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

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 is in the field of medicinal chemistry, specifically to provide 3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, its optical isomers and crystalline forms, and methods of preparation. [Background technology]

[0002] Depression is now the most common mental illness that harms the physical and mental health of humans. Currently, people with depression account for 3% to 5% of the world's population. It is predicted that by 2022, depression may become the second most common disease after heart disease.

[0003] Medications are the primary means of treating depression. These 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 dual 5-HT and NE reuptake inhibitors such as duloxetine.

[0004] There are many antidepressants in clinical use, but some drugs have low response rates, long onset times, and potential side effects, so many patients have tried various treatments without success, and some patients still need to resort to electroconvulsive therapy. Therefore, the development of antidepressants remains a hotspot in new drug research. Patent application WO2016101898A discloses 3-[(benzo[d][1,3]dioxolan-4-yl)-oxy]-3-arylpropylamine compounds with antidepressant activity, the specific structure of which is as follows:

[0005] [ka]

[0006] Further research has shown that (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride has excellent antidepressant activity, and the crystalline structure as a pharmaceutical active ingredient always affects the chemical stability of the drug, and the difference in crystalline form, preparation method and storage conditions may cause changes in the crystalline structure of the compound, and may sometimes be accompanied by the formation of other crystalline forms. In general, amorphous drug products do not have a regular crystalline structure, and always have other disadvantages such as poor product stability, difficulty in filtration, easy to solidify, poor flowability, etc., and these differences tend to cause difficulties in expanding production, so it is necessary to carry out intensive research to improve each property of the compound by crystalline form and find a new crystalline form with high crystalline purity and excellent chemical stability. Summary of the Invention

[0007] The technical problem that the present invention aims to solve is to provide 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, which is a compound represented by formula (I) and its crystal forms A, B and C. The crystal form A has good crystal form stability and chemical stability, and can be more suitably used in clinical practice.

[0008] [ka]

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

[0010] Specifically, it exhibits 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 shows six characteristic peaks at 8.77°, 12.00°, 14.84°, 21.34°, 21.87°, and 23.47°, and the error range may be ±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°, and the error range may be ±0.3°, ±0.2°, or ±0.1°.

[0015] In a preferred embodiment of the invention, the crystalline form A further exhibits characteristic peaks expressed in 2θ angles at one or more 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°.

[0016] In a preferred embodiment of the present invention, said crystalline form A further exhibits three characteristic peaks expressed in 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 crystalline form A further exhibits four characteristic peaks expressed in 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 crystalline form A further exhibits five characteristic peaks expressed in 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 crystalline form A further exhibits six characteristic peaks expressed in 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, said crystalline form A further exhibits seven characteristic peaks expressed in 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, said crystalline form A further exhibits eight characteristic peaks expressed in 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 crystalline form A further exhibits nine characteristic peaks expressed in 2θ angles at 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°. In a further preferred embodiment of the present invention, the Raman spectrum of the crystalline form A 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 spectrum shows one or more characteristic peaks.

[0023] In a further preferred embodiment of the present invention, the Raman spectrum of the crystalline form A is 3063.8±2 cm -1 , 3013.2±2 cm -1 , 2961.9±2 cm -1 Three characteristic peaks are shown in Fig.

[0024] In a further preferred embodiment of the present invention, the Raman spectrum of the crystalline form A is 3063.8±2 cm -1 , 3013.2±2 cm -1 , 2961.9±2 cm -1 , 2931.4±2 cm -1 Four characteristic peaks are shown in.

[0025] In a further preferred embodiment of the present invention, the Raman spectrum of the crystalline form A 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 Five characteristic peaks are shown in.

[0026] In a further preferred embodiment of the present invention, the Raman spectrum of the crystalline form A 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 Shown in are six characteristic peaks.

[0027] In a further preferred embodiment of the present invention, the Raman spectrum of the crystalline form A 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 Seven characteristic peaks are shown in Fig.

[0028] In a further preferred embodiment of the present invention, the Raman spectrum of the crystalline form A 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 Eight characteristic peaks are shown in Fig.

[0029] In a further preferred embodiment of the present invention, the Raman spectrum of the crystalline form A 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 Nine characteristic peaks are shown in Fig.

[0030] In a further preferred embodiment of the present invention, the Raman spectrum of the crystalline form A 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 Ten characteristic peaks are shown in.

[0031] In a further preferred embodiment of the present invention, the Raman spectrum of the crystalline form A 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 Eleven characteristic peaks are shown in Fig.

[0032] In a further preferred embodiment of the present invention, the Raman spectrum of the crystalline form A 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 Twelve characteristic peaks are shown in.

[0033] In a further preferred embodiment of the present invention, the Raman spectrum of the crystalline form A 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 Thirteen characteristic peaks are shown in Fig.

[0034] In a further preferred embodiment of the present invention, the Raman spectrum of the crystalline form A 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 Shown in are 14 characteristic peaks.

[0035] In a further preferred embodiment of the present invention, the Raman spectrum of the crystalline form A 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 Fifteen characteristic peaks are shown in Fig.

[0036] In a further preferred embodiment of the present invention, the melting endothermic peak value of the crystalline form A in DSC is selected from the range of 161.4°C to 168.5°C, and preferably 164.8°C.

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

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

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

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

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

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

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

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

[0045] Specifically, the melting endothermic peak values ​​of the DSC of the above crystal form A 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 be 66.8°C, 166.9°C, 167.0°C, 167.1°C, 167.2°C, 167.3°C, 167.4°C, 167.5°C, 167.6°C, 167.7°C, 167.8°C, 167.9°C, 168.0°C, 168.1°C, 168.2°C, 168.3°C, 168.4°C, or 168.5°C.

[0046] In a further preferred embodiment of the invention, said crystalline form A meets one or more of the following solid state characteristics: (I) An X-ray powder diffraction pattern essentially consistent with FIG. 1; (II) A DSC spectrum essentially consistent with Figure 2; (III) Raman spectrum essentially in agreement with that in Figure 3 .

[0047] The present invention provides a process for the preparation of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, comprising the steps of: The method includes the steps of: starting from acetophenone, obtaining (R)-3-(dimethylamino)-1-phenylpropanol mandelate through Mannich reaction, reduction, and chiral resolution; liberating the salt; reacting the salt with 3-fluoro-1,2-methylenedioxybenzene; and demethylating the salt to obtain (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]-dioxolan-4-yl)-oxy]propylamine; and forming a salt with a solution of hydrogen chloride and ethyl acetate.

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

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

[0050] Wherein, 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 is one or more of alcohols, halogenated hydrocarbons, N-methyl-2-pyrrolidone, nitriles, water, N,N-dimethylformamide, and dimethylsulfoxide, the alcohols are preferably methanol, ethanol, n-propanol, isopropanol, or n-butanol, the halogenated hydrocarbons are preferably dichloromethane or chloroform, the nitriles are preferably acetonitrile, and the poor solvent is C 5-10 Selected from saturated hydrocarbons, ketones, esters, and ethers, 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, butanone and the esters are selected from ethyl acetate, n-propyl acetate, isopropyl acetate or isobutyl acetate.

