WO2022057826A1 - Crystal form of pyrazol [3,4-c] pyridine compound, and preparation method therefor and use thereof - Google Patents

Crystal form of pyrazol [3,4-c] pyridine compound, and preparation method therefor and use thereof Download PDF

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WO2022057826A1
WO2022057826A1 PCT/CN2021/118509 CN2021118509W WO2022057826A1 WO 2022057826 A1 WO2022057826 A1 WO 2022057826A1 CN 2021118509 W CN2021118509 W CN 2021118509W WO 2022057826 A1 WO2022057826 A1 WO 2022057826A1
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crystal form
solvent
preparation
powder
ray diffraction
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PCT/CN2021/118509
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French (fr)
Chinese (zh)
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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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石药集团中奇制药技术（石家庄）有限公司
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Priority to CN202180053711.3A priority Critical patent/CN116583278A/en
Publication of WO2022057826A1 publication Critical patent/WO2022057826A1/en

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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

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to a crystal form of a pyrazolo[3,4-c]pyridine compound and a preparation method and application thereof.
  • Thrombosis is caused by thrombosis and embolism. Under certain pathological conditions, blood components form thrombus in blood vessels. The thrombus falls off from the formation site, and will partially or completely block the vein or supplying artery during the blood flow process, causing a series of pathological processes such as vascular or system ischemia, hypoxia and necrosis. Common thrombotic diseases include myocardial infarction, cerebral thrombosis, deep vein thrombosis, pulmonary embolism and peripheral arterial thromboembolism, which seriously endanger people's life and quality of life. Coronary heart disease is an important category of thrombotic diseases, including myocardial infarction and angina pectoris. In China, the mortality rate of coronary heart disease ranks fourth, and the mortality rate of cerebrovascular disease ranks second.
  • Coagulation factor X is a good target for antithrombotic therapy, and factor Xa is the most important drug target in the coagulation cascade.
  • Factor Xa inhibitors can tightly bind to the active site of factor Xa, resulting in the inactivation of free and fibrin-bound factor Xa and play an anticoagulant effect.
  • factor Xa inhibitors can significantly reduce the occurrence of venous thrombosis without increasing the incidence of bleeding. There is almost no interaction with drugs and can be taken at the same time.
  • factor Xa inhibitors Although the bleeding tendency of factor Xa inhibitors is lower than that of traditional anticoagulants, the main clinical adverse reaction is still bleeding. Therefore, reducing the risk of bleeding and improving the therapeutic window are research hotspots in this field.
  • Compound I is a factor Xa inhibitor with the chemical name 1-(4-ethoxyphenyl)-7-oxo-6-[3-methyl-4-(2-oxopiperidine-1- yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, which has good antithrombotic effect and lower bleeding risk.
  • Chinese patent CN105384739A discloses the compound of formula I and its analogs, preparation methods and uses. Since the crystal form of the drug is directly related to the quality and curative effect of the drug, different crystal forms will affect the stability of the drug during production, processing and storage to varying degrees. Therefore, the discovery of crystal forms with good properties is critical to subsequent drug development.
  • the present invention provides a crystal form A of compound I, which is characterized in that, using Cu-K ⁇ radiation, the powder X-ray diffraction pattern represented by 2 ⁇ angle (°) has characteristic diffraction peaks at the following positions: 5.0 ⁇ 0.2°, 7.4 ⁇ 0.2°, 8.7 ⁇ 0.2°, 10.3 ⁇ 0.2°, 17.5 ⁇ 0.2°.
  • the relative intensities of the above-mentioned characteristic peaks are:
  • the relative intensity of the above characteristic peak ( ⁇ 0.2°) is:
  • the crystal form A is characterized in that, using Cu-K ⁇ radiation, the powder X-ray diffraction pattern represented by 2 ⁇ angle (°) has characteristic diffraction 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°.
  • the relative intensity of the above characteristic peak ( ⁇ 0.2°) is:
  • the relative intensity of the above characteristic peak ( ⁇ 0.2°) is:
  • the crystal form A is characterized in that, using Cu-K ⁇ radiation, the powder X-ray diffraction pattern represented by 2 ⁇ angle (°) has characteristic diffraction 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°.
  • the relative intensity of the above characteristic peak ( ⁇ 0.2°) is:
  • the relative intensity of the above characteristic peak ( ⁇ 0.2°) is:
  • the crystal form A is characterized in that, using Cu-K ⁇ radiation, the powder X-ray diffraction pattern represented by 2 ⁇ angle (°) has characteristic diffraction 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°.
  • the relative intensity of the above characteristic peak ( ⁇ 0.2°) is:
  • the relative intensity of the above characteristic peak ( ⁇ 0.2°) is:
  • the crystal form A is characterized in that, using Cu-K ⁇ radiation, the powder X-ray diffraction pattern represented by 2 ⁇ angle (°) has characteristic diffraction 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°, 20.6 ⁇ 0.2°, 22.3 ⁇ 0.2°.
  • the relative intensity of the above characteristic peak ( ⁇ 0.2°) is:
  • the relative intensity of the above characteristic peak ( ⁇ 0.2°) is:
  • the crystal form A is characterized in that, using Cu-K ⁇ radiation, the powder X-ray diffraction pattern represented by 2 ⁇ angle (°) has characteristic diffraction 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°, 14.7 ⁇ 0.2°, 15.7 ⁇ 0.2°, 17.5 ⁇ 0.2°, 22.3 ⁇ 0.2°.
  • the relative intensity of the above characteristic peak ( ⁇ 0.2°) is:
  • the relative intensity of the above characteristic peak ( ⁇ 0.2°) is:
  • the crystal form A is characterized in that, using Cu-K ⁇ radiation, the powder X-ray diffraction pattern represented by 2 ⁇ angle (°) has characteristic diffraction 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°, 14.7 ⁇ 0.2°, 15.7 ⁇ 0.2°, 17.5 ⁇ 0.2°, 20.6 ⁇ 0.2°, 22.3 ⁇ 0.2°, 25.3 ⁇ 0.2°.
  • the relative intensity of the above characteristic peak ( ⁇ 0.2°) is:
  • the relative intensity of the above characteristic peak ( ⁇ 0.2°) is:
  • the crystal form A is characterized in that, using Cu-K ⁇ radiation, the powder X-ray diffraction pattern represented by 2 ⁇ angle (°) has characteristic diffraction 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°, 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°.
  • the relative intensity of the above characteristic peak ( ⁇ 0.2°) is:
  • the relative intensity of the above characteristic peak ( ⁇ 0.2°) is:
  • the crystal form A using Cu-K ⁇ radiation, has a powder X-ray diffraction pattern substantially as shown in FIG. 2 or FIG. 8 .
  • the crystal form A its XRPD pattern analysis data are shown in the following table:
  • the differential scanning calorimetry curve of the crystal form A has an onset of an endothermic peak at 242.10 ⁇ 3°C.
  • the differential scanning calorimetry curve of the crystal form A has an endothermic peak at 244.28 ⁇ 5°C.
  • the crystal form A has a DSC pattern substantially as shown in FIG. 3 .
  • the present invention also provides a method for preparing the above-mentioned crystal form A, the method comprising: adding the crude product of compound 1 into solvent 1, heating until it is completely dissolved, cooling to a target temperature, adding solvent 2, continuing to crystallize, and separating to obtain Form A.
  • the method includes: adding compound I into solvent 1, heating until it is completely dissolved, cooling to a target temperature, continuing to crystallize, and isolating Form A.
  • solvent 1 is selected from ROH, RCN, RCOR 1 , RCOOR 1 , DMSO, DMF, dichloromethane or heterocyclic organic solvents (for example, furan, tetrahydrofuran, pyridine , 1,4-dioxane, etc.)
  • solvent 2 is selected from water, n-hexane, n-heptane, petroleum ether, cyclohexane or methyl tert-butyl ether, wherein R, R 1 are selected from C 1 -C 4 Linear or branched alkyl; preferably, solvent 1 is ROH, solvent 2 is water, wherein R is selected from C 1 -C 4 linear or branched alkyl; further preferably, solvent 1 is methanol.
  • the solvent 1 is ROH or DMF
  • the solvent 2 is selected from water; further preferably, the solvent 1 is methanol, ethanol or DMF; further preferably, the solvent 1 is methanol.
  • 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 to 20, more preferably 1 to 5:1 to 10, still more preferably 1 to 5:1 to 5.
  • the mass-volume ratio of the crude compound I to solvent 1 is 1 g: 10-50 mL; preferably 1 g: 10-30 mL; more preferably 1 g: 15-25 mL.
  • the mass-volume ratio of the compound I to the solvent 1 is 1 g: 1-50 mL; preferably 1 g: 2-30 mL; more preferably 1 g: 3-25 mL; further preferably It is 1g: 3 ⁇ 20mL.
  • the heating temperature is 30°C to reflux temperature; alternatively, the heating temperature is 30-120°C; or the heating temperature is 30-100°C.
  • the continued crystallization time is 0.5h-5h; preferably 1h-3h; more preferably 1h-2h.
  • the temperature reduction target temperature is -30°C to 30°C; preferably, the target temperature is 0°C to 25°C; further preferably, the target temperature is 0°C °C to 15 °C; further preferably, the target temperature is 5 °C to 15 °C.
  • the separation step comprises using suitable methods such as filtration, centrifugation and the like to separate the obtained crystal form A from the crystallization liquid.
  • the above preparation method considering the removal of free solvent in the product, further includes a drying step after the separation step.
  • the drying method can adopt any suitable known method, preferably reduced pressure (vacuum) drying.
  • the specific drying conditions are, for example, the temperature is preferably 30-70°C, the temperature is more preferably 40-65°C, more preferably 55-65°C; the drying time is preferably 4-20h, more preferably 8-16h. No matter what drying method is used, it is advisable that the residual solvent content in the obtained product meets the quality standard.
  • the crude compound I or compound I described in the present invention can be prepared by the known method disclosed in CN105384739A, and can also be prepared by any known method disclosed in other prior art.
  • Another aspect of the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned crystal form A or the crystal form A prepared by the above-mentioned preparation method, optionally, the pharmaceutical composition further comprises other therapeutic components.
  • Said other therapeutic ingredients refer to other active ingredients or drugs that prevent and/or treat inhibiting the positive effects of factor Xa on diseases.
  • the other therapeutic components can synergize with Compound I.
  • Another aspect of the present invention also provides a pharmaceutical composition, comprising the above-mentioned crystal form A or the crystal form A prepared by the above-mentioned preparation method and a pharmaceutically acceptable carrier, optionally, the pharmaceutical composition further comprises other therapeutic groups point.
  • Said other therapeutic ingredients refer to other active ingredients or drugs that prevent and/or treat inhibiting the positive effects of factor Xa on diseases.
  • the other therapeutic components can synergize with Compound I.
  • compositions are prepared into clinically acceptable preparations, such as oral preparations, injection preparations, topical preparations, external preparations, etc., preferably oral preparations.
  • oral preparations are preferably solid preparations, such as tablets, capsules, granules and the like. These preparations can be prepared by using corresponding excipients known to those of ordinary skill in the art, and by adopting the preparation technology of correspondingly known pharmaceutical preparations.
