Method for preparing bupropion

Abstract

The invention discloses a method for preparing bupropion. According to the method disclosed by the invention, in the presence of an oxidizing agent, 3-chlorphenyl acetone, tert-butylamine and CuBr2 are subjected to a one-step reaction to generate bupropion, and the reaction yield reaches 85%. The method disclosed by the invention is simple to operate, safe, environment-friendly and suitable for industrial production.

Description

Technical Field:

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing bupropion. Background Art:

[0002] Bupropion is an antidepressant with dopaminergic and noradrenergic effects developed by GlaxoSmithKline. The US FDA approved its marketing in December 1985, and it can be used for the treatment of depression, smoking addiction and other diseases.

[0003] The chemical name of bupropion is (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone. The common substrate for preparing bupropion is 3-chlorophenylacetone, and the preparation methods are mainly divided into the following two types.

[0004] One is to first carry out a chlorination reaction and then an amination reaction, and the route is shown in Scheme 1.

[0005]

[0006] The chlorination reaction reagents disclosed in Patent CN101407469A are CuCl2 and chlorine gas, and the amination reaction reagents are acetonitrile and tert-butylamine. In this route, chlorine gas is a gas at normal temperature and pressure, which is not easy to store and transport, and the reaction amount of chlorine gas is not easy to control, and it is difficult to measure by volume or weight loss method.

[0007] The other is to first carry out a bromination reaction and then an amination reaction, and the route is shown in Scheme 2.

[0008]

[0009] The bromination reaction reagents disclosed in Patent CN108558686B are sodium bromide, sulfuric acid and hydrogen peroxide. In this experiment, when sulfuric acid is added to the system, it will release a large amount of heat violently. After the system is cooled to room temperature, sodium bromide is added, and then the temperature is raised and hydrogen peroxide, an explosive chemical, is slowly added dropwise to the reaction system. The amination reaction reagents are tert-butylamine and dichloromethane, and this reaction requires refluxing for 20 hours.

[0010] The bromination reaction reagent disclosed in Patent CN100560563C is liquid bromine. In this experiment, liquid bromine needs to be slowly added dropwise to the reaction system at 65-90 °C. The amination reaction reagent is tert-butylamine, and the post-treatment step of this reaction involves solvent concentration at 80-140 °C.

[0011] The bromination reaction reagent disclosed in Patent CN105968023A is hydrogen bromide and hydrogen peroxide. In this experiment, a part of hydrogen bromide must be added dropwise at a certain temperature first to ensure that the reaction is initiated, and then the remaining hydrogen bromide is added dropwise. Its amination reaction reagent is tert-butylamine and dichloromethane. This reaction requires temperature control to add tert-butylamine dropwise, and the reaction time is as long as 16 hours.

[0012] The existing methods for preparing bupropion generally have disadvantages such as high safety requirements and complex experimental operations. Therefore, we need to develop a preparation method that is simple to operate, safe, environmentally friendly and suitable for industrialization. Summary of the Invention:

[0013] The purpose of the present invention is to provide a method for preparing bupropion that is simple to operate and easy to industrialize in view of the deficiencies of the prior art.

[0014] The technical solution adopted by the present invention is as shown in Scheme 3:

[0015]

[0016] The present invention provides a method for preparing bupropion, which specifically includes the following steps: in the presence of an oxidant, 3-chlorophenylacetone reacts with tert-butylamine and CuBr2 to form bupropion.

[0017] Further, the oxidant is selected from air and oxygen.

[0018] Further, the volume-mass ratio of tert-butylamine to 3-chlorophenylacetone is 2:1 to 10:1, preferably 4:1 to 6:1.

[0019] Further, the equivalent ratio of CuBr2 to 3-chlorophenylacetone is 0.1:1 to 1.0:1, preferably 0.2:1 to 0.4:1.

[0020] Further, the reaction needs to control the temperature at 0 to 40 °C, preferably 20 to 25 °C.

[0021] Further, the reaction needs to control the reaction time at 2 to 70 hours, preferably 10 to 20 hours.

