Malic acid salt of Xanomeline derivative, crystal form A, and preparation method and use thereof

Abstract

The present invention relates to the field of pharmaceutical chemistry, and in particular to a malate salt of a xanomeline derivative having a structure shown in Formula I. The malate salt of the compound of Formula I has excellent effects in at least one aspect, such as physical stability, solubility, hygroscopicity, biological activity, safety, bioavailability, and toxic and side effects. #imgabs0#

Description

[0001] This application claims the priority of the following prior application: Patent application number 202111198168.4 filed with the State Intellectual Property Office of China on October 14, 2021, and the invention name is “Malate salt of Xanomeline derivative, crystal form A, and preparation method and use thereof”. The entire text of the prior application is incorporated into this application by reference. Technical Field

[0002] The present invention relates to the field of pharmaceutical chemistry, and in particular to a malate salt and a crystal form A of a xanomeline derivative and a preparation method thereof, and also includes application of the malate salt and the crystal form A of the xanomeline derivative in the preparation of drugs for preventing or treating central nervous system disorders. Background Art

[0003] Neurotransmitters are chemical messengers secreted by neurons to facilitate the flow of information and communicate with other cells in the central and peripheral nervous systems (such as muscle or similar nerve cells). Acetylcholine is one of the key neurotransmitters in the brain, and it has two different receptor classes: muscarinic receptors (M receptors, G protein-coupled receptors) and nicotinic receptors (N receptors, ion channel receptors).

[0004] The M receptor family includes five subtypes, M1 to M5, all of which are expressed in the brain and peripheral tissues and play many key physiological roles in cognition, behavior, sensation, movement, and autonomic processes. Disruption of M-type receptor signaling can lead to memory impairment and cognitive impairment, trigger a variety of diseases including schizophrenia and Alzheimer's disease (AD), and aggravate psychosis. On the contrary, third-party preclinical and clinical data show that enhancement of M-type receptor signaling improves these symptoms. In addition, M-type receptors, especially M1, M2, and M4 receptors, are also considered to be related to analgesia.

[0005] Xanomeline is a partial agonist of muscarinic receptors, which can stimulate all five subtypes of muscarinic receptors without selectivity. It was jointly developed and marketed by Eli Lilly and Company and Novo Nordisk in the United States. It is mainly used in the treatment of Alzheimer's disease. The chemical name of Xanomeline is 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine, and its chemical structure is as follows:

[0006]

[0007] Patent document CN94192681.8 discloses that xanomeline can be converted into oxalate, but oxalate has potential side effects on the renal function of patients and is therefore not suitable for pharmaceutical use, especially in the treatment of the elderly. It further discloses that among a series of twelve pharmaceutically acceptable acids (the names of the specific pharmaceutical acids are not disclosed), only xanomeline tartrate has good bioavailability, good handling properties and reproducible crystal forms.

[0008] Currently, common knowledge generally teaches that selecting a salt with a desired combination of properties remains a difficult semi-empirical choice requiring a compromise selection of the properties of the salt forms, but there remains the difficulty of assessing which salt form is most suitable for screening a particular drug candidate.

[0009] The screening of drug salts is a difficult semi-empirical selection. The hygroscopicity of drugs can seriously affect the fluidity of drugs and even the stability of drugs. The solubility of drugs has a crucial impact on the preparation of drugs, drug dissolution, absorption, etc. However, it is difficult to improve the solubility of drugs without sacrificing the hygroscopicity of drugs and obtain candidate drug salts with suitable stability, solubility and hygroscopicity.

[0010] In addition, Xanomeline, as an M receptor activator, has shown promising results in the treatment of psychosis and related behavioral symptoms in patients with schizophrenia and AD, but its potential has been limited by cholinergic side effects, including salivation, nausea, dizziness, etc., which are believed to be caused by stimulation of M receptors in peripheral nerve tissue. Xanomeline's metabolism in the human body is complex and unpredictable, and Xanomeline lacks selectivity for muscarinic receptor subtypes, which has caused difficulties in the drug development of Xanomeline.

[0011] Therefore, it is necessary to further search for new compounds suitable for drug formulation that have good therapeutic effects, few side effects, and better pharmacokinetic properties; it is also necessary to develop crystalline salts and polymorphs of the compounds that have suitable and reliable formulation and preparation characteristics. Summary of the invention

[0012] The object of the present invention is to provide a malate of a xanomeline derivative shown in formula I, which can be used to prepare a drug for preventing or treating central nervous system disorders and has improved solubility, storage stability, convenient administration, improved drug metabolism, and improved drug toxicity and side effects, and high patient compliance during administration.

[0013] Another object of the present invention is to provide a crystal form A of a malate salt of a xanomeline derivative shown in formula I, wherein the crystal form A has excellent thermodynamic stability and mechanical stability, good reproducibility, and is suitable for large-scale commercial production.

[0014] In a first aspect, the present invention provides a malate salt of a compound of formula I.

[0015]

[0016] In some embodiments of the present invention, the malate salt of the compound of formula I is as shown in formula II, wherein x is selected from 0.5 to 2.

[0017]

[0018] In some embodiments of the present invention, the above x is 0.5, 1.0, 1.5, or 2.0.

[0019] In some embodiments of the present invention, in the compound of formula II above, x is 1.0.

[0020] In some embodiments of the present invention, in the compound of the above formula II, the malic acid is L-malic acid.

[0021] In a second aspect, the present invention provides a malate crystal form A of a compound of formula I, whose X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 14.827±0.2°, 16.796±0.2°, 20.012±0.2° and 21.942±0.2°. The malate crystal form A of the compound of formula I is a compound of formula II in which x is 1.0, and the malic acid therein is L-malic acid.

[0022] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 14.827±0.2°, 16.796±0.2°, 20.012±0.2°, 21.942±0.2°, 22.473±0.2° and 25.333±0.2°.

[0023] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 13.288±0.2°, 14.827±0.2°, 16.796±0.2°, 20.012±0.2°, 21.942±0.2°, 22.473±0.2° and 25.333±0.2°.

[0024] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 13.288±0.2°, 14.827±0.2°, 15.399±0.2°, 16.796±0.2°, 20.012±0.2°, 20.327±0.2°, 21.942±0.2°, 22.473±0.2° and 25.333±0.2°.

[0025] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 13.288±0.2°, 14.827±0.2°, 15.399±0.2°, 16.796±0.2°, 20.012±0.2°, 20.327±0.2°, 21.942±0.2°, 22.473±0.2°, 24.996±0.2°, 25.333±0.2° and 27.718±0.2°.

