TW201605851A - A process for preparing crystalline forms of apixaban - Google Patents

Abstract

The present invention provides a novel process for preparing the crystalline form N-1 of apixaban.

Description

Method for preparing a crystalline form of apixaban

The present invention provides a novel process for the preparation of a crystalline form of apixaban N-1.

Apixaban is chemically known by the following names of formula (I): 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7 oxo 6-[4 -(2-oxo-l-piperidinyl)phenyl]-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (CAS name) or 1-(4-methoxyphenyl) -7 side oxygen 6-[4-(2-oxo 1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3- Formamide (IUPAC name).

Apixaban's dimethylformamide solvate crystalline form DMF-5 and formamide solvate crystalline form FA-2 are disclosed in U.S. Patent No. 2007/0203178 A1. Apixaban crystalline forms N-1 and H2-2 and methods for their preparation are disclosed in U.S. Patent No. 7,396,932. In U.S. Patent No. 7,396,932, the solvent for crystalline N-1 is N,N-dimethylformamide, which is difficult to remove and preserve, and is difficult to meet the limitations of the residual solvent of the pharmaceutical product. .

In view of the above, the present invention provides a crystalline form of apixaban N-1 which is a process which is low in cost and effective in the field of medicine.

In one aspect, the invention provides a process for the preparation of a crystalline form of apixaban N-1, the process comprising: (a) providing a solution of apixaban dissolved in a solvent; (b) a cooling step ( The solution obtained in a), and; (c) filtering the solution of step (b) to provide a crystalline form of apixaban N-1.

In a second aspect, the present invention provides a process for the preparation of a crystalline form of apixaban N-1, the process comprising: (a) providing a solution of apixaban dissolved in a solvent; (b) adding water To the solution obtained in the step (a); (c) separating the solution of the step (b) to provide a crystalline form of apixaban N-1.

Figure 1 shows an XRPD pattern of the crystalline form of apixaban N-1.

Figure 2 shows a TGA and DSC thermogram of the apixaban N-1 crystalline form.

The present invention provides a process for preparing a crystalline form of apixaban N-1.

In one aspect, the invention provides a process for the preparation of a crystalline form of apixaban N-1, the process comprising: (a) providing a solution of apixaban dissolved in a solvent; (b) a cooling step ( The solution obtained in a), and; (c) filtering the solution of step (b) to provide a crystalline form of apixaban N-1.

In some embodiments, the solvent of step (a) is selected from the group consisting of ethanol or ethyl acetate. In some implementations, the temperature at which step (b) is cooled is less than 10 °C. In some implementations, the temperature at which the cooling is carried out is 5 °C.

In a related aspect, the present invention provides a method for preparing a crystalline form of apixaban N-1, the method comprising: (a) providing a solution of apixaban dissolved in a solvent; (b) adding water to The solution obtained in the step (a); (c) isolating the solution of the step (b) to provide a crystalline form of apixaban N-1.

In some embodiments, the solvent of step (a) is dimethyl hydrazine. In some embodiments, the solution of step (a) is heated to 50 °C. In some embodiments, the solution was cooled to 20 ° C after the addition of water.

In some embodiments, the apixaban N-1 crystalline form is characterized by an XRPD pattern comprising 2θ degrees (±0.2 2θ degrees) as provided in Figure 1. The thermal analysis of the N-1 crystalline form was carried out with TGA and DSC. The TGA data was collected on a TA instrument TGA 2905. Each sample was loaded with a pre-weighing platinum crucible and a nitrogen purge scale and furnace with flow rates set to 55 ± 5 and 75 ± 5 mL/min, respectively, prior to analysis. The sample was dried using a heating program (temperature was heated from room temperature to 300 ° C at 10 ° C/min). The DSC curve was collected from a TA Instruments Q200 DSC. In this analysis, about 1.5 mg of the sample was sealed to an aluminum sealed type sample pan, which was then heated from 30 ° C to 300 ° C at a heating rate set at 10 ° C/min. Continuously dried nitrogen (flow rate of 50 mL/min) was used as the carrier gas. An overlay of apixaban N-1 crystalline TGA and DSC thermograms is shown in Figure 2. The TGA plot shows a weight loss of 0.16% at 150 °C. The DSC curve confirmed that the sample had an endothermic transition at a maximum temperature of 237.04 °C.

Example Comparative example

Apixaban crystalline Form N-1 and its preparation are disclosed in Example 9 of U.S. Patent No. 7,396,932.

