CN107365315B

CN107365315B - Pyrazole compound, crystal form and preparation method thereof

Info

Publication number: CN107365315B
Application number: CN201610316295.2A
Authority: CN
Inventors: 裘鹏程; 张福利; 潘林玉; 余俊; 蒋敏; 王震宇
Original assignee: Shanghai Institute of Pharmaceutical Industry; China National Medicines Guorui Pharmaceutical Co Ltd
Current assignee: Shanghai Institute of Pharmaceutical Industry; China National Medicines Guorui Pharmaceutical Co Ltd
Priority date: 2016-05-11
Filing date: 2016-05-11
Publication date: 2024-08-09
Anticipated expiration: 2036-05-11
Also published as: CN107365315A

Abstract

The invention discloses a pyrazole compound, a crystal form and a preparation method thereof. The pyrazole compound is di [1- (5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl) -6-methyl-1, 3-dihydrofuro [3,4-c ] pyridine-7-ol ] dihydrochloride monohydrate. The di TM2002 tri-hydrochloride monohydrate and the crystal form thereof have good stability, are beneficial to reducing the generation of impurities and improving the quality of products in the production and storage processes of bulk drugs and preparations. The preparation method provided by the invention is simple and rapid, mild in preparation condition, stable in yield and suitable for large-scale production.

Description

Pyrazole compound, crystal form and preparation method thereof

Technical Field

The invention relates to a pyrazole compound, a crystal form and a preparation method thereof.

Background

1- (5-Hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl) -6-methyl-1, 3-dihydrofuro [3,4-c ] pyridin-7-ol hydrochloride (hereinafter, referred to as TM2002 hydrochloride), is a protein modification inhibitor, and has a structural formula shown in 1:

TM2002 hydrochloride as a protein modifier production inhibitor has no side effects (such as vitamin B6 deficiency) of other protein modifier production inhibitors (such as edaravone), and simultaneously has a protective effect on kidney.

As is well known, the solubility effect of the crystal form on the stability of the drug substance and the preparation is very important, but the crystal form of TM2002 hydrochloride is not reported in the related literature at present. In patent document WO2005054205, crystallization from methanol and 2N hydrochloric acid methanol and concentration with ethanol gives crystalline TM2002 hydrochloride powder, but XRPD data are not reported.

Disclosure of Invention

The invention aims to solve the technical problem of providing a pyrazole compound, a crystal form and a preparation method thereof, and particularly provides a di (TM) 2002 tri-hydrochloride monohydrate, a crystal form and a preparation method thereof. The di-TM 2002 tri-hydrochloride monohydrate and the crystal form thereof have good stability, are beneficial to reducing the generation of impurities and improving the quality of products in the production and storage processes of bulk drugs and preparations. The preparation method provided by the invention is simple and rapid, mild in preparation condition, stable in yield and suitable for large-scale production.

The present inventors have found in the course of studying the hydrochloride salt of the compound TM2002 that when TM2002 is crystallized from a solution of methanol and hydrochloric acid in methanol (i.e., the crystallization conditions in WO 2005054205), ethanol and hydrochloric acid, or isopropanol and hydrochloric acid, the resulting crystal form is the same (hereinafter referred to as form i), and the characteristic absorption peaks, interplanar spacings, and relative intensities of 2 theta of the X-ray powder diffractogram are shown in table 1 below:

TABLE 1

A detailed test analysis of the form I shows that the form I is a monohydrochloride of TM 2002.

The present inventors have found a novel crystal form of TM2002 hydrochloride (hereinafter abbreviated as form iii) in further studies. Compared with the crystal form I, the crystal form III has better stability, especially high-temperature stability, is beneficial to reducing the generation of impurities and improving the product quality in the production and storage processes of raw materials and preparations.

The invention solves the technical problems through the following technical proposal.

The invention provides a pyrazole compound which is di [1- (5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl) -6-methyl-1, 3-dihydrofuro [3,4-c ] pyridine-7-ol ] dihydrochloride monohydrate.

