Pharmaceutical salt of (R)-5-cyclopentylpyrazolidine-3-ketone as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and relates to a pharmaceutical salt of (R)-5-cyclopentylpyrazolidine-3-ketone as well as a preparation method and application thereof. Specifically, the pharmaceutical salt is L-malate or D-malate of (R)-5-cyclopentylpyrazolidine-3-ketone, and the pharmaceutical salt can be obtained by splitting racemic 5-cyclopentylpyrazolidine-3-ketone by using an optically pure single malate; according to the method, the pharmaceutical salt with a good crystal form can be obtained with low cost, high yield and high purity, and post-treatment is easy; in addition, the medicinal salt can also be used for preparing medicines such as rucotinib and the like, and has good economic benefits and social benefits.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry. Specifically, it relates to a method for resolving 5-cyclopentylpyrazolidin-3-one to obtain a pharmaceutical salt of the R-isomer, as well as a pharmaceutical salt of (R)-5-cyclopentylpyrazolidin-3-one and its uses. Background Art

[0002] Ruxolitinib is a selective JAK1 / JAK2 tyrosine kinase inhibitor jointly developed by Incyte Corporation and Novartis. It was approved by the US FDA in November 2011 as the first drug for the treatment of myelofibrosis (trade name Jakafi).

[0003] The structure of ruxolitinib (shown as follows) contains a chiral center with the R configuration. The literature (Ruxolitinib. Tyrosine-protein kinase JAK1 / 2 inhibitor, Treatment of myelofibrosis, Treatment of myeloproliferative neoplasms, Treatment of psoriasis [J], Drugs of the Future, 2010, 35(6): 457-465) records that in the synthetic route of ruxolitinib, the chiral resolution is close to the finished product step, with low atom utilization rate, high cost, and a relatively complex structure of the chiral catalyst, and a high dosage of the catalyst. In addition, the ee value of the chiral resolution product is not high, and the chiral purity is only about 90%, and it still needs to be further resolved or further refined through multiple steps to obtain a product with pharmaceutical value. Therefore, it is necessary to develop a new method that can reduce costs and achieve industrialization.

[0004] (R)-5-Cyclopentylpyrazolidin-3-one (shown as follows) can be used as an intermediate for the preparation of ruxolitinib, and has the same chiral center with the R configuration as ruxolitinib. The chiral structure of the intermediate can be directly transferred to the ruxolitinib finished product in the synthesis process. Therefore, 5-cyclopentylpyrazolidin-3-one can be resolved to obtain the R-isomer or its salt, and finally ruxolitinib can be prepared.

[0005] Summary of the Invention

[0006] Problems to be Solved by the Invention

[0007] The present invention aims to provide a pharmaceutical salt of (R)-5-cyclopentylpyrazolidin-3-one suitable for industrial production and its preparation method, in particular, a pharmaceutical salt of the R-isomer obtained by resolving 5-cyclopentylpyrazolidin-3-one and its preparation method.

[0008] Solutions to Solve the Problems

[0009] In a first aspect, the present invention provides a pharmaceutical salt of a compound represented by Formula I,

[0010]

[0011] wherein,

[0012] the pharmaceutical salt is L-malate or D-malate.

[0013] Optionally, the pharmaceutical salt of the compound represented by Formula I is a compound represented by Formula III,

[0014]

[0015] Specifically, the compound represented by Formula III has Crystal Form A, and the Crystal Form A meets at least one of the following conditions:

[0016] 1) Its XRPD pattern shows diffraction peaks at 2θ values of 10.2 ± 0.2°, 16.0 ± 0.2°, 18.3 ± 0.2°, 18.7 ± 0.2°, 21.6 ± 0.2°;

[0017] Preferably, its XRPD pattern further shows diffraction peaks at 2θ values of 20.7 ± 0.2°, 25.6 ± 0.2°, 27.9 ± 0.2°, 31.0 ± 0.2°, 36.7 ± 0.2°;

[0018] More preferably, its XRPD pattern further shows diffraction peaks at 2θ values of 19.9 ± 0.2°, 23.2 ± 0.2°, 31.5 ± 0.2°, 32.3 ± 0.2°, 33.4 ± 0.2°;

[0019] Further preferably, its XRPD pattern is substantially as Figure 6 shown;

[0020] 2) Its DSC pattern shows an endothermic peak at 145.07 °C ± 5 °C;

[0021] Preferably, its DSC pattern is substantially as Figure 7 shown; and

[0022] 3) Its TGA pattern shows a weight loss within 8.0 wt%, preferably within 7.5 wt%;

[0023] Preferably, its TGA spectrum is substantially as Figure 8 shown.

[0024] Optionally, the pharmaceutical salt of the compound represented by formula I is a compound represented by formula IV,

[0025]

[0026] Specifically, the compound represented by formula IV has crystal form B, and the crystal form B meets at least one of the following conditions:

[0027] 1) Its XRPD spectrum shows diffraction peaks at 2θ values of 9.1±0.2°, 16.6±0.2°, 22.3±0.2°, and 23.5±0.2°;

[0028] Preferably, its XRPD spectrum shows diffraction peaks at 2θ values of 18.7±0.2°, 19.2±0.2°, 20.6±0.2°, and 21.9±0.2°;

[0029] More preferably, its XRPD spectrum shows diffraction peaks at 2θ values of 16.3±0.2°, 17.2±0.2°, 31.4±0.2°, and 33.0±0.2°;

[0030] Further preferably, its XRPD spectrum shows diffraction peaks at 2θ values of 20.9±0.2°, 25.0±0.2°, 27.6±0.2°, 29.0±0.2°, 30.5±0.2°, 33.3±0.2°, and 34.9±0.2°;

[0031] Even more preferably, its XRPD spectrum is substantially as Figure 10 shown;

[0032] 2) Its DSC spectrum shows an endothermic peak at 125.04°C±5°C;

[0033] Preferably, its DSC spectrum is substantially as Figure 11 shown; and

[0034] 3) Its TGA spectrum shows a weight loss within 10.0 wt, preferably within 9.5 wt%;

[0035] Preferably, its TGA spectrum is substantially as Figure 12 shown.

[0036] In a second aspect, the present invention provides a method for preparing a pharmaceutical salt of a compound represented by formula I.

[0037] When the medicinal salt of the compound shown by Formula I is the compound shown by Formula III, the preparation method comprises:

[0038] Mixing the compound shown by Formula II with L-malic acid in Solvent 1, first heating up and stirring, then cooling down and crystallizing, and filtering to obtain the compound of Formula III;

[0039]

[0040] Specifically, in the preparation method, in terms of mole percentage, the compound shown by Formula II consists of X% of the R isomer and (100 - X)% of the S isomer, where 50 ≤ X < 100, and preferably X = 50.

