Preparation method of dabigatran etexilate and intermediate thereof

Abstract

The invention provides a preparation method of a dabigatran etexilate intermediate as shown in a formula 6, which comprises the following steps: carrying out condensation reaction on a compound as shown in a formula 4 and a cyclization reagent as shown in a formula 5 in the presence of an organic solvent to obtain the dabigatran etexilate intermediate as shown in the formula 6, namely # imgabs0 #. The method has the advantages of simple post-treatment, less required purification solvent, low cost, high yield, cheap and easily available reagents, mild preparation reaction conditions of the starting material, simple post-treatment, and direct use in the condensation reaction step without separation and purification.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and in particular relates to a preparation method of dabigatran etexilate and an intermediate thereof. Background Art

[0002] Dabigatran Etexilate is an oral thrombin inhibitor developed by Boehringer Ingelheim in Germany. It is a new generation of oral anticoagulant drugs that directly inhibit thrombin. The drug was approved for marketing by the European EMA in 2008 and the US FDA in 2010. It is mainly used to prevent stroke and systemic embolism in patients with non-valvular atrial fibrillation. It has the characteristics of oral administration, strong efficacy, no special drug testing, and few drug interactions. Its chemical structure is shown in the following formula:

[0003]

[0004] Patent CN102612517B reports the original third generation synthetic route of dabigatran etcxilate, and this route is obtained hexyloxy acyl amidine intermediate 3 by p-aminobenzamidine intermediate 1 and n-hexyl chloroformate reaction.Meanwhile, hydride intermediate 4 is obtained dabigatran etcxilate intermediate chloro thing shown in formula 6 by cyclization with corresponding cyclization reagent.Finally, dabigatran etcxilate intermediate chloro thing coupling shown in hexyloxy acyl amidine intermediate 3 and formula 6 can be obtained, and reaction formula is as follows:

[0005]

[0006] In the above-mentioned route, the chloro intermediate of dabigatran etexilate shown in Formula 6 is the key intermediate of the route, and the patent is obtained by cyclization of the hydride intermediate shown in Formula 4 and the corresponding cyclization reagent, wherein the cyclization reagent can be chloroacetic acid, chloroacetyl chloride, chloroacetic anhydride or chloro orthoacetic triethyl ester. When chloroacetic acid is used, the yield is only 30%, and it is also necessary to use a large amount of molecular sieves for moisture control; when chloroacetyl chloride is used, the yield is about 71%, and due to the higher reaction activity, disubstituted impurity by-products are easily generated; when chloroacetic anhydride is used, the yield is about 90%, but chloroacetic anhydride is more expensive, so that the production cost is improved. In addition, the technical solution of triethyl chloroacetate has a yield of up to 95%, but the material is not commercialized and needs to be self-made. For example, in the preparation method disclosed in CN102838547A, raw material hydrochloride A (5 g, 32 mmol) and 8.7 g (190 mmol, 11 mL) of anhydrous ethanol are added to a reaction bottle, the solution is first stirred at room temperature to dissolve the solid, and then heated in an oil bath to keep the alcohol solution at 40°C. The reaction is stopped after 6 hours, and a large amount of solid is precipitated by cooling in an ice bath. 20 mL of ether is added, and the solid is first washed with an equal volume of 10% sodium carbonate solution, then washed with saturated sodium carbonate, dried with anhydrous sodium sulfate, and distilled under reduced pressure to obtain 3.5 g of triethyl chloroacetate. This method requires distillation for purification, the operation is relatively complicated, the yield is only 56%, and the material has poor stability, which is not conducive to industrial production.

[0007]

[0008] Patent CN102850325 discloses a method for synthesizing a chlorinated intermediate of dabigatran etexilate shown in Formula 6. The method comprises reacting a hydride intermediate shown in Formula 4 and a cyclization reagent under the catalysis of ammonium chloride to obtain a chlorinated intermediate of dabigatran etexilate shown in Formula 6. The yield can reach 80%. However, there is also the problem that the cyclization reagent is expensive and difficult to obtain. The reaction formula is as follows:

[0009]

[0010] Patent CN104447697B discloses a method for preparing a chlorinated intermediate of dabigatran etexilate shown in Formula 6, which comprises reacting a hydride intermediate shown in Formula 4 with ethyl chloroacetate under the catalysis of an immobilized enzyme, and then reflux cyclization in glacial acetic acid to obtain the chlorinated intermediate of dabigatran etexilate shown in Formula 6, with a yield of about 80%.