  • the present invention provides the use of the above crystal form A, or the crystal form A prepared by the above preparation method, or a pharmaceutical composition comprising the crystal form A in the preparation of a factor Xa inhibitor medicine.
  • the present invention provides the use of the above crystal form A, or the crystal form A prepared by the above preparation method or a pharmaceutical composition comprising the crystal form A in the preparation of anticoagulation, prevention or treatment of thrombosis or embolism.
  • the present invention provides the use of the above crystal form A, or the crystal form A prepared by the above preparation method or a pharmaceutical composition comprising the crystal form A in the preparation of a medicine for treating thromboembolism or disseminated intravascular coagulation.
  • the present invention provides the above crystalline form A, or the crystalline form A prepared by the above preparation method or the pharmaceutical composition comprising the crystalline form A in preparation for the treatment of myocardial infarction, angina pectoris, angioplasty or aortocoronary shunt Postoperative reocclusion and restenosis, stroke, transient local attack, peripheral arterial occlusive disease, pulmonary embolism, deep venous thrombosis, venous thromboembolism in adult patients undergoing elective hip or knee arthroplasty use.
  • the present invention also provides the above-mentioned crystal form A, or the crystal form A prepared according to the above preparation method or the pharmaceutical composition comprising the crystal form A in the preparation of related medicines for preventing and/or treating and inhibiting the positive effect of factor Xa on diseases applications in .
  • the present invention also relates to the above crystal form A, or the crystal form A prepared by the above preparation method or a pharmaceutical composition comprising the crystal form A, which is used for preventing and/or treating and inhibiting factor Xa positively affecting diseases.
  • the present invention also relates to a method for treating a patient, by administering to the patient the above-mentioned crystalline form A, or the crystalline form A prepared by the above-mentioned preparation method or a pharmaceutical composition comprising the crystalline form A, the patient's condition is Inhibition of factor Xa positively affects disease.
  • the disease of each of the above aspects is selected from thromboembolism or disseminated intravascular coagulation.
  • the disease of each of the above aspects is selected from myocardial infarction, angina pectoris, re-occlusion and restenosis after angioplasty or aortocoronary shunt, stroke, transient partial attack, peripheral arterial occlusive disease Disease, pulmonary embolism, deep vein thrombosis, venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery.
  • the above-mentioned "patient” includes all members of the animal kingdom, including, but not limited to, mammals (eg, mice, rats, cats, monkeys, dogs, etc.) and humans.
  • the “2 ⁇ , 2 ⁇ angle or 2 ⁇ angle” in the present invention refers to the diffraction angle, in degrees or degrees, and the error range of 2 ⁇ can be ⁇ 0.5, ⁇ 0.4, ⁇ 0.3, ⁇ 0.2 or ⁇ 0.1 °.
  • the "heating temperature, cooling temperature or crystallization temperature” described in the present invention is in °C or °C, and the error range can be ⁇ 10, ⁇ 5, ⁇ 4, ⁇ 3, ⁇ 2 or ⁇ 1 °C .
  • substantially as shown in the accompanying drawings refers to a crystal form that is substantially pure by at least 50%, or at least 60%, or at least 70% of its powder X-ray diffraction pattern or DSC pattern or crystal shape of crystalline particles. %, 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 present in the given spectrum. Further, when the content of a certain crystal form in the product gradually decreases, some diffraction peaks in the powder X-ray diffraction pattern that belong to the crystal form may be reduced due to the detection sensitivity of the instrument.
  • the intermediate compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives to, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • the crystal form A of the present invention has high purity and no organic solvent residue.
  • the crystal form A of the present invention has excellent stability.
  • crystal form A has good physical stability, especially thermal stability.
  • crystal form A has a relatively high melting temperature, and no crystal transformation occurs after grinding and pulverization. In subsequent transportation or preparation processing operations It has better stability; on the other hand, the crystal form A has good chemical stability.
  • the crystal form A obtained by the present invention is placed under the conditions of high temperature, high humidity and strong light, and the maximum single impurity and total impurities of the investigated sample are obtained. There is no obvious change in the content of impurities and the crystal form, so it is more suitable for storage and use as a raw material drug.
  • Figure 1 Powder X-ray diffraction pattern of Form B obtained in Preparation Example 1.
  • Figure 3 Differential scanning calorimetry curve of the crystal form A obtained in Example 1.
  • Figure 4 The powder X-ray diffraction pattern of the crystal form C obtained in Example 2.
  • Figure 5 Differential scanning calorimetry curve of the crystal form C obtained in Example 2.
  • Figure 6 Powder X-ray diffraction pattern of the crystal form B obtained in Preparation Example 1 after grinding.
  • Figure 7 Powder X-ray diffraction pattern of the crystal form A obtained in Example 1 after grinding.
  • Test method Take a sample (about 2 mg) and place it in a DSC aluminum pot for testing. Under the condition of 20 mL/min N2 , at a heating rate of 20 °C/min, heat the sample from 50 °C to 300 °C.
  • Test method take a sample (about 1 mg), dilute it with KBr and press it into tablets, and monitor at room temperature.
  • the specific parameters are: detection range: 4000-400 cm -1 wave number, resolution: 4 cm -1 .
  • the thickness of the test sample is generally about 1mm, and accurately weigh it (m 2 );
  • Weight gain percentage (m 3 -m 2 )/(m 2 -m 1 ) ⁇ 100%
  • compound I was prepared, and dried in a vacuum drying oven at 45° C. for 12 h to obtain an off-white solid.
  • crystal form B the result is shown in Table 1, and the spectrum is shown in accompanying drawing 1.
  • Example Crystal form before grinding Crystalline after grinding Preparation Example 1 Form B Mixed crystals containing Form A (see Figure 6)
  • Example 1 Form A Form A see Figure 7)
  • the crystal form A of Example 1 is relatively stable under high temperature, high humidity and strong light, the content does not change significantly, and the maximum single impurity and total impurity have no obvious trend of change, and the crystal form has not changed after testing. That is, the crystal form A has stable quality and is suitable for storage as a bulk drug; although the crystal form B of the preparation example did not undergo crystal transformation in the influencing factor experiment, the content of the largest single impurity and total impurity exceeded the general standard, and it was exposed to high temperature and low temperature. After being placed under light conditions for 5 days, the total impurity content increased, which did not meet the requirements of APIs.
  • Example 1 An appropriate amount of the crystal form A sample of Example 1 was taken, and a moisture absorption experiment was carried out. The results are shown in Table 11.
  • Example 1 The crystal form A of Example 1 is slightly hygroscopic, which meets the requirements of the raw material drug, and no crystal transformation occurs after the test. It can be seen that the crystal form A has stability in a humid environment.

Abstract

The present invention provides a crystal form A of compound (I) and a preparation method therefor and the use thereof. The resulting crystal form A has the characteristics of a high purity, no organic solvent residue, a good stability during the experimental process of machining, heating and influencing factors, and a simple preparation process operation, and is suitable for industrial use.

Description

一种吡唑并[3,4-c]吡啶化合物的晶型及其制备方法和用途A kind of crystal form of pyrazolo[3,4-c]pyridine compound and its preparation method and use 技术领域technical field
本发明属于药物化学领域，具体涉及一种吡唑并[3,4-c]吡啶化合物的晶型及其制备方法和用途。The invention belongs to the field of medicinal chemistry, and in particular relates to a crystal form of a pyrazolo[3,4-c]pyridine compound and a preparation method and application thereof.
背景技术Background technique
血栓病是由血栓形成和栓塞引起的。在一定的病理条件下，血液成分在血管内形成血栓。血栓由形成部位脱落，随血液流动过程中会部分或者全部堵塞静脉或者供血动脉，引起血管或者系统缺血、缺氧及坏死等一系列病理过程。常见的血栓病包括心肌梗塞、脑血栓、深静脉血栓形成、肺栓塞以及外周动脉血栓栓塞，严重危害人民生命和生活质量。冠心病是血栓类疾病中重要一类，包括心梗和心绞痛。在中国，冠心病的病死率占第四位，而脑血管病病死率占第二位。Thrombosis is caused by thrombosis and embolism. Under certain pathological conditions, blood components form thrombus in blood vessels. The thrombus falls off from the formation site, and will partially or completely block the vein or supplying artery during the blood flow process, causing a series of pathological processes such as vascular or system ischemia, hypoxia and necrosis. Common thrombotic diseases include myocardial infarction, cerebral thrombosis, deep vein thrombosis, pulmonary embolism and peripheral arterial thromboembolism, which seriously endanger people's life and quality of life. Coronary heart disease is an important category of thrombotic diseases, including myocardial infarction and angina pectoris. In China, the mortality rate of coronary heart disease ranks fourth, and the mortality rate of cerebrovascular disease ranks second.
凝血因子X是一个抗血栓治疗比较好的靶点，其中的Xa因子是凝血瀑布中最重要的药物靶点。Xa因子抑制剂能紧密结合到Xa因子的活性部位，导致游离和与纤维蛋白结合的Xa因子失活而起到抗凝作用。与低分子肝素相比，Xa因子抑制剂可显著减少静脉血栓的发生，且不增加出血发生率，与华法林相比，该类药物不但具有无需调整剂量、无需常规监测的方便，而且与食品和药物几乎不发生相互作用，可同时服用。Coagulation factor X is a good target for antithrombotic therapy, and factor Xa is the most important drug target in the coagulation cascade. Factor Xa inhibitors can tightly bind to the active site of factor Xa, resulting in the inactivation of free and fibrin-bound factor Xa and play an anticoagulant effect. Compared with low molecular weight heparin, factor Xa inhibitors can significantly reduce the occurrence of venous thrombosis without increasing the incidence of bleeding. There is almost no interaction with drugs and can be taken at the same time.
尽管Xa因子抑制剂的出血倾向比传统抗凝药要低，但是临床上主要的不良反应仍为出血，因此降低出血风险，改善治疗窗是该领域的研究热点。Although the bleeding tendency of factor Xa inhibitors is lower than that of traditional anticoagulants, the main clinical adverse reaction is still bleeding. Therefore, reducing the risk of bleeding and improving the therapeutic window are research hotspots in this field.
化合物I是一种Xa因子抑制剂，化学名为1-(4-乙氧基苯基)-7-氧代-6-[3-甲基-4-(2-氧代哌啶-1-基)苯基]-4,5,6,7-四氢-1H-吡唑[3,4-c]吡啶-3-甲酰胺，其具有良好的抗血栓效果和更低的出血风险。Compound I is a factor Xa inhibitor with the chemical name 1-(4-ethoxyphenyl)-7-oxo-6-[3-methyl-4-(2-oxopiperidine-1- yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, which has good antithrombotic effect and lower bleeding risk.
Figure PCTCN2021118509-appb-000001
Figure PCTCN2021118509-appb-000001
中国专利CN105384739A中公开了式I化合物及其类似物、制备方法及用途，由于药物晶型直接关系到药物的质量及疗效，不同的晶型会不同程度地影响生产加工及存储过程中的药物稳定性、生物利用度和安全性，因此，发现性质优良的晶型对后续药品研发十分关键。Chinese patent CN105384739A discloses the compound of formula I and its analogs, preparation methods and uses. Since the crystal form of the drug is directly related to the quality and curative effect of the drug, different crystal forms will affect the stability of the drug during production, processing and storage to varying degrees. Therefore, the discovery of crystal forms with good properties is critical to subsequent drug development.
