WO2020007256A1 - 一种氧代吡啶酰胺类衍生物的晶型及制备方法 - Google Patents

一种氧代吡啶酰胺类衍生物的晶型及制备方法 Download PDF

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WO2020007256A1
WO2020007256A1 PCT/CN2019/094170 CN2019094170W WO2020007256A1 WO 2020007256 A1 WO2020007256 A1 WO 2020007256A1 CN 2019094170 W CN2019094170 W CN 2019094170W WO 2020007256 A1 WO2020007256 A1 WO 2020007256A1
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compound
formula
ray powder
powder diffraction
product
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English (en)
French (fr)
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马亚辉
张浩宇
韩龙
邵启云
杜振兴
王捷
冯君
贺峰
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Priority to US17/257,528 priority Critical patent/US11225462B2/en
Priority to JP2020573323A priority patent/JP2021529201A/ja
Priority to KR1020217003246A priority patent/KR20210028232A/ko
Priority to EP19830889.2A priority patent/EP3822264A4/en
Priority to CN201980027589.5A priority patent/CN112004810B/zh
Publication of WO2020007256A1 publication Critical patent/WO2020007256A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • 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
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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

Definitions

  • the invention belongs to the field of medicinal chemistry and relates to a coagulation Xia inhibitor (S) -4- (4- (tert-butoxy) -2- (4- (5-chloro-2-propionylphenyl) -5- Crystal form of methoxy-2-oxopyridine-1 (2H) -yl) butyramido) benzoic acid and preparation method thereof.
  • cardiovascular and cerebrovascular diseases such as cerebrovascular, cerebral infarction, myocardial infarction, coronary heart disease, and arteriosclerosis take nearly 12 million lives, which is close to a quarter of the world's total deaths. More than 2.6 million people die of cardiovascular disease each year in China, 75% of surviving patients are disabled, and more than 40% are severely disabled. The problem of thrombosis caused by cardiovascular and cerebrovascular diseases, diabetes and its complications has become an urgent problem to be solved today.
  • the human blood coagulation process consists of an intrinsic pathway, an external pathway and a common pathway (Annu.Rev.Med.2011.62: 41–57), which are sequentially activated by multiple zymogens. A chain reaction in which the process is continuously strengthened and amplified.
  • the coagulation cascade is initiated by the endogenous pathway (also known as the contact activation pathway) and the exogenous pathway (also known as the tissue factor pathway) to produce FXa, and then through the common pathway to generate thrombin (FIIa), and finally forms fibrin.
  • the endogenous pathway refers to the process in which factor XII is activated to form the XIa-VIIIa-Ca2 ⁇ PL complex and activate factor X.
  • the exogenous coagulation pathway is formed by the release of tissue factor (TF) to the TF-VIIaCa2 + complex. And activate the process of factor X.
  • the common pathway refers to the process in which the two pathways merge into one after the formation of factor Xa, which activates prothrombin and finally generates fibrin.
  • FXI is necessary to maintain the endogenous pathway, and during the amplification of the coagulation cascade Play a key role.
  • FXIa activated FXI
  • FXI activity ⁇ 15U / dL Human FXI deficiency
  • type C hemophilia Human FXI deficiency
  • This type of patient has a mild bleeding phenotype and a small amount of spontaneous bleeding. The body's hemostatic function is not affected even when injured or during surgery. Patients with Friend C can have normal pregnancy and delivery (Arterioscler Thromb Vasc Biol. 2010; 30: 388-392). It can be seen that the safety of FXIa is significantly better than that of FXa. Therefore, the target FXIa has become a research hotspot of major companies and research institutions.
  • FXIa is an emerging target, and patent applications that disclose compounds with FXIa inhibitory activity are WO9630396, WO9941276, WO2013093484, WO2004002405, WO2013056060, WO2017005725 and US20050171148, WO2017023992, WO2018039094.
  • ASO Bayer's antisenseoligonucleotides
  • WO2018041122 discloses a series of oxopyridine amide FXIa inhibitors and has been characterized by structures, including compounds of formula (I).
  • the application also carried out a biological evaluation of the compound of the formula (I), and the results showed that the compound has a significant inhibitory effect on FXIa and a significant anticoagulant effect on human blood, and found that the above compounds have good pharmacological absorption, Has obvious pharmacokinetic absorption effect,
  • the crystalline form as a medicinal active ingredient often affects the chemical stability of the drug. Differences in crystallization conditions and storage conditions may cause changes in the crystalline structure of the compound, sometimes accompanied by the generation of other forms.
  • amorphous pharmaceutical products do not have a regular crystalline structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, and poor fluidity.
  • Polymorphic forms of drugs have different requirements for product storage, production, and scale-up. Therefore, it is necessary to further study the crystal form of the compound of formula (I) and improve various aspects of the properties of the compound of formula (I).
  • the present invention provides an FXIa inhibitor (S) -4- (4- (Tert-butoxy) -2- (4- (5-chloro-2-propionylphenyl) -5-methoxy-2-oxopyridine-1 (2H) -yl) butyramido) benzoic acid (Compound of formula (I)) Crystal form, preparation method and application.
  • the present invention provides a crystal form A of the compound of formula (I).
  • the X-ray powder diffraction pattern of the crystal form A has characteristic peaks at 2 ⁇ values of 7.420, 8.000, 8.642, 12.900, and 22.400, and the error range can be ⁇ 0.3, ⁇ 0.2 or ⁇ 0.1.
  • the X-ray powder diffraction pattern of the Form A has characteristic peaks at 2 ⁇ values of 7.420, 8.000, 8.642, 12.900, 16.281, 18.280, 20.018, 21.119, 22.400, and the error range may be ⁇ 0.3, ⁇ 0.2 or ⁇ 0.1.
  • the X-ray powder diffraction pattern of the form A has characteristic peaks at 2 ⁇ values of 7.420, 8.000, 8.642, 12.900, 16.281, 18.280, 20.018, 21.119, 22.400, 24.458, 26.100, and the error range may be ⁇ 0.3 , ⁇ 0.2 or ⁇ 0.1.
  • the invention provides a crystal form B of the compound of formula (I).
  • the X-ray powder diffraction pattern of the crystal form B has characteristic peaks at 2 ⁇ values of 7.620, 8.680, 11.042, 11.638, 12.339, 16.320, 19.381, and the error range can be It is ⁇ 0.3, ⁇ 0.2, or ⁇ 0.1.
  • the X-ray powder diffraction pattern of the crystal form B has characteristic peaks at 2 ⁇ values of 7.620, 8.680, 11.042, 11.638, 12.339, 14.461, 16.320, 18.123, 18.381, 19.381, and the error range may be ⁇ 0.3, ⁇ 0.2 or ⁇ 0.1.
  • the X-ray powder diffraction pattern of the Form B has characteristic peaks at 2 ⁇ values of 7.620, 8.680, 11.042, 11.638, 12.339, 14.461, 16.320, 18.123, 18.381, 19.381, 22.020, 25.038, 26.460, and error ranges. It can be ⁇ 0.3, ⁇ 0.2, or ⁇ 0.1.
  • the invention provides a crystal form C of the compound of formula (I).
  • the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at 2 ⁇ values of 7.283, 8.780, 10.664, 11.264, 14.744, 15.456, 16.587, 17.598, and errors.
  • the range can be ⁇ 0.3, ⁇ 0.2, or ⁇ 0.1.
  • the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at 2 ⁇ values of 7.283, 8.780, 10.664, 11.264, 14.744, 15.456, 16.587, 17.598, 18.165, 18.915, 20.158, 21.025, 22.363, and error ranges It can be ⁇ 0.3, ⁇ 0.2, or ⁇ 0.1.
  • the X-ray powder diffraction pattern of the C form has a 2 ⁇ value of 5.312, 6.704, 7.283, 8.780, 9.544, 10.664, 11.264, 12.335, 14.124, 14.744, 15.456, 16.587, 17.598, 18.165, 18.915, 20.158, There are characteristic peaks at 21.025, 22.363, 23.211, 24.504, 24.713, 26.042, 27.534, and the error range can be ⁇ 0.3, ⁇ 0.2, or ⁇ 0.1.
  • the present invention provides a crystal form D of a compound of formula (I).
  • the X-ray powder diffraction pattern of the crystal form D has a 2 ⁇ value of 7.021, 7.901, 8.259, 9.200, 10.639, 12.320, 13.821, 14.180, 14.580, 15.519, 16.120.
  • the X-ray powder diffraction pattern of the D crystal form has a 2 ⁇ value of 7.021, 7.901, 8.259, 9.200, 10.639, 12.320, 13.821, 14.180, 14.580, 15.519, 16.120, 16.661, 18.500, 19.919, 20.600, 21.320, There are characteristic peaks at 21.700, 22.358, 22.820, 23.221, 23.538, 24.241, 25.060, and the error range can be ⁇ 0.3, ⁇ 0.2, or ⁇ 0.1.
  • the X-ray powder diffraction pattern of the D crystal form has a 2 ⁇ value of 7.021, 7.901, 8.259, 9.200, 10.639, 12.320, 13.821, 14.180, 14.580, 15.519, 16.120, 16.661, 18.500, 19.919, 20.600, 21.320, 21.700, 22.358, 22.820, 23.221, 23.538, 24.241, 25.060, 25.520, 26.920, 27.420, 27.940, 28.720, 29.020, 29.420, 30.560, 31.402, 32.460, 35.380, 35.919, 37.261 have characteristic peaks, and the error range can be ⁇ 0.3 , ⁇ 0.2 or ⁇ 0.1.
  • the invention provides a crystal form E of the compound of formula (I).
  • the X-ray powder diffraction pattern of the crystal form E has characteristic peaks at 2 ⁇ values of 6.460, 7.480, 7.977, 16.220, 19.360, 21.720, and the error range can be ⁇ 0.3, ⁇ 0.2 or ⁇ 0.1.
  • the X-ray powder diffraction pattern of the E crystal form has characteristic peaks at 2 ⁇ values of 6.460, 7.480, 7.977, 8.662, 11.299, 12.140, 14.038, 16.220, 17.440, 18.560, 19.360, 21.720, and the error range may be ⁇ 0.3, ⁇ 0.2, or ⁇ 0.1.
  • the X-ray powder diffraction pattern of the E form has a 2 ⁇ value of 6.460, 7.480, 7.977, 8.662, 11.299, 12.140, 14.038, 16.220, 17.440, 18.560, 19.360, 21.720, 22.664, 24.922, 25.940, 26.840, There are characteristic peaks at 29.620, and the error range can be ⁇ 0.3, ⁇ 0.2, or ⁇ 0.1.
  • the present invention provides a crystal form F of a compound of formula (I).
  • the X-ray powder diffraction pattern of the crystal form F has 5.761, 9.800, 10.640, 11.621, 14.021, 16.180, 16.460, 17.520, 21.460, 24.580. Characteristic peaks with an error range of ⁇ 0.3, ⁇ 0.2, or ⁇ 0.1.
  • the X-ray powder diffraction pattern of the F crystal form has characteristic peaks at 2 ⁇ values of 5.761, 9.800, 10.640, 11.621, 14.021, 16.180, 16.460, 16.740, 17.520, 21.460, 22.820, 23.939, 24.580, 26.280,
  • the error range can be ⁇ 0.3, ⁇ 0.2, or ⁇ 0.1.
  • the X-ray powder diffraction pattern of the F crystal form has a 2 ⁇ value of 5.761, 9.800, 10.640, 11.621, 14.021, 16.180, 16.460, 16.740, 17.520, 18.560, 19.142, 19.820, 21.460, 22.820, 23.939, 24.580, There are characteristic peaks at 25.981, 26.280, 26.861, 27.700, 28.580, 28.921, 29.480, 30.840, 31.340, 32.801, 33.300, 33.921, 35.321, 36.843, 38.660, 40.101, 41.121, 41.600, and the error range can be ⁇ 0.3, ⁇ 0.2 or ⁇ 0.1.
  • the present invention also relates to a method for preparing A, B, C, C, D, E, and F compounds of the compound of formula (I), including: taking a certain amount of compound of formula (I), adding An appropriate amount of the solvent is crystallized, filtered, and dried to obtain the A-form, B-form, C-form, D-form, E-form or F-form of the compound of formula (I).
  • the crystalline solvent of Form A, Form B, Form C, Form D, Form E, Form F of the compound of formula (I) is selected from hydrocarbon solvents, ether solvents, alcohol solvents, ester solvents, One or more of a ketone solvent, a nitrile solvent, a halogenated hydrocarbon solvent, a nitrogen-containing solvent, water, and dimethyl sulfoxide.
  • the hydrocarbon solvents include, but are not limited to, cyclohexane, n-hexane, n-heptane, toluene, o-xylene, and para-xylene;
  • the ether solvents include, but are not limited to, tetrahydrofuran, diethyl ether, propylene glycol methyl ether, and methyl tertiary Butyl ether, isopropyl ether, or 1,4-dioxane;
  • the alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol, or trifluoroethanol;
  • the esters Solvents include, but are not limited to, ethyl acetate, ethyl formate, tert-butyl acetate, ethyl propionate, isopropyl acetate, or butyl acetate;
  • the crystallization method of the A, B, C, D, E, and F forms of the compound of formula (I) is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization, or adding crystals. Species induced crystallization.
  • the present invention also relates to a method for preparing a form A of a compound of formula (I), which comprises: taking a certain amount of a compound of formula (I), adding an appropriate amount of ethyl acetate to dissolve it, raising the temperature to dissolve it, adding n-hexane to just turbidity, and slowly reducing it to Crystallize with stirring at room temperature to obtain Form A.
  • the invention also relates to a method for preparing a form A of a compound of formula (I), which comprises: taking a certain amount of a compound of formula (I), adding an appropriate amount of dichloromethane to dissolve, raising the temperature to dissolve, adding an appropriate amount of isopropyl ether, and slowly reducing the temperature to room temperature.
  • the invention also relates to a method for preparing a form A of a compound of formula (I), which comprises: taking a certain amount of a compound of formula (I), adding an appropriate amount of acetone to dissolve, heating up and dissolving, adding an appropriate amount of n-heptane, slowly dropping to room temperature, and stirring Crystallize to obtain Form A.
  • the invention also relates to a method for preparing a form A of a compound of formula (I), which comprises: taking a certain amount of a compound of formula (I), adding an appropriate amount of ethyl acetate to dissolve, warming up and dissolving, adding an appropriate amount of n-heptane, and slowly reducing the temperature to room temperature.
  • the invention also relates to a method for preparing a form A of a compound of formula (I), which comprises: taking a certain amount of a compound of formula (I), adding an appropriate amount of toluene to dissolve, heating up and dissolving, adding an appropriate amount of n-heptane, slowly lowering to room temperature, and stirring Crystallize to obtain Form A.
