TWI722466B - Crystal forms of oxopicolinamide derivatives and preparation method thereof - Google Patents

Abstract

A crystal form of oxopicolinamide derivatives and preparation method thereof. Specifically, the invention relates to crystalline forms A, B, C, D, E, F of a compound of formula (I) and preparation method thereof. The crystalline forms of the compound of the formula (I) of the invention have good crystal form stability and may be better used clinically.

Description

Crystal form and preparation method of oxopyridine amide derivatives

This application claims the priority of the Chinese patent application CN201810710037.1 whose filing date is July 2, 2018. This application quotes the full text of the aforementioned Chinese patent application.

The invention belongs to the field of medicinal chemistry and relates to a blood coagulation XIa inhibitor ( S )-4-(4-(tert-butoxy)-2-(4-(5-chloro-2-propanylphenyl)-5- The crystal form of methoxy-2-oxopyridine-1( 2H )-yl)butyramido)benzoic acid and its preparation method.

Cardiovascular and cerebrovascular diseases such as cerebrovascular, cerebral infarction, myocardial infarction, coronary heart disease, and arteriosclerosis take nearly 12 million lives worldwide each year, which is close to a quarter of the world's total deaths. In China, more than 2.6 million people die from cardiovascular disease each year, and 75% of the surviving patients are disabled, of which more than 40% are severely disabled. Thrombosis caused by cardiovascular and cerebrovascular diseases and diabetes and its complications has become an urgent problem to be solved today.

According to data from the independent market analysis agency Datamonitor in 2011, it is estimated that with the production of generic drugs, the share of cardiovascular and metabolic diseases in the seven major markets will reach a peak in 2011, and then gradually decrease, and its sales will increase from 2010. US$109 billion fell to US$101 billion in 2019. Among them, the thrombus market remained basically stable, from USD 19.5 billion in 2010 to USD 18.9 billion in 2019 (Datamonitor: HC00034-001, HC00139-001). The research report of Guangzhou Punctuation in 2011 also showed that the market size of antithrombotic drugs in China in 2011 reached 8.135 billion yuan, a year-on-year increase of 20.52%, which has huge market potential (Antithrombotic Drug Market Research Report: Guangzhou Punctuation (2011)).

The blood coagulation process of human body is composed of intrinsic pathway, extrinsic pathway and common pathway (Annu. Rev. Med. 2011. 62: 41–57), which is continuously activated by multiple zymogens being sequentially activated. A chain reaction that is strengthened and amplified. The coagulation cascade is initiated by the internal pathway (also called the contact activation pathway) and the external pathway (also called the tissue factor pathway) to generate FXa, and then through the common pathway to generate thrombin (FIIa), and finally form fibrin.

The internal pathway refers to the process by which factor XII is activated to form the XIa-VIIIa-Ca2±PL complex and activate factor X, and the external coagulation pathway is the release of tissue factor (TF) to the formation and activation of factor X by the TF-VIIaCa2+ complex The process of X. The common pathway refers to the process in which the two pathways are combined into one after the formation of factor Xa, which activates prothrombin and finally generates fibrin. FXI is necessary to maintain the internal pathway and plays a key role in the amplification process of the coagulation cascade. effect. In the coagulation cascade, thrombin can feedback activation of FXI, and the activated FXI (FXIa) promotes the mass production of thrombin, thereby amplifying the coagulation cascade. Therefore, FXI antagonists have been widely developed for the treatment of various thrombosis.

Traditional anticoagulant drugs, such as warfarin, heparin, low molecular weight heparin (LMWH), and new drugs that have been on the market in recent years, such as FXa inhibitors (rivaroxaban, aquaxaban, etc.) and thrombin inhibitors (darby Gatran etexilate, hirudin, etc.) have good effects on reducing thrombosis, occupying the vast cardiovascular and cerebrovascular market with their significant effectiveness, but its side effects are becoming more and more significant. Among them, the "bleeding risk" is Bear the brunt of one of the most serious problems (N. Engl. J. Med. 1991; 325: 153-8, Blood. 2003; 101: 4783-4788).

Human FXI deficiency (FXI activity <15 U/dL) is also called hemophilia C. This type of patient has a mild bleeding phenotype and a little spontaneous bleeding occurs. The body’s hemostatic function is not affected even during injury or surgery. Patients with hemophilia C can be pregnant and give birth normally (Arterioscler Thromb Vasc Biol. 2010; 30: 388-392). It can be seen that FXIa is significantly safer than FXa. Therefore, the target FXIa has become a hot research topic for major companies and research institutions. Studies have found that in the thrombosis model, inhibiting FXIa factor can effectively inhibit the formation of thrombus, but in the case of more severe thrombosis, the effect of FXIa is minimal (Blood. 2010; 116(19): 3981-3989). Clinical statistics show that increasing the amount of FXIa increases the prevalence of VTE (Blood 2009; 114: 2878-2883), and people with severe FXIa deficiency have a reduced risk of DVT (Thromb Haemost 2011; 105: 269–273) .

FXIa is an emerging target, and patent applications disclosing compounds with FXIa inhibitory activity include WO9630396, WO9941276, WO2013093484, WO2004002405, WO2013056060, WO2017005725 and US20050171148, WO2017023992, WO2018039094. Among them, only Bayer's antisense oligonucleotides (ASO) BAY-2306001 entered the second phase of clinical research and achieved good results. In the clinical phase I trial of the drug, subjects experienced a sustained and dose-dependent decrease in FXI activity, accompanied by a prolongation of aPTT. Even if FXI in the body drops to a level that cannot be detected, there will be no drug-related effects. Bleeding symptoms, showing the potential of FXIa as an emerging target (Arterioscler Thromb Vasc Biol, 2013, 33(7)1670-1678). However, FXI ASO needs to be administered by injection and has a slower onset. It takes several weeks to form an antithrombotic effect. It may be limited when used as a preventive drug. In terms of small molecule inhibitors, only BMS's FXIa inhibitor BMS-962212 is currently in phase II clinical research, so the research on new FXIa inhibitors is of great significance.

。 WO2018041122 discloses a series of oxopyridamide FXIa inhibitors and has been structurally characterized, including compounds of formula (I). In addition, the application also carried out a biological evaluation of the compound of 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 it was found that the pharmacokinetic absorption of the above-mentioned compound is good. It has obvious pharmacokinetic absorption effect,

.

The crystal form of the medicinal active ingredient often affects the chemical stability of the drug. The difference in crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by the production of other forms of crystal form. Generally speaking, amorphous drug products do not have a regular crystal structure and often have other defects, such as poor product stability, finer crystallization, difficult filtration, easy agglomeration, and poor fluidity. Polymorphs of drugs have different requirements for product storage, production and scale-up. Therefore, it is necessary to in-depth study of the crystal form of the compound of formula (I) to improve various properties of the compound of formula (I).

In order to explore the relationship between the specific medicinal form of the FXIa inhibitor compound and its physical and chemical properties, and to develop a specific medicinal form that is more suitable as a drug, the present invention provides an FXIa inhibitor ( S )-4-(4-( Tert-Butoxy)-2-(4-(5-chloro-2-propanylphenyl)-5-methoxy-2-oxopyridin-1(2 H )-yl)butyramido) The crystal form, preparation method and application of benzoic acid (compound of formula (I)).

The present invention provides a crystal form of compound A of formula (I). The X-ray powder diffraction pattern of the crystal form A has characteristic peaks at 2θ 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.

Further, the X-ray powder diffraction pattern of the crystal form A has characteristic peaks at 2θ values of 7.420, 8.000, 8.642, 12.900, 16.281, 18.280, 20.018, 21.119, and 22.400, and the error range may be ±0.3, ±0.2 Or ±0.1.

Further, the X-ray powder diffraction pattern of the crystal form A has characteristic peaks at 2θ values of 7.420, 8.000, 8.642, 12.900, 16.281, 18.280, 20.018, 21.119, 22.400, 24.458, and 26.100, and the error range may be ± 0.3, ±0.2, or ±0.1.

The present invention provides a crystal form of compound B of formula (I). The X-ray powder diffraction pattern of the crystal form B has characteristic peaks at 2θ values of 7.620, 8.680, 11.042, 11.638, 12.339, 16.320, and 19.381, and the error range can be It is ±0.3, ±0.2, or ±0.1.

Further, the X-ray powder diffraction pattern of the B crystal form has characteristic peaks at 2θ values of 7.620, 8.680, 11.042, 11.638, 12.339, 14.461, 16.320, 18.123, 18.381, and 19.381, and the error range may be ±0.3, ±0.2 or ±0.1.

Further, the X-ray powder diffraction pattern of the B crystal form has characteristic peaks at 2θ 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, and 26.460, with errors The range can be ±0.3, ±0.2, or ±0.1.

The present invention provides a crystal form of compound C of formula (I). The X-ray powder diffraction pattern of the crystal form C has characteristic peaks at 2θ values of 7.283, 8.780, 10.664, 11.264, 14.744, 15.456, 16.587, and 17.598 with errors. The range can be ±0.3, ±0.2, or ±0.1.

Further, the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at 2θ 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 the error is The range can be ±0.3, ±0.2, or ±0.1.

Further, the X-ray powder diffraction pattern of the crystal form C has a 2θ 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 , 21.025, 22.363, 23.211, 24.504, 24.713, 26.042, 27.534 have characteristic peaks, and the error range can be ±0.3, ±0.2 or ±0.1.

The present invention provides a crystal form of compound D of formula (I). The X-ray powder diffraction pattern of the crystal form D has a 2θ 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 have characteristic peaks, the error range can be ±0.3, ±0.2 or ±0.1.

Further, the X-ray powder diffraction pattern of the D crystal form has a 2θ 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 have characteristic peaks, and the error range can be ±0.3, ±0.2 or ±0.1.

Further, the X-ray powder diffraction pattern of the D crystal form has a 2θ 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, the error range can be ± 0.3, ±0.2, or ±0.1.

The present invention provides a crystal form of compound E of formula (I). The X-ray powder diffraction pattern of the crystal form E has characteristic peaks at 2θ values of 6.460, 7.480, 7.997, 16.220, 19.360, 21.720, and the error range may be ± 0.3, ±0.2, or ±0.1.

Further, the X-ray powder diffraction pattern of the E crystal form has characteristic peaks at 2θ values of 6.460, 7.480, 7.77, 8.662, 11.299, 12.140, 14.038, 16.220, 17.440, 18.560, 19.360, 21.720, and the error range may be It is ±0.3, ±0.2, or ±0.1.

Further, the X-ray powder diffraction pattern of the E crystal form has a 2θ value of 6.460, 7.480, 7.77, 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 is a characteristic peak 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 the compound of formula (I). The X-ray powder diffraction pattern of the crystal form F has a 2θ value of 5.761, 9.800, 10.640, 11.621, 14.021, 16.180, 16.460, 17.520, 21.460, 24.580. For characteristic peaks, the error range can be ±0.3, ±0.2, or ±0.1.

