A preparation method of gamma-aminobutyramide

Abstract

The present invention discloses a method for preparing γ-aminobutanamide, characterized in that the method comprises the following steps: S1, under an inert atmosphere, γ-butyrolactone and ammonia are put into a reactor, and a closed reaction is carried out under the action of a catalyst; S2, after the reaction, the catalyst is removed to obtain an intermediate product; S3, the intermediate product is vacuum distilled to obtain γ-aminobutanamide. The present invention provides a new method for preparing γ-aminobutanamide, which significantly improves the yield of γ-aminobutanamide product, and the total product yield of the inventive method can reach more than 94%. The raw materials used in the inventive method are simple and easy to obtain, the preparation process is simple, the reaction conditions are mild and easy to control, and the reaction raw material utilization rate of the present invention is high.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemicals, and in particular to a method for preparing gamma-aminobutyramide. Background Art

[0002] γ-Aminobutyramide is a very important synthetic reagent and drug intermediate. It plays an important role in biosynthesis, medicine, and food processing. Its medicinal derivatives can release γ-aminobutyric acid through the action of amidase in the body, allowing it to exert its effects. γ-Aminobutyric acid is an inhibitory amino acid neurotransmitter widely present in the central nervous system of mammals.

[0003] The prior art provides a synthesis process for γ-aminobutyramide, which uses γ-aminobutyric acid as a raw material, first synthesizing a γ-aminobutyric acid methyl ester hydrochloride intermediate, and then subjecting the γ-aminobutyric acid methyl ester hydrochloride to an aminolysis reaction to produce a γ-aminobutyramide compound. Although the reaction conditions of this synthesis process are relatively mild, the entire synthesis process is relatively complex, the reaction time is long, and the overall yield is low (total yield is less than 80%).

[0004] Chinese patent CN107501120A discloses a "method for preparing 3-aminobutanamide compounds". Although the process has the advantages of mild reaction conditions and simple reaction process conditions, its total yield is about 77%, which still has the problem of low yield, which is not conducive to reducing production costs.

[0005] Chinese patent CN112142614B discloses a "method for preparing 3-aminobutanamide." This method has the advantages of a simple and efficient preparation process and low production cost. This method can be conducive to the large-scale industrial production of 3-aminobutanamide. However, the total yield of 3-aminobutanamide in this method is about 87%, which is still not high enough. In summary, it can be found that existing synthesis processes all have the problem of low product yield. Summary of the Invention

[0006] The purpose of the present invention is to address the problem that the existing synthesis process of aminobutanamide compounds generally has a low yield. The present invention designs a new method for preparing γ-aminobutanamide, which significantly improves the product yield.

[0007] The present invention is achieved through the following technical solutions:

[0008] A method for preparing γ-aminobutyramide, characterized in that the method comprises the following steps:

[0009] S1. Under an inert atmosphere, γ-butyrolactone and ammonia are added to a reaction vessel and a closed reaction is carried out under the action of a catalyst;

[0010] S2. After the reaction, removing the catalyst to obtain an intermediate product;

[0011] S3. Vacuum distilling the intermediate product to obtain γ-aminobutyramide.

[0012] Furthermore, a method for preparing γ-aminobutyramide: in step S1, the molar ratio of the γ-butyrolactone to the ammonia is 1:(2-3).

[0013] Furthermore, a method for preparing γ-aminobutyramide: the catalyst in step S1 is boron trioxide.

[0014] Furthermore, a method for preparing γ-aminobutyramide: the molar ratio of the catalyst to the γ-butyrolactone in step S1 is (0.05-0.1):1.

[0015] Furthermore, a method for preparing γ-aminobutyramide: the reaction temperature in step S1 is 85-95° C., and the reaction time is 8-12 hours.

[0016] Furthermore, a method for preparing γ-aminobutyramide: the reaction pressure in step S1 is 0.5-0.8 MPa.

[0017] Furthermore, a method for preparing γ-aminobutyramide is provided: during the reaction process of step S1, stirring is performed at a rate of 200 to 500 rpm.

[0018] Furthermore, a method for preparing γ-aminobutyramide: Step S2, after the reaction, introducing nitrogen to replace ammonia, recovering the ammonia, and then filtering to remove the catalyst.

[0019] Beneficial effects of the present invention:

[0020] The present invention provides a new method for preparing γ-aminobutyramide, which significantly improves the yield of the product, with the total yield of the product reaching over 94%. The raw materials used in the method are simple and readily available, the preparation process is simple, the reaction conditions are mild and easy to control, and the utilization rate of the reaction raw materials is high. DETAILED DESCRIPTION

[0021] The technical solutions of the present invention will be clearly and completely described below in conjunction with specific embodiments. Obviously, the embodiments described are only some embodiments of the present invention, rather than all embodiments. The following description of at least one exemplary embodiment is actually only illustrative and is in no way intended to limit the present invention and its application or use. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative work are within the scope of protection of the present invention.

