Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • 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
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• the present invention relates to a substituted piperazine derivative crystal and a preparation method thereof. Specifically, the present invention provides crystal forms A to I of a compound represented by formula 1 and a preparation method thereof.
• ADP-ribosylation is a post-transcriptional modification process of proteins, in which single or multiple adenosine diphosphate ribose (ADP-ribose) groups are embedded into the amino acid residues of proteins.
• ADP-ribosylation is a reversible process that involves physiological regulation such as cell signal transduction, DNA damage repair, transcription, gene expression regulation, and cell apoptosis.
• ADP-ribose is derived from the redox cofactor: Nicotinamide adenine dinucleotide (NAD+), and the enzyme that mediates the ADP-ribose embedding modification is ADP-ribosylase.
• N-glycosidic bond of NAD+ connecting the ADP-ribose molecule and the nicotinamide group is cleaved, and then it is captured and bonded to the corresponding amino acid residues of the target protein.
• ADP-ribosylase can perform two types of modifications: mono-ADP ribosylation and poly-ADP ribosylation. When DNA is damaged or cells are stressed, PARPs are activated, resulting in an increase in poly (ADP-ribose) and a decrease in NAD+.
• PARP1 has been considered the only poly (ADP-ribose) polymerase in mammalian cells, and therefore the enzyme has been studied the most.
• MonoPARPs occupy the majority of the PARP family and mediate important biological functions and various stress responses, such as: unfolded protein response, NF- ⁇ B signaling, antiviral response, and cytokine signaling.
• TCDD 2,3,7,8-Tetrachlorodibenzo-p-dioxin
• ADP-ribose ADP-ribose polymerase
• AHR TCDD-activated aryl hydrocarbon receptor
• AHR upregulates the expression of PARP-7, which interacts with the kinase TBK1 and makes it ADP-ribosylated, resulting in the inhibition of TBK1 activity and the downregulation of IFN-I (type I interferon) response, which in turn leads to the inhibition of the body's antiviral and tumor immune responses.
• PARP7 inhibitors no clinical results have been reported so far, so the research on PARP7 inhibitors is of great significance.
• PCT/CN2022/094124 provides a piperazine derivative, whose chemical name is (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one, providing patients with a new treatment option.
• the crystal structure often affects the chemical and physical stability of the drug. Different crystal forms, preparation methods and storage conditions may lead to changes in the crystal structure of the compound, and sometimes other forms of crystals may be produced. Generally speaking, amorphous drug products do not have a regular crystal structure and often have other defects, such as poor product stability, difficulty in filtration, easy agglomeration, poor fluidity, etc.
• the present invention provides a crystal of (S)-4-(trifluoromethyl)-5-((1-((5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propane-2-yl)amino)pyridazin-3(2H)-one (compound 1), wherein compound 1 has the following chemical structure:
• the crystal of the present invention exhibits at least one of the following advantages: good solubility, high stability, easy handling, processing, purification, improved oral bioavailability of drugs, extended drug storage period, and easy manufacture of various dosage forms.
• the crystal of the present invention exhibits pharmaceutical advantages over the amorphous form of compound 1.
• the crystal has enhanced chemical and physical stability, which is more conducive to the preparation of solid pharmaceutical dosage forms containing pharmacologically active ingredients.
• the crystalline forms of the present invention are present in about 5% to about 100% by weight of the bulk drug. In certain embodiments, the crystalline forms of the present invention are present in about 10% to about 100% by weight of the bulk drug. In certain embodiments, the crystalline forms of the present invention are present in about 15% to about 100% by weight of the bulk drug. In certain embodiments, the crystalline forms of the present invention are present in about 20% to about 100% by weight of the bulk drug. In certain embodiments, the crystalline forms of the present invention are present in about 25% to about 100% by weight of the bulk drug. In certain embodiments, the crystalline forms of the present invention are present in about 30% to about 100% by weight of the bulk drug.
• the crystalline forms of the present invention are present in about 35% to about 100% by weight of the bulk drug. In certain embodiments, the crystalline forms of the present invention are present in about 40% to about 100% by weight of the bulk drug. In certain embodiments, the crystalline forms of the present invention are present in about 45% to about 100% by weight of the bulk drug. In certain embodiments, the crystalline forms of the present invention are present in about 50% to about 100% by weight of the bulk drug.
