CN118871442A - Crystal form of fumarate of pyrrolo-heterocyclic derivative and preparation method thereof - Google Patents

Crystal form of fumarate of pyrrolo-heterocyclic derivative and preparation method thereof Download PDF

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CN118871442A
CN118871442A CN202380028721.0A CN202380028721A CN118871442A CN 118871442 A CN118871442 A CN 118871442A CN 202380028721 A CN202380028721 A CN 202380028721A CN 118871442 A CN118871442 A CN 118871442A
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formula
compound
cancer
fumarate salt
fumarate
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周先强
杨俊然
尤凌峰
冯君
杜振兴
王捷
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Shanghai Hengrui Pharmaceutical Co Ltd
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

The present disclosure relates to crystalline forms of fumarate salts of pyrrolo-heterocyclic derivatives and methods of making the same. Specifically, the present disclosure relates to a V-form of a fumarate salt of a compound represented by formula (I) and a preparation method thereof, and the V-form of a fumarate salt of a compound represented by formula (I) provided by the present disclosure has good stability, and can be better used for clinical treatment.

Description

Crystal form of fumarate of pyrrolo-heterocyclic derivative and preparation method thereof
The present application claims priority from China patent application 202210311269.6 with application date 2022/3/28. The present application incorporates the entirety of the above-mentioned chinese patent application.
Technical Field
The present disclosure relates to a new crystal form of fumarate of pyrrolo-heterocyclic derivative and a preparation method thereof, which belongs to the pharmaceutical field.
Background
Proliferation, differentiation, metabolism, and apoptosis of normal cells are strictly regulated by in vivo cell signaling pathways. Mitogen-activated protein kinases (MAPKs) play a very important role in the signaling pathway, and extracellular signal-regulated kinases (extracellular signal regulated kinase, ERKs) are a member of the MAPK family. Through RAS-RAF-MEK-ERK step, exogenous stimulation signal is transferred to ERK, activated ERK is transferred into cell nucleus to regulate transcription factor activity, so as to regulate cell proliferation, differentiation, apoptosis and other biological functions, or through phosphorylation of cytoskeletal component in cytosol to participate in regulation of cell morphology and redistribution of cytoskeletal.
RAS and RAF gene mutation causes continuous activation of MAPK-ERK signal pathway, promotes malignant transformation and abnormal proliferation of cells, and finally generates tumor (Roberts PJ et al, oncogene,2007, 26 (22), 3291-3310). The combination of a MEK inhibitor with a B-RAF inhibitor can further improve the effect of the B-RAF inhibitor on tumor growth inhibition and can significantly improve disease-free progression and overall survival of melanoma patients carrying the BRAF 600E and V600K mutations (FREDERICK DT et al, CLINICAL CANCER RESEARCH,2013.19 (5), 1225-1231). Although the B-RAF/MEK inhibitor combination may have a tumor-inhibiting effect, their efficacy is short-lived, and most patients develop resistance within 2-18 months, and the tumor is further exacerbated. The mechanism of resistance to B-RAF/MEK inhibitors is very complex and is mostly directly related to reactivation of the ERK signaling pathway (Smalley I et al, cancer Discovery,2018,8 (2), 140-142). Therefore, the development of new ERK inhibitors is effective not only for patients with mutations in the MAPK signaling pathway, but also for patients with B-RAF/MEK inhibitor resistance.
The B-RAF/MEK inhibitor can inhibit the growth of tumor and regulate the immune microenvironment of the tumor. The B-RAF/MEK inhibitor can enhance the expression of tumor specific antigen, improve the recognition and killing of antigen specific T cells on tumors, and promote the migration and infiltration of immune cells. In animal models, PD-L1 expression in tumor tissues is enhanced after treatment with B-RAF/MEK inhibitors, and when combined with antibodies to checkpoint (checkpoint) molecules (e.g., PD-1 antibodies, CTLA4 antibodies), they further show an effect of inhibiting tumor growth over B-RAF/MEK inhibitors alone (Boni A et al, CANCER RESEARCH,2010, 70 (13), 5213-5219). Research shows that ERK inhibitor is similar to B-RAF/MEK inhibitor, and can regulate tumor microenvironment, raise the function of cytotoxic T cell and inhibit tumor growth.
