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CN103539795A - Apixaban polymorph and preparation method thereof - Google Patents

Apixaban polymorph and preparation method thereof Download PDF

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Publication number
CN103539795A
CN103539795A CN201310479697.0A CN201310479697A CN103539795A CN 103539795 A CN103539795 A CN 103539795A CN 201310479697 A CN201310479697 A CN 201310479697A CN 103539795 A CN103539795 A CN 103539795A
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degrees
apixaban
crystal form
peaks
ray powder
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张明会
张占涛
张勇
林栋�
解先业
隋新
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Qilu Pharmaceutical Co Ltd
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Qilu Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The invention belongs to the technical field of pharmaceutical chemicals, and specifically relates to 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-formamide polymorph with antithrombotic activity, and a preparation method thereof. According to the invention, an apixaban crude product is crystallized under different conditions, such that crystal apixaban form with high purity and good yield and amorphous apixaban can be obtained. The method has the advantages of simple process, convenient operation, mild condition, and no requirement on special reaction conditions. Therefore, the method is suitable for industrialized productions.

Description

Apixaban polymorph and preparation method thereof
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1-piperidyl) phenyl ] -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-formamide polymorph with antithrombotic activity and a preparation method thereof.
Background
Apixaban (Apixaban), the chemical name of which is 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl ] -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide, has the chemical structure shown in formula I, and is a new generation of oral selective factor x-activating inhibitors developed by combining pfeifferi and bexaban. Among a plurality of blood coagulation factor Xa inhibitors, the apixaban shows high selectivity, good bioavailability and high-efficiency treatment effect, has performance greatly superior to that of Razaxaban (Razaxaban), and is mainly suitable for treating venous thrombosis including Deep Venous Thrombosis (DVT) and pulmonary embolism. Apixaban was approved for marketing in the european union in 5 months 2011 for the prevention of Venous Thromboembolic (VTE) events in adult patients undergoing elective hip or knee replacements; the FDA in us 12 months 2012 approved the drug for reducing stroke and systemic embolic risk in patients with non-valvular atrial fibrillation.
Figure BDA0000395245800000011
In the literature reported so far, WO2003026652 and its chinese family CN1578660A disclose apixaban compounds, their preparation methods and their use in the preparation of medicaments for the treatment of thromboembolic diseases. Patent document US2009076069 discloses various deuterated compounds of apixaban; WO03049681, CN101967145A, CN102675314A disclose in succession processes for the preparation of apixaban; WO2006078331 discloses a process for preparing an anhydrate crystal form from an apixaban solvate crystal form. However, the report of the crystalline form of apixaban is relatively few at present, only WO2012168364 discloses the crystalline form alpha of apixaban, WO2007001385 discloses the crystalline form of anhydrate (N-1) of apixaban, and simultaneously discloses the crystalline form of dihydrate (H2-2) thereof; US2007203178 discloses crystalline form DMF-5 of apixaban N, N-dimethylformamide solvate and crystalline form FA-2 of formamide solvate, therefore, more crystalline forms still need to be developed, providing a wider crystal form selection space for apixaban pharmaceutical applications.
Disclosure of Invention
The present inventors have made extensive experimental studies and have surprisingly found a novel crystalline form of apixaban, and the present invention has been completed based on this finding. The apixaban according to the present invention includes crystalline forms of apixaban and amorphous forms of apixaban.
The first aspect of the present invention provides apixaban in a crystal form, said apixaban in a crystal form being one or more of crystalline form I, crystalline form II, crystalline form III, crystalline form IV, crystalline form V of apixaban; wherein,
the crystalline form I of apixaban uses Cu-Kalpha radiation, and has characteristic peaks at 12.9 +/-0.2 degrees, 13.9 +/-0.2 degrees, 17.0 +/-0.2 degrees, 18.5 +/-0.2 degrees and 22.1 +/-0.2 degrees in X-ray powder diffraction represented by 2 theta angles.
Preferably, the Apixaban crystalline form I has a characteristic peak at 8.5 + -0.2 °, 12.3 + -0.2 °, 12.9 + -0.2 °, 13.9 + -0.2 °, 16.3 + -0.2 °, 17.0 + -0.2 °, 18.5 + -0.2 °, 18.9 + -0.2 °, 19.6 + -0.2 °, 21.1 + -0.2 °, 21.5 + -0.2 °, 22.1 + -0.2 °, 22.3 + -0.2 ° by X-ray powder diffraction expressed in terms of 2 θ angle using Cu-Ka radiation.
More preferably, the crystalline form I of apixaban has characteristic peaks at 8.5 ± 0.2 °, 10.0 ± 0.2 °, 10.5 ± 0.2 °, 11.2 ± 0.2 °, 12.3 ± 0.2 °, 16.3 ± 0.2 °, 17.0 ± 0.2 °, 18.5 ± 0.2 °, 18.9 ± 0.2 °, 19.6 ± 0.2 °, 21.1 ± 0.2 °, 21.5 ± 0.2 °, 22.0 ± 0.2 °, 22.3 ± 0.2 °, 24.8 ± 0.2 °, 27.0 ± 0.2 °, 29.9 ± 0.2 °, 32.7 ± 0.2 ° by X-ray powder diffraction expressed in terms of 2 θ angle using Cu-ka radiation.
In one embodiment of the present invention, the crystalline form I of apixaban has an X-ray powder diffraction pattern as depicted in figure 1.
The Differential Scanning Calorimetry (DSC) detection result of the apixaban crystal form I shows an endothermic peak within the range of 230.27-252.87 ℃, and more specifically, the Differential Scanning Calorimetry (DSC) detection of the apixaban crystal form I has an endothermic peak at 239.88 +/-2 ℃; in one embodiment, the crystalline form I of apixaban has a differential scanning calorimetry pattern as shown in figure 2.
The Apixaban crystal form II uses Cu-Kalpha radiation, and has characteristic peaks at 5.8 +/-0.2 degrees, 7.4 +/-0.2 degrees, 15.9 +/-0.2 degrees, 18.0 +/-0.2 degrees and 23.6 +/-0.2 degrees of X-ray powder diffraction represented by 2 theta angles.
Preferably, the Apixaban crystal form II has characteristic peaks at 5.8 + -0.2 °, 7.4 + -0.2 °, 13.5 + -0.2 °, 15.9 + -0.2 °, 16.2 + -0.2 °, 16.8 + -0.2 °, 18.0 + -0.2 °, 20.1 + -0.2 °, 20.8 + -0.2 °, 23.6 + -0.2 °, 25.2 + -0.2 ° by X-ray powder diffraction expressed by 2 θ angle using Cu-Ka radiation.
More preferably, the crystalline form II of apixaban has characteristic peaks at 5.8 ± 0.2 °, 7.4 ± 0.2 °, 11.7 ± 0.2 °, 13.5 ± 0.2 °, 15.9 ± 0.2 °, 16.2 ± 0.2 °, 16.8 ± 0.2 °, 18.0 ± 0.2 °, 18.8 ± 0.2 °, 20.1 ± 0.2 °, 20.5 ± 0.2 °, 20.8 ± 0.2 °, 21.3 ± 0.2 °, 22.3 ± 0.2 °, 23.6 ± 0.2 °, 25.2 ± 0.2 °, 25.9 ± 0.2 ° by X-ray powder diffraction expressed in terms of 2 θ angle using Cu-ka radiation.