  • the invention also relates to a method for preparing a form A of a compound of formula (I), which comprises: taking a certain amount of a compound of formula (I), adding an appropriate amount of ethyl formate to dissolve, heating up and dissolving, adding an appropriate amount of n-hexane, and precipitating a small amount of solids, Slowly drop to room temperature and stir to crystallize to obtain Form A.
  • the invention also relates to a method for preparing a crystal form A of a compound of formula (I), which comprises: taking a certain amount of a compound of formula (I), adding an appropriate amount of ethyl acetate to dissolve it, heating and dissolving, adding an appropriate amount of n-hexane, solid precipitation, and continuing Stir for a while under the temperature rising state, slowly drop to room temperature, and stir to crystallize to obtain Form A.
  • the invention also relates to a method for preparing a form A of a compound of formula (I), which comprises: taking a certain amount of a form B of a compound of formula (I), adding it to an appropriate amount of toluene, and beating at room temperature to obtain the form A.
  • the invention also relates to a method for preparing a form A of a compound of formula (I), which comprises: taking a certain amount of a form B of a compound of formula (I), adding an appropriate amount of a tetrahydrofuran / methyl t-butyl ether mixed solvent, and beating at room temperature to obtain A crystal form.
  • the invention also relates to a method for preparing a form A of a compound of formula (I), which comprises: taking a certain amount of form B of a compound of formula (I), adding an appropriate amount of a mixed solvent of ethyl acetate / n-hexane, and slurping at room temperature to obtain a form A type.
  • the invention also relates to a method for preparing a crystal form A of a compound of formula (I), which comprises: taking a certain amount of crystal form B of a compound of formula (I), adding an appropriate amount of ethyl acetate / n-heptane mixed solvent, and slurping at room temperature to obtain A Crystal form.
  • the invention also relates to a method for preparing a form A of a compound of formula (I), which comprises: taking a certain amount of form A and form B of a compound of formula (I), adding an appropriate amount of a dioxane / water mixed solvent, and beating at room temperature. , A crystal form is obtained.
  • the invention also relates to a method for preparing a form A of a compound of formula (I), which comprises: taking a certain amount of form A and form B of a compound of formula (I), adding it to an appropriate amount of acetonitrile, and beating at room temperature to obtain form A.
  • the invention also relates to a method for preparing a form A of a compound of formula (I), which comprises: taking a certain amount of form A of a compound of formula (I), adding an appropriate amount of water, and beating at room temperature to obtain the form A.
  • the invention also relates to a method for preparing the B-form of the compound of formula (I), which comprises: taking a certain amount of the compound of formula (I), adding an appropriate amount of ethyl acetate to dissolve it, dissolving at elevated temperature, adding n-heptane to just turbidity, and continuing to Stir for a while under the temperature rising state, slowly lower the temperature to 50 ° C, solids will precipitate, continue to add an appropriate amount of n-heptane, slowly drop to 10 ° C, and stir to crystallize to obtain Form B.
  • the invention also relates to a method for preparing the B-form of the compound of the formula (I), which comprises: taking a certain amount of the compound of the formula (I), adding an appropriate amount of tetrahydrofuran, and dropping the solution into a solution containing a certain amount of A-type crystal seeds at room temperature. Crystallization was carried out in a propyl ether solution with stirring to obtain Form B.
  • the invention also relates to a method for preparing the B-form of the compound of the formula (I), which comprises: taking a certain amount of the compound of the formula (I) in an amorphous form and adding an appropriate amount of a mixed solvent of t-butyl acetate / methyl t-butyl ether / n-hexane , Beating at room temperature to obtain Form B.
  • the invention also relates to a method for preparing the B crystal form of the compound of the formula (I), which comprises: taking a certain amount of the compound of the formula (I) as an amorphous form, adding an appropriate amount of a trifluoroethanol / isopropyl ether mixed solvent, and heating and beating to obtain the B crystal. type.
  • the invention also relates to a method for preparing the B-form of the compound of the formula (I), which comprises: taking a certain amount of the compound of the formula (I) to be amorphous, adding an appropriate amount of n-heptane, and heating up to obtain the B-form.
  • the invention also relates to a method for preparing the B crystal form of the compound of the formula (I), which comprises: taking a certain amount of the compound of the formula (I) as an amorphous form, adding an appropriate amount of a chloroform / methyl tert-butyl ether mixed solvent, and heating up to obtain B Crystal form.
  • the invention also relates to a method for preparing the B-form of the compound of the formula (I), which comprises: taking a certain amount of the compound of the formula (I) to be amorphous, adding an appropriate amount of methyl tert-butyl ether, beating at room temperature, and insoluble at elevated temperature to obtain the B-form .
  • the invention also relates to a method for preparing the B-form of the compound of the formula (I), which comprises: taking a certain amount of the compound of the formula (I) to be amorphous, adding an appropriate amount of cyclohexane, beating at room temperature, and insoluble at elevated temperature to obtain the B-form.
  • the invention also relates to a method for preparing the B-form of the compound of the formula (I), which comprises: taking a certain amount of the A-form and the B-form of the compound of the formula (I), adding an appropriate amount of ethyl acetate / n-heptane mixed solvent, and Beating to obtain the B crystal form.
  • the present invention also relates to a method for preparing Form B of a compound of formula (I), which comprises: taking a certain amount of Form A and Form B of a compound of formula (I), adding an appropriate amount of acetone / methyl t-butyl ether / n-hexane to mix In a solvent, beating at room temperature to obtain Form B.
  • the invention also relates to a method for preparing the B-form of the compound of formula (I), which comprises: taking a certain amount of the A-form and B-form of the compound of the formula (I), adding an appropriate amount of butyl acetate / methyl tert-butyl ether / n-hexane In a mixed solvent of alkane, beating at room temperature to obtain Form B.
  • the invention also relates to a method for preparing the crystal form C of the compound of the formula (I), which comprises: taking a certain amount of the compound of the formula (I), adding an appropriate amount of p-xylene, and slurping and crystallizing at room temperature to obtain the crystal form C.
  • the invention also relates to a method for preparing the D-form of the compound of the formula (I), which comprises: taking a certain amount of the compound of the formula (I), adding an appropriate amount of ethyl acetate to dissolve it, dissolving it at elevated temperature, and crystallizing by stirring at a reduced temperature to obtain the D-form.
  • the invention also relates to a method for preparing the D crystal form of the compound of the formula (I), which comprises: taking a certain amount of the compound of the formula (I), adding an appropriate amount of ethyl acetate to dissolve, heating up and dissolving, adding an appropriate amount of n-hexane dropwise, slowly lowering the temperature, and stirring Crystallize to obtain D crystal form.
  • the invention also relates to a method for preparing the D crystal form of the compound of the formula (I), which comprises: taking a certain amount of the compound of the formula (I), adding an appropriate amount of acetone to dissolve, heating up and dissolving, adding an appropriate amount of n-heptane dropwise, slowly lowering the temperature, stirring and analyzing Crystal to obtain D crystal form.
  • the invention also relates to a method for preparing the D crystal form of the compound of the formula (I), which comprises: taking a certain amount of the compound of the formula (I), adding an appropriate amount of ethyl acetate to dissolve, adding an appropriate amount of n-hexane containing about 4 mg of the crystal form A, and stirring Crystallize to obtain D crystal form.
  • the invention also relates to a method for preparing the D crystal form of the compound of the formula (I), which comprises: taking a certain amount of the compound of the formula (I), dissolving it by adding an appropriate amount of acetone, adding dropwise an appropriate amount of isopropyl ether containing about 4 mg of the crystal form A, and analyzing by stirring Crystal to obtain D crystal form.
  • the invention also relates to a method for preparing the D crystal form of the compound of the formula (I), which comprises: taking a certain amount of the compound of the formula (I), adding an appropriate amount of a mixed solvent of acetone / isopropyl ether, and slowly evaporating and crystallizing at room temperature to obtain the D crystal form .
  • the invention also relates to a method for preparing the D crystal form of the compound of the formula (I), which comprises: taking a certain amount of the compound of the formula (I) as an amorphous form, adding it to an appropriate amount of acetonitrile, and slurping at room temperature to obtain the D form.
  • the invention also relates to a method for preparing an E-form of a compound of formula (I), which comprises: taking a certain amount of a compound of formula (I), adding an appropriate amount of a mixed solvent of acetone / cyclohexane, and slowly evaporating and crystallizing at room temperature to obtain an E-form .
  • the invention also relates to a method for preparing the F crystal form of the compound of the formula (I), which comprises: taking a certain amount of the compound of the formula (I), adding an appropriate amount of ethyl acetate, heating and dissolving, continuing to stir with solid precipitation, and adding an appropriate amount of n-hexane dropwise , Slowly lower the temperature and stir to crystallize to obtain F crystal form.
  • the invention also relates to a method for preparing the F crystal form of the compound of the formula (I), which comprises: taking a certain amount of the compound of the formula (I), adding an appropriate amount of ethyl formate, adding it to the reflux solution, adding an appropriate amount of n-hexane dropwise, and adding the F crystal
  • the seed crystals are dissolved under reflux, slowly cooled, and crystallized by stirring to obtain the F crystal form.
  • the invention also relates to a method for preparing the F crystal form of the compound of formula (I), which comprises: taking a certain amount of the compound of formula (I) in an amorphous form, adding an appropriate amount of a 1,4-dioxane / water mixed solvent, and beating at room temperature; The F crystal form was obtained.
  • the invention also relates to a method for preparing the F crystal form of the compound of the formula (I), which comprises: taking a certain amount of the crystal form of the compound of the formula (I), adding an appropriate amount of an acetonitrile / water mixed solvent, and slurping at room temperature to obtain the F crystal form.
  • the invention also relates to a method for preparing the F crystal form of the compound of the formula (I), which comprises: taking a certain amount of the crystal form of the compound of the formula (I) A, adding an appropriate amount of a tetrahydrofuran / water mixed solvent, and beating at room temperature to obtain the F crystal form.
  • the invention also relates to a method for preparing the F crystal form of the compound of the formula (I), which comprises: taking a certain amount of the crystal form of the compound of the formula (I), adding an appropriate amount of an acetone / water mixed solvent, and slurping at room temperature to obtain the F crystal form.
  • the invention also relates to a method for preparing the F crystal form of the compound of the formula (I), comprising: taking a certain amount of the crystal form of the compound of the formula (I), adding an appropriate amount of an isopropanol / water mixed solvent, and beating at room temperature to obtain the F crystal form; .
  • the invention also relates to a method for preparing the F crystal form of the compound of formula (I), which comprises: taking a certain amount of the compound of formula (I) in an amorphous form, adding an appropriate amount of a ethyl propionate / n-heptane mixed solvent, and beating at room temperature to obtain F Crystal form.
  • the invention also relates to Form A, Form B, Form C, Form D, Form E, or Form F and optionally one or more pharmaceutically acceptable carriers and / or dilutions of a compound of formula (I) Agent pharmaceutical composition.
  • the pharmaceutical composition can be made into any pharmaceutically acceptable dosage form.
  • the pharmaceutical preparations comprising Form A, Form B, Form C, Form D, Form E, or Form F of the compound of formula (I) according to the present invention may be formulated as tablets, capsules, pills, Granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injections and concentrated solutions for injections), suppositories, inhalants or sprays.
  • the pharmaceutical composition of the present invention can also be administered to patients or subjects in need of such treatment in any suitable manner, such as oral, parenteral, rectal, pulmonary or topical administration.
  • the pharmaceutical composition can be made into oral preparations, such as oral solid preparations, such as tablets, capsules, pills, granules, etc .; or oral liquid preparations, such as oral solutions, oral suspensions, etc. Agents, syrups, etc.
  • the pharmaceutical preparation may further contain a suitable filler, a binder, a disintegrant, a lubricant, and the like.
  • the pharmaceutical preparation When used for parenteral administration, the pharmaceutical preparation can be made into injections, including injections, sterile powders for injections, and concentrated solutions for injections.
  • the pharmaceutical composition When prepared as an injection, the pharmaceutical composition can be produced by a conventional method in the existing pharmaceutical field.
  • an additional agent may not be added to the pharmaceutical preparation, or a suitable additional agent may be added according to the properties of the drug.
  • the pharmaceutical preparations When used for rectal administration, the pharmaceutical preparations can be made into suppositories and the like.
  • the pharmaceutical preparation When used for pulmonary administration, the pharmaceutical preparation can be made into an inhalant or a spray.
  • Form A, Form B, Form C, Form D, Form E, or Form F of a compound of Formula (I) of the invention is present in a pharmaceutical combination in a therapeutically and / or prophylactically effective amount. Substance or drug. In certain embodiments, Form A, Form B, Form C, Form D, Form E, or Form F of the compound of formula (I) of the present invention is present in the pharmaceutical composition in a unit dose form. Or in medicine.
  • the present invention further relates to a method for preparing a pharmaceutical composition, which comprises selecting a form A, B, C, C, D, E or F of a compound of formula (I) of the present invention.
  • One or more of the crystalline forms are mixed with at least one pharmaceutically acceptable carrier, diluent or excipient.
  • the invention further relates to Form A, Form B, Form C, Form D, Form E, or Form F of the compound of formula (I) for use in the treatment and / or prevention of factor XIa-mediated diseases Use in medicine.
  • the invention further relates to Form A, Form B, Form C, Form D, Form E, or Form F of the compound of formula (I) in the preparation of a medicament for treating and / or preventing cardiovascular and cerebrovascular diseases.
  • cardiovascular and cerebrovascular diseases are selected from the group consisting of thromboembolic diseases, preferably myocardial infarction, angina pectoris, re-occlusion and restenosis after angioplasty or aortic coronary shunt, disseminated intravascular coagulation, stroke, transient Ischemic attack, peripheral arterial occlusive disease, pulmonary embolism, or deep venous thrombosis.
  • ether solvent in the present invention refers to a chain compound or a cyclic compound containing an ether bond -O- and having 1 to 10 carbon atoms, and specific examples include, but are not limited to, tetrahydrofuran, ether, and propylene glycol methyl ether , Methyl tert-butyl ether, isopropyl ether, or 1,4-dioxane.
  • the "alcoholic solvent” in the present invention refers to a group derived by replacing one or more hydrogen atoms on a "C1-6 alkyl” with one or more "hydroxy", and the "hydroxy" and “C1- “6 alkyl” is as defined above, and specific examples include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol, or trifluoroethanol.
  • the “ester solvent” in the present invention refers to a combination of a lower organic acid having 1 to 4 carbon atoms and a lower alcohol having 1 to 6 carbon atoms. Specific examples include, but are not limited to, acetic acid Ethyl acetate, ethyl formate, tert-butyl acetate, ethyl propionate, isopropyl acetate or butyl acetate.