Further, the X-ray powder diffraction pattern of the F crystal form has characteristic peaks at 2θ 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.

Further, the X-ray powder diffraction pattern of the F crystal form has a 2θ 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 , 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 have characteristic peaks, the error range can be ±0.3, ±0.2 Or ±0.1.

The present invention also relates to the preparation method of crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, and crystal form F of the compound of formula (I), including: taking a certain amount of compound of formula (I) and adding A proper amount of solvent is used for crystallization, filtration, and drying to obtain crystal form A, crystal form B, crystal form C, crystal form D, crystal form E or crystal form F of the compound of formula (I).

The crystallization solvents of crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, and crystal form F of the compound of formula (I) are selected from hydrocarbon solvents, ether solvents, alcohol solvents, ester solvents, One or more of ketone solvents, nitrile solvents, halogenated hydrocarbon solvents, nitrogen-containing solvents, water, and dimethyl sulfoxide. The hydrocarbon solvents include, but are not limited to, cyclohexane, n-hexane, n-heptane, toluene, o-xylene, and p-xylene; the ether solvents include, but are not limited to, tetrahydrofuran, diethyl ether, propylene glycol methyl ether, methyl tertiary Butyl ether, isopropyl ether or 1,4-dioxane; the alcohols 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 ketone solvents include but are not limited to acetone, acetophenone, 4-methyl 2-pentanone, 2-butanone, methyl isobutyl ketone; the nitrile solvents include but are not limited to acetonitrile and propionitrile; the halogenated hydrocarbon solvents include but are not limited to methyl chloride, methylene chloride, 1,2-Dichloroethane, chloroform or carbon tetrachloride; the nitrogen-containing solvent includes but not limited to nitromethane, N,N-dimethylformamide, N,N-dimethylacetamide .

The crystallization method of the crystal form A, B crystal form, C crystal form, D crystal form, E crystal form, and F crystal form of the compound of formula (I) is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization or adding seed crystals Induce crystallization.

The present invention also relates to the preparation method of the A crystal form of the compound of formula (I), including: taking a certain amount of the compound of formula (I), adding an appropriate amount of ethyl acetate to dissolve, heating to clear, adding n-hexane to just turbidity, and slowly decreasing Stir and crystallize at room temperature to obtain crystal form A. The present invention also relates to the preparation method of the A crystal form of the compound of formula (I), which comprises: taking a certain amount of the compound of formula (I), adding an appropriate amount of dichloromethane to dissolve, heating to dissolve, adding an appropriate amount of isopropyl ether, and slowly lowering to the chamber. Warm, stir and crystallize to obtain crystal form A. The present invention also relates to the preparation method of the A crystal form of the compound of formula (I), including: taking a certain amount of the compound of formula (I), adding an appropriate amount of acetone to dissolve, heating to clear, adding an appropriate amount of n-heptane, and slowly reducing to room temperature, Stir and crystallize to obtain crystal form A. The present invention also relates to the preparation method of the A crystal form of the compound of formula (I), including: taking a certain amount of the compound of formula (I), adding an appropriate amount of ethyl acetate to dissolve, heating to clear, adding an appropriate amount of n-heptane, and slowly lowering to the chamber Warm, stir and crystallize to obtain crystal form A. The present invention also relates to the preparation method of the A crystal form of the compound of formula (I), which comprises: taking a certain amount of the compound of formula (I), adding an appropriate amount of toluene to dissolve, raising the temperature to clear, adding an appropriate amount of n-heptane, and slowly reducing to room temperature, Stir and crystallize to obtain crystal form A. The present invention also relates to the preparation method of the A crystal form of the compound of formula (I), including: taking a certain amount of the compound of formula (I), adding an appropriate amount of ethyl formate to dissolve, heating to clear, adding an appropriate amount of n-hexane, a small amount of solids are precipitated, Slowly lower to room temperature, stir and crystallize to obtain crystal form A. The present invention also relates to the preparation method of the A crystal form of the compound of formula (I), including: taking a certain amount of the compound of formula (I), adding an appropriate amount of ethyl acetate to dissolve, heating to clear, adding an appropriate amount of n-hexane, a solid precipitates, continue Stir for a period of time under elevated temperature, slowly lower to room temperature, stir and crystallize to obtain crystal form A.

The present invention also relates to the preparation method of the crystal form A of the compound of formula (I), which comprises: taking a certain amount of the crystal form of the compound B of the formula (I), adding an appropriate amount of toluene, and beating at room temperature to obtain the crystal form A. The present invention also relates to the preparation method of the A crystal form of the compound of formula (I), including: taking a certain amount of the compound B crystal form of the formula (I), adding an appropriate amount of tetrahydrofuran/methyl tert-butyl ether mixed solvent, and beating at room temperature, A crystal form is obtained. The present invention also relates to the preparation method of the A crystal form of the compound of formula (I), including: taking a certain amount of the compound B crystal form of the formula (I), adding an appropriate amount of ethyl acetate/n-hexane mixed solvent, and beating at room temperature to obtain A Crystal form. The present invention also relates to a preparation method of the A crystal form of the compound of formula (I), which comprises: taking a certain amount of the compound B crystal form of the formula (I), adding an appropriate amount of ethyl acetate/n-heptane mixed solvent, and beating at room temperature to obtain A crystal form. The present invention also relates to the preparation method of the crystal form A of the compound of formula (I), which comprises: taking a certain amount of the crystal form A and the crystal form B of the compound of formula (I), adding an appropriate amount of dioxane/water mixed solvent, at room temperature Beating to obtain crystal form A. The present invention also relates to a preparation method of the A crystal form of the compound of formula (I), which comprises: taking a certain amount of the compound A crystal form and the B crystal form of the formula (I), adding an appropriate amount of acetonitrile, and beating at room temperature to obtain the crystal form A. The present invention also relates to a preparation method of the crystal form A of the compound of formula (I), which comprises: taking a certain amount of the crystal form of the compound A of formula (I), adding an appropriate amount of water, and beating at room temperature to obtain the crystal form A.

The present invention also relates to the preparation method of the B crystal form of the compound of formula (I), including: taking a certain amount of the compound of formula (I), adding an appropriate amount of ethyl acetate to dissolve, heating to clear, adding n-heptane to just turbidity, continue to Stir for a period of time under the heating state, slowly decrease the temperature to 50°C, and solid precipitate, continue to add an appropriate amount of n-heptane, slowly reduce to 10°C, stir and crystallize to obtain crystal form B. The present invention also relates to the preparation method of the crystal form B of the compound of formula (I), which comprises: taking a certain amount of the compound of formula (I), adding an appropriate amount of tetrahydrofuran, and dropping the solution into a crystal containing a certain amount of crystal form A at room temperature. In the isopropyl ether solution, stir and crystallize to obtain crystal form B.

The present invention also relates to the preparation method of the B crystal form of the compound of formula (I), including: taking a certain amount of the amorphous compound of formula (I) and adding an appropriate amount of tert-butyl acetate/methyl tert-butyl ether/n-hexane mixed solvent , Beat at room temperature to get B crystal. The present invention also relates to the preparation method of the B crystal form of the compound of formula (I), which comprises: taking a certain amount of the amorphous compound of formula (I), adding an appropriate amount of trifluoroethanol/isopropyl ether mixed solvent, heating and beating to obtain crystal B type. The present invention also relates to the preparation method of the B crystal form of the compound of formula (I), which comprises: taking a certain amount of the amorphous compound of formula (I), adding an appropriate amount of n-heptane, heating and beating to obtain crystal form B. The present invention also relates to the preparation method of the B crystal form of the compound of formula (I), including: taking a certain amount of the amorphous compound of formula (I), adding an appropriate amount of chloroform/methyl tert-butyl ether mixed solvent, heating and beating to obtain B Crystal form. The present invention also relates to the preparation method of the crystal form B of the compound of formula (I), which comprises: taking a certain amount of the amorphous compound of formula (I), adding an appropriate amount of methyl tert-butyl ether, beating at room temperature, and being insoluble at elevated temperature to obtain crystal B type. The present invention also relates to the preparation method of the B crystal form of the compound of formula (I), which comprises: taking a certain amount of the amorphous compound of formula (I), adding an appropriate amount of cyclohexane, beating at room temperature and being insoluble at elevated temperature to obtain crystal form B. The present invention also relates to the preparation method of the B crystal form of the compound of formula (I), which comprises: taking a certain amount of the crystal form A and B crystal form of the compound of formula (I), adding an appropriate amount of ethyl acetate/n-heptane mixed solvent, and Warm beating to obtain crystal form B. The present invention also relates to a preparation method of the B crystal form of the compound of formula (I), including: taking a certain amount of the compound A crystal form and B crystal form of the formula (I), and adding an appropriate amount of acetone/methyl tert-butyl ether/n-hexane to mix Beat in the solvent at room temperature to obtain crystal form B. The present invention also relates to the preparation method of the B crystal form of the compound of formula (I), which comprises: taking a certain amount of the crystal form A and B crystal form of the compound of formula (I), and adding an appropriate amount of butyl acetate/methyl tert-butyl ether/n-hexane In an alkane mixed solvent, beating at room temperature to obtain crystal form B.

The present invention also relates to a preparation method of the crystal form C of the compound of formula (I), which comprises: taking a certain amount of the compound of formula (I), adding an appropriate amount of p-xylene, and beating and crystallizing at room temperature to obtain crystal form C.

The present invention also relates to the preparation method of the D crystal 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, raising the temperature to dissolve it, cooling and stirring to crystallize to obtain the D crystal form. The present invention also relates to the preparation method of the D crystal form of the compound of formula (I), including: taking a certain amount of the compound of formula (I), adding an appropriate amount of ethyl acetate to dissolve, raising the temperature to dissolve, dropping an appropriate amount of n-hexane, slowly cooling down, and stirring Crystallize to obtain crystal form D. The present invention also relates to the preparation method of the D crystal form of the compound of formula (I), including: taking a certain amount of the compound of formula (I), adding an appropriate amount of acetone to dissolve, raising the temperature to dissolve, adding an appropriate amount of n-heptane, slowly cooling down, and stirring Crystal, obtain D crystal form. The present invention also relates to the preparation method of the D crystal form of the compound of formula (I), including: taking a certain amount of the compound of formula (I), adding an appropriate amount of ethyl acetate to dissolve, adding dropwise an appropriate amount of n-hexane containing about 4 mg of crystal form A, and stirring Crystallize to obtain crystal form D. The present invention also relates to the preparation method of the D crystal form of the compound of formula (I), including: taking a certain amount of the compound of formula (I), adding an appropriate amount of acetone to dissolve it, dropping an appropriate amount of isopropyl ether containing about 4 mg of crystal form A, and stirring to separate out Crystal, obtain D crystal form. The present invention also relates to a method for preparing crystal form D of the compound of formula (I), including: taking a certain amount of compound of formula (I), adding an appropriate amount of acetone/isopropyl ether mixed solvent, and slowly volatilizing and crystallizing at room temperature to obtain crystal D type.