Ethyl acetate (1 kg) and anhydrous N,N-dimethylformamide (7.55 kg) and formamide (2.26 kg) were charged to a reactor. The foregoing mixture was stirred and heated to 48-52 °C. The water content of this solution was 0.18 wt% as determined by the Karl Fisher (KF) method. Trimethyl orthoformate (0.1376 kg) and trifluoroacetic acid (0.047 kg) were added and the mixture was stirred at 48-52 °C for 30 min. Repeated KF analysis measured 0.03 wt% of water. A solution of sodium methoxide in methanol (0.7866 kg) was added, and the mixture was stirred for 30 min, and the reaction was completed by HPLC. Water (0.4 kg) was added at 48-52 ° C, and the solution was stirred and cooled to 20-25 ° C over 2 hours. Add water (7.6 kg) at 17-20 ° C for about 1-2 hours. This slurry is a sample that completes crystallization.

The slurry (1 L) was transferred to a temporary tank, heated to 55-60 ° C, and sheared and agitated to convert the polycrystal from the H 2-2 crystalline form to the small particle N-1 crystal. After the crystallization conversion is completed, the remaining slurry is transferred to a temporary tank maintained to be heated to 55-60 ° C, and the above slurry is shear-stirred to form small-particle N-1 crystals. Pour the slurry into one Receive the tank and maintain the liquid volume at 1L. The receiving tank was cooled to 20 ° C for more than 2-3 hours. The slurry was filtered, washed with water (3 x 5 kg) and isopropyl alcohol (1 x 4 kg), and dried in a vacuum oven at 50 ° C to obtain the final product N-1 crystals (0.88 - 0.85 kg).

The following examples are provided to further describe but not to limit the invention.

Example 1

Apixaban (about 2 g) and 99.5% ethanol (about 200 mL) were placed in a suitable flask and heated to reflux. The solution was rapidly cooled to 5 °C. The resulting slurry was filtered, and the filtered solid was analyzed by XRPD and identified as crystalline N-1.

Example 2

Apixaban (about 5 g) and DMSO (about 80 mL) were placed in a suitable flask and heated to 50 °C. The solution was filtered and hot water was quickly added to the solution at 50 °C. The mixture was cooled to 20 ° C for 1 hour and stirred at 20 ° C for 16 hours. The resulting slurry was filtered, and the wet cake was filtered under nitrogen for 3 hr. The dried sample was analyzed by XRPD and identified as crystalline N-1.

Example 3

Apixaban (about 5 g) and DMSO (about 80 mL) were placed in a suitable flask and heated to 50 °C. The solution was filtered and cooled to 15 °C. The resulting slurry was used as a sample for completion of crystallization (unshaped).

The slurry was heated to 50 ° C, water (about 80 mL) was added at 50 ° C, and cooled from 50 ° C to 20 ° C. The slurry was filtered, washed with water, and the wet cake was filtered for not less than 1 hour under a nitrogen atmosphere. The final product was analyzed by XRPD and was crystalline N-1.

Example 4

Apixaban (about 10 g) and DMSO (about 160 mL) were placed in a suitable flask and heated to 50 °C. Water was added to the solution at 50 °C. The slurry was heated from 50 ° C to 60 ° C and stirred at 60 ° C overnight. The slurry was cooled from 60 ° C to 20 ° C and stirred at 20 ° C for 2 hours. The resulting slurry is filtered, washed with water, and the wet cake is filtered for not less than 1 hour under a nitrogen atmosphere, and vacuum-baked. The box was dried at 70 ° C for 18 hours. The final product was analyzed by XRPD and was crystalline N-1.

Example 5

Apixaban (about 4.6 g (wet cake 9.5 g)) and EtOAc (about 69 mL) were placed in a suitable flask and heated to reflux. The reaction mixture is stirred at reflux for not less than 1 hour and then cooled to 20-30 °C. The mixture was stirred at 20-30 ° C for 1 hour. The mixture was filtered and washed with EtOAc (~ 19 mL). The wet cake was evacuated overnight to afford a portion of aq. The final product was analyzed by XRPD and was crystalline N-1.

Claims (8)

A method for preparing a crystalline form of apixaban N-1, the method comprising: (a) providing a solution of apixaban dissolved in a solvent; (b) cooling the solution obtained in step (a) And (c) filtering the solution of step (b) to provide apixaban N-1 crystalline form. The method of claim 1, wherein the solvent is selected from the group consisting of ethanol or ethyl acetate. The method of claim 1, wherein the cooling is performed at a temperature below 10 °C. The method of claim 1, wherein the cooling is carried out at a temperature of 5 °C. A method for preparing a crystalline form of apixaban N-1, the method comprising: (a) providing a solution of apixaban dissolved in a solvent; (b) adding water to the step (a) This solution (c) separates the solution of step (b) to provide apixaban N-1 crystalline form. The method of claim 5, wherein the solvent is dimethyl hydrazine. The method of claim 5, wherein the solution of step (a) is heated to 50 °C. The method of claim 5, wherein after adding water, the solution is cooled to 20 °C.