CN104109158A - Rivaroxaban purification method - Google Patents

Abstract

The invention provides a method for purifying rivaroxaban, the method comprising the following steps: dissolving the crude product of rivaroxaban in ethylene glycol methyl ether or n-butanol under heating conditions, adding activated carbon after dissolving, and Hot suction filtration, cooling and crystallization of the mother liquor, and filtration to obtain the crystallized product rivaroxaban. The present invention has the advantages of using ethylene glycol methyl ether or n-butanol for recrystallization, which can avoid complex chromatographic purification; and compared with acetic acid, ethylene glycol methyl ether or n-butanol will not corrode reaction equipment and is convenient for industrialization Production.

Description

A method for purifying rivaroxaban

technical field

The invention relates to the field of medicinal chemistry, in particular to a method for purifying rivaroxaban.

Background technique

Rivaroxaban (Rivaroxaban, trade name: Xarelto) chemical name: 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl )phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene carboxamide, which corresponds to general formula (I), molecular formula is: C ₁₉ H ₁₈ N ₃ O ₅ SCl, molecular weight For: 435.88g/mol.

Rivaroxaban is an oral direct inhibitor of factor Xa jointly developed by Bayer and Johnson & Johnson. It was approved for marketing in Canada and the European Union in September and October 2008, and is mainly used clinically to prevent venous thromboembolism in patients undergoing hip or knee replacement. In 2011, the US FDA approved it for deep vein thrombosis. Compared with other anticoagulant drugs, rivaroxaban has predictable pharmacokinetic and pharmacodynamic properties, combined with rapid onset of action and low possibility of interaction with food and drugs, so routine coagulation function testing is not required, It makes anticoagulation easy, safe and effective. With the aging of the population and the increase in the incidence of cardiovascular diseases, the demand for anticoagulant drugs continues to increase, and direct factor Xa inhibitors are the development trend of anticoagulant drugs.

There are many reports on the synthesis methods of rivaroxaban, such as patent documents WO01/47919, US7351823, DE10300111.5 and so on. As we all know, recrystallization is the most commonly used method for purification, but there are few reports on the recrystallization method of rivaroxaban. Document WO2005/068456 describes a purification method, that is, the crude product of rivaroxaban is suspended in acetic acid and heated to dissolve, then cooled and precipitated, filtered with suction, washed with water and acetic acid, and then dried. However, because acetic acid has strong acidity and is easy to corrode reaction equipment, it is not suitable for industrial production. Document WO2012035057 also reports a method for refining rivaroxaban with a mixed solvent of DMSO and acetonitrile, but acetonitrile is highly toxic and unsuitable for industrialization. Therefore, it is necessary to find an economical recrystallization method.

Contents of the invention

The first aspect of the present invention provides a method for purifying rivaroxaban, comprising the following steps: dissolving the crude product of rivaroxaban in ethylene glycol methyl ether or n-butanol under heating conditions, adding activated carbon after dissolving, Suction filtration while hot, cooling and crystallization of the mother liquor, and filtration to obtain the crystalline product rivaroxaban.

More specifically, the method of the present invention comprises the following steps: suspending the crude product of rivaroxaban in ethylene glycol methyl ether or n-butanol, heating to dissolve, adding an appropriate amount of activated carbon, suction filtration while hot, cooling and crystallizing the mother liquor, and suction filtration , washed with ethylene glycol methyl ether or n-butanol, and dried to obtain the recrystallized product of rivaroxaban.

According to a preferred embodiment of the present invention, the mass volume ratio of the crude rivaroxaban product to ethylene glycol methyl ether or n-butanol is 1:5-20, preferably 1:5-15.

The mass-to-volume ratio described in the present invention refers to the ratio of the mass of the crude product of rivaroxaban to the volume of ethylene glycol methyl ether or n-butanol. For example: 1g of rivaroxaban crude product is dissolved in 15ml of ethylene glycol methyl ether, then the mass volume ratio is 1:15.

According to a preferred embodiment of the present invention, the mass volume ratio of the crude rivaroxaban product to activated carbon is 1:0.05-0.3, preferably 1:0.1-0.2.

According to another preferred embodiment of the present invention, the temperature for heating and dissolving the crude product of rivaroxaban is 60-140°C, preferably 100-125°C.

According to another preferred embodiment of the present invention, the cooling crystallization temperature of the mother liquor is 0-60°C, preferably 0-30°C.

The purified rivaroxaban obtained by the method of the present invention has a purity of 99.7% as determined by HPLC, and is crystal form I as determined by an X-powder diffraction method.

The second aspect of the present invention provides the application of ethylene glycol methyl ether or n-butanol in purifying the crude product of rivaroxaban.

