A process for the continuous hydroreductive synthesis of 1-(2-aminoethyl)pyrrolidine

Abstract

The application discloses a kind of continuous hydrogenation reduction synthesis 1-(2-aminoethyl) pyrrolidine method in the technical field of pharmaceutical synthesis, which takes aminoacetaldehyde acetal as raw material, by adding acid catalyst in the reaction system, in-situ generation aminoacetaldehyde, further and pyrrolidine form enamine, continuous hydrogenation reduction reaction in microreactor, high yield 1-(2-aminoethyl) pyrrolidine is obtained.The application has the advantages of low raw material cost, short reaction time, high product purity and yield, is friendly to environment, reaches the requirement of green chemical process.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, specifically to a method for synthesizing 1-(2-aminoethyl)pyrrolidine. Background Technology

[0002] 1-(2-aminoethyl)pyrrolidine, with CAS Registry Number(s): 7154-73-6, has a boiling point of 66-70℃ (23 mmHg) and its chemical structural formula is as follows:

[0003]

[0004] 1-(2-Aminoethyl)pyrrolidine can be used in the synthesis of various drugs. For example, Toceranib (SU 11654; PHA291639) is a kinase inhibitor with antitumor and antiangiogenic activities, inhibiting KIT, VEGFR2, and PDGFRβ. It is also used as an intermediate in the preparation of the anti-obesity candidate compound SYSU-3d.

[0005] The existing synthetic routes for 1-(2-aminoethyl)pyrrolidine include the following:

[0006] 1. The literature European Journal of Medicinal Chemistry, 166, 2019, 304-317 describes the reaction of potassium phthalimide and 1,2-dibromoethane as raw materials to prepare N-(2-bromoethyl)phthalimide, which is then reacted with pyrrolidine in DMF to generate 2-(2-(pyrrolidine-1-yl)ethyl)isoindoline-1,3-dione, which is then subjected to hydrazinolysis with hydrazine hydrate to generate 1-(2-aminoethyl)pyrrolidine.

[0007] The reaction equation is as follows:

[0008]

[0009] Its shortcomings are: the operation steps are complicated, DMF is difficult to remove and needs to be pumped out with an oil pump, and hydrazine hydrate is an easily explosive chemical with strong toxicity, making post-processing difficult and not in line with the requirements of green production.

[0010] 2. Chinese Patent CN117105884A uses 1,2-dichloroethane and pyrrolidine as raw materials, adds solvent and alkaline additives, and heats to react to obtain N-(2-chloroethyl)pyrrolidine solution. Then, it undergoes a high-pressure heating amination reaction with ammonia water. After the reaction is completed, it is cooled to room temperature, and then extracted and distilled under reduced pressure to obtain 1-(2-aminoethyl)pyrrolidine.

[0011] The reaction equation is as follows:

[0012]

[0013] Although the raw materials for this method are inexpensive and widely available, and the reaction operation is simple, the amination reaction requires high temperature and high pressure, which is not conducive to industrial production.

[0014] 3. The literature Recueil des Travaux Chimiques des Pays-Bas, 1939, vol. 58, p. 1105, 1106 reported the reaction using excess ethylenediamine and 1,4-dibromobutane. After the reaction was completed, sodium hydroxide was added, the mixture was filtered, the filtrate was washed in layers, and distilled to obtain 1-(2-aminoethyl)pyrrolidine.

[0015] The reaction equation is as follows:

[0016]

[0017] Its shortcomings are: there are many side reactions, ethylenediamine is easily explosive and is a raw material controlled by the state, and although the reaction operation is simple, it is not a very good production method.

[0018] In summary, finding a new method with advantages such as "low raw material cost, high product purity and yield, and less waste" is a technical problem that urgently needs to be solved in the synthesis of 1-(2-aminoethyl)pyrrolidine. Summary of the Invention

[0019] This invention provides a method for the continuous hydrogenation reduction synthesis of 1-(2-aminoethyl)pyrrolidine, which has the advantages of short reaction time, high product purity and yield, and is very environmentally friendly, meeting the requirements of green chemical processes.

[0020] The object of this invention is achieved as follows: a method for the continuous hydrogenation reduction synthesis of 1-(2-aminoethyl)pyrrolidine, characterized by preparation according to the following reaction formula:

[0021]

[0022] Wherein: R is one of methyl or ethyl;

[0023] The synthesis method includes the following steps:

[0024] S1-1: In a reaction vessel, pyrrolidine, aminoacetaldehyde diol, acid catalyst and solvent are mixed at 20-30°C to prepare solution A; the acid catalyst is at least one of formic acid, acetic acid, propionic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid and trifluoroacetic acid.

