Method for continuously preparing briracetam

Abstract

The invention provides a method for continuously preparing briracetam, which comprises the following steps: respectively diluting a hydrobromic acid acetic acid solution and SM1 with a solvent, introducing the diluted solution into a first reaction module through a preheating module, and concentrating the effluent to obtain a first intermediate; respectively diluting the first intermediate and concentrated sulfuric acid with absolute ethyl alcohol, introducing the diluted first intermediate and concentrated sulfuric acid into a second reaction module through a preheating module, concentrating effluent, diluting the concentrated effluent with a solvent, and washing the concentrated effluent once with a sodium bicarbonate solution to obtain a second intermediate; respectively introducing the second intermediate, S-2-aminobutanamide and diisopropylethylamine into a third reaction module through the preheating module; preheating and mixing the effluent in the third reaction module and 2-hydroxypyridine, introducing the mixture into a fourth reaction module, cooling the effluent, washing with diluted hydrochloric acid, and concentrating to obtain a crude product of briracetam; and refining the crude product of the briracetam to obtain the briracetam. The method can reduce environmental pollution, shorten the production cycle and improve the total yield, and is more suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of medicine and chemical industry, and in particular to a method for continuously preparing brivaracetam. Background Art

[0002] Brivaracetam (BRV) is a third-generation anti-epileptic drug developed by UCB Pharmaceuticals of Belgium. It exerts its anti-epileptic effect by selectively and reversibly binding to the central synaptic vesicle protein 2A and affecting synaptic function. The drug was launched in Europe and the United States on January 14 and February 18, 2016, respectively, for the adjuvant treatment of partial seizures with or without secondary generalized seizures in adolescents and adults with epilepsy aged 16 years and above. On September 15, 2017, it was approved by the U.S. Food and Drug Administration (FDA) for supplemental new drug application and can be used as a monotherapy for focal seizures in patients with epilepsy aged 16 years and above. Compared with the previous generation drug levetiracetam (LEV), the affinity of brivaracetam is 15 to 30 times that of levetiracetam, and the dosage is reduced by about 10 times.

[0003] There are three main synthesis processes of brivaracetam: chiral preparation, resolution and chiral synthesis.

[0004] In CN1404469 and CN1882535, a chiral preparation method is adopted, but the chiral preparation equipment of this method is expensive and more than half of the enantiomers are lost, which is not suitable for industrial application.

[0005]

[0006] In CN106748950A and CN107513031A, a splitting process is adopted, which avoids expensive equipment but has a low splitting yield and poor economic efficiency.

[0007]

[0008] A chiral synthesis route was reported in Org.Process Res.Dev.2016,20,9,1566–1575.

[0009]

[0010] This route avoids chiral splitting and preparative separation, and has good atom economy. However, the process uses a large excess of hydrobromic acid in the bromination step, which causes great environmental pollution; and uses a heterogeneous catalytic process in the cyclization step, which takes a long reaction time. Summary of the invention

[0011] In order to overcome the deficiencies of the prior art, the object of the present invention is to provide a method for continuously preparing brivaracetam, thereby reducing the discharge of waste acid and shortening the production cycle.

[0012] To achieve the above object, the present invention provides the following solutions:

[0013] A method for continuously preparing brivaracetam, comprising:

[0014] S1, diluting the hydrobromic acid acetic acid solution and SM1 with a solvent respectively, and then introducing them into the first reaction module through a preheating module, and concentrating the effluent to obtain a first intermediate;

[0015] S2, diluting the first intermediate and concentrated sulfuric acid with anhydrous ethanol respectively, and introducing the mixture into the second reaction module through a preheating module, concentrating the effluent, diluting the mixture with a solvent, and washing the mixture once with a sodium bicarbonate solution to obtain a second intermediate;

[0016] S3, introducing the second intermediate, S-2-aminobutyramide and diisopropylethylamine into the third reaction module through the preheating module respectively;

[0017] S4, introducing the effluent from the third reaction module and 2-hydroxypyridine into the fourth reaction module after preheating and mixing, cooling the effluent, washing with dilute hydrochloric acid, and concentrating to obtain a crude product of brivaracetam;

[0018] S5. Refining the crude product of Brivaracetam to obtain Brivaracetam.

[0019] Preferably, the solvent in step S1 is selected from one or more of methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, dimethyl sulfoxide and water.

[0020] Preferably, the reaction temperature of the first reaction module is 60-100°C.

[0021] Preferably, in step S1, the residence time of the material in the first reaction module is 10s-2min.

[0022] Preferably, the reaction temperature of the second reaction module is 60-100°C.

[0023] Preferably, in step S2, the residence time of the material in the second reaction module is 30s-2min.

[0024] Preferably, the reaction temperature of the third reaction module is 90-120°C.

[0025] Preferably, in step S3, the residence time of the material in the third reaction module is 1-10 min.

[0026] Preferably, the reaction temperature of the fourth reaction module is 100-180°C.

[0027] Preferably, in step S4, the residence time of the material in the fourth reaction module is 1-10 min.

