CN111470988A

CN111470988A - Method for continuously producing 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentylamine

Info

Publication number: CN111470988A
Application number: CN202010295422.1A
Authority: CN
Inventors: 黄志威; 李雪梅
Original assignee: Lanzhou Institute of Chemical Physics LICP of CAS
Current assignee: Lanzhou Institute of Chemical Physics LICP of CAS
Priority date: 2020-04-15
Filing date: 2020-04-15
Publication date: 2020-07-31
Anticipated expiration: 2040-04-15
Also published as: CN111470988B

Abstract

The invention discloses a method for continuously producing 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentylamine. It includes: continuously inputting a mixed solution containing 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentanone and a nitrogen source into a fixed bed reactor filled with a supported nano nickel-based catalyst in a reducing atmosphere at a pressure of 0.2-2 MPa, a temperature of 80-140 ℃ and a feeding mass space velocity of 0.2-1.0 h^‑1Under the conditions of (a) to carry out a reductive amination reactionTo obtain the 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentylamine. The method provided by the invention can realize continuous production of 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentylamine under the action of the supported nano Ni catalyst and the nitrogen source; meanwhile, the catalyst has the advantages of low cost, high production efficiency, good stability, simple operation, low production cost and convenient industrial production.

Description

Method for continuously producing 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentylamine

Technical Field

The invention belongs to the technical field of synthesis of medical intermediates, and particularly relates to a method for continuously producing 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentylamine.

Background

The chemical name of the hydroxychloroquine sulfate tablet is as follows: 2- [ [4- [ (7-chloro-4-quinolinyl) amino group]Pentyl radical]Ethylamino group]-ethanol sulfate, of the formula: c₁₈H₂₆ClN₃O·H₂SO₄Molecular weight 433.96, chemical formula:

hydroxychloroquine sulfate belongs to 4-aminoquinoline antimalarial drugs, and is composed of two aromatic rings, one ethyl group in chloroquine is replaced by one hydroxyethyl group, the chloroquine phosphate is a chloroquine phosphate derivative, the structure and the action mechanism of the chloroquine phosphate are similar to those of chloroquine phosphate, the chloroquine phosphate can be replaced clinically, the curative effect of the hydroxychloroquine sulfate for treating rheumatic diseases is determined along with the application of the antimalarial drugs in the treatment of systemic lupus erythematosus (S L E) and Rheumatoid Arthritis (RA) in the 50 th century, the application of the hydroxychloroquine sulfate in the field of clinical rheumatism is more and more extensive due to the unique action mechanism and the better safety of the hydroxychloroquine sulfate in the 90 th century, and more than 90% of clinical rheumatism is selected for treating.

The 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentylamine, commonly known as hydroxychloroquine side chain, is a key intermediate for synthesizing hydroxychloroquine. The synthesis methods of hydroxychloroquine side chains reported in the prior publication have three types: the first route is that 5-chloro-2-pentanone and N-ethylethanolamine react under the action of a catalyst to obtain 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentanone, and then the 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine is prepared by hydrogenation reduction amination under the catalysis of Raney nickel. CN 104803859a discloses its synthetic route as follows:

the second route is that 5-chloro-2-pentanone is converted into ketal for protection, reacting with N-ethylethanolamine, then removing protection to obtain 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentanone, and hydrogenating, reducing and aminating the 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentanone under the catalysis of Raney nickel to obtain 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine (Plumbum et al: synthesis of 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine, chemical and biological engineering, 2014,31(5), 54-56), wherein the synthesis route is as follows:

in the third route, a new side chain is obtained by adopting an ammonia-free technology to replace 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine, and CN 107266323 discloses the synthetic route as follows:

the invention takes N-ethylethanolamine and 5-chloro-2-pentanone as raw materials to carry out condensation, esterification, reduction and halogenation reactions to obtain a novel side chain for synthesizing hydroxychloroquine sulfate, and the synthesis of the side chain is an ammoniation-free process.

In conclusion, the raney nickel catalyst used in the reductive amination reaction of 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentanone in the first and second methods is prepared by dissolving nickel-aluminum alloy in strong alkali, so that serious environmental pollution is caused, and the catalyst is inactivated and lost in the using process. In addition, the process adopts an intermittent production mode, the production efficiency is low, and the waste discharge is high. The third method is a non-ammoniation and non-catalytic hydrogenation process, but has complex operation steps and long production period, and the reduction of the ketocarbonyl in the esterification product needs expensive hydroboration reagent, so the production cost is high and the waste is more. Therefore, the synthesis of the side chain compound needs to develop a novel efficient catalyst, and the production process is improved to improve the production efficiency and reduce the production cost.