[0025] S1-2: A 5% palladium-alumina catalyst (with palladium content of 5% by weight and alumina content of 95% by weight) is loaded into a micro-packed bed. Solution A and hydrogen are continuously introduced into the inlet of the gas-liquid mixer. The reaction temperature is 20-120℃. Gas-liquid phase separation is performed at the outlet of the micro-packed bed. Central sampling is carried out, and the reaction temperature and residence time are adjusted to keep the molar ratio controlled at 2 / (2+3+1)≤0.2% until the material reaction is completed. After the solution at the outlet of the micro-packed bed is cooled to about 20-25℃, the solution is concentrated to dryness to obtain an oily residue. Then, the residue is obtained by high vacuum distillation to obtain the 1-(2-aminoethyl)pyrrolidine.

[0026] In this invention, aminoacetaldehyde diacetate is used to form CN bonds, which is a classic reductive amination reaction. Since aminoacetaldehyde diacetate is very unstable in acid, an acid catalyst is added to the reaction system to generate aminoacetaldehyde 4 in situ, which further reacts with pyrrolidine 2 to form enamine 5, which then reacts with hydrogen under palladium catalysis to obtain 1-(2-aminoethyl)pyrrolidine 1 in high yield.

[0027] The reaction process is as follows:

[0028]

[0029] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0030] 1. This invention uses inexpensive aminoacetaldehyde diol as a raw material. By adding an acid catalyst to the reaction system, aminoacetaldehyde 4 is generated in situ, which further reacts with pyrrolidine 2 to form enamine 5. The reaction is then carried out by continuous hydrogenation reduction in a microreactor to obtain 1-(2-aminoethyl)pyrrolidine under mild reaction conditions.

[0031] 2. This invention has the advantages of low raw material cost, short reaction time, high product purity and yield, and is very environmentally friendly, meeting the requirements of green chemical processes.

[0032] Further, the solvent in step S1-1 is one of methanol, ethanol, isopropanol, n-propanol, ethyl acetate, and toluene. Methanol is preferred as the solvent.

[0033] Further, in step S1-1, the acid catalyst is formic acid.

[0034] Further, in step S1-1, the molar ratio of pyrrolidine 2 and aminoacetaldehyde diol 3 is 1:(1.0-6.0), preferably 1:(1.5-2.0).

[0035] Further, in steps S1-2, the flow rate of solution A into the gas-liquid mixer of the micro-packed bed is 1 mL / min; the pressure of hydrogen gas is 1.5 MPa and the flow rate is 50 mL / min.

[0036] In steps S1-2, the reaction temperature is preferably 80-100℃.

[0037] Furthermore, in steps S1-2, the residence time of the material in the micro-filled bed is 0.1-20 seconds, preferably 5 seconds. Attached Figure Description

[0038] Figure 1 This is the GC spectrum for purity detection of 1-(2-aminoethyl)pyrrolidine in Example 1. Detailed Implementation

[0039] The following examples will help researchers understand the key points of the preparation technology of this invention, but they cannot limit the scope of this invention.

[0040] Example 1

[0041] S1-1: In a reaction vessel, add pyrrolidine (71.12g, 1.0mol), 150ml methanol, aminoacetaldehyde dimethyl acetal (157.50g, 1.5mol), and 80% formic acid (4.62g, 0.1mol) and mix them at 20-30℃ to prepare solution A;

[0042] S1-2: A 5% palladium-alumina catalyst was packed into a micro-packed bed. Solution A and hydrogen were introduced into the inlet of a gas-liquid mixer at a flow rate of 1 mL / min, a hydrogen pressure of 1.5 MPa, a hydrogen flow rate of 50 mL / min, a reaction temperature of 80 °C, and a residence time of 5 seconds. Gas-liquid phase separation was performed at the outlet of the micro-packed bed, and samples were taken for testing. The reaction molar ratio 2 / (2+3+1) ≤ 0.2% was maintained until the reaction was complete. After the solution at the outlet of the micro-packed bed was cooled to approximately 20-25 °C, the pressure was released, the reaction mixture was filtered, and the solution was concentrated to dryness to obtain an oily residue. This residue was then subjected to high-vacuum distillation to obtain 109.9 g of the target product, 1-(2-aminoethyl)pyrrolidine. Yield: 96.4%.

