Method for synthesizing dopamine hydrochloride from eugenol

Abstract

Disclosed in the present invention is a method for synthesizing dopamine hydrochloride from eugenol. Environmentally friendly and cheap eugenol is used as a raw material, and is subjected to four steps of methylation, oxidation, reductive amination and acidolysis to synthesize dopamine hydrochloride. Compared with an existing synthesis scheme, the method of the present invention has the advantages of having a low cost, a high yield, being simple to operate and having mild reaction conditions; in addition, the method is environmentally friendly, only one organic solvent may be used during the reaction process, and by-products generated in the reaction can be recovered and reused, thereby facilitating large-scale production of dopamine hydrochloride.

Description

A method for synthesizing dopamine hydrochloride from eugenol Technical field:

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing dopamine hydrochloride from eugenol. Background technology:

[0002] Dopamine hydrochloride, also known as dopamine hydrochloride, is the most commonly used chemical form of dopamine. It can be used to treat conditions such as Alzheimer's disease, myocardial infarction, and renal failure. Dopamine hydrochloride can also be used to synthesize polydopamine, which is used as a coating material for surface corrosion resistance, anti-adhesion, and antibacterial properties, surface chemical modification, and the preparation of novel smart materials.

[0003] Traditional dopamine hydrochloride synthesis routes include biocatalysis and chemical synthesis. The biocatalytic method involves enzymatically synthesizing levodopa from a variety of substrates, which is then catalyzed by decarboxylase to form dopamine. The chemical method primarily uses vanillin as a raw material, which is then converted to dopamine after carbon and nitrogen addition with nitromethane, followed by hydrogenation and demethylation. However, these methods are time-consuming, require highly toxic and explosive reagents, and are difficult to separate. In recent years, several domestic companies and research institutes have filed new patents for dopamine synthesis, but the final synthesis cost remains high. This is mainly due to the low overall yield caused by the large number of synthesis steps, or the use of expensive raw materials.

[0004] The final step in the chemical synthesis of dopamine hydrochloride is typically concentrated acidolysis of the methoxy group, which involves treating dopamine precursors (e.g., piperidine, 3,4-dimethoxyphenylethylamine, homovanillylamine, 4-aminoethylguaiacol, etc.) with concentrated HCl or HBr at high temperatures. Therefore, the efficient and inexpensive synthesis of these expensive precursors is key to the low-cost production of dopamine hydrochloride. Summary of the invention:

[0005] The present invention provides a method for synthesizing 3,4-dimethoxyphenylethylamine hydrochloride from eugenol and further synthesizing dopamine hydrochloride. The method uses low-cost eugenol as a raw material and is rapidly synthesized under mild reaction conditions, thereby solving the problems of high cost, low yield and complex route in the prior art.

[0006] The present invention is achieved through the following technical solutions:

[0007] A method for synthesizing 3,4-dimethoxyphenylethylamine hydrochloride from eugenol comprises the following steps:

[0008] (1) Eugenol reacts with a methylating agent in an alkaline solution at 40-200°C for 0.5-12 hours to generate a methyl eugenol solution, which is then purified and separated to obtain methyl eugenol;

[0009] (2) dissolving the methyl eugenol obtained in step (1) and introducing an ozone flow into the resulting solution at a reaction temperature of -78 to 60° C. to obtain an oxidation product solution of methyl eugenol, and washing the oxidation product solution with concentrated brine;

[0010] (3) adding an aminating agent and a hydrogenation catalyst to the washed oxidation product solution obtained in step (2), reacting under a hydrogen atmosphere to obtain a 3,4-dimethoxyphenethylamine hydrochloride solution; filtering the catalyst and removing the solvent to obtain 3,4-dimethoxyphenethylamine hydrochloride.

[0011] Preferably, in step (1), the alkali solution is an aqueous solution of at least one of lithium hydroxide, sodium hydroxide and potassium hydroxide; the methylating agent is dimethyl carbonate, dimethyl sulfate or monochloromethane, and the solvent is at least one of methanol, ethanol, n-butanol, tetrahydrofuran and ethyl acetate.

[0012] Preferably, in step (1), the reaction temperature is 50-120° C., and the reaction time is 1-4 h.

[0013] Preferably, in step (1), the purification and separation comprises neutralizing the obtained methyl eugenol solution, separating the liquids and taking the organic phase, removing the organic phase solvent to obtain a product mixture, extracting the product mixture with an alkaline solution, wherein the obtained organic phase is methyl eugenol, and the obtained aqueous phase is a eugenol alkaline solution; the recovered eugenol alkaline solution is returned to step (1) as a raw material to react with a methylating agent to prepare methyl eugenol.