[0041] Specifically, in the preparation method, Solvent 1 is a ketone or a mixed solvent thereof with water.

[0042] Preferably, the ketone is acetone, butanone or methyl isobutyl ketone, and preferably acetone.

[0043] Preferably, the volume ratio of the ketone to water in the mixed solvent is 2:1 - 20:1, and preferably 5:1 - 10:1.

[0044] Specifically, in the preparation method, the dosage ratio of the compound shown by Formula II to Solvent 1 is 1 g:2 mL - 1 g:10 mL, and preferably 1 g:4 mL - 1 g:5 mL.

[0045] Specifically, in the preparation method, the molar ratio of the compound shown by Formula II to L-malic acid is 1:0.5 - 1:1.1, and preferably 1:0.55 - 1:1.1.

[0046] Specifically, in the preparation method, the target temperature for heating up is 35 - 60 °C, and preferably 45 - 50 °C.

[0047] Specifically, in the preparation method, the duration of stirring is 10 - 60 min, and preferably 30 - 40 min.

[0048] Specifically, in the preparation method, the target temperature for cooling down is 5 - 30 °C, and preferably 12 - 20 °C.

[0049] Specifically, in the preparation method, the duration of crystallization is 0.5 - 15 h, and preferably 5 - 12 h.

[0050] When the medicinal salt of the compound shown by Formula I is the compound shown by Formula IV, the preparation method comprises:

[0051] Mix the compound shown in Formula II with D-malic acid in Solvent 2. First, raise the temperature and stir, then lower the temperature and crystallize, and filter to obtain the compound of Formula IV;

[0052]

[0053] Specifically, in the preparation method, in terms of molar percentage, the compound shown in Formula II is composed of X% of the R-isomer and (100 - X)% of the S-isomer, where 50 ≤ X < 100, and preferably X = 50.

[0054] Specifically, in the preparation method, Solvent 2 is an organic solvent.

[0055] Preferably, the organic solvent is an alkane, an alcohol, an ester, an ether, or a nitrile, or a mixed solvent of any two of them.

[0056] More preferably, the alkane is n-hexane, n-heptane, or n-octane, and preferably n-heptane.

[0057] More preferably, the alcohol is methanol, ethanol, or isopropanol, and preferably ethanol.

[0058] More preferably, the ester is methyl acetate, ethyl acetate, or isopropyl acetate, and preferably ethyl acetate.

[0059] More preferably, the ether is tetrahydrofuran or 1,4-dioxane, and preferably tetrahydrofuran.

[0060] More preferably, the nitrile is acetonitrile, propyl ester, or isobutyl ester, and preferably acetonitrile.

[0061] Specifically, in the preparation method, the dosage ratio of the compound shown in Formula II to Solvent 2 is 1 g: 2 mL - 1 g: 10 mL, and preferably 1 g: 5 mL - 1 g: 6 mL.

[0062] Specifically, in the preparation method, the molar ratio of the compound shown in Formula II to the D-malic acid is 1: 0.5 - 1: 1.1, and preferably 1: 0.9 - 1: 1.1.

[0063] Specifically, in the preparation method, the target temperature for raising the temperature is 35 - 60 °C, and preferably 45 - 50 °C.

[0064] Specifically, in the preparation method, the duration of stirring is 10 - 60 min, and preferably 30 - 40 min.

[0065] Specifically, in the preparation method, the target temperature for lowering the temperature is 5 - 30 °C, and preferably 15 - 20 °C.

[0066] Specifically, in the preparation method, the crystallization time is 0.5 - 15 h, preferably 5 - 12 h.

[0067] In a third aspect, the present invention provides the use of L-malic acid or D-malic acid in resolving a compound represented by Formula II, particularly in the preparation of the R-isomer of the compound represented by Formula II or its malate salt,

[0068]

[0069] wherein,

[0070] In terms of mole percentage, the compound of Formula II is composed of X% of the R-isomer and (100 - X)% of the S-isomer, where 50 ≤ X < 100, preferably X = 50.

[0071] In a fourth aspect, the present invention provides the use of L-malic acid in the preparation of a compound represented by Formula III,

[0072]

[0073] In a fifth aspect, the present invention provides the use of D-malic acid in the preparation of a compound represented by Formula IV,

[0074]

[0075] In a sixth aspect, the present invention provides the use of a medicinal salt of the compound represented by Formula I (e.g., L-malate or D-malate), the compound represented by Formula III, or the compound represented by Formula IV in the preparation of a compound represented by Formula V,

[0076]

[0077] Effects of the Invention

[0078] The method of the present invention overcomes the technical defects in the prior art, such as low atomic utilization rate, high resolution cost, and complex resolution operation, and clearly points out the corresponding relationship between the resolution solvent and a cheap and easily available resolution reagent with a specific configuration (e.g., L-malic acid, D-malic acid). This method can obtain (R)-5-cyclopentylpyrazolidin-3-one or its L- / D-malate salt with low cost, high yield, and high purity. The obtained salt forms crystals with a dense structure and large particle size, with an average particle size > 50 μm, which is easy to post-process. The product has a good crystal morphology, high product purity, and excellent fluidity, compressibility, and stability. In summary, the method of the present invention has good economic and social benefits. Description of the Drawings

[0079] Figure 1The chiral HPLC chromatogram of the racemic compound of 5-cyclopentylpyrazolidin-3-one is shown.

[0080] Figure 2 The XRPD pattern of the racemic compound of 5-cyclopentylpyrazolidin-3-one is shown.

[0081] Figure 3 The DSC pattern of the racemic compound of 5-cyclopentylpyrazolidin-3-one is shown.

[0082] Figure 4 The TGA pattern of the racemic compound of 5-cyclopentylpyrazolidin-3-one is shown.

[0083] Figure 5 The PLM view (50-fold magnification) of (R)-5-cyclopentylpyrazolidin-3-one L-malate is shown.

[0084] Figure 6 The XRPD pattern of (R)-5-cyclopentylpyrazolidin-3-one L-malate is shown.

[0085] Figure 7 The DSC pattern of (R)-5-cyclopentylpyrazolidin-3-one L-malate is shown.

[0086] Figure 8 The TGA pattern of (R)-5-cyclopentylpyrazolidin-3-one L-malate is shown.

[0087] Figure 9 The PLM view (50-fold magnification) of (R)-5-cyclopentylpyrazolidin-3-one D-malate is shown.

