阅读说明：本技术 一种氨甲环酸及其制备方法 (Tranexamic acid and preparation method thereof ) 是由 孙学喜 杨会来 毛杰 于 2020-06-18 设计创作，主要内容包括：本发明公开了一种氨甲环酸及其制备方法,通过对溴甲苯为原料,将对溴甲苯制备成格氏试剂,格氏试剂进一步与二氧化碳加成反应,并在酸性条件下水解得到对甲基苯甲酸,对甲基苯甲酸与N-溴代琥珀酰亚胺进行溴的取代反应制得中间体1,将中间体1通过相转移催化反应制得中间体2,将中间体2与氨气的饱和甲苯溶液进行反应将中间体2上醇羟基替换成氨基,制得中间体3,中间体3与氢气在负载型镍催化剂的作用下氢化制得氨甲环酸,本发明制备氨甲环酸的制备方法制得的氨甲环酸的产率高,且与现有制备方法相比,使用的原料多为价格较低的原料,大大降低了氨甲环酸的生产成本。(The invention discloses tranexamic acid and a preparation method thereof, which comprises the steps of preparing a Grignard reagent from p-bromotoluene serving as a raw material, further performing addition reaction on the Grignard reagent and carbon dioxide, hydrolyzing under an acidic condition to obtain p-toluic acid, the preparation method of the invention has the advantages that the yield of the tranexamic acid prepared by the preparation method of the invention is high, compared with the existing preparation method, the used raw materials are mostly low-price raw materials, so that the production cost of tranexamic acid is greatly reduced.)

1. Tranexamic acid, characterized in that: the method comprises the following steps:

step S1: adding magnesium powder, iodine powder and tetrahydrofuran into a reaction kettle, using nitrogen for protection, dropwise adding p-bromotoluene under the conditions that the rotating speed is 100-160 ℃ and the temperature is 155-160 ℃, performing reflux reaction for 1-2h, introducing carbon dioxide to fill the reaction kettle, performing reaction for 30-40min under the condition that the temperature is 3-5 ℃, adding a hydrochloric acid solution, and performing reaction for 1-1.5h to prepare p-toluic acid;

step S2: adding the p-toluic acid, the N-bromosuccinimide and the carbon tetrachloride prepared in the step S1 into a reaction kettle, stirring at the rotation speed of 200-300r/min until the toluic acid and the N-bromosuccinimide are completely dissolved, adding dibenzoyl peroxide, and performing reflux reaction at the temperature of 80-90 ℃ for 2-4h to prepare an intermediate 1;

step S3: adding sodium carbonate and deionized water into a reaction kettle, stirring at the rotation speed of 200-300r/min until the sodium carbonate is completely dissolved, adding tetraethylammonium bromide and the intermediate 1 prepared in the step S2, and performing reflux reaction at the temperature of 110-120 ℃ for 1.5-2h to prepare an intermediate 2;

step S4: adding the intermediate 2 prepared in the step S3 and a saturated toluene solution of ammonia gas into a reaction kettle, stirring until the intermediate 2 is completely dissolved, adding activated alumina, and performing reflux reaction for 15-20h under the conditions that the pressure is 5-7MPa and the temperature is 200-220 ℃ to prepare an intermediate 3;

step S5: adding the intermediate 3 prepared in the step S4 and deionized water into a stirring kettle, stirring at the temperature of 60-70 ℃ until the intermediate 3 is completely dissolved to prepare a dissolving solution, wherein the pressure is 0.3-1MPa, the temperature is 320-350 ℃, and the airspeed of the dissolving solution is 5-8h^-1Under the condition of (1), the catalyst is contacted with a supported nickel catalyst to react to prepare the tranexamic acid.

2. Tranexamic acid according to claim 1, characterized in that: the use amount ratio of the magnesium powder, the iodine powder, the tetrahydrofuran, the p-bromotoluene and the hydrochloric acid solution in the step S1 is 3 g: 0.1 g: 5mL of: 3mL of: 2mL, and the mass fraction of the hydrochloric acid solution is 5-10%.

3. Tranexamic acid according to claim 1, characterized in that: the dosage ratio of the p-toluic acid, the N-bromosuccinimide, the carbon tetrachloride and the dibenzoyl peroxide in the step S2 is 1 g: 2 g: 5mL of: 0.5 g.

4. Tranexamic acid according to claim 1, characterized in that: the dosage ratio of the sodium carbonate, the deionized water, the tetraethylammonium bromide and the intermediate 1 in the step S3 is 1 g: 5mL of: 0.2 mL: 1g of the total weight of the composition.

5. Tranexamic acid according to claim 1, characterized in that: the dosage ratio of the intermediate 2, the saturated toluene solution of ammonia gas and the activated alumina in the step S4 is 2 g: 5mL of: 1g of the total weight of the composition.

