CN113929661A - Dabigatran etexilate intermediate and preparation method thereof - Google Patents
Dabigatran etexilate intermediate and preparation method thereof Download PDFInfo
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Abstract
The invention provides a dabigatran etexilate intermediate 3-alanine-N- [ [ 1-methyl-1H-benzimidazole-2-chloromethyl ] -5-carbonyl ] -N-2-pyridine-ethyl ester and a preparation method thereof, wherein the purity of the intermediate is not lower than 99.0%, the preparation method takes ethyl acetate as a solvent, and 3- [ (3-amino-4-methylamino benzoyl) (pyridine-2-yl) amino ] ethyl propionate, chloroacetic acid and CDI react to prepare the dabigatran etexilate intermediate.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for synthesizing dabigatran etexilate and a key intermediate thereof.
Background
Dabigatran etexilate is chemically known as beta-alanine, N- [ [2- [ [ [4- [ [ [ (hexyloxy) carbonyl ] amino ] iminomethyl ] phenyl ] amino ] methyl ] -1-methyl-1H-benzimidazol-5-yl ] carbonyl ] -N-2-pyrimidine-, hexyl ester, mesylate; the chemical structure is shown as formula I. Is an oral direct thrombin inhibitor developed by the company brigling invagrehn and is mainly used for: (1) prevention of stroke in patients with non-valvular atrial fibrillation; (2) deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) prophylaxis in patients who have been treated with anticoagulant injection for 5-10 days; (3) already treated patients reduce the risk of recurrence of DVT and PE; (4) prevention of DVT and PE following hip replacement.
Dabigatran etexilate is a novel synthetic direct thrombin inhibitor, is a prodrug of dabigatran, and belongs to a non-peptide thrombin inhibitor. After oral gastrointestinal absorption, the dabigatran etexilate is converted into dabigatran with direct anticoagulant activity in vivo. Dabigatran binds to the fibrin-specific binding site of thrombin, preventing cleavage of fibrinogen to fibrin, thereby blocking thrombosis. The dabigatran can be dissociated from the fibrin-thrombin combination to play a reversible anticoagulation role.
The dabigatran etexilate is a direct thrombin inhibitor and has the characteristics of oral administration, strong effect, no need of special medication monitoring, less drug interaction and the like. In vitro and in vivo tests and clinical researches all suggest that the dabigatran etexilate has good curative effect and pharmacokinetic characteristics, has an optimistic clinical application prospect, and is a great breakthrough in the field of anticoagulant drug research when successfully marketed.
The preparation method of dabigatran etexilate is disclosed in a compound patent W09837075, and comprises the following steps: 4-methylamino-3-nitrobenzoic acid (2) as a raw material forms 4-methylamino-3-nitrobenzoyl chloride (3) under the action of thionyl chloride; 3 and 3- (pyridine-2-ylamino) ethyl propionate (4) in the presence of triethylamine to produce 3- [ (3-nitro-4-methylaminobenzoyl) (pyridine-2-yl) amino ] ethyl propionate (5); reducing the obtained product by a reducing agent to obtain 3- [ (3-amino-4-methylamino benzoyl) (pyridine-2-yl) amino ] ethyl propionate (6); 6 and N- (4-cyanophenyl) aminoacetic acid (7) form amide in the presence of a condensing agent, and then a large excess of acetic acid is added for reflux to obtain ethyl 3- [ [ [2- [ [ (4-cyanophenyl) amino ] methyl ] -1-methyl-1H-benzimidazole-5-yl ] carbonyl ] pyridin-2-ylamino ] propionate (8); dissolving 8 in a saturated hydrogen chloride ethanol solution for alcoholysis to generate a hydrochloric acid ethanol solution of ethyl 3- [ [ [2- [ [ (4-ethoxycarboximidoylphenyl) amino ] methyl ] -1-methyl-1H-benzimidazole-5-yl ] carbonyl ] (pyridine-2-yl) amino ] propionate (9), distilling a part of hydrochloric acid gas under reduced pressure, and reacting with ammonia or ammonium carbonate to obtain ethyl 3- [ [ [2- [ [ (4-amidinophenyl) amino ] methyl ] -1-methyl-1H-benzimidazole-5-yl ] carbonyl ] (pyridine-2-yl) amino ] propionate (10); 10 and n-hexyl chloroformate under the action of alkali to prepare dabigatran etexilate (11); 11 and methanesulfonic acid in acetone solution to prepare the dabigatran etexilate mesylate. The route is shown below, and the method mainly has the following problems: (1) when the ethyl 3- [ (3-amino-4-methylaminobenzoyl) (pyridin-2-yl) amino ] propionate (6) and the N- (4-cyanophenyl) glycine (7) are condensed to generate the corresponding benzimidazole derivative, the yield is about 50 percent, and the benzimidazole derivative is low and needs to be purified by column chromatography; (2) the reaction for hydrolyzing a cyano group with a reagent such as ethanol hydrochloride to obtain an amidino group is complicated in operation and generates a large amount of waste acid.
In patent WO2011061080, an improvement is made to the synthesis route, as follows:
the focus of this route is the synthesis of the key intermediate 3-alanine-N- [ [ 1-methyl-1H-benzimidazole-2-halomethyl ] -5-carbonyl ] -N-2-pyridine-ethyl ester (16). And (3) cyclizing and condensing the intermediate 3- [ (3-amino-4-methylamino benzoyl) (pyridine-2-yl) amino ] ethyl propionate (15) and a coupling reagent to obtain a key intermediate 16. Wherein the coupling reagent used is chloroacetic acid, chloroacetyl chloride, chloroacetic anhydride or triethoxy chloroethane. When chloroacetic acid is used, the reaction yield is only 30%, and the reaction conditions are harsh because a control system such as a molecular sieve is used in an anhydrous environment; when chloracetyl chloride is used as a coupling reagent, diacylation byproduct impurities are easily generated, and the yield is only 71%; the chloroacetic anhydride is high in price, so that the production cost is increased; triethoxy chloroethane is not easy to obtain, needs to be self-made and has more complex preparation. Therefore, the route is not suitable for industrial production of the intermediate (16) and dabigatran etexilate.
