CN116583278A - Crystal form of pyrazolo [3,4-c ] pyridine compound, and preparation method and application thereof - Google Patents

Crystal form of pyrazolo [3,4-c ] pyridine compound, and preparation method and application thereof Download PDF

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Publication number
CN116583278A
CN116583278A CN202180053711.3A CN202180053711A CN116583278A CN 116583278 A CN116583278 A CN 116583278A CN 202180053711 A CN202180053711 A CN 202180053711A CN 116583278 A CN116583278 A CN 116583278A
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solvent
preparation
powder
ray diffraction
temperature
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Inventor
李志怀
杨欣欣
曹泽峰
郝红茹
唐琳
道硕
赵亮亮
张颜
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CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
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CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • C07D471/04—Ortho-condensed systems

Abstract

The invention provides a crystal form A of a compound (I), a preparation method and application thereof, and the obtained crystal form A has the characteristics of high purity, no organic solvent residue, good stability in the processes of machining, heating and influence factor experiments, and the preparation process is simple to operate and suitable for industrial use.

Description

Crystal form of pyrazolo [3,4-c ] pyridine compound, and preparation method and application thereof Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a crystal form of pyrazolo [3,4-c ] pyridine compound, and a preparation method and application thereof.
Background
Thrombotic diseases are caused by thrombosis and embolism. Under certain pathological conditions, blood components form thrombi within blood vessels. Thrombus falls off from the formed part, and the thrombus can partially or completely block veins or blood supply arteries in the blood flow process, so that a series of pathological processes such as ischemia, hypoxia and necrosis of blood vessels or systems are caused. Common thrombotic disorders include myocardial infarction, cerebral thrombosis, deep vein thrombosis, pulmonary embolism and peripheral arterial thromboembolism, which seriously jeopardize the life and quality of life of people. Coronary heart disease is an important group of thrombotic diseases, including myocardial infarction and angina pectoris. In China, the death rate of coronary heart disease is the fourth, and the death rate of cerebrovascular disease is the second.
The blood coagulation factor X is a better target point for antithrombotic treatment, wherein the Xa factor is the most important drug target point in a blood coagulation waterfall. Factor Xa inhibitors bind tightly to the active site of factor Xa, resulting in inactivation of free and fibrin-bound factor Xa to act as anticoagulants. Compared with low molecular heparin, the Xa factor inhibitor can obviously reduce the occurrence of venous thrombosis without increasing the bleeding rate, and compared with warfarin, the medicine has the advantages of convenience in dosage adjustment and conventional monitoring, almost no interaction with food and medicine, and simultaneous administration.
Although factor Xa inhibitors have a lower bleeding tendency than traditional anticoagulants, the major clinical adverse effect is bleeding, thus reducing the risk of bleeding and improving the therapeutic window is a research hotspot in this field.
Compound I is a factor Xa inhibitor, chemically named 1- (4-ethoxyphenyl) -7-oxo-6- [ 3-methyl-4- (2-oxopiperidin-1-yl) phenyl ] -4,5,6, 7-tetrahydro-1H-pyrazole [3,4-c ] pyridine-3-carboxamide, which has good antithrombotic effect and lower bleeding risk.
In chinese patent CN105384739a, a compound of formula I and its analogues, a preparation method and use are disclosed, and since the crystal forms of the drug are directly related to the quality and therapeutic effect of the drug, different crystal forms affect the stability, bioavailability and safety of the drug in the production, processing and storage processes to different extents, so that the discovery of a crystal form with good properties is critical for the development of subsequent drugs.
Disclosure of Invention
Through researches, the purity of a compound I sample prepared according to the method in Chinese patent CN105384739A cannot reach the medicinal standard, the residual quantity of an organic solvent exceeds the limit requirement, the compound I sample cannot be removed through washing and drying, the crystal form of the compound I sample is converted in the grinding and crushing process, and in addition, the total impurity content of the compound I sample is increased under the high-temperature and illumination conditions, so that the processing and safety requirements of a pharmaceutical preparation cannot be met.
In order to solve the problems in the prior art, the inventor carries out a great deal of experimental study on the crystal form of the compound I, and finally obtains the compound I crystal form A with high purity, no organic solvent residue and good stability, which is suitable for being stored and used as a raw material medicine and overcomes the defects in the prior art.
The invention provides a crystal form A of a compound I, which is characterized in that a powder X-ray diffraction pattern expressed in terms of a 2 theta angle (DEG) has characteristic diffraction peaks at the following positions by using Cu-K alpha radiation: 5.0 + -0.2 deg., 7.4 + -0.2 deg., 8.7 + -0.2 deg., 10.3 + -0.2 deg., 17.5 + -0.2 deg..
In some aspects of the invention, the characteristic peaks (±0.2°) have a relative intensity of:
2θ(°) relative intensity (%)
5.0 25～65
7.4 40～90
8.7 50～100
10.3 15～60
17.5 60～100
。
Note that: the relative intensities are in terms of peak area, as follows.
Preferably, the relative intensities of the characteristic peaks (±0.2°) are:
2θ(°) relative intensity (%)
5.0 25～65
7.4 40～85
8.7 50～100
10.3 15～50
17.5 60～100
。
In some aspects of the invention, the crystalline form a is characterized by a powder X-ray diffraction pattern in terms of 2Θ angles (°) using Cu-ka radiation, having characteristic diffraction peaks at: 5.0.+ -. 0.2 °, 7.4.+ -. 0.2 °, 8.7.+ -. 0.2 °, 10.3.+ -. 0.2 °, 11.3.+ -. 0.2 °, 12.8.+ -. 0.2 °, 17.5.+ -. 0.2 °.