[0088] Figure 10 The XRPD pattern of (R)-5-cyclopentylpyrazolidin-3-one D-malate is shown.

[0089] Figure 11 The DSC pattern of (R)-5-cyclopentylpyrazolidin-3-one D-malate is shown.

[0090] Figure 12 The TGA pattern of (R)-5-cyclopentylpyrazolidin-3-one D-malate is shown.

[0091] Figure 13 The chiral HPLC chromatogram of (R)-5-cyclopentylpyrazolidin-3-one D-malate is shown.

[0092] Figure 14 The chiral HPLC chromatogram of (R)-5-cyclopentylpyrazolidin-3-one L-malate is shown. Detailed Description of the Invention

[0093] The technical solution of the present invention will be further described below in conjunction with specific embodiments. Unless otherwise specified, the instruments, drugs, reagents, etc. used in the following embodiments can be obtained through conventional commercial means.

[0094] (R)-5-Cyclopentylpyrazolidin-3-one Medicinal Salt

[0095] In the present invention, a pharmaceutical salt of a compound of formula I is provided, wherein the absolute configuration of the chiral center in the structural formula is the R configuration, and it can be used as a key intermediate for preparing ruxolitinib.

[0096]

[0097] In the present invention, the pharmaceutical salt can be either the L-malate salt of the compound of formula I or its D-malate salt.

[0098] In one embodiment of the present invention, the molar ratio of the compound of formula I to L-malic acid or D-malic acid when forming a salt can be 1:1, that is, they form a salt in equimolar amounts.

[0099] In one embodiment of the present invention, the pharmaceutical salt of the compound of formula I can be a compound of formula III.

[0100]

[0101] In one embodiment of the present invention, the compound of formula III can exist in crystal form.

[0102] In one embodiment of the present invention, the compound of formula III can exist in the form of rod-shaped crystals.

[0103] In one embodiment of the present invention, the compound of formula III can exist in crystal form with a particle size greater than 30 μm.

[0104] In one embodiment of the present invention, the compound of formula III existing in crystal form can have crystal form A.

[0105] In one specific embodiment of the present invention, the X-ray powder diffraction (XRPD) pattern of crystal form A can show diffraction peaks at 2θ values of 10.2 ± 0.2°, 16.0 ± 0.2°, 18.3 ± 0.2°, 18.7 ± 0.2°, and 21.6 ± 0.2°.

[0106] In a specific embodiment of the present invention, the XRPD pattern of polymorph A may further show diffraction peaks at 2θ values of 20.7 ± 0.2°, 25.6 ± 0.2°, 27.9 ± 0.2°, 31.0 ± 0.2°, 36.7 ± 0.2°, that is, diffraction peaks at 2θ values of 10.2 ± 0.2°, 16.0 ± 0.2°, 18.3 ± 0.2°, 18.7 ± 0.2°, 20.7 ± 0.2°, 21.6 ± 0.2°, 25.6 ± 0.2°, 27.9 ± 0.2°, 31.0 ± 0.2°, 36.7 ± 0.2°.

[0107] In a specific embodiment of the present invention, the XRPD pattern of polymorph A may further show diffraction peaks at 2θ values of 19.9 ± 0.2°, 23.2 ± 0.2°, 31.5 ± 0.2°, 32.3 ± 0.2°, 33.4 ± 0.2°, that is, diffraction peaks at 2θ values of 10.2 ± 0.2°, 16.0 ± 0.2°, 18.3 ± 0.2°, 18.7 ± 0.2°, 19.9 ± 0.2°, 20.7 ± 0.2°, 21.6 ± 0.2°, 23.2 ± 0.2°, 25.6 ± 0.2°, 27.9 ± 0.2°, 31.0 ± 0.2°, 31.5 ± 0.2°, 32.3 ± 0.2°, 33.4 ± 0.2°, 36.7 ± 0.2°.

[0108] In a specific embodiment of the present invention, the XRPD pattern of polymorph A may be substantially as Figure 6 shown.

[0109] In a specific embodiment of the present invention, the differential scanning calorimetry (DSC) pattern of polymorph A may show an endothermic peak at 145.07°C ± 5°C.

[0110] In a specific embodiment of the present invention, the DSC pattern of polymorph A may be substantially as Figure 7 shown.

[0111] In a specific embodiment of the present invention, the thermogravimetric analysis (TGA) pattern of polymorph A may show a weight loss within 8.0 wt%.

[0112] In a specific embodiment of the present invention, the TGA pattern of polymorph A may show a weight loss within 7.5 wt%.

[0113] In a specific embodiment of the present invention, the TGA pattern of polymorph A may be substantially as Figure 8 shown.

[0114] In one embodiment of the present invention, the pharmaceutical salt of the compound of formula I may be the compound of formula IV.

[0115]

[0116] In one embodiment of the present invention, the compound of formula IV may exist in crystalline form.

[0117] In one embodiment of the present invention, the compound of formula IV may exist in columnar crystal form.

[0118] In one embodiment of the present invention, the compound of formula IV may exist in crystalline form with a particle size greater than 50 μm.

[0119] In one embodiment of the present invention, the compound of formula IV existing in crystalline form may have crystal form B.

[0120] In one specific embodiment of the present invention, the XRPD pattern of crystal form B may show diffraction peaks at 2θ values of 9.1 ± 0.2°, 16.6 ± 0.2°, 22.3 ± 0.2°, and 23.5 ± 0.2°.

[0121] In one specific embodiment of the present invention, the XRPD pattern of crystal form B may further show diffraction peaks at 2θ values of 18.7 ± 0.2°, 19.2 ± 0.2°, 20.6 ± 0.2°, and 21.9 ± 0.2°, i.e., diffraction peaks at 2θ values of 9.1 ± 0.2°, 16.6 ± 0.2°, 18.7 ± 0.2°, 19.2 ± 0.2°, 20.6 ± 0.2°, 21.9 ± 0.2°, 22.3 ± 0.2°, and 23.5 ± 0.2°.

[0122] In one specific embodiment of the present invention, the XRPD pattern of crystal form B may further show diffraction peaks at 2θ values of 16.3 ± 0.2°, 17.2 ± 0.2°, 31.4 ± 0.2°, and 33.0 ± 0.2°, i.e., diffraction peaks at 2θ values of 9.1 ± 0.2°, 16.3 ± 0.2°, 16.6 ± 0.2°, 17.2 ± 0.2°, 18.7 ± 0.2°, 19.2 ± 0.2°, 20.6 ± 0.2°, 21.9 ± 0.2°, 22.3 ± 0.2°, 23.5 ± 0.2°, 31.4 ± 0.2°, and 33.0 ± 0.2°.

