3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, its optical isomers, crystals, and method of preparation

Abstract

This application relates to 3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, its crystalline form and preparation method. The crystalline form A of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride obtained by the present invention has good crystalline form stability and chemical stability, and can be more suitable for use in clinical treatment.

Description

[Technical Field]

[0001] The present invention belongs to the field of medicinal chemistry and specifically relates to providing 3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, its optical isomers and crystalline forms, and methods for preparation. [Background technology]

[0002] Depression is currently the most common mental illness affecting human mental and physical health. Currently, 3% to 5% of the world's population suffers from depression. By 2022, depression is projected to become the second leading cause of illness after heart disease.

[0003] Drug therapy is the primary means of treating depression. Common medications include tricyclic antidepressants such as imipramine, monoamine oxidase inhibitors such as moclobemide, selective 5-HT reuptake inhibitors such as fluoxetine, selective NE reuptake inhibitors such as reboxetine, and 5-HT / NE dual reuptake inhibitors such as duloxetine.

[0004] While many antidepressants are used clinically, some have low response rates, long onset times, and potential side effects. As a result, many patients have undergone various treatments without success and still require electroconvulsive therapy. Therefore, antidepressant development remains a hot spot in novel drug research. Patent application WO2016101898A discloses a 3-[(benzo[d][1,3]dioxolan-4-yl)-oxy]-3-arylpropylamine compound with antidepressant activity, whose specific structure is as follows:

[0005] [ka]

[0006] Further research indicates that (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride possesses excellent antidepressant activity. The crystalline structure of the active pharmaceutical ingredient always affects the chemical stability of the drug, and differences in crystal form, preparation methods, and storage conditions can lead to changes in the crystalline structure of the compound, sometimes resulting in the formation of other crystalline forms. Generally, amorphous drug products lack a regular crystalline structure and always have other drawbacks such as poor product stability, difficulty in filtration, tendency to solidify, and poor fluidity. These differences tend to make it difficult to scale up production. Therefore, it is necessary to conduct diligent research to improve each property of the compound through crystalline form and to find new crystalline forms that have high crystalline purity and excellent chemical stability. [Overview of the Initiative]

[0007] The technical problem that the present invention aims to solve is to provide the compounds N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride and (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, wherein (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride is the compound represented by formula (I), as well as its crystal forms A, B, and C. The crystal form A has good crystalline stability and chemical stability and is more clinically suitable for use.

[0008] [ka]

[0009] The present invention provides the A crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, and obtains an X-ray powder diffraction pattern represented by a diffraction angle of 2θ ± 0.2° using Cu-Kα rays.

[0010] Specifically, it shows three characteristic peaks at 8.77°, 12.00°, and 14.84°, and the error range may be ±0.3°, ±0.2°, or ±0.1°.

[0011] Specifically, it shows four characteristic peaks at 8.77°, 12.00°, 14.84°, and 21.34°, and the error range may be ±0.3°, ±0.2°, or ±0.1°.

[0012] Specifically, it shows five characteristic peaks at 8.77°, 12.00°, 14.84°, 21.34°, and 21.87°, and the error range may be ±0.3°, ±0.2°, or ±0.1°.

[0013] Specifically, it exhibits six characteristic peaks at 8.77°, 12.00°, 14.84°, 21.34°, 21.87°, and 23.47°, with error ranges of ±0.3°, ±0.2°, or ±0.1°.

[0014] Specifically, it exhibits seven characteristic peaks at 8.77°, 12.00°, 14.84°, 21.34°, 21.87°, 23.47°, and 24.14°, with error ranges of ±0.3°, ±0.2°, or ±0.1°.

[0015] In a preferred embodiment of the present invention, the A crystal form further exhibits characteristic peaks represented by 2θ angles at one or more of the following angles: 7.78°, 16.58°, 19.66°, 23.03°, 25.46°, 26.65°, 26.97°, 27.41°, and 28.23°, with an error range of ±0.3°, ±0.2°, or ±0.1°.

[0016] In a preferred embodiment of the present invention, the above crystal form A further exhibits three characteristic peaks represented by 2θ angles at 7.78°, 16.58°, and 19.66°, and the error range may be ±0.3°, ±0.2°, or ±0.1°.

[0017] In a preferred embodiment of the present invention, the above crystal form A further exhibits four characteristic peaks represented by 2θ angles at 7.78°, 16.58°, 19.66°, and 23.03°, and the error range may be ±0.3°, ±0.2°, or ±0.1°.

[0018] In a preferred embodiment of the present invention, the above crystal form A further exhibits five characteristic peaks represented by 2θ angles at 7.78°, 16.58°, 19.66°, 23.03°, and 25.46°, and the error range may be ±0.3°, ±0.2°, or ±0.1°.

[0019] In a preferred embodiment of the present invention, the above crystal form A further exhibits six characteristic peaks represented by 2θ angles at 7.78°, 16.58°, 19.66°, 23.03°, 25.46°, and 26.65°, and the error range may be ±0.3°, ±0.2°, or ±0.1°.

[0020] In a preferred embodiment of the present invention, the above crystal form A further exhibits seven characteristic peaks represented by 2θ angles at 7.78°, 16.58°, 19.66°, 23.03°, 25.46°, 26.65°, and 26.97°, and the error range may be ±0.3°, ±0.2°, or ±0.1°.

[0021] In a preferred embodiment of the present invention, the above crystal form A further exhibits eight characteristic peaks represented by 2θ angles at 7.78°, 16.58°, 19.66°, 23.03°, 25.46°, 26.65°, 26.97°, and 27.41°, and the error range may be ±0.3°, ±0.2°, or ±0.1°.

[0022] In a preferred embodiment of the present invention, the above A crystal form further exhibits nine characteristic peaks represented by 2θ angles of 7.78°, 16.58°, 19.66°, 23.03°, 25.46°, 26.65°, 26.97°, 27.41°, and 28.23°, and the error range may be ±0.3°, ±0.2°, or ±0.1°. In a more preferred embodiment of the present invention, the Raman spectrum of the above A crystal form is 3063.8 ± 2 cm -1 , 3013.2 ± 2 cm -1 , 2961.9 ± 2 cm -1 , 2931.4 ± 2 cm -1 , 1599.5 ± 2 cm -1 , 1461.0 ± 2 cm -1 , 1267.6 ± 2 cm -1 , 1177.9 ± 2 cm -1 , 1047.8 ± 2 cm -1 , 996.6 ± 2 cm -1 , 827.9 ± 2 cm -1 , 740.3 ± 2 cm -1 , 688.9 ± 2 cm -1 , 615.4 ± 2 cm -1 , 591.9 ± 2 cm -1 and shows characteristic peaks in one or more of them.

[0023] In a more preferred embodiment of the present invention, the Raman spectrum of the above A crystal form is 3063.8 ± 2 cm -1 , 3013.2 ± 2 cm -1 , 2961.9 ± 2 cm -1 and shows three characteristic peaks.

[0024] In a more preferred embodiment of the present invention, the Raman spectrum of the above A crystal form is 3063.8 ± 2 cm -1 , 3013.2 ± 2 cm -1 , 2961.9 ± 2 cm -1 , 2931.4 ± 2 cm -1 and shows four characteristic peaks.

[0025] In a more preferred embodiment of the present invention, the Raman spectrum of the above crystal form A is 3063.8±2 cm⁻¹. -1 , 3013.2±2 cm -1 , 2961.9±2 cm -1 , 2931.4±2 cm -1 , 1599.5±2 cm -1 It shows five characteristic peaks.

[0026] In a more preferred embodiment of the present invention, the Raman spectrum of the above crystal form A is 3063.8±2 cm⁻¹. -1 , 3013.2±2 cm -1 , 2961.9±2 cm -1 , 2931.4±2 cm -1 , 1599.5±2 cm -1 , 1461.0±2 cm -1 It shows six characteristic peaks.

[0027] In a more preferred embodiment of the present invention, the Raman spectrum of the above crystal form A is 3063.8±2 cm⁻¹. -1 , 3013.2±2 cm -1 , 2961.9±2 cm -1 , 2931.4±2 cm -1 , 1599.5±2 cm -1 , 1461.0±2 cm -1 , 1267.6±2 cm -1 It shows seven characteristic peaks.

[0028] In a more preferred embodiment of the present invention, the Raman spectrum of the above crystal form A is 3063.8±2 cm⁻¹. -1 , 3013.2±2 cm -1 , 2961.9±2 cm -1 , 2931.4±2 cm -1 , 1599.5±2 cm -1 , 1461.0±2 cm -1 , 1267.6±2 cm -1 , 1177.9±2 cm -1 It shows eight characteristic peaks.

[0029] In a more preferred embodiment of the present invention, the Raman spectrum of the above crystal form A is 3063.8±2 cm⁻¹. -1 , 3013.2±2 cm -1 , 2961.9±2 cm -1 , 2931.4±2 cm -1 , 1599.5±2 cm -1 , 1461.0±2 cm -1 , 1267.6±2 cm -1 , 1177.9±2 cm -1 , 1047.8±2 cm -1 It shows nine characteristic peaks.

[0030] In a more preferred embodiment of the present invention, the Raman spectrum of the above crystal form A is 3063.8±2 cm⁻¹. -1 , 3013.2±2 cm -1 , 2961.9±2 cm -1 , 2931.4±2 cm -1 , 1599.5±2 cm -1 , 1461.0±2 cm -1 , 1267.6±2 cm -1 , 1177.9±2 cm -1 , 1047.8±2 cm -1 , 996.6±2 cm -1 It shows 10 characteristic peaks.

[0031] In a more preferred embodiment of the present invention, the Raman spectrum of the above crystal form A is 3063.8±2 cm⁻¹. -1 , 3013.2±2 cm -1 , 2961.9±2 cm -1 , 2931.4±2 cm -1 , 1599.5±2 cm -1 , 1461.0±2 cm -1 , 1267.6±2 cm -1 , 1177.9±2 cm -1 , 1047.8±2 cm -1 , 996.6±2 cm -1 , 827.9±2 cm -1 It shows 11 characteristic peaks.

[0032] In a further preferred embodiment of the present invention, the Raman spectrum of the above A crystal form is 3063.8 ± 2 cm -1 , 3013.2 ± 2 cm -1 , 2961.9 ± 2 cm -1 , 2931.4 ± 2 cm -1 , 1599.5 ± 2 cm -1 , 1461.0 ± 2 cm -1 , 1267.6 ± 2 cm -1 , 1177.9 ± 2 cm -1 , 1047.8 ± 2 cm -1 , 996.6 ± 2 cm -1 , 827.9 ± 2 cm -1 , 740.3 ± 2 cm -1 and shows 12 characteristic peaks at

[0033] In a further preferred embodiment of the present invention, the Raman spectrum of the above A crystal form is 3063.8 ± 2 cm -1 , 3013.2 ± 2 cm -1 , 2961.9 ± 2 cm -1 , 2931.4 ± 2 cm -1 , 1599.5 ± 2 cm -1 , 1461.0 ± 2 cm -1 , 1267.6 ± 2 cm -1 , 1177.9 ± 2 cm -1 , 1047.8 ± 2 cm -1 , 996.6 ± 2 cm -1 , 827.9 ± 2 cm -1 , 740.3 ± 2 cm -1 , 688.9 ± 2 cm -1 and shows 13 characteristic peaks at

[0034] In a further preferred embodiment of the present invention, the Raman spectrum of the above A crystal form is 3063.8 ± 2 cm -1 , 3013.2 ± 2 cm -1 , 2961.9 ± 2 cm -1 , 2931.4 ± 2 cm -1 , 1599.5 ± 2 cm -1, 1461.0±2 cm -1 , 1267.6±2 cm -1 , 1177.9±2 cm -1 , 1047.8±2 cm -1 , 996.6±2 cm -1 , 827.9±2 cm -1 740.3±2 cm -1 , 688.9±2 cm -1 , 615.4±2 cm -1 It shows 14 characteristic peaks.

[0035] In a more preferred embodiment of the present invention, the Raman spectrum of the above crystal form A is 3063.8±2 cm⁻¹. -1 , 3013.2±2 cm -1 , 2961.9±2 cm -1 , 2931.4±2 cm -1 , 1599.5±2 cm -1 , 1461.0±2 cm -1 , 1267.6±2 cm -1 , 1177.9±2 cm -1 , 1047.8±2 cm -1 , 996.6±2 cm -1 , 827.9±2 cm -1 740.3±2 cm -1 , 688.9±2 cm -1 , 615.4±2 cm -1 , 591.9±2 cm -1 It shows 15 characteristic peaks.

[0036] In a more preferred embodiment of the present invention, the melt endothermic peak value of the A crystal form DSC is selected from 161.4°C to 168.5°C, and is preferably 164.8°C.

[0037] Specifically, the melt endothermic peak value of the above-mentioned A crystal form DSC is selected from 161.4°C to 164.8°C.

[0038] Specifically, the melt endothermic peak value of the above-mentioned A crystal form DSC is selected from 161.4°C to 165.5°C.

[0039] Specifically, the melt endothermic peak value of the above-mentioned A crystal form DSC is selected from 161.4°C to 166.5°C.

[0040] Specifically, the melt endothermic peak value of the above-mentioned A crystal form DSC is selected from 161.4°C to 167.5°C.

[0041] Specifically, the melt endothermic peak value of the above-mentioned A crystal form DSC is selected from 164.8°C to 168.5°C.

[0042] Specifically, the melt endothermic peak value of the above-mentioned A crystal form DSC is selected from 164.8°C to 167.5°C.

[0043] Specifically, the melt endothermic peak value of the above-mentioned A crystal form DSC is selected from 164.8°C to 166.5°C.

[0044] Specifically, the melt endothermic peak value of the above-mentioned A crystal form DSC is selected from 164.8°C to 165.5°C.