Disclosure of Invention

The main object of the present invention is to provide a process for the continuous production of 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine, which overcomes the disadvantages of the prior art.

In order to achieve the purpose, the technical scheme adopted by the invention comprises the following steps:

the embodiment of the invention provides a method for continuously producing 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentylamine, which comprises the following steps:

continuously inputting a mixed solution containing 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentanone and a nitrogen source into a fixed bed reactor filled with a supported nano nickel-based catalyst in a reducing atmosphere at a pressure of 0.2-2 MPa, a temperature of 80-140 ℃ and a feeding mass space velocity of 0.2-1.0 h^-1To obtain 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentylamine.

In the invention, the 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentylamine is a hydroxychloroquine sulfate side chain compound and is a key intermediate of hydroxychloroquine medicaments.

Compared with the prior art, the invention has the beneficial effects that:

(1) the invention can continuously and efficiently produce 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentylamine, which takes 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentanone generated by the substitution reaction of 5-chloro-2-pentanone and N-ethylethanolamine and a nitrogen source as raw materials, and carries out continuous reductive amination reaction in a fixed bed reactor to produce 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentylamine, thereby realizing continuous flow production at lower reaction temperature and hydrogen pressure, having cheap and easily obtained production raw materials and simple and efficient reaction process;

(2) the method takes the supported non-noble metal nickel as the catalyst to realize the continuous stable reductive amination of 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentanone and a nitrogen source to produce the 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine, and the catalyst has low cost and small investment; the reaction product and the catalyst can be directly separated in the reaction process, separate filtration or centrifugal treatment is not needed, the catalyst has good service life stability and simple operation, the production efficiency is obviously improved, the production cost is reduced, the large-scale industrial production is convenient, and the economic benefit is improved.

Drawings

In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings needed to be used in the description of the embodiments or the prior art will be briefly introduced below, it is obvious that the drawings in the following description are only some embodiments described in the present application, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.

FIG. 1 is a graph showing the stability of the continuous reaction of catalyst No. 2 measured in example 8 of the present invention.

Detailed Description

In view of the defects of the prior art, the inventor of the present invention has long studied and largely practiced to propose the technical solution of the present invention, which will be clearly and completely described below, and it is obvious that the described embodiments are a part of the embodiments of the present invention, but not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making an invasive task, are within the scope of the present invention.

One aspect of an embodiment of the present invention provides a method for continuously producing 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine, comprising:

In some more specific embodiments, the nitrogen source includes any one or a combination of two or more of ammonia, and urea, without limitation.

Further, the molar ratio of the 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentanone to the nitrogen source is 1: 2-8.

In some more specific embodiments, the supported nano nickel-based catalyst comprises a carrier, and a main active component and an auxiliary agent which are supported on the carrier.

Further, the main active component includes Ni, but is not limited thereto, and preferably, the content of the main active component in the supported nano nickel-based catalyst is 15 to 75 wt%, and particularly preferably 20 to 70 wt%.

Furthermore, the auxiliary agent comprises any one or the combination of more than two of Fe, Co, Cu, Zn, Mn, L a, Y and Ce, and preferably, the content of the auxiliary agent in the supported nano nickel-based catalyst is 0.1-10 wt%.

Further, the carrier includes Al₂O₃、ZrO₂、SiO₂And MgO, and is not limited thereto.

In some more specific embodiments, the supported nano nickel-based catalyst is prepared by a coprecipitation method or a deposition precipitation method; the preparation method of the supported nano nickel-based catalyst comprises the following steps:

mixing any one solution of a mixed metal salt solution containing a main active component and an auxiliary agent, an alkali solution and the metal salt solution of the carrier, a carrier oxide powder solution and a carrier colloidal particle solution at a pH value of 9.5-10 to perform a precipitation reaction, then performing aging treatment at 30-100 ℃ for 2-24h, then calcining at 400-800 ℃ for 2-10h, and then performing reduction treatment at 400-750 ℃ in a reducing atmosphere for 2-8h to obtain the supported nano nickel-based catalyst.

Further, the alkali solution includes any one or a combination of two or more of a sodium hydroxide solution, a potassium hydroxide solution, a sodium carbonate solution, and a potassium carbonate solution, and is not limited thereto.

