Crystal form of (R)-3-[(benzodioxolane-4-yl) oxy]-N, N-dimethyl-3-(4-fluorophenyl) propylamine oxalate as well as preparation method and application of crystal form of (R)-3-[(benzodioxolane-4-yl) oxy]-N, N-dimethyl-3-(4-fluorophenyl) propylamine oxalate

Abstract

The invention relates to a compound (R)-3-[(benzo [d] [1, 3] dioxolane-4-yl) oxy]-N, N-dimethyl-3-(4-fluorophenyl) propylamine oxalate, a crystal form, a preparation method and application thereof, a pharmaceutical composition containing a therapeutically effective amount of salt and crystal form of the compound, and application of the pharmaceutical composition in preparation of medicines for preventing and / or treating mental diseases.

Description

[0001] This application claims the Chinese patent application No. 202311429289.4 filed on October 31, 2023, and the application The priority of Chinese patent application No. 202311429519.7, filed on October 31, 2023, is hereby incorporated by reference in its entirety. For reference. Technical Field

[0002] The present invention belongs to the technical field of drug synthesis, and particularly relates to a crystal form of (R)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate, a preparation method and an application thereof. Background Art

[0003] Depression is the most common mental illness that harms human physical and mental health. Currently, depression patients account for 3-5% of the world's population. Drug therapy is the main means of treating depression. The main therapeutic drugs include: tricyclic antidepressants, such as imipramine, etc.; monoamine oxidase inhibitors, such as moclobemide, etc.; selective 5-HT reuptake inhibitors, such as fluoxetine, etc.; selective NE reuptake inhibitors, such as boricetin, etc.; 5-HT and NE dual reuptake inhibitors, such as duloxetine, etc.

[0004] Although there are many antidepressants used in clinical practice, some drugs have low response rates, long onset time, and potential side effects. There are still a considerable number of patients who have not responded to various treatments, and some still need electroconvulsive therapy. Therefore, the development of antidepressants is still a hot topic in new drug research. Patent application WO2016101898A discloses a class of 3-[(benzo[d][1,3]dioxolan-4-yl)-oxy]-3-arylpropylamine compounds with antidepressant activity, all of which are hereby added to the present invention by reference. Summary of the invention

[0005] Based on patent application WO2016101898A, the inventors further discovered that a specific R-isomer of 3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate (hereinafter referred to as compound of formula I) has good antidepressant activity, and compared with the S-isomer and the racemate, the compound of formula I has a lower minimum effective dose, a half effective dose and less toxicity.

[0006] In addition, the crystal structure of the active pharmaceutical ingredient often affects the chemical stability of the drug. Different crystal forms, preparation methods and storage conditions may lead to changes in the crystal structure of the compound, and sometimes other forms of crystals may be produced. Generally speaking, amorphous drug products do not have a regular crystal structure and often have other defects, such as poor product stability, difficulty in filtration, easy agglomeration, poor fluidity, etc. These differences often lead to difficulties in production scale-up. Therefore, it is necessary to improve the properties of the compound in various aspects through crystal morphology, and in-depth research is needed to find new crystal forms with high crystal purity and good chemical stability.

[0007] The technical problem to be solved by the present invention is to provide a compound as shown in the following formula I, namely (R)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate, and its crystalline form I, crystalline form II and crystalline form III

[0008]

[0009] The present invention also provides methods for preparing the crystal form I, the crystal form II and the crystal form III, and uses of the crystal form I, the crystal form II or the crystal form III in preparing drugs for preventing and / or treating mental illnesses.

[0010] The above-mentioned crystal form has good crystal stability and chemical stability, is easier to obtain, is convenient for industrial preparation, and can be better applied in clinical practice. DETAILED DESCRIPTION

[0011] The object of the present invention is to provide a compound as shown in the following formula I, namely (R)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate

[0012]

[0013] The present invention also provides a crystalline form I of the compound (R)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate as shown in formula I, wherein: the X-ray powder diffraction spectrum of the crystalline form I comprises diffraction peaks at 2θ of 9.33±0.2°, 15.64±0.2° and 23.63±0.2°.

[0014] Preferably, the X-ray powder diffraction pattern of the crystalline form I further comprises diffraction peaks at 2θ of 16.48±0.2°, 19.77±0.2°, 20.06±0.2°, 22.09±0.2°, 23.06±0.2° and 24.21±0.2°.

[0015] Further preferably, the crystal form I uses Cu-Kα radiation, and its X-ray diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are as shown in Table 1.

[0016] Table 1 XRPD diffraction data of Form I

[0017]

[0018]

[0019] In one embodiment, the Raman spectrum of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate Form I is 3069.2±2 cm -1 、2966.6±2cm -1 、1753.3±2cm -1 、1603.0±2cm -1 、1447.2±2cm -1 、1354.6±2cm -1 、1218.8±2cm -1 、1158.8±2cm -1 、1051.4±2cm -1 、927.5±2cm -1 、867.0±2cm -1 、833.6±2cm -1 、721.2±2cm -1 and 674.3±2cm -1 One or more characteristic peaks are displayed in the .

[0020] In one embodiment, the melting endothermic peak of the DSC graph of (R)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate Form I is selected from 126.8°C-132.2°C, preferably 129.8°C.

[0021] More preferably, the X-ray powder diffraction pattern of (R)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate Form I is substantially as follows: Figure 1 As shown; its Raman spectrum is basically as Figure 2 As shown; its DSC spectrum is basically as Figure 3 As shown, its TG spectrum is basically as Figure 4 shown.

[0022] The present invention also provides a crystalline form II of (R)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate, wherein: the X-ray powder diffraction spectrum of the crystalline form II comprises diffraction peaks at 2θ of 15.07±0.2°, 16.71±0.2°, and 22.76±0.2°.

[0023] Preferably, the X-ray powder diffraction pattern of the crystalline form II further comprises diffraction peaks at 2θ of 11.38±0.2°, 16.01±0.2°, 19.71±0.2°, 22.05±0.2° and 29.03±0.2°.

[0024] Further preferably, the crystal form II uses Cu-Kα radiation, and its X-ray diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 2.

[0025] Table 2 XRPD diffraction data of Form II

[0026]

[0027]

[0028] In one embodiment, the Raman spectrum of (R)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate Form II is 3073.5±2 cm -1 、2972.0.±2cm -1 、1603.0±2cm -1 、1460.4±2cm -1 、1357.4±2cm -1 、1219.1±2cm -1 、1154.5±2cm -1 、886.5±2cm -1 、862.9±2cm -1 、826.3±2cm -1 、772.3±2cm -1 and 699.1±2cm -1 One or more characteristic peaks are displayed in the .

[0029] In one embodiment, the melting endothermic peak of the DSC chart of (R)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate Form II is selected from 116.9°C-123.0°C, preferably 120.2°C.

[0030] More preferably, the X-ray powder diffraction pattern of (R)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate Form II is substantially as follows: Figure 5 As shown; its Raman spectrum is basically as Figure 6 As shown; its DSC spectrum is basically as Figure 7 As shown, its TG spectrum is basically as Figure 8 shown.

