Synthesis method of cyclopropyl amine compound
Through the catalyzed cyclopropanation reaction and catalytic hydrogenation reaction, the yield and atomic economy of cyclopropylamine compounds were successfully improved, the problems of high costs and low yields in the prior art were solved, and the efficient, economical and reasonable industrial production of cyclopropylamine compounds were achieved.
Patent Information
- Application Number
- CN202411515676.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-29
- Publication Date
- 2025-03-07
AI Technical Summary
In the prior art, the industrial application cost of cyclopropylamine compounds is relatively high, with low yields, a lot of wastewater and poor atomic economy.
Diazomethane is used to catalyze the cyclopropanation reaction to obtain a nitrogen-containing cyclopropyl compound, and a cyclopropylamine compound is obtained by catalytic hydrogenation reaction.
The high yield of cyclopropylamine compounds (up to more than 95%) is achieved, the production cost is reduced, and the process is simple, the reaction conditions are mild, the post-treatment is convenient, and there are no obvious by-products and wastewater.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic synthesis, relates to pharmaceutical intermediates, and particularly relates to a method for synthesizing cyclopropylamine compounds. Background Art
[0002] Compounds containing cyclopropane structural units exhibit excellent biological and physiological activities, and many cyclopropane derivatives are also found as intermediates in biological metabolism. Therefore, cyclopropane structures have important applications in drug molecule design. Cyclopropylamine compounds, in particular, are highly reactive compounds that can serve as important intermediates for introducing cyclopropane structures into the synthesis of pharmaceuticals and pesticides, and have broad application prospects.
[0003] Currently, the main method for synthesizing aminocyclopropane compounds is to use halogenated nitropropane as a raw material, condense it under alkaline conditions to form a nitrocyclopropane compound, and then reduce it with a metal borohydride to obtain the aminocyclopropane compound (Helvetica Chimaca Acta, 1982, 65, 137-161; CN107935859). This method has a low yield (only 57%), produces a lot of wastewater, and has poor atom economy, resulting in high industrial application costs. Summary of the Invention
[0004] In view of the shortcomings of the prior art, the object of the present invention is to provide a method for synthesizing cyclopropylamine compounds to solve the technical problem in the prior art that the industrial application cost of cyclopropylamine compounds needs to be further reduced.
[0005] In order to solve the above technical problems, the present invention adopts the following technical solutions:
[0006] A method for synthesizing cyclopropylamine compounds. The method uses a nitroolefin compound as a substrate to carry out a diazomethane-catalyzed cyclopropanation reaction to obtain a nitrogen-containing cyclopropyl compound; secondly, the nitrogen-containing cyclopropyl compound is subjected to a catalytic hydrogenation reaction to obtain the cyclopropylamine compound.
[0007] Alternatively, the method uses amino olefin compounds as substrates and performs a diazomethane-catalyzed cyclopropanation reaction to obtain cyclopropylamine compounds.
[0008] The structural formula of the nitroolefin compound is
[0009] The structural formula of the amino olefin compound is
[0010] The structural formula of the nitrogen-containing cyclopropyl compound is
[0011] The structural formula of the cyclopropylamine compound is
[0012] Where:
[0013] n = 0 or 1;
[0014] R1, R2 and R3 are all hydrogen atoms or alkyl groups.
[0015] Preferably, R1, R2 and R3 are all -H, -CH3 or -CH2CH3.
[0016] The present invention also has the following technical features:
[0017] The method specifically comprises the following steps:
[0018] Step 1: Under N2 atmosphere, the substrate nitroolefin compound, the first solvent and the cyclization catalyst are uniformly mixed and added into the reactor.
[0019] Step 2: diazomethane gas is introduced into the reactor using nitrogen as a carrier gas to carry out cyclopropanation reaction. The reaction is stopped when the reaction conversion rate is greater than 99%. The reaction is stopped after nitrogen purging to obtain an organic phase.
[0020] Step 3: The organic phase is distilled to obtain a nitrogen-containing cyclopropyl compound with a purity greater than 99.5%.
