KR20180038694A - Novel hemi-salt of dabigatran etexilate and preparation method thereof - Google Patents

Abstract

The present invention relates to a dabigatran etexilate hemic acid added salt and a method for manufacturing the same. More specifically, the present invention relates to a dabigatran hemi fumarate and hemi citrate, and a method for manufacturing the same. Since the crystalline dabigatran etexilate hemi fumarate and hemi citrate of the present invention are stable to heat and excellent in filtering and drying properties, the hemic acid added salt of the present invention can be used as an active ingredient of a pharmaceutical composition for preventing and treating stroke of patients suffering from thromboembolism and atrial fibrillation.

Description

[0001] The present invention relates to a novel dabigatran et < RTI ID = 0.0 > hemiacetate < / RTI >

The present invention relates to dabigatran etexylate hemamic acid addition salts and processes for their preparation. More specifically, the present invention relates to dabigatran etexilate hemifumarate and hemicitrate, and a process for their preparation.

Dabigatran is an oral direct thrombin inhibitor approved by the United States Food and Drug Administration (FDA) for the reduction of stroke and systemic embolism in patients with nonventricular atrial fibrillation (AF). Dabigatran etexilate is useful for the prevention of thromboembolism in patients who have experienced total knee or hip arthroplasty and is particularly suitable for preventing stroke in patients with atrial fibrillation and is useful for preventing thromboembolism, systemic embolism, pulmonary embolism, It is used for prevention or treatment of venous thromboembolism.

Dabigatran et < RTI ID = 0.0 > ticylate < / RTI > was firstly known in International Publication No. WO 98/37075 (US 6,087,380; 6,469,039; 6,414,008; and 6,710,055), wherein thrombin inhibition- Methyl-2- [N- [4- (Nn-hexyloxycarbonylamidino) phenyl] aminomethyl] benzimidazol-5-ylcarboxylic acid-N- Yl) -N- (2-ethoxycarbonylethyl) amide.

Dabigatran is a more effective oral thrombin inhibitor than warfarin and other vitamin K antagonists (VKA). Dabigatran etexilate is a double prodrug of dabigatran and is converted into a substantially effective compound, darbigatran, in the body. Dabigatran etexilate is rapidly converted to darbigatran, a potent direct competing inhibitor of thrombin by serum estetase, with a serum half-life of 12-17 hours, which does not require periodic monitoring.

In U.S. Patent Application Publication No. 2006/0183779, darbiganthenecylate is preferably administered in its mesylate form, but may also be used as a salt with darbiganthenecetylate and other pharmaceutically acceptable acids. In the following numerous patent documents, the salt compounds of dabigatran etexylate are known. In International Publication No. WO 2006/114415, there have been disclosed dabigatran etexylate hydrochloride, maleate salt, tartarate salt, salicylate salt, citrate salt and malonic acid salt, and International Publication No. WO 2008/043759 discloses 2,5- But are not limited to, benzoic acid, benzoic acid, benzoic acid, hexylic acid, hydrochloric acid, cyclamic acid, eddylic acid, ethylacetic acid, fumaric acid, glucuronic acid, glycolic acid, isethionic acid, malic acid, mandelic acid, lead acid, oxalic acid, , Tartaric acid, tosylic acid and their crystalline forms have been disclosed.

Korean Patent Laid-Open Publication No. 2014/0002597 discloses dabigatranectexyl myristate, and 2014/0115423 discloses dabigatran etexylate hemisuccinate, and a comparative compound, darbiganthenecylate mesylate And have thermal stability and solubility equivalent to those of the prior art.

The present invention provides a dabigatranethexylate hemamic acid salt having a physicochemical property equal to or greater than that of a comparative compound, dabigatran etexylate mesylate, and a process for producing the dabigatranethexylate hemamic acid salt capable of mass production in high purity.

The present invention provides a dabigatranethexylate hemamic acid addition salt represented by the following formula (1), which is a powerful thrombin inhibitor suitable for preventing thromboembolism and preventing stroke in patients with atrial fibrillation.

In the present invention, the acid addition salt used as X in the formula (1) may be fumaric acid, citric acid, tartaric acid, malonic acid, malic acid, glutaric acid, oxalic acid or adipic acid.

Specifically, the present invention provides a dabigatran etexecylate hemifumarate represented by the following formula (2), a dabigatran ethoxylate hemocitrate represented by the following formula (3), and a process for their preparation.

