A new hydroxypiperidone free base crystal form and preparation method thereof

Abstract

The present invention relates to a crystalline form II of a free base of hydroxypiperidone and a method for preparing the crystalline form II in a ketone solvent. The crystalline form II of the free base of hydroxypiperidone provided by the present invention has a stable morphology, large particle size, and is easy to filter. The obtained product has high purity and good yield, and is very suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the field of chemical pharmacy, and more particularly to a hydroxypiperidone free base crystal form and a preparation method thereof. Technical Background

[0002] Hydroxypiperidone free base, chemical name is 1-[(1-benzyl-4-hydroxypiperidin-4-yl)-methyl]-pyridin-2(1H)-one, and its structural formula is shown below:

[0003]

[0004] CN102241667B discloses a hydroxypiperidone hydrochloride compound and a preparation method thereof. The compound can be used to prevent or treat central nervous system diseases related to 5-HT system dysfunction, including depression, mania, cognitive impairment, schizophrenia, pain, etc.

[0005] CN106892897A discloses a new crystal form I of hydroxypiperidone free base. The X-ray powder diffraction pattern of this crystal form has characteristic peaks at 2θ angles of 5.3°, 6.8°, 7.9°, 10.6°, 13.6°, 15.4°, 16.3°, 20.4°, and 23.9°. Its differential scanning calorimetry analysis pattern shows that the crystal form I has a melting endothermic peak at 146-150°C. When the method of this patent was reproduced, it was found that the product prepared by the above patent method had a small particle size, a long filtration time, a low yield, and a low purity. Summary of the Invention

[0006] The present invention aims to provide a hydroxypiperidone free base crystal form suitable for industrial production and a preparation method thereof.

[0007] The first aspect of the present invention provides a new crystalline form of hydroxypiperidone free base, named Form II, which has an X-ray powder diffraction pattern measured using Cu-Kα radiation with peaks at 5.8, 11.6, 14.8, 18.0, 18.1, and 23.4±0.2 degrees 2θ.

[0008] Furthermore, the X-ray powder diffraction pattern of the crystalline form II of the present invention measured using Cu-Kα radiation has peaks at 9.4, 12.9, 18.7, 20.0, 21.1, 24.4, 29.3, and 32.8±0.2 degrees 2θ.

[0009] The Cu-Kα radiation described in the present invention, wherein λ=0.154 nm.

[0010] The 2θ and relative intensity data of the X-ray powder diffraction pattern of the hydroxypiperidone free base crystal form II of the present invention are shown in Table 1:

[0011] Table 1

[0012]

[0013]

[0014] The hydroxypiperidone free base crystal form II of the present invention has an X-ray powder diffraction pattern as shown in FIG. Figure 1 shown.

[0015] The hydroxypiperidone free base crystal form II of the present invention is characterized in that a differential scanning calorimetry (DSC) analysis spectrum shows that the new crystal form has a maximum absorption peak in the range of 145 to 150°C.

[0016] The DSC spectrum of the hydroxypiperidone free base crystal form II of the present invention is as follows: Figure 2 shown.

[0017] The TGA spectrum of the hydroxypiperidone free base crystal form II of the present invention is as follows: Figure 3 shown.

[0018] Another object of the present invention is to provide a method for preparing hydroxypiperidone free base crystal form II, which comprises the following steps:

[0019] (a) mixing hydroxypiperidone free base with a ketone solvent and heating to dissolve it;

[0020] (b) slowly cooling the solution obtained in step (a) to crystallize;

[0021] (c) filtering and drying to obtain hydroxypiperidone free base crystal form II.

[0022] In the preparation method of the present invention, the preferred ketone solvent in step (a) is acetone or 2-butanone, more preferably acetone.

[0023] In the preparation method of the present invention, the weight-to-volume ratio of hydroxypiperidone free base to acetone is preferably 1:10-100 g / mL, more preferably 1:15-30 g / mL.

[0024] The preparation method of the present invention has a preferred crystallization temperature of -10°C to 40°C, and a more preferred crystallization temperature of -5°C to 30°C.