[0011] Patent CN113929661 discloses a method for preparing a chlorinated intermediate of dabigatran etexilate as shown in Formula 6. The method uses chloroacetic acid as a cyclization reagent and CDI as an activation reagent to carry out the reaction, and the yield is about 70%.

[0012]

[0013] To sum up, although the synthetic method of dabigatran etcxilate intermediate chloro product shown in the existing multiple formula 6 of prior art is reported, these methods have certain limitations in large-scale industrial production. Therefore, it is very significant to develop a kind of easy and simple to operate, raw material is easy to get, and it is very significant to have cost advantage and be suitable for the synthetic method of industrialized large-scale production. Summary of the invention

[0014] In view of the shortcomings and deficiencies in the prior art, the present invention provides a method for preparing a chlorinated intermediate of dabigatran etexilate as shown in Formula 6. The method has mild reaction conditions, cheap and readily available raw materials, high yield, and is easy to realize industrial production.

[0015] The technical solution adopted by the present invention is specifically as follows:

[0016] b) condensing the hydride intermediate shown in Formula 4 with the cyclization reagent shown in Formula 5 in the presence of an organic solvent to obtain

[0017] Dabigatran etexilate intermediate chloride shown in formula 6,

[0018]

[0019] In some embodiments, the organic solvent used in the condensation reaction is selected from one or more of ethyl acetate, butyl acetate, tetrahydrofuran, methyltetrahydrofuran, dioxane, dichloromethane, and toluene;

[0020] In some embodiments, the organic solvent for the condensation reaction is ethyl acetate, butyl acetate, tetrahydrofuran, toluene;

[0021] In some embodiments, the condensation reaction temperature is 20-100° C., and the condensation reaction time is 1 to 10 hours;

[0022] In some embodiments, the condensation reaction temperature is 40-70° C., and the condensation reaction time is 2-5 hours;

[0023] In some embodiments, the molar ratio of the compound of formula 4 to the cyclization reagent represented by formula 5 is 1:1 to 2, preferably 1:1.2 to 1.4;

[0024] In some embodiments, the mass volume ratio of the hydride intermediate represented by Formula 4 to the organic solvent of the condensation reaction is 1:4-7 g / ml.

[0025] In some embodiments, the cyclization reagent shown in Formula 5 can be obtained by reacting chloroacetic acid and pivaloyl chloride in the presence of a base and a reaction solvent in step a).

[0026]

[0027] In some embodiments, the base used in step a) is selected from one or more of organic amines or inorganic bases;

[0028] In some embodiments, the organic amine is selected from one or more of triethylamine, pyridine, N,N-diisopropylethylamine, tri-n-propylamine, and tri-n-butylamine; the inorganic base is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide;

[0029] In some embodiments, the base in step a) is selected from triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate.

[0030] In some embodiments, the reaction solvent of step a) is selected from one or more of ethyl acetate, butyl acetate, tetrahydrofuran, methyltetrahydrofuran, dioxane, dichloromethane, and toluene;

[0031] In some embodiments, the reaction solvent of step a) is ethyl acetate, butyl acetate, tetrahydrofuran, toluene;

[0032] In some embodiments, the molar ratio of chloroacetic acid, pivaloyl chloride and base in step a) is 1:1-2:1-2;

[0033] In some embodiments, the molar ratio of chloroacetic acid, pivaloyl chloride and base in step a) is 1:1.1-1.5:1.2-1.5;

[0034] In some embodiments, the reaction temperature in step a) is 0-60° C., and the reaction time is 1 to 10 hours;

[0035] In some embodiments, the reaction temperature in step a) is 10-30° C., and the reaction time is 3 to 6 hours;

[0036] In some embodiments, the cyclization reagent represented by Formula 5 obtained in step a) can be directly used in the next step reaction without separation and purification;

[0037] In some embodiments, in step a), pivaloyl chloride is dissolved in a reaction solvent to form a pivaloyl chloride solution, chloroacetic acid and a base are dissolved in the reaction solvent, and the pivaloyl chloride solution is slowly added dropwise.

