CN108727334B - Production process of dabigatran etexilate mesylate - Google Patents
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Abstract
The invention discloses a production process of dabigatran etexilate mesylate, which comprises the following steps of (1) preparing an intermediate PR-I; (2) preparing an intermediate PR-II; (3) preparing dabigatran etexilate PR-III; (4) refining dabigatran etexilate PR-III; (5) and preparing dabigatran etexilate mesylate and the like. The method has the advantages of mild reaction conditions in each step, simple reaction route, convenient operation and high selectivity, and can shorten the production period; the obtained dabigatran etexilate intermediate has low moisture content, and the prepared dabigatran etexilate mesylate has high yield and purity and low maximum single impurity content; the method has the advantages of less discharge of three wastes, environmental friendliness, no need of column chromatography purification, suitability for industrial production, capability of avoiding the requirement of palladium-carbon high-pressure hydrogenation on equipment and reduction of danger.
Description
Technical Field
The invention relates to a production process of dabigatran etexilate mesylate, belonging to the field of drug synthesis.
Background
Dabigatran etexilate mesylate is a novel oral anticoagulant drug developed by Boehringer Ingelheim, germany. Month 4, 2008, first in germany and uk under the trade name Pradaxa. Again, 10 months 2010 was FDA approved for reducing the risk of stroke and systemic embolism in non-valvular atrial fibrillation patients. Dabigatran etexilate was the first brand new oral direct anticoagulant drug to be marketed 50 years after warfarin. The appearance of the dabigatran etexilate mesylate is a great breakthrough in the field of anti-hemagglutination treatment and the field of potential lethal thrombus prevention, and has milestone significance. The chemical structural formula of the dabigatran etexilate mesylate is as follows:
several synthesis methods reported for the preparation of dabigatran etexilate mesylate at present are as follows:
1. developed by the company Bristle Vargham, Germany, and reported in patent CN 1972919B. The reaction yield of each step of the route is high, but the final step is palladium-carbon high-pressure catalytic reduction, palladium metal residue is likely to be large, and the synthesis risk is large.
2. A synthetic route for dabigatran etexilate was reported in 1998 (WO9837075a1) and 2002 (j.med.chem., 2002, 45, 1757-1766), respectively, by the company brigreger, germany. The total yield of the synthetic route is lower, the total yield is 36.6%, the separation of the final product and the intermediate is difficult, and a large amount of hydrogen chloride gas is needed when the phenylamidine intermediate is synthesized, so that the equipment is seriously corroded, and the environmental pollution is caused. Thionyl chloride is used in the second step, which is not beneficial to pilot-scale production; palladium carbon hydrogenation is used in the third step, so that the cost is relatively high and the risk is strong; in the literature, the products in each step are mostly separated by adopting a column chromatography method, and the pilot plant production is also not facilitated.
3. The synthesis condition of amidination of an dabigatran etexilate intermediate reported in the document "chenchen pine and the like", China journal of pharmaceutical industry, 2010, 41(5): 321-;
4. the synthesis conditions adopted in the literature of the Chinese medicinal chemistry 2012, 22(3):204-208 of the Ozobium japonicum Ohiouride et al are that the reaction is carried out with hydroxylamine hydrochloride, and then amidine products are obtained by reduction of amine formate and Pd/C, the conditions need to be catalyzed by noble metal palladium under the protection of nitrogen, the cost is higher, column chromatography purification is also needed, and the yield is 67%.
5. The literature "caishiqiang et al. improvements of dabigatran etexilate synthesis process. fine chemistry 2015, 32 (3): 308-311' takes a chemical I as an initial raw material, zinc chloride Lewis acid is adopted for catalysis to carry out Pinner reaction, cyano is subjected to alcoholysis to obtain an intermediate (II), the intermediate II is subjected to aminolysis by an ammonia water ethanol solution to obtain an amidinized product III, the intermediate III is acylated with n-hexyl chloroformate to obtain dabigatran etexilate IV, although a hydrogen chloride ethanol solution is used, the operation of introducing hydrogen chloride gas is also needed for preparing the solution, and the concentration of the solution is difficult to accurately quantify. Moreover, the operation of column chromatography is obviously disadvantageous for industrialization.
Therefore, the production process of the dabigatran etexilate mesylate at present needs to be further improved.
Disclosure of Invention
The invention aims to provide a production process of dabigatran etexilate mesylate, which has the advantages of mild reaction conditions in each step, simple operation of a synthesis method, high yield and purity, high efficiency and clean production, and is more easily controlled in quality of the dabigatran etexilate obtained by salt formation through refining of the dabigatran etexilate, and suitable for industrial production.
A production process of dabigatran etexilate mesylate comprises the following specific synthetic route:
a production process of dabigatran etexilate mesylate comprises the following steps:
preparation of S1 intermediate PR-I
Activating SM2 by CDI, amidating with SM1 in an organic solvent, evaporating the solvent, cyclizing in acetic acid, salifying with oxalic acid dihydrate, filtering, and drying to obtain intermediate PR-I;
preparation of S2 intermediate PR-II
The intermediate PR-I and the hydrochloric acid ethanol solution react through Pinner and then further react with ammonia to form amidine, and the amidine is filtered, concentrated, dissolved in an organic solvent, crystallized, centrifugally filtered and dried to obtain an intermediate PR-II;
preparation of S3 dabigatran etexilate PR-III
The intermediate PR-II reacts with batched n-hexyl chloroformate under the condition of a mixed system substance, and a crude product of dabigatran etexilate PR-III is obtained after liquid separation, concentration, dissolution, crystallization, filtration and drying;
s4 refining of dabigatran etexilate PR-III
Recrystallizing the PR-III crude product by using an organic solvent, water and ethyl acetate in sequence to obtain a PR-III refined product;
preparation of S5 dabigatran etexilate mesylate
Salifying and separating the PR-III refined product and methanesulfonic acid in acetone, filtering and drying to obtain dabigatran etexilate mesylate;
s6 pulverizing and sieving
And crushing and sieving the dabigatran etexilate mesylate to obtain a finished product.
