Method for continuously preparing 4-nitrophenylethylamine and salt thereof

Abstract

The invention provides a method for preparing 4-nitro (p-nitro) phenylethylamine through continuous flow. The method comprises the following step: carrying out nitration reaction on a beta-phenylethylamine solution and mixed acid containing concentrated sulfuric acid and nitric acid in a continuous reactor to generate 4-nitrophenylethylamine. According to the method, a continuous flow technology is used, so that the safety problem of heat release of nitration reaction in kettle reaction can be effectively solved, and the method is short in reaction retention time, few in side reaction, simple in post-treatment, high in yield and high in product purity.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and relates to a method for continuously preparing 4-nitrophenylethylamine and its salt. Background Art

[0002] Mirabegron is a novel selective β3 adrenergic receptor agonist developed by Astellas Pharmaceuticals Co., Ltd. of Japan for the treatment of overactive bladder. Its structural formula is shown below:

[0003]

[0004] 4-Nitrophenylethylamine is an important starting material for the synthesis of the drug mirabegron. Currently, there are several methods disclosed:

[0005] Method 1: Chinese patent CN104151170A discloses a method for preparing 4-nitrophenylethylamine hydrochloride, which comprises slowly adding phenylethylamine hydrochloride to a mixed acid of concentrated nitric acid and concentrated sulfuric acid at 0°C, stirring the reaction solution at this temperature until the reaction is complete, warming to room temperature, pouring it into water, adjusting the pH to 10 with NaOH, extracting with ether, extracting the ether phase with 1M hydrochloric acid, and drying the aqueous phase to obtain a yellow solid. After recrystallization, a light yellow solid 2, i.e., 4-nitrophenylethylamine hydrochloride, is obtained.

[0006] Method 2: Chinese patent CN107759477 A discloses a method for preparing p-nitrophenylethylamine hydrochloride, which comprises three steps: firstly protecting the amino group, then nitrifying, and finally deprotecting, and then salifying with hydrochloric acid to obtain the product. However, the reaction steps are long and a protection-deprotection reaction process is required, resulting in low atom economy.

[0007]

[0008] Method 3: Chinese patent CN104557566A discloses a method for preparing 4-nitrophenylethylamine hydrobromide, which is to use a mixed solution of β-phenylethylamine and acetic anhydride to back-titrate into a nitric acid and sulfuric acid mixed acid system, which to a certain extent alleviates the safety problem of the high heat release of the nitration reaction. However, it is still a kettle nitration process, with a large amount of online materials, and the safety risk is still high, and the yield is only about 40%.

[0009] The above three preparation methods all adopt a kettle nitration process. Since the nitration of the benzene ring requires a strong acid environment, and since phenylethylamine has an amino group, the amino group is highly active and is prone to produce by-products.

[0010] Therefore, it is particularly important to provide a method with high yield, high product purity, low production cost, safe production, and suitable for large-scale industrial production. Summary of the invention

[0011] The invention provides a method for preparing 4-nitrophenylethylamine in a continuous flow. The method comprises subjecting a beta-phenylethylamine solution and a mixed acid containing concentrated sulfuric acid and nitric acid to a nitration reaction in a continuous reactor to generate 4-nitrophenylethylamine.

[0012] The inventors unexpectedly discovered that the preparation method provided by the present invention can effectively solve the local overheating phenomenon caused by the nitration reaction and reduce the content of the isomer impurity 2-nitrophenylethylamine and other by-products caused by the local overheating reaction.

[0013]

[0014] In some embodiments, the solvent used in the β-phenylethylamine solution is selected from one or more of dichloromethane, dichloroethane, acetic acid, trifluoroacetic acid, and sulfuric acid, preferably dichloromethane, acetic acid, and sulfuric acid;

[0015] In some embodiments, the mass ratio of β-phenylethylamine to solvent in the β-phenylethylamine solution is 1:5 to 1:1, preferably 1:3 to 1:1; the mass ratio of concentrated sulfuric acid to nitric acid in the mixed acid is 1:0.9 to 1:3, preferably 1:1 to 1:2;

[0016] In some embodiments, the mass ratio of the β-phenylethylamine solution to the mixed acid in the continuous flow reactor is 1:5 to 1:1, preferably 1:3 to 1:1;

[0017] In some embodiments, the temperature of the nitration reaction is 20 to 80° C.; the residence time in the continuous flow reactor is 1 to 15 min;

[0018] In some embodiments, the continuous flow reactor is selected from a tubular reactor, a silicon carbide reactor, and a microchannel reactor.

[0019] In some embodiments, the continuous flow preparation method comprises:

[0020] (1) preparing solution A: dissolving β-phenylethylamine in an organic solvent to prepare solution 1; mixing sulfuric acid and nitric acid to prepare solution B;

[0021] (2) Two pumps are used to transport solution A and solution B respectively, which are mixed in a mixer and then enter a reactor for reaction.

