Oxygen-containing heterocyclic compound salt as well as crystal form and application thereof

Abstract

The invention discloses an oxygen-containing heterocyclic compound salt, and a crystal form and application thereof. The oxygen-containing heterocyclic compound salt disclosed by the invention has a structure as shown in a formula II. The oxygen-containing heterocyclic compound salt and the crystal form thereof provided by the invention have one or more improved characteristics, which are represented by extremely high water solubility, and high dissolution rate and high solubility in physiological related medium simulated gastrointestinal fluid, so that the stability of the oxygen-containing heterocyclic compound under an oxidation condition is remarkably improved, and the stability of the oxygen-containing heterocyclic compound is improved. Low hygroscopicity and good crystal form stability are achieved, and oral absorption and long-term storage of the medicine are facilitated; and the preparation method is simple and suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The invention relates to an oxygen-containing heterocyclic compound salt, its crystal form and application. Background Art

[0002] Ras (Rat sarcoma viral oncogene, murine sarcoma viral oncogene) was first discovered in rat sarcoma. The mammalian ras gene family has three members, namely H-ras, K-ras, and N-ras. The fourth exon of K-ras has two variants, A and B. Ras genes are widely present in various eukaryotic organisms such as mammals, fruit flies, fungi, nematodes, and yeast. The expression levels in different tissues vary. H-Ras is mainly expressed in the skin and skeletal muscle, K-Ras is mainly expressed in the colon and thymus, and N-Ras is highly expressed in the testis. Ras protein acts as a molecular switch in the process of cell signal transduction. It regulates signal transduction by switching with GTP / GDP, thereby regulating life processes such as cell proliferation, differentiation, aging, and apoptosis.

[0003] Ras mutations are closely related to the occurrence and development of tumors. Ras genes mutate in more than 30% of human tumors and are considered to be one of the most powerful cancer drivers. Ras proto-oncogene mutations are mainly caused by point mutations. More than 150 different Ras point mutations have been found, among which mutations at glycine at positions 12 and 13 and glutamine at position 61 are the most common.

[0004] Currently, only two KRas G12C inhibitor drugs have been approved by the FDA for marketing, namely Amgen's Sotorasib (trade name: LUMAKRAS) and MIRATI Therapeutics' Adagrasib (trade name: KRAZATI), both of which are approved for the treatment of non-small cell lung cancer (NSCLC) carrying KRas G12C gene mutations. Therefore, it is still necessary to develop new KRas G12C inhibitor drugs to provide more clinical treatment options for cancer patients.

[0005] Patent application CN112979664A discloses an oxygen-containing heterocyclic compound, the structure of which is shown in Formula I It can be used to treat and / or prevent various diseases mediated by Ras. Patent CN115385923A reported three crystal forms, which improved the stability of the compound to high temperature and light to varying degrees, but the study found that these crystal forms failed to solve the defects of the compound such as poor water solubility, poor stability, and easy decomposition under oxidative conditions. Summary of the invention

[0006] The technical problem to be solved by the present invention is to provide an oxygen-containing heterocyclic compound salt, its crystal form and application in view of the defects of the free base form of the oxygen-containing heterocyclic compound as shown in Formula I in the prior art, such as poor water solubility and easy decomposition under oxidative conditions. The solubility and dissolution rate of the oxygen-containing heterocyclic compound salt and its crystal form in pure water and physiologically relevant medium simulated gastrointestinal fluid are significantly improved, which can increase the oral absorption of the drug; the decomposition amount under oxidative conditions is less, and it has low hygroscopicity and good crystal stability, which is conducive to the long-term storage of the drug.

[0007] The present invention provides an oxygen-containing heterocyclic compound salt, the structure of which is shown in Formula II:

[0008]

[0009] in,

[0010] M is an acid;

[0011] x is 0.5, 1, or 2.

[0012] In one embodiment, M is one or more of methanesulfonic acid, fumaric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, citric acid, maleic acid, tartaric acid, succinic acid, malic acid, mandelic acid, adipic acid and benzenesulfonic acid.

[0013] In one embodiment, in the oxygen-containing heterocyclic compound salt as shown in Formula II, x is 1 or 2.

[0014] In a certain embodiment, when the M is one or more of methanesulfonic acid, hydrochloric acid, phosphoric acid, sulfuric acid, succinic acid, malic acid and adipic acid, M is one or more of methanesulfonic acid, succinic acid, malic acid and adipic acid, preferably methanesulfonic acid.

[0015] In a certain embodiment, when the M is one or more of methanesulfonic acid, succinic acid and malic acid, M is methanesulfonic acid.

[0016] In a certain embodiment, when the M is one or more of methanesulfonic acid, hydrochloric acid, hydrobromic acid, maleic acid and benzenesulfonic acid, M is one or more of methanesulfonic acid, hydrobromic acid and benzenesulfonic acid, preferably methanesulfonic acid.

[0017] In one embodiment, when M is methanesulfonic acid, x is 1 or 2.

[0018] In a certain embodiment, the oxygen-containing heterocyclic compound salt as described above is in a crystalline form, or in an amorphous form, or in a mixture of a crystalline form and an amorphous form, preferably a crystalline form.

[0019] The present invention also provides a method for preparing the oxygen-containing heterocyclic compound salt as described above, which is a natural volatilization method or a solution crystallization method.

[0020] The natural volatilization method is to form a solution with the oxygen-containing heterocyclic compound free base shown in Formula I and the acid, and then remove the solvent; the solvent removal can be carried out by naturally volatilizing the solvent.

[0021] The solution crystallization method is to form a solution with the oxygen-containing heterocyclic compound free base shown in Formula I and the acid, and then stir to allow natural crystallization or mix with a poor solvent until a precipitate is precipitated.

[0022] The present invention also provides a monomethanesulfonate of an oxygen-containing heterocyclic compound as shown in Formula I,

[0023]

[0024] Its X-ray powder diffraction pattern, expressed in terms of 2θ angle, has peaks at 4.3±0.2°, 9.0±0.2°, 14.5±0.2°, 15.2±0.2°, 15.7±0.2°, 16.7±0.2°, 23.0±0.2°, 23.5±0.2° and 28.5±0.2°, and further has peaks at 11.7±0.2°, 12.4±0.2°, 13.0±0.2°, 18.0±0.2°, 20.4±0.2°, 21.2±0.2°, 21.4±0.2°, 22.3±0.2°, 25.5±0.2° and 26.0±0.2°.

[0025] In one embodiment, the monomethanesulfonate of the oxygen-containing heterocyclic compound as shown in Formula I has Figure 1 The X-ray powder diffraction pattern shown is expressed in 2θ degrees.

[0026] In one embodiment, the oxygen-containing heterocyclic compound monomethanesulfonate shown in Formula I has Figure 2 The differential scanning calorimetry (DSC) graph shown shows that it has a melting endothermic peak with an onset temperature (onset) of 171.1°C.

[0027] In one embodiment, the oxygen-containing heterocyclic compound monomethanesulfonate shown in Formula I has Figure 3 The thermogravimetric analysis (TGA) graph shown shows that it is a hydrate with a weight loss of 2.4% before 150°C, equivalent to about 1 mol of water.

[0028] In a certain embodiment, the actual content of the free base of the oxygen-containing heterocyclic compound as shown in Formula I in the monomethanesulfonate of the oxygen-containing heterocyclic compound as shown in Formula I is 85.9% (excluding the amount of solvent) detected by HPLC, and the theoretical content of the free base of the oxygen-containing heterocyclic compound as shown in Formula I in the compound formed by the oxygen-containing heterocyclic compound as shown in Formula I and methanesulfonic acid in a molar ratio of 1:1 is 86.3%. Therefore, in the monomethanesulfonate of the oxygen-containing heterocyclic compound as shown in Formula I of the present invention, the oxygen-containing heterocyclic compound as shown in Formula I and methanesulfonic acid are salified in a molar ratio of 1:1.

