more in water, ethanol and acetone;
(2) naturally cool to 10 ~ 30 DEG C, then under 1 ~ 5 DEG C of condition crystallization 10 ~ 14 hours, filtration under diminished pressure, vacuum-drying.
Wherein, described Dobutamine Hydrochloride USP crude product is preferably obtained by following preparation method: with 3,4-dimethoxy-phenylethylamine is raw material, under tosic acid effect, imine structure is condensed into to anisole butanone, N-(3 is generated again with potassium borohydride reduction, 4-Dimethoxyphenethyl)-4-(4-p-methoxy-phenyl) butane-2-amine, then slough the methyl on three methoxyl groups with the Hydrogen bromide that concentration of volume percent is 48%, finally namely obtain Dobutamine Hydrochloride USP crude product with hydrochloric acid displaces Hydrogen bromide.More preferably obtained by following preparation method: by 3,4-dimethoxy-phenylethylamine, p-methoxy-acetophenone, tosic acid and benzene mix, be warming up to 80 ~ 83 DEG C of reactions, concentrating under reduced pressure, is dissolved in concentrated solution in methyl alcohol, add POTASSIUM BOROHYDRIDE, be warming up to backflow, remove solvent under reduced pressure, concentrated solution is soluble in water, by extracted with diethyl ether, ether layer drying concentrates to obtain solid; By the solid after concentrated and Hydrogen bromide mixing, stirring and refluxing, is cooled to 9 ~ 10 DEG C, centrifugal dobutamine hydrobromate crude product; Dobutamine hydrobromate crude product and purified water mixing, be heated to 80 ~ 83 DEG C, add hydrochloric acid and stir, be cooled to 9 ~ 10 DEG C, leave standstill, centrifugally can obtain Dobutamine Hydrochloride USP crude product.
Wherein, the mass ratio of described methyl alcohol and described Dobutamine Hydrochloride USP crude product is preferably (1 ~ 1.5): 1, is more preferably 1:1.
Wherein, described Dobutamine Hydrochloride USP crude product and the mass ratio of described solvent orange 2 A are preferably (0.5 ~ 0.8): 1, are more preferably 0.5:1.
Wherein, in step (1), the temperature of described heating is preferably 58 ~ 62 DEG C, is more preferably 60 DEG C.
Wherein, in step (1), the feed postition of described solvent orange 2 A is preferably for slowly to add solvent orange 2 A.
Wherein, in step (2), the temperature of described crystallization is preferably 4 DEG C, and the time of described crystallization is preferably 12 hours.
Wherein, in step (2), described vacuum drying temperature is preferably 50 ~ 60 DEG C, is more preferably 55 DEG C.
Wherein, in step (2), the described vacuum drying time is preferably 6 ~ 10 hours, is more preferably 8 hours.
Wherein, in step (2), described vacuum drying vacuum tightness is preferably 0.04 ~ 0.08MPa.
On the basis meeting this area general knowledge, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material are all commercially.
Positive progressive effect of the present invention is: purification process of the present invention only needs to add methyl alcohol heated and stirred and dissolves, then adds other solvents, then cooling crystallization, and solvent price is very cheap, and toxicity is low, and environmental pollution is little; Heating temperature is not high yet, is no more than 60 DEG C, consumes energy low, can not produce corrosive gases, is applicable to suitability for industrialized production; Whole technical process is simple, and the HPLC purity of obtained Dobutamine Hydrochloride USP is all more than 99%, and yield is higher.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
Prepared by embodiment 1 Dobutamine Hydrochloride USP crude product
By 3,4-dimethoxy-phenylethylamine 2.0kg, p-methoxy-acetophenone 2.2kg, tosic acid 150g and benzene 14kg drop in 20L lass lining reactor, be warming up to 80-83 DEG C of reaction 24h, concentrating under reduced pressure, is dissolved in 6.0kg methyl alcohol and pours in 30L lass lining reactor by concentrated solution, slowly add POTASSIUM BOROHYDRIDE 2.5kg, be warming up to backflow 12h, remove solvent under reduced pressure, concentrated solution is soluble in water, by extracted with diethyl ether, ether layer drying concentrates to obtain solid.Join in 50L lass lining reactor by the solid after concentrated and Hydrogen bromide, 180r/min stirring and refluxing 7h, be cooled to 10 DEG C, blowing dries in whizzer, rotating speed 8000r/min, obtains dobutamine hydrobromate crude product.Dobutamine hydrobromate crude product and purified water are dropped in 30L enamel reactor, be heated to 80 DEG C, add hydrochloric acid to stir, be cooled to 10 DEG C, leave standstill more than 4h, whizzer rejection filter is extremely dry, rotating speed 8000r/min, obtain Dobutamine Hydrochloride USP crude product (HPLC purity is 91%, detects by the method for effect example 1).
