A method for preparing cyclopropylamine starting from 1-aminocyclopropanecarboxylic acid
By using ketone compound catalysts and atmospheric distillation technology, the problems of atomic economy and high energy consumption in cypropylamine synthesis are solved, and the efficient and environmentally friendly preparation of cypropylamine is achieved.
Patent Information
- Application Number
- CN202310939263.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-07-28
- Publication Date
- 2025-07-22
- Estimated Expiration
- 2043-07-28
AI Technical Summary
The existing cypropylamine synthesis route has problems such as poor atomic economy, many cyclic by-products, high energy consumption and a lot of wastewater. Especially in traditional strong acid environments, the decarboxylation reaction is prone to ring-opening side reactions.
1-aminocyclopropane carboxylic acid is used as raw material, and the carboxylic groups are removed under normal pressure using a ketone compound catalyst. Combined with an atmospheric distillation system, the formation of cyclopropylamine is promoted by converting amino groups into electron-pulling groups, and strong acids and noble metal catalysts are avoided. Neutralization and atmospheric distillation are used.
The high-atomic economic preparation of cypropylamine is achieved, and only one molecule of carbon dioxide by-product is generated, which avoids the use of strong acids and precious metal catalysts, reduces energy consumption and cyclic by-products, and improves the preparation efficiency.
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Abstract
Description
Technical Field
[0001] The present invention relates to a method for preparing cyclopropylamine starting from 1-aminocyclopropanecarboxylic acid, belonging to the technical field of organic chemistry. Background Art
[0002] Cyclopropylamine is an important intermediate for pharmaceuticals and pesticides. It was first synthesized by Schlatter in 1941 during the synthesis of cyclopropene. After the quinolone antibiotic ciprofloxacin was launched in 1986, cyclopropylamine began to play an important role as a pharmaceutical intermediate. For example, the third-generation quinolone antibiotics ciprofloxacin, sparfloxacin, balofloxacin, and temafloxacin, which have high antibacterial activity and a broad antibacterial spectrum, all use cyclopropylamine as an important intermediate. Currently, the synthesis of cyclopropylamine mainly includes methods such as γ-butyrolactone, α-acetyl-γ-butyrolactone, epoxybutene method, 1,3-propanediol method, 1-chloro-3-bromopropane method, etc. At present, both domestic and foreign industries mostly use γ-butyrolactone as the starting material, and the industrial route for preparing cyclopropylamine through ring opening, esterification, cyclization, ammonolysis, and Hofmann degradation is adopted. Although this route has been industrialized, there are the following bottleneck problems: (1) A large amount of sulfur dioxide is generated during ring opening, resulting in poor atom economy; (2) There are many by-products in the cyclization reaction, low efficiency, and high energy consumption; (3) Large amounts of solvents and catalysts are used during the ammonolysis process; (4) A large amount of saline wastewater is generated during the Holfmann degradation reaction. In summary, the development of a new green method for preparing cyclopropylamine has always been a hot topic in the chemical field. Summary of the Invention
[0003] Aiming at the problems existing in the existing preparation technology for cyclopropylamine starting from γ-butyrolactone, such as a long route, poor atom economy in the ring-opening reaction, and many cyclization by-products due to multiple steps of reactions including ring opening, esterification, cyclization, ammonolysis, and Hofmann degradation, the present invention provides a method for preparing cyclopropylamine starting from 1-aminocyclopropanecarboxylic acid.
[0004] The technical solution of the present invention:
[0005] One of the objectives of the present invention is to provide a method for preparing cyclopropylamine. This method uses 1-aminocyclopropanecarboxylic acid as a raw material, and under heating conditions, a catalytic decarboxylation reaction is carried out to obtain cyclopropylamine; specifically, after mixing 1-aminocyclopropanecarboxylic acid with a solvent, a catalyst is added, the temperature is raised to remove the carboxyl group, and the cyclopropylamine fraction is collected synchronously, and cyclopropylamine is obtained after neutralization.