Preferably, the relative intensities of the characteristic peaks (±0.2°) are:
2θ(°) relative intensity (%) 2θ(°) Relative intensity (%)
5.0 25～65 11.3 30～90
7.4 40-90 12.8 15～50
8.7 50～100 17.5 60～100
10.3 15～60
。
Preferably, the relative intensities of the characteristic peaks (±0.2°) are:
2θ(°) relative intensity (%) 2θ(°) Relative intensity (%)
5.0 25～65 11.3 30～90
7.4 40～85 12.8 15～45
8.7 50～100 17.5 60～100
10.3 15～50
。
In some aspects of the invention, the crystalline form a is characterized by a powder X-ray diffraction pattern in terms of 2Θ angles (°) using Cu-ka radiation, having characteristic diffraction peaks at: 5.0.+ -. 0.2 °, 7.4.+ -. 0.2 °, 8.7.+ -. 0.2 °, 10.3.+ -. 0.2 °, 11.3.+ -. 0.2 °, 12.8.+ -. 0.2 °, 17.5.+ -. 0.2 °, 22.3.+ -. 0.2 °.
Preferably, the relative intensities of the characteristic peaks (±0.2°) are:
2θ(°) relative intensity (%) 2θ(°) Relative intensity (%)
5.0 25～65 11.3 30～90
7.4 40～90 12.8 15～50
8.7 50～100 17.5 60～100
10.3 15～60 22.3 60～100
。
Preferably, the relative intensities of the characteristic peaks (±0.2°) are:
2θ(°) relative intensity (%) 2θ(°) Relative intensity (%)
5.0 25～65 11.3 30～90
7.4 40～85 12.8 15～45
8.7 50～100 17.5 60～100
10.3 15～50 22.3 60～100
。
In some aspects of the invention, the crystalline form a is characterized by a powder X-ray diffraction pattern in terms of 2Θ angles (°) using Cu-ka radiation, having characteristic diffraction peaks at: 5.0.+ -. 0.2 °, 7.4.+ -. 0.2 °, 8.7.+ -. 0.2 °, 10.3.+ -. 0.2 °, 11.3.+ -. 0.2 °, 12.8.+ -. 0.2 °, 15.7.+ -. 0.2 °, 17.5.+ -. 0.2 °, 22.3.+ -. 0.2 °.
Preferably, the relative intensities of the characteristic peaks (±0.2°) are:
2θ(°) relative intensity (%) 2θ(°) Relative intensity (%)
5.0 25～65 12.8 15～50
7.4 40～90 15.7 30～70
8.7 50～100 17.5 60～100
10.3 15～60 22.3 60～100
11.3 30～90
。
Preferably, the relative intensities of the characteristic peaks (±0.2°) are:
2θ(°) relative intensity (%) 2θ(°) Relative intensity (%)
5.0 25～65 12.8 15～45
7.4 40～85 15.7 30～70
8.7 50～100 17.5 60～100
10.3 15～50 22.3 60～100
11.3 30～90
。
In some aspects of the invention, the crystalline form a is characterized by a powder X-ray diffraction pattern in terms of 2Θ angles (°) using Cu-ka radiation, having characteristic diffraction peaks at: 5.0.+ -. 0.2 °, 7.4.+ -. 0.2 °, 8.7.+ -. 0.2 °, 10.3.+ -. 0.2 °, 11.3.+ -. 0.2 °, 12.8.+ -. 0.2 °, 15.7.+ -. 0.2 °, 17.5.+ -. 0.2 °, 20.6.+ -. 0.2 °, 22.3.+ -. 0.2 °.
Preferably, the relative intensities of the characteristic peaks (±0.2°) are:
2θ(°) relative intensity (%) 2θ(°) Relative intensity (%)
5.0 25～65 12.8 15～50
7.4 40～90 15.7 30～70
8.7 50～100 17.5 60～100
10.3 15～60 20.6 35～80
11.3 30～90 22.3 60～100
。
Preferably, the relative intensities of the characteristic peaks (±0.2°) are:
2θ(°) relative intensity (%) 2θ(°) Relative intensity (%)
5.0 25～65 12.8 15～45
7.4 40～85 15.7 30～70
8.7 50～100 17.5 60～100
10.3 15～50 20.6 35～70
11.3 30～90 22.3 60～100
。
In some aspects of the invention, the crystalline form a is characterized by a powder X-ray diffraction pattern in terms of 2Θ angles (°) using Cu-ka radiation, having characteristic diffraction peaks at: 5.0.+ -. 0.2 °, 7.4.+ -. 0.2 °, 8.7.+ -. 0.2 °, 10.3.+ -. 0.2 °, 11.3.+ -. 0.2 °, 12.8.+ -. 0.2 °, 14.7.+ -. 0.2 °, 15.7.+ -. 0.2 °, 17.5.+ -. 0.2 °, 22.3.+ -. 0.2 °.
Preferably, the relative intensities of the characteristic peaks (±0.2°) are:
2θ(°) relative intensity (%) 2θ(°) Relative intensity (%)
5.0 25～65 12.8 15～50
7.4 40～90 14.7 30～90
8.7 50～100 15.7 30～70
10.3 15～60 17.5 60～100
11.3 30～90 22.3 60～100
。
Preferably, the relative intensities of the characteristic peaks (±0.2°) are:
2θ(°) relative intensity (%) 2θ(°) Relative intensity (%)
5.0 25～65 12.8 15～45
7.4 40～85 14.7 30～85
8.7 50～100 15.7 30～70
10.3 15～50 17.5 60～100
11.3 30～90 22.3 60～100
。
In some aspects of the invention, the crystalline form a is characterized by a powder X-ray diffraction pattern in terms of 2Θ angles (°) using Cu-ka radiation, having characteristic diffraction peaks at: 5.0.+ -. 0.2 °, 7.4.+ -. 0.2 °, 8.7.+ -. 0.2 °, 10.3.+ -. 0.2 °, 11.3.+ -. 0.2 °, 12.8.+ -. 0.2 °, 14.7.+ -. 0.2 °, 15.7.+ -. 0.2 °, 17.5.+ -. 0.2 °, 20.6.+ -. 0.2 °, 22.3.+ -. 0.2 °, 25.3.+ -. 0.2 °.