The present invention also relates to the preparation method of the D crystal form of the compound of formula (I), which comprises: taking a certain amount of the amorphous compound of the formula (I), adding an appropriate amount of acetonitrile, and beating at room temperature to obtain the D crystal form.

The present invention also relates to the preparation method of the E crystal form of the compound of formula (I), including: taking a certain amount of the compound of formula (I), adding an appropriate amount of acetone/cyclohexane mixed solvent, and slowly volatilizing and crystallizing at room temperature to obtain crystal E type.

The present invention also relates to the preparation method of the F crystal form of the compound of formula (I), including: taking a certain amount of the compound of formula (I), adding an appropriate amount of ethyl acetate, raising the temperature to dissolve it, continuing to stir to precipitate a solid, and adding an appropriate amount of n-hexane. , Slowly lower the temperature, stir and crystallize to obtain the F crystal form. The present invention also relates to the preparation method of the F crystal form of the compound of formula (I), including: taking a certain amount of the compound of formula (I), adding an appropriate amount of ethyl formate, adding to the reflux solution, adding an appropriate amount of n-hexane, and adding crystal F Form seed crystals, reflux and dissolve to clear, slowly cool down, stir and crystallize to obtain F crystal form.

The present invention also relates to the preparation method of the F crystal form of the compound of formula (I), including: taking a certain amount of the compound of formula (I) amorphous, adding an appropriate amount of 1,4-dioxane/water mixed solvent, and beating at room temperature , Get F crystal form. The present invention also relates to a preparation method of the F crystal form of the formula (I) compound, which comprises: taking a certain amount of the formula (I) compound A crystal form, adding an appropriate amount of acetonitrile/water mixed solvent, and beating at room temperature to obtain the F crystal form. The present invention also relates to a preparation method of the F crystal form of the compound of formula (I), comprising: taking a certain amount of the compound A crystal form of the formula (I), adding an appropriate amount of tetrahydrofuran/water mixed solvent, and beating at room temperature to obtain the F crystal form. The present invention also relates to a preparation method of the F crystal form of the compound of formula (I), including: taking a certain amount of the formula (I) compound A crystal form, adding an appropriate amount of acetone/water mixed solvent, and beating at room temperature to obtain the F crystal form. The present invention also relates to a preparation method of the F crystal form of the compound of formula (I), including: taking a certain amount of the compound A crystal form of the formula (I), adding an appropriate amount of isopropanol/water mixed solvent, and beating at room temperature to obtain crystal F type. The present invention also relates to the preparation method of the F crystal form of the compound of formula (I), including: taking a certain amount of the amorphous compound of formula (I), adding an appropriate amount of ethyl propionate/n-heptane mixed solvent, and beating at room temperature to obtain F crystal form.

The present invention also relates to a compound comprising a crystal form A, B crystal form, C crystal form, D crystal form, E crystal form or F crystal form and optionally one or more pharmaceutical carriers and/or diluents of the compound of formula (I) Pharmaceutical composition. The pharmaceutical composition can be made into any pharmaceutically acceptable dosage form. For example, the pharmaceutical preparations of the present invention comprising crystal form A, crystal form B, crystal form C, crystal form D, crystal form E or crystal form F of the compound of formula (I) can 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.

In addition, the pharmaceutical composition of the present invention can also be administered to patients or subjects in need of such treatment in any suitable way of administration, such as oral, parenteral, rectal, pulmonary or topical administration. When used for oral 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. Agent, syrup, etc. When made into oral preparations, the pharmaceutical preparations may also contain suitable fillers, binders, disintegrants, lubricants and the like. When used for parenteral administration, the pharmaceutical preparations can be made into injections, including injections, sterile powders for injections, and concentrated solutions for injections. When made into an injection, the pharmaceutical composition can be produced using conventional methods in the existing pharmaceutical field. When formulating injections, additives may not be added to the pharmaceutical preparations, or appropriate additives may be added according to the nature of the drug. When used for rectal administration, the pharmaceutical preparations can be made into suppositories and the like. When used for pulmonary administration, the pharmaceutical preparations can be made into inhalants or sprays. In certain embodiments, the crystal form A, crystal form B, crystal form C, crystal form D, crystal form E or crystal form F of the compound of formula (I) of the present invention is present in the pharmaceutical combination in a therapeutically and/or prophylactically effective amount In substances or drugs. In certain embodiments, the crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, or crystal form F of the compound of formula (I) of the present invention is present in the pharmaceutical composition in the form of a unit dose Or in medicine.

The present invention further relates to a method for preparing a pharmaceutical composition, which comprises making selected from the group consisting of crystal form A, crystal form B, crystal form C, crystal form D, crystal form E or crystal form F of the compound of formula (I) of the present invention One or more crystal forms are mixed with at least one pharmaceutically acceptable carrier, diluent or excipient.

The present invention further relates to the preparation of crystal form A, crystal form B, crystal form C, crystal form D, crystal form E or crystal form F of the compound of formula (I) for the treatment and/or prevention of diseases mediated by factor XIa Use in medicines.

The present invention further relates to the preparation of a crystalline form A, B crystalline form, C crystalline form, D crystalline form, E crystalline form or F crystalline form of the compound of formula (I) for the treatment and/or prevention of a medicament for the treatment and/or prevention of cardiovascular and cerebrovascular diseases The cardio-cerebrovascular disease is selected from thromboembolic diseases, preferably myocardial infarction, angina, re-occlusion and restenosis after angioplasty or aortic coronary bypass, diffuse intravascular coagulation, stroke, transient Of ischemic attacks, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis.

[Detailed Description of the Invention]

In the specification of this application and the scope of the patent application, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, in order to better understand the present invention, the definitions and explanations of some related terms are provided below. In addition, when the definitions and explanations of terms provided in this application are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of terms provided in this application shall prevail.

The "ether-based 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. Specific examples include, but are not limited to: tetrahydrofuran, diethyl ether, and propylene glycol methyl ether , Methyl tert-butyl ether, isopropyl ether or 1,4-dioxane.

The "alcohol solvent" in the present invention refers to a group derived from one or more "hydroxyl groups" substituted for one or more hydrogen atoms on the _{"C 1-6 alkyl group". The "hydroxyl group" and "C 1-6 alkyl group" "1-6} 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 with 1 to 4 carbon atoms and a lower alcohol with 1 to 6 carbon atoms. Specific examples include but are not limited to: acetic acid Ethyl, ethyl formate, tert-butyl acetate, ethyl propionate, isopropyl acetate or butyl acetate.

The "ketone solvent" in the present invention refers to a compound in which a carbonyl group (-C(O)-) is connected to two hydrocarbon groups. According to the difference in the hydrocarbon group in the molecule, ketones can be divided into aliphatic ketones, alicyclic ketones, aromatic ketones, Saturated ketones and unsaturated ketones, specific examples include but are not limited to: acetone, acetophenone, 4-methyl-2-pentanone, 2-butanone, methyl isobutyl ketone.

The "nitrile solvent" in the present invention refers to a _{group derived from one or more "cyano groups" substituted for one or more hydrogen atoms on the "C 1-6} alkyl group", the "cyano group" and "C _1-6 alkyl" is as defined above, and specific examples include, but are not limited to: acetonitrile or propionitrile.

The "halogenated hydrocarbon solvent" in the present invention refers to a _{group derived from one or more "halogen atoms" substituting one or more hydrogen atoms on the "C 1-6} alkyl group", the "halogen atom "And "C _1-6 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" described in the present invention is obtained by diffracting Cu-Kα rays.

The "differential scanning calorimetry or DSC" in the present invention refers to the measurement of the temperature difference and heat flow difference between the sample and the reference material during the temperature rise or constant temperature process of the sample to characterize all the physical changes and chemistry related to the thermal effect. Change, get the phase change information of the sample.

The "2θ or 2θ angle" in the present invention refers to the angle of diffraction, θ is the Bragg angle, and the unit is ° or degree. The error range of the 2θ is ±0.1~±0.5, preferably ±0.1~±0.3, more preferably ±0.2.

[Beneficial Effects of Invention]

(S )-4-(4-(tert-butoxy)-2-(4-(5-chloro-2-propionylphenyl)-5-methoxy-2-oxopyridine provided by the invention -1( 2H )-yl)butyramido)benzoic acid (formula (I) compound), the solubility of crystal form A, crystal form B, crystal form C, crystal form D, crystal form E and crystal form F, It has more advantages in terms of stability and hygroscopicity, and is more suitable for drug development, meets the requirements of bioavailability and efficacy, and can meet the medicinal requirements of production, transportation and storage, and the production process is stable, repeatable and controllable, and can be adapted to industrial production .

Hereinafter, the present invention will be explained in more detail in conjunction with the embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention, and do not limit the essence and scope of the present invention.

Test conditions of the equipment used in the experiment:

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in units of ^{10 -6 (ppm).} NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four Methyl Silane (TMS).

The MS was measured with a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

HPLC determination uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6mm chromatographic column).

XRPD is X-ray powder diffraction detection: the measurement is carried out using a BRUKER D8 X-ray diffractometer. The specific information is collected: Cu anode (40kV, 40mA), Cu-Kα1 rays (λ=1.54060Å), Kα2 rays (λ=1.54439) Å), Kβ rays (λ=1.39222Å). Scanning range (2q range): 3~64°, scanning step length 0.02, slit width (collimator) 1.0mm. The step-by-step scanning method is adopted, the number of scanning steps is 3, the scanning range of each step is 19°, the starting degree is 10°, and the ending degree is 48°, and the duration of each step is 45s.

DSC is differential scanning calorimetry: METTLER TOLEDO DSC 3+ differential scanning calorimeter is used for the measurement, the heating rate is 10℃/min, and the specific temperature range refers to the corresponding map (mostly 25-300 or 25-350℃), nitrogen blowing The scanning speed is 50 mL/min.

TGA is thermogravimetric analysis: the detection adopts METTLER TOLEDO TGA 2 thermogravimetric analyzer, the heating rate is 10℃/min, the specific temperature range refers to the corresponding graph (mostly 25-300 or 25-350℃), and the nitrogen purge speed is 20 mL /min.

