A method for preparing pyrrolidine-1-amine-dihydrochloride

Abstract

This invention discloses a method for preparing pyrrolidine-1-amine-dihydrochloride, comprising the following steps: using tert-butyl hydrazine carboxylate (compound II) as a raw material, first undergoing a cyclization reaction to obtain N-tert-butyloxycarbonyl-pyrrolidine-1-amine (compound III); finally reacting with hydrogen chloride to remove the tert-butyloxycarbonyl group to form a salt to obtain pyrrolidine-1-amine-dihydrochloride (compound I). This method is simple to operate, has mild reaction conditions, and the overall yield can reach 94.4%, making it suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis, specifically relating to a method for preparing pyrrolidine-1-amine-dihydrochloride. Background Technology

[0002] Pyrrolidine-1-amine-dihydrochloride has wide applications in drug synthesis, catalyst preparation and organic synthesis. It is a synthetic intermediate for many important compounds and has broad market prospects.

[0003] Patent EP0850930B1 discloses the following synthetic route:

[0004]

[0005] Reagents and conditions: (a) Inorganic acid, hydrazine hydrogen halide reaction, yield: 61%, where X represents a halogen atom.

[0006] This method reports the reaction of 1,4-butanediol or tetrahydrofuran with hydrazine hydrogen halides in the presence of inorganic acids to generate 1-aminopyrrolidine hydrogen halides. This route involves purification via methanol washing, vacuum concentration, and repeated recrystallization with methanol, resulting in complex steps, numerous byproducts, and low yields; it is unsuitable for industrial production.

[0007] Meanwhile, the method of synthesizing alicyclic hydrazine from alicyclic amines is a common method for synthesizing alicyclic hydrazine, but the stability and toxicity of the intermediate nitrosyl group are problems, making it unsuitable for industrial production. Summary of the Invention

[0008] Purpose of the invention: The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for preparing pyrrolidine-1-amine-dihydrochloride.

[0009] To achieve the above objectives, the technical solution provided by the present invention is as follows:

[0010]

[0011] In the step of preparing compound III from compound II, the base is sodium carbonate, potassium tert-butoxide, or potassium carbonate, wherein the molar ratio of compound II:1,4-dibromobutane:base ranges from 1:1 to 2:2 to 3, the reaction solvent is N,N-dimethylformamide, 1,4-dioxane, or 2-methyltetrahydrofuran, the reaction temperature is 80℃ to 135℃, and the reaction time is 4 to 18 h. In the step of preparing compound I from compound III, the molar ratio of compound III:hydrogen chloride ranges from 1:2 to 8, the reaction solvent is dichloromethane, 1,4-dioxane, ethyl acetate, or 2-methyltetrahydrofuran, the reaction temperature is 5℃ to 35℃, and the post-reaction treatment steps are: cooling the reaction solution to allow crystallization, filtering, and vacuum drying the filter cake to obtain compound I.

[0012] Beneficial effects: This invention uses tert-butyl hydrazine carboxylate (compound II) as the starting material, first undergoing a cyclization reaction to obtain N-tert-butyloxycarbonyl-pyrrolidine-1-amine (compound III); finally, it reacts with hydrogen chloride to de-tert-butyloxycarbonyl to form a salt, yielding pyrrolidine-1-amine-dihydrochloride (compound I). The preparation of compound I involves a total of two steps, with an overall yield of 94.4%. This route enables rapid laboratory preparation and large-scale industrial production of pyrrolidine-1-amine-dihydrochloride, overcoming the drawbacks of current known synthetic processes, such as cumbersome operation and environmental unfriendliness.

[0013] The abbreviations for the reaction reagents mentioned in the instructions are as follows:

[0014] DMF: N,N-dimethylformamide;

[0015] DCM: Dichloromethane. Attached Figure Description

[0016] Figure 1 Here is a purity graph of compound III from Example 4;

[0017] Figure 2 The hydrogen spectrum of compound III in Example 4;

[0018] Figure 3 The hydrogen spectrum of compound I in Example 4;

[0019] Figure 4 This is the carbon spectrum of compound I in Example 4. Detailed Implementation

[0020] The present invention will be further illustrated below with reference to specific embodiments. These embodiments are implemented under the premise of the technical solution of the present invention. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0021] Example 1

[0022] Synthesis of compounds III and I:

[0023]

[0024] Add 650 mL of LDMF and 66.1 g of compound II (0.5 mol, 1 eq) to a 1 L four-necked flask, start stirring, then add 127.2 g of sodium carbonate (1.2 mol, 2.4 eq). Heat in an oil bath, and add 108.0 g of 1,4-dibromobutane (0.5 mol, 1 eq) dropwise at 135 °C. After the addition is complete, maintain the reaction at 135 °C for 4 hours. Cool to 10 °C, filter, and concentrate the filtrate under reduced pressure to obtain a concentrated solution. Add 1000 mL of ethyl acetate and 100 mL of water, stir to dissolve, allow to stand for separation, add 40 g of anhydrous sodium sulfate to the organic phase and dry, filter, concentrate the filtrate under reduced pressure to 200 mL, add 400 mL of petroleum ether dropwise, cool to 5 °C to crystallize, filter, and dry the filter cake under vacuum to obtain 76.6 g of white solid compound II, GC purity 99.9%, yield 82.2%.