Preferably, the relative intensities of the characteristic peaks (±0.2°) are:
2θ(°) relative intensity (%) 2θ(°) Relative intensity (%)
5.0 25～65 14.7 30～90
7.4 40～90 15.7 30～70
8.7 50～100 17.5 60～100
10.3 15～60 20.6 35～80
11.3 30～90 22.3 60～100
12.8 15～50 25.3 30～75
。
Preferably, the relative intensities of the characteristic peaks (±0.2°) are:
2θ(°) relative intensity (%) 2θ(°) Relative intensity (%)
5.0 25～65 14.7 30～85
7.4 40～85 15.7 30～70
8.7 50～100 17.5 60～100
10.3 15～50 20.6 35～70
11.3 30～90 22.3 60～100
12.8 15～45 25.3 40～75
。
In some aspects of the invention, the crystalline form a is characterized by a powder X-ray diffraction pattern in terms of 2Θ angles (°) using Cu-ka radiation, having characteristic diffraction peaks at: 5.0.+ -. 0.2 °, 7.4.+ -. 0.2 °, 8.7.+ -. 0.2 °, 10.3.+ -. 0.2 °, 11.3.+ -. 0.2 °, 12.8.+ -. 0.2 °, 14.1.+ -. 0.2 °, 14.7.+ -. 0.2 °, 15.7.+ -. 0.2 °, 17.5.+ -. 0.2 °, 20.6.+ -. 0.2 °, 22.3.+ -. 0.2 °, 25.3.+ -. 0.2 °, 28.4.+ -. 0.2 °.
Preferably, the relative intensities of the characteristic peaks (±0.2°) are:
2θ(°) relative intensity (%) 2θ(°) Relative intensity (%)
5.0 25～65 14.7 30～90
7.4 40～90 15.7 30～70
8.7 50～100 17.5 60～100
10.3 15～60 20.6 35～80
11.3 30～90 22.3 60～100
12.8 15～50 25.3 30～75
14.1 15～50 28.4 10～40
。
Preferably, the relative intensities of the characteristic peaks (±0.2°) are:
2θ(°) relative intensity (%) 2θ(°) Relative intensity (%)
5.0 25～65 14.7 30～85
7.4 40～85 15.7 30～70
8.7 50～100 17.5 60～100
10.3 15～50 20.6 35～70
11.3 30～90 22.3 60～100
12.8 15～45 25.3 40～75
14.1 15～50 28.4 10～35
。
In some embodiments of the invention, form a, using Cu-ka radiation, has a powder X-ray diffraction pattern substantially as shown in fig. 2 or 8.
In some aspects of the invention, the XRPD pattern analysis data for form a is shown in the following table:
numbering device 2 theta angle (°) Relative intensity (%) Numbering device 2 theta angle (°) Relative intensity (%)
1 5.02 32.3 22 20.02 21.4
2 7.36 79.3 23 20.24 31.7
3 8.72 100.0 24 20.60 45.1
4 9.26 7.3 25 21.04 4.7
5 10.26 45.0 26 21.82 77.3
6 10.98 36.8 27 22.32 77.2
7 11.28 84.0 28 23.20 13.8
8 12.10 4.5 29 23.52 38.0
9 12.80 37.0 30 24.26 17.2
10 14.08 30.2 31 25.26 54.1
11 14.54 57.2 32 25.68 42.5
12 14.72 81.0 33 26.34 1.9
13 15.32 20.3 34 26.64 8.2
14 15.74 60.0 35 27.02 22.4
15 16.03 1.5 36 27.94 13.9
16 16.92 14.1 37 28.38 26.5
17 17.49 95.7 38 29.20 14.3
18 18.04 11.7 39 29.80 7.0
19 18.84 27.2 40 30.45 2.2
20 19.32 31.0 41 35.50 14.1
21 19.68 1.2
In some embodiments of the invention, the form a has a differential scanning calorimetry trace with a onset of an endothermic peak at 242.10 ±3 ℃.
In some embodiments of the invention, the form a has a differential scanning calorimetry curve with an endothermic peak at 244.28 ±5 ℃.
In some aspects of the invention, the form a has a DSC profile substantially as shown in figure 3.
In another aspect, the present invention also provides a method for preparing the above crystal form a, which includes: and adding the crude product of the compound I into the solvent 1, heating to dissolve completely, cooling to a target temperature, adding the solvent 2, continuing crystallization, and separating to obtain the crystal form A.
In some aspects of the invention, the method comprises: and adding the compound I into the solvent 1, heating to dissolve completely, cooling to a target temperature, continuing crystallization, and separating to obtain a crystal form A.
In some embodiments of the present invention, the above method of preparation, wherein the solvent 1 is selected from ROH, RCN, RCOR 1 、RCOOR 1 A DMSO, DMF, methylene chloride or heterocyclic organic solvent (such as furan, tetrahydrofuran, pyridine, 1, 4-dioxane, etc.), wherein solvent 2 is selected from water, n-hexane, n-heptane, petroleum ether, cyclohexane or methyl tert-butyl ether, R, R 1 Selected from C 1 -C 4 Linear or branched alkyl; preferably, solvent 1 is ROH and solvent 2 is water, wherein R is selected from C 1 -C 4 Linear or branched alkyl; further preferably, solvent 1 is methanol.
Preferably, the preparation method comprises the steps that the solvent 1 is ROH or DMF, and the solvent 2 is selected from water; further preferably, the solvent 1 is methanol, ethanol or DMF; further preferably, the solvent 1 is methanol.
In some embodiments of the present invention, the volume ratio of the solvent 1 to the solvent 2 is 1-10:1-100, preferably 1-10:1-50, more preferably 1-10:1-20, still more preferably 1-5:1-10, and still more preferably 1-5:1-5.
In some schemes of the invention, the preparation method comprises the steps that the mass volume ratio of the crude product of the compound I to the solvent 1 is 1 g:10-50 mL; preferably 1 g:10-30 mL; more preferably 1 g/15 to 25mL.