[0022] In some embodiments, the reaction solution that generates 4-nitrophenylethylamine flows into cold water for quenching, pH adjustment, and extraction;

[0023] In some embodiments, after the reaction solution for producing 4-nitrophenylethylamine flows into cold water for quenching, after the materials are gone, the pH value is adjusted to 9-10; then one or more selected from dichloromethane, dichloroethylene and toluene, preferably dichloromethane, is used for extraction;

[0024] In some embodiments, the reactants are extracted and further treated with an acid to form a salt, concentrated, and slurried with a solvent to obtain a 4-nitrophenylethylamine salt, wherein the acid is hydrochloric acid, acetic acid, hydrobromic acid, or p-toluenesulfonic acid;

[0025] In some embodiments, the pulping solvent is a mixed solvent of alcohol and water, wherein the alcohol solvent is selected from one or more of methanol, ethanol, and isopropanol, preferably ethanol; further, the volume ratio of alcohol to water is 10:1 to 5:1.

[0026] Compared with the prior art, the present invention has the following positive technical effects:

[0027] 1) The present invention uses a continuous flow technology to nitrate β-phenylethylamine in one step to obtain 4-nitrophenylethylamine, so that the reaction raw materials can be evenly mixed in the reactor, the amount of concentrated sulfuric acid and nitric acid is reduced, and the synthesis efficiency is improved; in addition, due to the short reaction residence time, less side reactions, simple post-processing, high yield and high product purity.

[0028] 2) The present invention effectively solves the safety problem of heat release in nitration reaction in kettle reaction by using continuous flow technology. The present invention is inherently safe, meets the modern chemical synthesis standards of green chemistry and environmental friendliness, and is easier to industrialize. Description of the drawings:

[0029] Figure 1 It is a schematic diagram of the reaction device of the present invention. Specific embodiments

[0030] The following examples are used to further describe the specific embodiments of the present invention. The following examples are only used to illustrate the present invention, but are not used to limit the scope of the present invention.

[0031] All ranges recited in the present invention include those endpoints of the range between two values, and no matter whether it is indicated, all values ​​recited in the present invention include the expected experimental error, technical error and instrument error of the given technology used to measure the value. When the error degree is not recorded, all values ​​recited in the present invention include the range of ± 10% of the recorded value.

[0032] In the present invention, unless otherwise specified, % is a percentage of weight / weight (w / w).

[0033] The HPLC analytical method used for measuring purity of the present invention is:

[0034] Chromatographic column: Waters XBridge Phenyl 150×3.0mm, 3.5μm

[0035] Mobile phase A: 0.1% trifluoroacetic acid in water

[0036] Mobile phase B: acetonitrile

[0037] Detection wavelength: 270nm

[0038] Flow rate: 1.0mL / min

[0039] Column temperature: 40°C

[0040] Running time: 20 minutes

[0041] The continuous flow reactor model used in the present invention is:

[0042] Tubular reactor Model: PFA Manufacturer: Homemade

[0043] Silicon carbide reactor model: WMRSIC0608 Manufacturer: Shandong Weijing Chemical Technology Co., Ltd.

[0044] Microchannel reactor model: C0 (60mL) Manufacturer: Shandong Jinde New Materials Co., Ltd.

[0045] The phenylethylamine used in the present invention comes from:

[0046] The supplier of phenylethylamine is: Changzhou Huayang Technology Co., Ltd.

[0047] Other reagents and raw materials used in the present invention are conventional reagents and are commercially available.

[0048] Embodiment 1:

[0049] 100 g of β-phenylethylamine and 200 g of acetic acid were mixed to form solution A, and 120 g of concentrated sulfuric acid and 120 g of concentrated nitric acid were mixed to form solution B.

[0050] Solution A and solution B were transported by a plunger pump at flow rates of 13.4 mL / min and 6.7 mL / min, respectively. After being mixed in a mixer, they entered a tubular reactor and reacted at 50°C for 5 min. The reaction solution flowed into 500 g of water at 5-10°C. After the material was exhausted, the pH was adjusted to 9-10 with liquid alkali, extracted twice with 400 mL DCM, the organic phases were combined, washed with 100 mL of water, 100 g of concentrated hydrochloric acid was added and stirred for 1 h, concentrated to dryness under reduced pressure, 400 mL of ethanol and 50 mL of water were added, pulped at 50-60°C and crystallized at 5-10°C, filtered and rinsed with 50 mL of ethanol to obtain a white solid, which was dried to obtain 100 g of 4-nitrophenylethylamine finished product with a yield of 60%, HPLC purity of 99.53%, and isomer 2-nitrophenylethylamine of 0.07%.

[0051] Embodiment 2:

[0052] 100 g of β-phenylethylamine and 200 mL of DCM were mixed to form solution A, and 120 g of concentrated sulfuric acid and 120 g of concentrated nitric acid were mixed to form solution B.