[0045] Specifically, the melt endothermic peak values ​​for the above A crystal form DSC are 161.4°C, 161.5°C, 161.6°C, 161.7°C, 161.8°C, 161.9°C, 162°C, 162.1°C, 162.2°C, 162.3°C, 162.4°C, 162.5°C, 162.6°C, 162.7°C, 162.8°C, and 162. 9℃, 163.0℃, 163.1℃, 163.2℃, 163.3℃, ​​163.4℃, 163.5℃, 163.6℃, ​​163.7℃, 163.8℃, 163.9℃, 164.0℃, 164.1℃, 164.2℃, 164.3℃, 164.4℃, 164.5℃, 164.6℃, 164.7℃, 164.8℃ , 164.9℃, 165.0℃, 165.1℃, 165.2℃, 165.3℃, 165.4℃, 165.5℃, 165.6℃, 165.7℃, 165.8℃, 165.9℃, 166.0℃, 166.1℃, 166.2℃, 166.3℃, 166.4℃, 166.5℃, 166.6℃, 166.7℃, 1 It may also be 66.8℃, 166.9℃, 167.0℃, 167.1℃, 167.2℃, 167.3℃, 167.4℃, 167.5℃, 167.6℃, 167.7℃, 167.8℃, 167.9℃, 168.0℃, 168.1℃, 168.2℃, 168.3℃, 168.4℃, or 168.5℃.

[0046] In a more preferred embodiment of the present invention, the above crystal form A matches one or more of the following solid characteristics: (I) X-ray powder diffraction pattern that is basically consistent with Figure 1, (II) DSC spectrum that is basically consistent with Figure 2, (III) Raman spectrum that is basically consistent with Figure 3.

[0047] The present invention relates to a method for preparing (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, The present invention provides a reaction step comprising using acetophenone as a starting material, obtaining (R)-3-(dimethylamino)-1-phenylpropanolmandelate by Mannich reaction, reduction, and chiral resolution, liberating it, and then reacting it with 3-fluoro-1,2-methylenedioxybenzene, followed by a demethylation reaction to obtain (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]-dioxolan-4-yl)-oxy]propylamine, and forming a salt with ethyl hydrogen chloride solution.

[0048] The present invention provides a method for preparing the A crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, selected from the following.

[0049] Method 1 (1) Dissolve (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride in a solvent to obtain a solution containing (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, (2) Remove the solvent from the solution prepared in step (1) by solvent removal method to obtain a precipitate.

[0050] Of these, the solvent in step (1) is selected from a good solvent or a mixed solvent of a good solvent and a poor solvent, the good solvent being one or more of alcohols, halogenated hydrocarbons, N-methyl-2-pyrrolidone, nitriles, water, N,N-dimethylformamide, or dimethyl sulfoxides, the alcohols being preferably methanol, ethanol, n-propanol, isopropanol, or n-butanol, the halogenated hydrocarbons being preferably dichloromethane or chloroform, the nitriles being preferably acetonitrile, and the poor solvent being C 5-10 Selected from saturated hydrocarbons, ketones, esters, or ethers, the above C 5-10The saturated hydrocarbons are preferably n-pentane, n-hexane, cyclohexane, or n-heptane; the ethers are selected from methyl tert-butyl ether, isopropyl ether, petroleum ether, or tetrahydrofuran; the ketones are selected from acetone or butanone; and the esters are selected from ethyl acetate, n-propyl acetate, isopropyl acetate, or isobutyl acetate.

[0051] In a more preferred embodiment of the present invention, the solvent in step (1) is selected from water, chloroform, methanol, ethanol, N,N-dimethylformamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone.

[0052] In a more preferred embodiment of the present invention, the solvent in step (1) is C 5-10 A mixed solvent consisting of saturated hydrocarbons and one or more selected from alcohols and halogenated hydrocarbons, a mixed solvent consisting of water and one or two selected from ketones and alcohols, or alcohols and C 5-10 It is a mixed solvent consisting of one or more selected from saturated hydrocarbons, esters, ethers, and ketones.

[0053] In a more preferred embodiment of the present invention, the mixed solvent is methanol / acetonitrile, methanol / ethyl acetate, methanol / water, methanol / methyl tert-butyl ether, methanol / isopropyl ether, methanol / petroleum ether, methanol / n-hexane, methanol / n-heptane, methanol / cyclohexane, methanol / dichloromethane, ethanol / water, ethanol / acetonitrile, ethanol / ethyl acetate, ethanol / methyl tert-butyl ether, ethanol / isopropyl ether, ethanol / petroleum ether, ethanol / n-hexane, ethanol / n-heptane, ethanol / cyclohexane, ethanol / dichloromethane, 95% ethanol / ethyl acetate, 95% ethanol / acetonitrile, 95% ethanol / n-hexane, 95% ethanol / cyclohexane, 95% ethanol / n-heptane, 95% ethanol / dichloromethane, n-propanol / water, n-propanol / acetonitrile, n-propanol / EA, n-propanol / methyl tert-butyl ether, n-propanol / isopropyl ether, n-propano Isopropanol / petroleum ether, n-propanol / n-hexane, n-propanol / n-heptane, n-propanol / cyclohexane, n-propanol / dichloromethane, isopropanol / water, isopropanol / acetonitrile, isopropanol / EA, isopropanol / methyl tert-butyl ether, isopropanol / isopropyl ether, isopropanol / petroleum ether, isopropanol / n-hexane, isopropanol / n-heptane, isopropanol / cyclohexane, isopropanol / dichloromethane, acetonitrile Acetone / Water, Acetonitrile / EA, Acetonitrile / Methyltert-butyl ether, Acetonitrile / Isopropyl ether, Acetonitrile / Dichloromethane, n-Butanol / Water, n-Butanol / Acetonitrile, n-Butanol / EA, n-Butanol / Methyltert-butyl ether, n-Butanol / Isopropyl ether, n-Butanol / Petroleum ether, n-Butanol / Dichloromethane, Acetone / Methanol, Acetone / Ethanol, Acetone / 95% Ethanol, Acetone / n-Propanol, Acetone / Isopropanol,Selected from acetone / n-butanol, acetone / acetonitrile, butanone / methanol, butanone / ethanol, butanone / 95% ethanol, butanone / n-propanol, butanone / n-butanol, butanone / isopropanol, chloroform / methanol, chloroform / ethanol, chloroform / n-propanol, chloroform / n-butanol, chloroform / isopropanol, chloroform / acetonitrile, chloroform / methyl tert-butyl ether, chloroform / isopropyl ether, chloroform / petroleum ether, chloroform / n-hexane, chloroform / n-heptane, chloroform / cyclohexane, chloroform / acetone, and chloroform / butanone.

[0054] In a more preferred embodiment of the present invention, the water content of the ethanol is ≤5% (v / v).

[0055] In another preferred embodiment of the present invention, step (1) further comprises a heating process having a heating temperature selected from temperatures below the boiling point of the solvent used in step (1).

[0056] In a preferred embodiment of the present invention, the solvent removal method in step (2) above is selected from vacuum solvent removal methods, the vacuum solvent removal method being preferably a vacuum evaporation method. In the vacuum solvent removal, the pressure is gradually reduced from 300 mbar to 10 mbar and the temperature is increased from 20°C to 90°C.

[0057] In a preferred embodiment of the present invention, the solvent removal method in step (2) above is selected from evaporation in a gas stream, the gas stream is preferably an air stream or an inert gas stream, and the inert gas is preferably an argon gas stream and a nitrogen gas stream.

[0058] Method 2 (1) Dissolve the (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride in a solvent to obtain a solution containing (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, (2) A precipitate is obtained from the solution obtained in step (1) by precipitation.

[0059] Of these, the solvent in step (1) is selected from a good solvent or a mixed solvent of a good solvent and a poor solvent, the good solvent being one or more of alcohols, halogenated hydrocarbons, N-methyl-2-pyrrolidone, nitriles, water, N,N-dimethylformamide, or dimethyl sulfoxides, the alcohols being preferably methanol, ethanol, n-propanol, isopropanol, or n-butanol, the halogenated hydrocarbons being preferably dichloromethane or chloroform, the nitriles being preferably acetonitrile, and the poor solvent being C 5-10 Selected from saturated hydrocarbons, ketones, esters, or ethers, the above C 5-10 The saturated hydrocarbons are preferably n-pentane, n-hexane, cyclohexane, or n-heptane; the ethers are selected from methyl tert-butyl ether, isopropyl ether, petroleum ether, or tetrahydrofuran; the ketones are selected from acetone or butanone; and the esters are selected from ethyl acetate, n-propyl acetate, isopropyl acetate, or isobutyl acetate.

[0060] In a more preferred embodiment of the present invention, the solvent in step (1) is selected from water, chloroform, methanol, ethanol, N,N-dimethylformamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone.

[0061] In a more preferred embodiment of the present invention, the solvent in step (1) is C 5-10A mixed solvent consisting of saturated hydrocarbons and one or more selected from alcohols and halogenated hydrocarbons, a mixed solvent consisting of water and one or two selected from ketones and alcohols, or alcohols and C 5-10 It is a mixed solvent consisting of one or more selected from saturated hydrocarbons, esters, ethers, and ketones.

[0062] In a more preferred embodiment of the present invention, the mixed solvent is selected from ethanol / methyl tert-butyl ether, ethanol / n-hexane, ethanol / n-heptane, methanol / methyl tert-butyl ether, methanol / isopropyl ether, methanol / ethyl acetate, methanol / acetone, ethanol / acetonitrile, methanol / ethyl acetate, ethanol / ethyl acetate, ethanol / methyl tert-butyl ether, acetonitrile / ethyl acetate, acetonitrile / methyl tert-butyl ether, acetonitrile / isopropyl ether, acetonitrile / petroleum ether, acetonitrile / n-heptane, n-propanol / cyclohexane, n-propanol / petroleum ether, isopropanol / ethyl acetate, isopropanol / methyl tert-butyl ether, chloroform / ethanol, chloroform / n-hexane, chloroform / methyl tert-butyl ether, chloroform / acetone, acetonitrile / butanone, and chloroform / acetone.

[0063] In a more preferred embodiment of the present invention, the water content of the ethanol is ≤5% (v / v).

[0064] In a preferred embodiment of the present invention, the precipitation method in step (2) is selected from a cooling method or a precipitating agent method.

[0065] In a preferred embodiment of the present invention, the cooling method in step (2) refers to cooling the solution obtained in step (1) to a specific temperature to precipitate the crystals, the specific temperature being selected from ≤30°C, preferably room temperature, preferably ≤20°C, preferably ≤9°C, and more preferably ≤0°C, with a temperature error range of ±5°C, preferably ±2°C.

[0066] In another preferred embodiment of the present invention, the cooling method in step (2) refers to cooling the solution obtained in step (1) to a specific temperature to precipitate the crystals, the specific temperature being selected from a temperature at least 20°C lower than the temperature of the solution obtained in step (1), preferably at least 30°C lower than the temperature of the solution obtained in step (1), more preferably at least 60°C lower than the temperature of the solution obtained in step (1), with a temperature error range of ±5°C, preferably ±2°C.

[0067] In a preferred embodiment of the present invention, the precipitating agent method in step (2) refers to adding a precipitating agent of the compound represented by formula (I) to the solution obtained in step (1) and precipitating the crystals, wherein the precipitating agent is C 5-10 It is one or more selected from saturated hydrocarbons, ketones, esters, or ethers.

[0068] In a more preferred embodiment of the present invention, C 5-10 Saturated hydrocarbons are one or more selected from n-pentane, n-hexane, cyclohexane, or n-heptane.

[0069] In the above more preferred embodiments of the present invention, the ethers are one or more selected from methyl tert-butyl ether, isopropyl ether, petroleum ether, or tetrahydrofuran, and are preferably one or more methyl tert-butyl ether or isopropyl ether.

[0070] In a more preferred embodiment of the present invention, the ketones are selected from acetone and butanone.

[0071] In the above more preferred embodiments of the present invention, the esters are selected from ethyl acetate, n-propyl acetate, isopropyl acetate, or isobutyl acetate.

[0072] In a preferred embodiment of the present invention, step (2) further includes a precipitation time after adding a precipitating agent to the solution obtained in step (1), wherein the precipitation time is selected from 0 to 120 minutes, 0 to 60 minutes, 0 to 30 minutes, 0 to 10 minutes, 0 to 5 minutes, 0 to 2 minutes, 0 to 30 seconds, or 0 seconds, preferably 0 to 10 minutes, 0 to 5 minutes, 0 to 2 minutes, 0 to 30 seconds, or 0 seconds, where "0" or "0 seconds" refers to the time when the precipitating agent is added immediately.

[0073] In a more preferred embodiment of the present invention, step (2) further comprises a precipitation time to obtain the maximum precipitate, the precipitation time for the maximum precipitate being selected from 0 to 90 minutes, 0 to 80 minutes, 0 to 70 minutes, or 0 to 60 minutes, preferably 0 to 70 minutes or 0 to 60 minutes, most preferably 0 to 60 minutes, where "0" refers to the time when the precipitating agent has been completely added, and "maximum precipitate" refers to the time when the compound of formula (I) has been completely precipitated from the solution obtained in step (1), or at least 85% of it has precipitated (mass ratio of precipitate amount to dissolved amount of compound represented by formula (I)).

[0074] In another preferred embodiment of the present invention, step (2) further includes a precipitation temperature, the precipitation temperature being selected from 0°C to 60°C, preferably 5°C to 40°C, more preferably 15°C to 25°C, and the temperature error range being ±5°C, preferably ±2°C.

[0075] In a preferred embodiment of the present invention, Method 1 or Method 2 is (3) A step of isolating the solid precipitate obtained in step (2) of Method 1 or Method 2, (4) Further comprising the step of drying the solid precipitate obtained in step (3).

[0076] In a preferred embodiment of the present invention, step (3) further includes an isolation temperature, which is selected from the above isolation temperatures of 0°C to 60°C, preferably 5°C to 40°C, more preferably 15°C to 25°C, with a temperature error range of ±5°C, preferably ±2°C.