[0029] The present invention also provides a dimethanesulfonate of an oxygen-containing heterocyclic compound as shown in Formula I,

[0030]

[0031] Its X-ray powder diffraction pattern, expressed in terms of 2θ angle, has peaks at 5.6±0.2°, 7.6±0.2°, 12.9±0.2°, 16.2±0.2°, 16.9±0.2°, 17.4±0.2°, 22.8±0.2°, 24.2±0.2° and 26.5±0.2°, and further has peaks at 8.2±0.2°, 12.0±0.2°, 14.3±0.2°, 16.4±0.2°, 20.4±0.2°, 20.9±0.2°, 21.7±0.2°, 23.5±0.2° and 26.9±0.2°.

[0032] In one embodiment, the oxygen-containing heterocyclic compound dimethanesulfonate as shown in Formula I has Fig.16 The X-ray powder diffraction pattern shown is expressed in 2θ degrees.

[0033] In one embodiment, the oxygen-containing heterocyclic compound dimethanesulfonate shown in Formula I has Fig.17 The differential scanning calorimetry (DSC) graph shown shows that it has a melting endothermic peak with an onset temperature (onset) of 180.0°C.

[0034] In one embodiment, the oxygen-containing heterocyclic compound dimethanesulfonate shown in Formula I has Fig.18 The thermogravimetric analysis (TGA) graph shown shows that it is a hydrate with a weight loss of 3.0% before 150°C, equivalent to about 1.4 moles of water.

[0035] In a certain embodiment, the actual content of the free base of the oxygen-containing heterocyclic compound as shown in Formula I in the dimethanesulfonate of the oxygen-containing heterocyclic compound as shown in Formula I is 76.6% as determined by HPLC, and the theoretical content of the free base of the oxygen-containing heterocyclic compound as shown in Formula I in the compound formed by the oxygen-containing heterocyclic compound as shown in Formula I and methanesulfonic acid in a molar ratio of 1:2 is 75.9%. Therefore, in the dimethanesulfonate of the oxygen-containing heterocyclic compound as shown in Formula I of the present invention, the oxygen-containing heterocyclic compound as shown in Formula I and methanesulfonic acid are salified in a molar ratio of 1:2.

[0036] The present invention also provides a method for preparing an oxygen-containing heterocyclic compound salt and a crystal form thereof, which is method one or method two, wherein:

[0037] Method 1 includes the following steps:

[0038] (1): mixing the oxygen-containing heterocyclic compound free base and acid as shown in Formula I with a benign solvent and stirring to form a salt solution;

[0039] (2) Natural evaporation and vacuum drying;

[0040] Method 2 includes the following steps:

[0041] (1): adding the oxygen-containing heterocyclic compound free base as shown in Formula I and an acid to a benign solvent and stirring to form a salt solution;

[0042] (2): If no precipitate is formed after stirring, concentrate under reduced pressure or mix with a poor solvent until turbidity appears. Filter the precipitate and dry it in vacuum.

[0043] In the above method 1 or method 2,

[0044] The molar ratio of the free base of the oxygen-containing heterocyclic compound shown in Formula I to the acid is 3:1 to 1:3, preferably 2:1.1 to 1:2.2, and more preferably 1:1 to 1:2.2.

[0045] The benign solvent is selected from one or more of methanol, ethanol, isopropanol, n-butanol, ethyl acetate, dichloromethane, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, toluene, 1,4-dioxane, dimethyl sulfoxide and N,N-dimethylformamide, preferably one or more of methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, acetone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran and toluene.

[0046] The acid is preferably one or more of methanesulfonic acid, fumaric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, citric acid, maleic acid, tartaric acid, succinic acid, malic acid, mandelic acid, adipic acid and benzenesulfonic acid.

[0047] The acid can be added to the benign solvent directly, or the acid can be dissolved and diluted with methanol, ethanol or water to obtain an acid solution and then added. Preferably, the concentration of the acid in the acid solution is 0.1 to 10 mol / L.

[0048] The stirring method to form the salt solution may be a conventional method of this type of operation in the art, such as stirring at room temperature or stirring under heating, and the temperature of the stirring under heating may be 30-60°C.

[0049] In the salt solution, the concentration of the free base of the oxygen-containing heterocyclic compound as shown in Formula I is 40 to 250 g / L.

[0050] The reduced pressure concentration may be a conventional method of such operation in the art. Preferably, the reduced pressure concentration is to evaporate the solvent at a vacuum degree of -0.1 MPa until the salt solution becomes turbid or until the remaining volume of the salt solution is one third to one fourth of the original volume.

[0051] The poor solvent is one or more of n-heptane, n-hexane, cyclohexane, water, isopropyl acetate, isopropyl ether or methyl tert-butyl ether; there is no specific requirement for the method of mixing with the poor solvent, and the mixing can be carried out by dropping a salt solution into the poor solvent, or by dropping a poor solvent into a salt solution; the volume ratio of the benign solvent to the poor solvent is 10:1 to 1:10.

[0052] The filtration may be a conventional method of this type of operation in the art, such as vacuum filtration.

[0053] The vacuum drying temperature is usually 40° C., and the drying time is usually 1 hour to overnight, that is, 1 to 24 hours.

[0054] The present invention also provides a pharmaceutical composition, which comprises the above oxygen-containing heterocyclic compound salt or its crystal form as shown in Formula II, and pharmaceutically acceptable excipients.

[0055] In the present invention, the above-mentioned oxygen-containing heterocyclic compound salt or its crystalline form as shown in Formula II can also be used in combination with one or more other active ingredients; when used in combination, the active ingredients can be separate compositions for simultaneous administration through the same or different administration routes or separate administration at different times in treatment, or they can also be administered together in the same pharmaceutical composition.

[0056] Another aspect of the present invention also provides the use of the oxygen-containing heterocyclic compound salt as shown in Formula II or the pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and / or prevent Ras-mediated diseases.

[0057] In some embodiments, the Ras may be a G12C mutation of one or more of K-Ras, H-Ras and N-Ras, for example a G12C mutation of K-Ras.

[0058] In some embodiments, the Ras-mediated disease is, for example, cancer. The cancer is, for example, one or more of colon cancer, appendix cancer, pancreatic cancer, MYH-associated polyposis, blood cancer, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophageal cancer, gastric cancer, thyroid cancer, bladder cancer, lymphoma, leukemia, and melanoma.

[0059] Another aspect of the present invention further provides the use of the oxygen-containing heterocyclic compound salt or its crystal form as shown in Formula II or the above pharmaceutical composition in the preparation of Ras inhibitors.

[0060] In some embodiments, the Ras is, for example, a G12C mutation of one or more of K-Ras, H-Ras, and N-Ras, and for example, a G12C mutation of K-Ras.

[0061] In some embodiments, the Ras inhibitor can be used in mammals in vivo; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of Ras inhibitory effects.

[0062] Another aspect of the present invention also provides the use of the above oxygen-containing heterocyclic compound salt or its crystal form as shown in Formula II or the above pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and / or prevent cancer.

[0063] In some embodiments, the cancer is, for example, one or more of colon cancer, appendix cancer, pancreatic cancer, MYH-associated polyposis, blood cancer, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophageal cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma.

[0064] Unless otherwise specified, the terms used in the specification or claims of the present invention have the following meanings:

[0065] The "oxygen-containing heterocyclic compound salt", or "oxygen-containing heterocyclic compound salt as shown in Formula II", or "oxygen-containing heterocyclic compound salt as shown in Formula I", or "salt" used in the present invention all have the same meaning, and refer to an oxygen-containing heterocyclic compound having a chemical structure as shown in Formula I below,

[0066]

[0067] The salt formed with an inorganic acid M or an organic acid M, wherein the inorganic acid M or the organic acid M is defined by the claims of the present invention.

[0068] In the present invention, the X-ray powder diffraction patterns are all measured using the Kα spectrum of the Cu target.

[0069] All numerical values ​​or expressions involving quantity, angle, temperature, time, rate, etc. used in the present invention should be understood to be modified by "about" in all cases. When the term "about" refers to a single number or numerical range, it means that the indicated quantity or numerical range is an approximate value within the experimental variability (or within the statistical experimental error), so the quantity or numerical range can deviate from the specific given quantity or numerical range by up to ±10%, preferably within ±5%, and optimally within ±2%; but when measuring the onset temperature and peak temperature of a thermal event in a differential scanning calorimetry (DSC) graph, no matter what the absolute value of the onset temperature or peak temperature is, the term "about" means that the onset temperature or peak temperature can usually differ by within ±3°C. As those skilled in the art will appreciate, a number is used for non-critical parameters for illustrative purposes only, not for limitation. 。

[0070] In the present invention, the "stirring" can be accomplished by conventional methods in the art, such as magnetic stirring, mechanical stirring, and the stirring speed is 50 to 1200 rpm, preferably 200 to 500 rpm.