• the crystalline forms of the present invention are present in about 55% to about 100% by weight of the bulk drug. In certain embodiments, the crystalline forms of the present invention are present in about 60% to about 100% by weight of the bulk drug. In certain embodiments, the crystalline forms of the present invention are present in about 65% to about 100% by weight of the bulk drug. In certain embodiments, the crystalline forms of the present invention are present in about 70% to about 100% by weight of the bulk drug. In certain embodiments, the crystalline forms of the present invention are present in about 75% to about 100% by weight of the bulk drug. In certain embodiments, the crystalline forms of the present invention are present in about 80% to about 100% by weight of the bulk drug.
• the crystalline forms of the present invention are present in about 85% to about 100% by weight of the bulk drug. In certain embodiments, the crystalline forms of the present invention are present in about 90% to about 100% by weight of the bulk drug. In certain embodiments, the crystalline forms of the present invention are present in about 95% to about 100% by weight of the bulk drug. In certain embodiments, the crystalline forms of the present invention are present in about 98% to about 100% by weight of the bulk drug. In certain embodiments, the crystalline form of the invention is present in about 99% to about 100% by weight of the drug substance. In certain embodiments, substantially all of the drug substance is a crystalline form of the invention, i.e., the drug substance is substantially phase-pure crystals.
• compound 1 of the present invention is the amorphous form of compound 1.
• crystal form A of compound 1 characterized in that the X-ray powder diffraction pattern of crystal form A has characteristic diffraction peaks at the following 2 ⁇ positions: 10.389° ⁇ 0.3°, 11.917° ⁇ 0.3°, 12.912° ⁇ 0.3°, 13.385° ⁇ 0.3°, 14.054° ⁇ 0.3°, 15.316° ⁇ 0.3°, and 16.636° ⁇ 0.3°.
• the X-ray powder diffraction pattern of crystal form A has characteristic diffraction peaks at the following 2 ⁇ positions: 6.716° ⁇ 0.3°, 10.043° ⁇ 0.3°, 10.389° ⁇ 0.3°, 11.917° ⁇ 0.3°, 12.912° ⁇ 0.3°, 13.385° ⁇ 0.3°, 14.054° ⁇ 0.3°, 15.316° ⁇ 0.3°, 16.636° ⁇ 0.3°, 18.003° ⁇ 0.3°, 20.014° ⁇ 0.3°, 20.794° ⁇ 0.3°, and 23.855° ⁇ 0.3°.
• the X-ray powder diffraction pattern of Form A is basically as shown in FIG1 .
• the TGA curve of the A crystal form described in the present invention is basically as shown in Figure 10.
• the DSC curve of the crystal form A described in the present invention is basically as shown in Figure 11.
• the present invention also relates to a method for preparing crystal form A, which is characterized in that the compound shown in formula 1 is crystallized in a solvent (1-A) to obtain crystal form A; the solvent (1-A) is selected from any one of acetonitrile, ethanol, n-propanol, acetone and water, or a mixed solvent of any several of them in any proportion.
• a method for preparing crystal form A is characterized in that the compound represented by formula 1 or its crude product is added to a solvent (1-A-1), heated to dissolve, then a solvent (1-A-2) and a solvent (1-A-3) are added, heated to dissolve, cooled and continued to stir, and allowed to stand for crystallization to obtain crystal form A; the solvent (1-A-1), the solvent (1-A-2) and the solvent (1-A-3) are selected from any one of acetonitrile, ethanol, n-propanol, acetone and water.
• One embodiment of the crystal of the present invention is the B crystal form of compound 1, characterized in that the X-ray powder
• the final diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.498° ⁇ 0.3°, 13.326° ⁇ 0.3°, 21.229° ⁇ 0.3°, 21.426° ⁇ 0.3°, and 22.195° ⁇ 0.3°.