[0077] In a preferred embodiment of the present invention, step (4) further includes a drying temperature, the drying temperature being selected from 0°C to 60°C, preferably 5°C to 40°C, more preferably 15°C to 25°C, and the temperature error range being ±5°C, preferably ±2°C.

[0078] In a preferred embodiment of the present invention, step (4) further includes conditions for a dry airflow, the dry airflow being selected from an argon gas or nitrogen gas flow.

[0079] The present invention provides a B crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, and obtains an X-ray powder diffraction pattern using Cu-Kα radiation, expressed at a diffraction angle of 2θ ± 0.2°, showing three characteristic peaks at 6.69°, 10.36°, and 11.90°, with an error range of ±0.3°, ±0.2°, or ±0.1°. Specifically, it shows four characteristic peaks at 6.69°, 10.36°, 11.90°, and 19.69°, with an error range of ±0.3°, ±0.2°, or ±0.1°. Specifically, it may show five characteristic peaks at 6.69°, 10.36°, 11.90°, 19.69°, and 21.80°, with an error range of ±0.3°, ±0.2°, or ±0.1°. Specifically, it may show six characteristic peaks at 6.69°, 10.36°, 11.90°, 19.69°, 21.80°, and 24.20°, with an error range of ±0.3°, ±0.2°, or ±0.1°. Specifically, it may show seven characteristic peaks at 6.69°, 10.36°, 11.90°, 19.69°, 21.80°, 24.20°, and 25.63°, with an error range of ±0.3°, ±0.2°, or ±0.1°. Specifically, it shows eight characteristic peaks at 6.69°, 10.36°, 11.90°, 19.69°, 21.80°, 24.20°, 25.63°, and 26.10°, and the error range may be ±0.3°, ±0.2°, or ±0.1°. Specifically, it shows nine characteristic peaks at 6.69°, 10.36°, 11.90°, 19.69°, 21.80°, 24.20°, 25.63°, 26.10°, and 28.07°, and the error range may be ±0.3°, ±0.2°, or ±0.1°.

[0080] In a more preferred embodiment of the present invention, the Raman spectrum of the above B crystal form is 3063.6±2 cm⁻¹. -1 , 3044.5±2 cm -1 , 2964.8±2 cm -1 It shows three characteristic peaks. Specifically, the Raman spectrum of the above B crystal form is 3063.6±2 cm⁻¹. -1, 3044.5±2 cm -1 , 2964.8±2 cm -1 , 2918.5±2 cm -1 It shows four characteristic peaks. Specifically, the Raman spectrum of the above B crystal form is 3063.6±2 cm⁻¹. -1 , 3044.5±2 cm -1 , 2964.8±2 cm -1 , 2918.5±2 cm -1 , 1715.2±2 cm -1 It shows five characteristic peaks. Specifically, the Raman spectrum of the above B crystal form is 3063.6±2 cm⁻¹. -1 , 3044.5±2 cm -1 , 2964.8±2 cm -1 , 2918.5±2 cm -1 , 1715.2±2 cm -1 , 1599.9±2 cm -1 It shows six characteristic peaks. Specifically, the Raman spectrum of the above B crystal form is 3063.6±2 cm⁻¹. -1 , 3044.5±2 cm -1 , 2964.8±2 cm -1 , 2918.5±2 cm -1 , 1715.2±2 cm -1 , 1599.9±2 cm -1 , 1458.7±2 cm -1 It shows seven characteristic peaks. Specifically, the Raman spectrum of the above B crystal form is 3063.6±2 cm⁻¹. -1 , 3044.5±2 cm -1 , 2964.8±2 cm -1 , 2918.5±2 cm -1 , 1715.2±2 cm -1 , 1599.9±2 cm -1 , 1458.7±2 cm -1 , 1277.4±2 cm -1 It shows eight characteristic peaks. Specifically, the Raman spectrum of the above B crystal form is 3063.6±2 cm⁻¹. -1 , 3044.5±2 cm -1 , 2964.8±2 cm -1 , 2918.5±2 cm-1 , 1715.2±2 cm -1 , 1599.9±2 cm -1 , 1458.7±2 cm -1 , 1277.4±2 cm -1 , 1177.7±2 cm -1 It shows nine characteristic peaks. Specifically, the Raman spectrum of the above B crystal form is 3063.6±2 cm⁻¹. -1 , 3044.5±2 cm -1 , 2964.8±2 cm -1 , 2918.5±2 cm -1 , 1715.2±2 cm -1 , 1599.9±2 cm -1 , 1458.7±2 cm -1 , 1277.4±2 cm -1 , 1177.7±2 cm -1 , 1048.2±2 cm -1 It shows 10 characteristic peaks. Specifically, the Raman spectrum of the above B crystal form is 3063.6±2 cm⁻¹. -1 , 3044.5±2 cm -1 , 2964.8±2 cm -1 , 2918.5±2 cm -1 , 1715.2±2 cm -1 , 1599.9±2 cm -1 , 1458.7±2 cm -1 , 1277.4±2 cm -1 , 1177.7±2 cm -1 , 1048.2±2 cm -1 , 996.9±2 cm -1 It shows 11 characteristic peaks. Specifically, the Raman spectrum of the above B crystal form is 3063.6±2 cm⁻¹. -1 , 3044.5±2 cm -1 , 2964.8±2 cm -1 , 2918.5±2 cm -1 , 1715.2±2 cm -1 , 1599.9±2 cm -1 , 1458.7±2 cm -1 , 1277.4±2 cm -1 , 1177.7±2 cm -1, 1048.2±2 cm -1 , 996.9±2 cm -1 , 838.0±2 cm -1 It shows 12 characteristic peaks. Specifically, the Raman spectrum of the above B crystal form is 3063.6±2 cm⁻¹. -1 , 3044.5±2 cm -1 , 2964.8±2 cm -1 , 2918.5±2 cm -1 , 1715.2±2 cm -1 , 1599.9±2 cm -1 , 1458.7±2 cm -1 , 1277.4±2 cm -1 , 1177.7±2 cm -1 , 1048.2±2 cm -1 , 996.9±2 cm -1 , 838.0±2 cm -1 , 739.9±2 cm -1 It shows 13 characteristic peaks. Specifically, the Raman spectrum of the above B crystal form is 3063.6±2 cm⁻¹. -1 , 3044.5±2 cm -1 , 2964.8±2 cm -1 , 2918.5±2 cm -1 , 1715.2±2 cm -1 , 1599.9±2 cm -1 , 1458.7±2 cm -1 , 1277.4±2 cm -1 , 1177.7±2 cm -1 , 1048.2±2 cm -1 , 996.9±2 cm -1 , 838.0±2 cm -1 , 739.9±2 cm -1 , 691.4±2 cm -1 It shows 14 characteristic peaks. Specifically, the Raman spectrum of the above B crystal form is 3063.6±2 cm⁻¹. -1 , 3044.5±2 cm -1 , 2964.8±2 cm -1 , 2918.5±2 cm -1 , 1715.2±2 cm -1 , 1599.9±2 cm-1 , 1458.7±2 cm -1 , 1277.4±2 cm -1 , 1177.7±2 cm -1 , 1048.2±2 cm -1 , 996.9±2 cm -1 , 838.0±2 cm -1 , 739.9±2 cm -1 , 691.4±2 cm -1 , 615.4±2 cm -1 It shows 15 characteristic peaks.

[0081] In a more preferred embodiment of the present invention, the above B crystal form matches one or more of the following solid characteristics: (I) X-ray powder diffraction pattern that is basically consistent with Figure 4, (II) Raman spectrum that is basically consistent with Figure 5.

[0082] This invention provides a method for preparing a B crystal form, selected from reflux recrystallization methods, and the specific method is as follows: (1) A step of dissolving the compound represented by formula (I) in glacial acetic acid, (2) A step of gradually adding to methyl tert-butyl ether to obtain a solid precipitate, (3) The step of drying the solid precipitate obtained in step (2).

[0083] The present invention provides a C crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, and obtains an X-ray powder diffraction pattern represented by a diffraction angle of 2θ ± 0.2° using Cu-Kα rays.

[0084] Specifically, it may show three characteristic peaks at 10.73°, 11.95°, and 14.82°, with an error range of ±0.3°, ±0.2°, or ±0.1°. Specifically, it may show four characteristic peaks at 10.73°, 11.95°, 14.82°, and 16.14°, with an error range of ±0.3°, ±0.2°, or ±0.1°. Specifically, it may show five characteristic peaks at 10.73°, 11.95°, 14.82°, 16.14°, and 16.53°, with an error range of ±0.3°, ±0.2°, or ±0.1°.

[0085] Specifically, it shows six characteristic peaks at 10.73°, 11.95°, 14.82°, 16.14°, 16.53°, and 18.72°, with error ranges of ±0.3°, ±0.2°, or ±0.1°. Specifically, it shows seven characteristic peaks at 10.73°, 11.95°, 14.82°, 16.14°, 16.53°, 18.72°, and 18.98°, with error ranges of ±0.3°, ±0.2°, or ±0.1°. Specifically, it exhibits eight characteristic peaks at 10.73°, 11.95°, 14.82°, 16.14°, 16.53°, 18.72°, 18.98°, and 19.52°, with error ranges of ±0.3°, ±0.2°, or ±0.1°.

[0086] Specifically, it shows nine characteristic peaks at 10.73°, 11.95°, 14.82°, 16.14°, 16.53°, 18.72°, 18.98°, 19.52°, and 21.78°, with an error range of ±0.3°, ±0.2°, or ±0.1°. Specifically, it shows ten characteristic peaks at 10.73°, 11.95°, 14.82°, 16.14°, 16.53°, 18.72°, 18.98°, 19.52°, 21.78°, and 23.00°, with an error range of ±0.3°, ±0.2°, or ±0.1°. Specifically, it shows 11 characteristic peaks at 10.73°, 11.95°, 14.82°, 16.14°, 16.53°, 18.72°, 18.98°, 19.52°, 21.78°, 23.00°, and 24.99°, with an error range of ±0.3°, ±0.2°, or ±0.1°. Specifically, it shows 12 characteristic peaks at 10.73°, 11.95°, 14.82°, 16.14°, 16.53°, 18.72°, 18.98°, 19.52°, 21.78°, 23.00°, 24.99°, and 26.75°, with an error range of ±0.3°, ±0.2°, or ±0.1°. Specifically, it exhibits 13 characteristic peaks at 10.73°, 11.95°, 14.82°, 16.14°, 16.53°, 18.72°, 18.98°, 19.52°, 21.78°, 23.00°, 24.99°, 26.75°, and 27.25°, with error ranges of ±0.3°, ±0.2°, or ±0.1°.

[0087] In a more preferred embodiment of the present invention, the above C crystal form matches one or more of the following solid characteristics: (I) X-ray powder diffraction pattern that is basically consistent with Figure 6.

[0088] The present invention provides a method for preparing the C crystalline form of a compound represented by formula (I), wherein the sample is completely dissolved in a water bath at approximately 65°C by adding an appropriate amount of water, pre-frozen in a refrigerator, freeze-dried in a freeze-dryer after completion, and then irradiated with light (5000 lx) for 10 days after freeze-drying is complete to obtain the C crystalline form.

[0089] The present invention further provides pharmaceutical compositions comprising one active ingredient selected from crystalline form A, crystalline form B, or crystalline form C, and a pharmaceutically acceptable excipient, vector, adjuvant, solvent, or combination thereof.

[0090] In a preferred embodiment of the present invention, the active ingredient contains at least 50% to 99% of the A crystalline form, preferably at least 70% to 99% of the above A crystalline form, and more preferably at least 90% to 99% of the A crystalline form.

[0091] Specifically, the content of the A crystalline form in the active ingredient is 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.

[0092] In preferred embodiments of the present invention, the active ingredient contains at least 50% to 99% of the B crystal form, preferably at least 70% to 99% of the above B crystal form, and more preferably at least 90% to 99% of the B crystal form.

[0093] Specifically, the content of the B crystalline form in the active ingredient is 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.

[0094] In preferred embodiments of the present invention, the active ingredient contains at least 50% to 99% of the C crystalline form, preferably at least 70% to 99% of the above C crystalline form, and more preferably at least 90% to 99% of the C crystalline form.

[0095] Specifically, the content of the C crystalline form in the active ingredient is 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.

[0096] In a more preferred embodiment of the present invention, one of crystalline forms A, B, or C is present in the active ingredient in essentially a pure form.

[0097] In preferred embodiments of the present invention, the pharmaceutical composition may be administered by any suitable route, for example, orally as a capsule, parenterally as an injection, topically as an ointment or lotion, rectally as a suppository, or transdermally as a patch delivery system. In preferred embodiments, the pharmaceutical composition is preferably administered orally.

[0098] The present invention further relates to the use of any one of the A, B, or C crystalline forms described herein in the preparation of a pharmaceutical composition preferably suitable for the treatment and / or prevention of mental disorders. Among these, the mental disorder is one or more selected from anxiety disorders, obsessive-compulsive disorders, depression, phobias, and schizophrenia, preferably depression.

[0099] The present invention further provides a method for treating and / or preventing a mental disorder, comprising administering to a patient N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, or (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, or A crystalline form, or the above pharmaceutical composition, wherein the mental disorder is selected from or two or more of anxiety disorders, obsessive-compulsive disorders, depression, phobias, and schizophrenia, and preferably depression.

[0100] [Detailed description of the invention] In a more preferred embodiment of the present invention, the above crystal form A matches one or more of the following solid characteristics: (I) X-ray powder diffraction pattern that is basically consistent with Figure 1, (II) DSC spectrum that is basically consistent with Figure 2, (III) Raman spectrum that is basically consistent with Figure 3.

[0101] The present invention relates to a method for preparing (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, The present invention provides a reaction step comprising using acetophenone as a starting material, obtaining (R)-3-(dimethylamino)-1-phenylpropanolmandelate by Mannich reaction, reduction, and chiral resolution, liberating it, and then reacting it with 3-fluoro-1,2-methylenedioxybenzene, followed by a demethylation reaction to obtain (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]-dioxolan-4-yl)-oxy]propylamine, and forming a salt with ethyl hydrogen chloride solution.