[0014] Preferably, in step (2), the solvent for dissolving methyl eugenol is at least one of n-butanol, tetrahydrofuran, ethyl acetate, and water; the molar ratio of methyl eugenol to the introduced ozone is 1:(1-3); and the concentrated brine is an aqueous solution of at least one of sodium chloride, potassium chloride, magnesium chloride, sodium sulfate, potassium sulfate, and magnesium sulfate with a concentration of 0.1 mol / L or more.

[0015] Preferably, in step (3), the aminating agent is at least one of ammonia, hydroxylamine, and hydroxylamine hydrochloride, and the molar ratio of the aminating agent to the methyl eugenol used in step (2) is (2-6):1. When the aminating agent is hydroxylamine or hydroxylamine hydrochloride, hydrochloric acid may be further added.

[0016] Preferably, in step (3), the reaction conditions are: hydrogen pressure of 0.1 to 10 MPa, reaction temperature of 40 to 220° C., and reaction time of 0.1 to 6 h; and the hydrogenation catalyst is a supported metal hydrogenation catalyst of palladium, ruthenium or nickel.

[0017] More preferably, in step (3), the reaction temperature is 60-140°C and the reaction time is 0.5-3h.

[0018] The present invention also protects a method for synthesizing dopamine hydrochloride from eugenol, wherein 3,4-dimethoxyphenethylamine hydrochloride is synthesized by utilizing the above-mentioned method for synthesizing 3,4-dimethoxyphenethylamine hydrochloride, and then reacted with concentrated hydrochloric acid at a reaction temperature of 80 to 220° C. to obtain dopamine hydrochloride.

[0019] Preferably, the molar ratio of 3,4-dimethoxyphenethylamine hydrochloride in the crude 3,4-dimethoxyphenethylamine hydrochloride to the hydrochloric acid in the concentrated hydrochloric acid is 1:(2-8), and the reaction time is 0.1 to 6 hours.

[0020] Preferably, chloromethane gas is obtained after the reaction and introduced into a solvent to obtain a chloromethane solution as the methylating agent in step (1); the solvent is at least one of methanol, ethanol, n-butanol, tetrahydrofuran, and ethyl acetate.

[0021] The beneficial effects of the present invention are:

[0022] 1) The method of the present invention has high yield and low cost. Under optimal experimental conditions, the overall yield of dopamine hydrochloride can reach over 70%. The raw material eugenol used is a common natural flavoring with a green and widespread source and low cost (~140 yuan / kg).

[0023] 2) The reaction conditions of the method of the present invention are mild and rapid, and steps (1) to (3) are highly active even at temperatures below 80°C.

[0024] 3) The method of the present invention is green and environmentally friendly. The reaction by-product monochloromethane can be recovered and used in step (1), thereby reducing the emission of waste acid and waste gas and lowering costs. Only one organic solvent can be used to complete all steps, thereby reducing separation and storage costs. Description of the drawings: Specific implementation method:

[0025] It will be appreciated by those skilled in the art that the techniques disclosed in the following examples represent techniques that the inventors have found to work well in the practice of the present invention. However, many changes can be made in the disclosed specific embodiments and still obtain the same or similar results without departing from the spirit and scope of the present invention.

[0026] Example 1

[0027] A method for synthesizing dopamine hydrochloride from eugenol comprises the following steps:

[0028] (1) 25.5 g of eugenol was reacted in 5 mol / L sodium hydroxide solution with 100 ml of 2 mol / L tetrahydrofuran solution of chloroform at 100°C for 30 min to generate a methyl eugenol solution; the reaction mixture was neutralized, the layers were separated, and the organic phase was collected. The solvent was evaporated, and the product was extracted with 5 mol / L sodium hydroxide solution. The layers were separated to form an aqueous phase and an organic phase; the aqueous phase was the eugenol solution and was recovered; the organic phase was found to contain 21.0 g of methyl eugenol.