[0123] In a specific embodiment of the present invention, the XRPD pattern of polymorph B may further show diffraction peaks at 2θ values of 20.9±0.2°, 25.0±0.2°, 27.6±0.2°, 29.0±0.2°, 30.5±0.2°, 33.3±0.2°, 34.9±0.2°, that is, at 2θ values of 9.1±0.2°, 16.3±0.2°, 16.6±0.2°, 17.2±0.2°, 18.7±0.2°, 19.2±0.2°, 20.6±0.2°, 20.9±0.2°, 21.9±0.2°, 22.3±0.2°, 23.5±0.2°, 25.0±0.2°, 27.6±0.2°, 29.0±0.2°, 30.5±0.2°, 31.4±0.2°, 33.0±0.2°, 33.3±0.2°, 34.9±0.2°.

[0124] In a specific embodiment of the present invention, the XRPD pattern of polymorph B may be substantially as Figure 10 shown.

[0125] In a specific embodiment of the present invention, the DSC pattern of polymorph B may show an endothermic peak at 125.04°C ± 5°C.

[0126] In a specific embodiment of the present invention, the DSC pattern of polymorph B may be substantially as Figure 11 shown.

[0127] In a specific embodiment of the present invention, the TGA pattern of polymorph B may show a weight loss within 10.0 wt.

[0128] In a specific embodiment of the present invention, the TGA pattern of polymorph B may show a weight loss within 9.5 wt%.

[0129] In a specific embodiment of the present invention, the TGA pattern of polymorph B may be substantially as Figure 12 shown.

[0130] (R)-5-Cyclopentylpyrazolidin-3-one Medicinal Salt Preparation Method (5-Cyclopentylpyrazolidin-3-one Racemization Compound Resolution Method)

[0131] In the present invention, a method for preparing a pharmaceutical salt (e.g., malate) of the above-mentioned compound of formula I is provided.

[0132]

[0133] In the present invention, this method can be applicable to the preparation of both the L-malate and D-malate of the compound of formula I, and the methodological parameters can also be adjusted according to different types of pharmaceutical salts.

[0134] In the above preparation method, the molar ratio of the compound of formula I to L-malic acid or D-malic acid when forming a salt can be 1:1, that is, they form a salt in equimolar amounts.

[0135] In one embodiment of the present invention, the pharmaceutical salt of the compound of formula I is the compound of formula III, and the corresponding preparation method may include the following steps:

[0136] Mix the compound of formula II with L-malic acid in solvent 1, first raise the temperature and stir, then lower the temperature and crystallize, and filter to obtain the compound of formula III.

[0137]

[0138] In one embodiment of the present invention, in terms of molar percentage, the compound of formula II may consist of X% of the R-isomer and (100 - X)% of the S-isomer, where 50 ≤ X < 100.

[0139] In a specific embodiment of the present invention, in terms of molar percentage, the compound of formula II may consist of 50% of the R-isomer and 50% of the S-isomer, that is, the compound of formula II may be an equimolar mixture or a racemate of the two isomers.

[0140] In one embodiment of the present invention, solvent 1 may be a ketone or a mixed solvent of a ketone and water.

[0141] In one embodiment of the present invention, solvent 1 may be a ketone.

[0142] In one embodiment of the present invention, solvent 1 may be acetone, butanone or methyl isobutyl ketone.

[0143] In one embodiment of the present invention, solvent 1 may be acetone.

[0144] In one embodiment of the present invention, solvent 1 may be a mixed solvent of a ketone and water.

[0145] In one embodiment of the present invention, solvent 1 may be a mixed solvent of acetone, butanone or methyl isobutyl ketone and water.

[0146] In one embodiment of the present invention, solvent 1 may be a mixed solvent of acetone and water.

[0147] In one embodiment of the present invention, in the mixed solvent, the volume ratio of the ketone (for example, acetone) to water may be 2:1 - 20:1 (for example, 2:1, 5:1, 10:1, 12:1, 15:1, 20:1 or any point value or range value within the above range).

[0148] In one embodiment of the present invention, in the mixed solvent, the volume ratio of the ketone (e.g., acetone) to water can be 5:1 - 10:1 (e.g., 5:1, 6:1, 7:1, 8:1, 9:1, 10:1 or any point value or range value within the above range).

[0149] In one embodiment of the present invention, the dosage ratio of the compound of formula II to solvent 1 (e.g., the mixed solvent of acetone and water) can be 1 g:2 mL - 1 g:10 mL (e.g., 1:2, 1:3, 1:5, 1:6, 1:8, 1:10 or any point value or range value within the above range).

[0150] In one embodiment of the present invention, the dosage ratio of the compound of formula II to solvent 1 (e.g., the mixed solvent of acetone and water) can be 1 g:4 mL - 1 g:5 mL (e.g., 1:4.0, 1:4.2, 1:4.4, 1:4.6, 1:4.8, 1:5.0 or any point value or range value within the above range).

[0151] In one embodiment of the present invention, the molar ratio of the compound of formula II to L - malic acid can be 1:0.5 - 1:1.1 (e.g., 1:0.5, 1:0.6, 1:0.8, 1:0.9, 1:1.0, 1:1.1 or any point value or range value within the above range).

[0152] In one embodiment of the present invention, the molar ratio of the compound of formula II to L - malic acid can be 1:0.55 - 1:1.1 (e.g., 1:0.55, 1:0.65, 1:0.85, 1:0.95, 1:1.05, 1:1.1 or any point value or range value within the above range).

[0153] In the above preparation method, the purpose of heating and stirring is to fully dissolve, disperse and interact (e.g., form a salt) the compound of formula II and L - malic acid in solvent 1, so as to preferentially precipitate the crystals of the R - type isomer L - malate in the subsequent cooling stage.

[0154] In one embodiment of the present invention, the target temperature for heating can be 35 - 60 °C (e.g., 35, 40, 45, 50, 55, 60 °C or any point value or range value within the above range).

[0155] In one embodiment of the present invention, the target temperature for heating can be 45 - 50 °C (e.g., 45, 46, 47, 48, 49, 50 °C or any point value or range value within the above range).

[0156] In one embodiment of the present invention, the stirring duration can be 10 - 60 min (for example, 10, 20, 30, 40, 50, 60 min or any point value or range value within the above range).

[0157] In one embodiment of the present invention, the stirring duration can be 30 - 40 min (for example, 30, 32, 34, 36, 38, 40 min or any point value or range value within the above range).

[0158] In one embodiment of the present invention, the target temperature for cooling can be 5 - 30 °C (for example, 5, 10, 15, 20, 25, 30 °C or any point value or range value within the above range).