[0031] The present invention also provides a crystalline form III of (R)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate, wherein: the X-ray powder diffraction spectrum of the crystalline form III comprises diffraction peaks at 2θ of 13.64±0.2°, 15.14±0.2° and 22.86±0.2°.

[0032] Preferably, the X-ray powder diffraction pattern of the crystalline form III further comprises diffraction peaks at 2θ of 8.27±0.2°, 11.24±0.2°, 16.18±0.2°, 17.06±0.2°, 18.01±0.2°, 18.36±0.2°, 18.99±0.2° and 23.18±0.2°.

[0033] Further preferably, the crystal form III uses Cu-Kα radiation, and its X-ray diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 3.

[0034] Table 3 XRPD diffraction data of Form III

[0035]

[0036]

[0037] In one embodiment, the Raman spectrum of (R)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate Form III is 3075.9±2cm -1 、2970.6±2cm -1 、1603.3±2cm -1 、1500.2±2cm -1 、1458.1±2cm -1 、1219.3±2cm -1 、1154.8±2cm -1 、1045.3±2cm -1 、885.7±2cm -1 、862.8±2cm-1 、826.5±2cm -1 、772.4±2cm -1 and 699.6±2cm -1 One or more characteristic peaks are displayed in the .

[0038] In one embodiment, the DSC melting endothermic peak of (R)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate form III is selected from 119.7°C-125.1°C, preferably 122.6°C.

[0039] More preferably, the X-ray powder diffraction pattern of (R)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate Form III is substantially as follows: Fig. 9 As shown; its Raman spectrum is basically as Fig.10 As shown; its DSC spectrum is basically as Fig.11 As shown, its TG spectrum is basically as Fig.12 shown.

[0040] According to any embodiment of the first aspect of the present invention, the crystalline form I, crystalline form II and crystalline form III can be prepared by conventional crystallization methods such as solvent removal method, anti-solvent method and static crystallization method. The selection of suitable solvents, crystallization conditions, etc. can be achieved by those skilled in the art through experiments and screening based on the technical knowledge they have mastered.

[0041] For example, the solvent removal method is to completely dissolve the sample using a suitable solvent system, and then remove the solvent slowly, at a normal speed or quickly under certain conditions (such as vacuum, specific temperature), thereby promoting the precipitation and formation of crystals.

[0042] The anti-solvent rule is a method of adding a solute in a good solvent into a poor solvent so that the solubility of the solute in the mixed solvent system is significantly reduced, thereby causing coagulation or precipitation to form solid crystals.

[0043] The static crystallization method is a process in which a solute is dissolved in a solvent and then allowed to stand to gradually aggregate, nucleate and grow into crystals under the influence of factors such as concentration gradient, temperature gradient or solvent evaporation.

[0044] The "good solvent" described in the present invention refers to a solvent that can effectively dissolve a specific solute, so that the solute molecules can be fully dispersed and stretched in the solvent, including soluble, soluble, slightly soluble or slightly soluble; the "poor solvent" refers to a solvent that cannot effectively dissolve a specific solute, resulting in a low solubility of the solute, such as almost insoluble or insoluble. According to the solubility experiment of Test Example 1 described in detail below, a good solvent or a poor solvent or a combination thereof suitable for the preparation of a crystal form can be conveniently selected. The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of (R)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate as described above or the crystalline form I as described above or the crystalline form II as described above or the crystalline form III as described above, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0045] The present invention further relates to the use of the (R)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate as described above, or the crystalline form I as described above, or the crystalline form II as described above, or the crystalline form III as described above, or a pharmaceutical composition thereof in the preparation of drugs.

[0046] In a preferred embodiment of the present invention, the drug is used in a drug for preventing and / or treating mental illness.

[0047] In a further preferred embodiment of the present invention, the mental illness is selected from one or more of anxiety disorder, obsessive-compulsive disorder, depression, phobia and schizophrenia.

[0048] In a further preferred embodiment of the present invention, the mental illness is depression.

[0049] General Terms and Definitions

[0050] Different terms such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" all express the same meaning, that is, X can be any one or more of A, B, C.

[0051] "Room temperature" refers to a temperature from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature from 15°C to 30°C; in other embodiments, "room temperature" refers to a temperature from 18°C ​​to 25°C.

[0052] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. The term "NMP" is N-methylpyrrolidone; the term "DMF" is N,N-dimethylformamide; the term "DMSO" is dimethyl sulfoxide; the term "EA" is ethyl acetate.

[0053] The "crystalline form I" described in the present invention refers to the crystalline form I of the compound of formula I.

[0054] The "crystalline form II" described in the present invention refers to the crystalline form II of the compound of formula I.

[0055] The "crystalline form III" described in the present invention refers to the crystalline form III of the compound of formula I.

[0056] The "boiling point" mentioned in the present invention refers to the boiling point or azeotropic point of a pure solvent or a mixed solvent.

[0057] "Pharmaceutical composition" refers to a mixture containing one or more compounds described in the present invention or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredients, and thus exert biological activity.

[0058] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.

[0059] The term "crystalline solid" as used herein means a crystal having a certain crystal form and formed by the regular arrangement of atoms, ions, molecules, etc. constituting the solid. Unless otherwise specified, "crystal" in this specification is synonymous with "crystalline solid" and "crystal form". The degree of crystallinity of a crystalline form can be measured by a variety of techniques, including, for example, X-ray powder diffraction measurement, water adsorption and desorption measurement, differential scanning calorimetry, solution colorimetry, solubility characteristics, etc.

[0060] The crystalline solid can be a single crystal, a twin crystal, a polycrystal, etc., usually a single crystal or a mixed crystal thereof. The morphology (appearance) of the crystal is not particularly limited, for example, it can be triclinic, monoclinic, orthorhombic (rectangular), tetragonal, cubic, trigonal (rhombohedral), hexagonal, etc., or it can be spherulite, skeleton crystal, bark-like crystal, needle-like crystal (e.g., whisker-like crystal), etc. The size of the crystal is not particularly limited, for example, based on the laser diffraction method, the average particle size of the crystal can be 0.5 μm to 1 mm, preferably about 1 to 500 μm.

[0061] In addition, the crystalline solid of the compound may also absorb water due to changes in relative humidity, that is, the water molecules in the air may easily enter and exit the crystalline solid in the lattice in the form of crystal water due to changes in external humidity; for such crystalline solid, even if the X-ray powder diffraction pattern changes slightly with changes in water content, as long as it has the characteristic peaks recorded in this specification, it can be interpreted as substantially the same crystalline solid. The water may be any of residual solvents such as crystal water and adhering water.

[0062] "Polymorph" or "polymorphs" refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms and or ions that make up the crystal. Although polymorphs have the same chemical composition, they differ in their packing and geometric arrangement and may exhibit different physical properties, such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution rate and the like. Depending on their temperature-stability relationship, the relative stability of the two solid phases is swapped. This phenomenon of a compound existing in different lattice structures is called pharmaceutical polymorphism.