DVS is dynamic moisture adsorption: the detection adopts SMS DVS Advantage, at 25℃, the humidity change is 50%-95%-0%-95%-50%, the step is 10% (the last step is 5%) (specific humidity range) Subject to the corresponding map, most of the methods listed here), the judgment standard is that dm/dt is not more than 0.02%, and Tmax is not more than 360min.

There is no special description in the examples, and the solution refers to an aqueous solution.

There are no special instructions in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.

The monitoring of the reaction progress in the examples adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used in the purification of the compound, and the developing reagent system of thin layer chromatography include: 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 also be added for adjustment.

Preparation example of the compound of formula (I) (the preparation method of Example 108 in WO2018041122A)

( S )-4-(4-(tert-butoxy)-2-(4-(5-chloro-2-propanylphenyl)-5-methoxy-2-oxopyridine-1(2 H )-yl)butyramido)benzoic acid 1

first step

2-(tert-Butoxy)ethyl triflate 1b

Dissolve 2-tert-butoxyethanol 1a (300 mg, 2.54 mmol) in 8 mL of dichloromethane, add 2,6-lutidine (299.22 mg, 2.79 mmol) under ice bath, and add trifluoromethane dropwise. Sulfonic anhydride (787.87 mg, 2.79 mmol), after dripping, was stirred and reacted in an ice bath for 1 hour, and naturally warmed to room temperature and stirred for 1 hour. 30 mL of dichloromethane was added to the reaction solution, washed with 20 mL of water, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude title compound 1b (550 mg). The product was directly reacted in the next step without purification.

Second step

1-(2-Bromo-4-chlorophenyl)propane-1-one 1e

Dissolve 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") In 1 mL of tetrahydrofuran, cool to -20°C, add isopropyl magnesium chloride (421.15 mg, 4.10 mmol), and react for 1 hour in advance. Add propyl chloride 1d (378.89 mg, 4.10 mmol), lithium chloride (11.42 mg, 189.00 μmol), cuprous chloride (9.36 mg, 94.50 μmol) and aluminum trichloride (12.61 mg, 94.50 μmol) into 1 mL Stir uniformly in tetrahydrofuran at room temperature, add dropwise the reaction solution that has been reacted for 1 hour to the above mixed solution, and react at room temperature for 2 hours. Add 20 mL of saturated ammonium chloride solution to the reaction solution to quench the reaction, extract with dichloromethane (20 mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue obtained was purified with eluent B to obtain the title compound 1e (640 mg, yield: 82.0%)

third step

1-(4-chloro-2-(2,5-dimethoxypyridin-4-yl)phenyl)propane-1-one 1g

Compound 1e (640 mg, 2.59 mmol), compound 1f (520.41 mg, 2.84 mmol, prepared by the method disclosed in the patent application "WO2015063093"), [1,1'-bis(diphenylphosphino) dicene Iron] palladium dichloride (191.8 mg, 0.259 mmol) and sodium carbonate (822.16 mg, 7.76 mmol) were added to a mixed solvent of 20 mL of 1,4-dioxane and 4 mL of water. After the addition was completed, the reaction solution was heated The temperature was raised to 85°C, and the reaction was stirred for 16 hours. The reaction solution was naturally cooled to room temperature, 20 mL of water was added, extracted with ethyl acetate (20 mL×3), the organic phases were combined, and the organic phases were washed with water (30 mL) and saturated sodium chloride solution (30 mL), anhydrous The residue was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1g (600 mg, yield: 75.9%).

MS m/z (ESI): 306.0 [M+1]

the fourth step

4-(5-Chloro-2-propanylphenyl)-5-methoxypyridine-2(1H)-one 1f

Compound 1g (600 mg, 1.96 mmol) was added to 10 mL of N,N-dimethylformamide, pyridine hydrobromide (1.51 g, 9.81 mmol) was added, after the addition, heated to 100°C, stirred for reaction 3. hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, 30 mL of water was added to the resulting residue, extracted with dichloromethane (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure The crude title compound 1f (550 mg) was obtained, and the product was directly reacted in the next step without purification.

MS m/z (ESI): 292.0 [M+1]

the fifth step

2-(4-(5-Chloro-2-propanylphenyl)-5-methoxy-2-oxopyridine-1(2H)-yl) tert-butyl acetate 1i

The crude compound 1f (550 mg, 1.89 mmol), cesium carbonate (1.84 g, 5.67 mmol) and compound 1h (551.61 mg, 2.83 mmol) were combined with the conventional method " Chemical Communications (Cambridge, United Kingdom) , 2012, 48( 22), synthesized by 2803-2805) dissolved in 10 mL of N , N -dimethylformamide, after the addition, the temperature of the reaction solution was raised to 65℃, and the reaction was stirred for 2 hours. Cool the temperature of the reaction solution to room temperature, and add 30 mL of water, extracted with ethyl acetate (30 mL×3), combined the organic phases, washed with saturated sodium chloride solution (30 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated the filtrate under reduced pressure. The residue obtained was purified with eluent B to obtain the title compound 1i (350 mg, yield: 51.0%).

MS m/z (ESI): 405.4 [M+1]

Sixth step

4-(tert-butoxy)-2-(4-(5-chloro-2-propanylphenyl)-5-methoxy-2-oxopyridine-1(2H)-yl)butyric acid tert Butyl 1j

Dissolve compound 1i (148 mg, 364.65 μmol) and crude compound 1b (182.50 mg, 729.30 μmol) in 15 mL of tetrahydrofuran, cool the reaction solution to -78°C, and add dropwise lithium bis(trimethylsilyl)amide solution (1.46 mL, 1.46 mmol), the reaction was stirred for 2 hours. At -78℃, slowly add 5 mL of water to the reaction solution to quench the reaction. The temperature of the reaction solution was naturally raised to room temperature. Add 20 mL of water and extract with ethyl acetate (35 mL×3). Combine the organic phases and use saturated chlorine. Wash with sodium chloride solution (25 mL×2) and dry with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with eluent system A to obtain the title compound 1j (120 mg, yield: 65.0%).

MS m/z (ESI): 506.5 [M+1]

Seventh step

4-(tert-Butoxy)-2-(4-(5-chloro-2-propanylphenyl)-5-methoxy-2-oxopyridine-1(2H)-yl)butanoic acid 1k

Compound 1j (120 mg, 237.14 μmol) was dissolved in a mixed solvent of 8 mL ethanol and 4 mL tetrahydrofuran, lithium hydroxide (49.75 mg, 1.19 mmol) was added, and the temperature was raised to 50° C. and the reaction was stirred for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure to spin off most of the organic solvent, added 15 mL of water, adjusted pH to 3 with 3M hydrochloric acid, extracted with ethyl acetate (20 mL×3), combined the organic phases, and used saturated sodium chloride The solution was washed (20 mL×2), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude title compound 1k (106 mg). The product was directly reacted in the next step without purification.

MS m/z (ESI): 450.4 [M+1]

Eighth step

4-(4-(tert-butoxy)-2-(4-(5-chloro-2-propanylphenyl)-5-methoxy-2-oxopyridine-1(2H)-yl) Butyramido) benzoic acid 1m

The crude compound 1k (106 mg, 235.59 μmol) was dissolved in 15 mL of ethyl acetate, and N , N -diisopropylethylamine (304.48 mg, 2.36 mmol) and compound 1l (35.54 mg, 259.16 μmol) were added in sequence. It is prepared by the conventional method " Angewandte Chemie -International Edition , 2012, 51(34), 8564-8567") and 2,4,6-tripropyl-1,3,5,2,4,6-tri Oxytriphosphoric acid-2,4,6-trioxide in ethyl acetate solution (50%, 599.70 mg, 942.38 μmol), after the addition, the reaction was heated to 80°C, and the reaction was stirred for 2 hours. The reaction solution was cooled to room temperature, 20 mL of water was added, the pH was adjusted to 5 with 3 M hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined and washed with saturated sodium chloride solution (20 mL×2). Dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the resulting residue with HPLC preparation (Waters 2767-SQ detecor2, elution system: acetonitrile, water) to obtain the title compound 1m (60 mg, yield: 44.8 %).

MS m/z (ESI): 569.5 [M+1]

Step 9

(S)-4-(4-(tert-butoxy)-2-(4-(5-chloro-2-propanylphenyl)-5-methoxy-2-oxopyridine-1(2H )-Yl)butyramido)benzoic acid 1

The compound 1m (60 mg, 105.44 μmol) was chirally prepared (separation conditions: column Superchiral S-AD (Chiralway), 2cm ID * 25 cm Length, 5 um; mobile phase: carbon dioxide: ethanol: diethylamine = 60 : 40:0.05, flow rate: 50 g/min), collect the corresponding components, and concentrate under reduced pressure to obtain the title compound 1 (22 mg).

After X-ray powder diffraction inspection, the product is amorphous, as shown in Figure 1.

Example 1. Preparation of Crystal Form A

The compound of formula (I) (3.3 g) was added to 10 mL of ethyl acetate, the reaction solution was heated to 80°C, stirred to dissolve, and slowly added n-hexane until it was just turbid (about 15 mL), and then slowly dropped to room temperature and precipitated White solid, stirring at room temperature for 3 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (2 g).

After X-ray powder diffraction detection, the product is defined as crystal form A, and the XRPD spectrum is shown in Figure 2.

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: Under the condition of 25℃, according to the relative mass change curve of the sample, between 10%RH-80%RH, as the humidity increases, the mass increase is about 1.781%, less than 2% but not less than 0.2%, according to " The guidelines for drug hygroscopicity test of the 2015 edition of Pharmacopoeia of the People's Republic of China, the sample has slight hygroscopicity. Under normal storage conditions (ie 25℃ 60%RH), the mass increase is about 1.156%; under accelerated test conditions (ie 70%RH), the mass increase is about 1.479%; under extreme conditions (ie 90%RH), the mass increases About 2.199%. In the 0%-95% humidity change process, the desorption process of the sample basically coincides with the adsorption process. The DVS detection spectrum is shown in Figure 5, and the X-ray powder diffraction comparison before and after DVS detection is shown in Figure 6. The crystal form before and after DVS detection is not transformed. Table 1. Characteristic peaks of crystal form A Peak number 2-Theta d(A) I% Peak 1 7.420 11.905 6.0 Peak 2 8.000 11.043 100.0 Peak 3 8.642 10.224 14.8 Peak 4 12.900 6.857 12.6 Peak 5 16.281 5.440 4.0 Peak 6 18.280 4.849 3.8 Peak 7 20.018 4.432 2.9 Peak 8 21.119 4.203 1.7 Peak 9 22.400 3.966 4.6 Peak 10 24.458 3.636 6.2 Peak 11 26.100 3.411 1.6

Example 2. Preparation of Crystal Form A

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 to clear, 0.8 mL of isopropyl ether was slowly added dropwise, and the mixture was slowly reduced to room temperature, and stirring was continued for 17 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (82 mg). After X-ray powder diffraction inspection, the product is in crystal form A.

