WO2021223425A1 - Method for refining dabigatran crude product - Google Patents

Abstract

The present invention relates to a method for refining a dabigatran crude product. The method is refining a dabigatran crude product by means of acetone/water, and then refining same using ethyl acetate to obtain refined dabigatran. The method features high dabigatran crude product refining yield, high product purity and a small number of refinements, can reduce the use amount of a solvent and improve working efficiency, and is prone to be industrialized.

Description

Method for refining crude dabigatran etexilate Technical field

The invention belongs to the field of medicine refining, and relates to a refining process of medicines, in particular to a refining process of crude dabigatran etexilate.

Background technique

Dabigatran etexilate mesylate is a new oral anticoagulant drug developed by Boehringer Ingelheim, Germany. Dabigatran etexilate mesylate was first marketed in Germany and the UK in April 2008 under the trade name Pradaxa. In October 2010, it was approved by the FDA to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. Dabigatran etexilate mesylate is the first new oral direct anticoagulant drug to be marketed in 50 years after warfarin. The launch of dabigatran etexilate mesylate is a major breakthrough in the field of anticoagulation therapy and the field of potentially fatal thrombosis prevention and is of milestone significance.

The total impurities of the existing dabigatran mesylate compounds generally require ≤3.6%, which has higher requirements for product purity. The current purification method of dabigatran etexilate mesylate is mainly to first refine the crude dabigatran etexilate, and then use the refined dabigatran etexilate to react with methanesulfonic acid to synthesize dabigatran etexilate mesylate. The difficulty in refining crude dabigatran etexilate lies in the following points: 1. There are too many refining times, which is not conducive to industrial production; 2. The yield after multiple refining is too low 3. There are multiple stubborn impurities and the content of impurities in the refining process The reduction is very slow, and the purity of the product is not up to standard;

The chemical structure of dabigatran etexilate is as follows:

Patent No. WO2014/020546A2 uses hexanol, tert-butanol, and toluene as solvents to refine dabigatran etexilate and prepare the corresponding crystal form. Except for toluene, the refining rate is only 60% to 70%. After being qualified, there is almost no yield, and the impurity content in the refining process continues to increase; although the refining rate of toluene as a solvent can reach 85%, there is almost no refining effect, and the impurity content hardly decreases.

Liu Xiaojun, Chen Guohua.Synthesis of dabigatran etexilate[J].Applied Chemistry, 2013, 30(4):373-377. Using eluent (V dichloromethane: V methanol=20:1) for dabigatran The crude gatran etexilate was purified by silica gel column, and the yield was only 70%.

The industrial production of drugs requires high yields and high timeliness, and the particularity of drugs requires high purity. Therefore, the development of a purification method with high purity, high yield and high aging has certain production and application value.

Summary of the invention

The purpose of the present invention is to provide a method for refining crude dabigatran etexilate, which improves product purity, improves refining rate, reduces refining times, reduces solvent usage, improves work efficiency, and is simple to operate and easy to realize industrialization .

The method for refining crude dabigatran etexilate provided by the present invention includes the following steps:

(1) Put the crude acetone and dabigatran etexilate into the reactor, dissolve it by heating, and filter while it is hot. Purified water was added to the filtrate, cooled and stirred for 4 hours to crystallize, and then filtered to obtain a solid. The solid was vacuum dried at 45°C (-0.1MPa) to constant weight (weight loss less than 2%) to obtain a refined product of dabigatran etexilate. .

(2) The primary refined dabigatran etexilate was heated and dissolved in ethyl acetate, cooled and stirred for 4 hours to crystallize, and filtered to obtain a solid. The solid was vacuum dried at 45°C (-0.1MPa) to a constant weight to obtain a refined product. Dabigatran etexilate.

Wherein, the volume of acetone added in step (1) is 10-15 times of the crude quality of dabigatran etexilate, and the volume of purified water added is 5-10 times of the crude quality of dabigatran etexilate.

Among them, the temperature for heating and dissolving in step (1) is 30-50°C, and the temperature for stirring and crystallization is 15-30°C

Among them, the volume of ethyl acetate added in step (2) is 10-15 times the mass of the solid

Among them, the temperature for heating and dissolving in step (2) is 70-80°C, and the temperature for stirring and crystallization is 15-25°C

The crude dabigatran etexilate was synthesized using the compounds 3-[(3-amino-4-methylaminobenzoyl)pyridin-2-ylamino]propionate ethyl and N-(4-cyanophenyl)amino Acetic acid is the starting material, CDI is used as a condensing agent, cyclized in acetic acid, and then the intermediate product is amidinated with hydrochloric acid ethanol and ammonia gas, and finally potassium carbonate is used as an acid binding agent to react with n-hexyl chloroformate to obtain the product. Crude dabigatran etexilate HPLC: purity 95%.