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

[0052] In a further preferred embodiment of the present invention, the solvent in step (1) is 5-10 A mixed solvent consisting of a saturated hydrocarbon 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 a mixed solvent consisting of an alcohol and C 5-10 The solvent is a mixed solvent containing one or more selected from saturated hydrocarbons, esters, ethers, and ketones.

[0053] In a further preferred embodiment of the present invention, the mixed solvent is selected from the group consisting of 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 ... 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 n-butanol / water, acetonitrile / EA, acetonitrile / methyl tert-butyl ether, acetonitrile / isopropyl ether, acetonitrile / dichloromethane, n-butanol / water, n-butanol / acetonitrile, n-butanol / EA, n-butanol / methyl tert-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,The mixture is 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 further preferred embodiment of the invention, the water content of said ethanol is ≦5% (v / v).

[0055] In another preferred embodiment of the present invention, the above step (1) further comprises a heating process having a heating temperature selected from temperatures equal to or lower than 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) is selected from a reduced pressure solvent removal method, which is preferably a vacuum evaporation method, in which 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) is selected from evaporation in an air stream, the air stream is preferably an air stream or an inert gas stream, the inert gas is preferably an argon gas stream and a nitrogen gas stream.

[0058] Method 2 (1) (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride is dissolved 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) Obtaining a precipitate from the solution obtained in step (1) by a precipitation method.

[0059] Wherein, 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 is one or more of alcohols, halogenated hydrocarbons, N-methyl-2-pyrrolidone, nitriles, water, N,N-dimethylformamide, and dimethylsulfoxide, the alcohols are preferably methanol, ethanol, n-propanol, isopropanol, or n-butanol, the halogenated hydrocarbons are preferably dichloromethane or chloroform, the nitriles are preferably acetonitrile, and the poor solvent is C 5-10 Selected from saturated hydrocarbons, ketones, esters, and ethers, 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, butanone and the esters are selected from ethyl acetate, n-propyl acetate, isopropyl acetate or isobutyl acetate.

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

[0061] In a further preferred embodiment of the present invention, the solvent in step (1) is 5-10A mixed solvent consisting of a saturated hydrocarbon 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 a mixed solvent consisting of an alcohol and C 5-10 The solvent is a mixed solvent containing one or more selected from saturated hydrocarbons, esters, ethers, and ketones.

[0062] In a further 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 further preferred embodiment of the invention, the water content of said 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 precipitant 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 or deposit crystals, and the specific temperature is selected from ≦30°C, preferably room temperature, or preferably ≦20°C, preferably ≦9°C, more preferably ≦0°C, and the temperature error range is ±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 or deposit crystals, and the specific temperature is selected from a range of temperatures 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 precipitant method in step (2) refers to adding a precipitant of the compound represented by formula (I) to the solution obtained in step (1) to precipitate or deposit crystals, and the precipitant is C 5-10 The alkyl group may be one or more selected from saturated hydrocarbons, ketones, esters, or ethers.

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

[0069] In a further preferred embodiment of the invention, the ethers are one or more selected from methyl tert-butyl ether, isopropyl ether, petroleum ether, or tetrahydrofuran, preferably one or more of methyl tert-butyl ether or isopropyl ether.

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

[0071] In a further preferred embodiment of the 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, the above step (2) further includes a precipitation time during which a precipitate begins to be obtained after adding a precipitant to the solution obtained in step (1), and the above precipitation time is selected from 0 minutes to 120 minutes, 0 minutes to 60 minutes, 0 minutes to 30 minutes, 0 minutes to 10 minutes, 0 minutes to 5 minutes, 0 minutes to 2 minutes, 0 seconds to 30 seconds, or 0 seconds, and is preferably 0 minutes to 10 minutes, 0 minutes to 5 minutes, 0 minutes to 2 minutes, 0 seconds to 30 seconds, or 0 seconds, wherein the above "0" or "0 seconds" refers to the time when the precipitant is immediately added.

[0073] In a further preferred embodiment of the present invention, the step (2) further includes a precipitation time for obtaining a maximum amount of precipitation, and the precipitation time for the maximum amount of precipitation is 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, and most preferably 0 to 60 minutes, in which the above "0" refers to the time when the precipitant has been completely added, and the "maximum amount of precipitation" refers to the compound of formula (I) being completely precipitated or being precipitated in an amount of at least 85% (mass ratio of the amount of precipitation to the amount of the compound represented by formula (I) dissolved) from the solution obtained in the step (1).

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

[0075] In a preferred embodiment of the present invention, method 1 or method 2 comprises: (3) isolating the solid precipitate obtained in step (2) of method 1 or method 2; and (4) drying the solid precipitate obtained in step (3).

[0076] In a preferred embodiment of the present invention, step (3) further includes an isolation temperature, wherein the isolation temperature is 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 is ±5°C, preferably ±2°C.

[0077] In a preferred embodiment of the present invention, step (4) further includes a drying temperature, wherein the drying temperature is 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 is ±5°C, preferably ±2°C.

[0078] In a preferred embodiment of the present invention, step (4) further comprises a dry gas flow condition, and the dry gas flow is selected from an argon gas flow or a nitrogen gas flow.

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

[0080] In a further preferred embodiment of the present invention, the Raman spectrum of the crystalline form B is 3063.6±2 cm -1 , 3044.5±2 cm -1 , 2964.8±2 cm -1 Specifically, the Raman spectrum of the B crystal form shows three characteristic peaks at 3063.6 ± 2 cm -1, 3044.5±2 cm -1 , 2964.8±2 cm -1 , 2918.5±2 cm -1 Specifically, the Raman spectrum of the B crystal form shows four characteristic peaks at 3063.6 ± 2 cm -1 , 3044.5±2 cm -1 , 2964.8±2 cm -1 , 2918.5±2 cm -1 , 1715.2±2 cm -1 Specifically, the Raman spectrum of the B crystal form shows five characteristic peaks at 3063.6 ± 2 cm -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 Specifically, the Raman spectrum of the B crystal form shows six characteristic peaks at 3063.6 ± 2 cm -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 Specifically, the Raman spectrum of the B crystal form shows seven characteristic peaks at 3063.6 ± 2 cm -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 Specifically, the Raman spectrum of the B crystal form shows eight characteristic peaks at 3063.6 ± 2 cm -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 Specifically, the Raman spectrum of the B crystal form shows nine characteristic peaks at 3063.6 ± 2 cm -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 Specifically, the Raman spectrum of the B crystalline form shows ten characteristic peaks at 3063.6 ± 2 cm -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 Specifically, the Raman spectrum of the B crystal form shows 11 characteristic peaks at 3063.6 ± 2 cm -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 Specifically, the Raman spectrum of the B crystalline form shows 12 characteristic peaks at 3063.6 ± 2 cm -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 Specifically, the Raman spectrum of the B crystal form shows 13 characteristic peaks at 3063.6 ± 2 cm -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 Specifically, the Raman spectrum of the B crystal form shows 14 characteristic peaks at 3063.6 ± 2 cm -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 Fifteen characteristic peaks are shown in Fig.

[0081] In a further preferred embodiment of the invention, said crystalline form B meets one or more of the following solid state characteristics: (I) An X-ray powder diffraction pattern essentially in accordance with FIG. (II) Raman spectrum essentially in agreement with that in Figure 5 .