6. Tranexamic acid according to claim 1, characterized in that: the using amount ratio of the intermediate 3 to the deionized water in the step S5 is 1 g: 3 mL.

7. The method for producing tranexamic acid according to claim 1, wherein: the method specifically comprises the following steps:

step S1: adding magnesium powder, iodine powder and tetrahydrofuran into a reaction kettle, using nitrogen for protection, dropwise adding p-bromotoluene under the conditions that the rotating speed is 100-160 ℃ and the temperature is 155-160 ℃, performing reflux reaction for 1-2h, introducing carbon dioxide to fill the reaction kettle, performing reaction for 30-40min under the condition that the temperature is 3-5 ℃, adding a hydrochloric acid solution, and performing reaction for 1-1.5h to prepare p-toluic acid;

step S2: adding the p-toluic acid, the N-bromosuccinimide and the carbon tetrachloride prepared in the step S1 into a reaction kettle, stirring at the rotation speed of 200-300r/min until the toluic acid and the N-bromosuccinimide are completely dissolved, adding dibenzoyl peroxide, and performing reflux reaction at the temperature of 80-90 ℃ for 2-4h to prepare an intermediate 1;

step S3: adding sodium carbonate and deionized water into a reaction kettle, stirring at the rotation speed of 200-300r/min until the sodium carbonate is completely dissolved, adding tetraethylammonium bromide and the intermediate 1 prepared in the step S2, and performing reflux reaction at the temperature of 110-120 ℃ for 1.5-2h to prepare an intermediate 2;

step S4: adding the intermediate 2 prepared in the step S3 and a saturated toluene solution of ammonia gas into a reaction kettle, stirring until the intermediate 2 is completely dissolved, adding activated alumina, and performing reflux reaction for 15-20h under the conditions that the pressure is 5-7MPa and the temperature is 200-220 ℃ to prepare an intermediate 3;

step S5: adding the intermediate 3 prepared in the step S4 and deionized water into a stirring kettle, stirring at the temperature of 60-70 ℃ until the intermediate 3 is completely dissolved to prepare a dissolving solution, wherein the pressure is 0.3-1MPa, the temperature is 320-350 ℃, and the airspeed of the dissolving solution is 5-8h^-1Under the condition of (1), the catalyst is contacted with a supported nickel catalyst to react to prepare the tranexamic acid.

Technical Field

The invention belongs to the technical field of chemical medicine preparation, and particularly relates to tranexamic acid and a preparation method thereof.

Background

Tranexamic acid: the alias tranexamic acid has the following advantages compared with the traditional hemostatic tranexamic acid, namely tranexamic acid 14: the hemostatic powder has the advantages of wide hemostatic range, quick action, less side effect, convenient use of various clinical preparations (such as small-volume injection, large-volume injection, tablets, freeze-dried powder injection and the like), and wide application, and can be widely used as a first-line hemostatic medicine in various departments clinically and daily chemical products such as skin care products, toothpaste and the like in daily life. The process deepening research of the product is significant, and the product has wider application range and larger dosage, and can not only create good economic benefit, but also create good social benefit.

The yield of the tranexamic acid prepared by the existing tranexamic acid preparation process is low, and the price of raw materials used for preparing the tranexamic acid is high, so that the preparation cost of the tranexamic acid is greatly improved, and further the market popularization is not facilitated.

Disclosure of Invention

The invention aims to provide tranexamic acid and a preparation method thereof.

The technical problems to be solved by the invention are as follows:

the yield of the tranexamic acid prepared by the existing tranexamic acid preparation process is low, and the price of raw materials used for preparing the tranexamic acid is high, so that the preparation cost of the tranexamic acid is greatly improved, and further the market popularization is not facilitated.

The purpose of the invention can be realized by the following technical scheme:

tranexamic acid is prepared by the following steps:

step S1: adding magnesium powder, iodine powder and tetrahydrofuran into a reaction kettle, using nitrogen for protection, dropwise adding p-bromotoluene under the conditions that the rotating speed is 100-160 ℃ and the temperature is 155-160 ℃, performing reflux reaction for 1-2h, introducing carbon dioxide to fill the reaction kettle, performing reaction for 30-40min under the condition that the temperature is 3-5 ℃, adding a hydrochloric acid solution, and performing reaction for 1-1.5h to prepare p-toluic acid;

step S2: adding the p-toluic acid, the N-bromosuccinimide and the carbon tetrachloride prepared in the step S1 into a reaction kettle, stirring at the rotation speed of 200-300r/min until the toluic acid and the N-bromosuccinimide are completely dissolved, adding dibenzoyl peroxide, and performing reflux reaction at the temperature of 80-90 ℃ for 2-4h to prepare an intermediate 1;

the reaction process is as follows:

step S3: adding sodium carbonate and deionized water into a reaction kettle, stirring at the rotation speed of 200-300r/min until the sodium carbonate is completely dissolved, adding tetraethylammonium bromide and the intermediate 1 prepared in the step S2, and performing reflux reaction at the temperature of 110-120 ℃ for 1.5-2h to prepare an intermediate 2;

the reaction process is as follows:

step S4: adding the intermediate 2 prepared in the step S3 and a saturated toluene solution of ammonia gas into a reaction kettle, stirring until the intermediate 2 is completely dissolved, adding activated alumina, and performing reflux reaction for 15-20h under the conditions that the pressure is 5-7MPa and the temperature is 200-220 ℃ to prepare an intermediate 3;

the reaction process is as follows:

step S5: deionizing the intermediate 3 obtained in step S4Adding water into a stirring kettle, stirring at 60-70 deg.C until the intermediate 3 is completely dissolved to obtain a solution at a pressure of 0.3-1MPa and a temperature of 320-350 deg.C, and an airspeed of 5-8h^-1Under the condition of (1), the catalyst is contacted with a supported nickel catalyst to react to prepare the tranexamic acid.

The reaction process is as follows:

further, in step S1, the ratio of the magnesium powder, iodine powder, tetrahydrofuran, p-bromotoluene, and hydrochloric acid solution is 3 g: 0.1 g: 5mL of: 3mL of: 2mL, and the mass fraction of the hydrochloric acid solution is 5-10%.

Further, in step S2, the dosage ratio of the p-toluic acid, the N-bromosuccinimide, the carbon tetrachloride and the dibenzoyl peroxide is 1 g: 2 g: 5mL of: 0.5 g.

Further, the dosage ratio of the sodium carbonate, the deionized water, the tetraethylammonium bromide and the intermediate 1 in the step S3 is 1 g: 5mL of: 0.2 mL: 1g of the total weight of the composition.

Further, the using ratio of the intermediate 2, the saturated toluene solution of ammonia gas and the activated alumina in the step S4 is 2 g: 5mL of: 1g of the total weight of the composition.

Further, the ratio of the intermediate 3 and the deionized water in the step S5 is 1 g: 3 mL.

Further, the preparation method of tranexamic acid specifically comprises the following steps:

step S1: adding magnesium powder, iodine powder and tetrahydrofuran into a reaction kettle, using nitrogen for protection, dropwise adding p-bromotoluene under the conditions that the rotating speed is 100-160 ℃ and the temperature is 155-160 ℃, performing reflux reaction for 1-2h, introducing carbon dioxide to fill the reaction kettle, performing reaction for 30-40min under the condition that the temperature is 3-5 ℃, adding a hydrochloric acid solution, and performing reaction for 1-1.5h to prepare p-toluic acid;

step S2: adding the p-toluic acid, the N-bromosuccinimide and the carbon tetrachloride prepared in the step S1 into a reaction kettle, stirring at the rotation speed of 200-300r/min until the toluic acid and the N-bromosuccinimide are completely dissolved, adding dibenzoyl peroxide, and performing reflux reaction at the temperature of 80-90 ℃ for 2-4h to prepare an intermediate 1;

step S3: adding sodium carbonate and deionized water into a reaction kettle, stirring at the rotation speed of 200-300r/min until the sodium carbonate is completely dissolved, adding tetraethylammonium bromide and the intermediate 1 prepared in the step S2, and performing reflux reaction at the temperature of 110-120 ℃ for 1.5-2h to prepare an intermediate 2;

step S4: adding the intermediate 2 prepared in the step S3 and a saturated toluene solution of ammonia gas into a reaction kettle, stirring until the intermediate 2 is completely dissolved, adding activated alumina, and performing reflux reaction for 15-20h under the conditions that the pressure is 5-7MPa and the temperature is 200-220 ℃ to prepare an intermediate 3;

step S5: adding the intermediate 3 prepared in the step S4 and deionized water into a stirring kettle, stirring at the temperature of 60-70 ℃ until the intermediate 3 is completely dissolved to prepare a dissolving solution, wherein the pressure is 0.3-1MPa, the temperature is 320-350 ℃, and the airspeed of the dissolving solution is 5-8h^-1Under the condition of (1), the catalyst is contacted with a supported nickel catalyst to react to prepare the tranexamic acid.

The invention has the beneficial effects that: the invention prepares tranexamic acid, p-bromotoluene is used as a raw material to prepare a Grignard reagent, the Grignard reagent is further subjected to addition reaction with carbon dioxide and is hydrolyzed under an acidic condition to obtain p-toluic acid, the preparation method of the invention has the advantages that the yield of the tranexamic acid prepared by the preparation method of the invention is high, compared with the existing preparation method, the used raw materials are mostly low-price raw materials, so that the production cost of tranexamic acid is greatly reduced.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described 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.