WO2022166121A1 - 瑞卢戈利新晶型及其制备方法 - Google Patents

瑞卢戈利新晶型及其制备方法 Download PDF

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WO2022166121A1
WO2022166121A1 PCT/CN2021/107493 CN2021107493W WO2022166121A1 WO 2022166121 A1 WO2022166121 A1 WO 2022166121A1 CN 2021107493 W CN2021107493 W CN 2021107493W WO 2022166121 A1 WO2022166121 A1 WO 2022166121A1
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apti
crystal form
formula
iii
compound
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PCT/CN2021/107493
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French (fr)
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张富昌
郭万成
段永立
段雄鹏
王国平
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奥锐特药业(天津)有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • the present invention relates to a new crystal form of relugolix and a preparation method thereof.
  • Relugolix is a once-daily, oral, gonadotropin-releasing hormone (GnRH) receptor antagonist that inhibits testosterone production, a hormone that stimulates prostate cancer growth.
  • GnRH gonadotropin-releasing hormone
  • relugolix also reduces ovarian production in women by blocking GnRH receptors in the pituitary gland, reducing ovarian estradiol production, and reducing the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH). estrogen levels and testosterone production in men.
  • GnRH gonadotropin-releasing hormone
  • FSH follicle stimulating hormone
  • Ruilugoli was approved by the Japan Pharmaceuticals and Medical Devices Agency (PMDA) for marketing, and was marketed by Takeda and Aska pharmaceutical under the trade name of 40 mg/tablet, approved for the treatment and symptomatic relief of uterine fibroids; approved by the U.S. Food and Drug Administration (FDA) on December 18, 2020, the trade name is ORGOVYX, 120 mg/tablet, and its structural formula is as follows :
  • WO2014051164 reports the tetrahydrofuran solvate crystalline form of relugolix and the crystalline form of relugolix (hereinafter referred to as crystal form I), and discloses that the tetrahydrofuran solvate crystalline form is used to purify relugolix, and the purity can be reduced. 99.37% of the crude product is purified to obtain 99.75% of the product, and the impurity RS-1 in the crude product can be reduced from 0.1% to 0.04%, the impurity RS-2 can be reduced from 0.16% to 0.07%, and the impurity RS-3 can be reduced from 0.08% to 0.02%.
  • the overall purification effect is not good, and the product purity is only increased by 0.38%.
  • the inventors found during impurity analysis and detection that no matter whether it is the tetrahydrofuran solvate crystal form or the product crystal form I, the HPLC analysis pattern failed to separate the impurity k from the product, in fact, the tetrahydrofuran Both the solvate crystal form and the crystal form I contain more than 0.15% impurity k.
  • WO2019178304 reports Form F, Form G, Form H, and Form J of relugolix.
  • Form F is a homogeneous polymorphic form with three forms of anhydrous, hemihydrate and monohydrate, which is difficult to control in production and difficult to measure in subsequent formulation processes.
  • Form G and Form H were prepared from the same solvent system (dichloromethane), and mixed crystals were easily obtained.
  • the crystal form J is a triclinic crystal system, which can be a solvate or a hydrate.
  • the crystal form J cannot be accurately characterized and is not suitable for preparations.
  • the low yield of these crystal forms is only about 40-50%, which is not suitable for process scale-up.
  • the purpose of the present invention is to provide a new crystal form or solvate of relugolix which is suitable for industrial production and has better drug-forming properties or purification ability.
  • the crystal form is crystal form APTI-II;
  • the X-ray powder diffraction pattern of the crystalline form APTI-II has a 2 ⁇ value of 7.0° ⁇ 0.2°, 9.5° ⁇ 0.2°, 10.6° ⁇ 0.2°, 15.7° ⁇ 0.2° and 20.7° ⁇ 0.2°. There are characteristic peaks at one or more places.
  • the crystal form APTI-II is the semi-acetonate crystal form of the compound of formula I.
  • the X-ray powder diffraction pattern of the crystalline form APTI-II also has 2 ⁇ values of 4.7 ⁇ 0.2°, 5.7 ⁇ 0.2°, 8.8 ⁇ 0.2°, 11.1 ⁇ 0.2°, 12.3 ⁇ 0.2°, Any one or more of 13.0 ⁇ 0.2°, 14.1 ⁇ 0.2°, 17.8 ⁇ 0.2°, 19.1 ⁇ 0.2°, and 20.0 ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form APTI-II has 2 ⁇ values of 4.7 ⁇ 0.2°, 5.7 ⁇ 0.2°, 7.0 ⁇ 0.2°, 8.8 ⁇ 0.2°, 9.5 ⁇ 0.2°, 10.6 ⁇ 0.2°, 11.1 ⁇ 0.2°, 12.3 ⁇ 0.2°, 13.0 ⁇ 0.2°, 14.1 ⁇ 0.2°, 15.7 ⁇ 0.2°, 17.8 ⁇ 0.2°, 19.1 ⁇ 0.2°, 20.0 ⁇ 0.2° and 20.7 ⁇ 0.2° has characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form APTI-II is substantially as shown in FIG. 6 .
  • the differential scanning calorimetry (DSC) of the crystalline form APTI-II has an endothermic peak in the range of 178°C to 195°C.
  • the initial value of the differential scanning calorimetry (DSC) of the crystalline form APTI-II is 180.8 ⁇ 2°C, and/or the peak value is 190.23 ⁇ 2°C.
  • the differential scanning calorimetry (DSC) of the crystalline form APTI-II is substantially as shown in FIG. 7 .
  • the infrared absorption spectrum of the crystalline form APTI-II is at 3250 ⁇ 10, 3211 ⁇ 10, 3055 ⁇ 10, 2978 ⁇ 10, 1717 ⁇ 10, 1678 ⁇ 10, and 1526 ⁇ 10 cm ⁇ 1 There is an absorption peak.
  • the infrared absorption spectrum of the crystalline form APTI-II is substantially as shown in FIG. 8 .
  • thermogravimetric analysis chart (TGA chart) of the crystal form APTI-II has a weight loss of about 0.15 ⁇ 0.2% in the range of 0°C to 60 ⁇ 3°C.
  • thermogravimetric analysis diagram of the crystalline form APTI-II is substantially as shown in FIG. 9 .
  • the raw material of the compound of formula I is the amorphous form of the compound of formula I or the crystalline form of the compound of formula I.
  • the raw material of the compound of formula I is the amorphous form of the compound of formula I or the crystalline form APTI-I of the compound of formula I (the crystalline form APTI-I is as defined in the seventh aspect).
  • the purity of the raw material of the compound of formula I is ⁇ 98%; preferably, ⁇ 97%.
  • the weight-to-volume (g:mL) ratio of the raw material of the compound of formula I to acetone is 1:1-20; preferably, 1:5-15; more preferably ground, 1:10 ⁇ 3.
  • stirring is performed at 30-50°C (preferably, 35-50°C; more preferably, 30-40°C).
  • the stirring time is 0.5-5 hours; preferably, 1-5 hours; more preferably, 1-3 hours.
  • step II-b after stirring, the step of optionally cooling the mixture to ⁇ 25°C (preferably, 15-25°C) is also included.
  • step II-c the solid in the mixture is collected by filtration.
  • step II-c the drying temperature T of the drying is T ⁇ 40°C.
  • the solvate is the semi-acetonate of the compound of formula I.
  • the NMR results of the solvate are as follows:
  • the NMR results of the solvate are basically as shown in FIG. 10 .
  • the raw material of the compound of formula I is as defined in the second aspect.
  • the weight-to-volume (g:mL) ratio of the raw material of the compound of formula I to acetone is 1:1-20; preferably, 1:5-15; more preferably, 1:10 ⁇ 3.
  • step S-b stirring is performed at 30-50°C (preferably, 35-50°C; more preferably, 30-40°C).
  • the stirring time is 0.5-5 hours; preferably, 1-5 hours; more preferably, 1-3 hours.
  • step S-b after stirring, it also includes the step of optionally cooling the mixture to ⁇ 25°C (preferably, 15-25°C).
  • step S-c the solid in the mixture is collected by filtration.
  • step S-c the drying temperature T of the drying is T ⁇ 40°C.
  • crystal form is crystal form APTI-III;
  • the X-ray powder diffraction pattern of the crystalline form APTI-III has 2 ⁇ values of 7.2° ⁇ 0.2°, 9.7° ⁇ 0.2°, 10.7° ⁇ 0.2°, 13.1° ⁇ 0.2°, 15.8° ⁇ 0.2° and 19.0° There are characteristic peaks at ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form APTI-III also has 2 ⁇ values of 4.9 ⁇ 0.2°, 5.8 ⁇ 0.2°, 9.0 ⁇ 0.2°, 11.2 ⁇ 0.2°, 12.6 ⁇ 0.2° , 14.3 ⁇ 0.2°, 16.4 ⁇ 0.2°, 18.0 ⁇ 0.2°, 20.0 ⁇ 0.2°, and 20.6 ⁇ 0.2° have characteristic peaks at any one or more locations.