[0082] The present invention provides a method for preparing crystalline form B, which is selected from reflux recrystallization methods, and the specific method is: (1) dissolving a compound of formula (I) in glacial acetic acid; (2) slowly dropping into methyl tert-butyl ether to obtain a solid precipitate; (3) 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, which has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ±0.2° using Cu-Kα radiation.

[0084] Specifically, it may show three characteristic peaks at 10.73°, 11.95°, 14.82°, and the error range may be ±0.3°, ±0.2°, or ±0.1°. Specifically, it may show four characteristic peaks at 10.73°, 11.95°, 14.82°, 16.14°, and the error range may be ±0.3°, ±0.2°, or ±0.1°. Specifically, it may show five characteristic peaks at 10.73°, 11.95°, 14.82°, 16.14°, 16.53°, and the error range may be ±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°, 18.72°, and the error range may be ±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°, 18.98°, and the error range may be ±0.3°, ±0.2°, or ±0.1°. Specifically, it shows eight characteristic peaks at 10.73°, 11.95°, 14.82°, 16.14°, 16.53°, 18.72°, 18.98°, and 19.52°, and the error range may be ±0.3°, ±0.2°, or ±0.1°.

[0086] Specifically, it shows 9 characteristic peaks at 10.73°, 11.95°, 14.82°, 16.14°, 16.53°, 18.72°, 18.98°, 19.52°, 21.78°, and the error range may be ±0.3°, ±0.2°, or ±0.1°. Specifically, it shows 10 characteristic peaks at 10.73°, 11.95°, 14.82°, 16.14°, 16.53°, 18.72°, 18.98°, 19.52°, 21.78°, 23.00°, and the error range may be ±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°, 24.99°, and the error range may be ±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°, and the error range may be ±0.3°, ±0.2°, or ±0.1°. Specifically, it shows 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°, and the error range may be ±0.3°, ±0.2°, or ±0.1°.

[0087] In a further preferred embodiment of the invention, the C crystalline form meets one or more of the following solid state characteristics: (I) X-ray powder diffraction pattern essentially consistent with FIG. 6 .

[0088] The present invention provides a method for preparing crystalline form C of the compound represented by formula (I), which comprises adding an appropriate amount of water to a sample and dissolving it completely in a water bath at about 65°C, placing it in a refrigerator to pre-freeze it, and after completion, placing it in a freeze-dryer to perform a freeze-drying experiment, and after completion of the freeze-drying, irradiating it with light (5000 lx) for 10 days to obtain crystalline form C.

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

[0090] In a preferred embodiment of the present invention, the active ingredient comprises at least 50%-99% of said crystalline form A, preferably at least 70%-99% of said crystalline form A, more preferably at least 90%-99% of said crystalline form A.

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

[0092] In a preferred embodiment of the present invention, the active ingredient contains at least 50%-99% of the crystalline form B, preferably at least 70%-99% of said crystalline form B, and more preferably at least 90%-99% of said crystalline form B.

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

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

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

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

[0097] In a preferred embodiment 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, transdermally as a patch delivery system, etc. In a preferred embodiment, the pharmaceutical composition is preferably administered in an oral mode.

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

[0099] The present invention further provides a method for treating and / or preventing a psychiatric disorder comprising administering 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 crystalline form A, or said pharmaceutical composition to a patient, wherein said psychiatric disorder is selected from or is two or more of anxiety disorder, obsessive-compulsive disorder, depression, phobia, schizophrenia, preferably depression.

[0100] [Detailed Description of the Invention] In a further preferred embodiment of the invention, said crystalline form A meets one or more of the following solid state characteristics: (I) An X-ray powder diffraction pattern essentially consistent with FIG. 1; (II) A DSC spectrum essentially consistent with Figure 2; (III) Raman spectrum essentially in agreement with that in Figure 3 .

[0101] The present invention provides a process for the preparation of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, comprising the steps of: The method includes the steps of: starting from acetophenone, obtaining (R)-3-(dimethylamino)-1-phenylpropanol mandelate through Mannich reaction, reduction, and chiral resolution; liberating the salt; reacting the salt with 3-fluoro-1,2-methylenedioxybenzene; and demethylating the salt to obtain (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]-dioxolan-4-yl)-oxy]propylamine; and forming a salt with a solution of hydrogen chloride and ethyl acetate.

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

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

[0104] Wherein, 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 is one or more of alcohols, halogenated hydrocarbons, N-methyl-2-pyrrolidone, nitriles, water, N,N-dimethylformamide, and dimethylsulfoxide, the alcohols are preferably methanol, ethanol, n-propanol, isopropanol, or n-butanol, the halogenated hydrocarbons are preferably dichloromethane or chloroform, the nitriles are preferably acetonitrile, and the poor solvent is C 5-10Selected from saturated hydrocarbons, ketones, esters, and ethers, 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, butanone and the esters are selected from ethyl acetate, n-propyl acetate, isopropyl acetate or isobutyl acetate.

[0105] In a further 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 further preferred embodiment of the present invention, the solvent in step (1) is selected from water, chloroform, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, and N-methyl-2-pyrrolidone.

[0107] In a further preferred embodiment of the present invention, the solvent in step (1) is 5-10 A mixed solvent consisting of a saturated hydrocarbon 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 a mixed solvent consisting of an alcohol and C 5-10The solvent is a mixed solvent containing one or more selected from saturated hydrocarbons, esters, ethers, and ketones.

[0108] In a further 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 further preferred embodiment of the invention, the water content of said ethanol is ≦5% (v / v).

[0110] In another preferred embodiment of the present invention, the above step (1) further comprises a heating process having a heating temperature selected from temperatures equal to or lower than 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) is selected from a reduced pressure solvent removal method, and the reduced pressure solvent removal method is preferably a vacuum solvent removal method, in which 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) is selected from evaporation in an air stream, the air stream is preferably an air stream or an inert gas stream, the inert gas is preferably an argon gas stream and a nitrogen gas stream.

[0113] Method 2 (1) (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride is dissolved 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) Obtaining a precipitate from the solution obtained in step (1) by a precipitation method.

[0114] Wherein, 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 is one or more of alcohols, halogenated hydrocarbons, N-methyl-2-pyrrolidone, nitriles, water, N,N-dimethylformamide, and dimethylsulfoxide, the alcohols are preferably methanol, ethanol, n-propanol, isopropanol, or n-butanol, the halogenated hydrocarbons are preferably dichloromethane or chloroform, the nitriles are preferably acetonitrile, and the poor solvent is C 5-10 Selected from saturated hydrocarbons, ketones, esters, and ethers, 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, butanone and the esters are selected from ethyl acetate, n-propyl acetate, isopropyl acetate or isobutyl acetate.

[0115] In a further 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 further preferred embodiment of the present invention, the solvent in step (1) is one or more selected from water, chloroform, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, and N-methyl-2-pyrrolidone.

[0117] In a further preferred embodiment of the present invention, the solvent in step (1) is 5-10 A mixed solvent consisting of a saturated hydrocarbon 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 a mixed solvent consisting of an alcohol and C 5-10 The solvent is a mixed solvent containing one or more selected from saturated hydrocarbons, esters, ethers, and ketones.