The present invention provides a process for preparing darbagantraethicylate hemic acid addition salts comprising the steps of:

(a) dissolving dabigatran ethoxylate and an acid addition salt in a solvent selected from the group consisting of a polar protic solvent, a polar aprotic solvent and a mixture thereof;

(b) adding an anti-solvent to the solution to form a solid; And

(c) recovering the resulting solid.

Also disclosed are a method for producing dabigatran etexylate hemifumarate by reacting dabigatranethexylate of Formula 4 and fumaric acid of Formula 5 in an organic solvent, The present invention provides a method for preparing dabigatran etexylate hemicitrate by reacting ethoxylate with citric acid of Formula 6 below.

The fumaric acid (E) -butenedioic acid used in the preparation of the dabigatran tecylate hemifumarate of the present invention is a dicarboxylic acid which is a Krebs cycle, Is an organic acid that is essential for human body and is safe enough that the allowable daily intake can not be determined. Fumaric acid can also be used as a food additive to add sourness of food.

Pure fumaric acid is a white crystalline powder with no odor and an unusual sour taste. The melting point is 286 ° C and the hygroscopicity is low and stable.

The citric acid (2-hydroxypropane-1,2,3-tricarboxylic acid) used in the preparation of the dabigatran etexylate hemicitrate of the present invention is a tricarboxylic acid, It acts as a component of the TCA circuit and plays an important role in the metabolism of higher animals. It is also known to have an action to promote calcium absorption in the body. Citric acid is a natural compound that is abundant in fruits, especially citrus and plum. It is a safe organic acid that is often used as a food additive in fruit juices, soft drinks, or as a sour taste for pharmaceuticals, diuretic drinks, or as an analytical reagent.

Pure citric acid is a white crystalline powder with no odor and an unusual sour taste. The melting point is 153 ℃.

The darbigantetersylate used in the present invention may be crystalline or amorphous.

Also, the dabigatranethexylate hemifumarate and hemicitrate salts according to the present invention may also be crystalline or amorphous.

The results obtained by confirming the crystal form of dabigatran tecylate hemifumarate and hemicurate by X-ray diffraction analysis (XRD) and differential scanning calorimetry (DSC) are shown in FIGS. 1, 2 and 4, respectively.

The dabigatran etexylate hemifumarate salt according to the present invention can be prepared by reacting dabigatran ethoxylate and fumaric acid in an organic solvent, as shown in the following reaction scheme (1). The dabigatran tecylate hemitricrate can also be prepared by reacting dabigatran etexylate with citric acid in an organic solvent, as shown in Scheme 2 below.

[Reaction Scheme 1]

[Reaction Scheme 2]

Specifically, the process for preparing the above-mentioned dabigatran ethicylate hemifumarate

(1) reacting dabigatran ethoxylate and fumaric acid in a solvent selected from the group consisting of a polar protic solvent, a polar aprotic solvent and a mixed solvent thereof, and

(2) The solution in which the reaction of the first step is completed is cooled to precipitate dabigatran ethoxylate hemifumarate to crystallize it, or an anti-solvent is added to the solution to prepare dabigatran ethoxylate hemifumarate And crystallizing.

The process for preparing the above-mentioned dabigatran et < RTI ID = 0.0 > octylate &

(1) reacting dabigatran ethoxylate and citric acid in a solvent selected from the group consisting of a polar protic solvent, a polar aprotic solvent and a mixed solvent thereof, and

(2) The solution in which the reaction of the first step is completed is cooled to precipitate dabigatran ethoxylate hemicitrate to crystallize, or an anti-solvent is added to the solution to form dabigatran ethoxylate hemicitrate And crystallizing.

More specifically, the process for preparing the darbigantraethicylate hemifumarate salt comprises:

(a) reacting dabigatran ethoxylate with fumaric acid in a solvent selected from the group consisting of a polar protic solvent, a polar aprotic solvent and a mixed solvent thereof, heating and dissolving the product, cooling the product to precipitate a solid, By separating the solids, it is possible to prepare darbagantra teicylate hemifumarate,

(b) reacting dabigatranethexylate with fumaric acid in a solvent selected from the group consisting of a polar protic solvent, a polar aprotic solvent and a mixed solvent thereof, heating and dissolving, and then adding an anti-solvent thereto to obtain a solid After the precipitation, the solid may be separated to obtain dabigatran ethoxylate hemifumarate.