Preferably, the production process of the dabigatran etexilate mesylate comprises the following steps:
preparation of S1 intermediate PR-I
Sequentially adding an organic solvent a, SM2 and CDI into a reaction kettle, stirring for reaction for 2.5-3.5 hours, sequentially adding SM1 and organic solvent b, continuing to stir for reaction for 11-13 hours, evaporating the solvent at 35-50 ℃ under reduced pressure, adding acetic acid into the reaction kettle, heating to 100 ℃ and 120 ℃ for reaction for 4.5-5.5 hours, evaporating the solvent at 100 ℃ under reduced pressure, adding dichloromethane, stirring for dissolution, washing with water, recovering the solvent by organic phase under reduced pressure, adding ethyl acetate into the obtained residue, stirring for dissolution, adding a solution containing oxalic acid dihydrate, stirring for crystallization for 1.5-2.5 hours at 20-25 ℃, centrifugally filtering, washing a filter cake with ethyl acetate, and drying the filter cake at 40-50 ℃ under reduced pressure for 5-7 hours to obtain a light yellow solid PR-I;
preparation of S2 intermediate PR-II
Adding a hydrochloric acid ethanol solution and PR-I into a reaction kettle, stirring for 4.5-5.5 hours for dissolution reaction, after the reaction is finished, evaporating the solvent under reduced pressure below 60 ℃, adding ethanol dissolution residues, controlling the temperature to carry out amination to form amidine, after the reaction is finished, filtering, washing a filter cake by using an organic solvent c, combining the filtrate, evaporating the solvent under reduced pressure below 60 ℃, dissolving the residues by using an organic solvent d, adding ethyl acetate, stirring and crystallizing at 20-25 ℃ for 3.5-4.5 hours, carrying out centrifugal filtration, washing by using ethyl acetate, and drying the filter cake under reduced pressure at 40-50 ℃ for 5-7 hours to obtain a white-like solid PR-II;
preparation of S3 dabigatran etexilate PR-III
Adding PR-II and a mixed system substance into a reaction kettle, stirring and dissolving at 35-40 ℃, adding n-hexyl chloroformate in batches until the reaction end point, separating liquid, recovering a solvent at 35-50 ℃ under reduced pressure of an organic phase, adding acetone into the obtained residue, heating and dissolving at 35-45 ℃, adding water, stirring and crystallizing at 20-25 ℃ for 2.5-3.5 hours, filtering, washing a filter cake with acetone and water, and drying the filter cake at 40-50 ℃ under reduced pressure for 5-7 hours to obtain a crude product of dabigatran etexilate PR-III;
s4 refining of dabigatran etexilate
Adding acetone and the PR-III crude product into a reaction kettle, heating and dissolving at 35-45 ℃, adding water, stirring and crystallizing for 2.5-3.5 hours at 20-25 ℃, filtering, washing a filter cake with acetone and water, drying the solid for 5-7 hours at 40-50 ℃ under reduced pressure to obtain a PR-III primary refined product, and recrystallizing and refining the PR-III refined product with ethyl acetate to obtain a PR-III refined product;
preparation of S5 dabigatran etexilate mesylate
Adding acetone and a PR-III refined product into a reaction kettle, heating to 35-45 ℃ for dissolving, filtering, adding methanesulfonic acid into filtrate, keeping the temperature and stirring for 1 hour, cooling to 20-25 ℃ for crystallization, filtering, washing a filter cake with acetone, and drying under reduced pressure for 5-7 hours at 40-50 ℃ to obtain dabigatran etexilate mesylate;
s6 pulverizing and sieving
Screening dabigatran etexilate mesylate by using a 40-mesh stainless steel screen in a rotary vibration screen, crushing the sieved particles by using a crusher, then screening by using a 100-mesh stainless steel screen in the rotary vibration screen, and continuously crushing and sieving the particles which do not pass through the screen until the particles completely pass through the screen.
Preferably, in step S1, the solution containing oxalic acid dihydrate is one of a methanol solution, an ethanol solution, a dichloromethane solution and a chloroform solution containing oxalic acid dihydrate, and the mass fraction of oxalic acid dihydrate in the solution is 2-20%.
Preferably, in step S1, at least one of the following features is further included:
the organic solvent a and the organic solvent b are one of tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide;
adding organic solvent a, SM2 and CDI, and stirring to react at 10-50 deg.C;
the mass ratio of the organic solvent a to the organic solvent b to the organic solvent SM1 to the organic solvent SM2 to the CDI is 1:1:1:1-2:1-1.5, and the mass ratio of other materials is SM 1: acetic acid 1:5-10, SM 1:1: 1-5, dichloromethane: water 1:1-5, SM 1: a solution containing oxalic acid dihydrate 1: 1-10;
preferably, in step S2, at least one of the following features is further included:
adding PR-I, a hydrochloric acid ethanol solution and ethanol in a mass ratio of 1:5-20:5-20, adding PR-I and an organic solvent d in a mass ratio of 1:1-5, wherein the mass ratio of the organic solvent d to ethyl acetate is 1: 1-5;
controlling the temperature of ammoniation to amidine to be 10-60 ℃, wherein one of ammonium carbonate, ammonium bicarbonate, urea and ammonia gas is used for ammoniation;
the organic solvent c and the organic solvent d are both one of methanol, ethanol, dichloromethane and trichloromethane.
Preferably, in the step S3, the mixed system substance is one of a dichloromethane/triethylamine system, a dichloromethane/potassium carbonate system and a tetrahydrofuran/potassium carbonate/water system, and the mass ratio of the mixed system to the PR-II is 10-30: 1.
More preferably, in step S3, the mixed system substance is a tetrahydrofuran/potassium carbonate/water system, and the mass ratio of tetrahydrofuran, potassium carbonate and water is 18:1: 7.2.
Preferably, in step S3, at least one of the following features is further included:
the mass ratio of the n-hexyl chloroformate to PR-II added for the first time is 0.5-2:1, and the mass ratio of the n-hexyl chloroformate to PR-II added in batches each time is 0.01-0.2: 1;
the mass ratio of the acetone to the PR-II is 8-12:1, and the mass ratio of the acetone to the water after dissolution is 2: 1.
Preferably, in step S4, at least one of the following features is further included:
during reaction, the mass ratio of the PR-III crude product to acetone to water is 1:1: 0.1-1;
the mass ratio of the primary refined PR-III product to the ethyl acetate is 1:0.5-1: 5;
the specific process of ethyl acetate refining is as follows: adding ethyl acetate and the primary refined PR-III product into a stainless steel reaction kettle, heating to 70-80 ℃ for dissolving, cooling to 20-25 ℃, stirring for crystallization for 3-4 hours, filtering, washing a filter cake with ethyl acetate, and drying the washed filter cake at 40-50 ℃ under reduced pressure for 3.5-4.5 hours to obtain the refined PR-III product.
Preferably, in step S5, at least one of the following technical features is further included:
the mass ratio of the PR-III refined product to the acetone is 1: 5-20;
the mass ratio of the PR-III refined product to the methanesulfonic acid is 5-10: 1.
The chemical name of SM1 described in the present invention is ethyl 3- [ (3-amino-4-methylaminobenzoyl) pyridin-2-ylamino ] propionate; the chemical name of SM2 is N- (4-cyanophenyl) aminoacetic acid, the chemical name of SM3 is N-hexyl chloroformate, and the chemical name of CDI is N, N' -carbonyldiimidazole.
The invention has the beneficial effects that:
1. in the process of preparing the intermediate PR-I, the organic solution containing oxalic acid dihydrate is used for purification, so that the intermediate PR-I is loose in property, good in color and relatively high in yield.
2. In the preparation process of the dabigatran etexilate PR-III, a system of a mixed organic solvent is adopted for reaction, and meanwhile, a mode of adding n-hexyl chloroformate in batches is adopted, so that the reaction is complete, no by-product is generated, and the impurity of the intermediate dabigatran etexilate PR-III crude product is less.
3. In the refining step of dabigatran etexilate, because the stability of the final product dabigatran etexilate mesylate in an aqueous solvent is poor, the moisture content of a subsequent salt forming reaction system is required to be controlled, the PR-III is purified by acetone and water firstly, small polar impurities are found to be difficult to remove, all single impurities can be controlled to be less than 0.1% by matching with ethyl acetate recrystallization, and meanwhile, the crystallization method can control the moisture in a refined product of dabigatran etexilate.
4. In the preparation step of the dabigatran etexilate mesylate, the dabigatran etexilate is refined firstly, and then the salification step is carried out, so that the obtained related substances of the dabigatran etexilate mesylate are basically consistent with those before salification, and the dabigatran etexilate mesylate meeting the quality standard can be obtained.
In conclusion, the method has mild reaction conditions in each step, simple reaction route, convenient operation and high selectivity, and can shorten the production period; the obtained dabigatran etexilate intermediate has low moisture content, and the prepared dabigatran etexilate mesylate has high yield and purity and low maximum single impurity content; the method has the advantages of less discharge of three wastes, environmental friendliness, no need of column chromatography purification, suitability for industrial production, capability of avoiding the requirement of palladium-carbon high-pressure hydrogenation on equipment and reduction of danger.
