A method for preparing substituted aminoethanol
By using a solid superacid resin catalyst loaded with cerium nitrate in a tubular fixed-bed reactor and controlling the reaction conditions, the safety risks and byproduct generation problems in the production of substituted aminoethanol were solved, achieving high yield and high purity.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- GAOYOU CITY ORGANIC CHEM FACOTRY
- Filing Date
- 2024-04-24
- Publication Date
- 2026-08-04
AI Technical Summary
In the existing technology, the production of substituted aminoethanol has problems such as high safety risks, low reaction efficiency, and low product purity and yield. In particular, the series reaction of ethylene oxide with substituted amines in the batch reactor generates polyhydroxyethyl substituted amine byproducts, resulting in serious product loss.
A pulsed continuous conveying device is used to transport substituted amines and ethylene oxide to a tubular fixed-bed reactor containing catalysts. The reaction is carried out by a solid superacid resin catalyst loaded with cerium nitrate. The reaction conditions are controlled to improve selectivity and reduce the formation of byproducts.
It achieves high-yield and high-purity production of substituted aminoethanol, reduces safety risks, is suitable for industrial applications, and represents a significant improvement and innovation.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical and chemical synthesis technology, and in particular to a method for preparing substituted aminoethanol. Background Technology
[0002] Substituted aminoethanols refer to aminoethanols whose substituents are selected from C1-C8 alkyl, C4-C8 cycloalkyl, aryl, or C7-C9 alkylaryl groups, or that form a C3-C7 ring with NH. Typical substituted aminoethanols include N,N-dimethylaminoethanol, N-ethylaminoethanol, N,N-diethylaminoethanol, N-butylaminoethanol, N,N-dibutylaminoethanol, tert-butylaminoethanol, N,N-diisopropylaminoethanol, hydroxyethylpyrrolidine, N-piperidineethanol, 2-morpholinoethanol, and N-methylbenzylaminoethanol, etc.
[0003] Substituted aminoethanols are important chemical products, mainly used as pharmaceutical intermediates, emulsifiers, surfactants, and acid gas absorbents. For example, N,N-diethylaminoethanol, as an important pharmaceutical intermediate, can be used to produce procaine hydrochloride, dextromethorphan hydrochloride, etc., and can also be used to produce fatty acid derivatives, fiber softeners, rust inhibitors, emulsifiers, and vulcanization catalysts for polyurethane foams.
[0004] For example, tert-butylaminoethanol (TBE), as a novel and highly efficient selective desulfurization solvent, exhibits significant energy-saving effects in the purification of acidic gases and does not corrode equipment during application. BASF in Germany has produced an even superior desulfurizer, 2-[2-(tert-butylamino)ethylthio]ethanol (TBESE), using tert-butylaminoethanol as a raw material. TBE exhibits high thermal stability in aqueous solutions and can be processed at slightly higher regeneration temperatures, making it widely applicable for the selective desulfurization of natural gas, associated gas from oil fields, and syngas.
[0005] For example, N,N-diisopropylaminoethanol is an important intermediate in the synthesis of brain function improvement drugs such as prasracetam, and also an intermediate in the synthesis of bromhexine (probenzin), a drug for functional gastrointestinal disorders.
[0006] For example, N-hydroxyethylpyrrolidine is used to prepare N-(2-chloroethyl)pyrrolidine hydrochloride, which is used to prepare various drug compounds, such as the estrogen receptor antagonist Nafoxidine (N212800) and its analogues, the multi-target kinase inhibitor TG100572 Hydrochloride, and the kinase inhibitor Pacritinib.
[0007] Substituted aminoethanols, especially N-alkylethanolamines, are typically obtained by reacting the corresponding primary or secondary amine with ethylene oxide via the following reaction:
[0008]
[0009] There are currently many publicly available technical methods, mainly the following four.