In one embodiment, the crystalline form II of apixaban has an X-ray powder diffraction pattern as shown in figure 3;
the Differential Scanning Calorimetry (DSC) detection pattern of the apixaban crystal form II has endothermic peaks at 33.4-92.3 ℃ and 220.1-248.6 ℃, and more particularly, the Differential Scanning Calorimetry (DSC) detection of the apixaban crystal form II has endothermic peaks at 70 +/-2 ℃ and 234.1 +/-2 ℃.
In addition, the Differential Scanning Calorimetry (DSC) detection of the Apixaban crystal form II shows that adjacent absorption peaks and exothermic peaks appear at 144.3-218.8 ℃; specifically, the Differential Scanning Calorimetry (DSC) detection of the apixaban crystal form II shows that an endothermic peak and an exothermic peak respectively appear at 144.3-181.5 ℃ and 181.5-218.8 ℃; more specifically, Differential Scanning Calorimetry (DSC) detection of the apixaban crystal form II shows that an endothermic peak and an exothermic peak appear at 171.9 +/-2 ℃ and 193.1 +/-2 ℃ respectively; in one embodiment, the apixaban crystalline form II has a differential scanning calorimetry pattern as shown in figure 4.
The Apixaban crystal form III uses Cu-Kalpha radiation, and has characteristic diffraction peaks when the X-ray powder diffraction represented by the angle of 2 theta is 12.8 +/-0.2 degrees, 13.9 +/-0.2 degrees, 16.9 +/-0.2 degrees, 18.4 +/-0.2 degrees and 22.1 +/-0.2 degrees;
preferably, the crystalline form III of apixaban, using Cu-ka radiation, has a characteristic diffraction peak at 5.4 ± 0.2 °, 8.4 ± 0.2 °, 10.9 ± 0.2 °, 12.2 ± 0.2 °, 12.8 ± 0.2 °, 13.9 ± 0.2 °, 16.2 ± 0.2 °, 16.9 ± 0.2 °, 18.4 ± 0.2 °, 18.7 ± 0.2 °, 19.5 ± 0.2 °, 21.1 ± 0.2 °, 21.5 ± 0.2 °, 22.2 ± 0.2 °, 22.1 ± 0.2 °, 24.6 ± 0.2 °, 26.9 ± 0.2 °, 27.6 ± 0.2 ° in X-ray powder diffraction expressed in 2 Θ angles;
more preferably, the crystalline form III of apixaban, using Cu-ka radiation, has a characteristic diffraction peak at 5.4 ± 0.2 °, 8.4 ± 0.2 °, 10.9 ± 0.2 °, 12.2 ± 0.2 °, 12.8 ± 0.2 °, 13.9 ± 0.2 °, 16.2 ± 0.2 °, 16.9 ± 0.2 °, 18.4 ± 0.2 °, 18.7 ± 0.2 °, 19.5 ± 0.2 °, 21.1 ± 0.2 °, 21.5 ± 0.2 °, 22.2 ± 0.2 °, 22.1 ± 0.2 °, 24.6 ± 0.2 °, 26.9 ± 0.2 °, 27.6 ± 0.2 °, 28.6 ± 0.2 °, 29.1 ± 0.2 °, 29.7 ± 0.2.2 ° at an X-ray powder diffraction angle of 2 Θ;
in one embodiment of the invention, the apixaban crystalline form III has an x-ray powder diffraction pattern as shown in figure 5;
the Apixaban crystal form IV uses Cu-Kalpha radiation, and has characteristic diffraction peaks at 6.0 +/-0.2 degrees, 7.1 +/-0.2 degrees, 13.6 +/-0.2 degrees, 16.1 +/-0.2 degrees, 17.6 +/-0.2 degrees, 21.7 +/-0.2 degrees and 22.8 +/-0.2 degrees of X-ray powder diffraction represented by a 2 theta angle;
preferably, the crystalline form IV of apixaban, using Cu-ka radiation, has an X-ray powder diffraction at an angle of 2 Θ, at 6.0 ± 0.2 °, 7.1 ± 0.2 °, 12.8 ± 0.2 °, 13.6 ± 0.2 °, 16.1 ± 0.2 °, 16.4 ± 0.2 °, 17.6 ± 0.2 °, 19.1 ± 0.2 °, 21.7 ± 0.2 °, 22.8 ± 0.2 °, 24.4 ± 0.2 °, 24.6 ± 0.2 °, exhibiting a characteristic diffraction peak;
more preferably, the crystalline form IV of apixaban, using Cu-ka radiation, has a characteristic diffraction peak at 6.0 ± 0.2 °, 7.1 ± 0.2 °, 11.0 ± 0.2 °, 12.8 ± 0.2 °, 13.6 ± 0.2 °, 15.1 ± 0.2 °, 15.7 ± 0.2 °, 16.1 ± 0.2 °, 16.4 ± 0.2 °, 17.6 ± 0.2 °, 18.0 ± 0.2 °, 19.1 ± 0.2 °, 20.6 ± 0.2 °, 21.7 ± 0.2 °, 22.8 ± 0.2 °, 24.4 ± 0.2 °, 24.6 ± 0.2 °, 26.1 ± 0.2 °, 28.9 ± 0.2 °, 30.1 ± 0.2 °, 31.0 ± 0.2 ° in X-ray powder diffraction, expressed in 2 θ degrees.
In one embodiment of the present invention, the crystalline form IV of apixaban has an X-ray powder diffraction pattern as shown in figure 6.
The apixaban crystal form IV has endothermic peaks in the ranges of 53.6-91.1 ℃ and 222.9-252.8 ℃ in Differential Scanning Calorimetry (DSC) detection, and more specifically, the apixaban crystal form IV has endothermic peaks at 81.7 +/-2 ℃ and 239.3 ℃ in Differential Scanning Calorimetry (DSC) detection.
In addition, Differential Scanning Calorimetry (DSC) detection of the Apixaban crystal form IV shows that adjacent absorption peaks and exothermic peaks appear successively at 141.4-201.2 ℃; specifically, the Apixaban crystal form IV has an endothermic peak and an exothermic peak respectively at 141.4-171.4 ℃ and 171.4-201.2 ℃ by Differential Scanning Calorimetry (DSC) detection; more specifically, the apixaban crystal form IV has an endothermic peak and an exothermic peak at 163.8 ± 2 ℃ and 186.0 ± 2 ℃ respectively as detected by Differential Scanning Calorimetry (DSC); in one embodiment, the crystalline form IV of apixaban has a differential scanning calorimetry pattern as shown in figure 7.
