CN117603068A - A kind of preparation method of tranexamic acid - Google Patents

Abstract

The invention relates to a preparation method of tranexamic acid. The method comprises the following steps: adding p-cyanobenzoic acid into an autoclave, adding platinum black and a solvent, and then carrying out hydrogenation reaction under the conditions of 50-100 ℃ and 0.05-0.2 Mpa. Finishing the reaction, cooling and filtering; and (3) introducing a certain amount of liquid ammonia into the filtrate. Adding 5% Pd-C catalyst, and hydrogenation reaction at 100-150 deg.C and 2-4 MPa. Finishing the reaction, cooling and filtering; concentrating the filtrate under reduced pressure until solid is separated out, cooling to 0 ℃, filtering, washing with ethanol, and vacuum drying the solid to obtain tranexamic acid with the yield of more than 90%. The invention adopts the low-cost and easily-obtained p-cyanobenzoic acid as the raw material, and synthesizes the tranexamic acid by one step through 2 times of hydrogenation (benzene ring hydrogenation and cyano hydrogenation). Greatly reduces the production cost, improves the production environment, avoids the generation and discharge of toxic solid wastes, and greatly improves the quality of products.

Description

A kind of preparation method of tranexamic acid

Technical field

The invention belongs to the technical field of medicine and chemical industry and relates to a preparation method of tranexamic acid (hemostatic agent).

Background technique

Tranexamic acid is an effective hemostatic drug that reversibly blocks lysine bound to the plasminogen molecule, thereby producing an anti-fibrinogen dissolving effect. Its hemostatic mechanism is the same as the hemostatic drug aminocaproic acid, and its hemostatic effect is 5-10 times stronger than that of aminocaproic acid. It is mainly used for upper gastrointestinal bleeding, bleeding, surgical bleeding, and obstetric and gynecological bleeding. In addition, aminocarbic acid has certain effects on treating tonsil inflammation, tuberculosis and hemoptysis, acne, chloasma, etc. Although tranexamic acid is not a new drug, it is still the best and irreplaceable hemostatic drug in the world. There are two main methods for synthesizing tranexamic acid. One is the methyl acrylate method, which generates hemostatic acid through a series of reactions between methyl acrylate and chlorobutadiene; the other is the p-aminomethylbenzoic acid method. , tranexamic acid is generated from p-aminomethylbenzoic acid through catalytic hydrogenation and translocation. Since highly toxic cyanide is used in the methyl acrylate method, the p-aminomethylbenzoic acid method is mainly used in industry to produce tranexamic acid. Patent document US 3932497 describes the use of a Ru catalyst, loading Ru onto an inert carrier such as alumina, diatomaceous earth, activated carbon, barium sulfate, and calcium carbonate. The content of Ru in the catalyst is 1 to 10 wt%. When reacting at a temperature of 150°C and a hydrogen pressure of 100 kg/cm2, the conversion rate of p-aminomethylbenzoic acid is 100%, and the yield of p-aminomethylcyclohexylcarboxylic acid is 97%. Patent document JP 49062444 describes the use of Ru-C catalyst, adding 45g of p-aminomethylbenzoic acid, 16.7 gKOH, 100 ml H20 and 25g5% Ru-C into an autoclave at a temperature of 90°C and a hydrogen pressure of 90 kg/cm2 After reaction, 43.5g of p-aminomethylcyclohexylcarboxylic acid was obtained after product treatment. Patent document JP 58032848 describes the use of Rh catalyst, loading Rh on activated carbon to prepare a 5% Rh-C catalyst, the reaction temperature is 40°C, the hydrogen pressure is 30kg/cm2, the reaction is 3 hours, and the yield of aminomethylcyclohexanecarboxylic acid reaches 90%. The above patents do not report the method of transposition of aminomethylcyclohexanecarboxylic acid to generate tranexamic acid. Patent documents CN201410079178. The hydrogenation conversion rate is over 99.5%, and the yield is not recorded.

At present, industrial production mostly uses aminomethylaromatic acid as raw material, and uses low-pressure hydrogenation in sulfuric acid aqueous solution under the catalysis of platinum black to obtain cis-trans p-aminomethylcyclohexanoic acid. Use barium hydroxide to remove acid, and then use barium hydroxide as a catalyst to react for more than 20 hours at a reaction temperature of 180-220°C and a reaction pressure of 1-2.5Mpa to perform a translocation reaction. After cooling and acidification, tranexamic acid is obtained. , the yield is about 80%. This process uses expensive platinum as a catalyst, which greatly increases the production cost; it uses barium hydroxide as a neutralizer and translocation catalyst, and the barium sulfate and barium carbonate produced are highly toxic and cause serious harm to the environment.

Contents of the invention

In view of the problems existing in the existing production technology, the present invention provides a preparation method of tranexamic acid, which includes the following steps:

(1) Add p-cyanobenzoic acid to the autoclave, add platinum black and solvent, and then hydrogenate at 50-100°C, 0.05-0.2Mpa. End the reaction, cool and then filter to obtain the first filtrate;

(2) Pour a certain amount of liquid ammonia into the first filtrate. Add 5% palladium carbon catalyst, and then hydrogenate at 100-150°C and 2-4Mpa. End the reaction, cool and then filter to obtain the second filtrate;

(3) Concentrate the second filtrate under reduced pressure until solid precipitates, add 5 times the weight of ethanol relative to the second filtrate, cool to 0°C, filter, wash with ethanol, and dry the solid in vacuum to obtain tranexamic acid, The yield is over 90%.