[0010] Prior art 1: US Patent US2337004(A) describes a two-step non-aqueous phase method for producing alkanolamines. The two-step process includes (1) reacting an amine with anhydrous ethylene oxide in a pressure reactor at 100-275°C, and (2) recovering the product alkanolamine by distillation, with a low yield of only 75%. By adding ethylene oxide in batches to a high-pressure reactor, which is a flammable and explosive gas with an explosion limit of 3% to 100% (volume fraction), this process poses significant safety risks and is unsafe to operate.
[0011] Prior art 2: US patents US3131132, US5663444, and US4567303 describe a two-step aqueous phase method for producing alkanolamines. This method involves reacting ethylene oxide with dialkylamines at a temperature of 95-170°C in the presence of 2.5-50% by weight water based on the reaction mixture, followed by distillation to separate water and high-boiling components under reduced pressure at 40-90°C. This method is not ideal because it requires additional dehydration operations in the post-processing.
[0012] Prior art 3: Chinese patents CN102126967 and CN101585776(A) disclose an aging reaction using zinc chloride and tetramethylammonium hydroxide as catalysts and water as a circulating medium; this reaction is carried out in a gas-liquid two-phase process and is produced in a batch reactor. Suzhou Feixiang New Materials disclosed in CN102557960(A) that under alkylation reaction conditions, ethylene oxide and alkylamine are contacted multiple times in a multi-point continuous reactor, which is a pipeline reactor. This poses difficulties for production operations, is cumbersome, and is not suitable for production.
[0013] Prior art 4: German patent DE1941859(A1) discloses a continuous process for preparing monochain alkanolamines from ammonia and epoxides. It describes a method for the selective synthesis of monochain alkanolamines from epoxides and ammonia in the presence of a cation exchange resin. The catalyst is typically present in a fixed-bed apparatus. The temperature of the catalyst reaction column and the flow rate of the reaction mixture through the catalyst are set to achieve the highest yield of monoethanolamine per unit time. Continuous flow processes for preparing monochain alkanolamines from substituted alkyl primary or secondary amines with epoxides have not been reported.
[0014] Current production processes mostly employ batch reactor or (semi-)continuous methods. During the reaction, ethylene oxide readily undergoes a series of reactions with substituted amines, generating polyhydroxyethyl substituted amine byproducts and polyether byproducts, as shown in the following reaction formula.
[0015] Equation 1:
[0016]
[0017] Equation 2:
[0018]
[0019] Based on existing knowledge, the reaction of ethylene oxide with substituted amines can be categorized into two types: aqueous phase reaction and non-aqueous phase reaction. Aqueous phase reactions are carried out at low temperatures (typically below 100°C) using water as a catalyst and are usually very rapid. Non-aqueous phase reactions are carried out at higher temperatures (typically above 100°C) and in the presence of a catalyst. When water is used as a catalyst, a separate step is required to remove water from the product, making the entire process a three-step process.
[0020] The challenge of this process lies in the timely separation of the product from ethylene oxide; otherwise, byproducts such as polyhydroxyethyl substituted amines will be generated, resulting in significant losses of substituted amines and low product yield. Most existing production technologies employ batch reactor processes, which suffer from the drawback of prolonged contact between the product and ethylene oxide within the reactor, leading to a series of ethoxylation reactions and consequently poor product purity and yield.
[0021] Ethylene oxide, being a flammable and explosive gas with an explosion limit of 3% to 100% (volume fraction), poses a significant safety risk in this process. The batch reactor suffers from low reaction efficiency, long reaction time, severe backmixing of materials, significant exothermic reaction, and poor safety. Improving reaction selectivity and ensuring inherent process safety in production operations are the two key technical challenges that this invention aims to address.
[0022] In summary, finding a continuous preparation method for substituted aminoethanol with advantages such as "low raw material cost, high product purity and yield, and less waste" has become an urgent technical problem to be solved. Summary of the Invention
[0023] The technical problem to be solved by the present invention is to provide a method for preparing substituted aminoethanol, which addresses the shortcomings and deficiencies of the prior art. The method uses the corresponding substituted amine and ethylene oxide as raw materials, which are respectively transported to a tubular fixed-bed reactor containing a catalyst through a pulse continuous conveying device to react, thereby reducing ethoxylation and improving the yield of the product.