The Apixaban crystal form V uses Cu-Kalpha radiation, and has characteristic diffraction peaks at 5.8 +/-0.2 degrees and 11.5 +/-0.2 degrees of X-ray powder diffraction represented by a 2 theta angle;
preferably, the crystalline form V of apixaban has characteristic diffraction peaks at 5.8 ± 0.2 °, 11.5 ± 0.2 °, 13.3 ± 0.2 °, 15.8 ± 0.2 °, 17.3 ± 0.2 °, 18.6 ± 0.2 °, 21.3 ± 0.2 °, 23.2 ± 0.2 °, 29.9 ± 0.2 °, 32.8 ± 0.2 ° in X-ray powder diffraction expressed in 2 θ angle using Cu-ka radiation;
more preferably, the crystalline form V of apixaban, using Cu-ka radiation, has characteristic diffraction peaks at 5.8 ± 0.2 °, 11.5 ± 0.2 °, 13.3 ± 0.2 °, 15.9 ± 0.2 °, 17.3 ± 0.2 °, 18.6 ± 0.2 °, 21.3 ± 0.2 °, 23.2 ± 0.2 °, 29.9 ± 0.2 °, 32.8 ± 0.2 ° in X-ray powder diffraction expressed in 2 Θ angle; in one embodiment, the crystalline form V has an X-ray powder diffraction pattern as shown in figure 8;
the apixaban crystal form V has endothermic peaks in the ranges of 53.5-81.9 ℃ and 218.7-248.6 ℃ in Differential Scanning Calorimetry (DSC) detection, and more specifically, the apixaban crystal form V has endothermic peaks in the ranges of 69.6 +/-2 ℃ and 234.8 ℃ in Differential Scanning Calorimetry (DSC) detection;
in addition, the Differential Scanning Calorimetry (DSC) detection of the Apixaban crystal form V shows that adjacent absorption peaks and exothermic peaks appear in sequence within the temperature range of 153.2-193.4 ℃; specifically, the Apixaban crystal form V has an endothermic peak and an exothermic peak respectively at 153.2-172.1 ℃ and 172.1-193.4 ℃ in Differential Scanning Calorimetry (DSC) detection; more specifically, the apixaban crystal form V has an endothermic peak and an exothermic peak at 168.6 ± 2 ℃ and 175.8 ± 2 ℃ respectively as detected by Differential Scanning Calorimetry (DSC); in one embodiment, the apixaban crystalline form V has a differential scanning calorimetry pattern as shown in figure 9.
The second aspect of the present invention provides an amorphous form of apixaban having smooth diffraction peaks at 8 ± 0.2 ° and 18 ± 0.2 ° in X-ray powder diffraction using Cu-ka radiation expressed at an angle of 2 θ;
in one embodiment of the invention, the amorphous form of apixaban has an X-ray powder diffraction pattern as shown in figure 10.
A third aspect of the invention provides a process for preparing crystalline form I, crystalline form II, crystalline form III, crystalline form IV, crystalline form V and amorphous apixaban, comprising the steps of:
(1) adding apixaban into an organic solvent, and heating for dissolving to obtain an organic solvent solution of apixaban;
(2) naturally cooling the apixaban organic solvent solution obtained in the step (1) to a solid precipitation temperature, and stirring to precipitate a solid;
(3) filtering and vacuum drying to obtain the product.
Wherein the mass-to-volume ratio (g/ml) of apixaban to organic solvent is 1: 10-60, preferably 1: 15-40, more preferably 1: 20-30;
the temperature of the solid precipitated by stirring is-10-15 ℃, preferably-10 ℃, more preferably-5 ℃, and most preferably 0 ℃;
stirring to separate out the solid for 1-3 h, preferably 1-2 h after the solid is separated out; and: when the organic solvent is methanol, the Apixaban crystal form I is obtained; when the organic solvent is ethyl acetate, obtaining apixaban crystal form II; when the organic solvent is isopropyl acetate, obtaining apixaban crystal form III; when the organic solvent is ethanol, apixaban crystal form IV is obtained; when the organic solvent is 1, 4-dioxane, the Apixaban crystal form V is obtained; when the organic solvent is dimethylsulfoxide, amorphous apixaban is obtained.
The fourth aspect of the invention provides a pharmaceutical composition, which comprises one or more of apixaban crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V and amorphous apixaban, or a mixed crystal thereof, and any pharmaceutically acceptable excipient.
The fifth aspect of the invention provides the use of apixaban in form I, form II, form III, form IV, form V and amorphous apixaban for the preparation of a medicament for the treatment or prevention of a thromboembolic disorder.
In a sixth aspect, the invention provides the use of a pharmaceutical composition according to the fourth aspect of the invention in the manufacture of a medicament for the treatment or prophylaxis of a thromboembolic disorder.
The crystalline apixaban and the amorphous apixaban provided by the invention have higher purity and better yield, the purity is more than 99.5%, and the method has the advantages of simple process, convenient operation and mild condition, and does not need special reaction conditions, thereby being suitable for industrial production.
In the invention, the apixaban crude product is prepared by referring to a method disclosed in patent document CN 1639147A; in the characteristic peaks of X-ray powder diffraction expressed in terms of 2 θ, the range of reasonable measurement errors allowed by the characteristic peak positions is expressed by "± 0.2 °".
Drawings
FIG. 1 is an X-ray powder diffraction pattern of crystalline form I of apixaban;
FIG. 2 is a DSC-TGA profile of crystalline form I of apixaban;
FIG. 3 is an X-ray powder diffraction pattern of crystalline form II apixaban;
FIG. 4 is a DSC-TGA profile of crystalline form II of apixaban;
FIG. 5 is an X-ray powder diffraction pattern of crystalline form III of apixaban;
FIG. 6 is an X-ray powder diffraction pattern of crystalline form IV of apixaban;
FIG. 7 is a DSC-TGA profile of crystalline form IV of apixaban;
FIG. 8 is an X-ray powder diffraction pattern of crystalline form V Apixaban;
FIG. 9 is a DSC-TGA profile of crystalline form V of apixaban;
figure 10 is an X-ray powder diffraction pattern of amorphous apixaban.
Detailed Description
The invention is further illustrated by the following specific preparation examples, but it should be understood that these examples are included merely for purposes of illustration and description in more detail, and are not intended to limit the invention in any way.
The reagents and methods employed in the examples of this invention are conventional in the art and are conventional in the practice of the invention. Although many materials and methods of operation are known in the art for the purpose of this invention, the invention is nevertheless described in detail as is practicable. It will be apparent to those skilled in the art that the materials and methods of operation used in the present invention are well known in the art, unless otherwise specified.
The inspection apparatus used in the present invention:
(1) x-ray powder diffractometer
The instrument model is as follows: panalytical
Radiation source: Cu-Ka radiation
Sample treatment: after the sample is ground, it is placed in a standard sample holder for measurement.
(2) TGA/DSC1 synchronous thermal analyzer
The instrument model is as follows: METTLERTGA/DSC 1.
And (3) testing conditions are as follows: initial measurement temperature: 30 deg.C
The heating rate is as follows: 10 ℃/min
Preparation example 1: preparation of 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl ] -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide (Compound I)
(a) Preparation of ethyl 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-piperidin-1-yl) -phenyl ] -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-C ] pyridine-3-carboxylate:
Figure BDA0000395245800000071
adding 3-morpholin-4-yl-1- [4- (2-oxo-piperidin-1-yl) -phenyl ] -5, 6-dihydro-1H-pyridin-2-one 100g, chloro [ (4-methoxyphenyl) hydrazono ] acetic acid ethyl ester 86.2g and triethylamine 56.7g into 1000ml toluene at 0-5 ℃ under the protection of nitrogen, stirring for reaction for 3H at 60-80 ℃, cooling to room temperature after the reaction is finished, evaporating toluene under reduced pressure to obtain a concentrate, dissolving the concentrate into ethyl acetate, washing with purified water for 3 times, drying the obtained ethyl acetate phase with anhydrous sodium sulfate, performing suction filtration, adding hydrochloric acid 4.0mol/L into the obtained ethyl acetate solution to adjust the pH of the obtained ethyl acetate filtrate to be between 3 and 4, then stirring for 2H at room temperature, and carrying out suction filtration to obtain 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-piperidin-1-yl) -phenyl ] -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-C ] pyridine-3-carboxylic acid ethyl ester, wherein the yield is 60 percent, and the HPLC purity is 95 percent.