Example 3 Preparation of Crystal Form A

The compound of formula (I) (100 mg) was added to 1 mL of acetone, the temperature was raised to 50° C., stirred to clear the solution, 1.4 mL of n-heptane was slowly added dropwise, and the mixture was slowly cooled to room temperature, and stirring was continued for 17 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (75 mg). After X-ray powder diffraction inspection, the product is in crystal form A.

Example 4 Preparation of Crystal Form A

The compound of formula (I) (100 mg) was added to 0.8 mL of ethyl acetate, the temperature was raised to 80° C., and the mixture was stirred to clear, 0.7 mL of n-heptane was slowly added dropwise, and the mixture was slowly reduced to room temperature, and stirring was continued for 17 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (74 mg). After X-ray powder diffraction inspection, the product is in crystal form A.

Example 5 Preparation of Crystal Form A

The compound of formula (I) (100 mg) was added to 1 mL of toluene, the temperature was raised to 110° C., and the mixture was stirred to clear the solution. 0.25 mL of n-heptane was slowly added dropwise, and the mixture was slowly reduced to room temperature, and stirring was continued for 17 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (41 mg). After X-ray powder diffraction inspection, the product is in crystal form A.

Example 6. Preparation of Crystal Form A

The compound of formula (I) (200 mg) was added to 4 mL of ethyl formate, the temperature was raised to 60°C, and the mixture was stirred to clear, and 5 mL of n-hexane was slowly added dropwise. After stirring for 15 minutes, a small amount of solid precipitated, and the temperature was slowly reduced to 20°C. About 3 hours), continue to stir for 13 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (100 mg). After X-ray powder diffraction inspection, the product is in crystal form A.

Example 7. Preparation of Crystal Form A

The compound of formula (I) (200 mg) was added to 1 mL of ethyl acetate, the temperature was raised to 80°C, and the mixture was stirred to clear. 1.5 mL of n-hexane was slowly added dropwise. A solid precipitated. Continue stirring at 80°C for 3 hours. Reduce to 15°C (about 3 hours) and continue stirring for 14 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (130 mg). After X-ray powder diffraction inspection, the product is in crystal form A.

Example 8. Preparation of Crystal Form B

The compound of formula (I) (4 g) was added to 8 mL ethyl acetate, heated to 80°C, stirred to dissolve, and 6 mL n-heptane was slowly added dropwise. A small amount of turbidity precipitated. Continue stirring at 80°C for 10 minutes , Slowly drop to 50 ℃, solid precipitation, continue to slowly add 6 mL n-heptane, slowly drop to 10 ℃, continue to stir for 17 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (3.5 g). After X-ray powder diffraction detection, the product was defined as crystal form B, and the spectrum is shown in Figure 7.

The DSC characterization is shown in Figure 8, the endothermic peak is 146.17℃, and the TGA characterization is shown in Figure 9, 25-130℃ weight loss is 2.90%. DVS characterization: The sample is at 25℃, according to the relative mass change curve, between 10%RH-80%RH, as the humidity increases, the mass increase is about 1.968%, less than 2% but not less than 0.2%, according to " The guidelines for drug hygroscopicity test of the 2015 edition of Pharmacopoeia of the People's Republic of China, the sample has slight hygroscopicity. Under normal storage conditions (ie 25℃60%RH), the mass increase is about 1.155%; under accelerated test conditions (ie 70%RH), the mass increase is about 1.530%; under extreme conditions (ie 90%RH), the mass increases About 3.963%. In the 0%-95% humidity change process, the desorption process of the sample basically coincides with the adsorption process. The DVS detection spectrum is shown in Fig. 10, and the X-ray powder diffraction comparison before and after DVS detection is shown in Fig. 11. The crystal form changed to A crystal form after DVS detection. Table 2. Characteristic peaks of crystal form B 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

Example 9. Preparation of Crystal Form B

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. A solid precipitated out. Continue stirring for 16 hours . The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (35 mg). After X-ray powder diffraction test, the product is B crystal.

Example 10, Preparation of Crystal Form B

The compound of formula (I) (100mg) was added to 5 mL of methyl tert-butyl ether, insoluble, pulped at room temperature for 24 hours, heated at 50°C for 2 hours, insoluble, cooled to room temperature, centrifuged, and the solid sample was dried in vacuum to obtain the product . After X-ray powder diffraction test, the product is B crystal.

Example 11. Preparation of Crystal Form B

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, cooled to room temperature, centrifuged, and the solid sample was dried in vacuum to obtain the product. After X-ray powder diffraction test, the product is B crystal.

Example 12. Preparation of Crystal Form C

The compound of formula (I) (100 mg) was added to 5 mL of p-xylene, insoluble, pulped at room temperature for 24 hours, heated at 50°C for 2 hours insoluble, cooled to room temperature, centrifuged, and the solid sample was vacuum dried to obtain the product. After X-ray powder diffraction detection, the product is defined as crystal form C, and the XRPD spectrum is shown in Figure 12.

The DSC spectrum is shown in Figure 13, with the endothermic peak at 141.44℃; the TGA spectrum is shown in Figure 14, with a weight loss of 5.22% at 25-130℃. Table 3. Characteristic peaks of crystal form C Peak number 2-Theta d(A) I% Peak 1 5.312 16.624 3.6 Peak 2 6.704 13.173 3.8 Peak 3 7.283 12.129 100.0 Peak 4 8.780 10.063 28.7 Peak 5 9.544 9.260 3.3 Peak 6 10.664 8.289 9.0 Peak 7 11.264 7.849 7.5 Peak 8 12.335 7.170 4.4 Peak 9 14.124 6.266 3.6 Peak 10 14.744 6.004 9.7 Peak 11 15.456 5.728 7.2 Peak 12 16.587 5.340 18.8 Peak 13 17.598 5.036 13.6 Peak 14 18.165 4.880 9.1 Peak 15 18.915 4.688 7.0 Peak 16 20.158 4.402 17.4 Peak 17 21.025 4.222 11.8 Peak 18 22.363 3.972 19.9 Peak 19 23.211 3.829 2.4 Peak 20 24.504 3.630 7.6 Peak 21 24.713 3.600 7.5 Peak 22 26.042 3.419 3.1 Peak 23 27.534 3.237 7.9

Example 13, Preparation of Crystal Form D

Add the compound of formula (I) (1.7 g) to 3.4 mL of ethyl acetate, heat to 80°C, stir to dissolve, and continue stirring for 1 hour. A solid precipitates out, slowly reducing to 15°C, and stirring at 15°C for 4 hours . The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (1.5 g). After X-ray powder diffraction detection, the product is defined as crystal form D, and the spectrum is shown in Fig. 15.

The DSC and TGA spectra are shown in Figure 16. The DSC characterizes the endothermic peak at 118.4℃, and the TGA characterizes the weight loss at 24.2-140℃.

DVS characterization: The sample is at 25℃, according to the relative mass change curve, between 10%RH-80%RH, with the increase of humidity, the mass increase is about 2.420%, less than 15% but not less than 2%, according to " The Guidelines for the Hygroscopicity Test of Drugs in the Pharmacopoeia of the People's Republic of China in 2015 edition, the sample has hygroscopicity. Under normal storage conditions (ie 25°C 60%RH), the mass increase is about 2.143%; under accelerated test conditions (ie 70%RH), the mass increase is about 2.494%; under extreme conditions (ie 90%RH), the mass increases About 3.422%. In the 0%-95% humidity change process, the desorption process of the sample does not coincide with the adsorption process. The DVS detection spectrum is shown in Figure 17, and the X-ray powder diffraction comparison before and after DVS detection is shown in Figure 18. The crystallinity of the crystal form becomes worse after DVS detection. Table 4. Characteristic peaks of crystal form D Peak number 2-Theta d(A) I% Peak 1 7.021 12.581 23.1 Peak 2 7.901 11.181 31.2 Peak 3 8.259 10.696 76.3 Peak 4 9.200 9.605 78.8 Peak 5 10.639 8.308 34.0 Peak 6 12.320 7.178 22.7 Peak 7 13.821 6.402 19.6 Peak 8 14.180 6.241 38.9 Peak 9 14.580 6.070 22.7 Peak 10 15.519 5.705 41.7 Peak 11 16.120 5.494 100.0 Peak 12 16.661 5.317 58.9 Peak 13 18.500 4.792 72.3 Peak 14 19.919 4.454 33.3 Peak 15 20.600 4.308 47.0 Peak 16 21.320 4.164 48.0 Peak 17 21.700 4.092 20.2 Peak 18 22.358 3.973 19.9 Peak 19 22.820 3.894 60.4 Peak 20 23.221 3.827 30.5 Peak 21 23.538 3.777 19.3 Peak 22 24.241 3.669 20.2 Peak 23 25.060 3.551 13.1 Peak 24 25.520 3.488 14.3 Peak 25 26.920 3.309 12.1 Peak 26 27.420 3.250 28.3 Peak 27 27.940 3.191 10.6 Peak 28 28.720 3.106 13.1 Peak 29 29.020 3.074 19.9 Peak 30 29.420 3.034 20.9 Peak 31 30.560 2.923 9.3 Peak 32 31.402 2.846 7.2 Peak 33 32.460 2.756 10.0 Peak 34 35.380 2.535 6.5 Peak 35 35.919 2.498 4.4 Peak 36 37.261 2.411 4.0

Example 14. Preparation of Crystal Form D

The compound of formula (I) (1 g) was added to 4.5 mL of ethyl acetate, heated to 80°C, stirred to clear, 4 mL of n-hexane was slowly added dropwise at 80°C, no solids precipitated, and the temperature was slowly reduced to 70°C. A solid precipitated out, slowly decreasing to 20°C (about 5 hours), and continuing to stir at 20°C for 15 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (0.89 g). After X-ray powder diffraction test, the product is D crystal form.

Example 15, Preparation of Crystal Form D

The compound of formula (I) (200 mg) was added to 2 mL of acetone, heated to 50°C, stirred to dissolve, and 3.5 mL of n-heptane was slowly added dropwise. No solid was precipitated. The solution was slowly reduced to 20°C. The solution was turbid. To 15-20°C, continue to stir for 16 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (130 mg). After X-ray powder diffraction test, the product is D crystal form.

Example 16. Preparation of Crystal Form D

The compound of formula (I) (100 mg) was dissolved in 1 mL of ethyl acetate, and 2 mL of n-hexane (approximately 4 mg of crystal form A seed crystals added, 15-20°C) was slowly added dropwise. A solid precipitated out. Continue stirring 3 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (35 mg). After X-ray powder diffraction test, the product is D crystal form.