A number of compounds have been developed. Wherein BioMed Valley Discoveries company BVD-523 is in clinical stage two, merck company MK-8353 and Astex company Astex-029 are in clinical stage one. Related patents are WO1999061440A1、WO2001056557A2、WO2001056993A2、WO2001057022A2、WO2002022601A1、WO2012118850A1、WO2013018733A1、WO2014179154A2、WO2015103133A1、WO2016192063A1、WO2017180817A1、WO2018049127A1.
Disclosure of Invention
The present disclosure provides a V-form of a fumarate salt of a compound represented by formula (I), wherein the fumarate salt of the compound represented by formula (I) has a molar ratio of the compound represented by formula (I) to the fumarate salt of 2:1, and an X-ray powder diffraction pattern thereof has characteristic peaks at angles of 2 theta of 13.763, 14.493, 17.975, 19.549, 25.502,
The present disclosure provides a V-crystalline form of a fumarate salt of a compound of formula (I), having an X-ray powder diffraction pattern with characteristic peaks at 2θ angles 11.684, 12.703, 13.763, 14.493, 16.740, 17.975, 19.549, 23.299, 23.711, 25.502, 26.448.
The present disclosure provides a V-crystalline form of a fumarate salt of a compound of formula (I), having an X-ray powder diffraction pattern with a characteristic peak at angle 7.756、8.278、11.684、12.703、13.763、14.493、15.305、16.740、17.975、19.549、21.221、22.519、23.299、23.711、24.132、25.502、26.448、27.356、29.725、30.822、36.057 of 2θ.
The present disclosure provides a V-crystalline form of the fumarate salt of a compound of formula (I), whose X-ray powder diffraction pattern is shown in fig. 2.
The present disclosure provides a V-form of a fumarate salt of a compound represented by formula (I), wherein the error range of the 2θ angle is ±0.2.
In another aspect, the present disclosure provides a method for preparing form V of fumarate salt of a compound of formula (I), comprising the steps of: 1) Dissolving a compound shown in a formula (I) and fumaric acid in an organic solvent, and 2) crystallizing and separating out, wherein the mol ratio of the compound shown in the formula (I) to the fumaric acid is selected from 10:1-2:1, and the organic solvent is selected from methanol, acetonitrile, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, acetone or a mixture thereof.
In an alternative embodiment, the present disclosure provides a method for preparing a V-form of a fumarate salt of a compound represented by formula (I), the step of dissolving the compound represented by formula (I) and fumaric acid in an organic solvent is operated under heating conditions at a temperature selected from 30 to 120 ℃, for example, 35 to 80 ℃, for example, 40 to 60 ℃, specifically, 30 ℃, 35 ℃, 40 ℃,45 ℃, 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, 95 ℃, 100 ℃, 105 ℃, 110 ℃, 115 ℃, 120 ℃.
In an alternative embodiment, the present disclosure provides a method for preparing the V-form of the fumarate salt of the compound of formula (I), wherein the crystallization step is performed under heating conditions at a temperature selected from 30 to 120 ℃, e.g., 35 to 80 ℃, e.g., 40 to 60 ℃, and more specifically selected from 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃,65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃,95 ℃, 100 ℃, 105 ℃, 110 ℃, 115 ℃, 120 ℃.
In an alternative embodiment, the present disclosure provides a process for preparing form V of the fumarate salt of a compound of formula (I), wherein the molar ratio of the compound of formula (I) to fumaric acid is selected from 20:1 to 2:1, e.g. 10:1 to 2:1.
In an alternative embodiment, the present disclosure provides a method for preparing the V crystalline form of the fumarate salt of a compound of formula (I), the step time of crystallization is greater than 1.5 hours, such as greater than 3 hours, such as greater than 7 hours, such as greater than 15 hours, such as greater than 24 hours.
In an alternative embodiment, the present disclosure provides a process for preparing form V of the fumarate salt of the compound of formula (I), wherein the organic solvent is selected from methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, acetone or mixtures thereof, preferably methanol.