[0159] In one embodiment of the present invention, the target temperature for cooling can be 12 - 20 °C (for example, 12, 14, 15, 16, 18, 20 °C or any point value or range value within the above range).

[0160] In one embodiment of the present invention, the crystallization duration can be 0.5 - 15 h (for example, 0.5, 1, 3, 5, 10, 15 h or any point value or range value within the above range).

[0161] In one embodiment of the present invention, the crystallization duration can be 5 - 12 h (for example, 5, 6, 8, 10, 11, 12 h or any point value or range value within the above range).

[0162] In one embodiment of the present invention, the pharmaceutical salt of the compound of formula I is the compound of formula IV, and the corresponding preparation method may include the following steps:

[0163] Mix the compound of formula II with D - malic acid in solvent 2, first heat up and stir, then cool down and crystallize, and filter to obtain the compound of formula IV.

[0164]

[0165] In one embodiment of the present invention, in terms of mole percentage, the compound of formula II can consist of X% of the R - isomer and (100 - X)% of the S - isomer, where 50 ≤ X < 100.

[0166] In one specific embodiment of the present invention, in terms of mole percentage, the compound of formula II can consist of 50% of the R - isomer and 50% of the S - isomer, that is, the compound of formula II can be an equimolar mixture or a racemate of the two isomers.

[0167] In one embodiment of the present invention, solvent 2 can be an organic solvent.

[0168] In one embodiment of the present invention, the solvent 2 can be an alkane, an alcohol, an ester, an ether, or a nitrile, or a mixed solvent of any two of them.

[0169] In one embodiment of the present invention, the solvent 2 can be an alcohol.

[0170] In one embodiment of the present invention, the solvent 2 can be methanol, ethanol, or isopropanol.

[0171] In one embodiment of the present invention, the solvent 2 can be ethanol.

[0172] In one embodiment of the present invention, the solvent 2 can be a mixed solvent of an alkane and an alcohol.

[0173] In one embodiment of the present invention, the solvent 2 can be a mixed solvent of n-hexane, n-heptane, or n-octane and methanol, ethanol, or isopropanol.

[0174] In one embodiment of the present invention, the solvent 2 can be a mixed solvent of n-heptane and ethanol.

[0175] In one embodiment of the present invention, in the mixed solvent, the volume ratio of the alkane (e.g., n-heptane) to the alcohol (e.g., ethanol) can be 1:1 - 10:1 (e.g., 1:1, 2:1, 3:1, 5:1, 8:1, 10:1, or any point value or range value within the above range).

[0176] In one embodiment of the present invention, in the mixed solvent, the volume ratio of the alkane (e.g., n-heptane) to the alcohol (e.g., ethanol) can be 2:1 - 5:1 (e.g., 2:1, 2.5:1, 3:1, 4:1, 5:1, or any point value or range value within the above range).

[0177] In one embodiment of the present invention, the solvent 2 can be a mixed solvent of an ester and an alcohol.

[0178] In one embodiment of the present invention, the solvent 2 can be a mixed solvent of methyl acetate, ethyl acetate, or isopropyl acetate and methanol, ethanol, or isopropanol.

[0179] In one embodiment of the present invention, the solvent 2 can be a mixed solvent of ethyl acetate and ethanol.

[0180] In one embodiment of the present invention, in the mixed solvent, the volume ratio of the ester (e.g., ethyl acetate alkane) to the alcohol (e.g., ethanol) can be 1:1 - 10:1 (e.g., 1:1, 2:1, 3:1, 5:1, 8:1, 10:1, or any point value or range value within the above range).

[0181] In one embodiment of the present invention, in the mixed solvent, the volume ratio of the ester (e.g., ethyl acetate) to the alcohol (e.g., ethanol) can be 3:1 - 5:1 (e.g., 3:1, 3.5:1, 4:1, 4.5:1, 5:1 or any point value or range value within the above range).

[0182] In one embodiment of the present invention, Solvent 2 can be an ether.

[0183] In one embodiment of the present invention, Solvent 2 can be tetrahydrofuran or 1,4 - dioxane.

[0184] In one embodiment of the present invention, Solvent 2 can be tetrahydrofuran.

[0185] In one embodiment of the present invention, Solvent 2 can be 1,4 - dioxane.

[0186] In one embodiment of the present invention, Solvent 2 can be a nitrile.

[0187] In one embodiment of the present invention, Solvent 2 can be acetonitrile, propyl cyanide or isobutyl cyanide.

[0188] In one embodiment of the present invention, Solvent 2 can be acetonitrile.

[0189] In one embodiment of the present invention, the dosage ratio of the compound of formula II to Solvent 2 (e.g., ethanol) can be 1 g:2 mL - 1 g:10 mL (e.g., 1:2, 1:3, 1:5, 1:6, 1:8, 1:10 or any point value or range value within the above range).

[0190] In one embodiment of the present invention, the dosage ratio of the compound of formula II to Solvent 2 (e.g., ethanol) can be 1 g:5 mL - 1 g:6 mL (e.g., 1:5.0, 1:5.2, 1:5.4, 1:5.6, 1:5.8, 1:6.0 or any point value or range value within the above range).

[0191] In one embodiment of the present invention, the molar ratio of the compound of formula II to D - malic acid can be 1:0.5 - 1:1.1 (e.g., 1:0.5, 1:0.6, 1:0.8, 1:0.9, 1:1.0, 1:1.1 or any point value or range value within the above range).

[0192] In one embodiment of the present invention, the molar ratio of the compound of formula II to D - malic acid can be 1:0.9 - 1:1.1 (e.g., 1:0.9, 1:0.95, 1:0.98, 1:1.0, 1:1.05, 1:1.1 or any point value or range value within the above range).

[0193] In the above preparation method, the purpose of heating and stirring is to fully dissolve, disperse and interact (for example, form a salt) the compound of formula II and D-malic acid in Solvent 2, so as to preferentially precipitate the crystals of the R-type isomer D-malic acid salt in the subsequent cooling stage.

[0194] In one embodiment of the present invention, the target temperature for heating can be 35 - 60 °C (for example, 35, 40, 45, 50, 55, 60 °C or any point value or range value within the above range).

[0195] In one embodiment of the present invention, the target temperature for heating can be 45 - 50 °C (for example, 45, 46, 47, 48, 49, 50 °C or any point value or range value within the above range).

[0196] In one embodiment of the present invention, the stirring duration can be 10 - 60 min (for example, 10, 20, 30, 40, 50, 60 min or any point value or range value within the above range).