The preparation method of the crude product of rivaroxaban in the present invention refers to the preparation method of the literature (J.Med.Chem.48:5900-5908, 2005). Specific steps are as follows:

2-[(2S)-Oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione (II) and 4-(4-aminophenyl)-3 - Morpholinone (III) was suspended in ethanol-water (9:1) solution, and refluxed for 14 hours (the raw material gradually dissolved, and a precipitate was formed after a period of time), the precipitate was filtered out, washed with ether and dried under vacuum. The combined mother liquors were concentrated under reduced pressure and a second portion of 2-[(2S)-oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione (II) in ethanol was added - In water (9:1) suspension, reflux for 13 h, filter, wash with ether, and dry under vacuum to obtain a white solid as compound IV.

Add N,N'-carbonyldiimidazole and p-dimethylaminopyridine (catalytic amount) to 2-((2R)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl)benzene base]amino}propyl)-1H-isoindole-1,3(2H)-dione (IV) in tetrahydrofuran suspension, the suspension was stirred at 60°C for 12h (the raw material gradually dissolved, and after a period of time Formation of a precipitate), adding a second portion of N, N'-carbonyldiimidazole and continuing to stir at 60°C for 12h, filtering out the precipitate, washing with tetrahydrofuran, and drying in vacuo to give a white solid as compound V

An aqueous solution of methylamine (40% in water) was added dropwise to 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3- In the ethanol solution of oxazolidin-5-yl}methyl)-1H-isoindoline-1,3(2H)-dione (V), the reaction mixture was refluxed for 1h, and the reaction solution was concentrated under reduced pressure to obtain the compound The VI crude product was used directly in the next step.

At 0°C, 5-chloro-2-thiophenoyl chloride was added dropwise to 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3- Base]-phenyl}morpholinone (VI) in pyridine solution, warming up to room temperature, stirring the reaction mixture for 1 h, mixing with water, adding dichloromethane and separating the phases, extracting the aqueous layer with dichloromethane, and combining the organic layers , added anhydrous sodium sulfate to dry, filtered, and spin-dried under reduced pressure to obtain a crude product of rivaroxaban as a white solid.

The present invention has the advantages of using ethylene glycol methyl ether or n-butanol for recrystallization, which can avoid complex chromatographic purification; and compared with acetic acid, ethylene glycol methyl ether or n-butanol will not corrode reaction equipment and is convenient for industrialization Production.

Description of drawings

Fig. 1 is the X-powder diffraction figure of the rivaroxaban that embodiment 1 makes;

Figure 2 is the DSC chart of rivaroxaban prepared in Example 1.

Detailed ways

The technical solution of the present invention will be further described through specific examples below; but the protection scope of the present invention is not limited to these examples. All data are based on weight percent unless otherwise indicated.

The following are the purchasing companies and production batch numbers of some chemical raw materials and reagents involved in the experiment:

Embodiment 1: Preparation of crude product of rivaroxaban

Preparation method of reference (J.Med.Chem.48:5900-5908, 2005).

The first step: 2-((2R)-2-hydroxyl-3-{[4-(3-oxomorpholin-4-yl)phenyl]amino}propyl)-1H-isoindole-1, Preparation of 3(2H)-diketone (IV)

2-[(2S)-Oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione (II) (5.68g, 27.9mmol) and 4-(4 -Aminophenyl)-3-morpholinone (III) (5.37g, 27.9mmol) was suspended in ethanol-water (9:1, 140ml) solution, and refluxed for 14h (the raw materials gradually dissolved and formed after a period of time) precipitate), the precipitate was filtered off, washed with ether and dried under vacuum, the combined mother liquors were concentrated under reduced pressure and a second portion of 2-[(2S)-oxiran-2-ylmethyl]-1H-isoindrate was added Indole-1,3(2H)-diketone (II) (2.84g, 14.0mmol) in ethanol-water (9:1, 70ml) suspension, reflux reaction for 13h, filtered, washed with ether, dried under vacuum, 10.14 g of white solid was obtained as compound IV, and the yield was 92%.

The second step: 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methanol base)-1H-isoindoline-1,3(2H)-dione (V)

Add N,N'-carbonyldiimidazole (2.94g, 18.1mmol) and p-dimethylaminopyridine (catalytic amount) to 2-((2R)-2-hydroxyl-3-{[4-(3-oxomorphol Lin-4-yl)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione (IV) (3.58g, 9.05mmol) in THF suspension, stirred at 60°C The suspension was 12h (the raw material was gradually dissolved, and a precipitate was formed after a period of time), and the second part of N,N'-carbonyldiimidazole (2.94g, 18.1mmol) was added and stirred at 60°C for 12h, and the precipitate was filtered out. Washed with tetrahydrofuran and dried in vacuo to obtain 3.32 g of white solid as Compound V with a yield of 87%.