Patent CN102850325 describes an improved synthesis method of dabigatran etexilate key intermediate 3-alanine-N- [ [ 1-methyl-1H-benzimidazole-2-halomethyl ] -5-carbonyl ] -N-2-pyridine-ethyl ester (16), as shown below:
the method takes 3- [ (3-amino-4-methylamino benzoyl) (pyridine-2-yl) amino ] ethyl propionate (15) as a raw material and obtains an intermediate 16 with a coupling reagent, the conditions are mild, the reaction yield is improved compared with that of the patent WO2011061080, but the coupling reagent is expensive and is not easy to obtain.
As described above, although many methods for synthesizing dabigatran etexilate have been reported in the literature, these methods have significant drawbacks, and it is difficult to industrially produce dabigatran etexilate and the intermediate 3-alanine-N- [ [ 1-methyl-1H-benzimidazole-2-chloromethyl ] -5-carbonyl ] -N-2-pyridine-ethyl ester. Particularly, no safe, environment-friendly, strong-operability, stable and reliable method exists for preparing an intermediate 3-alanine-N- [ [ 1-methyl-1H-benzimidazole-2-chloromethyl ] -5-carbonyl ] -N-2-pyridine-ethyl ester. On the other hand, in order to ensure the curative effect and safety of clinical medication, the quality standards established by various countries for pharmaceutical intermediates and raw material medicines are higher and higher, and the synthetic methods of dabigatran etexilate reported in the above documents lack the research and control on the process, do not establish perfect quality standards for raw materials and intermediates, cannot ensure the stability of the quality of the final product, and are difficult to be directly applied to the industrial preparation of dabigatran etexilate.
Disclosure of Invention
The technical problem to be solved by the invention is to provide an intermediate 3-alanine-N- [ [ 1-methyl-1H-benzimidazole-2-chloromethyl ] -5-carbonyl ] -N-2-pyridine-ethyl ester and a preparation method thereof, wherein the reaction condition is mild, and the intermediate is suitable for industrial production, and the purity of the obtained intermediate is not lower than 99.0%.
Firstly, the invention provides a dabigatran etexilate intermediate, the chemical name of which is 3-alanine-N- [ [ 1-methyl-1H-benzimidazole-2-chloromethyl ] -5-carbonyl ] -N-2-pyridine-ethyl ester, the structure of which is shown in formula II, the purity is not lower than 99.0%, wherein the content of a compound III is not higher than 0.5%, and the content of a compound IV is not higher than 0.3%.
The compound III and the compound IV are impurities in the intermediate of the formula (II), when the content of the compound III is not higher than 0.5% and the content of the compound IV is not higher than 0.3%, in the process of preparing the dabigatran etexilate bulk drug by using the intermediate of the formula (II), the content of the compound III and the compound IV in the intermediate of the formula (II) is low, and the compound III and the compound IV cannot be transferred to the final product dabigatran etexilate bulk drug, so that the quality of the dabigatran etexilate bulk drug is not influenced.
Furthermore, the purity of the dabigatran etexilate intermediate is not lower than 99.2%, the content of the compound III is not higher than 0.4%, and the content of the compound IV is not higher than 0.3%.
Furthermore, the purity of the dabigatran etexilate intermediate is not lower than 99.5%, the content of the compound III is not higher than 0.3%, and the content of the compound IV is not higher than 0.2%.
The invention further provides a preparation method of the dabigatran etexilate intermediate.
A preparation method of a dabigatran etexilate intermediate 3-alanine-N- [ [ 1-methyl-1H-benzimidazole-2-chloromethyl ] -5-carbonyl ] -N-2-pyridine-ethyl ester comprises the following steps:
step A: adding ethyl acetate and ethyl 3- [ (3-amino-4-methylamino benzoyl) (pyridine-2-yl) amino ] propionate into a reaction kettle 1, heating, stirring and dispersing, and cooling to 20 +/-10 ℃;
and B: adding ethyl acetate and chloroacetic acid into the reaction kettle 2, controlling the temperature to be 20 +/-10 ℃, adding CDI, and stirring until the system is clear;
and C: controlling the temperature to be 20 +/-10 ℃, and transferring the reaction liquid in the reaction kettle 2 into the reaction kettle 1; adding glacial acetic acid, heating to 40-60 deg.C, and reacting completely;
step D: cooling to 20 + -5 deg.C, adding purified water, extracting, mixing the water phase with ethyl acetate, concentrating under reduced pressure until no distillate flows out to obtain oily substance;
step E: and D, adding the oily substance obtained in the step D into an organic solvent 1, heating to 40 +/-5 ℃, stirring, dissolving, controlling the temperature to 40 +/-5 ℃, directly dripping an organic solvent 2 for crystallization, filtering and drying to obtain the intermediate.
In the preparation method, the step A and the step B are not in sequence, and the step C, the step D and the step E are carried out according to the sequence.