发明内容SUMMARY OF THE INVENTION
经研究，发现按中国专利CN105384739A中方法制备的化合物I样品纯度不能达到药用标准，有机溶剂残留量超出限度要求，无法通过洗涤和干燥除净，而且样品在研磨粉碎的过程中，晶型发生了转变，另外，在高温和光照条件下，总杂含量发生增长，因此，不能满足药物制剂加工和安全性需要。After research, it was found that the purity of the compound I sample prepared by the method in Chinese patent CN105384739A could not reach the medicinal standard, and the residual amount of organic solvent exceeded the limit requirements, which could not be cleaned by washing and drying, and the sample was in the process of grinding and pulverizing. In addition, under high temperature and light conditions, the total impurity content increases, therefore, it cannot meet the needs of pharmaceutical preparation processing and safety.
为了解决现有技术中的这些问题，发明人对化合物I的晶型进行了大量试验研究，终于得到了一种纯度高、无有机溶剂残留、稳定性好的化合物I晶型A，适宜作为原料药品存储和使用，克服了现有技术存在的缺陷。In order to solve these problems in the prior art, the inventors conducted a large number of experimental studies on the crystal form of compound I, and finally obtained a compound I crystal form A with high purity, no organic solvent residue and good stability, which is suitable as a raw material The storage and use of medicines overcomes the shortcomings of the prior art.
本发明提供了一种化合物I的晶型A，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：5.0±0.2°、7.4±0.2°、8.7±0.2°、10.3±0.2°、17.5±0.2°。The present invention provides a crystal form A of compound I, which is characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern represented by 2θ angle (°) has characteristic diffraction peaks at the following positions: 5.0±0.2°, 7.4±0.2°, 8.7±0.2°, 10.3±0.2°, 17.5±0.2°.
本发明的一些方案中，上述特征峰(±0.2°)的相对强度为：In some solutions of the present invention, the relative intensities of the above-mentioned characteristic peaks (±0.2°) are:
2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
5.05.0 25～6525～65
7.47.4 40～9040～90
8.78.7 50～10050～100
10.310.3 15～6015～60
17.517.5 60～10060～100
。.
注：相对强度以峰面积计，下同。Note: Relative intensity is calculated by peak area, the same below.
优选地，上述特征峰(±0.2°)的相对强度为：Preferably, the relative intensity of the above characteristic peak (±0.2°) is:
2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
5.05.0 25～6525～65
7.47.4 40～8540～85
8.78.7 50～10050～100
10.310.3 15～5015～50
17.517.5 60～10060～100
。.
本发明的一些方案中，所述晶型A，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：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°。In some solutions of the present invention, the crystal form A is characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern represented by 2θ angle (°) has characteristic diffraction 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°.
优选地，上述特征峰(±0.2°)的相对强度为：Preferably, the relative intensity of the above characteristic peak (±0.2°) is:
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
5.05.0 25～6525～65 11.311.3 30～9030～90
7.47.4 40-9040-90 12.812.8 15～5015～50
8.78.7 50～10050～100 17.517.5 60～10060～100
10.310.3 15～6015～60      
。.
优选地，上述特征峰(±0.2°)的相对强度为：Preferably, the relative intensity of the above characteristic peak (±0.2°) is:
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
5.05.0 25～6525～65 11.311.3 30～9030～90
7.47.4 40～8540～85 12.812.8 15～4515～45
8.78.7 50～10050～100 17.517.5 60～10060～100
10.310.3 15～5015～50      
。.
本发明的一些方案中，所述晶型A，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：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°。In some solutions of the present invention, the crystal form A is characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern represented by 2θ angle (°) has characteristic diffraction 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°.
优选地，上述特征峰(±0.2°)的相对强度为：Preferably, the relative intensity of the above characteristic peak (±0.2°) is:
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
5.05.0 25～6525～65 11.311.3 30～9030～90
7.47.4 40～9040～90 12.812.8 15～5015～50
8.78.7 50～10050～100 17.517.5 60～10060～100
10.310.3 15～6015～60 22.322.3 60～10060～100
。.
优选地，上述特征峰(±0.2°)的相对强度为：Preferably, the relative intensity of the above characteristic peak (±0.2°) is:
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
5.05.0 25～6525～65 11.311.3 30～9030～90
7.47.4 40～8540～85 12.812.8 15～4515～45
8.78.7 50～10050～100 17.517.5 60～10060～100
10.310.3 15～5015～50 22.322.3 60～10060～100
。.
本发明的一些方案中，所述晶型A，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：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°。In some solutions of the present invention, the crystal form A is characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern represented by 2θ angle (°) has characteristic diffraction 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°.
优选地，上述特征峰(±0.2°)的相对强度为：Preferably, the relative intensity of the above characteristic peak (±0.2°) is:
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
5.05.0 25～6525～65 12.812.8 15～5015～50
7.47.4 40～9040～90 15.715.7 30～7030～70
8.78.7 50～10050～100 17.517.5 60～10060～100
10.310.3 15～6015～60 22.322.3 60～10060～100
11.311.3 30～9030～90      
。.
优选地，上述特征峰(±0.2°)的相对强度为：Preferably, the relative intensity of the above characteristic peak (±0.2°) is:
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
5.05.0 25～6525～65 12.812.8 15～4515～45
7.47.4 40～8540～85 15.715.7 30～7030～70
8.78.7 50～10050～100 17.517.5 60～10060～100
10.310.3 15～5015～50 22.322.3 60～10060～100
11.311.3 30～9030～90      
。.
本发明的一些方案中，所述晶型A，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：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°。In some solutions of the present invention, the crystal form A is characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern represented by 2θ angle (°) has characteristic diffraction 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°, 20.6±0.2°, 22.3±0.2°.
优选地，上述特征峰(±0.2°)的相对强度为：Preferably, the relative intensity of the above characteristic peak (±0.2°) is:
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
5.05.0 25～6525～65 12.812.8 15～5015～50
7.47.4 40～9040～90 15.715.7 30～7030～70
8.78.7 50～10050～100 17.517.5 60～10060～100
10.310.3 15～6015～60 20.620.6 35～8035～80
11.311.3 30～9030～90 22.322.3 60～10060～100
。.
优选地，上述特征峰(±0.2°)的相对强度为：Preferably, the relative intensity of the above characteristic peak (±0.2°) is:
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
5.05.0 25～6525～65 12.812.8 15～4515～45
7.47.4 40～8540～85 15.715.7 30～7030～70
8.78.7 50～10050～100 17.517.5 60～10060～100
10.310.3 15～5015～50 20.620.6 35～7035～70
11.311.3 30～9030～90 22.322.3 60～10060～100
。.
本发明的一些方案中，所述晶型A，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：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°。In some solutions of the present invention, the crystal form A is characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern represented by 2θ angle (°) has characteristic diffraction 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°, 14.7±0.2°, 15.7±0.2°, 17.5±0.2°, 22.3±0.2°.
优选地，上述特征峰(±0.2°)的相对强度为：Preferably, the relative intensity of the above characteristic peak (±0.2°) is:
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
5.05.0 25～6525～65 12.812.8 15～5015～50
7.47.4 40～9040～90 14.714.7 30～9030～90
8.78.7 50～10050～100 15.715.7 30～7030～70
10.310.3 15～6015～60 17.517.5 60～10060～100
11.311.3 30～9030～90 22.322.3 60～10060～100
。.
优选地，上述特征峰(±0.2°)的相对强度为：Preferably, the relative intensity of the above characteristic peak (±0.2°) is:
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
5.05.0 25～6525～65 12.812.8 15～4515～45
7.47.4 40～8540～85 14.714.7 30～8530～85
8.78.7 50～10050～100 15.715.7 30～7030～70
10.310.3 15～5015～50 17.517.5 60～10060～100
11.311.3 30～9030～90 22.322.3 60～10060～100
。.
本发明的一些方案中，所述晶型A，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：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°。In some solutions of the present invention, the crystal form A is characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern represented by 2θ angle (°) has characteristic diffraction 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°, 14.7±0.2°, 15.7±0.2°, 17.5±0.2°, 20.6±0.2°, 22.3±0.2°, 25.3±0.2°.
优选地，上述特征峰(±0.2°)的相对强度为：Preferably, the relative intensity of the above characteristic peak (±0.2°) is:
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
5.05.0 25～6525～65 14.714.7 30～9030～90
7.47.4 40～9040～90 15.715.7 30～7030～70
8.78.7 50～10050～100 17.517.5 60～10060～100
10.310.3 15～6015～60 20.620.6 35～8035～80
11.311.3 30～9030～90 22.322.3 60～10060～100
12.812.8 15～5015～50 25.325.3 30～7530～75
。.
优选地，上述特征峰(±0.2°)的相对强度为：Preferably, the relative intensity of the above characteristic peak (±0.2°) is:
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
5.05.0 25～6525～65 14.714.7 30～8530～85
7.47.4 40～8540～85 15.715.7 30～7030～70
8.78.7 50～10050～100 17.517.5 60～10060～100
10.310.3 15～5015～50 20.620.6 35～7035～70
11.311.3 30～9030～90 22.322.3 60～10060～100
12.812.8 15～4515～45 25.325.3 40～7540～75
。.
本发明的一些方案中，所述晶型A，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰：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°。In some solutions of the present invention, the crystal form A is characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern represented by 2θ angle (°) has characteristic diffraction 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°, 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°.
优选地，上述特征峰(±0.2°)的相对强度为：Preferably, the relative intensity of the above characteristic peak (±0.2°) is:
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
5.05.0 25～6525～65 14.714.7 30～9030～90
7.47.4 40～9040～90 15.715.7 30～7030～70
8.78.7 50～10050～100 17.517.5 60～10060～100
10.310.3 15～6015～60 20.620.6 35～8035～80
11.311.3 30～9030～90 22.322.3 60～10060～100
12.812.8 15～5015～50 25.325.3 30～7530～75
14.114.1 15～5015～50 28.428.4 10～4010～40
。.
优选地，上述特征峰(±0.2°)的相对强度为：Preferably, the relative intensity of the above characteristic peak (±0.2°) is:
2θ(°)2θ(°) 相对强度(％)Relative Strength(%) 2θ(°)2θ(°) 相对强度(％)Relative Strength(%)
5.05.0 25～6525～65 14.714.7 30～8530～85
7.47.4 40～8540～85 15.715.7 30～7030～70
8.78.7 50～10050～100 17.517.5 60～10060～100
10.310.3 15～5015～50 20.620.6 35～7035～70
11.311.3 30～9030～90 22.322.3 60～10060～100
12.812.8 15～4515～45 25.325.3 40～7540～75
14.114.1 15～5015～50 28.428.4 10～3510～35
。.
本发明的一些方案中，所述晶型A，使用Cu-Kα辐射，其粉末X-射线衍射图谱基本上如图2或图8所示。In some embodiments of the present invention, the crystal form A, using Cu-Kα radiation, has a powder X-ray diffraction pattern substantially as shown in FIG. 2 or FIG. 8 .