• the X-ray powder diffraction pattern of form B has characteristic diffraction peaks at the following 2 ⁇ positions: 6.498° ⁇ 0.3°, 9.657° ⁇ 0.3°, 11.420° ⁇ 0.3°, 13.027° ⁇ 0.3°, 13.326° ⁇ 0.3°, 15.882° ⁇ 0.3°, 19.075° ⁇ 0.3°, 19.315° ⁇ 0.3°, 20.669° ⁇ 0.3°, 21.229° ⁇ 0.3°, 21.426° ⁇ 0.3°, 22.195° ⁇ 0.3°, 23.118° ⁇ 0.3°, and 23.362° ⁇ 0.3°.
• the X-ray powder diffraction pattern of Form B is basically as shown in FIG2 .
• the present invention also relates to a method for preparing the B crystal form, which is characterized in that the compound represented by formula 1 is slurried in a solvent (1-B) to obtain the B crystal form; the solvent (1-B) is selected from n-hexane.
• One embodiment of the crystal of the present invention is the C form of compound 1, characterized in that the X-ray powder diffraction pattern of the C form has characteristic diffraction peaks at the following 2 ⁇ positions: 19.066° ⁇ 0.3°, 20.300° ⁇ 0.3°, 20.978° ⁇ 0.3°, and 21.616° ⁇ 0.3°.
• the X-ray powder diffraction pattern of form C has characteristic diffraction peaks at the following 2 ⁇ positions: 6.790° ⁇ 0.3°, 9.917° ⁇ 0.3°, 11.533° ⁇ 0.3°, 12.600° ⁇ 0.3°, 13.556° ⁇ 0.3°, 13.793° ⁇ 0.3°, 14.275° ⁇ 0.3°, 15.008° ⁇ 0.3°, 16.452° ⁇ 0.3°, 17.877° ⁇ 0.3°, 19.066° ⁇ 0.3°, 19.774° ⁇ 0.3°, 20.300° ⁇ 0.3°, 20.978° ⁇ 0.3°, 21.616° ⁇ 0.3°, 22.585° ⁇ 0.3°, and 23.407° ⁇ 0.3°.
• the X-ray powder diffraction pattern of Form C is substantially as shown in FIG3 .
• the present invention also relates to a method for preparing crystal form C, which is characterized in that the compound represented by formula 1 is crystallized in a solvent (1-C) to obtain crystal form C; the solvent (1-C) is selected from isopropyl acetate, n-hexane or a mixed solvent of isopropyl acetate and n-hexane.
• One embodiment of the crystal of the present invention is the D crystal form of compound 1, characterized in that the D crystal form has characteristic diffraction peaks at the following 2 ⁇ positions in its X-ray powder diffraction pattern: 6.646° ⁇ 0.3°, 13.175° ⁇ 0.3°.
• the X-ray powder diffraction pattern of form D has characteristic diffraction peaks at the following 2 ⁇ positions: 6.646° ⁇ 0.3°, 13.175° ⁇ 0.3°, 13.489° ⁇ 0.3°, 16.450° ⁇ 0.3°, 20.950° ⁇ 0.3°, 21.585° ⁇ 0.3°, 22.369° ⁇ 0.3°, 23.036° ⁇ 0.3°, and 23.281° ⁇ 0.3°.
• the X-ray powder diffraction pattern of Form D is substantially as shown in FIG4 .
• the present invention also relates to a method for preparing the D crystal form, which is characterized in that the compound represented by formula 1 is extracted with a solvent (1-D), concentrated and vacuum dried to obtain the D crystal form; the solvent (1-D) is selected from ethyl acetate.
• One embodiment of the crystal of the present invention is the E crystal form of compound 1, characterized in that the E crystal form has characteristic diffraction peaks at the following 2 ⁇ positions in its X-ray powder diffraction pattern: 18.227° ⁇ 0.3°, 19.954° ⁇ 0.3°, and 22.449° ⁇ 0.3°.
• the X-ray powder diffraction pattern of the E crystal form has characteristic diffraction peaks at the following 2 ⁇ positions: 8.129° ⁇ 0.3°, 11.118° ⁇ 0.3°, 11.360° ⁇ 0.3°, 11.749° ⁇ 0.3°, 13.482° ⁇ 0.3°, 14.730° ⁇ 0.3°, 18.227° ⁇ 0.3°, 19.954° ⁇ 0. 3°, 20.712° ⁇ 0.3°, 21.092° ⁇ 0.3°, 22.449° ⁇ 0.3°, 22.813° ⁇ 0.3°, 24.399° ⁇ 0.3°, 24.560° ⁇ 0.3°, 25.923° ⁇ 0.3°, 26.429° ⁇ 0.3°, 27.060° ⁇ 0.3°, 27.446° ⁇ 0.3°.