[0021] Step 4: uniformly mix the nitrogen-containing cyclopropyl compound, the second solvent, and the hydrogenation catalyst and add the mixture into the autoclave.
[0022] Step 5: replace the autoclave with nitrogen and then hydrogen, start heating and stirring, introduce hydrogen, raise the temperature to 60-150° C., pressure 0.1-2 MPa, react for 6-12 hours, take samples for analysis, and when the hydrogenation conversion rate is greater than 99.8%, cool the autoclave and filter to obtain the organic phase reaction liquid.
[0023] Step 6: The organic phase reaction liquid is subjected to desolventizing and distillation to obtain a cyclopropylamine compound with a purity of >99.5%.
[0024] Or the method specifically includes the following steps:
[0025] Step 1: Under N2 atmosphere, the substrate amino olefin compound, the first solvent and the cyclization catalyst are uniformly mixed and added into the reactor.
[0026] Step 2: diazomethane gas is introduced into the reactor using nitrogen as a carrier gas to carry out cyclopropanation reaction. The reaction is stopped when the reaction conversion rate is greater than 99%. The reaction is stopped after nitrogen purging to obtain an organic phase.
[0027] Step 3: The organic phase is distilled to obtain a cyclopropylamine compound with a purity greater than 99.5%.
[0028] Preferably, in step 1, the first solvent is one or more of tetrahydrofuran, methyltetrahydrofuran, dichloromethane, 1,2-dichloroethane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and methyl tert-butyl ether, and the amount of the first solvent is 0.5 to 10 times the mass of the substrate.
[0029] Preferably, in step 1, the cyclization catalyst is one or a combination of more than one of PdCl2, Pd(OAc)2, CuCl and CuCl2, and the amount of the cyclization catalyst is 0.1% to 5wt.% of the substrate mass.
[0030] Preferably, in step 2, the reaction temperature of the cyclopropanation reaction is 5-50°C.
[0031] Preferably, in step 2, the molar ratio of diazomethane to substrate is (1-7):1.
[0032] Preferably, in step 4, the second solvent is a mixed solvent of one or more of methanol, ethanol, tetrahydrofuran and water, and the amount of the second solvent is 0.1 wt.% to 100 wt.% of the mass of the nitrogen-containing cyclopropyl compound.
[0033] Preferably, in step 4, the hydrogenation catalyst is a Raney nickel catalyst, a palladium carbon catalyst or a platinum carbon catalyst, and the amount of the hydrogenation catalyst is 0.1 wt.% to 5 wt.% of the mass of the nitrogen-containing cyclopropyl compound.
[0034] Compared with the prior art, the present invention has the following technical effects:
[0035] (I) The preparation method of the present invention directly cyclopropanates an aminoalkene compound with a nitroalkene compound or further undergoes a simple hydrogenation reaction to obtain an aminocyclopropane-based structure compound with a yield of over 95%. This method has the advantage of high atom economy and can greatly reduce production costs.
[0036] (II) The synthetic method for preparing cyclopropylamine compounds of the present invention has a simple process, mild reaction conditions, convenient post-treatment, no obvious by-products and wastewater, significantly reduced costs, and is more suitable for industrial large-scale production.
[0037] The specific contents of the present invention are further explained in detail below with reference to the embodiments. DETAILED DESCRIPTION
[0038] It should be noted that, unless otherwise specified, all raw materials in the present invention are raw materials known in the art.
[0039] The present invention provides a method for synthesizing cyclopropylamine compounds, the synthetic route of which is:
[0040]
[0041] Where:
[0042] n = 0 or 1;
[0043] R1, R2 and R3 are all hydrogen atoms or alkyl groups, preferably, they are all -H, -CH3 or -CH2CH3.
[0044] The cyclopropylamine compounds synthesized by the invention can be used as pharmaceutical intermediates.
[0045] Specific embodiments of the present invention are given below. It should be noted that the present invention is not limited to the following specific embodiments, and all equivalent changes made on the basis of the technical solution of this application fall within the protection scope of the present invention.
