CN114315597A

CN114315597A - Preparation method of meglumine

Info

Publication number: CN114315597A
Application number: CN202210069474.6A
Authority: CN
Inventors: 李强; 刘雅辉; 黎克湖; 王宇斌; 符朝业
Original assignee: Hainan Zhuoke Pharmaceutical Co ltd
Current assignee: Hainan Zhuoke Pharmaceutical Co ltd
Priority date: 2022-01-21
Filing date: 2022-01-21
Publication date: 2022-04-12
Anticipated expiration: 2042-01-21
Also published as: CN114315597B

Abstract

The invention relates to the field of medicine, in particular to a preparation method of meglumine, which is characterized in that when raney nickel is used for hydrogenation reduction, a powdery NaY molecular sieve is added, and the hydrogenation reduction process can be completed by normal pressure catalytic hydrogenation.

Description

Preparation method of meglumine

Technical Field

The invention relates to the field of medicines, in particular to a preparation method of meglumine.

Background

In the pharmaceutical industry, meglumine is widely used as an alkaline group to form a salt with an acidic drug to improve the solubility and stability of the drug, and as shown in figure 1, the preparation method comprises the steps of reacting methylamine with D-glucose, and then carrying out pressure hydrogenation reduction to obtain the meglumine.

Chinese patent application CN112479906A discloses a technical scheme for preparing skeleton nickel by using an aluminum nickel chromium rhodium alloy, which comprises the steps of introducing methylamine gas into absolute ethyl alcohol to obtain an ethanol solution of methylamine, adding glucose, reacting at 45 ℃ to prepare Schiff base, and then hydrogenating under the pressure of 0.3MPa by using the skeleton nickel to obtain meglumine.

The existing preparation method of meglumine is characterized in that the hydrogenation process is carried out under the condition of pressurization, the problem of safe use of hydrogenation pressurization equipment needs to be considered in the industrial application process, the use permission of a safety supervision and management department needs to be obtained, the safety is low, and the use is very inconvenient, so that the development of a preparation method of meglumine is urgently needed to overcome the defects in the current practical application.

Disclosure of Invention

The invention aims to provide a preparation method of meglumine, which aims to solve the problems in the background technology.

In order to achieve the purpose, the invention provides the following technical scheme:

a preparation method of meglumine comprises the following steps:

step 1: adding 95% ethanol, D-glucose, 30% methylamine alcohol solution, Raney nickel and NaY molecular sieve into a reaction bottle, stirring, and heating the reaction solution;

step 2: introducing hydrogen to carry out normal-pressure hydrogenation reduction, wherein the reaction end point is when the hydrogen absorption speed is zero;

and step 3: filtering Raney nickel and NaY molecular sieve, cooling the filtrate to 0-5 deg.C, stirring, and crystallizing;

and 4, step 4: and leaching the precipitated solid with 95% ethanol, and vacuum-drying at 80 +/-5 ℃ to obtain a finished product of meglumine.

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

when meglumine needs to be prepared, in the process of hydrogenation reduction by using raney nickel, a powdered NaY molecular sieve is added, and the hydrogenation reduction process can be completed by catalytic hydrogenation at normal pressure, so that a high-pressure hydrogenation reaction is avoided, the requirement on reaction equipment is lowered, the production safety is improved, convenience is provided for workers, and the method is worthy of popularization.

Drawings

FIG. 1 is a schematic diagram of the molecular structure of meglumine in an embodiment of the present invention.

Detailed Description

The technical solutions in the embodiments of the present invention will be described clearly and completely below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Specific implementations of the present invention are described in detail below with reference to specific embodiments.