Embodiment 2 Dobutamine Hydrochloride USP purifying crude
50g Dobutamine Hydrochloride USP crude product (by the preparation of embodiment 1 method) is added in the 250mL reaction flask that agitator, thermometer are housed, add methyl alcohol 50g, be heated to 60 DEG C of stirring and dissolving, slowly add purified water 100g again, stop heating, naturally cool to room temperature (25 DEG C), put into 4 DEG C of refrigerators and leave standstill 12h, filtration under diminished pressure, vacuum tightness 0.04 ~ 0.08MPa, vacuum drying oven 55 DEG C of dry 8h put into by filter cake, obtain Dobutamine Hydrochloride USP highly finished product 42g, HPLC purity is 99.4% (detecting by the method for effect example 1), yield 84%.
Embodiment 3 Dobutamine Hydrochloride USP purifying crude
50g Dobutamine Hydrochloride USP crude product (by the preparation of embodiment 1 method) is added in the 250mL reaction flask that agitator, thermometer are housed, add methyl alcohol 50g, be heated to 60 DEG C of stirring and dissolving, slowly add ethanol 100g again, stop heating, naturally cool to room temperature (25 DEG C), put into 4 DEG C of refrigerators and leave standstill 12h, filtration under diminished pressure, vacuum tightness 0.04 ~ 0.08MPa, vacuum drying oven 55 DEG C of dry 8h put into by filter cake, obtain Dobutamine Hydrochloride USP highly finished product 42.6g, HPLC purity is 99.2% (detecting by the method for effect example 1), yield 85.2%.
Embodiment 4 Dobutamine Hydrochloride USP purifying crude
50g Dobutamine Hydrochloride USP crude product (by the preparation of embodiment 1 method) is added in the 250mL reaction flask that agitator, thermometer are housed, add methyl alcohol 50g, be heated to 60 DEG C of stirring and dissolving, slowly add acetone 100g again, stop heating, naturally cool to room temperature (25 DEG C), put into 4 DEG C of refrigerators and leave standstill 12h, filtration under diminished pressure, vacuum tightness 0.04 ~ 0.08MPa, vacuum drying oven 55 DEG C of dry 8h put into by filter cake, obtain Dobutamine Hydrochloride USP highly finished product 41.3g, HPLC purity is 99.2% (detecting by the method for effect example 1), yield 82.4%.
Comparative example 1
50g Dobutamine Hydrochloride USP crude product (by the preparation of embodiment 1 method) is added in the 250mL reaction flask that agitator, thermometer are housed, add methyl alcohol 50g, be heated to 60 DEG C of stirring and dissolving, naturally cool to room temperature (25 DEG C), put into 4 DEG C of refrigerators and leave standstill 12h, filtration under diminished pressure, vacuum tightness 0.04 ~ 0.08MPa, vacuum drying oven 55 DEG C of dry 8h put into by filter cake, obtain Dobutamine Hydrochloride USP highly finished product 32.5g, HPLC purity is 99.5% (detecting by the method for effect example 1), yield 65%.
Comparative example 2
50g Dobutamine Hydrochloride USP crude product (by the preparation of embodiment 1 method) is added in the 250mL reaction flask that agitator, thermometer are housed, add methyl alcohol 50g, be heated to 60 DEG C of stirring and dissolving, slowly add tetrahydrofuran (THF) 100g again, stop heating, naturally cool to room temperature (25 DEG C), put into 4 DEG C of refrigerators and leave standstill 12h, filtration under diminished pressure, vacuum tightness 0.04 ~ 0.08MPa, vacuum drying oven 55 DEG C of dry 8h put into by filter cake, obtain Dobutamine Hydrochloride USP highly finished product 45.6g, HPLC purity is 96.5% (detecting by the method for effect example 1), yield 91.2%.
Comparative example 3
Agitator is being housed, 50g Dobutamine Hydrochloride USP crude product (by the preparation of embodiment 1 method) is added in the 250mL reaction flask of thermometer, add the mixed solution of methyl alcohol 50g and ethanol 100g, be heated to 60 DEG C stir 2 hours, Dobutamine Hydrochloride USP crude product does not all dissolve, stop heating, naturally cool to room temperature (25 DEG C), put into 4 DEG C of refrigerators and leave standstill 12h, filtration under diminished pressure, vacuum tightness 0.04 ~ 0.08MPa, vacuum drying oven 55 DEG C of dry 8h put into by filter cake, obtain Dobutamine Hydrochloride USP highly finished product 44.6g, HPLC purity is 98.4% (detecting by the method for effect example 1), yield 89.2%.