[0026] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 12.755±0.2°, 13.288±0.2°, 13.903±0.2°, 14.827±0.2°, 15.399±0.2°, 16.796±0.2°, 17.686±0.2°, 18.906±0.2°, 20.012±0.2°, 20.327±0.2°, 21.942±0.2°, 22.473±0.2°, 24.996±0.2°, 25.333±0.2° and 27.718±0.2°.

[0027] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 12.755±0.2°, 13.288±0.2°, 13.903±0.2°, 14.827±0.2°, 15.399±0.2°, 16.796±0.2°, 17.686±0.2°, 18.906±0.2°, 20.012±0.2°, 20.327±0.2°, 20.660±0.2°, 21.942±0.2°, 22.473±0.2°, 24.996±0.2°, 25.333±0.2°, 27.382±0.2° and 27.718±0.2°.

[0028] In some embodiments of the present invention, the above-mentioned A crystal form has substantially the following Figure 1 XRPD pattern shown.

[0029] In some embodiments of the present invention, the above-mentioned A crystal form has substantially the following Figure 2 DSC spectrum shown.

[0030] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form A has an endothermic peak at 111.03±3°C.

[0031] In some embodiments of the present invention, the above-mentioned A crystal form has substantially the following Figure 3 TGA curve shown.

[0032] In a third aspect, the present invention also provides a method for preparing a malate salt of a compound of formula I, comprising reacting the compound of formula I with malic acid.

[0033] In some embodiments of the present invention, the method for preparing the crystal form A of the malate salt of the compound of formula I comprises the following steps:

[0034] The compound of formula I, malic acid and a solvent are mixed, heated until completely dissolved, and then cooled to precipitate crystals; wherein the solvent is selected from ethanol, isopropanol, n-propanol, butanol, acetone, ethyl acetate, n-heptane, acetonitrile, tetrahydrofuran or a mixture of more than one thereof; preferably, ethanol, isopropanol, ethyl acetate, n-heptane or a mixture of more than one thereof; or

[0035] The compound of formula I, malic acid and a first solvent are mixed, heated until completely dissolved, and then a second solvent is added, cooled and crystallized. The first solvent is selected from one or a mixture of methanol, ethanol, isopropanol and n-butanol; the second solvent is selected from one or a mixture of methyl tert-butyl ether, esters, acetonitrile and alkanes, wherein the esters are selected from ethyl acetate and / or, the lipids are, for example, isopropyl acetate; the alkanes are selected from n-heptane and / or n-hexane.

[0036] In some embodiments of the present invention, the heating temperature is 50-80°C, such as 60-70°C.

[0037] In some embodiments of the present invention, the compound of formula I, malic acid and the solvent used to dissolve the compound or the first solvent are mixed and then stirred. The stirring time may be 1 to 5 hours, preferably 2 to 3 hours.

[0038] The weight / volume ratio (g / mL) of the compound of formula I to the solvent or the first solvent used to dissolve the compound is 1:4-10, preferably 1:6-8, such as 1:6, 1:7, 1:8.

[0039] In some embodiments of the present invention, the cooling may be to 0-30° C., preferably, to 2-8° C., for example, to 5° C. A filtration may be performed before cooling.

[0040] In some embodiments of the present invention, stirring is performed during the cooling process, and the stirring time may be 6 to 24 hours, preferably 18 hours.

[0041] According to the present invention, after the crystals are precipitated, they are filtered and dried; in some embodiments of the present invention, before drying, a step of optionally washing with a solvent is also included, and the washing solvent is selected from one or a mixture of more than one of ethanol, isopropanol, n-propanol, acetone, ethyl acetate, acetonitrile, and tetrahydrofuran.

[0042] In some embodiments of the present invention, the molar ratio of the compound of formula I to malic acid is 1:0.9-1.3. Preferably, the molar ratio of the compound of formula I to malic acid is 1:1-1.1, for example, 1:1, 1:1.05, or 1:1.1.

[0043] In a fourth aspect, the present invention provides a pharmaceutical composition comprising a malate salt of a compound of formula I or a malate A crystalline form of a compound of formula I, and an optional pharmaceutically acceptable excipient.

[0044] In a fifth aspect, the present invention provides the use of a malate of a compound of formula I, the malate Form A of the compound of formula I, or a pharmaceutical composition comprising the malate of a compound of formula I, or a pharmaceutical composition comprising the malate Form A of the compound of formula I in the preparation of a medicament for treating central nervous system disorders.

[0045] In some embodiments of the present invention, the central nervous system disorders include, but are not limited to, schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, drug addiction, pain, and neurodegeneration (eg, Tawe's disease or synucleinopathy).

[0046] In some embodiments of the present invention, the central nervous system disorder is schizophrenia.

[0047] In a sixth aspect, the present invention provides a method for treating or preventing a central nervous system disorder in a mammal (e.g., a human), the method comprising administering to the mammal (e.g., a human) a therapeutically effective amount of a malate salt of a compound of formula I, a malate Form A of a compound of formula I, a pharmaceutical composition comprising a malate salt of a compound of formula I, and a pharmaceutical composition comprising a malate Form A of a compound of formula I.

[0048] In some embodiments of the present invention, the central nervous system disorders include, but are not limited to, schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, drug addiction, pain, and neurodegeneration (eg, Tawe's disease or synucleinopathy).

[0049] In some embodiments of the present invention, the central nervous system disorder is schizophrenia.

[0050] Beneficial Effects

[0051] 1. The present invention provides for the first time a malate salt of a compound of formula I; the malate salt of a compound of formula I has excellent effects in at least one aspect, such as physical stability, solubility, hygroscopicity, biological activity, safety, bioavailability, and toxic and side effects.

[0052] 2. The malate form A of the compound of formula I has good stability, low hygroscopicity, good water solubility, small batch-to-batch differences, and good drug development prospects.

[0053] 3. The salt form and crystal form preparation process of the present invention is simple and suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 The XRPD pattern of the A crystal form of the L-malate salt of the compound of formula I;

[0055] Figure 2 The DSC spectrum of the A crystal form of the L-malate salt of the compound of formula I;

[0056] Figure 3 is the TGA spectrum of the A crystal form of the L-malate salt of the compound of formula I;

[0057] Figure 4 XRPD patterns of Form A of L-malate of the compound of Formula I at high temperature (60° C.) for 0 days, 6 days, 14 days, and 30 days;

[0058] Figure 5 XRPD patterns of Form A of L-malate of the compound of Formula I under high humidity (RH 92.5%) conditions at 0 days, 6 days, 14 days, and 30 days;

[0059] Figure 6 The XRPD spectra of Form A of L-malate of the compound of Formula I under illumination conditions (4500±500Lux) at 0 days, 6 days, 14 days and 30 days.

