CN114716331A - Preparation method of dopamine hydrochloride - Google Patents
Preparation method of dopamine hydrochloride Download PDFInfo
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- CN114716331A CN114716331A CN202210218360.3A CN202210218360A CN114716331A CN 114716331 A CN114716331 A CN 114716331A CN 202210218360 A CN202210218360 A CN 202210218360A CN 114716331 A CN114716331 A CN 114716331A
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- dopamine hydrochloride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a preparation method of dopamine hydrochloride, which takes 3, 4-dihydroxy benzaldehyde as a starting raw material, and sequentially carries out an upper protection reaction, an addition reaction and a reduction reaction to obtain a dopamine hydrochloride crude product, and finally, the dopamine hydrochloride crude product is refined by ethanol to obtain a finished product. The raw materials and auxiliary materials used in the invention are all easily available, high-pollution reagents are avoided in the reaction process, the preparation method is green and environment-friendly, the whole reaction route is moderate, the operation is simple and convenient, the reaction condition is mild, the yield of the obtained finished product dopamine hydrochloride is high, the quality is good, and the industrial production is favorably realized.
Description
Technical Field
The invention relates to the technical field of chemical drug synthesis, in particular to a preparation method of dopamine hydrochloride.
Background
The indications are shock syndrome caused by myocardial infarction, trauma, endotoxemia, cardiac operation, renal failure, congestive heart failure and the like; shock is not corrected after blood volume supplementation, especially in cases of oliguria and shock with normal or low peripheral vascular resistance. Since it can increase cardiac output, it is also used for cardiac insufficiency caused by digitalis and diuretic ineffectiveness.
At present, few reports exist in the literature of dopamine hydrochloride synthesis routes, and the routes have serious defects in industrial application, such as long process route, serious pollution of three wastes, low yield, complicated operation and the like.
The existing mainly relevant synthetic routes are reported as follows:
(1) in the university of Shandong light industry, Wang Young Yun reported that vanillin was used as a raw material, and dopamine was obtained by condensation, reduction, demethylation and salification. When zinc amalgam is used as a reducing agent in the reduction process, the defects of difficult acquisition of zinc amalgam, toxic mercury, three-waste pollution, high cost and the like exist, so the zinc amalgam is not easy to adopt; hydrobromic acid is adopted in the methyl removal process, and the defects of serious three-waste pollution and the like exist. The process route is relatively lagged, the pollution is serious, and the requirement of the existing green chemistry can not be met, so the process is not suitable for industrial production;
(2) the dopamine is obtained by taking 3, 4-dimethoxybenzaldehyde as a raw material and performing condensation, reduction, demethylation and salification. The only difference with the route (1) is that the starting materials are different, the reaction process and the used reagents are the same, and the requirements of the existing green chemistry can not be met, so the method is not suitable for industrial production;
(3) the northeast pharmaceutical industry refers to a report of dopamine synthesis new route, wherein homopiperony lamine is used as a starting raw material, and dopamine hydrochloride is directly obtained through one-step acid hydrolysis.
Disclosure of Invention
The invention aims to solve the technical problem of the prior art and provides a preparation method of dopamine hydrochloride, which has the advantages of low production cost, short reaction route, good reaction safety and high quality of the obtained product.
The technical scheme adopted by the invention for solving the technical problems is as follows:
a preparation method of dopamine hydrochloride is characterized by comprising the following steps:
(1) carrying out protective reaction on 3, 4-dihydroxy benzaldehyde, a protective group and an acid-binding agent in an organic solvent to obtain DBA-1;
(2) DBA-1 reacts with nitromethane, a catalyst and an organic solvent at a certain temperature and time to generate DBA-2;
(3) reducing nitro, double bond and removing benzyl to obtain dopamine hydrochloride by DBA-2 in an organic solvent under the action of a metal catalyst and a reducing agent;
(4) refining the dopamine hydrochloride crude product to obtain a target product dopamine hydrochloride,
preferably, in the step (1), the protecting group is any one of benzyl chloride and benzyl bromide, preferably benzyl chloride; the acid-binding agent is any one of sodium hydroxide, triethylamine and potassium carbonate, and preferably potassium carbonate; the molar ratio of the 3,4 dihydroxy benzaldehyde to the protecting group to the acid-binding agent is 1 (1-2.5) to 1-3.0; the reaction temperature is 20-80 ℃, and the reaction time is 3-5 h.