(b) Preparation of apixaban
Figure BDA0000395245800000072
At room temperature, 80g of 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-piperidin-1-yl) -phenyl ] -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-C ] pyridine-3-carboxylic acid ethyl ester and 368g of formamide are added into 400ml of N, N-dimethylformamide, then 40g of methanol solution (400 ml) of sodium methoxide is dropwise added, the reaction system is maintained at 0-5 ℃ for reaction for 30 minutes, then the reaction is maintained at 40-50 ℃, HPLC detection is carried out until the reaction is finished, then a proper amount of purified water is added into the reaction system, suction filtration is carried out, and the obtained filter cake is dried in vacuum to obtain 60.19g of apixaban, the yield is 80%, and the HPLC purity is 98%.
Example 1 preparation of crystalline form I of apixaban
Adding 5.0g of apixaban prepared in preparation example 1 into 300ml of methanol, heating for dissolving, then naturally cooling to 0-5 ℃ under stirring for crystallization, continuing stirring for 2h after crystallization, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 3.4g of apixaban crystal form I white crystals, wherein the yield is 68%, and the purity of HLPC is 99.3%.
The X-ray powder diffraction pattern is shown in figure 1, and the DSC-TGA pattern is shown in figure 2.
Example 2 preparation of crystalline form I of apixaban
The apixaban (5.0 g) prepared in preparation example 1 is added into methanol (200 ml), heated and dissolved, then naturally cooled to-5 ℃ under stirring, crystallized, continuously stirred for 3h, filtered, and dried under vacuum at 40 ℃ to obtain 3.75g of apixaban crystal form I white crystals, the yield is 75%, and the HPLC purity is 99.2%. The X-ray powder diffraction pattern is basically consistent with that of figure 1, and the DSC-TGA pattern is basically consistent with that of figure 2.
Example 3 preparation of crystalline form I of apixaban
Adding apixaban (50 g) prepared in preparation example 1 into methanol (1500 ml), heating for dissolving, then naturally cooling to 10 ℃ for crystallization under stirring, continuing stirring for 1h after crystallization, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 40.25g of apixaban crystal form I white crystals, wherein the yield is 80.5%, and the purity of HLPC is 99.5%. The X-ray powder diffraction pattern is basically consistent with that of figure 1, and the DSC-TGA pattern is basically consistent with that of figure 2.
Example 4 preparation of crystalline form I of apixaban
Adding apixaban (25 g) prepared in preparation example 1 into methanol (250 ml), heating for dissolving, then naturally cooling to-10 ℃ for crystallization under stirring, continuing stirring for 2h after crystallization, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 21.4g of apixaban crystal form I white crystals, wherein the yield is 85.6%, and the HPLC purity is 99.3%. The X-ray powder diffraction pattern is basically consistent with that of figure 1, and the DSC-TGA pattern is basically consistent with that of figure 2.
Example 5 preparation of crystalline form I of apixaban
The apixaban (25 g) prepared in preparation example 1 is added into methanol (500 ml), heated and dissolved, then naturally cooled to 0 ℃ under stirring for crystallization, and after crystallization, the mixture is continuously stirred for 2h, filtered by suction and dried under vacuum at 40 ℃ to obtain 20.4g of apixaban crystal form I white crystals, wherein the yield is 81.6 percent, and the HPLC purity is 99.4 percent. The X-ray powder diffraction pattern is basically consistent with that of figure 1, and the DSC-TGA pattern is basically consistent with that of figure 2.
Example 6 preparation of crystalline form I of apixaban
Adding apixaban (10 g) prepared in preparation example 1 into methanol (150 ml), heating for dissolving, then naturally cooling to 15 ℃ under stirring for crystallization, continuing stirring for 2h after crystallization, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 8.23g of apixaban crystal form I white crystals, wherein the yield is 82.3%, and the HPLC purity is 99.4%. The X-ray powder diffraction pattern is basically consistent with that of figure 1, and the DSC-TGA pattern is basically consistent with that of figure 2.
Example 7 preparation of crystalline form II Apixaban
Adding apixaban (5.0 g) prepared in preparation example 1 into ethyl acetate (300 ml), heating to dissolve, then naturally cooling to 0-5 ℃ while stirring for crystallization, continuing stirring for 2h after crystallization, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 3.0g of apixaban crystal form II white crystal, wherein the yield is 60% and the HLPC purity is 99.3%. The X-ray powder diffraction pattern is shown in figure 3, and the DSC-TGA pattern is shown in figure 4.
Example 8 preparation of crystalline form II Apixaban
Adding apixaban (5.0 g) prepared in preparation example 1 into ethyl acetate (200 ml), heating to dissolve, then naturally cooling to-5 ℃ under stirring, crystallizing, then continuing stirring for 3h, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 3.6g of apixaban crystal form II white crystals, wherein the yield is 72% and the HPLC purity is 99.4%. The X-ray powder diffraction pattern is determined to be basically consistent with that of figure 3, and the DSC-TGA pattern is determined to be basically consistent with that of figure 4.
Example 9 preparation of crystalline form II Apixaban
Adding apixaban (50 g) prepared in preparation example 1 into ethyl acetate (1500 ml), heating for dissolving, then naturally cooling to 10 ℃ for crystallization under stirring, continuing stirring for 1h after crystallization, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 41.2g of apixaban crystal form II white crystals, wherein the yield is 82.4%, and the purity of HLPC is 99.2%. The X-ray powder diffraction pattern is determined to be basically consistent with that of figure 3, and the DSC-TGA pattern is determined to be basically consistent with that of figure 4.
Example 10 preparation of crystalline form II Apixaban
Adding apixaban (25 g) prepared in preparation example 1 into ethyl acetate (250 ml), heating for dissolving, then naturally cooling to-10 ℃ for crystallization under stirring, continuing stirring for 2h after crystallization, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 21.4g of apixaban crystal form II white crystals, wherein the yield is 85.6%, and the HPLC purity is 99.3%. The X-ray powder diffraction pattern is determined to be basically consistent with that of figure 3, and the DSC-TGA pattern is determined to be basically consistent with that of figure 4.
Example 11 preparation of crystalline form II Apixaban
Adding apixaban (25 g) prepared in preparation example 1 into ethyl acetate (500 ml), heating for dissolving, then naturally cooling to 0 ℃ under stirring for crystallization, continuously stirring for 2h after crystallization, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 20.6g of apixaban crystal form II white crystals, wherein the yield is 82.4%, and the HPLC purity is 99.4%. The X-ray powder diffraction pattern is determined to be basically consistent with that of figure 3, and the DSC-TGA pattern is determined to be basically consistent with that of figure 4.