Drawings
FIG. 1 is a chemical structural formula of dabigatran etexilate mesylate.
Detailed Description
Embodiments of the present invention are further described below with reference to the accompanying drawings.
Example 1
A production process of dabigatran etexilate mesylate comprises the following steps:
preparation of S1 intermediate PR-I
Sequentially adding 1kg of organic solvent a, 1kg of SM2 and 1kg of CDI into a reaction kettle, stirring and reacting for 2.5 hours at the temperature of 10-50 ℃, sequentially adding 1kg of SM1 and 1kg of organic solvent b, continuously stirring and reacting for 11 hours, evaporating the solvent under reduced pressure at the temperature of 35 ℃, adding acetic acid into the reaction kettle, heating to 100 ℃ for reacting for 4.5 hours, evaporating the solvent under reduced pressure below 100 ℃, adding dichloromethane, stirring and dissolving, washing with water, recovering the solvent under reduced pressure by the organic phase, adding ethyl acetate into the obtained residue, stirring and dissolving, adding a solution containing oxalic acid dihydrate, stirring and crystallizing for 1.5 hours at the temperature of 20 ℃, centrifugally filtering, washing a filter cake with ethyl acetate, and drying the filter cake under reduced pressure at the temperature of 40 ℃ for 5 hours to obtain a light yellow solid PR-I;
wherein the solution of the oxalic acid dihydrate is a methanol solution containing the oxalic acid dihydrate, and the mass part of the oxalic acid dihydrate in the solution is 2%.
Wherein the organic solvent a and the organic solvent b are both tetrahydrofuran;
wherein, the mass ratio of other materials is SM 1: acetic acid 1:5, SM 1:1:1, dichloromethane: water 1:1, SM 1: a solution containing oxalic acid dihydrate is 1: 1;
preparation of S2 intermediate PR-II
Adding a hydrochloric acid ethanol solution and PR-I into a reaction kettle, stirring for 4.5 hours to dissolve and react, after the reaction is finished, decompressing below 60 ℃ to evaporate a solvent, adding ethanol to dissolve residues, controlling the temperature to be 10 ℃ to ammoniate to form amidine, after the reaction is finished, filtering, washing a filter cake by using an organic solvent c, combining filtrate, decompressing below 60 ℃ to evaporate the solvent, dissolving the residues by using an organic solvent d, adding ethyl acetate, stirring and crystallizing for 3.5 hours at 20 ℃, centrifugally filtering, washing by using ethyl acetate, decompressing and drying the filter cake for 5 hours at 40 ℃ to obtain a white-like solid PR-II;
wherein the mass ratio of the added PR-I to the ethanol solution of hydrochloric acid to the ethanol is 1:5:5, the mass ratio of the added PR-I to the organic solvent d is 1:1, and the mass ratio of the organic solvent d to the ethyl acetate is 1: 1;
wherein ammonium carbonate is used for ammoniation;
wherein, the organic solvent c and the organic solvent d are both methanol.
Preparation of S3 dabigatran etexilate PR-III
Adding PR-II and a mixed system substance into a reaction kettle, stirring and dissolving at 35 ℃, adding n-hexyl chloroformate in batches until the reaction end point, separating liquid, recovering a solvent from an organic phase at 35 ℃ under reduced pressure, adding acetone into the obtained residue, heating and dissolving at 35 ℃, adding water, stirring and crystallizing at 20 ℃ for 2.5 hours, filtering, washing a filter cake with acetone and water, and drying the filter cake at 40 ℃ under reduced pressure for 5 hours to obtain a crude product of the dabigatran etexilate PR-III;
wherein the mixed system substance is a dichloromethane/triethylamine system, the mass ratio of the mixed system to PR-II is 10:1, and the mass ratio of dichloromethane to triethylamine is 5: 1.
Wherein the mass ratio of the n-hexyl chloroformate to PR-II added for the first time is 0.5:1, 3 n-hexyl chloroformate is replenished in batches subsequently, the mass ratio of the replenished n-hexyl chloroformate to PR-II is 0.01:1, and the time interval of replenishment in batches is 1 h;
wherein the mass ratio of the acetone to the PR-II added into the residue is 8:1, and the mass ratio of the acetone added into the residue to the water added after dissolution is 2: 1.
S4 refining of dabigatran etexilate
Adding acetone and the PR-III crude product into a reaction kettle, heating and dissolving at 35 ℃, adding water, stirring and crystallizing for 2.5 hours at 20 ℃, filtering, washing a filter cake with acetone and water, drying the solid for 5 hours at 40 ℃ under reduced pressure to obtain a PR-III primary refined product, and refining the PR-III refined product with ethyl acetate to obtain a PR-III refined product;
wherein the mass ratio of the PR-III crude product, acetone and water in the reaction is 1:1: 0.1;
wherein the mass ratio of the primary PR-III refined product to the ethyl acetate is 1: 0.5;
wherein the specific process of ethyl acetate refining is as follows: adding ethyl acetate and the primary refined product of PR-III into a stainless steel reaction kettle, heating to dissolve at 70 ℃, cooling to 20 ℃, stirring, crystallizing for 3 hours, filtering, washing a filter cake with ethyl acetate, and drying the washed filter cake under reduced pressure at 40 ℃ for 3.5 hours to obtain the refined product of PR-III.
Preparation of S5 dabigatran etexilate mesylate
Adding acetone and a PR-III refined product into a reaction kettle, heating and dissolving at 35 ℃, filtering, adding methanesulfonic acid into filtrate, keeping the temperature and stirring for 1 hour, cooling to 20 ℃, crystallizing, filtering, washing a filter cake with acetone, and drying under reduced pressure at 40 ℃ for 5 hours to obtain dabigatran etexilate mesylate;
wherein the mass ratio of the PR-III refined product to the acetone is 1: 5;
wherein the mass ratio of the PR-III refined product to the methanesulfonic acid is 5: 1.
S6 pulverizing and sieving
Screening dabigatran etexilate mesylate by using a 40-mesh stainless steel screen in a rotary vibration screen, crushing the sieved particles by using a crusher, then screening by using a 100-mesh stainless steel screen in the rotary vibration screen, and continuously crushing and sieving the particles which do not pass through the screen until the particles completely pass through the screen.
Example 2
A production process of dabigatran etexilate mesylate comprises the following steps:
preparation of S1 intermediate PR-I
Sequentially adding 1kg of organic solvent a, 1.5kg of SM2 and 1.2kg of CDI into a reaction kettle, stirring and reacting for 3 hours at the temperature of 10-50 ℃, sequentially adding 1kg of SM1 and 1kg of organic solvent b, continuously stirring and reacting for 12 hours, evaporating the solvent under reduced pressure at the temperature of 40 ℃, adding acetic acid into the reaction kettle, heating to the temperature of 110 ℃ for reacting for 5 hours, evaporating the solvent under reduced pressure below 100 ℃, adding dichloromethane, stirring and dissolving, washing with water, recovering the solvent under reduced pressure by the organic phase, adding ethyl acetate into the obtained residue, stirring and dissolving, adding a solution containing oxalic acid dihydrate, stirring and crystallizing for 2 hours at the temperature of 22 ℃, centrifugally filtering, washing a filter cake with ethyl acetate, and drying the filter cake under reduced pressure at the temperature of 45 ℃ for 6 hours to obtain a light yellow solid PR-I;
wherein the solution of the oxalic acid dihydrate is an ethanol solution containing the oxalic acid dihydrate, and the mass part of the oxalic acid dihydrate in the solution is 10%.
