CN106854197A - A kind of polymorphic of pyridine derivate and preparation method thereof, purposes - Google Patents

A kind of polymorphic of pyridine derivate and preparation method thereof, purposes Download PDF

Info

Publication number
CN106854197A
CN106854197A CN201510896986.XA CN201510896986A CN106854197A CN 106854197 A CN106854197 A CN 106854197A CN 201510896986 A CN201510896986 A CN 201510896986A CN 106854197 A CN106854197 A CN 106854197A
Authority
CN
China
Prior art keywords
crystal formation
ray powder
compound
methyl
diffraction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201510896986.XA
Other languages
Chinese (zh)
Other versions
CN106854197B (en
Inventor
王颖
向永哲
李建国
周宁
付海霞
乔惠
张济兵
黄龙
刘建
岑国栋
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhejiang Yatai Pharmaceutical Co Ltd
Original Assignee
Chengdu Easton Biopharmaceuticals Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to CN202010740681.0A priority Critical patent/CN111848609A/en
Priority to CN202010740677.4A priority patent/CN111848608A/en
Priority to CN202010741117.0A priority patent/CN111718343A/en
Priority to CN202010741120.2A priority patent/CN111704612A/en
Priority to CN201510896986.XA priority patent/CN106854197B/en
Priority to CN202010740640.1A priority patent/CN111808099A/en
Priority to CN202010741119.XA priority patent/CN111763203A/en
Priority to CN202010741115.1A priority patent/CN111848610B/en
Application filed by Chengdu Easton Biopharmaceuticals Co Ltd filed Critical Chengdu Easton Biopharmaceuticals Co Ltd
Priority to CN202010741116.6A priority patent/CN111848611A/en
Publication of CN106854197A publication Critical patent/CN106854197A/en
Application granted granted Critical
Publication of CN106854197B publication Critical patent/CN106854197B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

A kind of polymorphic of pyridine derivate of the present invention and preparation method thereof, purposes, disclose the present invention relates to pharmaceutical chemistry synthesis field, specifically related to compound 1- (4- methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4,5,6,7- tetrahydrochysene -1H- pyrazolos [3,4-c] pyridine-3-carboxamide compound polymorphic and preparation method thereof and its as medicine, especially as the purposes in the medicine for preparing prevention or treatment thrombosis or embolism.