In the preparation method, the structure of the ethyl 3- [ (3-amino-4-methylamino benzoyl) (pyridin-2-yl) amino ] propionate is shown as the formula V:
the CDI is N, N-carbonyl-diimidazole, and the structural formula is shown as follows:
in the above preparation method, based on the amount of ethyl 3- [ (3-amino-4-methylaminobenzoyl) (pyridin-2-yl) amino ] propionate (formula V) added in step a:
the amount of ethyl acetate used in step A is 2-10ml/g (volume to weight), preferably 5-7ml/g, more preferably 6 ml/g.
In the step B, the amount of the ethyl acetate is 2 to 10ml/g (volume weight ratio), preferably 3 to 5ml/g, more preferably 3.5 to 4.5 ml/g, and more preferably 4 ml/g.
In the step B, chloroacetic acid is added in an amount of 1.35 to 1.80 molar equivalents (molar ratio, eq), preferably 1.35 to 1.65 molar equivalents (eq), more preferably 1.55 molar equivalents (eq); the CDI is added in an amount of 1.3 to 1.75 molar equivalents (eq), preferably 1.3 to 1.6 molar equivalents (eq), more preferably 1.5 molar equivalents (eq).
In the step C, the glacial acetic acid is added immediately after the transfer is finished.
In the step C, the volume dosage of the glacial acetic acid is 4-10ml/g, preferably 4-8ml/g, and more preferably 6 ml/g.
In the step E, the organic solvent 1 is selected from a mixed solvent of acetone and acetone isopropyl ether, and the organic solvent 2 is isopropyl ether.
In the step E, the volume usage amount of the organic solvent 1 is 3-6ml/g, preferably 3-4ml/g, and more preferably 3 ml/g.
In the step E, the volume dosage of the organic solvent 2 is 12-20ml/g, preferably 13-15 ml/g.
In the step E, the organic solvent 1 is a mixed solvent of acetone isopropyl ether, and the volume ratio of the acetone isopropyl ether is 1: 0.5-2; preferably 1: 1.
Further, the invention provides a detection method for detecting 3-alanine-N- [ [ 1-methyl-1H-benzimidazole-2-chloromethyl ] -5-carbonyl ] -N-2-pyridine-ethyl ester, a compound III and a compound IV.
A method for detecting the purity of 3-alanine-N- [ [ 1-methyl-1H-benzimidazole-2-chloromethyl ] -5-carbonyl ] -N-2-pyridine-ethyl ester, compound III and compound IV adopts high performance liquid chromatography, the chromatographic column is a C18 chromatographic column, the chromatographic column is 4.6mm multiplied by 250mm (diameter multiplied by length), the chromatographic column is 5 mu m (particle diameter), the detection wavelength is 231nm, the mobile phase A is ammonium acetate buffer solution with pH3.8, the mobile phase B is acetonitrile, and gradient elution is carried out according to the following table:
| Time | mobile phase A (%) | Mobile phase B (%) |
| 0 | 67-73 | 27-33 |
| 5 | 67-73 | 27-33 |
| 25 | 57-63 | 37-43 |
| 25.1 | 67-73 | 27-33 |
| 30 | 67-73 | 27-33 |
Further, the sample is dissolved in acetonitrile to prepare a solution containing 0.1-1mg/ml, and the solution is injected into liquid chromatography.
The purity of the intermediate, compound III, compound IV was calculated according to the area normalization method.
The dabigatran etexilate prepared by using the dabigatran etexilate intermediate provided by the invention has the purity of not less than 99.5%, and does not contain a compound III or a compound IV.
Description of the drawings:
FIG. 1: example 2 purity chromatogram of reaction System
FIG. 2 is a drawing: example 2 intermediate purity chromatogram
FIG. 3: example 4 intermediate purity chromatogram
FIG. 4 is a drawing: example 5 intermediate purity chromatogram
FIG. 5: comparative example 1 reaction System purity chromatogram
FIG. 6: comparative example 3-1 intermediate purity chromatogram
In the map:
VWD1B ultraviolet detector; wavelet length ═ 231 nm: detecting the wavelength; signal: signal
RT [ min ]: retention time [ min ]; width [ min ]: peak width; area: peak area; area%: peak area percentage;
height: peak height
The peak time of 3-alanine-N- [ [ 1-methyl-1H-benzimidazole-2-chloromethyl ] -5-carbonyl ] -N-2-pyridine-ethyl ester (formula V) is 13-14 minutes;
the relative retention time of compound III is 0.68-0.78, i.e. the peak-off time is 9.5-10.5 minutes.
The relative retention time of compound IV is 0.27-0.32, i.e. the peak time is 3.8-4.2 minutes.
Detailed Description
The invention discloses a dabigatran etexilate intermediate and a preparation method thereof, and a person skilled in the art can use the content of the invention for reference and combine the relevant principles of pharmaceutical chemistry to realize the dabigatran etexilate intermediate by properly improving the process parameters. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope of the invention. While the invention has been described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations may be applied, or changes and combinations may be made, in the methods and applications described herein to achieve and use the inventive techniques without departing from the spirit, scope, and content of the invention.