Example 17, Preparation of Crystal Form D

The compound of formula (I) (100 mg) was dissolved in 0.5 mL of acetone, and 2 mL of isopropyl ether (approximately 4 mg of crystal form A seed crystals added, 15-20℃) was slowly added dropwise. A solid precipitated out. Continue stirring for 5 hour. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (60 mg). After X-ray powder diffraction test, the product is D crystal form.

Example 18. Preparation of Crystal Form D

The compound of formula (I) (60 mg) was dissolved in 0.8 mL of a mixed solvent of acetone and isopropyl ether (V:V=1:3), filtered with a filter membrane, covered with a PE membrane, pierced, evaporated slowly, and cubic particles were precipitated. The ellipsoid diagram of the sampled single crystal to analyze the three-dimensional molecular structure is shown in Figure 19. After X-ray powder diffraction test, the product is D crystal form.

Example 19, Preparation of Crystal Form E

The compound of formula (I) (20 mg) was dissolved in 0.5 mL of a mixed solvent of acetone and cyclohexane (V:V=1:3), filtered with a filter membrane, covered with a PE membrane, pierced, naturally slowly volatilized, and solids were precipitated. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (8 mg). After X-ray powder diffraction detection, the product is defined as E crystal form, and the spectrum is shown in Fig. 20. Table 5. Characteristic peaks of E crystal form Peak number 2-Theta d(A) I% Peak 1 6.460 13.671 14.7 Peak 2 7.480 11.810 100.0 Peak 3 7.977 11.074 11.6 Peak 4 8.662 10.200 3.9 Peak 5 11.299 7.825 1.2 Peak 6 12.140 7.285 1.6 Peak 7 14.038 6.303 2.0 Peak 8 16.220 5.460 7.1 Peak 9 17.440 5.081 1.7 Peak 10 18.560 4.777 1.2 Peak 11 19.360 4.581 7.9 Peak 12 21.720 4.088 10.6 Peak 13 22.664 3.920 0.7 Peak 14 24.922 3.570 1.1 Peak 15 25.940 3.432 1.2 Peak 16 26.840 3.319 1.6 Peak 17 29.620 3.014 1.6

Example 20. Preparation of crystal form F

Add the compound of formula (I) (1 g) to 3 mL ethyl acetate, heat to 80°C, stir to dissolve, and continue stirring for 30 minutes. A solid precipitates out. Add 4.5 mL n-hexane slowly at 80°C. Reduce to 20°C (about 3 hours), and continue stirring at 20°C for 3 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (855 mg). After X-ray powder diffraction detection, the product was defined as F crystal form, and the spectrum is shown in Fig. 21.

The DSC spectrum is shown in Fig. 22, the endothermic peak is at 214.68°C; the TGA spectrum is shown in Fig. 23.

DVS characterization: The sample is under the condition of 25℃, according to the relative mass change curve, between 10%RH-80%RH, as the humidity increases, the mass increase is about 0.1464%, less than 2%, according to the "People's Republic of China Pharmacopoeia" In the 2015 version of the guidelines for drug hygroscopicity testing, the sample has almost no hygroscopicity. Under normal storage conditions (ie 25℃ 60%RH), the mass increase is about 0.0457%; under accelerated test conditions (ie 70%RH), the mass increase is about 0.0701%; under extreme conditions (ie 90%RH), the mass increases About 0.2744%. In the 0%-95% humidity change process, the desorption process and the adsorption process of the sample basically coincided, and the crystal form did not change before and after the DVS detection. The DVS curve is shown in Figure 24, and the comparison of X-ray powder diffraction before and after DVS detection is shown in Figure 25. Table 6. Characteristic peaks of crystal form F Peak number 2-Theta d(A) I% Peak 1 5.761 15.329 46.9 Peak 2 9.800 9.018 41.5 Peak 3 10.640 8.308 15.7 Peak 4 11.621 7.609 51.6 Peak 5 14.021 6.311 23.9 Peak 6 16.180 5.474 15.3 Peak 7 16.460 5.381 12.9 Peak 8 16.740 5.292 7.7 Peak 9 17.520 5.058 29.6 Peak 10 18.560 4.777 14.1 Peak 11 19.142 4.633 4.7 Peak 12 19.820 4.476 6.4 Peak 13 21.460 4.137 100.0 Peak 14 22.820 3.894 8.2 Peak 15 23.939 3.714 25.8 Peak 16 24.580 3.619 70.0 Peak 17 25.981 3.427 9.2 Peak 18 26.280 3.388 6.4 Peak 19 26.861 3.316 6.6 Peak 20 27.700 3.218 2.8 Peak 21 28.580 3.121 8.0 Peak 22 28.921 3.085 6.6 Peak 23 29.480 3.028 8.0 Peak 24 30.840 2.897 5.1 Peak 25 31.340 2.852 3.8 Peak 26 32.801 2.728 3.5 Peak 27 33.300 2.688 9.9 Peak 28 33.921 2.641 2.6 Peak 29 35.321 2.539 1.9 Peak 30 36.843 2.438 2.3 Peak 31 38.660 2.327 2.1 Peak 32 40.101 2.247 5.4 Peak 33 41.121 2.193 2.8 Peak 34 41.600 2.169 5.6

Example 21. Preparation of Form F

The compound of formula (I) (12 g) was added to 240 mL ethyl formate, heated to an internal temperature of 54 ℃ and refluxed, stirred to clear, slowly dripped 300 mL n-hexane under reflux conditions, and the clear solution was added to F under reflux conditions. The crystal form seed crystal, the solid is not dissolved, continue to reflux and stir for 30 minutes, and a solid precipitates out slowly, and it is slowly reduced to room temperature, and the stirring is continued for 16 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (8.2 g). After X-ray powder diffraction inspection, the product is F crystal.

Example 22. Preparation of Crystal Form A

The compound B crystalline form (25 mg) of formula (I) was added to 0.4 mL of toluene, and the mixture was stirred at room temperature for 90 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (13 mg). After X-ray powder diffraction inspection, the product is in crystal form A.

Example 23. Preparation of Crystal Form A

The compound B crystalline form (50 mg) of formula (I) was added to 0.4 mL of a mixed solvent of tetrahydrofuran and methyl tert-butyl ether (V:V=1:3), and the mixture was stirred at room temperature for 90 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (24 mg). After X-ray powder diffraction inspection, the product is in crystal form A.

Example 24. Preparation of Crystal Form A

The compound B crystalline form (25 mg) of formula (I) was added to 0.4 mL of ethyl acetate and n-hexane (V:V=1:1) mixed solvent, and the mixture was stirred at room temperature for 90 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (18 mg). After X-ray powder diffraction inspection, the product is in crystal form A.

Example 25. Preparation of Crystal Form A

The compound B crystalline form (25 mg) of formula (I) was added to 0.4 mL of ethyl acetate and n-heptane (V:V=1:1) mixed solvent, and the mixture was stirred at room temperature for 90 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (17 mg). After X-ray powder diffraction inspection, the product is in crystal form A.

Example 26. Preparation of Crystal Form A

Add crystal form A (20 mg) and crystal form B (20 mg) of compound of formula (I) into 0.5 mL of 1,4-dioxane and water (V:V=1:2) mixed solvent, and beat at room temperature Stir for 90 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (25 mg). After X-ray powder diffraction inspection, the product is in crystal form A.

Example 27. Preparation of Crystal Form A

The crystal form A (20 mg) and crystal form B (20 mg) of the compound of formula (I) were added to 0.5 mL of acetonitrile, and the mixture was stirred at room temperature for 90 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (18 mg). After X-ray powder diffraction inspection, the product is in crystal form A.

Example 28, Preparation of Crystal Form A

The crystal form (10 mg) of compound A of formula (I) was added to 1 mL of water, and the mixture was stirred at room temperature for 18 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (5 mg). After X-ray powder diffraction inspection, the product is in crystal form A.

Example 29, Preparation of Crystal Form B

Add the amorphous compound of formula (I) (200 mg) to 4 mL of a mixture solvent of tert-butyl acetate, methyl tert-butyl ether and n-hexane (V:V:V=1:1:2), and make a slurry at room temperature Stir for 72 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (80 mg). After X-ray powder diffraction test, the product is B crystal.

Example 30, Preparation of Crystal Form B

The amorphous compound of formula (I) (200 mg) was added to 0.27 mL of a mixture solvent of trifluoroethanol and isopropyl ether (V:V=2:25), the room temperature was raised to 50°C, and the slurry was stirred for 72 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was collected and dried in vacuo to obtain the product (18 mg). After X-ray powder diffraction test, the product is B crystal.

Example 31. Preparation of Crystal Form B

The amorphous (50 mg) compound of formula (I) was added to 0.5 mL of n-heptane, the room temperature was raised to 50° C., and the slurry was stirred for 72 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was collected and dried in vacuo to obtain the product (40 mg). After X-ray powder diffraction test, the product is B crystal.

Example 32, Preparation of Crystal Form B

The amorphous compound of formula (I) (50 mg) was added to 0.5 mL of a solvent mixture of chloroform and methyl tert-butyl ether (V:V=1:8), the room temperature was raised to 50°C, and the slurry was stirred for 72 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was collected and dried in vacuo to obtain the product (28 mg). After X-ray powder diffraction test, the product is B crystal.

Example 33. Preparation of Crystal Form B

Add crystalline form A (20 mg) and crystalline form B (20 mg) of compound of formula (I) into 0.5 mL of ethyl acetate and n-heptane (V:V=2:3) mixed solvent, beating and stirring at room temperature for 90 hours . The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (28 mg). After X-ray powder diffraction test, the product is B crystal.

Example 34. Preparation of Crystal Form B

Add the formula (I) compound A crystal form (20 mg) and B crystal form (20 mg) to 0.5 mL of acetone, methyl tert-butyl ether and n-hexane (V:V:V=1:1:4) and mix In the solvent, beating and stirring at room temperature for 90 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (20 mg). After X-ray powder diffraction test, the product is B crystal.

Example 35, Preparation of Crystal Form B

The formula (I) compound A crystal form (20 mg) and B crystal form (20 mg) were added to 0.5 mL of butyl acetate, methyl tert-butyl ether and n-hexane (V:V:V=1:1:2 ) In the mixed solvent, beating and stirring at room temperature for 90 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (21 mg). After X-ray powder diffraction test, the product is B crystal.

Example 36, Preparation of Crystal Form D

The compound B crystalline form (1.4 g) of formula (I) was added to 14 mL of acetonitrile, and the mixture was stirred at room temperature for 96 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (1.25 g). After X-ray powder diffraction test, the product is D crystal form.

Example 37. Preparation of Form F

The amorphous compound of formula (I) (30 mg) was added to 0.5 mL of a solvent mixture of 1,4-dioxane and water (V:V=1:2), and the mixture was stirred at room temperature for 72 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (21 mg). After X-ray powder diffraction inspection, the product is F crystal.