[0063] The crystal structures equivalent to the crystal structures disclosed or claimed in the present invention may show similar but not identical analytical characteristics within a reasonable error range according to experimental conditions, purity, equipment and other common variables known to those skilled in the art. Accordingly, it will be apparent to those skilled in the art that various modifications and changes can be made within the present invention without departing from the scope and spirit of the present invention. On the basis of considering the specification and practice of the present invention disclosed herein, other embodiments of the present invention are apparent to those skilled in the art. Applicants expect that the specification and embodiments are considered exemplary, rather than limiting their scope.

[0064] "X-ray powder diffraction pattern" or "XRPD" means the powder diffraction pattern of a particle according to the Bragg formula 2d sinθ = nλ (where λ is the wavelength of the X-rays, The diffraction order n is any positive integer, generally the first diffraction peak is taken, n=1), and the "2θ or 2θ angle" refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree. When X-rays are incident on a certain atomic plane with d lattice plane spacing of a crystal or a part of a crystal sample at a grazing angle θ (the complementary angle of the incident angle, also called the Bragg angle), the Bragg equation can be satisfied, thereby measuring this set of X-ray powder diffraction patterns.

[0065] It is well known to those skilled in the art that XRPD may produce certain displacement and intensity deviations due to sample tiling thickness, detection methods, conditions and instruments. The same sample of the same crystal form usually has the same main XRPD characteristic peak, but there may be certain operating errors. When the same crystal form sample obtained by the same method is detected by the same instrument and detection method by the ordinary technicians in the art, the characteristic peak error is usually within ±0.2°. However, different technicians using different instruments may occasionally have a few characteristic peaks with errors exceeding this range. For example, the error within ±0.5° or ±0.3° should be considered to belong to the XRPD characteristic peak of the same crystal form. Therefore, as a specific example of the crystal form of the present invention, its XRPD is shown in spectrum X, but the ordinary technicians understand that when the 2θ deviation of the key characteristic peak displacement is within ±0.5°, ±0.3° or ±0.2°, especially around ±0.2°, it can be identified as the same crystal form and can be interpreted as within the scope of protection of the present invention.

[0066] In addition, the absolute intensity and relative intensity of the peaks shown in the above tables and figures may vary due to various factors, such as the effect of the selective orientation of the crystalline solid on the X-ray beam, the influence of coarse particles, the purity of the substance being analyzed, or the crystallinity of the sample. In addition, the peak position may also shift according to the change in the sample height. Furthermore, if different wavelengths are used for measurement, different displacement values ​​are obtained according to the Bragg formula (nλ=2dsinθ), and such different XRPD patterns obtained by using different wavelengths are also included in the scope of the present invention.

[0067] "Interplanar spacing or interplanar spacing (d value)" refers to the selection of three non-parallel unit vectors a, b, c connecting two adjacent lattice points in the space lattice. They divide the lattice into juxtaposed parallelepiped units, which are called interplanar spacing. The space lattice is divided according to the determined parallelepiped unit connection lines to obtain a set of straight line grids, called space grids or lattices. The lattice and lattice use geometric points and lines to reflect the periodicity of the crystal structure. Different crystal planes have different interplanar spacings (that is, the distance between two adjacent parallel crystal planes); the unit is Or Angstrom.

[0068] “Relative intensity (I%)” refers to the ratio of the intensity of other peaks to the intensity of the first strongest peak among all diffraction peaks in an X-ray powder diffraction pattern (XRPD) when the intensity of the first strongest peak is 100%.

[0069] "Differential Scanning Calorimetry or DSC" measures the transition temperatures of a crystal when heat is absorbed or released as a result of changes in its crystal structure or melting of the crystal. For the same crystalline form of the same compound, the thermal transition temperatures and melting points can be within about 5°C, usually within about 3°C, in consecutive analyses. When a compound is described as having a given DSC peak or melting point, it is referred to as the DSC peak or melting point ±5°C, and this temperature variation is generally taken into account. DSC provides an auxiliary method for distinguishing different crystalline forms. Different crystal forms can be identified by their different transition temperature characteristics. It should be noted that for mixtures, the DSC peak or melting point may vary over a wider range. In addition, since decomposition is associated with the melting of a substance, the melting temperature is related to the heating rate.

[0070] "Thermogravimetric analysis (TG)" is a common method for determining the thermal stability of a compound. In the present invention, TG can also be used to determine the hydration state of the compound, and the heating rate during the test will have a certain impact on the spectrum. The error of TG can be within about ±0.5 mass%.

[0071] Fourier Raman spectroscopy (FT-Raman) is generally used to study the structure and chemical bonds of molecules, and can also be used as a method for characterizing and identifying chemical species. In the present invention, Fourier Raman spectroscopy is used to characterize molecular structure and crystal form. The peak position error range of FT-Raman can be ±2cm -1 .

[0072] "Amorphous", "amorphous" or "amorphous form" refers to the material formed when the particles (molecules, atoms, ions) of the material are arranged in three-dimensional space without periodicity, characterized by a diffuse X-ray powder diffraction pattern without peaks. Amorphous / form is a special physical form of solid matter, and its locally ordered structural characteristics suggest that it is inextricably linked to crystalline substances.

[0073] “Substantially as shown” means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern, DSC pattern, Raman spectrum pattern, or infrared spectrum pattern are shown in the pattern.

[0074] In the context of the present invention, when or whether the words "about" or "approximately" are used, it means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, for a person skilled in the art, the term "about" or "approximately" means within an acceptable standard error range of the mean. Whenever a number having a value of N is disclosed, any number having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8% or N+ / -10% will be explicitly disclosed, where "+ / -" means plus or minus.

[0075] Mental illness in the present invention refers to a disease in which mental activities such as cognition, emotion, will and behavior are affected by various biological, psychological and social environmental factors and brain dysfunction causes different degrees of obstacles as clinical manifestations. Mental activities include cognitive activities (composed of sensation, perception, attention, memory and thinking, etc.), emotional activities and will activities. These activities are closely connected and coordinated to maintain the unity and integrity of mental activities. It is mainly divided into light mental illness and heavy mental illness. Common light mental illnesses include obsessive-compulsive disorder, depression, etc. Common heavy mental illnesses include schizophrenia, etc. Light mental illnesses are mainly manifested in emotional disorders (such as anxiety, depression, etc.) and thinking disorders (such as obsessive-compulsive ideas, etc.), but the cognition, logical reasoning ability and self-awareness of the patient's thinking are basically intact. And the early patients of heavy mental illness such as schizophrenia may also have anxiety, obsessive-compulsive ideas, etc., but the cognition and logical reasoning ability of such patients will become very poor, and self-awareness is almost completely lost. Organic mental illness or toxic mental illness caused by brain lesions need to be distinguished from general functional mental illness. There are several types of mild mental illness: anxiety, obsessive-compulsive disorder, depression, phobia, etc. Severe mental illness includes schizophrenia, etc. When the body is affected by internal and external harmful factors and the brain function is disturbed, various mental illnesses will occur. When the entire mental activity is obviously abnormal or disordered, and the integrity and unity of the mental activity are destroyed, it manifests as a mental illness. If it is mainly the mental activity ability that is weakened without serious and lasting mental activity disorder, it manifests as neurosis; if the development of mental activity is blocked, it manifests as mental retardation.

[0076] The main manifestations of depression are low mood, decreased interest, pessimism, slow thinking, lack of initiative, self-blame and guilt, poor diet and sleep, worry about suffering from various diseases, feeling discomfort in many parts of the body, and in severe cases, suicidal thoughts and behaviors.