[0046] Example 1:
[0047] This embodiment provides a method for synthesizing cyclopropylamine compounds, which is carried out according to the following steps:
[0048] 730 g of nitroethylene, 800 g of tetrahydrofuran and 1 g of palladium chloride were stirred and mixed uniformly at 25 ° C. and then added to the reactor; after nitrogen purging, 630 g of diazomethane gas diluted with nitrogen (1.5 times the equivalent) was introduced, and the ventilation time was maintained at 2 to 3 hours. During this period, the temperature of the reactor was maintained between 20 and 30 degrees Celsius, and the tail gas was absorbed by acetic acid and then discharged; after the reaction was completed, the organic phase was directly evaporated to remove the solvent, and then subjected to vacuum distillation to obtain 850 g of nitrocyclopropane with a gas phase purity of 99.6%; 850 g of nitrocyclopropane and 240 g of ethanol were mixed and put into a 2 L autoclave, and 0.85 g of palladium carbon catalyst (palladium content was 5 wt%) was added. After nitrogen replacement three times and hydrogen replacement twice, stirring was started and the temperature was raised to 90 ° C to start hydrogenation. The hydrogen pressure was maintained at 1.5 MPa. After 3 hours, sampling and analysis showed a conversion rate of 99.9%, and the reaction was stopped. After gas replacement, the reaction liquid was liquidized and the catalyst was filtered out. The reaction solution was then rotary evaporated to remove the solvent and then subjected to reduced pressure distillation to obtain 546 g of cyclopropylamine with a gas phase purity of 99.7% and an overall yield of 95.8%.
[0049] The characterization data of the product prepared in this example are substantially the same as those of Example 2, indicating that the product prepared in this example is the target compound cyclopropylamine.
[0050] Example 2:
[0051] This embodiment provides a method for synthesizing cyclopropylamine compounds, which is carried out according to the following steps:
[0052] At 25°C, 870g of 3-nitropropene, 800g of tetrahydrofuran and 1g of palladium acetate were stirred and mixed uniformly and then added to a reactor; after nitrogen purging, 630g (1.5 equivalents) of diazomethane gas diluted with nitrogen was introduced, and the ventilation time was maintained at 2-3h, during which the temperature of the reactor was maintained at 20-30°C, and the tail gas was absorbed by acetic acid and then discharged; after the reaction, the organic phase was directly rotary distilled to remove the solvent, and then subjected to vacuum distillation to obtain 850g of nitrocyclopropane methane with a gas phase purity of 99.6%; 990g of nitrocyclopropane was obtained. Alkane and 300 g of ethanol were uniformly mixed and placed in a 2 L autoclave. 1 g of palladium-carbon catalyst (palladium content: 5 wt%) was added. After nitrogen substitution three times and hydrogen substitution twice, stirring was started, the temperature was raised to 90° C., and hydrogenation was started. The hydrogen pressure was maintained at 1.5 MPa. After 3 hours, sampling and analysis showed a conversion rate of 99.9%, and the reaction was stopped. After gas substitution, the reaction liquid was liquidized and the catalyst was filtered out. The reaction liquid was then rotary evaporated to remove the solvent, and then subjected to reduced pressure distillation to obtain 684 g of cyclopropanemethylamine with a gas phase purity of 99.6% and an overall yield of 96.3%.
[0053] The characterization data of the product obtained by the present invention are as follows:
[0054] 1 H NMR (400MHz, CDCl3) δ2.58-2.62(d,J=7.1Hz,2H),1.50(s,2H),1.04-0.86(m,1H)3.45-3.31(m,1H),0.40-0.24(m,4H)ppm.
[0055] 13 C NMR (101MHz, CDCl3) δ50.26, 13.78, 3.32ppm.
[0056] It can be seen from the above characterization data that the product obtained in this example is the target compound cyclopropylmethylamine.