Example 38. Preparation of Form F

The crystalline form (30 mg) of compound A of formula (I) was added to 1 mL of a solvent mixture of acetonitrile and water (V:V=1:4), and the mixture was stirred at room temperature for 96 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (18 mg). After X-ray powder diffraction inspection, the product is F crystal.

Example 39. Preparation of Form F

Add the crystalline form (30 mg) of compound A of formula (I) to 0.8 mL of tetrahydrofuran and water (V:V=1:3) mixture solvent, beating at room temperature, the powdery solid becomes sticky solid, continue beating, sticky The solid turned into a powdery solid, and the slurry was stirred for a total of 96 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (16 mg). After X-ray powder diffraction inspection, the product is F crystal.

Example 40. Preparation of crystal form F

The crystalline form (30 mg) of compound A of formula (I) was added to 1 mL of a solvent mixture of acetone and water (V:V=1:4), and the mixture was stirred at room temperature for 96 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (17 mg). After X-ray powder diffraction inspection, the product is F crystal.

Example 41. Preparation of Form F

The crystalline form (40 mg) of compound A of formula (I) was added to 0.6 mL of a solvent mixture of isopropanol and water (V:V=1:3), and the mixture was stirred at room temperature for 96 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (24 mg). After X-ray powder diffraction inspection, the product is F crystal.

Example 42, Preparation of Form F

The amorphous compound of formula (I) (20 mg) was added to 0.3 mL of a solvent mixture of ethyl propionate and n-heptane (V:V=1:0.5), and the mixture was stirred at room temperature for 96 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (14 mg). After X-ray powder diffraction inspection, the product is F crystal.

Example 43. Preparation of Crystal Form F

The amorphous compound of formula (I) (20 mg) was added to 0.3 mL of a solvent mixture of n-propanol and isopropyl ether (V:V=1:5), and the mixture was stirred at room temperature for 96 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (12 mg). After X-ray powder diffraction inspection, the product is F crystal.

Example 44. Preparation of Form F

The amorphous compound of formula (I) (20 mg) was added to 0.3 mL o-xylene, and the mixture was stirred at room temperature for 96 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (15 mg). After X-ray powder diffraction inspection, the product is F crystal.

Example 45. Preparation of Crystal Form F

The amorphous compound of formula (I) (20 mg) was added to 0.5 mL of a solvent mixture of 2-butanone and n-heptane (V:V=1:4), and the mixture was stirred at room temperature for 96 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (7 mg). After X-ray powder diffraction inspection, the product is F crystal.

Example 46. Preparation of Crystal Form F

The amorphous compound of formula (I) (20 mg) was added to 0.5 mL of a solvent mixture of 1,4-dioxane and isopropyl ether (V:V=1:4), and the mixture was stirred at room temperature for 96 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (10 mg). After X-ray powder diffraction inspection, the product is F crystal.

Example 47. Preparation of Form F

The compound of formula (I) A crystal form (15 mg), D crystal form (15 mg) and F crystal form (15 mg) 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 in vacuo to obtain the product (24 mg). X-ray powder diffraction inspection, the product is F crystal form.

Example 48. Preparation of Crystal Form F

Add crystal form A (15 mg), crystal form D (15 mg) and crystal form F (15 mg) of compound of formula (I) to 0.4 mL isopropyl ether, heat to 50°C, beat and stir for 120 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was collected and dried in vacuo to obtain the product (21 mg). After X-ray powder diffraction inspection, the product is F crystal.

Example 49. Preparation of Form F

Add crystal form A (15 mg), crystal form D (15 mg) and crystal form F (15 mg) of compound of formula (I) into 0.4 mL of chloroform and n-heptane (V:V=1:1.5) mixed solvent, 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 (20 mg). After X-ray powder diffraction inspection, the product is F crystal.

Example 50. Preparation of Form F

Add the formula (I) compound A crystal form (15 mg), D crystal form (15 mg) and F crystal form (15 mg) to 0.4 mL methyl isobutyl ketone and n-heptane (V:V=1:5) In the mixed solvent, 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 in vacuo to obtain the product (22 mg). After X-ray powder diffraction inspection, the product is F crystal.

Example 51. Preparation of Crystal Form F

Add the formula (I) compound A crystal form (10 mg), D crystal form (10 mg) and F crystal form (10 mg) into 0.5 mL of isopropanol and isopropyl ether (V:V=1:4) mixed solvent At room temperature, beating and stirring for 96 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (18 mg). After X-ray powder diffraction inspection, the product is F crystal.

Example 52. Preparation of Crystal Form F

Add the formula (I) compound A crystal form (10 mg), D crystal form (10 mg) and F crystal form (10 mg) into 0.5 mL of acetone and n-hexane (V:V=1:4) mixed solvent, Beat and stir at room temperature for 96 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (22 mg). After X-ray powder diffraction inspection, the product is F crystal.

Example 53, Preparation of Form F

Add the formula (I) compound A crystal form (10 mg), D crystal form (10 mg) and F crystal form (10 mg) into 0.5 mL of chloroform and isopropyl ether (V:V=1:4) mixed solvent , Beat and stir at room temperature for 96 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (21 mg). X-ray powder diffraction inspection, the product is F crystal form.

Example 54 Preparation of Crystal Form F

The compound of formula (I) A crystal form (10 mg), D crystal form (10 mg) and F crystal form (10 mg) were added to 0.3 mL of toluene, and the mixture was stirred at room temperature for 96 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (26 mg). After X-ray powder diffraction inspection, the product is F crystal.

Example 55. Preparation of Form F

The compound of formula (I) A crystal form (10 mg), D crystal form (10 mg) and F crystal form (10 mg) were added to 0.3 mL of acetonitrile, and the mixture was stirred at room temperature for 96 hours. The reaction solution was filtered, the filter cake was collected, and dried under vacuum to obtain the product (22 mg). After X-ray powder diffraction inspection, the product is F crystal.

Example 56, Preparation of Form F

The compound F crystal form (10 mg) of formula (I) was added to 1 mL of water, and the mixture was stirred at room temperature for 18 hours. The reaction solution was filtered, the filter cake was collected, and dried in vacuum to obtain the product. X-ray powder diffraction inspection, the product is F crystal form.

Example 57. Experiments on influencing factors of crystal forms A, B, D, and F of the present invention

Place the crystal samples of compound A, B, D, and F of formula (I) open and flat, and observe under high temperature (40℃, 60℃), light (4500 Lux), high humidity (RH 75%, RH 90%) conditions Under the stability of the sample, the sampling observation period is 30 days.

Experimental results: Table 7. Experimental results of influencing factors of crystal form A and crystal form B of compound of formula (I) condition Time (days) Crystal Form A Crystal Form B Color and character purity% Weight gain% Crystal form Color and character purity% Weight gain% Crystal form Start 0 Yellow solid 98.76 A Light yellow solid 99.65 B 4500 Lux 5 Yellow solid 98.74 - - - 10 Yellow solid 98.74 - - - 15 - - Yellow solid 99.01 30 Yellow solid 98.75 A Yellow solid 98.71 A 40℃ 5 Yellow solid 98.74 - - - 10 Yellow solid 98.70 - - - 15 - - Light yellow solid 98.99 30 Yellow solid 98.48 A Light yellow solid 98.57 A 60℃ 5 Yellow solid 98.73 - - - 10 Yellow solid 98.68 - - - 15 - - Light yellow solid 99.10 30 Yellow solid 98.50 A Light yellow solid 98.60 A RH 75% 5 Yellow solid 98.76 1.15 - - - - 10 Yellow solid 98.76 3.30 - - - - 15 - - - Light yellow solid 99.62 6.76 30 Yellow solid 98.76 5.85 A Light yellow solid 99.59 8.34 A RH 90% 5 Yellow solid 98.75 3.18 - - - - 10 Yellow solid 98.75 8.14 - - - - 15 - - - Light yellow solid 99.64 14.89 30 Yellow solid 98.76 11.37 A Light yellow solid 99.56 19.11 A Table 8. Experimental results of influencing factors of crystal form D and crystal form F of compound of formula (I) condition Time (days) Crystal Form D Crystal Form F Color and character purity% Weight gain% Crystal form Color and character purity% Weight gain% Crystal form Start 0 White solid 99.59 D 99.67 F 4500 Lux 5 White solid 99.58 99.66 10 White solid 99.57 99.64 30 White solid 99.26 Amorphous 99.64 F 40℃ 5 White solid 99.53 99.67 10 White solid 99.02 99.62 30 White solid 98.95 Amorphous 99.57 F 60℃ 5 White solid 99.40 99.68 10 White solid 99.31 99.65 30 White solid 99.09 Amorphous 99.59 F RH 75% 5 White solid 99.56 5.30 99.65 5.23 10 White solid 99.53 5.48 99.63 5.34 30 White solid 99.55 5.56 Amorphous 99.62 10.03 F RH 90% 5 White solid 99.57 7.45 99.66 7.26 10 White solid 99.54 8.67 99.63 8.40 30 White solid 99.55 9.53 Amorphous 99.65 12.83 F

Experimental results:

The experimental results of the influencing factors in Tables 7 and 8 show: under the conditions of light, high temperature 40℃, high temperature 60℃, high humidity 75%RH, high humidity 90%RH, placed for 30 days, the physical properties of crystal form A and crystal F Good chemical stability.

Example 58, Long-term accelerated stability test of crystal form A and crystal F of the present invention

The long-term (25°C, 60%RH) and accelerated (40°C, 75%RH) stability of compound A and F of formula (I) were investigated for 3 months.

Experimental results: Table 9. Long-term accelerated stability test results of compound A and F of formula (I) sample Placement conditions purity% purity% purity% Crystal form Start 1 month 2 months 3 months Crystal Form A 25℃，60%RH 98.79 98.80 98.77 98.76 A 40℃，75%RH 98.79 98.79 98.75 98.74 A Crystal Form F 25℃，60%RH 99.69 99.68 99.65 99.65 F 40℃，75%RH 99.69 99.68 99.67 99.66 F

The results of the long-term accelerated stability experiment in Table 9 show that: the physical and chemical stability of crystal form A and crystal form F for 3 months under long-term (25℃, 60%RH) and accelerated (40℃, 75%RH) stability conditions it is good.