[0118] In a further 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 further preferred embodiment of the invention, the water content of said 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 precipitant 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 or deposit crystals, and the specific temperature is selected from ≦30°C, preferably room temperature, or preferably ≦20°C, preferably ≦9°C, more preferably ≦0°C, and the temperature error range is ±5°C, preferably ±2°C.

[0122] Specifically, the specific temperature may 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 or deposit crystals, and the specific temperature is selected from a range of temperatures 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 particular temperature is selected to be at least 25° C. lower than the temperature of the solution obtained in step (1).

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

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

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

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

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

[0130] Specifically, the specific temperature is selected from temperatures that are 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 precipitant method in step (2) refers to adding a precipitant of the compound represented by formula (I) to the solution obtained in step (1) to precipitate or deposit crystals, and the precipitant is C 5-10 The alkyl group may be one or more selected from saturated hydrocarbons, ketones, esters, or ethers.

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

[0133] In a further preferred embodiment of the invention, the ethers are one or more selected from methyl tert-butyl ether, isopropyl ether, petroleum ether, or tetrahydrofuran, preferably one or more of methyl tert-butyl ether or isopropyl ether.

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

[0135] In a further preferred embodiment of the 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, the above step (2) further includes a precipitation time during which a precipitate begins to be obtained after adding a precipitant to the solution obtained in step (1), and the above precipitation time is selected from 0 minutes to 120 minutes, 0 minutes to 60 minutes, 0 minutes to 30 minutes, 0 minutes to 10 minutes, 0 minutes to 5 minutes, 0 minutes to 2 minutes, 0 seconds to 30 seconds, or 0 seconds, and is preferably 0 minutes to 10 minutes, 0 minutes to 5 minutes, 0 minutes to 2 minutes, 0 seconds to 30 seconds, or 0 seconds, wherein the above "0" or "0 seconds" refers to the time when the precipitant is immediately added.

[0137] Specifically, the precipitation 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, 53 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, 101 minutes, 1 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 further preferred embodiment of the present invention, the step (2) further includes a precipitation time for obtaining a maximum amount of precipitation, and the precipitation time for the maximum amount of precipitation is 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, and most preferably 0 to 60 minutes, in which the above "0" refers to the time when the precipitant has been completely added, and the "maximum amount of precipitation" refers to the compound of formula (I) being completely precipitated or being precipitated in an amount of at least 85% (mass ratio of the amount of precipitation to the amount of the compound represented by formula (I) dissolved) from the solution obtained in the step (1).

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

[0140] Specifically, the precipitation temperature is 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 comprises: (3) isolating the solid precipitate obtained in step (2) of method 1 or method 2; and (4) drying the solid precipitate obtained in step (3).

[0142] In a preferred embodiment of the present invention, step (3) further includes an isolation temperature, wherein the isolation temperature is 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 is ±5°C, preferably ±2°C.

[0143] Specifically, the isolation temperature 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, wherein the drying temperature is 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 is ±5°C, preferably ±2°C.

[0145] Specifically, the drying temperature 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 comprises a dry gas flow condition, and the dry gas flow is selected from an argon gas flow or a nitrogen gas flow.

[0147] In the specification and claims of this application, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art unless otherwise specified. However, in order to better understand the present invention, the definitions and explanations of some relevant terms are provided below. In addition, if the definitions and explanations of terms provided in this application are not consistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of terms provided in this application shall prevail.

[0148] "Crystal Form A" according to the present invention refers to crystal form A of the compound of formula (I).

[0149] The "alcohols" described in the present invention are "C 1-6 It refers to a group formed by replacing one or more hydrogen atoms on an alkyl group with one or more hydroxy groups. 1-6 An "alkyl group" is a saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms, including, but not limited to, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a n-butyl group, a pentyl group, and an isopentyl group; specific examples of "alcohols" include, but are not limited to, methanol, ethanol, n-propanol, or isopropanol.

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

[0151] The term "ethers" as used herein refers to linear or cyclic compounds containing an ether bond -O- and having 1 to 10 carbon atoms, and specific examples include, but are not limited to, diethyl ether, isopropyl ether, propylene glycol methyl ether, tetrahydrofuran, methyl tert-butyl ether, and 1,4-dioxane.

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

[0153] The term "ketones" as used herein refers to compounds in which a carbonyl group (-C(O)-) is linked to two hydrocarbon groups. According to the differences in the 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 It refers to a group formed by replacing one or more hydrogen atoms on an alkyl group with one or more cyano groups. 1-6 The "alkyl group" is as defined above, and the "cyano group" is a group in which a carbon atom and a nitrogen atom are connected by a triple bond and has the chemical formula -CN, and specific examples include, but are not limited to, acetonitrile or propionitrile.

[0155] The "saturated hydrocarbon" according to the present invention is 5-10 It refers to a compound in which all carbon atoms in the molecule are connected by single bonds and all other valence bonds are connected to hydrogen, and specific examples include, but are not limited to, n-pentane, n-hexane, cyclohexane, or n-heptane.

[0156] The "mixed solvent" according to the present invention refers to a solvent in which one or more different types of solvents are mixed at a certain ratio, and 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 "precipitant" described in the present invention refers to an "anti-solvent" or "anti-solvent", and means that when isolating or removing a certain component, the substance is dissolved in a suitable solvent in advance, and a solvent insoluble in the component to be isolated is added, and the above precipitant is co-soluble with the solvent that dissolves the compound represented by formula (I).

[0158] The good solvent is a solvent that has good solubility for the compound of the present application, and the poor solvent is a solvent that has poor solubility or is insoluble in the compound of the present application.

[0159] "Boiling point" according to the present invention refers to the boiling point or azeotropic point of a pure solvent or a mixture of solvents.

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

[0161] The term "2θ or 2θ angle" as used herein refers to the diffraction angle, where θ is the Bragg angle in degrees, and the error range of 2θ is ±0.1 to ±0.5, preferably ±0.1 to ±0.3, and more preferably ±0.2.

[0162] The "interplanar spacing or interplanar spacing (d value)" in the present invention refers to the interplanar spacing obtained by connecting two adjacent lattice points in a space lattice and selecting three unit vectors a, b, and c that are not parallel to each other, and dividing the lattice into parallel parallelepiped units. The space lattice is divided by the connecting lines of the determined parallelepiped units to obtain a set of linear lattices, which are called space lattice or crystal lattice. The lattice and crystal lattice respectively reflect the periodicity of the crystal structure by geometric points and lines, and different crystal planes have different interplanar spacings (i.e., the distance between two adjacent parallel crystal planes), and the unit is Å or angstrom.

[0163] "Differential scanning calorimetry or DSC" as described in this invention measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or melting of the crystal. The same crystalline form of the same compound may have thermal transition temperatures and melting points within about 5°C in successive analyses, usually within about 3°C. When a compound is said to have a certain DSC peak or melting point, it refers to ±5°C of the DSC peak or melting point. "Basically" also takes such temperature changes into account. DSC provides an auxiliary method to distinguish different crystalline forms. Different crystalline forms can be distinguished by their different transition temperature characteristics. It should be noted that for mixtures, their DSC peaks or melting points can vary over a wider range. Also, since a substance undergoes decomposition in the melting process, the melting temperature correlates with the heating rate.