[0057] Example 3:
[0058] This embodiment provides a method for synthesizing cyclopropylamine compounds, which is carried out according to the following steps:
[0059] At 25°C, 870 g of 3-nitropropene, 400 g of tetrahydrofuran, and 1 g of chloropalladium were stirred and mixed uniformly and then added to a reactor. After nitrogen purging, 630 g (1.5 equivalents) of diazomethane gas diluted with nitrogen was introduced for 2 to 3 hours, during which the reactor temperature was maintained between 20 and 30°C. The tail gas was absorbed in acetic acid and then discharged. After 3 hours, sampling and analysis showed a conversion rate of 99.9%, and the reaction was stopped. After gas replacement, the reaction liquid was fluidized and the catalyst was filtered out. The solvent was then removed by rotary evaporation of the reaction solution, and 675 g of cyclopropanemethylamine was obtained by vacuum distillation with a gas phase purity of 99.6% and an overall yield of 95.0%.
[0060] The characterization data of the product prepared in the present invention are substantially the same as those in Example 2, indicating that the product prepared in this example is the target compound cyclopropylmethylamine.
[0061] Example 4:
[0062] This embodiment provides a method for synthesizing cyclopropylamine compounds, which is carried out according to the following steps:
[0063] At 25°C, 430g of aminoethylene, 400g of tetrahydrofuran, and 4g of cuprous chloride were stirred and mixed uniformly and then added to a reactor; after nitrogen purging, 630g (1.5 equivalents) of diazomethane gas diluted with nitrogen was introduced for 2 to 3 hours, during which the temperature of the reactor was maintained between 20 and 30°C. The tail gas was absorbed in acetic acid and then discharged; after the reaction, the organic phase was directly evaporated to remove the solvent, and then subjected to vacuum distillation to obtain 542g of cyclopropylamine with a gas phase purity of 99.2% and an overall yield of 95.1%.
[0064] The characterization data of the product prepared in the present invention are substantially the same as those of Example 2, indicating that the product prepared in this example is the target compound cyclopropylamine.
[0065] Example 5:
[0066] This embodiment provides a method for synthesizing cyclopropylamine compounds, which is carried out according to the following steps:
[0067] At 25°C, 430g of aminoethylene, 400g of tetrahydrofuran and 1g of palladium acetate were stirred and mixed uniformly and then added to a reactor; after nitrogen purging, 630g (1.5 equivalents) of diazomethane gas diluted with nitrogen was introduced for 2-3h, during which the temperature of the reactor was maintained between 20-30°C, and the tail gas was absorbed by acetic acid and discharged; after 3 hours, sampling and analysis showed a conversion rate of 99.9%, and the reaction was stopped; after gas replacement, the reaction liquid was fluidized and the catalyst was filtered out, and the reaction liquid was then rotary evaporated to remove the solvent, and then subjected to reduced pressure distillation to obtain 547g of cyclopropylamine with a gas phase purity of 99.8% and an overall yield of 96.0%.
[0068] The characterization data of the product prepared in the present invention are substantially the same as those of Example 2, indicating that the product prepared in this example is the target compound cyclopropylamine.
[0069] Example 6:
[0070] This embodiment provides a method for synthesizing cyclopropylamine compounds, which is carried out according to the following steps:
[0071] At 25°C, 570g of 3-aminopropylene, 400g of tetrahydrofuran, and 1g of palladium acetate were stirred and mixed uniformly and then added to a reactor; after nitrogen purging, 630g (1.5 equivalents) of diazomethane gas diluted with nitrogen was introduced for 2-3h, during which the reactor temperature was maintained between 20-30°C. The tail gas was absorbed in acetic acid and then discharged; after 3 hours, sampling and analysis showed a conversion rate of 99.9%, and the reaction was stopped; after gas replacement, the reaction liquid was fluidized and the catalyst was filtered out, then the reaction liquid was rotary evaporated to remove the solvent, and then subjected to reduced pressure distillation to obtain 675g of cyclopropanemethylamine with a gas phase purity of 99.6% and an overall yield of 95.0%.
[0072] The characterization data of the product prepared in the present invention are substantially the same as those in Example 2, indicating that the product prepared in this example is the target compound cyclopropylmethylamine.
Claims
1. A method for synthesizing cyclopropylamine compounds, characterized in that: The method uses nitroolefin compounds as substrates, performs a diazomethane-catalyzed cyclopropanation reaction to obtain nitrogen-containing cyclopropyl compounds; secondly, performs a catalytic hydrogenation reaction on the nitrogen-containing cyclopropyl compounds to obtain cyclopropylamine compounds; Alternatively, the method uses amino olefin compounds as substrates and performs a diazomethane-catalyzed cyclopropanation reaction to obtain cyclopropylamine compounds.