[0006] Further defined, this method includes the following steps:
[0007] S1, dissolve 1-aminocyclopropanecarboxylic acid in solvent A, heat and stir to obtain a 1-aminocyclopropanecarboxylic acid solution;
[0008] S2. Add a catalyst to the 1-aminocyclopropanecarboxylic acid solution, heat for reaction, and condense and reflux the solvent back into the reaction solution. Use a mixed solution of solvent B and an acid to receive the product to obtain a solution containing cyclopropylamine. The gas generated by the reaction is introduced into a receiving flask.
[0009] S3. Add a base to the solution containing cyclopropylamine to adjust the pH value, and finally collect cyclopropylamine by distillation.
[0010] Further specified, in S2, the reaction temperature is 80 - 160 °C, and the condensation temperature is 5 - 30 °C.
[0011] Further specified, solvent A is one or a mixture of several of N,N-dimethylformamide, N,N-dimethylacetamide, xylene, ethylene glycol monomethyl ether, cyclohexanol, dimethyl sulfoxide, N-methylpyrrolidone, and water.
[0012] More specifically specified, the mass-volume ratio of 1-aminocyclopropanecarboxylic acid to solvent A is 1 g : (3 - 10) mL.
[0013] Further specified, in S1, the heating and stirring temperature is 20 - 30 °C, and the rotation speed is 50 - 200 rpm.
[0014] Further specified, the catalyst is one or a mixture of several of 4-methyl-3-penten-2-one, 3-methyl-2-cyclohexen-1-one, cyclohexenone, methoxyacetophenone, tetrahydronaphthone, and 2,3-dimethyl-5-isopropenyl-cyclohexanone-1.
[0015] More specifically specified, the mass ratio of 1-aminocyclopropanecarboxylic acid to the catalyst is 1 : (0.01 - 0.15).
[0016] Further specified, solvent B is one or a mixture of several of N,N-dimethylformamide, 1,4-dioxane, acetonitrile, ethanol, ethyl acetate, and water.
[0017] More specifically specified, the mass-volume ratio of 1-aminocyclopropanecarboxylic acid to solvent B is 1 g : (5 - 10) mL.
[0018] Further specified, in S2, the acid is one or a mixture of several of formic acid, hydrochloric acid, glacial acetic acid, and citric acid.
[0019] More specifically specified, the mass ratio of 1-aminocyclopropanecarboxylic acid to the acid is 1 : (0.5 - 1.2).
[0020] Further specified, in S3, the base is a solution of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, or potassium carbonate, and the pH is adjusted to 9 - 10 using the base.
[0021] Further defined, the distillation treatment method is atmospheric distillation or vacuum distillation, and the boiling point for collecting the cyclopropylamine fraction is 49-50 °C.
[0022] Further defined, the purity of 1-aminocyclopropanecarboxylic acid is above 95%.
[0023] The present invention uses 1-aminocyclopropanecarboxylic acid as a raw material. By utilizing its α-amino acid structure as a non-protein amino acid, cyclopropylamine can be prepared after removing the carboxyl group, and only one molecule of carbon dioxide by-product is generated, which has high atom economy and environmental friendliness. Compared with the prior art, it has the following beneficial effects:
[0024] (1) Aiming at the problems that 1-aminocyclopropanecarboxylic acid has a relatively high active strain ring, is prone to decarboxylation and ring-opening side reactions in an environment such as traditional strong acids, and the electron-donating amino group connected to the α-C makes decarboxylation difficult, for the first time, a ketone compound catalyst is used to convert the amino group into an electron-withdrawing group by combination, thereby improving the leaving activity of the carboxyl group, and promoting the formation of cyclopropylamine through an atmospheric distillation system. In the whole process, no strong acid, precious metal or heavy metal catalyst is required, nor expensive cofactors under the catalysis of biological enzymes, and a new route for cheaply catalyzing the decarboxylation of 1-aminocyclopropanecarboxylic acid to prepare cyclopropylamine is established.