  • keton solvent in the present invention refers to a compound in which a carbonyl group (-C (O)-) is connected to two hydrocarbon groups.
  • ketones can be divided into fatty ketones, alicyclic ketones, aromatic ketones, Specific examples of saturated ketones and unsaturated ketones include, but are not limited to, acetone, acetophenone, 4-methyl-2-pentanone, 2-butanone, and methyl isobutyl ketone.
  • nitrile solvent in the present invention refers to a group derived by replacing one or more hydrogen atoms on the "C1-6 alkyl” with one or more "cyano", and the "cyano” and “ “C1-6 alkyl” is as defined above, and specific examples include, but are not limited to, acetonitrile or propionitrile.
  • halogenated hydrocarbon solvent in the present invention refers to a group derived by replacing one or more hydrogen atoms on the “C1-6 alkyl” with one or more “halogen atoms”, and the “halogen atom” And “C1-6 alkyl” are as defined above, and specific examples include, but are not limited to, methyl chloride, methylene chloride, 1,2-dichloroethane, chloroform, or carbon tetrachloride.
  • the "X-ray powder diffraction pattern or XRPD" in the present invention is obtained by Cu-K ⁇ ray diffraction.
  • the “differential scanning calorimetry or DSC” in the present invention refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the temperature rising or constant temperature of the sample to characterize all physical changes and chemistry related to the thermal effect. Change to get the phase transition information of the sample.
  • the “2 ⁇ or 2 ⁇ angle” in the present invention refers to a diffraction angle, ⁇ is a Bragg angle, and the unit is ° or degree.
  • the error range of the 2 ⁇ is ⁇ 0.1 to ⁇ 0.5, preferably ⁇ 0.1 to ⁇ 0.3, and more preferably ⁇ 0.2.
  • FIG. 2 is an XRPD pattern of a compound of formula (I) in the form of Form A;
  • FIG. 7 is an XRPD pattern of the compound of formula (I) in the form of B-form
  • FIG. 8 is a DSC chart of a compound of formula (I) in the B-form
  • FIG. 9 is a TGA diagram of a compound of formula (I) in the form of B-form.
  • FIG. 10 is a DVS hygroscopic diagram of a compound of formula (I) in the form of Form B;
  • FIG. 11 is a comparison chart of XRPD before and after DVS detection of the compound of formula (I) in the form of B form;
  • FIG. 12 is an XRPD pattern of the compound of formula (I) in the form of the C form
  • FIG. 13 is a DSC chart of a compound of formula (I) in the form of C form
  • FIG. 14 is a TGA diagram of a compound of formula (I) in the form of C crystal form
  • FIG. 16 is a DSC and TGA diagram of a compound of formula (I) in the D crystal form
  • FIG. 17 is a DVS hygroscopic diagram of a compound of formula (I) in the form of D form;
  • FIG. 18 is a comparison chart of XRPD before and after DVS detection of a compound of formula (I) in the D crystal form
  • FIG. 19 is an ellipsoidal diagram of a three-dimensional molecular structure of a single crystal of a compound of formula (I) in the form of D form;
  • FIG. 20 is an XRPD pattern of a compound of formula (I) in the form of an E-form
  • FIG. 21 is an XRPD pattern of the compound of formula (I) in the F-form
  • FIG. 22 is a DSC chart of a compound of formula (I) in the F crystal form
  • FIG. 23 is a TGA diagram of a compound of formula (I) in an F-form
  • FIG. 24 is a DVS hygroscopic diagram of a compound of formula (I) in the F-form
  • FIG. 25 is a comparison chart of XRPD before and after DVS detection of a compound of formula (I) in the F-form.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR measurement was performed using Bruker AVANCE-400 nuclear magnetic analyzer.
  • the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD).
  • the internal standard was four.
  • Methylsilane (TMS) Methylsilane
  • MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • XRPD is X-ray powder diffraction detection: The measurement is performed using a BRUKER D8 X-ray diffractometer.
  • the specific collection information Cu anode (40kV, 40mA), Cu-K ⁇ 1 ray K ⁇ 2 rays K ⁇ rays Scanning range (2q range): 3 to 64 °, scanning step 0.02, slit width (collimator) 1.0mm.
  • the stepwise scanning method is adopted, the number of scanning steps is 3 steps, the scanning range of each step is 19 °, the starting degree is 10 °, the ending degree is 48 °, and the length of each step is 45s.
  • DSC is differential scanning calorimetry: The measurement uses a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10 ° C / min, and the specific temperature range refers to the corresponding map (mostly 25-300 or 25-350 ° C). Nitrogen blowing Sweep speed is 50mL / min.
  • TGA thermogravimetric analysis: The test uses a METTLER TOLEDO TGA 2 thermogravimetric analyzer, with a heating rate of 10 ° C / min, and the specific temperature range refers to the corresponding map (mostly 25-300 or 25-350 ° C). min.
  • DVS dynamic moisture adsorption: The detection uses SMS DVS Advantage. At 25 ° C, the humidity change is 50% -95% -0% -95% -50%, and the step is 10% (the last step is 5%) (the specific range of humidity) Based on the corresponding map, most of the methods are listed here). The judgment criteria are dm / dt is not more than 0.02%, and Tmax is not more than 360min.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature, which is 20 ° C to 30 ° C.
  • the monitoring of the reaction progress in the examples uses thin layer chromatography (TLC), a developing agent used in the reaction, a column chromatography eluent system for purifying compounds, and a thin layer chromatography developing system including: A: Dichloromethane / methanol system, B: n-hexane / ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can be added to adjust.
  • TLC thin layer chromatography
  • A Dichloromethane / methanol system
  • B n-hexane / ethyl acetate system
  • the volume ratio of the solvent is adjusted according to the polarity of the compound
  • a small amount of basic or acidic reagents such as triethylamine and acetic acid can be added to adjust.
  • 2-bromo-4-chloro-1-iodobenzene 1c (1.0 g, 3.15 mmol, prepared by a known method "Angewandte Chemie, International Edition, 2010, 49 (46), 8729-8732") was dissolved in 1 mL In tetrahydrofuran, it was cooled to -20 ° C, and isopropylmagnesium chloride (421.15 mg, 4.10 mmol) was added, and the reaction was performed for 1 hour in advance.
  • Propionyl chloride 1d (378.89 mg, 4.10 mmol), lithium chloride (11.42 mg, 189.00 ⁇ mol), cuprous chloride (9.36 mg, 94.50 ⁇ mol), and aluminum trichloride (12.61 mg, 94.50 ⁇ mol) were added to 1 mL of tetrahydrofuran , Stir well at room temperature, add the reaction solution reacted for 1 hour in advance to the above mixture, and react at room temperature for 2 hours. The reaction solution was quenched by adding 20 mL of saturated ammonium chloride solution, and extracted with dichloromethane (20 mL ⁇ 3).
  • reaction solution was naturally cooled to room temperature, 20 mL of water was added, and extracted with ethyl acetate (20 mL ⁇ 3). The organic phases were combined, and the organic phases were washed with water (30 mL), saturated sodium chloride solution (30 mL), and dried over anhydrous sodium sulfate. It was filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B to obtain 1 g (600 mg, yield: 75.9%) of the title compound.
  • the product was found to be amorphous by X-ray powder diffraction, as shown in Figure 1.
  • the DSC spectrum is shown in Figure 3, the endothermic peak is 150.77 ° C, and the TGA spectrum is shown in Figure 4, with a weight loss of 2.51% at 25-140 ° C.
  • DVS characterization According to the relative mass change curve of the sample at 25 ° C, between 10% RH and 80% RH, with the increase of humidity, the mass increase is about 1.781%, less than 2% but not less than 0.2%, according to " The Pharmacopoeia of the People's Republic of China 2015 Guidelines for Drug Hygroscopicity Test, this sample is slightly hygroscopic. Under normal storage conditions (ie, 25 ° C and 60% RH), the mass increase is approximately 1.156%; under accelerated test conditions (ie, 70% RH), the mass increase is approximately 1.479%; under extreme conditions (ie, 90% RH), the mass increase About 2.199%.
  • the desorption process of the sample and the adsorption process basically coincide.
  • the DVS detection spectrum is shown in Fig. 5.
  • the comparison of X-ray powder diffraction before and after DVS detection is shown in Fig. 6.
  • the crystal form did not change before and after DVS detection.
  • the compound of formula (I) (100 mg) was added to 1 mL of dichloromethane, the temperature was raised to 50 ° C., and the solution was stirred, 0.8 mL of isopropyl ether was slowly added dropwise, the temperature was slowly dropped to room temperature, and the stirring was continued for 17 hours.
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (82 mg).
  • the product was found to be in Form A by X-ray powder diffraction.
  • the compound of formula (I) (100 mg) was added to 1 mL of acetone, the temperature was raised to 50 ° C., the solution was stirred, and 1.4 mL of n-heptane was slowly added dropwise, the temperature was slowly dropped to room temperature, and the stirring was continued for 17 hours.
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (75 mg).
  • the product was found to be in Form A by X-ray powder diffraction.
  • the compound of formula (I) (100 mg) was added to 0.8 mL of ethyl acetate, the temperature was raised to 80 ° C., the solution was stirred, 0.7 mL of n-heptane was slowly added dropwise, the temperature was slowly dropped to room temperature, and the stirring was continued for 17 hours.
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (74 mg).
  • the product was found to be in Form A by X-ray powder diffraction.
  • the compound of formula (I) (100 mg) was added to 1 mL of toluene, the temperature was raised to 110 ° C., the solution was stirred, and 0.25 mL of n-heptane was slowly added dropwise, slowly dropped to room temperature, and the stirring was continued for 17 hours.
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (41 mg).
  • the product was found to be in Form A by X-ray powder diffraction.
  • the DSC characterization is shown in Figure 8, the endothermic peak is 146.17 ° C, and the TGA characterization is shown in Figure 9, with a weight loss of 2.90% at 25-130 ° C.
  • DVS characterization According to the relative mass change curve of the sample at 25 ° C, between 10% RH and 80% RH, with the increase of humidity, the mass increase is about 1.968%, less than 2% but not less than 0.2%, according to " The Pharmacopoeia of the People's Republic of China 2015 Guidelines for Drug Hygroscopicity Test, this sample is slightly hygroscopic.
  • the mass increase is approximately 1.155%; under accelerated test conditions (ie, 70% RH), the mass increase is approximately 1.530%; under extreme conditions (ie, 90% RH), the mass increase About 3.963%.
  • the DVS detection spectrum is shown in Fig. 10, and the comparison of X-ray powder diffraction before and after DVS detection is shown in Fig. 11. After DVS detection, the crystal form is changed to Form A.
  • Peak number 2-Theta d (A) I% Peak 1 7.620 11.593 100.0 Peak 2 8.680 10.179 83.4 Peak 3 11.042 8.006 8.6 Peak 4 11.638 7.598 8.3 Peak 5 12.339 7.167 9.2 Peak 6 14.461 6.120 7.7 Peak 7 16.320 5.427 16.6 Peak 8 18.123 4.891 6.1 Peak 9 18.381 4.823 4.9 Peak 10 19.381 4.576 15.3 Peak 11 22.020 4.033 9.8 Peak 12 25.038 3.554 14.4 Peak 13 26.460 3.366 4.6
  • the compound of formula (I) (100 mg) was dissolved in 0.5 mL of tetrahydrofuran, and the solution was slowly added dropwise to 2 mL of isopropyl ether (containing about 4 mg of A seed crystals) at room temperature, and a solid was precipitated, and the stirring was continued for 16 hours.
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (35 mg).
  • the product was in the B-form by X-ray powder diffraction detection.
  • the compound of formula (I) (100 mg) was added to 5 mL of methyl tert-butyl ether, insoluble, slurried at room temperature for 24 hours, heated at 50 ° C for 2 hours, insoluble, lowered to room temperature, centrifuged, and the solid sample was dried under vacuum to obtain the product.
  • the product was in the B-form by X-ray powder diffraction detection.
  • the compound of formula (I) (100 mg) was added to 5 mL of cyclohexane, insoluble, pulped at room temperature for 24 hours, heated at 50 ° C. for 2 hours, insoluble, lowered to room temperature, centrifuged, and the solid sample was dried under vacuum to obtain the product.
  • the product was in the B-form by X-ray powder diffraction detection.
  • the compound of formula (I) (100 mg) was added to 5 mL of p-xylene, insoluble, slurried at room temperature for 24 hours, heated at 50 ° C for 2 hours, insoluble, lowered to room temperature, centrifuged, and the solid sample was dried under vacuum to obtain the product. After X-ray powder diffraction detection, the product was defined as the crystal form C, and the XRPD spectrum is shown in FIG. 12.
  • the DSC spectrum is shown in Figure 13 and the endothermic peak is 141.44 ° C; the TGA spectrum is shown in Figure 14, and the weight loss at 25-130 ° C is 5.22%.
  • the compound of formula (I) (1.7 g) was added to 3.4 mL of ethyl acetate, heated to 80 ° C., stirred to dissolve, and continued to stir for 1 hour. Solids precipitated, slowly dropped to 15 ° C., and continued to stir at 15 ° C. for 4 hours. .
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (1.5 g). After X-ray powder diffraction detection, the product was defined as the D crystal form, and the spectrum is shown in FIG. 15.
  • DSC indicates the endothermic peak at 118.4 ° C
  • TGA indicates a weight loss of 24.2-140 ° C at 5.25%.
  • DVS characterization According to the relative mass change curve of the sample at 25 ° C, between 10% RH and 80% RH, with the increase of humidity, the mass increase is about 2.420%, less than 15% but not less than 2%.
  • the desorption process of the sample does not overlap with the adsorption process.
  • the DVS detection spectrum is shown in Figure 17, the X-ray powder diffraction comparison before and after DVS detection is shown in Figure 18, and the crystallinity of the crystal form becomes worse after DVS detection.
  • the compound of formula (I) (100 mg) was dissolved in 1 mL of ethyl acetate, and 2 mL of n-hexane (with about 4 mg of seed crystal A, 15-20 ° C) was slowly added dropwise. A solid precipitated, and the stirring was continued for 3 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (35 mg). The product was in the D-form by X-ray powder diffraction detection.
  • the compound of formula (I) (100 mg) was dissolved in 0.5 mL of acetone, and 2 mL of isopropyl ether (with about 4 mg of seed crystal A, 15-20 ° C) was slowly added dropwise, and a solid precipitated, and the stirring was continued for 5 hours.
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (60 mg).
  • the product was in the D-form by X-ray powder diffraction detection.