[0028] According to the specific embodiments provided by the present invention, the present invention discloses the following technical effects:

[0029] (1) The micro-reaction continuous process is used to prepare brivaracetam, which reduces the amount of hydrobromic acid and hydrochloric acid used in the original process, reduces pollution, and has a higher overall yield, making it more suitable for industrial production.

[0030] (2) The micro-reaction continuous process makes it easy to monitor and control the reaction progress.

[0031] (3) The micro-reaction continuous process has a smaller characteristic size, which enhances the mass transfer effect of the reaction materials, has excellent heat exchange capacity, short reaction time, small equipment footprint, and can be mass-produced. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative labor.

[0033] Figure 1 A flow chart of a method provided by an embodiment of the present invention;

[0034] Figure 2 A first schematic diagram of a method for continuously preparing brivaracetam provided by an embodiment of the present invention;

[0035] Figure 3 A second schematic diagram of the method for continuously preparing brivaracetam provided by an embodiment of the present invention;

[0036] Figure 4 The third schematic diagram of the method for continuous preparation of brivaracetam provided by an embodiment of the present invention. DETAILED DESCRIPTION

[0037] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0038] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the present invention is further described in detail below with reference to the accompanying drawings and specific embodiments.

[0039] Figure 1 A flow chart of a method provided by an embodiment of the present invention, such as Figure 1 As shown, the present invention provides a method for continuously preparing brivaracetam, comprising:

[0040] S1, diluting the hydrobromic acid acetic acid solution and SM1 with a solvent respectively, and then introducing them into the first reaction module through a preheating module, and concentrating the effluent to obtain a first intermediate;

[0041] S2, diluting the first intermediate and concentrated sulfuric acid with anhydrous ethanol respectively, and introducing the mixture into the second reaction module through a preheating module, concentrating the effluent, diluting the mixture with a solvent, and washing the mixture once with a sodium bicarbonate solution to obtain a second intermediate;

[0042] S3, introducing the second intermediate, S-2-aminobutyramide and diisopropylethylamine into the third reaction module through the preheating module respectively;

[0043] S4, introducing the effluent from the third reaction module and 2-hydroxypyridine into the fourth reaction module after preheating and mixing, cooling the effluent, washing with dilute hydrochloric acid, and concentrating to obtain a crude product of brivaracetam;

[0044] S5. Refining the crude product of Brivaracetam to obtain Brivaracetam.

[0045] Literature process reproduction (Org.Process Res.Dev.2016,20,9,1566–1575):

[0046]

[0047] 33% HBr acetic acid solution (44 ml, 0.25 mol) and SM1 (8.2 g, 0.06 mol) were added to the reaction flask, reacted at 80°C for 2.5 hours, then cooled to room temperature, 50 ml of water and 50 ml of dichloromethane were added for extraction, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain intermediate 1 as a light yellow oil with a yield of 95.5%.

[0048] Add intermediate 1 (10 g, 0.05 mol), 40 ml ethanol and 1 ml hydrochloric acid to the reaction flask and stir at 40°C for 19 h. Ethanol is evaporated and 40 ml ethyl acetate is added to dilute. Wash with 40 ml 5% sodium hydroxide aqueous solution and 40 ml water in turn. Then concentrate to obtain intermediate 2 with a yield of 88.4%.

[0049] Add intermediate 2 (10 g, 0.04 mol), S-2-aminobutyramide (6.7 g, 0.066 mol), tetrabutylammonium iodide (4.8 g, 0.01 mol), potassium carbonate (9.3 g, 0.09 mol) and 50 ml of isopropyl acetate to the reaction flask. Reflux for 28 hours and filter. Add 2 g of acetic acid to the filtrate, then stir at 60 ° C for 1 hour. Then cool to room temperature and filter. Adjust the pH of the filtrate to neutral with potassium carbonate and separate the liquids. The organic phase is concentrated to obtain a yellow oily solid, which is a crude product of brivaracetam with a yield of 93.1%.

[0050] Example 1 Preparation of Intermediate 1 (First Intermediate)

[0051]

[0052] like Figure 2 As shown, in this embodiment, 500 ml of 200 g / L ethyl acetate solution of SM1 was prepared and entered into reaction module 1 (first reaction module) at a flow rate of 5 ml / min after preheating.

[0053] Prepare 1000 ml of 250 g / L 33% HBr-acetic acid in ethyl acetate solution and allow it to enter reaction module 1 at a flow rate of 10 ml / min after preheating.

[0054] The material of the microreactor reaction pipeline is a silicon carbide reactor, the residence time of the reaction module is 44s, the reaction temperature is adjusted to 80°C, and the back pressure valve pressure is 0.2MPa.

[0055] The reaction solution flowing out of the outlet was collected and concentrated under reduced pressure to obtain intermediate 1 as a yellow oily liquid.

[0056] Example 2 Synthesis of Intermediate 2 (Second Intermediate)

[0057]

[0058] like Figure 3 As shown, in this embodiment, 500 ml of 300 g / L ethanol solution of intermediate 1 is prepared and enters reaction module 2 (second reaction module) at a flow rate of 5 ml / min after preheating.