Wherein the organic solvent a and the organic solvent b are both N, N-dimethylformamide;
wherein, the mass ratio of other materials is SM 1: acetic acid 1:8, SM 1:1: 3, dichloromethane: water 1:3, SM 1: a solution containing oxalic acid dihydrate ═ 1: 5;
preparation of S2 intermediate PR-II
Adding a hydrochloric acid ethanol solution and PR-I into a reaction kettle, stirring for 5 hours to dissolve and react, after the reaction is finished, decompressing below 60 ℃ to evaporate a solvent, adding ethanol to dissolve residues, controlling the temperature to be 30 ℃ to ammoniate to form amidine, after the reaction is finished, filtering, washing a filter cake with an organic solvent c, combining filtrate, decompressing below 60 ℃ to evaporate the solvent, dissolving the residues with an organic solvent d, adding ethyl acetate, stirring at 22 ℃ to crystallize for 4 hours, centrifugally filtering, washing with ethyl acetate, decompressing and drying the filter cake at 45 ℃ for 6 hours to obtain a white-like solid PR-II;
wherein the mass ratio of the added PR-I to the ethanol solution of hydrochloric acid to the ethanol is 1:10:10, the mass ratio of the added PR-I to the organic solvent d is 1:3, and the mass ratio of the organic solvent d to the ethyl acetate is 1: 3;
wherein ammonia gas is used for ammoniation;
wherein, the organic solvent c and the organic solvent d are both ethanol.
Preparation of S3 dabigatran etexilate PR-III
Adding PR-II and a mixed system substance into a reaction kettle, stirring and dissolving at 38 ℃, adding n-hexyl chloroformate in batches until the reaction end point, separating liquid, recovering a solvent from an organic phase at 40 ℃ under reduced pressure, adding acetone into the obtained residue, heating and dissolving at 40 ℃, adding water, stirring and crystallizing at 22 ℃ for 3 hours, filtering, washing a filter cake with acetone and water, and drying the filter cake at 45 ℃ under reduced pressure for 6 hours to obtain a crude product of dabigatran etexilate PR-III;
wherein the mixed system substance is a tetrahydrofuran/potassium carbonate/water system, the mass ratio of tetrahydrofuran, potassium carbonate and water is 18:1:7.2, and the mass ratio of the mixed system to PR-II is 20: 1.
Wherein the mass ratio of the n-hexyl chloroformate to PR-II added for the first time is 1:1, 3 n-hexyl chloroformate is replenished in batches subsequently, the mass ratio of the replenished n-hexyl chloroformate to PR-II is 0.1:1, and the time interval of replenishment in batches is 1 h;
wherein the mass ratio of the acetone to the PR-II added into the residue is 10:1, and the mass ratio of the acetone added into the residue to the water added after dissolution is 2: 1.
S4 refining of dabigatran etexilate
Adding acetone and the PR-III crude product into a reaction kettle, heating to dissolve at 40 ℃, adding water, stirring and crystallizing for 3 hours at 22 ℃, filtering, washing a filter cake with acetone and water, drying the solid for 6 hours at 45 ℃ under reduced pressure to obtain a PR-III primary refined product, and recrystallizing and refining the PR-III refined product with ethyl acetate to obtain a PR-III refined product;
wherein the mass ratio of the PR-III crude product, acetone and water in the reaction is 1:1: 0.5;
wherein the mass ratio of the primary PR-III refined product to the ethyl acetate is 1: 0.8;
wherein the specific process of ethyl acetate refining is as follows: adding ethyl acetate and the primary refined product of PR-III into a stainless steel reaction kettle, heating to dissolve at 75 ℃, cooling to 22 ℃, stirring, crystallizing for 3.5 hours, filtering, washing a filter cake with ethyl acetate, and drying the washed filter cake at 45 ℃ under reduced pressure for 4 hours to obtain the refined product of PR-III.
Preparation of S5 dabigatran etexilate mesylate
Adding acetone and a PR-III refined product into a reaction kettle, heating and dissolving at 40 ℃, filtering, adding methanesulfonic acid into filtrate, keeping the temperature and stirring for 1 hour, cooling to 22 ℃ for crystallization, filtering, washing a filter cake with acetone, and drying under reduced pressure at 45 ℃ for 6 hours to obtain dabigatran etexilate mesylate;
wherein the mass ratio of the PR-III refined product to the acetone is 1: 10;
wherein the mass ratio of the PR-III refined product to the methanesulfonic acid is 8: 1.
The rest is the same as example 1.
Example 3
A production process of dabigatran etexilate mesylate comprises the following steps:
preparation of S1 intermediate PR-I
Adding 1kg of organic solvent a, 1.8kg of SM2 and 1.3kg of CDI into a reaction kettle in sequence, stirring and reacting for 4 hours at the temperature of 10-50 ℃, then adding 1kg of SM1 and 1kg of organic solvent b in sequence, continuously stirring and reacting for 11.5 hours, evaporating the solvent under reduced pressure at the temperature of 45 ℃, adding acetic acid into the reaction kettle, heating to the temperature of 105 ℃, reacting for 5 hours, evaporating the solvent under reduced pressure at the temperature of 100 ℃, adding dichloromethane, stirring and dissolving, washing with water, recovering the solvent by organic phase under reduced pressure, adding ethyl acetate into the obtained residue, stirring and dissolving, adding a solution containing oxalic acid dihydrate, stirring and crystallizing for 2 hours at the temperature of 23 ℃, centrifugally filtering, washing a filter cake with ethyl acetate, and drying the filter cake under reduced pressure at the temperature of 48 ℃ for 6.5 hours to obtain a light yellow solid PR;
wherein the solution of the oxalic acid dihydrate is dichloromethane solution containing the oxalic acid dihydrate, and the mass part of the oxalic acid dihydrate in the solution is 15%.
Wherein the organic solvent a and the organic solvent b are both N, N-dimethylacetamide;
wherein, the mass ratio of other materials is SM 1: acetic acid 1:6, SM 1: dichloromethane ═ 1:2, dichloromethane: water 1:2, SM 1: a solution containing oxalic acid dihydrate ═ 1: 8;
preparation of S2 intermediate PR-II
Adding a hydrochloric acid ethanol solution and PR-I into a reaction kettle, stirring for 5 hours to dissolve and react, after the reaction is finished, decompressing below 60 ℃ to evaporate a solvent, adding ethanol to dissolve residues, controlling the temperature to 50 ℃ to carry out amination to form amidine, after the reaction is finished, filtering, washing a filter cake with an organic solvent c, combining filtrate, decompressing below 60 ℃ to evaporate the solvent, dissolving the residues with an organic solvent d, adding ethyl acetate, stirring at 23 ℃ to crystallize for 4 hours, centrifuging, filtering, washing with ethyl acetate, decompressing and drying the filter cake at 46 ℃ for 6 hours to obtain a white-like solid PR-II;
wherein the mass ratio of the added PR-I to the ethanol solution of hydrochloric acid to the ethanol is 1:15:15, the mass ratio of the added PR-I to the organic solvent d is 1:2, and the mass ratio of the organic solvent d to the ethyl acetate is 1: 2;
wherein, ammonium bicarbonate is used for ammoniation;
wherein, the organic solvent c and the organic solvent d are both dichloromethane.