[0102] The present invention provides a method for preparing the A crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, selected from the following.

[0103] Method 1 (1) Dissolve (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride in a solvent to obtain a solution containing (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, (2) Remove the solvent from the solution prepared in step (1) by solvent removal method to obtain a precipitate.

[0104] Of these, the solvent in step (1) is selected from a good solvent or a mixed solvent of a good solvent and a poor solvent, the good solvent being one or more of alcohols, halogenated hydrocarbons, N-methyl-2-pyrrolidone, nitriles, water, N,N-dimethylformamide, or dimethyl sulfoxides, the alcohols being preferably methanol, ethanol, n-propanol, isopropanol, or n-butanol, the halogenated hydrocarbons being preferably dichloromethane or chloroform, the nitriles being preferably acetonitrile, and the poor solvent being C 5-10Selected from saturated hydrocarbons, ketones, esters, or ethers, the above C 5-10 The saturated hydrocarbons are preferably n-pentane, n-hexane, cyclohexane, or n-heptane; the ethers are selected from methyl tert-butyl ether, isopropyl ether, petroleum ether, or tetrahydrofuran; the ketones are selected from acetone or butanone; and the esters are selected from ethyl acetate, n-propyl acetate, isopropyl acetate, or isobutyl acetate.

[0105] In a more preferred embodiment of the present invention, the alcohols are selected from methanol, ethanol, n-propanol, isopropanol, or n-butanol; the esters are selected from ethyl acetate, n-propyl acetate, isopropyl acetate, or isobutyl acetate; the ketones are selected from acetone, 2-butanone, pentan-2-one, pentan-3-one, hexane-2-one, or hexane-3-one; the ethers are selected from methyl tert-butyl ether, isopropyl ether, petroleum ether, or tetrahydrofuran; the nitriles are selected from acetonitrile; the halogenated hydrocarbons are selected from dichloromethane or chloroform; and the C 5-10 The saturated hydrocarbons are selected from n-pentane, n-hexane, cyclohexane, or n-heptane.

[0106] In a more preferred embodiment of the present invention, the solvent in step (1) is selected from water, chloroform, methanol, ethanol, N,N-dimethylformamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone.

[0107] In a more preferred embodiment of the present invention, the solvent in step (1) is C 5-10 A mixed solvent consisting of saturated hydrocarbons and one or more selected from alcohols and halogenated hydrocarbons, a mixed solvent consisting of water and one or two selected from ketones and alcohols, or alcohols and C 5-10It is a mixed solvent consisting of one or more selected from saturated hydrocarbons, esters, ethers, and ketones.

[0108] In a more preferred embodiment of the present invention, the mixed solvent is selected from ethanol / methyl tert-butyl ether, ethanol / n-heptane, methanol / methyl tert-butyl ether, methanol / isopropyl ether, methanol / petroleum ether, methanol / n-hexane, methanol / n-heptane, methanol / cyclohexane, ethanol / acetonitrile, ethanol / ethyl acetate, ethanol / methyl tert-butyl ether, acetonitrile / ethyl acetate, acetonitrile / methyl tert-butyl ether, acetonitrile / isopropyl ether, acetonitrile / petroleum ether, n-propanol / dichloromethane (1:2), n-propanol / dichloromethane (1:3), methanol / water, isopropanol / ethyl acetate, isopropanol / methyl tert-butyl ether, chloroform / ethanol, and chloroform / n-hexane.

[0109] In a more preferred embodiment of the present invention, the water content of the ethanol is ≤5% (v / v).

[0110] In another preferred embodiment of the present invention, step (1) further comprises a heating process having a heating temperature selected from temperatures below the boiling point of the solvent used in step (1).

[0111] In a preferred embodiment of the present invention, the solvent removal method in step (2) above is selected from a vacuum solvent removal method, which is preferably a vacuum solvent removal method. In the vacuum solvent removal, the pressure is gradually reduced from 300 mbar to 10 mbar and the temperature is increased from 20°C to 90°C.

[0112] In a preferred embodiment of the present invention, the solvent removal method in step (2) above is selected from evaporation in a gas stream, the gas stream is preferably an air stream or an inert gas stream, and the inert gas is preferably an argon gas stream and a nitrogen gas stream.

[0113] Method 2 (1) Dissolve the (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride in a solvent to obtain a solution containing (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, (2) A precipitate is obtained from the solution obtained in step (1) by precipitation.

[0114] Of these, the solvent in step (1) is selected from a good solvent or a mixed solvent of a good solvent and a poor solvent, the good solvent being one or more of alcohols, halogenated hydrocarbons, N-methyl-2-pyrrolidone, nitriles, water, N,N-dimethylformamide, or dimethyl sulfoxides, the alcohols being preferably methanol, ethanol, n-propanol, isopropanol, or n-butanol, the halogenated hydrocarbons being preferably dichloromethane or chloroform, the nitriles being preferably acetonitrile, and the poor solvent being C 5-10 Selected from saturated hydrocarbons, ketones, esters, or ethers, the above C 5-10 The saturated hydrocarbons are preferably n-pentane, n-hexane, cyclohexane, or n-heptane; the ethers are selected from methyl tert-butyl ether, isopropyl ether, petroleum ether, or tetrahydrofuran; the ketones are selected from acetone or butanone; and the esters are selected from ethyl acetate, n-propyl acetate, isopropyl acetate, or isobutyl acetate.

[0115] In a more preferred embodiment of the present invention, the alcohols are selected from methanol, ethanol, n-propanol, isopropanol, or n-butanol; the esters are selected from ethyl acetate, n-propyl acetate, isopropyl acetate, or isobutyl acetate; the ketones are selected from acetone, 2-butanone, pentan-2-one, pentan-3-one, hexane-2-one, or hexane-3-one; the ethers are selected from methyl tert-butyl ether, isopropyl ether, petroleum ether, or tetrahydrofuran; the nitriles are selected from acetonitrile; the halogenated hydrocarbons are selected from dichloromethane or chloroform; and the C 5-10 The saturated hydrocarbon is selected from n-pentane, n-hexane, cyclohexane, or n-heptane.

[0116] In a more preferred embodiment of the present invention, the solvent in step (1) is one or more selected from water, chloroform, methanol, ethanol, N,N-dimethylformamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone.

[0117] In a more preferred embodiment of the present invention, the solvent in step (1) is C 5-10 A mixed solvent consisting of saturated hydrocarbons and one or more selected from alcohols and halogenated hydrocarbons, a mixed solvent consisting of water and one or two selected from ketones and alcohols, or alcohols and C 5-10 It is a mixed solvent consisting of one or more selected from saturated hydrocarbons, esters, ethers, and ketones.

[0118] In a more preferred embodiment of the present invention, the mixed solvent is selected from ethanol / methyl tert-butyl ether, ethanol / n-heptane, methanol / methyl tert-butyl ether, methanol / isopropyl ether, methanol / petroleum ether, methanol / n-hexane, methanol / n-heptane, methanol / cyclohexane, ethanol / acetonitrile, ethanol / ethyl acetate, ethanol / methyl tert-butyl ether, acetonitrile / ethyl acetate, acetonitrile / methyl tert-butyl ether, acetonitrile / isopropyl ether, acetonitrile / petroleum ether, n-propanol / dichloromethane (1:2), n-propanol / dichloromethane (1:3), methanol / water, isopropanol / ethyl acetate, isopropanol / methyl tert-butyl ether, chloroform / ethanol, and chloroform / n-hexane.

[0119] In a more preferred embodiment of the present invention, the water content of the ethanol is ≤5% (v / v).

[0120] In a preferred embodiment of the present invention, the precipitation method in step (2) is selected from a cooling method or a precipitating agent method.

[0121] In a preferred embodiment of the present invention, the cooling method in step (2) refers to cooling the solution obtained in step (1) to a specific temperature to precipitate the crystals, the specific temperature being selected from ≤30°C, preferably room temperature, preferably ≤20°C, preferably ≤9°C, and more preferably ≤0°C, with a temperature error range of ±5°C, preferably ±2°C.

[0122] Specifically, the above-mentioned temperatures may also be 30°C, 29°C, 28°C, 27°C, 26°C, 25°C, 24°C, 23°C, 22°C, 21°C, 20°C, 19°C, 18°C, 17°C, 16°C, 15°C, 14°C, 13°C, 12°C, 11°C, 10°C, 9°C, 8°C, 7°C, 6°C, 5°C, 4°C, 3°C, 2°C, 1°C, 0°C, -1°C, -2°C, -3°C, -4°C, or -5°C, etc.

[0123] In another preferred embodiment of the present invention, the cooling method in step (2) refers to cooling the solution obtained in step (1) to a specific temperature to precipitate the crystals, the specific temperature being selected from a temperature at least 20°C lower than the temperature of the solution obtained in step (1), preferably at least 30°C lower than the temperature of the solution obtained in step (1), more preferably at least 60°C lower than the temperature of the solution obtained in step (1), with a temperature error range of ±5°C, preferably ±2°C.

[0124] Specifically, the aforementioned temperature is selected from a temperature at least 25°C lower than the temperature of the solution obtained in step (1).

[0125] Specifically, the aforementioned temperature is selected from a temperature at least 35°C lower than the temperature of the solution obtained in step (1).

[0126] Specifically, the aforementioned temperature is selected from a temperature at least 40°C lower than the temperature of the solution obtained in step (1).

[0127] Specifically, the aforementioned temperature is selected from a temperature at least 45°C lower than the temperature of the solution obtained in step (1).

[0128] Specifically, the aforementioned temperature is selected from a temperature at least 50°C lower than the temperature of the solution obtained in step (1).

[0129] Specifically, the aforementioned temperature is selected from a temperature at least 55°C lower than the temperature of the solution obtained in step (1).

[0130] Specifically, the above-mentioned specific temperature is selected from a temperature that is at least 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, or 60°C lower than the temperature of the solution obtained in step (1).

[0131] In a preferred embodiment of the present invention, the precipitating agent method in step (2) refers to adding a precipitating agent of the compound represented by formula (I) to the solution obtained in step (1) and precipitating the crystals, wherein the precipitating agent is C 5-10 It is one or more selected from saturated hydrocarbons, ketones, esters, or ethers.

[0132] In a more preferred embodiment of the present invention, C 5-10 Saturated hydrocarbons are one or more selected from n-pentane, n-hexane, cyclohexane, or n-heptane.

[0133] In the above more preferred embodiments of the present invention, the ethers are one or more selected from methyl tert-butyl ether, isopropyl ether, petroleum ether, or tetrahydrofuran, and are preferably one or more methyl tert-butyl ether or isopropyl ether.

[0134] In a more preferred embodiment of the present invention, the ketones are selected from acetone and butanone.

[0135] In the above more preferred embodiments of the present invention, the esters are selected from ethyl acetate, n-propyl acetate, isopropyl acetate, or isobutyl acetate.

[0136] In a preferred embodiment of the present invention, step (2) further includes a precipitation time after adding a precipitating agent to the solution obtained in step (1), wherein the precipitation time is selected from 0 to 120 minutes, 0 to 60 minutes, 0 to 30 minutes, 0 to 10 minutes, 0 to 5 minutes, 0 to 2 minutes, 0 to 30 seconds, or 0 seconds, preferably 0 to 10 minutes, 0 to 5 minutes, 0 to 2 minutes, 0 to 30 seconds, or 0 seconds, where "0" or "0 seconds" refers to the time when the precipitating agent is added immediately.

[0137] Specifically, the above fermentation times are 0 minutes, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 21 minutes, 22 minutes, 23 minutes, 24 minutes, 25 minutes, 26 minutes, 27 minutes, 28 minutes, 29 minutes, 30 minutes, 31 minutes, 32 minutes, 33 minutes, 34 minutes, 35 minutes, 36 minutes, 37 minutes, 38 minutes, 39 minutes, 40 minutes, 41 minutes, 42 minutes, 43 minutes, 44 minutes, 45 minutes, 46 minutes, 47 minutes, 48 ​​minutes, 49 minutes, 50 minutes, 51 minutes, 52 minutes, 5 The durations are 3 minutes, 54 minutes, 55 minutes, 56 minutes, 57 minutes, 58 minutes, 59 minutes, 60 minutes, 61 minutes, 62 minutes, 63 minutes, 64 minutes, 65 minutes, 66 minutes, 67 minutes, 68 minutes, 69 minutes, 70 minutes, 71 minutes, 72 minutes, 73 minutes, 74 minutes, 75 minutes, 76 minutes, 77 minutes, 78 minutes, 79 minutes, 80 minutes, 81 minutes, 82 minutes, 83 minutes, 84 minutes, 85 minutes, 86 minutes, 87 minutes, 88 minutes, 89 minutes, 90 minutes, 91 minutes, 92 minutes, 93 minutes, 94 minutes, 95 minutes, 96 minutes, 97 minutes, 98 minutes, 99 minutes, 100 minutes, 105 minutes, 110 minutes, 115 minutes, or 120 minutes.

[0138] In a more preferred embodiment of the present invention, step (2) further comprises a precipitation time to obtain the maximum precipitate, the precipitation time for the maximum precipitate being selected from 0 to 90 minutes, 0 to 80 minutes, 0 to 70 minutes, or 0 to 60 minutes, preferably 0 to 70 minutes or 0 to 60 minutes, most preferably 0 to 60 minutes, where "0" refers to the time when the precipitating agent has been completely added, and "maximum precipitate" refers to the time when the compound of formula (I) has been completely precipitated from the solution obtained in step (1), or at least 85% of it has precipitated (mass ratio of precipitate amount to dissolved amount of compound represented by formula (I)).

[0139] In another preferred embodiment of the present invention, step (2) further includes a precipitation temperature, the precipitation temperature being selected from 0°C to 60°C, preferably 5°C to 40°C, more preferably 15°C to 25°C, and the temperature error range being ±5°C, preferably ±2°C.