  • FIG. 19 The ellipsoid diagram of the three-dimensional structure of the single crystal analytical molecule is shown in FIG. 19.
  • the product was in the D-form by X-ray powder diffraction detection.
  • the DSC spectrum is shown in Figure 22, and the endothermic peak is 214.68 ° C; the TGA spectrum is shown in Figure 23.
  • DVS characterization The sample at 25 ° C according to the relative mass change curve, between 10% RH and 80% RH, with increasing humidity, the mass increase is about 0.1464%, less than 2%, according to the "Pharmacopoeia of the People's Republic of China" Guidance for the 2015 edition of the Hygroscopicity Test for Drugs shows that the sample is almost non-hygroscopic. Under normal storage conditions (ie, 25 ° C and 60% RH), the mass increase is approximately 0.0457%; under accelerated test conditions (ie, 70% RH), the mass increase is approximately 0.0701%; and under extreme conditions (ie, 90% RH), the mass increase About 0.2744%.
  • Form A (20 mg) and Form B (20 mg) of the compound of formula (I) were added to 0.5 mL of acetonitrile, and stirred at room temperature for 90 hours.
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (18 mg).
  • the product was found to be in Form A by X-ray powder diffraction.
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (80 mg).
  • the product was in the B-form by X-ray powder diffraction detection.
  • Amorphous compound (50 mg) of the compound of formula (I) was added to 0.5 mL of n-heptane, and the temperature was raised to 50 ° C at room temperature, followed by stirring for 72 hours.
  • the reaction solution was cooled to room temperature, filtered, and the filter cake was collected and dried under vacuum to obtain the product (40 mg).
  • the product was in the B-form by X-ray powder diffraction detection.
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (28 mg).
  • the product was in the B-form by X-ray powder diffraction detection.
  • the crystal form (1.4 g) of the compound B of formula (I) was added to 14 mL of acetonitrile, and the mixture was beaten and stirred at room temperature for 96 hours.
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (1.25 g).
  • the product was in the D crystal form by X-ray powder diffraction detection.
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (21 mg).
  • the product was in the F-form by X-ray powder diffraction detection.
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (14 mg).
  • the product was in the F-form by X-ray powder diffraction detection.
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (12 mg).
  • the product was in the F-form by X-ray powder diffraction detection.
  • Amorphous compound (20 mg) of the compound of formula (I) was added to 0.3 mL of o-xylene, and stirred at room temperature for 96 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (15 mg). The product was in the F-form by X-ray powder diffraction detection.
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (7 mg).
  • the product was in the F-form by X-ray powder diffraction detection.
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (10 mg).
  • the product was in the F-form by X-ray powder diffraction detection.
  • Form A (15 mg), Form D (15 mg), and Form F (15 mg) of the compound of formula (I) were added to 0.4 mL of n-heptane, the temperature was raised to 50 ° C., and the slurry was stirred for 120 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was collected and dried under vacuum to obtain the product (24 mg). X-ray powder diffraction examination showed that the product was in the F crystal form.
  • Form A (15 mg), Form D (15 mg) and Form F (15 mg) of the compound of formula (I) were added to 0.4 mL of isopropyl ether, the temperature was raised to 50 ° C., and the slurry was stirred for 120 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was collected and dried under vacuum to obtain the product (21 mg). The product was in the F-form by X-ray powder diffraction detection.
  • Form A (10 mg), Form D (10 mg), and Form F (10 mg) of the compound of formula (I) were added to 0.3 mL of toluene, and stirred at room temperature for 96 hours.
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (26 mg).
  • the product was in the F-form by X-ray powder diffraction detection.
  • Form A (10 mg), Form D (10 mg), and Form F (10 mg) of compound of formula (I) were added to 0.3 mL of acetonitrile, and stirred at room temperature for 96 hours.
  • the reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain the product (22 mg).
  • the product was in the F-form by X-ray powder diffraction detection.
  • the samples of the crystal form A, B, D, and F of the compound of formula (I) were placed flat and open, and the conditions of high temperature (40 ° C, 60 ° C), light (4500 Lux), and high humidity (RH 75%, RH 90%) were examined. Under the stability of the sample, the sampling inspection period is 30 days.
  • Example 58 Long-term accelerated stability experiments of Form A and Form F of the present invention
  • Form A and Form F of the compound of formula (I) were subjected to a long-term (25 ° C, 60% RH), accelerated (40 ° C, 75% RH) stability study for 3 months.

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Abstract

本发明涉及一种氧代吡啶酰胺类衍生物的晶型及制备方法。具体地，本发明涉及式(I)化合物的A、B、C、D、E、F晶型及制备方法。本发明式(I)化合物的晶型具备良好的晶型稳定性，可更好地用于临床。

Description

一种氧代吡啶酰胺类衍生物的晶型及制备方法
本申请要求申请日为2018年7月2日的中国专利申请CN201810710037.1的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于药物化学领域，涉及一种凝血XIa抑制剂(S)-4-(4-(叔丁氧基)-2-(4-(5-氯-2-丙酰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酰氨基)苯甲酸的晶型及其制备方法。
背景技术
全球每年脑血管、脑梗塞、心肌梗塞、冠心病、动脉硬化等心脑血管疾病夺走近1200万人的生命，接近世界总死亡人数的1/4。中国每年死于心血管疾病的人数达到260万人以上，存活的患者75％致残，其中40％以上重残。由心脑血管疾病和糖尿病及其并发症引起的血栓问题，成为当今要解决的刻不容缓的问题。
据独立市场分析机构Datamonitor 2011年数据预计，随着仿制药的生产，心血管及代谢疾病在七大主要市场的份额将在2011年达到顶峰，之后逐渐降低，其销售额将从2010年的1090亿美元降至2019年的1010亿美元。其中血栓市场保持基本稳定，由2010年的195亿美元微降至2019年的189亿美元(Datamonitor:HC00034-001、HC00139-001)。广州标点2011年的调研报告也显示，2011年中国抗血栓药物市场规模可达81.35亿元，同比增长20.52％，具有巨大的市场潜力(抗血栓药物市场研究报告：广州标点(2011))。
人体血液凝固过程由内源性途径(intrinsic pathway)、外源性途径(extrinsic pathway)和共同通路组成(Annu.Rev.Med.2011.62:41–57)，是通过多种酶原被顺序激活而过程不断得到加强和放大的一种连锁反应。凝血级联反应由内源性途径(又称接触激活途径)及外源性途径(又称组织因子途径)启动生成FXa，再经共同途径生成凝血酶(FIIa)，最终形成纤维蛋白。
内源性途径是指由XII因子被激活形XIa-VIIIa-Ca2±PL复合物、并激活X因子的过程，外源性凝血途径则是从组织因子(TF)释放到TF-VIIaCa2+复合物形成并激活因子X的过程。共同通路是指因子Xa形成后，两条途径合二为一，激活凝血酶原并最终生成纤维蛋白的过程，其中FXI是维持内源性途径所必需的，而且在凝血级联反应放大过程中发挥关键作用。在凝血级联反应中，凝血酶可反馈激活FXI，活化的FXI(FXIa)又促使凝血 酶的大量产生，从而使凝血级联反应放大。因此，FXI的拮抗剂被广泛开发，用于各种血栓的治疗。
传统的抗凝药物，如华法林、肝素、低分子量肝素(LMWH)，以及近年上市的新药，如FXa抑制剂(利伐沙班、阿哌沙班等)和凝血酶抑制剂(达比加群酯、水蛭素等)，对减少血栓形成均具有较好效果，以其显著有效性占据广大心脑血管市场，然而其副作用也越来越显著，其中“出血风险(bleeding risk)”是首当其冲最为严峻的问题之一(N Engl J Med 1991；325:153-8、Blood.2003；101:4783-4788)。
人类FXI缺陷症(FXI活性＜15U/dL)又称C型血友病，该类病人出血表型温和，少许发生自发性出血，即使在受伤或手术中机体的止血功能也不受影响，血友病C患者可以正常怀孕分娩(Arterioscler Thromb Vasc Biol.2010；30:388-392)。由此可知FXIa安全性显著优于FXa。因此，靶点FXIa成为各大公司及研究机构的研究热门。研究发现，在血栓模型中，抑制FXIa因子可以有效抑制血栓的形成，但在更为严重的血栓情况下，FXIa的作用微乎其微(Blood.2010；116(19):3981-3989)。临床统计显示，提高FXIa的量会增加VTE的患病率(Blood 2009；114:2878-2883)，而FXIa严重不足者其患有DVT的风险性减少(Thromb Haemost 2011；105:269–273)。