In some embodiments of the present invention, the above preparation method, wherein the mass-to-volume ratio of the compound I to the solvent 1 is 1 g:1-50 mL; preferably 1 g:2-30 mL; further preferably 1 g/3 to 25mL; more preferably 1 g/3 to 20mL.
In some embodiments of the present invention, the above preparation method, wherein the heating temperature is 30 ℃ to reflux temperature; or the heating temperature is 30-120 ℃; alternatively, the heating temperature is 30 to 100 ℃.
In some schemes of the invention, the preparation method is characterized in that the continuous crystallization time is 0.5-5 h; preferably 1 to 3 hours; more preferably 1 to 2 hours.
In some embodiments of the present invention, the above preparation method, wherein the temperature of the cooling target is-30 ℃ to 30 ℃; preferably, the target temperature is 0 ℃ to 25 ℃; further preferably, the target temperature is 0 ℃ to 15 ℃; further preferably, the target temperature is 5 ℃ to 15 ℃.
In some embodiments of the present invention, the above-mentioned preparation method, wherein the separation step comprises separating the obtained form a from the crystallization liquid by a suitable method such as filtration and centrifugation.
In some embodiments of the invention, the above-described preparation method, in view of removing the free solvent from the product, further comprises, after the separation step, a drying step, which may be any suitable known method, preferably reduced pressure (vacuum) drying. Specific drying conditions are, for example, a temperature of preferably 30 to 70 ℃, more preferably 40 to 65 ℃, still more preferably 55 to 65 ℃; the drying time is preferably 4 to 20 hours, more preferably 8 to 16 hours. Regardless of the drying means, the residual solvent content in the obtained product is suitable for meeting the quality standard.
The crude compound I or compound I described in the present invention is prepared using known methods disclosed in CN105384739a, but may also be prepared using any other known methods disclosed in the prior art.
In another aspect, the invention also provides a pharmaceutical composition comprising form a as described above or prepared according to the preparation method described above, optionally, the pharmaceutical composition further comprising other therapeutic components. The other therapeutic component refers to other active ingredients or drugs that prevent and/or treat diseases that inhibit factor Xa positive effects. Preferably, the additional therapeutic component is capable of producing a synergistic effect with compound I.
In another aspect, the present invention also provides a pharmaceutical composition comprising the above-described form a or form a prepared according to the above-described preparation method and a pharmaceutically acceptable carrier, optionally, the pharmaceutical composition further comprising other therapeutic components. The other therapeutic component refers to other active ingredients or drugs that prevent and/or treat diseases that inhibit factor Xa positive effects. Preferably, the additional therapeutic component is capable of producing a synergistic effect with compound I.
The above pharmaceutical composition is formulated into clinically acceptable preparations such as oral preparations, injectable preparations, topical preparations, external preparations, etc., preferably oral preparations. The oral preparation is preferably solid preparation such as tablet, capsule, granule, etc. These formulations can be prepared by using corresponding auxiliary materials known to those skilled in the art and using corresponding known pharmaceutical preparation techniques.
In another aspect, the invention provides the use of form a as described above, or form a prepared according to the above method of preparation, or a pharmaceutical composition comprising form a, in the preparation of a factor Xa inhibitor drug.
In another aspect, the invention provides the use of the above-described form a, or the form a prepared according to the above-described preparation method, or a pharmaceutical composition comprising the form a, in the preparation of a medicament for anticoagulation, prevention or treatment of thrombosis or embolism.
In another aspect, the invention provides the use of form a as described above, or of form a prepared according to the above preparation method, or of a pharmaceutical composition comprising form a, in the preparation of a medicament for the treatment of thromboembolism or disseminated intravascular coagulation.
In another aspect, the invention provides the use of form a as described above, or a pharmaceutical composition comprising form a prepared according to the above-described preparation method, in the preparation of a medicament for the treatment of reocclusion and restenosis following myocardial infarction, angina pectoris, angioplasty or aortic coronary bypass, stroke, transient local attacks, peripheral arterial occlusive disease, pulmonary embolism, deep vein thrombosis, venous thromboembolism formation in adult patients undergoing a choreography of hip or knee joint replacement.
On the other hand, the invention also provides the application of the crystal form A or the crystal form A prepared by the preparation method or the pharmaceutical composition containing the crystal form A in preparing related medicines for preventing and/or treating diseases inhibiting positive influence of Xa factor.
In another aspect, the invention also relates to the above-mentioned form a, or the form a prepared by the above-mentioned preparation method, or a pharmaceutical composition comprising the form a, for use in the prevention and/or treatment of a factor Xa positive effect disease. A step of
In another aspect, the invention also relates to a method of treating a patient whose condition is inhibition of factor Xa positive-working disease by administering to the patient form A, or form A prepared by the above-described method or a pharmaceutical composition comprising form A.
In some aspects of the invention, the disease described in the above aspects is selected from thromboembolism or disseminated intravascular coagulation.
In some aspects of the invention, the condition described in the above aspects is selected from the group consisting of reocclusion and restenosis following myocardial infarction, angina, angioplasty or aortic coronary bypass, stroke, transient local attacks, peripheral arterial occlusive disease, pulmonary embolism, deep vein thrombosis, venous thromboembolic formation in adult patients undergoing preferential hip or knee replacement.
The above "patient" includes all members of the animal kingdom including, but not limited to, mammals (e.g., mice, rats, cats, monkeys, dogs, etc.) and humans.
Definition and description
The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular phrase or terminology, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products as their active ingredients.
The "2θ,2θ angle, or 2θ angle" as used herein refers to diffraction angles in degrees or degrees, and the error range of 2θ may be ±0.5, ±0.4, ±0.3, ±0.2, or ±0.1°, unless otherwise specified.
The "heating temperature, cooling temperature or crystallization temperature" as used herein, unless otherwise specified, is in degrees centigrade or degrees centigrade, and the error range may be + -10, + -5, + -4, + -3, + -2 or + -1 degrees centigrade.