The method for producing the above-mentioned dabigatranethexylate hemicitrate is

(a) reacting dabigatran ethoxylate with citric acid in a solvent selected from the group consisting of a polar protic solvent, a polar aprotic solvent and a mixed solvent thereof, heating and dissolving the product, cooling the product to precipitate a solid, By separating the solids, it is possible to prepare darbagantra teicylate hemifumarate,

(b) a solvent selected from the group consisting of a polar protic solvent, a polar aprotic solvent, and a mixed solvent thereof, and then heating and dissolving the resultant mixture with a solution of a tartaric acid and a tartaric acid. After the precipitation, the solid is separated to obtain dabigatran etexylate hemicitrate.

The fumaric acid used in Reaction Scheme 1 is capable of binding with 1 and 2 molecules of Darviganteferatilate as a transgendronic acid and can be used in an amount of 0.40 to 0.70 equivalents based on 1 equivalent of Darvigantechnetate , Preferably in an amount of 0.48 to 0.52 equivalents.

Citric acid used in Reaction Scheme 2 may be combined with 1, 2 and 3 molecules of Darbiganthenate as a dihydric acid and used in an amount of from 0.40 to 0.70 equivalents per 1 equivalent of Darbiganthenate And preferably in an amount of 0.48 to 0.52 equivalents.

The polar protic solvents used in the above reaction schemes 1 and 2 include methyl alcohol, ethyl alcohol, isopropyl alcohol, t-butyl alcohol, sec-butyl alcohol, n-butyl alcohol, n-amyl alcohol, Or a mixed solvent of this solvent and water may be used. Examples of the polar aprotic solvent used in Reaction Schemes 1 and 2 include dichloromethane, chloroform, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dimethyl formamide, dimethylacetamide, dimethylsulfoxide, A solvent, or a mixed solvent of this solvent and water may be used.

The polar protic solvent and the polar aprotic solvent may be used in an amount of 1 to 50 ml, preferably 5 to 20 ml, per 1 g of dabigatran ethoxylate. The mixing ratio of the polar protic solvent to the polar aprotic solvent may be 1: 50 to 50: 1 by volume, preferably 1: 10 to 10: 1 by volume.

The half-solvent used in the above reaction schemes 1 and 2 may be selected from the group consisting of hexane, heptane, toluene, diethyl ether, isopropyl ether, t-butyl methyl ether, ethyl acetate, isopropyl acetate, . The semi-solvent may be used in an amount of 5 to 50 ml per 1 g of Darvigantechnetylate, preferably 10 to 20 ml.

The reaction of dabigatran ethoxylate with fumaric acid and the reaction of dabigatran ethoxylate with citric acid may proceed at 0 to 70 ° C and most preferably at 25 to 50 ° C.

Since the crystalline darbagatlan ethacetate hemifumarate and hemicitrate of the present invention are stable to heat and excellent in filtration and drying properties, the active ingredient of the pharmaceutical composition for the prevention and treatment of stroke of patients suffering from thromboembolism and atrial fibrillation . ≪ / RTI >

Fig. 1 shows the XRD analysis results of the darbigatran ethoxylate hemifumarate prepared in Example 1. Fig.
2 is a DSC analysis result of the darbagantraethicylate hemifumarate prepared in Example 1. Fig.
FIG. 3 is a nuclear magnetic resonance analysis (1 H NMR) result of the darbigatran ethoxylate hemifumarate prepared in Example 1. FIG.
Fig. 4 shows the XRD analysis results of the darbigatran ethoxylate hemicitrate prepared in Example 5. Fig.
5 is a DSC analysis result of the darbigatran ethecylate hemicitrate prepared in Example 5. Fig.
6 is a nuclear magnetic resonance analysis (1 H NMR) result of the darbigatran ethecylate hemicitrate prepared in Example 5. Fig.
Fig. 7 shows the XRD analysis results of dabigatran etexilate.
Figure 8 shows the nuclear magnetic resonance analysis (1 H NMR) results of dabigatran etexilate.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the examples.

In addition, the reagents and solvents mentioned below were purchased from Sigma-Aldrich Korea and TCI Korea unless otherwise noted, and the 1 H NMR data was measured using a Bruker 400 Ultrashield NMR Spectrometer.

Dabigatran Ethoxylate Hemifumarate  Preparation (acetone / heptane)

To the flask, 100.0 g of Dabigatran etexylate and 1000.0 mL of acetone were added, and the temperature was raised to 40 ° C to dissolve completely. After 9.25 g of fumaric acid was added to the reaction solution, the mixture was stirred for about 30 minutes and then cooled to 25 DEG C and stirred. 1000.0 mL of heptane was gradually added dropwise to the above stirring solution, and the mixture was stirred for about 2 hours. The resulting solid was filtered, washed with 200.0 mL of a mixed solution (acetone: heptane = 1: 1) and dried to obtain 101.0 g of dabigatran ethoxylate hemifumarate.