[0071] In the present invention, the "room temperature" refers to 10 to 25°C.

[0072] In the present invention, the term "natural evaporation" or "natural drying" refers to covering the mouth of a vial containing the solution with aluminum foil and piercing a small hole therein, and placing it in a laboratory environment to slowly evaporate the solvent. For example, covering the mouth of a vial containing the solution with aluminum foil and piercing a small hole therein, and placing it in a fume hood to slowly evaporate the solvent.

[0073] As used herein, "treating" refers to ameliorating a disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of its clinical symptoms); or, improving at least one physical parameter, which may not be detectable by the subject; or slowing disease progression.

[0074] As used herein, "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder (i.e., resulting in at least one clinical symptom of the disease not occurring in a subject who may have been exposed to a disease-causing agent or who was susceptible to the disease prior to the onset of the disease).

[0075] The term "pharmaceutically acceptable excipients" refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in drug preparations except active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) Part IV or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0076] The oxygen-containing heterocyclic compound represented by formula I used in the present invention is synthesized with reference to paragraphs

[1072] to

[1098] of the specification of patent CN112979664A and paragraphs

[0172] to

[0185] of the specification of patent CN115385923A, and the remaining reagents and raw materials are commercially available.

[0077] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0078] The positive and progressive effects of the present invention are:

[0079] The oxygen-containing heterocyclic compound salt as shown in Formula I and its crystal form provided by the present invention have one or more improved properties, which are manifested in extremely high water solubility, high dissolution rate and high solubility in physiologically relevant media simulating gastrointestinal fluid, significantly improved stability of the oxygen-containing heterocyclic compound as shown in Formula I under oxidative conditions, low hygroscopicity and good crystal stability, which are beneficial to oral absorption and long-term storage of drugs; and the preparation method thereof is simple and suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0080] Figure 1 The X-ray powder diffraction (XRPD) pattern of the monomethanesulfonate salt is shown in FIG.

[0081] Figure 2 The differential scanning calorimetry (DSC) spectrum of the monomethanesulfonate.

[0082] Figure 3 This is the thermogravimetric analysis (TGA) spectrum of the monomethanesulfonate.

[0083] Figure 4 It is the XRPD pattern of the monofumarate salt.

[0084] Figure 5 XRPD pattern of the monohydrochloride salt.

[0085] Figure 6 The XRPD pattern of the monohydrobromide salt is shown in FIG.

[0086] Figure 7 It is the XRPD pattern of the monophosphate.

[0087] Figure 8 The XRPD pattern of the monocitrate salt is shown in FIG.

[0088] Fig. 9 The XRPD pattern of the monomaleate salt is shown in FIG.

[0089] Fig.10 The XRPD pattern of the mono-L-tartrate salt is shown in FIG.

[0090] Fig.11 The XRPD pattern of the monosuccinate salt is shown in FIG.

[0091] Fig.12 The XRPD pattern of the mono-L-malate salt is shown in FIG.

[0092] Fig.13 The XRPD pattern of mono-D-mandelate salt is shown in FIG.

[0093] Fig.14 XRPD pattern of monoadipate salt.

[0094] Fig.15 It is the XRPD pattern of the monobenzenesulfonate salt.

[0095] Fig.16 The XRPD pattern of dimethanesulfonate.

[0096] Fig.17 This is the DSC spectrum of the dimethanesulfonate.

[0097] Fig.18 This is the TGA spectrum of the dimethanesulfonate.

[0098] Fig.19 It is the XRPD pattern of hemifumarate.

[0099] Fig. 20 XRPD pattern of dihydrochloride.

[0100] Fig.21 The XRPD pattern of the mono-D-malate salt is shown in FIG.

[0101] Fig. 22 The XRPD pattern of the oxygen-containing heterocyclic compound crystalline form A as shown in Formula I. DETAILED DESCRIPTION

[0102] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0103] The solvents involved in the following examples are all analytically pure or chromatographically pure. When the solvent is a mixed solvent, the ratio is by volume unless otherwise specified.

[0104] The X-ray powder diffraction (XRPD) test conditions used in the experiments of the present invention are:

[0105] The X-ray powder diffractometer D8 Advance from Bruker was used to detect the Kα spectrum of Cu target. The voltage was 40 kV, the current was 40 mA, the divergence slit was 1.0 mm, the Soller slit was 0.4°, the scanning mode was continuous scanning, the scanning angle range was 3° to 45° or 4° to 40°, the step size was 0.02°, the scanning speed was 8° / min, and the detector was LynxEye.

[0106] The Differential Scanning Calorimeter (DSC) test conditions used in the experiments of the present invention are:

[0107] The test was performed using a DSC25 differential scanning calorimeter from TA Instruments, with a nitrogen atmosphere, a heating rate of 10°C / min, and a heating range of 25°C to 300°C.

[0108] Thermo Gravimetric Analysis (TGA) test conditions used in the experiments of the present invention are:

[0109] The samples were tested by using a Q500 thermogravimetric analyzer from TA Instruments, with a nitrogen atmosphere and heating to 350°C at a heating rate of 10°C / min.

[0110] The Proton Nuclear Magnetic Resonance (PNR) spectrum used in the experiment of the present invention is 1 H-NMR) was acquired on a Bruker 400 MHz nuclear magnetic resonance spectrometer after dissolving the sample in dimethyl sulfoxide-d6.

[0111] Example 1 Preparation of the oxygen-containing heterocyclic compound salt shown in Formula I by natural volatilization method

[0112] 1. In order to evaluate which acids can form salts with good solid form with the oxygen-containing heterocyclic compound shown in Formula I, the following steps were used for preparation experiments. The experimental results are shown in Table 1.

[0113] (1) Dissolve 50 mg of the free base of the oxygen-containing heterocyclic compound represented by Formula I in 1 mL of acetone to obtain a free base solution, and prepare 12 portions in parallel.

[0114] (2): Weigh an appropriate amount of acid and dissolve it in ethanol to obtain an acid solution with a concentration of 0.1 mol / L.

[0115] (3): 1 mL of acid solution (equivalent to 1.2 times the amount of free base) was added to the free base solution to obtain a salt solution, which was naturally evaporated and dried in vacuum at 40°C overnight.

[0116] Table 1

[0117] Acid Name Product properties Methanesulfonic acid White solid Fumaric Acid White solid hydrochloric acid White solid Hydrobromic acid White solid sulfuric acid Yellow oil Phosphoric acid White solid Citric Acid White solid Maleic acid White solid L-Tartaric acid White solid Succinic acid White solid L-Malic Acid White solid p-Toluenesulfonic acid Yellow oil

[0118] 2.XRPD, DSC, TGA and 1 H-NMR characterization test

[0119] The above-mentioned other solid products were tested by XRPD, DSC and TGA respectively and compared with the data of the free base. The results showed that the above-mentioned 10 acids except sulfuric acid and p-toluenesulfonic acid can form solid salts with the oxygen-containing heterocyclic compound shown in Formula I and each solid salt exists in a crystalline form. The test results of various salts are as follows Figures 1 to 12 As shown,

[0120] Figure 1 XRPD pattern of the monomethanesulfonate salt.

[0121] Figure 2 The DSC spectrum of the monomethanesulfonate.

[0122] Figure 3 This is the TGA spectrum of the monomethanesulfonate.

[0123] Figure 4 It is the XRPD pattern of the monofumarate salt.

[0124] Figure 5 XRPD pattern of the monohydrochloride salt.

[0125] Figure 6 The XRPD pattern of the monohydrobromide salt is shown in FIG.

[0126] Figure 7 It is the XRPD pattern of the monophosphate.

[0127] Figure 8 The XRPD pattern of the monocitrate salt is shown in FIG.

[0128] Fig. 9 The XRPD pattern of the monomaleate salt is shown in FIG.