• the X-ray powder diffraction pattern of Form E is substantially as shown in FIG5 .
• the present invention also relates to a method for preparing the E crystal form, characterized in that the compound shown in formula 1 is crystallized in a solvent (1-E) to obtain the E crystal form; the solvent (1-E) is selected from ethyl acetate, n-hexane or a mixed solvent of ethyl acetate and n-hexane.
• An embodiment of the crystal of the present invention is the F crystal form of compound 1, characterized in that the F crystal form has characteristic diffraction peaks at the following 2 ⁇ positions in its X-ray powder diffraction pattern: 6.717° ⁇ 0.3°, 13.484° ⁇ 0.3°.
• the X-ray powder diffraction pattern of form F has characteristic diffraction peaks at the following 2 ⁇ positions: 6.717° ⁇ 0.3°, 9.812° ⁇ 0.3°, 11.426° ⁇ 0.3°, 12.501° ⁇ 0.3°, 13.484° ⁇ 0.3°, 14.915° ⁇ 0.3°, 16.374° ⁇ 0.3°, 16.884° ⁇ 0.3°, 17.828° ⁇ 0.3°, 18.975° ⁇ 0.3°, 20.241° ⁇ 0.3°, 20.902° ⁇ 0.3°, 21.593° ⁇ 0.3°, 22.506° ⁇ 0.3°, 22.918° ⁇ 0.3°, and 23.412° ⁇ 0.3°.
• the X-ray powder diffraction pattern of Form F is basically as shown in FIG6 .
• the TGA curve of the F crystal form described in the present invention is basically as shown in Figure 12.
• the DSC curve of the F crystal form described in the present invention is basically as shown in Figure 13.
• the present invention also relates to a method for preparing the F crystal form, which is characterized in that the compound represented by formula 1 is crystallized in a solvent (1-F) to obtain the F crystal form; the solvent (1-F) is selected from n-propanol, n-heptane or a mixed solvent of n-propanol and n-heptane.
• One embodiment of the crystal of the present invention is the G crystal form of compound 1, characterized in that the G crystal form has characteristic diffraction peaks at the following 2 ⁇ positions in its X-ray powder diffraction pattern: 6.743° ⁇ 0.3°, 13.503° ⁇ 0.3°.
• the X-ray powder diffraction pattern of the G crystal form has characteristic diffraction peaks at the following 2 ⁇ positions: 6.743° ⁇ 0.3°, 13.503° ⁇ 0.3°, 16.901° ⁇ 0.3°, 18.996° ⁇ 0.3°, 20.260° ⁇ 0.3°, 20.920° ⁇ 0.3°, 21.604 ⁇ 0.3°. Further, the X-ray powder diffraction pattern of the G crystal form is substantially as shown in FIG7.
• the present invention also relates to a method for preparing the G crystal form, which is characterized in that the compound represented by formula 1 is crystallized in a solvent (1-G) to obtain the G crystal form; the solvent (1-G) is selected from ethanol, n-heptane or a mixed solvent of ethanol and n-heptane.
• One embodiment of the crystal of the present invention is the H crystal form of compound 1, characterized in that the H crystal form has characteristic diffraction peaks at the following 2 ⁇ positions in its X-ray powder diffraction pattern: 12.366° ⁇ 0.3°, 13.115° ⁇ 0.3°, 14.359° ⁇ 0.3°, 15.617° ⁇ 0.3°, and 16.909° ⁇ 0.3°.
• the X-ray powder diffraction pattern of the H crystalline form has characteristic diffraction peaks at the following 2 ⁇ positions: 6.514° ⁇ 0.3°, 10.074° ⁇ 0.3°, 10.684° ⁇ 0.3°, 12.366° ⁇ 0.3°, 13.115° ⁇ 0.3°, 14.359° ⁇ 0.3°, 15.617° ⁇ 0.3°, 16.909° ⁇ 0.3°, 19.839° ⁇ 0.3°, 20.092° ⁇ 0.3°, 20.687° ⁇ 0.3°, 22.919° ⁇ 0.3°.