  • the X-ray powder diffraction pattern of the crystalline form APTI-III has 2 ⁇ values of 4.9 ⁇ 0.2°, 5.8 ⁇ 0.2°, 7.2 ⁇ 0.2°, 9.0 ⁇ 0.2°, 9.7 ⁇ 0.2°, 10.7 ⁇ 0.2°, 11.2 ⁇ 0.2°, 12.6 ⁇ 0.2°, 13.1 ⁇ 0.2°, 14.3 ⁇ 0.2°, 15.8 ⁇ 0.2°, 16.4 ⁇ 0.2°, 18.0 ⁇ 0.2°, 19.0 ⁇ 0.2°, 20.0 ⁇ 0.2°, There is a characteristic peak at 20.6 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form APTI-III is basically as shown in FIG. 11 .
  • the differential scanning calorimetry (DSC) of the crystalline form APTI-III has an endothermic peak in the range of 169°C to 190°C.
  • the onset of the differential scanning calorimetry (DSC) of the crystalline form APTI-III is 171.4 ⁇ 2°C, and/or the peak value is 183.4 ⁇ 2°C.
  • the differential scanning calorimetry (DSC) diagram of the crystalline form APTI-III is substantially as shown in FIG. 12 .
  • the infrared absorption spectrum of the crystalline form APTI-III is at 3248 ⁇ 10, 3210 ⁇ 10, 3110 ⁇ 10, 2946 ⁇ 10, 1718 ⁇ 10, 1678 ⁇ 10, and 1526 ⁇ 10 cm- There is an absorption peak at 1.
  • the infrared absorption spectrum of the crystal form APTI-III is basically as shown in FIG. 13 .
  • thermogravimetric analysis chart (TGA chart) of the crystal form APTI-III has a weight loss of about 0.48 ⁇ 0.2% in the range of 0°C to 60 ⁇ 3°C.
  • thermogravimetric analysis diagram (TGA diagram) of the crystal form APTI-III is basically as shown in FIG. 14 .
  • the crystalline form APTI-III is the crystalline form of the compound of formula I in free form.
  • step 3a) adding step 3a) solution a to solvent B;
  • III-c optionally cooling to 0-10°C and stirring;
  • step III-a the temperature of the solution a is 30-50°C.
  • the solvent A is selected from the group consisting of DMSO, DMF, NMP, DMAC, or a combination thereof.
  • the solvent B is selected from the group consisting of alcohol solvents, wherein alcohol solvents (preferably, (C 1-6 fatty alcohol)).
  • the solvent B is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, n-butanol, or a combination thereof.
  • the weight-to-volume (g:mL) ratio of the raw material of the compound of formula I to solvent A is 1:1-10; preferably, it is 1:1-3.
  • step III-b the weight-to-volume ratio of the raw material of the compound of formula I to the solvent B is 1:3-20.
  • the raw material of the compound of formula I is the amorphous form of the compound of formula I or the crystalline form of the compound of formula I.
  • the purity of the raw material of the compound of formula I is ⁇ 98%; preferably, ⁇ 97%.
  • the crystal form is crystal form APTI-I
  • the X-ray powder diffraction pattern of the crystalline form APTI-I has characteristic peaks at 2 ⁇ values of 5.2° ⁇ 0.2°, 10.5° ⁇ 0.2°, 15.3° ⁇ 0.2°, and 19.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form APTI-I also has 2 ⁇ values of 6.4 ⁇ 0.2°, 8.0 ⁇ 0.2°, 12.5 ⁇ 0.2°, 15.9 ⁇ 0.2°, and 21.1 ⁇ 0.2 Any one or more of (eg 1, 2, 3, 4 or 5) have characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form APTI-I has 2 ⁇ values of 5.2 ⁇ 0.2°, 6.4 ⁇ 0.2°, 8.0 ⁇ 0.2°, 10.5 ⁇ 0.2°, 12.5 ⁇ 0.2°, 15.3° There are characteristic peaks at ⁇ 0.2°, 15.9 ⁇ 0.2°, 19.1 ⁇ 0.2° and 21.1 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the crystalline form APTI-I is substantially as shown in FIG. 1 .
  • the differential scanning calorimetry (DSC) of the crystalline form APTI-II has an endothermic peak in the range of 133°C to 152°C.
  • the differential scanning calorimetry (DSC) of the crystalline form APTI-I has an onset value of 135.08 ⁇ 2°C, and/or a peak value of 143.23 ⁇ 2°C.
  • the differential scanning calorimetry (DSC) diagram of the crystalline form APTI-I is substantially as shown in FIG. 2 .
  • the infrared absorption spectrum of the crystalline form APTI-I is at 3311 ⁇ 10, 3168 ⁇ 10, 3062 ⁇ 10, 1719 ⁇ 10, 1673 ⁇ 10, 1524 ⁇ 10, and 1410 ⁇ 10 cm ⁇ 1 There is an absorption peak.
  • the infrared absorption spectrum of the crystalline form APTI-I is basically as shown in FIG. 3 .
  • thermogravimetric analysis chart (TGA chart) of the crystal form APTI-I has a weight loss of about 0.94 ⁇ 0.2% in the range of 0°C to 60 ⁇ 3°C, and has a weight loss of about 0.94 ⁇ 0.2% in the range of 60 ⁇ 3°C to 140 ⁇ 3°C. There is about 1.98 ⁇ 0.2% weight loss in the range of 3°C.
  • thermogravimetric analysis diagram of the crystalline form APTI-I is substantially as shown in FIG. 4 .
  • step I-b) adding water to the solution of step I-a), allowing solids to precipitate out of the solution, and optionally continuing to stir;
  • step I-b the stirring time is 1-3 hours.
  • step I-a the temperature of the solution is 15-30°C.
  • step 1-b) is to be cooled to 0-10 °C, drip water to the system until there is solid precipitation, continue to keep stirring for 1-3 hours; or add water dropwise to the system under insulation until there is solid separation, continue Stir for 1-3 hours.
  • the organic solvent 1 is selected from the group consisting of nitrogen- or sulfur-containing highly polar aprotic solvents, ketone-based solvents, alcohol-based solvents, ester-based solvents, ether-based solvents, or a combination thereof.
  • the organic solvent 1 is a highly polar aprotic solvent containing nitrogen or sulfur, or a mixed solvent consisting of a highly polar aprotic solvent containing nitrogen or sulfur and a solvent selected from the group consisting of: ketone Solvent-like and/or alcohol-based solvent, ester-based solvent, ether-based solvent, or a combination thereof.
  • the volume content of the highly polar aprotic solvent containing nitrogen or sulfur is 50-100%.
  • the nitrogen- or sulfur-containing highly polar aprotic solvent includes: DMSO, DMF, NMP, acetonitrile, or a combination thereof; preferably, it is selected from the following group: DMSO, DMF, NMP, or its combination.
  • the ketone solvent includes: acetone, methyl ethyl ketone, methyl ethyl ketone, methyl isobutyl ketone, or a combination thereof; preferably, acetone.
  • the alcoholic solvent is an aliphatic alcohol containing 1-6 carbon atoms; preferably, preferably, selected from the following group: methanol, ethanol, isopropanol, n-propanol, n-propanol butanol, or a combination thereof.
  • the ester solvent includes: ethyl acetate, isopropyl acetate, ethyl formate, methyl formate, methyl acetate, or a combination thereof.
  • the ether solvent includes: tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, anisole, 1,4-dioxane, or a combination thereof; preferably, selected from The next group: tetrahydrofuran, 1,4-dioxane, or a combination thereof.
  • the organic solvent 1 is selected from the group consisting of DMSO, DMF, NMP, acetonitrile, acetone, methyl ethyl ketone, methyl ethyl ketone, methyl isobutyl ketone, aliphatic alcohols of 1-6 carbon atoms (including: methanol, ethanol, propanol, or a combination thereof), ethyl acetate, isopropyl acetate, ethyl formate, methyl formate, methyl acetate, tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, anisole, 1,4-dioxane, or a combination thereof.
  • the organic solvent 1 is selected from a highly polar aprotic solvent containing nitrogen or sulfur, or a mixed solvent consisting of a highly polar aprotic solvent containing nitrogen or sulfur and a solvent selected from the following group : Acetone, methyl ethyl ketone, methyl ethyl ketone, methyl isobutyl ketone, aliphatic alcohols of 1-6 carbon atoms (including: methanol, ethanol, propanol, or a combination thereof), ethyl acetate, isopropyl acetate, ethyl formate , methyl formate, methyl acetate, tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, anisole, 1,4-dioxane, or a combination thereof, or a combination thereof; wherein, nitrogen- or sulfur-containing
  • the highly polar aprotic solvent is selected from: DMSO, DMF, NMP
  • step I-a the weight-to-volume (g:mL) ratio of the compound of formula I to the organic solvent 1 is 1:1-20; preferably, 1:2-6.
