Synthesis method of 4-(methylamine) pyrrolidine-2-ketone
Through the two-step reaction of raw materials such as ethyl acetate, dioxane hydrochloride and benzyl chloroformate, combined with hydrogenation reaction, the synthesis path of 4-(methylamine)pyrrolidine-2-one was successfully simplified and the product was improved Yield, solves the problems of long and low synthesis paths in the prior art.
Patent Information
- Application Number
- CN202411317427.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-20
- Publication Date
- 2024-12-27
- Estimated Expiration
- Not applicable · inactive patent
AI Technical Summary
In the prior art, the synthesis path of 4-(methylamine)pyrrolidine-2-one is long, the product yield is low, and there is a lack of efficient synthesis methods.
Ethyl acetate, tert-butyl 3-aminomethylformate pyrrolidine-5-one and dioxane hydrochloride mixture were used to react, followed by addition of benzyl chloroformate and potassium carbonate, and 3- pyrrolidin-5-one methyl-3-aminomethylformate was then hydrogenated with wet palladium carbon and methanol to obtain 4-(methylamine)pyrrolidin-2-one.
The simplification of the synthesis path and the improvement of product yield have been achieved, with product yields reaching more than 99.01%.
Smart Images
Figure CN119192050A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing 4-(methylamino)pyrrolidin-2-one. Background Art
[0002] Oxazole ring is an important five-membered nitrogen-oxygen heterocyclic ring, which has the characteristics of easy formation of hydrogen bonds, coordination with metal ions, hydrophobic interaction, π-π stacking, electrostatic interaction, etc. Therefore, oxazole compounds can produce a variety of non-covalent interactions and show good biological activities such as insecticide, herbicide and antibacterial. Oxazole compounds are widely used in the pharmaceutical field, such as the herbicide isoxadifen, clinical antibacterial drugs linezolid and virginiamycin, etc. Pyrrolidine is a five-membered nitrogen heterocyclic alkaloid compound with low ring tension and good stability. It is a component of many drugs and an important chemical intermediate. The synthesis of pyrrolidine derivatives and the study of their biological activities are receiving more and more attention.
[0003] 4-(Methylamino)pyrrolidin-2-one is an important pesticide intermediate, so the synthesis research of this compound has important practical significance. Summary of the invention
[0004] The purpose of the present invention is to solve the shortcomings of the prior art and to propose a synthesis method of 4-(methylamino)pyrrolidin-2-one. The synthesis method has a short synthesis path and a high product yield.
[0005] In order to achieve the above object, the present invention adopts the following technical solutions:
[0006] A method for synthesizing 4-(methylamino)pyrrolidin-2-one comprises the following steps:
[0007] Step 1, add ethyl acetate and 3-methyl-3-aminomethylformic acid tert-butyl pyrrolidone-5-one to a reaction bottle, stir and dissolve, start to dropwise add a mixture of hydrochloric acid and dioxane at 25°C, and react for 12 hours. After the reaction is completed, evaporate the ethyl acetate, add it to water, then add potassium carbonate, stir, cool to 0-5°C, and then dropwise add benzyl chloroformate. The reaction time is 12 hours. After the reaction is completed, extract the reaction solution with ethyl acetate 4 times, evaporate to dryness, and obtain 3-methyl-3-aminomethylformic acid benzyl pyrrolidone-5-one;
[0008] Step 2: Add methanol, 3-methyl-3-aminomethylbenzyl formate pyrrolidin-5-one and wet palladium on carbon into the reaction bottle, start stirring, raise the temperature to 40°C, and carry out hydrogenation reaction with 0.4MPa hydrogen for 12h. After the reaction, filter out the wet palladium on carbon, evaporate the methanol to obtain 4-(methylamine)pyrrolidin-2-one.
[0009] Preferably, in step 1, the ratio of hydrochloric acid to dioxane in the hydrochloric acid-dioxane mixture is 1:6.38-7.75 by mass.
[0010] Preferably, in step 1, the ratio of 3-methyl-3-aminomethylformic acid tert-butyl pyrrolidone-5-one, dioxane hydrochloride, benzyl chloroformate, ethyl acetate, potassium carbonate and water is 1:4.08-4.55:0.86-1.29:3.41-4.17:1.05-1.35:7.58-9.09 by mass.
[0011] Preferably, in step 2, the ratio of 3-methyl-3-aminomethylformic acid benzyl pyrrolidin-5-one, wet palladium carbon and methanol is 1:0.04-0.08:2.99-3.79 by mass.
[0012] Compared with the prior art, the present invention has the following beneficial effects:
[0013] The invention uses 3-methyl-3-aminomethylformic acid tert-butyl ester pyrrolidine-5-one, dioxane hydrochloride and benzyl chloroformate as raw materials, and synthesizes 4-(methylamino)pyrrolidine-2-one through a two-step reaction. The synthesis path is short, the synthesis method is simple, and the product yield is high. BRIEF DESCRIPTION OF THE DRAWINGS
[0014] Figure 1 Schematic diagram of the synthesis method of the present invention. DETAILED DESCRIPTION
[0015] The technical solutions in the embodiments of the present invention will be described clearly and completely below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments.