[0025] (2) Aiming at the problem that the cyclopropyl structure has poor stability during the decarboxylation process of 1-aminocyclopropanecarboxylic acid, an atmospheric distillation system is selected to collect the low-boiling cyclopropylamine during the reaction process, which promotes the forward reaction and inhibits the decomposition of the cyclopropyl intermediate after decarboxylation. For the first time, cyclopropylamine is prepared by a decarboxylation method. Description of the Drawings
[0026] Figure 1 It is a mass spectrometry result diagram of the cyclopropylamine obtained in Example 1 after PITC derivatization;
[0027] Figure 2 It is the gas phase determination result of the cyclopropylamine obtained in Example 1;
[0028] Figure 3 It is the 1 1H NMR determination result of the cyclopropylamine obtained in Example 1;
[0029] Figure 4 It is the 13 13C NMR determination result of the cyclopropylamine obtained in Example 1. Detailed Embodiments
[0030] To make the above objects, features and advantages of the present invention more obvious and understandable, the following detailed description of the specific embodiments of the present invention is given in conjunction with the embodiments of the specification.
[0031] In the following description, numerous specific details are set forth to provide a thorough understanding of the present invention. However, the present invention may be practiced in other ways than those specifically described herein. Those skilled in the art can make similar extensions without departing from the spirit of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed below.
[0032] Secondly, as used herein, an "embodiment" or "embodiments" refer to specific features, structures, or characteristics that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it an isolated or alternative embodiment mutually exclusive of other embodiments.
[0033] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods. The materials, reagents, methods, and instruments used, unless otherwise specified, are all conventional materials, reagents, methods, and instruments in the art, and those skilled in the art can obtain them through commercial channels.
[0034] The mass spectrometry detection method of cyclopropylamine in the following examples:
[0035] Solution A (PITC acetonitrile solution, 0.1 M): Take 6 mL of phenyl isothiocyanate and add 44 mL of acetonitrile, and mix well.
[0036] Solution B (triethylamine acetonitrile solution, 1 M): Take 14 mL of triethylamine and add 86 mL of acetonitrile, and mix well.
[0037] Prepare a 0.01 mmol / mL cyclopropylamine solution (500 μL), add 250 μL of Solution A and 250 μL of Solution B, mix well, ultrasonicate for 10 min, let stand at room temperature for 1 h, take the solution, and filter through a 0.22 μm filter membrane to measure the liquid mass spectrometry.
[0038]
[0039] Example 1
[0040] The process for preparing cyclopropylamine in this example is as follows:
[0041] Step 1: In a 100 mL eggplant-shaped flask, under the condition of a stirring speed of 100 rpm at room temperature, add 1-aminocyclopropanecarboxylic acid (7.7 g, 76.3 mmol), and add water (60 mL);
[0042] Step 2: Add cyclohexenone (1.0 g, 10.4 mmol), heat to 100 °C, the water is condensed and refluxed into the reaction solution, and the gas generated by the reaction is introduced into a receiving flask, and a mixed solution of 1,4-dioxane (60 mL) and formic acid (3.5 g, 76.3 mmol) is used to receive cyclopropylamine;
[0043] Step 3: Add 10 wt% aqueous sodium hydroxide solution to adjust the pH of the cyclopropylamine solution to 9 - 10. Distill under atmospheric pressure to collect pure cyclopropylamine at 49 - 50 °C. The mass of the distillate is 518 mg. Perform gas chromatography analysis on the distillate. The results are as Figure 2 shown. The gas phase purity of cyclopropylamine in the distillate is 98.5%, and the yield of cyclopropylamine is 11.9%.
[0044] Perform mass spectrometry detection on the obtained cyclopropylamine. The results are as shown in Figure 1, M+H + = 193.0687.
[0045] Perform NMR characterization on the obtained cyclopropylamine. The results are as Figure 3 and Figure 4 shown. The results indicate that the product prepared in this example is cyclopropylamine.
