Preparation method of homopiperony lamine
By avoiding the catalytic hydrogenation step in the preparation of pepper ethylamine, a mixed reaction method performed at 70-150°C is adopted, and a safer and more efficient production process is achieved.
Patent Information
- Application Number
- CN202510196923.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-21
- Publication Date
- 2025-05-27
AI Technical Summary
The existing preparation methods for pepper ethylamine require a large amount of metal catalyst and hydrogen pressure, resulting in a high risk of industrial production.
A new preparation method is adopted to avoid the catalytic hydrogenation step by mixing the organic solvent, succinimide, alkali, catalyst and raw materials under 70-150°C.
This method greatly improves the industrial production safety of pepper ethylamine, which is easy to operate, energy-saving, has high product yield and high purity.
Smart Images
Figure CN120040410A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of compound synthesis, and in particular to a method for preparing piperonyl ethylamine. Background Art
[0002] Piperine is a key intermediate of berberine and dopamine, and its structure is as follows:
[0003] In the prior art, the preparation method thereof is generally to use piperonyl acetonitrile or piperonyl ethylidene imine through catalytic hydrogenation. This method uses a large amount of metal catalyst and hydrogen pressurization, and the industrial production risk is very high.
[0004] In view of this, the present invention is proposed. Summary of the invention
[0005] The object of the present invention is to provide a method for preparing piperidine. The embodiment of the present invention provides a new method for preparing piperidine, which does not require catalytic hydrogenation, greatly improves the industrial production safety of piperidine, and is more suitable for industrial production of piperidine.
[0006] The present invention is achieved in that:
[0007] In a first aspect, the present invention provides a method for preparing piperidine, comprising: synthesizing according to the following synthesis path:
[0008]
[0009] Here, R represents a halogen.
[0010] In an optional embodiment, the operation of step a includes: mixing an organic solvent, succinimide, a base, a catalyst and raw material 1 at 70 to 150° C. for reaction;
[0011] Preferably, the reaction temperature is 75-85°C;
[0012] More preferably, the reaction time is 8-12 hours, further preferably 10-11 hours.
[0013] In an optional embodiment, the organic solvent is selected from one of THF, DMF and DMSO, preferably DMF;
[0014] Preferably, the base is selected from a metal inorganic base, preferably a carbonate, more preferably potassium carbonate;
[0015] Preferably, the catalyst is selected from iodides; preferably potassium iodide;
[0016] Preferably, R is selected from any one of Cl, Br and I. Preferably, the raw material 1 is 5-(2-chloroethyl)-1,3-benzodioxetine.
[0017] In an optional embodiment, the molar ratio of raw material 1, succinimide, base and catalyst is 1:(2-3):(3-4):(0.1-0.2).
[0018] In an optional embodiment, the operation of step b includes: reacting raw material 2 with ammonia at 15-30° C.;
[0019] Preferably, the reaction temperature is 20-25°C;
[0020] Preferably, the reaction time is 1-4 hours, preferably 2-3 hours.
[0021] In an alternative embodiment, ammonia is added in the form of a solution;
[0022] Preferably, it is an alcohol solution of ammonia, more preferably ammonia methanol; most preferably, the concentration of ammonia methanol is 2-7M, preferably 4M.
[0023] In an optional embodiment, the molar ratio of raw material 2 to ammonia is 1:(9-10).
[0024] In an optional embodiment, after the reaction in step b is completed, the reaction system is concentrated.
[0025] In an alternative embodiment, the concentration temperature is 40-45°C.
[0026] In an optional embodiment, before step b, the reaction system of step a is post-treated;
[0027] Preferably, the post-treatment comprises: extracting and concentrating by water washing to obtain a crude product;
[0028] Preferably, the extraction solvent used for extraction is selected from one of ethyl acetate, methyl tert-ether and dichloromethane, preferably ethyl acetate.