[0164] As used herein, "FT-Raman spectrum (FT-Raman)" is used to study the structure and chemical bonds of molecules and may be a method for characterizing and identifying chemical species. In the present invention, FT-Raman spectrum is used to characterize molecular structures and crystalline forms. The error range of FT-Raman peak positions is ±2 cm. -1 may be also possible.

[0165] Mental illness in the present invention refers to a disease that presents different degrees of impairment in mental activities such as cognition, emotion, will, and behavior as clinical expressions due to brain dysfunction under the influence of various biological, psychological, and social environmental factors. Mental activity includes cognitive activity, emotional activity, and will activity consisting of sensation, perception, attention, memory, and thinking, and such activity processes are interconnected and cooperate closely with each other to maintain the unity and integrity of mental activity. Mental illness is mainly divided into mild mental illness and severe mental illness. Common mild mental illnesses include obsessive-compulsive disorder and depression. Common severe mental illnesses include schizophrenia. Mild mental illnesses are mainly expressed in emotional disorders such as anxiety and depression, and thought disorders such as obsessions, but the patient's cognition of thinking, logical reasoning ability, and self-knowledge are basically intact. On the other hand, patients in the early stages of severe mental illnesses such as schizophrenia may show expressions such as anxiety and obsessions, but the cognition and logical reasoning ability of such patients become very weak and their self-knowledge is almost lost. Organic or toxic mental disorders caused by brain lesions must be differentiated from general functional mental disorders. Mild mental disorders include anxiety disorders, obsessive-compulsive disorders, depression, and phobias. Severe mental disorders include schizophrenia. Various mental disorders occur when the functional activity of the brain is impaired by the action of internal or external harmful factors on the organism. When the overall mental activity is significantly abnormal or the integrity and unity of mental activity is impaired, it is expressed as a mental disorder. When there is no severe or persistent disorder of mental activity and the decline of mental activity ability is the main feature, 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 expressed as low mood, loss of interest, pessimism, slow thinking, lack of initiative, self-blame and punishment, poor eating and sleeping habits, worries about developing various illnesses, and a general feeling of discomfort, and in severe cases may exhibit suicidal thoughts and behavior.

[0167] The compound hydrochloride salts described in the present invention may contain one or more asymmetric centers and therefore may 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 may be in the form of stereoisomeric mixtures, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures 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, isomers can be prepared by asymmetric synthetic methods. See, for example, 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, p. 268 (E.L. Eliel, ed., Univ. Of Notre Dame Press, Notre Dame, IN 1972). The present invention further covers the hydrochloride salts of the compounds described herein in the form of each individual isomer essentially free of other isomers, and alternatively in the form of a mixture of isomers.

[0168] As used herein, a pure enantiomer compound is essentially free of the other enantiomer or stereoisomer of said compound (i.e., in enantiomeric excess). In other words, the "S" form of said compound is essentially free of the "R" form of said compound, and is thereby in enantiomeric excess of the "S" form.

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

[0170] As used herein, the term "isomers" refers to compounds having the same atomic number and types, and therefore the same molecular weight, but differing in the structural or spatial arrangement of said 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 isomeric form to another.

[0172] As will be apparent to one of ordinary skill in the art, some of the compounds of the present invention may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the present invention.

[0173] The term "treating / treatment" refers to the successful treatment or amelioration of any symptom of an injury, disease, lesion, or illness, including any objective or subjective parameter, such as elimination, alleviation, reduction of symptoms, or making the injury, lesion, or illness more tolerable to the patient, slowing the rate of degeneration or deterioration, making the end result of degeneration less likely to be frail, improving the physical or psychological well-being of the patient. Treating or ameliorating symptoms may be based on objective or subjective parameters, including the results of a physical exam, neuropsychiatric testing, and / or psychiatric evaluation.

[0174] The term "treatment" and related phrases include prevention of a pathology, disease, or disorder (eg, preventing the progression of one or more symptoms of a disease, condition, or disorder described herein).

[0175] An "effective amount" is an amount sufficient to achieve a specified purpose (e.g., to achieve the effect of its administration, to treat a disease, to reduce enzyme activity, to increase enzyme activity, or to reduce one or more symptoms of a disease or disorder).

[0176] An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of one or more symptoms of a disease, which can also be referred to as a "therapeutically effective amount." A "prophylactically effective amount" of a drug is an amount of a drug that has a desired prophylactic effect when administered to a subject, for example, prevents or delays the onset (or recurrence) of an injury, disease, lesion, or illness, or reduces the likelihood of the onset (or recurrence) of an injury, disease, lesion, or illness, or its symptoms. A complete prophylactic effect may not occur after administration of a single dose, but may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more doses. The appropriate dosage will depend on the purpose of the treatment and may be determined by one of ordinary skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th edition, 2003, edited by Gennaro, Lippincott, Williams & Wilkins).

[0177] A "reduction" of one or more symptoms (and grammatical equivalents of the above phrases) refers to a decrease in the severity or frequency of the symptoms, or the elimination of the symptoms.

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

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

[0180] [Beneficial 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 is more soluble than N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine oxalate. The compound represented by formula (I) has better activity, lower toxicity and is more suitable for medicinal use than N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, and among them, 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 in the mouse forced swimming efficacy test, and 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 in the mouse acute toxicity test. The crystalline form A of the compound represented by formula (I) of the present invention has high purity and good crystalline form stability, and when crystalline form A absorbs moisture, it increases its weight by 0.01%, and it has little or no hygroscopicity, and when measured by HPLC, it has little change in purity and high chemical stability, and the crystalline form A of the compound represented by formula (I) obtained by the technical solution of the present invention can meet the pharmaceutical requirements for production, transportation, storage, and the production process is stable, reproducible and controllable, and is suitable for industrialized production. In addition, the crystalline form A of the present application has good solubility, hygroscopicity, and bioavailability. [Brief description of the drawings]

[0181] [Figure 1] FIG. 2 is an X-ray powder diffraction pattern for crystalline form A of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride. [Diagram 2] FIG. 2 is a DSC spectrum of crystalline form A of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride. [Diagram 3]FIG. 2 is a Raman spectrum of crystalline form A of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride. [Figure 4] FIG. 2 is an X-ray powder diffraction pattern of the B crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride. [Diagram 5] FIG. 2 is a Raman spectrum of the B crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride. [Figure 6] FIG. 2 is the X-ray powder diffraction pattern of the C crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride. [Figure 7] FIG. 2 is a DSC spectrum of the C crystalline form of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0182] The present invention will be described in more detail with reference to the following examples. However, the examples are merely for illustrating the technical solutions of the present invention and are not intended to limit the substance and scope of the present invention.

[0183] Test conditions for the equipment used in the experiment: 1. X-ray Powder Diffraction (XRPD) Instrument model number: Bruker D8 Focus powder X-ray diffractometer. X-ray parameters: Cu / Kα(λ=1.540598Å) Voltage: 40 kilovolts (kV) Current: 40 milliamps (mA) Scanning range: 3.0 degrees to 60 degrees Scan step size: 0.02 degrees Scanning speed: 0.5 seconds / step 2. DSC thermal analysis method (Differential Scanning Calorimeter, DSC) Model number: Germany's Netsch DSC 200F3 differential scanning calorimeter 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: 150mw 4. High Performance Liquid Chromatography (HPLC) 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] JPEG2025502497000003.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), and 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 with reference to the method of Example 4 of CN105777706A.