Preferably, in the step (1), the organic solvent is any one of acetone, acetonitrile and N, N-dimethylformamide, preferably acetonitrile, and the amount of the organic solvent is 5-10 times of the mass of the 3, 4-dihydroxybenzaldehyde; after the reaction is finished, the purification is carried out, wherein a purification solvent is any one of methanol, ethanol and acetone, preferably ethanol, and the using amount of the ethanol is 5-10 times of the mass of the 3, 4-dihydroxy benzaldehyde.
Preferably, in the step (2), the organic solvent is any one of methanol, ethanol, acetic acid and isopropanol, preferably acetic acid, and the dosage of the organic solvent is 5-10 times of that of DBA-1; the catalyst is any one of sodium methoxide, ammonium acetate and triethylamine, and ammonium acetate is preferred; the raw material molar ratio of DBA-1 to nitromethane to the catalyst is 1 (1-6) to 1-2; the reaction temperature is 20-100 ℃, and the reaction time is 2-4 h.
Preferably, in the step (3), the organic solvent is any one of methanol and ethanol, preferably methanol; the dosage of the organic solvent is 5-10 times of the mass of DBA-2.
Preferably, in the step (3), the reducing agent is any one of hydrogen and ammonium formate, preferably hydrogen; the catalyst is Pd (OH)2Any one of Pd/C, Pd/C, preferably Pd/C; the dosage of the catalyst is 1-10% of the mass of DBA-2; the reaction pressure is 0.3-1.0 MPa; the reaction temperature is 30-60 ℃; the reaction time is 5-12 h.
Preferably, in the step (4), the refined organic solvent is any one of methanol, absolute ethyl alcohol, ethanol and acetone, preferably ethanol; the dosage of the organic solvent is 5-20 times of the mass of the dopamine hydrochloride.
Preferably, in the step (4), the crystallization temperature of the refined organic solvent is-5 to 30 ℃, preferably-5 to 0 ℃.
Compared with the prior art, the invention has the advantages that: the raw materials and auxiliary materials used in the invention are all easily available, high-pollution reagents are avoided in the reaction process, the preparation method is green and environment-friendly, the whole reaction route is moderate, the operation is simple and convenient, the reaction condition is mild, the yield of the obtained finished product dopamine hydrochloride is high, the quality is good, and the industrial production is favorably realized.
Drawings
FIG. 1 is a reaction scheme of various embodiments of the present invention;
FIG. 2 shows DBA-1 obtained in example 1 of the present invention1H-NMR spectrum;
FIG. 3 shows DBA-2 obtained in example 1 of the present invention1H-NMR spectrum;
FIG. 4 shows the dopamine hydrochloride obtained in example 1 of the present invention1H-NMR spectrum.
Detailed Description
The invention is described in further detail below with reference to the accompanying examples.
The reaction mechanism of the present invention is shown in FIG. 1.
Example 1:
the preparation method of dopamine hydrochloride in the embodiment comprises the following steps:
(1) preparation of DBA-1
Adding 34.6g (0.25mol) of potassium carbonate, 30.4g (0.24mol) of benzyl chloride and 110.0g of acetonitrile into a 500mL reaction bottle, adding 13.8g (0.1mol) of 3, 4-dihydroxybenzaldehyde under stirring, heating to 75 ℃, preserving heat for reaction for 4h, cooling to room temperature after the reaction is finished, carrying out suction filtration, washing a filter cake with a small amount of acetonitrile, carrying out reduced pressure concentration on the filtrate, adding 85mL of ethanol, refluxing for 0.5h, cooling to 0 ℃, filtering, and drying the solid to obtain DBA-1, wherein the DBA-1 is shown in figure 2, 29.9g and the yield is 94%.