[0038] At this time, hydrochloride of the base may be precipitated. There is no need to separate the precipitated salt. Continue stirring to obtain a reaction solution containing a mixed acid anhydride.

[0039] Preferably, the reaction solvent is ethyl acetate.

[0040] In some embodiments, in step b), the reaction solution containing the mixed anhydride obtained in step a) is cooled to 0-5° C., and then the compound shown in Formula 4 is directly added to the reaction solution. After the addition is completed, the temperature is raised to the reaction temperature of the condensation reaction to react. After the reaction is completed, the reaction solution is cooled to room temperature, washed with water, desalted, and concentrated to obtain the dabigatran etexilate intermediate shown in Formula 6;

[0041] In some embodiments, the brown-black oil is purified by beating with tertiary methyl ether and dried to obtain a compound of Formula 6.

[0042] In some embodiments, in the slurrying step, the mass volume ratio of the compound represented by Formula 6 to methyl tert-butyl ether is 1:3 to 10 g / ml.

[0043] Another aspect of the present invention is the use of the method of the present invention in the preparation of dabigatran etexilate or its salt;

[0044] In some embodiments, the hydride intermediate shown in Formula 4 is subjected to a condensation reaction with a cyclization reagent shown in Formula 5 in the presence of an organic solvent to obtain the dabigatran etexilate intermediate chloride shown in Formula 6, which is further converted into dabigatran etexilate or a salt thereof.

[0045] Compared with the prior art, the present invention has the following positive technical effects:

[0046] 1. The preparation method of the dabigatran etcxilate intermediate shown in formula 6 provided by the present invention has the advantages of mild reaction, simple aftertreatment, less required purification solvent, low cost and high yield, and is suitable for industrialized amplified production.

[0047] 2. The reagents used in the preparation method provided by the present invention are cheap and easily available, the preparation reaction conditions of the starting materials are mild, and the post-treatment is simple, and they can be directly used in the condensation reaction step without separation and purification. DETAILED DESCRIPTION

[0048] The following examples are used to further describe the specific embodiments of the present invention. The following examples are only used to illustrate the present invention, but are not used to limit the scope of the present invention.

[0049] All ranges recited in the present invention include those endpoints of the range between two values, and no matter whether it is indicated, all values ​​recited in the present invention include the expected experimental error, technical error and instrument error of the given technology used to measure the value. When the error degree is not recorded, all values ​​recited in the present invention include the range of ± 10% of the recorded value.

[0050] In the present invention, unless otherwise specified, % is a percentage of weight / weight (w / w).

[0051] Unless otherwise specified, the materials used in the present invention were obtained from commercial sources.

[0052] The HPLC method of the dabigatran etcxilate intermediate chloride shown in the determination formula 6 of the present invention:

[0053] Instrument: High performance liquid chromatography equipped with UV detector

[0054] Chromatographic column: YMC-Pack ODS-A250*4.6mm, 5μm

[0055] Buffer: 10 mM diammonium phosphate aqueous solution (e.g. 1.32 g diammonium phosphate dissolved in 1000 mL water), Adjust pH to 6.0 with phosphoric acid

[0057] Mobile phase A: Buffer: Acetonitrile = 70:30 (% V / V)

[0058] Mobile phase B: Buffer: Acetonitrile = 25:75 (% V / V)

[0059] Detection wavelength: 220nm

[0060] Flow rate: 1.0mL / min

[0061] Injection volume: 20μL

[0062] Column temperature: 40℃

[0063] Run time: 70min

[0064] Needle wash solution: Methanol

[0065] gradient:

[0066] Time (min) Mobile phase A (% V / V) Mobile phase B (% V / V) 0 100 0 50 0 100 55 0 100 55.1 100 0 70 100 0

[0067] Embodiment 1:

[0068] Dissolve chloroacetic acid (6.9 g) and triethylamine (7.4 g) in ethyl acetate (80 mL), slowly add pivaloyl chloride ethyl acetate solution dropwise at 25° C. (preparation method: dissolve 8.5 g of pivaloyl chloride in 20 mL of ethyl acetate to form pivaloyl chloride ethyl acetate solution), then a large amount of white triethylamine hydrochloride solid is precipitated, stir at 25° C. for 4-5 h to obtain a mixed anhydride reaction solution containing a cyclization reagent shown in Formula 5;

