CN111100018A

CN111100018A - Preparation method of N-ethyl-D-glucosamine

Info

Publication number: CN111100018A
Application number: CN201911399896.4A
Authority: CN
Inventors: 沈建伟
Original assignee: Suzhou Jingye Medicine & Chemical Co ltd
Current assignee: Suzhou Jingye Medicine & Chemical Co ltd
Priority date: 2019-12-30
Filing date: 2019-12-30
Publication date: 2020-05-05

Abstract

The invention discloses a preparation method of N-ethyl-D-glucosamine, which is characterized by sequentially comprising the following steps: (1) according to the mass ratio of glucose to an alcohol solvent to monoethylamine = 1: 2-10: 1-1.1, firstly dissolving glucose in the alcohol solvent, then introducing monoethylamine gas, heating to 35-55 ℃ under the condition of stirring, and keeping for 0.5-1 hour; (2) adding a nickel-containing ternary powder catalyst into the reaction system obtained in the step (1) according to the mass ratio of glucose to the nickel-containing ternary catalyst = 1: 0.02-0.1, introducing hydrogen into the system after nitrogen conversion, and reacting at the temperature of 50-100 ℃ for 12 hours, wherein the pressure is 0.5-3.0 Mpa; (3) after the reaction is finished, the pressure is released, the catalyst is recovered by filtration, and the filtrate is subjected to post-treatment to obtain the N-ethyl-D-glucosamine. The product obtained by the method has high purity and high yield, and the production cost is reduced. Overcomes the difficulties of low product purity and repeated recrystallization in the prior art.

Description

Preparation method of N-ethyl-D-glucosamine

Technical Field

The invention relates to a preparation method of a saccharide derivative, in particular to a preparation method of N-ethyl-D-glucosamine which can be used as a drug synthesis intermediate.

Background

N-Ethyl-D-glucosamine (N-Ethyl-D-glucosamine), also known as glucosamine, is a white crystalline powder with a melting point of 136-142 ℃. The structural formula is as follows:

。

N-ethyl-D-glucosamine is an important drug synthesis intermediate, can be used for drug synthesis and chiral drug and intermediate resolution, and can also form salts or compounds with certain drugs, thereby improving the lipid solubility of the drugs and leading the drugs to play the greatest pharmacological action, such as cyclic adenosine monophosphate and the like.

In the prior art, the main preparation method is as follows:

one method is disclosed in US patent application US4246193A, which is obtained by catalytic hydrogenation using aqueous solution of glucose and ethylamine as raw materials, methanol as reaction solvent, raney nickel as catalyst, with yield of 74.16%. In the specific embodiments herein are disclosed: adding 18 g of D-glucose, 20 ml of 70% ethylamine solution and 1 g of Raney nickel into a mixed solution of 140 ml of methanol and 30 ml of water, reacting for 2 hours at 160 Pa 60 ℃ in a hydrogen atmosphere, filtering off the catalyst, concentrating the solvent at low pressure, dissolving the precipitate in 50 ml of methanol, filtering the obtained solution, and cooling to obtain 15.5 g of N-ethyl-D-glucosamine, wherein the melting point is: 132-.

Another method is disclosed in US2016962A, which is obtained by catalytic hydrogenation under hydrogen pressure with glucose and monoethylamine solution as raw materials, methanol as reaction solvent, and reduced nickel as catalyst. In embodiment 10, specifically disclosed are: 84 g of glucose, 228 g of a 33% monoethylamine solution and 8 g of a catalyst containing 20% reduced nickel were vigorously shaken under 1500 lbs of hydrogen in a pressure vessel. The temperature is increased, the hydrogen absorption is completed within two hours from 90 ℃, and the reaction temperature reaches 100 at most. Separating the product, wherein the melting point is 133-134 ℃, and the molecular weight is 209.

The two methods have the defects that the obtained product has high impurity content, can be removed by repeated recrystallization, has a melting point of only 132-134 ℃ and an optical rotation of-15.4 ℃, and has low overall quality.