[0060] Figure 7 The pharmacokinetic curve of the compound of formula I in rat plasma after oral administration of the A crystal form of the L-malate of the compound of formula I (sample of Example 2) and the compound of formula I (sample of Example 1). DETAILED DESCRIPTION

[0061] The following will be further described in detail with reference to specific examples of the general formula compound of the present invention and its preparation method and application. It should be understood that the following examples are only for exemplary description and explanation of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies realized based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0062] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0063] The present invention uses the following abbreviations: rt stands for room temperature; aq stands for aqueous solution; DCM stands for dichloromethane; THF stands for tetrahydrofuran; MeOH stands for methanol; EtOH stands for ethanol; IPA stands for isopropanol; DSC stands for differential scanning calorimeter; TGA stands for thermogravimetric analysis; 1 H-NMR stands for proton nuclear magnetic resonance; XRPD stands for X-ray powder diffraction; eq stands for molar equivalent.

[0064] The compounds were named manually or using ChemDraw software, and commercially available compounds were named according to the supplier's catalog names.

[0065] The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0066] The test methods and instruments used in the embodiments of the present invention to characterize salts and crystals are as follows:

[0067] Powder X-ray diffraction (also known as "X-ray powder diffraction", X-ray powder diffractometer, XRPD) method

[0068] Instrument model: Bruker D8 advance X-ray diffractometer

[0069] Test method: About 10-20 mg of sample was used for XRPD detection.

[0070] The detailed XRPD parameters are as follows:

[0071] Light pipe: Cu, kα,

[0072] Light tube voltage: 40kV, light tube current: 40mA

[0073] Divergence slit: 0.60mm

[0074] Detector slit: 10.50mm

[0075] Anti-scatter slit: 7.10mm

[0076] Scanning range: 4-40 degrees

[0077] Step diameter: 0.02deg

[0078] Step length: 0.12 seconds

[0079] It should be noted that in the X-ray powder diffraction spectrum (XRPD), the diffraction spectrum obtained by the crystalline compound is often characteristic for a specific crystal, wherein the relative intensity of the spectral band (especially at low angles) may vary due to the preferred orientation effect caused by differences in crystallization conditions, particle size and other measurement conditions. Therefore, the relative intensity of the diffraction peak is not characteristic for the crystal targeted, and when judging whether it is the same as a known crystal, more attention should be paid to the relative position of the peak rather than their relative intensity. In addition, for any given crystal, there may be a slight error in the position of the peak, which is also well known in the field of crystallography. For example, due to changes in temperature, sample movement, or calibration of the instrument when analyzing the sample, the position of the peak can move, and the measurement error of the 2θ value is sometimes about ± 0.2 °. Therefore, this error should be taken into account when determining each crystalline structure. In XRPD spectra, the peak position is usually represented by the 2θ angle or the interplanar distance d, and there is a simple conversion relationship between the two: d = λ / 2sinθ, where d represents the interplanar distance (also known as "interplanar spacing"), λ represents the wavelength of the incident X-ray, and θ is the diffraction angle. For the same type of crystals of the same compound, the peak positions of their XRPD spectra are similar overall, and the relative intensity errors may be large. It should also be pointed out that in the identification of mixtures, some diffraction lines may be missing due to factors such as decreased content. At this time, there is no need to rely on all the bands observed in high-purity samples, and even one band may be characteristic for a given crystal.

[0080] The measurement differences associated with such X-ray powder diffraction analysis results are caused by a variety of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration differences, (d) operator errors (including errors that occur when determining peak positions), and (e) the nature of the material (e.g., preferred orientation errors). Calibration errors and sample height errors often result in displacements of all peaks in the same direction. When a flat support is used, small differences in sample height will result in large displacements of XRPD peak positions. Systematic studies have shown that sample height differences of 1 mm can result in peak displacements of up to 1° of 2θ. These displacements can be identified from the X-ray diffraction pattern and can be eliminated by compensating for the displacements (applying the system calibration factor to all peak position values) or recalibrating the instrument. As described above, by applying the system calibration factor to make the peak positions consistent, measurement errors from different instruments can be corrected.

[0081] Differential thermal analysis (also known as "Differential Scanning Calorimeter", DSC) method

[0082] Instrument model: METTLER TOLEDO DSC3+ Differential Scanning Calorimeter

[0083] Test method: Take a sample (~1 mg) and place it in a DSC aluminum pan for testing. Under 50mL / minN2 conditions, heat the sample from 25°C to 300°C at a heating rate of 10°C / min. Differential scanning calorimetry (DSC) is used in the present invention to determine the melting point. DSC measures the transition temperature when a crystal absorbs or releases heat due to changes in its crystal structure or melting of the crystal. For the same crystal of the same compound, in continuous analysis, the error of the thermal transition temperature and melting point is typically within about 5°C, usually within about 3°C. When we say that a compound has a given DSC peak or melting point, this refers to the DSC peak or melting point ±5°C. DSC provides an auxiliary method for distinguishing different crystals. Different crystalline forms can be identified based on their different transition temperature characteristics. It should be noted that for a mixture, its DSC peak or melting point may vary over a larger range. In addition, since decomposition is accompanied by the melting of the substance, the melting temperature is related to the heating rate.

[0084] Thermogravimetric analysis (TGA) method

[0085] Instrument model: TAQ5000IR thermogravimetric analyzer

[0086] Test method: Take a sample (2-5 mg) and place it in a TGA platinum pot for testing. Under 25 mL / min N2 conditions, heat the sample from room temperature to 350°C at a heating rate of 10°C / min.

[0087] High performance liquid chromatography (HPLC) analysis method:

[0088] The instrument used was Waters ARC 2998HPLC; chromatographic column: Agilent Poroshell bonus-RP 4.6×100mm, 2.7μm;

[0089] The measurement conditions are as follows:

[0090] Injection volume: 10ul;

[0091] Flow rate: 1.0 mL / min;

[0092] Detection wavelength: 275nm;

[0093] Sample concentration: 1.0 mg / mL;

[0094] Diluent: 20% acetonitrile aqueous solution;

[0095] Column temperature: 40°C;

[0096] Mobile phase A: 0.2% phosphoric acid in water;

[0097] Mobile phase B: acetonitrile-methanol (1:1) solution;

[0098] The elution gradient is shown in Table 1:

[0099] Table 1 Elution gradient conditions

[0100]

[0101]

[0102] Currently, common knowledge generally teaches that selecting a salt with a desired combination of properties remains a difficult semi-empirical choice requiring a compromise selection of the properties of the salt forms, but there remains the difficulty of assessing which salt form is most suitable for screening a particular drug candidate.