The detection method of the intermediate comprises the following steps:
a chromatographic column: XDB-C18 (4.6X 250mm, 5 μm) at a flow rate of 1.0ml/min
Mobile phase A10 mmol ammonium acetate added with acetic acid to adjust the pH to 3.8
Mobile phase B: acetonitrile, elution according to the following gradient, column temperature 40 deg.C, sample size 10 μ l, wavelength 231nm
| | A | B | |
| 0 | 70 | 30 | |
| 5 | 70 | 30 | |
| 25 | 60 | 40 | |
| 25.1 | 70 | 30 | |
| 30 | 70 | 30 |
Example 1: preparation of dabigatran etexilate intermediates
Step A: adding 600ml of ethyl acetate and 100g (0.29mol, 1.0eq) of the compound shown in the formula (V) into a reaction kettle 1, heating to 40 +/-5 ℃, stirring for dispersing, and cooling to 20-30 ℃;
and B: adding 400ml of ethyl acetate and 43g (0.46mol, 1.55eq) of chloroacetic acid into a reaction kettle 2, controlling the temperature to be 20 +/-10 ℃, adding 71.2g (0.44mol, 1.50eq) of CDI, and stirring until the system is clear;
and C: controlling the temperature to be 20 +/-10 ℃, and transferring the reaction liquid in the reaction kettle 2 into the reaction kettle 1; after the transfer is finished, 600ml of glacial acetic acid is immediately added, the addition is finished within 10min, the temperature is raised to 50-60 ℃, the reaction is kept for 3h, and the TLC tracking reaction is complete;
step D: cooling to 20 + -5 deg.C, adding 1000ml of purified water, extracting, separating, extracting water phase with ethyl acetate, mixing ethyl acetate phases, and concentrating under reduced pressure until no fraction flows out;
step E: and D, adding 150ml of mixed solvent of acetone and 150ml of isopropyl ether into the oily substance obtained in the step D, heating to 40 +/-5 ℃, stirring to dissolve, controlling the temperature to be 40 +/-5 ℃, adding 1350ml of isopropyl ether, keeping the temperature and stirring for 1h after the addition is finished, naturally cooling to 15 +/-5 ℃, keeping the temperature and crystallizing for 2h, filtering and drying to obtain the intermediate compound shown in the formula (II). The intermediate weight was 89.2g, and the molar yield was 76.0%.
The detection method comprises the following steps: the intermediate obtained by the preparation is taken and added with acetonitrile to be dissolved, and a solution with the purity of 99.62 percent, 0.17 percent of compound III, 0.14 percent of compound IV and 0.07 percent of other impurities is prepared according to the detection method of the intermediate.
Example 2: preparation of dabigatran etexilate intermediates
Step A: adding 300ml of ethyl acetate and 50g (0.15mol, 1.0eq) of the compound shown in the formula (V) into a reaction kettle 1, heating to 40 +/-5 ℃, stirring for dispersing, and cooling to 20-30 ℃;
and B: adding 200ml of ethyl acetate and 21.5g (0.23mol, 1.55eq) of chloroacetic acid into a reaction kettle 2, controlling the temperature to be 20 +/-10 ℃, adding 35.6g (0.22mol, 1.50eq) of CDI, and stirring until the system is clear;
and C: controlling the temperature to be 20 +/-10 ℃, and transferring the reaction liquid in the reaction kettle 2 into the reaction kettle 1; after the transfer is finished, 300ml of glacial acetic acid is immediately added, the addition is finished within 8min, the temperature is raised to 55-60 ℃, the reaction is kept for 3.5h, and the TLC tracking reaction is complete; diluting the reaction solution with acetonitrile, and detecting the purity of the reaction system according to the detection method of the intermediate, wherein the purity of the intermediate is 93.83%, and the method is shown in figure 1.
Step D: cooling to 20 + -5 deg.C, adding 550ml of purified water, extracting, separating, extracting water phase with ethyl acetate, mixing ethyl acetate phases, and concentrating under reduced pressure until no fraction flows out;
step E: and D, adding 150ml of acetone into the oily substance obtained in the step D, heating to 40 +/-5 ℃, stirring to dissolve, controlling the temperature to 40 +/-5 ℃, adding 675ml of isopropyl ether, keeping the temperature and stirring for 1h after the addition is finished, naturally cooling to 15 +/-5 ℃, keeping the temperature and crystallizing for 2h, filtering and drying to obtain the intermediate compound shown in the formula (II). Intermediate body weight 44.3g, molar yield 75.5%.
The detection method comprises the following steps: dissolving the prepared intermediate in acetonitrile to prepare 0.5mg/ml solution, and determining according to intermediate detection method to obtain intermediate chromatogram with purity of 99.59%, compound III 0.20%, compound IV 0.14%, and other impurities 0.08%, and shown in figure 2.
Example 3: preparation of dabigatran etexilate intermediates
Step A: adding 800ml of ethyl acetate and 84.5g (0.89mol, 1.53eq) of chloroacetic acid into a reaction kettle 2, controlling the temperature to be 20 +/-10 ℃, adding 142.5g (0.88mol, 1.50eq) of CDI, and stirring until the system is clear;
and B: adding 1200ml of ethyl acetate and 200g (0.59mol, 1.0eq) of the compound shown in the formula (V) into a reaction kettle 1, heating to 40 +/-5 ℃, stirring for dispersing, and cooling to 20-30 ℃;
and C: controlling the temperature to be 20 +/-10 ℃, and transferring the reaction liquid in the reaction kettle 2 into the reaction kettle 1; after the shift is finished, 1200ml of glacial acetic acid is immediately added, the addition is finished within 10min, the temperature is raised to 50-60 ℃, the reaction is kept for 3h, and the TLC tracking reaction is complete;
step D: cooling to 20 + -5 deg.C, adding 1800ml of purified water, extracting, separating, extracting the water phase with ethyl acetate, mixing ethyl acetate phases, and concentrating under reduced pressure until no fraction flows out;
step E: and D, adding 300ml of acetone and 300ml of isopropyl ether mixed solvent into the oily substance obtained in the step D, heating to 40 +/-5 ℃, stirring and dissolving, controlling the temperature to be 40 +/-5 ℃, adding 2700ml of isopropyl ether, preserving heat and stirring for 1h after the addition is finished, naturally cooling to 15 +/-5 ℃, preserving heat and crystallizing for 2h, filtering and drying to obtain the intermediate compound shown in the formula (II). The intermediate weight was 176.2g, molar yield 75.0%.