Description

A kind of polymorphic of pyridine derivate and preparation method thereof, purposes
Technical field
The present invention relates to pharmaceutical chemistry synthesis field, specifically related to compound 1- (4- methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4,5,6,7- tetrahydrochysene -1H- pyrazolos [3,4-c] pyridine-3-carboxamide compound polymorphic and preparation method thereof and its as medicine, especially as the purposes in the medicine for preparing prevention or treatment thrombosis or embolism.
Background technology
Thrombotic diseases are the diseases of serious harm human health, according to thrombosis position, condition and property, are broadly divided into arterial thrombus and phlebothrombosis.Arterial thrombosis are that since arterial blood tube wall atherosclerotic lesion and platelet activation, its caused bad clinical reaction is mainly acute myocardial infarction AMI, cerebral apoplexy；Phlebothrombosis is induced by many reasons in vein blood vessel and is formed, VTE (venous thrombo embolism can be caused, VTE), its main clinical manifestation is Deep vain thrombosis (deep venous thrombosis,) and pulmonary embolism (pulmonary embolism, PE) DVT.VTE is the third-largest angiocardiopathy after acute coronary syndrome and cerebral apoplexy.In all deaths of hospital, VTE accounts for 10%, and annual symptomatic VTE occurs sum 1,000,000 in state of European Union 6, and death number exceedes AIDS, breast cancer, prostate cancer and the murderous summation of traffic accident.U.S.'s death is then more than 29.6 ten thousand/year, and lethal PE is only made a definite diagnosis less than 50% before death.Prevention VTE is classified as one of reduction most important strategy of the inpatient death rate by international associated guideline.
Clinical trial evidence shows, anticoagulant therapy can prevent spreading and recurring for thrombus, and further reduce the incidence and the death rate of palsy, PE etc..Therefore, anticoagulant therapy has turned into core and the basis of current clinical prevention and treatment thrombotic disease, and the research and development of anticoagulant are also the focuses of new drug development all the time, especially the medicament research and development with Xa factor inhibitor as target spot.
The present invention is in constantly research process, groped by experiment, unexpectedly obtain new 1- (4- methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4,5,6, the polymorphic of 7- tetrahydrochysene -1H- pyrazolo [3,4-c] pyridine-3-carboxamide compound.It is known that, for the polymorphic of medicine, different crystal formations can have different chemically and physically characteristics, including chemical stability, solubility, optically and mechanically etc. property, these properties can directly affect treatment and the production process of bulk drug and preparation, and stability, solubility and the bioavilability of preparation are influenced whether, therefore, polymorphous quality studied for pharmaceutical preparation, security and validity are significant.For Xa factor inhibitor, this area exists such more suitable for the excellent 1- of industrialized production, physicochemical property (4- methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4,5,6, the polymorphic of 7- tetrahydrochysene -1H- pyrazolo [3,4-c] pyridine-3-carboxamide compound.
The content of the invention
The invention discloses 1- (4- the methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4 shown in a kind of following structural formula I, 5,6,7- tetrahydrochysene -1H- pyrazolos [3,4-c] pyridine-3-carboxamide compound polymorphic, and each crystal formation preparation method, and its purposes of each crystal formation in the medicine treated to Xa factor inhibitor relevant disease is prepared.More specifically, the purposes is the purposes in prevention or treatment thrombus or thrombosis drug is prepared.
The polymorphic of Formulas I structural compounds disclosed by the invention specifically includes crystal formation B, M1, O, P, Q, T, U, V and X.
The invention provides the crystal formation B of compound of formula I, x-ray powder measure is carried out using Cu-ka rays, its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Further, the spectrogram of crystal formation B has the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Further, crystal formation B has X-ray powder diffraction pattern substantially as shown in Figure 2.
The invention provides the crystal formation M1 of compound of formula I, x-ray powder measure is carried out using Cu-ka rays, collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Further, the spectrogram of crystal formation M1 has the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Further, crystal formation M1 has X-ray powder diffraction pattern substantially as shown in Figure 3.
Another aspect of the invention provides the crystal formation O of compound of formula I, and x-ray powder measure is carried out using Cu-ka rays, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Further, the spectrogram of crystal formation O has the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Further, crystal formation O has X-ray powder diffraction pattern substantially as shown in Figure 4.
Another aspect of the invention provides the crystal formation P of compound of formula I, and x-ray powder measure is carried out using Cu-ka rays, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Further, crystal formation P spectrograms have the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Further, crystal formation P has X-ray powder diffraction pattern substantially as shown in Figure 5.
Another aspect of the invention provides the crystal formation Q of compound of formula I, and x-ray powder measure is carried out using Cu-ka rays, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Further, the spectrogram of crystal formation Q has the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Further, crystal formation Q has X-ray powder diffraction pattern substantially as shown in Figure 6.
Another aspect of the invention provides the crystal formation T of compound of formula I, and x-ray powder measure is carried out using Cu-ka rays, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Further, crystal formation T spectrograms have the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Further, crystal formation T has X-ray powder diffraction pattern substantially as shown in Figure 7.
Another aspect of the invention provides the crystal formation U of compound of formula I, and x-ray powder measure is carried out using Cu-ka rays, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Further, crystal formation U spectrograms have the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Further, crystal formation U has X-ray powder diffraction pattern substantially as shown in Figure 8.
Another aspect of the invention provides the crystal formation V of compound of formula I, and x-ray powder measure is carried out using Cu-ka rays, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Further, crystal formation V spectrograms have the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Further, crystal formation V has X-ray powder diffraction pattern as of fig. 9 shown substantially.
Another aspect of the invention provides the crystal formation X of compound of formula I, and x-ray powder measure is carried out using Cu-ka rays, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Further, crystal formation X spectrograms have the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Further, crystal formation X has X-ray powder diffraction pattern substantially as shown in Figure 10.
Invention additionally discloses the polymorphic of Formulas I structural compounds specifically include crystal formation C, D, F, H, I, J, L, M, R and S.
Another aspect of the invention provides the crystal formation C of compound of formula I, and x-ray powder measure is carried out using Cu-ka rays, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity.
The error of the 2 θ angles of diffraction is ± 0.2.
Another aspect of the invention provides the crystal formation D of compound of formula I, and x-ray powder measure is carried out using Cu-ka rays, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Another aspect of the invention provides the crystal formation F of compound of formula I, and x-ray powder measure is carried out using Cu-ka rays, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Another aspect of the invention provides the crystal formation H of compound of formula I, and x-ray powder measure is carried out using Cu-ka rays, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Another aspect of the invention provides the crystal formation I of compound of formula I, and x-ray powder measure is carried out using Cu-ka rays, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity.
The error of the 2 θ angles of diffraction is ± 0.2.
Another aspect of the invention provides the crystal formation J of compound of formula I, and x-ray powder measure is carried out using Cu-ka rays, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Another aspect of the invention provides the crystal formation L of compound of formula I, and x-ray powder measure is carried out using Cu-ka rays, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Another aspect of the invention provides the crystal formation M of compound of formula I, and x-ray powder measure is carried out using Cu-ka rays, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity.
The error of the 2 θ angles of diffraction is ± 0.2.
Another aspect of the invention provides the crystal formation R of compound of formula I, and x-ray powder measure is carried out using Cu-ka rays, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
Another aspect of the invention provides the crystal formation S of compound of formula I, and x-ray powder measure is carried out using Cu-ka rays, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
The error of the 2 θ angles of diffraction is ± 0.2.
The invention also discloses compound of formula I 1- (4- methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4,5, the preparation method of 6,7- tetrahydrochysene -1H- pyrazolo [3,4-c] pyridine-3-carboxamide：
Under the conditions of room temperature (10~25 DEG C), initiation material 2- methyl-4-nitrophenylamines and 5- chloro valeric chloride reacting generating compounds a, there is intramolecular cyclization generation compound b in the basic conditions in compound a, compound b generates compound c in the presence of phosphorus pentachloride, the compound c of generation further generates compound d in the presence of morpholine, compound e is generated after nitro reduction in compound d, compound e again with 4- chlorobutyroyl chloride reacting generating compounds f, there is intramolecular cyclization generation compound g again in compound f, compound g and [(4- methoxyphenyls) diazanyl] ethyl chloroacetate generation compound h, compound of formula I is obtained after compound h amine solutions.
Formula I 1- (4- methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4,5,6, crystal formation B, M1, O, P, Q, T, U, V and X of 7- tetrahydrochysene -1H- pyrazolo [3,4-c] pyridine-3-carboxamide can be prepared via a method which：
(1) compound shown in Formulas I structure is added in sample bottle, adds positive solvent, it is completely dissolved under room temperature or counterflow condition, directly or after anti-solvent is added dropwise be cooled to crystallizing at room temperature；
(2) normal pressure or vacuum drying under suction filtration, room temperature or heating condition, obtain different crystal formations；And it is optional, the crystal formation is added in anti-solvent and forms stirring, suction filtration, dry acquisition different crystal forms after suspension.
Wherein, positive solvent refer to Compounds of structural formula I of the invention in the solvent dissolubility preferably, positive solvent be chosen in particular from methyl alcohol, ethanol, tetrahydrofuran, acetone, DMF, dioxane, dichloromethane and with ethyl acetate in one or more；It is preferred that methyl alcohol, ethanol, dichloromethane, N,N-dimethylformamide and with ethyl acetate in one or more；Anti-solvent refers to that Compounds of structural formula I of the invention dissolubility in the solvent is poor, and anti-solvent is chosen in particular from one or more in water, methyl tertiary butyl ether(MTBE), normal heptane, n-hexane and hexamethylene；It is preferred that one or more in water, methyl tertiary butyl ether(MTBE) and normal heptane.
Further, crystal formation B, M1, O, P, Q, T, U, V and X of formula I can be prepared via a method which：
(1) compound shown in Formulas I structure is added in sample bottle, adds positive solvent, it is completely dissolved under room temperature or counterflow condition, directly or after anti-solvent is added dropwise be cooled to crystallizing at room temperature；
(2) normal pressure or vacuum drying under suction filtration, room temperature or heating condition, obtain different crystal formations.
Or, further, crystal formation B, M1, O, P, Q, T, U, V and X of formula I can be prepared via a method which：
(1) compound shown in Formulas I structure is added in sample bottle, adds positive solvent, it is completely dissolved under room temperature or counterflow condition, directly or after anti-solvent is added dropwise be cooled to crystallizing at room temperature；
(2) normal pressure or vacuum drying under suction filtration, room temperature or heating condition, obtain different crystal formations, the crystal formation is added in anti-solvent and forms stirring, suction filtration, dry acquisition different crystal forms after suspension.