  • the weight-volume (g:mL) ratio of the raw material of the compound of formula I to water is 1:1-20; preferably, 1:2-20; more preferably, 1:2-10.
  • the raw material of the compound of formula I is the amorphous form of the compound of formula I or the crystalline form of the compound of formula I.
  • a crystalline form as described in the first aspect a solvate as described in the third aspect or the crystalline form as described in the fifth aspect in the preparation of high-purity formula I Use in a pharmaceutical crystalline form of a compound.
  • the pharmaceutical crystal form is crystal form I of WO2014051164.
  • the purity of the pharmaceutical crystal form is >99.5% (preferably, >99.8%).
  • the content of impurity and/or impurity RS-1 and/or impurity RS-2 and/or impurity RS-3 of the pharmaceutical crystal form is ⁇ 0.1% (preferably, ⁇ 0.05%).
  • Figure 1 shows the PXRD pattern of a typical example of crystal form APTI-I
  • Figure 2 shows the DSC spectrum of a typical example of crystal form APTI-I
  • Figure 3 shows the IR spectrum of a typical example of crystal form APTI-I
  • Figure 4 shows the TGA spectrum of a typical example of crystal form APTI-I
  • Figure 5 shows the 1H-NMR spectrum of a typical example of crystal form APTI-I
  • Figure 6 shows the PXRD pattern of a typical example of crystal form APTI-II
  • Figure 7 shows the DSC spectrum of a typical example of crystal form APTI-II
  • Figure 8 shows the IR spectrum of a typical example of crystal form APTI-II
  • Figure 9 shows the TGA spectrum of a typical example of crystal form APTI-II
  • Figure 10 shows the 1H-NMR spectrum of a typical example of crystal form APTI-II
  • Figure 11 shows the PXRD pattern of a typical example of crystal form APTI-III
  • Figure 12 shows the DSC spectrum of a typical example of crystal form APTI-III
  • Figure 13 shows the IR spectrum of a typical example of crystal form APTI-III
  • Figure 14 shows the TGA pattern of a typical example of crystal form APTI-III
  • Figure 15 shows the 1H-NMR spectrum of a typical example of the crystal form APTI-III.
  • each impurity is as follows:
  • the first object of the present invention is to provide a new crystalline form APTI-I of Relugolix (formula I), which uses Cu-K ⁇ radiation, and its X-ray powder diffraction has a diffraction angle 2 ⁇ value of 5.2° ⁇ 0.2° , 10.5° ⁇ 0.2°, ,15.3° ⁇ 0.2°, 19.1° ⁇ 0.2° have characteristic peaks.
  • the rugolix crystal form APTI-I provided by the present invention, its X-ray powder diffraction pattern has 2 ⁇ values of 5.2 ⁇ 0.2°, 6.4 ⁇ 0.2°, 8.0 ⁇ 0.2°, 10.5 ⁇ 0.2°, 12.5 ⁇ There are characteristic peaks at 0.2°, 15.3 ⁇ 0.2°, 15.9 ⁇ 0.2°, 19.1 ⁇ 0.2°, and 21.1 ⁇ 0.2.
  • Relugolix crystal form APTI-I provided by the present invention, its X-ray powder diffraction data are shown in Table 1;
  • the X-ray powder diffraction pattern of the Relugolix crystal form APTI-I provided by the present invention is basically as shown in FIG. 1 .
  • the initial onset and peak value of the differential scanning calorimetry (DSC) of the relugolix crystal form APTI-I provided by the present invention are 135.08 ⁇ 2°C and 143.23 ⁇ 2°C, respectively.
  • differential scanning calorimetry (DSC) of the relugolix crystal form APTI-I provided by the present invention is basically shown in FIG. 2 .
  • the relugolix crystal form APTI-I provided by the present invention has an infrared absorption spectrum at 3311 ⁇ 10, 3168 ⁇ 10, 3062 ⁇ 10, 1719 ⁇ 10, 1673 ⁇ 10, 1524 ⁇ 10, and 1410 ⁇ 10. There is an absorption peak at 10cm-1.
  • thermogravimetric analysis chart (TGA) of Relugolix crystal form APTI-I provided by the present invention has a weight loss of about 0.94 ⁇ 0.2% at 0-60 ⁇ 3°C, and has a weight loss of about 1.98 ⁇ 0.2% at 60-140 ⁇ 3°C. 0.2% weight loss,
  • thermogravimetric analysis chart (TGA) of the relugolix crystal form APTI-I provided by the present invention is basically as shown in FIG. 4 .
  • the second object of the present invention is a kind of preparation method of Ruilugoli crystal form APTI-I, comprises the following steps:
  • I-b optionally cooling to 0-10° C., adding (eg, dropwise) water to the relugolix-containing mixture, and continuing to keep stirring for 1-3 hours; or
  • the organic solvent 1 described in the step I-a is selected from nitrogen-containing or sulfur-based high-polarity aprotic solvents (DMSO, DMF, NMP, acetonitrile), ketones (acetone, methyl ethyl ketone, methyl ethyl ketone, methyl isobutyl ketone) ) solvents, alcohols (fatty alcohols containing 1-6 carbon atoms), esters (ethyl acetate, isopropyl acetate, ethyl formate, methyl formate, methyl acetate) solvents, ethers (tetrahydrofuran, methyl acetate) base tert-butyl ether, isopropyl ether, anisole, 1,4-dioxane) solvent or a mixture of any two or more thereof.
  • nitrogen-containing or sulfur-based high-polarity aprotic solvents DMSO, DMF, NMP, acetonitrile
  • ketones acetone,
  • the organic solvent 1 is a nitrogen- or sulfur-based high-polarity aprotic solvent (DMSO, DMF, NMP, acetonitrile), or a nitrogen- or sulfur-based high-polarity aprotic solvent (DMSO, DMF, NMP).
  • acetonitrile and a mixed solvent consisting of a solvent selected from the group consisting of ketones (acetone, methyl ethyl ketone, methyl ethyl ketone, methyl isobutyl ketone) solvents, alcohols (aliphatic alcohols containing 1-6 carbon atoms), esters (ethyl acetate, isopropyl acetate, ethyl formate, methyl formate, methyl acetate) solvents, ethers (tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, anisole, 1,4-dioxo hexacyclic) solvent.
  • ketones acetone, methyl ethyl ketone, methyl ethyl ketone, methyl isobutyl ketone
  • alcohols aliphatic alcohols containing 1-6 carbon atoms
  • esters ethyl acetate, isopropyl
  • the volume content of nitrogen-containing or sulfur-based highly polar aprotic solvents (DMSO, DMF, NMP, acetonitrile) in the organic solvent 1 is 50-100%.
  • nitrogen-containing or sulfur-based high-polarity aprotic solvent is preferably one or more of DMSO, DMF, NMP, and alcoholic solvent is preferably methanol, ethanol, isopropanol, n-propanol or n-butanol
  • ketone solvents are preferably acetone
  • the ether solvents are preferably one or more of tetrahydrofuran or 1,4-dioxane.
  • step I-a the weight volume ratio of the raw material Relugolix and the organic solvent 1 is 1:1-20.
  • step I-b the weight volume ratio of raw material Relugoli to water is 1:4-20.
  • the third object of the present invention provides a new relugolix crystal form APTI-II, using Cu-K ⁇ radiation, its X-ray powder diffraction at diffraction angle 2 ⁇ values of 7.0° ⁇ 0.2°, 9.5° ⁇ 0.2 °, 10.6° ⁇ 0.2°, 15.7° ⁇ 0.2°, and characteristic peaks at 20.7° ⁇ 0.2°.
  • the relugolix crystal form APTI-II provided by the present invention has an X-ray powder diffraction pattern with 2 ⁇ values of 4.7 ⁇ 0.2°, 5.7 ⁇ 0.2°, 7.0 ⁇ 0.2°, 8.8 ⁇ 0.2°, 9.5 ⁇ 0.2°, 10.6 ⁇ 0.2°, 11.1 ⁇ 0.2°, 12.3 ⁇ 0.2°, 13.0 ⁇ 0.2°, 14.1 ⁇ 0.2°, 15.7 ⁇ 0.2°, 17.8 ⁇ 0.2°, 19.1 ⁇ 0.2°, 20.0 ⁇ 0.2°, 20.7 ⁇ There is a characteristic peak at 0.2°.
  • Relugolix crystal form APTI-II provided by the present invention has the X-ray powder diffraction data as shown in Table 2;
  • the X-ray powder diffraction pattern of the Relugolix crystal form APTI-II provided by the present invention is basically as shown in FIG. 6 .
  • PXRD shows that this structure is different from that reported in the patent publication.
