A method for synthesizing 2-aminobutyramide

Abstract

The present invention discloses a method for synthesizing 2-aminobutyramide, which is characterized in that the method comprises the following specific steps: S1. Dissolve butyramide in an organic solvent, and then add a catalyst and stir evenly to obtain reaction solution A; S2. Add an ammonia source to the organic solvent to obtain reaction solution B; S3. Add the reaction solution A and reaction solution B to a high-pressure reactor and heat for reaction; S4. After the reaction, cool, discharge, and remove the solvent to obtain the crude product of 2-aminobutyramide; S5. Recrystallize the crude product of 2-aminobutyramide, filter, and dry to obtain the crystals of 2-aminobutyramide hydrochloride; S6. Neutralize the crystals of 2-aminobutyramide hydrochloride to obtain 2-aminobutyramide. The synthesis method provided by the present invention has simple process, high safety and high yield.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemical synthesis, and particularly relates to a method for synthesizing 2-aminobutyramide. Background Art

[0002] Epilepsy is a neurological disease with a relatively high incidence rate. Currently, the drug with a good therapeutic effect on epilepsy is levetiracetam. As a pharmaceutical intermediate, 2-aminobutyramide can be used to synthesize anti-epileptic drugs such as levetiracetam.

[0003] Chinese Patent CN102020584A discloses "a method for synthesizing the chiral drug levetiracetam intermediate L-2-aminobutyramide hydrochloride". It uses 2-bromobutyric acid as the starting material, first undergoes amidation with ammonia water to generate the 2-bromobutyramide intermediate; then reacts with ammonia water to generate 2-aminobutyramide, and finally obtains L-2-aminobutyramide hydrochloride through salting out purification and alkalization. The problems of this method are that the reaction process is relatively complex, the cost is high, and there are many three wastes.

[0004] Chinese Patent CN110204453A discloses "a method for preparing 2-aminobutyramide". The method is to generate 2-hydroxybutyronitrile from hydrogen cyanide and n-propionaldehyde under the action of a catalyst; then, through the action of a catalyst, 2-hydroxybutyronitrile reacts with ammonia / liquid ammonia to generate 2-aminobutyronitrile; then strong base and a catalyst are added for hydrolysis reaction to prepare 2-aminobutyramide. The problem of this method is that it uses highly toxic hydrocyanic acid as a raw material, and its synthesis process is not safe enough.

[0005] Chinese Patent CN105198768B discloses "a method for synthesizing 2-aminobutyramide". This method uses 2-chlorobutyric acid as the raw material, phosphorus trichloride or phosphorus pentachloride as the catalyst, reacts with thionyl chloride to obtain 2-chlorobutyryl chloride, and then ammoniates 2-chlorobutyryl chloride to obtain 2-aminobutyramide. In this method, 2-chlorobutyric acid needs to be first reacted with highly toxic chlorine gas, and the product yield of this method is not ideal.

[0006] In summary, the existing synthesis methods of 2-aminobutyramide generally have problems such as low synthesis safety, complex processes, high costs, and low yields. Therefore, there is an urgent need for a new synthesis method of 2-aminobutyramide that can achieve high yields, high safety, simplicity, and low costs. Summary of the Invention

[0007] The purpose of the present invention is to provide a new method for synthesizing 2-aminobutyramide to solve the above problems, aiming at the problems of low product yields, complex synthesis processes, and low safety generally existing in the existing 2-aminobutyramide synthesis processes.

[0008] The present invention is achieved through the following technical solutions:

[0009] A method for synthesizing 2-aminobutyramide, characterized in that the method comprises the following specific steps:

[0010] S1. Dissolve butyramide in an organic solvent, and then add a catalyst and stir evenly to obtain reaction solution A;

[0011] S2. Add an ammonia source to the organic solvent to obtain reaction solution B;

[0012] S3. Add the reaction solution A and reaction solution B to a high-pressure reactor, and heat for reaction;

[0013] S4. After the reaction, cool, discharge, and remove the solvent to obtain crude 2-aminobutyramide;

[0014] S5. Recrystallize the crude 2-aminobutyramide, filter, and dry to obtain 2-aminobutyramide hydrochloride crystals;

[0015] S6. Neutralize the 2-aminobutyramide hydrochloride crystals to obtain 2-aminobutyramide.

[0016] Further, a method for synthesizing 2-aminobutyramide: The organic solvent is selected as tetrahydrofuran (THF).

[0017] Further, a method for synthesizing 2-aminobutyramide: The catalyst in step S1 is potassium iodide (KI).

[0018] Further, a method for synthesizing 2-aminobutyramide: In step S1, the molar volume ratio of butyramide to the organic solvent is 3.0 - 5.0 mol / L; the molar ratio of butyramide to the catalyst is 1:(0.01 - 0.02).