The weight ratio of the above reaction materials is preferably: p-cyanobenzoic acid: platinum black: liquid ammonia: 5% palladium carbon catalyst: solvent =1:0.001:0.1:0.05:3;

The above solvent is methanol or ethanol;

Beneficial effects of the present invention: using cheap and easily available p-cyanobenzoic acid as raw material, tranexamic acid is synthesized in one step through two hydrogenations (benzene ring hydrogenation and cyano group hydrogenation), with a yield of more than 90%. It greatly reduces production costs, improves the production environment, avoids the generation and discharge of toxic solid waste, and greatly improves product quality.

Implementation

The following examples are used to further illustrate the content of the present invention and do not limit the application of the present invention. The percentages in the examples are always mass fractions.

Example 1

A preparation method of tranexamic acid, which includes the following steps:

(1) Add 147g of p-cyanobenzoic acid to a 1000ml autoclave, add 0.15g of platinum black and 441g of methanol, hydrogenate at 100°C, 0.05Mpa, and track with HPLC. After the reaction is completed, cool and filter to obtain the first The filtrate and separated catalyst can be used directly;

(2) Pour 14.7g of liquid ammonia into the first filtrate. Add 7.35g of 5% palladium on carbon catalyst, and then perform hydrogenation reaction at 100°C and 4Mpa. HPLC tracking, after the reaction is completed, cool and filter to obtain the second filtrate, and the separated catalyst can be used directly;

(3) Concentrate the second filtrate under reduced pressure until solid precipitates, add 5 times the amount of ethanol (weight ratio), cool to 0°C, filter, wash with ethanol, and dry the solid in vacuum to obtain 142g of tranexamic acid.

Example 2

A preparation method of tranexamic acid, which includes the following steps:

(1) Add 147g of p-cyanobenzoic acid to a 1000ml autoclave, add 0.15g of platinum black and 441g of methanol, hydrogenate at 50°C, 0.2Mpa, and track with HPLC. After the reaction is completed, cool and filter to obtain the first The filtrate and separated catalyst can be used directly;

(2) Pour 14.7g of liquid ammonia into the first filtrate. Add 7.35g of 5% palladium on carbon catalyst, and then perform hydrogenation reaction at 150°C and 2Mpa. HPLC tracking, after the reaction is completed, cool and filter to obtain the second filtrate, and the separated catalyst can be used directly;

(3) Concentrate the second filtrate under reduced pressure until solid precipitates, add 5 times the amount of ethanol (weight ratio), cool to 0°C, filter, wash with ethanol, and dry the solid in vacuum to obtain 144g of tranexamic acid.

Example 3

A preparation method of tranexamic acid, which includes the following steps:

(1) Add 147g of p-cyanobenzoic acid to a 1000ml autoclave, add 0.15g of platinum black and 441g of methanol, hydrogenate at 75°C, 0.13Mpa, and track with HPLC. After the reaction is completed, cool and filter to obtain the first The filtrate and separated catalyst can be used directly;

(2) Pour 14.7g of liquid ammonia into the first filtrate. Add 7.35 g of 5% palladium carbon catalyst, and then perform hydrogenation reaction at 125°C and 3Mpa. HPLC tracking, after the reaction is completed, cool and filter to obtain the second filtrate, and the separated catalyst can be used directly;

(3) Concentrate the second filtrate under reduced pressure until solid precipitates, add 5 times the amount of ethanol (weight ratio), cool to 0°C, filter, wash with ethanol, and dry the solid in vacuum to obtain 143g of tranexamic acid.

The above embodiments are only for illustrating the technical concepts and features of the present invention. Their purpose is to enable those familiar with the technology to understand the content of the present invention, and they are not intended to limit the scope of protection of the present invention. All equivalent changes and modifications made based on the essence of the spirit of the present invention should be included in the protection scope of the present invention.

Claims (3)

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

(1) Adding p-cyanobenzoic acid into an autoclave, adding platinum black and a solvent, and then carrying out hydrogenation reaction under the conditions of 50-100 ℃ and 0.05-0.2 Mpa; after finishing the reaction, cooling and filtering to obtain a first filtrate;

(2) Introducing liquid ammonia into the first filtrate, adding 5% palladium-carbon catalyst, and then carrying out hydrogenation reaction at 100-150 ℃ and 2-4 Mpa; after finishing the reaction, cooling and filtering to obtain a second filtrate;

(3) Concentrating the second filtrate under reduced pressure until solid is separated out, adding ethanol which is 5 times of the weight of the second filtrate, cooling to 0 ℃, filtering, washing with ethanol, and drying the solid in vacuum to obtain tranexamic acid.

2. The preparation method according to claim 1, wherein the p-cyanobenzoic acid is as follows: platinum black: liquid ammonia: 5% palladium carbon catalyst: solvent = 1:0.001:0.1:0.05:3.

3. the process according to claim 1 or 2, wherein the solvent is methanol or ethanol.