[0029] (2) dissolving the organic phase obtained in step (1) in 600 ml of ethyl acetate, and introducing an ozone flow into the resulting solution at -78°C in an amount of 3 times the molar amount of methyl eugenol in the solution to obtain an oxidation product solution of methyl eugenol, and washing the oxidation product solution with 100 ml of a 1 mol / L magnesium sulfate solution;

[0030] (3) adding an aminating agent and a Pd / C catalyst to the washed oxidation product solution obtained in step (2); the aminating agent is an aqueous solution of ammonia and hydroxylamine hydrochloride, and the molar ratio of methyl eugenol to the aminating agent used in step (2) is 1:(0.5 (ammonia) + 2.0 (hydroxylamine hydrochloride)); the resulting mixture is reacted under a 10 MPa hydrogen atmosphere at 40°C for 6 hours; the catalyst is filtered from the resulting product and the solvent is removed to obtain a product containing 17.8 g of 3,4-dimethoxyphenylethylamine (hydrochloride form).

[0031] (4) Concentrated hydrochloric acid is added to the product, wherein the molar ratio of the methyl eugenol used in step (2) to the hydrochloric acid in the concentrated hydrochloric acid is 1:4; the mixture is reacted at 140° C. for 3 hours to obtain a product containing 15.8 g of dopamine hydrochloride (the yield of dopamine hydrochloride is 71%); the gaseous product is dissolved and collected in tetrahydrofuran to obtain a tetrahydrofuran solution of monochloromethane.

[0032] Example 2

[0033] The Example 1 was carried out three times, and the eugenol alkali solutions recovered in step (1) were combined to obtain the raw material of this example; and the tetrahydrofuran solutions of monochloromethane collected in step (4) were combined to obtain the methylating reagent of this example.

[0034] (1) The recovered eugenol alkali solution and the methylating agent were mixed and reacted at 50°C for 2 hours to generate a methyl eugenol solution; the mixture was neutralized and separated into layers, and the organic phase was taken. The solvent was evaporated, and the product was extracted with a 5 mol / L potassium hydroxide alkali solution, and the layers were separated into aqueous and organic phases; the aqueous phase was the eugenol alkali solution and was recovered; and the organic phase was found to contain 19.8 g of methyl eugenol.

[0035] (2) dissolving the organic phase obtained in step (1) in 800 ml of tetrahydrofuran and 100 ml of water, and introducing an ozone flow into the resulting solution at room temperature, wherein the amount of ozone introduced is 1.5 times the molar amount of methyl eugenol in the solution, to obtain an oxidation product solution of methyl eugenol, and washing the oxidation product solution with 100 ml of a 3 mol / L potassium chloride solution;

[0036] (3) adding an aminating agent and a Ru / C catalyst to the washed oxidation product solution obtained in step (2); the aminating agent is an aqueous solution of hydroxylamine and hydrochloric acid, and the molar ratio of methyl eugenol used in step (2) to the aminating agent is 1:(1 (hydroxylamine) + 4 (hydrochloric acid)); the resulting mixture is reacted under a 3 MPa hydrogen atmosphere at 150° C. for 1 hour; the catalyst is filtered from the resulting product and the solvent is removed to obtain a product containing 16.8 g of 3,4-dimethoxyphenylethylamine (hydrochloride form).

[0037] (4) Concentrated hydrochloric acid is added to the product, wherein the molar ratio of the methyl eugenol used in step (2) to the hydrochloric acid in the concentrated hydrochloric acid is 1:2; the mixture is reacted at 160° C. for 2 h to obtain a product containing 14.9 g of dopamine hydrochloride.

[0038] The comprehensive yield of dopamine hydrochloride was 70% after implementing Example 1 three times and Example 2 once.

[0039] Example 3

[0040] Using methyl eugenol as raw material, the specific steps are as follows:

[0041] (1) 20 g of methyl eugenol was dissolved in 800 ml of tetrahydrofuran, 100 ml of n-butanol, and 100 ml of water. Ozone was introduced into the resulting solution at 60° C. The amount of ozone introduced was 1.0 times the molar amount of methyl eugenol in the solution to obtain an oxidation product solution of methyl eugenol. The oxidation product solution was then washed with 200 ml of a 5 mol / L sodium chloride solution.

[0042] (2) adding an aminating agent and a Ni / SiO2 catalyst to the washed oxidation product solution obtained in step (1); the aminating agent is an aqueous solution of hydroxylamine hydrochloride and hydrochloric acid, and the molar ratio of methyl eugenol to the aminating agent used in step (1) is 1:2 (hydroxylamine hydrochloride):2 (hydrochloric acid); the resulting mixture is reacted under a 0.1 MPa hydrogen atmosphere at 60°C for 2.5 hours; the resulting product is filtered, the catalyst is removed, and the solvent is removed to obtain a product containing 16.5 g of 3,4-dimethoxyphenylethylamine hydrochloride.