[0019] Further, a method for synthesizing 2-aminobutyramide: The ammonia source in step S2 is ammonia gas.

[0020] Further, a method for synthesizing 2-aminobutyramide: The molar volume ratio of the ammonia source to the organic solvent is 4.0 - 5.0 mol / L; the molar ratio of butyramide to the ammonia source is 1:(1.2 - 1.5).

[0021] Further, a method for synthesizing 2-aminobutyramide: In step S3, the reaction temperature is 65 - 70 °C, the reaction time is 1 - 3 hours, and the reaction pressure is 0.5 - 1.0 MPa.

[0022] Advantages of the present invention:

[0023] The present invention provides a new process route for catalytic synthesis of 2-aminobutyramide using butyramide as the starting material and potassium iodide as the catalyst; the synthesis process of the present invention does not require the use of highly toxic reaction raw materials, and its synthesis process has high safety. In the synthesis method of the present invention, iodine first reacts with butyramide to form 2-iodobutyramide, and then ammonia substitutes to form stable 2-aminobutyramide. The synthesis process of the present invention is not only simpler, but also has good process stability. Most importantly, the synthesis method provided by the present invention has a high yield, and the yield can reach more than 93%. Detailed Description of the Invention

[0024] The technical solutions of the present invention will be clearly and completely described below in conjunction with specific embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. The following description of at least one exemplary embodiment is actually only illustrative and in no way limits the present invention and its application or use. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative work fall within the scope of protection of the present invention.

[0025] Example 1

[0026] A method for synthesizing 2-aminobutyramide is provided, which is characterized in that the method comprises the following specific steps:

[0027] S1. Dissolve 1.0 mol of butyramide in 240 mL of tetrahydrofuran (organic solvent), and then add 0.01 mol of potassium iodide (catalyst) and stir evenly to obtain reaction solution A;

[0028] S2. Introduce 1.23 mol of ammonia gas into 300 mL of tetrahydrofuran (organic solvent) to obtain reaction solution B;

[0029] S3. Add the above reaction solution A and reaction solution B together into a stainless steel autoclave, heat to 68 °C, stir and react for 2 hours, and the reaction pressure is 0.8 MPa;

[0030] S4. After the reaction, cool to room temperature, discharge the material, remove the solvent (tetrahydrofuran) to obtain the crude product of 2-aminobutyramide;

[0031] S5. Recrystallize the obtained crude product of 2-aminobutyramide with 5.0 wt% dilute hydrochloric acid, then filter and dry to obtain the crystals of 2-aminobutyramide hydrochloride;

[0032] S6. Add the obtained crystals of 2-aminobutyramide hydrochloride to 30.0 wt% sodium hydroxide solution for neutralization, then add dichloromethane for extraction, remove the solution to obtain 131.4 g of 2-aminobutyramide; the yield is 93.7% and the purity is 99.1%.

[0033] The obtained product was identified by 1H NMR: 1H NMR (DMSO-d6, 400 MHz): 0.95 (t, 3H, CH3); 1.83 (m, 2H, CH2); 3.57 (m, H, CH); 2.0 (2H, NH2); 5.9 (2H, -CONH2).

[0034] The reaction process of the present invention is as follows:

[0035]

[0036] Example 2

[0037] Provided is a method for synthesizing 2-aminobutyramide, characterized in that the method comprises the following specific steps:

[0038] S1. Dissolve 1.0 mol of butyramide in 330 mL of tetrahydrofuran (organic solvent), and then add 0.02 mol of potassium iodide (catalyst) and stir evenly to obtain reaction solution A;

[0039] S2. Pass 1.35 mol of ammonia gas into 300 mL of tetrahydrofuran (organic solvent) to obtain reaction solution B;

[0040] S3. Add the above reaction solution A and reaction solution B together into a stainless steel autoclave, heat to 70 °C, stir and react for 1 hour, and the reaction pressure is 1.0 MPa;

[0041] S4. After the reaction, cool to room temperature, discharge, remove the solvent (tetrahydrofuran) to obtain the crude product of 2-aminobutyramide;

[0042] S5. Recrystallize the obtained crude product of 2-aminobutyramide with 5.0 wt% dilute hydrochloric acid, then filter and dry to obtain 2-aminobutyramide hydrochloride crystals;

[0043] S6. Add the obtained 2-aminobutyramide hydrochloride crystals to 30.0 wt% sodium hydroxide solution for neutralization, then add dichloromethane for extraction, remove the solution to obtain 2-aminobutyramide; the yield is 93.5% and the purity is 99.0%.

[0044] The obtained product was identified by 1H NMR: 1H NMR (DMSO-d6, 400 MHz): 0.95 (t, 3H, CH3); 1.83 (m, 2H, CH2); 3.57 (m, H, CH); 2.0 (2H, NH2); 5.9 (2H, -CONH2).