[0046] Example 2
[0047] The process for preparing cyclopropylamine in this example is as follows:
[0048] Step 1: In a 100 mL eggplant-shaped flask, add 1-aminocyclopropanecarboxylic acid (7.7 g, 76.3 mmol) under stirring at room temperature with a rotation speed of 100 rpm, and add xylene (60 mL);
[0049] Step 2: Add 4-methyl-3-penten-2-one (981 mg, 10 mmol), heat up to 150 °C, and the xylene is condensed and refluxed into the reaction solution. The gas generated by the reaction is introduced into a receiving flask, and a mixed solution of 1,4-dioxane (60 mL) and formic acid (3.5 g, 76.3 mmol) is used to receive cyclopropylamine;
[0050] Step 3: Add 10 wt% aqueous sodium hydroxide solution to adjust the pH of the cyclopropylamine solution to 9 - 10. Distill under atmospheric pressure to collect pure cyclopropylamine at 49 - 50 °C. The mass of the distillate is 370 mg. The purity of cyclopropylamine is 98.1%, and the yield is 8.5%.
[0051] Example 3
[0052] The process for preparing cyclopropylamine in this example is as follows:
[0053] Step 1: In a 100 mL eggplant-shaped flask, add 1-aminocyclopropanecarboxylic acid (7.7 g, 76.3 mmol) under stirring at room temperature with a rotation speed of 150 rpm, and add xylene (60 mL);
[0054] Step 2: Add 2,3-dimethyl-5-isopropenyl-cyclohexanone-1 (1.16 g, 7.6 mmol), heat up to 150 °C, the xylene is condensed and refluxed back to the reaction solution, the gas generated by the reaction is passed into the receiving flask, and the cyclopropylamine is received with a mixed solution of 1,4-dioxane (60 mL) and formic acid (3.5 g, 76.3 mmol);
[0055] Step 3: Add 10 wt% aqueous sodium hydroxide solution to adjust the pH of the cyclopropylamine solution to 9 - 10, and distill under atmospheric pressure to collect the pure cyclopropylamine at 49 - 50 °C. The mass of the fraction is 522 mg, the purity of cyclopropylamine is 98.6%, and the yield is 12.0%.
[0056] Example 4
[0057] The process for preparing cyclopropylamine in this example is as follows:
[0058] Step 1: In a 100 mL eggplant-shaped flask, under the condition of stirring at room temperature with a rotation speed of 150 rpm, add 1-aminocyclopropanecarboxylic acid (7.7 g, 76.3 mmol), and add xylene (60 mL);
[0059] Step 2: Add tetralone (906 mg, 6.2 mmol), heat up to 150 °C, the xylene is condensed and refluxed back to the reaction solution, the gas generated by the reaction is passed into the receiving flask, and the cyclopropylamine is received with a mixed solution of 1,4-dioxane (60 mL) and formic acid (3.5 g, 76.3 mmol);
[0060] Step 3: Add 10 wt% aqueous sodium hydroxide solution to adjust the pH of the cyclopropylamine solution to 9 - 10, and distill under atmospheric pressure to collect the pure cyclopropylamine at 49 - 50 °C. The mass of the fraction is 470 mg, the purity of cyclopropylamine is 99.0%, and the yield is 10.8%.
[0061] Example 5
[0062] The process for preparing cyclopropylamine in this example is as follows:
[0063] Step 1: In a 100 mL eggplant-shaped flask, under the condition of stirring at room temperature with a rotation speed of 150 rpm, add 1-aminocyclopropanecarboxylic acid (7.7 g, 76.3 mmol), and add ethylene glycol monomethyl ether (60 mL);
[0064] Step 2: Add cyclohexenone (0.6 g, 6.2 mmol), heat up to 125 °C, the ethylene glycol monomethyl ether is condensed and refluxed back to the reaction solution, the gas generated by the reaction is passed into the receiving flask, and the cyclopropylamine is received with a mixed solution of water (50 mL) and formic acid (3.5 g, 76.3 mmol);
[0065] Step 3: Add 10 wt% aqueous sodium carbonate solution to adjust the pH of the cyclopropylamine solution to 9 - 10, and distill under atmospheric pressure to collect pure cyclopropylamine at 49 - 50 °C. The mass of the fraction is 335 mg, the purity of cyclopropylamine is 98.0%, and the yield is 7.7%.