The present invention has found that crystal formation B, crystal formation M1, crystal formation O, crystal formation P, crystal formation Q, crystal formation T, crystal formation U, the crystal formation V or crystal formation X of compound of formula I have good dissolubility by solubility test；Experiment is investigated by the chemical stabilities of 5 days and 10 days find that the crystal formation B of compound of formula I, crystal formation M1, crystal formation O, crystal formation P, crystal formation Q, crystal formation T, crystal formation U, crystal formation V and crystal formation X are respectively provided with excellent chemical stability.Further, investigate experiment by the physical stability of 10 days to find, crystal formation of the present invention has good physical stability.Further, the present invention has investigated amorphous, the moisture absorption that crystal formation B, crystal formation M1, crystal formation O, crystal formation P, crystal formation Q, crystal formation T, crystal formation U, crystal formation V and crystal formation X are under the conditions of ambient temperature and moisture of compound of formula I, result shows crystal formation B of the present invention, crystal formation X no hygroscopicities, crystal formation M1, crystal formation O, crystal formation P, crystal formation Q, crystal formation T, crystal formation V slightly have hygroscopicity, and crystal formation U has hygroscopicity.
Found by the Experiment on Function to normal mouse APTT, unformed and various crystal formation prepared by the present invention has the effect of significantly extension mouse APTT values, is significantly better than positive drug Eliquis；And compared with unformed, the APTT values pole of B crystal form of the present invention dramatically increases (P ＜ 0.01), the APTT values of crystal formation M1, O, Q, X crystal formation are dramatically increased (P ＜ 0.05)；Illustrate crystal formation B, crystal formation M1, crystal formation O, crystal formation Q, crystal formation X effect it is relatively more preferable.Crystal formation B, M1, O, Q, X of the compound of formula I for preparing i.e. of the invention can be used to prepare anti-freezing, prevent or treat the purposes in thrombus or thrombosis drug, particularly the purposes in the purposes in preparing anticoagulant or preparation Xa factor inhibitor medicine.
Brief description of the drawings
The unformed XRPD collection of illustrative plates of Fig. 1 compound of formula I
The XRPD collection of illustrative plates of Fig. 2 compound of formula I crystal formations B
The XRPD collection of illustrative plates of Fig. 3 compound of formula I crystal formations M1
The XRPD collection of illustrative plates of Fig. 4 compound of formula I crystal formations O
The XRPD collection of illustrative plates of Fig. 5 compound of formula I crystal formations P
The XRPD collection of illustrative plates of Fig. 6 compound of formula I crystal formations Q
The XRPD collection of illustrative plates of Fig. 7 compound of formula I crystal formations T
The XRPD collection of illustrative plates of Fig. 8 compound of formula I crystal formations U
The XRPD collection of illustrative plates of Fig. 9 compound of formula I crystal formations V
The XRPD collection of illustrative plates of Figure 10 compound of formula I crystal formations X
Specific embodiment
Below with reference to embodiment, the present invention is described in further detail, and embodiments of the invention are merely to illustrate technical scheme, not limit the spirit and scope of the invention.
The structure of compound be by nuclear magnetic resonance (1H NMR) come what is determined.Nuclear magnetic resonance (1H NMR) displacement (δ) with hundred a ten thousandths (ppm) for unit is given；Nuclear magnetic resonance (1H NMR) measure be to be carried out with BrukerAVANCE-400 nuclear magnetic resonance spectrometers, measure solvent be hexadeuterated dimethyl sulfoxide (CDCl3), inside it is designated as tetramethylsilane (TMS).
The measure of mass spectrum (MS) is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer：Therm, model：Finnigan LCQ advantage MAX) carry out.
The measure of HPLC spectrograms is carried out using Agilent Agilent1260DAD types liquid chromatograph.
Refer to that reaction bulb is for example connected into a nitrogen balloon for 1L volumes in term of the invention " blanket of nitrogen ".
Thin layer silica gel uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates.
The measure of X-ray powder diffraction (XRPD) is carried out using Panalytical Empyrean X-ray powder diffractions analyzers, and design parameter see the table below：
Thermogravimetric analysis (TGA) and differential scanning calorimeter (DSC) determination data are gathered in TA Q500 thermogravimetric analysis and TA Q200 differential scanning calorimeters respectively, and instrument parameter is listed in the table below：
Term " room temperature " in the present invention refers to that temperature is between 10 DEG C to 25 DEG C.
The preparation of compound 1- (4- the methoxyphenyls)-7- oxos of embodiment 1-6- [2- methyl-4- (2- oxo-pyrrolidine-1- bases) phenyl]-4,5,6,7- tetrahydrochysene-1H- pyrazolo [3,4-c] pyridine-3-carboxamide
Preparation scheme is as follows：
The first step：The preparation of a
By 2- methyl-4-nitrophenylamines (3g, 19.7mmol) it is dissolved in dichloromethane (60ml), add N, N- diisopropylethylamine (6.4g, 49.5mmol), ice bath cools to less than 5 DEG C, and 5- chloracetyl chlorides (3.7g is added dropwise, 23.9mmol) to obtain reactant mixture, the reactant mixture is set to react at room temperature overnight.Thin-layer chromatography tracks reaction process, and after reaction completely, to pouring into water in reaction solution, dividing liquid, washing 3 times, anhydrous magnesium sulfate to dry, filtering, vacuum distillation obtains compound a (4.2g, yellow solid), yield after removing solvent：78.8%.
MS m/z(ES):271.1[M+1]
Second step：The preparation of b
A (4.2g, 15.5mmol) is dissolved in tetrahydrofuran (80ml), sodium hydride (0.75g, 31.3mmol) is dividedly in some parts under ice bath to obtain reactant mixture, the reactant mixture is reacted at room temperature overnight.Thin-layer chromatography tracks reaction process, after reaction completely, to adding frozen water in reactant mixture under ice bath, sodium hydride is quenched, after vacuum distillation removes tetrahydrofuran, residue purifies to obtain b (3.27g, yellow solid), yield through column chromatography after ethyl acetate extracts 2 times, anhydrous magnesium sulfate is dried, filtered, vacuum distillation removes solvent：90.1%.
MS m/z(ES)：235.1[M+1]
3rd step：The preparation of c
B (3.27g, 14.0mmol) is dissolved in dichloromethane (100ml), phosphorus pentachloride (8.7g, 41.8mmol) is dividedly in some parts under ice bath to obtain reactant mixture, make reactant mixture back flow reaction at 40 DEG C.Question response liquid-based originally not effervescent when, thin-layer chromatography tracks reaction process, after reaction completely, c (4g are obtained after phosphorus pentachloride being quenched, divides liquid, washing 3 times, anhydrous magnesium sulfate drying, filtering, vacuum distillation removing solvent to addition frozen water in reactant mixture under ice bath, yellow solid), yield：94.6%.
MS m/z(ES)：303.0,305.0 [M+1]
4th step：The preparation of d
By c (4g, 13.2mmol) it is dissolved in morpholine (40ml) to obtain reactant mixture, make reactant mixture back flow reaction 2 hours at 120 DEG C, thin-layer chromatography tracks reaction process, after reaction completely, add ethyl acetate to dissolve, wash 3 times, anhydrous magnesium sulfate is dried, filter, vacuum distillation obtains d (3.98g, black solid), yield after removing solvent：95.0%.
MS m/z(ES)：318.1[M+1]
5th step：The preparation of e
By d (3.98g, 12.5mmol) it is dissolved in ethanol (50ml), adds nine water vulcanized sodium (9g, 37.5mmol), water (20ml) is added to obtain reactant mixture, back flow reaction is overnight at 50 DEG C to make the reactant mixture.Thin-layer chromatography tracking reaction process, after reacting complete, e (3.2g, yellow solid), yield is obtained after the removing ethanol that is concentrated under reduced pressure, ethyl acetate extraction three times, merging organic phase, anhydrous magnesium sulfate drying, filtering, vacuum distillation removing solvent：88.9%.
MS m/z(ES)：288.2[M+1]
6th step：The preparation of f
By e (3.2g, 11.1mmol) it is dissolved in dichloromethane (50ml), add N, N- diisopropylethylamine (3.6g, 27.9mmol), under ice bath, 4- chlorobutanoylchlorides (2.4g is added dropwise, 17.0mmol) to obtain reactant mixture, the reactant mixture is set to react at room temperature overnight.Thin-layer chromatography tracks reaction process, after reaction completely, to adding water, point liquid, washing 3 times, anhydrous magnesium sulfate to dry in reaction solution, filtering, vacuum distillation remove after solvent to obtain f (3.5g, yellow solid), yield：80.3%.
MS m/z(ES)：392.2[M+1]
7th step：The preparation of g
F (3.5g, 8.9mmol) is dissolved in tetrahydrofuran (50ml), sodium hydride (0.6g, 25mmol) is dividedly in some parts under ice bath to obtain reactant mixture, the reactant mixture is reacted at room temperature overnight.Thin-layer chromatography tracks reaction process, after reaction completely, sodium hydride is quenched to frozen water is added in reaction solution, after vacuum distillation removes tetrahydrofuran, after adding dichloromethane extraction 2 times, merging organic phase, anhydrous magnesium sulfate drying, filtering, vacuum distillation to remove solvent, residue purifies to obtain g (2.59g, yellow solid), yield through column chromatography：81.7%.
MS m/z(ES)：356.2[M+1]
8th step：The preparation of h
By g (280mg, 0.79mmol) it is dissolved in toluene (10ml), [(4- methoxyphenyls) diazanyl] ethyl chloroacetate (214mg is added at room temperature, 0.83mmol), triethylamine (252mg, 2.5mmol) obtaining reactant mixture, back flow reaction is overnight at 120 DEG C to make the reactant mixture.Thin-layer chromatography tracks reaction process, after reaction completely, vacuum distillation removes toluene, after residue adds dichloromethane (20ml) dissolving, add trifluoroacetic acid (2ml) to obtain reactant mixture at room temperature, the reactant mixture is reacted at room temperature overnight.Thin-layer chromatography tracks reaction process, after reaction completely, h (300mg, yellow solid), yield is purified to obtain through column chromatography：77.9%.
MS m/z(ES)：489.2[M+1]
9th step：The preparation of Compounds of structural formula I 1- (4- methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4,5,6,7- tetrahydrochysene -1H- pyrazolo [3,4-c] pyridine-3-carboxamide
H (300mg, 0.61mmol) is dissolved in methyl alcohol (4ml), ammoniacal liquor (2ml) is added obtaining reactant mixture, back flow reaction is overnight at 70 DEG C to make the reactant mixture.Thin-layer chromatography tracks reaction process, after reaction completely, Compounds of structural formula I (208mg, light yellow solid), yield is purified to obtain through column chromatography：73.8%.
MS m/z(ES)：460.2[M+1]
1H NMR(400MHz,CDCl3) δ 7.51-7.46 (m, 4H), 7.17 (d, J=8.5Hz, 1H), 6.93 (d, J=8.8Hz, 2H), 6.87 (br s, 1H), 5.54 (br s, 1H), 4.09-4.02 (m, 1H), 3.84-3.79 (m, 6H), 3.45-3.32 (m, 2H), 2.60 (t, J=8.0Hz, 2H), 2.26 (s, 3H), 2.19-2.13 (m, 2H)
The sample that column chromatography is obtained carries out solid-state analysis with X-ray powder diffraction (XRPD) image, as a result find the sample in XRPD without obvious characteristic peak, therefore judge that the sample, as unformed, is shown in accompanying drawing 1.The product obtained by TLC separation has carried out the analysis of XRPD methods, it is found that sample is still unformed.
The preparation of the crystal formation B of the compound of formula I of embodiment 2
Compound of formula I 1- (4- the methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4,5,6 that 100mg is prepared according to embodiment 1,7- tetrahydrochysene -1H- pyrazolos [3,4-c] pyridine-3-carboxamide add sample bottle in, add 3ml methyl alcohol, heating be completely dissolved it after, it is cooled to room temperature, suction filtration, collects the crystal for separating out, 150 DEG C of vacuum drying, obtain 82mg light yellow solids, yield 82%.
The X-ray powder diffraction collection of the crystallized sample is shown in accompanying drawing 2, and its collection of illustrative plates has the characteristic peak of the angle of diffraction shown in following table, interplanar distance and relative intensity：
The DSC of the crystallized sample has characteristic absorption peak at about 202 DEG C, and it is weightless for 0.25% at 150 DEG C that TGA shows that the crystallized sample is heated to.Learnt according to result above, the crystal formation is anhydrous crystal forms, is defined as crystal formation B.
The preparation of the crystal formation M1 of the compound of formula I of embodiment 3
Compound of formula I 1- (4- the methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4 that 30mg is prepared according to embodiment 2,5,6, the crystal formation B of 7- tetrahydrochysene -1H- pyrazolo [3,4-c] pyridine-3-carboxamide is added in sample bottle, adds 0.5ml acetone, the suspension of formation is stirred overnight at room temperature, the sample drying at room temperature obtained after centrifugation, obtains 26mg light yellow solids, yield 86.7%.
The X-ray powder diffraction collection of the crystallized sample is shown in accompanying drawing 3, and its collection of illustrative plates has the characteristic peak of the angle of diffraction shown in following table, interplanar distance and relative intensity：
The DSC of the crystallized sample has multiple feature endothermic/exothermic peaks in about 85 DEG C, 106 DEG C, 144 DEG C, 149 DEG C, 179 DEG C and 208 DEG C, and it is weightless for 7.40% at 100 DEG C that TGA shows that the crystallized sample is heated to.The crystallized sample1HNMR test results show fraction containing acetone quality 0.2% in sample, with reference to heat run gained TGA data, can speculate that acetone is adsorption solvent.Determination of moisture is carried out with KF methods to the crystallized sample and show that its water content is 7.2%.Learnt according to result above, the crystal formation is dihydrate, is defined as crystal formation M1.
The preparation of the crystal formation O of the compound of formula I of embodiment 4
Compound of formula I 1- (4- the methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4 that 30mg is prepared according to embodiment 1; 5; 6; 7- tetrahydrochysene -1H- pyrazolos [3; 4-c] pyridine-3-carboxamide add sample bottle in; 1ml dichloromethane is added to be dissolved; slow volatilization at room temperature makes it separate out solid; suction filtration; it is cool but to room temperature after the solid of gained is heated into 180 DEG C under nitrogen protection; obtain 25mg light yellow solids, yield 83.3%.