The structural formula of the pyrazole compound is shown as formula 2:

The invention provides a crystal form III of 1- (5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl) -6-methyl-1, 3-dihydrofuro [3,4-c ] pyridine-7-alkoxide, wherein the characteristic absorption peaks of 2 theta of an X-ray powder diffraction pattern of the crystal form III are ：6.48±0.2、12.68±0.2、12.96±0.2、13.20±0.2、13.46±0.2、14.68±0.2、15.34±0.2、16.16±0.2、16.77±0.2、18.33±0.2、19.24±0.2、19.61±0.2、21.17±0.2、21.41±0.2、21.59±0.2、23.12±0.2、23.60±0.2、24.21±0.2、25.90±0.2、26.50±0.2、27.25±0.2、28.39±0.2、29.16±0.2、29.68±0.2、30.61±0.2、31.05±0.2、31.55±0.2、32.12±0.2、32.64±0.2、33.58±0.2、34.83±0.2、36.03±0.2 and 36.72 +/-0.2;

The crystal form III is di [1- (5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl) -6-methyl-1, 3-dihydrofuro [3,4-c ] pyridin-7-ol ] dihydrochloride monohydrate.

Preferably, the data of the X-ray powder diffraction pattern of form iii are shown in table 2 below:

TABLE 2

More preferably, the X-ray powder diffraction pattern of form iii is substantially as shown in figure 7.

In a preferred embodiment of the present invention, form III is a single crystal, and the form III belongs to a triclinic system, space group P-1, unit cell parameters: α= 106.70 °, β= 102.35 °, γ=99.08 °, unit cell volume The number of asymmetric units Z=2 in the unit cell and the crystal density is 1.430g/cm ³.

In the present invention, it is preferable that the crystal form III has endothermic peaks at 144 to 145℃and 224 to 225℃as detected by Differential Scanning Calorimetry (DSC). More preferably, the DSC profile of form iii is substantially as shown in figure 8.

In the invention, the infrared spectrum of the crystal form III has absorption peaks at least at 3038.7cm^-1,2652.3cm^-1,1546.4cm^-1,1419.8cm^-1,1305.6cm^-1,1038.5cm^-1 and 701.7cm ^-1. More preferably, the infrared spectrum of form iii is substantially as shown in fig. 9.

The invention also provides a preparation method of the crystal form III of the 1- (5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl) -6-methyl-1, 3-dihydrofuro [3,4-c ] pyridine-7-alkoxide, which comprises the following steps: dissolving 1- (5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl) -6-methyl-1, 3-dihydrofuro [3,4-c ] pyridine-7-alcohol in a solvent, cooling and crystallizing to obtain the compound; the solvent comprises hydrochloric acid and water; the initial temperature of crystallization is below 40 ℃.

Wherein 1- (5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl) -6-methyl-1, 3-dihydrofuro [3,4-c ] pyridin-7-ol is also known as TM2002.

Wherein the solvent may contain alcohol and/or ethyl acetate in addition to hydrochloric acid and water. The alcohol may be an alcohol conventionally used in the art, preferably one or more of methanol, ethanol and isopropanol.

In the solvent, the concentration of the hydrochloric acid is preferably 1 to 11mol/L, more preferably 6 to 9mol/L.

The volume concentration of the alcohol in the solvent is preferably 20% to 90%, more preferably 33% to 65%.

In the solvent, the volume concentration of the ethyl acetate is preferably 20% to 80%, more preferably 50% to 71%.

According to the general knowledge in the art, after being dissolved in a solvent, active carbon can be added to remove a heat source, and the active carbon can be filtered out before being cooled and crystallized.

Wherein the method and conditions of dissolution may be conventional in the art, and the temperature of dissolution is preferably 40 to 100 ℃.

Wherein, the method and conditions for cooling crystallization can be conventional methods and conditions in the art, and the target temperature of the cooling crystallization is preferably 0 to 40 ℃, more preferably 0 to 10 ℃. The initial temperature of the crystallization is preferably 15 to 40 ℃.

In the invention, filtering and/or drying operation can be performed after the cooling crystallization. The filtration and/or drying methods and conditions may be conventional in the art, and the drying temperature is preferably 30 to 50 ℃.