In an alternative embodiment, the present disclosure provides a process for preparing form V of the fumarate salt of a compound of formula (I), comprising the steps of: 1) Dissolving a compound shown in a formula (I) and fumaric acid in an organic solvent under heating condition, 2) crystallizing and separating out under heating condition, wherein the temperature of the step 1) and the step 2) is selected from 30-120 ℃, optionally the same or different, wherein the molar ratio of the compound shown in the formula (I) to the fumaric acid is selected from 10:1-2:1, the time of the step 2) is more than 1.5 hours, and the organic solvent is methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, acetone or a mixture thereof.
In certain embodiments, the methods of making the crystalline forms described in the present disclosure further comprise a filtration, washing, or drying step.
In another aspect, the present disclosure provides a composition prepared from the V-form of the fumarate salt of the compound of formula (I).
Another aspect of the present disclosure provides a pharmaceutical composition. It comprises the following components: i) A crystalline form V of the fumarate salt of the compound of formula (I); and ii) one or more pharmaceutically acceptable carriers, diluents or excipients.
Another aspect of the present disclosure provides a method for preparing the above pharmaceutical composition, comprising the steps of: the components are mixed.
The disclosure also provides the use of the aforementioned form V of the fumarate salt of a compound of formula (I), or a composition prepared by the aforementioned method, in the manufacture of a medicament for the treatment or prevention of cancer, inflammation, or other proliferative diseases, preferably cancer; the cancer is selected from melanoma, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, colorectal cancer, colon cancer, rectal cancer, pancreatic cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, prostate cancer, leukemia, head and neck squamous cell carcinoma, cervical cancer, thyroid cancer, lymphoma, sarcoma, neuroblastoma, brain tumor, myeloma, astrocytoma and glioma.
The "2θ or 2θ angle" described in the present disclosure refers to a diffraction angle, θ is a bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2 theta is +/-0.20, which can be -0.20、-0.19、-0.18、-0.17、-0.16、-0.15、-0.14、-0.13、-0.12、-0.11、-0.10、-0.09、-0.08、-0.07、-0.06、-0.05、-0.04、-0.03、-0.02、-0.01、0.00、0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.10、0.11、0.12、0.13、0.14、0.15、0.16、0.17、0.18、0.19、0.20.
The term "crystallization" as used in this disclosure includes, but is not limited to, stirred crystallization, slurried crystallization, and volatilized crystallization.
The drying temperature in the disclosure is generally 25-100 ℃, preferably 40-70 ℃, and the drying temperature can be normal pressure drying or reduced pressure drying.
Drawings
FIG. 1. Amorphous XRPD patterns of compounds of formula (I);
FIG. 2 XRPD patterns of the fumarate salt form V of the compound of formula (I);
FIG. 3 DSC of the fumarate salt form V of the compound of formula (I);
FIG. 4 TGA spectrum of the fumarate salt form V of the compound of formula (I);
FIG. 5. DVS spectrum of the fumarate salt form V of the compound of formula (I);
FIG. 6 XRPD patterns before and after DVS of the fumarate salt form V of the compound of formula (I);
FIG. 7 XRPD patterns of the hydrobromide alpha form of the compound of formula (I);
Figure 8 XRPD pattern of the beta crystalline form of the hydrobromide of the compound of formula (I).
Detailed Description
The present invention will be explained in more detail with reference to the following examples, which are only for illustrating the technical aspects of the present invention and do not limit the spirit and scope of the present invention.
Test conditions of the instrument used for the experiment:
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). The NMR shift (. Delta.) is given in units of 10 -6 (ppm). NMR was performed using Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO M with deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl 3), deuterated methanol (CD 3 OD) and Tetramethylsilane (TMS) as internal standard.
MS was measured using an Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC-MS (manufacturer: agilent, MS model: 6110/6120 Quadrupole MS).
Waters ACQuity UPLC-QD/SQD (manufacturers: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector)
THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive)
High Performance Liquid Chromatography (HPLC) analysis used AGILENT HPLC DAD, AGILENT HPLC VWD, and WATERS HPLC E2695-2489 high pressure liquid chromatographs.
Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.
The high performance liquid phase was prepared by using Waters 2545-2767, waters 2767-SQ Detecor2, shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.