(2) Preparation of DBA-2
Adding DBA-131.8 g (0.1mol), nitromethane 24.4g (0.4mol), ammonium acetate 7.7g (0.1mol) and 180mL of acetic acid into a 1L reaction bottle, heating to 100 ℃, preserving heat for reaction for 3 hours, cooling to room temperature after the reaction is finished, performing suction filtration, and drying the solid to obtain DBA-2, wherein the yield is 90% as shown in figure 3 and 32.5 g.
(3) Preparation of dopamine hydrochloride
Adding DBA-216.7 g, methanol 120ml, concentrated hydrochloric acid 50.0g and 10% palladium carbon 1.0g into a 1L hydrogenation kettle, controlling the temperature at 50 ℃ and the pressure at 0.6MPa, reacting for 8h until no hydrogen is absorbed, filtering after the reaction is finished, and concentrating the filtrate under reduced pressure to obtain dopamine hydrochloride 8.3g with the yield of 95%.
(4) Purification of dopamine hydrochloride
Adding 8.0g of dopamine hydrochloride and 100ml of ethanol into a reaction bottle, refluxing, stirring and dissolving, cooling to-5-0 ℃, separating out a solid, and performing suction filtration to obtain 7.5g of dopamine hydrochloride, wherein the yield is 94% as shown in figure 4.
Example 2:
the preparation method of dopamine hydrochloride in the embodiment comprises the following steps:
(1) preparation of DBA-1
Adding 34.6g (0.25mol) of potassium carbonate, 41.0g (0.24mol) of benzyl bromide and 110.0g of acetonitrile into a 500mL reaction bottle, adding 13.8g (0.1mol) of 3, 4-dihydroxybenzaldehyde under stirring, heating to 75 ℃, preserving heat for reaction for 4h, cooling to room temperature after the reaction is finished, carrying out suction filtration, washing a filter cake with a small amount of acetonitrile, carrying out reduced pressure concentration on the filtrate, adding 85mL of ethanol, refluxing for 0.5h, cooling to 0 ℃, filtering, and drying the solid to obtain DBA-1, 29.2g and the yield of 92%.
(2) Preparation of DBA-2
Adding DBA-131.8 g (0.1mol), nitromethane 24.4g (0.4mol), sodium methoxide 5.4g (0.1mol) and 200mL of methanol into a 1L reaction bottle, heating to 100 ℃, preserving heat for reaction for 3h, cooling to room temperature after the reaction is finished, performing suction filtration, and drying the solid to obtain DBA-2, 18.1g and the yield is 50%
(3) Preparation of dopamine hydrochloride
Adding DBA-216.7 g, 150ml of ethanol, 50.0g of concentrated hydrochloric acid and 1.0g of 10% palladium-carbon into a 1L hydrogenation kettle, controlling the temperature at 50 ℃ and the pressure at 0.6MPa, reacting for 8 hours until no hydrogen is absorbed, filtering after the reaction is finished, and concentrating the filtrate under reduced pressure to obtain 7.4g of dopamine hydrochloride with the yield of 85%.
(4) Purification of dopamine hydrochloride
Adding 8.0g of dopamine hydrochloride and 120ml of ethanol into a reaction bottle, refluxing and stirring, cooling to-5-0 ℃ to precipitate a solid, and performing suction filtration to obtain 6.1g of dopamine hydrochloride with the yield of 76%.
Example 3:
the preparation method of dopamine hydrochloride in the embodiment comprises the following steps:
(1) preparation of DBA-1
10.0g (0.25mol) of sodium hydroxide, 30.4g (0.24mol) of benzyl chloride and 110.0g of acetonitrile are added into a 500mL reaction bottle, 13.8g (0.1mol) of 3, 4-dihydroxybenzaldehyde is added under stirring, the temperature is raised to 75 ℃, the reaction is kept warm for 4 hours, after the reaction is finished, the reaction is cooled to room temperature for suction filtration, a filter cake is washed by a small amount of acetonitrile, the filtrate is concentrated under reduced pressure and dried, 85mL of ethanol is added, the reflux is carried out for 0.5 hour, the filtrate is cooled to 0 ℃, the filtration is carried out, and the solid is dried to obtain DBA-1, 26.0g and the yield is 82%.