The X-ray powder diffraction collection of the crystallized sample is shown in accompanying drawing 4, and its collection of illustrative plates has the characteristic peak of the angle of diffraction shown in following table, interplanar distance and relative intensity：
The DSC of the crystallized sample has the endothermic peak of overlap in about 199 DEG C and 208 DEG C, and it is weightless for 0.82% at 180 DEG C that TGA shows that the crystallized sample is heated to.Learnt according to result above, the crystal formation is anhydrous crystal forms, is defined as crystal formation O.
The preparation of the crystal formation P of the compound of formula I of embodiment 5
Compound of formula I 1- (4- the methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4 that 30mg is prepared according to embodiment 1; 5; 6; 7- tetrahydrochysene -1H- pyrazolos [3; 4-c] pyridine-3-carboxamide add sample bottle in; 1ml dichloromethane is added to be dissolved; slow volatilization at room temperature makes it separate out solid; suction filtration; it is cool but to room temperature after the solid of gained is heated into 205 DEG C under nitrogen protection; obtain 24mg light yellow solids, yield 80.0%.
The X-ray powder diffraction collection of the crystallized sample is shown in accompanying drawing 5, and its collection of illustrative plates has the characteristic peak of the angle of diffraction shown in following table, interplanar distance and relative intensity：
The DSC of the crystallized sample has characteristic absorption peak at about 211 DEG C, and it is weightless for 0.24% at 200 DEG C that TGA shows that the crystallized sample is heated to.Learnt according to result above, the crystal formation is anhydrous crystal forms, is defined as crystal formation P.
The preparation of the crystal formation Q of the compound of formula I of embodiment 6
Compound of formula I 1- (4- the methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4 that 30mg is prepared according to embodiment 1; 5; 6; 7- tetrahydrochysene -1H- pyrazolos [3; 4-c] pyridine-3-carboxamide add sample bottle in; 1ml dichloromethane is added to be dissolved; slow volatilization at room temperature makes it separate out solid; suction filtration; it is cool but to room temperature after the solid of gained is heated into 140 DEG C under nitrogen protection; obtain 26mg light yellow solids, yield 86.7%.
The X-ray powder diffraction collection of the crystallized sample is shown in accompanying drawing 6, and its collection of illustrative plates has the characteristic peak of the angle of diffraction shown in following table, interplanar distance and relative intensity：
The DSC of the crystallized sample has multiple endothermic/exothermic peaks in about 156 DEG C, 168 DEG C, 189 DEG C, 200 DEG C and 208 DEG C, and it is weightless for 1.1% at 150 DEG C that TGA shows that the crystallized sample is heated to.Learnt according to result above, the crystal formation is anhydrous crystal forms, is defined as crystal formation Q.
The preparation of the crystal formation T of the compound of formula I of embodiment 7
Compound of formula I 1- (4- the methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4 that 30mg is prepared according to embodiment 1,5,6,7- tetrahydrochysene -1H- pyrazolos [3,4-c] pyridine-3-carboxamide compound add sample bottle in, 0.5ml tetrahydrofurans, the suspension of formation is added to be stirred overnight at 50 DEG C, room temperature vacuum drying after centrifugation.The solid of gained is dissolved in 1.5ml pure water, the suspension of formation is stirred overnight at 50 DEG C, after centrifugation after room temperature vacuum drying, obtains 22mg light yellow solids, yield 73.3%.
The X-ray powder diffraction collection of the crystallized sample is shown in accompanying drawing 7, and its collection of illustrative plates has the characteristic peak of the angle of diffraction shown in following table, interplanar distance and relative intensity：
The DSC of the crystallized sample has multiple feature endothermic/exothermic peaks in about 83 DEG C, 107 DEG C, 148 DEG C and 208 DEG C, and it is weightless for 7.7% at 120 DEG C that TGA shows that the crystallized sample is heated to.The crystallized sample1HNMR test results show mass fraction containing tetrahydrofuran 0.3% in sample.Determination of moisture is carried out with KF methods to the crystallized sample and show that its water content is 7.3%.Learnt according to result above, the crystal formation is dihydrate, is defined as crystal formation T.
The preparation of the crystal formation U of the compound of formula I of embodiment 8
Compound of formula I 1- (4- the methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4 that 15mg is prepared according to embodiment 7,5,6,7- tetrahydrochysene -1H- pyrazolos [3,4-c] pyridine-3-carboxamide crystal formation T purge 40min in the nitrogen atmosphere after, obtain 13.5mg light yellow solids, yield 90.0%.
The X-ray powder diffraction collection of the crystallized sample is shown in accompanying drawing 8, and its collection of illustrative plates has the characteristic peak of the angle of diffraction shown in following table, interplanar distance and relative intensity：
After the crystallized sample exposes in atmosphere again, can rapidly absorb water and be changed into crystal formation T.Learnt according to result above, the crystal formation is anhydrous crystal forms, is defined as crystal formation U.
The preparation of the crystal formation V of the compound of formula I of embodiment 9
Compound of formula I 1- (4- the methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4 that 30mg is prepared according to embodiment 1,5,6,7- tetrahydrochysene -1H- pyrazolos [3,4-c] pyridine-3-carboxamide compound add sample bottle in, 0.9ml methyl alcohol is added to be completely dissolved, slow volatilization at room temperature makes it separate out solid.Obtain cool but to room temperature after solid is heated to 120 DEG C under nitrogen protection after centrifugation, obtain 18mg light yellow solids, yield 60.0%.
The X-ray powder diffraction collection of the crystallized sample is shown in accompanying drawing 9, and its collection of illustrative plates has the characteristic peak of the angle of diffraction shown in following table, interplanar distance and relative intensity：
The DSC of the crystallized sample has multiple feature endothermic/exothermic peaks in about 168 DEG C, 175 DEG C and 208 DEG C, and it is weightless for 1.9% at 15 DEG C that TGA shows that the crystallized sample is heated to.The crystallized sample1HNMR test results show fraction containing methanol quality 0.2% in sample.Determination of moisture is carried out with KF methods to the crystallized sample and show that its water content is 2.1%.Learnt according to result above, the crystal formation is hydrate crystal forms, is defined as crystal formation V.
The preparation of the crystal formation X of the compound of formula I of embodiment 10
Compound of formula I 1- (4- the methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4 that 200mg is prepared according to embodiment 1,5,6,7- tetrahydrochysene -1H- pyrazolos [3,4-c] pyridine-3-carboxamide add sample bottle in, add 1.6ml N, dinethylformamide, be heated to 80 DEG C be completely dissolved it after, be added dropwise 1.2ml water, naturally it is cool but to room temperature, suction filtration, collects the crystal for separating out, 70 DEG C of dryings, obtain 166mg light yellow solids, yield 83.0%.
The X-ray powder diffraction collection of the crystallized sample is shown in accompanying drawing 10, and its collection of illustrative plates has the characteristic peak of the angle of diffraction shown in following table, interplanar distance and relative intensity：
The DSC of the crystallized sample has characteristic absorption peak at about 214 DEG C, and it is weightless for 0.32% at 150 DEG C that TGA shows that the crystallized sample is heated to.Learnt according to result above, the crystal formation is anhydrous crystal forms, is defined as crystal formation X.
The preparation of the crystal formation B of the compound of formula I of embodiment 11
Compound of formula I 1- (4- the methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4,5,6 that 100mg is prepared according to embodiment 1,7- tetrahydrochysene -1H- pyrazolos [3,4-c] pyridine-3-carboxamide add sample bottle in, add 10ml ethyl acetate, heating be completely dissolved it after, it is cooled to room temperature, suction filtration, collects the crystal for separating out, 150 DEG C of vacuum drying, obtain 86mg light yellow solids, yield 86%.
Powder diffraction spectrum is consistent with embodiment 2.
The preparation of the crystal formation M1 of the compound of formula I of embodiment 12
Compound of formula I 1- (4- the methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4 that 50mg is prepared according to embodiment 2,5,6, the crystal formation B of 7- tetrahydrochysene -1H- pyrazolo [3,4-c] pyridine-3-carboxamide is added in sample bottle, adds 0.45ml tetrahydrofurans, the suspension of formation is stirred overnight at room temperature, the sample drying at room temperature obtained after centrifugation, obtains 42mg light yellow solids, yield 84%.
Powder diffraction spectrum is consistent with embodiment 3.
The preparation of the crystal formation O of the compound of formula I of embodiment 13
Compound of formula I 1- (4- the methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4 that 40mg is prepared according to embodiment 1; 5; 6; 7- tetrahydrochysene -1H- pyrazolos [3; 4-c] pyridine-3-carboxamide add sample bottle in; 0.5ml tetrahydrofurans and 0.6ml ethyl acetate is added to be dissolved; slow volatilization at room temperature makes it separate out solid; suction filtration; it is cool but to room temperature after the solid of gained is heated into 180 DEG C under nitrogen protection; obtain 34mg light yellow solids, yield 85%.
Powder diffraction spectrum is consistent with embodiment 4.
The preparation of the crystal formation P of the compound of formula I of embodiment 14
Compound of formula I 1- (4- the methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4 that 40mg is prepared according to embodiment 1; 5; 6; 7- tetrahydrochysene -1H- pyrazolos [3; 4-c] pyridine-3-carboxamide add sample bottle in; 0.5ml tetrahydrofurans and 0.6ml ethyl acetate is added to be dissolved; slow volatilization at room temperature makes it separate out solid; suction filtration; it is cool but to room temperature after the solid of gained is heated into 205 DEG C under nitrogen protection; obtain 28mg light yellow solids, yield 70%.
Powder diffraction spectrum is consistent with embodiment 5.
The preparation of the crystal formation Q of the compound of formula I of embodiment 15
Compound of formula I 1- (4- the methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4 that 40mg is prepared according to embodiment 1; 5; 6; 7- tetrahydrochysene -1H- pyrazolos [3; 4-c] pyridine-3-carboxamide add sample bottle in; 0.5ml tetrahydrofurans and 0.6ml ethyl acetate is added to be dissolved; slow volatilization at room temperature makes it separate out solid; suction filtration; it is cool but to room temperature after the solid of gained is heated into 140 DEG C under nitrogen protection; obtain 30mg light yellow solids, yield 75%.
Powder diffraction spectrum is consistent with embodiment 6.
The preparation of the crystal formation T of the compound of formula I of embodiment 16
Compound of formula I 1- (4- the methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4 that 30mg is prepared according to embodiment 1,5,6,7- tetrahydrochysene -1H- pyrazolos [3,4-c] pyridine-3-carboxamide compound add sample bottle in, 0.6ml acetone, the suspension of formation is added to be stirred overnight at 50 DEG C, room temperature vacuum drying after centrifugation.The solid of gained is dissolved in 1.5ml water, the suspension of formation is stirred overnight at 50 DEG C, after centrifugation after room temperature vacuum drying, obtains 24mg light yellow solids, yield 80%.
Powder diffraction spectrum is consistent with embodiment 7.
The preparation of the crystal formation U of the compound of formula I of embodiment 17
Compound of formula I 1- (4- the methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4 that 20mg is prepared according to embodiment 16,5,6,7- tetrahydrochysene -1H- pyrazolos [3,4-c] pyridine-3-carboxamide crystal formation T purge 40min in the nitrogen atmosphere after, obtain 18.5mg light yellow solids, yield 92.5%.
Powder diffraction spectrum is consistent with embodiment 8.
The preparation of the crystal formation V of the compound of formula I of embodiment 18
Compound of formula I 1- (4- the methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4 that 20mg is prepared according to embodiment 1,5,6,7- tetrahydrochysene -1H- pyrazolos [3,4-c] pyridine-3-carboxamide compound add sample bottle in, 0.7ml dioxane is added to be completely dissolved, slow volatilization at room temperature makes it separate out solid.Obtain cool but to room temperature after solid is heated to 120 DEG C under nitrogen protection after centrifugation, obtain 14mg light yellow solids, yield 70.0%.
Powder diffraction spectrum is consistent with embodiment 9.
The preparation of the crystal formation X of the compound of formula I of embodiment 19
Compound of formula I 1- (4- the methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4 that 100mg is prepared according to embodiment 1,5,6,7- tetrahydrochysene -1H- pyrazolos [3,4-c] pyridine-3-carboxamide add sample bottle in, add 0.9ml N, dinethylformamide and 0.5ml water, it is naturally cool but to room temperature, suction filtration after being heated to 80 DEG C and being completely dissolved it, collect the crystal for separating out, 70 DEG C of dryings, obtain 73mg light yellow solids, yield 73.0%.
Powder diffraction spectrum is consistent with embodiment 10.
The dissolubility of test example 1 investigates experiment