XRPD is X-ray powder diffraction detection: the measurement was performed using a Bruker D8 Discovery-type X-ray diffractometer, and information was collected specifically: cu anode (40 kV,40 mA), cu-K alpha ray Scanning mode: θ/2θ, scan range (2θ range): 5-50 deg.
DSC is differential scanning calorimeter: the measurement adopts METTLER TOLEDO DSC & lt3+ & gt differential scanning calorimeter, the heating rate is 10 ℃ per minute, the specific temperature range refers to the corresponding map (25-300 ℃ or 25-350 ℃), and the nitrogen purging speed is 50mL/min.
TGA is thermogravimetric analysis: the detection adopts METTLER TOLEDO TGA type 2 thermogravimetric analyzer, the heating rate is 10 ℃/min, the specific temperature range refers to the corresponding map (25-300 ℃ at most), and the nitrogen purging speed is 50mL/min.
DVS is dynamic moisture adsorption: SMS DVS ADVANTAGE is adopted for detection, the humidity change is 50% -95% -0% -95% -50% at 25 ℃, the step is 10% (the last step is 5%) (the specific range of the humidity is based on the corresponding spectrum, the specific range is the most using method, and the judgment standard is dm/dt is not more than 0.002%).
The examples are not specifically described, and the solution refers to an aqueous solution.
The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.
The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound and the developing reagent system of thin layer chromatography included: a: the volume ratio of the methylene dichloride to the methanol is adjusted according to the polarity of the compound, and small amounts of alkaline or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.
Ion chromatography: the detection was performed using Thermo Scientific Dionex Intergrion ion chromatograph, column DionexIonPacTM AS-HC (4 μm, 4X 250 cm).
Example 1 (preparation method of example 10 in WO2020200069A 1)
Example 1
(S) -2- (1- (3-chlorophenyl) -2-hydroxyethyl) -6- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -1, 2-dihydro-3H-pyrrolo [1,2-c ] imidazol-3-one 1
First step
(S) -2- ((tert-Butyldimethylsilanyloxy) -1- (3-chlorophenyl) ethanamine 1b
(S) -2-amino-2- (3-chlorophenyl) ethanol 1a (4 g,23.3mmol, shanghai Bi-pharmaceutical technologies Co., ltd.) was dissolved in 80mL of methylene chloride, and t-butyldimethylchlorosilane (5.2 g,35 mmol) was added under ice bath and stirred for 14 hours. Water was added thereto, and the mixture was extracted with methylene chloride (80 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by column chromatography with eluent system C to give the title compound 1b (6.5 g), yield: 97%.
MS m/z(ESI)：286.1[M+1]
Second step
(S) -N- ((4-bromo-1H-pyrrol-2-yl) methyl) -2- ((tert-butyldimethylsilyl) oxy) -1- (3-chlorophenyl) ethanamine 1d
4-Bromo-1H-pyrrole-2-carbaldehyde 1c (2.37 g,13.62mmol, shanghai Bi) and Compound 1b (3.9 g,13.64 mmol) were reacted for 3 hours with stirring. 100mL of methanol was added for dilution, the temperature was lowered to 0℃and sodium borohydride (516 mg,13.64 mmol) was added for reaction with stirring for 2 hours. Water was added thereto, and the reaction mixture was concentrated under reduced pressure, followed by extraction with ethyl acetate (40 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by column chromatography with eluent system C to give the title compound 1d (4.8 g), yield: 79%.
MS m/z(ESI)：444.2[M+1]
Third step
(S) -6-bromo-2- (2- ((tert-butyldimethylsilyl) oxy) -1- (3-chlorophenyl) ethyl) -1H-pyrrolo [1,2-c ] imidazol-3 (2H) -one 1e
Compound 1d (4.8 g,10.81 mmol) was dissolved in 100mL of tetrahydrofuran, N' -carbonyldiimidazole (2.45 g,15.11 mmol) was added under ice-bath stirring for 0.5 hours, sodium hydride (60%, 6271 mg,16.22 umol) was added, and the reaction was stirred at room temperature for 14 hours. Saturated ammonium chloride was added. The reaction solution was concentrated under reduced pressure, and purified by column chromatography with eluent system C to give the title compound 1e (4.0 g), yield: 78%.