[0129] Fig.10 The XRPD pattern of the mono-L-tartrate salt is shown in FIG.

[0130] Fig.11 The XRPD pattern of the monosuccinate salt is shown in FIG.

[0131] Fig.12 The XRPD pattern of the mono-L-malate salt is shown in FIG.

[0132] Characterization results of monomethanesulfonate:

[0133] In the X-ray powder diffraction pattern expressed as 2θ angle, d spacing, peak height percentage and peak area percentage, the 2θ angle, d spacing, peak height percentage and peak area percentage of the main diffraction peak of the monomethanesulfonate salt are shown in Table 2 below.

[0134] Table 2 XRPD diffraction data of monomethanesulfonate

[0135]

[0136] pass 1 The H-NMR spectrum confirmed that in the monomethanesulfonate, the molar ratio of the oxygen-containing heterocyclic compound as shown in Formula I to methanesulfonic acid was about 1:0.98, and no obvious crystallization solvent signal peak was observed.

[0137] The DSC spectrum of the monomethanesulfonate is as follows Figure 2 As shown, the melting endothermic peak onset temperature (onset) of the monomethanesulfonate salt is about 171.1°C; the TGA spectrum is as shown Figure 3 As shown, the salt has a weight loss of 2.436% before 150°C, and is a hydrate, containing about 1 mole of water.

[0138] The content of the oxygen-containing heterocyclic compound as shown in Formula I in the monomethanesulfonate solid was determined by HPLC external standard method to be 85.9% (excluding the amount of solvent), which is close to the theoretical content of the oxygen-containing heterocyclic compound as shown in Formula I in the monomethanesulfonate of 86.3%, indicating that the oxygen-containing heterocyclic compound as shown in Formula I and methanesulfonic acid are salified in a molar ratio of 1:1.

[0139] Characterization data of the other 9 salts:

[0140] In the X-ray powder diffraction pattern expressed as 2θ angle, d spacing, peak height percentage and peak area percentage, the 2θ angle, d spacing, peak height percentage and peak area percentage of the main diffraction peaks of other salts obtained in Example 1 are shown in the following Tables 3 to 11.

[0141] Table 3 XRPD diffraction data of monofumarate salt

[0142]

[0143] Table 4 XRPD diffraction data of monohydrochloride

[0144]

[0145]

[0146] Table 5 XRPD diffraction data of monohydrobromide salt

[0147]

[0148]

[0149] Table 6 XRPD diffraction data of monophosphate

[0150]

[0151] Table 7 XRPD diffraction data of monocitrate salt

[0152]

[0153]

[0154] Table 8 XRPD diffraction data of monomaleate

[0155]

[0156]

[0157] Table 9 XRPD diffraction data of mono-L-tartrate salt

[0158]

[0159]

[0160] Table 10 XRPD diffraction data of monosuccinate

[0161]

[0162] Table 11 XRPD diffraction data of mono-L-malate salt

[0163]

[0164] By testing the liquid NMR hydrogen spectrum and comparing it with the data of the free base, the results showed that in the liquid NMR hydrogen spectra of the other 9 solid salts, the molar ratio of the oxygen-containing heterocyclic compound shown in Formula I to the acid was about 1:0.9 to about 1:1, and no obvious crystallization solvent signal peak was observed, indicating that the above 9 solid salts are salts formed by the oxygen-containing heterocyclic compound shown in Formula I and the acid in a molar ratio of 1:1.

[0165] Example 2 Preparation of the oxygen-containing heterocyclic compound salt shown in Formula I by solution crystallization method

[0166] 1. Select a good solvent to dissolve the oxygen-containing heterocyclic compound shown in Formula I and the acid. If no precipitate is formed after stirring, add a poor solvent dropwise until a precipitate is formed. The experimental results are shown in Table 12.

[0167] Experimental steps:

[0168] (1) 100 mg of the free base of the oxygen-containing heterocyclic compound represented by Formula I and an acid (dissolved in methanol, ethanol or water, approximately equivalent to 1.05 times the amount of the free base) are added to a benign solvent and stirred to obtain a salt solution.

[0169] (2): If there is no precipitation after stirring, add a poor solvent dropwise until turbidity appears.

[0170] (3): Collect the solid by filtration under reduced pressure and dry in vacuum at 40°C overnight.

[0171] Table 12

[0172]

[0173]

[0174] 2. XRPD characterization test

[0175] The XRPD test results of the above solid products were compared with the data of the free base. The results showed that acetic acid and benzoic acid failed to form salts with the free base, while the other 10 acids could form solid salts with the oxygen-containing heterocyclic compound shown in Formula I and each solid salt existed in a crystalline form. Among them, the XRPD test results of mono-D-mandelate, mono-adipate and mono-benzenesulfonate were as follows: Figures 13-15 As shown, the XRPD of other salt-forming products was confirmed to be consistent with that of the corresponding salt prepared in Example 1 through comparison.

[0176] Fig.13 The XRPD pattern of mono-D-mandelate salt is shown in FIG.

[0177] Fig.14 XRPD pattern of monoadipate salt.

[0178] Fig.15 It is the XRPD pattern of the monobenzenesulfonate salt.

[0179] In the X-ray powder diffraction pattern expressed as 2θ angle, d spacing, peak height percentage and peak area percentage, the 2θ angle, d spacing, peak height percentage and peak area percentage of the main diffraction peaks of mono D-mandelate, mono adipate and mono benzenesulfonate are shown in the following Tables 13 to 15.

[0180] Table 13 XRPD diffraction data of mono-D-mandelate salt

[0181]

[0182]

[0183] Table 14 XRPD diffraction data of monoadipate salt

[0184]

[0185]

[0186] Table 15 XRPD diffraction data of monobenzenesulfonate

[0187]

[0188]

[0189] 3. Liquid state H NMR spectrum ( 1 H-NMR) characterization test

[0190] The mono-D-mandelic acid salt, the mono-adipate salt and the mono-benzenesulfonate salt were dissolved in dimethyl sulfoxide-d6, and then the liquid NMR hydrogen spectra were tested on a Bruker 400 MHz NMR spectrometer and compared with the data of the free base. The results showed that in the liquid NMR hydrogen spectra of the three solid salts, the molar ratio of the oxygen-containing heterocyclic compound shown in Formula I to the acid was about 1:0.9 to about 1:1, and no obvious crystallization solvent signal peak was observed, indicating that the above three solid salts were salts formed by the oxygen-containing heterocyclic compound shown in Formula I and D-mandelic acid, adipic acid, and benzenesulfonic acid in a molar ratio of 1:1.

[0191] Example 3 Preparation of monomethanesulfonate

[0192] 1.0008 g of the oxygen-containing heterocyclic compound shown in Formula I and 0.1671 g of methanesulfonic acid were added to 15 mL of acetone at 50 ° C and stirred for 1 hour, cooled to room temperature and stirred overnight, filtered, and the filter cake was placed in a vacuum oven at 40 ° C and dried overnight to obtain 0.9821 g of a white solid. The obtained solid was determined by X-ray powder diffraction to have a crystalline form consistent with the monomethanesulfonate prepared in Example 1.

[0193] Example 4 Preparation of Monomethanesulfonate

[0194] 1.0191 g of the oxygen-containing heterocyclic compound shown in Formula I and 0.1677 g of methanesulfonic acid were added to 15 mL of isopropanol at 50° C. and stirred for 2 hours. The mixture was filtered and the filter cake was dried in a vacuum oven at 40° C. for 4 hours to obtain 0.4882 g of a white solid. The obtained solid was determined by X-ray powder diffraction to have a crystalline form consistent with the monomethanesulfonate prepared in Example 1.

[0195] Example 5 Preparation of monomethanesulfonate

[0196] 1.0035 g of the oxygen-containing heterocyclic compound shown in Formula I and 0.1674 g of methanesulfonic acid were added to 20 mL of isopropanol and stirred for 1 hour at room temperature, 20 mL of methyl tert-butyl ether was slowly added dropwise and stirred overnight, filtered, and the filter cake was placed in a vacuum oven at 40 ° C and dried overnight to obtain 0.7979 g of a white solid. The obtained solid was determined by X-ray powder diffraction to have a crystalline form consistent with the monomethanesulfonate prepared in Example 1.