The term "substantially as shown in the accompanying drawings" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% of the peaks in the powder X-ray diffraction pattern or DSC pattern or crystal shape pattern of crystalline particles of a substantially pure crystalline form appear in the given pattern. Further, as the content of a certain crystal form in a product gradually decreases, some diffraction peaks ascribed to the crystal form in the powder X-ray diffraction pattern thereof may be reduced due to factors of the detection sensitivity of the instrument.
Intermediate compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.
The chemical reactions of the embodiments of the present invention are accomplished in a suitable solvent that is compatible with the chemical changes of the present invention and the reagents and materials required therefor. In order to obtain the compounds of the present invention, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the embodiments already present.
The invention will now be described in more detail by way of examples, which are used without further purification.
The solvent used in the present invention is commercially available.
Technical effects
The crystal form A has the beneficial effects that:
(1) The crystal form A of the invention has high purity and no organic solvent residue.
(2) The crystal form A of the invention has excellent stability. On the one hand, the crystal form A has good physical stability, particularly thermal stability, for example, the crystal form A has higher melting temperature, and has better stability in subsequent transportation or preparation processing operation without crystal form transformation after grinding and crushing; on the other hand, the crystal form A has good chemical stability, and the maximum single impurity, total impurity and content of the inspected sample are not obviously changed when the crystal form A is placed under the conditions of high temperature, high humidity and strong light, so that the crystal form A is not changed and is more suitable for being stored and used as a raw material medicament.
Drawings
Fig. 1: powder X-ray diffraction pattern of crystalline form B obtained in preparative example 1.
Fig. 2: powder X-ray diffraction pattern of form a obtained in example 1.
Fig. 3: differential scanning calorimetric profile of form a obtained in example 1.
Fig. 4: powder X-ray diffraction pattern of form C obtained in example 2.
Fig. 5: differential scanning calorimetric profile of form C obtained in example 2.
Fig. 6: powder X-ray diffraction pattern of the milled form B of preparation example 1.
Fig. 7: powder X-ray diffraction pattern of form a obtained in example 1 after milling.
Fig. 8: powder X-ray diffraction pattern of the crystalline form a obtained in example 3.
Detailed Description
1. Powder X-ray diffraction (X-ray powder diffractometer, XRPD)
Instrument model: bruck D8 advanced X-ray diffractometer
Sample dosage: 100mg of
And (3) target: cu (40 KV,150 mA)
Step angle: 0.02 degree
Scanning range: 0.0 to 40.0 DEG
Scanning speed: 0.02 DEG/0.30 s.
2. Differential thermal analysis (Differential Scanning Calorimeter, DSC)
Instrument model: perkinElmer Diamond differential scanning calorimeter
The testing method comprises the following steps: sample (about 2 mg) was taken and placed in DSC aluminum pan for testing at 20mL/min N 2 Under the condition, the sample is heated from 50 ℃ to 300 ℃ at a heating rate of 20 ℃/min.
3. Infrared spectrum (Infrared Spectroscopy, IR)
Detection instrument: perkin Elmer infrared spectrum analyzer
The testing method comprises the following steps: samples (about 1 mg) were taken, diluted with KBr and tableted, monitored at room temperature, the specific parameters being: detection range: 4000-400cm -1 Wavenumber, resolution: 4cm -1 。
4. Moisture permeability
The method in Chinese pharmacopoeia is adopted for determination, and the specific test method is as follows:
1) The dried glass weighing bottle with plug (with the outer diameter of 50mm and the height of 15 mm) is taken, placed in a proper constant temperature drying box (with ammonium chloride or ammonium sulfate saturated solution placed at the lower part) or a climatic box (with the set temperature of 25 ℃ +/-1 ℃ and the relative humidity of 80% +/-2%) at the temperature of 25 ℃ +/-1 ℃ for one day before the test, and precisely weighed (m 1 )；
2) Spreading the sample in the weighing bottle, wherein the sample is about 1mm thick, and precisely weighing (m 2 )；
3) The weighing bottle is opened, and the bottle cap is placed under the constant temperature and humidity condition for 24 hours;
4) The lid of the weighing flask was closed, and the weight (m 3 )；
Percentage of weight gain= (m 3 -m 2 )/(m 2 -m 1 )×100％；
5) Characterization of hygroscopicity and definition of the weight gain by hygroscopicity:
characteristic of moisture absorption Weight gain ratio
Has very good moisture permeability The weight gain of the wet-induced hair is not less than 15 percent
Having moisture-permeability The weight gain of the wet-induced weight is less than 15 percent but not less than 2 percent
Slightly moisture-absorbing property The weight gain of the wet-drawing is less than 2 percent but not less than 0.2 percent
No or almost no hygroscopicity The weight gain of the wet-induced weight is less than 0.2 percent
Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings. The examples are presented for better illustration of the present invention, but are not intended to limit the scope of the present invention to the examples. Those skilled in the art will appreciate that various modifications and adaptations of the embodiments described above are possible and can be made without departing from the scope of the invention.
Preparation example 1 preparation of Compound I
The preparation of compound I was carried out by reference to the method disclosed in CN105384739a and dried in a vacuum oven at 45 ℃ for 12h to give an off-white solid. The sample was taken and subjected to powder X-ray diffraction, shown as form B, the results are shown in Table 1, and the spectrogram is shown in FIG. 1.