  • the initial value and peak value of the differential scanning calorimetry (DSC) of the relugolix crystal form APTI-II provided by the present invention are 180.8 ⁇ 2°C and 190.23 ⁇ 2°C respectively;
  • the calorimetry diagram (DSC) is substantially as shown in FIG. 7 .
  • the relugolix crystal form APTI-II provided by the present invention has an infrared absorption spectrum at 3250 ⁇ 10, 3211 ⁇ 10, 3055 ⁇ 10, 2978 ⁇ 10, 1717 ⁇ 10, 1678 ⁇ 10, and 1526 ⁇ 10. There is an absorption peak at 10cm-1.
  • thermogravimetric analysis chart (TGA) of Relugolix crystal form provided by the present invention has a weight loss of about 0.15 ⁇ 0.2% at 0-60 ⁇ 3°C.
  • thermogravimetric analysis chart TGA
  • the fourth object of the present invention provides a kind of preparation method of Ruilugoli crystal form APTI-II, comprises the following steps:
  • stirring such as stirring for 1-5 hours, optionally cooling to ⁇ 25°C (preferably, 15-25°C);
  • step II-a the weight-to-volume ratio of the raw material relugolix to acetone is 1:1-20.
  • the fifth object of the present invention is to provide a new relugolix crystal form APTI-III, which uses Cu-K ⁇ radiation, and its X-ray powder diffraction has a diffraction angle 2 ⁇ value of 7.2° ⁇ 0.2°, 9.7° ⁇ 0.2 °, 10.7° ⁇ 0.2°, 13.1° ⁇ 0.2°, 15.8° ⁇ 0.2°, 19.0° ⁇ 0.2° have characteristic peaks.
  • the crystalline form APTI-III of relugolix provided by the present invention has an X-ray powder diffraction pattern with 2 ⁇ values of 4.9 ⁇ 0.2°, 5.8 ⁇ 0.2°, 7.2 ⁇ 0.2°, 9.0 ⁇ 0.2°, 9.7 ⁇ 0.2°, 10.7 ⁇ 0.2°, 11.2 ⁇ 0.2°, 12.6 ⁇ 0.2°, 13.1 ⁇ 0.2°, 14.3 ⁇ 0.2°, 15.8 ⁇ 0.2°, 16.4 ⁇ 0.2°, 18.0 ⁇ 0.2°, 19.0 ⁇ 0.2°, 20.0 There are characteristic peaks at ⁇ 0.2° and 20.6 ⁇ 0.2°.
  • Relugolix crystal form APTI-III provided by the present invention, its X-ray powder diffraction data are shown in Table 3;
  • the X-ray powder diffraction pattern of the crystal form APTI-III of relugolix provided by the present invention is basically as shown in FIG. 11 .
  • PXRD shows that this structure is different from that reported in the patent publication.
  • the initial onset of the differential scanning calorimetry (DSC) of the crystal form APTI-III of relugolix provided by the present invention the peaks are respectively 171.4 ⁇ 2°C and 183.4 ⁇ 2°C; Scanning calorimetry (DSC) is substantially as shown in FIG. 12 .
  • the crystal form APTI-III of Relugolix provided by the present invention has an infrared absorption spectrum at 3248 ⁇ 10, 3210 ⁇ 10, 3110 ⁇ 10, 2946 ⁇ 10, 1718 ⁇ 10, 1678 ⁇ 10, 1526 There is an absorption peak at ⁇ 10cm-1.
  • the crystalline form APTI-III of relugolix provided by the present invention has an infrared absorption spectrum as shown in FIG. 13 .
  • thermogravimetric analysis chart (TGA) of the crystalline form of relugolix provided by the present invention has a weight loss of about 0.48 ⁇ 0.2% at 0-60 ⁇ 3°C.
  • thermogravimetric analysis (TGA) of the crystal form APTI-III of relugolix provided by the present invention is basically as shown in FIG. 14 .
  • the sixth object of the present invention is to provide a kind of preparation method of Ruilugoli crystal form APTI-III, comprises the following steps:
  • the solvent A described in step III-a is one or a combination of DMSO, DMF, NMP, and DMAC.
  • the organic solvent B is selected from alcohol (aliphatic alcohol containing 1-6 carbon atoms) solvents, wherein the alcohol solvent is preferably methanol, ethanol, isopropanol, n-propanol or n-butanol.
  • step a III- The weight volume ratio of raw material Relugolix and organic solvent described in step a III- is 1:1-10; and/or
  • step III-b the weight volume ratio of raw material rilugoli to solvent B is 1:3-20.
  • the raw materials used in the examples are relugolix amorphous, prepared with reference to WO2004067535, and the purity is 96.1%.
  • X-ray powder diffractometer BRUKER AXS D2 PHASER X-ray powder diffractometer; radiation source: The intensity ratio ⁇ 1/ ⁇ 2 is 0.5; Generator kv: 30.0kv; Generator mA: 10.0mA; Initial 2 ⁇ : 2.000°, scanning range: 2.0000-40.000°.
  • METTLEER DSC1 differential scanning calorimeter heating program: 25°C ⁇ 210°C heating 10°C per minute.
  • the crystal form APTI-II and the crystal form APTI-III have good impurity removal effect, and the product purity can be easily increased from 96% to more than 99.5%.
  • crystal form and solvate of the present invention can effectively remove impurities such as RS-1, RS2, RS-3 and impurity k in relugolix.
  • crystal forms such as crystal form APTI-II
  • solvates of the present invention are easily converted into medicinal crystal forms, so that high-purity medicinal crystal forms can be obtained.
  • the obtained solid is tested by XRPD, and its X-ray powder diffraction data is shown in Table 1, and its X-ray powder diffraction pattern is shown in Figure 1; the DSC test is carried out, and its spectrum is shown in Figure 2; IR test is carried out , the spectrum is shown in Figure 3; the TGA test is performed, and the spectrum is shown in Figure 4; the H NMR test is performed, and the spectrum is shown in Figure 5, which is the Relugoli crystal form APTI-I.
  • the obtained solid was tested by XRPD, and its X-ray powder diffraction pattern was shown in Figure 1; the DSC test was performed, and its spectrum was shown in Figure 2; the IR test was performed, and its spectrum was shown in Figure 3; and a TGA test was performed , its spectrum is shown in Figure 4; the H NMR test is carried out, and its spectrum is shown in Figure 5, the solid is the crystal form APTI-I of Relugoli.
  • the obtained solid was tested by XRPD, and its X-ray powder diffraction pattern was shown in Figure 1; the DSC test was performed, and its spectrum was shown in Figure 2; the IR test was performed, and its spectrum was shown in Figure 3; and a TGA test was performed , its spectrum is shown in Figure 4; the H NMR test is carried out, and its spectrum is shown in Figure 5, the solid is Relugoli crystal form APTI-I.
  • the obtained solid was tested by XRPD, and its X-ray powder diffraction data was shown in Table 2, and its X-ray powder diffraction pattern was shown in Figure 1; DSC test was performed, and its spectrum was shown in Figure 7; IR test was performed , the spectrum is shown in Figure 8; the TGA test is performed, and the spectrum is shown in Figure 9; the H NMR test is performed, and the spectrum is shown in Figure 10, the solid is the crystal form APTI-II of Relugoli .
  • Relugolix amorphous form Take 1.0 g of Relugolix amorphous form, add it to 10 ml of acetone, beat at 30-35 °C for 1.5 hours, cool down to 15 °C, filter, and dry at T ⁇ 40 °C to obtain 0.90 g of solid, the purity detected by HPLC is 99.67%, and the yield is 90%. .
  • the obtained solid was tested by XRPD, and its X-ray powder diffraction pattern was shown in Figure 1; the DSC test was performed, and its spectrum was shown in Figure 7; the IR test was performed, and its spectrum was shown in Figure 8; and the TGA test was performed , its spectrum is shown in Figure 9; the H NMR test is carried out, and its spectrum is shown in Figure 10, the solid is the crystal form APTI-II of Relugoli.
  • the obtained solid was tested by XRPD, and its X-ray powder diffraction pattern was shown in Figure 1; the DSC test was performed, and its spectrum was shown in Figure 7; the IR test was performed, and its spectrum was shown in Figure 8; and a TGA test was performed , its spectrum is shown in Figure 9; the H NMR test is carried out, and its spectrum is shown in Figure 10, the solid is the crystal form APTI-II of Relugoli.
  • Relugoli Amorphous Take 2.0 g of Relugoli Amorphous, add it to 4 ml of DMSO, dissolve it at 30-40 °C, add dropwise to 15 ml of ethanol, keep at 30-40 °C for 2 hours, cool at 5 °C, filter, and dry to obtain 1.81 g of solid, The purity was 99.68% detected by HPLC, and the yield was 90.5%.