For the dissolubility of crystal formation B, M1, O, P, Q, T, U, V and X prepared by the amorphous and embodiment 2~10 for investigating the preparation of the embodiment of the present invention 1, the present invention is respectively under the conditions of 25 DEG C, 37 DEG C in the hydrochloric acid of pH=1.0 (0.1N) and the acetic acid-sodium acetate buffer solution of pH=4.0, determine the amorphous of the preparation of embodiment 1, the equilbrium solubility (saturated solution) of crystal formation B, M1, O, P, Q, T, U, V and X prepared by embodiment 2~10, it is as a result as shown in table 1 below：
The dissolubility test of table 1
Dissolubility test result shows, 25 DEG C, under the conditions of 37 DEG C in the hydrochloric acid of pH=1.0 (0.1N) and the acetic acid-sodium acetate buffer solution of pH=4.0, the unformed of compound of formula I, crystal formation B, crystal formation M1, crystal formation O, crystal formation P, crystal formation Q, crystal formation T, crystal formation U, crystal formation V and crystal formation X have balance dissolubility well.
The chemical stability of test example 2 investigates experiment
Opening divides placement during crystal formation B, M1, O, P, Q, T, U, V and X sample that embodiment 1 prepares the preparation of unformed and embodiment 2~10 is respectively put into the culture dish of cleaning, investigate the stability of the sample under the conditions of high temperature (60 DEG C), high humidity (25 DEG C, RH90% ± 5%), high light (4500Lx ± 500Lx), sample time is investigated for 5 days and 10 days, is placed 10 days.It was measured by sampling at 5 days and 10 days respectively, HPLC purity detecting results see the table below 2：
The stability test (purity %) of table 2
Study on the stability result shows, it is unformed shown in Formulas I structure, crystal formation B, crystal formation M1, crystal formation O, crystal formation P, crystal formation Q, crystal formation T, crystal formation U, crystal formation V and crystal formation X is under conditions of opening is placed, through high temperature (60 DEG C), (25 DEG C of high humidity, RH90% ± 5%), stability under the conditions of high light (4500Lx ± 500Lx) etc. compares discovery, crystal formation B of the present invention, crystal formation M1, crystal formation O, crystal formation P, crystal formation Q, crystal formation T, crystal formation U, crystal formation V and crystal formation X are in high humidity, high temperature, illumination condition purity is without significant change, the chemical stability of various crystal formations i.e. of the invention is preferable；And unformed product purity under conditions of high humidity is without purity is decreased obviously under significant change, but hot conditions and under illumination condition.Illustrate under illumination, high temperature, super-humid conditions, the embodiment of the present invention 2~10 prepare crystal formation B, M1, O, P, Q, T, U, V and X stability be substantially better than it is unformed.
The physical stability of test example 3 investigates experiment
Sample crystal formation B prepared by embodiment 2 is (as 0 day reference data of crystal formation B,Lot number 20140408),Sample crystal formation P prepared by embodiment 5 is (as 0 day reference data of crystal formation P,Lot number 20140415),Sample crystal formation Q prepared by embodiment 6 is (as 0 day reference data of crystal formation Q,Lot number 20140418),Sample crystal formation T prepared by embodiment 7 is (as 0 day reference data of crystal formation T,Lot number 20140421),Sample crystal formation X prepared by embodiment 10 is (as 0 day reference data of crystal formation X,Lot number 20140427),Opening divides placement in being respectively put into the culture dish of cleaning,Investigate at high temperature (60 DEG C),(25 DEG C of high humidity,RH90% ± 5%),Under the conditions of high light (4500Lx ± 500Lx),The physical stability of each crystal form samples,Sample time is investigated for 10 days.Sampled at the 10th day, solid-state analysis is carried out with X-ray powder diffraction (XRPD) figure, powder diffraction data result is as shown in table 3 below~7.Result shows, under conditions of opening is placed, under the conditions of high temperature, high humidity, high light etc., after 10 days, X-ray powder diffraction angle value (being represented with the 2 θ angles of diffraction) and sample crystal formation B, P, Q, T, X reference data of 0 day of crystal formation B, P, Q, T, X are consistent, that is, illustrate that the physical stability of crystal formation of the present invention is good.
Powder diffraction angle-datas (the 2 θ angle of diffraction) of the crystal formation B of table 3 under high temperature, high humidity, illumination condition
Powder diffraction angle-datas (the 2 θ angle of diffraction) of the crystal formation P of table 4 under high temperature, high humidity, illumination condition
Peak No. Crystal formation P 0 day High temperature 10 days Illumination 10 days High humidity 10 days
1 6.601970 6.654891 6.625926 6.574135
2 8.155473 8.216963 8.135899 8.152156
3 10.870700 10.826325 10.921263 10.895623
4 11.885930 11.841358 11.931625 11.862592
5 12.954900 12.892692 12.931592 13.024856
6 14.975110 14.945862 14.982356 15.025889
7 15.581570 15.558268 15.623893 15.581662
8 20.268180 20.316932 20.245811 20.285583
9 23.829680 23.871669 23.794946 23.861449
Powder diffraction angle-datas (the 2 θ angle of diffraction) of the crystal formation Q of table 5 under high temperature, high humidity, illumination condition
Peak No. Crystal formation Q 0 day High temperature 10 days Illumination 10 days High humidity 10 days
1 6.483622 6.548856 6.521635 6.455923
2 6.700818 6.651698 6.716552 6.745691
3 10.199690 10.234916 10.185921 10.158916
4 12.299440 12.271561 12.356456 12.321583
5 12.958730 13.015916 12.981514 12.921162
6 13.387550 13.421592 13.358461 13.378141
7 14.980960 15.047895 14.945468 14.994681
8 21.322250 21.345812 21.278618 21.371592
9 24.849810 24.795123 24.824586 24.871686
Powder diffraction angle-datas (the 2 θ angle of diffraction) of the crystal formation T of table 6 under high temperature, high humidity, illumination condition
Peak No. Crystal formation T 0 day High temperature 10 days Illumination 10 days High humidity 10 days
1 11.288110 11.325896 11.315859 11.294583
2 11.833850 11.824893 11.792661 11.814692
3 15.940380 15.981456 15.954826 15.895492
4 16.549990 16.574892 16.498262 16.582262
5 18.911510 18.948562 18.889262 18.894825
6 19.280690 19.248613 19.315658 19.325491
7 19.744570 19.781561 19.714592 19.754816
8 21.793840 21.845912 21.831491 21.768911
9 23.679410 23.681613 23.721464 23.644513
Powder diffraction angle-datas (the 2 θ angle of diffraction) of the crystal formation X of table 7 under high temperature, high humidity, illumination condition
The moisture absorption of test example 4 investigates experiment
Opening divides placement during crystal formation B, M1, O, P, Q, T, U, V and X sample prepared by unformed, embodiment 2~10 prepared by embodiment 1 is respectively put into the culture dish of cleaning, investigate and placed under the conditions of ambient temperature and moisture (25 DEG C, RH50%), check that its quality increases percentage, it is as a result as shown in table 8 below：
The wettability test of table 8
Lot number Crystal formation 6h 12h 24h 48h
20140309 It is unformed 0.2% 0.4% 0.7% 0.9%
20140408 Crystal formation B 0.01% 0.03% 0.05% 0.08%
20140409 Crystal formation M1 0.3% 0.5% 0.6% 0.7%
20140414 Crystal formation O 0.2% 0.5% 0.7% 0.9%
20140415 Crystal formation P 0.3% 0.5% 0.7% 0.9%
20140418 Crystal formation Q 0.2% 0.4% 0.5% 0.7%
20140421 Crystal formation T 0.3% 0.7% 1.2% 1.8%
20140424 Crystal formation U 5.6% 7.7% 9.1% 9.4%
20140425 Crystal formation V 0.3% 0.6% 0.8% 1.0%
20140427 Crystal formation X 0.02% 0.04% 0.07% 0.09%
Result of the test shows, under the conditions of ambient temperature and moisture (25 DEG C, RH50%), the crystal formation B of formula I, crystal formation X, quality increase percentage and is respectively less than 0.2%, i.e. no hygroscopicity；Crystal formation M1, crystal formation O, crystal formation P, crystal formation Q, crystal formation T, crystal formation V mass increase percentage in the range of 0.2%-2%, i.e. slightly hygroscopicity；Crystal formation U mass increases percentage and is more than in the range of 2%, that is, have hygroscopicity.
Effect example compound of formula I and its each crystal formation are to the Experiment on Function of normal mouse APTT
Test objective：The crystal formation that under investigation 5mg/kg dosages prepared by each embodiment is upon administration to the effect of mouse APTT.
1. test material：
1.1. medicine：
By reagent：Prepared by compound of formula I (unformed), embodiment 1, provided by Chengdu Easton Pharmaceutical Co., Ltd.'s study on the synthesis room, light yellow solid, lot number：20140309；
Positive control drug：Eliquis, purchased from Shanghai Chemexpress Technology Co., Ltd., purity 99.9%, lot number HM-038_13-20140427；
By reagent：Prepared by crystal formation B, embodiment 2, provided by Chengdu Easton Pharmaceutical Co., Ltd.'s study on the synthesis room, light yellow solid, lot number：20140408；
By reagent：Prepared by crystal formation M1, embodiment 3, provided by Chengdu Easton Pharmaceutical Co., Ltd.'s study on the synthesis room, light yellow solid, lot number：20140409；
By reagent：Prepared by crystal formation O, embodiment 4, provided by Chengdu Easton Pharmaceutical Co., Ltd.'s study on the synthesis room, light yellow solid, lot number：20140414；
By reagent：Prepared by crystal formation P, embodiment 5, provided by Chengdu Easton Pharmaceutical Co., Ltd.'s study on the synthesis room, light yellow solid, lot number：20140415；
By reagent：Prepared by crystal formation Q, embodiment 6, provided by Chengdu Easton Pharmaceutical Co., Ltd.'s study on the synthesis room, light yellow solid, lot number：20140418；
By reagent：Prepared by crystal formation T, embodiment 7, provided by Chengdu Easton Pharmaceutical Co., Ltd.'s study on the synthesis room, light yellow solid, lot number：20140421；
By reagent：Prepared by crystal formation U, embodiment 8, provided by Chengdu Easton Pharmaceutical Co., Ltd.'s study on the synthesis room, light yellow solid, lot number：20140424；
By reagent：Prepared by crystal formation V, embodiment 9, provided by Chengdu Easton Pharmaceutical Co., Ltd.'s study on the synthesis room, light yellow solid, lot number：20140425；
By reagent：Prepared by crystal formation X, embodiment 10, provided by Chengdu Easton Pharmaceutical Co., Ltd.'s study on the synthesis room, light yellow solid, lot number：20140427；
1.2 test equipments：
Sysmex CA7000 type full-automatic blood coagulation analyzers；
Roche C501 automatic clinical chemistry analyzers；
Heparin tube, operating scissors, syringe etc.；
1.3 experimental animals：
KM mouse, 22~24g of body weight, 120, male and female half and half are provided, production facility licensing by Chengdu up to large bio tech ltd:SCXK (river) 2013-24.Animal is raised in Animal House after buying back, adaptability observation at least 3 days, quarantines qualified rear for testing.
2.1 packets：
Mouse is grouped according to body weight according to table 9, every group 10, male and female half and half, no difference of science of statistics between group；
The experiment of table 9 packet and dosage regimen
2.2APTT is determined：Corresponding by reagent (blank group gives physiological saline) is given to each group gavage respectively according to table 9, after administration 1h, eye socket takes blood in the 0.5ml vacuum test tubes containing sodium citrate, and the APTT of each animal is determined after collection blood sample；
3. statistical method：
Counted using Excel, experimental data is usedRepresent, it is multigroup between compare statistics comparing carried out using the bilateral T methods of inspection.
4. result of the test：
Influence of the table 10 to normal mouse APTT
Group Tested material Dosage (mg/kg) APTT values (s)
Blank group Physiological saline 5 16.11±1.05
Positive group Eliquis 5
1 group of embodiment It is unformed 5
2 groups of embodiment Crystal formation B 5
3 groups of embodiment Crystal formation M1 5
4 groups of embodiment Crystal formation O 5
5 groups of embodiment Crystal formation P 5
6 groups of embodiment Crystal formation Q 5
7 groups of embodiment Crystal formation T 5
8 groups of embodiment Crystal formation U 5
9 groups of embodiment Crystal formation V 5
10 groups of embodiment Crystal formation X 5
Note：Compared with blank group*P ＜ 0.05；*P ＜ 0.01；
Compared with positive group△P ＜ 0.05；△△P ＜ 0.01；
Compared with 1 group of embodiment◇P ＜ 0.05；◇◇P ＜ 0.01.
5. conclusion：
(1) as can be seen from Table 10, compared with blank group, after administration 1h, positive group, APTT (activated partial thromboplastin time) the values pole of each embodiment group dramatically increase (P ＜ 0.01), illustrate that positive drug Eliquis, embodiment 1 and its each crystal formation extremely can significantly extend the APTT values of mouse after 1h is administered；
(2) compared with positive group, the APTT values pole of each embodiment group dramatically increases (P ＜ 0.01), illustrates that the compound of embodiment 1 (unformed) and its each crystal formation are superior to positive group to extension mouse APTT values；
(3) compared with 1 group of embodiment, the APTT values pole of 2 groups of embodiment dramatically increases (P ＜ 0.01) and the APTT values of 3,4,6,10 groups of embodiment dramatically increase (P ＜ 0.05), illustrate the crystal formation B of the compound of embodiment 2, the crystal formation M1 of the compound of embodiment 3, the compound crystal form O of embodiment 4, the compound crystal form Q of embodiment 6, the compound crystal form X of embodiment 10 effect it is relatively more preferable.
For the ordinary skill in the art it is apparent that; in the case of without departing from spirit or scope of the present invention; can to the compounds of this invention, composition with and preparation method thereof various modification and transformations for carrying out; therefore; protection scope of the present invention covers the various modification and transformations carried out to the present invention, as long as in the range of the modification or change cover in claim and its equivalent embodiments.