The third step: 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}morpholinone (VI) preparation

Aqueous methylamine (40% in water, 10.2ml, 0.142mmol) was added dropwise to 2-({(5S)-2-oxo-3-[4-(3oxomorpholin-4-yl)phenyl ]-1,3-oxazolidin-5-yl}methyl)-1H-isoindoline-1,3(2H)-dione (V) (4.45g, 10.6mmol) in ethanol (102ml) In , the reaction mixture was refluxed for 1 h, and the reaction solution was concentrated under reduced pressure to obtain the crude product of compound VI, which was directly used in the next step.

The fourth step: (S)-5-chloro-N-((2-oxo-3-(4-(3-oxo-morpholinyl)phenyl)oxazolidin-5-yl)methyl) Preparation of thiophene-2-carboxamide (I)

At 0°C, 5-chloro-2-thiophenoyl chloride (2.29 g, 12.7 mmol) was added dropwise to 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3 -Oxazolidin-3-yl]-phenyl}morpholinone (VI) (3.08g, 10.6mmol) in pyridine (90ml) solution, warming up to room temperature, stirring the reaction mixture for 1h, mixing with water, adding dichloro After methane and phase separation, the aqueous layer was extracted with dichloromethane, the organic layers were combined, dried by adding anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to obtain 3.92 g of white solid, which was the crude product of rivaroxaban. Yield: 86%.

Embodiment 2: the refinement of rivaroxaban crude product

Suspend the crude product of 4 g of rivaroxaban in 60 ml of ethylene glycol methyl ether and heat it to 125 ° C, add 0.4 g of activated carbon, stir the resulting solution at this temperature for 10 minutes, then filter while it is hot, and cool the mother liquor to room temperature. Suction filtration, the precipitated product was filtered out, washed with ethylene glycol methyl ether, and dried to obtain 3.46 g of white solid, recrystallization yield: 86.5%. HPLC purity 99.74%, ee%: 99.96%. DSC melting temperature: 230°C. ¹ HNMR (400MHz, d ₆ -DMSO): 9.00-8.93 (t, J = 5.6Hz, 6Hz, 1H), 7.70 (d, J = 4Hz, 1H), 7.60-7.53 (d, J = 8.8Hz, 2H ), 7.44-7.37(d, J=8.2Hz, 2H), 7.21-7.17(d, J=4Hz, 1H), 4.80-4.89(m, 1H), 4.24-4.15(m, 3H), 4.00-3.94 (m, 2H), 3.89-3.82(m, 1H), 3.75-3.68(m, 2H), 3.64-3.58(t, J=5.6Hz, 2H); the 2θ angles of powder diffraction are: 8.960°, 16.481° , 25.582°, 26.608°, 19.483°, 19.877°, 21.654°, 22.481°, 23.291°.

Embodiment 3: the refinement of rivaroxaban crude product

Suspend the crude product of 5 g of rivaroxaban in 50 ml of ethylene glycol methyl ether and heat it to 140 ° C, add 1.5 g of activated carbon, stir the resulting solution at this temperature for 10 minutes, then filter while it is hot, and cool the mother liquor to 60°C. Suction filtration, the precipitated product was filtered out, washed with ethylene glycol methyl ether, and dried to obtain 4.3 g of white solid; recrystallization yield: 86.0%. HPLC purity 99.67%.

Embodiment 4: the refinement of rivaroxaban crude product

Suspend the crude product of 5 g of rivaroxaban in 100 ml of ethylene glycol methyl ether and heat it to 60 ° C, add 0.25 g of activated carbon, stir the resulting solution at this temperature for 10 minutes, then filter while it is hot, and cool the mother liquor to 0°C. Suction filtration, the precipitated product was filtered out, washed with ethylene glycol methyl ether, and dried to obtain 3.70 g of white solid, recrystallization yield: 74.0%. HPLC purity 99.62%.

Embodiment 5: the refinement of rivaroxaban crude product

Suspend the crude product of 1 g of rivaroxaban in 5 ml of ethylene glycol methyl ether and heat it to 110 ° C, add 0.2 g of activated carbon, stir the resulting solution at this temperature for 10 minutes, then filter while it is hot, and cool the mother liquor to 30°C. Suction filtration, the precipitated product was filtered out, washed with ethylene glycol methyl ether, and dried to obtain 0.80 g of white solid, recrystallization yield: 80.0%. HPLC purity 99.52%.