[0024] To solve the above-mentioned technical problems, the present invention adopts the following technical solution: a method for preparing substituted aminoethanol, which uses ethylene oxide and substituted amines as raw materials, and obtains substituted aminoethanol through a catalytic reaction, the reaction equation being:
[0025]
[0026] In the formula, 1 is substituted aminoethanol, 2 is substituted amine, and 3 is ethylene oxide. The substituted amine is a primary or secondary amine, wherein R1 and R2 are one or two of C1-C8 alkyl, C4-C8 cycloalkyl, aryl or C7-C9 alkylaryl, or R1 and R2 together with NH form a C3-C7 ring.
[0027] The catalyst used is at least one of acetic acid, nitric acid, sulfuric acid, hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium methoxide, and potassium methoxide;
[0028] The preparation method includes the following steps:
[0029] (1) Preparation of reaction solution A: The substituted amine and the catalyst are mixed at a weight ratio of 1000:(0.1-5);
[0030] (2) Continuous flow reaction operation: The reaction solution A obtained in step (1) and ethylene oxide are transported to a tubular fixed bed reactor containing solid superacid resin loaded with cerium nitrate through a pulse continuous conveying device. The liquid flow rate weight ratio of solution A to ethylene oxide is (1-10):1, the reaction pressure is 8-12 MPa, the reaction temperature is 100-200℃, and the reaction time is 1-5 minutes. The flow rate weight ratio is the weight ratio of the liquid flowing through per unit time.
[0031] (3) Reaction processing: According to GC analysis, when the mass concentration of ethylene oxide raw material in the product is less than 1%, the product is continuously discharged under reduced pressure through a pressure reducing valve and sent to a crude product receiving vessel. The reaction mixture is stripped with nitrogen at 45-55℃ to remove unreacted ethylene oxide and obtain a reaction product without ethylene oxide. Then, the crude product is distilled under reduced pressure of 50-100 mbar to obtain substituted aminoethanol.
[0032] A further preferred embodiment is that the catalyst in step (1) is potassium hydroxide.
[0033] A further preferred embodiment is that the weight ratio of solution A to ethylene oxide liquid flow rate in step (2) is (4-6):1.
[0034] A further preferred feature is that the internal temperature of the tubular fixed bed in step (2) is 120-130°C.
[0035] A further preferred embodiment is that R1 and R2 are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, benzyl, n-pentyl, hexyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
[0036] A further preferred embodiment is that R1, R2 together with NH form azacyclobutane, pyrrolidine, piperidine, morpholine, or piperazine.
[0037] A further preferred embodiment is that the substituted amine is one of ethylamine, diethylamine, dimethylamine, butylamine, tert-butylamine, diisopropylamine, dibutylamine, aziridine, pyrrolidine, piperidine, or morpholine.
[0038] The substituted aminoethanols include N,N-dimethylaminoethanol, N-ethylaminoethanol, N,N-diethylaminoethanol, N-butylaminoethanol, N,N-dibutylaminoethanol, tert-butylaminoethanol, N,N-diisopropylaminoethanol, 1-azacyclobutaneethanol, N-(2-hydroxyethyl)pyrrolidine, N-piperidineethanol, 2-morpholinoethanol, or N-methylbenzylaminoethanol.
[0039] The beneficial effects of this invention are as follows:
[0040] 1. This invention provides a method for preparing substituted aminoethanols from ethylene oxide. The method employs a continuous flow reaction process, using the corresponding substituted amine and ethylene oxide as raw materials, reacting in a tubular fixed bed packed with solid superacid resin supported on cerium nitrate. This significantly improves the selectivity of the monohydroxyethylation reaction. It overcomes the drawback of traditional processes where ethylene oxide easily undergoes a series of reactions with the substituted amine, generating polyhydroxyethyl substituted amine byproducts and polyether byproducts.