(2) Preparation of DBA-2
Adding DBA-131.8 g (0.1mol), nitromethane 12.2g (0.2mol), ammonium acetate 7.7g (0.1mol) and 180mL of acetic acid into a 1L reaction bottle, heating to 100 ℃, preserving heat for reaction for 3h, cooling to room temperature, filtering, and drying the solid to obtain DBA-2, 7.0g with the yield of 80%
(3) Preparation of dopamine hydrochloride
Adding DBA-216.7 g, methanol 120ml, concentrated hydrochloric acid 50.0g and ammonium formate 14.5(0.23mol) g into a 1L hydrogenation kettle, controlling the temperature at 50 ℃ and the pressure at 0.6MPa, reacting for 8h until no hydrogen is absorbed, filtering after the reaction is finished, and concentrating the filtrate under reduced pressure to obtain dopamine hydrochloride 6.3g with the yield of 72%.
(4) Purification of dopamine hydrochloride
Adding 8.0g of dopamine hydrochloride and 50ml of methanol into a reaction bottle, refluxing, stirring and dissolving, cooling to-5-0 ℃, separating out a solid, and performing suction filtration to obtain 4.4g of dopamine hydrochloride with the yield of 50%.
Example 4:
the preparation method of dopamine hydrochloride in this example:
(1) preparation of DBA-1
Adding 34.6g (0.25mol) of potassium carbonate, 30.4g (0.24mol) of benzyl chloride and 110.0g of acetone into a 500mL reaction bottle, adding 13.8g (0.1mol) of 3, 4-dihydroxybenzaldehyde under stirring, heating to 75 ℃, preserving heat for reaction for 4h, cooling to room temperature after the reaction is finished, carrying out suction filtration, washing a filter cake with a small amount of acetonitrile, carrying out reduced pressure concentration on the filtrate, adding 85mL of ethanol, refluxing for 0.5h, cooling to 0 ℃, filtering, and drying the solid to obtain DBA-1, 27.0g and the yield of 85%.
(2) Preparation of DBA-2
Adding DBA-131.8 g (0.1mol), nitromethane 24.4g (0.4mol), triethylamine 10.0g (0.1mol) and 180mL of ethanol into a 1L reaction bottle, heating to 100 ℃, preserving heat for reaction for 3h, cooling to room temperature after the reaction is finished, performing suction filtration, and drying the solid to obtain DBA-2, 23.4g, wherein the yield is 65%
(3) Preparation of dopamine hydrochloride
Adding DBA-216.7 g, methanol 120ml, concentrated hydrochloric acid 50.0g and 10% palladium carbon 0.5g into a 1L hydrogenation kettle, controlling the temperature at 50 ℃ and the pressure at 0.6MPa, reacting for 8h until no hydrogen is absorbed, filtering after the reaction is finished, and concentrating the filtrate under reduced pressure to obtain dopamine hydrochloride 6.0g with the yield of 68%.
(4) Purification of dopamine hydrochloride
Adding 8.0g of dopamine hydrochloride and 100ml of ethanol into a reaction bottle, refluxing, stirring and dissolving, cooling to 20-30 ℃ to separate out a solid, and performing suction filtration to obtain 6.7g of dopamine hydrochloride with the yield of 78%.
Claims (9)
1. A preparation method of dopamine hydrochloride is characterized by comprising the following steps:
(1) reacting 3, 4-dihydroxy benzaldehyde with a protecting group and an acid-binding agent in an organic solvent to obtain DBA-1;
(2) DBA-1 reacts with nitromethane, a catalyst and an organic solvent to generate DBA-2;
(3) in an organic solvent, under the action of a metal catalyst and a reducing agent, DBA-2 reduces nitro groups, double bonds and removes benzyl groups to obtain a dopamine hydrochloride crude product;
(4) refining the dopamine hydrochloride crude product to obtain a target product dopamine hydrochloride,
2. the method for preparing dopamine hydrochloride according to claim 1, characterized in that: in the step (1), the protecting group is any one of benzyl chloride and benzyl bromide; the acid-binding agent is any one of sodium hydroxide, triethylamine and potassium carbonate.