[0069] The reaction solution was cooled to 0-5°C, and then the compound shown in formula 4 (20g) was directly added to the reaction solution. After addition, the temperature was raised to 60°C for reaction for 3h. TLC confirmed the end point of the reaction. The reaction solution was cooled to room temperature, 100mL of water was added to extract and remove the salt, the organic phase was separated, and then the water layer was extracted once with 100mL of ethyl acetate, the organic phases were combined and concentrated to obtain a brown-black oil. At 40°C, the oil was mixed and stirred with 100mL of methyl tert-butyl ether for 1 hour, and a large amount of gray solid was precipitated. Then it was cooled to 0-5°C and kept warm for 1h, filtered, and washed with methyl tert-butyl ether.

[0070] The mixture was dried under vacuum at 50° C. to obtain a gray solid, namely the dabigatran etexilate intermediate shown in Formula 6, with a yield of 95.7% and a purity of 99.168%.

[0071] Embodiment 2:

[0072] Dissolve chloroacetic acid (34.5 g) and triethylamine (36.9 g) in ethyl acetate (450 mL), slowly add pivaloyl chloride ethyl acetate solution dropwise at 30° C. (preparation method: dissolve 42.3 g pivaloyl chloride in 50 mL ethyl acetate to form pivaloyl chloride ethyl acetate solution), then a large amount of white triethylamine hydrochloride solid is precipitated, stir at 30° C. for 4-5 h, and obtain a mixed anhydride reaction solution containing a cyclization reagent shown in Formula 5;

[0073] The reaction solution is cooled to 0-5 ℃, then directly compound (100g) shown in formula 4 is added in the reaction solution. Finish, be warming up to 65 ℃ of reactions 2h. TLC confirms reaction end. The reaction solution is cooled to room temperature, adds 300mL water extraction to remove salt, separates organic phase, then uses 300mL ethyl acetate extraction water layer once, merges organic phase, concentrates, obtains brownish black oily matter. At 40 ℃, this oily matter and methyl tertiary butyl ether 500mL mixed stirring 1 hour, separate out a large amount of grey solids, be cooled to 0-5 ℃ of insulation 1h subsequently, filter, methyl tertiary butyl ether washing, 50 ℃ of vacuum dryings obtain grey solid, i.e. the dabigatran etcxilate intermediate shown in formula 6, yield 96.2%, purity is 99.868%.

[0074] Embodiment 3:

[0075] Dissolve chloroacetic acid (3.4 g) and triethylamine (3.6 g) in tetrahydrofuran (40 mL), slowly add pivaloyl chloride tetrahydrofuran solution (preparation method: dissolve 4.2 g of pivaloyl chloride in 10 mL of tetrahydrofuran to form pivaloyl chloride tetrahydrofuran solution) at 25°C, then a large amount of white triethylamine hydrochloride solid is precipitated, stir at 25°C for 4-5 hours to obtain a mixed anhydride reaction solution containing the cyclization reagent shown in Formula 5.

[0076] The reaction solution is cooled to 0-5 ℃, directly compound (10g) shown in formula 4 is added in the above-mentioned reaction solution subsequently. Finish, be warming up to 50 ℃ of reactions 3h. TLC confirms reaction end. The reaction solution is cooled to room temperature, adds 30mL water and 50mL ethyl acetate extraction to remove salt, separates organic phase, then uses 20mL ethyl acetate extraction water layer once, merges organic phase, concentrates, obtains brownish black oily matter. At 40 ℃, this oily matter and methyl tertiary butyl ether 50mL mixed stirring 1 hour, separate out a large amount of grey solids, be cooled to 0-5 ℃ of insulation 1h subsequently, filter, methyl tertiary butyl ether washing, 50 ℃ of vacuum dryings obtain grey solid, i.e. the dabigatran etcxilate intermediate shown in formula 6, yield 95%, purity is 99.280%.