• the DSC curve of the H crystal form described in the present invention is basically as shown in Figure 15.
• the present invention also relates to a method for preparing the H crystal form, which is characterized in that the compound shown in formula 1 is crystallized in a solvent (1-H) to obtain the H crystal form;
• the solvent (1-H) is selected from any one of acetonitrile, ethanol, n-propanol, acetone and water, or a mixed solvent of any several of them in any proportion.
• One embodiment of the crystal of the present invention is Form I of compound 1, characterized in that the X-ray powder diffraction pattern of Form I has characteristic diffraction peaks at the following 2 ⁇ positions: 4.968° ⁇ 0.3°, 19.770° ⁇ 0.3°, and 21.752° ⁇ 0.3°.
• the X-ray powder diffraction pattern of Form I has characteristic diffraction peaks at the following 2 ⁇ positions: 4.968° ⁇ 0.3°, 8.863° ⁇ 0.3°, 12.739° ⁇ 0.3°, 13.896° ⁇ 0.3°, 14.848° ⁇ 0.3°, 18.840° ⁇ 0.3°, 19.179° ⁇ 0.3°, 19.770° ⁇ 0.3°, 21.155° ⁇ 0.3°, 21.752° ⁇ 0.3°, and 24.053° ⁇ 0.3°.
• the present invention also relates to a method for preparing crystal form I, characterized in that the compound represented by formula 1 is crystallized in a solvent (1-I) to obtain crystal form I; the solvent (1-I) is selected from acetonitrile, water or a mixed solvent of acetonitrile and water.
• the present invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount of the crystalline compound of the present invention and one or more pharmaceutically acceptable carriers or excipients.
• the crystal of the present invention can be used as an active pharmaceutical ingredient, or a pharmaceutical composition containing the crystal as an active ingredient, in drugs for treating and/or preventing cancer.
• the crystal of the present invention as an active pharmaceutical ingredient, or a pharmaceutical composition containing the crystal as an active ingredient in the preparation of a drug for treating and/or preventing solid tumors.
• the solid tumor of the present invention is selected from non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, hormone receptor positive (HR+) breast cancer, colon cancer or PARP7 amplified advanced solid tumor.
• the X-ray powder diffraction pattern disclosed in the present invention and those substantially the same also belong to the scope of the present invention.
• the melting peak height of a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline compound of the present invention is characterized by a DSC pattern with a characteristic peak position, having substantially the same properties as the DSC pattern provided in the accompanying drawings of the present invention, with an error tolerance of ⁇ 3 ° C.
• an "effective amount” is an amount of a compound that will elicit a physiological or medical response in a tissue, system, or subject.
• the invention includes an amount of the compound that, when administered to a subject, is sufficient to prevent the occurrence of one or more symptoms of the disorder or condition being treated or to alleviate them to some extent.
• IC50 refers to the half inhibitory concentration, which is the concentration at which half of the maximal inhibitory effect is achieved.
• crystal structures of the present invention can be analyzed using various analytical techniques known to those of ordinary skill in the art, including, but not limited to, X-ray powder diffraction (XRD).
• XRD X-ray powder diffraction
• crystals of the present invention are not limited to characteristic spectra that are completely identical to the characteristic spectra described in the accompanying drawings disclosed in the present invention, such as XRD. Any crystal form having characteristic spectra that are substantially the same or essentially the same as those described in the accompanying drawings falls within the scope of the present invention.
• FIG1 is an X-ray powder diffraction pattern of Form A.
• FIG2 is an X-ray powder diffraction pattern of Form B.
• FIG3 is an X-ray powder diffraction pattern of Form C.
• FIG4 is an X-ray powder diffraction pattern of Form D.
• FIG5 is an X-ray powder diffraction pattern of Form E.
• FIG6 is an X-ray powder diffraction pattern of Form F.
• FIG. 7 is an X-ray powder diffraction pattern of Form G.
• FIG. 10 is a TGA chart of Form A.