Disclosure of Invention

The invention aims to provide a novel preparation method of N-ethyl-D-glucosamine, which can reduce side reactions and obtain higher yield and purity.

In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows: a preparation method of N-ethyl-D-glucosamine sequentially comprises the following steps:

(1) according to the mass ratio of glucose to an alcohol solvent to monoethylamine = 1: 2-10: 1-1.1, firstly dissolving glucose in the alcohol solvent, then introducing monoethylamine gas, heating to 35-55 ℃ under the condition of stirring, and keeping for 0.5-1 hour;

(2) adding a nickel-containing ternary powder catalyst into the reaction system obtained in the step (1) according to the mass ratio of glucose to the nickel-containing ternary powder catalyst = 1: 0.02-0.1, introducing hydrogen into the system after nitrogen conversion, and reacting for 12 hours at the temperature of 50-100 ℃ under the pressure of 0.5-3.0 Mpa;

(3) after the reaction is finished, the pressure is released, the catalyst is recovered by filtration, and the filtrate is subjected to post-treatment to obtain the N-ethyl-D-glucosamine.

In the above technical scheme, the nickel-containing ternary powder catalyst is alnico, alnico or alnico.

In the nickel-containing ternary powder catalyst, the content of aluminum is 46-48% by mass, the content of nickel is 48-51% by mass, and the content of a third component is 2-4% by mass. Preferably, the aluminum content is 47%, the nickel content is 50%, and the third component content is 3%.

Preferably, the nickel-containing ternary powder catalyst is alnico.

In the step (1), the alcohol solvent is methanol, ethanol, isopropanol or propanol.

Preferably, the alcoholic solvent is methanol or ethanol.

According to the preferable technical scheme, in the step (1), the ratio of glucose to alcohol solvent is 1: 5-6. In the step (2), the ratio of glucose to the nickel-containing ternary powder catalyst is = 1: 0.05. In the step (2), the pressure of hydrogen is 1.0-2.0 MPa.

In the technical scheme, in the step (3), the post-treatment comprises cooling the filtrate to 0-10 ℃ for crystallization, filtering, and drying the solid to obtain the N-ethyl-D-glucosamine.

In the above technical solution, the stirring in step (1) may be mechanical stirring or magnetic stirring, preferably magnetic stirring.

Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:

1. the invention firstly dissolves glucose in alcohol, and then introduces monoethylamine gas, and then adopts a nickel ternary catalyst to carry out catalytic hydrogenation reaction, so that the obtained product has high purity (the titration content is more than 99.6 percent), high yield and reduced production cost. Overcomes the difficulties of low product purity and repeated recrystallization in the prior art.

2. The preparation method has the characteristics of milder and safer reaction conditions, simple and convenient operation, high yield, low cost, good quality and the like, and has wide application prospect.

Drawings

FIG. 1 is a reaction equation for preparing N-ethyl-D-glucosamine in example 1 of the present invention;

FIG. 2 is an infrared spectrum of the N-ethyl-D-glucosamine compound prepared in example 1 of the present invention.

Detailed Description

The invention is further described with reference to the following figures and examples:

example 1:

adding 250g of methanol into a hydrogenation kettle, adding 50g (0.278 mol) of glucose, introducing 50g (1.11 mol) of monoethylamine under stirring, and keeping the temperature at 25-35 ℃ for 30 min; adding 2.5g of aluminum-nickel-iron ternary powder catalyst, sealing, performing nitrogen replacement on the system, keeping the hydrogen pressure at 1.0-2.0 MPa and the system temperature at 60-80 ℃, and stirring for reaction for 12 hours. Cooling, decompressing, filtering to remove the catalyst, freezing, crystallizing, filtering and drying the solid under stirring to obtain 55g of N-ethyl-D-glucosamine with the yield of 94.73 percent. The titration content was 99.8%.

The reaction process of this example can be expressed by the reaction equation of fig. 1.