The detection method comprises the following steps: dissolving the prepared intermediate in acetonitrile to prepare 0.5mg/ml solution, and determining according to the detection method of the intermediate, wherein the purity is 99.68%, the compound III is 0.15%, the compound IV is 0.17%, and other impurities are not detected.
Example 4: preparation of dabigatran etexilate intermediates
Step A: adding 210ml of ethyl acetate and 22.1g (0.23mol, 1.60eq) of chloroacetic acid into a reaction kettle 2, controlling the temperature to be 20 +/-10 ℃, adding 35.6g (0.22mol, 1.50eq) of CDI, and stirring until the system is clear;
and B: adding 330ml of ethyl acetate and 50g (0.15, 1.0eq) of the compound shown in the formula (V) into the reaction kettle 1, heating to 40 +/-5 ℃, stirring for dispersing, and cooling to 20-30 ℃;
and C: controlling the temperature to be 20 +/-10 ℃, and transferring the reaction liquid in the reaction kettle 2 into the reaction kettle 1; after the transfer is finished, 300ml of glacial acetic acid is immediately added, the addition is finished within 8min, the temperature is raised to 45-55 ℃, the reaction is kept for 2.8h, and the TLC tracking reaction is complete;
step D: cooling to 20 + -5 deg.C, adding 500ml of purified water, extracting, separating, extracting water phase with ethyl acetate, mixing ethyl acetate phases, and concentrating under reduced pressure until no fraction flows out;
step E: and D, adding 200ml of acetone into the oily substance obtained in the step D, heating to 40 +/-5 ℃, stirring to dissolve, controlling the temperature to 40 +/-5 ℃, adding 675ml of isopropyl ether, keeping the temperature and stirring for 1.5h after the addition is finished, naturally cooling to 15 +/-5 ℃, keeping the temperature and crystallizing for 3h, filtering and drying to obtain the intermediate compound shown in the formula (II). Intermediate body weight 43.2g, molar yield 73.6%.
Dissolving the intermediate in acetonitrile to obtain 0.5mg/ml solution, and determining according to intermediate detection method, wherein the purity is 99.22%, compound III is 0.37%, compound IV is 0.19%, and other impurities are 0.23%, and chromatogram is shown in figure 3.
Example 5: preparation of dabigatran etexilate intermediates
Step A: adding 250ml of ethyl acetate and 50g (0.15, 1.0eq) of the compound shown as the formula (V) into a reaction kettle 1, heating to 40 +/-5 ℃, stirring for dispersing, and cooling to 20-30 ℃;
and B: adding 225ml of ethyl acetate and 21.3g (0.23mol, 1.54eq) of chloroacetic acid into a reaction kettle 2, controlling the temperature to be 20 +/-10 ℃, adding 35.7g (0.22mol, 1.50eq) of CDI, and stirring until the system is clear;
and C: controlling the temperature to be 20 +/-10 ℃, and transferring the reaction liquid in the reaction kettle 2 into the reaction kettle 1; after the shift is finished, 300ml of glacial acetic acid is immediately added, the addition is finished within 10min, the temperature is raised to 40-50 ℃, the reaction is kept for 3.5h, and the TLC tracking reaction is complete;
step D: cooling to 20 + -5 deg.C, adding 600ml of purified water, extracting, separating, extracting water phase with ethyl acetate, mixing ethyl acetate phases, and concentrating under reduced pressure until no fraction flows out;
step E: and D, adding 50ml of acetone and 100ml of isopropyl ether mixed solvent into the oily substance obtained in the step D, heating to 40 +/-5 ℃, stirring to dissolve, controlling the temperature to be 40 +/-5 ℃, adding 750ml of isopropyl ether, keeping the temperature and stirring for 1h after the addition is finished, naturally cooling to 15 +/-5 ℃, keeping the temperature and crystallizing for 2h, filtering, and drying to obtain the intermediate compound shown in the formula (II). The intermediate weight was 42.9g, molar yield 73.1%. Dissolving the intermediate in acetonitrile to obtain 0.5mg/ml solution, and determining according to intermediate detection method, wherein the purity is 99.46%, compound III is 0.32%, compound IV is 0.16%, and other impurities are 0.06%, and chromatogram is shown in figure 4.
Example 6: preparation of dabigatran etexilate intermediates
Step A: adding 175ml of ethyl acetate and 21.2g (0.22mol, 1.53eq) of chloroacetic acid into a reaction kettle 2, controlling the temperature to be 20 +/-10 ℃, adding 35.7g (0.22mol, 1.50eq) of CDI, and stirring until the system is clear;
and B: adding 350ml of ethyl acetate and 50g (0.15, 1.0eq) of the compound shown in the formula (V) into a reaction kettle 1, heating to 40 +/-5 ℃, stirring for dispersing, and cooling to 20-30 ℃;
and C: controlling the temperature to be 20 +/-10 ℃, and transferring the reaction liquid in the reaction kettle 2 into the reaction kettle 1; after the shift is finished, 300ml of glacial acetic acid is immediately added, the addition is finished within 10min, the temperature is raised to 50-60 ℃, the reaction is kept for 2.5h, and the TLC tracking reaction is complete;
step D: cooling to 20 + -5 deg.C, adding 400ml of purified water, extracting, separating, extracting water phase with ethyl acetate, mixing ethyl acetate phases, and concentrating under reduced pressure until no fraction flows out;
step E: and D, adding 100ml of acetone and 50ml of isopropyl ether mixed solvent into the oily substance obtained in the step D, heating to 40 +/-5 ℃, stirring to dissolve, controlling the temperature to be 40 +/-5 ℃, adding 600ml of isopropyl ether, keeping the temperature and stirring for 1h after the addition is finished, naturally cooling to 15 +/-5 ℃, keeping the temperature and crystallizing for 2h, filtering, and drying to obtain the intermediate compound shown in the formula (II). The intermediate weight was 42.5g, molar yield 72.4%. The intermediate obtained by the preparation is taken and added with acetonitrile to be dissolved, and a solution with the purity of 99.33 percent, 0.28 percent of compound III, 0.19 percent of compound IV and 0.20 percent of other impurities is prepared according to the detection method of the intermediate.