[0029] The present invention has the following beneficial effects: the embodiment of the present invention provides a new method for preparing piperidine, which is simple to operate, energy-saving and convenient in the entire production process, and the obtained product has high yield and high purity. Catalytic hydrogenation will not be performed in the entire preparation process, which can improve production safety. BRIEF DESCRIPTION OF THE DRAWINGS
[0030] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments are briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without creative work.
[0031] Figure 1 The liquid phase spectrum of the reaction system of step a provided in Example 1 of the present invention;
[0032] Figure 2 The liquid phase spectrum of the reaction system of step a provided in Example 2 of the present invention;
[0033] Figure 3 The liquid phase spectrum of the reaction system of step a provided in Example 3 of the present invention;
[0034] Figure 4 The liquid phase spectrum of the reaction system of step a provided in Example 4 of the present invention;
[0035] Figure 5 The liquid phase spectrum of the reaction system of step a provided in Example 5 of the present invention;
[0036] Figure 6 The liquid phase spectrum of piperidine provided in Example 1 of the present invention;
[0037] Figure 7 The liquid phase spectrum of piperidine provided by Example 2 of the present invention;
[0038] Figure 8 The liquid phase spectrum of piperidine provided by Example 3 of the present invention;
[0039] Fig. 9 The liquid phase spectrum of piperidine provided by Example 4 of the present invention;
[0040] Fig.10 The liquid phase spectrum of piperidine provided in Example 5 of the present invention. DETAILED DESCRIPTION
[0041] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.
[0042] In a first aspect, the present invention provides a method for preparing piperidine, comprising: synthesizing according to the following synthesis path:
[0043]
[0044] , wherein R represents a halogen, for example, R is any one of Cl, Br and I, for example, raw material 1 is 5-(2-chloroethyl)-1,3-benzodioxetine.
[0045] Specifically, the operation of step a is as follows: an organic solvent, succinimide, a base, a catalyst and raw material 1 are mixed for reaction; wherein the reaction temperature is 70 to 150° C., for example, 70° C., 80° C., 90° C., 100° C., 110° C., 120° C., 130° C., 140° C. and 150° C., and preferably 80° C. The reaction time is 8 to 12 hours, for example, 8 hours, 9 hours, 10 hours, 11 hours and 12 hours, and preferably 10 to 11 hours.
[0046] The organic solvent is selected from one of THF, DMF and DMSO, preferably DMF. The base is selected from a metal inorganic base, preferably a carbonate, such as but not limited to potassium carbonate. The catalyst is selected from an iodide, such as but not limited to potassium iodide.
[0047] The molar ratio of the raw material 1, succinimide, base and catalyst is 1:(2-3):(3-4):(0.1-0.2). Specifically, the molar ratio of 5-(2-chloroethyl)-1,3-benzodioxetane to succinimide is 1:2-3. For example, it is any value between 1:2-3, such as 1:2.2, 1:2.5, 1:2.8 and 1:3.
[0048] Adopting the above conditions is conducive to the reaction and improves the yield and purity of the product.
[0049] After the reaction is completed, the reaction system is post-treated, and the post-treatment includes: washing, extracting and concentrating to obtain a crude product; wherein the extraction solvent used for the extraction is selected from one of ethyl acetate, tert-methyl ether and dichloromethane, preferably ethyl acetate.
[0050] Specifically, after the reaction is completed, the reaction system is naturally cooled to 20° C., and the reaction system is slowly added dropwise to a mixed solvent of water and ethyl acetate. After extraction and drying, the mixture is concentrated at 45° C. to obtain an oily crude product.
[0051] Then, the raw material 2 is mixed with ammonia for reaction, wherein the ammonia is added in the form of a solution; that is, an alcohol solution of ammonia, such as ammonia methanol; the concentration of ammonia methanol can be 2-7M, such as 2M, 3M, 4M, 5M and any value between 2M-7M; preferably 4M.
[0052] Specifically, the operation steps of step b include: mixing the above crude product with ammonia solution at 15-30° C. for 1-4 hours; specifically, the temperature is any value between 15-30° C., such as 15° C., 18° C., 20° C., 22° C., 25° C., 28° C. and 30° C., for example, preferably 20-25° C. The reaction time is any value between 1-4 hours, such as 1 hour, 2 hours, 3 hours and 4 hours, for example, preferably 2-3 hours.
