RU2791235C1 - METHOD FOR PRODUCING N-METHYLGLUCOSAMINE BY REDUCTIVE CONDENSATION REACTION USING Ni-Ru CATALYST BASED ON HYPERCROSSLINKED POLYSTYRENE - Google Patents

Abstract

FIELD: method for producing N-methylglucosamine.

SUBSTANCE: method uses a reductive condensation reaction with an aminate agent methylamine in a hydrogen atmosphere using a Ni-Ru catalyst based on hypercrosslinked polystyrene and can be used in medical and pharmaceutical discipline to increase solubilization and stabilize biologically active drugs. obtaining a Ni-Ru catalyst based on hypercrosslinked polystyrene by reacting 10 g of hypercrosslinked polystyrene with 10 g of nickel acetate solution Ni(Ac)₂ in 200 ml of deionized water, evaporating the resulting suspension in an evaporator to a free flowing state, followed by drying in a thermostated cabinet at a temperature 90°C, reduction with hydrogen in a glass tube at 300°C for six hours, cooling to room temperature and impregnation with an aqueous solution of 0.3 g of ruthenium hydroxychloride in 100 ml of deionized water, washing with water, evaporation in a vacuum evaporator, drying in a thermostated cabinet at a temperature of 90°C, then reduction with hydrogen and reductive condensation with an aminate agent methylamine, for which an alcoholic solution of D-glucose and methylamine are added to the resulting catalyst in a ratio of 1:1 to 1:1.2, purged three times with nitrogen at a pressure of 0.2 MPa, hydrogen is supplied under pressure from 5 MPa to 10 MPa, heated to a temperature of 60°C to 120°C and incubated for 1 hour to 4 hours in ethanol.

EFFECT: increased yield of N-methylglucosamine, efficiency and stability of the reductive condensation process.

1 cl, 5 dwg, 4 tbl, 9 ex

Description

This invention relates to a method for producing N-methylglucosamine (according to the trivial nomenclature aminopolyol, glucosamine), using the reductive condensation process and can be used in medical and pharmaceutical practice to increase solubilization and stabilize biologically active drugs.

To carry out the reductive condensation reaction to obtain N-methylglucamine, bimetallic catalysts based on platinum transition metals, such as Pt, Pd, Ru, are used using various kinds of modified supports (The current state of reductive amination (Mikhailov S.P., Doluda V.Yu. , Sulman M.G., Matveeva V.G. Bulletin of Tver State University. Series: Chemistry. 2022. No. 1 (47), pp. 24-36. However, such methods of reductive condensation are distinguished by the complexity of preparing catalysts and high cost applied metals.

To reduce the cost of the catalytic system used to obtain N-methyglucosamine, a catalyst based on Raney nickel, as well as on Ni/Al ₂ O ₃ aluminum compounds, was proposed. The amount of metal in such a catalyst is up to 44 wt. %, the yield of N-methylglucosamine reaches 91% (Study of the synthesis of N-methylglucosimine Mikhailov S.P., Sulman AM, Sulman M.G., Grebennikova O.V., Sulman E.M., Doluda V.Yu., Matveeva V G. Bulletin of Tver State University, Series: Chemistry, 2020, No. 1 (39), pp. 40-46.

Also known is a method for producing N-methylglucosamine using Ni-catalyst based on hypercrosslinked polystyrene (SPS). The amount of metal for the preparation of the catalyst is 10-25 wt. %, and the yield of N-methylglucosamine is 97.6-97.8%. (Ni catalyst based on hypercrosslinked polystyrene for highly efficient synthesis of N-methyl-D-glucosamine S.P. Mikhailov, V.Yu. Doluda, V.P. Molchanov, M.G. Sulman. In the book: Roskatalysis. Collection of abstracts. Institute of Catalysis Sulman M.G., Mikhailov S.P., Sulman A.M. In the collection: The current state of economic systems: economics and management. Collection of scientific papers of the II International Scientific Conference Edited by D. V. Rozov and G. G. Skvortsova, 2020, pp. 279-284).

The prior art method for producing N-methylglucosamine using a reductive condensation reaction, including mixing corn syrup and ammonia in a volume ratio of 1:60 - 1:3 to a homogeneous state, the resulting mixture is subjected to hydrogenation at a temperature of 150-200 ° C, a pressure of 17 MPa , for 20-21 hours, in the presence of a Raney nickel catalyst (US No. 4540821, class C07C 85/08, 09/10/1985).

However, this method is characterized by the formation of a large amount of transamination products and high energy costs associated with the use of high temperatures in the process of the reductive condensation reaction.