[0025] The preparation method of the present invention has a preferred crystallization time of 1 to 36 hours, and a more preferred crystallization time of 3 to 10 hours.

[0026] The hydroxypiperidone free base crystal form II provided by the present invention has a stable morphology, large particle size, and a particle size distribution of: D(90): 300-400 μm, D(50): 70-180 μm, and D(10): 15-50 μm; it is easy to filter, and the obtained product has high purity and good yield, and is very suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The X-ray powder diffraction pattern of the new crystal form of hydroxypiperidone free base obtained in Example 1 of the present invention.

[0028] Figure 2 Differential scanning calorimetry analysis of the new crystalline form of hydroxypiperidone free base obtained in Example 1 of the present invention.

[0029] Figure 3 Thermogravimetric analysis spectrum of the new crystalline form of hydroxypiperidone free base obtained in Example 1 of the present invention. Specific embodiments

[0030] The following specific preparation examples are intended to illustrate the present invention in detail. The examples are only used for more detailed description and are not intended to limit the present invention in any form.

[0031] Analytical instruments used in the present invention:

[0032] (1) X-ray powder diffraction analysis

[0033] Instrument Model: X'Pert-Pro-MPD (Multi-Purpose Diffractometer)

[0034] Test method: A finely ground sample (100 mg) was placed in a groove on a glass plate. After scraping the groove flush with the glass surface with a glass slide, the sample was placed in an X'Pert-Pro-MPD analyzer using a Cu-Ka radiation source (λ = 0.154 nm) with a voltage and current of 45 kV and 40 mA. The scanning range was 3-50° (2θ), the step size was 0.0167° (2θ), the counting time per step was 50 s, and the total scanning time was 20 min.

[0035] (2)DSC thermal analyzer

[0036] Instrument model: Discovery DSC-250

[0037] Test method: Place the sample to be tested (about 2 mg) in a sample pan, keep it in equilibrium at 30°C, and then heat it to 260°C at a rate of 10°C / min.

[0038] (3) TGA analyzer

[0039] Instrument model: Discovery TGA-5500

[0040] Test method: The sample to be tested (about 10 mg) is placed in a sample pan, kept in equilibrium at 30°C, and then heated to 350°C at a rate of 10°C / min.

[0041] (4) Laser particle size analyzer

[0042] Instrument model: LS-POP(9)

[0043] Test method: Take about 200 mg of the sample to be tested, add 1 ml of surfactant, stir evenly, then add 20 ml of dispersant, ultrasonicate for 20 seconds, add sample until the refractive index is between 10% and 20%, circulate for 1 minute to stabilize, measure 3 times and take the average value.

[0044] Comparative Example 1

[0045] At room temperature, 5 kg of hydroxypiperidone free base was weighed, 100 L of trifluoroethanol was added, and the mixture was heated to 60 ° C for complete dissolution. The solution was filtered and added to 100 L of n-butanol solution to precipitate solids. After stirring for 20 minutes, the mixture was filtered. The filtration time was 5.5 hours and dried to obtain 4.1 kg of hydroxypiperidone free base. The yield was 82%, the purity was 98.3%, and the particle size distribution was shown in Table 2 below:

[0046] Table 2

[0047]

[0048] Example 1

[0049] At room temperature, 5 kg of hydroxypiperidone free base was weighed, 75 L of acetone was added, and the mixture was heated to 55-65 ° C for complete dissolution. The cooling rate was controlled to cool the solution to room temperature, and a transparent to white solid was precipitated. The solid was filtered for 21 minutes and dried to obtain 4.8 kg of hydroxypiperidone free base with a yield of 96% and a purity of 100%. The particle size distribution is shown in Table 3 below:

[0050] Table 3

[0051]

[0052] The diffraction pattern of the X-ray diffractometer is as follows: Figure 1 As shown, it is named as Form II.