本发明的一些方案中，所述晶型A，其XRPD图谱解析数据如下表所示：In some solutions of the present invention, the crystal form A, its XRPD pattern analysis data are shown in the following table:
编号serial number 2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%) 编号serial number 2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%)
11 5.025.02 32.332.3 22twenty two 20.0220.02 21.421.4
22 7.367.36 79.379.3 23twenty three 20.2420.24 31.731.7
33 8.728.72 100.0100.0 24twenty four 20.6020.60 45.145.1
44 9.269.26 7.37.3 2525 21.0421.04 4.74.7
55 10.2610.26 45.045.0 2626 21.8221.82 77.377.3
66 10.9810.98 36.836.8 2727 22.3222.32 77.277.2
77 11.2811.28 84.084.0 2828 23.2023.20 13.813.8
88 12.1012.10 4.54.5 2929 23.5223.52 38.038.0
99 12.8012.80 37.037.0 3030 24.2624.26 17.217.2
1010 14.0814.08 30.230.2 3131 25.2625.26 54.154.1
1111 14.5414.54 57.257.2 3232 25.6825.68 42.542.5
1212 14.7214.72 81.081.0 3333 26.3426.34 1.91.9
1313 15.3215.32 20.320.3 3434 26.6426.64 8.28.2
1414 15.7415.74 60.060.0 3535 27.0227.02 22.422.4
1515 16.0316.03 1.51.5 3636 27.9427.94 13.913.9
1616 16.9216.92 14.114.1 3737 28.3828.38 26.526.5
1717 17.4917.49 95.795.7 3838 29.2029.20 14.314.3
1818 18.0418.04 11.711.7 3939 29.8029.80 7.07.0
1919 18.8418.84 27.227.2 4040 30.4530.45 2.22.2
2020 19.3219.32 31.031.0 4141 35.5035.50 14.114.1
21twenty one 19.6819.68 1.21.2         
本发明的一些方案中，所述晶型A，其差示扫描量热曲线在242.10±3℃有一个吸热峰的起始点。In some embodiments of the present invention, the differential scanning calorimetry curve of the crystal form A has an onset of an endothermic peak at 242.10±3°C.
本发明的一些方案中，所述晶型A，其差示扫描量热曲线在244.28±5℃有吸热峰。In some embodiments of the present invention, the differential scanning calorimetry curve of the crystal form A has an endothermic peak at 244.28±5°C.
本发明的一些方案中，所述晶型A，其具有基本上如图3所示的DSC图。In some embodiments of the present invention, the crystal form A has a DSC pattern substantially as shown in FIG. 3 .
另一方面，本发明还提供上述晶型A的制备方法，该方法包括：将化合物I的粗品加入溶剂1中，加热至全部溶解，降温至目标温度，加入溶剂2，继续析晶，分离得晶型A。On the other hand, the present invention also provides a method for preparing the above-mentioned crystal form A, the method comprising: adding the crude product of compound 1 into solvent 1, heating until it is completely dissolved, cooling to a target temperature, adding solvent 2, continuing to crystallize, and separating to obtain Form A.
本发明的一些方案中，该方法包括：将化合物I加入溶剂1中，加热至全部溶解，降温至目标温度，继续析晶，分离得晶型A。In some solutions of the present invention, the method includes: adding compound I into solvent 1, heating until it is completely dissolved, cooling to a target temperature, continuing to crystallize, and isolating Form A.
本发明的一些方案中，上述制备方法，其中，所述溶剂1选自ROH、RCN、RCOR 1、RCOOR 1、DMSO、DMF、二氯甲烷或杂环类有机溶剂(例如，呋喃、四氢呋喃、吡啶、1，4-二氧六环等)，溶剂2选自水、正己烷、正庚烷、石油醚、环己烷或甲基叔丁醚，其中R、R 1选自C 1-C 4直链或支链烷基；优选地，溶剂1为ROH，溶剂2为水，其中R选自C 1-C 4直链或支链烷基；进一步优选地，溶剂1为甲醇。 In some aspects of the present invention, the above preparation method, wherein the solvent 1 is selected from ROH, RCN, RCOR 1 , RCOOR 1 , DMSO, DMF, dichloromethane or heterocyclic organic solvents (for example, furan, tetrahydrofuran, pyridine , 1,4-dioxane, etc.), solvent 2 is selected from water, n-hexane, n-heptane, petroleum ether, cyclohexane or methyl tert-butyl ether, wherein R, R 1 are selected from C 1 -C 4 Linear or branched alkyl; preferably, solvent 1 is ROH, solvent 2 is water, wherein R is selected from C 1 -C 4 linear or branched alkyl; further preferably, solvent 1 is methanol.
优选地，上述制备方法，其中，所述溶剂1为ROH或DMF，溶剂2选自水；进一步优选地，所述溶剂1为甲醇、乙醇或DMF；进一步优选地，所述溶剂1为甲醇。Preferably, in the above preparation method, 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.
本发明的一些方案中，上述制备方法，其中，所述溶剂1和溶剂2的体积比为1～10:1～100，优选为1～10:1～50，更进一步优选为1～10:1～20，更进一步优选为1～5:1～10，更进一步优选为1～5:1～5。In some solutions of the present invention, in the above preparation method, 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 to 20, more preferably 1 to 5:1 to 10, still more preferably 1 to 5:1 to 5.
本发明的一些方案中，上述制备方法，其中，所述化合物I粗品与溶剂1的质量体积比为1g:10～50mL；优选为1g:10～30mL；进一步优选为1g:15～25mL。In some solutions of the present invention, in the above preparation method, the mass-volume ratio of the crude compound I to solvent 1 is 1 g: 10-50 mL; preferably 1 g: 10-30 mL; more preferably 1 g: 15-25 mL.
本发明的一些方案中，上述制备方法，其中，所述化合物I与溶剂1的质量体积比为1g:1～50mL；优选为1g:2～30mL；进一步优选为1g:3～25mL；进一步优选为1g:3～20mL。In some solutions of the present invention, in the above preparation method, the mass-volume ratio of the compound I to the solvent 1 is 1 g: 1-50 mL; preferably 1 g: 2-30 mL; more preferably 1 g: 3-25 mL; further preferably It is 1g: 3～20mL.
本发明的一些方案中，上述制备方法，其中，所述加热温度为30℃～回流温度；或者，所述加热温度为30～120℃；或者，所述加热温度为30～100℃。In some aspects of the present invention, in the above preparation method, the heating temperature is 30°C to reflux temperature; alternatively, the heating temperature is 30-120°C; or the heating temperature is 30-100°C.
本发明的一些方案中，上述制备方法，其中，所述继续析晶时间为0.5h～5h；优选为1h～3h；进一步优选为1h～2h。In some solutions of the present invention, in the above preparation method, the continued crystallization time is 0.5h-5h; preferably 1h-3h; more preferably 1h-2h.
本发明的一些方案中，上述制备方法，其中，所述降温目标温度为-30℃～30℃；优选地，所述目标温度为0℃～25℃；进一步优选地，所述目标温度为0℃～15℃；进一步优选地，所述目标温度为5℃～15℃。In some solutions of the present invention, in the above preparation method, the temperature reduction target temperature is -30°C to 30°C; preferably, the target temperature is 0°C to 25°C; further preferably, the target temperature is 0°C °C to 15 °C; further preferably, the target temperature is 5 °C to 15 °C.
本发明的一些方案中，上述制备方法，其中，所述分离步骤包括采用过滤、离心等适宜的方法将所得晶型A从结晶液中分离出来。In some aspects of the present invention, in the above preparation method, wherein the separation step comprises using suitable methods such as filtration, centrifugation and the like to separate the obtained crystal form A from the crystallization liquid.
本发明的一些方案中，上述制备方法，从去除产品中游离溶剂考虑，在分离步骤后，还包括干燥步骤，干燥方法可采用任何适宜的已知方法，优选为减压(真空)干燥。具体的干燥条件是，例如，温度优选30～70℃，温度进一步优选40～65℃，更优选为55～65℃；干燥时间优选为4～20h，更优选为8～16h。无论采用何种干燥手段，都以所得产品中溶剂残留量符合质量标准为宜。In some solutions of the present invention, the above preparation method, considering the removal of free solvent in the product, further includes a drying step after the separation step. The drying method can adopt any suitable known method, preferably reduced pressure (vacuum) drying. The specific drying conditions are, for example, the temperature is preferably 30-70°C, the temperature is more preferably 40-65°C, more preferably 55-65°C; the drying time is preferably 4-20h, more preferably 8-16h. No matter what drying method is used, it is advisable that the residual solvent content in the obtained product meets the quality standard.
本发明中所述的化合物I粗品或化合物I，采用CN105384739A中公开的已知方法进行制备，也可使用其它现有技术中公开的任何已知方法进行制备。The crude compound I or compound I described in the present invention can be prepared by the known method disclosed in CN105384739A, and can also be prepared by any known method disclosed in other prior art.
本发明另一方面还提供一种药物组合物，包含上述晶型A或按上述制备方法制备的晶型A，任选地，所述药物组合物还包含其他治疗组分。所述其它治疗组分是指预防和/或治疗抑制Xa因子正性影响疾病的其它活性成分或药物。优选的，所述其他治疗组分能与化合物I产生协同作用。Another aspect of the present invention also provides a pharmaceutical composition comprising the above-mentioned crystal form A or the crystal form A prepared by the above-mentioned preparation method, optionally, the pharmaceutical composition further comprises other therapeutic components. Said other therapeutic ingredients refer to other active ingredients or drugs that prevent and/or treat inhibiting the positive effects of factor Xa on diseases. Preferably, the other therapeutic components can synergize with Compound I.
本发明另一方面还提供一种药物组合物，包含上述晶型A或按上述制备方法制备的晶型A及药学上可接受的载体，任选地，所述药物组合物还包含其他治疗组分。所述其它治疗组分是指预防和/或治疗抑制Xa因子正性影响疾病的其它活性成分或药物。优选的，所述其他治疗组分能与化合物I产生协同作用。Another aspect of the present invention also provides a pharmaceutical composition, comprising the above-mentioned crystal form A or the crystal form A prepared by the above-mentioned preparation method and a pharmaceutically acceptable carrier, optionally, the pharmaceutical composition further comprises other therapeutic groups point. Said other therapeutic ingredients refer to other active ingredients or drugs that prevent and/or treat inhibiting the positive effects of factor Xa on diseases. Preferably, the other therapeutic components can synergize with Compound I.
上述药物组合物制成临床接受的制剂，例如口服制剂、注射制剂、局部给药制剂、外用制剂等，优选口服制剂。所述口服制剂优选固体制剂，如片剂、胶囊、颗粒剂等。这些制剂可采用本领域一般技术人员公知的相应辅料，采用相应公知的药物制剂的制备技术制得。The above-mentioned pharmaceutical compositions are prepared into clinically acceptable preparations, such as oral preparations, injection preparations, topical preparations, external preparations, etc., preferably oral preparations. The oral preparations are preferably solid preparations, such as tablets, capsules, granules and the like. These preparations can be prepared by using corresponding excipients known to those of ordinary skill in the art, and by adopting the preparation technology of correspondingly known pharmaceutical preparations.
另一方面，本发明提供了上述晶型A、或按上述制备方法制备的晶型A或包含晶型A的药物组合物在制备Xa因子抑制剂药物中的用途。In another aspect, the present invention provides the use of the above crystal form A, or the crystal form A prepared by the above preparation method, or a pharmaceutical composition comprising the crystal form A in the preparation of a factor Xa inhibitor medicine.