In a preferred embodiment of the invention, seed crystal III is added prior to said cooling crystallization. The seed crystal III is solid particles which are determined to be the crystal form III through XRPD detection.

The invention also provides a preparation method of the pyrazole compound, which has the same steps as the preparation method of the crystal form II of the 1- (5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl) -6-methyl-1, 3-dihydrofuro [3,4-c ] pyridine-7-alkoxide. The preferred operating conditions are as described above. The prepared bis [1- (5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl) -6-methyl-1, 3-dihydrofuro [3,4-c ] pyridin-7-ol ] dihydrochloride monohydrate.

On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.

The reagents and materials used in the present invention are commercially available.

In the present invention, the X-ray powder diffraction pattern is collected by using a Bruker D8ADVANCE type powder X-ray diffractometer, and the 2 theta value ranges from 3 degrees to 45 degrees, and is continuously scanned from 3 degrees to 45 degrees in 0.02 DEG/step size under the testing condition of 40kV/40mA (tube pressure/tube flow), and the scanning speed is 8.0 DEG/min, and the reproducible range 2 theta is +/-0.20 DEG (preferably 2 theta +/-0.10 DEG).

In the present invention, differential Scanning Calorimetry (DSC) was collected on NETZSCH DSC 204F1, crucible type: aluminum crucible (needle punched hole), purge gas: high purity nitrogen; 20mL/min, shielding gas: high purity nitrogen; 60mL/min, heating rate: 10 ℃/min.

In the invention, an infrared testing instrument is NICOLET-FTIR, and potassium bromide tabletting is adopted.

In the present invention, the room temperature is a room temperature conventional in the art, and is generally 10 to 30 ℃.

The invention has the positive progress effects that:

The TM2002 hydrochloride crystal form III has good stability, especially high-temperature stability, is beneficial to reducing the generation of impurities and improving the product quality in the production and storage processes of bulk drugs and preparations. The preparation method provided by the invention is simple and rapid, mild in preparation condition, stable in yield and suitable for large-scale production.

Drawings

FIG. 1 is an X-ray powder diffraction pattern of comparative example 1 for form I of TM2002 hydrochloride.

FIG. 2 is a DSC of comparative example 1 of form I of the TM2002 hydrochloride.

FIG. 3 is an IR chart of comparative example 1 showing the form I of TM2002 hydrochloride.

FIG. 4 is a TGA plot of comparative example 1 for form I of TM2002 hydrochloride.

FIG. 5 is a projection view showing the molecular structure of single crystal I of comparative example 2.

FIG. 6 is a unit cell stacking projection of the single crystal I of comparative example 2.

FIG. 7 is an X-ray powder diffraction pattern of form III of the TM2002 hydrochloride of example 1.

FIG. 8 is a DSC of example 1, form III of the TM2002 hydrochloride.

FIG. 9 is an IR chart of the TM2002 hydrochloride form III of example 1.

FIG. 10 is a TGA plot of the TM2002 hydrochloride form III of example 1.

FIG. 11 is a perspective view showing the molecular structure of single crystal III of example 2.

FIG. 12 is a unit cell stacking projection of single crystal III of example 2.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

The measurement methods used in the following examples and comparative examples are as follows:

The X-ray powder diffraction pattern was collected using a Bruker D8ADVANCE type powder X-ray diffractometer, and measured under 40kV/40mA (tube pressure/tube flow) under K.alpha.line of Cu target, 2 theta values ranged from 3 degrees to 45 degrees, continuously scanned at 0.02 DEG/step from 3 DEG to 45 DEG, at a scanning speed of 8.0 DEG/min, and reproducible ranges of 2 theta.+ -. 0.20 DEG (preferably 2 theta.+ -. 0.10 DEG).

Differential Scanning Calorimetry (DSC) was collected on NETZSCH DSC 204F1, crucible type: aluminum crucible (needle punched hole), purge gas: high purity nitrogen; 20mL/min, shielding gas: high purity nitrogen; 60mL/min, heating rate: 10 ℃/min.

