CN114315597B

CN114315597B - Preparation method of meglumine

Info

Publication number: CN114315597B
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: 2022-10-28
Anticipated expiration: 2042-01-21
Also published as: CN114315597A

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 skeletal nickel by using an aluminum nickel chromium rhodium alloy, methylamine gas is introduced into absolute ethyl alcohol to obtain an ethanol solution of methylamine, glucose is added, schiff base is prepared by reacting at 45 ℃, and then the skeletal nickel is used for hydrogenation under the pressure of 0.3MPa 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 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 obtained by a person skilled in the art without inventive step based on the embodiments of the present invention, are within the scope of protection 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 (150g, 0.833mol, 1.0eq.), adding 30% methylamine ethanol solution (121g, 1.166mol, 1.4eq.), adding Raney nickel (24 g), adding powdered 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 is 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 135.71g is obtained, and the yield is 83.5%.

Example 2

Adding 95% ethanol (560 g) into a reaction bottle, adding D-glucose (150g, 0.833mol, 1.0eq.), adding 30% methylamine ethanol solution (121g, 1.166mol, 1.4eq.), adding Raney nickel (15 g), adding powdered 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 is 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 134.09g, and 82.5%.

Example 3

Adding 95% ethanol (560 g) into a reaction bottle, adding D-glucose (150g, 0.833mol, 1.0eq.), adding 30% methylamine ethanol solution (103g, 0.999mol, 1.2eq.), adding Raney nickel (30 g), adding powdered NaY molecular sieve (12 g), stirring at 250rpm, heating to 40-50 ℃, and carrying out normal-pressure hydrogenation by using hydrogen until the hydrogen absorption speed is basically 0 to serve as the reaction 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 137.66g is obtained, and the yield is 84.7%.

Example 4

Adding 95% ethanol (560 g) into a reaction bottle, adding D-glucose (150g, 0.833mol, 1.0eq.), adding 30% methylamine ethanol solution (121g, 1.166mol, 1.4eq.), adding Raney nickel (24 g), adding powdered 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 is 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, namely 125.31g in total, wherein the yield is 77.1%.

Example 5

Adding 95% ethanol (560 g) into a reaction bottle, adding D-glucose (150g, 0.833mol, 1.0eq.), adding 30% methylamine ethanol solution (121g, 1.166mol, 1.4eq.), 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 is 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, namely 127.10g in total, and the yield is 78.2%.

Example 6

Adding 95% ethanol (560 g) into a reaction bottle, adding D-glucose (150g, 0.833mol, 1.0eq.), adding 30% methylamine ethanol solution (172g, 1.665mol, 2eq.), adding Raney nickel (24 g), adding powdered NaY molecular sieve (15 g), stirring at 250rpm, heating to 40-50 ℃, and carrying out normal-pressure hydrogenation by using hydrogen until the hydrogen absorption speed is basically 0, wherein the reaction is 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 in total 136.04g with the yield of 83.7%.

Example 7

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

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 (150g, 0.833mol, 1.0eq.), adding 40% methylamine methanol solution (91g, 1.166mol, 1.4eq.), adding Raney nickel (24 g), adding powdered NaY molecular sieve (12 g), stirring at the speed of 300rpm, heating to 40-50 ℃, and performing hydrogenation under normal pressure by using hydrogen until the hydrogen absorption speed is basically 0, wherein the reaction end point is set;

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:

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

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

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

wherein, in the step 1, the methylamine alcohol solution is methylamine ethanol solution or methylamine methanol solution; the stirring speed in the reaction process is 50-300rpm, and the reaction temperature is 40-50 ℃;

the NaY molecular sieve is in a powder shape;

in the step 1-2, the weight ratio of D-glucose, raney nickel and NaY molecular sieve is 1 (0.1-0.2) to 0.02-0.1;

the molar ratio of the D-glucose to the methylamine is 1 (1.2-2.0).