2. The method for synthesizing cyclopropylamine compounds according to claim 1, wherein: The structural formula of the nitroolefin compound is The structural formula of the amino olefin compound is The structural formula of the nitrogen-containing cyclopropyl compound is The structural formula of the cyclopropylamine compound is Where: n = 0 or 1; R1, R2 and R3 are all hydrogen atoms or alkyl groups.
3. The method for synthesizing cyclopropylamine compounds according to claim 1, characterized in that: The method specifically comprises the following steps: Step 1, under N2 atmosphere, uniformly mixing the substrate nitroolefin compound, the first solvent and the cyclization catalyst and adding them into the reactor; Step 2, diazomethane gas is introduced into the reactor using nitrogen as a carrier gas to carry out a cyclopropanation reaction, and the reaction is stopped when the reaction conversion rate is monitored to be greater than 99%, and the reaction is stopped after nitrogen purging to obtain an organic phase; Step 3, the organic phase is distilled to obtain a nitrogen-containing cyclopropyl compound with a purity of >99.5%; Step 4, mixing the nitrogen-containing cyclopropyl compound, the second solvent, and the hydrogenation catalyst uniformly and adding the mixture into an autoclave; Step 5, replace the autoclave with nitrogen and then hydrogen, start heating and stirring, introduce hydrogen, raise the temperature to 60-150°C, pressure 0.1-2MPa, react for 6-12h, take a sample and analyze the hydrogenation conversion rate>99.8%, then cool down, filter after cooling to obtain an organic phase reaction liquid; Step 6, the organic phase reaction liquid is subjected to desolventizing and distillation to obtain a cyclopropylamine compound with a purity of >99.5%; Or the method specifically comprises the following steps: Step 1, under N2 atmosphere, uniformly mixing the substrate amino olefin compound, the first solvent and the cyclization catalyst and adding them into the reactor; Step 2, diazomethane gas is introduced into the reactor using nitrogen as a carrier gas to carry out a cyclopropanation reaction, and the reaction is stopped when the reaction conversion rate is monitored to be greater than 99%, and the reaction is stopped after nitrogen purging to obtain an organic phase; Step 3: The organic phase is distilled to obtain a cyclopropylamine compound with a purity of >99.5%.
4. The method for synthesizing cyclopropylamine compounds according to claim 3, characterized in that: In step 1, the first solvent is one or more of tetrahydrofuran, methyltetrahydrofuran, dichloromethane, 1,2-dichloroethane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and methyl tert-butyl ether. The amount of the first solvent is 0.5 to 10 times the mass of the substrate.
5. The method for synthesizing cyclopropylamine compounds according to claim 3, characterized in that: In step 1, the cyclization catalyst is one or a combination of PdCl2, Pd(OAc)2, CuCl and CuCl2, and the amount of the cyclization catalyst is 0.1% to 5wt.% of the substrate mass.
6. The method for synthesizing cyclopropylamine compounds according to claim 3, characterized in that: In step 2, the reaction temperature of the cyclopropanation reaction is 5 to 50°C.
7. The method for synthesizing cyclopropylamine compounds according to claim 3, characterized in that: In step 2, the molar ratio of diazomethane to substrate is (1-7):
1.
8. The method for synthesizing cyclopropylamine compounds according to claim 3, characterized in that: In step 4, the second solvent is a mixed solvent of one or more of methanol, ethanol, tetrahydrofuran and water, and the amount of the second solvent used is 0.1wt.% to 100wt.% of the mass of the nitrogen-containing cyclopropyl compound.
9. The method for synthesizing cyclopropylamine compounds according to claim 3, characterized in that: In step 4, the hydrogenation catalyst is a Raney nickel catalyst, a palladium carbon catalyst or a platinum carbon catalyst, and the amount of the hydrogenation catalyst is 0.1wt.% to 5wt% of the mass of the nitrogen-containing cyclopropyl compound.