[0077] The present invention is further described above by specific embodiment.This industry technician should understand that embodiment does not limit the scope of the present invention in any way.Those skilled in the art obviously can change or suitably change and combine the dabigatran etcxilate intermediate preparation method shown in formula 6 as herein described without departing from content of the present invention, spirit and scope, realize the technology of the present invention.It should be particularly noted that all similar replacements and changes are obvious to those skilled in the art, and they are all regarded as being included in the spirit, scope and content of the present invention.

Claims

1. A method for preparing a dabigatran etexilate intermediate shown in formula 6, characterized in that, The method comprises the following steps: subjecting a compound of formula 4 to a cyclization reagent shown in formula 5 for condensation reaction in the presence of an organic solvent to obtain a dabigatran etexilate intermediate shown in formula 6, 2. The preparation method according to claim 1, characterized in that: The organic solvent for the condensation reaction is selected from one or more of ethyl acetate, butyl acetate, tetrahydrofuran, methyltetrahydrofuran, dioxane, dichloromethane, and toluene; preferably ethyl acetate, butyl acetate, tetrahydrofuran, and toluene; more preferably ethyl acetate.

3. The preparation method according to claim 1, characterized in that: The condensation reaction temperature is 20-100° C., preferably 40-70° C.; the condensation reaction time is 1 to 10 hours, preferably 2 to 5 hours.

4. The preparation method according to claim 1, characterized in that: The molar ratio of the compound of formula 4 to the cyclization reagent shown in formula 5 is 1:1-2, preferably 1:1.2-1.4; the mass volume ratio of the compound of formula 4 to the organic solvent for the condensation reaction is 1:4-7 g / ml.

5. The preparation method according to claim 1, characterized in that: The cyclization reagent shown in Formula 5 is obtained by reacting chloroacetic acid and pivaloyl chloride in the presence of a base and a reaction solvent in step a).

6. The preparation method according to claim 5, characterized in that: The base in step a) is selected from one or more organic amines or inorganic bases; preferably, the organic amine is selected from one or more of triethylamine, pyridine, N,N-diisopropylethylamine, tri-n-propylamine, tri-n-butylamine; the inorganic base is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide; more preferably, the base is selected from triethylamine, N,N-diisopropylethylamine, sodium carbonate and potassium carbonate.

7. The preparation method according to claim 5, characterized in that: The reaction solvent in step a) is selected from one or more of ethyl acetate, butyl acetate, tetrahydrofuran, methyltetrahydrofuran, dioxane, dichloromethane and toluene; preferably ethyl acetate, butyl acetate, tetrahydrofuran and toluene.

8. The preparation method according to claim 5, characterized in that: The molar ratio of chloroacetic acid, pivaloyl chloride and base in step a) is 1:1-2:1-2; preferably 1:1.1-1.5:1.2-1.

5.

9. The preparation method according to claim 5, characterized in that: The reaction temperature in step a) is 0-60°C, preferably 10-30°C; the reaction time is 1 to 10 hours, preferably 3 to 6 hours.

10. The preparation method according to claim 5, characterized in that: The prepared cyclization reagent represented by Formula 5 is directly used in the next step reaction without separation and purification.

11. The preparation method according to claim 5, characterized in that: The step a) is to dissolve pivaloyl chloride in a reaction solvent to form a pivaloyl chloride solution, dissolve chloroacetic acid and alkali in the reaction solvent, and then slowly drop the pivaloyl chloride solution.

12. The preparation method according to claim 5, characterized in that: The reaction solution containing the cyclization reagent of formula 5 obtained in step a) is cooled to 0-5° C., and then the compound shown in formula 4 is directly added to the reaction solution. After the addition is completed, the temperature is raised to the reaction temperature of the condensation reaction for reaction. After the reaction is completed, the reaction solution is cooled to room temperature, washed with water, desalted, and concentrated to obtain the dabigatran etexilate intermediate shown in formula 6.

13. The preparation method according to any one of claims 1 to 12, characterized in that: The dabigatran etexilate intermediate shown in Formula 6 is purified by pulping with methyl tert-butyl ether, wherein the mass volume ratio of the dabigatran etexilate intermediate shown in Formula 6 to methyl tert-butyl ether is 1:3-10 g / ml.

14. The application of any one of claims 1-12 or claim 13 in the preparation of dabigatran etcxilate or its salt.

Images