• FIG. 11 is a DSC graph of Form A.
• FIG. 12 is a TGA chart of Form F.
• FIG. 13 is a DSC graph of Form F.
• FIG. 14 is a TGA chart of Form H.
• FIG. 15 is a DSC graph of Form H.
• the solution refers to an aqueous solution.
• the experimental conditions for crystallization are generally room temperature (20-30° C., 30-70% RH), and the solvent ratio refers to the volume ratio.
• reaction solution was slowly poured into 1.0 L of ice-water mixture to quench, and extracted with dichloromethane (2 ⁇ 500 mL). The organic layers were combined and concentrated. The solid was washed with methanol (500 mL ⁇ 2), 1b was obtained as a yellow solid (48.4 g, yield 66%).
• Trifluoroacetic acid (3.4 mL) and trifluoromethanesulfonic acid (0.42 mL, 4.7 mmol, 8.0 equiv) were added to a 10 mL reaction flask containing 3a (359.8 mg, 0.588 mmol, 1.0 equiv) in sequence. After the addition, the reaction was stirred at 25 °C for 1 h. Subsequently, the reaction solution was placed in a 70 °C oil bath and stirred. After the reaction was completed, 15 mL of water was added to the reaction solution to quench. The resulting solution was extracted with ethyl acetate (3 ⁇ 15 mL).
• the crude compound 1 (5.20 g) was added to acetonitrile (16.50 g), the temperature was raised to 60-65°C and dissolved for 0.5 h; then water (52.43 g) and n-propanol (8.40 g) were added in sequence, the temperature was raised to 65 ⁇ 5°C and dissolved for 0.5 h, the temperature was lowered to 30 ⁇ 5°C and stirring was continued for 11 h, the mixture was allowed to stand for 16 h for crystallization, the temperature was maintained at 25 ⁇ 5°C for further crystallization for 6 h, filtered, washed with water (6.09 g), and dried at 55 ⁇ 5°C for 16 h to obtain Form A.
• TGA and DSC were collected on a Mettler thermogravimetric analyzer (Mettler TGA/DSC 3+) and a Mettler differential scanning calorimeter (Mettler DSC 3), respectively.
• Table 2 lists the TGA and DSC test parameters. The test results are shown in Figures 10 and 11, respectively.
• the TGA spectrum shows that the weight loss is 0.1737% when heated to 105°C; the DSC spectrum shows that the peak value of the endothermic peak is 139.02°C.
• the compound 1 (10 g) prepared in the reverse direction was dissolved in n-hexane (100 mL), slurried at room temperature for 2 h, filtered, and the solid was dried in vacuo at 55° C. to obtain Form B.
• Form F of Compound 1 was subjected to thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), respectively.
• TGA thermogravimetric analysis
• DSC differential scanning calorimetry
• Compound 1 (500 mg) was placed in a 50 mL reaction bottle, and 2 mL of ethanol was added. The temperature was raised to reflux, and after the solution was dissolved, 2 mL of n-heptane was added dropwise. After the solution was dissolved again, the temperature was lowered to room temperature and stirred for 60 min to crystallize, and the filter cake was vacuum dried at 55 ° C for 9 h to obtain 350 mg of white solid (Compound 1 G crystal form).
• the H-type of compound 1 was tested by X-ray diffractometer (Bruker D8 advance), and the graphite monochromatic Cu K ⁇ radiation was used at room temperature.
• the X-ray powder diffraction data of Form H are shown in Table 9.
• thermogravimetric analysis TGA
• DSC differential scanning calorimetry
• the crude compound 1 (60 g) was placed in a reaction bottle, acetonitrile (120 mL) was added at room temperature and stirred to dissolve, water (180 mL) was added and stirred to crystallize for 3 h, acetonitrile (120 mL)/H 2 O (180 mL) mixed solvent was added, crystallization was continued for 2 h, and the filter cake was vacuum dried at 55°C to obtain Form I (40.5 g).
• the compound was tested at a temperature of 40°C ⁇ 2°C and a relative humidity of 75% ⁇ 5%.
• the compound was tested at a temperature of 25°C ⁇ 2°C and a relative humidity of 60% ⁇ 5%.

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