[0022] The beneficial effect of the present invention is that in the preparation method disclosed by the present invention, in the presence of an oxidant, 3-chlorophenylacetone reacts with tert-butylamine and CuBr2 through a one-step reaction to form bupropion, and the reaction yield reaches 85%. This route is not only simple to operate, safe and environmentally friendly, but also easy to industrialize. Brief Description of the Drawings:

[0023] Figure 1 LC-MS diagram of bupropion hydrochloride in Example 6

[0024] Figure 2Example 6 Bupropion Hydrochloride 1 HNMR Spectrum Specific Embodiment:

[0025] The technical content of the present invention will be further elaborated below in combination with specific embodiments, with the aim of better understanding the content of the present invention, but the protection scope of the present invention is not limited thereto.

[0026] Example 1 Preparation of Bupropion

[0027] 3-Chlorophenylacetone (2.5 g, 1.0 eq), CuBr2 (3.30 g, 1.0 eq), tetrahydrofuran (25 mL, 10V), and tert-butylamine (2.16 g, 2.0 eq) were successively added to a 50 mL single-necked flask. A 3 L air balloon was installed, and the reaction was carried out at 20 °C for 20 hours. The reaction was monitored by TLC plate until completion. The organic solvent was removed by reduced pressure concentration. Then, 10 mL of ethyl acetate and 20 mL of water were added to the flask, and the pH was adjusted to 1 with 6N hydrochloric acid. After extraction three times, the aqueous phases were combined. 15 mL of dichloromethane was added to the aqueous phase, and the pH of the aqueous phase was adjusted to 14 with 20% NaOH. A solid precipitated. After filtering off the solid, dichloromethane extraction was carried out three more times, and the organic phases were combined. After concentration under reduced pressure, 1.15 g of bupropion was obtained, with a yield of 32.4%.

[0028] Example 2 Optimization of Reaction Conditions - Selection of Solvent

[0029] Based on the experimental results of Example 1, the solvent in the reaction process was optimized. The solvents were selected from tetrahydrofuran (THF), N-methylpyrrolidone (NMP), dimethyl sulfoxide

[0030] (DMSO), tert-butylamine, and dioxane. 3-Chlorophenylacetone (2.5 g, 1.0 eq), CuBr2 (3.30 g, 1.0 eq), tert-butylamine (2.16 g, 2.0 eq), and 25 mL of different solvents were successively added to the reaction flask. A 3 L air balloon was installed, and the reaction was carried out at 20 °C for 20 hours. The reaction was monitored by TLC until completion. Samples were taken and sent for HPLC detection, and the reaction results were analyzed. The specific data are shown in Table 1. The screening results showed that when the solvent was tert-butylamine, the conversion effect was the best.

[0031] Table 1 Optimization Results of Different Solvents

[0032]

[0033] Example 3 Optimization of Reaction Conditions - Selection of the Dosage of tert-Butylamine

[0034] Based on the optimization results of Example 2, the amount of tert-butylamine used in the reaction process was optimized. The volume-mass ratio of tert-butylamine to 3-chlorophenylacetone was 2:1 to 10:1. 3-Chlorophenylacetone (2.5 g, 1.0 eq), CuBr2 (3.30 g, 1.0 eq), and different volumes of tert-butylamine were successively added to the reaction flask. A 3 L air balloon was installed, and the reaction was carried out at 20 °C for 20 hours. The reaction was monitored by TLC until completion, samples were taken and sent for HPLC detection, and the reaction results were analyzed. The specific data are shown in Table 2. The screening results showed that when the volume-mass ratio of tert-butylamine to 3-chlorophenylacetone was 4:1 to 6:1, the conversion effect was better and the solvent consumption was less.