另一方面，本发明提供了上述晶型A、或按上述制备方法制备的晶型A或包含晶型A的药物组合物在制备抗凝、预防或治疗血栓或栓塞药物中的用途。In another aspect, the present invention provides the use of the above crystal form A, or the crystal form A prepared by the above preparation method or a pharmaceutical composition comprising the crystal form A in the preparation of anticoagulation, prevention or treatment of thrombosis or embolism.
另一方面，本发明提供了上述晶型A、或按上述制备方法制备的晶型A或包含晶型A的药物组合物在制备治疗血栓栓塞或弥散性血管内凝血的药物中的用途。In another aspect, the present invention provides the use of the above crystal form A, or the crystal form A prepared by the above preparation method or a pharmaceutical composition comprising the crystal form A in the preparation of a medicine for treating thromboembolism or disseminated intravascular coagulation.
另一方面，本发明提供了上述晶型A、或按上述制备方法制备的晶型A或包含晶型A的药物组合物在在制备治疗心肌梗塞、心绞痛、血管成形术或主动脉冠状动脉分流术后的再阻塞和再狭窄、中风、短暂的局部发作、周围动脉闭塞性疾病、肺栓塞、深部静脉血栓、接受择期髋关节或膝关节置换术的成年患者出现静脉血栓栓塞形成的药物中的用途。In another aspect, the present invention provides the above crystalline form A, or the crystalline form A prepared by the above preparation method or the pharmaceutical composition comprising the crystalline form A in preparation for the treatment of myocardial infarction, angina pectoris, angioplasty or aortocoronary shunt Postoperative reocclusion and restenosis, stroke, transient local attack, peripheral arterial occlusive disease, pulmonary embolism, deep venous thrombosis, venous thromboembolism in adult patients undergoing elective hip or knee arthroplasty use.
另一方面，本发明还提供了上述晶型A、或按上述制备方法制备的晶型A或包含晶型A的药物组合物在制备预防和/或治疗抑制Xa因子正性影响疾病的相关药物中的应用。On the other hand, the present invention also provides the above-mentioned crystal form A, or the crystal form A prepared according to the above preparation method or the pharmaceutical composition comprising the crystal form A in the preparation of related medicines for preventing and/or treating and inhibiting the positive effect of factor Xa on diseases applications in .
另一方面，本发明还涉及上述晶型A、或按上述制备方法制备的晶型A或包含晶型A的药物组合物，其用于预防和/或治疗抑制Xa因子正性影响疾病。、On the other hand, the present invention also relates to the above crystal form A, or the crystal form A prepared by the above preparation method or a pharmaceutical composition comprising the crystal form A, which is used for preventing and/or treating and inhibiting factor Xa positively affecting diseases. ,
另一方面，本发明还涉及一种治疗患者的方法，通过向患者施用上述晶型A、或按上述制备方法制备的晶型A或包含晶型A的药物组合物，所述患者的病症为抑制Xa因子正性影响疾病。In another aspect, the present invention also relates to a method for treating a patient, by administering to the patient the above-mentioned crystalline form A, or the crystalline form A prepared by the above-mentioned preparation method or a pharmaceutical composition comprising the crystalline form A, the patient's condition is Inhibition of factor Xa positively affects disease.
本发明的一些方案中，上述各方面所述的疾病选自血栓栓塞或弥散性血管内凝血。In some embodiments of the present invention, the disease of each of the above aspects is selected from thromboembolism or disseminated intravascular coagulation.
本发明的一些方案中，上述各方面所述的疾病选自心肌梗塞、心绞痛、血管成形术或主动脉冠状动脉分流术后的再阻塞和再狭窄、中风、短暂的局部发作、周围动脉闭塞性疾病、肺栓塞、深部静脉血栓、接受择期髋关节或膝关节置换术的成年患者出现静脉血栓栓塞形成。In some embodiments of the present invention, the disease of each of the above aspects is selected from myocardial infarction, angina pectoris, re-occlusion and restenosis after angioplasty or aortocoronary shunt, stroke, transient partial attack, peripheral arterial occlusive disease Disease, pulmonary embolism, deep vein thrombosis, venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery.
上述的“患者”包括动物界的所有成员，包括但不限于，哺乳动物(例如，小鼠、大鼠、猫、猴子、狗等)和人。The above-mentioned "patient" includes all members of the animal kingdom, including, but not limited to, mammals (eg, mice, rats, cats, monkeys, dogs, etc.) and humans.
定义和说明Definition and Explanation
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品其活性成分。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered indeterminate or unclear without a specific definition, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name and its active ingredient.
如无特别说明，本发明所述的“2θ、2θ角或2θ角度”是指衍射角，单位为°或度，2θ的误差范围可以为±0.5、±0.4、±0.3、±0.2或±0.1°。Unless otherwise specified, the “2θ, 2θ angle or 2θ angle” in the present invention refers to the diffraction angle, in degrees or degrees, and the error range of 2θ can be ±0.5, ±0.4, ±0.3, ±0.2 or ±0.1 °.
如无特别说明，本发明所述的“加热温度、降温温度或析晶温度”，单位为℃或摄氏度，误差范围可以为±10、±5、±4、±3、±2或±1℃。Unless otherwise specified, the "heating temperature, cooling temperature or crystallization temperature" described in the present invention is in °C or °C, and the error range can be ±10, ±5, ±4, ±3, ±2 or ±1 °C .
术语“基本上如附图所示”是指基本上纯净的某种晶型其粉末X-射线衍射图谱或DSC图谱或结晶颗粒的晶体形状图中至少50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少96％，或至少97％，或至少98％，或至少99％的峰 出现在所给出图谱中。进一步的，当产品中某种晶型的含量逐渐降低时，其粉末X-射线衍射图谱中的一些归属于该晶型的衍射峰可能会由于仪器的检测灵敏度的因素而变少。The term "substantially as shown in the accompanying drawings" refers to a crystal form that is substantially pure by at least 50%, or at least 60%, or at least 70% of its powder X-ray diffraction pattern or DSC pattern or crystal shape of crystalline particles. %, 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 present in the given spectrum. Further, when the content of a certain crystal form in the product gradually decreases, some diffraction peaks in the powder X-ray diffraction pattern that belong to the crystal form may be reduced due to the detection sensitivity of the instrument.
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The intermediate compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives to, preferred embodiments include, but are not limited to, the embodiments of the present invention.
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reactions of specific embodiments of the present invention are carried out in suitable solvents suitable for the chemical changes of the present invention and their required reagents and materials. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthetic steps or reaction schemes on the basis of the existing embodiments.
下面会通过实施例具体描述本发明，无需进一步纯化即可使用。The present invention will be specifically described by the examples below, which can be used without further purification.
本发明所使用的溶剂可经市售获得。The solvent used in the present invention is commercially available.
技术效果technical effect
本发明的晶型A的有益效果在于：The beneficial effect of crystal form A of the present invention is:
(1)本发明的晶型A纯度高，无有机溶剂残留。(1) The crystal form A of the present invention has high purity and no organic solvent residue.
(2)本发明的晶型A具有优良的稳定性。一方面，晶型A具备良好的物理稳定性，特别是热稳定性，例如，晶型A具备较高的熔融温度，且在研磨粉碎后未发生晶型转变，在后续运输或制剂加工操作中具有更好的稳定性；另一方面，晶型A具备良好的化学稳定性，将本发明所得的晶型A置于高温、高湿和强光条件下，被考察样品的最大单杂、总杂和含量均无明显变化，晶型未改变，更适宜作为原料药物储存和使用。(2) The crystal form A of the present invention has excellent stability. On the one hand, crystal form A has good physical stability, especially thermal stability. For example, crystal form A has a relatively high melting temperature, and no crystal transformation occurs after grinding and pulverization. In subsequent transportation or preparation processing operations It has better stability; on the other hand, the crystal form A has good chemical stability. The crystal form A obtained by the present invention is placed under the conditions of high temperature, high humidity and strong light, and the maximum single impurity and total impurities of the investigated sample are obtained. There is no obvious change in the content of impurities and the crystal form, so it is more suitable for storage and use as a raw material drug.
附图说明Description of drawings
图1：制备例1所得晶型B的粉末X-射线衍射图谱图。Figure 1: Powder X-ray diffraction pattern of Form B obtained in Preparation Example 1.
图2：实施例1所得晶型A的粉末X-射线衍射图谱图。Figure 2: Powder X-ray diffraction pattern of the crystal form A obtained in Example 1.
图3：实施例1所得晶型A的差示扫描量热曲线图谱。Figure 3: Differential scanning calorimetry curve of the crystal form A obtained in Example 1.
图4：实施例2所得晶型C的粉末X-射线衍射图谱图。Figure 4: The powder X-ray diffraction pattern of the crystal form C obtained in Example 2.
图5：实施例2所得晶型C的差示扫描量热曲线图谱。Figure 5: Differential scanning calorimetry curve of the crystal form C obtained in Example 2.
图6：制备例1所得晶型B研磨后的粉末X-射线衍射图谱图。Figure 6: Powder X-ray diffraction pattern of the crystal form B obtained in Preparation Example 1 after grinding.
图7：实施例1所得晶型A研磨后的粉末X-射线衍射图谱图。Figure 7: Powder X-ray diffraction pattern of the crystal form A obtained in Example 1 after grinding.
图8：实施例3所得晶型A的粉末X-射线衍射图谱图。Figure 8: Powder X-ray diffraction pattern of the crystal form A obtained in Example 3.
具体实施方式detailed description
1、粉末X-射线衍射(X-ray powder diffractometer,XRPD)1. Powder X-ray diffraction (X-ray powder diffractometer, XRPD)
仪器型号：布鲁克D8 Advance X射线衍射仪Instrument model: Bruker D8 Advance X-ray diffractometer
样品用量：100mgSample dosage: 100mg
靶：Cu(40KV，150mA)Target: Cu (40KV, 150mA)
阶跃角：0.02°Step angle: 0.02°
扫描范围：0.0～40.0°Scanning range: 0.0～40.0°
扫描速度：0.02°/0.30s。Scanning speed: 0.02°/0.30s.
2、差热分析(Differential Scanning Calorimeter,DSC)2. Differential Thermal Analysis (Differential Scanning Calorimeter, DSC)
仪器型号：PerkinElmer Diamond差示扫描量热仪Instrument model: PerkinElmer Diamond Differential Scanning Calorimeter
测试方法：取样品(约2mg)置于DSC铝锅内进行测试，在20mL/min N 2条件下，以20℃/min的升温速率，加热样品从50℃到300℃。 Test method: Take a sample (about 2 mg) and place it in a DSC aluminum pot for testing. Under the condition of 20 mL/min N2 , at a heating rate of 20 °C/min, heat the sample from 50 °C to 300 °C.
3、红外光谱(Infrared Spectroscopy,IR)3. Infrared Spectroscopy (IR)
检测仪器：Perkin Elmer红外光谱分析仪Detection instrument: Perkin Elmer infrared spectrum analyzer
测试方法：取样品(约1mg)，用KBr稀释压片，室温下进行监测，具体参数为：检测范围：4000-400cm -1波数，分辨率：4cm -1。 Test method: take a sample (about 1 mg), dilute it with KBr and press it into tablets, and monitor at room temperature. The specific parameters are: detection range: 4000-400 cm -1 wave number, resolution: 4 cm -1 .