[0025] 400 mL of DCM and 74.5 g of compound III (0.4 mol, 1 eq) were added to a four-necked flask and stirred to dissolve. 29.2 g of hydrogen chloride gas (0.8 mol, 2 eq) was then introduced, resulting in exothermic reaction. After cooling, the reaction was continued at 5 °C with gas flow. A large amount of solid precipitated. After gas flow was complete, the mixture was stirred at 5 °C for 1 h. TLC was performed to confirm the complete reaction of the reactants. The mixture was then placed in an ice bath and cooled to 5 °C with stirring to induce crystallization for 1 h. After filtration, the filter cake was dried under vacuum at 45 °C to obtain 57.4 g of white solid compound I, with a purity of 98.6% and a yield of 90.2%.

[0026] Example 2

[0027] Synthesis of compounds III and I:

[0028]

[0029] Add 1000 mL of 1,4-dioxane and 66.1 g of compound II (0.5 mol, 1 eq) to a 2 L four-necked flask, start stirring, then add 168.3 g of potassium tert-butoxide (1.5 mol, 3 eq). Heat in an oil bath, and add 129.6 g of 1,4-dibromobutane (0.6 mol, 1.2 eq) dropwise at 100 °C. After the addition is complete, maintain the reaction at 100 °C for 10 hours. Cool to 10 °C, filter, and concentrate the filtrate under reduced pressure to obtain a concentrated solution. Add 1000 mL of methyl tert-butyl ether and 100 mL of water, stir to dissolve, allow to stand and separate into layers, add 40 g of anhydrous sodium sulfate to the organic phase and dry, filter, concentrate the filtrate under reduced pressure to 200 mL, add 400 mL of petroleum ether dropwise, cool to 5 °C to crystallize, filter, and dry the filter cake under vacuum to obtain 78.9 g of white solid compound III, GC purity 99.5%, yield 84.7%.

[0030] 400 mL of 1,4-dioxane and 74.5 g of compound III (0.4 mol, 1 eq) were added to a four-necked flask and stirred to dissolve. 116.8 g of hydrogen chloride gas (3.2 mol, 8 eq) was then introduced, resulting in exothermic reaction. After cooling, the reaction was continued at an internal temperature of 5°C. A large amount of solid precipitated. After the gas was introduced, the mixture was stirred at 5°C for 1 h. TLC was performed to confirm the complete reaction of the reactants. The mixture was then placed in an ice bath and cooled to 5°C with stirring to induce crystallization for 1 h. After filtration, the filter cake was dried under vacuum at 45°C to obtain 59.5 g of white solid compound I, with a purity of 99.1% and a yield of 93.5%.

[0031] Example 3

[0032] Synthesis of compounds III and I:

[0033]

[0034] Add 650 mL of 2-methyltetrahydrofuran and 66.1 g of compound II (0.5 mol, 1 eq) to a 1 L four-necked flask, start stirring, then add 138.2 g of potassium carbonate (1.0 mol, 2 eq). Heat in an oil bath, and add 215.9 g of 1,4-dibromobutane (1.0 mol, 2 eq) dropwise at 80 °C. After the addition is complete, maintain the reaction at 80 °C for 18 hours. Cool to 10 °C, filter, and concentrate the filtrate under reduced pressure to obtain a concentrated solution. Add 1000 mL of ethyl acetate and 100 mL of water, stir to dissolve, allow to stand for separation, add 40 g of anhydrous sodium sulfate to the organic phase and dry, filter, concentrate the filtrate under reduced pressure to 200 mL, add 400 mL of petroleum ether dropwise, cool to 5 °C to crystallize, filter, and dry the filter cake under vacuum to obtain 80.2 g of white solid compound III, GC purity 99.6%, yield 86.1%.