MS m/z(ESI)：469.1[M+1]
Fourth step
(S) -2- (2- ((tert-Butyldimethylsilanyloxy) -1- (3-chlorophenyl) ethyl) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [1,2-c ] imidazol-3 (2H) -one 1f
Compound 1e (4.0 g,8.51 mmol) was dissolved in 50mL of 1, 4-dioxane under argon, 4', 5' -octamethyl-2, 2 '-bis (1, 3, 2-dioxaborolane) (3.24 g,12.76 mmol), potassium acetate (3.34 g,34.04 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (1.24 g,1.70 mmol) were added sequentially and stirred at 90℃for 2 hours. Cooled, filtered through celite, the filtrate concentrated and purified by column chromatography with eluent system C to give the title compound 1f (2.0 g), yield: 45%.
MS m/z(ESI)：517.2[M+1]
Fifth step
4-Chloro-N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine 1i
N- (1-methyl-1H-pyrazol-5-yl) carboxamide (324.82 mg,2.60mmol, prepared as disclosed in patent application WO 2017/80979) was dissolved in 15mL of N, N-dimethylformamide, sodium hydride (60%, 311.47mg,7.79 mmol) was added at 0deg.C, the reaction was stirred for 0.5 hours, and 1g (500 mg,2.60mm0 l) of 4-chloro-2- (methylsulfonyl) pyrimidine was added, and the reaction was continued for 2 hours. 20mL of water, ethyl acetate extraction (20 mL. Times.3) and concentration of the combined organic phases under reduced pressure, and purification of the resulting residue by thin layer chromatography with developer system C gave the title compound 1i (270 mg), yield: 49.6%.
MS m/z(ESI)：210.3[M+1]
Sixth step
(S) -2- (2- ((tert-Butyldimethylsilanyloxy) -1- (3-chlorophenyl) ethyl) -6- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -1, 2-dihydro-3H-pyrrolo [1,2-c ] imidazol-3 (2H) -one 1j
Compound 1f (98.6 mg,0.19 mmol) was suspended in 20mL 1, 4-dioxane and 4mL water under argon, and the mixture of 4-chloro-N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine 1i, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (28 mg,0.02 mmol), cesium carbonate (124 mg,0.2 mmol) was heated to 80 ℃ and stirred for 14 hours. Cooled, filtered through celite, the filtrate was collected, extracted with ethyl acetate (20 ml×3), the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography with eluent system a to give the title compound 1j (100 mg), yield: 92%.
MS m/z(ESI)：564.3[M+1]
Seventh step
(S) -2- (1- (3-chlorophenyl) -2-hydroxyethyl) -6- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -1, 2-dihydro-3H-pyrrolo [1,2-c ] imidazol-3-one 1
Compound 1j (100 mg,0.17 mmol) was dissolved in 20mL of dichloromethane, 1mL of trifluoroacetic acid was added dropwise, and the reaction was stirred for 4 hours after the addition. The pH was adjusted to 7 with saturated sodium bicarbonate, extracted with dichloromethane (20 mL. Times.2), the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography with eluent system A to give the title compound 1 (15 mg), yield: 18%. The product was amorphous as measured by X-ray powder diffraction and the XRPD pattern is shown in FIG. 1.
MS m/z(ESI)：450.1[M+1]
1H NMR(400MHz,CDCl3)：δ8.33(d,1H),7.72(s,1H),7.48(d,1H),7.41-7.33(m,3H),7.28-7.24(m,1H),7.18(s,1H),6.92(d,1H),6.51(s,1H),6.32(d,1H),5.17(dd,1H),4.46(d,1H),4.32(dd,1H),4.27-4.17(m,3H),3.82(s,3H).
EXAMPLE 2 preparation of crystalline form V of fumarate salt of Compound of formula (I)
Dissolving 0.5g of compound and 64mg of fumaric acid in 2mL of absolute methanol at 50 ℃, cooling to 37 ℃, preserving heat for 3 hours, cooling to room temperature, reacting overnight, carrying out suction filtration, drying to obtain 0.328g of solid, and detecting the fumaric acid content by ion chromatography, wherein the mol ratio of the compound shown in the formula (I) to the fumaric acid is 2:1; the product is in crystal form V through X-ray powder diffraction detection, the XRPD spectrum is shown in figure 2, and the specific peak positions are shown in table 1.