4、引湿性4. Moisture
采用中国药典中的方法进行测定，具体试验方法如下：The method in the Chinese Pharmacopoeia is used to measure, and the specific test method is as follows:
1)取干燥的具塞玻璃称量瓶(外径为50mm，高为15mm)，于试验前一天置于适宜的25℃±1℃恒温干燥箱(下部放置氯化铵或硫酸铵饱和溶液)或人工气候箱(设定温度为25℃±1℃，相对湿度为80％±2％)内，精密称定重量(m 1)； 1) Take a dry stoppered glass weighing bottle (outer diameter is 50mm, height is 15mm), and place it in a suitable constant temperature drying oven at 25℃±1℃ the day before the test (the lower part is placed with ammonium chloride or ammonium sulfate saturated solution) Or in an artificial climate box (the set temperature is 25°C±1°C, and the relative humidity is 80%±2%), and the weight (m 1 ) is precisely weighed;
2)取供试品适量，平铺于上述称量瓶中，供试品厚度一般约为1mm，精密称定重量(m 2)； 2) Take an appropriate amount of the test sample, spread it in the above weighing bottle, the thickness of the test sample is generally about 1mm, and accurately weigh it (m 2 );
3)将称量瓶敞口，并于瓶盖同置于上述恒温恒湿条件下24h；3) Open the weighing bottle and place the bottle cap under the above-mentioned constant temperature and humidity conditions for 24h;
4)盖好称量瓶盖子，精密称定重量(m 3)； 4) Close the lid of the weighing bottle and accurately weigh the weight (m 3 );
增重百分率＝(m 3-m 2)/(m 2-m 1)×100％； Weight gain percentage=(m 3 -m 2 )/(m 2 -m 1 )×100%;
5)引湿性特征描述与引湿性增重的界定：5) Characterization of hygroscopicity and definition of hygroscopicity weight gain:
引湿性特征hygroscopic characteristics 增重比例Weight gain ratio
极具引湿性Very hygroscopic 引湿增重不小于15％Moisture gain not less than 15%
有引湿性hygroscopic 引湿增重小于15％但不小于2％Moisture gain is less than 15% but not less than 2%
略有引湿性slightly hygroscopic 引湿增重小于2％但不小于0.2％Wet weight gain is less than 2% but not less than 0.2%
无或几乎无引湿性No or almost no hygroscopicity 引湿增重小于0.2％Wet weight gain is less than 0.2%
以下将参照附图，对本发明的优选实施例进行详细描述。所举实施例是为了更好地对本发明的内容进行说明，但并不是本发明的内容仅限于所举实施例。本领域的技术人员根据上述发明内容对实施方案进行非本质的改进和调整，仍属于本发明的保护范围。Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings. The cited embodiments are used to better illustrate the content of the present invention, but the content of the present invention is not limited to the cited embodiments. Those skilled in the art make non-essential improvements and adjustments to the embodiments according to the above-mentioned contents of the invention, which still belong to the protection scope of the present invention.
制备例1 化合物I的制备Preparation Example 1 Preparation of Compound I
参照CN105384739A中公开的方法进行化合物I的制备，于真空干燥箱中45℃干燥12h，得类白色固体。取样品进行粉末X-射线衍射，显示为晶型B，结果见表1，谱图 见附图1。According to the method disclosed in CN105384739A, compound I was prepared, and dried in a vacuum drying oven at 45° C. for 12 h to obtain an off-white solid. Take the sample and carry out powder X-ray diffraction, it is shown as crystal form B, the result is shown in Table 1, and the spectrum is shown in accompanying drawing 1.
表1 制备例1所得的晶型B的粉末-X射线衍射峰数据Table 1 Powder-X-ray diffraction peak data of crystal form B obtained in Preparation Example 1
编号serial number 2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%) 编号serial number 2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%)
11 6.266.26 42.742.7 1919 22.8722.87 43.243.2
22 7.937.93 52.552.5 2020 23.6023.60 26.026.0
33 8.848.84 5.05.0 21twenty one 24.1124.11 12.412.4
44 11.2511.25 50.050.0 22twenty two 24.8724.87 100.0100.0
55 12.5812.58 70.870.8 23twenty three 25.8325.83 11.911.9
66 13.1513.15 34.934.9 24twenty four 26.4426.44 5.45.4
77 13.5713.57 12.612.6 2525 27.3027.30 4.94.9
88 14.4314.43 33.833.8 2626 28.2728.27 5.15.1
99 15.7715.77 76.876.8 2727 28.5428.54 11.511.5
1010 16.4416.44 24.624.6 2828 29.6529.65 8.58.5
1111 17.1917.19 64.164.1 2929 31.1931.19 5.75.7
1212 17.7517.75 38.438.4 3030 31.7731.77 3.33.3
1313 18.7818.78 27.927.9 3131 32.4732.47 4.64.6
1414 18.8818.88 39.539.5 3232 33.8133.81 6.06.0
1515 20.4220.42 19.119.1 3333 35.0035.00 3.03.0
1616 20.9320.93 17.917.9 3434 35.5635.56 2.52.5
1717 21.6621.66 5.35.3 3535 37.3937.39 4.14.1
1818 22.3522.35 15.815.8 3636 39.0039.00 3.73.7
实施例1 化合物I的晶型A的制备Example 1 Preparation of Crystal Form A of Compound I
将制备例1样品5.6g加入到反应瓶中，加入甲醇(约100mL)，搅拌加热回流至溶清，降温至5℃±5℃，待有较多固体析出后加入纯化水(约80mL)，加毕继续搅拌2h，抽滤，滤饼先后用纯化水(约10mL)和甲醇(约6mL)洗涤，于真空干燥箱中55～65℃干燥11h，得类白色固体4.38g，收率87.19％，HPLC纯度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。取样品进行粉末X-射线衍射，显示为晶型A，结果见表1，谱图见附图2。取样品进行TGA测试，显示其为无水晶型。 Add 5.6 g of the sample of Preparation Example 1 into the reaction flask, add methanol (about 100 mL), stir and heat under reflux until the solution is clear, cool down to 5 ℃ ± 5 ℃, add purified water (about 80 mL) after more solids are precipitated, After the addition was completed, stirring was continued for 2 h, suction filtration, and the filter cake was washed with purified water (about 10 mL) and methanol (about 6 mL) successively, and dried in a vacuum drying oven at 55-65 ° C for 11 h to obtain 4.38 g of an off-white solid with a yield of 87.19%. , HPLC purity 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. A sample was taken for powder X-ray diffraction, and it was shown as crystal form A, the results are shown in Table 1, and the spectrum is shown in Figure 2. A sample was taken for TGA testing, which showed it to be anhydrous.
表2 实施例1所得的晶型A的粉末-X射线衍射峰数据Table 2 Powder-X-ray diffraction peak data of crystal form A obtained in Example 1
编号serial number 2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%) 编号serial number 2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%)
11 5.025.02 32.332.3 22twenty two 20.0220.02 21.421.4
22 7.367.36 79.379.3 23twenty three 20.2420.24 31.731.7
33 8.728.72 100.0100.0 24twenty four 20.6020.60 45.145.1
44 9.269.26 7.37.3 2525 21.0421.04 4.74.7
55 10.2610.26 45.045.0 2626 21.8221.82 77.377.3
66 10.9810.98 36.836.8 2727 22.3222.32 77.277.2
77 11.2811.28 84.084.0 2828 23.2023.20 13.813.8
88 12.1012.10 4.54.5 2929 23.5223.52 38.038.0
99 12.8012.80 37.037.0 3030 24.2624.26 17.217.2
1010 14.0814.08 30.230.2 3131 25.2625.26 54.154.1
1111 14.5414.54 57.257.2 3232 25.6825.68 42.542.5
1212 14.7214.72 81.081.0 3333 26.3426.34 1.91.9
1313 15.3215.32 20.320.3 3434 26.6426.64 8.28.2
1414 15.7415.74 60.060.0 3535 27.0227.02 22.422.4
1515 16.0316.03 1.51.5 3636 27.9427.94 13.913.9
1616 16.9216.92 14.114.1 3737 28.3828.38 26.526.5
1717 17.4917.49 95.795.7 3838 29.2029.20 14.314.3
1818 18.0418.04 11.711.7 3939 29.8029.80 7.07.0
1919 18.8418.84 27.227.2 4040 30.4530.45 2.22.2
2020 19.3219.32 31.031.0 4141 35.5035.50 14.114.1
21twenty one 19.6819.68 1.21.2         
实施例2 化合物I的晶型C的制备Example 2 Preparation of Crystal Form C of Compound I
将制备例1样品5.6g加入到反应瓶中，加入N-甲基吡咯烷酮(约45mL)，搅拌至溶清，缓慢滴加纯化水(约50mL)，有稳定固体析出后暂停滴加纯化水，0.5～1h后继续缓慢加入纯化水(约140mL)，搅拌析晶2h，过滤，滤饼用纯化水洗涤(约50mL)，于真空干燥箱中45℃干燥12h，获得类白色固体5.03g，收率95.4％，HPLC纯度99.26％。取样品进行粉末X-射线衍射，显示为晶型C，结果见表3，谱图见附图4。Add 5.6 g of the sample of Preparation Example 1 into the reaction flask, add N-methylpyrrolidone (about 45 mL), stir until it dissolves, slowly add purified water (about 50 mL) dropwise, and pause the dropwise addition of purified water after a stable solid is precipitated. After 0.5 to 1 h, purified water (about 140 mL) was added slowly, stirred and crystallized for 2 h, filtered, and the filter cake was washed with purified water (about 50 mL), and dried in a vacuum drying oven at 45°C for 12 h to obtain 5.03 g of an off-white solid. The yield was 95.4%, and the HPLC purity was 99.26%. A sample was taken for powder X-ray diffraction, and it was shown as crystal form C, the results are shown in Table 3, and the spectrum is shown in accompanying drawing 4.