Preparation of S3 dabigatran etexilate PR-III
Adding PR-II and a mixed system substance into a reaction kettle, stirring and dissolving at 36 ℃, adding n-hexyl chloroformate in batches until the reaction end point, separating liquid, recovering a solvent from an organic phase at 45 ℃ under reduced pressure, adding acetone into the obtained residue, heating and dissolving at 38 ℃, adding water, stirring and crystallizing at 24 ℃ for 3 hours, filtering, washing a filter cake with acetone and water, and drying the filter cake at 48 ℃ under reduced pressure for 5.5 hours to obtain a crude product of the dabigatran etexilate PR-III;
wherein the mixed system substance is a dichloromethane/potassium carbonate system, the mass ratio of dichloromethane to potassium carbonate is 3:1, and the mass ratio of the mixed system to PR-II is 15: 1.
Wherein the mass ratio of the n-hexyl chloroformate to PR-II added for the first time is 1.5:1, the n-hexyl chloroformate is replenished for 3 times in batches subsequently, the mass ratio of the replenished n-hexyl chloroformate to PR-II is 0.15:1, and the time interval of replenishing in batches is 1 h; wherein the mass ratio of the acetone to the PR-II added into the residue is 9:1, and the mass ratio of the acetone added into the residue to the water added after dissolution is 2: 1.
S4 refining of dabigatran etexilate
Adding acetone and the PR-III crude product into a reaction kettle, heating to 42 ℃ for dissolving, adding water, stirring at 24 ℃ for crystallization for 3 hours, filtering, washing a filter cake with acetone and water, drying the solid at 46 ℃ under reduced pressure for 6.5 hours to obtain a PR-III primary refined product, and recrystallizing and refining the PR-III refined product with ethyl acetate to obtain a PR-III refined product;
wherein the mass ratio of the PR-III crude product, acetone and water in the reaction is 1:1: 0.8;
wherein the mass ratio of the primary PR-III refined product to the ethyl acetate is 1: 0.8;
wherein the specific process of ethyl acetate refining is as follows: adding ethyl acetate and the primary refined product of PR-III into a stainless steel reaction kettle, heating to dissolve at 76 ℃, cooling to 24 ℃, stirring, crystallizing for 3.5 hours, filtering, washing a filter cake with ethyl acetate, and drying the washed filter cake at 42 ℃ under reduced pressure for 4 hours to obtain the refined product of PR-III.
Preparation of S5 dabigatran etexilate mesylate
Adding acetone and a PR-III refined product into a reaction kettle, heating to 38 ℃ for dissolving, filtering, adding methanesulfonic acid into filtrate, keeping the temperature and stirring for 1 hour, cooling to 22 ℃ for crystallization, filtering, washing a filter cake with acetone, and drying under reduced pressure at 46 ℃ for 5.5 hours to obtain dabigatran etexilate mesylate;
wherein the mass ratio of the PR-III refined product to the acetone is 1: 15;
wherein the mass ratio of the PR-III refined product to the methanesulfonic acid is 3: 1.
The rest is the same as example 1.
Example 4
A production process of dabigatran etexilate mesylate comprises the following steps:
preparation of S1 intermediate PR-I
Adding 1kg of solvent a, 2kg of SM2 and 1.5kg of CDI into a reaction kettle in sequence, stirring and reacting for 3.5 hours at the temperature of 10-50 ℃, then adding 1kg of SM1 and 1kg of organic solvent b in sequence, continuing stirring and reacting for 13 hours, evaporating the solvent under reduced pressure at the temperature of 50 ℃, adding acetic acid into the reaction kettle, heating to 120 ℃, reacting for 5.5 hours, evaporating the solvent under reduced pressure below 100 ℃, adding dichloromethane, stirring and dissolving, washing with water, recovering the solvent under reduced pressure by the organic phase, adding ethyl acetate into the obtained residue, stirring and dissolving, adding a solution containing oxalic acid dihydrate, stirring and crystallizing for 2.5 hours at the temperature of 25 ℃, centrifugally filtering, washing a filter cake with ethyl acetate, and drying the filter cake under reduced pressure at the temperature of 50 ℃ for 7 hours to obtain light yellow solid PR-I;
wherein the solution of the oxalic acid dihydrate is a trichloromethane solution, and the mass part of the oxalic acid dihydrate in the solution is 20%.
Wherein the organic solvent a and the organic solvent b are both dimethyl sulfoxide;
wherein, the mass ratio of other materials is SM 1: acetic acid 1:10, SM 1: dichloromethane ═ 1:5, dichloromethane: water 1:5, SM 1: a solution containing oxalic acid dihydrate ═ 1: 10;
preparation of S2 intermediate PR-II
Adding a hydrochloric acid ethanol solution and PR-I into a reaction kettle, stirring for 5.5 hours to dissolve and react, after the reaction is finished, decompressing below 60 ℃ to evaporate a solvent, adding ethanol to dissolve residues, controlling the temperature to be 60 ℃ to ammoniate to form amidine, after the reaction is finished, filtering, washing a filter cake by using an organic solvent c, combining filtrate, decompressing below 60 ℃ to evaporate the solvent, dissolving the residues by using an organic solvent d, adding ethyl acetate, stirring and crystallizing for 4.5 hours at 25 ℃, centrifugally filtering, washing by using ethyl acetate, decompressing and drying the filter cake for 7 hours at 50 ℃ to obtain a white-like solid PR-II;
wherein the mass ratio of the added PR-I to the ethanol solution of hydrochloric acid to the ethanol is 1:20:20, the mass ratio of the added PR-I to the organic solvent d is 1:5, and the mass ratio of the organic solvent d to the ethyl acetate is 1: 5;
wherein, urea is used for ammoniation;
wherein, the organic solvent c and the organic solvent d are both trichloromethane.
Preparation of S3 dabigatran etexilate PR-III
Adding PR-II and a mixed system substance into a reaction kettle, stirring and dissolving at 40 ℃, adding n-hexyl chloroformate in batches until the reaction end point, separating liquid, recovering a solvent from an organic phase at 50 ℃ under reduced pressure, adding acetone into the obtained residue, heating and dissolving at 45 ℃, adding water, stirring and crystallizing at 25 ℃ for 3.5 hours, filtering, washing a filter cake with acetone and water, and drying the filter cake at 50 ℃ under reduced pressure for 7 hours to obtain a crude product of the dabigatran etexilate PR-III;
wherein the mixed system substance is one of tetrahydrofuran/potassium carbonate/water system, the mass ratio of tetrahydrofuran, potassium carbonate and water is 18:1:7.2, and the mass ratio of the mixed system to PR-II is 30: 1.
Wherein the mass ratio of the n-hexyl chloroformate to PR-II added for the first time is 2:1, 3 n-hexyl chloroformate is replenished in batches subsequently, the mass ratio of the replenished n-hexyl chloroformate to PR-II is 0.2:1, and the time interval of replenishment in batches is 1 h;
wherein the mass ratio of the acetone to the PR-II added into the residue is 12:1, and the mass ratio of the acetone added into the residue to the water added after dissolution is 2: 1.
S4 refining of dabigatran etexilate
Adding acetone and the PR-III crude product into a reaction kettle, heating and dissolving at 45 ℃, adding water, stirring and crystallizing at 25 ℃ for 3.5 hours, filtering, washing a filter cake with acetone and water, drying the solid at 50 ℃ under reduced pressure for 7 hours to obtain a PR-III primary refined product, and recrystallizing and refining the PR-III refined product with ethyl acetate to obtain a PR-III refined product;
wherein the mass ratio of the PR-III crude product, acetone and water in the reaction is 1:1: 1;
wherein the mass ratio of the primary PR-III refined product to the ethyl acetate is 1: 1;
wherein the specific process of ethyl acetate refining is as follows: adding ethyl acetate and the primary refined product of PR-III into a stainless steel reaction kettle, heating to dissolve at 80 ℃, cooling to 25 ℃, stirring, crystallizing for 4 hours, filtering, washing a filter cake with ethyl acetate, and drying the washed filter cake under reduced pressure at 50 ℃ for 4.5 hours to obtain the refined product of PR-III.