The infrared test instrument was NICOLET-FTIR, and potassium bromide was used for tabletting.

The thermogravimetric analysis instrument is collected on a NETZSCH TG 209F1, and the crucible type is as follows: alumina crucible, purge gas: high purity nitrogen; 20mL/min, shielding gas: high purity nitrogen; 10mL/min, heating rate: 10 ℃/min.

In the examples and comparative examples, the concentration of concentrated hydrochloric acid used was 12mol/L.

Comparative example 1

TM2002 hydrochloride was prepared according to the method of WO 2005054205. And (5) marking the crystal as a crystal I, and marking the corresponding crystal form as a crystal form I.

The specific method comprises the following steps: adding 2mol/L hydrochloric acid methanol solution (15 ml) into TM2002 crude product (5 g), adding methanol (250 ml), heating to complete dissolution, concentrating under reduced pressure, adding ethanol (100 ml) when crystallization starts, replacing solvent and concentrating, repeating operation for 2 times, concentrating to about 50ml, cooling and placing in a refrigerator (4 ℃) overnight, filtering, washing filter cake with ethanol, and drying to obtain TM2002 hydrochloride 4.5g with purity of 98.6%. The powder X-ray diffraction pattern of the crystal I is shown in figure 1, and the specific data are shown in the following table 3. The DSC, IR and TGA test results of this crystal I are shown in FIGS. 2, 3 and 4, respectively.

TABLE 3 Table 3

Comparative example 2

The crystal I prepared by the literature method is subjected to single crystal cultivation to obtain a single crystal, and the specific preparation method is as follows:

1g of crude TM2002 is added with 4mol/L of hydrogen chloride methanol solution (5 ml), methanol (30 ml) is added, the mixture is heated until the mixture is completely dissolved, ethanol (30 ml) is added, the mixture is stood at room temperature for overnight to separate out solid, and granular crystals are taken as single crystals of the crystal form I and marked as single crystals I.

The single crystal I obtained was subjected to single crystal X-ray diffraction experiments, and the results were as follows:

Diffraction experiment

The crystal is colorless and transparent, the size of the crystal for diffraction experiment is 0.11 multiplied by 0.13 multiplied by 0.19mm, and belongs to a triclinic system, a space group P-1 and unit cell parameters: a= 7.0972 (14), b= 9.6880 (19),Α= 104.89 (3) °, β= 97.70 (3) °, γ= 96.80 (3) °, unit cell volumeThe number of asymmetric units z=2 in the unit cell.

Diffraction intensity data were collected using Bruker SMART APEX-II diffractometer, cukα radiation, graphite monochromator, single catheter diameter phi=0.50 mm, crystal to CCD detector distance d=60.3 mm, tube pressure 40kV, tube flow 30mA, scanning mode: Scanning, wherein the total diffraction points are 10621, the independent diffraction points are 3734, and the observable points (i F|2 is more than or equal to 2 sigma|F|2) are 2596.

Two structure resolution

The crystal structure was resolved by direct method (Shelxs, 97), all 25 non-hydrogen atom positions were obtained from the E-plot, structural parameters and discrimination atomic species were corrected using least squares, all hydrogen atom positions were obtained using geometry calculation and difference Fourier method, and finally the reliability factor r1=0.0468, wr2= 0.1288 (w=1/σ|f| 2), s=1.026. The final stoichiometric formula was C ₁₈H₁₇N₃O₃. HCl, the calculated molecular weight was 359.80, and the calculated crystal density was 1.456g/cm ³.

The molecular relative configuration diagram of the single crystal I corresponds to the compound of formula 1, the molecular three-dimensional structure projection diagram of the single crystal I is shown in FIG. 5, the unit cell stacking projection diagram of the single crystal I along the a-axis direction is shown in FIG. 6, and the atomic coordinate parameter values of non-hydrogen atoms are shown in FIG. 4.