  • the obtained solid was tested by XRPD, and its X-ray powder diffraction data was shown in Table 3, and its X-ray powder diffraction pattern was shown in Figure 11; the DSC test was carried out, and its spectrum was shown in Figure 12; IR test was carried out , the spectrum is shown in Figure 13; the TGA test is performed, and the spectrum is shown in Figure 14; the H NMR test is performed, and the spectrum is shown in Figure 15, the solid is the crystal form APTI-III of Relugoli .
  • the temperature was controlled at 30-40°C, and 30 ml of ethanol was added dropwise to the 7.5ml DMSO solution of Ruilugoli (APTI-II 5.0g obtained in Example 6). , and dried to obtain 4.39 g of solid, the purity detected by HPLC was 99.88%, and the yield was 92.0%.
  • crystal form APTI-II of the present application can be conveniently converted into a crystal form of a pharmaceutical preparation (ie, crystal form I) as a raw material.
  • Comparative Example 13 Amorphous crude product was purified by pulping in methyl tert-butyl ether
  • Comparative Example 15 Amorphous crude product was purified by slurry in dichloromethane/ethyl acetate
  • Example 6 Crystal form APTI-II 99.64 N.D. 0.05 0.06 0.04
  • Example 7 Crystal form APTI-III 99.68 0.03 0.12 0.08 0.05
  • Example 8 Form I 99.88 N.D. 0.03 0.04 0.03 Comparative Example 9 97.14 0.45 0.60 0.13 0.11 Comparative Example 10 96.67 0.50 0.62 0.11 0.12 Comparative Example 11 96.85 0.51 0.58 0.20 0.12 Comparative Example 12 99.01 0.12 0.25 0.13 0.08 Comparative Example 13 97.03 0.48 0.46 0.12 0.12 Comparative Example 14 98.23 0.25 0.35 0.14 0.09 Comparative Example 15 99.01 0.10 0.23 0.05 0.12
  • the crystal form APTI-II and crystal form APTI-III of the present invention have good impurity removal effects, especially crystal form APTI-II has excellent impurity removal effects, impurity RS-1, impurity RS-2, impurity RS- 3.
  • the impurity k can be reduced to below 0.1%.
  • the purity of the crystal form I prepared from the crystal form of the present invention is as high as 99.88% and the content of each impurity is below 0.05%.

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Abstract

瑞卢戈利新晶型及制备方法。具体地，提供了瑞卢戈利的三种新晶型APTI-I、APTI-II、APTI-III及其制备方法。晶型APTI-II、APTI-III除杂效果好。三种晶型均易于制备、操作简便，均适用于工业化大生产。

Description

瑞卢戈利新晶型及其制备方法
本申请要求申请日为2021年2月2日的中国专利申请CN202110145332.9的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及瑞卢戈利的新晶型及其制备方法。
背景技术
瑞卢戈利是一种每日一次、口服、促性腺激素释放激素(GnRH)受体拮抗剂，能抑制睾丸睾酮的生成，这种激素可刺激前列腺癌的生长。此外，瑞卢戈利也可通过阻断垂体腺中的GnRH受体，减少卵巢雌二醇的生成，减少促黄体生成激素(LH)和卵泡刺激素(FSH)的释放，从而降低女性卵巢生成的雌激素水平和男性睾丸激素的产生。
瑞卢戈利于2019年1月8日获日本医药品医疗器械综合机构(PMDA)批准上市，由武田和Aska pharmaceutical上市销售，商品名为
Figure PCTCN2021107493-appb-000001
40毫克/片，被批准用于子宫肌瘤的治疗和症状缓解；于2020年12月18日美国食品药品监督管理局(FDA)批准上市，商品名为ORGOVYX，120毫克/片，其结构式如下：
Figure PCTCN2021107493-appb-000002
WO2014051164报道了瑞卢戈利的四氢呋喃溶剂合物晶型和瑞卢戈利的晶型(以下称晶型I)，并披露其中四氢呋喃溶剂合物晶型用以纯化瑞卢戈利，可以将纯度为99.37％的粗品纯化得到99.75％的产品，且可将粗品中的杂质RS-1由0.1％降至0.04％，杂质RS-2由0.16％降至0.07％，杂质RS-3由0.08％降至0.02％。从纯化工艺来看，其实整体纯化效果并不佳，产品纯度仅提高0.38％。而且发明人在重复WO2014051164工艺后，进行杂质分析检测时发现，无论是四氢呋喃溶剂合物晶型还是产物晶型I，其HPLC分析图谱中均没能将杂质k与产物分离开来，实际上四氢呋喃溶剂合物晶型和晶型I均含有0.15％ 以上的杂质k。
WO2019178304报道了瑞卢戈利的晶型F、晶型G、晶型H、和晶型J。晶型F是存在无水、半水、一水合物三种形式的同质多晶形式，生产上不易控制，后续制剂工艺中也不易计量。晶型G和晶型H从相同的溶剂体系(二氯甲烷)制备得到，非常容易得到混晶。晶型J是三斜晶系，可以是溶剂合物，也可以是水合物，晶型J不能精准定性，不适应于制剂。此外，这些晶型的收率低仅在40～50％左右，不适合工艺放大。
综上所述，本领域迫切需要开发一种适合工业化生产、成药性能或者纯化能力更好的瑞卢戈利新晶型。
发明内容
本发明的目的就是提供一种适合工业化生产、成药性能或者纯化能力更好的瑞卢戈利新晶型或溶剂合物。
在本发明的第一方面，提供了一种式I化合物的晶型，
Figure PCTCN2021107493-appb-000003
其中，所述的晶型为晶型APTI-II；
并且所述晶型APTI-II的X射线粉末衍射图在2θ值为7.0°±0.2°、9.5°±0.2°、10.6°±0.2°、15.7°±0.2°和20.7°±0.2°中的一处或多处有特征峰。
在另一优选例中，所述晶型APTI-II为式I化合物的半丙酮合物晶型。
在另一优选例中，所述晶型APTI-II的X射线粉末衍射图还在2θ值为4.7±0.2°、5.7±0.2°、8.8±0.2°、11.1±0.2°、12.3±0.2°、13.0±0.2°、14.1±0.2°、17.8±0.2°、19.1±0.2°、和20.0±0.2°中的任意一处或多处具有特征峰。
在另一优选例中，所述晶型APTI-II的X射线粉末衍射图在2θ值为4.7±0.2°、5.7±0.2°,、7.0±0.2°、8.8±0.2°、9.5±0.2°、10.6±0.2°、11.1±0.2°、12.3±0.2°、13.0±0.2°、14.1±0.2°、15.7±0.2°、17.8±0.2°、19.1±0.2°、20.0±0.2°和20.7±0.2°处具有特征峰。
在另一优选例中，所述晶型APTI-II的X射线粉末衍射图基本如图6所示。
在另一优选例中，所述的晶型APTI-II的差示扫描量热分析图(DSC图)在178℃～195℃范围内有一个吸热峰。
在另一优选例中，所述晶型APTI-II的差示扫描量热分析图(DSC图)的起始值为180.8±2℃、和/或峰值为190.23±2℃。
在另一优选例中，所述晶型APTI-II的差示扫描量热分析图(DSC)基本如图7所示。
在另一优选例中，所述晶型APTI-II的红外吸收谱图在3250±10、3211±10、3055±10、2978±10、1717±10、1678±10、和1526±10cm -1处有吸收峰。
在另一优选例中，所述晶型APTI-II的红外吸收谱图基本如图8所示。
在另一优选例中，所述晶型APTI-II热重分析图(TGA图)在0℃至60±3℃范围内有约0.15±0.2％的失重。
在另一优选例中，所述晶型APTI-II的热重分析图(TGA图)基本如图9所示。
在本发明的第二方面提供了一种如第一方面所述的晶型的制备方法，其中，所述的制备方法包括步骤：
II-a)提供式I化合物原料于丙酮中的混合物；
II-b)搅拌步骤II-a)的混合物；和
II-c)收集所述混合物中的固体，干燥，从而得到晶型APTI-II。
在另一优选例中，所述的式I化合物原料为式I化合物的无定型或式I化合物的晶型。
在另一优选例中，所述的式I化合物原料为式I化合物的无定型或式I化合物的晶型APTI-I(晶型APTI-I如第七方面中定义)。
在另一优选例中，所述的式I化合物原料的纯度＜98％；较佳地，＜97％。
在另一优选例中，步骤II-a)中，所述式I化合物原料与丙酮的重量体积(g：mL)比为1：1-20；较佳地，1:5～15；更佳地，1:10±3。
在另一优选例中，步骤II-b)中，在30～50℃(较佳地，35～50℃；更佳地，30～40℃)下搅拌。
在另一优选例中，步骤II-b)中，搅拌时间为0.5～5小时；较佳地，1～5小时；更佳地，1～3小时。
在另一优选例中，步骤II-b)中，在搅拌后，还包括任选地将混合物降温至≤25℃(较佳地，15～25℃)的步骤。
在另一优选例中，步骤II-c)中，通过过滤收集所述混合物中的固体。
在另一优选例中，步骤II-c)中，所述干燥的干燥温度T为T＜40℃。
在本发明的第三方面中，提供了一种式I化合物的溶剂合物，
Figure PCTCN2021107493-appb-000004
所述的溶剂合物为式I化合物的半丙酮合物。
在另一优选例中，所述溶剂合物的核磁结果如下：
1H-NMR(300MHz,CDCl3)δ:2.13(6H,s),2.17(3H,s),3.40～3.79(2H,br.),3.81(3H,s),4.18(3H,s),5.34(2H,br.),6.85～7.00(2H,t,J＝8.1Hz),7.10～7.18(1H,d,J＝9.0Hz),7.20～7.38(1H,m),7.40(1H,d,J＝9.1Hz),7.40～7.70(5H,m),7.70(1H,s).