Preparation of S5 dabigatran etexilate mesylate
Adding acetone and a PR-III refined product into a reaction kettle, heating and dissolving at 45 ℃, filtering, adding methanesulfonic acid into filtrate, keeping the temperature and stirring for 1 hour, cooling to 25 ℃, crystallizing, filtering, washing a filter cake with acetone, and drying under reduced pressure at 50 ℃ for 7 hours to obtain dabigatran etexilate mesylate;
wherein the mass ratio of the PR-III refined product to the acetone is 1: 20;
wherein the mass ratio of the PR-III refined product to the methanesulfonic acid is 10: 1.
The rest is the same as example 1.
Example 5
A production process of dabigatran etexilate mesylate comprises the following steps:
preparation of S1 intermediate PR-I
Adding an organic solvent a, SM2 and CDI into a reaction kettle in sequence, stirring and reacting for 2.5 hours at the temperature of 10-50 ℃, then adding SM1 and organic solvent b into the reaction kettle in sequence, continuing to stir and react for 11 hours, evaporating the solvent under reduced pressure at the temperature of 35 ℃, adding acetic acid into the reaction kettle, heating to the temperature of 100 ℃ for reaction for 4.5 hours, evaporating the solvent under reduced pressure below 100 ℃, adding dichloromethane, stirring and dissolving, washing with water, recovering the solvent under reduced pressure by using the organic phase, adding ethyl acetate into the obtained residue, stirring and dissolving, adding a solution containing oxalic acid dihydrate, stirring and crystallizing for 1.5 hours at the temperature of 20 ℃, performing centrifugal filtration, washing a filter cake by using the ethyl acetate, and drying the filter cake under reduced pressure for 5 hours at the temperature of 40 ℃;
preparation of S2 intermediate PR-II
Adding a hydrochloric acid ethanol solution and PR-I into a reaction kettle, stirring for 5 hours to dissolve and react, after the reaction is finished, decompressing below 60 ℃ to evaporate a solvent, adding ethanol to dissolve residues, controlling the temperature to be 30 ℃ to ammoniate to form amidine, after the reaction is finished, filtering, washing a filter cake with an organic solvent c, combining filtrate, decompressing below 60 ℃ to evaporate the solvent, dissolving the residues with an organic solvent d, adding ethyl acetate, stirring at 22 ℃ to crystallize for 4 hours, centrifugally filtering, washing with ethyl acetate, decompressing and drying the filter cake at 45 ℃ for 6 hours to obtain a white-like solid PR-II;
preparation of S3 dabigatran etexilate PR-III
Adding PR-II and a mixed system substance into a reaction kettle, stirring and dissolving at 36 ℃, adding n-hexyl chloroformate in batches until the reaction end point, separating liquid, recovering a solvent from an organic phase at 45 ℃ under reduced pressure, adding acetone into the obtained residue, heating and dissolving at 38 ℃, adding water, stirring and crystallizing at 24 ℃ for 3 hours, filtering, washing a filter cake with acetone and water, and drying the filter cake at 48 ℃ under reduced pressure for 5.5 hours to obtain a crude product of the dabigatran etexilate PR-III;
s4 refining of dabigatran etexilate
Adding acetone and the PR-III crude product into a reaction kettle, heating and dissolving at 45 ℃, adding water, stirring and crystallizing at 25 ℃ for 3.5 hours, filtering, washing a filter cake with acetone and water, drying the solid at 50 ℃ under reduced pressure for 7 hours to obtain a PR-III primary refined product, and recrystallizing and refining the PR-III refined product with ethyl acetate to obtain a PR-III refined product;
preparation of S5 dabigatran etexilate mesylate
Adding acetone and a PR-III refined product into a reaction kettle, heating and dissolving at 35 ℃, filtering, adding methanesulfonic acid into filtrate, keeping the temperature and stirring for 1 hour, cooling to 20 ℃, crystallizing, filtering, washing a filter cake with acetone, and drying under reduced pressure at 40 ℃ for 5 hours to obtain dabigatran etexilate mesylate;
the rest is the same as example 2.
Example 6
A production process of dabigatran etexilate mesylate comprises the following steps:
preparation of S1 intermediate PR-I
Adding an organic solvent a, SM2 and CDI into a reaction kettle in sequence, stirring and reacting for 3 hours at 10-50 ℃, then adding SM1 and organic solvent b in sequence, continuing to stir and react for 12 hours, evaporating the solvent under reduced pressure at 40 ℃, adding acetic acid into the reaction kettle, heating to 110 ℃, reacting for 5 hours, evaporating the solvent under reduced pressure below 100 ℃, adding dichloromethane, stirring and dissolving, washing with water, recovering the solvent under reduced pressure by using the organic phase, adding ethyl acetate into the obtained residue, stirring and crystallizing for 2 hours at 22 ℃, performing centrifugal filtration, washing a filter cake by using the ethyl acetate, and drying the filter cake under reduced pressure at 45 ℃ for 6 hours to obtain a light yellow solid PR-I;
preparation of S2 intermediate PR-II
Adding a hydrochloric acid ethanol solution and PR-I into a reaction kettle, stirring for 5 hours to dissolve and react, after the reaction is finished, decompressing below 60 ℃ to evaporate a solvent, adding ethanol to dissolve residues, controlling the temperature to 50 ℃ to carry out amination to form amidine, after the reaction is finished, filtering, washing a filter cake with an organic solvent c, combining filtrate, decompressing below 60 ℃ to evaporate the solvent, dissolving the residues with an organic solvent d, adding ethyl acetate, stirring at 23 ℃ to crystallize for 4 hours, centrifuging, filtering, washing with ethyl acetate, decompressing and drying the filter cake at 46 ℃ for 6 hours to obtain a white-like solid PR-II;
preparation of S3 dabigatran etexilate PR-III
Adding PR-II and a mixed system substance into a reaction kettle, stirring and dissolving at 40 ℃, adding n-hexyl chloroformate in batches until the reaction end point, separating liquid, recovering a solvent from an organic phase at 50 ℃ under reduced pressure, adding acetone into the obtained residue, heating and dissolving at 45 ℃, adding water, stirring and crystallizing at 25 ℃ for 3.5 hours, filtering, washing a filter cake with acetone and water, and drying the filter cake at 50 ℃ under reduced pressure for 7 hours to obtain a crude product of the dabigatran etexilate PR-III;
s4 refining of dabigatran etexilate
Adding acetone and the PR-III crude product into a reaction kettle, heating and dissolving at 35 ℃, adding water, stirring and crystallizing for 2.5 hours at 20 ℃, filtering, washing a filter cake with acetone and water, drying the solid for 5 hours at 40 ℃ under reduced pressure to obtain a PR-III primary refined product, and recrystallizing and refining the PR-III refined product with ethyl acetate to obtain a PR-III refined product;
preparation of S5 dabigatran etexilate mesylate
Adding acetone and a PR-III refined product into a reaction kettle, heating and dissolving at 40 ℃, filtering, adding methanesulfonic acid into filtrate, keeping the temperature and stirring for 1 hour, cooling to 22 ℃ for crystallization, filtering, washing a filter cake with acetone, and drying under reduced pressure at 45 ℃ for 6 hours to obtain dabigatran etexilate mesylate;
the rest is the same as example 4.