[0077] The term "treating" or "treatment" refers to any indication of successful treatment or improvement of an injury, disease, lesion, or disorder, including any objective or subjective parameter, such as elimination, alleviation, reduction of symptoms, or making the injury, lesion, or disorder more tolerable to the patient; slowing the rate of degeneration or deterioration; making the end result of degeneration less debilitating; improving the patient's physical or mental health. Treatment or improvement of symptoms can be based on objective or subjective parameters; including the results of physical examination, neuropsychiatric examination, and / or psychiatric evaluation.

[0078] The terms "treating," "treating," "treating," "treating," "treating," and related expressions include preventing a disease, disorder, condition, or disease (eg, preventing the development of one or more symptoms of a disease, condition, or disorder described herein).

[0079] An "effective amount" is an amount sufficient to achieve the intended purpose, such as to achieve the effect of its administration, to treat a disease, to reduce enzyme activity, to increase enzyme activity, or to reduce one or more symptoms of a disease or disorder.

[0080] An example of an "effective amount" is an amount sufficient to promote the treatment, prevention, or reduction of one or more symptoms of a disease, which may also be referred to as a "therapeutically effective amount". A "prophylactically effective amount" of a drug is an amount of the drug that, when administered to a subject, will have the intended prophylactic effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, lesion, or disorder, or reducing the likelihood of the onset (or recurrence) of an injury, disease, lesion, or disorder, or its symptoms. A complete prophylactic effect may not occur with a single dose, and may occur only after a series of doses are administered. Therefore, a prophylactically effective amount may be administered in one or more administrations. The exact dosage will depend on the purpose of the treatment, and can be determined by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th edition, 2003, Gennaro, ed., Lippincott, Williams & Wilkins).

[0081] "Reduction" of one or more symptoms (and grammatical equivalents of such phrases) means a decrease in the severity or frequency of the symptom, or an elimination of the symptom.

[0082] "Control" or "controlled experiment" is used according to its ordinary meaning and refers to an experiment in which the experimental subjects or reagents are treated as in parallel experiments, but the experimental procedures, reagents or variables are omitted. In some cases, the control is used as a comparison standard for evaluating the effects of the experiment.

[0083] As used herein, the term "administer" means oral administration, administration in the form of a suppository, surface contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration to a subject, or implantation of a slow release device, such as a miniature osmotic pump. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, jaw, gum, nasal, vaginal, rectal or transdermal) administration. Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial administration. Other delivery modes include, but are not limited to, the use of liposome preparations, intravenous infusions, transdermal patches, etc.

[0084] Beneficial Effects

[0085] The compound of formula I of the present invention has good antidepressant activity, and relative to the S-isomer and the racemate, the compound of formula I has a lower minimum effective dose, a half effective dose and a lower toxicity. In addition, the salt crystal purity is high and the crystal stability is good; specifically, the crystal has a small change in purity as measured by HPLC, high chemical stability, good solubility, and good bioavailability. In particular, the crystal form I of the compound shown in formula I has high purity, good crystal stability, almost no hygroscopicity, and good bioavailability; it can meet the pharmaceutical requirements of production, transportation, and storage, is easy to prepare, is convenient for industrial preparation, has a stable production process, is repeatable and controllable, and can be adapted to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0086] Figure 1 This is an XRPD diagram of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate Form I.

[0087] Figure 2 This is a Raman diagram of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate Form I.

[0088] Figure 3 This is a DSC diagram of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate Form I.

[0089] Figure 4This is a TG diagram of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate Form I.

[0090] Figure 5 This is an XRPD diagram of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate Form II.

[0091] Figure 6 This is a Raman diagram of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate form II.

[0092] Figure 7 This is a DSC diagram of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate Form II.

[0093] Figure 8 This is a TG diagram of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate form II.

[0094] Fig. 9 This is an XRPD diagram of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate Form III.

[0095] Fig.10 This is a Raman diagram of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate form III.

[0096] Fig.11 This is a DSC diagram of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate Form II I.

[0097] Fig.12 This is a TG diagram of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate form II I.

[0098] Fig.13 This is a 30-day XPRD diagram of Form I under different influencing factors.

[0099] Fig.14This is a graphical representation of the 30-day XPRD of Form II under different influencing factors.

[0100] Fig.15 This is a 30-day XPRD diagram of Form III under different influencing factors. Specific embodiments

[0102] Below in conjunction with specific embodiment, further elaborate the present invention.Should be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.In addition, should be understood that after reading the content of the present invention's teaching, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall equally within the scope limited by the appended claims of the application.

[0103] Experimental instruments or reagents:

[0104] Reagent Source

[0105] Table 4 Sources of reagents

[0106]

[0107]

[0108] Experimental instruments and test conditions

[0109] 1. X-ray Powder Diffraction (XRPD)

[0110] Instrument model: Bruker D8 Focus powder X-ray diffractometer.

[0111] X-ray parameters: Cu / Kα

[0112] Voltage: 40 kilovolts (kV)

[0113] Current: 40 milliamperes (mA)

[0114] Scanning range: from 3.0 to 60 degrees

[0115] Scanning step: 0.02 degrees

[0116] Scanning speed: 0.5 seconds / step

[0117] 2. DSC thermal analysis (Differential Scanning Calorimeter, DSC) Instrument model: German NETZSCH DSC 200F3 differential scanning calorimeter

[0118] Purge gas: Nitrogen

[0119] Heating rate: 10.0K / min

[0120] Temperature range: 35-160℃

[0121] 3. TG Thermogravimetric Analyzer (TG)

[0122] Instrument model: German NETZSCH TG209F3 thermogravimetric analyzer

[0123] Purge gas: Nitrogen

[0124] Heating rate: 10.0K / min

[0125] Temperature range: 35-250℃

[0126] 4. Fourier Raman Spectrometer (FT-Raman Spectrometer, FT-RM)

[0127] Instrument model: Thermo Scientific DXR Smart Raman spectrometer Aperture: 50μm

[0128] Exposure time: 10s

[0129] Number of exposures: 32

[0130] Laser: 780nm

[0131] Laser energy: 150mw

[0132] Synthesis Example

[0133] Example 1 Preparation of (R)-N,N-dimethyl-3-(4-fluorophenyl)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine oxalate (Compound of Formula I)

[0134]

[0135] 1.1. Preparation of 3-(dimethylamino)-1-(4-fluorophenyl)-1-propanone hydrochloride (Intermediate Ⅰ)

[0136] Add 2 kg (14.48 mol) of p-fluoroacetophenone, 868.6 g (28.96 mol) of paraformaldehyde, 1.77 kg (21.71 mol) of N,N-dimethylamine hydrochloride and 6 L of anhydrous ethanol into a 20 L glass reaction bottle, start stirring, heat to 60 ° C, add 120 mL of concentrated hydrochloric acid, heat to 90 ° C after addition, and react for 17 hours.