[0197] Example 6 Preparation of dimethanesulfonate

[0198] 8.0 g of the oxygen-containing heterocyclic compound of formula I and 2.66 g of methanesulfonic acid were added to 200 mL of acetone at room temperature and stirred to obtain a clear liquid. The reaction solution was concentrated under reduced pressure until the remaining reaction liquid volume was about 50-60 mL. Solid began to precipitate from the reaction solution. The mixture was stirred overnight and filtered. The filter cake was dried in a vacuum oven at 40° C. for 4 hours to obtain 7.12 g of a white solid.

[0199] The obtained solid is a dimethanesulfonate of an oxygen-containing heterocyclic compound as shown in Formula I, and its X-ray powder diffraction pattern is as follows: Fig.16 As shown, in the X-ray powder diffraction pattern expressed as 2θ angle, d spacing, peak height percentage and peak area percentage, the 2θ angle, d spacing, peak height percentage and peak area percentage of the main diffraction peaks are shown in Table 16 below.

[0200] Table 16

[0201]

[0202] The DSC spectrum of dimesylate is as follows Fig.17 As shown, the melting endothermic peak onset temperature (onset) of dimesylate is about 180.0°C; the TGA spectrum is as shown Fig.18 As shown, the salt has a weight loss of 2.954% before 150°C, and is a hydrate, containing about 1.4 moles of water.

[0203] The content of the oxygen-containing heterocyclic compound as shown in Formula I in the dimethanesulfonate was determined by HPLC external standard method to be 76.6% (excluding the amount of solvent), which is close to the theoretical content of the oxygen-containing heterocyclic compound as shown in Formula I in the dimethanesulfonate of 75.9%, indicating that the oxygen-containing heterocyclic compound as shown in Formula I in the obtained solid and methanesulfonic acid are salted in a molar ratio of 1:2.

[0204] Example 7 Preparation of dimethanesulfonate

[0205] 0.5004 g of the oxygen-containing heterocyclic compound shown in Formula I and 0.166 g of methanesulfonic acid were added to 7.5 mL of acetone at 50° C. and stirred to obtain a clear liquid. After 4 hours, the precipitated solid was filtered and the filter cake was dried in a vacuum oven at 40° C. for 4 hours to obtain 0.6114 g of a white solid. The X-ray powder diffraction pattern of the obtained solid was consistent with that of the dimethanesulfonate prepared in Example 6.

[0206] Example 8 Preparation of Monofumarate

[0207] 1.0004 g of the oxygen-containing heterocyclic compound shown in Formula I and 0.2022 g of fumaric acid were added to 20 mL of ethanol at room temperature and stirred overnight, filtered, and the filter cake was placed in a vacuum oven at 40° C. and dried overnight to obtain 0.7338 g of a white solid. The X-ray powder diffraction pattern of the obtained solid was consistent with that of the monofumarate prepared in Example 1.

[0208] The content of the oxygen-containing heterocyclic compound as shown in Formula I in the obtained solid was determined by HPLC external standard method to be 81.8%, which is close to the theoretical content of the oxygen-containing heterocyclic compound as shown in Formula I in the monofumarate of 83.9%, indicating that the oxygen-containing heterocyclic compound as shown in Formula I in the obtained solid and fumaric acid are salted in a molar ratio of 1:1.

[0209] Example 9 Preparation of Hemifumarate

[0210] 0.5002 g of the oxygen-containing heterocyclic compound of formula I and 0.0482 g of fumaric acid were added to 7.5 mL of acetone at 50° C. and stirred for 2 hours, then cooled to room temperature and stirred overnight. The filter cake was dried in a vacuum oven at 40° C. overnight to obtain 0.3547 g of a white solid.

[0211] The obtained solid is a hemifumarate of an oxygen-containing heterocyclic compound as shown in Formula I, and its X-ray powder diffraction pattern is as follows: Fig.19 As shown, in the X-ray powder diffraction pattern expressed as 2θ angle, d spacing, peak height percentage and peak area percentage, the 2θ angle, d spacing, peak height percentage and peak area percentage of the main diffraction peaks are shown in Table 17 below.

[0212] Table 17

[0213]

[0214]

[0215] The content of the oxygen-containing heterocyclic compound as shown in Formula I in the obtained solid was determined by HPLC external standard method to be 88.3%, which is close to the theoretical content of the oxygen-containing heterocyclic compound as shown in Formula I in the hemifumarate of 91.2%, indicating that the oxygen-containing heterocyclic compound as shown in Formula I in the obtained solid and fumaric acid are salted in a molar ratio of 2:1.

[0216] Example 10 Preparation of monohydrochloride

[0217] 1.0291 g of an oxygen-containing heterocyclic compound as shown in Formula I and 0.15 mL of concentrated hydrochloric acid solution (mass fraction 37%) were added to 15 mL of methanol at 50°C and stirred for 1 hour. 45 mL of isopropyl acetate was slowly added dropwise, cooled to room temperature and stirred overnight, filtered, and the filter cake was placed in a vacuum oven at 40°C and dried overnight to obtain 1.0219 g of a white solid. The X-ray powder diffraction pattern of the obtained solid was consistent with the monohydrochloride prepared in Example 1.

[0218] The content of the oxygen-containing heterocyclic compound as shown in Formula I in the obtained solid was determined by HPLC external standard method to be 92.6%, which is close to the theoretical content of the oxygen-containing heterocyclic compound as shown in Formula I in the monohydrochloride salt of 94.3%, indicating that the oxygen-containing heterocyclic compound as shown in Formula I in the obtained solid and hydrochloric acid are salted in a molar ratio of 1:1.

[0219] Example 11 Preparation of dihydrochloride

[0220] 5.0 g of the oxygen-containing heterocyclic compound of formula I and 1.5 mL of concentrated salt solution (mass fraction 37%) were added to 30 mL of methanol at room temperature and stirred for 1 hour. 225 mL of isopropyl acetate was slowly added dropwise, stirred overnight, filtered, and the filter cake was placed in a vacuum oven at 40°C and dried overnight to obtain 5.09 g of a white solid.

[0221] The obtained solid is a dihydrochloride salt of an oxygen-containing heterocyclic compound as shown in Formula I, and its X-ray powder diffraction pattern is as follows: Fig. 20 As shown, in the X-ray powder diffraction pattern expressed as 2θ angle, d spacing, peak height percentage and peak area percentage, the 2θ angle, d spacing, peak height percentage and peak area percentage of the main diffraction peaks are shown in Table 18 below.

[0222] Table 18

[0223]

[0224]

[0225] The content of the oxygen-containing heterocyclic compound as shown in Formula I in the obtained solid was determined by HPLC external standard method to be 86.7%, which is close to the theoretical content of the oxygen-containing heterocyclic compound as shown in Formula I in the dihydrochloride salt of 89.2%, indicating that the oxygen-containing heterocyclic compound as shown in Formula I in the obtained solid and hydrochloric acid are salted in a molar ratio of 1:2.

[0226] Example 12 Preparation of Monohydrobromide

[0227] 1.0547 g of the oxygen-containing heterocyclic compound of formula I and 0.309 g of a 48% hydrobromic acid aqueous solution were added to 15 mL of acetone at 50° C. and stirred for 2 hours to precipitate a white solid. The mixture was cooled to room temperature and stirred overnight, filtered, and the filter cake was dried in a vacuum oven at 40° C. for 4 hours to obtain 0.9612 g of a white solid. The X-ray powder diffraction pattern of the obtained solid was consistent with that of the monohydrobromide prepared in Example 1.

[0228] The content of the oxygen-containing heterocyclic compound as shown in Formula I in the obtained solid was determined by HPLC external standard method to be 86.7%, which is close to the theoretical content of the oxygen-containing heterocyclic compound as shown in Formula I in the monohydrobromide salt of 88.2%, indicating that the oxygen-containing heterocyclic compound as shown in Formula I in the obtained solid and hydrobromic acid are salted in a molar ratio of 1:1.