[0053] The molar ratio of the raw material 2 to ammonia is 1:(9-10), for example, 1:9, 1:9.5, 1:10, or any other value between 1:9.0 and 10.0.
[0054] After the above reaction is completed, the reaction system is concentrated at a temperature of 40-45°C.
[0055] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.
[0056] Example 1
[0057] The present embodiment provides a method for preparing piperidine, comprising:
[0058] Clean the reactor, replace with nitrogen, add DMF (100ml), and start stirring. Then, add succinimide (10.73g), potassium carbonate (22.46g), potassium iodide (1.8g) and 5-(2-chloroethyl)-1,3-benzodioxetane (10g) in sequence at room temperature, and then start heating to 80℃ for reaction. After keeping warm for 11h, take samples for analysis. LCMS detection shows that 5-(2-chloroethyl)-1,3-benzodioxetane is less than 0.5%. The spectrum of its liquid phase is shown in Figure 1 .
[0059] Cool naturally to 20°C, and slowly add the reaction system to a mixed solvent of water and ethyl acetate. After extraction, dry to obtain an oily crude product. Dissolve the oil in 100 ml of ammonia methanol, stir at 25°C for 1 hour, and then concentrate to obtain 7.28 g of colorless liquid, with a content of 99.2% and a molar yield of 80.6%. The spectrum of its liquid phase can be found in Figure 6 .
[0060] Example 2
[0061] The present embodiment provides a method for preparing piperidine, comprising:
[0062] Clean the reactor, replace with nitrogen, add DMF (100ml), and start stirring. Then, add succinimide (16.09g), potassium carbonate (29.9g), potassium iodide (1.35g) and 5-(2-chloroethyl)-1,3-benzodioxetane (10g) in sequence at room temperature, and then start heating to 80℃ for reaction. After keeping warm for 11h, take samples for analysis. LCMS detection shows that 5-(2-chloroethyl)-1,3-benzodioxetane is less than 0.5%. The spectrum of its liquid phase is shown in Figure 2 .
[0063] Cool naturally to 20°C, and slowly add the reaction system to a mixed solvent of water and ethyl acetate. After extraction, dry to obtain an oily crude product. The oil was dissolved in 100 ml of ammonia methanol, stirred at 25°C for 1 hour, and concentrated to obtain 7.29 g of colorless liquid, with a content of 94.6% and a molar yield of 79.3%. The spectrum of its liquid phase can be found in Figure 7 .
[0064] Example 3
[0065] The present embodiment provides a method for preparing piperidine, comprising:
[0066] Clean the reactor, replace with nitrogen, add DMF (100ml), and start stirring. Then, add succinimide (8.65g), potassium carbonate (18.08g), potassium iodide (1.09g) and 5-(2-bromoethyl)-1,3-benzodioxetane (10g) in sequence at room temperature, and then start heating to 80℃ for reaction. After keeping warm for 11h, take samples for analysis. LCMS detection shows that 5-(2-chloroethyl)-1,3-benzodioxetane is less than 0.5%. The spectrum of its liquid phase is shown in Figure 3 .
[0067] Cool naturally to 20°C, and slowly add the reaction system to a mixed solvent of water and ethyl acetate. After extraction, dry to obtain an oily crude product. The oil was dissolved in 100 ml of ammonia methanol, stirred at 25°C for 1 hour, and concentrated to obtain 6.01 g of colorless liquid, with a content of 99.1% and a molar yield of 82.5%. The spectrum of its liquid phase can be found in Figure 8 .
[0068] Example 4
[0069] The present embodiment provides a method for preparing piperidine, comprising:
[0070] Clean the reactor, replace with nitrogen, add DMF (100ml), and start stirring. Then, add succinimide (12.98g), potassium carbonate (24.11g), potassium iodide (1.45g) and 5-(2-bromoethyl)-1,3-benzodioxetane (10g) in sequence at room temperature, and then start heating to 80℃ for reaction. After keeping warm for 11h, take samples for analysis. LCMS detection shows that 5-(2-chloroethyl)-1,3-benzodioxetane is less than 0.5%. The spectrum of its liquid phase is shown in Figure 4 .