[0140] Specifically, the precipitation temperatures mentioned above are 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, or 60°C.

[0141] In a preferred embodiment of the present invention, Method 1 or Method 2 is (3) A step of isolating the solid precipitate obtained in step (2) of Method 1 or Method 2, (4) Further comprising the step of drying the solid precipitate obtained in step (3).

[0142] In a preferred embodiment of the present invention, step (3) further includes an isolation temperature, which is selected from the above isolation temperatures of 0°C to 60°C, preferably 5°C to 40°C, more preferably 15°C to 25°C, with a temperature error range of ±5°C, preferably ±2°C.

[0143] Specifically, the isolation temperatures mentioned above may be 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, or 60°C.

[0144] In a preferred embodiment of the present invention, step (4) further includes a drying temperature, the drying temperature being selected from 0°C to 60°C, preferably 5°C to 40°C, more preferably 15°C to 25°C, and the temperature error range being ±5°C, preferably ±2°C.

[0145] Specifically, the above drying temperatures may be 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, or 60°C.

[0146] In a preferred embodiment of the present invention, step (4) further includes conditions for a dry airflow, the dry airflow being selected from an argon gas or nitrogen gas flow.

[0147] In the specification and claims of this application, scientific and technical terms used herein have meanings that are generally understood by those skilled in the art unless otherwise specified. However, for the purpose of further understanding the present invention, definitions and explanations of some relevant terms are provided below. In the event that the definitions and explanations of terms provided herein do not coincide with meanings that are generally understood by those skilled in the art, the definitions and explanations provided herein shall prevail.

[0148] In this invention, "crystal form A" refers to the crystal form A of the compound of formula (I).

[0149] The "alcohols" described in this invention are "C 1-6 This refers to a group formed when one or more hydrogen atoms on an alkyl group are replaced by one or more hydroxyl groups, as described above. 1-6 "Alkyl groups" are saturated aliphatic hydrocarbon groups having 1 to 6 carbon atoms, and include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, pentyl, and isopentyl groups. Specific examples of "alcohols" include, but are not limited to, methanol, ethanol, n-propanol, or isopropanol.

[0150] The term "esters" as used in this invention refers to compounds having fewer than 15 carbon atoms produced by a dehydration reaction between an organic acid and an alcohol or phenol, or lower ester compounds containing a functional group -C(O)O- and having fewer than 15 carbon atoms. Specific examples include, but are not limited to, ethyl acetate, dimethyl phthalate, butyl acetate, or propyl acetate.

[0151] The "ethers" described in this invention refer to chain-like or cyclic compounds containing ether-bonded -O- atoms and having 1 to 10 carbon atoms. Specific examples include, but are not limited to, diethyl ether, isopropyl ether, propylene glycol methyl ether, tetrahydrofuran, methyl tert-butyl ether, or 1,4-dioxane.

[0152] The "halogenated hydrocarbons" described in this invention are "C 1-6 This refers to a group formed by substituting one or more hydrogen atoms on an alkyl group with one or more halogen atoms, as described above. 1-6 "Alkyl alkyl groups" are defined above, and specific examples include, but are not limited to, chloromethane, dichloromethane, dichloroethane, chloroform, or carbon tetrachloride.

[0153] The "ketones" described in this invention refer to compounds in which a carbonyl group (-C(O)-) is linked to two hydrocarbon groups. Depending on the difference in hydrocarbon groups in the molecule, ketones can be classified into aliphatic ketones, alicyclic ketones, aromatic ketones, saturated ketones, and unsaturated ketones. Specific examples include, but are not limited to, acetone, butanone (e.g., 2-butanone), pentanone (e.g., pentan-2-one or pentan-3-one), hexanone (e.g., hexane-2-one or hexane-3-one), acetophenone, methyl isobutyl ketone, or methylpyrrolidone.

[0154] The "nitriles" described in this invention are "C 1-6 This refers to a group formed by substituting one or more hydrogen atoms on an alkyl group with one or more cyano groups, as described above. 1-6 An alkyl group is defined as described above, and a cyano group is a group with the chemical formula -CN, in which a carbon atom and a nitrogen atom are linked by a triple bond. Specific examples include, but are not limited to, acetonitrile or propionitrile.

[0155] The "saturated hydrocarbon" described in this invention is C 5-10 This refers to a chain or cyclic alkane compound in which all carbon atoms in the molecule are linked by single bonds and all other valence bonds are linked to hydrogen. Specific examples include, but are not limited to, n-pentane, n-hexane, cyclohexane, or n-heptane.

[0156] The "mixed solvent" described in the present invention refers to a solvent obtained by mixing one or more different types of solvents in a certain ratio, where the certain ratio is 0.05:1 to 1:0.05, preferably 1:1, 1:2, 1:3, 1:4, 1:5, 1:8, or 1:10.

[0157] The term "precipitating agent" in this invention refers to an "antisolvent" or "reverse solvent," and means that when isolating or removing a certain component, the substance is first dissolved in a suitable solvent, and then a solvent insoluble in the component to be isolated is added. The precipitating agent is co-soluble with the solvent that dissolves the compound shown in formula (I).

[0158] The above-mentioned good solvents are solvents that have good solubility for the compounds of this application, and poor solvents are solvents that have poor solubility or are insoluble for the compounds of this application.

[0159] In this invention, "boiling point" refers to the boiling point or azeotropic point of a pure solvent or a mixed solvent.

[0160] The "X-ray powder diffraction pattern or XRPD" described in this invention refers to a set of X-ray powder diffraction patterns measured by satisfying Bragg's formula 2d sinθ=nλ (wherein λ is the wavelength of the X-ray, λ=1.54056 Å, and the diffraction order n is any positive integer, generally taking a first-order diffraction peak when n=1), when X-rays are incident on a certain atomic plane having a d-lattice spacing of a crystal or some crystalline sample at a graze angle θ (complementary angle of incidence, also called Bragg angle).

[0161] In this invention, "2θ or 2θ angle" refers to the diffraction angle, where θ is a Bragg angle in degrees or degrees, and the error range of 2θ is ±0.1 to ±0.5, preferably ±0.1 to ±0.3, more preferably ±0.2.

[0162] The "interplanar spacing or interplanar spacing (d value)" described in this invention refers to the interplanar spacing obtained by connecting two adjacent lattice points in a spatial lattice, selecting three non-parallel unit vectors a, b, and c, and dividing the lattice into parallel parallelepiped units. The spatial lattice is divided by the connecting lines of the determined parallelepiped units to obtain a set of linear lattices, which are called spatial lattices or crystal lattices. Lattices and crystal lattices reflect the periodicity of the crystal structure through geometric points and lines, respectively, and different crystal planes have different interplanar spacings (i.e., the distance between two adjacent parallel crystal planes), with units of Å or angstroms.

[0163] The “differential scanning calorimetry or DSC” described in this invention measures the transition temperature at which a crystal absorbs or releases heat due to a change in its crystal structure or melting. For the same crystalline form of the same compound, the error in thermal transition temperature and melting point in a continuous analysis may be within about 5°C, and is usually within about 3°C. When it is stated that a compound has a particular DSC peak or melting point, it refers to ±5°C of that DSC peak or melting point. “Basically” takes such temperature variations into account. DSC provides an auxiliary method for identifying different crystalline forms. Different crystalline forms can be identified by their different transition temperature characteristics. For mixtures, it should be noted that their DSC peak or melting point may vary over a wider range. Also, since substances undergo decomposition in the melting process, the melting temperature correlates with the heating rate.

[0164] The "FT-Raman spectrum" used in this invention is used to study the structure and chemical bonding of molecules and may also be used as a method for characterizing and identifying chemical species. In this invention, the FT-Raman spectrum is used to characterize molecular structure and crystal form. The error range of the FT-Raman peak position is ±2 cm. -1 That's fine.

[0165] In this invention, mental illness refers to a disorder that presents with varying degrees of impairment in mental activities such as cognition, emotion, will, and behavior as a clinical manifestation, due to brain dysfunction under the influence of various biological, psychological, and social environmental factors. Mental activities include cognitive activities such as sensation, perception, attention, memory, and thinking, as well as emotional and volitional activities. These activity processes are interconnected and work closely together to maintain the unity and completeness of mental activity. Mental illnesses are mainly divided into mild and severe mental illnesses. Common mild mental illnesses include obsessive-compulsive disorder and depression. Common severe mental illnesses include schizophrenia. Mild mental illnesses mainly manifest as emotional disorders such as anxiety and depression, and thought disorders such as obsessions, but the patient's cognitive, logical reasoning, and self-awareness are basically complete. On the other hand, early-stage patients with severe mental illnesses such as schizophrenia may show expressions such as anxiety and obsessions, but the cognitive and logical reasoning abilities of such patients become very weak, and their self-awareness is almost completely lost. Organic mental disorders or toxic mental disorders caused by brain lesions need to be distinguished from common functional mental disorders. Mild mental disorders include anxiety disorders, obsessive-compulsive disorder, depression, and phobias. Severe mental disorders include schizophrenia. When brain function is impaired due to the effects of endogenous or exogenous harmful factors on the body, various mental disorders occur. When overall mental activity is significantly abnormal, or when the integrity and unity of mental activity are impaired, it is expressed as a mental disorder. When there is no severe or persistent disturbance of mental activity, and the main issue is a decline in mental capacity, it is expressed as a neurosis, and when the development of mental activity is inhibited, it is expressed as mental failure.

[0166] Depression is primarily characterized by low mood, loss of interest, pessimism, slow thinking, lack of initiative, self-blame and self-punishment, poor eating and sleeping habits, anxiety about having various illnesses, and general discomfort. In severe cases, suicidal thoughts and behaviors may occur.

[0167] The compound hydrochloride salts described in the present invention may contain one or more chiral centers and thereby exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compound hydrochloride salts described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of stereoisomerized mixtures, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be isolated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferably, the isomers may be prepared by asymmetric synthesis. For example, see Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977), Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (edited by E.L. Eliel, Univ. Of Notre Dame Press, Notre Dame, IN 1972). The present invention further covers the hydrochlorides of the compounds described herein in each isomeric form that does not essentially contain other isomers, and alternatively in the form of mixtures of multiple isomers.

[0168] As used herein, a pure enantiomerized compound essentially contains no other enantiomers or stereoisomers of the compound (i.e., it is enantiomerized). In other words, the "S" form of the compound essentially contains no "R" form of the compound, and is therefore enantiomerized in the "S" form.

[0169] Some of the compounds of the present invention have an asymmetric carbon atom (optical or chiral center) or a double bond and are enantiomers, racemates, diastereomers, tautomers, geometric isomers, or stereoisomers definable by absolute stereochemistry, e.g., (R)- or (S)-. The compounds of the present invention do not include compounds of the art that are known to be too unstable to be synthesized and / or isolated. The present invention is intended to include compounds in racemic and optically pure forms. Optically active (R)- and (S)- isomers can be prepared with chiral synthons or chiral reagents or resolved by common techniques.

[0170] As used herein, the term "isomer" refers to a compound having the same atomic number and type, and therefore the same molecular weight, but differing in the structural or stereochemical arrangement of the atoms.

[0171] As used herein, the term “tautomer” refers to one of two or more structural isomers that exist in equilibrium and can be readily converted from one isomer to another.

[0172] As will be apparent to those skilled in the art, some of the compounds of the present invention may exist in tautomeristic forms, and all such tautomeristic forms of the above compounds are within the scope of the present invention.

[0173] The term “treating / treatment” refers to the successful treatment or improvement of any injury, disease, lesion, or symptom of illness, and includes any objective or subjective parameters, such as the elimination, relief, or reduction of symptoms, or enabling the patient to tolerate the injury, lesion, or disease more effectively, slowing the rate of regression or deterioration, making the final outcome of degeneration less likely to result in frailty, or improving the patient’s physical or psychological health. Treatment or improvement of symptoms may be based on objective or subjective parameters, including the results of health examinations, neuropsychiatric tests, and / or psychiatric evaluations.

[0174] The term “treatment” and related expressions include the prevention of a lesion, disease, or disorder (for example, the prevention of the progression of one or more symptoms of a disease, disorder, or disorder as described herein).

[0175] An "effective dose" is a sufficient amount to achieve the specified purpose (for example, to achieve the effect of administration, treatment of a disease, reduction of enzyme activity, increase of enzyme activity, or reduction of one or more symptoms of a disease or illness).

[0176] An example of an "effective dose" is an amount sufficient to contribute to the treatment, prevention, or reduction of one or more symptoms of a disease, and may also be called a "therapeutic effective dose." The "preventive effective dose" of a drug is the amount of drug administered to a subject that, when administered, has the desired preventive effect, for example, prevents or delays the onset (or recurrence) of injury, disease, lesion, or illness, or reduces the likelihood of the onset (or recurrence) of injury, disease, lesion, or illness, or its symptoms. Complete preventive effect may not occur after a single dose, but may only occur after a series of doses. Therefore, the preventive effective dose may be administered in one or more doses. The appropriate dose depends on the therapeutic purpose and may be determined by the art by known techniques (see, for example, 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, edited by Gennaro, Lippincott, Williams & Wilkins).

[0177] A “reduction” (and the grammatical equivalent of the above phrase) of one or more symptoms refers to a reduction in the severity or frequency of symptoms, or the resolution of symptoms.

[0178] "Control" or "control experiment" is used according to its ordinary meaning and refers to an experiment in which a subject or reagent is treated as in a parallel experiment, but with an omission of an experimental procedure, reagent, or variable. In some cases, the control is used as a comparison baseline for evaluating an experimental effect.

[0179] As used herein, the term "administer" refers to oral administration to a subject, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal, or subcutaneous administration, or implantation of a sustained release device such as a miniosmotic pump. Administration is by any route including parenteral and mucosal administration (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other delivery methods include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like.