FXIa作为新兴靶点，公开具有FXIa抑制活性的化合物的专利申请有WO9630396、WO9941276、WO2013093484、WO2004002405、WO2013056060、WO2017005725和US20050171148、WO2017023992、WO2018039094。其中，仅拜耳公司的反义寡核苷酸(antisense oligonucleotides，ASO)BAY-2306001进入了临床二期研究，并取得良好效果。在该药的临床I期试验中，受试者FXI活性出现持续的、剂量依赖地减少，并伴随着aPTT延长，即使体内FXI降至不能被检测的水平时，也不会出现与药物相关的出血症状，显示出FXIa作为新兴靶点的潜力(Arterioscler Thromb Vasc Biol,2013,33(7)1670-1678)。但FXI ASO需注射给药，且起效较慢，需要数周时间才能形成抗栓效果，在作为防治药物时可能会受到一定限制。在小分子抑制剂方面，仅有BMS公司的FXIa抑制剂BMS-962212目前进入临床二期研究，因此新型FXIa抑制剂的研究具有重要意义。
WO2018041122公开了一系列氧代吡啶酰胺类FXIa抑制剂，并进行了结构表征，其中包括式(I)化合物。另外，该申请还对式(I)化合物进行了生物学评价，结果显示该化合物对FXIa具有明显的抑制作用，对人血液具有明显的抗凝血作用，而且发现上述化合物的药代吸收良好，具有明显的药代吸收效果，
Figure PCTCN2019094170-appb-000001
作为药用活性成分的晶型往往影响到该药物的化学稳定性，结晶条件及储存条件的不同有可能导致化合物的晶型结构的变化，有时还会伴随着产生其他形态的晶型。一般来说，无定形的药物产品没有规则的晶型结构，往往具有其它缺陷，比如产物稳定性较差，析晶较细，过滤较难，易结块，流动性差等。药物的多晶型对产品储存、生产及放大有不同的要求。因此，深入研究式(I)化合物的晶型，改善式(I)化合物的各方面性质是很有必要的。
发明内容
为了探究FXIa抑制剂化合物的具体药用形式与其理化性质之间的关系，进而开发出更加适合作为药品的特定药用形式，本发明提供了一种FXIa抑制剂(S)-4-(4-(叔丁氧基)-2-(4-(5-氯-2-丙酰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酰氨基)苯甲酸(式(I)化合物)的晶型、制备方法和应用。
本发明提供一种式(I)化合物A晶型，所述A晶型的X射线粉末衍射图在2θ值为7.420、8.000、8.642、12.900、22.400处具有特征峰，误差范围可以是±0.3、±0.2或±0.1。
进一步地，所述A晶型的X射线粉末衍射图在2θ值为7.420、8.000、8.642、12.900、16.281、18.280、20.018、21.119、22.400处具有特征峰，误差范围可以是±0.3、±0.2或±0.1。
进一步地，所述A晶型的X射线粉末衍射图在2θ值为7.420、8.000、8.642、12.900、16.281、18.280、20.018、21.119、22.400、24.458、26.100处具有特征峰，误差范围可以是±0.3、±0.2或±0.1。
本发明提供一种式(I)化合物B晶型，所述B晶型的X射线粉末衍射图在2θ值为7.620、8.680、11.042、11.638、12.339、16.320、19.381处具有特征峰，误差范围可以是±0.3、±0.2或±0.1。
进一步地，所述B晶型的X射线粉末衍射图在2θ值为7.620、8.680、11.042、11.638、12.339、14.461、16.320、18.123、18.381、19.381处具有特征峰，误差范围可以是±0.3、±0.2或±0.1。
进一步地，所述B晶型的X射线粉末衍射图在2θ值为7.620、8.680、11.042、11.638、12.339、14.461、16.320、18.123、18.381、19.381、22.020、25.038、26.460处具有特征峰，误差范围可以是±0.3、±0.2或±0.1。
本发明提供一种式(I)化合物C晶型，所述C晶型的X射线粉末衍射图在2θ值为7.283、8.780、10.664、11.264、14.744、15.456、16.587、17.598处具有特征峰，误差范围可以是±0.3、±0.2或±0.1。
进一步地，所述C晶型的X射线粉末衍射图在2θ值为7.283、8.780、10.664、11.264、14.744、15.456、16.587、17.598、18.165、18.915、20.158、21.025、22.363处具有特征峰，误差范围可以是±0.3、±0.2或±0.1。
进一步地，所述C晶型的X射线粉末衍射图在2θ值为5.312、6.704、7.283、8.780、9.544、10.664、11.264、12.335、14.124、14.744、15.456、16.587、17.598、18.165、18.915、20.158、21.025、22.363、23.211、24.504、24.713、26.042、27.534处具有特征峰，误差范围可以是±0.3、±0.2或±0.1。
本发明提供一种式(I)化合物D晶型，所述D晶型的X射线粉末衍射图在2θ值为7.021、7.901、8.259、9.200、10.639、12.320、13.821、14.180、14.580、15.519、16.120、16.661、18.500、19.919、20.600处具有特征峰，误差范围可以是±0.3、±0.2或±0.1。
进一步地，所述D晶型的X射线粉末衍射图在2θ值为7.021、7.901、8.259、9.200、10.639、12.320、13.821、14.180、14.580、15.519、16.120、16.661、18.500、19.919、20.600、21.320、21.700、22.358、22.820、23.221、23.538、24.241、25.060处具有特征峰，误差范围可以是±0.3、±0.2或±0.1。
进一步地，所述D晶型的X射线粉末衍射图在2θ值为7.021、7.901、8.259、9.200、10.639、12.320、13.821、14.180、14.580、15.519、16.120、16.661、18.500、19.919、20.600、21.320、21.700、22.358、22.820、23.221、23.538、24.241、25.060、25.520、26.920、27.420、27.940、28.720、29.020、29.420、30.560、31.402、32.460、35.380、35.919、37.261处具有特征峰，误差范围可以是±0.3、±0.2或±0.1。
本发明提供一种式(I)化合物E晶型，所述E晶型的X射线粉末衍射图在2θ值为6.460、7.480、7.977、16.220、19.360、21.720处具有特征峰，误差范围可以是±0.3、± 0.2或±0.1。
进一步地，所述E晶型的X射线粉末衍射图在2θ值为6.460、7.480、7.977、8.662、11.299、12.140、14.038、16.220、17.440、18.560、19.360、21.720处具有特征峰，误差范围可以是±0.3、±0.2或±0.1。
进一步地，所述E晶型的X射线粉末衍射图在2θ值为6.460、7.480、7.977、8.662、11.299、12.140、14.038、16.220、17.440、18.560、19.360、21.720、22.664、24.922、25.940、26.840、29.620处具有特征峰，误差范围可以是±0.3、±0.2或±0.1。
本发明提供一种式(I)化合物F晶型，所述F晶型的X射线粉末衍射图在2θ值为5.761、9.800、10.640、11.621、14.021、16.180、16.460、17.520、21.460、24.580处具有特征峰，误差范围可以是±0.3、±0.2或±0.1。
进一步地，所述F晶型的X射线粉末衍射图在2θ值为5.761、9.800、10.640、11.621、14.021、16.180、16.460、16.740、17.520、21.460、22.820、23.939、24.580、26.280处具有特征峰，误差范围可以是±0.3、±0.2或±0.1。
进一步地，所述F晶型的X射线粉末衍射图在2θ值为5.761、9.800、10.640、11.621、14.021、16.180、16.460、16.740、17.520、18.560、19.142、19.820、21.460、22.820、23.939、24.580、25.981、26.280、26.861、27.700、28.580、28.921、29.480、30.840、31.340、32.801、33.300、33.921、35.321、36.843、38.660、40.101、41.121、41.600处具有特征峰，误差范围可以是±0.3、±0.2或±0.1。
本发明还涉及式(I)化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型的制备方法，包括：取一定量的式(I)化合物，加入适量溶剂，析晶、过滤、干燥，得到式(I)化合物的A晶型、B晶型、C晶型、D晶型、E晶型或F晶型。
式(I)化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型的结晶溶剂选自烃类溶剂、醚类溶剂、醇类溶剂、酯类溶剂、酮类溶剂、腈类溶剂、卤代烃类溶剂、含氮溶剂、水、二甲基亚砜的一种或者多种。所述烃类溶剂包括但不限于环己烷、正己烷、正庚烷、甲苯、邻二甲苯、对二甲苯；所述醚类溶剂包括但不限于四氢呋喃、乙醚、丙二醇甲醚、甲基叔丁基醚、异丙醚或1,4-二氧六环；所述醇类溶包括但不限于甲醇、乙醇、异丙醇、正丙醇、异戊醇或三氟乙醇；所述酯类溶剂包括但不限于乙酸乙酯、甲酸乙酯、乙酸叔丁酯、丙酸乙酯、乙酸异丙酯或乙酸丁酯；所述酮类溶剂包括但不限于丙酮、苯乙酮、4-甲基-2-戊酮、2-丁酮、甲基异丁酮；所述腈类溶剂包括但不限于乙腈、丙腈；所述卤代烃类溶剂包括但不限于氯甲烷、二氯甲烷、1,2-二氯乙烷、氯仿或四氯化碳；所述含氮溶 剂包括但不限于硝基甲烷、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺。
式(I)化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型的析晶方法选自室温析晶、冷却析晶、挥发溶剂析晶或加入晶种诱导析晶。
本发明还涉及式(I)化合物的A晶型的制备方法，包括：取一定量的式(I)化合物，加入适量乙酸乙酯溶解，升温溶清，加入正己烷至恰好浑浊，缓慢降至室温，搅拌析晶，得到A晶型。本发明还涉及式(I)化合物的A晶型的制备方法，包括：取一定量的式(I)化合物，加入适量二氯甲烷溶解，升温溶清，加入适量异丙醚，缓慢降至室温，搅拌析晶，得到A晶型。本发明还涉及式(I)化合物的A晶型的制备方法，包括：取一定量的式(I)化合物，加入适量丙酮溶解，升温溶清，加入适量正庚烷，缓慢降至室温，搅拌析晶，得到A晶型。本发明还涉及式(I)化合物的A晶型的制备方法，包括：取一定量的式(I)化合物，加入适量乙酸乙酯溶解，升温溶清，加入适量正庚烷，缓慢降至室温，搅拌析晶，得到A晶型。本发明还涉及式(I)化合物的A晶型的制备方法，包括：取一定量的式(I)化合物，加入适量甲苯溶解，升温溶清，加入适量正庚烷，缓慢降至室温，搅拌析晶，得到A晶型。本发明还涉及式(I)化合物的A晶型的制备方法，包括：取一定量的式(I)化合物，加入适量甲酸乙酯溶解，升温溶清，加入适量正己烷，有少量固体析出，缓慢降至室温，搅拌析晶，得到A晶型。本发明还涉及式(I)化合物的A晶型的制备方法，包括：取一定量的式(I)化合物，加入适量乙酸乙酯溶解，升温溶清，加入适量正己烷，有固体析出，继续在升温状态下搅拌一段时间，缓慢降至室温，搅拌析晶，得到A晶型。
本发明还涉及式(I)化合物的A晶型的制备方法，包括：取一定量的式(I)化合物B晶型，加入适量甲苯中，室温打浆，得到A晶型。本发明还涉及式(I)化合物的A晶型的制备方法，包括：取一定量的式(I)化合物B晶型，加入适量四氢呋喃/甲基叔丁基醚混合溶剂中，室温打浆，得到A晶型。本发明还涉及式(I)化合物的A晶型的制备方法，包括：取一定量的式(I)化合物B晶型，加入适量乙酸乙酯/正己烷混合溶剂中，室温打浆，得到A晶型。本发明还涉及式(I)化合物的A晶型的制备方法，包括：取一定量的式(I)化合物B晶型，加入适量乙酸乙酯/正庚烷混合溶剂中，室温打浆，得到A晶型。本发明还涉及式(I)化合物的A晶型的制备方法，包括：取一定量的式(I)化合物A晶型和B晶型，加入适量二氧六环/水混合溶剂中，室温打浆，得到A晶型。本发明还涉及式(I)化合物的A晶型的制备方法，包括：取一定量的式(I)化合物A晶型和B晶型，加入适量乙腈中，室温打浆，得到A晶型。本发明还涉及式(I)化合物的A晶型的制备方法，包括：取一定量的式(I)化合物A晶型，加入适量水中，室温打浆，得到A晶型。
本发明还涉及式(I)化合物的B晶型的制备方法，包括：取一定量的式(I)化合物，加入适量乙酸乙酯溶解，升温溶清，加入正庚烷至恰好浑浊，继续在升温状态下搅拌一段时间，缓慢降温至50℃，有固体析出，继续加入适量正庚烷，缓慢降至10℃，搅拌析晶，得到B晶型。本发明还涉及式(I)化合物的B晶型的制备方法，包括：取一定量的式(I)化合物，加入适量四氢呋喃，室温下将该溶液滴入含一定量A晶型晶种的异丙醚溶液中，搅拌析晶，得到B晶型。
本发明还涉及式(I)化合物的B晶型的制备方法，包括：取一定量的式(I)化合物无定形，加入适量乙酸叔丁酯/甲基叔丁基醚/正己烷混合溶剂中，室温打浆，得到B晶型。本发明还涉及式(I)化合物的B晶型的制备方法，包括：取一定量的式(I)化合物无定形，加入适量三氟乙醇/异丙醚混合溶剂中，升温打浆，得到B晶型。本发明还涉及式(I)化合物的B晶型的制备方法，包括：取一定量的式(I)化合物无定形，加入适量正庚烷中，升温打浆，得到B晶型。本发明还涉及式(I)化合物的B晶型的制备方法，包括：取一定量的式(I)化合物无定形，加入适量氯仿/甲基叔丁基醚混合溶剂中，升温打浆，得到B晶型。本发明还涉及式(I)化合物的B晶型的制备方法，包括：取一定量的式(I)化合物无定形，加入适量甲基叔丁基醚，室温打浆，升温不溶，得到B晶型。本发明还涉及式(I)化合物的B晶型的制备方法，包括：取一定量的式(I)化合物无定形，加入适量环己烷，室温打浆，升温不溶，得到B晶型。本发明还涉及式(I)化合物的B晶型的制备方法，包括：取一定量的式(I)化合物A晶型和B晶型，加入适量乙酸乙酯/正庚烷混合溶剂中，室温打浆，得到B晶型。本发明还涉及式(I)化合物的B晶型的制备方法，包括：取一定量的式(I)化合物A晶型和B晶型，加入适量丙酮/甲基叔丁基醚/正己烷混合溶剂中，室温打浆，得到B晶型。本发明还涉及式(I)化合物的B晶型的制备方法，包括：取一定量的式(I)化合物A晶型和B晶型，加入适量乙酸丁酯/甲基叔丁基醚/正己烷混合溶剂中，室温打浆，得到B晶型。
本发明还涉及式(I)化合物的C晶型的制备方法，包括：取一定量的式(I)化合物，加入适量对二甲苯，室温打浆析晶，得到C晶型。
本发明还涉及式(I)化合物的D晶型的制备方法，包括：取一定量的式(I)化合物，加入适量乙酸乙酯溶解，升温溶清，降温搅拌析晶，得到D晶型。本发明还涉及式(I)化合物的D晶型的制备方法，包括：取一定量的式(I)化合物，加入适量乙酸乙酯溶解，升温溶清，滴加适量正己烷，缓慢降温，搅拌析晶，得到D晶型。本发明还涉及式(I)化合物的D晶型的制备方法，包括：取一定量的式(I)化合物，加入适量丙酮溶解，升温溶清， 滴加适量正庚烷，缓慢降温，搅拌析晶，得到D晶型。本发明还涉及式(I)化合物的D晶型的制备方法，包括：取一定量的式(I)化合物，加入适量乙酸乙酯溶解，滴加适量约含有4mg A晶型的正己烷，搅拌析晶，得到D晶型。本发明还涉及式(I)化合物的D晶型的制备方法，包括：取一定量的式(I)化合物，加入适量丙酮溶解，滴加适量约含有4mg A晶型的异丙醚，搅拌析晶，得到D晶型。本发明还涉及式(I)化合物的D晶型的制备方法，包括：取一定量的式(I)化合物，加入适量丙酮/异丙醚混合溶剂，室温下缓慢挥发析晶，得到D晶型。
本发明还涉及式(I)化合物的D晶型的制备方法，包括：取一定量的式(I)化合物无定形，加入适量乙腈中，室温打浆，得到D晶型。
本发明还涉及式(I)化合物的E晶型的制备方法，包括：取一定量的式(I)化合物，加入适量丙酮/环己烷混合溶剂，室温下缓慢挥发析晶，得到E晶型。