[0229] Example 13 Preparation of monophosphate

[0230] 1.0123 g of the oxygen-containing heterocyclic compound of formula I and 0.106 mL of phosphoric acid were added to 25 mL of acetone at room temperature and stirred overnight. The mixture was filtered and the filter cake was dried in a vacuum oven at 40° C. overnight to obtain 1.0971 g of a white solid. The X-ray powder diffraction pattern of the obtained solid was consistent with that of the monophosphate prepared in Example 1.

[0231] Example 14 Preparation of monocitrate

[0232] 1.0018 g of the oxygen-containing heterocyclic compound of formula I and 0.340 g of citric acid were added to 25 mL of acetone at room temperature and stirred for 1 hour. 25 mL of n-heptane was slowly added dropwise and stirred overnight. The mixture was filtered and the filter cake was dried in a vacuum oven at 40 ° C overnight to obtain 0.7894 g of a white solid. The X-ray powder diffraction pattern of the obtained solid was consistent with that of the monocitrate prepared in Example 1.

[0233] Example 15 Preparation of Monomaleate

[0234] 1.0138 g of the oxygen-containing heterocyclic compound shown in Formula I and 0.2072 g of maleic acid were added to 15 mL of acetone at 50° C. and stirred to obtain a clear liquid. The reaction solution was concentrated under reduced pressure until the remaining reaction solution volume was about 4 to 5 mL. Solid began to precipitate from the reaction solution. The solution was stirred overnight at room temperature and filtered. The filter cake was placed in a vacuum oven at 40° C. and dried overnight to obtain 0.5947 g of a white solid. The X-ray powder diffraction pattern of the obtained solid was consistent with that of the monomaleate prepared in Example 1.

[0235] The content of the oxygen-containing heterocyclic compound as shown in Formula I in the obtained solid was determined by HPLC external standard method to be 80.1%, which is close to the theoretical content of the oxygen-containing heterocyclic compound as shown in Formula I in the monomaleate salt of 83.9%, indicating that the oxygen-containing heterocyclic compound as shown in Formula I in the obtained solid and maleic acid are salted in a molar ratio of 1:1.

[0236] Example 16 Preparation of mono-L-tartrate

[0237] 0.6002 g of the oxygen-containing heterocyclic compound of formula I and 0.156 g of L-tartaric acid were added to 10 mL of ethanol and 5 mL of tetrahydrofuran and stirred at 50° C. for 4 hours, cooled to room temperature and stirred overnight, filtered, and the filter cake was dried in a vacuum oven at 40° C. overnight to obtain 0.7198 g of a white solid. The X-ray powder diffraction pattern of the obtained solid was consistent with that of the mono-L-tartaric acid salt prepared in Example 1.

[0238] The content of the oxygen-containing heterocyclic compound as shown in Formula I in the obtained solid was determined by HPLC external standard method to be 78.4%, which is close to the theoretical content of 80.1% of the oxygen-containing heterocyclic compound as shown in Formula I in the mono-L-tartrate, indicating that the oxygen-containing heterocyclic compound as shown in Formula I in the obtained solid and L-tartaric acid are salted in a molar ratio of 1:1.

[0239] Example 17 Preparation of Monosuccinate

[0240] 0.9312 g of the oxygen-containing heterocyclic compound shown in Formula I and 0.190 g of succinic acid were added to 4 mL of dichloromethane and 4 mL of isopropanol at 50° C. and stirred for 1 hour. The reaction solution was slowly added dropwise to 20 mL of methyl tert-butyl ether and stirred for 2 hours. The filter cake was placed in a vacuum oven at 40° C. and dried overnight to obtain 0.9562 g of a white solid. The X-ray powder diffraction pattern of the obtained solid was consistent with that of the monosuccinate prepared in Example 1.

[0241] The content of the oxygen-containing heterocyclic compound as shown in Formula I in the obtained solid was determined by HPLC external standard method to be 80.4%, which is close to the theoretical content of the oxygen-containing heterocyclic compound as shown in Formula I in the monosuccinate of 83.7%, indicating that the oxygen-containing heterocyclic compound as shown in Formula I in the obtained solid and succinic acid form a salt in a molar ratio of 1:1.

[0242] Example 18 Preparation of Mono L-Malate

[0243] 1.0121 g of the oxygen-containing heterocyclic compound of formula I and 0.235 g of L-malic acid were added to 5 mL of dichloromethane and 5 mL of isopropanol at 50° C. and stirred for 1 hour. The mixture was cooled to room temperature. The reaction solution was slowly added dropwise to 30 mL of methyl tert-butyl ether and stirred for 2 hours. The mixture was filtered and the filter cake was dried in a vacuum oven at 40° C. overnight to obtain 0.7012 g of a white solid. The X-ray powder diffraction pattern of the obtained solid was consistent with that of the mono L-malate prepared in Example 1.

[0244] The content of the oxygen-containing heterocyclic compound as shown in Formula I in the obtained solid was determined by HPLC external standard method to be 78.3%, which is close to the theoretical content of the oxygen-containing heterocyclic compound as shown in Formula I in the mono-L-malate salt of 81.9%, indicating that the oxygen-containing heterocyclic compound as shown in Formula I in the obtained solid and L-malic acid are salted in a molar ratio of 1:1.

[0245] Example 19 Preparation of Mono-D-Mandelate

[0246] 2.0 g of the oxygen-containing heterocyclic compound shown in Formula I and 0.532 g of D-mandelic acid were added to 10 mL of methanol at room temperature and stirred for 2 hours. 30 mL of methyl tert-butyl ether was slowly added dropwise and stirred at room temperature overnight. The mixture was filtered and the filter cake was dried in a vacuum oven at 40° C. overnight to obtain 1.84 g of a khaki solid. The X-ray powder diffraction pattern of the obtained solid was consistent with that of the mono D-mandelate prepared in Example 2.

[0247] Example 20 Preparation of monoadipate

[0248] 1.0812 g of the oxygen-containing heterocyclic compound of formula I and 0.2771 g of adipic acid were added to 15 mL of acetone at 50°C and stirred for 1 hour. 15 mL of n-heptane was slowly added dropwise and the mixture was cooled to room temperature and stirred overnight. The mixture was filtered and the filter cake was dried in a vacuum oven at 40°C overnight to obtain 0.7542 g of a white solid. The X-ray powder diffraction pattern of the obtained solid was consistent with that of the monoadipic acid salt prepared in Example 2.

[0249] Example 21 Preparation of Monobenzenesulfonate

[0250] 1.0074 g of the oxygen-containing heterocyclic compound shown in Formula I and 0.3171 g of benzenesulfonic acid monohydrate were added to 15 mL of acetone at 50°C and stirred for 1 hour. 30 mL of methyl tert-butyl ether was slowly added dropwise, and the system became slightly turbid. The temperature was cooled to room temperature and stirred overnight. The filter cake was dried in a vacuum oven at 40°C overnight to obtain 0.3942 g of a white solid. The X-ray powder diffraction pattern of the obtained solid was consistent with that of the monobenzenesulfonate prepared in Example 2.

[0251] Example 22 Preparation of amorphous monobenzenesulfonate

[0252] 1.0110 g of an oxygen-containing heterocyclic compound (1.670 mM) of formula I and 0.2750 g of benzenesulfonic acid (1.721 mM) were added to 2 mL of dichloromethane and 2 mL of isopropanol at 50°C and stirred for 1 hour. The clarified reaction solution was slowly added dropwise to 20 mL of methyl tert-butyl ether, and solids precipitated immediately. The solids were filtered and the filter cake was dried in a vacuum oven at 40°C overnight to obtain 0.1684 g of a white solid.

[0253] The obtained solid is a monobenzenesulfonate of an oxygen-containing heterocyclic compound as shown in Formula I. The sample is determined to be amorphous by X-ray powder diffraction test.

[0254] Example 23 Preparation of amorphous monosulfate

[0255] 1.0128 g of an oxygen-containing heterocyclic compound (1.673 mM) of formula I and 1 mL of sulfuric acid solution (0.19 mL of concentrated hydrochloric acid was diluted with water to 2 mL) (1.748 mM) were added to 15 mL of acetone at 50°C and stirred for 1 hour. 60 mL of methyl tert-butyl ether was slowly added dropwise, and the system became turbid. After standing, the system was separated into layers, and the lower layer was a yellow oil. After standing overnight, a powdery solid precipitated from the lower layer, which was filtered and the filter cake was dried in a vacuum oven at 40°C overnight to obtain 0.4987 g of a light khaki solid.