TABLE 1 powder-X-ray diffraction peak data for form B obtained in PREPARATION EXAMPLE 1
Numbering device 2 theta angle (°) Relative intensity (%) Numbering device 2 theta angle (°) Relative intensity (%)
1 6.26 42.7 19 22.87 43.2
2 7.93 52.5 20 23.60 26.0
3 8.84 5.0 21 24.11 12.4
4 11.25 50.0 22 24.87 100.0
5 12.58 70.8 23 25.83 11.9
6 13.15 34.9 24 26.44 5.4
7 13.57 12.6 25 27.30 4.9
8 14.43 33.8 26 28.27 5.1
9 15.77 76.8 27 28.54 11.5
10 16.44 24.6 28 29.65 8.5
11 17.19 64.1 29 31.19 5.7
12 17.75 38.4 30 31.77 3.3
13 18.78 27.9 31 32.47 4.6
14 18.88 39.5 32 33.81 6.0
15 20.42 19.1 33 35.00 3.0
16 20.93 17.9 34 35.56 2.5
17 21.66 5.3 35 37.39 4.1
18 22.35 15.8 36 39.00 3.7
EXAMPLE 1 preparation of Compound I in form A
5.6g of the sample of preparation 1 is added into a reaction bottle, methanol (about 100 mL) is added, stirred, heated and refluxed until the solution is clear, cooled to 5+/-5 ℃ until more solid is presentAfter the precipitation, purified water (about 80 mL) is added, stirring is continued for 2h after the addition, suction filtration is carried out, the filter cake is washed by the purified water (about 10 mL) and methanol (about 6 mL) in sequence, and the filter cake is dried for 11h at 55-65 ℃ in a vacuum drying oven, so that 4.38g of off-white solid is obtained, the yield is 87.19%, and the HPLC purity is 99.43%. IR (KBr, cm) -1 ) 3081.8, 3060.1, 3026.3, 3002.4, 2923.6, 2850.1, 1678.55,1505.09,1330.28,1300.05,1247.59. The sample was taken and subjected to powder X-ray diffraction, shown as form A, the results are shown in Table 1, and the spectrogram is shown in FIG. 2. A sample was taken for TGA testing, showing it to be the anhydrous crystalline form.
TABLE 2 powder-X-ray diffraction peak data for form A obtained in example 1
Numbering device 2 theta angle (°) Relative intensity (%) Numbering device 2 theta angle (°) Relative intensity (%)
1 5.02 32.3 22 20.02 21.4
2 7.36 79.3 23 20.24 31.7
3 8.72 100.0 24 20.60 45.1
4 9.26 7.3 25 21.04 4.7
5 10.26 45.0 26 21.82 77.3
6 10.98 36.8 27 22.32 77.2
7 11.28 84.0 28 23.20 13.8
8 12.10 4.5 29 23.52 38.0
9 12.80 37.0 30 24.26 17.2
10 14.08 30.2 31 25.26 54.1
11 14.54 57.2 32 25.68 42.5
12 14.72 81.0 33 26.34 1.9
13 15.32 20.3 34 26.64 8.2
14 15.74 60.0 35 27.02 22.4
15 16.03 1.5 36 27.94 13.9
16 16.92 14.1 37 28.38 26.5
17 17.49 95.7 38 29.20 14.3
18 18.04 11.7 39 29.80 7.0
19 18.84 27.2 40 30.45 2.2
20 19.32 31.0 41 35.50 14.1
21 19.68 1.2
EXAMPLE 2 preparation of Compound I in form C
5.6g of the sample of preparation example 1 is added into a reaction bottle, N-methylpyrrolidone (about 45 mL) is added, stirring is carried out until the mixture is clear, purified water (about 50 mL) is slowly added dropwise, the dropwise addition of the purified water is suspended after stable solid precipitation, the dropwise addition of the purified water is continuously carried out slowly after 0.5-1 h, the purified water (about 140 mL) is continuously added slowly, stirring and crystallization are carried out for 2h, filtering is carried out, a filter cake is washed with the purified water (about 50 mL), and the filter cake is dried in a vacuum drying oven at 45 ℃ for 12h, thus obtaining 5.03g of off-white solid with the yield of 95.4% and the HPLC purity of 99.26%. The sample was taken and subjected to powder X-ray diffraction, shown as form C, the results are shown in Table 3, and the spectrogram is shown in FIG. 4.
TABLE 3 powder-X-ray characteristic peak data for form C obtained in example 2
Numbering device 2 theta angle (°) Relative intensity (%) Numbering device 2 theta angle (°) Relative intensity (%)
1 5.03 1.3 22 20.52 14.5
2 6.32 60.0 23 20.96 5.8
3 7.36 5.6 24 21.60 4.1
4 7.88 17.6 25 22.34 14.1
5 8.76 5.4 26 22.86 16.8
6 10.26 1.6 27 23.56 9.4
7 11.26 29.0 28 23.90 2.8
8 12.40 64.9 29 24.38 2.8
9 12.66 100.0 30 24.88 56.3
10 13.20 20.3 31 25.90 2.6
11 13.56 2.2 32 26.64 3.8
12 14.08 3.9 33 27.41 2.7
13 14.48 15.5 34 28.24 10.7
14 14.77 2.1 35 28.56 6.4
15 15.78 37.2 36 29.60 3.6
16 16.50 13.6 37 31.08 1.9
17 17.20 26.5 38 31.88 2.6
18 17.74 18.5 39 34.04 5.1
19 18.96 37.4 40 35.00 1.9
20 19.32 8.2 41 37.46 3.4
21 20.28 10.3
EXAMPLE 3 preparation of Compound I in form A
The sample of preparation 1 (0.5 g) is added into a reaction bottle, ethanol (about 12 mL) is added, stirring and heating are carried out to reflux until the solution is clear, the temperature is reduced to 5-15 ℃, purified water (10 mL) is slowly added after more solid is separated out, stirring is continued for 2h after the addition, suction filtration is carried out, a filter cake is washed by the purified water (about 3 mL) and ethanol (about 3 mL) in sequence, and the solution is dried in a vacuum drying oven at 50-65 ℃ to obtain white solid (0.43 g) with the yield of 86%. The sample was taken and subjected to powder X-ray diffraction, shown as form A, the results are shown in Table 4, and the spectrogram is shown in FIG. 8.