[0045] Example 3

[0046] A method for synthesizing 2-aminobutyramide, characterized in that the method comprises the following specific steps:

[0047] S1. Dissolve 1.0 mol of butyramide in 200 mL of tetrahydrofuran (organic solvent), then add 0.015 mol of potassium iodide (catalyst) and stir evenly to obtain reaction solution A;

[0048] S2. Pass 1.5 mol of ammonia gas into 300 mL of tetrahydrofuran (organic solvent) to obtain reaction solution B;

[0049] S3. Add the above reaction solution A and reaction solution B together into a stainless steel autoclave, heat to 65 °C, stir and react for 3 hours, and the reaction pressure is 0.5 MPa;

[0050] S4. After the reaction, cool to room temperature, discharge the material, remove the solvent (tetrahydrofuran) to obtain crude 2-aminobutyramide;

[0051] S5. Recrystallize the obtained crude 2-aminobutyramide with 5.0 wt% dilute hydrochloric acid, then filter and dry to obtain 2-aminobutyramide hydrochloride crystals;

[0052] S6. Add the obtained 2-aminobutyramide hydrochloride crystals to 30.0 wt% sodium hydroxide solution for neutralization, then add dichloromethane for extraction, remove the solution to obtain 2-aminobutyramide; the yield is 94.1% and the purity is 99.3%.

[0053] The obtained product was identified by 1H NMR: 1H NMR (DMSO-d6, 400 MHz): 0.95 (t, 3H, CH3); 1.83 (m, 2H, CH2); 3.57 (m, H, CH); 2.0 (2H, NH2); 5.9 (2H, -CONH2).

[0054] Comparative Example 1

[0055] A method for synthesizing L-2-aminobutyramide hydrochloride, which comprises the following steps:

[0056] (1) Add 2-bromobutyric acid, ammonia water and diisopropyl ether (solvent) to a reaction flask, cool the mixed system to 0 °C, then dropwise add thionyl chloride under stirring conditions, and stir and react at 5 °C for 6 hours after the addition is completed. After the reaction, separate the layers, wash the organic layer with water, and concentrate to obtain a white solid (2-bromobutyramide), and the yield is 90.4%; this step is an amidation reaction;

[0057] (2) Add 2-bromobutyramide and ammonia water to a reaction flask, heat to 35 °C, stir and react for 12 hours. After the reaction is completed, concentrate under reduced pressure, and refine the residual solid with methanol to obtain racemic 2-aminobutyramide, and the yield is 83%;

[0058] (3) Add racemic 2-aminobutyramide and ethanol into a reaction flask, heat to 60 °C, then add L-tartaric acid, stir, filter, wash with ethanol, and the filter cake is L-2-aminobutyramide L-tartrate solid; Suspend the L-2-aminobutyramide L-tartrate solid in ethanol, introduce ammonia gas until saturated, stir at room temperature, filter, concentrate under reduced pressure, dropwise add 30% hydrochloric acid / ethanol solution to adjust the pH to 1-2, filter, wash the solid with ethanol, and dry it under vacuum to obtain L-2-aminobutyramide hydrochloride with a yield of 40%.

[0059] It can be seen from the above Comparative Example 1 that this synthesis method not only has a very complex synthesis process, but also uses a variety of reagents, with a long synthesis time, high cost and low efficiency. Most importantly, the yield of this synthesis scheme is very low, and the overall yield of the three-step synthesis is about 30%. The synthesis scheme provided by the present invention not only greatly simplifies the synthesis steps compared with this process, making the synthesis process simpler, but also the synthesis efficiency of the present invention has been significantly improved compared with it, with a shorter synthesis time. At the same time, the yield of the present invention has been extremely significantly improved compared with it, and the yield of the process of the present invention is high.

[0060] Comparative Example 2

[0061] Provide a preparation method of 2-aminobutyramide, and this method includes the following specific steps:

[0062] (1) Take 58.0 g of propionaldehyde and 0.5 g of triethylamine (the first catalyst) and add them into a four-necked flask. Under stirring and at 15-25 °C, introduce 29.0 g of hydrocyanic acid for reaction. After the reaction, keep the temperature at 15-20 °C for 1 hour to obtain an 88.0 g reaction solution of 2-hydroxybutyronitrile;

[0063] (2) Add 3.1 g of a 30.0 wt% aqueous sodium cyanide solution (the second catalyst) into an autoclave, then add all the above 2-hydroxybutyronitrile reaction solution, introduce ammonia gas, keep the pressure at 3 kg, and react at 20 °C for 4 hours to obtain a 128.0 g reaction solution of 2-aminobutyronitrile;

[0064] (3) Transfer the above 2-aminobutyronitrile reaction solution to a four-necked flask equipped with a stirrer and a thermometer, evacuate ammonia at -0.096 Mpa at 0 °C for 1 hour to obtain a 96.8 g deammoniated solution, then add 128.0 g of water and 14 mL of acetone (the third catalyst), dropwise add 2.8 g of a 50.0 wt% aqueous sodium hydroxide solution for hydrolysis reaction at -5 °C to 0 °C, the dropping time is 0.5 hour, after keeping the temperature for 1 hour, add 1.0 g of 37.0 wt% hydrochloric acid to neutralize to pH = 7, concentrate under reduced pressure to evaporate water, and obtain 101.7 g of solid product (2-aminobutyramide) with a yield of 95.7%.