[0043] (3) Concentrated hydrochloric acid was added to the product, wherein the molar ratio of the methyl eugenol used in step (1) to the hydrochloric acid in the concentrated hydrochloric acid was 1:2; the mixture was reacted at 180° C. for 0.5 h to obtain a product containing 14.9 g of dopamine hydrochloride (the yield of dopamine hydrochloride was 70%).

[0044] Example 4

[0045] A method for synthesizing dopamine hydrochloride from eugenol comprises the following steps:

[0046] (1) 30.0 g of eugenol was reacted in 5 mol / L sodium hydroxide solution with 200 ml of 1.3 mol / L monochloromethane in ethyl acetate at 200°C for 30 min to generate a methyl eugenol solution; the reaction was neutralized, the layers were separated, and the organic phase was collected. The solvent was evaporated, and the product was extracted with 5 mol / L sodium hydroxide solution. The layers were separated to form an aqueous phase and an organic phase; the aqueous phase was the eugenol solution and was recovered; the organic phase was found to contain 23.8 g of methyl eugenol.

[0047] (2) dissolving the organic phase obtained in step (1) in 500 ml of ethyl acetate and 100 ml of water, and introducing an ozone flow into the resulting solution at 20° C., wherein the ozone flow rate is 2.5 times the molar amount of methyl eugenol in the solution, to obtain an oxidation product solution of methyl eugenol, and washing the oxidation product solution with 100 ml of 0.1 mol / L potassium sulfate solution;

[0048] (3) adding an aminating agent and a Pd / C catalyst to the washed oxidation product solution obtained in step (2); the aminating agent is a hydroxylamine aqueous solution plus hydrochloric acid, and the molar ratio of methyl eugenol, hydroxylamine, and hydrochloric acid used in step (2) is 1:2:5; the resulting mixture is reacted under a 10 MPa hydrogen atmosphere at 220° C. for 0.1 h; the resulting product is filtered, the catalyst is removed, and the solvent is removed to obtain a product containing 19.8 g of 3,4-dimethoxyphenylethylamine (hydrochloride form).

[0049] (4) Concentrated hydrochloric acid is added to the product, wherein the molar ratio of the methyl eugenol used in step (2) to the hydrochloric acid in the concentrated hydrochloric acid is 1:4; the mixture is reacted at 220° C. for 0.1 h to obtain a product containing 16.6 g of dopamine hydrochloride (the yield of dopamine hydrochloride is 66%); the gaseous product is dissolved and collected in ethyl acetate to obtain a solution of monochloromethane in ethyl acetate.

[0050] Example 5

[0051] A method for synthesizing dopamine hydrochloride from eugenol comprises the following steps:

[0052] (1) 27.0 g of eugenol was reacted in 5 mol / L potassium hydroxide solution with 100 ml of 2 mol / L dimethyl sulfate in ethyl acetate at 40°C for 12 h to generate a methyl eugenol solution; the mixture was neutralized, the layers were separated, and the organic phase was collected. The solvent was evaporated, and the product was extracted with 5 mol / L sodium hydroxide solution. The layers were separated to form an aqueous phase and an organic phase; the aqueous phase was the eugenol solution and was recovered; the organic phase was found to contain 26.6 g of methyl eugenol.

[0053] (2) dissolving the organic phase obtained in step (1) in 500 ml of ethyl acetate and 100 ml of water, and introducing an ozone flow into the resulting solution at 20° C., wherein the ozone flow rate is 1.5 times the molar amount of methyl eugenol in the solution, to obtain an oxidation product solution of methyl eugenol, and washing the oxidation product solution with 50 ml of 0.5 mol / L potassium sulfate solution;

[0054] (3) adding an aminating agent and a Pd / C catalyst to the washed oxidation product solution obtained in step (2); the aminating agent is an aqueous solution of ammonia and hydroxylamine hydrochloride, and the molar ratio of methyl eugenol, ammonia, and hydroxylamine hydrochloride used in step (2) is 1:1:3; the resulting mixture is reacted at 80°C under a 10 MPa hydrogen atmosphere for 2 h; the catalyst is filtered from the resulting product and the solvent is removed to obtain a product containing 23.5 g of 3,4-dimethoxyphenylethylamine (hydrochloride form).