[0197] In one embodiment of the present invention, the stirring duration can be 30 - 40 min (for example, 30, 32, 34, 36, 38, 40 min or any point value or range value within the above range).

[0198] In one embodiment of the present invention, the target temperature for cooling can be 5 - 30 °C (for example, 5, 10, 15, 20, 25, 30 °C or any point value or range value within the above range).

[0199] In one embodiment of the present invention, the target temperature for cooling can be 15 - 20 °C (for example, 15, 16, 17, 18, 19, 20 °C or any point value or range value within the above range).

[0200] In one embodiment of the present invention, the crystallization duration can be 0.5 - 15 h (for example, 0.5, 1, 3, 5, 10, 15 h or any point value or range value within the above range).

[0201] In one embodiment of the present invention, the crystallization duration can be 5 - 12 h (for example, 5, 6, 8, 10, 11, 12 h or any point value or range value within the above range).

[0202] Use of the Resolution Reagent

[0203] In the present invention, the use of L-malic acid or D-malic acid as a resolution reagent in the resolution of the compound of formula II is provided.

[0204]

[0205] In one embodiment of the present invention, the compound of formula II may consist of X% of the R-isomer and (100 - X)% of the S-isomer in mole percentage, where 50 ≤ X < 100.

[0206] In a specific embodiment of the present invention, the compound of formula II may consist of 50% of the R-isomer and 50% of the S-isomer in mole percentage, that is, the compound of formula II may be an equimolar mixture or a racemate of the two isomers.

[0207] Accordingly, in the present invention, the use of L-malic acid or D-malic acid in the preparation of the R-isomer of the compound of formula II or its malate salt is also provided.

[0208] Accordingly, in the present invention, the use of L-malic acid in the preparation of the compound of formula III is also provided.

[0209]

[0210] Accordingly, in the present invention, the use of D-malic acid in the preparation of the compound of formula IV is also provided.

[0211]

[0212] Use of the Target Resolution Product

[0213] In the present invention, the use of the medicinal salt (for example, L-malate or D-malate) of the compound of formula I, the compound of formula III or the compound of formula IV as the target resolution product in the preparation of the compound of formula V (i.e., ruxolitinib) is provided.

[0214]

[0215] Example 1: Preparation of 5-cyclopentylpyrazolidin-3-one racemic compound

[0216] Referring to the synthetic route reported in J. Med. Chem., 2010, 53, 5979 - 6002, using cyclopentyl formaldehyde (Compound A) as the raw material, ethyl 3-cyclopentylacrylate (Compound B) was prepared through the Horner–Wadsworth–Emmons reaction, and then the 5-cyclopentylpyrazolidin-3-one racemic compound (Compound of formula II) was prepared through the Michael addition reaction with hydrazine. The reaction route is as follows:

[0217]

[0218] The compound of Formula II was characterized by HPLC, XRPD, DSC and TGA. Its chiral HPLC chromatogram (chromatographic conditions are as follows: instrument model: Agilent HPLC 1260; chromatographic column: CHIRALPAK AD-H, 4.6 mm × 250 mm, 5 μm; mobile phase: V n-hexane:V isopropanol:V diethylamine = 90:10:0.05) is shown in Figure 1 , Figure 1 which shows two main chromatographic peaks with retention times of 13.471 min and 14.753 min respectively, and the peak areas of the two are roughly equivalent; its XRPD pattern is shown in Figure 2 , Figure 2 The diffraction peaks shown have sharp peak shapes and high intensities, indicating high crystallinity of the sample; its DSC pattern is shown in Figure 3 , Figure 3 which shows a single main peak (peak value at 133.26 °C); its TGA pattern is shown in Figure 4 , Figure 4 which shows no weight loss before decomposition, indicating that the sample contains almost no solvent in the form of crystallization, adsorption or inclusion. Judging from the combined results of the HPLC, XRPD, DSC and TGA patterns, the 5-cyclopentylpyrazolidin-3-one, which is the starting material for resolution, is a racemic compound with an equimolar mixture of two enantiomers, that is, the ratio of the R-type and S-type isomers of 5-cyclopentylpyrazolidin-3-one is about 1:1.

[0219] Example 2: Preparation of (R)-5-cyclopentylpyrazolidin-3-one L-malate

[0220] The racemic 5-cyclopentylpyrazolidin-3-one (617.02 mg, 4.0 mmol, 1.0 eq.) was added to a mixed solvent of acetone and water (3 mL, V 丙酮 :V 水 = 10:1), stirred until dissolved clearly, L-malate (295.37 mg, 2.2 mmol, 0.55 eq.) was added, the temperature was raised to 45 °C, stirred for 30 min, cooled to 12 °C, crystallized for 12 h, filtered, the filter cake was rinsed with acetone (3 mL), and dried at 45 °C to obtain (R)-5-cyclopentylpyrazolidin-3-one L-malate (0.28 g, yield 97%, chiral HPLC purity 97.5%, chromatographic conditions the same as in Example 1; as shown in Figure 14 the retention time of the main peak is 13.649 min).

[0221] 1 1H NMR (400 MHz, DMSO-d 6): δ 4.266 - 4.234 (q, J = 4.8, 3.2 Hz, 1H), 3.192 - 3.130 (q, J = 8.8, 7.6 Hz, 1H), 2.631 - 2.579 (q, J = 4.8, 5.2 Hz, 1H), 2.459 - 2.400 (q, J = 7.6, 8.0 Hz, 1H), 2.322 - 2.264 (q, J = 7.2, 16.0 Hz, 1H), 2.044 - 1.983 (q, J = 8.8, 8.4 Hz, 1H), 1.925 - 1.823 (m, 1H), 1.702 - 1.606 (m, 2H), 1.584 - 1.418 (m, 4H), 1.291 - 1.224 (m, 1H), 1.171 - 1.083 (m, 1H).

[0222] The crystallized product has good crystal morphology, presenting rod-shaped crystals. Its PLM view is shown in Figure 5 , and most of the particle sizes in the microscopic field of view are greater than 30 μm. The crystallized product is easy to post-process, has low residual solvents, excellent product fluidity, and no static electricity. Its XRPD pattern is shown in Figure 6 , and the relevant data are listed in the following table. Its DSC pattern is shown in Figure 7 , Figure 7 showing a single main peak (peak value 145.07 °C). Its TGA pattern is shown in Figure 8 , Figure 8 showing that there is no weight loss of the sample before melting and decomposition, and it is a non-solvent compound / anhydrous crystal form.