表3 实施例2所得的晶型C的粉末-X射线特征峰数据Table 3 Powder-X-ray characteristic peak data of crystal form C obtained in Example 2
编号serial number 2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%) 编号serial number 2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%)
11 5.035.03 1.31.3 22twenty two 20.5220.52 14.514.5
22 6.326.32 60.060.0 23twenty three 20.9620.96 5.85.8
33 7.367.36 5.65.6 24twenty four 21.6021.60 4.14.1
44 7.887.88 17.617.6 2525 22.3422.34 14.114.1
55 8.768.76 5.45.4 2626 22.8622.86 16.816.8
66 10.2610.26 1.61.6 2727 23.5623.56 9.49.4
77 11.2611.26 29.029.0 2828 23.9023.90 2.82.8
88 12.4012.40 64.964.9 2929 24.3824.38 2.82.8
99 12.6612.66 100.0100.0 3030 24.8824.88 56.356.3
1010 13.2013.20 20.320.3 3131 25.9025.90 2.62.6
1111 13.5613.56 2.22.2 3232 26.6426.64 3.83.8
1212 14.0814.08 3.93.9 3333 27.4127.41 2.72.7
1313 14.4814.48 15.515.5 3434 28.2428.24 10.710.7
1414 14.7714.77 2.12.1 3535 28.5628.56 6.46.4
1515 15.7815.78 37.237.2 3636 29.6029.60 3.63.6
1616 16.5016.50 13.613.6 3737 31.0831.08 1.91.9
1717 17.2017.20 26.526.5 3838 31.8831.88 2.62.6
1818 17.7417.74 18.518.5 3939 34.0434.04 5.15.1
1919 18.9618.96 37.437.4 4040 35.0035.00 1.91.9
2020 19.3219.32 8.28.2 4141 37.4637.46 3.43.4
21twenty one 20.2820.28 10.310.3         
实施例3 化合物I的晶型A的制备Example 3 Preparation of Crystal Form A of Compound I
将制备例1样品(0.5g)加入到反应瓶中，加入乙醇(约12mL)，搅拌加热回流至溶清，降温至5～15℃，待有较多固体析出后缓慢加入纯化水(10mL)，加毕继续搅拌2h，抽滤，滤饼先后用纯化水(约3mL)和乙醇(约3mL)洗涤，于真空干燥箱中50～65℃干燥，得白色固体(0.43g)，收率86％。取样品进行粉末X-射线衍射，显示为晶型A，结果见表4，谱图见附图8。Add the sample (0.5g) of Preparation Example 1 into the reaction flask, add ethanol (about 12mL), stir and heat under reflux until the solution is clear, cool down to 5-15°C, and slowly add purified water (10mL) after more solids are precipitated. , continue to stir for 2h after the addition, suction filtration, the filter cake is washed with purified water (about 3mL) and ethanol (about 3mL) successively, and dried in a vacuum drying box at 50-65°C to obtain a white solid (0.43g), the yield is 86 %. A sample was taken for powder X-ray diffraction, and it was shown as crystal form A, the results are shown in Table 4, and the spectrum is shown in Figure 8.
表4 实施例3所得晶型A的粉末-X射线衍射峰数据Table 4 Powder-X-ray diffraction peak data of crystal form A obtained in Example 3
编号serial number 2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%) 编号serial number 2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%)
11 5.105.10 32.032.0 1515 18.9218.92 23.723.7
22 7.427.42 85.285.2 1616 19.4619.46 26.626.6
33 8.788.78 100.0100.0 1717 20.1320.13 48.048.0
44 9.229.22 10.110.1 1818 20.5920.59 61.661.6
55 10.3510.35 49.749.7 1919 21.8021.80 58.958.9
66 11.3411.34 84.884.8 2020 22.2122.21 74.974.9
77 12.0012.00 4.14.1 21twenty one 23.5823.58 25.225.2
88 12.8212.82 38.838.8 22twenty two 24.3824.38 16.616.6
99 14.1114.11 27.027.0 23twenty three 25.3125.31 39.939.9
1010 14.7314.73 69.569.5 24twenty four 27.0927.09 11.611.6
1111 15.8015.80 59.359.3 2525 28.3928.39 20.420.4
1212 17.0517.05 11.411.4 2626 29.1729.17 6.36.3
1313 17.5317.53 79.779.7 2727 29.9329.93 4.54.5
1414 18.1218.12 16.016.0         
注：表中仅列举了相对峰强度>4％衍射峰。Note: Only diffraction peaks with relative peak intensity >4% are listed in the table.
实施例4 化合物I的晶型A的制备Example 4 Preparation of Crystal Form A of Compound I
将制备例1样品(0.5g)加入到反应瓶中，加入甲醇(约9mL)，搅拌加热回流至溶清，保持温度搅拌30min后缓慢降温至0～15℃，继续搅拌2h，抽滤，滤饼用甲醇(约3mL)洗涤，于真空干燥箱中50～65℃干燥，得白色固体(0.38g)，收率76％，取样品进行粉末X-射线衍射，显示为晶型A。Add the sample (0.5 g) of Preparation Example 1 into the reaction flask, add methanol (about 9 mL), stir and heat under reflux until the solution is clear, keep the temperature and stir for 30 min, then slowly cool down to 0-15 ° C, continue to stir for 2 h, suction filtration, filter The cake was washed with methanol (about 3 mL), and dried in a vacuum drying oven at 50-65° C. to obtain a white solid (0.38 g) with a yield of 76%.
实施例5 化合物I的晶型A的制备Example 5 Preparation of Crystal Form A of Compound I
将制备例1样品(1g)加入到反应瓶中，加入N,N-二甲基甲酰胺(DMF)(约4mL)，搅拌加热至60-80℃，保持温度缓慢向溶液中滴加纯化水(共计约16mL，时间共计约2h)，保持温度继续搅拌1h，降温至5～15℃，继续搅拌1h，抽滤，滤饼用纯化水(约3mL)洗涤，于真空干燥箱中50～65℃干燥，得白色固体(0.67g)，收率67％，取样品进行粉末X-射线衍射，显示为晶型A。Add the sample (1g) of Preparation Example 1 into the reaction flask, add N,N-dimethylformamide (DMF) (about 4mL), stir and heat to 60-80°C, keep the temperature and slowly add purified water dropwise to the solution (Total about 16mL, total time about 2h), keep the temperature and continue to stir for 1h, cool down to 5～15℃, continue to stir for 1h, suction filter, wash the filter cake with purified water (about 3mL), put it in a vacuum drying box for 50～65 It was dried at °C to obtain a white solid (0.67 g) with a yield of 67%. A sample was taken for powder X-ray diffraction, and it was shown as crystal form A.
实验例1 DSC测试Experimental example 1 DSC test
取实施例1及实施例2所得晶型样品进行DSC测试，测试结果如下表所示：Get embodiment 1 and embodiment 2 gained crystal samples and carry out DSC test, test result is as shown in the following table:
表5 不同样品的DSC结果Table 5 DSC results of different samples
Figure PCTCN2021118509-appb-000002
Figure PCTCN2021118509-appb-000002
结论：实施例2所得晶型C在DSC测试过程中，首先发生晶型C熔融，熔化完全后随即发生晶型转变，即转变为晶型A，后呈现出晶型A的熔点，继续加热未发现吸热峰，说明晶型A在受热时能维持稳定，更适宜作为原料药存储和使用。Conclusion: During the DSC test process of the crystal form C obtained in Example 2, the crystal form C first melted, and then the crystal form transformation occurred after the melting was complete, that is, it transformed into crystal form A, and then showed the melting point of crystal form A. The endothermic peak was found, indicating that Form A can maintain stability when heated, and is more suitable for storage and use as an API.
实验例2 研磨实验Experimental Example 2 Grinding Experiment
将适量(约300mg)制备例1与实施例1所得样品分别置于研钵中进行研磨，约 20-30min，收集样品进行XRPD检测，测试结果如下表所示：An appropriate amount (about 300mg) of the samples obtained from Preparation Example 1 and Example 1 was placed in a mortar and ground respectively, and about 20-30min, the samples were collected and carried out XRPD detection, and the test results were as shown in the following table:
表6 不同样品的研磨试验结果Table 6 Grinding test results of different samples
实施例Example 研磨前晶型Crystal form before grinding 研磨后晶型Crystalline after grinding
制备例1Preparation Example 1 晶型BForm B 包含晶型A的混晶(参见图6)Mixed crystals containing Form A (see Figure 6)
实施例1Example 1 晶型AForm A 晶型A(参见图7)Form A (see Figure 7)
表7 制备例1样品研磨后的粉末-X射线衍射峰数据Table 7 Powder-X-ray diffraction peak data of the sample of Preparation Example 1 after grinding
Figure PCTCN2021118509-appb-000003
Figure PCTCN2021118509-appb-000003
表8 实施例1样品研磨后的粉末-X射线衍射峰数据Table 8 Powder-X-ray diffraction peak data of the sample of Example 1 after grinding
编号serial number 2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%) 编号serial number 2θ角(°)2θ angle (°) 相对强度(％)Relative Strength(%)
11 5.025.02 38.838.8 22twenty two 20.2420.24 42.242.2
22 7.347.34 66.666.6 23twenty three 20.5820.58 44.544.5
33 8.748.74 100.0100.0 24twenty four 21.0421.04 3.93.9
44 9.289.28 5.65.6 2525 21.6421.64 65.665.6
55 10.2610.26 40.240.2 2626 21.8221.82 60.660.6
66 10.9410.94 20.820.8 2727 22.3022.30 65.065.0
77 11.3011.30 53.953.9 2828 23.1823.18 9.09.0
88 12.1312.13 2.82.8 2929 23.5623.56 23.923.9
99 12.8012.80 28.828.8 3030 24.3224.32 13.013.0
1010 14.0814.08 25.925.9 3131 25.3225.32 46.346.3
1111 14.7414.74 62.062.0 3232 25.6425.64 33.633.6
1212 15.3615.36 30.130.1 3333 26.3626.36 4.24.2
1313 15.7215.72 42.942.9 3434 26.7226.72 6.76.7
1414 16.1016.10 4.74.7 3535 27.0427.04 16.316.3
1515 16.8816.88 16.316.3 3636 27.9027.90 9.89.8
1616 17.4817.48 71.971.9 3737 28.3228.32 19.119.1
1717 18.0418.04 8.48.4 3838 29.1629.16 6.56.5
1818 18.8618.86 11.911.9 3939 29.9229.92 4.94.9
1919 19.3419.34 21.321.3 4040 30.3830.38 2.92.9
2020 19.6719.67 2.12.1 4141 35.5235.52 6.26.2
21twenty one 20.0020.00 37.537.5         
实验例3 有机溶剂残余量检测Experimental Example 3 Detection of residual amount of organic solvent
由于制备例1、实施例1～实施例5所得样品的制备均涉及有机溶剂，为了保障用药安全，对五份样品进行有机溶剂残余量检测，测试结果如下表所示：Since the preparation of the samples obtained in Preparation Example 1 and Example 1 to Example 5 all involved organic solvents, in order to ensure the safety of medication, five samples were tested for the residual amount of organic solvents. The test results are shown in the following table:
表9 不同样品的有机溶剂残余量检测结果Table 9 Detection results of organic solvent residues in different samples
Figure PCTCN2021118509-appb-000004
Figure PCTCN2021118509-appb-000004
注：①乙二醇、甲醇、N-甲基吡咯烷酮和DMF均属于第二类溶剂(应该限制使用)，其限度应分别不超过0.062％、0.300％、0.053％和0.088％；乙醇属于第三类溶剂，其限度应不超过0.5％(参考《化学药物残留溶剂研究的技术指导原则》2005版)；②制备例1样品使用核磁氢谱检测，发现存在明显的乙二醇溶剂峰，含量约0.695％。Note: ①Ethylene glycol, methanol, N-methylpyrrolidone and DMF belong to the second category of solvents (the use should be restricted), and their limits should not exceed 0.062%, 0.300%, 0.053% and 0.088% respectively; ethanol belongs to the third category The limit should not exceed 0.5% (refer to "Technical Guidelines for Research on Residual Solvents of Chemical Drugs" 2005 edition); ② The sample of Preparation Example 1 was detected by H NMR, and it was found that there was an obvious ethylene glycol solvent peak, with a content of about 0.695%.