In some more specific embodiments, the preparation method of the supported nano nickel-based catalyst comprises:

weighing active metal nickel and metal salt of an auxiliary agent according to a proportion at room temperature, adding deionized water to prepare a solution A with the total concentration of the active metal and the auxiliary agent salt being 0.1-1 mol/L, preparing an alkali liquor B with the concentration being 1-6 mol/L, adding metal salt of a carrier or commercially available oxide powder or colloidal particles according to a proportion in a reaction tank, adding deionized water (the addition amount is 10 times of the carrier metal salt or commercially available oxide powder or colloidal particles) to fully stir and mix uniformly, then dropping the salt solution A and the alkali solution B into the reaction tank simultaneously under rapid stirring, keeping the pH value of 9-11 in the precipitation process, heating to 30-100 ℃ after the precipitation is finished, aging for 2-24h, filtering after the aging is finished, washing with the deionized water until the filtrate is neutral, roasting at the temperature of 400-800 ℃ for 2-10h, tabletting and screening 20-40 mesh catalyst particles, filling 4g in a fixed bed reactor, and finally heating to 400-8 h in a hydrogen atmosphere (the flow rate of 80-100m L/min) to 750 ℃ to obtain an activated catalyst.

In some more specific embodiments, the reducing atmosphere is formed from a reducing gas.

Further, the reducing gas includes hydrogen and/or a mixed gas containing hydrogen.

Further, the molar ratio of the reducing gas to the 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentanone is 5-20: 1.

In some more specific embodiments, the method further comprises: 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentanone, a nitrogen source, and an alcoholic solvent were mixed to form a mixed solution. The alcoholic solvent can increase the miscibility of 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentanone with the nitrogen source.

Further, the alcohol solvent includes any one or a combination of two or more of methanol, ethanol, propanol, and isopropanol, and is not limited thereto.

Further, the mass ratio of the alcohol solvent to 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentanone is 1-3: 1.

The invention provides a method for continuously and efficiently synthesizing a target hydroxychloroquine sulfate key side chain compound (5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentylamine), which uses a cheap, efficient and stable supported nano non-noble metal catalyst to realize the continuous reductive amination reaction of 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentanone in a fixed bed reactor, obviously improves the production efficiency of the hydroxychloroquine sulfate key side chain compound, reduces the production cost and reduces three wastes.

The technical solution of the present invention is further described in detail with reference to several preferred embodiments, which are implemented on the premise of the technical solution of the present invention, and detailed embodiments and specific operation procedures are provided, but the scope of the present invention is not limited to the following embodiments.

Example 1

66.88g of Ni (NO)₃)₂·6H₂O、2.17g Cu(NO₃)₂·3H₂O、117.0g Al(NO₃)₃·9H₂Adding O into 1100ml deionized water in turn to prepare 0.5 mol/L metal salt solution A, adding 40g NaOH and 21.2g Na₂CO₃Adding 200ml deionized water to prepare mixed alkali solution B, simultaneously dripping a salt solution A and the alkali solution B into a 2000ml three-necked bottle under rapid stirring, keeping the pH value of the precipitation process to be 10 +/-0.2, heating to 80 ℃ after the precipitation is finished, aging for 4H, filtering after the aging is finished, washing the filtrate with deionized water until the filtrate is neutral, drying the filter cake at 110 ℃ for 12H, roasting at 400 ℃ for 10H, tabletting and screening for 20-40 mesh catalyst particles, filling 4g into a fixed bed reactor, heating to 550 ℃ in a hydrogen atmosphere (the flow is 100m L/min) for reduction for 4H to obtain an activated catalyst 1, wherein the composition of the catalyst and the grain size of active metal Ni are shown in table 1, weighing 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentanone, methanol and 25% concentrated ammonia water according to the mass ratio of 1:1:3 to prepare a reaction solution, and preparing the reaction solution at the reaction temperature of 100 ℃ and the reaction temperature of H₂Pressure 0.5MPa, H₂The molar ratio of the raw materials to the 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentanone is 10:1 and the feed mass space velocity is 0.20h^-1Under the condition, the amination performance of the catalyst is considered, a sample after 12h of stabilization is taken for gas chromatography analysis, the conversion rate of 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentanone is 99.6%, the selectivity of the target product 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine is 93.7%, and the yield is 93.3%.