[0103] During the experiment, the inventors found that drug hygroscopicity can seriously affect the fluidity of the drug and even the stability of the drug. The solubility of the drug has a crucial impact on the preparation of the drug, drug dissolution, absorption, etc. However, it is difficult to improve the solubility of the drug without sacrificing the hygroscopicity of the drug and obtain a candidate drug salt with suitable drug stability, solubility and hygroscopicity.

[0104] After extensive and in-depth research, the inventors unexpectedly found that the malate of the compound of formula I has a high melting point as determined by DSC and confirmed by stability experiments: the malate of the compound of formula I has high stability. In addition, the malate of the compound of formula I has low hygroscopicity and appropriate solubility. The combination of high stability, low hygroscopicity and appropriate solubility of the malate of the compound of formula I is unexpected, which makes the malate of the compound of formula I (especially the L-malate of the compound of formula I) suitable for the preparation of oral solid preparations, especially the preparation of tablets.

[0105] The solubility of the active ingredient is of great significance for the choice of dosage form, because the dosage form has a direct impact on bioavailability. For oral dosage forms, it is generally believed that a higher solubility of the active ingredient is advantageous because it leads to improved bioavailability.

[0106] On this basis, the inventors discovered that the A crystal form of the malate salt of the compound of formula I has advantages in at least one aspect, namely, physical stability, thermodynamic stability and mechanical stability; the prepared A crystal form of the malate salt of the compound of formula I has a suitable crystal size and is suitable for industrial production.

[0107] A malate A crystal form of a compound of formula I can significantly improve the water solubility of the compound of formula I, and has good stability and extremely low hygroscopicity, which is conducive to preparing an oral solid preparation. The preparation made of the malate of the compound of formula I can maintain an effective physiological concentration of the free base of formula I in the body for a long time and is easy to administer, thereby having the advantages of improving patient compliance.

[0108] Example 1. Synthesis of compounds of formula I

[0109]

[0110] Step 1, Preparation of 2-hydroxy-2-(3-pyridyl)acetonitrile (Intermediate 1)

[0111] Add 3-pyridinecarboxaldehyde (6.00 g, 56.02 mmol, 1.0 eq), glacial acetic acid (3.36 g, 56.02 mmol, 1.0 eq) and 6 mL of pure water to a 100 mL single-mouth reaction bottle, and stir to mix at room temperature. Add trimethylsilyl cyanide (7.42 g, 74.42 mmol, 1.3 eq) in water at 2-8 °C, stir to react, and confirm the reaction is complete by TLC (thin layer chromatography). Cool to -5 °C in an ice-salt bath and stir to precipitate crystals. Filter, wash the filter cake with ice water (5 mL*3), and obtain a white solid (6.72 g, yield 89%).

[0112] 1 H NMR (400MHz, CDCl3) δ8.66–8.52(m,2H),7.96(m,1H),7.45(dd,J=8.0,4.9Hz,1H),5.64(s,1H).MS m / z:134.9[M+H] + .

[0113] Step 2, Preparation of 2-amino-2-(3-pyridyl)acetonitrile (Intermediate 2)

[0114] Add NH4Cl (1.81 g, 33.80 mmol, 1.5 eq), water (15.00 mL) and aqueous ammonia (4.80 mL, 25%, 1.1 eq) to a 50 mL two-necked reaction bottle in sequence, stir at room temperature until dissolved, add intermediate 1 (3.00 g, 22.37 mmol, 1.0 eq), and continue stirring for 20 hours. Extract with dichloromethane (15 mL*7), combine the organic phases, and dry with 2 g of anhydrous sodium sulfate for 5 minutes. Filter and evaporate to dryness under reduced pressure to obtain a reddish brown oil (1.30 g, yield 43%). Use it directly in the next step without purification.

[0115] Step 3, Preparation of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (Intermediate 3)

[0116] Add S2Cl2 (13.99 g, 103.62 mmol, 2.0 eq) and DMF (56.00 mL) to a 250 mL three-necked reaction bottle, cool in an ice-water bath and stir, then drop DMF (28.00 mL) to dissolve the intermediate 2 (6.90 g, 51.82 mmol, 1.0 eq) at 0-5 °C. Stir and react for 40 minutes, add 9 M NaOH (60 mL) at the same temperature and filter. Extract the aqueous phase with dichloromethane (120 mL*3), combine the organic phases, wash with pure water (80 mL*3), dry over anhydrous sodium sulfate and filter. Evaporate under reduced pressure to obtain a brown solid (7.99 g, yield 78%).

[0117] 1 H NMR (400MHz, CDCl3) δ9.24(s,1H),8.75(d,J=4.8Hz,1H),8.29(m,1H),7.46(dd,J=8.1,4.9Hz,1H).MS m / z: 197.8, 199.8[M+H] + .

[0118] Step 4, Preparation of 3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)pyridine (Intermediate 4)

[0119] To a 100mL three-necked reaction flask, 60% NaH (6.21g, 155.28mmol, 9.0eq) and tetrahydrofuran (9.00mL) were added in turn, and n-hexanol (6.27g, 61.47mmol, 3.0eq) diluted with tetrahydrofuran (18.00mL) was added dropwise at 0-5°C, and stirred at room temperature for 2 hours. Intermediate 3 (3.41g, 17.25mmol, 1.0eq) dissolved in tetrahydrofuran (15.00mL) was added dropwise to the system at room temperature and stirred magnetically for 3 hours. The reaction solution was washed with saturated sodium bicarbonate aqueous solution (30mL), and the aqueous phase was extracted with dichloromethane (30mL*3) and concentrated under reduced pressure. The crude product was subjected to column chromatography (petroleum ether (60-90) / ethyl acetate 5:1-3:1) to obtain an off-white solid (3.61g, yield 79%).

[0120] 1 H NMR (400MHz, CDCl3) δ9.40(d,J=2.2Hz,1H),8.65(dd,J=4.8,1.7Hz,1H),8.43(dt,J=8.0,2.0Hz,1H),7.40(dd ,J=8.1,4.8Hz,1H),4.53(t,J=6.6Hz,2H),1.89(m,2H),1.71(s,2H),1.44–1.29(m,4H),0.97–0.87(m,3H).MS m / z:264.0[M+H] + .

[0121] Step 5, Preparation of iodinated 1-deuterated methyl-3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)pyridine (Intermediate 5)

[0122] In a 100 mL three-necked reaction bottle, intermediate 4 (3.47 g, 13.2 mmol, 1.0 eq), acetone (50.00 mL) and deuterated iodomethane (5.72 g, 39.5 mmol, 3.0 eq) were added in sequence and stirred at room temperature for 24 hours. Intermediate 5 precipitated from the system and was filtered to obtain a bright yellow solid (5.18 g, yield 96%).