[0041] 2. The continuous flow reaction process provided by this invention achieves inherent safety in the hydroxyethylation reaction of substituted amines and ethylene oxide during the preparation of substituted aminoethanol. It represents a significant improvement and innovation over existing technologies, is particularly suitable for industrial applications, and has excellent promotional value.
[0042] This method is used for the production of various substituted aminoethanols, including but not limited to N,N-dimethylaminoethanol, N-ethylaminoethanol, N,N-diethylaminoethanol, N-butylaminoethanol, N,N-dibutylaminoethanol, tert-butylaminoethanol, N,N-diisopropylaminoethanol, 1-azacyclobutaneethanol, N-(2-hydroxyethyl)pyrrolidine, N-piperidineethanol, 2-morpholinoethanol, or N-methylbenzylaminoethanol. Detailed Implementation
[0043] 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.
[0044] Example 1
[0045] Pyrrolidine reacts with ethylene oxide to produce N-(2-hydroxyethyl)pyrrolidine, as shown in the following reaction formula:
[0046]
[0047] The specific preparation method includes the following steps:
[0048] (1) Preparation of reaction solution A: Pyrrolidine and potassium hydroxide are mixed at a weight ratio of 1000:0.5;
[0049] (2) Continuous flow reaction operation:
[0050] The reaction solution A obtained in step (1) and ethylene oxide are continuously pulsed and transported to a tubular fixed-bed reactor containing solid superacid resin loaded with cerium nitrate at a process set temperature. The flow rate weight ratio of reaction solution A to ethylene oxide is (4-5):1, the reaction pressure is 8-12 MPa, the reaction temperature is 120-130℃, and the reaction time is 1-5 minutes.
[0051] (3) Reaction treatment:
[0052] After being discharged under reduced pressure via a pressure reducing valve, the product was analyzed by GC, and the substituted aminoethanol product contained less than 1% ethylene oxide feedstock. The product was continuously discharged under reduced pressure via a pressure reducing valve and sent to a crude product receiving vessel. The reaction mixture was stripped under nitrogen at 50°C to remove unreacted ethylene oxide, yielding a reaction product free of ethylene oxide. The crude product was then distilled under reduced pressure of 50-100 mbar to obtain N-(2-hydroxyethyl)pyrrolidine, with a yield of 76.5% and a purity of 99.6%.
[0053] Catalyst selection for the reaction system in step (1):
[0054] With other substances remaining constant, different catalysts were compared, and the data listed in Table 1 below were obtained:
[0055]
[0056]
[0057] In conclusion, potassium hydroxide exhibits better catalytic performance, with a product yield exceeding 75%.
[0058] Selection of internal temperature for the fixed bed piping in step (2):
[0059] With other substances remaining constant, the data obtained from screening the process temperature are shown in Table 2 below:
[0060]
[0061] Conclusion: The product yield is over 60% when the temperature is between 100-200℃, and the product yield is over 70% when the temperature is between 120-130℃.
[0062] With all other substances remaining constant, the flow rate ratio of solution A to ethylene oxide was changed, resulting in the data listed in Table 3 below:
[0063]
[0064] Conclusion: The flow rate to weight ratio can be selected as (1-10):1, preferably (4-6):1, within which the yield of N-(2-hydroxyethyl)pyrrolidine is higher.
[0065] Example 2
[0066] tert-butylamine reacts with ethylene oxide to produce tert-butylaminoethanol.
[0067]
[0068] The preparation method differs from that of Example 1 in that, with all other substances remaining unchanged, pyrrolidine in Example 1 is replaced with tert-butylamine to obtain tert-butylaminoethanol, with a yield of 78.5% and a purity of 99.5%.
[0069] Example 3
[0070] N,N-diisopropylaminoethanol is produced by reacting diisopropylamine with ethylene oxide.