There are many types of impurities in the crude dabigatran etexilate, which makes recrystallization difficult. In the small-scale research process of the present invention, methanol, ethanol, and DMF are first tried as recrystallization solvents, and it is found that the crude dabigatran etexilate is stable in alcohol solvents. The performance is poor, and then try to recrystallize with acetone, and the total impurities can be reduced to less than 2.8%. Subsequent recrystallization with acetone/water, DMF/water, and acetone/methyl tert-butyl ether systems found that acetone/water recrystallization can reduce the total impurities to within 1.1%, and the effect is better. The crude dabigatran etexilate was used to try different volume ratios of acetone/water recrystallization, and the HPLC purity was not much different. The 2/1 volume ratio of acetone/water recrystallization yield was higher:

Refining process

Yield

Purity (area normalized)

Maximum single miscellaneous

Acetone crystal 1 time	82.1%	97.216%	1.410%
Acetone/water (1/1) crystallize once	90.4%	98.912%	0.215%
Acetone/water (2/1) crystallize once	94.1%	98.938%	0.208%
Acetone/water (3/1) crystallize once	91.7%	98.915%	0.245%
Acetone/water (4/1) crystallize once	85.0%	98.907%	0.221%

In subsequent studies, it was found that the crude dabigatran etexilate purified by acetone/water had small polar impurities that were difficult to remove, and the effect of recrystallization with acetone/water was not good. To control all single impurities below 0.1%, it is necessary to consider recrystallization with other solvents. In the experiment, it was found that impurities with small polarity are difficult to remove. Try chloroform, dichloromethane, ethyl acetate, and tetrahydrofuran as the recrystallization Solvent, the result of ethyl acetate recrystallization yield is the best, and the maximum single impurity energy is effectively controlled within 0.1%:

Acetone/water recrystallization can effectively remove large-polar impurities, while ethyl acetate recrystallization can effectively remove small-polar impurities. In addition, due to the poor stability of the final product dabigatran etexilate mesylate in aqueous solvents, it is required to control the water content of the subsequent salt-forming reaction system. Therefore, it is finally formulated to recrystallize with acetone/water (volume ratio greater than 1) and then use it. The purification scheme of ethyl acetate recrystallization, this acetone/water dosage ratio and crystallization sequence facilitates the control of the moisture in the refined dabigatran etexilate.

The present invention uses acetone/water and ethyl acetate as solvents to refine the crude dabigatran etexilate, analyzes the different impurities in the crude dabigatran etexilate, and selects a suitable variety of solvents and a suitable amount of solvent to ensure The yield of the product is improved, and the purity of the product is guaranteed. There are only two refining times, which reduces the amount of solvent used and improves production efficiency; using acetone/water and ethyl acetate as refining solvents, the refining yield is high, reaching more than 83%; the product purity is high, and the refined dabiga The HPLC content of group esters can reach more than 99.7%, and the maximum single impurities can be controlled within 0.05%.

Detailed ways

Example 1:

Put 180 mL of acetone and 15.0 g of crude dabigatran etexilate into the reactor, heat to dissolve at 50°C, and filter while hot. The filtrate was heated to 50°C, 60mL purified water was added to the filtrate, and the temperature was reduced to 25°C for about 1.5h. The mixture was stirred at 25°C for 4h to crystallize and filtered to obtain a solid. The solid was vacuum dried at 45°C (-0.1MPa) to a constant weight. (The weight loss is less than 2%), and 14.1 g of dabigatran etexilate primary refined product is obtained. Dissolve 14.1g of the primary refined product of dabigatran etexilate with 169mL of ethyl acetate by heating at 75°C, cooling to 25°C for about 4h, stirring at 25°C for 4h, suction filtration to obtain a solid, and drying the solid at 45°C under vacuum (-0.1 MPa) to constant weight to obtain refined dabigatran etexilate. Yield: 83.6%, HPLC: purity 99.78%, maximum single impurities: 0.042%. Moisture: 0.25%

Example 2:

Put 11.4L of acetone and 1.14Kg of crude dabigatran etexilate into the reactor, dissolve by heating at 40°C, and filter while hot. The filtrate was heated to 40°C, 5.7L of purified water was added to the filtrate, the temperature was reduced to 20°C for about 1.5h, and the mixture was stirred at 20°C for 4h to crystallize. The solid was filtered off with suction. The solid was vacuum dried at 45°C (-0.1MPa) to Constant weight (weight loss less than 2%), to obtain 1.07kg of dabigatran etexilate once refined product. Dissolve 1.07 kg of dabigatran etexilate primary refined product with 10.7L ethyl acetate at 70°C and dissolve it by heating at 70°C, cooling down to 20°C for about 4h, stirring at 20°C for 4h, filtering to obtain a solid, and vacuum drying the solid at 45°C (-0.1MPa) to constant weight to obtain refined dabigatran etexilate. Yield: 85.2%, HPLC: purity 99.82%, maximum single impurities: 0.045%. Moisture: 0.22%

Claims (5)

1. A method for refining crude dabigatran etexilate, which is characterized by comprising the following steps:

   (1) Put the crude acetone and dabigatran etexilate into the reactor, dissolve it by heating, and filter while it is hot. Purified water was added to the filtrate, cooled and stirred for 4 hours to crystallize, and then filtered to obtain a solid. The solid was vacuum dried at 45°C (-0.1MPa) to constant weight (weight loss less than 2%) to obtain a refined product of dabigatran etexilate. .

   (2) The primary refined dabigatran etexilate was heated and dissolved in ethyl acetate, cooled and stirred for 4 hours to crystallize, and then filtered to obtain a solid, dried under vacuum at 45°C (-0.1MPa) to constant weight (weight loss less than 2%), The refined dabigatran etexilate was obtained.
2. The refining method according to claim 1, characterized in that the volume of acetone added in step (1) is 10-15 times the crude quality of dabigatran etexilate, and the volume of purified water added is the crude quality of dabigatran etexilate. 5-10 times.
3. The refining method according to claim 1, characterized in that the temperature for heating and dissolving in step (1) is 30-50°C, and the temperature for stirring and crystallization is 15-30°C.
4. The refining method according to claim 1, wherein the volume of ethyl acetate added in step (2) is 10-15 times the mass of the solid.
5. The refining method according to claim 1, wherein in step (2), the temperature for heating and dissolving is 70-80°C, and the temperature for stirring and crystallization is 15-25°C.