[0137] After the reaction was complete, 3 L of ethanol was removed by concentration under reduced pressure, the temperature was gradually reduced, crystallization was performed, the mixture was cooled to 0-10°C, and stirred for 1.5 hours; the mixture was filtered, the filter cake was washed with ethyl acetate, and the obtained solid was dried to constant weight to obtain 2.52 kg of white solid.

[0138] 1.2. Preparation of 3-(dimethylamino)-1-(4-fluorophenyl)-1-propanol (Intermediate II)

[0139] Add 2.5 kg (10.81 mol) of 3-(dimethylamino)-1-(4-fluorophenyl)-1-propanone hydrochloride and 3.0 kg of methanol to a 20 L reaction bottle, start stirring, control the temperature at -20 to 0 ° C, add sodium hydroxide aqueous solution (432.4 g of sodium hydroxide, 1.0 kg of purified water), add 265.8 g (7.03 mol) of sodium borohydride in batches, and after the addition, heat to 20 ° C and react for 2 hours.

[0140] After the reaction is completed, the filtrate is filtered and transferred to a 20L glass reaction bottle, concentrated under reduced pressure to remove methanol, and then 2.0kg of drinking water and 1kg of ethyl acetate are added for extraction. After separation, the aqueous phase is extracted with ethyl acetate twice (500g / time), the organic phases are combined, washed twice with 20% sodium chloride solution, the organic phase is dried with 500g of anhydrous magnesium sulfate, filtered, the filter cake is rinsed with 500g of ethyl acetate, and then concentrated under reduced pressure to remove ethyl acetate to obtain 2.0kg of light yellow oil.

[0141] 1.3. Preparation of (R)-3-(dimethylamino)-1-(4-fluorophenyl)-1-propanol R-mandelate (Intermediate III)

[0142] Add 2.0 kg (10.27 mol) of 3-(dimethylamino)-1-(4-fluorophenyl)-1-propanol and 2.5 kg of toluene into a 20 L reaction bottle, start stirring, add 0.9 kg of anhydrous ethanol, heat to 55 ° C, add 1.25 kg of R-(-)-mandelic acid, heat to 90 ° C, and react for 1 hour.

[0143] After the reaction, the temperature was lowered to crystallize, the temperature was controlled at 10-20°C, and the mixture was stirred for 1.5 hours. The mixture was filtered, the filter cake was washed with 0.6 kg of anhydrous ethanol, and the obtained solid was dried to constant weight to obtain 1.6 kg of white solid.

[0144] 1.4. Preparation of (R)-N,N-dimethyl-3-(4-fluorophenyl)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine p-hydroxybenzoate (Intermediate IV)

[0145] Add 1.3 kg of (R)-3-(dimethylamino)-1-(4-fluorophenyl)-1-propanol R-mandelate to a 20 L reaction bottle, add sodium hydroxide solution (148 g of sodium hydroxide and 738 g of drinking water), start stirring, stir for 30 minutes, add 1 kg of ethyl acetate for extraction, and extract the aqueous phase with ethyl acetate twice (500 g / time), combine the organic phases, wash twice with saturated sodium chloride solution, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 695 g of colorless liquid for standby use.

[0146] Add 690g (R)-3-(dimethylamino)-1-(4-fluorophenyl)-1-propanol and 2.3kg dimethyl sulfoxide into a 20L reaction bottle, start stirring, add 589g potassium tert-butoxide in batches, control the temperature to about 45°C, then add 637g 3-fluoro-1,2-methylenedioxybenzene, after the addition, raise the temperature to 70°C and react for 5 hours.

[0147] After the reaction was completed, the temperature was lowered to room temperature, 1.7 kg of drinking water and 1.4 kg of ethyl acetate were added for extraction, the aqueous phase was extracted once with 1.0 kg of ethyl acetate, the organic phases were combined, washed three times with saturated sodium chloride solution, the organic phase was dried over anhydrous magnesium sulfate, filtered, the filter cake was rinsed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain 1.15 kg of brown-black oil; a vacuum distillation apparatus was built, the oil was added to a 2L (24#) single-mouth bottle, and vacuum distillation was performed with the external temperature controlled at 160-200°C and the steam temperature at 140-170°C. The fractions were collected and weighed to obtain 645 g of a light yellow oily liquid.

[0148] Add 637 g of the above-mentioned light yellow oily liquid and 2.0 kg of ethyl acetate into a 20 L reaction bottle, then add 291 g of p-hydroxybenzoic acid, start stirring, heat, raise the temperature to 70°C and react for 1 hour; gradually cool and crystallize, filter, wash the filter cake twice with ethyl acetate, and dry the obtained solid to constant weight to obtain 570 g of white solid.

[0149] Add 570 g of the above crude product to a 5 L reaction bottle, add 1.7 kg of anhydrous ethanol, reflux at 80 ° C for 1 hour, cool naturally to room temperature, and stir in an ice bath for 1 hour; filter, wash the filter cake with 285 g of anhydrous ethanol, and dry the obtained solid to constant weight to obtain 450 g of white solid.

[0150] 1.5. Preparation of (R)-N,N-dimethyl-3-(4-fluorophenyl)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine oxalate

[0151] Add 440 g of the above white solid into a 5 L reaction bottle, add sodium hydroxide solution, stir for 30 minutes, extract with ethyl acetate 3 times (400 mL / time), wash the organic phase with saturated sodium chloride solution 3 times, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to obtain 298 g of residue.

[0152] Oxalic acid salt formation: Add 596g of ethyl acetate to 298g of the above residue, heat to 70°C, add oxalic acid (84.55g) in ethyl acetate in batches, adjust pH to about 5, precipitate solid, add 70g of ethanol and 300g of ethyl acetate, stir for 1 hour, cool to room temperature, place in an ice bath to cool and crystallize, filter, wash the filter cake with ethyl acetate, dry the obtained solid to constant weight, and obtain 340g of white solid. HPLC: 99.64%. mp = 125-127°C; [α] D 20 =45.6; 1 H-NMR (500MHz, DMSO-d6) δ: 7.47 (dd, J=8.5, 5.5Hz, 2H), 7.19 (t, J=8.9Hz, 2H), 6.6 6(t,J=8.2Hz,1H), 6.51(dd,J=19.2,8.2,1.1Hz,2H), 5.98(dd,J=13.8,1.2Hz,2H), 5.50 (dd, J = 8.5, 4.6 Hz, 1H), 3.17 (td, J = 11.7, 5.0 Hz, 1H), 3.07 (td, J = 12.1, 11.7, 4.8 Hz, 1H), 2.73 (s, 6H), 2.40–2.27 (m, 1H), 2.25–2.09 (m, 1H). HRMS (ESI) m / z: calculated: C 18 H 20 FNO3(M+H) + :318.1500; measured value:318.1494.

[0153] Example 2 Preparation of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate Form I

[0154] 2.1 Using static recrystallization method

[0155] 2.1.1 Weigh 0.5 g of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 15 mL of a mixed solution of dichloromethane-n-propanol (volume ratio 2:1), shake thoroughly until the sample is completely dissolved, let stand at room temperature, and filter, wash, and dry in vacuo at 60°C to obtain Form I.

[0156] 2.1.2 Weigh 0.5 g of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 5 mL of a mixed solution of methanol-anhydrous ethanol (volume ratio 1:1), shake thoroughly until the sample is completely dissolved, let stand at room temperature, and filter, wash, and dry in vacuo at 60°C to obtain Form I.