Purity: 99.85% by HPLC

DSC: 130 ° C

_{^{1 H NMR (400㎒, CD 3}} OD-d 4): 0.9 (t, 3H), 1.2 (t, 3H), 1.3 (m, 4H), 1.5 (m, 2H), 1.7 (quin, 2H), 2H), 4.6 (s, 2H), 6.6 (s, 1H), 6.8 (s, 2H) (d, 2H), 6.9 (d, 1H), 7.1 (dd, 1H), 7.2 d, 2 H), 8.3 (m, 1 H)

Dabigatran Ethoxylate Hemifumarate  Manufacturing (acetone)

To the flask was added Dabigatranethexylate (350.0 g) and acetone (4200.0 mL), and the temperature was raised to 40 占 폚 to dissolve completely. To the reaction solution, 32.35 g of fumaric acid was added, followed by stirring for about 1 hour, followed by cooling to 25 占 폚 and stirring. The stirring solution was cooled to 0 캜 and stirred for about 2 hours. The resulting solid was filtered, washed with 350.0 mL of acetone and dried to obtain 350.0 g of dabigatran ethoxylate hemifumarate.

Purity: 99.86% by HPLC

Dabigatran Ethoxylate Hemifumarate  Preparation (acetone / Isopropyl ether )

3.0 g of Dabigatran etexylate and 15.0 mL of acetone were added to the flask, and the temperature was raised to 50 DEG C to dissolve completely. After adding 0.26 g of fumaric acid to the reaction solution, the mixture was stirred for about 30 minutes and then cooled to 25 캜 and stirred. 45.0 mL of isopropyl ether was slowly added dropwise to the above-mentioned solution, and the mixture was stirred for about 2 hours. The resulting solid was filtered, washed with 6.0 mL of isopropyl ether and dried to obtain 3.2 g of Darbigatran ethoxylate hemifumarate.

Dabigatran Ethoxylate Hemifumarate  Preparation (ethanol / heptane)

3.0 g of Dabigatran etexylate and 15.0 mL of ethanol were added to the flask and stirred for 30 minutes to completely dissolve. 0.26 g of fumaric acid was added to the reaction solution, followed by stirring for about 30 minutes. 45.0 mL of heptane was slowly added dropwise to the above stirring solution, and the mixture was stirred for about 2 hours. The resulting solid was filtered, washed with 6.0 mL of heptane and dried to obtain 3.2 g of Darbigatran etexylate hemifumarate.

Dabigatran Ethoxylate Hemicitrate  Preparation (acetone / heptane)

To the flask, 10.0 g of dabigatran ethoxylate and 50.0 mL of acetone were added and the temperature was raised to 50 ° C to dissolve completely. 1.53 g of citric acid was added to the above-mentioned eluting solution, followed by stirring for about 30 minutes. After cooling the above mixture to 25 DEG C, 150.0 mL of heptane was slowly added dropwise, and the mixture was stirred for about 2 hours. The resulting solid was filtered, washed with 20.0 mL of a mixed solution (acetone: heptane = 1: 1) and dried to obtain 11.45 g of dabigatran ethoxylate hemicitrate.

Purity: 99.87% by HPLC

DSC: 161.9 ° C

_{^{1 H NMR (400㎒, CD 3}} OD-d 4): 0.9 (t, 3H), 1.2 (t, 3H), 1.3 (m, 4H), 1.5 (m, 2H), 1.7 (quin, 2H), 2H), 4.6 (s, 2H), 6.8 (d, 2H), 6.9 (s, 2H) (d, 1H), 7.1 (dd, 1H), 7.2 (dd, 1H), 7.3 m, 1H)

Dabigatran Ethoxylate Hemicitrate  Preparation (ethanol / heptane)

10.0 g of Dabigatran etexylate and 50.0 mL of ethanol were added to the flask and stirred for 30 minutes to completely dissolve the flask. 1.53 g of citric acid was added to the above-mentioned eluting solution, followed by stirring for about 30 minutes. After cooling the above mixture to 25 DEG C, 150.0 mL of heptane was slowly added dropwise, and the mixture was stirred for about 2 hours. The resulting solid was filtered, washed with 20.0 mL of heptane and dried to obtain 10.8 g of dabigatran ethoxylate hemicitrate.