TABLE 4 powder-X-ray diffraction peak data for form A obtained in example 3
Numbering device 2 theta angle (°) Relative intensity (%) Numbering device 2 theta angle (°) Relative intensity (%)
1 5.10 32.0 15 18.92 23.7
2 7.42 85.2 16 19.46 26.6
3 8.78 100.0 17 20.13 48.0
4 9.22 10.1 18 20.59 61.6
5 10.35 49.7 19 21.80 58.9
6 11.34 84.8 20 22.21 74.9
7 12.00 4.1 21 23.58 25.2
8 12.82 38.8 22 24.38 16.6
9 14.11 27.0 23 25.31 39.9
10 14.73 69.5 24 27.09 11.6
11 15.80 59.3 25 28.39 20.4
12 17.05 11.4 26 29.17 6.3
13 17.53 79.7 27 29.93 4.5
14 18.12 16.0
Note that: only diffraction peaks with relative peak intensities >4% are listed in the table.
EXAMPLE 4 preparation of Compound I in form A
The sample of preparation 1 (0.5 g) was added to a reaction flask, methanol (about 9 mL) was added, stirred and heated to reflux to the solution, the temperature was maintained for 30min, then slowly cooled to 0-15℃and stirring was continued for 2h, suction filtration was performed, the filter cake was washed with methanol (about 3 mL), and dried in a vacuum oven at 50-65℃to give a white solid (0.38 g), yield 76% and the sample was subjected to powder X-ray diffraction, which showed form A.
EXAMPLE 5 preparation of Compound I in form A
The sample of preparation 1 (1 g) was added to a reaction flask, N-Dimethylformamide (DMF) (about 4 mL) was added, stirred and heated to 60-80 ℃, purified water (total about 16mL, time total about 2 h) was slowly added dropwise to the solution at the holding temperature, stirring was continued for 1h at the holding temperature, cooling to 5-15 ℃, stirring was continued for 1h, suction filtration was performed, the filter cake was washed with purified water (about 3 mL), and dried in a vacuum oven at 50-65℃to give a white solid (0.67 g), yield 67%, and the sample was subjected to powder X-ray diffraction, which showed form A.
Experimental example 1 DSC test
DSC testing was performed on samples of the crystalline forms obtained in example 1 and example 2, and the test results are shown in the following Table:
TABLE 5 DSC results of different samples
Conclusion: in the DSC test process, the crystal form C obtained in the embodiment 2 is melted first, and then the crystal form C is transformed into the crystal form A immediately after the melting is completed, and then the crystal form A presents the melting point of the crystal form A, and no endothermic peak is found after continuous heating, so that the crystal form A can be kept stable when heated, and is more suitable for being stored and used as a bulk drug.
Experimental example 2 grinding experiment
An appropriate amount (about 300 mg) of the samples obtained in preparation example 1 and example 1 were each ground in a mortar for about 20 to 30 minutes, and the samples were collected for XRPD detection, and the test results are shown in the following table:
TABLE 6 results of grinding tests on different samples
Examples Pre-grinding crystalline forms Post-grinding crystalline forms
Preparation example 1 Crystal form B Mixed crystals comprising form A (see FIG. 6)
Example 1 Crystal form A Crystal form A (see FIG. 7)
TABLE 7 preparation example 1 powder-X-ray diffraction peak data after sample milling
Table 8 example 1 powder-X-ray diffraction peak data after sample milling
Numbering device 2 theta angle (°) Relative intensity (%) Numbering device 2 theta angle (°) Relative intensity (%)
1 5.02 38.8 22 20.24 42.2
2 7.34 66.6 23 20.58 44.5
3 8.74 100.0 24 21.04 3.9
4 9.28 5.6 25 21.64 65.6
5 10.26 40.2 26 21.82 60.6
6 10.94 20.8 27 22.30 65.0
7 11.30 53.9 28 23.18 9.0
8 12.13 2.8 29 23.56 23.9
9 12.80 28.8 30 24.32 13.0
10 14.08 25.9 31 25.32 46.3
11 14.74 62.0 32 25.64 33.6
12 15.36 30.1 33 26.36 4.2
13 15.72 42.9 34 26.72 6.7
14 16.10 4.7 35 27.04 16.3
15 16.88 16.3 36 27.90 9.8
16 17.48 71.9 37 28.32 19.1
17 18.04 8.4 38 29.16 6.5
18 18.86 11.9 39 29.92 4.9
19 19.34 21.3 40 30.38 2.9
20 19.67 2.1 41 35.52 6.2
21 20.00 37.5
Experimental example 3 detection of residual amount of organic solvent
Since the preparation of the samples obtained in preparation example 1 and examples 1 to 5 all involve organic solvents, five samples were tested for residual amounts of organic solvents in order to ensure medication safety, and the test results are shown in the following table:
TABLE 9 detection results of residual organic solvent amounts for different samples
Note that: (1) ethylene glycol, methanol, N-methylpyrrolidone and DMF all belong to the second class of solvents (should be restricted to use) with limits of not more than 0.062%, 0.300%, 0.053% and 0.088%, respectively; ethanol belongs to the third class of solvents, and the limit of the ethanol should not exceed 0.5 percent (refer to 2005 edition of technical guidelines for research on residual solvents of chemical drugs); (2) the sample of preparation 1 was tested using nuclear magnetic resonance hydrogen spectroscopy and found to have a significant ethylene glycol solvent peak, at a level of about 0.695%.
Conclusion: from the above results, it was found that the residual solvent contents of the samples of form B and form C obtained in preparation examples 1 and 2 were both beyond the prescribed limits, and did not meet the pharmaceutical quality requirements, and the sample of form C of example 2 was washed with an organic solvent, and the residual solvent was not completely removed. The crystal form A samples obtained in the examples 1 and 3-5 do not contain organic solvents, and are suitable for being used and developed as bulk drugs.
Experimental example 4 influence factor test
The preparation example 1 and the example 1 were taken as a sample of form B and a sample of form A, respectively, and placed in a low density polyethylene bag for medical use, and after 10 days of placing under conditions of high temperature (60 ℃ + -2 ℃), high humidity (92.5% RH) and strong light (4500 Lx), respectively, the results of the experiments are shown in Table 10.