[0157] 2.1.3 Weigh 0.5 g of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 12 mL of dichloromethane, shake thoroughly until the sample is completely dissolved, let stand at room temperature, and filter, wash, and dry in vacuo at 60°C to obtain Form I.

[0158] 2.1.4 Weigh 0.5 g of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 9 mL of acetone, shake thoroughly until the sample is completely dissolved, let stand at room temperature, and filter, wash, and dry in vacuo at 60°C to obtain Form I.

[0159] 2.1.5 Weigh 0.5 g of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 6 mL of a mixed solution of N-methylpyrrolidone-isopropanol (volume ratio 1:5), heat at 60°C until the sample is completely dissolved, let stand at room temperature, and if solid precipitates, filter, wash, and dry in vacuo at 60°C to obtain Form I.

[0160] 2.1.6 Weigh 0.5 g of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 45 mL of a mixed solution of butanone-methyl tert-butyl ether (volume ratio 1:8), shake thoroughly until the sample is completely dissolved, let stand at room temperature, and if solid precipitates, filter, wash, and dry in vacuo at 60°C to obtain Form I.

[0161] 2.2 Preparation by solvent removal method

[0162] 2.2.1 Weigh 0.5 g of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 30 mL of a mixed solution of acetonitrile-n-heptane (volume ratio 1:2), heat at 60°C to dissolve, then transfer to a rotary evaporator to remove the solvent. At the end of the experiment, collect the solid and dry to obtain Form I.

[0163] 2.2.2 Weigh 0.5 g of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 20 mL of a mixed solution of methanol-ethyl acetate (volume ratio 1:4), heat at 60°C to dissolve, and then transfer to a rotary evaporator to remove the solvent. At the end of the experiment, collect the solid and dry it to obtain Form I.

[0164] 2.2.3 Weigh 0.5 g of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 10 mL of 95% ethanol, heat at 60°C to dissolve, and then transfer to a rotary evaporator to remove the solvent. At the end of the experiment, collect the solid to obtain Form I.

[0165] 2.2.4 Weigh 0.5 g of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 45 mL of a mixed solution of n-propanol-methyl tert-butyl ether (volume ratio 8:1), shake thoroughly until the sample is completely dissolved, and then transfer to a rotary evaporator to remove the solvent. At the end of the experiment, collect the solid to obtain Form I.

[0166] 2.2.5 Weigh 0.5 g of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 20 mL of acetonitrile, heat at 60°C to dissolve, and then transfer to a rotary evaporator to remove the solvent. At the end of the experiment, collect the solid to obtain Form I.

[0167] 2.2.6 Weigh 0.5 g of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 60 mL of a mixed solution of chloroform-n-hexane (volume ratio 5:1), shake thoroughly until the sample is completely dissolved, then transfer to a rotary evaporator to remove the solvent. At the end of the experiment, collect the solid to obtain Form I.

[0168] 2.3 Preparation by anti-solvent method

[0169] 2.3.1 Weigh about 0.5 g of sample, add 10 mL of acetonitrile and fully dissolve at 60 °C, then quickly pour in about 80 mL of methyl tert-butyl ether and let stand until solid precipitates. Filter, wash and vacuum dry at 60 °C to obtain Form I.

[0170] 2.3.2 Weigh about 0.5 g of the sample, add 5 mL of ethanol and fully dissolve it at 60°C, then quickly pour in about 30 mL of n-hexane and let it stand. If solid precipitates, filter it, wash it, and dry it in a vacuum at 60°C to obtain Form I.

[0171] 2.3.3 Weigh about 0.5 g of the sample, add 2 mL of dimethyl sulfoxide and fully dissolve it at 60°C, then quickly pour in about 20 mL of isopropyl ether and let it stand. Solid precipitates, filter, wash and dry in vacuo at 60°C to obtain Form I.

[0172] 2.3.4 Weigh about 0.5 g of the sample, add 2 mL of N,N-dimethylformamide and fully dissolve it at 60°C, then quickly pour in about 40 mL of ethyl acetate and let it stand. If solid precipitates, filter it, wash it, and dry it in a vacuum at 60°C to obtain Form I.

[0173] 2.3.5 Weigh about 0.5 g of the sample, add 2 mL of methanol and fully dissolve it at 60°C, then quickly pour in about 20 mL of methyl tert-butyl ether and let it stand. Solid precipitates, filter, wash and dry in vacuo at 60°C to obtain Form I.

[0174] 2.3.6 Weigh about 0.5 g of sample, add 10 mL of chloroform and shake thoroughly until the sample is completely dissolved, then quickly pour in about 30 mL of n-hexane and let stand. If solid precipitates, filter, wash and dry in vacuo at 60°C to obtain Form I.

[0175] After testing and analysis, the above-mentioned crystal form I has the following Figure 1 The XRPD pattern shown; Figure 2 The Raman map shown; Figure 3 The DSC diagram shown and Figure 4 TG diagram shown.

[0176] Example 3 Preparation of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate Form II

[0177] Form II can be prepared, for example, by solvent removal.

[0178] 3.1.1 Weigh 0.5 g of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 25 mL of a mixed solution of acetone-isopropanol (volume ratio 2:3), shake thoroughly until the sample is completely dissolved, then transfer to a rotary evaporator to remove the solvent. At the end of the experiment, collect the solid and dry it to obtain Form II.

[0179] 3.1.2 Weigh 0.5 g of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate into a large test tube, add 30 mL of a mixed solution of ethanol-n-butanol (volume ratio 1:2), heat at 60°C to dissolve, then transfer to a rotary evaporator to remove the solvent. After the reaction is completed, collect the solid and dry to obtain Form II.

[0180] After testing and analysis, Form II has the following characteristics: Figure 5 The XRPD pattern shown; Figure 6 The Raman map shown; Figure 7 The DSC diagram shown and Figure 8 TG diagram shown.

[0181] Example 4 Preparation of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate Form II

[0182] Form III can be prepared, for example, by an anti-solvent method.

[0183] 4.1.1 Weigh about 0.5 g of (R)-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate, add 5 mL of acetonitrile to fully dissolve it, then quickly pour in about 30 mL of isopropyl ether and let it stand until solid precipitates. Filter, wash, and dry in vacuo at 60°C to obtain Form III.

[0184] After testing and analysis, the crystal form III has the following Fig. 9 The XRPD pattern shown; Fig.10 The Raman map shown; Fig.11 The DSC diagram shown and Fig.12 TG diagram shown.

[0185] Test Case

[0186] Test Example 1 Solubility Test

[0187] 1.1 Experimental Purpose

[0188] The solubility of compound (R)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate in different solvents was investigated.

[0189] 1.2 Experimental methods

[0190] Experimental conditions: 25°C, humidity 40%, the solubility of the sample was measured. The amount of the compound represented by each experimental formula I was 5-10 mg, and the solubility of the compound represented by formula I in different solvents was measured respectively.