Embodiment 6: the refinement of rivaroxaban crude product

Suspend the crude product of 3 g of rivaroxaban in 45 ml of ethylene glycol methyl ether and heat it to 100 ° C, add 0.45 g of activated carbon, stir the resulting solution at this temperature for 10 minutes, then filter while it is hot, and cool the mother liquor to 0°C. Suction filtration, the precipitated product was filtered out, washed with ethylene glycol methyl ether, and dried to obtain 2.49 g of white solid, recrystallization yield: 83.0%. HPLC purity 99.55%.

Embodiment 7: the refinement of rivaroxaban crude product

Suspend 5 g of the crude product of rivaroxaban in 75 ml of n-butanol and heat it to 125° C., add 0.5 g of activated carbon, stir the resulting solution at this temperature for 10 minutes, then filter while hot, and cool the mother liquor to room temperature. Suction filtration, the precipitated product was filtered out, washed with n-butanol, and dried to obtain 4.20 g of white solid, recrystallization yield: 84.0%. HPLC purity 99.7%.

Embodiment 8: Refining of crude product of rivaroxaban

Suspend 3 g of the crude product of rivaroxaban in 30 ml of n-butanol and heat it to 140 ° C, add 0.9 g of activated carbon, stir the resulting solution at this temperature for 10 minutes, then filter while it is hot, and cool the mother liquor to 60 ° C . Suction filtration, the precipitated product was filtered out, washed with n-butanol, and dried to obtain 2.58 g of white solid; recrystallization yield: 86.0%. HPLC purity 99.64%.

Embodiment 9: Refining of crude product of rivaroxaban

Suspend 4 g of the crude product of rivaroxaban in 80 ml of n-butanol and heat it to 60 ° C, add 0.20 g of activated carbon, stir the resulting solution at this temperature for 10 minutes, then filter while it is hot, and cool the mother liquor to 0 ° C . Suction filtration, the precipitated product was filtered out, washed with n-butanol, and dried to obtain 3.4 g of white solid, recrystallization yield: 85.0%. HPLC purity 99.63%.

Embodiment 10: Refining of crude product of rivaroxaban

Suspend 1 g of the crude product of rivaroxaban in 5 ml of n-butanol and heat it to 110 °C, add 0.2 g of activated carbon, stir the resulting solution at this temperature for 10 minutes, then filter while it is hot, and cool the mother liquor to 30 °C . Suction filtration, the precipitated product was filtered out, washed with ethylene glycol methyl ether, and dried to obtain 0.81 g of white solid, recrystallization yield: 81.0%. HPLC purity 99.52%.

Embodiment 11: Refining of crude product of rivaroxaban

Suspend 3 g of the crude product of rivaroxaban in 45 ml of n-butanol and heat it to 100 °C, add 0.45 g of activated carbon, stir the resulting solution at this temperature for 10 minutes, then filter while it is hot, and cool the mother liquor to 0 °C . Suction filtration, the precipitated product was filtered out, washed with ethylene glycol methyl ether, and dried to obtain 2.49 g of white solid, recrystallization yield: 83.0%. HPLC purity 99.54%.

Claims (10)

1. A method for purifying rivaroxaban, said method comprising the steps of: dissolving the crude product of rivaroxaban in ethylene glycol methyl ether or n-butanol under heating conditions, adding gac after dissolving and clearing, while hot Suction filtration, cooling and crystallization of the mother liquor, and filtration to obtain the crystalline product rivaroxaban. 2. The method according to claim 1, characterized in that the mass volume ratio of the crude product of rivaroxaban to ethylene glycol methyl ether or n-butanol is 1:5-1:20. 3. The method according to claim 2, characterized in that the mass volume ratio of the crude product of rivaroxaban to ethylene glycol methyl ether or n-butanol is 1:5-1:15. 4. The method according to claim 1, characterized in that, the mass volume ratio of the crude rivaroxaban product to activated carbon is 1:0.05-0.3. 5. The method according to claim 4, characterized in that the mass volume ratio of the crude rivaroxaban product to the activated carbon is 1:0.1-0.2. 6. The method according to claim 1, characterized in that the temperature for heating and dissolving the crude product of rivaroxaban is 60-140°C. 7. The method according to claim 6, characterized in that the temperature for heating and dissolving the crude product of rivaroxaban is 100-125°C. 8. The method according to claim 1, characterized in that, the cooling crystallization temperature of the mother liquor is 0-60°C. 9. The method according to claim 8, characterized in that, the cooling crystallization temperature of the mother liquor is 0-30°C. 10. The application of ethylene glycol methyl ether or n-butanol in purifying the crude product of rivaroxaban.