Example 1

Adding 95% ethanol (560 g) into a reaction bottle, adding D-glucose (150 g, 0.833mol, 1.0 eq.), adding 30% methylamine ethanol solution (121 g, 1.166mol, 1.4 eq.), adding Raney nickel (24 g), adding powdery NaY molecular sieve (12 g), stirring at 250rpm, heating to 40-50 ℃, and hydrogenating under normal pressure by using hydrogen until the hydrogen absorption speed is basically 0, wherein the reaction end point is determined;

cooling the reaction liquid to 20 +/-5 ℃, filtering the reaction mixture, leaching a filter cake with 95% ethanol (300 g), cooling the filtrate to 0-5 ℃ for crystallization, filtering to obtain a wet meglumine product, and drying in vacuum at 80 +/-5 ℃ to obtain a finished meglumine product which is an off-white solid, wherein the yield is 135.71.5%.

Example 2

Adding 95% ethanol (560 g) into a reaction bottle, adding D-glucose (150 g, 0.833mol, 1.0 eq.), adding 30% methylamine ethanol solution (121 g, 1.166mol, 1.4 eq.), adding Raney nickel (15 g), adding powdery NaY molecular sieve (12 g), stirring at 250rpm, heating to 40-50 ℃, and hydrogenating under normal pressure by using hydrogen until the hydrogen absorption speed is basically 0, wherein the reaction end point is determined;

cooling the reaction liquid to 20 +/-5 ℃, filtering the reaction mixture, leaching a filter cake with 95% ethanol (300 g), cooling the filtrate to 0-5 ℃ for crystallization, filtering to obtain a wet meglumine product, and drying in vacuum at 80 +/-5 ℃ to obtain a finished meglumine product which is a white-like solid, wherein the yield is 134.09g, and 82.5%.

Example 3

Adding 95% ethanol (560 g) into a reaction bottle, adding D-glucose (150 g, 0.833mol, 1.0 eq.), adding 30% methylamine ethanol solution (103 g, 0.999mol, 1.2 eq.), adding raney nickel (30 g), adding powdery NaY molecular sieve (12 g), stirring at 250rpm, heating to 40-50 ℃, and hydrogenating under normal pressure by using hydrogen until the hydrogen absorption speed is basically 0, wherein the reaction end point is determined;

cooling the reaction liquid to 20 +/-5 ℃, filtering the reaction mixture, leaching a filter cake with 95% ethanol (300 g), cooling the filtrate to 0-5 ℃ for crystallization, filtering to obtain a wet meglumine product, and drying in vacuum at 80 +/-5 ℃ to obtain a finished meglumine product which is an off-white solid, wherein the yield is 137.66g, and the yield is 84.7%.

Example 4

Adding 95% ethanol (560 g) into a reaction bottle, adding D-glucose (150 g, 0.833mol, 1.0 eq.), adding 30% methylamine ethanol solution (121 g, 1.166mol, 1.4 eq.), adding Raney nickel (24 g), adding powdery NaY molecular sieve (3 g), stirring at 250rpm, heating to 40-50 ℃, and hydrogenating under normal pressure by using hydrogen until the hydrogen absorption speed is basically 0, wherein the reaction end point is determined;

cooling the reaction liquid to 20 +/-5 ℃, filtering the reaction mixture, leaching a filter cake with 95% ethanol (300 g), cooling the filtrate to 0-5 ℃ for crystallization, filtering to obtain a wet meglumine product, and drying in vacuum at 80 +/-5 ℃ to obtain a finished meglumine product which is an off-white solid, wherein the yield is 125.31g, and the yield is 77.1%.

Example 5

Adding 95% ethanol (560 g) into a reaction bottle, adding D-glucose (150 g, 0.833mol, 1.0 eq.), adding 30% methylamine ethanol solution (121 g, 1.166mol, 1.4 eq.), adding Raney nickel (24 g), adding powdery NaY molecular sieve (6 g), stirring at 250rpm, heating to 40-50 ℃, and hydrogenating under normal pressure by using hydrogen until the hydrogen absorption speed is basically 0, wherein the reaction end point is determined;

cooling the reaction liquid to 20 +/-5 ℃, filtering the reaction mixture, leaching a filter cake with 95% ethanol (300 g), cooling the filtrate to 0-5 ℃ for crystallization, filtering to obtain a wet meglumine product, and drying in vacuum at 80 +/-5 ℃ to obtain a finished meglumine product which is a white-like solid, wherein the yield is 127.10.2%.