[0180] [Advantageous Effects of the Invention] Compared with the prior art, the technical solution of the present invention has the following advantages: Studies have shown that N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride provided by the present invention has better solubility than N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine oxalate. The compound represented by formula (I) has good activity, low toxicity, and is suitable for medicinal use compared with N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride. Among them, in the mouse forced swimming efficacy test, it was shown that the compound represented by formula (I) has better activity than N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, and in the mouse acute toxicity test, it was shown that the compound represented by formula (I) has lower toxicity than N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride. The A crystal form of the compound represented by formula (I) of the present invention has high purity and good crystal form stability. When the A crystal form absorbs moisture, its weight increases by 0.01%, and it has no or almost no hygroscopicity. When measured by HPLC, the purity change is small and the chemical stability is high. The A crystal form of the compound represented by formula (I) obtained by the technical solution of the present invention can meet the medicinal requirements of production, transportation and storage, the production process is stable, reproducible and controllable, and it is suitable for industrial production. In addition, the A crystal form of the present application has good solubility, hygroscopicity, and biological availability.

Brief Description of the Drawings

[0181] [Figure 1] (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride A crystal form X-ray powder diffraction pattern. [Figure 2] (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride A crystal form DSC spectrum. [Figure 3]This is the Raman spectrum of the A crystal form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride. [Figure 4] This is the X-ray powder diffraction pattern of the B crystal form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride. [Figure 5] This is the Raman spectrum of the B crystal form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride. [Figure 6] This is the X-ray powder diffraction pattern of the C crystal form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride. [Figure 7] This is the DSC spectrum of the C crystal form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride. [Modes for carrying out the invention]

[0182] The present invention will be described in more detail below with reference to examples, but the examples of the present invention are merely for illustrating the technical concept of the present invention and do not limit the substance or scope of the present invention.

[0183] Test conditions for the equipment used in the experiment: 1. X-ray Powder Diffraction Pattern (XRPD) Instrument model number: Bruker D8 Focus powder X-ray diffractometer. X-ray parameters: Cu / Kα (λ=1.540598 Å) Voltage: 40 kilovolts (kV) Current: 40 milliamperes (mA) Scanning range: 3.0 degrees to 60 degrees Scanning step size: 0.02 degrees Scanning speed: 0.5 seconds / step 2. DSC thermal analysis method (Differential Scanning Calorimeter, DSC) Equipment model number: DSC 200F3 differential scanning calorimeter (Germany) NETC GmbH Purge gas: Nitrogen gas Heating rate: 10.0 K / min Temperature range: 30℃~250℃ 3. FT-Raman Spectrometer (FT-RM) Instrument model number: Thermo Scientific DXR Smart Raman spectrometer Aperture: 50μm Exposure time: 10 s Number of exposures: 32 Laser: 780 nm Laser energy: 150 mW 4. High-Performance Liquid Chromatography (HPLC) Equipment model number: Agilent 1260 (DAD) Binary pump liquid chromatography Column: Agilent Eclipse XDB (4.6*150 mm, 5μm) C18 column Mobile phase: A: 0.01 mol / L KH2PO4 (pH 3.0) - methanol (90:10) B: Methanol-Water (90:10) Flow rate: 1.0 mL / min Column temperature: 35℃ Wavelength: 210 nm, Injection volume: 5 μL Gradient conditions (volume ratio):

[0184] JPEG0007846774000003.jpg32153

[0185] 5. Reagents used in the experiment: Dichloromethane (analytical reagent), ethanol (analytical reagent), n-heptane (analytical reagent), methanol (analytical reagent), ethyl acetate (analytical reagent), 95% ethanol (analytical reagent), methyl tert-butyl ether (analytical reagent), n-hexane (analytical reagent), isopropyl ether (analytical reagent) were all purchased from Shanghai Lingfeng Reagent. 3-[(Benzo[d][1,3]dioxolan-4-yl)-oxy]-N-methyl-3-phenylpropylamine oxalate was prepared by referring to the method of Example 4 of CN105777706A.

[0186] Example: Example 1: 1.1 Preparation of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride (i.e., the compound of formula I) 1.1.1 Preparation of 3-(dimethylamino)propiophenone hydrochloride 100 g (0.832 mol) of acetophenone, 37.5 g (1.24 mol) of paraformaldehyde, 95.0 g (1.16 mol) of dimethylamine hydrochloride, and 300 mL of ethanol were added to a 1 L glass reaction flask, stirred mechanically, heated to 50 °C - 60 °C, 5 mL of concentrated hydrochloric acid was added, and the temperature was controlled at 80 °C - 90 °C for a 15 h reaction.

[0187] After the reaction was completed, the reaction solution was cooled down, crystallized, cooled to 5 °C - 15 °C, stirred for 1 h, filtered, the filter cake was washed twice with anhydrous ethanol, and the obtained solid was dried with a blower dryer to obtain 140.84 g of a white solid.

[0188] 1.1.2 Preparation of 3-(dimethylamino)-1-phenylpropanol 100 g (0.47 mol) of 3-(dimethylamino)propiophenone hydrochloride and 250 mL of methanol were added to a 1 L reaction bottle and stirred mechanically. An aqueous sodium hydroxide solution (18.7 g of sodium hydroxide and 100 mL of water) was added, the temperature was controlled to 0°C to 20°C, and 10.66 g (0.28 mol) of sodium borohydride was added in batches. The temperature was then controlled to 15°C to 25°C and the reaction was allowed to proceed for 2 hours.

[0189] After the reaction was complete, the solution was filtered, the filtered cake was washed with 100 mL of methanol, the residue was discarded, the filtrate was concentrated under reduced pressure to remove methanol, and then 200 mL of water and 250 mL of ethyl acetate were added for extraction. The aqueous phase was further extracted twice with ethyl acetate (150 mL / time), the organic phase was combined, washed twice with saturated sodium chloride solution (200 mL / time), the organic phase was dried over anhydrous magnesium sulfate for 1 hour, filtered, and then concentrated under reduced pressure to remove ethyl acetate, yielding 80.54 g of a colorless oily substance.

[0190] 1.1.3 Preparation of (R)-3-(dimethylamino)-1-phenylpropanolmandelate 80 g (0.45 mol) of 3-(dimethylamino)-1-phenylpropanol, 300 mL of toluene, and 100 mL of anhydrous ethanol were added to a 1 L reaction bottle, stirred mechanically, and the temperature was controlled to 50°C to 60°C. 54.72 g of R-(-)-mandelic acid was added, the temperature was raised to 90°C, and the reaction was allowed to proceed for 1 hour.

[0191] After the reaction was complete, the temperature was lowered to allow crystallization, and the temperature was controlled to 10°C to 20°C and stirred for 1 hour. The mixture was filtered, the filtered cake was washed with 250 mL of anhydrous ethanol, the filtrate was discarded, and the resulting solid was dried in a forced-air dryer to obtain 62.63 g of a white solid. 62.63 g of the above white solid was added to a 500 mL reaction bottle, and 100 mL of toluene and 250 mL of anhydrous ethanol were added to recrystallize the mixture to obtain 56.1 g of a white solid.

[0192] 1.1.4 Preparation of (R)-N,N-dimethyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine oxalate First, (R)-3-(dimethylamino)-1-phenylpropanol mandelate was liberated to obtain 28.3 g of base. 28.0 g (0.16 mol) of (R)-3-(dimethylamino)-1-phenylpropanol and dimethyl sulfoxide (250 mL) were added to a 500 mL reaction bottle and stirred mechanically. 23.3 g (0.21 mol) of potassium tert-butoxide was added in batches, followed by 33.6 g (0.24 mol) of 3-fluoro-1,2-methylenedioxybenzene. The mixture was heated to 50°C to 55°C and reacted for 4 hours.

[0193] After the reaction was complete, the temperature was lowered to 15°C to 30°C, and the mixture was extracted with 200 mL of water and 250 mL of ethyl acetate. The aqueous phase was further extracted once with 200 mL of ethyl acetate, and the organic phase was combined with the aqueous phase. The mixture was washed twice with saturated sodium chloride solution, the organic phase was dried over anhydrous magnesium sulfate, filtered, the filtered cake was washed with ethyl acetate, and then chlorided with oxalic acid to obtain 36.14 g of an off-white solid. Anhydrous ethanol was then added to recrystallize the mixture, yielding 27.87 g of an off-white solid.

[0194] 1.1.5 Preparation of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylcarbamate phenyl First, (R)-N,N-dimethyl-3-phenyl-3-[(benzo[d][1,3]-dioxolan-4-yl)oxy]propylamine oxalate was liberated to obtain 20.68 g of base. 20.0 g (0.067 mol) of this base was added to a 500 mL reaction bottle, followed by 2.59 g (0.02 mol) of N,N-diisopropylethylamine and 200 mL of toluene. The mixture was stirred magnetically, and 12.5 g (0.08 mol) of phenyl chloroformate was added in batches. The mixture was then heated to 80°C and reacted for 2 hours.

[0195] After the reaction was complete, the temperature was lowered to 15°C to 30°C, 200 mL of water was added for extraction and washing, the lower aqueous phase was discarded, then washed twice with 1% hydrochloric acid, and then twice with saturated sodium chloride solution. The organic phase was concentrated under reduced pressure to remove toluene, yielding 26.99 g of a yellowish-brown liquid.

[0196] 1.1.6 Preparation of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]-dioxolan-4-yl)oxypropylamine hydrochloride] 26 g (0.064 mol) of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]-dioxolan-4-yl)oxy]propylcarbamate phenyl and 250 mL of dimethyl sulfoxide were added to a 500 mL reaction bottle, stirred magnetically, and sodium hydroxide solution (prepared by mixing 20 g of sodium hydroxide with 50 mL of water and clarifying it) was added. The mixture was heated to 85°C and reacted for 12 hours.

[0197] After the reaction was complete, the temperature was lowered to 15°C to 30°C, and the mixture was extracted with 250 mL of water and 200 mL of ethyl acetate. The aqueous phase was further extracted twice with ethyl acetate (200 mL / time), and the organic phase was combined. The mixture was washed twice with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, the filter cake was washed with ethyl acetate, and then concentrated under reduced pressure to remove the solvent, yielding 14.03 g of base. This was then dissolved in 150 mL of ethyl acetate, stirred magnetically, and ethyl acetate hydrogen chloride solution was gradually added to adjust the pH to 3-5, allowing the solid to gradually precipitate. The mixture was continued stirring for 1 hour, filtered, the filter cake was washed with ethyl acetate, and the resulting solid was dried in a forced-air dryer to obtain 12.5 g of off-white solid. HPLC: 99.54%. mp = 162-164°C; [α] D 20 = 48.0; 1H-NMR (400MHz, DMSO-d6) δ: 7.40-7.26(m, 4H),7.28 (t, J = 6.7 Hz, 1H), 6.64(t, J = 8.1 Hz, 1H), 6.50(d, J =7.6 Hz, 2H), 5.96(d, J =11.0 Hz, 2H), 5.54-5.51(m, 1H), 3.08-2.95(m, 2H), 2.55(s, 3H), 2.32-2.28(m, 1H), 2.25-2.10(m, 1H); 13 C-NMR (100MHz, DMSO-d6) δ:148.89, 141.71, 140.64, 136.15, 129.14, 128.60, 125.48, 122.31, 111.47, 103.12, 101.39, 78.20, 45.78, 34.35, 32.97; HRMS (ESI) m / z: calcd for: C 17 H 19 NO3 (M+H) + : 286.1438; found: 286.1432.

[0198] 1.2 Preparation of N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride 1.2.1 Preparation of 3-(dimethylamino)propiophenone hydrochloride For the preparation method, refer to 1.1.1 of Example 1.

[0199] 1.2.2 Preparation of 3-(dimethylamino)-1-phenylpropanol For the preparation method, refer to 1.1.2 of Example 1.

[0200] 1.2.3 Preparation of N,N-dimethyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine oxalate The preparation method was as described in 1.1.4 of Example 1, but 3-(dimethylamino)-1-phenylpropanol was added to the reaction instead of (R)-3-(dimethylamino)-1-phenylpropanol mandelate.

[0201] 1.2.4 Preparation of N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylcarbamate phenyl For the preparation method, refer to 1.1.5 of Example 1.

[0202] 1.2.5 Preparation of N-methyl-3-phenyl-3-[(benzo[d][1,3]-dioxolan-4-yl)oxypropylamine hydrochloride] For the preparation method, refer to 1.1.6 of Example 1. 20.1 g of an off-white solid was obtained, and HPLC analysis showed 99.22%. 1 H-NMR (400MHz, DMSO-d6) δ: 7.47-7.33 (m, 4H), 7.30 (d, J = 6.5 Hz, 1H), 6.65 (t, J = 8.1 Hz, 1H), 6.51 (d, J = 15.2, 8.1 Hz, 2H), 5.99 (d, J = 11.4 Hz, 2H), 5.52 (dd, J = 7.7, 4.4 Hz, 1H), 3.12-2.90 (m, 2H), 2.54 (s, 3H), 2.26 (d, J = 8.7 Hz, 1H), 2.19-2.04 (m, 1H); 13 C-NMR (100MHz, DMSO-d6) δ: 164.39, 148.94, 141.77, 140.78, 136.15, 129.11, 128.51, 125.46, 122.24, 111.40, 103.06, 101.39, 78.16, 45.64, 34.37, 32.94; HRMS (ESI) m / z: calcd for: C 17 H 19 NO3 (M+H) + : 286.1438; found: 286.1435.

[0203] Example 2: Preparation of the A crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride: Recrystallization by standing: Approximately 500 mg of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride was weighed into a beaker, 20 mL of anhydrous ethanol was gradually added, and the mixture was heated at 60°C to 65°C to facilitate dissolution. Crystallization was then allowed to stand at room temperature (around 25°C), the precipitate was collected, filtered, and dried at 60°C. The X-ray powder diffraction pattern is shown in Figure 1, the DSC spectrum in Figure 2, and the Raman spectrum in Figure 3. In the DSC heating process, the start point of the endothermic peak was 161.4°C, the end point was 168.5°C, and the peak value was 164.8°C. This crystal form is defined as crystal form A, and the position of its characteristic peak is shown in Table 1 below:

[0204] [Table 1]

[0205] Example 3: Preparation of the A crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride: Approximately 500 mg of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride was weighed into a beaker, 12 mL of anhydrous methanol was gradually added, and the mixture was heated at 60°C to 65°C to facilitate dissolution. After complete dissolution, 120 mL of methyl tert-butyl ether was quickly added to precipitate the solid. The precipitate was collected, filtered, dried at 60°C, and detected as crystal form A.