[0066] Example 6
[0067] The process for preparing cyclopropylamine in this example is as follows:
[0068] Step 1: In a 100 mL eggplant-shaped flask, add 1-aminocyclopropanecarboxylic acid (7.7 g, 76.3 mmol) and cyclohexanol (60 mL) under stirring at room temperature with a speed of 150 rpm.
[0069] Step 2: Add methoxyacetophenone (570 mg, 3.8 mmol), heat up to 150 °C, and cyclohexanol is condensed and refluxed back into the reaction solution. The gas generated by the reaction is introduced into a receiving flask, and cyclopropylamine is received with a mixed solution of acetonitrile (50 mL) and formic acid (3.5 g, 76.3 mmol).
[0070] Step 3: Add 10 wt% aqueous sodium carbonate solution to adjust the pH of the cyclopropylamine solution to 9 - 10, and distill under atmospheric pressure to collect pure cyclopropylamine at 49 - 50 °C. The mass of the fraction is 296 mg, the purity of cyclopropylamine is 97.9%, and the yield is 6.8%.
[0071] Example 7
[0072] The process for preparing cyclopropylamine in this example is as follows:
[0073] Step 1: In a 100 mL eggplant-shaped flask, add 1-aminocyclopropanecarboxylic acid (7.7 g, 76.3 mmol) and dimethyl sulfoxide (75 mL) under stirring at room temperature with a speed of 150 rpm.
[0074] Step 2: Add 3-methyl-2-cyclohexen-1-one (837 mg, 7.6 mmol), heat up to 160 °C, and the solvent is condensed and refluxed back into the reaction solution. The gas generated by the reaction is introduced into a receiving flask, and cyclopropylamine is received with a mixed solution of acetonitrile (50 mL) and formic acid (3.5 g, 76.3 mmol).
[0075] Step 3: Add 10 wt% aqueous sodium carbonate solution to adjust the pH of the cyclopropylamine solution to 9 - 10, and distill under atmospheric pressure to collect pure cyclopropylamine at 49 - 50 °C. The mass of the fraction is 135 mg, the purity of cyclopropylamine is 98.0%, and the yield is 3.1%.
[0076] Example 8
[0077] The process for preparing cyclopropylamine in this example is as follows:
[0078] Step 1: In a 100 mL eggplant-shaped flask, under the condition of stirring at room temperature with a rotation speed of 150 rpm, add 1-aminocyclopropanecarboxylic acid (7.7 g, 76.3 mmol), and add N-methylpyrrolidone (60 mL).
[0079] Step 2: Add methoxyacetophenone (570 mg, 3.8 mmol), heat up to 160 °C, the solvent is condensed and refluxed back into the reaction solution, and the gas generated by the reaction is passed into a receiving flask, and cyclopropylamine is received with a mixed solution of acetonitrile (50 mL) and hydrochloric acid (4.1 mL, 50 mmol).
[0080] Step 3: Add 10 wt% aqueous sodium carbonate solution to adjust the pH of the cyclopropylamine solution to 9 - 10, and distill under atmospheric pressure to collect pure cyclopropylamine at 49 - 50 °C. The mass of the distillate is 427 mg, the purity of cyclopropylamine is 98.1%, and the yield is 9.8%.
[0081] Example 9
[0082] The process for preparing cyclopropylamine in this example is as follows:
[0083] Step 1: In a 2000 mL eggplant-shaped flask, under the condition of stirring at room temperature with a rotation speed of 150 rpm, add 1-aminocyclopropanecarboxylic acid (128.3 g, 1.27 mol), and add ethylene glycol monomethyl ether (1000 mL).
[0084] Step 2: Add cyclohexenone (10 g, 104 mmol), heat up to 125 °C, ethylene glycol monomethyl ether is condensed and refluxed back into the reaction solution, and the gas generated by the reaction is passed into a receiving flask, and cyclopropylamine is received with a mixed solution of water (250 mL) and formic acid (50 g, 108 mmol).