TABLE 1 peak position of the fumarate salt form V of the Compound of formula (I)
The DSC spectrum is shown in figure 3, and the endothermic peak is 153.63 ℃;
The TGA spectrum is shown in figure 4, the weight loss at 25-140 ℃ is 0.44%, the weight loss at 140-270 ℃ is 8.46%.
The DVS spectrum is shown in fig. 5, and the water absorption is about 0.18% under normal storage conditions (i.e., 60% humidity at 25 ℃); under accelerated test conditions (i.e., 70% humidity), water absorption was about 0.23%; at extreme conditions (i.e., 90% humidity), the water uptake was about 0.44%. In the humidity change process of 0% -95%, the desorption process and the adsorption process of the sample are basically coincident; the X-ray powder diffraction pattern before and after DVS shows that no conversion of the DVS front and back crystalline forms occurred (see fig. 6).
Example 3 stability study of influencing factors
The compound fumarate of formula (I) is placed in an open and flat state, and the stability of the sample under the conditions of illumination (4500 Lux), high temperature (40 ℃ and 60 ℃) and high humidity (RH 75% and RH 92.5%) is examined, and the sampling examination period is 30 days.
TABLE 2 stability of Compound fumarate salt form V factors of formula (I)
Conclusion: the influence factor experiment shows that: the compound fumarate V crystal form shown in the formula (I) has good physical and chemical stability under the conditions of high temperature of 40 ℃ and 60 ℃ and high humidity of 75% and 92.5%.
Example 4 long term/accelerated stability study
The compound fumarate V crystal form shown in the formula (I) is respectively placed at 25 ℃,60 percent RH and 40 ℃ and 75 percent RH to examine the stability
TABLE 3 Long-term/accelerated stability Studies of the crystalline form V of the fumarate salt of Compound of formula (I)
Long term/accelerated stability experiments showed that: the compound fumarate V crystal form shown in the formula (I) has good physical and chemical property stability after being placed for 6 months under the condition of long-term acceleration stability.
EXAMPLE 5 preparation of the alpha Crystal form of the hydrobromide salt of Compound of formula (I)
100Mg of the free base of the compound of formula (I) are weighed, 7ul hydrobromic acid and 5ml of acetonitrile are added, stirring is carried out at 50 ℃/800rpm for 2-36h, suction filtration is carried out, drying is carried out at 40 ℃ for 1h, and the product is detected by ion chromatography, wherein the bromine ion content is 7.6%. The molar ratio of the compound of formula (I) to hydrobromic acid in the salt is 2:1, the product is defined as crystalline form α, the XRPD pattern is shown in FIG. 7, and the peak positions are shown in Table 4.
TABLE 4 peak positions of the crystalline form alpha of the hydrobromide salt of the compound of formula (I)
EXAMPLE 6 preparation of the beta Crystal form of the hydrobromide salt of Compound of formula (I)
100Mg of the free base of the compound of formula (I) are weighed, 14ul hydrobromic acid and 5ml of acetonitrile are added, stirring is carried out at 50 ℃/800rpm for 2 hours, suction filtration is carried out, drying is carried out at 40 ℃ for 1 hour, and the product is detected by ion chromatography, wherein the bromine ion content is 14.3%. The molar ratio of the compound of formula (I) to hydrobromic acid in the salt is 1:1, the product is defined as crystalline form beta, the XRPD pattern is shown in FIG. 8, and the peak positions are shown in Table 5.
TABLE 5 peak positions of the beta crystalline form of the hydrobromide of the compound of formula (I)
Example 7 influence factor stability study
The compound hydrobromide alpha crystal form shown in the formula (I) and the compound hydrobromide beta crystal form shown in the formula (I) are placed in an open and flat way, the stability of a sample is inspected under the condition of high temperature (40 ℃ and 60 ℃), and the sampling inspection period is 30 days.