Comparative example 1
A production process of dabigatran etexilate mesylate comprises the following steps:
preparation of S1 intermediate PR-I
Adding an organic solvent a, SM2 and CDI into a reaction kettle in sequence, stirring and reacting for 2 hours at 40 ℃, then adding SM1 and organic solvent b in sequence, continuing to stir and react for 14 hours, evaporating the solvent under reduced pressure at 60 ℃, adding acetic acid into the reaction kettle, heating to 130 ℃, reacting for 6 hours, evaporating the solvent under reduced pressure below 100 ℃, adding dichloromethane, stirring and dissolving, washing with water, recovering the solvent under reduced pressure by using the organic phase, adding ethyl acetate into the obtained residue, stirring and crystallizing for 3 hours at 30 ℃, performing centrifugal filtration, washing a filter cake by using the ethyl acetate, and drying the filter cake under reduced pressure at 30 ℃ for 8 hours to obtain a light yellow solid PR-I;
preparation of S2 intermediate PR-II
Adding a hydrochloric acid ethanol solution and PR-I into a reaction kettle, stirring for 6 hours to dissolve and react, after the reaction is finished, decompressing below 60 ℃ to evaporate a solvent, adding ethanol to dissolve residues, controlling the temperature to 70 ℃ to ammoniate to form amidine, after the reaction is finished, filtering, washing a filter cake with an organic solvent c, combining filtrate, decompressing below 60 ℃ to evaporate the solvent, dissolving the residues with an organic solvent d, adding ethyl acetate, stirring and crystallizing for 3 hours at the temperature of 20-25 ℃, centrifugally filtering, washing the ethyl acetate, decompressing and drying the filter cake for 8 hours at the temperature of 60 ℃ to obtain a white-like solid PR-II;
preparation of S3 dabigatran etexilate PR-III
Adding PR-II and a mixed system substance into a reaction kettle, stirring and dissolving at 30 ℃, adding n-hexyl chloroformate in batches until the reaction end point, separating liquid, recovering a solvent from an organic phase at 60 ℃ under reduced pressure, adding acetone into the obtained residue, heating and dissolving at 50 ℃, adding water, stirring and crystallizing at 30 ℃ for 2 hours, filtering, washing a filter cake with acetone and water, and drying the filter cake at 30 ℃ under reduced pressure for 4 hours to obtain a crude product of the dabigatran etexilate PR-III;
s4 refining of dabigatran etexilate
Adding acetone and the PR-III crude product into a reaction kettle, heating and dissolving at 50 ℃, adding water, stirring and crystallizing for 2 hours at 30 ℃, filtering, washing a filter cake with acetone and water, drying the solid for 4 hours at 60 ℃ under reduced pressure to obtain a PR-III primary refined product, and recrystallizing and refining the PR-III refined product with ethyl acetate to obtain a PR-III refined product;
preparation of S5 dabigatran etexilate mesylate
Adding acetone and a PR-III refined product into a reaction kettle, heating and dissolving at 50 ℃, filtering, adding methanesulfonic acid into filtrate, keeping the temperature and stirring for 1 hour, cooling to 15 ℃, crystallizing, filtering, washing a filter cake with acetone, and drying under reduced pressure at 30 ℃ for 8 hours to obtain dabigatran etexilate mesylate;
the rest is the same as example 1.
Comparative example 2
This comparative example differs from example 2 in that:
the solution of oxalic acid dihydrate is a methane chloride solution containing oxalic acid dihydrate.
Comparative example 3
This comparative example differs from example 3 in that:
the mixed system substance is a dichloromethane/tetrahydrofuran/potassium carbonate system, and the mass ratio of dichloromethane to tetrahydrofuran to potassium carbonate is 10:1: 7.
Comparative example 4
This comparative example differs from example 4 in that:
in the preparation of S3 dabigatran etexilate PR-III, n-hexyl chloroformate is added at one time until the reaction end point.
Comparative example 5
This comparative example differs from example 4 in that:
s4 refining of dabigatran etexilate
Adding acetone and the PR-III crude product into a reaction kettle, heating and dissolving at 45 ℃, adding water, stirring and crystallizing at 25 ℃ for 3.5 hours, filtering, washing a filter cake with ethyl acetate and water, drying the solid at 50 ℃ under reduced pressure for 7 hours to obtain a PR-III primary refined product, and refining the PR-III refined product with acetone to obtain a PR-III refined product;
wherein the mass ratio of the PR-III crude product, acetone and water in the reaction is 1:1: 1;
wherein the mass ratio of the primary PR-III refined product to acetone is 1: 1;
wherein the specific process of acetone refining is as follows: adding acetone and the primary refined product of PR-III into a stainless steel reaction kettle, heating to dissolve at 80 ℃, cooling to 25 ℃, stirring, crystallizing for 4 hours, filtering, washing a filter cake with acetone, and drying the washed filter cake at 50 ℃ under reduced pressure for 4.5 hours to obtain the refined product of PR-III.
The present invention is not limited to the above-described embodiments, and various changes may be made by those skilled in the art, and any changes equivalent or similar to the present invention are intended to be included within the scope of the claims.
Test examples
The moisture content of the dabigatran etexilate intermediate and the product quality of dabigatran etexilate mesylate obtained in each example and comparative example are shown in the following table.
TABLE 1 Effect of dabigatran etexilate and dabigatran etexilate mesylate obtained in each example and comparative example
As can be seen from the data in the table, the dabigatran etexilate obtained in the examples 1 to 6 in the process range of the invention has low moisture content, the prepared dabigatran etexilate mesylate has higher purity and yield, the maximum single impurity content is low, and the effect is better than that of the comparative example 1: different process parameters, comparative example 2: other organic solvents containing oxalic acid dihydrate in step S1, comparative example 3: step S3, a system of mixing other organic solvents, comparative example 4: step S3 was performed using a one-shot addition of n-hexyl chloroformate, comparative example 5: the reagents used for purification and crystallization in step S4 are different and are particularly optimized for the performance of example 2. In the production process of the dabigatran etexilate mesylate, provided by the invention, a specific organic solution containing oxalic acid dihydrate is adopted for purification in the process of preparing the intermediate PR-I; in the preparation process of the dabigatran etexilate PR-III, a system of a mixed organic solvent is selected for reaction, and meanwhile, a mode of adding n-hexyl chloroformate in batches is adopted; in the refining step of the dabigatran etexilate, PR-III is purified by using acetone and water, and then an ethyl acetate recrystallization process is matched, and the processes are combined, so that the moisture content of the obtained dabigatran etexilate intermediate is lower than 0.2%, the purity of the prepared dabigatran etexilate is higher than 98%, the yield is higher than 85%, the maximum single impurity is lower than 0.06%, and meanwhile, the three-waste discharge is low, so that the method is environment-friendly and suitable for industrial production.