[0071] Cool naturally to 20°C, and slowly add the reaction system to a mixed solvent of water and ethyl acetate. After extraction, dry to obtain an oily crude product. Dissolve the oil in 100 ml of ammonia methanol, stir at 25°C for 1 hour, and then concentrate to obtain 6.25 g of colorless liquid, with a content of 99.1% and a molar yield of 85.8%. The spectrum of its liquid phase is shown in Fig. 9 .
[0072] Example 5
[0073] The present embodiment provides a method for preparing piperidine, comprising:
[0074] Clean the reactor, replace with nitrogen, add THF (20ml), start stirring, and add NaH (8.67g, 60%). Dissolve succinimide (26.84g) in DMF (60ml) at 0℃, add it dropwise into the above NaH / THF suspension after dissolving, stir at 30℃ until the bubbles disappear completely. Dissolve 5-(2-chloroethyl)-1,3-benzodioxetane (10g) in THF (20ml), add it to the system and heat to 50℃, keep it warm for 24h, take samples for analysis, LCMS detection shows that 5-(2-chloroethyl)-1,3-benzodioxetane is less than 0.5%, and its liquid phase spectrum is shown in Figure 5 .
[0075] Cool naturally to 20°C, and slowly add the reaction system to a mixed solvent of water and ethyl acetate. After extraction, dry to obtain an oily crude product. The oil was dissolved in 100 ml of ammonia methanol, stirred at 25°C for 1 hour, and concentrated to obtain 7.77 g of colorless liquid, with a content of 91.7% and a molar yield of 79.6%. The spectrum of its liquid phase is shown in Fig.10 .
[0076] Comparative Example 1
[0077] This comparative example provides a method for preparing piperidine, and piperidine is synthesized by referring to the following synthetic route:
[0078]
[0079] , specifically as follows:
[0080] Clean the autoclave, replace with nitrogen, add DMF (100ml), and start stirring. Then add catechol (10g) at room temperature, add 50ml of 5mol / L potassium hydroxide aqueous solution to the system, and heat the system to 110℃ for reaction. After keeping warm for 11h, take samples for analysis. Liquid phase detection shows that catechol is less than 0.5%. Adjust the pH to 8-9 with dilute hydrochloric acid, extract with dichloromethane 3 times, combine the organic phases, dry, and concentrate to obtain an oily crude product. Column chromatography gives 7g of brown oil (piperine ring), with a yield of 63%.
[0081] Clean the reactor, replace with nitrogen, add 7g of piperonyl cyanide, add 7.8g of anhydrous aluminum chloride in batches while stirring at 0-5℃, add 6.24g of acrylonitrile after the system temperature stabilizes. Control the temperature at 5-10℃ and introduce stable hydrogen chloride gas into the system. Remove the temperature control after 0.5h to allow the system to heat up naturally. When the system temperature begins to decrease, control the temperature at 65℃. After 8h of heat preservation, take samples for analysis. Liquid phase detection of piperonyl cyanide <0.5%, remove the hydrogen chloride gas pipeline, cool the system to 5℃, and slowly pour it into ice water. Extract with dichloromethane 3 times, combine the organic phases, dry, and concentrate to obtain an oily crude product. Column chromatography obtains 7g of yellow liquid (piperonitrile) with a yield of 69.6%.
[0082] A clean reactor was prepared, and nitrogen was replaced. 6.7 g of 86% sulfuric acid was added. 7 g of piperonitrile was added under stirring. The system was allowed to heat up naturally. When the system temperature began to decrease, the temperature was controlled at 80°C. After keeping warm for 0.5 h, the system solidified and could not be stirred. The system was cooled to -30 to -20°C, 20 ml of dichloromethane, 20 ml of ice water and 25 ml of aqueous ammonia were added, and the mixture was stirred until dissolved. The mixture was extracted with dichloromethane 3 times. The organic phases were combined, dried and concentrated to obtain a crude oil. 6.1 g of a yellow oil (piperonyl propionamide) was obtained by column chromatography with a yield of 79%.