[0035] 400 mL of 2-methyltetrahydrofuran and 74.5 g of compound III (0.4 mol, 1 eq) were added to a four-necked flask and stirred to dissolve. 87.6 g of hydrogen chloride gas (2.4 mol, 6 eq) was then introduced, resulting in exothermic reaction. After cooling, the reaction was continued at 35 °C with the internal temperature maintained during the gas-gas reaction. A large amount of solid precipitated. After the gas-gas reaction was complete, the mixture was stirred at 35 °C for 1 h. TLC was performed to monitor the reaction, confirming complete reaction of the starting material. The mixture was then placed in an ice bath and cooled to 5 °C with stirring to induce crystallization for 1 h. After filtration, the filter cake was dried under vacuum at 45 °C to obtain 59.9 g of white solid compound I, with a purity of 99.5% and a yield of 94.1%.

[0036] Example 4

[0037] Synthesis of compounds III and I:

[0038]

[0039] Add 650 mL of 2-methyltetrahydrofuran and 66.1 g of compound II (0.5 mol, 1 eq) to a 1 L four-necked flask, start stirring, add 103.7 g of potassium carbonate (0.75 mol, 1.5 eq), heat in an oil bath, and add 161.9 g of 1,4-dibromobutane (0.75 mol, 1.5 eq) dropwise at 80 °C. After the addition is complete, maintain the reaction at 80 °C for 18 hours. Cool to 10 °C, filter, and concentrate the filtrate under reduced pressure to obtain a concentrated solution. Add 1000 mL of ethyl acetate and 100 mL of water, stir to dissolve, allow to stand and separate into layers, add 40 g of anhydrous sodium sulfate to the organic phase and dry, filter, concentrate the filtrate under reduced pressure to 200 mL, add 600 mL of petroleum ether dropwise, cool to 5 °C to crystallize, filter, and dry the filter cake under vacuum to obtain 80.9 g of white solid compound III. The purity of compound III is as follows: Figure 1 As shown, the elution time is 8.799 minutes, the GC purity is 99.9%, and the proton NMR spectrum of compound III is as follows. Figure 2 As shown, the yield was 86.9%. 1 HNMR (400MHz, CDCl3, δppm): 5.36 (s, 1H), 2.91~2.81 (m, 4H), 1.86~1.79 (m, 4H), 1.46 (s, 9H).

[0040] 400 mL of ethyl acetate and 74.5 g of compound III (0.4 mol, 1 eq) were added to a four-necked flask and stirred to dissolve. 58.4 g of hydrogen chloride gas (1.6 mol, 4 eq) was then introduced, resulting in exothermic reaction. After cooling, the reaction was continued at 20 °C with gas flow. A large amount of solid precipitated. After gas flow was complete, the mixture was stirred at 20 °C for 1 h. TLC was performed to monitor the reaction, indicating complete reaction of the starting material. The mixture was then placed in an ice bath and cooled to 5 °C with stirring to induce crystallization for 1 h. After filtration, the filter cake was dried under vacuum at 45 °C to obtain 60.1 g of a white solid, compound I. The 1H NMR spectrum of compound I is shown below. Figure 3 The carbon spectrum of compound I is as follows Figure 4 As shown, the GC purity is 99.5%, the chloride ion content is 44.5% (titration), and the yield is 94.4%. 1 HNMR (400MHz, DMSO-d6, δppm): 3.23~3.11(m, 4H), 1.92~1.88(m, 4H), 13 CNMR (400MHz, DMSO-d6, δppm): 56.49, 22.16.

[0041] The above specific embodiments further illustrate the purpose, technical solution and beneficial effects of this application. It should be understood that the above are only specific embodiments of this application and are not intended to limit the scope of protection of this application. Any modifications, equivalent substitutions, improvements, etc., made on the basis of the technical solution of this application should be included within the scope of protection of this application.

Claims

1. A method for preparing pyrrolidine-1-amine-dihydrochloride, characterized in that, include: In the step of preparing compound III from compound II, the base is sodium carbonate, potassium tert-butoxide, or potassium carbonate; wherein the molar ratio of compound II: 1,4-dibromobutane: base is in the range of 1:1 to 2:2 to 3; the reaction solvent is N,N-dimethylformamide, 1,4-dioxane, or 2-methyltetrahydrofuran; the reaction temperature is 80℃ to 135℃; and the reaction time is 4 to 18 h. In the preparation of compound I from compound III, the molar ratio of compound III to hydrogen chloride ranges from 1:2 to 8. In the preparation of compound I from compound III, the reaction solvent is dichloromethane, 1,4-dioxane, ethyl acetate or 2-methyltetrahydrofuran; In the preparation of compound I from compound III, the reaction temperature was 5℃~35℃; The reaction solution was cooled to allow crystals to precipitate, filtered, and the filter cake was dried under vacuum to obtain compound I.

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