本发明还涉及式(I)化合物的F晶型的制备方法，包括：取一定量的式(I)化合物，加入适量乙酸乙酯，升温溶清，继续搅拌有固体析出，滴加适量正己烷，缓慢降温，搅拌析晶，得到F晶型。本发明还涉及式(I)化合物的F晶型的制备方法，包括：取一定量的式(I)化合物，加入适量甲酸乙酯，加入至回流溶清，滴加适量正己烷，加入F晶型晶种，回流溶清，缓慢降温，搅拌析晶，得到F晶型。
本发明还涉及式(I)化合物的F晶型的制备方法，包括：取一定量的式(I)化合物无定形，加入适量1,4-二氧六环/水混合溶剂中，室温打浆，得到F晶型。本发明还涉及式(I)化合物的F晶型的制备方法，包括：取一定量的式(I)化合物A晶型，加入适量乙腈/水混合溶剂中，室温打浆，得到F晶型。本发明还涉及式(I)化合物的F晶型的制备方法，包括：取一定量的式(I)化合物A晶型，加入适量四氢呋喃/水混合溶剂中，室温打浆，得到F晶型。本发明还涉及式(I)化合物的F晶型的制备方法，包括：取一定量的式(I)化合物A晶型，加入适量丙酮/水混合溶剂中，室温打浆，得到F晶型。本发明还涉及式(I)化合物的F晶型的制备方法，包括：取一定量的式(I)化合物A晶型，加入适量异丙醇/水混合溶剂中，室温打浆，得到F晶型。本发明还涉及式(I)化合物的F晶型的制备方法，包括：取一定量的式(I)化合物无定形，加入适量丙酸乙酯/正庚烷混合溶剂中，室温打浆，得到F晶型。
本发明还涉及包括式(I)化合物的A晶型、B晶型、C晶型、D晶型、E晶型或F晶型和任选的一种或多种药用载体和/或稀释剂的药物组合物。所述药物组合物可以制成药学上可接受的任一剂型。例如，本发明所述包含式(I)化合物的A晶型、B晶型、C晶型、 D晶型、E晶型或F晶型的药物制剂可以配制为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂。
此外，本发明所述药物组合物还可以以任何合适的给药方式，例如口服、肠胃外、直肠、经肺或局部给药等方式施用于需要这种治疗的患者或受试者。当用于口服给药时，所述药物组合物可制成口服制剂，例如口服固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；或口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。当制成口服制剂时，所述药物制剂还可包含适宜的填充剂、粘合剂、崩解剂、润滑剂等。当用于肠胃外给药时，所述药物制剂可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。当制成注射剂时，所述药物组合物可采用现有制药领域中的常规方法来进行生产。当配制注射剂时，所述药物制剂中可以不加入附加剂，也可根据药物的性质加入适宜的附加剂。当用于直肠给药时，所述药物制剂可制成栓剂等。用于经肺给药时，所述药物制剂可制成吸入剂或喷雾剂等。在某些实施方案中，本发明式(I)化合物的A晶型、B晶型、C晶型、D晶型、E晶型或F晶型以治疗和/或预防有效量存在于药物组合物或药物中。在某些实施方案中，本发明所述式(I)化合物的A晶型、B晶型、C晶型、D晶型、E晶型或F晶型以单位剂量的形式存在于药物组合物或药物中。
本发明进一步涉及一种制备药物组合物的方法，包括使选自本发明的式(I)化合物的A晶型、B晶型、C晶型、D晶型、E晶型或F晶型中的一种或多种晶型与至少一种药学上可接受的载体、稀释剂或赋形剂混合。
本发明进一步涉及所述式(I)化合物的A晶型、B晶型、C晶型、D晶型、E晶型或F晶型在制备用于治疗和/或预防XIa因子介导的疾病的药物中的用途。
本发明进一步涉及所述式(I)化合物的A晶型、B晶型、C晶型、D晶型、E晶型或F晶型在制备用于治疗和/或预防心脑血管疾病的药物中的用途，所述心脑血管疾病选自血栓栓塞性疾病，优选心肌梗塞、心绞痛、血管成形术或主动脉冠状动脉分流术后的再阻塞和再狭窄、弥散性血管内凝血、中风、短暂的局部缺血发作、周围动脉闭塞性疾病、肺栓塞或深部静脉血栓形成。
发明详述
在本申请的说明书和权利要求书中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。然而，为了更好地理解本发明，下面提供了部分相关术语的定义和解释。另外，当本申请所提供的术语的定义和解释与本领域技 术人员所通常理解的含义不一致时，以本申请所提供的术语的定义和解释为准。
本发明所述的“醚类溶剂”是指含有醚键-O-且碳原子数为1至10个的链状化合物或环状化合物，具体实例包括但不限于：四氢呋喃、乙醚、丙二醇甲醚、甲基叔丁基醚、异丙醚或1,4-二氧六环。
本发明所述的“醇类溶剂”是指一个或多个“羟基”取代“C1-6烷基”上的一个或多个氢原子所衍生的基团，所述“羟基”和“C1-6烷基”如前文所定义，具体实例包括但不限于：甲醇、乙醇、异丙醇、正丙醇、异戊醇或三氟乙醇。
本发明所述的“酯类溶剂”是指含碳原子数为1至4个的低级有机酸与含碳原子数为1至6个的低级醇的结合物，具体实例包括但不限于：乙酸乙酯、甲酸乙酯、乙酸叔丁酯、丙酸乙酯、乙酸异丙酯或乙酸丁酯。
本发明所述的“酮类溶剂”是指羰基(-C(O)-)与两个烃基相连的化合物，根据分子中烃基的不同，酮可分为脂肪酮、脂环酮、芳香酮、饱和酮和不饱和酮，具体实例包括但不限于：丙酮、苯乙酮、4-甲基-2-戊酮、2-丁酮、甲基异丁酮。
本发明所述的“腈类溶剂”是指一个或多个“氰基”取代“C1-6烷基”上的一个或多个氢原子所衍生的基团，所述“氰基”和“C1-6烷基”如前文所定义，具体实例包括但不限于：乙腈或丙腈。
本发明所述的“卤代烃类溶剂”是指一个或多个“卤素原子”取代“C1-6烷基”上的一个或多个氢原子所衍生的基团，所述“卤素原子”和“C1-6烷基”如前文所定义，具体实例包括但不限于：氯甲烷、二氯甲烷、1,2-二氯乙烷、氯仿或四氯化碳。
本发明所述的“X-射线粉末衍射图谱或XRPD”是经Cu-Kα射线衍射得到。
本发明所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。
本发明所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度，所述2θ的误差范围为±0.1～±0.5，优选±0.1～±0.3，更优选±0.2。
发明的有益效果
本发明提供的(S)-4-(4-(叔丁氧基)-2-(4-(5-氯-2-丙酰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酰氨基)苯甲酸(式(I)化合物)的A晶型、B晶型、C晶型、D晶型、E晶型和F晶型的溶解度、稳定性、吸湿性方面更有优势，更适合于药物开发，满足生物利用度和药效要求，能够满足生产运输储存的药用要求，生产工艺稳定、可重复可控，能够适 应于工业化生产。
附图说明
图1为以无定形形式存在的式(I)化合物的XRPD图；
图2为以A晶型形式存在的式(I)化合物的XRPD图；
图3为以A晶型形式存在的式(I)化合物的DSC图；
图4为以A晶型形式存在的式(I)化合物的TGA图；
图5为以A晶型形式存在的式(I)化合物的DVS吸湿图；
图6为以A晶型形式存在的式(I)化合物DVS检测前后XRPD对比图；
图7为以B晶型形式存在的式(I)化合物的XRPD图；
图8为以B晶型形式存在的式(I)化合物的DSC图；
图9为以B晶型形式存在的式(I)化合物的TGA图；
图10为以B晶型形式存在的式(I)化合物的DVS吸湿图；
图11为以B晶型形式存在的式(I)化合物DVS检测前后XRPD对比图；
图12为以C晶型形式存在的式(I)化合物的XRPD图；
图13为以C晶型形式存在的式(I)化合物的DSC图；
图14为以C晶型形式存在的式(I)化合物的TGA图；
图15为以D晶型形式存在的式(I)化合物的XRPD图；
图16为以D晶型形式存在的式(I)化合物的DSC和TGA图；
图17为以D晶型形式存在的式(I)化合物的DVS吸湿图；
图18为以D晶型形式存在的式(I)化合物DVS检测前后XRPD对比图；
图19为以D晶型形式存在的式(I)化合物单晶解析分子立体结构椭球图；
图20为以E晶型形式存在的式(I)化合物的XRPD图；
图21为以F晶型形式存在的式(I)化合物的XRPD图；
图22为以F晶型形式存在的式(I)化合物的DSC图；
图23为以F晶型形式存在的式(I)化合物的TGA图；
图24为以F晶型形式存在的式(I)化合物的DVS吸湿图；
图25为以F晶型形式存在的式(I)化合物DVS检测前后XRPD对比图。
具体实施方式
以下将结合实施例更详细地解释本发明，本发明的实施例仅用于说明本发明的技术方案，并非限定本发明的实质和范围。
实验所用仪器的测试条件：
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商：Thermo，型号：Finnigan LCQ advantage MAX)。
HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
XRPD为X射线粉末衍射检测：测定使用BRUKER D8型X射线衍射仪进行，具体采集信息：Cu阳极(40kV，40mA)，Cu-Kα1射线
Figure PCTCN2019094170-appb-000002
Kα2射线
Figure PCTCN2019094170-appb-000003
Kβ射线
Figure PCTCN2019094170-appb-000004
扫描范围(2q范围)：3～64°、扫描步长0.02、狭缝宽度(准直器)1.0mm。采用分步扫描法，扫描步数为3步，每步扫描范围19°，起始度数10°，终止度数48°，每步时长45s。
DSC为差示扫描量热：测定采用METTLER TOLEDO DSC 3+差示扫描量热仪，升温速率10℃/min，温度具体范围参照相应图谱(多为25-300或25-350℃)，氮气吹扫速度50mL/min。
TGA为热重分析：检测采用METTLER TOLEDO TGA 2型热重分析仪，升温速率10℃/min，温度具体范围参照相应图谱(多为25-300或25-350℃)，氮气吹扫速度20mL/min。
DVS为动态水分吸附：检测采用SMS DVS Advantage，在25℃，湿度变化为50％-95％-0％-95％-50％，步进为10％(最后一步为5％)(湿度具体范围以相应图谱为准，此处所列为大多使用方法)，判断标准为dm/dt不大于0.02％，Tmax不大于360min。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
式(I)化合物制备例(WO2018041122A中实施例108的制备方法)
(S)-4-(4-(叔丁氧基)-2-(4-(5-氯-2-丙酰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酰氨基)苯甲酸1
Figure PCTCN2019094170-appb-000005
第一步
2-(叔丁氧基)乙基三氟甲磺酸酯1b
将2-叔丁氧基乙醇1a(300mg，2.54mmol)溶于8mL二氯甲烷中，冰浴下加入2,6-二甲基吡啶(299.22mg，2.79mmol)，滴加三氟甲磺酸酐(787.87mg，2.79mmol)，滴加完后在冰浴下搅拌反应1小时，自然升温至室温搅拌反应1小时。反应液中加入30mL二氯甲烷，用20mL水洗涤，有机相用无水硫酸钠干燥，过滤，减压浓缩得粗品标题化合物1b(550mg)，产物不经纯化直接下步反应。
第二步
1-(2-溴-4-氯苯基)丙烷-1-酮1e
将2-溴-4-氯-1-碘苯1c(1.0g，3.15mmol，采用公知的方法“Angewandte Chemie,International Edition,2010,49(46),8729-8732”制备而得)溶于1mL四氢呋喃中，冷却至-20℃，加入异丙基氯化镁(421.15mg，4.10mmol)，预先反应1小时。将丙酰氯1d(378.89mg，4.10mmol)、氯化锂(11.42mg，189.00μmol)、氯化亚铜(9.36mg，94.50μmol)和三氯化铝(12.61mg，94.50μmol)加入1mL四氢呋喃中，室温搅拌均匀，将预先反应了1小时的反应液滴加到以上混合液中，室温反应2小时。反应液中加入20mL饱和氯化铵溶液淬灭反应，用二氯甲烷萃取(20mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用CombiFlash快速制备仪以洗脱剂B纯化所得残余物，制得标题化合物1e(640mg，产率：82.0％)
第三步
1-(4-氯-2-(2,5-二甲氧基吡啶-4-基)苯基)丙烷-1-酮1g
将化合物1e(640mg，2.59mmol)、化合物1f(520.41mg，2.84mmol，采用专利申请“WO2015063093”公开的方法制备而得)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(191.8mg，0.259mmol)和碳酸钠(822.16mg，7.76mmol)加入到20mL 1,4-二氧六环和4mL水的混合溶剂中，加毕，反应液加热至85℃，搅拌反应16小时。反应液自然冷却至室温，加入20mL水，用乙酸乙酯萃取(20mL×3)，合并有机相，有机相分别用水(30mL)，饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物1g(600mg，产率：75.9％)。
MS m/z(ESI):306.0[M+1]
第四步
4-(5-氯-2-丙酰基苯基)-5-甲氧基吡啶-2(1H)-酮1f
将化合物1g(600mg，1.96mmol)加入到10mL N,N-二甲基甲酰胺中，加入吡啶氢溴酸盐(1.51g，9.81mmol)，加毕，加热至100℃，搅拌反应3小时。反应液冷却至室温，减压浓缩除去有机溶剂，所得残余物中加入30mL水，用二氯甲烷萃取(20mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题化合物1f(550mg)，产物不经纯化直接下一步反应。
MS m/z(ESI):292.0[M+1]
第五步
2-(4-(5-氯-2-丙酰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)乙酸叔丁酯1i
将粗品化合物1f(550mg，1.89mmol)、碳酸铯(1.84g，5.67mmol)和化合物1h(551.61mg，2.83mmol，采用公知的方法“Chemical Communications(Cambridge,United Kingdom),2012,48(22),2803-2805合成得到)溶于10mL N,N-二甲基甲酰胺，加毕，反应液温度升至65℃，搅拌反应2小时。冷却反应液温度至室温，加入30mL水，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤(30mL×3)无水硫酸钠干燥，过滤，滤液减压浓缩，用CombiFlash快速制备仪以洗脱剂B纯化所得残余物，得到标题化合物1i(350mg，产率：51.0％)。
MS m/z(ESI):405.4[M+1]
第六步
4-(叔丁氧基)-2-(4-(5-氯-2-丙酰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酸叔丁酯1j
将化合物1i(148mg，364.65μmol)和粗品化合物1b(182.50mg，729.30μmol)溶于15mL四氢呋喃中，反应液冷却至-78℃，滴加二(三甲基硅基)氨基锂溶液(1.46mL，1.46mmol)，搅拌反应2小时。-78℃下，向反应液中缓慢加入5mL水淬灭反应，反应液温度自然升至室温，加入20mL水，用乙酸乙酯萃取(35mL×3)，合并有机相，用饱和氯化钠溶液洗涤(25mL×2)，无水硫酸钠干燥。过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得标题化合物1j(120mg，产率：65.0％)。
MS m/z(ESI):506.5[M+1]
第七步
4-(叔丁氧基)-2-(4-(5-氯-2-丙酰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酸1k