[0053] Example 2

[0054] At room temperature, 5 kg of hydroxypiperidone free base was weighed, 75 L of 2-butanone was added, and the mixture was heated to 70-80 ° C for complete dissolution. The cooling rate was controlled to cool the solution to room temperature to precipitate a transparent to white solid. The solid was filtered for 27 min and dried to obtain 4.8 kg of hydroxypiperidone free base with a yield of 96% and a purity of 99.9%. The X-ray powder diffraction pattern was determined to be hydroxypiperidone free base Form II.

[0055] Example 3

[0056] At room temperature, 100 g of hydroxypiperidone free base was weighed, 1000 ml of acetone was added, and the mixture was heated to 55-65 ° C for complete dissolution. The cooling rate was controlled to cool the solution to room temperature to precipitate a transparent to white solid. The solid was filtered for 2 min 30 s and dried to obtain 95 g of hydroxypiperidone free base with a yield of 95% and a purity of 99.9%. The X-ray powder diffraction pattern was determined to be hydroxypiperidone free base Form II.

[0057] Example 4

[0058] At room temperature, 100 g of hydroxypiperidone free base was weighed, 3000 ml of acetone was added, and the mixture was heated to 55-65 ° C for complete dissolution. The cooling rate was controlled to cool the solution to room temperature to precipitate a transparent to white solid. The solid was filtered for 2 min 48 s and dried to obtain 96.9 g of hydroxypiperidone free base with a yield of 96.9% and a purity of 99.9%. The X-ray powder diffraction pattern was determined to be hydroxypiperidone free base Form II.

[0059] Example 5

[0060] At room temperature, 100 g of hydroxypiperidone free base was weighed, 5000 ml of acetone was added, and the mixture was heated to 55-65 ° C for complete dissolution. The cooling rate was controlled to cool the solution to room temperature to precipitate a transparent to white solid. The solid was filtered for 3 minutes and dried to obtain 95.4 g of hydroxypiperidone free base with a yield of 95.4% and a purity of 99.9%. The X-ray powder diffraction pattern was determined to be hydroxypiperidone free base Form II.

[0061] Example 6

[0062] At room temperature, 100 g of hydroxypiperidone free base was weighed, 10 L of acetone was added, and the mixture was heated to 55-65 ° C for complete dissolution. The cooling rate was controlled to cool the solution to room temperature to precipitate a transparent to white solid. The solid was filtered for 2 min 51 s and dried to obtain 96.2 g of hydroxypiperidone free base with a yield of 96.2% and a purity of 99.9%. The X-ray powder diffraction pattern was determined to be hydroxypiperidone free base Form II.

[0063] The X-ray powder diffraction spectra of the products obtained in Examples 2-6 are the same as those in Example 1 and are not repeated here.

[0064] Comparative Example 1

[0065] The crystal form I prepared in Preparation Example 1 and the crystal form II obtained in Example 1 of the present invention were subjected to filtration speed comparison experiments and particle size comparison experiments, respectively. The results are shown in Table 4, wherein the filter used was the same filter.

[0066] Table 4

[0067]

Claims

1. A method for preparing hydroxypiperidone free base crystal form II, the method comprising the following steps: (a) mixing hydroxypiperidone free base with a ketone solvent and heating to dissolve it; (b) slowly cooling the solution obtained in step (a) to crystallize; (c) filtering and drying to obtain hydroxypiperidone free base crystal form II, The ketone solvent in step (a) is acetone or 2-butanone, and the crystallization temperature is -10°C to 40°C. The X-ray powder diffraction pattern of the hydroxypiperidone free base crystal form II measured using Cu-Kα radiation has peaks at 5.8, 9.4, 11.6, 12.9, 14.8, 18.0, 18.1, 18.7, 20.0, 23.4, 21.1, 24.4, 29.3, and 32.8±0.2 degrees 2θ.

2. The preparation method according to claim 1, wherein the weight-to-volume ratio of the hydrochloric acid free base to acetone is 1:10 to 100 g / mL.

3. The preparation method according to claim 2, wherein the weight-to-volume ratio of the hydrochloric acid free base to acetone is 1:15-30 g / mL. The preparation method according to claim 1 , wherein the crystallization temperature is -5° C. to 30° C.

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