Example 2

60.45g of NiSO₄·6H₂O、8.71g CoSO₄·7H₂O、95.97g Al₂(SO₄)₃·18H₂O is added into 810ml deionized water in turnPreparing 0.5 mol/L metal salt solution A, mixing alkali solution B and catalyst precipitation, heating to 90 ℃ after precipitation, aging for 24H, filtering after aging, washing with deionized water until the filtrate is neutral, drying the filter cake at 110 ℃ for 12H, roasting at 500 ℃ for 6H, tabletting and screening 20-40 mesh catalyst particles, filling 4g in a fixed bed reactor, heating to 500 ℃ in hydrogen atmosphere (flow 100m L/min) for reduction for 6H to obtain an activated catalyst 2, wherein the composition of the catalyst and the grain size of active metal Ni are shown in table 1, weighing 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentanone, ethanol and 25% concentrated ammonia water according to the mass ratio of 1:1:3, preparing reaction liquid at 120 ℃, and H at 120 ℃, and precipitating with the catalyst in the same example 1₂Pressure 0.2MPa, H₂The molar ratio of the raw materials to the 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentanone is 5:1 and the feed mass space velocity is 0.50h^-1Under the condition, the amination performance of the catalyst is considered, a sample after 12h stabilization is taken for gas chromatography analysis, the conversion rate of 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentanone is 99.0%, the selectivity of the target product 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine is 96.7%, and the yield is 95.7%.

Example 3

29.66g of Ni (NO)₃)₂·6H₂O、4.77g Ce(NO₃)₂·6H₂O、48.39g Al(NO₃)₃·9H₂O·18H₂O、55.38g Zr(NO₃)₄·5H₂Adding O into 740ml deionized water to prepare 0.5 mol/L metal salt solution A, adding 56g KOH and 27.6g K₂CO₃Adding 200ml deionized water to prepare mixed alkali solution B, precipitating the catalyst in the same process as the example 1, heating to 100 ℃ after precipitation is finished, aging for 2H, filtering after aging, washing with deionized water until the filtrate is neutral, drying the filter cake at 110 ℃ for 12H, roasting at 800 ℃ for 2H, tabletting and screening for 20-40 mesh catalyst particles, filling 4g of the catalyst particles into a fixed bed reactor, heating to 750 ℃ in a hydrogen atmosphere (the flow is 80m L/min), reducing for 2H to obtain an activated catalyst 3, wherein the composition of the catalyst and the grain size of active metal Ni are shown in the table 1, weighing 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentanone, ethanol and 25% concentrated ammonia water according to the mass ratio of 1:2:2 to prepare a reaction solution, and preparing the reaction solution at the reaction temperature of 140 ℃ and H by using the concentrated ammonia water with the mass₂Pressure 0.8MPa，H₂The molar ratio of the raw material to the 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentanone is 20:1 and the feed mass space velocity is 1.0h^-1Under the condition, the amination performance of the catalyst is considered, a sample after 12h of stabilization is taken for gas chromatography analysis, the conversion rate of 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentanone is 99.7%, the selectivity of the target product 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine is 92.7%, and the yield is 92.4%.

Example 4

Mixing 110.5g of Ni (NO)₃)₂·6H₂O、3.83g Y(NO₃)₂·6H₂O、14.48g Al(NO₃)₃·9H₂O、29.69gMg(NO₃)₄·6H₂Adding O into 550ml deionized water in turn to prepare 1.0 mol/L metal salt solution A, mixing alkali solution B and catalyst precipitation process as in example 1, heating to 80 ℃ after precipitation, aging for 12H, filtering after aging, washing with deionized water until the filtrate is neutral, drying the filter cake at 110 ℃ for 12H, roasting at 600 ℃ for 3H, tabletting and screening 20-40 mesh catalyst particles, filling 4g in a fixed bed reactor, heating to 400 ℃ in hydrogen atmosphere (flow 100m L/min) and reducing for 8H to obtain activated catalyst 4, wherein the composition of the catalyst and the grain size of active metal Ni are shown in Table 1, weighing 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentanone, ethanol and 25% ammonia water according to mass ratio of 1:1:8 to prepare reaction solution, reacting at 100 ℃ and H at 100 ℃₂Pressure 0.6MPa, H₂The molar ratio of the raw materials to the 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentanone is 10:1 and the feed mass space velocity is 0.4h^-1Under the condition, the amination performance of the catalyst is considered, a sample after 12h stabilization is taken for gas chromatography analysis, the conversion rate of 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentanone is 99.8%, the selectivity of the target product 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine is 96.1%, and the yield is 95.9%.