Claims (25)

1. a kind of 1- (4- methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) benzene as shown in structural formula I Base] -4,5,6,7- tetrahydrochysene -1H- pyrazolo [3,4-c] pyridine-3-carboxamide compounds crystal formation B, it is characterised in that use Cu-k Ray carries out x-ray powder measure, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
2. crystal formation B according to claim 1, it is characterised in that it has x-ray powder substantially as shown in Figure 2 Diffracting spectrum.
3. a kind of 1- (4- methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4,5,6,7- tetrahydrochysenes -1H- The crystal formation M1 of pyrazolo [3,4-c] pyridine-3-carboxamide compound, it is characterised in that carry out X-ray using Cu-ka rays Powder is determined, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
4. crystal formation M1 according to claim 3, it is characterised in that it has x-ray powder substantially as shown in Figure 3 Diffracting spectrum.
5. a kind of 1- (4- methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4,5,6,7- tetrahydrochysenes -1H- The crystal formation O of pyrazolo [3,4-c] pyridine-3-carboxamide compound, it is characterised in that carry out X-ray powder using Cu-ka rays End determines, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
6. crystal formation O according to claim 5, it is characterised in that it has x-ray powder substantially as shown in Figure 4 Diffracting spectrum.
7. a kind of 1- (4- methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4,5,6,7- tetrahydrochysenes -1H- The crystal formation P of pyrazolo [3,4-c] pyridine-3-carboxamide compound, it is characterised in that carry out X-ray powder using Cu-ka rays End determines, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
8. crystal formation P according to claim 7, it is characterised in that it has x-ray powder substantially as shown in Figure 5 Diffracting spectrum.
9. a kind of 1- (4- methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4,5,6,7- tetrahydrochysenes -1H- The crystal formation Q of pyrazolo [3,4-c] pyridine-3-carboxamide compound, it is characterised in that carry out X-ray powder using Cu-ka rays End determines, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
10. crystal formation Q according to claim 9, it is characterised in that it has x-ray powder substantially as shown in Figure 6 Diffracting spectrum.
A kind of 11. 1- (4- methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4,5,6,7- tetrahydrochysenes -1H- The crystal formation T of pyrazolo [3,4-c] pyridine-3-carboxamide compound, it is characterised in that carry out X-ray powder using Cu-ka rays End determines, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
12. crystal formation T according to claim 11, it is characterised in that it has x-ray powder substantially as shown in Figure 7 Diffracting spectrum.
A kind of 13. 1- (4- methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4,5,6,7- tetrahydrochysenes -1H- The crystal formation U of pyrazolo [3,4-c] pyridine-3-carboxamide compound, it is characterised in that carry out X-ray powder using Cu-ka rays End determines, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
14. crystal formation U according to claim 13, it is characterised in that it has X-ray powder substantially as shown in Figure 8 Last diffracting spectrum.
A kind of 15. 1- (4- methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4,5,6,7- tetrahydrochysenes -1H- The crystal formation V of pyrazolo [3,4-c] pyridine-3-carboxamide compound, it is characterised in that carry out X-ray powder using Cu-ka rays End determines, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
16. crystal formation V according to claim 15, it is characterised in that it has X-ray powder as of fig. 9 shown substantially Last diffracting spectrum.
A kind of 17. 1- (4- methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) phenyl] -4,5,6,7- tetrahydrochysenes -1H- The crystal formation X of pyrazolo [3,4-c] pyridine-3-carboxamide compound, it is characterised in that carry out X-ray powder using Cu-ka rays End determines, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
18. crystal formation X according to claim 17, it is characterised in that it has X-ray powder substantially as shown in Figure 10 Last diffracting spectrum.
A kind of 19. 1- (4- methoxyphenyls) -7- oxos -6- [2- methyl -4- (2- oxo-pyrrolidine -1- bases) benzene as shown in structural formula I Base] -4,5,6,7- tetrahydrochysene -1H- pyrazolo [3,4-c] pyridine-3-carboxamide compounds it is unformed, it is characterised in that it has substantially X-ray powder diffraction pattern as shown in Figure 1.
A kind of 20. methods of the crystal formation for preparing the compound shown in claim 1~19 any one Formulas I structure, it is characterised in that Comprise the following steps：
(1) compound shown in Formulas I structure is added in sample bottle, adds positive solvent, make its complete under room temperature or counterflow condition CL, directly or after anti-solvent is added dropwise is cooled to crystallizing at room temperature；
(2) normal pressure or vacuum drying under suction filtration, room temperature or heating condition, obtain different crystal formations；And it is optional, by the crystal formation It is added in anti-solvent and forms stirring, suction filtration after suspension, dries acquisition different crystal forms.
21. preparation methods according to claim 20, it is characterised in that described positive solvent is selected from methyl alcohol, ethanol, tetrahydrochysene One or more in furans, acetone, N,N-dimethylformamide, dioxane, dichloromethane and ethyl acetate；It is described anti- Solvent is selected from one or more in water, methyl tertiary butyl ether(MTBE), normal heptane, n-hexane and hexamethylene.
22. preparation method according to claim 20 or 21, it is characterised in that described positive solvent methanol, ethanol, two One or more in chloromethanes, N,N-dimethylformamide and ethyl acetate；Described anti-solvent is selected from water, methyl tertbutyl One or more in ether and normal heptane.
23. purposes according to claim 1~19, it is characterised in that the purposes is to prepare prevention or treatment thrombus or bolt Purposes in turunda thing.
24. purposes according to claim 23, it is characterised in that the purposes is the purposes in anticoagulant is prepared.
25. purposes according to any one of claim 23 crystal formation in Xa factor inhibitor medicine is prepared.
CN201510896986.XA 2015-12-08 2015-12-08 Polycrystal of pyridine derivative and preparation method and application thereof Active CN106854197B (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
CN202010741117.0A CN111718343A (en) 2015-12-08 2015-12-08 T crystal form of pyridine derivative, and preparation method and application thereof
CN202010741120.2A CN111704612A (en) 2015-12-08 2015-12-08 P crystal form of pyridine derivative, and preparation method and application thereof
CN201510896986.XA CN106854197B (en) 2015-12-08 2015-12-08 Polycrystal of pyridine derivative and preparation method and application thereof
CN202010740640.1A CN111808099A (en) 2015-12-08 2015-12-08 M1 crystal form of pyridine derivative, and preparation method and application thereof
CN202010740681.0A CN111848609A (en) 2015-12-08 2015-12-08 U crystal form of pyridine derivative, and preparation method and application thereof
CN202010741115.1A CN111848610B (en) 2015-12-08 2015-12-08 X crystal form of pyridine derivative, and preparation method and application thereof
CN202010740677.4A CN111848608A (en) 2015-12-08 2015-12-08 V crystal form of pyridine derivative, preparation method and application thereof
CN202010741116.6A CN111848611A (en) 2015-12-08 2015-12-08 Q crystal form of pyridine derivative, and preparation method and application thereof
CN202010741119.XA CN111763203A (en) 2015-12-08 2015-12-08 O crystal form of pyridine derivative, and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510896986.XA CN106854197B (en) 2015-12-08 2015-12-08 Polycrystal of pyridine derivative and preparation method and application thereof