[0035] Table 2 Optimization results of the amount of tert-butylamine used

[0036]

[0037] Optimization of the reaction conditions in Example 4 - Selection of the amount of CuBr2 used

[0038] Based on the optimization results of Example 3, the amount of CuBr2 used in the reaction process was optimized. The equivalent ratio of CuBr2 to 3-chlorophenylacetone was 0.1:1 to 1.0:1. 3-Chlorophenylacetone (2.5 g, 1.0 eq), tert-butylamine (15 mL, 6V), and different masses of CuBr2 were successively added to the reaction flask. A 3 L air balloon was installed, and the reaction was carried out at 20 °C for 20 hours. The reaction was monitored by TLC until completion, samples were taken and sent for HPLC detection, and the reaction results were analyzed. The specific data are shown in Table 3. The screening results showed that when the equivalent ratio of CuBr2 to 3-chlorophenylacetone was 0.2:1 to 0.4:1, the conversion effect was better and the amount of CuBr2 used was less.

[0039] Table 3 Optimization results of the amount of CuBr2 used

[0040]

[0041] Optimization of the reaction conditions in Example 5 - Selection of the reaction temperature

[0042] Based on the optimization results of Example 4, the reaction temperature in the reaction process was optimized. The reaction temperature was set to 10 - 40 °C. 3-Chlorophenylacetone (2.5 g, 1.0 eq), CuBr2 (0.66 g, 0.2 eq), and tert-butylamine (15 mL, 6V) were successively added to the reaction flask. A 3 L air balloon was installed, and the reaction was carried out at different temperatures for 20 hours. The reaction was monitored by TLC until completion, samples were taken and sent for HPLC detection, and the reaction results were analyzed. The specific data are shown in Table 4. The screening results showed that when the reaction temperature was 20 - 25 °C, the conversion effect was better.

[0043] Table 4 Optimization results of the reaction temperature

[0044]

[0045] Example 6 Preparation of Bupropion Hydrochloride

[0046] To a 50 mL single-necked flask, add 3-chlorophenylacetone (2.5 g, 1.0 eq), CuBr2 (0.66 g, 0.2 eq), and tert-butylamine (15 mL, 6V) in sequence. Install a 3 L air balloon and react at 25 °C for 20 hours. Monitor the reaction by TLC plate until the reaction is complete. Concentrate under reduced pressure to remove the organic solvent. Then add 10 mL of ethyl acetate and 20 mL of water to the flask, and adjust the pH to 1 with 6N hydrochloric acid. Extract three times and combine the aqueous phases. Add 15 mL of dichloromethane to the aqueous phase, and then adjust the pH of the aqueous phase to 14 with 20% NaOH. A solid precipitates. Filter off the solid and then extract three times with dichloromethane. Combine the organic phases and concentrate under reduced pressure to obtain bupropion. Then add 6 mL of isopropanol to the flask to dissolve bupropion, and then dropwise add 8.1 g of 10% hydrogen chloride isopropanol solution. Stir at 0 - 5 °C for 1 hour and then filter. The obtained solid is dried in vacuo at 40 °C for 3 hours to finally obtain 3.48 g of bupropion hydrochloride, with a conversion rate of 90.5% and a yield of

[0047] 85.0%, and the purity is 99.1%. The LC-MS spectrum of bupropion hydrochloride is as Figure 1 shown,

[0048] 1 The 1H NMR spectrum is as Figure 2 shown.

Claims

1. A method for preparing bupropion, characterized in that, In the presence of an oxidizing agent, 3-chlorophenylacetone reacts with tert-butylamine and CuBr₂ to obtain bupropion, and the reaction equation is as follows:

2. The preparation method according to claim 1, characterized in that, The oxidizing agent is selected from air and oxygen.

3. The preparation method according to claim 1, characterized in that, The volume-mass ratio of tert-butylamine to 3-chlorophenylacetone is 2:1 to 10:

1.

4. The preparation method according to claim 1, characterized in that, The equivalent ratio of CuBr₂ to 3-chlorophenylacetone is 0.1:1 to 0.5:

1.

5. The preparation method according to claim 1, characterized in that, The reaction needs to control the reaction temperature at 0 to 40 °C.

6. The preparation method according to claim 1, characterized in that, The reaction needs to control the reaction time at 2 to 70 hours.

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