[0256] The obtained solid is a monosulfate of an oxygen-containing heterocyclic compound as shown in Formula I. The sample is determined to be amorphous by X-ray powder diffraction test.

[0257] Example 24 Preparation of amorphous mono-D-tartrate

[0258] 2.0 g of the oxygen-containing heterocyclic compound of formula I (3.305 mM) and 5 mL of D-tartaric acid tetrahydrofuran solution (0.52 g of D-tartaric acid dissolved in 5 mL of tetrahydrofuran) (3.470 mM) were added to 34 mL of toluene at room temperature and stirred for 1 hour. 30 mL of methyl tert-butyl ether was slowly added dropwise and stirred at room temperature overnight. The mixture was filtered and the filter cake was dried in a vacuum oven at 40°C overnight to obtain 2.31 g of a light yellow solid.

[0259] The obtained solid is a mono-D-tartrate of an oxygen-containing heterocyclic compound as shown in Formula I. The sample is determined to be amorphous by X-ray powder diffraction test.

[0260] Example 25 Preparation of mono-D-malate

[0261] 2.0 g of the oxygen-containing heterocyclic compound of Formula I (3.305 mM) and 2 mL of D-malic acid tetrahydrofuran solution (0.465 g of D-malic acid dissolved in 2 mL of tetrahydrofuran) (3.467 mM) were added to 30 mL of acetonitrile at room temperature and stirred overnight. The mixture was filtered and the filter cake was dried in a vacuum oven at 40° C. overnight to obtain 1.27 g of a white solid.

[0262] The obtained solid is a mono-D-malate of an oxygen-containing heterocyclic compound as shown in Formula I, and its X-ray powder diffraction pattern is as follows: Fig.21 As shown, in the X-ray powder diffraction pattern expressed as 2θ angle, d spacing, peak height percentage and peak area percentage, the 2θ angle, d spacing, peak height percentage and peak area percentage of the main diffraction peaks are shown in Table 19 below.

[0263] Table 19

[0264]

[0265]

[0266] Test Example 1 Water Solubility Experiment

[0267] In order to evaluate the water solubility of the oxygen-containing heterocyclic compound shown in Formula I after forming salts with various acids, the test was carried out according to the following steps.

[0268] Accurately weigh 5 mg of each free base and salt, gradually add pure water to each sample at room temperature, oscillate for 30 seconds and ultrasonically oscillate for 1 minute, and repeat the process several times. Calculate the water solubility based on the actual weight of the sample and the amount of water. The results are shown in Table 20.

[0269] Table 20

[0270]

[0271]

[0272] It can be seen from the above experimental results that the water solubility of various salts of the present invention is twice or more than that of the free base crystal form A in the prior art.

[0273] Test Example 2: Solubility experiment in simulated gastrointestinal fluid

[0274] The free base and various salts were prepared into suspensions with FaSSGF (simulated artificial gastric juice in fasting state) and FaSSIF (simulated artificial intestinal juice in fasting state) and then rotated at room temperature for equilibrium. Appropriate amounts of the suspensions were taken out at predetermined time intervals of 1 hour and 24 hours and filtered with a 0.45 μm nylon filter membrane. The solubility of the compound represented by Formula I in the filtrate was analyzed by high performance liquid chromatography (HPLC). The results are shown in Table 21.

[0275] Table 21

[0276]

[0277]

[0278] It can be seen from the above experimental results that, compared with the free base crystal form A in the prior art, the dissolution rate and solubility of the various salts of the present invention in FaSSGF and FaSSIF are greatly improved, which is beneficial to improving the oral absorption of the drug.

[0279] Test Example 3 Stability Test under Oxidative Conditions

[0280] The salt and free base of the present invention were tested under the following conditions to examine the stability of the compound in free state and after salt formation under oxidative conditions. The results are shown in Tables 22-23.

[0281] Liquid oxidation conditions: About 5 mg of free base form A sample and about 6 mg of salt sample were spread evenly in 25 mL volumetric flasks, 5 mL of 3% hydrogen peroxide solution was added, the volumetric flask was covered and sealed, and placed in a 40°C oven for 24 hours, taken out, dissolved with a diluent (methanol / water = 7 / 3), and the changes in related substances were determined by HPLC, and compared with the sample on day 0.

[0282] Solid-state oxidation conditions: About 5 mg of the free base form A sample and about 6 mg of the salt sample were spread evenly in 25 mL volumetric flasks, and the volumetric flasks were opened and placed in a closed desiccator filled with urea hydrogen peroxide. After being placed in an oven at 40°C for 1 week, they were taken out and dissolved with a diluent (methanol / water = 7 / 3). The changes in related substances were determined by HPLC and compared with the samples on day 0.

[0283] Table 22

[0284]

[0285] Table 23

[0286]

[0287] It can be seen from the above experimental results that under liquid oxidation conditions, compared with the free base crystal form A in the prior art, the decomposition amount of various salts of the present invention is significantly lower; under solid oxidation conditions, the decomposition amount of the mono-methanesulfonate and dimethanesulfonate of the present invention is significantly lower than that of the free base crystal form A in the prior art and the dihydrochloride of the present invention. It can be seen that the methanesulfonate of the present invention has better antioxidant properties, which is beneficial to the long-term storage of drugs.

[0288] Test Example 4: Evaluation of Moisture Absorption

[0289] According to the "Guidelines for Drug Hygroscopicity Tests" (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 9103), the salts of the present invention were placed open in a constant temperature dryer at 25°C ± 1°C (a saturated ammonium chloride solution was placed at the bottom) for 24 hours, and the hygroscopicity of each salt was evaluated by measuring the weight change of the samples. The experimental results are shown in Table 24.

[0290] Table 24

[0291] Test samples Moisture absorption weight gain at 80% relative humidity Moisture-absorbing properties Free base form A 0.18％ Almost no hygroscopicity Monomethanesulfonate 1.3％ Slightly hygroscopic Dimesylate 1.4％ Slightly hygroscopic Monofumarate 0.17％ Almost no hygroscopicity Monohydrochloride 1.6％ Slightly hygroscopic Dihydrochloride 5.1％ Hygroscopic Monophosphate 1.4％ Slightly hygroscopic Monocitrate 1.8％ Slightly hygroscopic Mono L-tartrate 0.70％ Slightly hygroscopic Monosuccinate 1.8％ Slightly hygroscopic Mono L-malate 1.5％ Slightly hygroscopic

[0292] According to the definition of drug hygroscopicity in the "Chinese Pharmacopoeia 2020 Edition", the dihydrochloride salt of the present invention has strong hygroscopicity and requires appropriate storage conditions; while other types of salts are non-hygroscopic or slightly hygroscopic, and can remain stable during production, transportation and use without specific humidity control conditions, and can better meet the requirements of drug production and use.

[0293] Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Guidelines for hygroscopicity testing of drugs in Part IV of the Chinese Pharmacopoeia 2020 Edition, 9103):

[0294] Deliquescent: Absorbs sufficient water to form a liquid.

[0295] Highly hygroscopic: weight gain due to moisture absorption is not less than 15%.

[0296] Hygroscopic: Weight gain due to moisture absorption is less than 15% but not less than 2%.

[0297] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%.

[0298] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%.

[0299] Test Example 5 Crystal Stability

[0300] The salt of the present invention and the free base crystal form A were tested under the following conditions to examine whether the crystal form changes after suspension equilibrium in the solvent. The results are shown in Table 25.

[0301] The test sample is dispersed in a solvent to obtain a suspension, which is sealed and placed on a shaker. The suspension is rotated and balanced at room temperature for a period of time. Samples are taken and vacuum filtered. The filter cake is placed at room temperature to evaporate the solvent and then tested for XRPD.

[0302] Table 25

[0303]

[0304] It can be seen from the above experimental results that compared with the free base crystal form A in the prior art, the salt of the present invention has better stability and will not undergo crystal form transformation after long-term suspension equilibrium in the solvent; and the stability of the monomethanesulfonate is better than that of the dimethanesulfonate, and the dimethanesulfonate is transformed into the monomethanesulfonate after suspension equilibrium in the solvent.