[0055] (4) Concentrated hydrochloric acid is added to the product, wherein the molar ratio of the methyl eugenol used in step (2) to the hydrochloric acid in the concentrated hydrochloric acid is 1:8; the mixture is reacted at 80° C. for 6 h to obtain a product containing 19.2 g of dopamine hydrochloride (the yield of dopamine hydrochloride is 68%); the gaseous product is dissolved and collected in tetrahydrofuran to obtain a tetrahydrofuran solution of monochloromethane.

Claims

1. A method for synthesizing 3,4-dimethoxyphenylethylamine hydrochloride from eugenol, characterized in that: The following steps are involved: (1) Eugenol is reacted with a methylating agent in an alkaline solution at 40-200° C. for 0.5-12 h to generate a methyl eugenol solution, which is purified and separated to obtain methyl eugenol; (2) dissolving the methyl eugenol obtained in step (1), and introducing an ozone gas flow into the obtained solution at a reaction temperature of -78 to 60° C. to obtain an oxidation product solution of methyl eugenol, and washing the oxidation product solution with concentrated brine; (3) adding an aminating agent and a hydrogenation catalyst to the washed oxidation product solution obtained in step (2), reacting under a hydrogen atmosphere to obtain a 3,4-dimethoxyphenethylamine hydrochloride solution; filtering the catalyst and removing the solvent to obtain a crude 3,4-dimethoxyphenethylamine hydrochloride product.

2. The method according to claim 1, characterized in that In step (1), the alkali solution is an aqueous solution of at least one of lithium hydroxide, sodium hydroxide and potassium hydroxide; the methylating agent is dimethyl carbonate, dimethyl sulfate or monochloromethane, and the solvent is at least one of methanol, ethanol, n-butanol, tetrahydrofuran and ethyl acetate.

3. The method according to claim 1, characterized in that In step (1), the reaction temperature is 50-120° C. and the reaction time is 1-4 h.

4. The method according to claim 1 or 2, characterized in that: In step (1), the purification and separation comprises neutralizing the obtained methyl eugenol solution, separating the liquids and taking the organic phase, removing the organic phase solvent to obtain a product mixture, extracting the product mixture with an alkali solution, wherein the obtained organic phase is methyl eugenol, and the obtained aqueous phase is a eugenol alkali solution; the recovered eugenol alkali solution is returned to step (1) as a raw material to react with a methylating agent to prepare methyl eugenol.

5. The method according to claim 1, characterized in that In step (2), the solvent for dissolving methyl eugenol is at least one of n-butanol, tetrahydrofuran, ethyl acetate and water; the molar ratio of methyl eugenol to the introduced ozone is 1:(1-3); and the concentrated brine is an aqueous solution of at least one of sodium chloride, potassium chloride, magnesium chloride, sodium sulfate, potassium sulfate and magnesium sulfate with a concentration of more than 0.1 mol / L.

6. The method according to claim 1, characterized in that In step (3), the aminating agent is at least one of ammonia, hydroxylamine, and hydroxylamine hydrochloride, and the molar ratio of the aminating agent to the methyl eugenol used in step (2) is (2-6):1; the hydrogenation catalyst is a supported metal hydrogenation catalyst of palladium, ruthenium or nickel; in step (3), the reaction conditions are: hydrogen pressure of 0.1 to 10 MPa, temperature of 40 to 220° C., and time of 0.1 to 6 h.

7. The method according to claim 6, characterized in that In step (3), the reaction temperature is 60-140° C. and the reaction time is 0.5-3 h.

8. A method for synthesizing dopamine hydrochloride from eugenol, characterized in that: 3,4-dimethoxyphenethylamine hydrochloride is synthesized by the method for synthesizing 3,4-dimethoxyphenethylamine hydrochloride according to any one of claims 1 to 7, and then reacted with concentrated hydrochloric acid at a reaction temperature of 80 to 220° C. to obtain dopamine hydrochloride.

9. The method according to claim 8, characterized in that The molar ratio of 3,4-dimethoxyphenethylamine hydrochloride in the crude 3,4-dimethoxyphenethylamine hydrochloride to the hydrochloric acid in the concentrated hydrochloric acid is 1:(2-8), and the reaction time is 0.1 to 6 hours.

10. The method according to claim 8, characterized in that After the reaction, methyl chloride gas is obtained, which is introduced into a solvent to obtain a methyl chloride solution as the methylating agent in step (1), wherein the solvent is at least one of methanol, ethanol, n-butanol, tetrahydrofuran, and ethyl acetate.

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