Example 7: investigating the influence of the addition of the chloroacetic acid and the CDI in the step B on the preparation of the dabigatran etexilate intermediate
The amount of chloroacetic acid/CDI added in step B is shown in the table below, and the rest steps and parameters are the same as those in example 2; the detection method was the same as in example 2.
The purity of the prepared intermediate is higher than 99%, the content of the compound III is not higher than 0.5%, and the content of the compound IV is not higher than 0.3% when the addition molar equivalent of chloroacetic acid and CDI influences the yield and the purity of the intermediate, the addition amount of chloroacetic acid is 1.35-1.80 molar equivalent (eq), and the addition amount of CDI is 1.3-1.75 molar equivalent (eq).
When the addition amount of chloroacetic acid is less than 1.35eq and the addition amount of CDI is less than 1.3eq (such as example 7-1 and example 7-2), the molar yields of the prepared intermediates are obviously reduced, and are respectively less than 61%, the purity is less than 99%, and the content of the compound III is more than 0.5%.
Since yield is not increased with increase in the amount of chloroacetic acid and CDI, the amount of chloroacetic acid added is preferably 1.35 to 1.65 molar equivalents (eq), more preferably 1.55 molar equivalents (eq), in view of cost; when the amount of CDI added is 1.3 to 1.6 molar equivalents (eq), 1.5 molar equivalents (eq) are more preferable.
Example 8: investigating the influence of the addition amount of acetic acid in the step C on the preparation of the dabigatran etexilate intermediate
The amount of acetic acid added in step C is shown in the following table, and other steps and parameters are the same as those in example 2; the detection method was the same as in example 2.
The amount of acetic acid used in step C affects the purity of the intermediate, and when the amount of acetic acid used is low (2 ml/g in comparative example 8-1), the intermediate of formula (II) prepared not only has a reduced yield, but also has a low purity (less than 99%) and a high content of compound IV (1.15%). When the using amount of acetic acid is 4-8ml/g, the purity of the prepared intermediate is higher than 99%, the content of the compound III is not higher than 0.5%, and the content of the compound IV is not higher than 0.3%.
Comparative example 1: effect of reaction solvent on the preparation of dabigatran etexilate intermediates
Tetrahydrofuran was used in place of ethyl acetate in steps A and B, and the remaining steps and parameters were the same as in example 2;
the purity of the reaction system in step C, the purity of the intermediate of formula (II) is 84.84%, see FIG. 5;
the weight of the intermediate obtained in the step E is 34.8g, the molar yield is 59.3 percent, and the purity of the intermediate of the formula (II) is 93.83 percent.
Compared with ethyl acetate, tetrahydrofuran is used as a reaction solvent, and the following two problems exist: (1) and D, taking tetrahydrofuran as a reaction solvent, wherein the purity of the intermediate of the formula (II) in the reaction system after the step C is finished is 84.84%. Ethyl acetate is used as a reaction solvent, and the purity of the reaction solution after the step C in the example 2 is 93.83%, which indicates that tetrahydrofuran is used as a solution, a large amount of byproducts are generated, and the yield and the purity of the intermediate in the formula (II) are influenced; (2) because tetrahydrofuran and water are mutually soluble, extraction and liquid separation are difficult after the extraction is finished, and the water washing and liquid separation operation is carried out after the replacement by ethyl acetate, so that the operation complexity and the production cost are increased. And the ethyl acetate is used as a reaction solvent, so that the method has the advantages of simplified process, reduced cost, improved yield, improved purity and the like.
Comparative example 2: effect of glacial acetic acid addition time in step C on dabigatran etexilate intermediate preparation
Changing the adding time of the glacial acetic acid in the step C, replacing the step 2 with the step of adding 300ml of glacial acetic acid immediately after the transfer is finished by the step of stirring for 0.5h after the transfer is finished, and adding 300ml of glacial acetic acid, and carrying out the same steps and parameters as the step 2.
The weight of the intermediate of the formula (II) obtained in the step E is 41.8g, the molar yield is 71.2%, the purity of the intermediate of the formula (II) is 96.47%, the compound III is 0.42%, the compound IV is 0.25%, the impurity VI is 2.59%, and other impurities are 0.27%.
It can be seen that different modes of addition affect the purity of the intermediates, especially the time of addition of glacial acetic acid in step C. Example 2 "transfer the reaction solution in reaction vessel 2 to reaction vessel 1; after the conversion is finished, glacial acetic acid is added immediately, the purity of the intermediate reaches 99.59 percent, and no impurity VI can be detected. In contrast, in comparative example 2 ", the reaction solution in the reaction vessel 2 was transferred to the reaction vessel 1; after the conversion is finished, stirring for 0.5h, adding glacial acetic acid ", easily generating byproduct impurity VI, obviously increasing the impurity VI content in the obtained intermediate, and obviously reducing the purity of the intermediate in the formula (II) to only 96.47%.
Comparative example 3: influence of the addition of organic solvents 1, 2 in step E on the preparation of dabigatran etexilate intermediates
The amounts of the organic solvent 1 and the organic solvent 2 added in the step E are shown in the following table, the rest steps and parameters are the same as those in example 2, and the detection method is the same as that in example 2.