[0223] Serial Number 2θ Relative Peak Intensity R% Serial Number 2θ Relative Peak Intensity R% 1 10.2 100.0 21 28.2 2.3 2 11.8 1.5 22 29.2 0.5 3 14.8 1.6 23 30.0 1.2 4 15.1 2.3 24 30.6 3.5 5 16.0 90.1 25 31.0 10.7 6 18.3 25.1 26 31.5 4.5 7 18.7 28.9 27 32.3 5.0 8 19.2 0.6 28 32.9 1.7 9 19.9 6.0 29 33.4 5.2 10 20.7 18.3 30 33.6 2.1 11 21.6 63.6 31 34.4 1.8 12 22.1 1.8 32 34.6 2.5 13 23.2 6.1 33 35.4 0.2 14 23.7 0.9 34 36.0 0.7 15 24.7 1.1 35 36.7 10.4 16 25.6 15.2 36 38.0 3.9 17 26.0 4.0 37 38.4 0.7 18 26.5 2.2 38 39.3 2.4 19 27.3 0.3 39 39.7 3.3 20 27.9 12.6

[0224] Example 3: Preparation of (R)-5-cyclopentylpyrazolidin-3-one L-malate

[0225] Racemic 5-cyclopentylpyrazolidin-3-one (15.42 g, 0.1 mol, 1.0 eq.) was added to a mixed solvent of acetone and water (74 mL, V 丙酮 :V 水 = 5:1), stirred until dissolved clearly, L-malate (14.75 g, 0.11 mmol, 1.1 eq.) was added, the temperature was raised to 45 °C, stirred for 30 min, cooled to 15 - 20 °C, crystallized for 12 h, filtered, the filter cake was rinsed with acetone (70 mL), and dried at 45 °C to obtain (R)-5-cyclopentylpyrazolidin-3-one L-malate (12.8 g, yield 88.8%, chiral HPLC purity 99.5%, chromatographic conditions the same as in Example 1). The crystallized product also has good crystal morphology.

[0226] Example 4: Preparation of (R)-5-cyclopentylpyrazolidin-3-one D-malate

[0227] The racemic 5-cyclopentylpyrazolidin-3-one (357.6 g, 2.3 mol, 1.0 eq.) was added to ethanol (2.1 L), and the mixture was stirred until clear. D-Malic acid (281.3 g, 2.1 mol, 0.9 eq.) was added, and the temperature was raised to 50 °C. The mixture was stirred for 30 min, then cooled to 15 - 20 °C and crystallized for 12 h. The crystals were filtered, and the filter cake was rinsed with ethanol (200 mL) and dried at 45 °C to obtain (R)-5-cyclopentylpyrazolidin-3-one D-malate (185.0 g, yield 55.4%, chiral HPLC purity 99.6%, chromatographic conditions the same as in Example 1; as Figure 13 shown, the retention time of the main peak was 13.622 min).

[0228] 1 H NMR (400 MHz, DMSO-d 6 ): δ 4.266 - 4.234 (q, J = 4.8, 3.2 Hz, 1H), 3.192 - 3.130 (q, J = 8.8, 7.6 Hz, 1H), 2.631 - 2.579 (q, J = 4.8, 5.2 Hz, 1H), 2.459 - 2.400 (q, J = 7.6, 8.0 Hz, 1H), 2.322 - 2.264 (q, J = 7.2, 16.0 Hz, 1H), 2.044 - 1.983 (q, J = 8.8, 8.4 Hz, 1H), 1.925 - 1.823 (m, 1H), 1.702 - 1.606 (m, 2H), 1.584 - 1.418 (m, 4H), 1.291 - 1.224 (m, 1H), 1.171 - 1.083 (m, 1H).

[0229] The crystallized product had good crystal morphology, showing dense columnar crystals. Its PLM view is shown in Figure 9 As shown, most of the particle sizes in the microscope field of view were greater than 50 μm. The crystallized product was easy to post-process, had low residual solvents, excellent product fluidity, and no static electricity. Its XRPD pattern is shown in Figure 10 , and the relevant data are listed in the following table; its DSC pattern is shown in Figure 11 As shown, Figure 11 it showed a single main peak (peak value 125.04 °C); its TGA pattern is shown in Figure 12 , Figure 12 showing no weight loss of the sample before decomposition, being an anhydrous crystal form / non-solvent compound.

[0230] Serial Number 2θ Relative Peak Intensity R% Serial Number 2θ Relative Peak Intensity R% 1 8.3 7.5 22 29.3 8.9 2 9.1 77.5 23 29.6 5.2 3 11.6 3.5 24 29.9 8.1 4 14.9 2.2 25 30.5 10.8 5 15.1 1.3 26 31.4 18.3 6 16.3 19.2 27 32.0 1.4 7 16.6 71.4 28 32.4 0.7 8 17.2 18.8 29 33.0 19.5 9 18.7 30.4 30 33.3 14.3 10 19.2 32.7 31 33.9 8.2 11 20.6 36.7 32 34.9 10.3 12 20.9 15.7 33 35.4 1.1 13 21.9 48.5 34 35.7 0.6 14 22.3 79.0 35 36.1 1.3 15 23.5 100.0 36 36.3 1.5 16 25.0 13.1 37 36.8 4.8 17 25.3 9.7 38 37.3 5.5 18 26.0 4.3 39 37.7 3.6 19 26.8 8.5 40 38.5 0.6 20 27.6 11.5 41 38.9 1.3 21 29.0 11.8

[0231] Comparative Example 1

[0232] Weigh approximately 154 g of the racemic compound of 5-cyclopentylpyrazolidin-3-one, correspondingly weigh 1.1 eq. of various chiral acids, add solvents with different volume multiples (for 1 g of solid, using 1 mL of solvent is 1 volume multiple, denoted as 1V), cool down to 0 - 4 °C for crystallization, collect the precipitated solid, and submit it for chiral HPLC (chromatographic conditions are the same as in Example 1) to detect the resolution situation. The results are shown in Table 1.

[0233] Table 1. Results of resolving 5-cyclopentylpyrazolidin-3-one using different chiral salts and solvents

[0234]

[0235]

[0236]

[0237] Note: " / " indicates no crystallization or the sample amount is too small to be detected.

[0238] As can be seen from Table 1, for the racemic compound of 5-cyclopentylpyrazolidin-3-one, there are differences in the resolution effects of different salt-forming resolving agents. Among them, D-malic acid, L-malic acid, and L-arginine have obvious resolution effects. However, the solubility of L-arginine in the acetone / water solvent system is poor, and the residual amount of L-arginine solid in the solid after resolution is relatively high, which is not convenient for the subsequent scale-up of the resolution process. In addition, even if some chiral acids have resolution effects, there are still significant differences in the corresponding resolution effects when using different crystallization solvents.