[0022] Example 1

[0023] Provided is a method for preparing γ-aminobutyramide, characterized in that the method comprises the following specific steps:

[0024] S1. 5.0 mol of γ-butyrolactone was added to an autoclave, followed by 0.5 mol of porous boron trioxide (catalyst), followed by nitrogen gas to remove oxygen from the autoclave, followed by 14.0 mol of ammonia gas, and the autoclave was sealed; the autoclave was then heated to 90° C. and stirred at 300 rpm under a pressure of 0.5 MPa for 10 hours;

[0025] Wherein: the porous boron trioxide is prepared by vacuum thermal dehydration of analytical pure boric acid under the assistance of ultrasound;

[0026] S2. After the reaction, nitrogen is continuously introduced to displace the unreacted ammonia and recover the ammonia, and then the catalyst is removed by filtration to obtain an intermediate product;

[0027] S3. The intermediate product is placed in a distillation flask and subjected to vacuum distillation to obtain γ-aminobutyramide with a yield of about 94.2%.

[0028] The nitrogen content was determined to be 99.16%; H NMR spectrum: 1HNMR (CDCl3, 400 MHz): 1.84 (m, 2H, CH2); 2.18 (t, 2H, CH2); 2.66 (m, 2H, CH2); 2.0 (m, 2H, NH2); 6.0 (2H, NH2).

[0029] The synthesis process of above-described embodiment 1 is as follows:

[0030]

[0031] Example 2

[0032] Provided is a method for preparing γ-aminobutyramide, characterized in that the method comprises the following specific steps:

[0033] S1. 5.0 mol of γ-butyrolactone was added to an autoclave, followed by 0.25 mol of porous boron trioxide (catalyst), followed by nitrogen gas to remove oxygen from the autoclave, followed by 11.0 mol of ammonia gas, and the autoclave was sealed; the autoclave was then heated to 85° C. and stirred at 500 rpm under a pressure of 0.8 MPa for 8 hours;

[0034] S2. After the reaction, nitrogen is continuously introduced to displace the unreacted ammonia and recover the ammonia, and then the catalyst is removed by filtration to obtain an intermediate product;

[0035] S3. The intermediate product is placed in a distillation flask and subjected to vacuum distillation to obtain γ-aminobutyramide with a yield of about 94.5%.

[0036] The nitrogen content was determined to be 99.21%; H NMR spectrum: 1HNMR (CDCl3, 400 MHz): 1.84 (m, 2H, CH2); 2.18 (t, 2H, CH2); 2.66 (m, 2H, CH2); 2.0 (m, 2H, NH2); 6.0 (2H, NH2).

[0037] Example 3

[0038] Provided is a method for preparing γ-aminobutyramide, characterized in that the method comprises the following specific steps:

[0039] S1. 5.0 mol of γ-butyrolactone was added to an autoclave, followed by 0.4 mol of porous boron trioxide (catalyst), followed by nitrogen gas to remove oxygen from the autoclave, followed by 15.0 mol of ammonia gas, and the autoclave was sealed; the autoclave was then heated to 95° C. and stirred at 200 rpm under a pressure of 0.6 MPa for 12 hours;

[0040] S2. After the reaction, nitrogen is continuously introduced to displace the unreacted ammonia and recover the ammonia, and then the catalyst is removed by filtration to obtain an intermediate product;

[0041] S3. The intermediate product is placed in a distillation flask and subjected to vacuum distillation to obtain γ-aminobutyramide with a yield of about 94.1%.

[0042] The nitrogen content was determined to be 99.18%; H NMR spectrum: 1HNMR (CDCl3, 400 MHz): 1.84 (m, 2H, CH2); 2.18 (t, 2H, CH2); 2.66 (m, 2H, CH2); 2.0 (m, 2H, NH2); 6.0 (2H, NH2).

[0043] Comparative Example 1

[0044] Provided is a method for synthesizing γ-aminobutyramide, the method comprising the following specific steps:

[0045] (1) Cool 25 ml of methanol to -10°C, then add 1.8 ml of thionyl chloride dropwise to it, and stir for 2 hours after the addition is complete;

[0046] (2) adding 2.6 g of γ-aminobutyric acid to the system of step (1) above and heating under reflux for 1 hour, and then distilling under reduced pressure to remove residual methanol and dichloride to obtain a solid product;

[0047] (3) The solid product was dissolved in 25 ml of 2.0 mol / L HCl-methanol solution, and the mixture was heated under reflux for 1 hour. The methanol was then removed under reduced pressure to obtain a white solid.

[0048] (4) The white solid was recrystallized from ethanol-ether (1:2) and dried to obtain 3.62 g of white crystals, namely, γ-aminobutyric acid methyl ester hydrochloride, with a yield of 94%;

[0049] (5) 3.06 g of methyl γ-aminobutyrate hydrochloride was mixed with anhydrous methanol and then cooled to -10°C. 5.5 ml of isopropylamine was added dropwise to the mixture and stirred for 10 minutes. The mixture was then stirred in a sealed reaction vessel at room temperature for 36 hours.