Related Child Applications (8)

Application Number Title Priority Date Filing Date
CN202010740677.4A Division CN111848608A (en) 2015-12-08 2015-12-08 V crystal form of pyridine derivative, preparation method and application thereof
CN202010741120.2A Division CN111704612A (en) 2015-12-08 2015-12-08 P crystal form of pyridine derivative, and preparation method and application thereof
CN202010740640.1A Division CN111808099A (en) 2015-12-08 2015-12-08 M1 crystal form of pyridine derivative, and preparation method and application thereof
CN202010741119.XA Division CN111763203A (en) 2015-12-08 2015-12-08 O crystal form of pyridine derivative, and preparation method and application thereof
CN202010741115.1A Division CN111848610B (en) 2015-12-08 2015-12-08 X crystal form of pyridine derivative, and preparation method and application thereof
CN202010740681.0A Division CN111848609A (en) 2015-12-08 2015-12-08 U crystal form of pyridine derivative, and preparation method and application thereof
CN202010741116.6A Division CN111848611A (en) 2015-12-08 2015-12-08 Q crystal form of pyridine derivative, and preparation method and application thereof
CN202010741117.0A Division CN111718343A (en) 2015-12-08 2015-12-08 T crystal form of pyridine derivative, and preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN106854197A true CN106854197A (en) 2017-06-16
CN106854197B CN106854197B (en) 2020-09-01