And D, dissolving the oily substance obtained in the step D in isopropyl ether, and directly pulping and purifying the oily substance by using the isopropyl ether to obtain an intermediate, wherein the mode has greater potential safety hazard during production amplification, and the purity of the obtained intermediate in the formula (II) is 98.49 percent and is lower than 99.0 percent (see the attached figure 6 specifically). The inventors of the present application have also found that: when the amount of the organic solvent 1 (acetone or a mixed solvent of acetone and isopropyl ether) is less than 3ml/g (e.g., 1ml/g in comparative example 3-2, 2ml/g in comparative example 3-3, 2ml/g in comparative example 3-4 and 2.5ml/g in comparative example 3-5), the oily matter cannot be completely dissolved, and the purity of the obtained intermediate is not desirable and is less than 99%.
Comparative example 4: effect of reaction temperature in step C on preparation of dabigatran etexilate intermediate
The reaction temperature in step C is shown in the following table, and the other steps and parameters are the same as those in example 2.
From comparative example 4 and examples 1 to 8, it can be seen that: c, when the reaction temperature after adding the glacial acetic acid in the step C is lower (30-40 ℃ in a comparative example 4-1), and after 3.5 hours of reaction, TLC (thin layer chromatography) tracking shows that the reaction is incomplete, and the reaction yield and the purity of the obtained intermediate are influenced; at higher reaction temperatures (60-70 ℃ in comparative example 4-2), the content of compound III in the intermediate obtained increases to more than 0.5%. The reaction temperature is therefore preferably from 40 to 60 ℃.
Example 9: preparation of dabigatran etexilate
1. Preparation of acylamidine:
adding purified water and sodium hydroxide into a reaction kettle, and stirring to dissolve; cooling to 5-15 ℃, adding acetone and p-aminobenzamidine, and stirring until the mixture is basically dissolved; controlling the temperature to be 10-20 ℃, and dropwise adding n-hexyl chloroformate under rapid stirring; after dripping, carrying out heat preservation reaction for 1-2 h, and tracking by TLC;
separating liquid, extracting water phase with ethyl acetate, combining organic phases, backwashing for 2 times by using 10% sodium chloride aqueous solution, and concentrating the organic phase under reduced pressure until no fraction flows out;
thirdly, adding acetonitrile, stirring to dissolve, controlling the temperature to be 0-10 ℃, dropwise adding concentrated hydrochloric acid under rapid stirring, and stirring for 1-2 hours while keeping the temperature after dropwise adding; filtering and drying to obtain the acylamidine.
2. Preparation of dabigatran etexilate
Adding purified water, sodium bicarbonate, tetrahydrofuran and amidine into a reaction kettle in sequence, stirring for 10min, adding the intermediate prepared in example 3, NaI and tetrahydrofuran, and stirring; heating the system to 50 +/-5 ℃, and carrying out heat preservation reaction for 6 +/-1 h;
cooling to 20 +/-5 ℃ after the reaction is finished, separating liquid, extracting a water phase by using tetrahydrofuran, combining organic phases, and backwashing by using 20% sodium chloride water solution to 5V;
thirdly, controlling the temperature to be 20 +/-5 ℃, dropwise adding n-hexane into the organic phase, and keeping the temperature and stirring for 2 hours after dropwise adding; and filtering to obtain a crude product of the dabigatran etexilate.
And fourthly, sequentially adding acetonitrile and the dabigatran etexilate crude product into a reaction bottle, heating to 65 +/-5 ℃, dissolving and clearing, cooling to 35-45 ℃, and carrying out heat preservation and crystallization for 1h to obtain the dabigatran etexilate (white-like solid, yield of 55% and purity of more than 99%).
3. Preparation of dabigatran etexilate mesylate:
sequentially adding acetone and dabigatran etexilate at room temperature, stirring at 35-45 deg.C for dissolving, adding 5% active carbon for decolorizing for 30min, hot filtering, and cooling the filtrate to 25-35 deg.C; dropwise adding 0.98eq of acetone-2V solution of methanesulfonic acid, stirring after dropwise adding, and precipitating crystals to obtain dabigatran etexilate mesylate.
The dabigatran etexilate is obtained, the purity is 99.92%, and the compound III and the compound IV are not contained.
And (4) conclusion: the intermediate of the formula (II) prepared by the method has low content of the compound III and the compound IV, and the final product dabigatran etexilate has no residue of the compound III and the compound IV.
Example 10: preparation of dabigatran etexilate
1. Preparation of acylamidine:
adding purified water and sodium hydroxide into a reaction kettle, and stirring to dissolve; cooling to 5-15 ℃, adding acetone and p-aminobenzamidine, and stirring until the mixture is basically dissolved; controlling the temperature to be 10-20 ℃, and dropwise adding n-hexyl chloroformate under rapid stirring; after dripping, carrying out heat preservation reaction for 1-2 h, and tracking by TLC;
separating liquid, extracting water phase with ethyl acetate, combining organic phases, backwashing for 2 times by using 10% sodium chloride aqueous solution, and concentrating the organic phase under reduced pressure until no fraction flows out;
thirdly, adding acetonitrile, stirring to dissolve, controlling the temperature to be 0-10 ℃, dropwise adding concentrated hydrochloric acid under rapid stirring, and stirring for 1-2 hours while keeping the temperature after dropwise adding; filtering and drying to obtain the acylamidine.