3. The method for preparing dopamine hydrochloride according to claim 1, characterized in that: in the step (1), the molar ratio of the 3, 4-dihydroxybenzaldehyde to the protecting groups to the acid-binding agent is 1 (1-2.5) to 1-3.0; the reaction temperature is 20-80 ℃, and the reaction time is 3-5 h.
4. The method for preparing dopamine hydrochloride according to claim 1, characterized in that: the organic solvent in the step (1) is any one of acetone, acetonitrile and N, N-dimethylformamide, and the amount of the organic solvent is 5-10 times of the mass of 3, 4-dihydroxybenzaldehyde; and after the reaction is finished, purifying the product, wherein the purifying solvent is any one of methanol, ethanol and acetone, and the using amount of the purifying solvent is 5-10 times of the mass of the 3, 4-dihydroxy benzaldehyde.
5. The method for preparing dopamine hydrochloride according to any one of claims 1 to 4, wherein: the organic solvent in the step (2) is any one of methanol, ethanol, acetic acid and isopropanol, and the dosage of the organic solvent is 5-10 times of that of DBA-1; the catalyst is any one of sodium methoxide, ammonium acetate and triethylamine.
6. The method for producing dopamine hydrochloride according to any of claims 1 to 4, characterized in that: in the step (2), the raw material molar ratio of DBA-1 to nitromethane and the catalyst is 1 (1-6) to 1-2; the reaction temperature is 20-100 ℃, and the reaction time is 2-4 h.
7. The method for preparing dopamine hydrochloride according to any one of claims 1 to 4, wherein: in the step (3), the organic solvent for the reduction reaction is any one of methanol and ethanol, preferably methanol; the dosage of the organic solvent is 5-10 times of the mass of DBA-2.
8. The method for preparing dopamine hydrochloride according to any one of claims 1 to 4, wherein: in the step (3), the reducing agent is any one of hydrogen and ammonium formate; the catalyst is Pd (OH)2And Pd/C, Pd/C; the dosage of the catalyst is 1 to 10 percent of the mass of DBA-2; the reaction pressure is 0.3-1.0 MPa, the reaction temperature is 30-60 ℃, and the reaction time is 5-12 h.
9. The method for producing dopamine hydrochloride according to any of claims 1 to 4, characterized in that: in the step (4), the organic solvent for refining is any one of methanol, absolute ethyl alcohol, ethanol and acetone, and the amount of the organic solvent is 5-20 times of the mass of dopamine hydrochloride; the crystallization temperature of the refined organic solvent is-5 to 30 ℃.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116675611A (en) * | 2023-04-17 | 2023-09-01 | 常州亚邦制药有限公司 | Dopamine hydrochloride crystal form and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0327345A (en) * | 1989-06-26 | 1991-02-05 | Ube Ind Ltd | Production of phenetylamines |
| CN111925293A (en) * | 2020-08-24 | 2020-11-13 | 山东达冠医药科技有限公司 | Preparation method of dopamine hydrochloride |
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- 2022-03-03 CN CN202210218360.3A patent/CN114716331A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0327345A (en) * | 1989-06-26 | 1991-02-05 | Ube Ind Ltd | Production of phenetylamines |
| CN111925293A (en) * | 2020-08-24 | 2020-11-13 | 山东达冠医药科技有限公司 | Preparation method of dopamine hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| YIXIAN LIAO等: ""Synthesis and SARs of dopamine derivatives as potential inhibitors of influenza virus PAN endonuclease"", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》, vol. 189, no. 112048, pages 1 - 12 * |
| 荣国斌主编: "《大学有机化学基础（第二版）下册》", 上海：华东理工大学出版社, pages: 655 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116675611A (en) * | 2023-04-17 | 2023-09-01 | 常州亚邦制药有限公司 | Dopamine hydrochloride crystal form and preparation method thereof |
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