Family

ID=59132291

Family Applications (9)

Application Number Title Priority Date Filing Date
CN202010741119.XA Pending CN111763203A (en) 2015-12-08 2015-12-08 O crystal form of pyridine derivative, and preparation method and application thereof
CN201510896986.XA Active CN106854197B (en) 2015-12-08 2015-12-08 Polycrystal of pyridine derivative and preparation method and application thereof
CN202010741115.1A Active CN111848610B (en) 2015-12-08 2015-12-08 X crystal form of pyridine derivative, and preparation method and application thereof
CN202010740640.1A Pending CN111808099A (en) 2015-12-08 2015-12-08 M1 crystal form of pyridine derivative, and preparation method and application thereof
CN202010740677.4A Pending CN111848608A (en) 2015-12-08 2015-12-08 V crystal form of pyridine derivative, preparation method and application thereof
CN202010741117.0A Pending CN111718343A (en) 2015-12-08 2015-12-08 T crystal form of pyridine derivative, and preparation method and application thereof
CN202010741116.6A Pending CN111848611A (en) 2015-12-08 2015-12-08 Q crystal form of pyridine derivative, and preparation method and application thereof
CN202010741120.2A Pending CN111704612A (en) 2015-12-08 2015-12-08 P crystal form of pyridine derivative, and preparation method and application thereof
CN202010740681.0A Pending CN111848609A (en) 2015-12-08 2015-12-08 U crystal form of pyridine derivative, and preparation method and application thereof

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN202010741119.XA Pending CN111763203A (en) 2015-12-08 2015-12-08 O crystal form of pyridine derivative, and preparation method and application thereof

Family Applications After (7)

Application Number Title Priority Date Filing Date
CN202010741115.1A Active CN111848610B (en) 2015-12-08 2015-12-08 X crystal form of pyridine derivative, and preparation method and application thereof
CN202010740640.1A Pending CN111808099A (en) 2015-12-08 2015-12-08 M1 crystal form of pyridine derivative, and preparation method and application thereof
CN202010740677.4A Pending CN111848608A (en) 2015-12-08 2015-12-08 V crystal form of pyridine derivative, preparation method and application thereof
CN202010741117.0A Pending CN111718343A (en) 2015-12-08 2015-12-08 T crystal form of pyridine derivative, and preparation method and application thereof
CN202010741116.6A Pending CN111848611A (en) 2015-12-08 2015-12-08 Q crystal form of pyridine derivative, and preparation method and application thereof
CN202010741120.2A Pending CN111704612A (en) 2015-12-08 2015-12-08 P crystal form of pyridine derivative, and preparation method and application thereof
CN202010740681.0A Pending CN111848609A (en) 2015-12-08 2015-12-08 U crystal form of pyridine derivative, and preparation method and application thereof

Country Status (1)

Country Link
CN (9) CN111763203A (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013119328A1 (en) * 2012-02-07 2013-08-15 Assia Chemical Industries Ltd. Solid state forms of apixaban
CN103342704A (en) * 2013-07-25 2013-10-09 甘肃皓天化学科技有限公司 Preparation method of Apixaban as anti-thrombotic drug
CN104650072A (en) * 2013-11-18 2015-05-27 成都苑东药业有限公司 Pyridine derivatives

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101065378A (en) * 2004-09-28 2007-10-31 布里斯托尔-迈尔斯斯奎布公司 Crystalline forms of a pyrazolo[3,4-c]pyridine factor xa inhibitor
US8633317B2 (en) * 2010-06-09 2014-01-21 Abbvie Inc. Crystalline salts of thieno[3,2-c]pyridine kinase inhibitors with improved cpy safety profile
CN102964349A (en) * 2011-08-31 2013-03-13 江苏恒瑞医药股份有限公司 Tosilate of benzodiazepine derivative, its crystal forms, their preparation method and application
FR2992314B1 (en) * 2012-06-22 2015-10-16 Sanofi Sa NOVEL 2,3-DIHYDRO-1H-IMIDAZO {1,2-A} PYRIMIDIN-5-ONE AND 1,2,3,4-TETRAHYDRO-PYRIMIDO {1,2-A} PYRIMIDIN-6-ONE DERIVATIVES COMPRISING A SUBSTITUTED MORPHOLINE, THEIR PREPARATION AND THEIR PHARMACEUTICAL USE
CN103539795A (en) * 2013-03-18 2014-01-29 齐鲁制药有限公司 Apixaban polymorph and preparation method thereof
CN104292228B (en) * 2013-07-16 2016-03-30 成都苑东生物制药股份有限公司 Polymorphic of a kind of Xanthine compounds and preparation method thereof, purposes
CN104513239B (en) * 2014-12-10 2017-08-22 沈阳药科大学 The ketone compounds of pyrazolo [3,4 c] pyridine 7 and its application

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013119328A1 (en) * 2012-02-07 2013-08-15 Assia Chemical Industries Ltd. Solid state forms of apixaban
CN103342704A (en) * 2013-07-25 2013-10-09 甘肃皓天化学科技有限公司 Preparation method of Apixaban as anti-thrombotic drug
CN104650072A (en) * 2013-11-18 2015-05-27 成都苑东药业有限公司 Pyridine derivatives

Also Published As

Publication number Publication date
CN111718343A (en) 2020-09-29
CN111704612A (en) 2020-09-25
CN111848611A (en) 2020-10-30
CN111848609A (en) 2020-10-30
CN111848610A (en) 2020-10-30
CN106854197B (en) 2020-09-01
CN111848608A (en) 2020-10-30
CN111763203A (en) 2020-10-13
CN111808099A (en) 2020-10-23
CN111848610B (en) 2022-11-18

Similar Documents

Publication Publication Date Title
JP7444957B2 (en) Crystal polymorph of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
JP6790183B2 (en) Solid form of ASK1 inhibitor
US20160207904A1 (en) Crystalline 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde ansolvate salts
CN105131003B (en) Crystal of 6,7 unsaturated 7 carbamoyl morphinan derivatives and preparation method thereof
WO2015031285A1 (en) Crystalline 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde ansolvate salts
JP6649511B2 (en) Crystal form E of tafamidis meglumine salt, its production method and use
CN105025898A (en) Benzoimidazol-2-yl pyrimidine modulators of the histamine H4 receptor
CN102232070A (en) Synthesis and novel salt forms of (R)-5-((E)-2-(pyrrolidin-3-ylvinyl)pyrimidine
CN103804357A (en) Rupatadine fumarate compound as well as synthesis method and pharmaceutical composition thereof
CN101679355A (en) benzimidazole cannabinoid agonists
BR112020002892A2 (en) solid form of 3- (5-fluoro-benzofuran-3-yl) -4- (5-methyl-5h- [1,3] dioxolo [4,5-f] indol-7-yl) pyrrole-2,5 -dione, process for preparing the solid form, pharmaceutical composition, process for preparing a pharmaceutical composition, method for treating cancer in a patient and method for treating traumatic brain injury in a patient
CN106854197A (en) A kind of polymorphic of pyridine derivate and preparation method thereof, purposes
CN108047145B (en) 2-arylquinoxaline compound with affinity with Tau protein and preparation method and application thereof
JP5864046B2 (en) 11C-labeled isoquinoline derivative, production method thereof, precursor thereof, PET probe using the same, and tissue imaging method
CN104130207A (en) Acotiamide hydrobromide hydrate and preparation method of crystal form thereof
CN111909174B (en) Crystal form of pyridone derivative, preparation method and application
RU2712169C2 (en) Novel polymorphic forms of icotinib phosphate and uses thereof
CN102171219A (en) Crystalline forms of a pyridine derivative
CN111566102A (en) Substituted pyrrolopyridines as activin receptor-like kinase inhibitors
TW201912642A (en) Salt of compound and its crystal form
RU2710013C2 (en) Polymorphic forms of icotinib and uses thereof
CN112004810B (en) Crystal form of oxopyridine amide derivative and preparation method thereof
WO2023072292A1 (en) Efficient antiviral compound and use thereof
JP2021511375A (en) Crystal form, salt form and method for producing the tricyclic compound
CN103664738B (en) A kind of crystalline polymorph of carboxamide compounds L MALIC ACID salt

Legal Events

Date Code Title Description
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
TA01 Transfer of patent application right
TA01 Transfer of patent application right

Effective date of registration: 20190103

Address after: 312030 No. 1152 Yunji Road, Keqiao District, Shaoxing City, Zhejiang Province

Applicant after: Zhejiang Yatai Pharmaceutical Co., Ltd.

Address before: 611731 No. 8 Xiyuan Avenue, Chengdu High-tech Zone, Sichuan Province

Applicant before: CHENGDU EASTON BIOPHARMACEUTICALS CO., LTD.

GR01 Patent grant
GR01 Patent grant