Example 12 preparation of crystalline form III of Apixaban
Adding the apixaban (5.0 g) prepared in preparation example 1 into isopropyl acetate (300 ml), heating for dissolving, then naturally cooling to 0-5 ℃ for crystallization under stirring, continuing stirring for 2h after crystallization, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 3.4g of apixaban crystal form III white crystals, wherein the yield is 68%, and the purity of HLPC is 99.3%. The X-ray powder diffraction pattern is shown in figure 5.
Example 13 preparation of crystalline form III of Apixaban
Adding apixaban (5.0 g) prepared in preparation example 1 into isopropyl acetate (200 ml), heating for dissolving, then naturally cooling to-5 ℃ under stirring, crystallizing, then continuing stirring for 3h, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 3.8g of apixaban crystal form III white crystals, wherein the yield is 76%, and the HPLC purity is 99.3%. The X-ray powder diffraction pattern was determined to be substantially in accordance with figure 5.
Example 14 preparation of crystalline form III of Apixaban
Adding apixaban (50 g) prepared in preparation example 1 into isopropyl acetate (1500), heating for dissolving, then naturally cooling to 10 ℃ for crystallization under stirring, continuing stirring for 1h after crystallization, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 40.25g of apixaban crystal form III white crystals, wherein the yield is 80.5%, and the purity of HLPC is 99.5%. The X-ray powder diffraction pattern was determined to be substantially in accordance with figure 5.
Example 15 preparation of crystalline form III of Apixaban
Adding apixaban (25 g) prepared in preparation example 1 into isopropyl acetate (500 ml), heating for dissolving, then naturally cooling to 0 ℃ under stirring for crystallization, continuously stirring for 2h after crystallization, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 20.8g of apixaban crystal form III white crystals, wherein the yield is 83.2%, and the HPLC purity is 99.4%. The X-ray powder diffraction pattern was determined to be substantially in accordance with figure 5.
EXAMPLE 16 preparation of crystalline form III of Apixaban
Adding apixaban (25 g) prepared in preparation example 1 into isopropyl acetate (250 ml), heating for dissolving, then naturally cooling to-10 ℃ for crystallization under stirring, continuing stirring for 2h after crystallization, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 22.6g of apixaban crystal form I white crystals, wherein the yield is 90.4%, and the HPLC purity is 99.3%. The X-ray powder diffraction pattern was determined to be substantially in accordance with figure 5.
Example 17 preparation of crystalline form IV of apixaban
Adding apixaban (5.0 g) prepared in preparation example 1 into ethanol (300 ml), heating for dissolving, then naturally cooling to 0-5 ℃ for crystallization under stirring, continuing stirring for 2h after crystallization, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 3.2g of apixaban crystal form IV white crystal, wherein the yield is 64% and the HLPC purity is 99.5%. The X-ray powder diffraction pattern is shown in figure 6, and the DSC-TGA pattern is shown in figure 7.
Example 18 preparation of crystalline form IV of Apixaban
Adding apixaban (5.0 g) prepared in preparation example 1 into ethanol (200 ml), heating for dissolving, then naturally cooling to-5 ℃ under stirring, crystallizing, then continuing stirring for 3h, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 3.6g of apixaban crystal form IV white crystals, wherein the yield is 72% and the HPLC purity is 99.4%. The X-ray powder diffraction pattern is determined to be basically consistent with that of figure 6, and the DSC-TGA pattern is determined to be basically consistent with that of figure 7.
Example 19 preparation of crystalline form IV of apixaban
Adding apixaban (50 g) prepared in preparation example 1 into ethanol (1500 ml), heating for dissolving, then naturally cooling to 10 ℃ for crystallization under stirring, continuing stirring for 1h after crystallization, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 39.8 apixaban crystal form IV white crystals, wherein the yield is 79.6%, and the purity of HLPC is 99.6%. The X-ray powder diffraction pattern is determined to be basically consistent with that of figure 6, and the DSC-TGA pattern is determined to be basically consistent with that of figure 7.
Example 20 preparation of crystalline form IV of Apixaban
Adding apixaban (25 g) prepared in preparation example 1 into ethanol (500 ml), heating for dissolving, then naturally cooling to 0 ℃ under stirring for crystallization, continuously stirring for 2h after crystallization, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 20.4g of apixaban crystal form IV white crystals, wherein the yield is 80.8%, and the HPLC purity is 99.4%. The X-ray powder diffraction pattern is determined to be basically consistent with that of figure 6, and the DSC-TGA pattern is determined to be basically consistent with that of figure 7.
Example 21 preparation of crystalline form IV of apixaban
Adding apixaban (25 g) prepared in preparation example 1 into ethanol (250 ml), heating for dissolving, then naturally cooling to-10 ℃ for crystallization under stirring, continuing stirring for 2h after crystallization, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 20.4g of apixaban crystal form IV white crystals, wherein the yield is 81.6%, and the HPLC purity is 99.4%. The X-ray powder diffraction pattern is determined to be basically consistent with that of figure 6, and the DSC-TGA pattern is determined to be basically consistent with that of figure 7.
EXAMPLE 22 preparation of crystalline form V of Apixaban
Adding apixaban (5.0 g) prepared in preparation example 1 into 1, 4-dioxane (300 ml), heating to dissolve, then naturally cooling to 0-5 ℃ while stirring for crystallization, continuing stirring for 2h after crystallization, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 3.3g of apixaban crystal form V white crystal, wherein the yield is 66%, and the purity of HLPC is 99.3%. The X-ray powder diffraction pattern is shown in figure 8, and the DSC-TGA pattern is shown in figure 9.
Example 23 preparation of crystalline form V Apixaban
The apixaban (5.0 g) prepared in preparation example 1 is added into 1, 4-dioxane (200 ml), heated and dissolved, then naturally cooled to-5 ℃ under stirring, crystallized, continuously stirred for 3h, filtered, and vacuum-dried at 40 ℃ to obtain 3.45g of apixaban crystal form V white crystals, the yield is 69%, and the HPLC purity is 99.3%. The X-ray powder diffraction pattern is basically consistent with that of figure 8, and the DSC-TGA pattern is basically consistent with that of figure 9.
Example 24 preparation of crystalline form V Apixaban
Adding apixaban (50 g) prepared in preparation example 1 into 1, 4-dioxane (1500 ml), heating to dissolve, then naturally cooling to 10 ℃ while stirring for crystallization, continuing stirring for 1h after crystallization, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 40.6g of apixaban crystal form V white crystal, wherein the yield is 81.2%, and the purity of HLPC is 99.2%. The X-ray powder diffraction pattern is basically consistent with that of figure 8, and the DSC-TGA pattern is basically consistent with that of figure 9.
Example 25 preparation of crystalline form V Apixaban
The apixaban (25 g) prepared in preparation example 1 is added into 1, 4-dioxane (500 ml), heated to dissolve, then naturally cooled to 0 ℃ under stirring for crystallization, and after crystallization, stirring is continued for 2h, and then suction filtration and vacuum drying is carried out at 40 ℃ to obtain 21.8g of apixaban crystal form V white crystals, wherein the yield is 83.6%, and the HPLC purity is 99.2%. The X-ray powder diffraction pattern is basically consistent with that of figure 8, and the DSC-TGA pattern is basically consistent with that of figure 9.