[0050] (6) After the reaction, the residual methanol and isopropylamine were removed by distillation under reduced pressure and dried to obtain about 2.25 g of γ-amino-N-isopropylbutyramide (pale yellow oily substance) with a yield of 78%.

[0051] It can be seen that the product yield of the synthesis method provided in Comparative Example 1 is much lower than that of the method provided in the present application, and it can be seen that although the reaction conditions of the synthesis process in Comparative Example 1 are not harsh, its synthesis process is relatively complicated and cumbersome. Compared with Comparative Example 1, the preparation method of the present application not only greatly improves the product yield, but also has a simple synthesis process, and the entire synthesis process can be achieved in one step.

[0052] Comparative Example 2

[0053] Provided is a method for preparing a 3-aminobutanamide compound, the method comprising the following specific steps:

[0054] (1) 91 g of 37.5 wt% ammonia water and 11.6 g of methyl 3-oxobutyrate were added to a four-necked round-bottom flask equipped with a mechanical stirrer, and then reacted at 30° C. After the reaction was completed by liquid chromatography, the reaction liquid was filtered, and the resulting filter cake was rinsed with clean water 2 to 3 times and dried in an oven at 50 to 60° C. to obtain 8.65 g of 3-aminobuteneamide, with a purity of 98.2% and a yield of 84.8% as determined by liquid chromatography; wherein the liquid chromatography detection conditions were: C18 column, mobile phase volume ratio of acetonitrile:water = 60:40;

[0055] (2) 100 mL of methanol, 8.16 g of 3-aminobutyramide and 0.4 g of Raney nickel (catalyst) were added to an autoclave equipped with a mechanical stirrer, and hydrogen was introduced while maintaining the pressure at 0.1 MPa. The mixture was reacted at 40° C. After the reaction was complete as determined by liquid chromatography, the catalyst was filtered out and the solvent was removed by reduced pressure distillation to obtain 7.98 g of 3-aminobutyramide. The purity as determined by liquid chromatography was 98.0%, and the yield was 97.8%. The liquid chromatography detection conditions were: C18 column, and the mobile phase volume was: acetonitrile: 0.05% (v:v) formic acid aqueous solution = 60:40.

[0056] It can be calculated that the total yield of the above-mentioned comparative example 2 is about 82.9% (84.8%×97.8%). It can be seen that the product yield of the method provided in comparative example 2 is also much lower than that of the solution of the present application.

[0057] In summary, it can be seen that the present invention provides a new method for preparing γ-aminobutyramide. The preparation method of the present invention is different from the existing synthesis method. The method of the present invention not only has a simple synthesis process, its raw materials are easily available, and the reaction conditions are mild, but most importantly, the method provided by the present invention significantly improves the yield of the γ-aminobutyramide product, and the total yield of the product of the method of the present invention can reach more than 94%.

[0058] Comparative Example 3

[0059] The difference between Comparative Example 3 and Example 1 is that the catalyst used in Comparative Example 3 is boron trioxide, and the other conditions are the same.

[0060] The yield of γ-aminobutyramide in Comparative Example 3 was measured to be about 80%. This shows that the porous boron trioxide catalyst used in the present invention can also significantly improve the product yield.

[0061] The above preferred embodiments of the present invention are only used to explain the present invention and are not used to limit the present invention. Any obvious changes or modifications derived from the technical solution of the present invention are still within the scope of protection of the present invention.

Claims

1. A method for preparing γ-aminobutyramide, characterized in that: The method comprises the following steps: S1. Under an inert atmosphere, γ-butyrolactone and ammonia are added to a reactor and a closed reaction is carried out under the action of a catalyst, wherein the catalyst is porous boron trioxide; S2. After the reaction, removing the catalyst to obtain an intermediate product; S3. Vacuum distilling the intermediate product to obtain γ-aminobutyramide.

2. The method for preparing γ-aminobutyramide according to claim 1, wherein The molar ratio of the γ-butyrolactone to the ammonia in step S1 is 1: (2～3)。 3. The method for preparing γ-aminobutyramide according to claim 1, wherein: The molar ratio of the catalyst to the γ-butyrolactone in step S1 is (0.05-0.1):

1.

4. The method for preparing γ-aminobutyramide according to claim 1, wherein The reaction temperature in step S1 is 85-95° C., and the reaction time is 8-12 hours.

5. The method for preparing γ-aminobutyramide according to claim 1, wherein The reaction pressure in step S1 is 0.5 to 0.8 MPa.

6. The method for preparing γ-aminobutyramide according to claim 1, wherein: During the reaction of step S1, stirring is performed at a rate of 200 to 500 rpm.

7. The method for preparing γ-aminobutyramide according to claim 1, wherein: Step S2: After the reaction, nitrogen is introduced to replace the ammonia, and the ammonia is recovered, and then the catalyst is filtered to remove.

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