[0186] Working 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 bottle, stirred mechanically, heated to 50-60°C, 5 mL of concentrated hydrochloric acid was added, and the temperature was controlled at 80-90°C for 15 h.

[0187] After the reaction was completed, the reaction solution was cooled to 5°C to 15°C, stirred for 1 h, filtered, the filter cake was washed twice with absolute ethanol, and the obtained solid was dried in 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, mechanically stirred, sodium hydroxide aqueous solution (18.7 g of sodium hydroxide and 100 mL of water) was added, the temperature was controlled at 0°C to 20°C, 10.66 g (0.28 mol) of sodium borohydride was added in batches, and the temperature was controlled at 15°C to 25°C to react for 2 h.

[0189] After the reaction was completed, the mixture was filtered, the filter cake was washed with 100 mL of methanol, the residue was discarded, and 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, and the aqueous phase was further extracted twice with ethyl acetate (150 mL each time), and the organic phase was combined and washed twice with saturated sodium chloride solution (200 mL each time). The organic phase was dried over anhydrous magnesium sulfate for 1 h, filtered, and then concentrated under reduced pressure to remove ethyl acetate, obtaining 80.54 g of a colorless oil.

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

[0191] After the reaction was completed, the temperature was lowered to crystallize, and the temperature was controlled to 10°C to 20°C and stirred for 1 h. After filtration, the filter cake was washed with 250 mL of absolute ethanol, the filtrate was discarded, and the obtained solid was dried in a blower 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 absolute ethanol were added to recrystallize, obtaining 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, mechanically stirred, 23.3 g (0.21 mol) of potassium tert-butoxide was added in batches, and then 33.6 g (0.24 mol) of 3-fluoro-1,2-methylenedioxybenzene was added, and the mixture was heated to 50°C to 55°C and reacted for 4 h.

[0193] After the reaction was completed, the temperature was lowered to 15°C to 30°C, 200 mL of water and 250 mL of ethyl acetate were added for extraction, the aqueous phase was further extracted once with 200 mL of ethyl acetate, the organic phase was combined and washed twice with saturated sodium chloride solution, the organic phase was dried over anhydrous magnesium sulfate, filtered, the filter cake was washed with ethyl acetate, and then salified with oxalic acid to obtain 36.14 g of off-white solid, which was then recrystallized by adding anhydrous ethanol to obtain 27.87 g of off-white solid.

[0194] 1.1.5. Preparation of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propyl phenylcarbamate 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 the base was added to a 500 mL reaction bottle, 2.59 g (0.02 mol) of N,N-diisopropylethylamine and 200 mL of toluene were added, and the mixture was stirred magnetically. 12.5 g (0.08 mol) of phenyl chloroformate was added in batches, and the mixture was heated to 80 °C and reacted for 2 h.

[0195] After the reaction was completed, 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, and the mixture was then washed twice with 1% hydrochloric acid and twice with a saturated sodium chloride solution. The organic phase was concentrated under reduced pressure to remove toluene, and 26.99 g of a yellowish brown liquid was obtained.

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

[0197] After the reaction is completed, the temperature is lowered to 15℃-30℃, 250 mL of water and 200 mL of ethyl acetate are added for extraction, the aqueous phase is further extracted with ethyl acetate twice (200 mL each time), the organic phase is combined, washed twice with saturated sodium chloride solution, the organic phase is dried with anhydrous sodium sulfate, filtered, the filter cake is washed with ethyl acetate, and then concentrated under reduced pressure to remove the solvent, obtaining 14.03 g of base, then adding 150 mL of ethyl acetate to dissolve, stirring magnetically, gradually adding hydrogen chloride ethyl acetate solution, adjusting the ph to 3-5 to gradually precipitate the solid, continuing to stir for 1 h, filtering, washing the filter cake with ethyl acetate, drying the obtained solid with a blower dryer, obtaining 12.5 g of off-white solid, HPLC: 99.54%. mp = 162-164℃; [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, see 1.1.1 of Example 1.

[0199] 1.2.2 Preparation of 3-(dimethylamino)-1-phenylpropanol For the preparation method, see 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, except that 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]propyl phenylcarbamate For the preparation method, see 1.1.5 of Example 1.

[0202] 1.2.5 Preparation of N-methyl-3-phenyl-3-[(benzo[d][1,3]-dioxolan-4-yl)oxy]propylamine hydrochloride The preparation method is described in 1.1.6 of Example 1. 20.1 g of off-white solid was obtained, HPLC: 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 crystalline form A 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 to 60°C-65°C for auxiliary dissolution, and the mixture was left to stand at room temperature (around 25°C) for crystallization, and the precipitate was collected, filtered, and dried at 60°C. Its X-ray powder diffraction pattern is shown in Figure 1, its DSC spectrum in Figure 2, and its Raman spectrum in Figure 3. In the DSC heating process, the start point of the endothermic peak is 161.4°C, the end point is 168.5°C, and the peak value is 164.8°C. This crystal form is defined as crystal form A, and the positions of its characteristic peaks are shown in Table 1 below:

[0204] [Table 1]

[0205] Example 3: Preparation of crystalline form A 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 assist dissolution. After complete dissolution, 120 mL of methyl tert-butyl ether was quickly added to precipitate a solid. The precipitate was collected, filtered, dried at 60°C, and detected as crystal form A.

[0206] Example 4: Preparation of crystalline form A 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, 30 mL of a mixed solvent of dichloromethane and ethanol (volume ratio 1:1) was gradually added, and the mixture was heated to 60°C to 65°C for auxiliary dissolution, and then transferred to a Buchi parallel reactor. The pressure for solvent removal was gradually reduced from 700 mba to 10 mba, and the temperature was increased from 30°C to 70°C. After complete precipitation, the sample was collected and detected as crystal form A.

[0207] Example 5: Preparation of crystalline form A 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, gradually added with a mixed solvent of methanol / n-hexane (volume ratio 5:1), heated to 60℃-65℃ for auxiliary dissolution, transferred to a Buchi parallel reactor, the pressure for solvent removal was gradually reduced from 700 mba to 10 mba, and the temperature was increased from 30℃ to 70℃. After complete precipitation, the sample was collected and detected as crystal form A.

[0208] Example 6: Preparation of crystalline form A 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 dissolve the mixture. After complete dissolution, the mixture was allowed to stand at room temperature to crystallize, and then 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 crystalline form.

[0209] Example 7: Preparation of crystalline form A 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, 80 mL of a mixed solvent of n-propanol / acetone (volume ratio 3:1) was gradually added, and the mixture was heated at 60°C to 65°C to dissolve it. After complete dissolution, the mixture was left to stand at room temperature to crystallize, filtered under reduced pressure, and 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 crystalline form.

[0210] Example 8: Preparation of crystalline form A 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, 100 mL of a mixed solvent of acetonitrile / butanone (volume ratio 5:1) was gradually added, and the mixture was heated at 60°C to 65°C to dissolve it. After complete dissolution, the mixture was allowed to stand at room temperature to crystallize, filtered under reduced pressure, and 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 crystalline form.