[0123] 1 H NMR (400MHz, CDCl3) δ9.68(m,1H),9.44(m,1H),9.14(dt,J=8.4,1.5Hz,1H),8.29(dd,J=8.3,6.0Hz,1 H),4.61(t,J=6.9Hz,2H),1.95(m,2H),1.55–1.45(m,2H),1.45–1.28(m,4H),0.92(t,J=7.0Hz,3H).MS m / z:281.0.

[0124] Step 6, preparation of deuterated Xanomeline (compound of formula I)

[0125] Add intermediate 5 (2.00 g, 4.9 mmol, 1.0 eq) and ethanol (24.00 mL) to a 250 mL three-necked reaction bottle and stir to dissolve. Add a suspension of NaBH4 (371 mg, 9.8 mmol, 2.0 eq) in ethanol (16.00 mL) dropwise at -5 to 0 °C and stir for 1 hour at the same temperature. Add pure water (100.00 mL) to quench, and extract the aqueous phase with dichloromethane (100 mL*3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was subjected to column chromatography (dichloromethane / methanol 20:1) to obtain a tan solid (1.11 g, yield 79%). Melting point: 38.26 °C.

[0126] 1 H NMR (400MHz, CDCl3) δ7.07(m,1H),4.44(t,J=6.6Hz,2H),3.46(m,2H),2.58(t,J=5.7H z,2H),2.46(m,2H),1.88–1.79(m,2H),1.46(m,2H),1.34(m,4H),0.91–1.79(m,3H).MS m / z:285.1[M+H] + .

[0127] Example 2. Preparation of L-malate A crystal form of the compound of formula I

[0128] Weigh the compound of formula I (10.0 g, 35.2 mmol) and L-malic acid (4.81 g, 35.8 mmol) into a flask, add 70 mL of isopropanol, heat to 60-70°C, stir and mix to completely dissolve the mixture, filter while hot to obtain a clear liquid, cool, reduce the temperature to 2-8°C, stir and crystallize, filter to obtain the product, wash with ice isopropanol to obtain a wet product, place the wet product at 40°C in a vacuum dryer to obtain a white solid (13.83 g, yield 93.9%) after drying, melting point 11.03°C. 1 H NMR (400MHz, CDCl3) δ7.22(m,1H),4.47(t,J=6.7Hz,2H),4.25(dd,J=9.6,4.5Hz,1H),4.12(s,2H), 3.29(s,2H),2.85–2.69(m,4H),1.85(m,2H),1.50–1.41(m,2H),1.35(m,4H),0.95–0.86(t,J=6.5Hz 3H).MS m / z:285.1[M+H] + .

[0129] The obtained white solid was sent for XRPD, DSC and TGA testing. After testing, it was found that the obtained white solid existed in the form of crystals. The obtained crystal form was named as L-malate crystal form A of the compound of formula I, referred to as crystal form A. The XRPD graph, DSC graph and TGA graph of the obtained crystal form A were basically as follows: Figure 1 , Figure 2 and Figure 3 In the X-ray powder diffraction pattern of the obtained crystal, the peak position and intensity of the characteristic peak are shown in Table 2; the diffraction angle data of the XRPD pattern of the obtained crystal form are basically shown in Table 3, where the 2θ value error range is ±0.2°.

[0130] Table 2. Peak positions and intensities of characteristic peaks in the X-ray powder diffraction pattern of Form A

[0131] serial number 2θ angle (°) Relative strength (%) serial number 2θ angle (°) Relative strength (%) 1 12.007 26.3 10 20.012 39.9 2 12.755 3.9 11 20.327 26.3 3 13.288 4.7 12 20.660 8.6 4 13.903 7.4 13 21.942 100.0 5 14.827 25.7 14 22.473 24.0 6 15.399 20.3 15 24.996 21.1 7 16.796 21.6 16 25.333 30.4 8 17.686 6.1 17 27.382 7.8 9 18.906 11.3 18 27.718 17.5

[0132] Table 3. XRPD analysis data of Form A

[0133]

[0134] Example 3: Preparation of L-malate A Crystalline Form of the Compound of Formula I

[0135] Add the compound of formula I (10.0 g, 35.2 mmol), L-malic acid (4.72 g, 35.2 mmol) and 40 mL of isopropanol into a 100 mL flask, heat the mixture until it is completely dissolved, and filter it while hot to obtain a clear solution. Slowly cool the solution to 2-8 ° C under stirring to crystallize, collect the product by filtration, wash with cold isopropanol, and vacuum dry at 40 ° C to obtain a white solid (13.3 g, yield 90.3%). The obtained product is the L-malate A crystal form of the compound of formula I.

[0136] Example 4. Preparation of L-malate A crystal form of the compound of formula I

[0137] Add the compound of formula I (4.9 g, 17.2 mmol), L-malic acid (2.54 g, 18.9 mmol) and 5 mL of methanol to a 100 mL flask, heat the mixture until it is completely dissolved, filter it while hot to obtain a clear solution. Then add 34 mL of ethyl acetate. Slowly cool the solution to 2-8 ° C under stirring to crystallize, collect the product by filtration, wash with cold ethyl acetate, and vacuum dry at 40 ° C to obtain a white solid (6.6 g, yield 91.7%). The obtained product is the L-malate A crystal form of the compound of formula I.

[0138] Example 5. Preparation of L-malate A crystal form of the compound of formula I

[0139] Add the compound of formula I (5.0 g, 17.6 mmol), L-malic acid (2.83 g, 21.1 mmol) and 12 mL of isopropanol to a 100 mL flask, heat the mixture until it is completely dissolved, filter it while hot to obtain a clear solution. Then add 38 mL of ethyl acetate. Slowly cool the solution to 2-8 ° C under stirring to crystallize, collect the product by filtration, wash with cold isopropanol, and vacuum dry at 40 ° C to obtain a white solid (6.8 g, yield 92.4%). The obtained product is the malate A crystal form of the compound of formula I.

[0140] Example 6. Preparation of L-malate A crystal form of the compound of formula I

[0141] Add the compound of formula I (1.0 g, 3.52 mmol), L-malic acid (0.6 g, 4.47 mmol) and 0.5 mL of methanol, 0.5 mL of methyl tert-butyl ether to a 50 mL flask, heat the mixture until it is completely dissolved, filter while hot to obtain a clear solution. Then add 5 mL of methyl tert-butyl ether to the solution. Slowly cool the solution to 2-8 ° C under stirring to crystallize, filter and collect the product, wash with cold methyl tert-butyl ether, and vacuum dry at 40 ° C to obtain a white solid (1.3 g, yield 88.4%). The obtained product is the malate A crystal form of the compound of formula I after testing.