[0085] Step 3: Add 10 wt% aqueous NaOH solution to adjust the pH of the cyclopropylamine solution to 9 - 10, and distill under atmospheric pressure to collect pure cyclopropylamine at 49 - 50 °C. The mass of the distillate is 8.98 g, the purity of cyclopropylamine is 98.7%, and the yield is 12.4%.
[0086] Although the present invention has been disclosed above with preferred embodiments, it is not intended to limit the present invention. Anyone familiar with this technology can make various modifications and decorations without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention should be defined by the claims.
Claims
1. A method for preparing cyclopropylamine, characterized in that, After mixing 1-aminocyclopropanecarboxylic acid with a solvent, a catalyst is added, and the temperature is raised to remove the carboxyl group. The cyclopropylamine fraction is collected synchronously, and cyclopropylamine is obtained after neutralization. The catalyst is one or a mixture of 4-methyl-3-penten-2-one, 3-methyl-2-cyclohexen-1-one, cyclohexenone, methoxyacetophenone, tetrahydronaphthone, 2,3-dimethyl-5-isopropenyl-cyclohexanone-1.
2. The preparation method of cyclopropylamine according to claim 1, wherein This method includes: S1. Dissolve 1-aminocyclopropanecarboxylic acid in solvent A, heat and stir to obtain a 1-aminocyclopropanecarboxylic acid solution. S2. Add a catalyst to the 1-aminocyclopropanecarboxylic acid solution, heat and react. The solvent is condensed and refluxed to the reaction solution. A mixed solution of solvent B and an acid is used to receive the product to obtain a solution containing cyclopropylamine. The gas generated by the reaction is introduced into a receiving bottle. S3. Add a base to the solution containing cyclopropylamine to adjust the pH value, and finally collect cyclopropylamine by distillation.
3. The preparation method of cyclopropylamine according to claim 2, wherein In S2, the reaction temperature is 80-160 °C, and the condensation temperature is 5-30 °C.
4. The preparation method of cyclopropylamine according to claim 2, characterized in that, Solvent A is one or a mixture of N,N-dimethylformamide, N,N-dimethylacetamide, xylene, ethylene glycol monomethyl ether, cyclohexanol, dimethyl sulfoxide, N-methylpyrrolidone, water; the mass-volume ratio of 1-aminocyclopropanecarboxylic acid to solvent A is 1 g:(3-10) mL.
5. The preparation method of cyclopropylamine according to claim 2 or 4, characterized in that, In S1, the heating and stirring temperature is 20-30 °C, and the rotation speed is 50-200 rpm.
6. The preparation method of cyclopropylamine according to claim 1 or 2, characterized in that, The mass ratio of 1-aminocyclopropanecarboxylic acid to the catalyst is 1:(0.01-0.15).
7. The preparation method of cyclopropylamine according to claim 2, characterized in that, Solvent B is one or a mixture of N,N-dimethylformamide, 1,4-dioxane, acetonitrile, ethanol, ethyl acetate, water; the mass-volume ratio of 1-aminocyclopropanecarboxylic acid to solvent B is 1 g:(5-10) mL.
8. The preparation method of cyclopropylamine according to claim 2, characterized in that, In S2, the acid is one or a mixture of formic acid, hydrochloric acid, glacial acetic acid, citric acid; the mass ratio of 1-aminocyclopropanecarboxylic acid to the acid is 1:(0.5-1.2).
9. The preparation method of cyclopropylamine according to claim 2, wherein, In S3, the base is a solution of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate or potassium carbonate. The pH is adjusted to 9-10 with the base; the distillation treatment method is atmospheric distillation or vacuum distillation, and the boiling point for collecting the cyclopropylamine fraction is 49-50 °C.
10. The method for preparing cyclopropylamine according to claim 1 or 2, characterized in that, The purity of 1-aminocyclopropanecarboxylic acid is above 95%.
Citation Information
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