TABLE 4 Table 4

The results show that: the molecular arrangement in the crystalline state belongs to the second space group, so that the sample has no optical activity, and the relative configuration of the compound in the crystal can be determined as shown in the formula 1. In the crystalline state, hydrogen bond connection exists between molecules, and the molecules are arranged in a stable space through Van der Waals force and hydrogen bond.

Example 1

1G of crude TM2002 is dissolved in 6mol/L hydrochloric acid aqueous solution (20 mL), the solution is heated to 90 ℃ to fully dissolve the crude TM2002, 0.2g of active carbon is added, the reflux is carried out for 15min, the filtration is carried out while the solution is hot, the filtrate is cooled to precipitate solid, the crystallization initial temperature is 35 ℃, the ice water bath at 0-5 ℃ is kept for 1.5h, the filtration is carried out, and the solution is dried at 50 ℃ to obtain 0.6g of TM2002 hydrochloride. The purity is greater than 99.0% and the yield is 60% through detection.

In this example, the MS and NMR data for the product are shown below:

EMS-MS m/z:324.1[M+H]⁺。

¹H-NMR(400MHz,CDCl₃+CF₃COOH)δ：2.35(s,3H,CH₃),2.68(s,3H,CH₃),5.32-5.43(m,2H,CH₂),6.64(s,1H,CH),7.26-7.51(m,7H),8.10(s,1H).

The XRPD and DSC tests were performed and the test results are shown in fig. 7 and 8, with specific XRPD data shown in table 5. The hydrochloride of TM2002 obtained in example 1 was designated as crystal III, and the corresponding crystal form was designated as form III. The IR and TGA test results of this crystal III are shown in FIGS. 9 and 10, respectively.

TABLE 5

Example 2

The crystal III is subjected to single crystal cultivation to obtain a single crystal, and the preparation method specifically comprises the following steps:

1g of crude TM2002 is dissolved in a mixed solvent of 6mL of concentrated hydrochloric acid, 2mL of water and 4mL of ethanol, the mixture is heated to 80 ℃ to fully dissolve the crude TM2002, the mixture is cooled to 35 ℃, seed crystal III is added, the mixture is stood at room temperature for overnight to separate out solid, granular crystals are taken to be single crystals of the crystal, and the single crystals are measured as crystal form III by XRPD and recorded as single crystals III.

Single crystal X-ray diffraction experiments were performed on the single crystal iii obtained, with the following results:

Diffraction experiment

The crystal is colorless transparent block, the size of the crystal for diffraction experiment is 0.20 multiplied by 0.23 multiplied by 0.31mm, and the crystal belongs to a triclinic system, a space group P-1 and unit cell parameters: a= 9.4217 (19), b= 14.1143 (3),Α= 106.70 (3), β= 102.35 (3), γ=99.08 (3) °, unit cell volumeThe number of asymmetric units z=2 in the unit cell.

Diffraction intensity data were collected using Bruker SMART APEX-II diffractometer, cukα radiation, graphite monochromator, single catheter diameter phi=0.50 mm, crystal to CCD detector distance d=60.3 mm, tube pressure 40kV, tube flow 30mA, scanning mode: scanning, wherein the total diffraction points are 21719, the independent diffraction points are 8037, and the observable points (i F|2 is more than or equal to 2 sigma|F|2) are 6584.

Two structure resolution

Analyzing the crystal structure by adopting a direct method (Shelxs-97), obtaining all 52 non-hydrogen atom positions from an E diagram, correcting structural parameters and judging atom types by using a least square method, obtaining all hydrogen atom positions by using a geometric calculation method and a difference Fourier method, and finally obtaining a reliability factor R ₁＝0.1352,wR₂＝0.4615(w＝1/σ|F|²), wherein S= 1.118. The final stoichiometry was determined to be 2 (C ₁₈H₁₇N₃O₃)·3HCl·H₂ O, calculated molecular weight 773.07, calculated crystal density 1.430g/cm ³.

The molecular relative configuration diagram of the single crystal III corresponds to the compound of formula 2, FIG. 11 is a projected diagram of the molecular three-dimensional structure of the single crystal III, FIG. 12 is a projected diagram of unit cell stacking of the single crystal III along the a-axis direction, and Table 6 is the atomic coordinate parameter value of the non-hydrogen atom.