[0142] Example 7. Preparation of Nitrate Salt of Compound of Formula I

[0143] Add 1085 mg of the compound of formula I and 3 mL of ethyl acetate to a 25 mL flask, stir the mixture until it is completely dissolved, and filter it while hot to obtain a clear solution. Add nitric acid to it while stirring until the pH value is between 3 and 4, then add 12 mL of methyl tert-butyl ether to it, stir and crystallize, filter and collect the product, wash with cold methyl tert-butyl ether, and vacuum dry at 40°C to obtain 1000 mg of a white solid with a yield of 75.5%. The obtained product is tested to be the nitrate of the compound of formula I. Melting point: 64.5°C (DSC). 1 H NMR (400MHz, CDCl3): δ12.31(brs,1H),7.26–7.23(m,1H),4.75–4.38(m,1H),4.47(t,J=6.7Hz,2H),4.00–3.56(m, 2H),3.26–2.86(m,2H),2.73–2.49(m,1H),1.85(quint,J=6.8Hz,2H),1.57–1.25(m,6H),0.91(t,J=6.9Hz,3H).MS m / z:285.2[M+H] + .

[0144] Example 8. Preparation of the succinate salt of the compound of formula I

[0145] Add 505 mg of the compound of formula I, 210 mg of succinic acid and 2 mL of isopropanol to a 50 mL flask, heat the mixture until it is completely dissolved, filter it while hot to obtain a clear solution, and then add 18 mL of ethyl acetate to it. Slowly cool the solution to 2-8 ° C under stirring to crystallize, filter and collect the product, wash with cold ethyl acetate, and vacuum dry at 40 ° C to obtain 630 mg of a white solid with a yield of 88.2%. The obtained product is tested to be the succinate of the compound of formula I. Melting point: 93.4 ° C (DSC). 1 H NMR (400MHz, CDCl3): δ7.23–7.12(m,1H),4.46(t,J=6.7Hz,2H),4.05–3.85(m,2H),3.22–2.98(m,2H), 2.77–2.52(m,2H),2.57(s,4H),1.85(quint,J=6.8Hz,2H),1.55–1.27(m,6H),0.91(t,J=6.6Hz,3H).MS m / z:285.1[M+H] + .

[0146] Example 9. Preparation of p-toluenesulfonate of compound of formula I

[0147] Add 501 mg of the compound of formula I, 337 mg of p-toluenesulfonic acid and 2 mL of isopropanol to a 50 mL flask, heat the mixture until it is completely dissolved, filter it while hot to obtain a clear solution, and then add 18 mL of ethyl acetate to it. Slowly cool the solution to 2-8 ° C under stirring to crystallize, filter and collect the product, wash it with cold ethyl acetate, and vacuum dry it at 40 ° C to obtain 720 mg of a white solid with a yield of 90%. The obtained product is p-toluenesulfonate of the compound of formula I after testing. 1 H NMR (400MHz, CDCl3): δ11.41(brs,1H),7.72(d,J=7.9Hz,2H),7.23–7.16(m,1H),7.12(d,J=7.9Hz,2H),4.60–4.40(m,1H),4.45(t,J=6.7Hz,2H ),3.90–3.66(m,2H),3.20–2.94(m,2H),2.70–2.45(m,1H),2.33(s,3H),1.84(quint,J=6.8Hz,1H),1.56–1.18(m,6H),0.91(t,J=6.8Hz,3H).MS m / z:285.1[M+H] + .

[0148] Example 10. Preparation of tartrate salt of compound of formula I

[0149] Add 3.0 g of the compound of formula I, 1.6 g of L-tartaric acid and 15 mL of isopropanol to a 100 mL flask, heat the mixture until it is completely dissolved, filter it while hot to obtain a clear solution, and then add 45 mL of ethyl acetate to it. Slowly cool the solution to 2-8 ° C under stirring to crystallize, filter and collect the product, wash with cold ethyl acetate, and vacuum dry at 40 ° C to obtain 4.2 g of a white solid with a yield of 91.5%. The obtained product is tested to be a tartrate of the compound of formula I. 1 H NMR(400MHz, CDCl3)δ7.16(1H,brs),4.43(4H,m),4.09(2H,brs),3.29(2H,brs) ,2.69(2H,brs),1.83(2H,m),1.43(2H,m),1.40(4H,m),0.9(t,J=6.5Hz,3H).MS m / z:285.1[M+H] + .

[0150] Example 11. Preparation of other salts of the compound of formula I

[0151] Methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, and adipic acid were selected and salted with the compound of formula I according to the preparation method of Examples 2-10, but no salt of the compound of formula I in solid form was obtained.

[0152] Test Example 1 Experimental determination of the physicochemical properties of the compounds and salts synthesized in Examples 1-10

[0153] 1. Melting point determination experiment

[0154] The melting points of the compound of formula I synthesized in Examples 1-10 (sample obtained in Example 1), L-malate A form of the compound of formula I (sample obtained in Example 2), nitrate of the compound of formula I (sample obtained in Example 7), succinate of the compound of formula I (sample obtained in Example 8), p-toluenesulfonate of the compound of formula I (sample obtained in Example 9), and tartrate of the compound of formula I (sample obtained in Example 10) were determined by differential scanning calorimetry (DSC). The melting points of different salt forms are shown in Table 4.

[0155] 2. Solubility Determination Experiment

[0156] Take seven portions of 2 mL of purified water and add the compound of formula I (sample obtained in Example 1), L-malate A crystal form of the compound of formula I (sample obtained in Example 2), nitrate of the compound of formula I (sample obtained in Example 7), succinate of the compound of formula I (sample obtained in Example 8), p-toluenesulfonate of the compound of formula I (sample obtained in Example 9), and tartrate of the compound of formula I (sample obtained in Example 10) successively until insoluble, and record the corresponding amount m, and visually estimate the solubility S=m / 2mL. After stirring for another 24 hours, take the supernatant and send it to HPLC for analysis, and the measured solution concentration is the solubility determined by the HPLC analysis method. The solubility results of different salt forms in water are shown in Table 4. The solubility in this experiment was determined at ambient temperature (the actual measured ambient temperature was 10°C).

[0157] 3. Hygroscopicity investigation

[0158] Take appropriate amount of each sample synthesized in Examples 1, 2, 7-10, accurately weigh, and weigh to obtain a weight of m1. Spread the sample flat in a flat weighing bottle, and weigh the total weight to obtain m2. After placing it at 25±1°C and 80±1%RH for 24 hours, weigh it to obtain m3. The moisture absorption weight gain ΔW is calculated by the following formula: ΔW=(m3-m2) / m1*100%. The moisture absorption weight gain results of different salt types are shown in Table 4.