结论：根据以上结果可知，制备例1和实施例2所得晶型B和晶型C样品的残留溶剂含量均超出规定的限度，不符合药品质量要求，且实施例2晶型C样品经有机溶剂洗涤，仍未能完全除去残留溶剂。其中，实施例1、实施例3-5所得晶型A样品均不含有机溶剂，适宜作为原料药进行使用和开发。Conclusion: According to the above results, the residual solvent content of the crystal form B and crystal form C samples obtained in Preparation Example 1 and Example 2 both exceeded the prescribed limit and did not meet the quality requirements of medicines. After washing, the residual solvent could not be completely removed. Among them, the samples of crystal form A obtained in Example 1 and Example 3-5 do not contain organic solvents, and are suitable for use and development as APIs.
实验例4 影响因素试验Experimental example 4 Influencing factor test
取制备例1晶型B样品和实施例1晶型A样品适量，分别置于药用低密度聚乙烯袋中，分别在高温(60℃±2℃)、高湿(92.5％RH)、强光(4500Lx)条件下放置10天后，与0天数据比较，实验结果见表10。Take an appropriate amount of the crystal form B sample of Preparation Example 1 and the crystal form A sample of Example 1, and put them in medicinal low-density polyethylene bags respectively. After being placed under light (4500Lx) conditions for 10 days, compared with the data of 0 days, the experimental results are shown in Table 10.
表10 实施例1和制备例1所得样品的影响因素实验结果Table 10 Experimental results of influencing factors of samples obtained in Example 1 and Preparation Example 1
Figure PCTCN2021118509-appb-000005
Figure PCTCN2021118509-appb-000005
结论：实施例1晶型A在高温、高湿和强光下均较稳定，含量未发生明显改变，最大单杂、总杂也无明显变化趋势，且经检测，晶型亦未发生改变，即晶型A质量稳定，适宜作为原料药进行存贮；制备例晶型B在影响因素实验中虽未发生晶型转变，但最大单杂和总杂的含量均超出一般标准，且在高温和光照条件下放置5天后，总杂含量有所增长，不符合原料药要求。Conclusion: The crystal form A of Example 1 is relatively stable under high temperature, high humidity and strong light, the content does not change significantly, and the maximum single impurity and total impurity have no obvious trend of change, and the crystal form has not changed after testing. That is, the crystal form A has stable quality and is suitable for storage as a bulk drug; although the crystal form B of the preparation example did not undergo crystal transformation in the influencing factor experiment, the content of the largest single impurity and total impurity exceeded the general standard, and it was exposed to high temperature and low temperature. After being placed under light conditions for 5 days, the total impurity content increased, which did not meet the requirements of APIs.
实验例5 引湿性实验Experimental Example 5 Humidity Experiment
取实施例1晶型A样品适量，进行引湿性实验，结果见表11。An appropriate amount of the crystal form A sample of Example 1 was taken, and a moisture absorption experiment was carried out. The results are shown in Table 11.
表11 实施例1晶型A样品的引湿性结果Table 11 The results of wettability of the crystal form A sample of Example 1
样品sample 引湿性(％)Moisture (%) 晶型Crystal form
实施例1晶型AExample 1 Crystal Form A 0.3％0.3% 不变constant
结论：实施例1晶型A略有引湿性，符合原料药要求，且测试结束后，未发生晶型转变，可见，晶型A在潮湿环境中具备稳定性。Conclusion: The crystal form A of Example 1 is slightly hygroscopic, which meets the requirements of the raw material drug, and no crystal transformation occurs after the test. It can be seen that the crystal form A has stability in a humid environment.

Claims (9)

  1. 一种化合物I的晶型A，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征峰：5.0±0.2°、7.4±0.2°、8.7±0.2°、10.3±0.2°、17.5±0.2°。A crystalline form A of compound I, characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern represented by 2θ angle (°) has characteristic peaks at the following positions: 5.0±0.2°, 7.4±0.2°, 8.7±0.2°, 10.3±0.2°, 17.5±0.2°.
  2. 如权利要求1所述的晶型A，其特征在于，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征峰：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°；The crystal form A according to claim 1, characterized in that, using Cu-Kα radiation, the powder X-ray diffraction pattern represented by 2θ angle (°) 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°;
    或者，其粉末X-射线衍射图谱在以下位置有特征峰：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°, 17.5±0.2° , 22.3±0.2°;
    或者，其粉末X-射线衍射图谱在以下位置有特征峰：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, 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°;
    或者，其粉末X-射线衍射图谱基本上如图2或图8所示。Alternatively, its powder X-ray diffraction pattern is substantially as shown in FIG. 2 or FIG. 8 .
  3. 如权利要求1或2所述的晶型A，其特征在于，其差示扫描量热曲线在244.28±5℃有吸热峰；The crystal form A according to claim 1 or 2, wherein the differential scanning calorimetry curve has an endothermic peak at 244.28±5°C;
    或者，其具有基本上如图3所示的DSC图。Alternatively, it has a DSC pattern substantially as shown in FIG. 3 .
  4. 一种如权利要求1至3任一项所述的晶型A的制备方法，包括：将化合物I的粗品加入溶剂1中，加热至全部溶解，降温至目标温度，加入溶剂2，继续析晶，分离得晶型A；A preparation method of crystal form A as claimed in any one of claims 1 to 3, comprising: adding the crude product of compound 1 to solvent 1, heating to full dissolution, cooling to target temperature, adding solvent 2, and continuing to crystallize , and isolated crystal form A;
    或者，该方法包括：将化合物I加入溶剂1中，加热至全部溶解，降温至目标温度，继续析晶，分离得晶型A；Alternatively, the method includes: adding Compound I to Solvent 1, heating until it is completely dissolved, cooling to a target temperature, continuing to crystallize, and isolating Form A;
    其中，所述溶剂1为所述溶剂1选自ROH、RCN、RCOR 1、RCOOR 1、DMSO、DMF、二氯甲烷或杂环类有机溶剂，溶剂2选自水、正己烷、正庚烷、石油醚、环己烷或甲基叔丁醚，其中R、R 1选自C 1-C 4直链或支链烷基。 Wherein, the solvent 1 is that the solvent 1 is selected from ROH, RCN, RCOR 1 , RCOOR 1 , DMSO, DMF, dichloromethane or a heterocyclic organic solvent, and the solvent 2 is selected from water, n-hexane, n-heptane, Petroleum ether, cyclohexane or methyl tert-butyl ether, wherein R and R 1 are selected from C 1 -C 4 straight or branched chain alkyl groups.
  5. 如权利要求4所述的晶型A的制备方法，所述溶剂1与溶剂2的体积比为1～10:1～100；进一步优选为1～10:1～50；更进一步优选为1～10:1～20，更进一步优选为1～5:1～10；The preparation method of crystal form A according to claim 4, wherein the volume ratio of the solvent 1 to the solvent 2 is 1-10:1-100; more preferably 1-10:1-50; still more preferably 1- 10:1-20, more preferably 1-5:1-10;
    优选地，所述化合物I粗品与溶剂1的质量体积比为1g:1～50mL；优选为1g:2～30mL；进一步优选为1g:3～25mL；Preferably, the mass-volume ratio of the crude compound I to solvent 1 is 1 g: 1-50 mL; preferably 1 g: 2-30 mL; more preferably 1 g: 3-25 mL;
    优选地，所述加热温度为30～120℃；优选地，所述加热温度为30～100℃；Preferably, the heating temperature is 30-120°C; preferably, the heating temperature is 30-100°C;
    优选地，所述降温目标温度为-30℃～30℃；优选地，所述降温目标温度为0℃～25℃；进一步优选地，所述降温目标温度为0℃～15℃。Preferably, the cooling target temperature is -30°C to 30°C; preferably, the cooling target temperature is 0°C to 25°C; further preferably, the cooling target temperature is 0°C to 15°C.
  6. 一种药物组合物，包含如权利要求1至3任一项所述的晶型A、或权利要求4或5所述的制备方法制备的晶型A；任选地，所述药物组合物还存在其它治疗组分。A pharmaceutical composition, comprising the crystal form A according to any one of claims 1 to 3, or the crystal form A prepared by the preparation method according to claim 4 or 5; optionally, the pharmaceutical composition further Other therapeutic components are present.
  7. 如权利要求6所述的药物组合物，其特征在于，所述药物组合物制成临床 接受的制剂，所述制剂包括口服制剂、注射制剂、局部给药制剂、外用制剂等；优选为口服制剂，进一步优选片剂和胶囊。The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is prepared into clinically acceptable preparations, and the preparations include oral preparations, injection preparations, topical preparations, external preparations, etc.; preferably oral preparations , further preferred are tablets and capsules.
  8. 如权利要求1至3任一项所述的晶型A、或权利要求4或5所述的制备方法制备的晶型A、或权利要求6或7所述的药物组合物在制备预防和/或治疗抑制Xa因子正性影响疾病的相关药物中的应用。The crystal form A according to any one of claims 1 to 3, or the crystal form A prepared by the preparation method according to claim 4 or 5, or the pharmaceutical composition according to claim 6 or 7 is used in the preparation of preventive and/or Or the application of related drugs that inhibit the positive effect of factor Xa on the disease.
  9. 如权利要求8所述的应用，其特征在于，所述疾病选自血栓栓塞或弥散性血管内凝血；优选地，所述疾病选自心肌梗塞、心绞痛、血管成形术或主动脉冠状动脉分流术后的再阻塞和再狭窄、中风、短暂的局部发作、周围动脉闭塞性疾病、肺栓塞或深部静脉血栓形成。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, angioplasty or aortocoronary bypass surgery subsequent reocclusion and restenosis, stroke, transient local attack, peripheral arterial occlusive disease, pulmonary embolism, or deep vein thrombosis.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104513239A (en) * 2014-12-10 2015-04-15 沈阳药科大学 Pyrazolo[3, 4-c]pyridine-7-one compound and application thereof
CN105384739A (en) * 2014-09-02 2016-03-09 石药集团中奇制药技术（石家庄）有限公司 Pyrazolo[3,4-c]pyridine derivative
EP3098221A1 (en) * 2014-10-15 2016-11-30 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Process for preparing apixaban form n-1
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

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105384739A (en) * 2014-09-02 2016-03-09 石药集团中奇制药技术（石家庄）有限公司 Pyrazolo[3,4-c]pyridine derivative
EP3098221A1 (en) * 2014-10-15 2016-11-30 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Process for preparing apixaban form n-1
CN104513239A (en) * 2014-12-10 2015-04-15 沈阳药科大学 Pyrazolo[3, 4-c]pyridine-7-one compound and application thereof
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

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
AGRAWAL, RITESH; JAIN, PRATIMA; DIKSHIT, S. N.: "Apixaban: a new player in the anticoagulant class", CURRENT DRUG TARGETS, vol. 13, no. 6, 1 June 2012 (2012-06-01), US , pages 863 - 875, XP008159967, ISSN: 1389-4501, DOI: 10.2174/138945012800564059 *
TAO HAI-YAN;MI BIN;GUO GUO-XIAN;GONG PING: "Study on the Synthesis of Apixaban", CHINESE JOURNAL OF MEDICINAL CHEMISTRY, vol. 23, no. 5, 20 October 2013 (2013-10-20), pages 385 - 389, XP055912813, ISSN: 1005-0108, DOI: 10.14142/j.cnki.cn21-1313/r.2013.05.001 *

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