[0071]
[0072] With all other substances remaining unchanged, the inventors replaced the pyrrolidine in Example 1 with diisopropylamine to obtain N,N-diisopropylaminoethanol with a yield of 85.2% and a purity of 99.6%.
[0073] Example 4
[0074] 1-Azacyclobutaneethanol is prepared by reacting ethylene oxide with azacyclobutane.
[0075]
[0076] With all other substances remaining unchanged, the inventors replaced the pyrrolidine in Example 1 with azacyclobutane to obtain 1-azacyclobutane ethanol with a yield of 68.5% and a purity of 99.8%.
[0077] Example 5
[0078] N,N-diethylaminoethanol is produced by reacting diethylamine with ethylene oxide.
[0079]
[0080] With all other substances remaining unchanged, the inventors replaced the pyrrolidine in Example 1 with diethylamine to obtain N,N-diethylaminoethanol with a yield of 68.5% and a purity of 99.6%.
[0081] Example 6
[0082] 2-morpholinoethanol is produced by reacting morpholine with ethylene oxide.
[0083]
[0084] With all other substances remaining unchanged, the inventors replaced the pyrrolidine in Example 1 with morpholine to obtain 2-morpholinoethanol, with a yield of 73.5% and a purity of 99.3%.
[0085] Example 7
[0086] Ethylamine reacts with ethylene oxide to produce N-ethylaminoethanol.
[0087]
[0088] With all other substances remaining unchanged, the inventors replaced the pyrrolidine in Example 1 with ethylamine to obtain N-ethylaminoethanol, with a yield of 61.5% and a purity of 99.3%.
[0089] Example 8
[0090] N-Methyl-N-benzylamine reacts with ethylene oxide to produce N-methylbenzylaminoethanol.
[0091]
[0092] With all other substances remaining unchanged, the inventors replaced the pyrrolidine in Example 1 with N-methyl-N-benzylamine to obtain N-methylbenzylamine ethanol with a yield of 81.5% and a purity of 99.0%.
[0093] Although the yield and purity of the final product differ in Examples 2-8 above, the preferred range is consistent when the experimental data obtained are analyzed using the same experimental methods as in Example 1. Therefore, the preferred formulation of the catalyst of the present invention, which is potassium hydroxide, with a liquid flow rate weight ratio of solution A to ethylene oxide of (4-6):1, and an internal temperature of 120-130°C in the tubular fixed bed, is also applicable to Examples 2-8.
[0094] 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 preparing substituted aminoethanol, characterized in that, Using ethylene oxide and substituted amines as raw materials, substituted aminoethanol is obtained through a catalytic reaction. The reaction equation is as follows: ； In the formula, 1 is substituted aminoethanol, 2 is substituted amine, 3 is ethylene oxide, and the substituted amine is pyrrolidine; the catalyst is potassium hydroxide; The preparation method includes the following steps: (1) Preparation of reaction solution A: The substituted amine and the catalyst are mixed at a weight ratio of 1000:(0.1-5); (2) Continuous flow reaction operation: The reaction solution A obtained in step (1) and ethylene oxide are transported to a tubular fixed bed reactor containing solid superacid resin loaded with cerium nitrate through a pulse continuous conveying device. The flow rate weight ratio of solution A to liquid ethylene oxide is (4-6):1, the reaction pressure is -12MPa, the reaction temperature is 120-130℃, and the reaction time is 1-5 minutes. (3) Reaction processing: According to GC analysis, when the mass concentration of ethylene oxide raw material in the product is less than 1%, the product is continuously discharged under reduced pressure through a pressure reducing valve and sent to a crude product receiving vessel. The reaction mixture is stripped with nitrogen at 45-55℃ to remove unreacted ethylene oxide and obtain a reaction product without ethylene oxide. Then, the crude product is distilled under reduced pressure of 50-100 mbar to obtain substituted aminoethanol.