[0206] Example 4: Preparation of the A crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride: Approximately 500 mg of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride was weighed into a large test tube, and 30 mL of a mixed solvent of dichloromethane and ethanol (volume ratio 1:1) was gradually added. The mixture was heated to 60°C to 65°C to facilitate dissolution, and the mixture was transferred to a Buch parallel reactor. The solvent removal pressure was gradually reduced from 700 mba to 10 mba, and the temperature was raised from 30°C to 70°C. The sample was collected after complete precipitation and detected as crystal form A.

[0207] Example 5: Preparation of the A crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride: Approximately 500 mg of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride was weighed into a large test tube, and a methanol / n-hexane mixed solvent (volume ratio 5:1) was gradually added. The mixture was heated to 60°C-65°C for auxiliary dissolution, and the mixture was transferred to a Buch parallel reactor. The solvent removal pressure was gradually reduced from 700 mba to 10 mba, and the temperature was raised from 30°C to 70°C. The sample was collected after complete precipitation and detected as crystal form A.

[0208] Example 6: Preparation of the A crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride: Approximately 500 mg of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride was weighed into a beaker, and a mixed solvent of ethanol / isopropyl ether (volume ratio 7:1) was gradually added. The mixture was heated at 60°C to 65°C to facilitate dissolution. After complete dissolution, the mixture was allowed to stand at room temperature to crystallize. The mixture was then filtered under reduced pressure, the filtered cake was washed twice with petroleum ether, and the filtered cake was recovered and dried at 60°C to obtain the target product A in crystalline form.

[0209] Example 7: Preparation of the A crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride: Approximately 500 mg of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride was weighed into a beaker, and 80 mL of a mixed solvent of n-propanol / acetone (volume ratio 3:1) was gradually added. The mixture was heated at 60°C to 65°C to facilitate dissolution. After complete dissolution, the mixture was allowed to stand at room temperature to crystallize, filtered under reduced pressure, and the filtered cake was washed twice with petroleum ether. The filtered cake was collected and dried at 60°C to obtain the target product A in crystalline form.

[0210] Example 8: Preparation of the A crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride: Approximately 500 mg of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride was weighed into a beaker, and 100 mL of acetonitrile / butanone mixed solvent (volume ratio 5:1) was gradually added. The mixture was heated at 60°C to 65°C to facilitate dissolution. After complete dissolution, the mixture was allowed to stand at room temperature to crystallize, filtered under reduced pressure, and the filtered cake was washed twice with petroleum ether. The filtered cake was collected and dried at 60°C to obtain the target product A in crystalline form.

[0211] Example 9: Preparation of the A crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride: 500 mg of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride was dissolved in 20 mL of dimethyl sulfoxide, and 200 mL of methyl tert-butyl ether was rapidly added to the solution to precipitate a large amount of off-white precipitate and form a suspension. The suspension was allowed to stand, filtered under reduced pressure, the filter cake was washed twice with petroleum ether, the filter cake was collected and dried at 60°C to obtain the target product A in crystalline form.

[0212] Example 10: Preparation of the A crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride: 500 mg of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride was dissolved in 20 mL of N,N-dimethylformamide, and 200 mL of isopropyl ether was rapidly added to the solution to precipitate a large amount of off-white precipitate and form a suspension. The suspension was allowed to stand, filtered under reduced pressure, the filter cake was washed twice with petroleum ether, the filter cake was collected and dried at 60°C to obtain the target product A in crystalline form.

[0213] Example 11: Preparation of the A crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride: 500 mg of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride was dissolved in 20 mL of N,N-dimethylformamide, and 200 mL of isopropyl ether was rapidly added to the solution to precipitate a large amount of off-white precipitate and form a suspension. The suspension was allowed to stand, filtered under reduced pressure, the filter cake was washed twice with petroleum ether, the filter cake was collected and dried at 60°C to obtain the target product A in crystalline form.

[0214] Example 12: Preparation of the B crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride Approximately 2 g of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride was weighed into a beaker, 11 mL of glacial acetic acid was added, and the mixture was heated to around 65°C to perform auxiliary dissolution until completely dissolved. After aspirating with a syringe, the mixture was gradually added dropwise through a filtration membrane to a container containing a large amount of methyl tert-butyl ether to precipitate the solid. The mixture was then filtered by suction and dried at 60°C. The X-ray powder diffraction pattern is shown in Figure 4, and the Raman spectrum is shown in Figure 5. This crystal form is defined as the B crystal form, and the positions of its characteristic peaks are shown in Table 2 below:

[0215] [Table 2]

[0216] Example 13: Preparation of the C crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride 5 g of the sample (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride was weighed out, and an appropriate amount of water was added to completely dissolve the sample in a water bath at approximately 65°C. The sample was then pre-frozen in a refrigerator, and after completion, freeze-drying was performed in a freeze-dryer. After freeze-drying was complete, the sample was irradiated with light (5000 lx) for 10 days to obtain the C crystal form. The X-ray powder diffraction pattern is shown in Figure 6, and the DSC spectrum in Figure 7. In the DSC heating process, the endothermic peak began at 161.2°C, ended at 166.0°C, and peaked at 163.9°C. This crystal form is defined as the C crystal form, and its characteristic peak positions are shown in Table 3 below:

[0217] [Table 3]

[0218] Example 14: Experiment on the influence of the A crystal form of the compound of formula (I). Experimental method High-temperature experiment: Approximately 1 g each of crystal forms A, B, and C was weighed out, placed in a clean watch glass, and left at 60°C for 10 days. Samples were taken on days 0, 5, 10, and 30, and XRPD analysis was performed. High humidity test: Approximately 1 g each of crystal form samples A, B, and C was weighed out, placed on a clean watch glass, and left at a relative humidity of 92.5% for 10 days. Samples were then taken on days 0, 5, 10, and 30, and XRPD analysis was performed. Light irradiation experiment: Approximately 1 g each of crystal form samples A, B, and C was weighed out, placed on a clean watch glass, spread flat, and left in a light irradiation box (illuminance 5000 lx) for 10 days. Samples were taken on day 0, day 5, day 10, and day 30, and XRPD analysis was performed. Experimental results The stability studies of the A, B, and C crystalline forms of the compound of formula (I) under high temperature, high humidity, and light irradiation conditions are shown in Tables 4, 5, and 6 below.

[0219] [Table 4]

[0220] [Table 5]

[0221] [Table 6]

[0222] Experimental conclusions: Crystal form A can maintain stability under high temperature, high humidity, and light irradiation without changing its crystal form; crystal form B becomes a mixed crystal of crystal forms A and B under high temperature and high humidity; and crystal form C becomes crystal form A under high humidity.

[0223] Example 15: Pharmacokinetic study This is a pharmacokinetic study of the A crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride (compound of formula I), and N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine oxalate.

[0224] [Table 7]

[0225] Each group consisted of six Beagle dogs, half male and half female. The Beagle dogs were purchased from the College of Agriculture at Shanghai Jiao Tong University.

[0226] Solution preparation: 1) Intravenous injection: Using 0.9% physiological saline as the solvent, 2) Oral administration: At a dose of 10 mg / kg (based on base), the corresponding weight of the drug was weighed according to the actual body weight of the animal, then filled into capsules and administered to the animal. The test results are shown in Table 8.

[0227] [Table 8]

[0228] Experimental conclusions: Pharmacokinetic experiments showed that the A crystalline form of compound (I) has better bioavailability than the hydrochloride, and the bioavailability value of compound (I) is better than that of N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine oxalate.

[0229] Example 16, Solubility Experiment This is a solubility experiment of the A crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride (compound of formula I), and N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine oxalate.

[0230] 16.1. Sample preparation (aqueous medium is deaerated purified water) Test solution: Precisely weigh approximately 2 g each of the samples ((R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine oxalate, N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, the compound of formula I and its A crystalline form, and N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine oxalate), place them in separate volumetric flasks, accurately measure out 2 mL of water to make a concentrated test solution, shake overnight in a shaker with a constant temperature of 20°C water bath (supersaturated), filter, take the filtrate, accurately measure out 1 mL, place it in a 100 mL volumetric flask, add diluent (water) to dilute to the marked level, shake uniformly, accurately measure out 1 mL, and 10 The solution was placed in a volumetric flask, diluted with the diluent to the marked level, and then shaken uniformly to obtain the test solution. Control solution: Appropriate amounts of each of the five samples were taken, precisely weighed, and an appropriate amount of diluent was added. The samples were dissolved and diluted using ultrasound to prepare a solution containing approximately 0.1 mg of sample per 1 mL. Two parallel samples were prepared per batch.

[0231] 16.2 Preparation of the mobile phase (1) Preparation of buffer solution: Approximately 2.6428 g of ammonium sulfate was weighed out, dissolved in 1000 mL of water, 2 mL of triethylamine was added, and the pH was adjusted to 4.0 with dilute sulfuric acid. (2) Preparation of mobile phase: 1000 mL of methanol-ammonium sulfate solution (2 mL of triethylamine per 1000 mL, pH adjusted to 4.0 with dilute sulfuric acid) (45:55) was prepared, homogenized, filtered, and sonicated before use.

[0232] 16.3 Chromatography conditions Detection wavelength: 230 nm, flow rate: 1.0 mL / min, column temperature: 35°C, injection volume: 20 μL, column: Agilent Eclipse XDB-C18 column (4.6*150 mm, 5 μm), mobile phase: methanol-0.02 mol / L ammonium sulfate solution (2 mL of triethylamine added per 1000 mL, pH adjusted to 4.0 with dilute sulfuric acid) (45:55).

[0233] 16.4. Measurement of the sample Each solution was precisely measured in 20 μL portions, dispensed into a liquid chromatograph, and the chromatogram was recorded. The solubility of the compounds was measured using an external standard method, and the results are shown in Table 9.

[0234] [Table 9]

[0235] Experimental conclusions: Solubility experiments showed that N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride is more soluble than the compound of formula (I), the A crystal form of the compound of formula (I) is more soluble than the compound of formula (I), and the compound of formula (I) is more soluble than N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine oxalate.

[0236] Example 17: Hygroscopicity test: 17.1 A dry glass stoppered volumetric flask (outer diameter 50 mm, height 15 mm) was taken and placed in a suitable 25°C±1°C constant temperature drying oven (with a saturated solution of ammonium chloride or ammonium sulfate placed in the bottom) or an artificial weather chamber (temperature set to 25°C±1°C, relative humidity 80%±2%) the day before the test, and its weight (m1) was precisely weighed.

[0237] 17.2. An appropriate amount of the A crystal form of the compound of formula (I) was taken and spread flat in the volumetric flask described above. The thickness of the test specimen was generally about 1 mm, and the weight (m2) was precisely weighed.

[0238] 17.3 The volumetric flask was opened and left with the lid in place for 24 hours under the above conditions of constant temperature and humidity.

[0239] 17.4 The lid was placed on the volumetric flask, and the weight (m³) was precisely measured. The test results are shown in Table 10.

[0240]

number

[0241] [Table 10]

[0242] Experimental conclusion: Crystalline form A of compound (I) is non-hygroscopic or has little hygroscopicity and does not require strict packaging requirements during storage.

[0243] Example 18: Forced swimming test of mice: 18.1 Test Method SPF-grade ICR mice were selected, divided into groups of 12 animals each based on body weight, and allowed to adapt for at least 3 days before behavioral tests were conducted. Behavioral testing was initiated 1 hour after intragastric administration. Mice were placed in a clear glass cylinder filled with water (water depth 15 cm, water temperature 23°C-25°C), and video recording was performed for 6 minutes (with an LED light-emitting panel as the background). After recording, the mice were removed from the water, and the next batch of mouse behavioral testing was performed. The water was changed after every three batches of testing. After the tests, the behavioral test videos were exported and sent to Forced Swim Scan. TM Using software version 2.0, we analyzed the cumulative immobility time of mice 4 minutes after a 6-minute forced swimming period. The test results are shown as mean ± SD. A t-test was used to compare each group with the solvent group, and a difference of P < 0.05 indicates statistical significance.

[0244] 18.2, Test Results Duloxetine, N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, (S)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, and the compound of formula (I) all showed good dose-response relationships at their respective doses. The minimum effective dose of duloxetine was 5 mg / kg, and ED 50 The dose was 6.93 mg / kg. The minimum effective dose (MED) of N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxypropylamine hydrochloride was 0.4 mg / kg, and the median effective dose (ED) was 0.4 mg / kg. 50 The MED of formula (S)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride is 1.6 mg / kg, ED 50 The ED is 1.74 mg / kg, and the minimum effective dose of the compound of formula (I) is 0.4 mg / kg. 50 The value was 0.96 mg / kg. The specific results are shown in Table 11 below.

[0245] [Table 11]

[0246] 18.3. Experimental conclusion: In terms of minimum effective dose, N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride is the same as the compound of formula (I) (0.4 mg / kg) and lower than (S)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride (1.6 mg / kg). ED 50Viewed from , the compound of formula (I) <(S)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride> is N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride. Overall evaluated, the compound of formula (I) in mice has relatively good anti-depressant effect in the mouse forced swimming test.

[0247] Example 19 Mouse Acute Toxicity Test: 19.1, Test Method Based on the doses at which the compound caused 100% and 0% mortality in mice in the preliminary experiment, the dosing amounts in this test were determined. During this test, ICR mice were taken, randomly divided into groups of 10 each with half males and half females, and administered intragastrically at 10 mL / kg. The status and mortality of the animals within 7 days were observed.