A known method for producing N-methylglucosamine (aminopolyols) by carrying out the reductive condensation of D-sorbitol and ammonia at a temperature of 100-400°C, a pressure of 1-40 MPa, for 32 hours, in the presence of catalysts consisting of metals of 8-11 groups of the periodic system elements D.I. Mendeleev (US No. 9067863 B2, class C07C 209/00, C07C 209/16, C04B 24/12, C04B 28/02, C07B 213/02, C07D 241/04, C07D B295/02, C07D B295/023, 30.06 .2015).

However, the complexity of the hardware for the process of obtaining amino polyols and the long-term maintenance of the amination process leads to an increase in the cost of the final product, which makes the method economically inefficient.

The closest analogue of the claimed invention is a method for producing N-methylglucosamine (glucamine) using a reductive condensation reaction, including mixing D-glucose and alkylamine in a volume ratio of 1:1 to 1:1.2, the resulting mixture was subjected to hydrogenation at a temperature of 60-100 °C, pressure 5-20 MPa, for 1-3 hours, in the presence of a skeletal nickel catalyst promoted with titanium or chromium. The yield of N-methylglucosamine (glucamine) was 90% (SU No. 1754707 A1, class C07C 213/02, C07C 215/12, 15.08.1992).

However, the use of toxic metals in the catalyst preparation process makes the process unfriendly, and the use of a larger amount of a transition group metal increases the cost of the catalyst system.

The objective of the invention is to develop a method for producing N-methylglucosamine by carrying out a reductive condensation reaction in a hydrogen atmosphere using nickel-ruthenium deposited on hypercrosslinked polystyrene as a catalyst.

The technical result of the invention is to increase the yield of N-methylglucosamine, the efficiency and stability of the reductive condensation process.

The set task and the specified technical result are achieved by the fact that the method of obtaining N-methylglucosamine by the reaction of reductive condensation with an aminating agent methylamine in a hydrogen environment using a Ni-Ru catalyst based on hypercrosslinked polystyrene includes the production of a Ni-Ru catalyst based on hypercrosslinked polystyrene by the interaction of 10 g of hypercrosslinked polystyrene with 10 g of a solution of nickel acetate Ni(Ac) ₂ in 200 ml of deionized water, evaporation of the resulting suspension in an evaporator to a free flowing state, followed by drying in a thermostated cabinet at a temperature of 90°C, hydrogen reduction in a glass tube at 300°C for six hours, cooling to room temperature and impregnation with an aqueous solution of 0.3 g of ruthenium hydroxychloride in 100 ml of deionized water, washing with water, evaporation in a vacuum evaporator, drying in a thermostated cabinet at a temperature of 90°C, then reduction with hydrogen and carrying out reductive condensation with an aminating agent methylamine, for which an alcoholic solution of D-glucose and methylamine are added to the resulting catalyst in a ratio of 1:1 to 1:1.2, it is blown three times with nitrogen at a pressure of 0.2 MPa, hydrogen is supplied at a pressure of 5 MPa to 10 MPa, heated to a temperature of from 60°C to 120°C and incubated for 1 hour to 4 hours in an ethanol environment.

The use of ruthenium as an additional additive to the catalyst makes it possible to increase the activity of nickel metal particles.

The use of hypercrosslinked polystyrene as a support for the catalyst ensures uniform distribution of nickel and ruthenium metal particles in the active polyvalent form and gives the catalyst high mechanical strength and resistance to acids and alkalis.

The use of hypercrosslinked polystyrene as a carrier for the catalyst increases the selectivity of the process for N-methylglucosamine due to its high sorption capacity for various organic compounds, which creates an increased concentration of the substrate around the reaction centers of the catalyst.

An increase in the surface concentration of the active metal leads to an increase in the rate of the catalytic synthesis of N-methylglucosamine and the selectivity to N-methylglucosamine.

The catalyst weight less than 3.0 g, as well as an increase in the catalyst weight above 7.0 g, leads to a decrease in the selectivity of the process of reductive condensation with methylamine, which is due to an increase in the rate of side reactions.

Changing the molar ratio of D-glucose to the aminating agent methylamine below 1:1 or above 1:1.2 leads to a decrease in the rate of the condensation process and a decrease in the yield of N-methylglucosamine.

When the temperature decreases below 60°C, the process of reductive condensation of D-glucose slows down, which leads to a low yield of N-methylglucosamine, and when the temperature rises above 120°C, the formation of a large amount of D-glucose isomerization products is observed.

With a decrease in pressure below 5 MPa, the process of reductive condensation of D-glucose slows down, which leads to a low yield of N-methylglucosamine, and with an increase in pressure above 10 MPa, the formation of by-products of complete reduction with the formation of sorbitol and ammonia is observed.