Dabigatran Ethoxylate  Purification (ethyl acetate)

The flask was charged with 10.0 g of dabigatranethexylate and 150.0 mL of ethyl acetate, heated to 60 ° C and stirred for 30 minutes to completely dissolve. The stirring solution was cooled to 25 캜, stirred for 1 hour, cooled to 0 캜 and stirred for 2 hours. The resulting solid was filtered, washed with 20.0 mL of ethyl acetate, and dried to obtain 9.5 g of purified dabigatran ethoxylate.

[Comparative Example]

Dabigatran Ethoxylate Mesylate  Manufacturing (acetone)

10.0 g of Dabigatran etexylate and 70.0 mL of acetone were added to the flask, and the temperature was raised to 45 ° C to dissolve completely. After the above solution was cooled to about 35 ° C, a previously prepared methanesulfonic acid acetone solution (methanesulfonic acid 1.75 g / acetone 30.0 mL) was slowly added dropwise. The reaction solution was further stirred for 60 minutes, then cooled to 25 DEG C and stirred for 80 minutes. The resulting solid was filtered, washed with 20.0 mL of acetone and dried to obtain 12.1 g of dabigatran ethoxylate methanesulfonate.

[Test Example 1]

Dabigatran Mesylate - Dabigatran Hemami  Comparative Stability Experiment

The stability test of medicines means to confirm the stability of certain quality over time under certain conditions in order to set the storage method and period of use of medicines. In other words, by setting appropriate standards, evaluating significant changes based on the analytical method determined, and evaluating the conformity of specifications, the validity period of the product is set.

[Acceleration condition]

The dabigatranethexylate hemifumarate salt and the hemicitrate salt prepared in Examples 1 and 5 were compared with the dabigatran etexylate mesylate prepared in Comparative Examples in terms of stability.

Specifically, the stability test under the acceleration condition according to the ICH guideline was carried out and analyzed using high performance liquid chromatography (HPLC) analysis, and the results are shown in Table 1.

Acceleration (40 ° C ± 2 ° C, RH 75% ± 5%) Initial purity 1 week 3 weeks 7 weeks Dabigatran ethoxylate hemifumarate 99.90% 99.90% 99.90% 99.83% Dabigatran etexilate
Hemicritate 99.87% 99.85% 99.85% 99.81% Dabigatran ethoxylate mesylate 99.92% 99.89% 99.89% 99.86%

As shown in Table 1, the dabigatranethexylate hemifumarate and the dabigatran etexrate hemicitrate exhibited a very small purity change of 0.07 and 0.06% as a result of the stability test for seven weeks under accelerated conditions And showed a purity change similar to that of dabigatran etexylate mesylate and was confirmed to have stability equivalent to dabigatran etexylate mesylate.

[Severe conditions]

Severe (60 ° C ± 2 ° C) Initial purity 1 week 3 weeks 7 weeks Dabigatran ethoxylate hemifumarate 99.90% 99.86% 99.85% 99.75% Dabigatran etexilate
Hemicritate 99.87% 99.83% 99.80% 99.53% Dabigatran ethoxylate mesylate 99.92% 99.87% 99.81% 99.80%

As shown in the above Table 2, the dabigatran etexylate hemifumarate showed a very small purity change of 0.15% as a result of the stability test for 7 weeks under the harsh conditions, and the dabigatran etexilate mesylate And showed stability equivalent to that of dabigatran etexylate mesylate.

[Test Example 2]

Differential scanning calorimetry DSC )

In the present invention, the differential scanning calorimetry analysis was performed to compare the physical properties of the present dabigatranethexylate hemifumarate salt and hemicritate and the starting material dabigatranethexylate. Calorimetric analysis of the samples in Table 3 below was obtained using a scan rate of 10 ° C per minute under nitrogen. Calorimetric scans were obtained using a differential scanning calorimeter (Mettler Toledo DSC 823) and the amount of sample used was 2.0 to 4.0 mg.

sample Onset Peak Dabigatran ethoxylate hemifumarate 125.2 DEG C 130.5 DEG C Dabigatran ethoxylate hemocitrate 145.4 DEG C 148.6 DEG C Dabigatran ethoxylate mesylate 178.4 DEG C 182.1 DEG C Dabigatran etexilate 129.8 ° C 133.4 DEG C

[Test Example 3]

Solubility analysis

The solubility of dabigatran etexylate hemifumarate of the present invention prepared in Example 1 in water to pH was compared with that of dabigatran etexilate.