[0065] It can be seen that for the method for synthesizing 2-aminobutyramide provided in Comparative Example 2, although the yield is relatively high, its synthesis process is also relatively complex. Moreover, this synthesis method in Comparative Example 2 uses highly toxic hydrocyanic acid, and the safety of the entire process is very low. Compared with the synthesis method provided in Comparative Example 2, the yields of the two are close, but the synthesis method of the present invention does not require the use of highly toxic reaction raw materials. The present invention provides a new method that is completely different from the synthesis process of Comparative Example 2, and the synthesis method of the present invention has higher safety.

[0066] Comparative Example 3

[0067] Provide a method for synthesizing 2-aminobutyramide, and the method comprises the following specific steps:

[0068] (1) First, add 122.6 g of 2-chlorobutyric acid and 130.9 g of thionyl chloride into a reaction vessel, then start stirring, and then add 13.8 g of phosphorus trichloride (catalyst), and react at 50 °C for 6 hours;

[0069] (2) After the reaction is completed, raise the temperature of the reaction solution to 75 °C and stir under reflux for 4 hours to obtain a 2-chlorobutyryl chloride reaction solution. Put the obtained 2-chlorobutyryl chloride reaction solution into an ammoniation reactor equipped with a mechanical stirring device and a thermometer and dried, add 300 mL of methanol thereto, then slowly introduce 51.0 g of ammonia gas, and then raise the temperature in the reactor to 60 °C, and react at a pressure of 0.1 - 0.3 MPa for 48 hours;

[0070] (3) After the reaction is completed, cool the reaction solution to 0 °C, then filter, distill the filtrate under reduced pressure at 40 °C until a solid precipitates, then cool to 0 °C, stir for 2 hours, filter, and dry to obtain about 80.4 g of 2-aminobutyramide, and the yield is 80.1%.

[0071] It can be seen that the synthesis method provided by the present invention is obviously different from the method of Comparative Example 3, and the product yield of the synthesis method of the present invention is significantly higher than that of this method.

[0072] In summary, the present invention provides a new method for synthesizing 2-aminobutyramide. The method of the present invention has the advantages of high product yield, good safety, simple synthesis process, and low cost.

[0073] The above are the preferred embodiments of the present invention, which are only used to explain the present invention and are not used to limit the present invention. Any obvious changes or variations derived from the technical solutions of the present invention are still within the protection scope of the present invention.

Claims

1. A method for synthesizing 2-aminobutyramide, characterized in that, The method comprises the following steps: S1. Dissolve butyramide in an organic solvent, and then add a catalyst and stir evenly to obtain reaction solution A; S2. Add an ammonia source to the organic solvent to obtain reaction solution B; S3. Add reaction solution A and reaction solution B to a high-pressure reactor and heat for reaction; S4. After the reaction, cool, discharge, and remove the solvent to obtain crude 2-aminobutyramide; S5. Recrystallize the crude 2-aminobutyramide, filter, and dry to obtain 2-aminobutyramide hydrochloride crystals; S6. Neutralize the 2-aminobutyramide hydrochloride crystals to obtain 2-aminobutyramide; Wherein, the catalyst in step S1 is potassium iodide, and the ammonia source in step S2 is ammonia gas.

2. The synthesis method of 2-aminobutyramide according to claim 1, characterized in that, The organic solvent selected is tetrahydrofuran.

3. A method for synthesizing 2-aminobutyramide according to claim 1, characterized in that, In step S1, the molar volume ratio of butyramide to the organic solvent is 3.0 - 5.0 mol / L; the molar ratio of butyramide to the catalyst is 1:(0.01 - 0.02).

4. A method for synthesizing 2-aminobutyramide according to claim 1, characterized in that, The molar volume ratio of the ammonia source to the organic solvent is 4.0 - 5.0 mol / L; the molar ratio of butyramide to the ammonia source is 1:(1.2 - 1.5).

5. A method for synthesizing 2-aminobutyramide according to claim 1, characterized in that, In step S3, the reaction temperature is 65 - 70 °C, the reaction time is 1 - 3 hours, and the reaction pressure is 0.5 - 1.0 MPa.

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