Although the specific embodiments of the present invention are described above, those skilled in the art should understand that these are only examples, and various changes or modifications can be made to these embodiments without departing from the principle and essence of the present invention. . Therefore, the scope of protection of the present invention is limited by the scope of the attached patent application.

no

Figure 1 is an XRPD diagram of a compound of formula (I) in an amorphous form; Figure 2 is an XRPD diagram of the compound of formula (I) in the form of crystal form A; Figure 3 is a DSC chart of the compound of formula (I) in the form of crystal form A; Figure 4 is a TGA diagram of the compound of formula (I) in the form of crystal form A; Figure 5 is a DVS moisture absorption diagram of the compound of formula (I) in the form of crystal form A; Fig. 6 is a comparison diagram of XRPD of the compound of formula (I) in the form of crystal form A before and after DVS detection; Figure 7 is an XRPD diagram of the compound of formula (I) in the form of crystal form B; Figure 8 is a DSC chart of the compound of formula (I) in the form of crystal form B; Figure 9 is a TGA diagram of the compound of formula (I) in the form of crystal form B; Figure 10 is a DVS moisture absorption diagram of the compound of formula (I) in the form of crystal form B; FIG. 11 is a comparison diagram of XRPD before and after DVS detection of the compound of formula (I) in the form of crystal form B; Figure 12 is an XRPD diagram of the compound of formula (I) in the form of crystal form C; Figure 13 is a DSC chart of the compound of formula (I) in the form of crystal form C; Figure 14 is a TGA chart of the compound of formula (I) in the form of crystal form C; Figure 15 is an XRPD pattern of the compound of formula (I) in the form of D crystal form; Figure 16 is a DSC and TGA chart of the compound of formula (I) in the form of D crystal form; Figure 17 is a DVS moisture absorption diagram of the compound of formula (I) in the form of D crystal form; Fig. 18 is a comparison diagram of XRPD before and after DVS detection of the compound of formula (I) in the form of crystal form D; Fig. 19 is an ellipsoid diagram of the analytical molecular three-dimensional structure of a compound of formula (I) in the form of crystal form D; Figure 20 is an XRPD pattern of the compound of formula (I) in the form of E crystal form; Figure 21 is an XRPD diagram of the compound of formula (I) in the form of F crystal; Figure 22 is a DSC chart of the compound of formula (I) in the form of F crystal; Figure 23 is a TGA chart of the compound of formula (I) in the form of F crystal; Figure 24 is a DVS moisture absorption diagram of the compound of formula (I) in the form of F crystal; FIG. 25 is a comparison diagram of XRPD before and after DVS detection of the compound of formula (I) in the form of F crystal form.

Claims (13)

A kind of formula (I) compound ( S )-4-(4-(tert-butoxy)-2-(4-(5-chloro-2-propanylphenyl)-5-methoxy-2-oxy The crystal form A of pyridin-1( 2H )-butyramido)benzoic acid, in which the X-ray powder diffraction pattern has characteristics at 2θ of 7.420, 8.000, 8.642, 12.900, and 22.400 peak,

The crystal form A according to claim 1, wherein the X-ray powder diffraction pattern has characteristics at 2θ of 7.420, 8.000, 8.642, 12.900, 16.281, 18.280, 20.018, 21.119, 22.400, 24.458, 26.100 peak. A kind of formula (I) compound ( S )-4-(4-(tert-butoxy)-2-(4-(5-chloro-2-propanylphenyl)-5-methoxy-2-oxy The F crystal form of pyridin-1( 2H )-butyramido)benzoic acid, in which the X-ray powder diffraction pattern in the 2θ is 5.761, 9.800, 10.640, 11.621, 14.021, 16.180, There are characteristic peaks at 16.460, 17.520, 21.460, and 24.580,

The crystal form F according to claim 3, wherein in its X-ray powder diffraction pattern, the 2θ is 5.761, 9.800, 10.640, 11.621, 14.021, 16.180, 16.460, 16.740, 17.520, 21.460, 22.820, 23.939, There are characteristic peaks at 24.580 and 26.280. The crystal form F according to claim 3, wherein in its X-ray powder diffraction pattern, the 2θ is 5.761, 9.800, 10.640, 11.621, 14.021, 16.180, 16.460, 16.740, 17.520, 18.560, 19.142, 19.820, There are characteristic peaks at 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. A compound of formula (I) as described in claim 1 or 2 ( S )-4-(4-(tert-butoxy)-2-(4-(5-chloro-2-propanylphenyl)- The method for preparing crystal form A of 5-methoxy-2-oxopyridine-1( 2H )-yl)butyramido)benzoic acid can be any of the following methods: Method 1, including: taking a certain amount A quantity of the compound of formula (I) is dissolved by adding an appropriate amount of ethyl acetate, the temperature is heated to dissolve it, and n-hexane is added until it is just turbid, slowly reducing to room temperature, stirring and crystallizing to obtain crystal form A; method 2, including: taking a certain amount Compound of formula (I), add appropriate amount of dichloromethane to dissolve, warm up to dissolve, add appropriate amount of isopropyl ether, slowly reduce to room temperature, stir and crystallize to obtain crystal form A; Method 3 includes: take a certain amount of formula (I ) Compound, add proper amount of acetone to dissolve, warm up to dissolve, add proper amount of n-heptane, slowly reduce to room temperature, stir and crystallize to obtain crystal form A; Method 4 includes: take a certain amount of formula (I) compound, add proper amount Ethyl acetate was dissolved, heated to dissolve, and an appropriate amount of n-heptane was added, slowly lowered to room temperature, stirred and crystallized to obtain crystal form A; Method 5 includes: taking a certain amount of the compound of formula (I), adding an appropriate amount of toluene to dissolve, Dissolve at elevated temperature, add appropriate amount of n-heptane, slowly lower to room temperature, stir and crystallize to obtain crystal form A; Method 6, including: take a certain amount of compound of formula (I), add appropriate amount of ethyl formate to dissolve, and warm to clear , Add a proper amount of n-hexane, a small amount of solid precipitates, slowly reduce to room temperature, stir and crystallize to obtain crystal form A; Method 7, including: take a certain amount of the compound of formula (I), add a proper amount of ethyl acetate to dissolve, and heat to dissolve Clear, add an appropriate amount of n-hexane, solids will precipitate, continue to stir for a period of time under elevated temperature, slowly drop to room temperature, stir and crystallize to obtain crystal form A; Method 8, including: taking a certain amount of compound B of formula (I) Crystal form, add an appropriate amount of toluene, beaten at room temperature to obtain crystal form A; Method 9, including: take a certain amount of compound B crystal form of formula (I), add an appropriate amount of tetrahydrofuran/methyl tert-butyl ether mixed solvent, compartment Warm pulping to obtain crystal form A; method 10, including: taking a certain amount of compound B crystal form of formula (I), adding an appropriate amount of ethyl acetate/n-hexane mixed solvent, and beating at room temperature to obtain crystal form A; method 11, Including: taking a certain amount of compound B crystal form of formula (I), adding an appropriate amount of ethyl acetate/n-heptane mixed solvent, and beating at room temperature to obtain crystal form A; method 12 includes: taking a certain amount of formula (I) Compound A crystal form and B crystal form, add an appropriate amount of dioxane/water mixed solvent, and beat at room temperature to obtain crystal form A; method 13, including: taking a certain amount of formula (I) compound A crystal form and B crystal Form A, adding an appropriate amount of acetonitrile and beating at room temperature to obtain crystal form A; Method 14, including: taking a certain amount of compound A of formula (I), adding an appropriate amount of water, and beating at room temperature to obtain crystal form A; The X-ray powder diffraction pattern of the crystal form has characteristic peaks at 2θ values of 7.620, 8.680, 11.042, 11.638, 12.339, 16.320, 19.381, and the error range is ±0.3, ±0 .2 or ±0.1. A compound of formula (I) as described in any one of claims 3-5 ( S )-4-(4-(tert-butoxy)-2-(4-(5-chloro-2-propanylbenzene) (2H )-yl)-5-methoxy-2-oxopyridine-1(2H)-yl)butyramido)benzoic acid crystal form F preparation method, which is any of the following methods: Method 1, including : Take a certain amount of the compound of formula (I), add an appropriate amount of ethyl acetate, raise the temperature to dissolve it, continue to stir for solid precipitation, drop an appropriate amount of n-hexane, slowly lower the temperature, stir and crystallize to obtain crystal form F; Method 2, including: Take a certain amount of the compound of formula (I), add an appropriate amount of ethyl formate, add to the reflux solution, drop an appropriate amount of n-hexane, add F crystal crystals, reflux the solution, slowly cool down, stir and crystallize to obtain F crystal Method 3, including: taking a certain amount of the amorphous compound of formula (I), adding an appropriate amount of 1,4-dioxane/water mixed solvent, beating at room temperature to obtain crystal form F; method 4, including: taking a certain amount An amount of the crystal form of compound A of formula (I) is added to an appropriate amount of acetonitrile/water mixed solvent, and the mixture is beaten at room temperature to obtain crystal form F; method 5 includes: taking a certain amount of compound of formula (I) crystal form A and adding an appropriate amount of tetrahydrofuran In a mixed solvent of acetone/water, beating at room temperature to obtain crystal form F; method 6, including: taking a certain amount of compound A crystal form of formula (I), adding an appropriate amount of acetone/water mixed solvent, and beating at room temperature to obtain crystal form F Method 7, including: taking a certain amount of compound A crystal form of formula (I), adding an appropriate amount of isopropanol/water mixed solvent, and beating at room temperature to obtain crystal form F; method 8, including: taking a certain amount of formula ( I) The compound is amorphous, add an appropriate amount of ethyl propionate/n-heptane mixed solvent, and beat at room temperature to obtain crystal form F; the X-ray powder diffraction pattern of the crystal form A has 2θ values of 7.420, 8.000, 8.642 , 12.900, 22.400 have characteristic peaks, the error range is ±0.3, ±0.2 or ±0.1. The crystal form according to any one of claims 1-5, wherein the error range of its 2θ value is ±0.2. A pharmaceutical composition, which contains at least one crystal form according to any one of claims 1-5 and 8, and also contains one or more pharmaceutically acceptable carriers, diluents or excipients. A method for preparing the pharmaceutical composition according to claim 9, wherein at least one crystal form according to any one of claims 1-5 and 8 is combined with at least one pharmaceutically acceptable carrier, diluent or excipient Mixing of propellants. A medicine for treating and/or preventing diseases mediated by factor XIa, which is prepared by using the crystal form according to any one of claims 1-5 and 8. A medicine for treating and/or preventing cardiovascular and cerebrovascular diseases, which is prepared by using the crystal form according to any one of claims 1-5 and 8, wherein the cardiovascular and cerebrovascular diseases are selected from thromboembolic diseases. The drug according to claim 12, wherein the cardiovascular and cerebrovascular diseases are selected from the group consisting of myocardial infarction, angina pectoris, re-occlusion and restenosis after angioplasty or aortic coronary bypass, diffuse intravascular coagulation, stroke, transient Ischemic attack, peripheral arterial occlusive disease, pulmonary embolism, or deep vein thrombosis.

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