在另一优选例中，所述溶剂合物的核磁结果基本如图10所示。
在本发明的第四方面中，提供了一种如第七方面所述的溶剂合物的制备方法，所述制备方法包括步骤：
S-a)提供式I化合物原料于丙酮中的混合物；
S-b)搅拌步骤S-a)的混合物；和
S-c)收集所述混合物中的固体，干燥，从而得到式I化合物的半丙酮合物。
在另一优选例中，所述的式I化合物原料如第二方面中定义。
在另一优选例中，步骤S-a)中，所述式I化合物原料与丙酮的重量体积(g：mL)比为1：1-20；较佳地，1:5～15；更佳地，1:10±3。
在另一优选例中，步骤S-b)中，在30～50℃(较佳地，35～50℃；更佳地，30～40℃)下搅拌。
在另一优选例中，步骤S-b)中，搅拌时间为0.5～5小时；较佳地，1～5小时；更佳地，1～3小时。
在另一优选例中，步骤S-b)中，在搅拌后，还包括任选地将混合物降温至≤25℃(较佳地，15～25℃)的步骤。
在另一优选例中，步骤S-c)中，通过过滤收集所述混合物中的固体。
在另一优选例中，步骤S-c)中，所述干燥的干燥温度T为T＜40℃。
在本发明的第五方面中，提供了一种式I化合物的晶型，
Figure PCTCN2021107493-appb-000005
其特征在于，所述的晶型为晶型APTI-III；
并且所述晶型APTI-III的X射线粉末衍射图在2θ值为7.2°±0.2°、9.7°±0.2°、10.7°±0.2°、13.1°±0.2°、15.8°±0.2°和19.0°±0.2°处有特征峰。
在另一优选例中，所述的晶型APTI-III的X射线粉末衍射图还在2θ值为4.9±0.2°、5.8±0.2°、9.0±0.2°、11.2±0.2°、12.6±0.2°、14.3±0.2°、16.4±0.2°、18.0±0.2°、20.0±0.2°、和20.6±0.2°中的任意一处或多处具有特征峰。
在另一优选例中，所述的晶型APTI-III的X射线粉末衍射图在2θ值为4.9±0.2°、5.8±0.2°、7.2±0.2°、9.0±0.2°、9.7±0.2°、10.7±0.2°、11.2±0.2°、12.6±0.2°、13.1±0.2°、14.3±0.2°、15.8±0.2°、16.4±0.2°、18.0±0.2°、19.0±0.2°、20.0±0.2°、20.6±0.2°处具有特征峰。
在另一优选例中，所述的晶型APTI-III的X射线粉末衍射图基本如图11所示。
在另一优选例中，所述的晶型APTI-III的差示扫描量热分析图(DSC图)在169℃～190℃范围内有一个吸热峰。
在另一优选例中，所述的晶型APTI-III的差示扫描量热分析图(DSC图)的起始值(onset)为171.4±2℃，和/或峰值为183.4±2℃。
在另一优选例中，所述的晶型APTI-III的差示扫描量热分析图(DSC图)基本如图12所示。
在另一优选例中，所述的晶型APTI-III的红外吸收谱图在3248±10、3210±10、3110±10、2946±10、1718±10、1678±10、和1526±10cm-1处有吸收峰。
在另一优选例中，所述的晶型APTI-III的红外吸收谱图基本如图13所示。
在另一优选例中，所述的晶型APTI-III热重分析图(TGA图)在0℃至60±3℃的范围内有约0.48±0.2％的失重。
在另一优选例中，所述的晶型APTI-III的热重分析图(TGA图)基本如图14所示。
在另一优选例中，所述晶型APTI-III为游离形式的式I化合物的晶型。
在本发明的第六方面中，提供了一种如第五方面所述的晶型的制备方法，包括步骤：
III-a)提供式I化合物原料于溶剂A中的溶液a；
III-b)将步骤3a)溶液a加入至溶剂B中；
III-c)任选地降温至0～10℃并搅拌；和
III-d)收集析出固体，干燥，从而得到所述的晶型APTI-III。
在另一优选例中，步骤III-a)中，所述溶液a的温度为30～50℃。
在另一优选例中，步骤III-a)中，所述溶剂A选自下组：DMSO、DMF、NMP、DMAC，或其组合。
在另一优选例中，步骤III-b)中，所述溶剂B选自下组：醇类溶剂，其中醇类溶剂(较佳地，(C 1-6脂肪醇))。
在另一优选例中，步骤III-b)中，所述溶剂B选自下组：甲醇、乙醇、异丙醇、正丙醇、正丁醇，或其组合。
在另一优选例中，步骤III-a)中，所述式I化合物原料与溶剂A的重量体积(g：mL)比为1：1-10；较佳地，为1：1～3。
在另一优选例中，步骤III-b)中，所述式I化合物原料与溶剂B的重量体积比为1：3-20。
在另一优选例中，所述的式I化合物原料为式I化合物的无定型或式I化合物的晶型。
在另一优选例中，所述的式I化合物原料的纯度＜98％；较佳地，＜97％。
在本发明的第七方面中，提供了一种式I化合物的晶型，
Figure PCTCN2021107493-appb-000006
其中，所述晶型为晶型APTI-I；
并且所述晶型APTI-I的X射线粉末衍射图在2θ值为5.2°±0.2°、10.5°±0.2°、、15.3°±0.2°、和19.1°±0.2°处有特征峰。
在另一优选例中，所述晶型APTI-I的X射线粉末衍射图还在2θ值为6.4±0.2°、 8.0±0.2°、12.5±0.2°、15.9±0.2°、和21.1±0.2中的任意一处或多处(如1、2、3、4或5处)具有特征峰。
在另一优选例中，所述晶型APTI-I的X射线粉末衍射图在2θ值为5.2±0.2°、6.4±0.2°、8.0±0.2°、10.5±0.2°、12.5±0.2°,15.3±0.2°、15.9±0.2°、19.1±0.2°和21.1±0.2处具有特征峰。
在另一优选例中，所述晶型APTI-I的X射线粉末衍射图基本如图1所示。
在另一优选例中，所述的晶型APTI-II的差示扫描量热分析图(DSC图)在133℃～152℃范围内有一个吸热峰。
在另一优选例中，所述晶型APTI-I的差示扫描量热分析图(DSC图)的起始(onset)值为135.08±2℃，和/或峰值为143.23±2℃。
在另一优选例中，所述晶型APTI-I的差示扫描量热分析图(DSC图)基本如图2所示。
在另一优选例中，所述晶型APTI-I的红外吸收谱图在3311±10、3168±10、3062±10、1719±10、1673±10、1524±10、和1410±10cm -1处有吸收峰。
在另一优选例中，所述晶型APTI-I的红外吸收谱图基本如图3所示。
在另一优选例中，所述晶型APTI-I热重分析图(TGA图)在0℃至60±3℃范围内有约0.94±0.2％的失重，且在60±3℃至140±3℃的范围内有约1.98±0.2％的失重。
在另一优选例中，所述晶型APTI-I的热重分析图(TGA图)基本如图4所示。
在本发明的第八方面中，提供了一种如第七方面所述的晶型的制备方法，其中，所述的方法包括步骤：
I-a)提供式I化合物原料于有机溶剂1中的溶液；
I-b)向步骤I-a)的溶液中加入水，使溶液中析出固体，并任选地继续搅拌；和
I-c)收集析出的固体，干燥，从而得到所述的晶型。
在另一优选例中，步骤I-b)中，搅拌时间为1～3小时。
在另一优选例中，步骤I-a)中，所述溶液的温度为15～30℃。
在另一优选例中，步骤I-b)为降温至0-10℃，向体系中滴加水至有固体析出，继续保温搅拌1-3小时；或保温下向体系中滴加水至有固体析出，继续搅拌1-3小时。