For the solubility test, add 5 mL of purified water, pH 1.2, pH 4.0, and pH 6.8 to approximately 200 mg of each sample and dissolve. After stirring for 24 hours, PVDF filter was prepared and the calibration curve (range: 0.1 ~ 250 ㎍ / mL) was prepared by HPLC method. The concentration of the saturated solution was determined from the linear function of the calibration curve. The results of the test by the solubility test method are shown in Table 4 below.

Dissolution condition Solubility (mg / ml) Dabigatran etexilate Dabigatranhefumarate Purified water 0.01 1.78 pH 1.2 11.44 6.88 pH 4.0 0.003 0.95 pH 6.8 0.01 0.04

As shown in Table 4, the dabigatran etexilate hemifumarate salt has a high solubility in the purified water and the experimental range of pH 4.0 and pH 6.8, and is 4 to 300 times higher than the control group, Times or more. Therefore, the dabigatran etexilate hemifumarate of the present invention greatly improves the physicochemical properties of the poorly soluble drug Darbagantraethicillate, which is advantageous for the absorption and dissolution of the drug, which is very advantageous for commercialization of the drug Able to know.

[Solubility test apparatus operating conditions]

  1) Detector: Ultraviolet absorptiometer (measuring wavelength: 224 nm)

  2) Column: Kromasil C18 (5 [mu] m, 4.6 * 150 mm)

  3) Column temperature: constant temperature around 35 ° C

  4) Amount of injection: 10 μL

  5) Flow rate: 1.2 mL / min

  6) Phase: Buffer: Acetonitrile (35:65)

  7) Diluent solution: A solution prepared by dissolving 2.0 g of potassium dihydrogenphosphate in 1 L of purified water and adjusting to pH 6.0 with sodium hydroxide solution

  8) Diluent solution: mobile phase

Claims (12)

A dabigatran ethoxylate hemamic acid salt represented by the following formula (1)
[Chemical Formula 1]

Wherein X is a pharmaceutically acceptable salt. The dabigatran etexylate hemiacid salt according to claim 1, wherein X is selected from the group consisting of fumaric acid, citric acid, tartaric acid, malonic acid, malic acid, glutaric acid, oxalic acid and adipic acid. A dabigatran ethoxylate hemifumarate represented by the following formula (2).
(2)

A dabigatran ethoxylate hemicitrate represented by the following formula (3).
(3)

CLAIMS 1. A process for preparing darbagtranectecylate hemic acid addition salt comprising the steps of:
(a) dissolving dabigatran ethoxylate and an acid addition salt in a solvent selected from the group consisting of a polar protic solvent, a polar aprotic solvent and a mixture thereof;
(b) adding an anti-solvent to the solution to form a solid; And
(c) recovering the resulting solid. 6. The process of claim 5 wherein the polar protic solvent is selected from the group consisting of methyl alcohol, ethyl alcohol, isopropyl alcohol, t-butyl alcohol, sec-butyl alcohol, n-butyl alcohol, n-amyl alcohol, , Or a mixed solvent of the solvent and water. ≪ RTI ID = 0.0 > 8. < / RTI > The process of claim 5, wherein the polar aprotic solvent is selected from the group consisting of dichloromethane, chloroform, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dimethyl formamide, dimethylacetamide, dimethylsulfoxide, , Or a mixed solvent of this solvent and water. ≪ RTI ID = 0.0 > 11. < / RTI > 6. The process of claim 5, wherein the semi-solvent is selected from the group consisting of hexane, heptane, toluene, diethyl ether, isopropyl ether, t-butyl methyl ether, ethyl acetate, isopropyl acetate, , ≪ / RTI > a process for preparing dabigatran tecylate hemibutate. A pharmaceutical composition for inhibiting blood clotting, which comprises darbaganthenate leflumarate as an active ingredient. A pharmaceutical composition for the inhibition of blood clotting, the composition comprising darbaganthenate hemitocate as an active ingredient. A pharmaceutical composition for preventing or treating thromboembolism, systemic embolism, pulmonary embolism, venous thromboembolism, or stroke, which comprises darbagantectilate hemifumarate as an active ingredient. A pharmaceutical composition for the prevention or treatment of thromboembolism, systemic embolism, pulmonary embolism, venous thromboembolism, or stroke, which comprises Darvitra teectilate hemicitrate as an active ingredient.

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