TABLE 6

The results show that: the molecular arrangement in the crystalline state belongs to the second space group, so that the sample has no optical activity, and the relative configuration of the compound in the crystal can be determined as shown in the formula 2. In the crystalline state, hydrogen bond connection exists between molecules, and the molecules are arranged in a stable space through Van der Waals force and hydrogen bond.

Example 3

1G of crude TM2002 is added into a mixed solvent of 4mL of concentrated hydrochloric acid, 4mL of water and 20mL of ethyl acetate, the mixture is heated to 80 ℃ until the crude TM2002 is completely dissolved, the mixture is cooled to precipitate solid, the crystallization initial temperature is 40 ℃, the ice water bath is kept for 1h, the mixture is filtered, the filter cake is washed by ethyl acetate, and 0.66g of TM2002 hydrochloride is obtained after drying at 30 ℃. The purity of the obtained TM2002 hydrochloride is 99.9 percent, the single impurity is less than 0.1 percent, and the obtained TM2002 hydrochloride is the same as the sample of the example 1 by XRPD measurement, and is di TM2002 tri-hydrochloride monohydrate, and the corresponding crystal form is a crystal form III.

Example 4

129G of TM2002 crude product is dissolved in 780mL of concentrated hydrochloric acid, 250mL of water and 500mL of ethanol, the mixture is heated to 90 ℃ until the TM2002 crude product is completely dissolved, 1g of active carbon is added, the mixture is refluxed for 15min, the mixture is filtered while the mixture is hot, the filtrate is cooled, seed crystal III which is solid particles with the crystal form of the crystal form III determined by XRPD test is added at 35 ℃, the solid is separated out, the ice water bath is kept for 1h, the mixture is filtered, the filter cake is washed by ethanol, and 113.5g of TM2002 hydrochloride is obtained by drying at 50 ℃. The purity of the obtained TM2002 hydrochloride is 99.9 percent, the single impurity is less than 0.1 percent, and the obtained TM2002 hydrochloride is the same as the sample of the example 1 by XRPD measurement, and is di TM2002 tri-hydrochloride monohydrate, and the corresponding crystal form is a crystal form III.

Example 5

TM2002 hydrochloride is prepared following the procedure of example 4, except that in solvent: the concentration of hydrochloric acid is 1mol/L, and the volume concentration of methanol is 90%. The obtained TM2002 hydrochloride was identical to the sample of example 1 as measured by XRPD, and was dittm 2002 tri hydrochloride monohydrate, the corresponding crystalline form being crystalline form iii.

Example 6

TM2002 hydrochloride is prepared following the procedure of example 4, except that in solvent: the concentration of hydrochloric acid is 8mol/L, and the volume concentration of isopropanol alcohol is 20%. The obtained TM2002 hydrochloride was identical to the sample of example 1 as measured by XRPD, and was dittm 2002 tri hydrochloride monohydrate, the corresponding crystalline form being crystalline form iii.

Example 7

TM2002 hydrochloride is prepared following the procedure of example 1, except that in solvent: the concentration of hydrochloric acid is 11mol/L, and the initial crystallization temperature is 15 ℃. The obtained TM2002 hydrochloride was identical to the sample of example 1 as measured by XRPD, and was dittm 2002 tri hydrochloride monohydrate, the corresponding crystalline form being crystalline form iii.

Example 8

TM2002 hydrochloride is prepared following the procedure of example 3, except that in solvent: the concentration of hydrochloric acid is 4mol/L, and the volume concentration of ethyl acetate is 50%. The obtained TM2002 hydrochloride was identical to the sample of example 1 as measured by XRPD, and was dittm 2002 tri hydrochloride monohydrate, the corresponding crystalline form being crystalline form iii.

Effect examples

The crystals obtained in example 1 and comparative example 1 were subjected to stability comparison (10 days at 60 ℃) by HPLC analysis, and the results are shown in Table 7 below.