Example 5

Mixing 22.39Ni (NO)₃)₂·6H₂O、6.50g Fe(NO₃)₃·9H₂O、1.81g La(NO₃)₂·6H₂O is added into 1000ml deionized water in turn to prepare 0.1 mol/L metal salt solution A, 60g NaOH is weighed and added into 250m L deionized water to prepare alkaliSolution B; 400ml of deionized water were placed in a 2000ml three-necked flask and 24g of ZrO were added with mechanical stirring₂Continuously stirring the powder for 1H, dripping a metal salt solution A and an alkali solution B into the powder, keeping the pH value of the precipitation process to be 9 +/-0.2, heating the solution to 30 ℃ after the precipitation is finished, aging the solution for 8H, washing and drying the aged catalyst, roasting the catalyst for 6H at 500 ℃, tabletting and screening catalyst particles of 20-40 meshes, filling 4g of the catalyst into a fixed bed reactor, heating the catalyst in a hydrogen atmosphere (with the flow rate of 100m L/min) to 550 ℃ for reduction for 6H to obtain an activated catalyst 5, wherein the composition of the catalyst and the grain size of active metal Ni are shown in a table 1, weighing 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentanone, propanol and 25% concentrated ammonia water according to the mass ratio of 1:3:2 to prepare a reaction solution, and H is carried out at the reaction temperature of 80 ℃ under the reaction₂Pressure 2.0MPa, H₂The molar ratio of the raw materials to the 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentanone is 10:1 and the feed mass space velocity is 0.2h^-1Under the condition, the amination performance of the catalyst is considered, a sample after 12h stabilization is taken for gas chromatography analysis, the conversion rate of 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentanone is 96.3%, the selectivity of the target product 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine is 93.7%, and the yield is 90.2%.

Example 6

40.21g of NiSO₄·6H₂O、14.06g Mn(NO₃)₂·6H₂Adding O into 1000ml deionized water in turn to prepare 0.1 mol/L metal salt solution A, weighing 63.6g Na₂CO₃Adding the mixture into 600ml of deionized water to prepare an alkali solution B; a2000 ml three-necked flask was charged with 400ml of deionized water and sequentially charged with commercial SiO under mechanical agitation₂-Al₂O₃18.4g of powder, continuously stirring for 1h, simultaneously dropwise adding the metal salt solution A and the mixed alkali solution B, and keeping the pH value of 11 +/-0.2 in the precipitation process; after the precipitation, the temperature is raised to 60 ℃ for aging for 5h, and after the aging and precipitation, the catalyst treatment and the reduction activation are the same as in example 5, so as to obtain an activated catalyst 6, wherein the composition of the catalyst and the grain size of the active metal Ni are shown in Table 1. Weighing 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentanone, isopropanol and 25% concentrated ammonia water according to the mass ratio of 1:1:3 to prepare reaction liquid, and reacting at the temperature of 130 ℃ and H₂Pressure 1.0MPa, H₂With 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentanone molar ratio 5:1 and feed mass space velocity 0.6h^-1Under the conditions, the amination performance conditions of the catalyst are considered to be the same as the example, a 12h stabilized sample is taken for gas chromatographic analysis, the conversion rate of the 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentanone is 99.3 percent, the selectivity of the target product 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine is 95.0 percent, and the yield is 94.3 percent.

Example 7

74.44Ni (NO)₃)₂·6H₂O、6.61g ZnSO₄·7H₂O、0.167g Ga(NO₃)₂·6H₂Adding O into 600ml deionized water in turn to prepare 0.5 mol/L metal salt solution A, preparing mixed alkali solution in the same example 1, adding 300ml deionized water into 2000ml three-neck bottle, adding 44.9g of 30 wt% silica sol under mechanical stirring, preparing and processing catalyst in the same example 6, tabletting and screening 20-40 mesh catalyst particles, filling 4g in a fixed bed reactor, weighing 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentanone, ethanol, 25% concentrated ammonia water and urea according to the mass ratio of 1:1:1 to prepare reaction liquid, reacting at 120 ℃, H₂Pressure 0.5MPa, H₂The molar ratio of the raw materials to the 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentanone is 5:1 and the feed mass space velocity is 0.4h^-1Under the condition, the amination performance of the catalyst is considered, a sample after 12h stabilization is taken for gas chromatography analysis, the conversion rate of 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentanone is 99.2%, the selectivity of the target product 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine is 95.9%, and the yield is 95.1%.