在另一优选例中，所述有机溶剂1选自下组：含氮或硫的高极性非质子溶剂、酮类溶剂、醇类溶剂、酯类溶剂、醚类溶剂，或其组合。
在另一优选例中，所述有机溶剂1为含氮或硫的高极性非质子溶剂，或者为含氮或 硫的高极性非质子溶剂与选自下组溶剂组成的混合溶剂：酮类溶剂和/或醇类溶剂、酯类溶剂、醚类溶剂，或其组合。
在另一优选例中，有机溶剂1中，含氮或硫的高极性非质子溶剂的体积含量为50～100％。
在另一优选例中，所述含氮或硫的高极性非质子溶剂包括：DMSO、DMF、NMP、乙腈，或其组合；较佳地，选自下组：DMSO、DMF、NMP，或其组合。
在另一优选例中，所述酮类溶剂包括：丙酮、甲乙酮、丁酮、甲基异丁酮，或其组合；较佳地，为丙酮。
在另一优选例中，所述醇类溶剂为含有1-6个碳原子的脂肪醇；较佳地，较佳地，选自下组：甲醇、乙醇、异丙醇、正丙醇、正丁醇，或其组合。
在另一优选例中，所述酯类溶剂包括：乙酸乙酯、乙酸异丙酯、甲酸乙酯、甲酸甲酯、乙酸甲酯，或其组合。
在另一优选例中，所述醚类溶剂包括：四氢呋喃、甲基叔丁基醚、异丙醚、苯甲醚、1,4-二氧六环，或其组合；较佳地，选自下组：四氢呋喃、1,4-二氧六环，或其组合。
在另一优选例中，所述有机溶剂1选自下组：DMSO、DMF、NMP、乙腈、丙酮、甲乙酮、丁酮、甲基异丁酮、1-6个碳原子的脂肪醇(包括：甲醇、乙醇、丙醇，或其组合)、乙酸乙酯、乙酸异丙酯、甲酸乙酯、甲酸甲酯、乙酸甲酯、四氢呋喃、甲基叔丁基醚、异丙醚、苯甲醚、1,4-二氧六环，或其组合。
在另一优选例中，所述有机溶剂1为选自含氮或硫的高极性非质子溶剂，或者为含氮或硫的高极性非质子溶剂与选自下组溶剂组成的混合溶剂：丙酮、甲乙酮、丁酮、甲基异丁酮、1-6个碳原子的脂肪醇(包括：甲醇、乙醇、丙醇，或其组合)、乙酸乙酯、乙酸异丙酯、甲酸乙酯、甲酸甲酯、乙酸甲酯、四氢呋喃、甲基叔丁基醚、异丙醚、苯甲醚、1,4-二氧六环，或其组合，或其组合；其中，含氮或硫的高极性非质子溶剂选自：DMSO、DMF、NMP、乙腈，或其组合。
在另一优选例中，步骤I-a)中，所述式I化合物与有机溶剂1的重量体积(g：mL)比为1：1-20；较佳地，1：2-6。
在另一优选例中，步骤I-b)中，所述式I化合物原料与水的重量体积(g：mL)比为1：1～20；较佳地，1:2～20；更佳地，1：2-10。
在另一优选例中，所述的式I化合物原料为式I化合物的无定型或式I化合物的晶型。
在本发明的第九方面中，提供了一种如第一方面所述的晶型、如第三方面所述的溶剂合物或如第五方面所述的晶型在制备高纯度的式I化合物的药用晶型中的用途。
在另一优选例中，所述的药用晶型为WO2014051164的晶型I。
在另一优选例中，所述药用晶型的纯度＞99.5％(较佳地，＞99.8％)。
在另一优选例中，所述药用晶型的杂质和/或杂质RS-1和/或杂质RS-2和/或杂质RS-3含量＜0.1％(较佳地，＜0.05％)。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了晶型APTI-I典型实例的PXRD图谱；
图2显示了晶型APTI-I典型实例的DSC图谱；
图3显示了晶型APTI-I典型实例的IR图谱；
图4显示了晶型APTI-I典型实例的TGA图谱；
图5显示了晶型APTI-I典型实例的1H-NMR图谱；
图6显示了晶型APTI-II典型实例的PXRD图谱；
图7显示了晶型APTI-II典型实例的DSC图谱；
图8显示了晶型APTI-II典型实例的IR图谱；
图9显示了晶型APTI-II典型实例的TGA图谱；
图10显示了晶型APTI-II典型实例的1H-NMR图谱
图11显示了晶型APTI-III典型实例的PXRD图谱；
图12显示了晶型APTI-III典型实例的DSC图谱；
图13显示了晶型APTI-III典型实例的IR图谱；
图14显示了晶型APTI-III典型实例的TGA图谱；
图15显示了晶型APTI-III典型实例的1H-NMR图谱。
具体实施方式
经过广泛而深入地研究。发明人意外地发现了制备简单且除杂效果十分优异的如式I 所示的瑞卢戈利的新晶型和新溶剂合物。这些晶型(尤其是本发明的晶型APTI-II)和溶剂合物(半丙酮合物)具有对瑞卢戈利中的杂质RS-1、RS2、RS-3和杂质k的优异去除效果，使这些晶型和溶剂合物的纯度＞99.5％，各单杂含量基本＜0.1，进而使得由本发明的晶型和溶剂合物制得的的药用晶型具有高达＞99.8％的纯度和＜0.05％的单杂含量。基于此，发明人完成了本发明。
各杂质结构如下：
Figure PCTCN2021107493-appb-000007
瑞卢戈利的新晶型及其制备方法
本发明的第一个目的是提供了一种新的瑞卢戈利(式I)晶型APTI-I，使用Cu-Kα辐射，其X射线粉末衍射在衍射角2θ值为5.2°±0.2°，10.5°±0.2°，，15.3°±0.2°，19.1°±0.2°处有特征峰。
更进一步的，本发明提供的瑞卢戈利晶型APTI-I，其X射线粉末衍射图在2θ值为5.2±0.2°，6.4±0.2°，8.0±0.2°，10.5±0.2°，12.5±0.2°,15.3±0.2°，15.9±0.2°，19.1±0.2°，21.1±0.2处具有特征峰。
更进一步的，本发明提供的瑞卢戈利晶型APTI-I，其X射线粉末衍射数据如表1所示；
表1
NO. 2θ(°) 相对强度(％)
1 5.2±0.2° 100
2 6.4±0.2° 21.8
3 8.0±0.2° 13.5
4 10.5±0.2° 30.1
5 12.5±0.2° 12.8
6 15.3±0.2° 26.5
7 15.9±0.2° 11.5
8 19.1±0.2° 46.7
9 21.1±0.2° 24.0
更进一步地，本发明提供的瑞卢戈利晶型APTI-I，其X射线粉末衍射图基本如图1所示。
更进一步地，本发明提供的瑞卢戈利晶型APTI-I的差示扫描量热分析图(DSC)的起始onset、峰值分别为135.08±2℃、143.23±2℃。
更进一步地，本发明提供的瑞卢戈利晶型APTI-I的差示扫描量热分析图(DSC)基本如图2所示。
更进一步地，本发明提供的瑞卢戈利晶型APTI-I，其红外吸收谱图在3311±10、3168±10、3062±10、1719±10、1673±10、1524±10、1410±10cm-1处有吸收峰。
更进一步地，本发明提供的瑞卢戈利晶型APTI-I，其红外吸收谱图基本如图3所示。
更进一步地，本发明提供的瑞卢戈利晶型APTI-I热重分析图(TGA)在0-60±3℃有约0.94±0.2％的失重，60-140±3℃有约1.98±0.2％的失重，
更进一步地，本发明提供的瑞卢戈利晶型APTI-I的热重分析图(TGA)基本如图4所示。
更进一步地，经核磁确认晶型APTI-I为瑞卢戈利,基本如图5所示，核磁结果如下：
1H-NMR(300MHz,CDCl3)δ:2.13(6H,s),3.40～3.79(2H,br.),(3.80(3H,s),4.18(3H,s),5.10～5.64(2H,br.),6.85～7.00(2H,t,J＝8.1 8.1Hz),7.10～7.18(1H,d,J＝9.0Hz),7.20～7.38(1H,m),7.40(1H,d,J＝9.1Hz),7.40～7.60(6H,m),7.73(1H,s).