[0043] Hydrogenation was performed using the H-Flow-H10 fully automated hydrogenation reactor from Ousheng (Beijing) Technology Co., Ltd. The H-Flow reactor is a fully automated hydrogenation reactor based on continuous flow microreactor hydrogenation technology. According to the principles of green chemistry, it was found that continuous flow hydrogenation achieves better reaction results than batch high-pressure hydrogenation, yielding 1-(2-aminoethyl)pyrrolidine, thus forming a safer and more efficient continuous hydrogenation process.

[0044] With other substances remaining constant, different catalysts were compared, and the data listed in Table 1 below were obtained:

[0045] Experiment No. Acid catalyst of the reaction Yield of compound 1 (%) Purity (%) 1 Phosphoric acid 86.2 98.20 2 Formic acid 96.4 99.58 3 Acetic acid 92.5 99.30 4 Hydrochloric acid 86.2 99.31 5 Sulfuric acid 83.2 98.56 6 Methanesulfonic acid 86.5 99.35 7 p-Toluenesulfonic acid monohydrate 83.2 99.87 8 Trifluoroacetic acid 81.3 99.63

[0046] In conclusion, formic acid showed the best reaction, with a total yield of 96.4% and a purity of 99.58% for product 1.

[0047] With other substances remaining constant, different reaction solvents were compared, and the data listed in Table 2 below were obtained:

[0048] Experiment No. Solvent of the reaction Yield of compound 1 (%) Purity (%) 1 Methanol 96.4 99.58 2 Ethanol 85.2 99.26 3 Isopropanol 82.6 99.10 4 Ethyl acetate 76.2 98.60 5 Toluene 78.3 98.05

[0049] In conclusion, methanol exhibits the best reaction performance, therefore methanol should be the preferred reaction solvent.

[0050] With all other substances remaining constant, different molar ratios of pyrrolidine 2 and aminoacetaldehyde diol 3 were compared, and the data listed in Table 3 below were obtained:

[0051]

[0052]

[0053] In conclusion, the molar ratio of pyrrolidine 2 and aminoacetaldehyde diol 3 is 1:(1.0-6.0), preferably 1:(1.5-2.0).

[0054] With other substances remaining constant, the reaction temperatures of S1-2 were compared, and the data listed in Table 4 below were obtained:

[0055]

[0056]

[0057] In conclusion, the product purity reached 99.8% when reacted at 80-100℃.

[0058] Example 2

[0059] S1-1: In a reaction vessel, add pyrrolidine (71.12g, 1.0mol), 150ml ethanol, aminoacetaldehyde diethanol (202.80g, 1.5mol) and 80% formic acid (4.62g, 0.1mol) and mix them at 20-30℃ to prepare solution A;

[0060] S1-2: A 5% palladium-alumina catalyst was packed into a micro-packed bed. Solution A was introduced into the inlet of a gas-liquid mixer at a controlled flow rate of 1 mL / min, hydrogen pressure of 1.5 MPa, hydrogen flow rate of 50 mL / min, reaction temperature of 80 °C, and residence time of 5 seconds. Gas-liquid phase separation was performed at the outlet of the micro-packed bed. Sampling was carried out during the reaction until the molar ratio 2 / (2+3+1) ≤ 0.2%. After cooling to approximately 20-25 °C, the pressure was released, the reaction mixture was filtered, and the solution was concentrated to dryness. The oily residue was distilled under high vacuum to obtain 109.21 g of the target product 1-(2-aminoethyl)pyrrolidine. Yield: 95.8%, with pyrrolidine as the starting material. Purity (% area, GC): 99.72%, pyrrolidine: not detected.

[0061] Comparative Examples

[0062] In a hydrogenation reactor, pyrrolidine (71.12 g, 1.0 mol), 150 ml methanol, aminoacetaldehyde dimethyl acetal (157.50 g, 1.5 mol), 5% Pd / C (1.00 g, 50.2% water content), and 80% formic acid (4.62 g, 0.1 mol) were added and mixed at 20-25 °C, and the reactor was sealed. The reaction mixture was heated to approximately 80 °C and stirred at this temperature for 5 hours under a hydrogen pressure of approximately 4.0-5.0 bar. Samples were taken during the reaction, and the reaction was continued until the molar ratio 2 / (2+3+1) ≤ 0.2%. After cooling to approximately 20-25 °C, the pressure was released, the reaction mixture was filtered, and the solution was concentrated to dryness. The oily residue was distilled under high vacuum to give 83.30 g of the target product, 1-(2-aminoethyl)pyrrolidine. Yield: 72.5%, with pyrrolidine as the starting material. Purity (% area, GC): 92.79%, pyrrolidine: not detected.