TABLE 6 stability data for the form of the compound hydrobromide alpha shown in formula (I)
TABLE 7 stability data for the effect factors of the beta crystalline form of the hydrobromide of the compound of formula (I)
Conclusion: the compound hydrobromide alpha crystal form shown in the formula (I) and the compound hydrobromic acid beta crystal form shown in the formula (I) are unstable when placed at 60 ℃.
Example 8 dispersion of the Compound hydrobromide alpha form of formula (I), the Compound hydrobromic acid beta form of formula (I), the Compound fumaric acid V form of formula (I) in physiological Medium
The excessive amount of the compound fumarate V crystal form shown in the formula (I) and the compound hydrobromide alpha and beta crystal form samples shown in the formula (I) (the target concentration is about 5 mg/ml) are respectively placed in FaSSGF, feSSIF, faSSIF physiologically relevant mediums, and are balanced for 1h and 24h at 37 ℃ and 120rpm, and the observation phenomenon is shown in a table 8.
TABLE 8 dispersion of the alpha form of hydrobromide, beta form of hydrobromide, and V form of fumarate
Results: the compound fumarate V crystal form shown in the formula (I) has better dispersion behavior in a physiological medium.

Claims (10)

  1. A V-form of a fumarate salt of a compound of formula (I), wherein the molar ratio of the compound of formula (I) to the fumarate salt is 2:1, and the X-ray powder diffraction pattern has characteristic peaks at angles 2θ of 13.763, 14.493, 17.975, 19.549, 25.502,
  2. The crystalline form V of the fumarate salt of the compound of formula (I) according to claim 1, having an X-ray powder diffraction pattern with characteristic peaks at 2Θ angles 11.684, 12.703, 13.763, 14.493, 16.740, 17.975, 19.549, 23.299, 23.711, 25.502, 26.448.
  3. The crystalline form V of the fumarate salt of the compound of formula (I) according to claim 1, having an X-ray powder diffraction pattern with a characteristic peak at angle 7.756、8.278、11.684、12.703、13.763、14.493、15.305、16.740、17.975、19.549、21.221、22.519、23.299、23.711、24.132、25.502、26.448、27.356、29.725、30.822、36.057 of 2Θ.
  4. The crystalline form V of the fumarate salt of the compound of formula (I) according to claim 1, having an X-ray powder diffraction pattern as shown in figure 2.
  5. The V-form of the fumarate salt of a compound of formula (I) according to any one of claims 1-4, wherein the error of 2Θ angle is in the range of ± 0.2.
  6. A process for preparing form V of the fumarate salt of a compound of formula (I) according to any one of claims 1 to 5, comprising the steps of: 1) Dissolving a compound shown in a formula (I) and fumaric acid in an organic solvent, and 2) crystallizing and separating out, wherein the mol ratio of the compound shown in the formula (I) to the fumaric acid is selected from 10:1-2:1, and the organic solvent is selected from methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, acetone or a mixture thereof, preferably methanol.
  7. A composition prepared from the V-form of a compound of formula (I) according to any one of claims 1 to 5.
  8. A pharmaceutical composition comprising the following components:
    i) A crystalline form V of the fumarate salt of a compound of formula (I) according to any one of claims 1 to 5; and
    Ii) one or more pharmaceutically acceptable carriers, diluents or excipients.
  9. A method of preparing the pharmaceutical composition of claim 8, comprising the steps of: the components are mixed.
  10. Use of the crystalline form V of the fumarate salt of a compound of formula (I) according to any one of claims 1 to 5, or of a composition according to any one of claims 7 to 8, for the manufacture of a medicament for the treatment or prophylaxis of cancer, inflammation, or other proliferative disorders, preferably cancer; the cancer is selected from melanoma, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, colorectal cancer, colon cancer, rectal cancer, pancreatic cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, prostate cancer, leukemia, head and neck squamous cell carcinoma, cervical cancer, thyroid cancer, lymphoma, sarcoma, neuroblastoma, brain tumor, myeloma, astrocytoma and glioma.
CN202380028721.0A 2022-03-28 2023-03-28 Crystal form of fumarate of pyrrolo-heterocyclic derivative and preparation method thereof Pending CN118871442A (en)

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