Effect example 1 Dobutamine Hydrochloride USP HPLC detection method
Be weighting agent with octadecylsilane chemically bonded silica; With perfluorooctane sulfonate 2.6g, the 1000ml that adds water makes dissolving, adds triethylamine 3ml, shakes up, and is mobile phase A by phosphoric acid adjust ph to 2.5; Acetonitrile-methanol (18:82, volume ratio) is Mobile phase B; Get this product appropriate, accurately weighed, dissolve by mobile phase A-Mobile phase B (65:35, volume ratio) and make the solution about containing 5.0mg in every 1ml, as solution to be measured; Precision measures solution 20 μ l to be measured, and injection liquid chromatography, carries out gradient elution by following gradient; Flow velocity is 1.0ml/min; Determined wavelength is 280nm.
Claims (10)
1. a purification process for Dobutamine Hydrochloride USP, it comprises the steps:
(1) by Dobutamine Hydrochloride USP crude product and methanol mixed, heated and stirred, then add solvent orange 2 A, described solvent orange 2 A is one or more in water, ethanol and acetone;
(2) naturally cool to 10 ~ 30 DEG C, then under 1 ~ 5 DEG C of condition crystallization 10 ~ 14 hours, filtration under diminished pressure, vacuum-drying.
2. purification process as claimed in claim 1, it is characterized in that, described Dobutamine Hydrochloride USP crude product is obtained by following preparation method: with 3,4-dimethoxy-phenylethylamine is raw material, with to the condensation under tosic acid effect of anisole butanone, N-(3 is generated again with potassium borohydride reduction, 4-Dimethoxyphenethyl)-4-(4-p-methoxy-phenyl) butane-2-amine, then slough the methyl on three methoxyl groups with the Hydrogen bromide that concentration of volume percent is 48%, finally namely obtain Dobutamine Hydrochloride USP crude product with hydrochloric acid displaces Hydrogen bromide.
3. purification process as claimed in claim 1, it is characterized in that, the mass ratio of described methyl alcohol and described Dobutamine Hydrochloride USP crude product is (1 ~ 1.5): 1, is preferably 1:1.
4. purification process as claimed in claim 1, it is characterized in that, described Dobutamine Hydrochloride USP crude product and the mass ratio of described solvent orange 2 A are (0.5 ~ 0.8): 1, are preferably 0.5:1.
5. purification process as claimed in claim 1, it is characterized in that, in step (1), the temperature of described heating is 58 ~ 62 DEG C, is preferably 60 DEG C.
6. purification process as claimed in claim 1, it is characterized in that, in step (1), the feed postition of described solvent orange 2 A is for slowly to add solvent orange 2 A.
7. purification process as claimed in claim 1, it is characterized in that, in step (2), the temperature of described crystallization is 4 DEG C, and the time of described crystallization is 12 hours.
8. purification process as claimed in claim 1, it is characterized in that, in step (2), described vacuum drying temperature is 50 ~ 60 DEG C, is preferably 55 DEG C.
9. purification process as claimed in claim 1, it is characterized in that, in step (2), the described vacuum drying time is 6 ~ 10 hours, is preferably 8 hours.
10. purification process as claimed in claim 1, it is characterized in that, in step (2), described vacuum drying vacuum tightness is 0.04 ~ 0.08MPa.
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| CN201510216051.2A CN104860833A (en) | 2015-04-30 | 2015-04-30 | Purification method of dobutamine hydrochloride |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105669476A (en) * | 2016-02-23 | 2016-06-15 | 上海上药第一生化药业有限公司 | Dobutamine hydrochloride crystal form and preparation method and application thereof |
| CN108707079A (en) * | 2018-06-19 | 2018-10-26 | 浙江瑞新药业股份有限公司 | The synthesis technology of dobutamine 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 |
| CN114702398A (en) * | 2022-04-12 | 2022-07-05 | 安徽普利药业有限公司 | Preparation method of dobutamine hydrochloride |
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| CN88100990A (en) * | 1987-02-24 | 1988-09-07 | 伊莱利利公司 | Improving one's methods of dobutamine salt |
| 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 |
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2015
- 2015-04-30 CN CN201510216051.2A patent/CN104860833A/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 |
| CN88100990A (en) * | 1987-02-24 | 1988-09-07 | 伊莱利利公司 | Improving one's methods of dobutamine salt |
| 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 |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105669476A (en) * | 2016-02-23 | 2016-06-15 | 上海上药第一生化药业有限公司 | Dobutamine hydrochloride crystal form and preparation method and application thereof |
| 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 |
| CN109851511B (en) * | 2017-11-30 | 2022-12-06 | 浙江普利药业有限公司 | Method for synthesizing dobutamine hydrochloride |
| CN108707079A (en) * | 2018-06-19 | 2018-10-26 | 浙江瑞新药业股份有限公司 | The synthesis technology of dobutamine hydrochloride |
| CN114702398A (en) * | 2022-04-12 | 2022-07-05 | 安徽普利药业有限公司 | Preparation method of dobutamine hydrochloride |
| CN114702398B (en) * | 2022-04-12 | 2023-12-26 | 安徽普利药业有限公司 | Preparation method of dobutamine hydrochloride |
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Application publication date: 20150826 |