WO2022057826A1 - Forme cristalline d'un composé pyrazol [3,4-c] pyridine, son procédé de préparation et son utilisation - Google Patents

Forme cristalline d'un composé pyrazol [3,4-c] pyridine, son procédé de préparation et son utilisation 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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English (en)
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/zh
Publication of WO2022057826A1 publication Critical patent/WO2022057826A1/fr

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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.

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Abstract

La présente invention concerne une forme cristalline A d'un composé (I), son procédé de préparation et son utilisation. La forme cristalline A résultante présente les caractéristiques d'une pureté élevée, aucun résidu de solvant organique, une bonne stabilité pendant le processus expérimental d'usinage, de grands facteurs de chauffage et d'influence, et un mode opératoire du procédé de préparation simple, et est appropriée pour une utilisation industrielle.
PCT/CN2021/118509 2020-09-18 2021-09-15 Forme cristalline d'un composé pyrazol [3,4-c] pyridine, son procédé de préparation et son utilisation WO2022057826A1 (fr)

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CN202180053711.3A CN116583278A (zh) 2020-09-18 2021-09-15 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

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CN202010988516.7 2020-09-18

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CN104513239A (zh) * 2014-12-10 2015-04-15 沈阳药科大学 吡唑并[3,4-c]吡啶-7-酮类化合物及其应用
CN105384739A (zh) * 2014-09-02 2016-03-09 石药集团中奇制药技术（石家庄）有限公司 吡唑并[3,4-c]吡啶类衍生物
EP3098221A1 (fr) * 2014-10-15 2016-11-30 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Procédé de préparation de forme apixaban n-1
CN110862389A (zh) * 2018-08-28 2020-03-06 江苏康缘药业股份有限公司 一种阿哌沙班晶型的制备方法

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