[0159] See Table 5 for the hygroscopicity evaluation index:

[0160] Table 4. Physicochemical properties of each sample

[0161] sample Melting point / ℃ Solubility S (mg / mL) Moisture absorption weight gain ΔW / % Compound of formula I (Example 1) 38.26 <![CDATA[S<1.07 a ]]> NA L-malate A crystal form of the compound of formula I (Example 2) 111.03 <![CDATA[40.48 a ]]> 1.97 Nitrate of the compound of formula I (Example 7) 64.59 <![CDATA[S>244.2 b ]]> Forms liquid after absorbing moisture Succinate of the compound of formula I (Example 8) 93.43 <![CDATA[7.99 a ]]> 17.00 p-Toluenesulfonate of the compound of formula I (Example 9) 112.50 <![CDATA[5.39 a ]]> 1.00 Tartrate of the compound of formula I (Example 10) 95.9 <![CDATA[86.05<S<98.9 b ]]> 3.03

[0162] In Table 4, a: solubility was measured by HPLC; b: solubility was measured by visual observation. NA means not measured.

[0163] Table 5. Hygroscopicity evaluation index

[0164] Hygroscopicity classification Moisture absorption weight gain (ΔW%) deliquescence Absorbs enough water to form a liquid Highly hygroscopic ΔW%≥15% Hygroscopic 2%≤ΔW%<15% Slightly hygroscopic 0.2%≤ΔW%<2% No or almost no hygroscopicity ΔW%<0.2%

[0165] Melting point determination experimental results: The melting point of the L-malate of the compound of formula I is 111.03° C., and the L-malate of the compound of formula I has good stability.

[0166] Solubility determination experimental results: The solubility of L-malate of the compound of formula I is 40.48 mg / mL, and the solubility of L-malate of the compound of formula I is good.

[0167] Hygroscopicity test results: The moisture absorption weight gain of the L-malate of the compound of formula I at 25±1°C and 80±1%RH is 1.97%, indicating that the L-malate of the compound of formula I is slightly hygroscopic.

[0168] Analysis of experimental results: The L-malate salt of the compound of formula I has a higher melting point (ie, higher stability), lower hygroscopicity, and appropriate solubility, which makes the malate salt of the compound of formula I suitable for the preparation of oral solid preparations, especially tablets.

[0169] Test Example 2. Study on the physical stability of the salts prepared in Examples 2, 7-10

[0170] The L-malate A form of the compound of formula I (sample obtained in Example 2), the nitrate of the compound of formula I (sample obtained in Example 7), the succinate of the compound of formula I (sample obtained in Example 8), the p-toluenesulfonate of the compound of formula I (sample obtained in Example 9), and the tartrate of the compound of formula I (sample obtained in Example 10) were respectively opened and spread out flat, and the stability test of the samples was carried out under high temperature (60°C), high humidity (RH92.5%), and light (4500±500Lux) conditions, and the contents of the active substance (compound of formula I or xanomeline) and related substances in the samples at different sampling times (0 day, 6 days, 14 days, and 30 days) were determined, as shown in Table 6.

[0171] Table 6. Stability test of salt forms

[0172]

[0173]

[0174] In Table 6, a: Nitrate of the compound of formula 1 is liquid under high temperature conditions and its physical properties are unstable. NA means not determined.

[0175] From the results in Table 6 above, it can be seen that the impurity content of the L-malate A crystal form of the compound of formula I of the present invention is very low, and the stability under high temperature, high humidity and light conditions is very good, and it has good drug development prospects; unexpectedly, the malate A crystal form of the compound of formula I is more stable than other salt forms under light conditions, which is convenient for the storage of raw materials and pharmaceutical preparations.

[0176] Test Example 3. Study on the toxicity and side effects of different salt types

[0177] Experimental materials: SD rats (purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., production license number: SCXK (Beijing) 2016-0006), compound of formula I (Example 1), malate of compound of formula I (Example 2), tartrate of compound of formula I (Example 10), and purified water (homemade).

[0178] Experimental method: 24 SD rats were randomly divided into 4 groups (6 rats in each group) and administered by oral gavage. The malate solution of the compound of formula I (the sample obtained in Example 2), the tartrate solution of the compound of formula I (the sample obtained in Example 10), the aqueous solution of xanomeline (the sample obtained in Example 1) and an appropriate amount of purified water were administered at a dose of 30 mg / kg (in terms of free base). The mental state of the SD rats was observed before and after administration, and the salivation of the SD rats in each group after administration was observed, and the number of salivating rats was recorded. If any abnormality occurs before and during administration, it should be recorded in time. The specific results are shown in Table 7.

[0179] Table 7. Side effects induced by different salt types

[0180] Group Number of salivating rats L-malate A crystal form of the compound of formula I (Example 2) 0 Tartrate of the compound of formula I (Example 10) 1 Compound of formula I (Example 1) 1 Purified water 0

[0181] Analysis of experimental results: Xanomeline is an M receptor activator, which can not only act on the central nervous system, but also stimulate M receptors in peripheral nerve tissue, thereby causing cholinergic side effects such as salivation, nausea, dizziness, etc. This experiment evaluated the toxic and side effects of each compound by observing the salivation of SD rats in each group. The experimental results show that the L-malate A crystal form of the formula I compound has small cholinergic side effects and good safety.

[0182] Test Example 4 Study on the polymorphic form of L-malate salt of Formula I compound

[0183] The L-malate A crystal form of the compound of formula I prepared by the method of Example 2 was suspended and slurried in the solvent shown in Table 8, stirred at 40° C. in the dark for 2 days, and the solution was centrifuged to remove the precipitate and dried, and then detected by XRPD. The results are shown in Table 8:

[0184] Table 8. Test solvents

[0185]

[0186] The results in the above table show that Form A has good stability and can remain stable in different solvent systems.

[0187] Test Example 5. Accelerated experimental study on the stability of the L-malate A crystal form of the compound of formula I

[0188] The L-malate A crystal form sample of the compound of formula I obtained by the method of Example 2 was laid open to examine the chemical stability of the sample under high temperature (60°C), high humidity (RH92.5%) and light conditions (4500±500Lux). A certain amount of samples were taken at 0 days, 7 days, 14 days and 30 days to detect the sample purity (detected by HPLC) and the sample crystal form, so as to evaluate the stability of the deuterated xanomeline malate A crystal form. The experimental results are shown in Table 9.