[0305] Test Example 6 Study on reaction stoichiometric ratio

[0306] The stability of the stoichiometric ratio of the salt of the present invention generated by adding acids in different molar reaction ratios under given crystallization process conditions was investigated.

[0307] The molar ratio of the free base to the acid in the salt-forming reaction was designed to be 3:1, 2:1, 1:1, 1:2 and 1:3 to investigate the stability of the salt-forming crystallization process and the stoichiometric ratio of the salt-forming reaction. The product crystal form was characterized by XRPD; the mass percentage of the free base in the salt-forming reaction product was determined by HPLC and the external standard method, and compared with the mass percentage of the theoretical reaction stoichiometric ratio. The experimental results are shown in Table 26.

[0308] Table 26

[0309]

[0310]

[0311] By X-ray powder diffraction analysis and by quantitatively determining the content of free base in the product, it is determined that the oxygen-containing heterocyclic compound shown in Formula I can form salts with different reaction molar ratios with the acid. Comprehensively evaluating the complete salt formation rate and the molar yield of the salt-type product, the molar ratio of the free base to the methanesulfonic acid in the monomethanesulfonate of the present invention is preferably 1:1 to 1:1.2, and the molar ratio of the free base to the methanesulfonic acid in the dimethanesulfonate is preferably 1:2 to 1:2.2.

[0312] Comparative Example Preparation of Form A of the Oxygen-containing Heterocyclic Compound Shown in Formula I

[0313] Referring to paragraphs

[0198] -

[0199] of the specification of patent CN115385923A, the oxygen-containing heterocyclic compound crystalline form A as shown in formula I was prepared.

[0314] The obtained sample was identified as an oxygen-containing heterocyclic compound as shown in Formula I, 1H-NMR (400MHz, CDCl3): δ7.97 (d, 1H, J = 7.2Hz), 7.84 (t, 2H, J = 9.2Hz), 7.62-7. 50(m,2H),7.36(t,1H,J=7.8Hz),6.52(dd,1H,J1=3.2Hz,J2=11.1Hz),5.42(d, 1H, J=47.2Hz), 5.25 (dd, 1H, J1=3.6Hz, J2=16.4Hz), 4.98 (d, 1H, J=13.7Hz), 4. 82(d,1H,J=13.6Hz),5.04-4.72(m,1H),4.38(dd,1H,J1=4.9Hz,J2=10.6Hz),4. 15(dd,1H,J1=6.8Hz,J2=10.6Hz),3.98(d,1H,dd,1H,J=14.2Hz),3.87-3.73(m ,1H),3.60(dd,1H,J1=2.4Hz,J2=18.6Hz),3.66-3.54(m,1H),3.54-3.41(m,1H) ,3.16-2.98(m,2H),2.95-2.71(m,3H),2.71-2.61(m,1H),2.46(s,3H),2.33-2 .19(m,1H),2.10-1.98(m,1H),1.90-1.66(m,4H); LC-MS(ESI):m / z=605.3[M+H] + The obtained sample is further confirmed by XRPD to be the crystalline form A of the oxygen-containing heterocyclic compound as shown in Formula I, and its XRPD spectrum is as follows Fig. 22 shown.

[0315] It should be understood that the embodiments described herein are only for illustrative purposes, will contribute to further understanding of the present invention by embodiments, but are not intended to limit content of the present invention. For those skilled in the art, many changes for both materials and methods can be implemented without departing from the scope of the present invention, and these changes or improvements are included in the spirit and scope of the application and the scope of the appended claims.

Claims

1. An oxygen-containing heterocyclic compound salt, the structure of which is shown in Formula II, in, M is an acid; x is 0.5, 1, or 2.

2. The oxygen-containing heterocyclic compound salt according to claim 1, characterized in that The M is one or more of methanesulfonic acid, fumaric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, citric acid, maleic acid, tartaric acid, succinic acid, malic acid, mandelic acid, adipic acid and benzenesulfonic acid; And / or, x is 1 or 2.

3. The oxygen-containing heterocyclic compound salt according to claim 2, characterized in that When the M is one or more of methanesulfonic acid, hydrochloric acid, phosphoric acid, sulfuric acid, succinic acid, malic acid and adipic acid, M is one or more of methanesulfonic acid, succinic acid, malic acid and adipic acid, preferably methanesulfonic acid; and / or, when said M is one or more of methanesulfonic acid, succinic acid and malic acid, M is methanesulfonic acid; And / or, when M is one or more of methanesulfonic acid, hydrochloric acid, hydrobromic acid, maleic acid and benzenesulfonic acid, M is one or more of methanesulfonic acid, hydrobromic acid and benzenesulfonic acid, preferably methanesulfonic acid.

4. The oxygen-containing heterocyclic compound salt according to any one of claims 1 to 3, characterized in that When the M is methanesulfonic acid, x is 1 or 2; And / or, the oxygen-containing heterocyclic compound salt is in a crystalline form, or in an amorphous form, or in a mixture of a crystalline form and an amorphous form, preferably in a crystalline form.

5. A method for preparing the oxygen-containing heterocyclic compound salt according to any one of claims 1 to 4, which is a natural volatilization method or a solution crystallization method; the natural volatilization method is to form a solution with the oxygen-containing heterocyclic compound free base shown in formula I and the acid, and then remove the solvent; The solution crystallization method is to form a solution with the oxygen-containing heterocyclic compound free base shown in Formula I and the acid, and then stir to allow natural crystallization or mix with a poor solvent until a precipitate is precipitated.

6. A crystalline form of a monomethanesulfonate of an oxygen-containing heterocyclic compound as shown in Formula I, Its X-ray powder diffraction pattern, expressed in terms of 2θ angle, has peaks at 4.3±0.2°, 9.0±0.2°, 14.5±0.2°, 15.2±0.2°, 15.7±0.2°, 16.7±0.2°, 23.0±0.2°, 23.5±0.2° and 28.5±0.2°, and further has peaks at 11.7±0.2°, 12.4±0.2°, 13.0±0.2°, 18.0±0.2°, 20.4±0.2°, 21.2±0.2°, 21.4±0.2°, 22.3±0.2°, 25.5±0.2° and 26.0±0.2°.

7. The crystalline form of the monomethanesulfonate of the oxygen-containing heterocyclic compound as shown in Formula I according to claim 6, characterized in that: It has an X-ray powder diffraction pattern expressed in 2θ angles as shown in FIG1 ; And / or, the monomethanesulfonate of the oxygen-containing heterocyclic compound as shown in Formula I has a differential scanning calorimetry diagram as shown in FIG2 , showing that it has a melting endothermic peak with an onset temperature of 171.1° C.; And / or, the monomethanesulfonate of the oxygen-containing heterocyclic compound as shown in Formula I has a thermogravimetric analysis (TGA) diagram as shown in FIG3 , indicating that it is a hydrate with a weight loss of 2.4% before 150° C.; And / or, in the monomethanesulfonate of the oxygen-containing heterocyclic compound as shown in Formula I, the oxygen-containing heterocyclic compound as shown in Formula I and methanesulfonic acid are salified in a molar ratio of 1:

1.

8. A dimethanesulfonate of an oxygen-containing heterocyclic compound as shown in formula I, Its X-ray powder diffraction pattern, expressed in terms of 2θ angle, has peaks at 5.6±0.2°, 7.6±0.2°, 12.9±0.2°, 16.2±0.2°, 16.9±0.2°, 17.4±0.2°, 22.8±0.2°, 24.2±0.2° and 26.5±0.2°, and further has peaks at 8.2±0.2°, 12.0±0.2°, 14.3±0.2°, 16.4±0.2°, 20.4±0.2°, 20.9±0.2°, 21.7±0.2°, 23.5±0.2° and 26.9±0.2°.

9. A pharmaceutical composition comprising the oxygen-containing heterocyclic compound salt or a crystal form thereof according to any one of claims 1 to 8, and a pharmaceutically acceptable excipient.

10. Use of the oxygen-containing heterocyclic compound salt according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating and / or preventing Ras-mediated diseases.

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