When the reaction time is reduced to less than 1 hour, incomplete transformation of the reaction components occurs with the formation of N-methylglucosamine. With an increase in the reaction time over 4 hours, the presence of hydrolytic degradation products of N-methylglucosamine is observed.

The use of ethanol as a reaction medium makes it possible to shift the chemical equilibrium towards the formation of reaction products and the possibility of carrying out the synthesis of N-methylglucosamine in one stage, without isolation of intermediate compounds.

The invention is illustrated by the following graphics. Figure 1 shows the scheme of a one-stage reaction for obtaining N-methylglucosamine; figure 2 shows the dependence of the yield of N-methylglucosamine on the reaction temperature; figure 3 shows the dependence of the yield of N-glucosamine on the pressure of hydrogen in the reactor; figure 4 shows the dependence of the yield of N-glucosamine on the mass of the catalyst in the reductive condensation reaction; figure 5 shows the dependence of the yield of N-glucosamine on the molar ratio of D-glucose to methylamine.

The method of obtaining N-methylglucosamine by the reaction of reductive condensation with an aminating agent methylamine in a hydrogen atmosphere during heating is carried out as follows.

A catalyst is preliminarily prepared, for which 10 g of hypercrosslinked polystyrene is added to a solution of 10 g of nickel acetate Ni(Ac) ₂ in 200 ml of deionized water in order to form active nickel particles inside the SPS, the resulting suspension is evaporated in an evaporator to a free flowing state, dried in thermostated cabinet at a temperature of 90°C, the resulting product is reduced with hydrogen in a glass tube at 300°C for six hours, cooled to room temperature and impregnated with an aqueous solution of 0.3 g of ruthenium hydroxychloride in 100 ml of deionized water to evenly distribute ruthenium particles on the nickel surface .

The resulting catalyst is washed with water, evaporated in a vacuum evaporator, dried in a thermostated Cabinet at a temperature of 90°and then reduced with hydrogen.

To carry out the reductive condensation reaction with the aminating agent methylamine in a hydrogen atmosphere, a high-pressure reactor Parr Instruments 4307 (USA) with a total flask volume of 250 cm ³ and a maximum operating pressure of 60 MPa is used.

A portion of the catalyst from 3.0 g to 7.0 g is added to the reactor flask, an alcoholic solution of D-glucose and methylamine are added in a ratio of 1:1 to 1:1.2, it is purged three times with nitrogen at a pressure of 0.2 MPa in order to remove the residual amount of atmospheric oxygen to minimize side processes of amination. Then, hydrogen is supplied under pressure from 5 MPa to 10 MPa. The reactor is heated to a temperature of 60°C to 120°C and held for 1 to 4 hours.

The efficiency of the reductive condensation reaction of D-glucose and methylamine is evaluated by the yield of the final product of the reaction of N-methylglucosamine.

Analysis of the reaction medium for the presence of monosaccharides, polyols, and N-methylglucosamine is carried out using a high-performance liquid chromatograph (HPLC, ChromatechkKristall 2014, Russia) equipped with a refractive index detector and a column field with a Reprogel-H column (Dr. MaischGmbh, Germany), characterized by a length of 500 mm, 10 mm in diameter, and a theoretical number of plates 40,000. Separation conditions: eluent flow rate (9 Mmol H ₂ SO ₄ solution) 0.5 ml/min; column temperature 25°C; eluent pressure 65 atm; analysis time 30 min. Qualitative identification of reductive condensation reaction products is carried out using standards of pure substances.

The output of N-methylglucosamine according to the method of the present invention is up to 94.5%.

The invention is illustrated by the following examples.

Example 1

The catalyst is preliminarily prepared, for which 10 g of nickel acetate Ni(Ac) ₂ are dissolved in 200 ml of deionized water, and 10 g of hypercrosslinked polystyrene are added to the solution. The suspension is evaporated in a vacuum evaporator. Then dried in a thermostated Cabinet at a temperature of 90°C. The resulting product is reduced with hydrogen in a glass tube at 300°C for six hours, cooled to room temperature and subjected to impregnation with an aqueous solution of 0.3 g of ruthenium hydroxychloride in 100 ml of deionized water. The resulting catalyst is washed with water, evaporated in a vacuum evaporator, dried in a thermostated Cabinet at a temperature of 90°and then reduced with hydrogen.

Into a flask of a Parr Instruments 4307 high-pressure reactor (USA) with a total flask volume of ²⁵⁰ cm 1:1.2).

The reactor is purged three times with nitrogen at a pressure of 0.2 MPa, after which hydrogen is supplied at a pressure of 5 MPa. The reactor is heated to a temperature of 60°C, and start counting the reaction time. The reaction is carried out for 1-4 hours (60-240 min). The reaction parameters and the yield of N-methylglucosamine are presented in Table 1.