TABLE 7

Wherein, the impurity A is an impurity generated in the preparation process of TM 2002. The results show that: the crystal form III has good stability at high temperature, the impurity growth of the crystal form III is only 10%, and the impurity growth of the crystal form I is 58%.

Claims

1. A crystalline form III of 1- (5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl) -6-methyl-1, 3-dihydrofuro [3,4-c ] pyridin-7-ol hydrochloride, characterized in that,

The data of the X-ray powder diffraction pattern of the crystal form III are shown in the following table:

The crystal form III is di [1- (5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl) -6-methyl-1, 3-dihydrofuro [3,4-c ] pyridin-7-ol ] dihydrochloride monohydrate;

the crystal form III is a single crystal, and belongs to a triclinic system, a space group P-1 and unit cell parameters: α= 106.70 °, β= 102.35 °, γ=99.08 °, unit cell volume The number of asymmetric units Z=2 in the unit cell, and the crystal density is 1.430g/cm ³;

The preparation method of the crystal form III comprises the following steps: dissolving 1- (5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl) -6-methyl-1, 3-dihydrofuro [3,4-c ] pyridine-7-alcohol in a solvent, cooling and crystallizing to obtain the compound; the solvent comprises hydrochloric acid and water; the initial temperature of crystallization is below 40 ℃.

2. Form iii of claim 1, wherein the X-ray powder diffraction pattern of form iii is substantially as shown in figure 7.

3. Form iii according to claim 1 or 2, characterized in that said form iii has an endothermic peak at 144-145 ℃ and 224-225 ℃ as measured by differential scanning calorimetry;

And/or, the infrared spectrum of the crystal form III has absorption peaks at least at 3038.7cm^-1,2652.3cm^-1,1546.4cm^-1,1419.8cm^-1,1305.6cm^-1,1038.5cm^-1 and 701.7cm ^-1.

4. A form iii according to claim 3, wherein the differential scanning calorimetry trace of form iii is substantially as shown in figure 8;

And/or, the infrared spectrum of form iii is substantially as shown in fig. 9.

5. A process for the preparation of crystalline form iii of 1- (5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl) -6-methyl-1, 3-dihydrofuro [3,4-c ] pyridin-7-ol hydrochloride according to any one of claims 1 to 4, characterized in that it comprises the following steps: dissolving 1- (5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl) -6-methyl-1, 3-dihydrofuro [3,4-c ] pyridine-7-alcohol in a solvent, cooling and crystallizing to obtain the compound; the solvent comprises hydrochloric acid and water; the initial temperature of crystallization is 15-40 ℃.

6. The method according to claim 5, wherein the concentration of the hydrochloric acid in the solvent is 1 to 11mol/L;

and/or the solvent also contains alcohol and/or ethyl acetate.

7. The method according to claim 6, wherein the concentration of the hydrochloric acid in the solvent is 6 to 9mol/L;

and/or, when the solvent further contains an alcohol, the alcohol is one or more of methanol, ethanol, and isopropanol;

And/or, when the solvent also contains ethyl acetate, the volume concentration of the ethyl acetate is 20-80%.

8. The method according to claim 6, wherein when the solvent further contains an alcohol, the alcohol is contained in a volume concentration of 20% to 90%;

and/or, when the solvent also contains ethyl acetate, the volume concentration of the ethyl acetate is 50-71%.

9. The method according to claim 6, wherein when the solvent further contains an alcohol, the alcohol is contained in a concentration of 33 to 65% by volume.

10. The method of any one of claims 5-9, wherein after "dissolving in a solvent", activated carbon is added, which is filtered before "cooling crystallization";

and/or, the dissolution temperature is 40-100 ℃;

and/or the target temperature of cooling crystallization is 0-40 ℃;

and/or filtering and/or drying after the cooling crystallization.

11. The method of claim 10, wherein the target temperature for cooling crystallization is 0-10 ℃;

And/or when filtering and/or drying operations are performed after said cooling crystallization; the drying temperature is 30-50 ℃.

12. The method of any one of claims 5-9, wherein seed crystal iii is added prior to the cooling crystallization, the seed crystal iii being solid particles identified as form iii by XRPD detection.