TABLE 10 influence factor experiment results of the samples obtained in example 1 and preparation example 1
Conclusion: the embodiment 1 has the advantages that the crystal form A is stable at high temperature, high humidity and strong light, the content is not obviously changed, the maximum single impurity and the total impurity have no obvious change trend, and the crystal form A is not changed after detection, namely the crystal form A has stable quality and is suitable for being stored as a bulk drug; in the preparation example, although the crystal form B is not changed in the influence factor experiment, the maximum single impurity content and the total impurity content are beyond the common standard, and after the preparation example is placed for 5 days under the high temperature and illumination condition, the total impurity content is increased to some extent, and the requirements of the raw material medicines are not met.
Experimental example 5 hygroscopicity test
The results of the hygroscopicity test of the sample of form A of example 1, which was taken in the appropriate amount, are shown in Table 11.
TABLE 11 results of hygroscopicity of the example 1 form A samples
Sample of Moisture-wicking property (%) Crystal form
EXAMPLE 1 form A 0.3％ Unchanged
Conclusion: the crystal form A of the embodiment 1 has slightly hygroscopicity, meets the requirements of raw materials, and has no crystal form transformation after the test is finished, so that the crystal form A has stability in a humid environment.

Claims (9)

  1. Form a of compound I characterized by a powder X-ray diffraction pattern expressed in terms of 2Θ angles (°) having characteristic peaks using Cu-ka radiation at the following positions: 5.0 + -0.2 deg., 7.4 + -0.2 deg., 8.7 + -0.2 deg., 10.3 + -0.2 deg., 17.5 + -0.2 deg..
  2. Form a of claim 1, wherein the powder X-ray diffraction pattern in terms of 2Θ angles (°) using Cu-ka radiation has characteristic peaks at: 5.0+ -0.2 °, 7.4+ -0.2 °, 8.7+ -0.2 °, 10.3+ -0.2 °, 11.3+ -0.2 °, 12.8+ -0.2 °, 17.5+ -0.2 °;
    alternatively, its powder X-ray diffraction pattern has characteristic peaks at the following positions: 5.0+ -0.2 °, 7.4+ -0.2 °, 8.7+ -0.2 °, 10.3+ -0.2 °, 11.3+ -0.2 °, 12.8+ -0.2 °, 17.5+ -0.2 °, 22.3+ -0.2 °;
    alternatively, its powder X-ray diffraction pattern has characteristic peaks at the following positions: 5.0+ -0.2 °, 7.4+ -0.2 °, 8.7+ -0.2 °, 10.3+ -0.2 °, 11.3+ -0.2 °, 12.8+ -0.2 °, 15.7+ -0.2 °, 17.5+ -0.2 °, 22.3+ -0.2 °;
    alternatively, the powder X-ray diffraction pattern thereof is substantially as shown in fig. 2 or 8.
  3. Form a according to claim 1 or 2, characterized by a differential scanning calorimetry curve having an endotherm at 244.28 ±5 ℃;
    alternatively, it has a DSC profile substantially as shown in figure 3.
  4. A process for the preparation of form a as claimed in any one of claims 1 to 3 comprising: adding the crude product of the compound I into the solvent 1, heating to dissolve completely, cooling to a target temperature, adding the solvent 2, continuing crystallization, and separating to obtain a crystal form A;
    alternatively, the method comprises: adding the compound I into the solvent 1, heating to dissolve completely, cooling to a target temperature, continuing crystallization, and separating to obtain a crystal form A;
    wherein the solvent 1 is selected from ROH, RCN, RCOR 1 、RCOOR 1 DMSO, DMF, dichloromethane or heterocyclesAn organic-like solvent, solvent 2 is selected from water, n-hexane, n-heptane, petroleum ether, cyclohexane or methyl tert-butyl ether, wherein R, R 1 Selected from C 1 -C 4 Linear or branched alkyl.
  5. The process for preparing form a according to claim 4, wherein the volume ratio of solvent 1 to solvent 2 is 1-10:1-100; further preferably 1 to 10:1 to 50; more preferably 1 to 10:1 to 20, still more preferably 1 to 5:1 to 10;
    preferably, the mass volume ratio of the crude product of the compound I to the solvent 1 is 1 g:1-50 mL; preferably 1 g:2-30 mL; further preferably 1 g/3 to 25mL;
    preferably, the heating temperature is 30-120 ℃; preferably, the heating temperature is 30-100 ℃;
    preferably, the temperature of the cooling target is-30 ℃; preferably, the temperature of the cooling target is 0-25 ℃; further preferably, the temperature reduction target temperature is 0 ℃ to 15 ℃.
  6. A pharmaceutical composition comprising form a according to any one of claims 1 to 3, or form a prepared by the preparation method of claim 4 or 5; optionally, other therapeutic components are also present in the pharmaceutical composition.
  7. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is formulated into a clinically acceptable formulation, including an oral formulation, an injectable formulation, a topical formulation, an external formulation, etc.; oral formulations are preferred, and tablets and capsules are further preferred.
  8. Use of form a according to any one of claims 1 to 3, or form a prepared by the preparation method according to claim 4 or 5, or the pharmaceutical composition according to claim 6 or 7, for the preparation of a related medicament for the prevention and/or treatment of a disease positively affected by factor Xa.
  9. The use according to claim 8, wherein the disease is selected from thromboembolism or disseminated intravascular coagulation; preferably, the disease is selected from myocardial infarction, angina pectoris, reocclusion and restenosis following angioplasty or aortic coronary bypass, stroke, transient local attacks, peripheral arterial occlusive disease, pulmonary embolism or deep venous thrombosis.
CN202180053711.3A 2020-09-18 2021-09-15 Crystal form of pyrazolo [3,4-c ] pyridine compound, and preparation method and application thereof Pending CN116583278A (en)

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