Example 2

The method of obtaining the same as described in example 1, only the reaction temperature is 100°C. The reaction parameters and the yield of N-methylglucosamine are presented in Table 1.

Example 3

The method of obtaining the same as described in example 1, only the reaction temperature is 120°C. The reaction parameters and the yield of N-methylglucosamine are presented in Table 1.

As can be seen from Table 1 and the plot of N-methylglucosamine yield versus reaction temperature shown in FIG. 2, the maximum yield of N-methylglucosamine is observed at a reaction temperature of 60°C and a reductive condensation reaction time of 120 minutes.

Example 4

The production method is the same as described in example 1, only hydrogen is supplied under a pressure of 10 MPa. The reaction parameters and the yield of N-methylglucosamine are presented in Table 2.

Example 5

The production method is the same as described in example 1, only hydrogen is supplied under a pressure of 7 MPa. The reaction parameters and the yield of N-methylglucosamine are presented in Table 2.

As can be seen from table 2 and the plot of the yield of N-methylglucosamine from the pressure of hydrogen shown in figure 3, the maximum yield of N-methylglucosamine is observed at a hydrogen pressure of 5 MPa.

Example 6

The production method is the same as in example 1, only the mass of the catalyst is 3 g. The reaction parameters and the yield of N-methylglucosamine are presented in table 3.

Example 7

The production method is the same as in example 1, only the mass of the catalyst is 7 g. The reaction parameters and the yield of N-methylglucosamine are presented in table 3.

As can be seen from table 3 and the plot of the yield of N-methylglucosamine on the amount of catalyst shown in figure 4, the maximum yield of N-methylglucosamine is observed with a catalyst amount of 5 g, which allows us to recommend this particular amount of catalyst for the production of N-methylglucosamine

Example 8

The production method is the same as in example 1, only the molar ratio of D-glucose to methylamine is 1:1.2. The reaction parameters and the yield of N-methylglucosamine are presented in Table 4.

Example 9

The method of obtaining the same as in example 1, only the molar ratio of D-glucose to methylamine is 1:1. The reaction parameters and the yield of N-methylglucosamine are presented in Table 4.

As can be seen from table 4 and the graph of the dependence of the output of N-methylglucosamine on the molar ratio of D-glucose to methylamine, shown in Fig.5, the maximum yield of N-methylglucosamine is observed at a molar ratio of D-glucose to methylamine 1:1.2, which makes it possible to recommend this particular molar ratio to obtain N-methylglucosamine.

As can be seen from the examples, tables and graphs, during the reductive condensation of D-glucose and methylamine to obtain N-methylglucosamine using a nickel-ruthenium catalyst, the maximum yield of the reaction product (up to 94.5%) is achieved at a molar ratio of D-glucose to methylamine 1: 1.2, the optimum temperature is 60°C, and the hydrogen pressure is 5.0 MPa.

The proposed method for producing N-methylglucosamine using a Ni-Ru catalyst based on hypercrosslinked polystyrene also provides a lower cost for the process of obtaining N-methylglucosamine, since the optimal distribution of ruthenium on the nickel surface allows the use of a minimum amount of expensive metal and accelerates the process of obtaining N-methylglucosamine.

Claims (1)

A method for producing N-methylglucosamine by a reductive condensation reaction with an aminating agent methylamine in a hydrogen atmosphere using a Ni-Ru catalyst based on hypercross-linked polystyrene, including obtaining a Ni-Ru catalyst based on hyper-cross-linked polystyrene by reacting 10 g of hyper-cross-linked polystyrene with 10 g of Ni(Ac) nickel acetate solution ) ₂ in 200 ml of deionized water, evaporation of the resulting suspension in an evaporator to a free-flowing state, followed by drying in a thermostated cabinet at a temperature of 90°C, hydrogen reduction in a glass tube at 300°C for six hours, cooling to room temperature and impregnation with water solution of 0.3 g of ruthenium hydroxychloride in 100 ml of deionized water, washing with water, evaporation in a vacuum evaporator, drying in a thermostated cabinet at a temperature of 90°C, then reduction with hydrogen and carrying out reductive condensation with an aminating agent methylamine, for which the resulting catalyst an alcohol solution of D-glucose and methylamine are added in a ratio of 1:1 to 1:1.2, purged three times with nitrogen at a pressure of 0.2 MPa, hydrogen is supplied at a pressure of 5 MPa to 10 MPa, heated to a temperature of 60 ° C to 120 ° C and incubated for 1 hour to 4 hours in ethanol.

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