[0063] Data shows that using intermittent hydrogenation reactions results in low yields and low purity, further demonstrating that micro-packed bed continuous hydrogenation technology has significant advantages over traditional batch hydrogenation.

[0064] This invention is not limited to the above embodiments. Based on the technical solutions disclosed in this invention, those skilled in the art can make some substitutions and modifications to some of the technical features without creative effort, and all such substitutions and modifications are within the protection scope of this invention.

Claims

1. A method for the continuous hydrogenation reduction synthesis of 1-(2-aminoethyl)pyrrolidine, characterized in that, Prepared according to the following reaction formula: ； Wherein: R is one of methyl or ethyl; The synthesis method includes the following steps: S1-1: In a reaction vessel, pyrrolidine, aminoacetaldehyde diol, acid catalyst and solvent are mixed at 20-30°C to prepare solution A; the acid catalyst is at least one of formic acid, acetic acid, propionic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid and trifluoroacetic acid. S1-2: A 5% palladium-alumina catalyst is packed into a micro-packed bed. Solution A and hydrogen are continuously introduced into the inlet of the gas-liquid mixer. The reaction temperature is 20-120℃. Gas-liquid phase separation is performed at the outlet of the micro-packed bed. Central sampling is carried out, and the reaction temperature and residence time are adjusted to control the molar ratio at 2 / (2+3+1)≤0.2% until the material reaction is completed. After the solution at the outlet of the micro-packed bed is cooled to 20-25℃, the solution is concentrated to dryness to obtain an oily residue. Then, the residue is obtained by high-vacuum distillation to obtain the 1-(2-aminoethyl)pyrrolidine.

2. The method for continuous hydrogenation reduction synthesis of 1-(2-aminoethyl)pyrrolidine according to claim 1, characterized in that, The solvent in step S1-1 is one of methanol, ethanol, isopropanol, n-propanol, ethyl acetate, and toluene.

3. The method for continuous hydrogenation reduction synthesis of 1-(2-aminoethyl)pyrrolidine according to claim 2, characterized in that, The solvent in step S1-1 is methanol.

4. The method for continuous hydrogenation reduction synthesis of 1-(2-aminoethyl)pyrrolidine according to claim 1, characterized in that, In step S1-1, the acid catalyst is formic acid.

5. The method for continuous hydrogenation reduction synthesis of 1-(2-aminoethyl)pyrrolidine according to claim 1, characterized in that, The molar ratio of pyrrolidine 2 and aminoacetaldehyde diol 3 in step S1-1 is 1:(1.0-6.0).

6. The method for continuous hydrogenation reduction synthesis of 1-(2-aminoethyl)pyrrolidine according to claim 5, characterized in that, The molar ratio of pyrrolidine 2 and aminoacetaldehyde diol 3 in step S1-1 is 1:(1.5-2.0).

7. A method for the continuous hydrogenation reduction synthesis of 1-(2-aminoethyl)pyrrolidine according to any one of claims 1-6, characterized in that, In steps S1-2, the inlet flow rate of solution A into the gas-liquid mixer of the micro-packed bed is 1 mL / min; the pressure of the hydrogen gas is 1.5 MPa and the flow rate is 50 mL / min.

8. The method for the continuous hydrogenation reduction synthesis of 1-(2-aminoethyl)pyrrolidine according to claim 7, characterized in that, In steps S1-2, the reaction temperature is 80-100℃.

9. The method for the continuous hydrogenation reduction synthesis of 1-(2-aminoethyl)pyrrolidine according to claim 7, characterized in that, In steps S1-2, the residence time of the material in the micro-filled bed is 0.1-20 seconds.

10. The method for continuous hydrogenation reduction synthesis of 1-(2-aminoethyl)pyrrolidine according to claim 9, characterized in that, In steps S1-2, the residence time of the material in the micro-filled bed is 5 seconds.

Images