Claims

1. The pharmaceutical salts of the compound of formula I, wherein, the pharmaceutical salt is L - malate or D - malate.

2. The compound of formula III, 3. The compound of formula III according to claim 2, characterized in that, the compound of formula III has crystal form A, and the crystal form A meets at least one of the following conditions: 1) Its XRPD pattern shows diffraction peaks at 2θ values of 10.2 ± 0.2°, 16.0 ± 0.2°, 18.3 ± 0.2°, 18.7 ± 0.2°, 21.6 ± 0.2°, preferably also has diffraction peaks at 2θ values of 20.7 ± 0.2°, 25.6 ± 0.2°, 27.9 ± 0.2°, 31.0 ± 0.2°, 36.7 ± 0.2°, more preferably also has diffraction peaks at 2θ values of 19.9 ± 0.2°, 23.2 ± 0.2°, 31.5 ± 0.2°, 32.3 ± 0.2°, 33.4 ± 0.2°; preferably, its XRPD pattern is as shown in Figure 6; 2) Its DSC pattern shows an endothermic peak at 145.07°C ± 5°C; preferably, its DSC pattern is as shown in Figure 7; and 3) Its TGA pattern shows a weight loss within 8.0 wt%, preferably within 7.5 wt%; preferably, its TGA pattern is as shown in Figure 8.

4. The preparation method of the compound of formula III according to claim 2 or 3, which comprises: mixing the compound of formula II with L - malic acid in solvent 1, first heating and stirring, then cooling and crystallizing, and filtering to obtain the compound of formula III; wherein, in terms of mole percentage, the compound of formula II consists of X% of the R - isomer and (100 - X)% of the S - isomer, where 50 ≤ X < 100, preferably X = 50; and / or, the solvent 1 is a ketone or a mixed solvent thereof with water; preferably, the ketone is acetone, butanone or methyl isobutyl ketone, preferably acetone; and / or, preferably, the volume ratio of the ketone to water in the mixed solvent is 2:1 - 20:1, preferably 5:1 - 10:1; and / or, the dosage ratio of the compound of formula II to the solvent 1 is 1 g:2 mL - 1 g:10 mL, preferably 1 g:4 mL - 1 g:5 mL; and / or, the molar ratio of the compound of formula II to the L - malic acid is 1:0.5 - 1:1.1, preferably 1:0.55 - 1:1.1; and / or, the target temperature for heating is 35 - 60°C, preferably 45 - 50°C; and / or, the duration of stirring is 10 - 60 min, preferably 30 - 40 min; and / or, the target temperature for cooling is 5 - 30°C, preferably 12 - 20°C; and / or, the duration of crystallization is 0.5 - 15 h, preferably 5 - 12 h.

5. The use of L - malic acid in resolving the compound of formula II or preparing the compound of formula III according to claim 2 or 3, wherein, in terms of mole percentage, the compound of formula II consists of X% of the R - isomer and (100 - X)% of the S - isomer, where 50 ≤ X < 100, preferably X = 50.

6. The compound of formula IV, 7. The compound of formula IV according to claim 6, wherein, the compound of formula IV has crystal form B, and the crystal form B meets at least one of the following conditions: 1) Its XRPD pattern shows diffraction peaks at 2θ values of 9.1±0.2°, 16.6±0.2°, 22.3±0.2°, and 23.5±0.2°, preferably also has diffraction peaks at 2θ values of 18.7±0.2°, 19.2±0.2°, 20.6±0.2°, and 21.9±0.2°, more preferably also has diffraction peaks at 2θ values of 16.3±0.2°, 17.2±0.2°, 31.4±0.2°, and 33.0±0.2°, and further preferably also has diffraction peaks at 2θ values of 20.9±0.2°, 25.0±0.2°, 27.6±0.2°, 29.0±0.2°, 30.5±0.2°, 33.3±0.2°, and 34.9±0.2°; preferably, its XRPD pattern is as shown in Figure 10; 2) Its DSC pattern shows an endothermic peak at 125.04°C ± 5°C; preferably, its DSC pattern is as shown in Figure 11; and 3) Its TGA pattern shows a weight loss within 10.0 wt%, preferably within 9.5 wt%; preferably, its TGA pattern is as shown in Figure 12.

8. The preparation method of the compound of formula IV according to claim 6 or 7, which comprises: mixing the compound of formula II with D-malic acid in solvent 2, first heating and stirring, then cooling and crystallizing, and filtering to obtain the compound of formula IV; wherein, in terms of molar percentage, the compound of formula II consists of X% of the R-isomer and (100 - X)% of the S-isomer, where 50 ≤ X < 100, preferably X = 50; and / or, the solvent 2 is an organic solvent; preferably, the organic solvent is an alkane, an alcohol, an ester, an ether, or a nitrile, or a mixed solvent of any two of them; more preferably, the alkane is n-hexane, n-heptane, or n-octane, preferably n-heptane; and / or, more preferably, the alcohol is methanol, ethanol, or isopropanol, preferably ethanol; and / or, more preferably, the ester is methyl acetate, ethyl acetate, or isopropyl acetate, preferably ethyl acetate; and / or, more preferably, the ether is tetrahydrofuran or 1,4-dioxane, preferably tetrahydrofuran; and / or, more preferably, the nitrile is acetonitrile, propyl ester, or isobutyl ester, preferably acetonitrile; and / or, the dosage ratio of the compound of formula II to the solvent 2 is 1 g:2 mL - 1 g:10 mL, preferably 1 g:5 mL - 1 g:6 mL; and / or, the molar ratio of the compound of formula II to the D-malic acid is 1:0.5 - 1:1.1, preferably 1:0.9 - 1:1.1; and / or, the target temperature for heating is 35 - 60°C, preferably 45 - 50°C; and / or, the duration of stirring is 10 - 60 min, preferably 30 - 40 min; and / or, the target temperature for cooling is 5 - 30°C, preferably 15 - 20°C; and / or, the duration of crystallization is 0.5 - 15 h, preferably 5 - 12 h. Use of D-malic acid in resolving a compound of formula II or in preparing a compound of formula IV according to claim 6 or 7, wherein, in terms of mole percentage, the compound of formula II consists of X% of the R-isomer and (100-X)% of the S-isomer, where 50 ≤ X < 100, preferably X = 50.

10. Use of a pharmaceutical salt of the compound of formula I according to claim 1, a compound of formula III according to claim 2 or 3, or a compound of formula IV according to claim 6 or 7 in preparing a compound of formula V,

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