[0211] Example 9: Preparation of crystalline form A 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 quickly poured into the solution to precipitate a large amount of off-white precipitate to form a suspension, the suspension was allowed to settle, and filtered under reduced pressure, the filter cake was washed twice with petroleum ether, and the filter cake was collected and dried at 60°C to obtain the target product A crystalline form.

[0212] Example 10: Preparation of crystalline form A 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, 200 mL of isopropyl ether was quickly poured into the above solution, and a large amount of off-white precipitate was precipitated to form a suspension, the above suspension was allowed to stand, and filtered under reduced pressure, and the filter cake was washed twice with petroleum ether, and the filter cake was collected and dried at 60°C to obtain the target product A crystalline form.

[0213] Example 11: Preparation of crystalline form A 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, 200 mL of isopropyl ether was quickly poured into the above solution, and a large amount of off-white precipitate was precipitated to form a suspension, the above suspension was allowed to stand, and filtered under reduced pressure, and the filter cake was washed twice with petroleum ether, and the filter cake was collected and dried at 60°C to obtain the target product A crystalline form.

[0214] Example 12: Preparation of Crystal Form B 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 about 65°C for assisted dissolution until it was completely dissolved. The mixture was then drawn up with a syringe, and gradually dripped through a filter membrane into a container containing a large amount of methyl tert-butyl ether to precipitate a solid, which was then suction filtered 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 was defined as crystal form B, and the positions of its characteristic peaks are shown in Table 2 below:

[0215] [Table 2]

[0216] Example 13: Preparation of Crystalline Form C of (R)-N-Methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine Hydrochloride 5 g of 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 around 65 ° C., then placed in a refrigerator for pre-freezing, and after completion, placed in a freeze-dryer for a freeze-drying experiment, and after freeze-drying was completed, irradiated with light (5000 lx) for 10 days to obtain crystal form C. Its X-ray powder diffraction pattern is shown in Figure 6, and its DSC spectrum is shown in Figure 7. In the DSC heating process, the start point of the endothermic peak is 161.2 ° C, the end point is 166.0 ° C, and the peak value is 163.9 ° C. This crystal form is defined as crystal form C, and the positions of its characteristic peaks are shown in Table 3 below:

[0217] [Table 3]

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

[0219] [Table 4]

[0220] [Table 5]

[0221] [Table 6]

[0222] Experimental conclusion: Crystal form A can maintain stability under high temperature, high humidity and light exposure 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 studies Pharmacokinetic study of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride (compound of formula I), crystalline form A, 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, purchased from Shanghai Jiaotong University College of Agriculture.

[0226] Preparation of solutions: 1) Intravenous administration: 0.9% saline solution as a solvent. 2) Oral administration: At a dose of 10 mg / kg (by base), the corresponding weight of drug was weighed out according to the actual body weight of the animals, and then filled into capsules and administered to the animals, the test results are shown in Table 8.

[0227] [Table 8]

[0228] Experimental Conclusion: The pharmacokinetic experiments showed that the crystalline form A of the compound of formula (I) has better bioavailability than the hydrochloride salt, and the bioavailability value of the compound of formula (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 Experiments Solubility experiment of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride (compound of formula I), crystalline form A, N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine oxalate.

[0230] 16.1. Sample preparation (water medium is degassed purified water) Test solution: Accurately weigh approximately 2 g of 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 crystalline form A, and N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine oxalate) and place them in separate measuring flasks. Accurately measure 2 mL of water to prepare a test solution. Place the shaker in a water bath at a constant temperature of 20°C and shake overnight (supersaturation). Then filter the filtrate, accurately measure 1 mL, place it in a 100 mL measuring flask, dilute to the scale with diluent (water), shake uniformly, accurately measure 1 mL, and add 1 mL of the filtrate to a 100 mL measuring flask. The solution was placed in a 100 mL measuring flask, diluted up to the mark with dilution solution, and shaken evenly to prepare the test sample solution. Control solution: Take an appropriate amount of each of the five samples, weigh it precisely, add an appropriate amount of diluent, dissolve and dilute by ultrasonication to prepare a solution containing approximately 0.1 mg of sample per mL, and prepare two parallel samples per batch.

[0231] 16.2 Preparation of mobile phase (1) Preparation of a buffer solution: Approximately 2.6428 g of ammonium sulfate was weighed out and 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-0.02 mol / L ammonium sulfate solution (2 mL of triethylamine was added per 1000 mL, and the pH was adjusted to 4.0 with dilute sulfuric acid) (45:55) was prepared, mixed uniformly, filtered, and ultrasonically treated before use.

[0232] 16.3 Chromatographic 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 (add 2 mL of triethylamine per 1000 mL, adjust pH to 4.0 with dilute sulfuric acid) (45:55).

[0233] 16.4. Sample Measurement 20 μL of each solution was precisely measured and dispensed into a liquid chromatograph, the chromatograms were recorded, and the solubility of the compounds was measured by the external standard method. The results are shown in Table 9.

[0234] [Table 9]

[0235] Experimental Conclusion: The solubility experiments show 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), crystalline form A 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. Take a dry glass stoppered measuring flask (outer diameter 50 mm, height 15 mm) and place it in a suitable 25℃±1℃ thermostatic oven (with ammonium chloride or ammonium sulfate saturated solution placed in the bottom) or an artificial weather chamber (temperature set at 25℃±1℃, relative humidity set at 80%±2%) on the day before the test, and accurately weigh its weight (m1).

[0237] 17.2. Take an appropriate amount of crystalline form A of compound of formula (I) and spread it evenly in the above-mentioned measuring flask. The thickness of the sample is generally about 1 mm, and the weight (m2) is precisely weighed.

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

[0239] 17.4 The volumetric flask was capped and its weight (m3) was accurately measured. The test results are shown in Table 10.

[0240]

number

[0241] [Table 10]

[0242] Experimental Conclusion: Crystalline form A of the compound of formula (I) is non- or slightly hygroscopic and does not require strict packaging requirements during storage.

[0243] Example 18 Mouse forced swimming test: 18.1 Test Method SPF grade ICR mice are taken and animals are grouped by weight with 12 animals per group, and the animals are allowed to acclimate for at least 3 days before behavioral testing. Behavioral testing began 1 h after intragastric administration. The mouse was placed in a transparent glass cylinder with water (15 cm deep, water temperature 23°C to 25°C) and videotaped for 6 min (LED light-emitting panel in the background). After the videotaping ended, the mouse was removed from the water and the next batch of mouse behavioral testing was performed. Water was changed every 3 batches of testing. After the test, the video of the behavioral test was exported and Forced Swim Scan TM The cumulative immobility time of mice was analyzed for 4 min after the 6 min forced swimming period using the 2.0 software. The test results are shown as mean ± SD, and t-test was used to compare each group with the vehicle group, with differences of P<0.05 being considered statistically significant.