Example 26 preparation of crystalline form V of apixaban
Adding apixaban (25 g) prepared in preparation example 1 into 1, 4-dioxane (250 ml), heating to dissolve, then naturally cooling to-10 ℃ under stirring for crystallization, continuing stirring for 2h after crystallization, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 22.6g of apixaban crystal form V white crystals, wherein the yield is 90.4%, and the HPLC purity is 99.3%. The X-ray powder diffraction pattern is basically consistent with that of figure 8, and the DSC-TGA pattern is basically consistent with that of figure 9.
Example 27 preparation of amorphous Apixaban
Adding the apixaban (5.0 g) prepared in preparation example 1 into dimethyl sulfoxide (300 ml), heating to dissolve, naturally cooling to 0-5 ℃ under stirring, separating out solid, continuing stirring for 2h, performing suction filtration, and performing vacuum drying at 40 ℃ to obtain 3.6g of amorphous apixaban, wherein the yield is 72%, and the purity of HLPC is 99.6%. The X-ray powder diffraction pattern is shown in figure 10.
Example 28 preparation of amorphous Apixaban
The apixaban (5.0 g) prepared in preparation example 1 was added to dimethyl sulfoxide (200 ml), heated to dissolve, then cooled naturally to-5 ℃ with stirring, the solid was precipitated and then stirred for 3h, filtered with suction, and dried under vacuum at 40 ℃ to obtain 3.8g of amorphous apixaban, with a yield of 76% and an HPLC purity of 99.6%. The X-ray powder diffraction pattern was determined to be substantially in accordance with figure 10.
Example 29 preparation of amorphous Apixaban
The apixaban (50 g) prepared in preparation example 1 was added to dimethyl sulfoxide (1500 ml), heated to dissolve, then cooled naturally to 10 ℃ under stirring, the solid precipitated was stirred for 1h, filtered, and dried under vacuum at 40 ℃ to obtain 41.5g amorphous apixaban, yield 83%, HLPC purity 99.5%. The X-ray powder diffraction pattern was determined to be substantially in accordance with figure 10.
Example 30 preparation of amorphous Apixaban
The apixaban (25 g) prepared in preparation example 1 was added to dimethylsulfoxide (500 ml), heated to dissolve, then naturally cooled to 0 ℃ under stirring, and after solid precipitation, stirring was continued for 2h, suction filtration was performed, and vacuum drying was performed at 40 ℃ to obtain 21.4g of amorphous apixaban, the yield was 85.6%, and the HPLC purity was 99.4%. The X-ray powder diffraction pattern was determined to be substantially in accordance with figure 10.
Example 31 preparation of amorphous Apixaban
The apixaban (25 g) prepared in preparation example 1 was added to dimethylsulfoxide (250 ml), heated to dissolve, then naturally cooled to-10 ℃ under stirring, the solid was precipitated and then continuously stirred for 2h, filtered under suction, and vacuum-dried at 40 ℃ to obtain 22.6g of amorphous apixaban, the yield was 90.4%, and the HPLC purity was 99.3%. The X-ray powder diffraction pattern was determined to be substantially in accordance with figure 10.

Claims (12)

1. Apixaban in crystal form, wherein the crystal form of Apixaban is one or more of crystal form I, crystal form II, crystal form III, crystal form IV and crystal form V of Apixaban, or a mixed crystal thereof,
the Apixaban crystal form I uses Cu-Kalpha radiation, and has characteristic peaks at 12.9 +/-0.2 degrees, 13.9 +/-0.2 degrees, 17.0 +/-0.2 degrees, 18.5 +/-0.2 degrees and 22.1 +/-0.2 degrees of X-ray powder diffraction represented by 2 theta angles;
the crystalline form II of apixaban uses Cu-Kalpha radiation, and has characteristic peaks at 5.8 +/-0.2 degrees, 7.4 +/-0.2 degrees, 15.9 +/-0.2 degrees, 18.0 +/-0.2 degrees and 23.6 +/-0.2 degrees of X-ray powder diffraction represented by 2 theta angles;
the Apixaban crystal form III uses Cu-Kalpha radiation, and has characteristic diffraction peaks when the X-ray powder diffraction represented by the angle of 2 theta is 12.8 +/-0.2 degrees, 13.9 +/-0.2 degrees, 16.9 +/-0.2 degrees, 18.4 +/-0.2 degrees and 22.1 +/-0.2 degrees;
the Apixaban crystal form IV uses Cu-Kalpha radiation, and has characteristic diffraction peaks at 6.0 +/-0.2 degrees, 7.1 +/-0.2 degrees, 13.6 +/-0.2 degrees, 16.1 +/-0.2 degrees, 17.6 +/-0.2 degrees, 21.7 +/-0.2 degrees and 22.8 +/-0.2 degrees of X-ray powder diffraction represented by a 2 theta angle;
the Apixaban crystal form V uses Cu-Kalpha radiation, and has characteristic diffraction peaks at 5.8 +/-0.2 degrees and 11.5 +/-0.2 degrees of X-ray powder diffraction represented by 2 theta angles.
2. Apixaban in crystalline form according to claim 1, characterized in that,
the Apixaban crystal form I uses Cu-Kalpha radiation, and has characteristic peaks at 8.5 +/-0.2 degrees, 12.3 +/-0.2 degrees, 12.9 +/-0.2 degrees, 13.9 +/-0.2 degrees, 16.3 +/-0.2 degrees, 17.0 +/-0.2 degrees, 18.5 +/-0.2 degrees, 18.9 +/-0.2 degrees, 19.6 +/-0.2 degrees, 21.1 +/-0.2 degrees, 21.5 +/-0.2 degrees, 22.1 +/-0.2 degrees and 22.3 +/-0.2 degrees by X-ray powder diffraction represented by a 2 theta angle;
the Apixaban crystal form II uses Cu-Kalpha radiation, and the X-ray powder diffraction represented by the angle of 2 theta is at 5.8 +/-0.2 degrees, 7.4 +/-0.2 degrees, 13.5 +/-0.2 degrees, 15.9 +/-0.2 degrees, 16.2 +/-0.2 degrees, 16.8 +/-0.2 degrees, 18.0 +/-0.2 degrees, 20.1 +/-0.2 degrees, 20.8 +/-0.2 degrees, 23.6 +/-0.2 degrees, 25.2 +/-0.2 degrees and has characteristic peaks;
the Apixaban crystal form III uses Cu-Kalpha radiation, and has characteristic diffraction peaks at the positions of 5.4 +/-0.2 degrees, 8.4 +/-0.2 degrees, 10.9 +/-0.2 degrees, 12.2 +/-0.2 degrees, 12.8 +/-0.2 degrees, 13.9 +/-0.2 degrees, 16.2 +/-0.2 degrees, 16.9 +/-0.2 degrees, 18.4 +/-0.2 degrees, 18.7 +/-0.2 degrees, 19.5 +/-0.2 degrees, 21.1 +/-0.2 degrees, 21.5 +/-0.2 degrees, 22.2 +/-0.2 degrees, 22.1 +/-0.2 degrees, 24.6 +/-0.2 degrees, 26.9 +/-0.2 degrees and 27.6 +/-0.2 degrees, which are expressed by the angle of 2 theta;
the Apixaban crystal form IV uses Cu-Kalpha radiation, and the X-ray powder diffraction represented by the angle of 2 theta is 6.0 +/-0.2 degrees, 7.1 +/-0.2 degrees, 12.8 +/-0.2 degrees, 13.6 +/-0.2 degrees, 16.1 +/-0.2 degrees, 16.4 +/-0.2 degrees, 17.6 +/-0.2 degrees, 19.1 +/-0.2 degrees, 21.7 +/-0.2 degrees, 22.8 +/-0.2 degrees, 24.4 +/-0.2 degrees, 24.6 +/-0.2 degrees and has a characteristic diffraction peak;
the Apixaban crystal form V uses Cu-Kalpha radiation, and has characteristic diffraction peaks at 5.8 +/-0.2 degrees, 11.5 +/-0.2 degrees, 13.3 +/-0.2 degrees, 15.8 +/-0.2 degrees, 17.3 +/-0.2 degrees, 18.6 +/-0.2 degrees, 21.3 +/-0.2 degrees, 23.2 +/-0.2 degrees, 29.9 +/-0.2 degrees and 32.8 +/-0.2 degrees in X-ray powder diffraction represented by a 2 theta angle.