Claims (6)
1. A production process of dabigatran etexilate mesylate is characterized by comprising the following steps: the method comprises the following steps:
preparation of S1 intermediate PR-I
Sequentially adding an organic solvent a, SM2 and CDI into a reaction kettle, stirring for reaction for 2.5-3.5 hours, sequentially adding SM1 and organic solvent b, continuing to stir for reaction for 11-13 hours, evaporating the solvent at 35-50 ℃ under reduced pressure, adding acetic acid into the reaction kettle, heating to 100 ℃ and 120 ℃ for reaction for 4.5-5.5 hours, evaporating the solvent at 100 ℃ under reduced pressure, adding dichloromethane, stirring for dissolution, washing with water, recovering the solvent by organic phase under reduced pressure, adding ethyl acetate into the obtained residue, stirring for dissolution, adding a solution containing oxalic acid dihydrate, stirring for crystallization for 1.5-2.5 hours at 20-25 ℃, centrifugally filtering, washing a filter cake with ethyl acetate, and drying the filter cake at 40-50 ℃ under reduced pressure for 5-7 hours to obtain a light yellow solid PR-I;
preparation of S2 intermediate PR-II
Adding a hydrochloric acid ethanol solution and PR-I into a reaction kettle, stirring for 4.5-5.5 hours for dissolution reaction, after the reaction is finished, evaporating the solvent under reduced pressure below 60 ℃, adding ethanol dissolution residues, controlling the temperature to carry out amination to form amidine, after the reaction is finished, filtering, washing a filter cake by using an organic solvent c, combining the filtrate, evaporating the solvent under reduced pressure below 60 ℃, dissolving the residues by using an organic solvent d, adding ethyl acetate, stirring and crystallizing at 20-25 ℃ for 3.5-4.5 hours, carrying out centrifugal filtration, washing by using ethyl acetate, and drying the filter cake under reduced pressure at 40-50 ℃ for 5-7 hours to obtain a white-like solid PR-II;
preparation of S3 dabigatran etexilate PR-III
Adding PR-II and a mixed system substance into a reaction kettle, stirring and dissolving at 35-40 ℃, adding n-hexyl chloroformate in batches until the reaction end point, separating liquid, recovering a solvent at 35-50 ℃ under reduced pressure of an organic phase, adding acetone into the obtained residue, heating and dissolving at 35-45 ℃, adding water, stirring and crystallizing at 20-25 ℃ for 2.5-3.5 hours, filtering, washing a filter cake with acetone and water, and drying the filter cake at 40-50 ℃ under reduced pressure for 5-7 hours to obtain a crude product of dabigatran etexilate PR-III;
s4 refining of dabigatran etexilate
Adding acetone and the PR-III crude product into a reaction kettle, heating and dissolving at 35-45 ℃, adding water, stirring and crystallizing for 2.5-3.5 hours at 20-25 ℃, filtering, washing a filter cake with acetone and water, drying the solid for 5-7 hours at 40-50 ℃ under reduced pressure to obtain a PR-III primary refined product, and recrystallizing and refining the PR-III refined product with ethyl acetate to obtain a PR-III refined product;
preparation of S5 dabigatran etexilate mesylate
Adding acetone and a PR-III refined product into a reaction kettle, heating to 35-45 ℃ for dissolving, filtering, adding methanesulfonic acid into filtrate, keeping the temperature and stirring for 1 hour, cooling to 20-25 ℃ for crystallization, filtering, washing a filter cake with acetone, and drying under reduced pressure for 5-7 hours at 40-50 ℃ to obtain dabigatran etexilate mesylate;
s6 pulverizing and sieving
Screening dabigatran etexilate mesylate by using a 40-mesh stainless steel screen in a rotary vibration screen, crushing the sieved particles by using a crusher, then screening by using a 100-mesh stainless steel screen in the rotary vibration screen, and continuously crushing and screening the particles which do not pass through the screen until the particles completely pass through the screen;
in the step S3, the mixed system substance is a dichloromethane/triethylamine system or a dichloromethane/potassium carbonate system, and the mass ratio of the mixed system to PR-II is 10-30: 1;
in the step S1, the solution containing oxalic acid dihydrate is one of a methanol solution, an ethanol solution, a dichloromethane solution and a chloroform solution containing oxalic acid dihydrate, and the mass fraction of oxalic acid dihydrate in the solution is 2-20%;
wherein, SM1 is:
SM2 is:
PR-I is:
PR-II is:
PR-III is:
2. the process for producing dabigatran etexilate mesylate according to claim 1, wherein: in step S1, at least one of the following features is further included:
the organic solvent a and the organic solvent b are one of tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide;
adding organic solvent a, SM2 and CDI, and stirring to react at 10-50 deg.C;
the mass ratio of the organic solvent a to the organic solvent b to the organic solvent SM1 to the organic solvent SM2 to the CDI is 1:1:1:1-2:1-1.5, and the mass ratio of other materials is SM 1: acetic acid 1:5-10, SM 1:1: 1-5, dichloromethane: water 1:1-5, SM 1: a solution containing oxalic acid dihydrate ═ 1: 1-10.
3. The process for producing dabigatran etexilate mesylate according to claim 1, wherein: in step S2, at least one of the following features is further included:
adding PR-I, a hydrochloric acid ethanol solution and ethanol in a mass ratio of 1:5-20:5-20, adding PR-I and an organic solvent d in a mass ratio of 1:1-5, wherein the mass ratio of the organic solvent d to ethyl acetate is 1: 1-5;
controlling the temperature of ammoniation to amidine to be 10-60 ℃, wherein one of ammonium carbonate, ammonium bicarbonate, urea and ammonia gas is used for ammoniation;
the organic solvent c and the organic solvent d are both one of methanol, ethanol, dichloromethane and trichloromethane.
4. The process for producing dabigatran etexilate mesylate according to claim 1, wherein: in step S3, at least one of the following features is further included:
the mass ratio of the n-hexyl chloroformate to PR-II added for the first time is 0.5-2:1, and the mass ratio of the n-hexyl chloroformate to PR-II added in batches each time is 0.01-0.2: 1;
the mass ratio of the acetone to the PR-II is 8-12:1, and the mass ratio of the acetone to the water after dissolution is 2: 1.
5. The process for producing dabigatran etexilate mesylate according to claim 1, wherein: in step S4, at least one of the following features is further included:
during reaction, the mass ratio of the PR-III crude product to acetone to water is 1:1: 0.1-1;
the mass ratio of the primary refined PR-III product to the ethyl acetate is 1:0.5-1: 5;
the specific process of ethyl acetate refining is as follows: adding ethyl acetate and the primary refined PR-III product into a stainless steel reaction kettle, heating to 70-80 ℃ for dissolving, cooling to 20-25 ℃, stirring for crystallization for 3-4 hours, filtering, washing a filter cake with ethyl acetate, and drying the washed filter cake at 40-50 ℃ under reduced pressure for 3.5-4.5 hours to obtain the refined PR-III product.
6. The process for producing dabigatran etexilate mesylate according to claim 1, wherein: in step S5, at least one of the following features is also included:
the mass ratio of the PR-III refined product to the acetone is 1: 5-20;
the mass ratio of the PR-III refined product to the methanesulfonic acid is 5-10: 1.
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| CN111393412A (en) * | 2020-05-08 | 2020-07-10 | 江西国药有限责任公司 | Refining method of dabigatran etexilate crude product |
| CN114716411B (en) * | 2022-04-29 | 2024-03-15 | 天方药业有限公司 | Method for recovering and preparing dabigatran etexilate mesylate from production mother liquor |
| CN115417855A (en) * | 2022-09-22 | 2022-12-02 | 安徽美诺华药物化学有限公司 | Synthesis process of dabigatran etexilate mesylate |
| CN116621815A (en) * | 2023-07-21 | 2023-08-22 | 成都苑东生物制药股份有限公司 | Industrial preparation method of dabigatran etexilate mesylate |
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| WO2014009966A2 (en) * | 2012-07-12 | 2014-01-16 | Rao Davuluri Ramamohan | An improved process for the preparation of dabigatran etexilate mesylate and its intermediates thereof |
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