[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 a good dose-effect relationship at each dose. The minimum effective dose of duloxetine was 5 mg / kg, and the ED 50 The minimal effective dose (MED) of N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride was 0.4 mg / kg, and the median effective dose (ED 50 ) was 1.81 mg / kg, the MED of (S)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride was 1.6 mg / kg, and the ED 50 The ED was 1.74 mg / kg, and the minimum effective dose of the compound of formula (I) was 0.4 mg / kg, ED 50 The concentration 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 the minimum effective dose, N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride has the same minimum effective dose as the compound of formula (I) (0.4 mg / kg) and is 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 evaluation shows that the compound of formula (I) in mice has relatively good efficacy in the mouse forced swimming test.

[0247] Example 19 Mouse Acute Toxicity Test: 19.1, Test Method In a preliminary experiment, the dosage in this test was determined based on the dosages at which the compound caused 100% and 0% mortality in mice. During this test, ICR mice were used, randomly divided into groups of 10 each with an equal number of males and 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 administered intragastrically once to mice was 112.3 mg / kg, and the 95% confidence interval was 102.1 mg / kg - 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 - 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 - 125.0 mg / kg.

[0249] 19.3, Conclusions of the Test Viewed 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 50) was calculated, and the results showed that the compound of formula (I) had the largest 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 can be seen that N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride, the compound of formula (I), and the crystalline form A of the compound of formula (I) all have good solubility, minimum effective dose, and low toxicity, and the compound of formula (I) and the crystalline form A of the compound of formula (I) all have better bioavailability than their oxalates, and remain stable under high temperature, high humidity, and light irradiation of 5000 lx.

[0252] The above description is merely a preferred embodiment of the present application, and does not limit the present application. Various modifications and variations of the present application may be made by those skilled in the art. Any modifications, equivalent replacements, improvements, etc. made within the scope of the present application without departing from the spirit and principles of the present application are also included in the scope of protection of the present application.

Claims

1. N-Methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride.

2. (R)-N-Methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride.

3. The crystalline form A of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride according to claim 2, which has an X-ray powder diffraction pattern using Cu-Kα radiation, which shows characteristic peaks at 2θ angles of 8.77°, 12.00°, and 14.84°, wherein the error range of 2θ for each characteristic peak is ±0.2°. A crystalline form characterized by:

4. The characteristic peaks are expressed by 2θ angles at 8.77°, 12.00°, 14.84°, 21.34°, and 21.87°, and the error range of 2θ for each characteristic peak is ±0.2°.

4. Crystalline form A according to claim 3.

5. The characteristic peaks expressed in 2θ angles are 8.77°, 12.00°, 14.84°, 21.34°, 21.87°, 23.47°, and 24.14°, among which the error range of 2θ for each characteristic peak is ±0.2°.

4. Crystalline form A according to claim 3.

6. The X-ray powder diffraction pattern of crystalline form A further exhibits characteristic peaks expressed in 2θ angles at one or more of 7.78°, 16.58°, 19.66°, 23.03°, 25.46°, 26.65°, 26.97°, 27.41°, and 28.23°, wherein the error range of 2θ for each characteristic peak is ±0.2°, and preferably has an X-ray powder diffraction pattern essentially in accordance with FIG. Crystalline form A according to any one of claims 3 to 5.

7. The Raman spectrum 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 exhibiting a peak characteristic of one or more of the following:

7. Crystalline form A according to claim 6.

8. The melting endothermic peak value of the DSC of the crystalline form A is selected from the range of 161.4°C to 168.5°C, preferably 164.8°C.

8. Crystalline form A according to claim 7.

9. A process for preparing (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride according to claim 2, comprising the steps of: the step of liberating (R)-3-(dimethylamino)-1-phenylpropanol mandelate, reacting it with 3-fluoro-1,2-methylenedioxybenzene, and then demethylating it to obtain (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]-dioxolan-4-yl)-oxy]propylamine, and forming a salt with a hydrogen chloride ethyl acetate solution; A method comprising:

10. A process for preparing crystalline form A according to any one of claims 3 to 8, comprising the steps of: (1) dissolving (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) removing the solvent in the solution prepared in step (1) by a solvent removal method to obtain a precipitate; Wherein, 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 is one or more of alcohols, halogenated hydrocarbons, N-methyl-2-pyrrolidone, nitriles, water, N,N-dimethylformamide, and dimethylsulfoxide, the alcohols are preferably selected from methanol, ethanol, n-propanol, isopropanol, and n-butanol, the halogenated hydrocarbons are preferably selected from dichloromethane or chloroform, the nitriles are preferably selected from acetonitrile, and the poor solvent is C 5-10 C is selected from saturated hydrocarbons, ketones, esters, and ethers; 5-10 The saturated hydrocarbons are preferably selected from n-pentane, n-hexane, cyclohexane, or n-heptane, the ketones are preferably selected from acetone, 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, A method comprising:

11. A process for preparing crystalline form A according to any one of claims 3 to 8, comprising the steps of: (1) dissolving (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) 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 is one or more of alcohols, halogenated hydrocarbons, N-methyl-2-pyrrolidone, nitriles, water, N,N-dimethylformamide, or dimethylsulfoxide, the alcohols are preferably selected from methanol, ethanol, n-propanol, isopropanol, or n-butanol, the halogenated hydrocarbons are preferably selected from dichloromethane or chloroform, the nitriles are preferably selected from acetonitrile, and the poor solvent is C 5-10 C is selected from saturated hydrocarbons, ketones, esters, and ethers; 5-10 The saturated hydrocarbons are preferably selected from n-pentane, n-hexane, cyclohexane, or n-heptane, the ketones are preferably selected from acetone, 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 a cooling method or a precipitant method; The cooling method is a method of precipitating or depositing crystals by cooling the solution obtained in step (1) to 0°C to room temperature, The precipitant method is a method of precipitating and depositing crystals by adding a precipitant of (R)-N-methyl-3-phenyl-3-[(benzo[d][1,3]dioxolan-4-yl)oxy]propylamine hydrochloride to the solution obtained in step (1). A method comprising:

12. The precipitating agent is C 5-10 C is selected from saturated hydrocarbons, ketones, esters, and ethers; 5-10 The saturated hydrocarbons are preferably selected from n-pentane, n-hexane, cyclohexane, or n-heptane, the ketones are preferably selected from acetone, 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, 12. A process for preparing crystalline form A according to claim 11.

13. A pharmaceutical composition comprising the hydrochloride salt according to claim 1, or the hydrochloride salt according to claim 2, or crystalline form A according to any one of claims 3 to 8, and one or more excipients, vectors, adjuvants, solvents, or combinations thereof. Pharmaceutical compositions.

14. Use of the hydrochloride salt according to claim 1 or 2, or the crystalline form A according to any one of claims 3 to 8, or the pharmaceutical composition according to claim 13, in the preparation of a medicament for treating and / or preventing a psychiatric disorder, wherein said psychiatric disorder is one or more selected from anxiety disorder, obsessive-compulsive disorder, depression, phobia, schizophrenia, preferably depression. use.

15. A method for treating and / or preventing a psychiatric disorder, comprising administering to a patient the hydrochloride salt according to claim 1 or 2, or the crystalline form A according to any one of claims 3 to 8, or the pharmaceutical composition according to claim 13, The psychiatric disorder is one or more selected from the group consisting of anxiety disorder, obsessive-compulsive disorder, depression, phobia, and schizophrenia, and is preferably depression. method.

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