[0191] 1.3 Experimental results: The results are shown in Table 5 below:

[0192] Table 5 Solubility of compounds of formula I

[0193]

[0194]

[0195] (1) Easily soluble: anhydrous methanol, NMP, DMF, DMSO;

[0196] (2) Dissolution: glacial acetic acid;

[0197] (3) Slightly soluble: purified water, anhydrous ethanol, acetone, dichloromethane, chloroform, acetonitrile, 95% ethanol;

[0198] (4) Slightly soluble: n-propanol, isopropanol, n-butanol, butanone;

[0199] (5) Almost insoluble in: n-hexane, cyclohexane, n-heptane, methyl tert-butyl ether, petroleum ether, isopropyl ether, ethyl acetate.

[0200] Test Example 2: Mouse tail suspension test

[0201] 2.1 Test methods

[0202] SPF ICR mice were taken and divided into groups according to body weight, with 12 mice in each group. The animals were allowed to adapt for at least 3 days before behavioral testing.

[0203] Behavioral testing began 1 hour after oral administration. The mice were placed in a transparent glass cylinder with water (water depth 15 cm, water temperature 23-25°C) and video recorded for 6 minutes (background with LED light board). When the time was up, the mice were taken out of the water and the next batch of mice were tested for behavior. The water was changed after every 3 batches of tests. After the test, the video of the behavioral test was exported and recorded using Forced Swim Scan. TM 2.0 software was used to analyze the cumulative immobility time of mice for 4 min after the 6 min forced swimming period.

[0204] The test results are expressed as mean ± SD, and each group was compared with the vehicle group using t-test, with P < 0.05 as statistically significant.

[0205] 2.2 Test results

[0206] All dosage groups of duloxetine, 3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate, S-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate and R-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate (compounds of formula I) showed good dose-effect relationships.

[0207] The minimum effective dose (MED) of duloxetine is 8 mg / kg, and the median effective dose (ED 50 ) is 15.8 mg / kg. The MED of 3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate is 3.2 mg / kg, and the ED 50 The MED of S-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate is 6.4 mg / kg, and the ED 50 The lowest effective dose of the compound of formula I is 1.6 mg / kg, and ED 50 The specific results are shown in Table 6.

[0208] Table 6 Results of the mouse tail suspension test for each group of compounds

[0209]

[0210] Note: *P<0.05, **P<0.01 compared with the vehicle group.

[0211] Test Example 3 Acute toxicity test in mice

[0212] 3.1 Test methods

[0213] The dosage and number of groups in the formal test were determined based on the doses of the pre-experimental compound that caused 100% and 0% death in mice. In the formal test, ICR mice were randomly divided into 10 groups, half male and half female, and intragastrically administered at 10 mL / kg. The animals were observed for 7 days for their status and death.

[0214] 3.2 Test results

[0215] In a single-dose toxicity study in mice, the median lethal dose (LD50) of 3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate was 50 ) is 228 mg / kg, 95% confidence interval 195.9-287.7 mg / kg; the LD of S-3-[(Benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate 50 The LD of the compound of formula I is 170.5 mg / kg, with a 95% confidence interval of 142.0-208.6 mg / kg. 50 It is 207 mg / kg, with a 95% confidence interval of 179.0-239.7 mg / kg.

[0216] 3.3 Test conclusion

[0217] The therapeutic index (TI = LD 50 / ED 50 ), the results show that the compound of formula I is superior to 3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate and S-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate. Specific data are shown in Table 7.

[0218] Table 7 Results of acute toxicity test in mice

[0219]

[0220] Test Example 4 Experiment on factors affecting crystal stability

[0221] Experimental methods

[0222] High temperature experiment: Weigh about 0.3 g of each of Form I, II, and III, place in a clean watch glass, place at 60°C for 30 days, and take samples on the 0th, 5th, 10th, and 30th days for XRPD analysis.

[0223] High humidity experiment: Weigh about 0.3 g of Form I, II, and III samples respectively, place them in a clean surface dish, and place them at a relative humidity of 92.5% for 30 days. Samples are taken on the 0th, 5th, 10th, and 30th days for XRPD analysis.

[0224] Illumination experiment: Weigh about 0.3 g of each of the crystal forms I, II, and III, place them in a clean surface dish, spread them flat, and place them in an illumination box (illuminance of 5000 lx) for 30 days. Take samples on the 0th, 5th, 10th, and 30th days for XRPD analysis.

[0225] Table 8 Experimental study on factors affecting crystal form I

[0226] condition 5 days 10 days 30 days high temperature Unchanged Unchanged Unchanged High humidity Unchanged Unchanged Unchanged illumination Unchanged Unchanged Unchanged

[0227] Table 9 Experimental study on factors affecting crystal form II

[0228] condition 5 days 10 days 30 days high temperature Unchanged Unchanged Unchanged High humidity Crystal Transformation Crystal Transformation Crystal Transformation illumination Unchanged Unchanged Unchanged

[0229] Table 10 Experimental study on factors affecting Form III

[0230] condition 5 days 10 days 30 days high temperature Unchanged Unchanged Unchanged High humidity Unchanged Unchanged Unchanged illumination Unchanged Unchanged Unchanged

[0231] Test Example 5 Solubility Experiment

[0232] 5.1 Sample preparation

[0233] Test solution: Weigh appropriate amounts of different crystalline forms of the compound of formula I, place them in different test tubes, add 2 mL of water, place in a Buchi equilibrium reactor and shake at 25°C for 24 hours (supersaturated), filter, take the filtrate, accurately measure 1 mL of each filtrate, place in different 50 mL volumetric flasks, add diluent (70% methanol) to dilute to the scale, shake well, and use as the test solution.

[0234] Reference substance solution: Accurately weigh an appropriate amount of reference substance, add an appropriate amount of diluent, ultrasonically dissolve and dilute to make a solution containing about 0.15 mg of sample per 1 mL.

[0235] 5.2 Preparation of mobile phase

[0236] (1) Preparation of buffer solution: Weigh about 2.3460 g of ammonium dihydrogen phosphate, dissolve it in 1000 mL of water, add 2 mL of triethylamine, and adjust the pH value to 2.5 with phosphoric acid.

[0237] (2) Preparation of mobile phase

[0238] Mobile phase A: 0.02 mol / L ammonium dihydrogen phosphate solution (add 2 mL of triethylamine to every 1000 mL and adjust the pH to 2.5 with phosphoric acid)-acetonitrile (80:20), prepare 1000 mL, mix well, and filter.

[0239] Mobile phase B: 0.02 mol / L ammonium dihydrogen phosphate solution (add 2 mL of triethylamine to every 1000 mL and adjust the pH to 2.5 with phosphoric acid)-acetonitrile (20:80), prepare 1000 mL, mix well, and filter.

[0240] Diluent: 70% methanol

[0241] 5.3 Chromatographic conditions

[0242] Detection wavelength: 215 nm; flow rate: 1.0 mL / min; column temperature: 35°C; injection volume: 10 μL; chromatographic column: Agilent Eclipse Plus C18 column (4.6*250 mm, 5 μm).

[0243] Table 11 Gradient program

[0244] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 100 0 3 100 0 20 85 15 30 85 15 40 75 25 55 20 80 60 20 80 61 100 0 70 100 0

[0245] 5.4. Sample determination

[0246] Accurately pipette 10 μL of each solution and inject it into the liquid chromatograph respectively. Record the chromatogram and determine the solubility of the compound by the external standard method. The results are shown in Table 12.