[0189] Table 9. Results of the physical and chemical stability test of Form A

[0190]

[0191] After experiments and Figure 4 , Figure 5 and Figure 6 The XRPD patterns shown in FIG. 1 show that the XRPD patterns of the malate A crystal form of the compound of formula I at 0 days, 6 days, 14 days, and 30 days are similar to those of the malate A crystal form under high temperature (60°C), high humidity (RH92.5%), and light conditions (4500±500Lux). Figure 1 The XRPD patterns of crystal form A are basically the same, and the stability of crystal form A is good. After 30 days of accelerated stability test under high temperature (60°C), high humidity (RH92.5%) and light conditions (4500±500Lux), the purity of crystal form A remained basically unchanged, no impurities were generated, and crystal form A did not change.

[0192] Test Example 6. Pharmacokinetic study of different salt forms

[0193] Experimental materials: male SD rats (weight 180-220 g, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., production license number: SCXK (Beijing) 2016-0006), L-malate A form of the compound of formula I (Example 2), the compound of formula I (Example 1), and purified water (self-made).

[0194] Experimental method: Six male SD rats were randomly divided into two groups (3 rats in each group). They were allowed to drink water freely during the experiment, fasted for more than 12 hours before administration, and fed 4 hours after administration. The two groups of SD rats were given an aqueous solution of the malate A crystal form of the compound of formula I and an aqueous solution of the compound of formula I at a dose of 30 mg / kg (in terms of free base) by oral gavage. Blood samples were collected into K2EDTA anticoagulant tubes at 0 min before administration, 15 min, 30 min, 45 min, 1.0 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 10 h after administration, and temporarily stored on ice until centrifugation. Plasma must be centrifuged within 60 min after blood collection (centrifuged at 8000 rpm for 5 min at 2-8 ° C). After centrifugation, the plasma was transferred to a 96-well plate or centrifuge tube, transported in an ice box, and stored at ≤-15 ° C until LC-MS / MS detection. The drug concentration in SD rat plasma was determined by LC-MS / MS bioanalysis, and the non-compartmental model was used to analyze the drug concentration in SD rat plasma using WinNonlin TM (Version 8.3, Certara, USA) was used to analyze the blood drug concentration-time data and evaluate its pharmacokinetic (PK) properties in SD rats. The data are shown in Table 10.

[0195] Table 10. Pharmacokinetic parameters of different compounds

[0196]

[0197] It can be seen from the data in Table 10 that after rats were given L-malate A crystal form of the compound of formula I, T max (peak time) is short and can quickly reach therapeutically effective concentrations; C max (Peak concentration) is moderate, and while achieving a good therapeutic effect, it can effectively reduce cholinergic side effects and has good bioavailability.

[0198] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A malate salt of a compound of formula I, in, The malate salt of the compound of formula I is shown in formula II, Wherein, the malate salt of the compound of formula I is crystal form A, which is a compound of formula II wherein x is 1.0, and the malic acid therein is L-malic acid, The X-ray powder diffraction pattern of the A crystal form has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 13.288±0.2°, 14.827±0.2°, 15.399±0.2°, 16.796±0.2°, 20.012±0.2°, 20.327±0.2°, 21.942±0.2°, 22.473±0.2° and 25.333±0.2°.

2. The malate salt of the compound of formula (I) according to claim 1, wherein The X-ray powder diffraction pattern of the A crystal form has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 13.288±0.2°, 14.827±0.2°, 15.399±0.2°, 16.796±0.2°, 20.012±0.2°, 20.327±0.2°, 21.942±0.2°, 22.473±0.2°, 24.996±0.2°, 25.333±0.2° and 27.718±0.2°.

3. The malate salt of the compound of formula I according to claim 1, wherein The X-ray powder diffraction pattern of the A crystal form has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 12.755±0.2°, 13.288±0.2°, 13.903±0.2°, 14.827±0.2°, 15.399±0.2°, 16.796±0.2°, 17.686±0.2°, 18.906±0.2°, 20.012±0.2°, 20.327±0.2°, 21.942±0.2°, 22.473±0.2°, 24.996±0.2°, 25.333±0.2° and 27.718±0.2°.

4. The malate salt of the compound of formula I according to claim 1, wherein The X-ray powder diffraction pattern of the A crystal form has characteristic diffraction peaks at the following 2θ angles: 12.007±0.2°, 12.755±0.2°, 13.288±0.2°, 13.903±0.2°, 14.827±0.2°, 15.399±0.2°, 16.796±0.2°, 17.686±0.2°, 18.906±0.2°, 20.012±0.2°, 20.327±0.2°, 20.660±0.2°, 21.942±0.2°, 22.473±0.2°, 24.996±0.2°, 25.333±0.2°, 27.382±0.2° and 27.718±0.2°.

5. The malate salt of the compound of formula I according to claim 1, wherein The Form A has an XRPD pattern substantially as shown in FIG1 .

6. The malate salt of the compound of formula (I) according to claim 1, wherein The A crystal form has a DSC spectrum substantially as shown in FIG2 .

7. The malate salt of the compound of formula (I) according to claim 1, wherein The differential scanning calorimetry curve of the A crystal form has an endothermic peak at 111.03±3°C.

8. The malate salt of the compound of formula (I) according to claim 1, wherein The A crystal form has a TGA curve substantially as shown in FIG. 3 .

9. A method for preparing a malate salt of a compound of formula I according to any one of claims 1 to 8, comprising reacting the compound of formula I with malic acid.

10. The preparation method according to claim 9, wherein The preparation method of the A crystal form of malate of the compound of formula I comprises the following steps: mixing the compound of formula I, malic acid and a solvent, heating, cooling, and precipitating crystals; wherein the solvent is selected from one or a mixture of more than one of ethanol, isopropanol, n-propanol, butanol, acetone, ethyl acetate, n-heptane, acetonitrile, and tetrahydrofuran; or; The compound of formula I, malic acid and a first solvent are mixed, heated until completely dissolved, and then a second solvent is added, cooled, and crystallized; wherein the first solvent is selected from one or a mixture of methanol, ethanol, isopropanol, and n-butanol; the second solvent is selected from one or a mixture of methyl tert-butyl ether; ethyl acetate, isopropyl acetate; acetonitrile; and n-heptane and n-hexane.

11. A pharmaceutical composition, wherein: The pharmaceutical composition comprises a malate salt of a compound of formula I according to any one of claims 1 to 8 and an optional pharmaceutically acceptable excipient.

12. Use of a malate salt of a compound of formula I according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 11 in the preparation of a medicament for treating a central nervous system disorder; the central nervous system disorder is selected from schizophrenia and Alzheimer's disease.

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