3. Apixaban in crystalline form according to claim 1, characterized in that,
the Apixaban crystal form I uses Cu-Kalpha radiation, and has characteristic peaks at positions of 8.5 +/-0.2 degrees, 10.0 +/-0.2 degrees, 10.5 +/-0.2 degrees, 11.2 +/-0.2 degrees, 12.3 +/-0.2 degrees, 16.3 +/-0.2 degrees, 17.0 +/-0.2 degrees, 18.5 +/-0.2 degrees, 18.9 +/-0.2 degrees, 19.6 +/-0.2 degrees, 21.1 +/-0.2 degrees, 21.5 +/-0.2 degrees, 22.0 +/-0.2 degrees, 22.3 +/-0.2 degrees, 24.8 +/-0.2 degrees, 27.0 +/-0.2 degrees, 29.9 +/-0.2 degrees and 32.7 +/-0.2 degrees by X-ray powder diffraction represented by a 2 theta angle;
the Apixaban crystal form II uses Cu-Kalpha radiation, and has characteristic peaks at 2 theta angles of 5.8 +/-0.2 degrees, 7.4 +/-0.2 degrees, 11.7 +/-0.2 degrees, 13.5 +/-0.2 degrees, 15.9 +/-0.2 degrees, 16.2 +/-0.2 degrees, 16.8 +/-0.2 degrees, 18.0 +/-0.2 degrees, 18.8 +/-0.2 degrees, 20.1 +/-0.2 degrees, 20.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 21.3 +/-0.2 degrees, 22.3 +/-0.2 degrees, 23.6 +/-0.2 degrees, 25.2 +/-0.2 degrees and 25.9 +/-0.2 degrees;
the Apixaban crystal form III uses Cu-Kalpha radiation, and has characteristic diffraction peaks at positions of 5.4 +/-0.2 degrees, 8.4 +/-0.2 degrees, 10.9 +/-0.2 degrees, 12.2 +/-0.2 degrees, 12.8 +/-0.2 degrees, 13.9 +/-0.2 degrees, 16.2 +/-0.2 degrees, 16.9 +/-0.2 degrees, 18.4 +/-0.2 degrees, 18.7 +/-0.2 degrees, 19.5 +/-0.2 degrees, 21.1 +/-0.2 degrees, 21.5 +/-0.2 degrees, 22.2 +/-0.2 degrees, 22.1 +/-0.2 degrees, 24.6 +/-0.2 degrees, 26.9 +/-0.2 degrees, 27.6 +/-0.2 degrees, 28.6 +/-0.2 degrees, 29.1 +/-0.2 degrees, 29.7 +/-0.2 degrees and 32.7 +/-0.2 degrees, wherein the X-ray powder diffraction peaks are expressed by a 2 theta angle;
the Apixaban crystal form IV uses Cu-Kalpha radiation, and has characteristic diffraction peaks at the positions of 6.0 +/-0.2 degrees, 7.1 +/-0.2 degrees, 11.0 +/-0.2 degrees, 12.8 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.1 +/-0.2 degrees, 15.7 +/-0.2 degrees, 16.1 +/-0.2 degrees, 16.4 +/-0.2 degrees, 17.6 +/-0.2 degrees, 18.0 +/-0.2 degrees, 19.1 +/-0.2 degrees, 20.6 +/-0.2 degrees, 21.7 +/-0.2 degrees, 22.8 +/-0.2 degrees, 24.4 +/-0.2 degrees, 24.6 +/-0.2 degrees, 26.1 +/-0.2 degrees, 28.9 +/-0.2 degrees, 30.1 +/-0.2 degrees and 31.0 +/-0.2 degrees, which are expressed by the angle of 2 theta;
the Apixaban crystal form V uses Cu-Kalpha radiation, and has characteristic diffraction peaks at 5.8 +/-0.2 degrees, 11.5 +/-0.2 degrees, 13.3 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.3 +/-0.2 degrees, 18.6 +/-0.2 degrees, 21.3 +/-0.2 degrees, 23.2 +/-0.2 degrees, 29.9 +/-0.2 degrees and 32.8 +/-0.2 degrees in X-ray powder diffraction represented by a 2 theta angle.
4. Apixaban in crystalline form according to claim 1, characterized in that,
the Apixaban crystal form I has an X-ray powder diffraction pattern shown in figure 1;
the Apixaban crystal form II has an X-ray powder diffraction pattern as shown in figure 3;
the crystalline form III of apixaban has an X-ray powder diffraction pattern as shown in figure 5;
the crystalline form IV of apixaban has an X-ray powder diffraction pattern as shown in figure 6;
the Apixaban crystal form V has an X-ray powder diffraction pattern as shown in figure 8.
5. Apixaban in crystalline form according to any one of claims 1-4, characterized in that,
the Apixaban crystal form I has an endothermic peak at 230.27-252.87 ℃ through differential scanning calorimetry analysis and detection;
the Apixaban crystal form II has endothermic peaks at 33.4-92.3 ℃ and 220.1-248.6 ℃ in differential scanning calorimetry, and adjacent absorption peaks and exothermic peaks appear at 144.3-218.8 ℃, preferably endothermic peaks and exothermic peaks appear at 144.3-181.5 ℃ and 181.5-218.8 ℃ respectively;
the Apixaban crystal form IV has endothermic peaks at 53.6-91.1 ℃ and 222.9-252.8 ℃ in differential scanning calorimetry, and adjacent absorption peaks and exothermic peaks appear at 141.4-201.2 ℃, preferably endothermic peaks and exothermic peaks appear at 141.4-171.4 ℃ and 171.4-201.2 ℃ respectively;
the Apixaban crystal form V has endothermic peaks at 53.5-81.9 ℃ and 218.7-248.6 ℃ in differential scanning calorimetry detection, and adjacent absorption peaks and exothermic peaks appear at 153.2-193.4 ℃, preferably the endothermic peaks and the exothermic peaks appear at 153.2-172.1 ℃ and 172.1-193.4 ℃ respectively.