FIG. 2 is an infrared spectrum of the product of this example (test analysis of the department of chemistry and chemistry at the university of Suzhou).

Example 2:

adding 1000g of methanol into a hydrogenation kettle, adding 180g (1 mol) of glucose, introducing 180g (4 mol) of monoethylamine under stirring, and keeping the temperature at 25-35 ℃ for 30 min; adding 9g of aluminum-nickel-iron ternary powder catalyst, sealing, replacing the nitrogen in the system, keeping the hydrogen pressure at 1.0-2.0 MPa and the system temperature at 60-80 ℃, and stirring for reaction for 12 hours. Cooling, decompressing, filtering to remove the catalyst, freezing, crystallizing, filtering and drying the solid under stirring to obtain 200g of N-ethyl-D-glucosamine with the yield of 95.69 percent. The titration content was 99.6%.

Example 3:

adding 1000g of ethanol into a hydrogenation kettle, adding 180g (1 mol) of glucose, introducing 180g (4 mol) of monoethylamine under stirring, and keeping the temperature at 25-35 ℃ for 30 min; adding 9g of aluminum-nickel-iron ternary powder catalyst, sealing, replacing the nitrogen in the system, keeping the hydrogen pressure at 1.0-2.0 MPa and the system temperature at 60-80 ℃, and stirring for reaction for 12 hours. Cooling, decompressing, filtering to remove the catalyst, freezing, crystallizing, filtering and drying the solid under stirring to obtain 195g of N-ethyl-D-glucosamine with the yield of 93.3 percent. The titration content was 99.6%.

Example 4:

synthesis according to example 2; the aluminum nickel molybdenum ternary powder catalyst is used for replacing an aluminum nickel iron ternary powder catalyst, and the balance is not changed, so that 190g of N-ethyl-D-glucosamine is obtained, and the yield is 90.9%. The titration content was 99.8%.

Example 5:

synthesis according to example 2; the Al-Ni-Co ternary powder catalyst is used for replacing an Al-Ni-Fe ternary powder catalyst, and the balance is unchanged, so that 194g of N-ethyl-D-glucosamine is obtained, and the yield is 92.8%. The titration content was 99.7%.

Claims

1. A preparation method of N-ethyl-D-glucosamine is characterized by sequentially comprising the following steps:

2. The process for producing N-ethyl-D-glucosamine according to claim 1, wherein: the nickel-containing ternary powder catalyst is aluminum nickel iron, aluminum nickel zinc, aluminum nickel copper, aluminum nickel cobalt or aluminum nickel molybdenum.

3. The process for producing N-ethyl-D-glucosamine according to claim 2, wherein: in the nickel-containing ternary powder catalyst, the content of aluminum is 46-48% by mass, the content of nickel is 48-51% by mass, and the content of a third component is 2-4% by mass.

4. The process for producing N-ethyl-D-glucosamine according to claim 2, wherein: the nickel-containing ternary powder catalyst is aluminum nickel iron.

5. The process for producing N-ethyl-D-glucosamine according to claim 1, wherein: in the step (1), the alcohol solvent is methanol, ethanol, isopropanol or propanol.

6. The process for producing N-ethyl-D-glucosamine according to claim 5, wherein: in the step (1), the alcohol solvent is methanol or ethanol.

7. The process for producing N-ethyl-D-glucosamine according to claim 1, wherein: in the step (1), the ratio of glucose to an alcohol solvent is 1: 5-6.

8. The process for producing N-ethyl-D-glucosamine according to claim 1, wherein: in the step (2), the ratio of glucose to the nickel-containing ternary powder catalyst is = 1: 0.05.

9. The process for producing N-ethyl-D-glucosamine according to claim 1, wherein: in the step (2), the pressure of hydrogen is 1.0-2.0 MPa.

10. The process for producing N-ethyl-D-glucosamine according to claim 1, wherein: in the step (3), the post-treatment is to cool the filtrate to 0-10 ℃ for crystallization, filter and dry the solid to obtain the N-ethyl-D-glucosamine.