[0248] 19.2, Test Results The median lethal dose (LD 50 ) of N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride by single intragastric administration to mice was 112.3 mg / kg, and the 95% confidence interval was 102.1 mg / kg to 121.9 mg / kg. The LD 50 of (S)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride was 66.8 mg / kg, and the 95% confidence interval was 13.1 mg / kg to 91.3 mg / kg. The LD 50 of the compound of formula (I) was 115.6 mg / kg, and the 95% confidence interval was 106.5 mg / kg to 125.0 mg / kg.

[0249] 19.3, Conclusions of the Test Judging from the results of the mouse acute toxicity test, the compound of formula (I) has the lowest toxicity. Based on the results of the mouse acute toxicity and efficacy tests, the therapeutic index (TI = LD 50 / ED 50The results of the calculation showed that the compound in formula (I) had the highest therapeutic index. Specific data are shown in Table 12 below:

[0250] [Table 12]

[0251] Conclusion: From Examples 1 to 19 and Tables 1 to 12, it was found that N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, the compound of formula (I), and the A crystalline form of the compound of formula (I) all have good solubility, minimum effective amount, and low toxicity. Furthermore, the compound of formula (I) and the A crystalline form of the compound of formula (I) both have superior bioavailability compared to their oxalates and remain stable under high temperature, high humidity, and light irradiation at 5000 lx.

[0252] The foregoing description is merely a preferred embodiment of this application and does not limit it, and various modifications and changes are possible for those skilled in the art. Any modifications, equivalent substitutions, and improvements made without departing from the spirit and principles of this application are also included within the scope of protection of this application. The present invention further provides the following embodiments. [Item 1] N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxypropylamine hydrochloride. [Item 2] (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride. [Item 3] Crystal form A of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride as described in item 2, characterized in that an X-ray powder diffraction pattern is obtained using Cu-Kα rays, where the diffraction angle is 2θ and characteristic peaks are represented by 2θ at 8.77°, 12.00°, and 14.84°, and the error range of 2θ for each characteristic peak is ±0.2°. [Item 4] The A crystal form described in item 3 is characterized by exhibiting characteristic peaks represented by an angle of 2θ at 8.77°, 12.00°, 14.84°, 21.34°, and 21.87°, with the error range of 2θ for each characteristic peak being ±0.2°. [Item 5] The A crystal form described in item 3 is characterized by exhibiting characteristic peaks represented by an angle of 2θ at 8.77°, 12.00°, 14.84°, 21.34°, 21.87°, 23.47°, and 24.14°, with the error range of 2θ for each characteristic peak being ±0.2°. [Item 6] The A crystal form according to item 3, characterized in that the X-ray powder diffraction pattern of the A crystal form further shows characteristic peaks represented by 2θ angles at one or more of the following angles: 7.78°, 16.58°, 19.66°, 23.03°, 25.46°, 26.65°, 26.97°, 27.41°, and 28.23°, of which the 2θ error range of each characteristic peak is ±0.2°, and preferably has an X-ray powder diffraction pattern that basically matches Figure 1. [Item 7] The Raman spectrum of the aforementioned crystal form A is 3063.8±2 cm⁻¹. -1 , 3013.2±2cm-1 , 2961.9±2cm -1 , 2931.4±2cm -1 , 1599.5±2cm -1 , 1461.0±2cm -1 , 1267.6±2cm -1 , 1177.9±2cm -1 , 1047.8±2cm -1 , 996.6±2cm -1 , 827.9±2cm -1 740.3±2cm -1 , 688.9±2cm -1 , 615.4±2cm -1 , 591.9±2cm -1 The A crystal form according to item 6, characterized by exhibiting one or more characteristic peaks. [Item 8] The A crystal form according to item 7, characterized in that the melt endothermic peak value of the DSC of the A crystal form is selected from 161.4°C to 168.5°C, and preferably 164.8°C. [Item 9] A method for preparing (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride as described in item 2, A method characterized by comprising the reaction step of liberating (R)-3-(dimethylamino)-1-phenylpropanolmandelate, reacting it with 3-fluoro-1,2-methylenedioxybenzene, and obtaining (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]-dioxolan-4-yl)-oxy]propylamine by a demethylation reaction, and forming a salt with an ethyl hydrogen chloride solution. [Item 10] A method for preparing the A crystal form described in item 3, (1) Dissolve (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride in a solvent to obtain a solution containing (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, (2) The step of removing the solvent from the solution prepared in step (1) by a solvent removal method to obtain a precipitate, Of these, the solvent in step (1) is selected from a good solvent or a mixed solvent of a good solvent and a poor solvent, the good solvent being one or more of alcohols, halogenated hydrocarbons, N-methyl-2-pyrrolidone, nitriles, water, N,N-dimethylformamide, or dimethyl sulfoxides, the alcohols being preferably selected from methanol, ethanol, n-propanol, isopropanol, or n-butanol, the halogenated hydrocarbons being preferably selected from dichloromethane or chloroform, the nitriles being preferably selected from acetonitrile, and the poor solvent being C 5-10 Selected from saturated hydrocarbons, ketones, esters, or ethers, the C 5-10 A method characterized in that the saturated hydrocarbons are preferably selected from n-pentane, n-hexane, cyclohexane, or n-heptane; the ketones are preferably selected from acetone and butanone; the esters are preferably selected from ethyl acetate, n-propyl acetate, isopropyl acetate, or isobutyl acetate; and the ethers are preferably selected from methyl tert-butyl ether, isopropyl ether, petroleum ether, or tetrahydrofuran. [Item 11] A method for preparing the A crystal form described in item 3, (1) A step of dissolving formula (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride in a solvent to obtain a solution containing (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, (2) The step of obtaining a precipitate from the solution obtained in step (1) by precipitation, The solvent in step (1) is selected from a good solvent or a mixed solvent of a good solvent and a poor solvent, the good solvent being one or more of alcohols, halogenated hydrocarbons, N-methyl-2-pyrrolidone, nitriles, water, N,N-dimethylformamide, or dimethyl sulfoxides, the alcohols being preferably selected from methanol, ethanol, n-propanol, isopropanol, or n-butanol, the halogenated hydrocarbons being preferably selected from dichloromethane or chloroform, the nitriles being preferably selected from acetonitrile, and the poor solvent being C 5-10 Selected from saturated hydrocarbons, ketones, esters, or ethers, the C 5-10 The saturated hydrocarbons are preferably selected from n-pentane, n-hexane, cyclohexane, or n-heptane; the ketones are preferably selected from acetone and butanone; the esters are preferably selected from ethyl acetate, n-propyl acetate, isopropyl acetate, or isobutyl acetate; and the ethers are preferably selected from methyl tert-butyl ether, isopropyl ether, petroleum ether, or tetrahydrofuran. The precipitation method is selected from the cooling method or the precipitant method. The aforementioned cooling method involves cooling the solution obtained in step (1) to 0°C to room temperature to precipitate the crystals. The aforementioned precipitating agent method involves adding a precipitating agent, (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, to the solution obtained in step (1) to precipitate crystals. A method characterized by the following features. [Item 12] The precipitating agent is C 5-10 Selected from saturated hydrocarbons, ketones, esters, or ethers, the C 5-10 A method for preparing the A crystal form according to item 11, characterized in that the saturated hydrocarbons are preferably selected from n-pentane, n-hexane, cyclohexane, or n-heptane; the ketones are preferably selected from acetone and butanone; the esters are preferably selected from ethyl acetate, n-propyl acetate, isopropyl acetate, or isobutyl acetate; and the ethers are preferably selected from methyl tert-butyl ether, isopropyl ether, petroleum ether, or tetrahydrofuran. [Item 13] A pharmaceutical composition comprising the hydrochloride salt described in item 1, or the hydrochloride salt described in item 2, or the A crystalline form described in any one of items 3 to 8, and one or more excipients, vectors, adjuvants, solvents, or combinations thereof. [Item 14] A pharmaceutical composition according to item 13, used to treat and / or prevent a mental disorder, wherein the mental disorder is one or more selected from anxiety disorders, obsessive-compulsive disorder, depression, phobias, and schizophrenia, preferably depression.

Claims

1. A crystal of the A-crystal form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, wherein an X-ray powder diffraction pattern is obtained using Cu-Kα rays, showing characteristic peaks expressed at a diffraction angle of 2θ at 8.77°, 12.00°, 14.84°, 16.58°, 19.66°, 21.34°, 21.87°, 23.47°, 24.14°, and 27.41°, and the error range of 2θ for each characteristic peak is ±0.2°.

2. The crystal of crystal type A according to claim 1, characterized in that the X-ray powder diffraction pattern of the crystal of crystal type A further shows characteristic peaks represented by one or more 2θ angles at 7.78°, 23.03°, 25.46°, 26.65°, 26.97°, and 28.23°, of which the 2θ error range of each characteristic peak is ±0.2°.

3. The Raman spectrum of the crystal of the A crystal form is 3063.8 ± 2 cm －１ , 3013.2 ± 2 cm －１ , 2961.9 ± 2 cm －１ , 2931.4 ± 2 cm －１ , 1599.5 ± 2 cm －１ , 1461.0 ± 2 cm －１ , 1267.6 ± 2 cm －１ , 1177.9 ± 2 cm －１ , 1047.8 ± 2 cm －１ , 996.6 ± 2 cm －１ , 827.9 ± 2 cm －１ , 740.3 ± 2 cm －１ , 688.9 ± 2 cm －１ , 615.4 ± 2 cm －１ , 591.9 ± 2 cm －１ The crystal of the A crystal form according to claim 2, which shows characteristic peaks in one or more of them.

4. The crystal of crystal type A according to claim 3, characterized in that the melt endothermic peak value of the DSC of the crystal of crystal type A is selected from 161.4°C to 168.5°C.

5. The crystal of crystal type A according to claim 3, wherein the melt endothermic peak value of the DSC of the crystal of crystal type A is 164.8°C.

6. A method for preparing crystals of crystal type A according to any one of claims 1 to 5, (1) Dissolve (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride in a solvent to obtain a solution containing (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, (2) The step of removing the solvent from the solution prepared in step (1) by a solvent removal method to obtain a precipitate, Of these, the solvent in step (1) is selected from a good solvent or a mixed solvent of a good solvent and a poor solvent, the good solvent being one or more of alcohols, halogenated hydrocarbons, N-methyl-2-pyrrolidone, nitriles, water, N,N-dimethylformamide, or dimethyl sulfoxides, and the poor solvent being C ５－１０ A method characterized by being selected from saturated hydrocarbons, ketones, esters, or ethers.

7. The alcohols are selected from methanol, ethanol, n-propanol, isopropanol, or n-butanol. The halogenated hydrocarbons are selected from dichloromethane or chloroform. The aforementioned nitriles are acetonitrile, The C5-10 saturated hydrocarbons are selected from n-pentane, n-hexane, cyclohexane, or n-heptane. The aforementioned ketones are selected from acetone and butanone. The esters are selected from ethyl acetate, n-propyl acetate, isopropyl acetate, or isobutyl acetate, and The method for preparing crystals of crystal form A according to claim 6, wherein the ethers are selected from methyl tert-butyl ether, isopropyl ether, petroleum ether, or tetrahydrofuran.

8. A method for preparing crystals of crystal type A according to any one of claims 1 to 5, (1) Dissolve formula (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride in a solvent to obtain a solution containing (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, (2) The step of obtaining a precipitate from the solution obtained in step (1) by a precipitation method, The solvent in step (1) is selected from a good solvent or a mixed solvent of a good solvent and a poor solvent, the good solvent being one or more of alcohols, halogenated hydrocarbons, N-methyl-2-pyrrolidone, nitriles, water, N,N-dimethylformamide, or dimethyl sulfoxides, and the poor solvent being C ５－１０ Selected from saturated hydrocarbons, ketones, esters, or ethers, The precipitation method is selected from the cooling method or the precipitant method. The aforementioned cooling method involves cooling the solution obtained in step (1) to 0°C to room temperature to precipitate the crystals. The aforementioned precipitating agent method is characterized by adding a precipitating agent of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride to the solution obtained in step (1) to precipitate and deposit crystals.

9. The alcohols are selected from methanol, ethanol, n-propanol, isopropanol, or n-butanol. The halogenated hydrocarbons are selected from dichloromethane or chloroform. The aforementioned nitriles are acetonitrile, The C5-10 saturated hydrocarbons are selected from n-pentane, n-hexane, cyclohexane, or n-heptane. The aforementioned ketones are selected from acetone and butanone. The esters are selected from ethyl acetate, n-propyl acetate, isopropyl acetate, or isobutyl acetate, and The method for preparing crystals of crystal form A according to claim 8, wherein the ethers are selected from methyl tert-butyl ether, isopropyl ether, petroleum ether, or tetrahydrofuran.

10. The precipitating agent is C ５－１０ A method for preparing crystals of crystal form A according to claim 8, selected from saturated hydrocarbons, ketones, esters, or ethers.

11. The C5-10 saturated hydrocarbons are selected from n-pentane, n-hexane, cyclohexane, or n-heptane. The aforementioned ketones are selected from acetone and butanone. The esters are selected from ethyl acetate, n-propyl acetate, isopropyl acetate, or isobutyl acetate, and The aforementioned ethers are selected from methyl tert-butyl ether, isopropyl ether, petroleum ether, or tetrahydrofuran. A method for preparing crystals of crystal type A as described in claim 10.

12. A pharmaceutical composition comprising a crystal of the A crystalline form described in any one of claims 1 to 5, and one or more excipients, vectors, adjuvants, solvents, or combinations thereof.

13. A pharmaceutical composition used to treat and / or prevent a mental disorder, wherein the mental disorder is one or more selected from anxiety disorders, obsessive-compulsive disorder, depression, phobias, and schizophrenia, according to claim 12.

14. A pharmaceutical composition used to treat and / or prevent the mental disorder according to claim 13, wherein the mental disorder is depression.

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