将化合物1j(120mg，237.14μmol)溶于8mL乙醇和4mL四氢呋喃的混合溶剂中，加入氢氧化锂(49.75mg，1.19mmol)，升温至50℃搅拌反应2小时。反应液冷却至室温，减压浓缩旋去大部分有机溶剂，加入15mL水，用3M盐酸调节pH至3，乙酸乙酯萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤(20mL×2)，无水硫酸钠干燥，过滤，滤液浓缩，得到粗品标题化合物1k(106mg)，产物不经纯化直接下步反应。
MS m/z(ESI):450.4[M+1]
第八步
4-(4-(叔丁氧基)-2-(4-(5-氯-2-丙酰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酰氨基)苯甲酸1m
将粗品化合物1k(106mg，235.59μmol)溶于15mL乙酸乙酯中，依次加入N,N-二异 丙基乙胺(304.48mg，2.36mmol)、化合物1l(35.54mg，259.16μmol，采用公知的方法“Angewandte Chemie-International Edition，2012,51(34),8564-8567”制备而得)和2,4,6-三丙基-1,3,5,2,4,6-三氧三磷酸-2,4,6-三氧化物的乙酸乙酯溶液(50％，599.70mg，942.38μmol)，加毕，反应升温至80℃，搅拌反应2小时。反应液冷却至室温，加入20mL水，用3M盐酸调节pH至5，乙酸乙酯萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤(20mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用高效液相制备(Waters 2767-SQ detecor2，洗脱体系：乙腈，水)纯化所得残余物，制得标题化合物1m(60mg，产率：44.8％)。
MS m/z(ESI):569.5[M+1]
第九步
(S)-4-(4-(叔丁氧基)-2-(4-(5-氯-2-丙酰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酰氨基)苯甲酸1
将化合物1m(60mg，105.44μmol)进行手性制备(分离条件：色谱柱Superchiral S-AD(Chiralway),2cm I.D.*25cm Length,5um；流动相：二氧化碳：乙醇：二乙胺＝60：40：0.05，流速：50g/min)，收集其相应组分，减压浓缩，得到标题化合物1(22mg)。
经X-射线粉末衍射检测，该产物为无定形，如图1。
实施例1、A晶型的制备
将式(I)化合物(3.3g)加入到10mL乙酸乙酯中，反应液升温至80℃，搅拌溶清，缓慢加入正己烷至恰好浑浊(约15mL)，缓慢降至室温，析出白色固体，室温继续搅拌3小时。反应液过滤，收集滤饼，真空干燥，得到产物(2g)。
经X-射线粉末衍射检测，将该产物定义为A晶型，XRPD谱图如图2。
DSC谱图如图3，吸热峰峰值150.77℃，TGA谱图如图4，25-140℃失重2.51％。
DVS表征：样品在25℃条件下，根据相对质量变化曲线，在10％RH-80％RH之间，随着湿度增加，质量增加约为1.781％，小于2％但不小于0.2％，根据《中华人民共和国药典》2015年版药物引湿性试验指导原则，该样品略有引湿性。在正常储存条件(即25℃60％RH)，质量增加约为1.156％；在加速试验条件(即70％RH)，质量增加约为1.479％；在极端条件(即90％RH)，质量增加约为2.199％。在0％-95％的湿度变化过程中，该样品的解吸附过程与吸附过程基本重合。DVS检测谱图如图5，DVS检测前后X-射线粉末衍射对比如图6，DVS检测前后晶型未转变。
表1、A晶型的特征峰
Figure PCTCN2019094170-appb-000006
Figure PCTCN2019094170-appb-000007
实施例2、A晶型的制备
将式(I)化合物(100mg)加入到1mL二氯甲烷中，升温至50℃，搅拌溶清，缓慢滴加0.8mL异丙醚，缓慢降至室温，继续搅拌17小时。反应液过滤，收集滤饼，真空干燥，得到产物(82mg)。经X-射线粉末衍射检测，该产物为A晶型。
实施例3、A晶型的制备
将式(I)化合物(100mg)加入到1mL丙酮中，升温至50℃，搅拌溶清，缓慢滴加1.4mL正庚烷，缓慢降至室温，继续搅拌17小时。反应液过滤，收集滤饼，真空干燥，得到产物(75mg)。经X-射线粉末衍射检测，该产物为A晶型。
实施例4、A晶型的制备
将式(I)化合物(100mg)加入到0.8mL乙酸乙酯中，升温至80℃，搅拌溶清，缓慢滴加0.7mL正庚烷，缓慢降至室温，继续搅拌17小时。反应液过滤，收集滤饼，真空干燥，得到产物(74mg)。经X-射线粉末衍射检测，该产物为A晶型。
实施例5、A晶型的制备
将式(I)化合物(100mg)加入到1mL甲苯中，升温至110℃，搅拌溶清，缓慢滴加0.25mL正庚烷，缓慢降至室温，继续搅拌17小时。反应液过滤，收集滤饼，真空干燥，得到产物(41mg)。经X-射线粉末衍射检测，该产物为A晶型。
实施例6、A晶型的制备
将式(I)化合物(200mg)加入到4mL甲酸乙酯中，升温至60℃，搅拌溶清，缓慢滴加5mL正己烷，搅拌15分钟有少量固体析出，缓慢降至20℃(约3小时)，继续搅拌13小时。反应液过滤，收集滤饼，真空干燥，得到产物(100mg)。经X-射线粉末衍射检测，该产物为A晶型。
实施例7、A晶型的制备
将式(I)化合物(200mg)加入到1mL乙酸乙酯中，升温至80℃，搅拌溶清，缓慢滴加 1.5mL正己烷，有固体析出，继续在80℃下搅拌3小时，缓慢降至15℃(约3小时)，继续搅拌14小时。反应液过滤，收集滤饼，真空干燥，得到产物(130mg)。经X-射线粉末衍射检测，该产物为A晶型。
实施例8、B晶型的制备
将式(I)化合物(4g)加入到8mL乙酸乙酯中，升温至80℃，搅拌溶清，缓慢滴加6mL正庚烷，有少量浑浊析出，继续在80℃下搅拌10分钟，缓慢降至50℃，有固体析出，继续缓慢滴加6mL正庚烷，缓慢降至10℃，继续搅拌17小时。反应液过滤，收集滤饼，真空干燥，得到产物(3.5g)。经X-射线粉末衍射检测，将该产物定义为B晶型，谱图如图7。
DSC表征如图8，吸热峰峰值146.17℃，TGA表征如图9，25-130℃失重2.90％。DVS表征：样品在25℃条件下，根据相对质量变化曲线，在10％RH-80％RH之间，随着湿度增加，质量增加约为1.968％，小于2％但不小于0.2％，根据《中华人民共和国药典》2015年版药物引湿性试验指导原则，该样品略有引湿性。在正常储存条件(即25℃60％RH)，质量增加约为1.155％；在加速试验条件(即70％RH)，质量增加约为1.530％；在极端条件(即90％RH)，质量增加约为3.963％。在0％-95％的湿度变化过程中，该样品的解吸附过程与吸附过程基本重合。DVS检测谱图如图10，DVS检测前后X-射线粉末衍射对比如图11，DVS检测后晶型转变为A晶型。
表2、B晶型的特征峰
峰序号 2-Theta d(A) I％
峰1 7.620 11.593 100.0
峰2 8.680 10.179 83.4
峰3 11.042 8.006 8.6
峰4 11.638 7.598 8.3
峰5 12.339 7.167 9.2
峰6 14.461 6.120 7.7
峰7 16.320 5.427 16.6
峰8 18.123 4.891 6.1
峰9 18.381 4.823 4.9
峰10 19.381 4.576 15.3
峰11 22.020 4.033 9.8
峰12 25.038 3.554 14.4
峰13 26.460 3.366 4.6
实施例9、B晶型的制备
将式(I)化合物(100mg)溶于0.5mL四氢呋喃中，室温下将该溶液缓慢滴加到2mL异 丙醚(约含4mg A晶种)中，有固体析出，继续搅拌16小时。反应液过滤，收集滤饼，真空干燥，得到产物(35mg)。经X-射线粉末衍射检测，该产物为B晶型。
实施例10、B晶型的制备
将式(I)化合物(100mg)加入到5mL甲基叔丁基醚中，不溶，室温打浆24小时，50℃加热2小时不溶，降至室温，离心，固体样品真空干燥，得到产物。经X-射线粉末衍射检测，该产物为B晶型。
实施例11、B晶型的制备
将式(I)化合物(100mg)加入到5mL环己烷中，不溶，室温打浆24小时，50℃加热2小时不溶，降至室温，离心，固体样品真空干燥，得到产物。经X-射线粉末衍射检测，该产物为B晶型。
实施例12、C晶型的制备
将式(I)化合物(100mg)加入到5mL对二甲苯中，不溶，室温打浆24小时，50℃加热2小时不溶，降至室温，离心，固体样品真空干燥，得到产物。经X-射线粉末衍射检测，将该产物定义为C晶型，XRPD谱图如图12。
DSC谱图如图13，吸热峰峰值141.44℃；TGA谱图如图14，25-130℃失重5.22％。
表3、C晶型的特征峰
Figure PCTCN2019094170-appb-000008
Figure PCTCN2019094170-appb-000009
实施例13、D晶型的制备
将式(I)化合物(1.7g)加入到3.4mL乙酸乙酯中，加热至80℃，搅拌溶清，继续搅拌1小时，有固体析出，缓慢降至15℃，继续在15℃搅拌4小时。反应液过滤，收集滤饼，真空干燥，得到产物(1.5g)。经X-射线粉末衍射检测，将该产物定义为D晶型，谱图如图15。
DSC和TGA谱图如图16，DSC表征吸热峰峰值118.4℃，TGA表征24.2-140℃失重5.25％。
DVS表征：样品在25℃条件下，根据相对质量变化曲线，在10％RH-80％RH之间，随着湿度增加，质量增加约为2.420％，小于15％但不小于2％，根据《中华人民共和国药典》2015年版药物引湿性试验指导原则，该样品有引湿性。在正常储存条件(即25℃60％RH)，质量增加约为2.143％；在加速试验条件(即70％RH)，质量增加约为2.494％；在极端条件(即90％RH)，质量增加约为3.422％。在0％-95％的湿度变化过程中，该样品的解吸附过程与吸附过程不重合。DVS检测谱图如图17，DVS检测前后X-射线粉末衍射对比如图18，DVS检测后晶型的结晶度变差。
表4、D晶型的特征峰
Figure PCTCN2019094170-appb-000010
Figure PCTCN2019094170-appb-000011
实施例14、D晶型的制备
将式(I)化合物(1g)加入到于4.5mL乙酸乙酯中，加热至80℃，搅拌溶清，80℃下缓慢滴加4mL正己烷，无固体析出，缓慢降至70℃，有固体析出，缓慢降至20℃(约5小时)，继续在20℃搅拌15小时。反应液过滤，收集滤饼，真空干燥，得到产物(0.89g)。经X-射线粉末衍射检测，该产物为D晶型。
实施例15、D晶型的制备
将式(I)化合物(200mg)加入到2mL丙酮中，加热至50℃，搅拌溶清，缓慢滴加3.5mL正庚烷，无固体析出，缓慢降至20℃，溶液浑浊，缓慢降至15-20℃，继续搅拌16小时。反应液过滤，收集滤饼，真空干燥，得到产物(130mg)。经X-射线粉末衍射检测，该产物为D晶型。
实施例16、D晶型的制备
将式(I)化合物(100mg)溶于1mL乙酸乙酯中，缓慢滴加入2mL正己烷(加有约4mg A晶型晶种，15-20℃)，有固体析出，继续搅拌3小时。反应液过滤，收集滤饼，真空干燥，得到产物(35mg)。经X-射线粉末衍射检测，该产物为D晶型。
实施例17、D晶型的制备
将式(I)化合物(100mg)溶于0.5mL丙酮中，缓慢滴加入2mL异丙醚(加有约4mg A晶型晶种，15-20℃)，有固体析出，继续搅拌5小时。反应液过滤，收集滤饼，真空干燥，得到产物(60mg)。经X-射线粉末衍射检测，该产物为D晶型。
实施例18、D晶型的制备
将式(I)化合物(60mg)溶于0.8mL丙酮和异丙醚(V:V＝1:3)混合溶剂中，滤膜过滤，PE膜覆盖，扎孔，慢挥发，析出立方体颗粒，取样单晶解析分子立体结构椭球图如图19。经X-射线粉末衍射检测，该产物为D晶型。
实施例19、E晶型的制备
将式(I)化合物(20mg)溶于0.5mL丙酮和环己烷(V:V＝1:3)混合溶剂中，滤膜过滤，PE膜覆盖，扎孔，自然慢挥发，析出固体，反应液过滤，收集滤饼，真空干燥，得到产物(8mg)。经X-射线粉末衍射检测，将该产物定义为E晶型，谱图如图20。
表5、E晶型的特征峰
峰序号 2-Theta d(A) I％
峰1 6.460 13.671 14.7
峰2 7.480 11.810 100.0
峰3 7.977 11.074 11.6
峰4 8.662 10.200 3.9
峰5 11.299 7.825 1.2
峰6 12.140 7.285 1.6
峰7 14.038 6.303 2.0
峰8 16.220 5.460 7.1
峰9 17.440 5.081 1.7
峰10 18.560 4.777 1.2
峰11 19.360 4.581 7.9
峰12 21.720 4.088 10.6
峰13 22.664 3.920 0.7
峰14 24.922 3.570 1.1
峰15 25.940 3.432 1.2
峰16 26.840 3.319 1.6
峰17 29.620 3.014 1.6
实施例20、F晶型的制备
将式(I)化合物(1g)加入到于3mL乙酸乙酯中，加热至80℃，搅拌溶清，继续搅拌30分钟，有固体析出，80℃下缓慢滴加4.5mL正己烷，缓慢降至20℃(约3小时)，20℃继续搅拌3小时。反应液过滤，收集滤饼，真空干燥，得到产物(855mg)。经X-射线粉 末衍射检测，将该产物定义为F晶型，谱图如图21。
DSC谱图如图22，吸热峰峰值为214.68℃；TGA谱图如图23。
DVS表征：样品在25℃条件下，根据相对质量变化曲线，在10％RH-80％RH之间，随着湿度增加，质量增加约为0.1464％，小于2％，根据《中华人民共和国药典》2015年版药物引湿性试验指导原则，该样品几乎无引湿性。在正常储存条件(即25℃60％RH)，质量增加约为0.0457％；在加速试验条件(即70％RH)，质量增加约为0.0701％；在极端条件(即90％RH)，质量增加约为0.2744％。在0％-95％的湿度变化过程中，该样品的解吸附过程与吸附过程基本重合，DVS检测前后晶型没有发生变化。DVS曲线如图24，DVS检测前后X-射线粉末衍射对比如图25。
表6、F晶型的特征峰
Figure PCTCN2019094170-appb-000012
Figure PCTCN2019094170-appb-000013
实施例21、F晶型的制备
将式(I)化合物(12g)加入到240mL甲酸乙酯中，加热至内温54℃回流，搅拌溶清，回流条件下缓慢滴加300mL正己烷，清液，回流条件下加入F晶型晶种，固体未溶解，继续回流搅拌30分钟，有固体慢慢析出，缓慢降至室温，继续搅拌16小时。反应液过滤，收集滤饼，真空干燥，得到产物(8.2g)。经X-射线粉末衍射检测，该产物为F晶型。
实施例22、A晶型的制备
将式(I)化合物B晶型(25mg)加入到0.4mL甲苯中，室温打浆搅拌90小时。反应液过滤，收集滤饼，真空干燥，得到产物(13mg)。经X-射线粉末衍射检测，该产物为A晶型。
实施例23、A晶型的制备
将式(I)化合物B晶型(50mg)加入到0.4mL四氢呋喃和甲基叔丁基醚(V:V＝1:3)混合溶剂中，室温打浆搅拌90小时。反应液过滤，收集滤饼，真空干燥，得到产物(24mg)。经X-射线粉末衍射检测，该产物为A晶型。
实施例24、A晶型的制备
将式(I)化合物B晶型(25mg)加入到0.4mL乙酸乙酯和正己烷(V:V＝1:1)混合溶剂中，室温打浆搅拌90小时。反应液过滤，收集滤饼，真空干燥，得到产物(18mg)。经X-射线粉末衍射检测，该产物为A晶型。
实施例25、A晶型的制备
将式(I)化合物B晶型(25mg)加入到0.4mL乙酸乙酯和正庚烷(V:V＝1:1)混合溶剂中，室温打浆搅拌90小时。反应液过滤，收集滤饼，真空干燥，得到产物(17mg)。经X-射线粉末衍射检测，该产物为A晶型。
实施例26、A晶型的制备
将式(I)化合物A晶型(20mg)和B晶型(20mg)加入到0.5mL 1,4-二氧六环和水(V:V＝1:2)混合溶剂中，室温打浆搅拌90小时。反应液过滤，收集滤饼，真空干燥，得到产物(25mg)。经X-射线粉末衍射检测，该产物为A晶型。
实施例27、A晶型的制备
将式(I)化合物A晶型(20mg)和B晶型(20mg)加入到0.5mL乙腈中，室温打浆搅拌90小时。反应液过滤，收集滤饼，真空干燥，得到产物(18mg)。经X-射线粉末衍射检测，该产物为A晶型。
实施例28、A晶型的制备