[0053] Solution A and solution B were transported by a plunger pump at flow rates of 3.6 mL / min and 1.8 mL / min, respectively. After being mixed in a mixer, they entered a silicon carbide plate reactor (Shandong Weijing) and reacted at 40°C for 10 min. The reaction solution flowed into 500 g of water at 5-10°C. After the material was exhausted, the pH was adjusted to 9-10 with liquid alkali, extracted twice with 300 mL DCM, the organic phases were combined, washed with 100 mL of water, 100 g of concentrated hydrochloric acid was added and stirred for 1 h, concentrated to dryness under reduced pressure, 400 mL of ethanol and 50 mL of water were added, pulped at 50-60°C and crystallized at 5-10°C, filtered and rinsed with 50 mL of ethanol to obtain a white solid, which was dried to obtain 99.5 g of 4-nitrophenylethylamine finished product with a yield of 59.5%, HPLC purity of 99.55%, and 0.08% of isomer 2-nitrophenylethylamine.

[0054] Embodiment 3:

[0055] 100 g of β-phenylethylamine and 200 mL of sulfuric acid were mixed to form solution A, and 80 g of concentrated sulfuric acid and 120 g of concentrated nitric acid were mixed to form solution B.

[0056] A plunger pump was used to transport solution A and solution B at flow rates of 7.2 mL / min and 4.8 mL / min, respectively. After mixing in a mixer, the mixture was introduced into a microchannel reactor and reacted at 40°C for 5 min. The reaction solution flowed into 500 g of water at 5-10°C. After the material was exhausted, the pH was adjusted to 9-10 with liquid alkali, extracted twice with 400 mL DCM, the organic phases were combined, washed with 100 mL of water, 145 g of p-toluenesulfonic acid monohydrate was added, and stirred for 1 h. The mixture was concentrated to dryness under reduced pressure, 400 mL of ethanol and 50 mL of water were added, and the mixture was beaten at 50-60°C and crystallized at 5-10°C. The mixture was filtered and rinsed with 50 mL of ethanol to obtain a white solid. The solid was dried to obtain 165 g of 4-nitrophenylethylamine finished product, with a yield of 59.0%, a HPLC purity of 99.60%, and an isomer of 2-nitrophenylethylamine of 0.06%. Comparative Example 1:

[0057] Repeat the example of CN104151170A: at 0°C, 20 g of β-phenylethylamine was slowly added dropwise to a mixture of concentrated nitric acid (35 mL) and concentrated sulfuric acid (65 mL), and then stirred at this temperature for 1 h until the reaction was complete. HPLC detection results: 40.98% of 4-nitrophenylethylamine product, 1.2% of β-phenylethylamine, 4.2% of isomer 2-nitrophenylethylamine, 47.0% of 2,4-dinitrophenylethylamine, and a large amount of dinitro substances were produced.

[0058] The specific embodiments described in the present invention are merely examples of the spirit of the present invention. Those skilled in the art of the present invention may make various modifications or additions to the specific embodiments described or replace them in similar ways, but they will not deviate from the spirit of the present invention or exceed the scope defined by the attached claims.

Claims

1. A method for preparing 4-nitrophenylethylamine and its salts by continuous flow, characterized in that: The method comprises the steps of subjecting a beta-phenylethylamine solution and a mixed acid containing concentrated sulfuric acid and nitric acid to a nitration reaction in a continuous reactor to generate 4-nitrophenylethylamine.

2. The method according to claim 1, characterized in that The solvent used in the β-phenylethylamine solution is selected from one or more of dichloromethane, dichloroethane, acetic acid, trifluoroacetic acid, and sulfuric acid, preferably dichloromethane and acetic acid.

3. The method according to claim 1, characterized in that The mass ratio of β-phenylethylamine to solvent in the β-phenylethylamine solution is 1:5 to 1:1, preferably 1:3 to 1:1; the mass ratio of concentrated sulfuric acid to nitric acid in the mixed acid is 1:0.9 to 1:3, preferably 1:1 to 1:

2.

4. The method according to claim 1, characterized in that: The mass ratio of the β-phenylethylamine solution to the mixed acid in the continuous flow reactor is 1:5 to 1:1, preferably 1:3 to 1:

1.

5. The method according to claim 1, characterized in that The temperature of the nitration reaction is 20-80°C; The residence time in the continuous flow reactor is 1 to 15 minutes.

6. The method according to claim 1, characterized in that The continuous flow reactor is selected from a tubular reactor, a silicon carbide reactor, and a microchannel reactor.

7. The method according to claim 1, characterized in that The reaction solution for generating 4-nitrophenylethylamine is quenched by cold water, the pH value is adjusted, and extraction is performed.

8. The method according to claim 7, characterized in that The pH value is 9-10; the solvent used in the extraction is selected from one or more of dichloromethane, dichloroethane and toluene, preferably dichloromethane.

9. The method according to claim 7, characterized in that: The reaction solution is quenched with cold water, the pH value is adjusted, and after extraction, it is further treated with acid to form a salt, concentrated, and slurried with a solvent to obtain 4-nitrophenylethylamine salt.

10. The method according to claim 9, characterized in that The acid is selected from hydrochloric acid, acetic acid, hydrobromic acid and p-toluenesulfonic acid.

11. The method according to claim 9, characterized in that The solvent is a mixed solvent of alcohol and water, wherein the alcohol solvent is selected from one or more of methanol, ethanol, and isopropanol, preferably ethanol.

12. The method according to claim 11, characterized in that The volume ratio of the alcohol to water is 10:1 to 5:1.

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