[0059] Prepare 250 ml of 300 g / L concentrated sulfuric acid ethanol solution, and enter reaction module 2 at a flow rate of 2.5 ml / min after preheating.

[0060] The material of the microreactor reaction pipeline is a silicon carbide reactor, the residence time of the reaction module is 1 min, the reaction temperature is adjusted to 85°C, and the back pressure valve pressure is 0.2 MPa.

[0061] The reaction solution flowing out of the outlet was collected, concentrated under reduced pressure, diluted with isopropyl acetate, and then washed once with a 5% sodium bicarbonate solution to obtain an isopropyl acetate solution of intermediate 2.

[0062] Example 3 Synthesis of Brivaracetam

[0063]

[0064] like Figure 3 As shown, in this embodiment, the isopropyl acetate solution of intermediate 2 is prepared into a 200 g / L isopropyl acetate solution, which is preheated and then enters reaction module 3 (the third reaction module) at a flow rate of 10 ml / min.

[0065] S-2-aminobutyramide was prepared into a 200 g / L isopropyl acetate solution and preheated before entering reaction module 3 at a flow rate of 7 ml / min.

[0066] Diisopropylethylamine is preheated and then introduced into reaction module 3 at a flow rate of 2.2 ml / min.

[0067] The material of the microreactor reaction pipeline is a silicon carbide reactor, the residence time of the reaction module is 3 minutes, the reaction temperature is adjusted to 106°C, and the back pressure valve pressure is 0.2MPa.

[0068] The reaction liquid flowing out of the outlet enters the reaction module 4 (the fourth reaction module) after being preheated.

[0069] 2-Hydroxypyridine is prepared into a 200 g / L isopropyl acetate solution and enters the reaction module 4 after preheating at a flow rate of 6 ml / min.

[0070] The material of the microreactor reaction pipeline is selected as a silicon carbide reactor, the residence time of the reaction module is 5 minutes, the reaction temperature is adjusted to 153°C, and the back pressure valve pressure is 0.2MPa.

[0071] The effluent was cooled and washed with 2M dilute hydrochloric acid. After concentration, crude brivaracetam was obtained with a crude yield of 89%. After further purification, brivaracetam was obtained.

[0072] The various embodiments in this specification are described in a progressive manner, and each embodiment focuses on the differences from other embodiments. The same or similar parts between the various embodiments can be referenced to each other.

[0073] The principles and implementation methods of the present invention are described in this article using specific examples. The description of the above embodiments is only used to help understand the method and core idea of ​​the present invention. At the same time, for those skilled in the art, according to the idea of ​​the present invention, there will be changes in the specific implementation methods and application scope. In summary, the content of this specification should not be understood as limiting the present invention.

Claims

1. A method for continuously preparing brivaracetam, characterized in that: include: S1, diluting the hydrobromic acid acetic acid solution and SM1 with a solvent respectively, and then introducing them into the first reaction module through a preheating module, and concentrating the effluent to obtain a first intermediate; S2, diluting the first intermediate and concentrated sulfuric acid with anhydrous ethanol respectively, and introducing the mixture into the second reaction module through a preheating module, concentrating the effluent, diluting the mixture with a solvent, and washing the mixture once with a sodium bicarbonate solution to obtain a second intermediate; S3, introducing the second intermediate, S-2-aminobutyramide and diisopropylethylamine into the third reaction module through the preheating module respectively; S4, introducing the effluent from the third reaction module and 2-hydroxypyridine into the fourth reaction module after preheating and mixing, cooling the effluent, washing with dilute hydrochloric acid, and concentrating to obtain a crude product of brivaracetam; S5. Refining the crude product of Brivaracetam to obtain Brivaracetam.

2. The method for continuous preparation of brivaracetam according to claim 1, characterized in that: The solvent in step S1 is selected from one or more of methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, and water.

3. The method for continuous preparation of brivaracetam according to claim 1, characterized in that: The reaction temperature of the first reaction module is 60-100°C.

4. The method for continuous preparation of brivaracetam according to claim 1, characterized in that: In step S1, the residence time of the material in the first reaction module is 10s-2min.

5. The method for continuous preparation of brivaracetam according to claim 1, characterized in that: The reaction temperature of the second reaction module is 60-100°C.

6. The method for continuous preparation of brivaracetam according to claim 1, characterized in that: In step S2, the residence time of the material in the second reaction module is 30s-2min.

7. The method for continuously preparing brivaracetam according to claim 1, characterized in that: The reaction temperature of the third reaction module is 90-120°C.

8. The method for continuous preparation of brivaracetam according to claim 1, characterized in that: In step S3, the material stays in the third reaction module for 1-10 minutes.

9. The method for continuously preparing brivaracetam according to claim 1, characterized in that: The reaction temperature of the fourth reaction module is 100-180°C.

10. The method for continuous preparation of brivaracetam according to claim 1, characterized in that: In step S4, the residence time of the material in the fourth reaction module is 1-10 min.

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