[0247] Table 12 Crystal solubility

[0248]

[0249] The experimental results show that the crystalline forms of the compound represented by Formula I all have good solubility.

[0250] Test Example 6: Moisture absorption test

[0251] 6.1 Take a dry stoppered glass weighing bottle and place it in a suitable 25℃±1℃ constant temperature dryer (with ammonium chloride or ammonium sulfate saturated solution placed at the bottom) or an artificial climate box (set temperature at 25℃±1℃, relative humidity at 80%±2%) one day before the test, and accurately weigh the weight (m1).

[0252] 6.2 Take an appropriate amount of the crystalline form of the test compound of formula I and spread it evenly in the above-mentioned weighing bottle. The thickness of the test sample is generally about 1 mm. Accurately weigh the weight (m2).

[0253] 6.3 Open the weighing bottle and place it with the bottle cap under the above constant temperature and humidity conditions for 24 hours.

[0254]

[0255] 6.4 Cover the weighing bottle and accurately weigh the weight (m3). The test results are shown in Table 13.

[0256] Table 13 Moisture absorption test

[0257] Drug Name <![CDATA[m1(g)]]> <![CDATA[m2(g)]]> <![CDATA[m3(g)]]> Weight gain (%) Crystal form I 35.21288 35.66194 35.66227 0.07 Crystal form III 33.99131 34.49240 34.49262 0.04

[0258] Experimental conclusion: Different crystalline forms of the compound of formula I all show no or almost no hygroscopicity, and therefore no strict packaging requirements are required during storage.

[0259] Test Example 7 Pharmacokinetic Experiment

[0260] Table 14 Dosage regimen

[0261]

[0262] Each group consisted of 2 beagle dogs, half male and half female, purchased from Jiangsu Lingfu Zhaoshengyuan Biotechnology Co., Ltd.

[0263] Solution preparation:

[0264] 1) Intravenous administration: 0.9% saline as the solvent;

[0265] 2) Oral administration: According to the dose of 5 mg / kg, the corresponding mass of the drug was weighed according to the actual body weight of the animal, and then filled into capsules and administered to the animal. The test results are shown in Table 15.

[0266] Table 15 Pharmacokinetic test results of different crystal forms

[0267] Group Crystalline Form I Crystalline Form I Form III Route of administration vein oral oral Dosage (mg / kg) 0.5 5 5 Pharmacokinetic parameters Mean Mean Mean <![CDATA[t 1 / 2 (h)]]> 2.67 3.48 3.86 <![CDATA[T max (h)]]> 0.29 0.63 0.75 <![CDATA[C max (ng / mL)]]> 70.96 49.75 19.75 <![CDATA[AUC (0-t) (μg / L*h)]]> 148.21 198.64 103.58 <![CDATA[AUC (0-∞) (μg / L*h)]]> 156.52 200.65 105.28 Bioavailability (%) / 12.82 6.73

[0268] Experimental conclusion: Pharmacokinetic experiments show that the crystalline forms of the compound of formula I have good bioavailability, especially the crystalline form I.

[0269] The above description is only the preferred embodiment of the present application and is not intended to limit the present application. For those skilled in the art, the present application may have various changes and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application.

Claims

1. A (R)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate as shown in Formula I, 2. A crystalline form I of (R)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate according to claim 1, characterized in that: The X-ray powder diffraction pattern of the crystalline form I comprises diffraction peaks at 2θ of 9.33±0.2°, 15.64±0.2° and 23.63±0.2°.

3. The crystalline form I according to claim 2, characterized in that The X-ray powder diffraction pattern of the crystalline form I also includes diffraction peaks located at 2θ of 16.48±0.2°, 19.77±0.2°, 20.06±0.2°, 22.09±0.2°, 23.06±0.2° and 24.21±0.2°.

4. The crystalline form I according to any one of claims 2-3, characterized in that The melting endothermic peak of the DSC graph of the crystal form I is selected from 126.8°C to 132.2°C, preferably 129.8°C.

5. The crystalline form I according to any one of claims 2 to 4, characterized in that: The X-ray powder diffraction pattern of the crystalline form I is substantially as shown in FIG1 ; or The DSC spectrum of the crystal form I is basically shown in Figure 3.

6. A crystalline form II of (R)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate according to claim 1, characterized in that: The X-ray powder diffraction pattern of the crystalline form II comprises diffraction peaks at 2θ of 15.07±0.2°, 16.71±0.2° and 22.76±0.2°.

7. The crystal form II according to claim 6, characterized in that The X-ray powder diffraction pattern of the crystalline form II also includes diffraction peaks located at 2θ of 11.38±0.2°, 16.01±0.2°, 19.71±0.2°, 22.05±0.2° and 29.03±0.2°.

8. The crystalline form II according to any one of claims 6-7, characterized in that The melting endothermic peak of the DSC graph of the crystal form II is selected from 116.9°C to 123.0°C, preferably 120.2°C.

9. The crystalline form II according to any one of claims 6 to 8, characterized in that The X-ray powder diffraction pattern of the crystalline form II is substantially as shown in FIG5 ; or The DSC spectrum of the crystal form II is basically shown in Figure 7.

10. A crystalline form III of (R)-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]-N,N-dimethyl-3-(4-fluorophenyl)propylamine oxalate according to claim 1, characterized in that: The X-ray powder diffraction pattern of the crystalline form III comprises diffraction peaks at 2θ of 13.64±0.2°, 15.14±0.2°, and 22.86±0.2°.

11. The crystalline form III according to claim 10, characterized in that: The X-ray powder diffraction pattern of the crystalline form III also includes diffraction peaks at 2θ of 8.27±0.2°, 11.24±0.2°, 16.18±0.2°, 17.06±0.2°, 18.01±0.2°, 18.36±0.2°, 18.99±0.2° and 23.18±0.2°.

12. The crystalline form III according to any one of claims 10-11, characterized in that The melting endothermic peak of the DSC graph of the crystalline form III is selected from 119.7°C-125.1°C, preferably 122.6°C.

13. The crystalline form III according to any one of claims 10 to 12, characterized in that The X-ray powder diffraction pattern of the crystalline form III is substantially as shown in FIG9 ; or The DSC spectrum of the crystalline form III is basically shown in Figure 11.

14. A pharmaceutical composition comprising a therapeutically effective dose of the oxalate of claim 1, the crystalline form I of any one of claims 2-5, the crystalline form II of any one of claims 6-9, or the crystalline form III of any one of claims 10-13, and one or more pharmaceutically acceptable carriers, diluents or excipients.

15. Use of the oxalate according to claim 1, the crystalline form I according to any one of claims 2-5, the crystalline form II according to any one of claims 6-9, the crystalline form III according to any one of claims 10-13, or the pharmaceutical composition according to claim 14 in the preparation of a drug, wherein the drug is preferably used to prevent and / or treat mental illness.

16. The use according to claim 15, wherein the mental illness is selected from one or more of anxiety, obsessive-compulsive disorder, depression, phobia and schizophrenia, preferably depression.

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