[0016] like Figure 1 As shown, the present invention provides a method for synthesizing 4-(methylamino)pyrrolidin-2-one, comprising the following steps:
[0017] (1) Ethyl acetate and tert-butyl 3-methyl-3-aminomethylformate pyrrolidine-5-one were added to a reaction flask, stirred and dissolved, and a mixture of hydrochloric acid and dioxane was added dropwise at 25° C. for a reaction time of 12 hours. After the reaction was completed, ethyl acetate was evaporated and added to water, and potassium carbonate was added. The mixture was stirred and cooled to 0 to -5° C., and benzyl chloroformate was added dropwise for a reaction time of 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate 4 times and evaporated to dryness to obtain 3-methyl-3-aminomethylformate pyrrolidine-5-one;
[0018] (2) Methanol, 3-methyl-3-aminomethylformic acid benzyl ester pyrrolidin-5-one and wet palladium on carbon were added to the reaction flask, stirring was started, the temperature was raised to 40° C., and hydrogenation reaction was carried out with 0.4 MPa hydrogen for 12 h. After the reaction was completed, the wet palladium on carbon was filtered out, and the methanol was evaporated to obtain 4-(methylamino)pyrrolidin-2-one.
[0019] The specific synthesis path is as follows:
[0020] Specifically, ethyl acetate and tert-butyl 3-methyl-3-aminomethylformate pyrrolidine-5-one were added to the reaction bottle, stirred to dissolve, and a mixture of hydrochloric acid and dioxane was added dropwise at 25°C for 12 hours. After the reaction was completed, ethyl acetate was evaporated and added to water, and potassium carbonate was added, stirred, and cooled to 0 to -5°C. Benzyl chloroformate was added dropwise for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate 4 times and evaporated to dryness to obtain 3-methyl-3-aminomethylformate pyrrolidine-5-one. In the present invention, the usage ratio of hydrochloric acid and dioxane in the hydrochloric acid and dioxane mixed solution is 1:6.38-7.75 by mass; the usage ratio of 3-methyl-3-aminomethylformic acid tert-butyl pyrrolidone-5-one, dioxane hydrochloride, benzyl chloroformate, ethyl acetate, potassium carbonate and water is 1:4.08-4.55:0.86-1.29:3.41-4.17:1.05-1.35:7.58-9.09 by mass.
[0021] Methanol, 3-methyl-3-aminomethyl formic acid benzyl pyrrolidine-5-one and wet palladium carbon are added to the reaction bottle, stirring is turned on, the temperature is raised to 40°C, and 0.4MPa of hydrogen is used for hydrogenation reaction. The reaction time is 12h. After the reaction is completed, the wet palladium carbon is filtered out, and the methanol is evaporated to obtain 4-(methylamine)pyrrolidine-2-one. In the present invention, the usage ratio of 3-methyl-3-aminomethyl formic acid benzyl pyrrolidine-5-one, wet palladium carbon and methanol is 1:0.04-0.08:2.99-3.79 by mass.
[0022] Example 1
[0023] (1) Synthesis of 3-methyl-3-aminomethylformic acid benzyl pyrrolidin-5-one:
[0024] 450 g of ethyl acetate and 132 g of tert-butyl 3-methyl-3-aminomethylformate pyrrolidine-5-one were added to the reaction flask, stirred and dissolved, and 539 g of a mixture of hydrochloric acid and dioxane was added dropwise at 25 ° C. The reaction time was 12 h. After the reaction was completed, ethyl acetate was distilled off and added to 1000 g of water. Then 138 g of potassium carbonate was added, stirred, and cooled to 0-5 ° C. Finally, 113 g of benzyl chloroformate was added dropwise. The reaction time was 12 h. After the reaction was completed, the reaction solution was extracted 4 times with ethyl acetate (2 × 250 mL), evaporated to dryness, and 119 g of 3-methyl-3-aminomethylformate pyrrolidine-5-one was obtained. The product yield was 85.80%.
[0025] (2) Synthesis of 4-(methylamino)pyrrolidin-2-one:
[0026] Add 395 g of methanol, 132 g of 3-methyl-3-aminomethylbenzylpyrrolidin-5-one and 5 g of wet palladium on carbon into the reaction flask, start stirring, raise the temperature to 40°C, and carry out hydrogenation reaction with 0.4 MPa of hydrogen. The reaction time is 12 h. After the reaction, filter out the wet palladium on carbon, evaporate the methanol to obtain 54 g of 4-(methylamine)pyrrolidin-2-one, and the product yield is 99.01%.
[0027] Example 2
[0028] (1) Synthesis of 3-methyl-3-aminomethylformic acid benzyl pyrrolidin-5-one:
[0029] 550 g of ethyl acetate and 132 g of tert-butyl 3-methyl-3-aminomethylformate pyrrolidine-5-one were added to the reaction flask, stirred to dissolve, and 600 g of a mixture of hydrochloric acid and dioxane was added dropwise at 25 ° C. The reaction time was 12 h. After the reaction was completed, ethyl acetate was distilled off and added to 1200 g of water. Then 178 g of potassium carbonate was added, stirred, and cooled to 0-5 ° C. After the reaction was completed, 170 g of benzyl chloroformate was added dropwise. The reaction time was 12 h. After the reaction was completed, the reaction solution was extracted 4 times with ethyl acetate (2 × 250 mL), evaporated to dryness, and 115 g of 3-methyl-3-aminomethylformate pyrrolidine-5-one was obtained. The product yield was 82.94%.