将式(I)化合物A晶型(10mg)加入到1mL水中，室温打浆搅拌18小时。反应液过滤，收集滤饼，真空干燥，得到产物(5mg)。经X-射线粉末衍射检测，该产物为A晶型。
实施例29、B晶型的制备
将式(I)化合物无定形(200mg)加入到4mL乙酸叔丁酯、甲基叔丁基醚和正己烷(V:V:V＝1:1:2)混合物溶剂中，室温打浆搅拌72小时。反应液过滤，收集滤饼，真空干燥，得到产物(80mg)。经X-射线粉末衍射检测，该产物为B晶型。
实施例30、B晶型的制备
将式(I)化合物无定形(200mg)加入到0.27mL三氟乙醇和异丙醚(V:V＝2:25)混合物溶剂中，室温升温至50℃，打浆搅拌72小时。反应液冷却至室温，过滤，收集滤饼，真空干燥，得到产物(18mg)。经X-射线粉末衍射检测，该产物为B晶型。
实施例31、B晶型的制备
将式(I)化合物无定形(50mg)加入到0.5mL正庚烷中，室温升温至50℃，打浆搅拌72小时。反应液冷却至室温，过滤，收集滤饼，真空干燥，得到产物(40mg)。经X-射线粉末衍射检测，该产物为B晶型。
实施例32、B晶型的制备
将式(I)化合物无定形(50mg)加入到0.5mL氯仿和甲基叔丁基醚(V:V＝1:8)混合物溶剂中，室温升温至50℃，打浆搅拌72小时。反应液冷却至室温，过滤，收集滤饼，真空干燥，得到产物(28mg)。经X-射线粉末衍射检测，该产物为B晶型。
实施例33、B晶型的制备
将式(I)化合物A晶型(20mg)和B晶型(20mg)加入到0.5mL乙酸乙酯和正庚烷(V:V＝2:3)混合溶剂中，室温打浆搅拌90小时。反应液过滤，收集滤饼，真空干燥，得到产物(28mg)。经X-射线粉末衍射检测，该产物为B晶型。
实施例34、B晶型的制备
将式(I)化合物A晶型(20mg)和B晶型(20mg)加入到0.5mL丙酮、甲基叔丁基醚和正己烷(V:V:V＝1:1:4)混合溶剂中，室温打浆搅拌90小时。反应液过滤，收集滤饼，真 空干燥，得到产物(20mg)。经X-射线粉末衍射检测，该产物为B晶型。
实施例35、B晶型的制备
将式(I)化合物A晶型(20mg)和B晶型(20mg)加入到0.5mL乙酸丁酯、甲基叔丁基醚和正己烷(V:V:V＝1:1:2)混合溶剂中，室温打浆搅拌90小时。反应液过滤，收集滤饼，真空干燥，得到产物(21mg)。经X-射线粉末衍射检测，该产物为B晶型。
实施例36、D晶型的制备
将式(I)化合物B晶型(1.4g)加入到14mL乙腈中，室温打浆搅拌96小时。反应液过滤，收集滤饼，真空干燥，得到产物(1.25g)。经X-射线粉末衍射检测，该产物为D晶型。
实施例37、F晶型的制备
将式(I)化合物无定形(30mg)加入到0.5mL 1,4-二氧六环和水(V:V＝1:2)混合物溶剂中，室温打浆搅拌72小时。反应液过滤，收集滤饼，真空干燥，得到产物(21mg)。经X-射线粉末衍射检测，该产物为F晶型。
实施例38、F晶型的制备
将式(I)化合物A晶型(30mg)加入到1mL乙腈和水(V:V＝1:4)混合物溶剂中，室温打浆搅拌96小时。反应液过滤，收集滤饼，真空干燥，得到产物(18mg)。经X-射线粉末衍射检测，该产物为F晶型。
实施例39、F晶型的制备
将式(I)化合物A晶型(30mg)加入到0.8mL四氢呋喃和水(V:V＝1:3)混合物溶剂中，室温打浆，粉末状固体变粘状固体，继续打浆，粘状固体转变为粉末状固体，打浆搅拌共计96小时。反应液过滤，收集滤饼，真空干燥，得到产物(16mg)。经X-射线粉末衍射检测，该产物为F晶型。
实施例40、F晶型的制备
将式(I)化合物A晶型(30mg)加入到1mL丙酮和水(V:V＝1:4)混合物溶剂中，室温打浆搅拌96小时。反应液过滤，收集滤饼，真空干燥，得到产物(17mg)。经X-射线粉末衍射检测，该产物为F晶型。
实施例41、F晶型的制备
将式(I)化合物A晶型(40mg)加入到0.6mL异丙醇和水(V:V＝1:3)混合物溶剂中，室温打浆搅拌96小时。反应液过滤，收集滤饼，真空干燥，得到产物(24mg)。经X-射线粉末衍射检测，该产物为F晶型。
实施例42、F晶型的制备
将式(I)化合物无定形(20mg)加入到0.3mL丙酸乙酯和正庚烷(V:V＝1:0.5)混合物溶剂中，室温打浆搅拌96小时。反应液过滤，收集滤饼，真空干燥，得到产物(14mg)。经X-射线粉末衍射检测，该产物为F晶型。
实施例43、F晶型的制备
将式(I)化合物无定形(20mg)加入到0.3mL正丙醇和异丙醚(V:V＝1:5)混合物溶剂中，室温打浆搅拌96小时。反应液过滤，收集滤饼，真空干燥，得到产物(12mg)。经X-射线粉末衍射检测，该产物为F晶型。
实施例44、F晶型的制备
将式(I)化合物无定形(20mg)加入到0.3mL邻二甲苯中，室温打浆搅拌96小时。反应液过滤，收集滤饼，真空干燥，得到产物(15mg)。经X-射线粉末衍射检测，该产物为F晶型。
实施例45、F晶型的制备
将式(I)化合物无定形(20mg)加入到0.5mL 2-丁酮和正庚烷(V:V＝1:4)混合物溶剂中，室温打浆搅拌96小时。反应液过滤，收集滤饼，真空干燥，得到产物(7mg)。经X-射线粉末衍射检测，该产物为F晶型。
实施例46、F晶型的制备
将式(I)化合物无定形(20mg)加入到0.5mL 1,4-二氧六环和异丙醚(V:V＝1:4)混合物溶剂中，室温打浆搅拌96小时。反应液过滤，收集滤饼，真空干燥，得到产物(10mg)。经X-射线粉末衍射检测，该产物为F晶型。
实施例47、F晶型的制备
将式(I)化合物A晶型(15mg)、D晶型(15mg)和F晶型(15mg)加入到0.4mL正庚烷中，升温至50℃，打浆搅拌120小时。反应液冷却至室温，过滤，收集滤饼，真空干燥，得到产物(24mg)。X-射线粉末衍射检测，该产物为F晶型。
实施例48、F晶型的制备
将式(I)化合物A晶型(15mg)、D晶型(15mg)和F晶型(15mg)加入到0.4mL异丙醚中，升温至50℃，打浆搅拌120小时。反应液冷却至室温，过滤，收集滤饼，真空干燥，得到产物(21mg)。经X-射线粉末衍射检测，该产物为F晶型。
实施例49、F晶型的制备
将式(I)化合物A晶型(15mg)、D晶型(15mg)和F晶型(15mg)加入到0.4mL氯 仿和正庚烷(V:V＝1:1.5)混合溶剂中，升温至50℃，打浆搅拌120小时。反应液冷却至室温，过滤，收集滤饼，真空干燥，得到产物(20mg)。经X-射线粉末衍射检测，该产物为F晶型。
实施例50、F晶型的制备
将式(I)化合物A晶型(15mg)、D晶型(15mg)和F晶型(15mg)加入到0.4mL甲基异丁酮和正庚烷(V:V＝1:5)混合溶剂中，升温至50℃，打浆搅拌120小时。反应液冷却至室温，过滤，收集滤饼，真空干燥，得到产物(22mg)。经X-射线粉末衍射检测，该产物为F晶型。
实施例51、F晶型的制备
将式(I)化合物A晶型(10mg)、D晶型(10mg)和F晶型(10mg)加入到0.5mL异丙醇和异丙醚(V:V＝1:4)混合溶剂中，室温打浆搅拌96小时。反应液过滤，收集滤饼，真空干燥，得到产物(18mg)。经X-射线粉末衍射检测，该产物为F晶型。
实施例52、F晶型的制备
将式(I)化合物A晶型(10mg)、D晶型(10mg)和F晶型(10mg)加入到0.5mL丙酮和正己烷(V:V＝1:4)混合溶剂中，室温打浆搅拌96小时。反应液过滤，收集滤饼，真空干燥，得到产物(22mg)。经X-射线粉末衍射检测，该产物为F晶型。
实施例53、F晶型的制备
将式(I)化合物A晶型(10mg)、D晶型(10mg)和F晶型(10mg)加入到0.5mL氯仿和异丙醚(V:V＝1:4)混合溶剂中，室温打浆搅拌96小时。反应液过滤，收集滤饼，真空干燥，得到产物(21mg)。X-射线粉末衍射检测，该产物为F晶型。
实施例54、F晶型的制备
将式(I)化合物A晶型(10mg)、D晶型(10mg)和F晶型(10mg)加入到0.3mL甲苯中，室温打浆搅拌96小时。反应液过滤，收集滤饼，真空干燥，得到产物(26mg)。经X-射线粉末衍射检测，该产物为F晶型。
实施例55、F晶型的制备
将式(I)化合物A晶型(10mg)、D晶型(10mg)和F晶型(10mg)加入到0.3mL乙腈中，室温打浆搅拌96小时。反应液过滤，收集滤饼，真空干燥，得到产物(22mg)。经X-射线粉末衍射检测，该产物为F晶型。
实施例56、F晶型的制备
将式(I)化合物F晶型(10mg)加入到1mL水中，室温打浆搅拌18小时。反应液过 滤，收集滤饼，真空干燥，得到产物。X-射线粉末衍射检测，该产物为F晶型。
实施例57、本发明A、B、D、F晶型影响因素实验
将式(I)化合物A、B、D、F晶型样品敞口平摊放置，考察在高温(40℃、60℃)、光照(4500Lux)、高湿(RH 75％、RH 90％)条件下样品的稳定性，取样考察期为30天。
实验结果：
表7、式(I)化合物A晶型和B晶型影响因素实验结果
Figure PCTCN2019094170-appb-000014
表8、式(I)化合物D晶型和F晶型影响因素实验结果
Figure PCTCN2019094170-appb-000015
Figure PCTCN2019094170-appb-000016
实验结论：
由表7、8的影响因素实验结果表明：在光照、高温40℃、高温60℃、高湿75％RH、高湿90％RH条件下，放置30天，A晶型和F晶型的物理化学稳定性好。
实施例58、本发明A晶型和F晶型长期加速稳定性实验
式(I)化合物A晶型和F晶型进行3个月的长期(25℃、60％RH)、加速(40℃、75％RH)稳定性考察。
实验结果：
表9、式(I)化合物A晶型和F晶型长期加速稳定性实验结果：
Figure PCTCN2019094170-appb-000017
由表9的长期加速稳定性实验结果显示：A晶型及F晶型长期(25℃、60％RH)、加速(40℃、75％RH)稳定性条件下放置3个月物理化学稳定性好。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (15)

  1. 式(I)化合物(S)-4-(4-(叔丁氧基)-2-(4-(5-氯-2-丙酰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酰氨基)苯甲酸的A晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为7.420、8.000、8.642、12.900、22.400处有特征峰，
    Figure PCTCN2019094170-appb-100001
  2. 如权利要求1所述的A晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为7.420、8.000、8.642、12.900、16.281、18.280、20.018、21.119、22.400、24.458、26.100处有特征峰。
  3. 式(I)化合物(S)-4-(4-(叔丁氧基)-2-(4-(5-氯-2-丙酰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酰氨基)苯甲酸的B晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为7.620、8.680、11.042、11.638、12.339、16.320、19.381处有特征峰，
    Figure PCTCN2019094170-appb-100002
  4. 式(I)化合物(S)-4-(4-(叔丁氧基)-2-(4-(5-氯-2-丙酰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酰氨基)苯甲酸的C晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为7.283、8.780、10.664、11.264、14.744、15.456、16.587、17.598处有特征峰，
    Figure PCTCN2019094170-appb-100003
  5. 式(I)化合物(S)-4-(4-(叔丁氧基)-2-(4-(5-氯-2-丙酰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酰氨基)苯甲酸的D晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为7.021、7.901、8.259、9.200、10.639、12.320、13.821、14.180、14.580、15.519、16.120、16.661、18.500、19.919、20.600处有特征峰，
    Figure PCTCN2019094170-appb-100004
  6. 式(I)化合物(S)-4-(4-(叔丁氧基)-2-(4-(5-氯-2-丙酰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酰氨基)苯甲酸的E晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为6.460、7.480、7.977、16.220、19.360、21.720处有特征峰，
    Figure PCTCN2019094170-appb-100005
  7. 式(I)化合物(S)-4-(4-(叔丁氧基)-2-(4-(5-氯-2-丙酰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酰氨基)苯甲酸的F晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为5.761、9.800、10.640、11.621、14.021、16.180、16.460、17.520、21.460、24.580处有特征峰，
    Figure PCTCN2019094170-appb-100006
  8. 如权利要求7所述的F晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为5.761、9.800、10.640、11.621、14.021、16.180、16.460、16.740、17.520、21.460、22.820、23.939、24.580、26.280处有特征峰。
  9. 如权利要求7所述的F晶型，其特征在于，其X-射线粉末衍射图谱中，在2θ为5.761、9.800、10.640、11.621、14.021、16.180、16.460、16.740、17.520、18.560、19.142、19.820、21.460、22.820、23.939、24.580、25.981、26.280、26.861、27.700、28.580、28.921、29.480、30.840、31.340、32.801、33.300、33.921、35.321、36.843、38.660、40.101、41.121、41.600处有特征峰。
  10. 如权利要求1-9任一项所述的式(I)化合物(S)-4-(4-(叔丁氧基)-2-(4-(5-氯-2-丙酰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基)丁酰氨基)苯甲酸的A、B、C、D、E或F晶型的制备方法，包括：取一定量的式(I)化合物，加入适量溶剂，析晶、过滤、干燥，得到式(I)化合物的A晶型、B晶型、C晶型、D晶型、E晶型或F晶型。
  11. 如权利要求1-9任一项所述的晶型，其特征在于其2θ值误差范围为±0.2。
  12. 一种药物组合物，其特征在于含有至少一种如权利要求1-9、11任一项所述的晶型，还包含一种或多种药学上可接受的载体、稀释剂或赋形剂。
  13. 一种制备如权利要求12所述的药物组合物的方法，其特征在于使至少一种如权利要求1-9、11任一项所述的晶型与至少一种药学上可接受的载体、稀释剂或赋形剂混合。
  14. 如权利要求1-9、11任一项所述的晶型在制备用于治疗和/或预防XIa因子介导的疾病的药物中的用途。
  15. 如权利要求1-9、11任一项所述的晶型在制备用于治疗和/或预防心脑血管疾病的药物中的用途，所述心脑血管疾病选自血栓栓塞性疾病，优选心肌梗塞、心绞痛、血管成形术或主动脉冠状动脉分流术后的再阻塞和再狭窄、弥散性血管内凝血、中风、短暂的局部缺血发作、周围动脉闭塞性疾病、肺栓塞或深部静脉血栓形成。
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