Example 6

Adding 95% ethanol (560 g) into a reaction bottle, adding D-glucose (150 g, 0.833mol, 1.0 eq.), adding 30% methylamine ethanol solution (172 g, 1.665mol, 2 eq.), adding Raney nickel (24 g), adding powdery NaY molecular sieve (15 g), stirring at 250rpm, heating to 40-50 ℃, and hydrogenating under normal pressure by using hydrogen until the hydrogen absorption speed is basically 0, wherein the reaction end point is determined;

cooling the reaction liquid to 20 +/-5 ℃, filtering the reaction mixture, leaching a filter cake with 95% ethanol (300 g), cooling the filtrate to 0-5 ℃ for crystallization, filtering to obtain a wet meglumine product, and drying in vacuum at 80 +/-5 ℃ to obtain a finished meglumine product which is a white-like solid in total of 136.04g, wherein the yield is 83.7%.

Example 7

Adding 95% ethanol (560 g) into a reaction bottle, adding D-glucose (150 g, 0.833mol, 1.0 eq.), adding 30% methylamine ethanol solution (121 g, 1.166mol, 1.4 eq.), adding Raney nickel (24 g), adding powdery NaY molecular sieve (12 g), stirring at 50rpm, heating to 40-50 ℃, and hydrogenating under normal pressure by using hydrogen until the hydrogen absorption speed is basically 0, wherein the reaction end point is determined;

cooling the reaction liquid to 20 +/-5 ℃, filtering the reaction mixture, leaching a filter cake with 95% ethanol (300 g), cooling the filtrate to 0-5 ℃ for crystallization, filtering to obtain a wet meglumine product, and drying in vacuum at 80 +/-5 ℃ to obtain a finished meglumine product which is a white-like solid, wherein the yield is 109.22g, and 67.2%.

Example 8

Adding 95% ethanol (560 g) into a reaction bottle, adding D-glucose (150 g, 0.833mol, 1.0 eq.), adding 40% methylamine methanol solution (91 g, 1.166mol, 1.4 eq.), adding Raney nickel (24 g), adding powdery NaY molecular sieve (12 g), stirring at 300rpm, heating to 40-50 ℃, and hydrogenating under normal pressure by using hydrogen until the hydrogen absorption speed is basically 0, wherein the reaction is at the end point;

cooling the reaction liquid to 20 +/-5 ℃, filtering the reaction mixture, leaching a filter cake with 95% ethanol (300 g), cooling the filtrate to 0-5 ℃ for crystallization, filtering to obtain a wet meglumine product, and drying in vacuum at 80 +/-5 ℃ to obtain a finished meglumine product which is a white-like solid, wherein the yield is 137.37g and 84.5%.

Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.

Claims

1. The preparation method of meglumine is characterized by comprising the following steps:

2. The method for producing meglumine according to claim 1, wherein in step 1, the methylamine alcohol solution is a methylamine ethanol solution or a methylamine methanol solution.

3. The process for producing meglumine according to claim 1, wherein in step 1, the stirring speed during the reaction is 50 to 300rpm, and the reaction temperature is 40 to 50 ℃.

4. The method of claim 1, wherein the NaY molecular sieve is in powder form.

5. The method for preparing meglumine according to claim 1, wherein the silicon-aluminum ratio of the NaY molecular sieve is 1 (5-6).

6. The method for preparing meglumine according to claim 1, wherein in step 1-2, the weight ratio of D-glucose to Raney nickel to NaY molecular sieve is 1 (0.1-0.2) to (0.02-0.1).

7. The method for preparing meglumine according to claim 6, wherein the weight ratio of D-glucose to Raney nickel to NaY molecular sieve is 1:0.16: 0.08.

8. The process for producing meglumine according to claim 1, wherein the molar ratio of D-glucose to methylamine is 1 (1.2-2.0).