TABLE 1 catalyst Synthesis conditions, compositions and Ni grain sizes

^*Arabic numerals in front of the active metal and the auxiliary agent represent mass percentage, and the proportion in brackets is a molar ratio;

example 8: continuous reaction stability study of catalyst

Weighing 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentanone, ethanol and 25% concentrated ammonia water according to the mass ratio of 1:1:3 to prepare reaction liquid at 120 DEG C、0.5MPa H₂Pressure, 0.3h^-1Mass space velocity, H₂The continuous reaction stability of the No. 2 catalyst is studied under the condition that the molar ratio of the catalyst to the hydroxyethyl amino pentanone is 5:1, and samples are taken every 6-10 hours for gas chromatography analysis. From the results in FIG. 1, it can be seen that the catalyst maintains good stability, and the yield of 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine is maintained at about 94% after 300 hours of operation (catalyst stability is shown in FIG. 1).

In addition, the inventors of the present invention have also made experiments with reference to the above examples and by using other raw materials, process operations, and process conditions described in the present specification, and have obtained preferable results.

The aspects, embodiments, features and examples of the present invention should be considered as illustrative in all respects and not intended to be limiting of the invention, the scope of which is defined only by the claims. Other embodiments, modifications, and uses will be apparent to those skilled in the art without departing from the spirit and scope of the claimed invention.

The use of headings and chapters in this disclosure is not meant to limit the disclosure; each section may apply to any aspect, embodiment, or feature of the disclosure.

Throughout this specification, where a composition is described as having, containing, or comprising specific components or where a process is described as having, containing, or comprising specific process steps, it is contemplated that the composition of the present teachings also consist essentially of, or consist of, the recited components, and the process of the present teachings also consist essentially of, or consist of, the recited process steps.

It should be understood that the order of steps or the order in which particular actions are performed is not critical, as long as the teachings of the present invention remain operable. Further, two or more steps or actions may be performed simultaneously.

While the invention has been described with reference to illustrative embodiments, it will be understood by those skilled in the art that various other changes, omissions and/or additions may be made and substantial equivalents may be substituted for elements thereof without departing from the spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from its scope. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims. Moreover, unless specifically stated any use of the terms first, second, etc. do not denote any order or importance, but rather the terms first, second, etc. are used to distinguish one element from another.

Claims

1. A process for continuously producing 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine, comprising:

2. The method of claim 1, wherein: the nitrogen source comprises any one or the combination of more than two of ammonia water, ammonia gas and urea.

3. The method of claim 1, wherein: the molar ratio of the 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentanone to the nitrogen source is 1: 2-8.

4. The method of claim 1, wherein: the supported nano nickel-based catalyst comprises a carrier, and a main active component and an auxiliary agent which are supported on the carrier.

5. The method of claim 4, wherein: the main active component comprises Ni; preferably, the content of the main active component in the supported nano nickel-based catalyst is 15-75 wt%, and particularly preferably 20-70 wt%;

and/or the auxiliary agent comprises any one or the combination of more than two of Fe, Co, Cu, Zn, Mn, L a, Y and Ce, preferably, the content of the auxiliary agent in the supported nano nickel-based catalyst is 0.1-10 wt%;

and/or, the carrier comprises Al₂O₃、ZrO₂、SiO₂And MgO, or a combination of two or more thereof.

6. The method of claim 4, wherein: preparing the supported nano nickel-based catalyst by adopting a coprecipitation method or a deposition precipitation method; preferably, the preparation method of the supported nano nickel-based catalyst comprises the following steps:

mixing any one solution of a mixed metal salt solution containing a main active component and an auxiliary agent, an alkali liquor and the metal salt solution of the carrier, a carrier oxide powder solution and a carrier colloidal particle solution at a pH value of 9.5-10 to perform a precipitation reaction, then performing aging treatment at 30-100 ℃ for 2-24h, roasting at 400-800 ℃ after washing and drying for 2-10h, and then performing reduction treatment at 400-750 ℃ in a reducing atmosphere for 2-8h to obtain the supported nano nickel-based catalyst.

7. The method of claim 1, wherein: the reducing atmosphere is formed by a reducing gas; preferably, the reducing gas comprises hydrogen and/or a mixed gas containing hydrogen; preferably, the molar ratio of the reducing gas to the 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentanone is 5-20: 1.

8. The method of claim 1, further comprising: 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentanone, a nitrogen source, and an alcoholic solvent were mixed to form a mixed solution.

9. The method of claim 8, wherein: the alcohol solvent comprises any one or combination of more than two of methanol, ethanol, propanol and isopropanol.

10. The method of claim 8, wherein: the mass ratio of the alcohol solvent to the 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentanone is 1-3: 1.