6. Apixaban in crystalline form according to claim 5, characterized in that,
the apixaban crystal form I has an endothermic peak at 239.88 +/-2 ℃ through differential scanning calorimetry analysis and detection;
the Apixaban crystal form II has endothermic peaks at 70 + -2 deg.C and 234.1 + -2 deg.C by differential scanning calorimetry, and has absorption peaks and exothermic peaks at 171.9 + -2 deg.C and 193.1 + -2 deg.C
The Apixaban crystal form IV has endothermic peaks at 81.7 +/-2 ℃ and 239.3 ℃ in differential scanning calorimetry analysis and detection; and an endothermic peak and an exothermic peak appear at 163.8 + -2 ℃ and 186.0 + -2 ℃ respectively;
the apixaban crystal form V has endothermic peaks at 69.6 +/-2 ℃ and 234.8 ℃ in differential scanning calorimetry analysis and detection; and adjacent exothermic peaks and endothermic peaks appear at 168.6 + -2 deg.C and 175.8 + -2 deg.C, respectively.
7. Apixaban in crystalline form according to claim 5, characterized in that,
the apixaban crystal form I has a differential scanning calorimetry analysis pattern as shown in figure 2;
the Apixaban crystal form II has a differential scanning calorimetry analysis map as shown in figure 4;
the apixaban crystal form IV has a differential scanning calorimetry analysis map as shown in figure 7;
the apixaban crystal form V has a differential scanning calorimetry analysis pattern as shown in figure 9.
8. An amorphous form of apixaban, characterized in that it has smooth diffraction peaks at 8 ± 0.2 ° and 18 ± 0.2 ° in X-ray powder diffraction using Cu-ka radiation expressed in 2 Θ angles; preferably, the amorphous form of apixaban has an X-ray powder diffraction pattern as shown in figure 10.
9. A process for the preparation of apixaban in the form of any one of claims 1-8, characterized in that it comprises the following steps:
(1) adding apixaban into an organic solvent, and heating for dissolving to obtain an organic solvent solution of apixaban;
(2) naturally cooling the apixaban organic solvent solution obtained in the step (1) to a solid precipitation temperature, and stirring to precipitate a solid;
(3) filtering and vacuum drying to obtain the product.
Wherein the mass-to-volume ratio (g/ml) of apixaban to organic solvent is 1: 10-60, preferably 1: 15-40, more preferably 1: 20-30;
the temperature of the precipitated solid is-10-15 ℃, preferably-10 ℃, more preferably-5 ℃, and most preferably 0 ℃;
the stirring time for separating out the solid is that the solid is continuously stirred for 1-3 h, preferably 1-2 h after separating out the solid; and:
when the organic solvent is methanol, the Apixaban crystal form I is obtained;
when the organic solvent is ethyl acetate, obtaining apixaban crystal form II;
when the organic solvent is isopropyl acetate, obtaining apixaban crystal form III;
when the organic solvent is ethanol, apixaban crystal form IV is obtained;
when the organic solvent is 1, 4-dioxane, the Apixaban crystal form V is obtained;
when the organic solvent is dimethylsulfoxide, amorphous apixaban is obtained.
10. An apixaban pharmaceutical composition comprising the apixaban of any one of claims 1-8 and any one pharmaceutically acceptable excipient.
11. Use of apixaban according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment or prevention of a thromboembolic disorder.
12. Use of the pharmaceutical composition of claim 10 for the manufacture of a medicament for the treatment or prevention of a thromboembolic disorder.
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1578660A (en) * 2001-09-21 2005-02-09 百时美施贵宝公司 Lactam-containing compounds and derivatives thereof as factor xa inhibitors
CN1639147A (en) * 2001-12-10 2005-07-13 布里斯托尔-迈尔斯斯奎布公司 Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
WO2006078331A2 (en) * 2005-01-19 2006-07-27 Bristol-Myers Squibb Company Crystallization via high-shear transformation
CN101065379A (en) * 2004-09-28 2007-10-31 布里斯托尔-迈尔斯斯奎布公司 Process for preparing 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
CN101967145A (en) * 2010-09-09 2011-02-09 华东理工大学 Method for preparing antithrombotic medicament apixaban
CN102675314A (en) * 2012-06-14 2012-09-19 南京正科制药有限公司 Method for synthesizing apixaban
WO2012168364A1 (en) * 2011-06-10 2012-12-13 Dipharma Francis S.R.L. Apixaban preparation process

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1578660A (en) * 2001-09-21 2005-02-09 百时美施贵宝公司 Lactam-containing compounds and derivatives thereof as factor xa inhibitors
CN1639147A (en) * 2001-12-10 2005-07-13 布里斯托尔-迈尔斯斯奎布公司 Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
CN101065379A (en) * 2004-09-28 2007-10-31 布里斯托尔-迈尔斯斯奎布公司 Process for preparing 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
WO2006078331A2 (en) * 2005-01-19 2006-07-27 Bristol-Myers Squibb Company Crystallization via high-shear transformation
CN101967145A (en) * 2010-09-09 2011-02-09 华东理工大学 Method for preparing antithrombotic medicament apixaban
WO2012168364A1 (en) * 2011-06-10 2012-12-13 Dipharma Francis S.R.L. Apixaban preparation process
CN102675314A (en) * 2012-06-14 2012-09-19 南京正科制药有限公司 Method for synthesizing apixaban

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ANTONIO RAMIREZ等: "A Mechanistic Study on the Amidation of Esters Mediated by Sodium Formamide", 《J. ORG. CHEM.》, vol. 77, 16 November 2011 (2011-11-16), pages 775 - 779, XP055180461, DOI: 10.1021/jo2021828 *
DONALD J. P. PINTO等: "Discovery of 1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Apixaban, BMS-562247), a Highly Potent, Selective, Efficacious, and Orally Bioavailable Inhibitor of Blood Coagulation...", 《J. MED. CHEM.》, vol. 50, no. 22, 3 October 2007 (2007-10-03), pages 5339 - 5356, XP007915445, DOI: 10.1021/jm070245n *
JIAN’AN JIANG等: "ALTERNATE SYNTHESIS OF APIXABAN (BMS-562247), AN INHIBITOR OF BLOOD COAGULATION FACTOR XA", 《SYNTHETIC COMMUNICATIONS》, vol. 43, no. 1, 5 September 2002 (2002-09-05), pages 72 - 79, XP055200031, DOI: 10.1080/00397911.2011.591956 *

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* Cited by examiner, † Cited by third party
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CN105503859A (en) * 2014-10-10 2016-04-20 江苏豪森药业集团有限公司 Apixaban purification method
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CN105985336A (en) * 2015-02-13 2016-10-05 浙江京新药业股份有限公司 Preparation method for crystal form of apixaban N-1
CN106008497A (en) * 2015-03-24 2016-10-12 徐州万邦金桥制药有限公司 Apixaban crystal form and preparation method thereof
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CN105037349A (en) * 2015-05-04 2015-11-11 西安泰科迈医药科技有限公司 Apixaban in [gamma]-crystal form and preparation method thereof
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CN106279149A (en) * 2015-06-02 2017-01-04 天津药物研究院有限公司 A kind of method preparing high-purity Eliquis
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CN106496221A (en) * 2016-08-31 2017-03-15 成都倍特药业有限公司 A kind of method for preparing 1 crystal formations of Eliquis N
CN110862389A (en) * 2018-08-28 2020-03-06 江苏康缘药业股份有限公司 Preparation method of Apixaban crystal form
WO2023072967A1 (en) 2021-10-27 2023-05-04 Pharma-Data S.A. Apixaban suspension and preparation method
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