[0083] Clean the reactor, replace with nitrogen, add 100ml of anhydrous THF, add LiAlH4 (1M in THF, 2.4g) in batches, cool to -5℃ after adding, slowly add piperonyl propionamide solution (6.1g dissolved in 10ml of anhydrous THF) at -10~-5℃. Keep warm for 0.5h and take samples for analysis. Liquid phase detection shows piperonyl propionamide <0.5%, extract with dichloromethane 3 times, combine the organic phases, dry, and concentrate to obtain 4.17g of yellow liquid (piperonyl ethylamine), with a yield of 80%.
[0084] The total yield of the reaction route is 27.7%. The method has a long route, low yield, expensive raw materials and complicated operations.
[0085] Comparative Example 2
[0086] Clean the reactor, replace with nitrogen, add DMF (100ml), and start stirring. Then add succinimide (10.73g), potassium carbonate (22.46g), tetrabutylammonium iodide (3.98g) and 5-(2-chloroethyl)-1,3-benzodioxetane (10g) in sequence at room temperature, and then start heating to 80℃ for reaction. After keeping warm for 11h, take samples for analysis. LCMS detection shows that 5-(2-chloroethyl)-1,3-benzodioxetane is less than 0.5%, and the target product is about 20%. The system is disordered and no further treatment is done.
[0087] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.
Claims
1. A method for preparing piperidine, characterized in that: include: The synthesis was carried out according to the following synthesis route: Here, R represents a halogen.
2. The preparation method of piperidine according to claim 1, characterized in that The operation of step a comprises: mixing an organic solvent, succinimide, a base, a catalyst and raw material 1 at 70 to 150° C. to react; Preferably, the reaction temperature is 75-85°C; More preferably, the reaction time is 8-12 hours, further preferably 10-11 hours.
3. The preparation method of pepperethylamine according to claim 1 or 2, characterized in that, The organic solvent is selected from one of THF, DMF and DMSO, preferably DMF; Preferably, the base is selected from a metal inorganic base, preferably a carbonate, more preferably potassium carbonate; Preferably, the catalyst is selected from iodides; preferably potassium iodide; Preferably, R is selected from any one of Cl, Br and I. Preferably, the raw material 1 is 5-(2-chloroethyl)-1,3-benzodioxetine.
4. The preparation method of pepperethylamine according to claim 1 or 2, characterized in that, The molar ratio of raw material 1, succinimide, base and catalyst is 1:(2-3):(3-4):(0.1-0.2).
5. The preparation method of pepperethylamine according to claim 1, characterized in that, The operation of step b comprises: reacting raw material 2 with ammonia at 15-30° C.; Preferably, the reaction temperature is 20-25°C; Preferably, the reaction time is 1-4 hours, preferably 2-3 hours.
6. The preparation method of pepperethylamine according to claim 1 or 5, characterized in that, Ammonia is added as a solution; Preferably, it is an alcohol solution of ammonia, more preferably ammonia methanol; most preferably, the concentration of ammonia methanol is 2-7M, preferably 4M.
7. The method for preparing piperidine according to claim 6, wherein The molar ratio of raw material 2 to ammonia is 1:(9-10).
8. The preparation method of pepperethylamine according to claim 1 or 5, characterized in that, After the reaction in step b is completed, the reaction system is concentrated.
9. The method for preparing piperidine according to claim 8, wherein The concentration temperature is 40-45°C.
10. The method for preparing piperidine according to claim 1, characterized in that: Before step b, the reaction system of step a is post-treated; Preferably, the post-treatment comprises: extracting and concentrating by water washing to obtain a crude product; Preferably, the extraction solvent used for extraction is selected from one of ethyl acetate, methyl tert-ether and dichloromethane, preferably ethyl acetate.