[0030] (2) Synthesis of 4-(methylamino)pyrrolidin-2-one:
[0031] Add 500 g of methanol, 132 g of 3-methyl-3-aminomethylbenzylpyrrolidin-5-one and 10.5 g of wet palladium on carbon into the reaction flask, start stirring, raise the temperature to 40°C, and carry out hydrogenation reaction with 0.4 MPa of hydrogen. The reaction time is 12 h. After the reaction, filter out the wet palladium on carbon, evaporate the methanol to obtain 52.6 g of 4-(methylamino)pyrrolidin-2-one, and the product yield is 96.58%.
[0032] Example 3
[0033] (1) Synthesis of 3-methyl-3-aminomethylformic acid benzyl pyrrolidin-5-one:
[0034] 500 g of ethyl acetate and 132 g of tert-butyl 3-methyl-3-aminomethylformate pyrrolidine-5-one were added to the reaction flask, stirred and dissolved, and 570 g of a mixture of hydrochloric acid and dioxane was added dropwise at 25 ° C. The reaction time was 12 h. After the reaction was completed, ethyl acetate was distilled off and added to 1000 g of water. Then 158 g of potassium carbonate was added, stirred, and cooled to 0-5 ° C. After the reaction was completed, 142 g of benzyl chloroformate was added dropwise. The reaction time was 12 h. After the reaction was completed, the reaction solution was extracted 4 times with ethyl acetate (2 × 250 mL), evaporated to dryness, and 117.9 g of 3-methyl-3-aminomethylformate pyrrolidine-5-one was obtained. The product yield was 84.97%.
[0035] (2) Synthesis of 4-(methylamino)pyrrolidin-2-one:
[0036] Add 445 g of methanol, 132 g of 3-methyl-3-aminomethylbenzylpyrrolidin-5-one and 7.8 g of wet palladium on carbon into the reaction flask, start stirring, raise the temperature to 40°C, and carry out hydrogenation reaction with 0.4 MPa of hydrogen. The reaction time is 12 h. After the reaction, filter out the wet palladium on carbon, evaporate the methanol to obtain 53.5 g of 4-(methylamino)pyrrolidin-2-one, and the product yield is 98.16%.
[0037] In summary, the present invention uses 3-methyl-3-aminomethylformic acid tert-butyl ester pyrrolidine-5-one, dioxane hydrochloride and benzyl chloroformate as raw materials to synthesize 4-(methylamino)pyrrolidine-2-one through a two-step reaction. The synthesis path is short, the synthesis method is simple, and the product yield is high.
[0038] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.
Claims
1. A method for synthesizing 4-(methylamino)pyrrolidin-2-one, characterized in that: The following steps are involved: Step 1, add ethyl acetate and 3-methyl-3-aminomethylformic acid tert-butyl pyrrolidone-5-one to a reaction bottle, stir and dissolve, start to dropwise add a mixture of hydrochloric acid and dioxane at 25°C, and react for 12 hours. After the reaction is completed, evaporate the ethyl acetate, add it to water, then add potassium carbonate, stir, cool to 0-5°C, and then dropwise add benzyl chloroformate. The reaction time is 12 hours. After the reaction is completed, extract the reaction solution with ethyl acetate 4 times, evaporate to dryness, and obtain 3-methyl-3-aminomethylformic acid benzyl pyrrolidone-5-one; Step 2: Add methanol, 3-methyl-3-aminomethylbenzyl formate pyrrolidin-5-one and wet palladium on carbon into the reaction bottle, start stirring, raise the temperature to 40°C, and carry out hydrogenation reaction with 0.4MPa hydrogen for 12h. After the reaction, filter out the wet palladium on carbon, evaporate the methanol to obtain 4-(methylamine)pyrrolidin-2-one.
2. The method for synthesizing 4-(methylamino)pyrrolidin-2-one according to claim 1, characterized in that: In the step 1, the ratio of hydrochloric acid to dioxane in the hydrochloric acid-dioxane mixture is 1:6.38-7.75 by mass.
3. The method for synthesizing 4-(methylamino)pyrrolidin-2-one according to claim 1, characterized in that: In the step 1, the usage ratio of 3-methyl-3-aminomethylformic acid tert-butyl pyrrolidone-5-one, dioxane hydrochloride, benzyl chloroformate, ethyl acetate, potassium carbonate and water is 1:4.08-4.55:0.86-1.29:3.41-4.17:1.05-1.35:7.58-9.09 by mass.
4. The method for synthesizing 4-(methylamino)pyrrolidin-2-one according to claim 1, characterized in that: In the step 2, the ratio of 3-methyl-3-aminomethylformic acid benzyl pyrrolidin-5-one, wet palladium carbon and methanol is 1:0.04-0.08:2.99-3.79 by mass.