2. Preparation of dabigatran etexilate
Adding purified water, sodium bicarbonate, tetrahydrofuran and amidine into a reaction kettle in sequence, stirring for 10min, adding the intermediate prepared in example 7, NaI and tetrahydrofuran, and stirring; heating the system to 50 +/-5 ℃, and carrying out heat preservation reaction for 6 +/-1 h;
cooling to 20 +/-5 ℃ after the reaction is finished, separating liquid, extracting a water phase by using tetrahydrofuran, combining organic phases, and backwashing by using 20% sodium chloride water solution to 5V;
thirdly, controlling the temperature to be 20 +/-5 ℃, dropwise adding n-hexane into the organic phase, and keeping the temperature and stirring for 2 hours after dropwise adding; and filtering to obtain a crude product of the dabigatran etexilate.
And fourthly, sequentially adding acetonitrile and the dabigatran etexilate crude product into a reaction bottle, heating to 65 +/-5 ℃, dissolving and clearing, cooling to 35-45 ℃, and carrying out heat preservation and crystallization for 1h to obtain the dabigatran etexilate (white-like solid, yield of 55% and purity of more than 99%).
3. Preparation of dabigatran etexilate mesylate:
sequentially adding acetone and dabigatran etexilate at room temperature, stirring at 35-45 deg.C for dissolving, adding 5% active carbon for decolorizing for 30min, hot filtering, and cooling the filtrate to 25-35 deg.C; dropwise adding 0.98eq of acetone-2V solution of methanesulfonic acid, stirring after dropwise adding, and precipitating crystals to obtain dabigatran etexilate mesylate. The purity is 99.89%, and compound III and compound IV are not contained.
And (4) conclusion: the intermediate of the formula (II) prepared by the method has low content of the compound III and the compound IV, and the final product dabigatran etexilate has no residue of the compound III and the compound IV.
Example 11: stability test of intermediate
Taking a proper amount of the intermediates of the embodiment 1, the embodiment 7 and the embodiment 8, and carrying out reaction at the temperature of 40 +/-2 ℃; the sample was left at 75% + -5% relative humidity for 6 months, and samples were taken at the end of 0, 3 and 6 months, respectively, to determine the substances involved.
The intermediate prepared by the invention has stable quality and no obvious change in the content after long-term storage.
Claims (10)
1. A preparation method of a dabigatran etexilate intermediate is disclosed, wherein the intermediate has a structure shown in a formula II,
the method is characterized by comprising the following steps:
step A: adding ethyl acetate and a compound shown in a formula (V) into a reaction kettle 1, heating, stirring and dispersing, and cooling to 20 +/-10 ℃;
and B: adding ethyl acetate and chloroacetic acid into the reaction kettle 2, controlling the temperature to be 20 +/-10 ℃, adding CDI, and stirring until the system is clear;
and C: controlling the temperature to be 20 +/-10 ℃, and transferring the reaction liquid in the reaction kettle 2 into the reaction kettle 1; after the conversion is finished, adding glacial acetic acid immediately, heating to 40-60 ℃, and reacting completely;
step D: cooling to 20 + -5 deg.C, adding purified water, extracting, mixing the water phase with ethyl acetate, concentrating under reduced pressure until no distillate flows out to obtain oily substance;
step E: d, adding the oily substance obtained in the step D into an organic solvent 1, heating to 40 +/-5 ℃, stirring to dissolve, controlling the temperature to 40 +/-5 ℃, directly dripping an organic solvent 2 for crystallization, filtering and drying to obtain an intermediate;
in the preparation method, the step A and the step B are not in sequence, and the step C, the step D and the step E are carried out according to the sequence; in the step E, the organic solvent 1 is selected from a mixed solvent of acetone and acetone isopropyl ether, and the organic solvent 2 is isopropyl ether.
2. The process according to claim 1, wherein glacial acetic acid is used in a volume of 4 to 10ml/g, preferably 4 to 8ml/g, more preferably 6ml/g, based on the amount of compound of formula (V) added, in step C.
3. The process according to claim 1, wherein the organic solvent 1 is used in an amount of 3 to 6ml/g, preferably 3 to 4ml/g, more preferably 3ml/g, based on the amount of the compound of formula (V) added in step E; the volume dosage of the organic solvent 2 is 12-20ml/g, preferably 13-15 ml/g.
4. The method according to claim 1, wherein in step E, the organic solvent 1 is a mixed solvent of acetone isopropyl ether, and the volume ratio of acetone isopropyl ether is 1: 0.5-2; preferably 1: 1.
5. The process according to claim 1, wherein chloroacetic acid is added in step B in an amount of 1.35 to 1.80 molar equivalents, preferably 1.35 to 1.65 molar equivalents, more preferably 1.55 molar equivalents, based on the amount of the compound of formula (V).
6. The process according to claim 1, wherein in step B, CDI is added in an amount of 1.3 to 1.6 molar equivalents, preferably 1.5 molar equivalents, based on the amount of the compound of formula (V).
7. An intermediate prepared according to the process of any one of claims 1 to 6, having the structure of formula II.
8. The intermediate of claim 7, wherein: the purity of the intermediate shown in formula II is not less than 99.0%, wherein the content of the compound III is not more than 0.5%, and the content of the compound IV is not more than 0.3%
9. The method for detecting the dabigatran etexilate intermediate as claimed in claim 7, wherein the high performance liquid chromatography is adopted, the chromatographic column is a C18 chromatographic column with 4.6mm x 250mm and 5 μm, the detection wavelength is 231nm, the mobile phase A is ammonium acetate buffer solution with pH3.8, the mobile phase B is acetonitrile, and gradient elution is carried out according to the following table:
。
10. The detection method according to claim 9, wherein the sample is dissolved in acetonitrile to prepare a solution containing 0.1 to 1mg/ml, and the solution is injected into the liquid chromatography.
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