本发明的第二个目的是一种瑞卢戈利晶型APTI-I的制备方法，包括以下步骤：
I-a)15-30℃下，将瑞卢戈利(式I)原料用溶解于有机溶剂1中，从而得到瑞卢戈利于有机溶剂1中的溶液；
I-b)任选地降温至0-10℃，向所述含瑞卢戈利的混合物中加入(如滴加)水，继续保温搅拌1-3小时；或
保温下向所述含瑞卢戈利的混合物加入如滴加水，继续搅拌1-3小时；
I-c)过滤，干燥，得到瑞卢戈利晶型APTI-I。
进一步地，步骤I-a中所述的有机溶剂1选自含氮或者硫类高极性非质子溶剂 (DMSO、DMF、NMP、乙腈)、酮类(丙酮、甲乙酮、丁酮、甲基异丁酮)溶剂、醇类(含有1-6个碳原子的脂肪醇)、酯类(乙酸乙酯、乙酸异丙酯、甲酸乙酯、甲酸甲酯、乙酸甲酯)溶剂、醚类(四氢呋喃、甲基叔丁基醚、异丙醚、苯甲醚、1，4-二氧六环)溶剂或其中的任意两种或多种的混合。
更进一步地，所述有机溶剂1为含氮或者硫类高极性非质子溶剂(DMSO、DMF、NMP、乙腈)，或者为含氮或者硫类高极性非质子溶剂(DMSO、DMF、NMP、乙腈)与选自下组的溶剂组成的混合溶剂：酮类(丙酮、甲乙酮、丁酮、甲基异丁酮)溶剂、醇类(含有1-6个碳原子的脂肪醇)、酯类(乙酸乙酯、乙酸异丙酯、甲酸乙酯、甲酸甲酯、乙酸甲酯)溶剂、醚类(四氢呋喃、甲基叔丁基醚、异丙醚、苯甲醚、1，4-二氧六环)溶剂。
更进一步地，所述有机溶剂1中含氮或者硫类高极性非质子溶剂(DMSO、DMF、NMP、乙腈)的体积含量为50～100％。
更进一步地，含氮或者硫类高极性非质子溶剂优选为DMSO、DMF、NMP中的一种或多种，醇类溶剂优选为甲醇、乙醇、异丙醇、正丙醇或正丁醇中的一种或多种；酮类溶剂优选丙酮；醚类溶剂优选四氢呋喃或1,4-二氧六环中的一种或多种。
更进一步地，步骤I-a中所述原料瑞卢戈利与有机溶剂1的重量体积比为1：1-20。
更进一步地，步骤I-b中原料瑞卢戈利与水的重量体积比为1：4-20。
本发明的第三个目的提供了一种新的瑞卢戈利晶型APTI-II，使用Cu-Kα辐射，其X射线粉末衍射在衍射角2θ值为7.0°±0.2°，9.5°±0.2°，10.6°±0.2°，15.7°±0.2°，20.7°±0.2°处有特征峰。
更进一步地，本发明提供的瑞卢戈利晶型APTI-II，其X射线粉末衍射图在2θ值为4.7±0.2°,5.7±0.2°,7.0±0.2°,8.8±0.2°,9.5±0.2°,10.6±0.2°,11.1±0.2°,12.3±0.2°，13.0±0.2°,14.1±0.2°,15.7±0.2°,17.8±0.2°,19.1±0.2°,20.0±0.2°,20.7±0.2°处具有特征峰。
更进一步的，本发明提供的瑞卢戈利晶型APTI-II，其X射线粉末衍射数据如表2所示；
表2
NO. 2θ(°) 相对强度(％)
1 4.7±0.2° 0.7
2 5.7±0.2° 9.0
3 7.0±0.2° 28.7
4 8.8±0.2° 14.9
5 9.5±0.2° 32.5
6 10.6±0.2° 100
7 11.1±0.2° 6.5
8 12.3±0.2° 7.0
9 13.0±0.2° 16.5
10 14.1±0.2° 5.3
11 15.7±0.2° 54.2
12 17.8±0.2° 7.2
13 19.1±0.2° 11.5
14 20.0±0.2° 12.1
15 20.7±0.2° 41.8
更进一步地，本发明提供的瑞卢戈利晶型APTI-II，其X射线粉末衍射图基本如图6所示。PXRD显示此结构和专利公开报道的均不同。
更进一步地，本发明提供的瑞卢戈利晶型APTI-II的差示扫描量热分析图(DSC)的起始值和峰值分别为180.8±2℃、190.23±2℃；其差示扫描量热分析图(DSC)基本如图7所示。
更进一步地，本发明提供的瑞卢戈利晶型APTI-II，其红外吸收谱图在3250±10、3211±10、3055±10、2978±10、1717±10、1678±10、1526±10cm-1处有吸收峰。
更进一步地，本发明提供的瑞卢戈利晶型APTI-II，其红外吸收谱图基本如图8所示。
更进一步地，本发明提供的瑞卢戈利晶型APTI-II热重分析图(TGA)在0-60±3℃有约0.15±0.2％的失重。
更进一步地，本发明提供的瑞卢戈利晶型APTI-II，其热重分析图(TGA)如图9所示。
更进一步地，经核磁确认晶型APTI-II为瑞卢戈利半丙酮合物。核磁结果和如下和如 图10所示：
1H-NMR(300MHz,CDCl3)δ:2.13(6H,s),2.17(3H,s),3.40～3.79(2H,br.),3.81(3H,s),4.18(3H,s),5.34(2H,br.),6.85～7.00(2H,t,J＝8.1Hz),7.10～7.18(1H,d,J＝9.0Hz),7.20～7.38(1H,m),7.40(1H,d,J＝9.1Hz),7.40～7.70(5H,m),7.70(1H,s).
本发明的第四个目的提供了一种瑞卢戈利晶型APTI-II的制备方法，包括以下步骤：
II-a)将瑞卢戈利原料加入丙酮中，任选地升温至30-50℃，从而得到瑞卢戈利(式I)原料于丙酮中的混合物；
II-b)搅拌如搅拌1-5小时，任选地降温至＜25℃(较佳地，15-25℃)；
II-c)过滤，干燥得到瑞卢戈利的晶型APTI-II。
进一步地，步骤II-a中，所述原料瑞卢戈利与丙酮的重量体积比为1：1-20。
本发明的第五个目的是提供一种新的瑞卢戈利晶型APTI-III，使用Cu-Kα辐射，其X射线粉末衍射在衍射角2θ值为7.2°±0.2°，9.7°±0.2°，10.7°±0.2°，13.1°±0.2°，15.8°±0.2°，19.0°±0.2°处有特征峰。
更进一步地，本发明提供的瑞卢戈利的晶型APTI-III，其X射线粉末衍射图在2θ值为4.9±0.2°,5.8±0.2°,7.2±0.2°,9.0±0.2°,9.7±0.2°,10.7±0.2°,11.2±0.2°,12.6±0.2°,13.1±0.2°,14.3±0.2°,15.8±0.2°,16.4±0.2°,18.0±0.2°,19.0±0.2°,20.0±0.2°,20.6±0.2°处具有特征峰。
更进一步的，本发明提供的瑞卢戈利晶型APTI-III，其X射线粉末衍射数据如表3所示；
表3
NO. 2θ(°) 相对强度(％)
1 4.9±0.2° 17.2
2 5.8±0.2° 14.3
3 7.2±0.2° 81.1
4 9.0±0.2° 30.4
5 9.7±0.2° 79.2
6 10.7±0.2° 100
7 11.2±0.2° 41.8
8 12.6±0.2° 32.1
9 13.1±0.2° 58.4
10 14.3±0.2° 7.2
11 15.8±0.2° 46.5
12 16.4±0.2° 5.6
13 18.0±0.2° 24.2
14 19.0±0.2° 44.3
15 20.0±0.2° 28.1
16 20.6±0.2° 39.5
更进一步地，本发明提供的瑞卢戈利的晶型APTI-III，其X射线粉末衍射图基本如图11所示。PXRD显示此结构和专利公开报道的均不同。
更进一步地，本发明提供的瑞卢戈利的晶型APTI-III的差示扫描量热分析图(DSC)的起始onset,峰值分别为171.4±2℃、183.4±2℃；其差示扫描量热分析图(DSC)基本如图12所示。
更进一步地，本发明提供的瑞卢戈利的晶型APTI-III，其红外吸收谱图在3248±10、3210±10、3110±10、2946±10、1718±10、1678±10、1526±10cm-1处有吸收峰。
更进一步地，本发明提供的瑞卢戈利的晶型APTI-III，其红外吸收谱图基本如图13所示。
更进一步地，本发明提供的瑞卢戈利的晶型APTI-III热重分析图(TGA)在0-60±3℃有约0.48±0.2％的失重。
更进一步地，本发明提供的瑞卢戈利的晶型APTI-III，其热重分析图(TGA)基本如图14所示。
更进一步地，经核磁确认晶型APTI-III为瑞卢戈利，如图15所示，核磁数据如下：
1H-NMR(300MHz,DMSO-d6)δ:2.04(6H,s),3.40～3.70(2H,br.),3.64(3H,s),4.09(3H,s),5.10～5.50(2H,br.),7.10～7.20(2H,t,J＝8.2Hz),7.40-7.60(4H,m),7.80～7.92(3H,m),9.10(1H,s),9.63(1H,s).
本发明的第六个目的是提供一种瑞卢戈利晶型APTI-III的制备方法，包括以下步骤：
III-a)将瑞卢戈利原料加入到溶剂A中，搅拌下升温至30-50℃，得到溶液a；
III-b)将溶液a滴加到溶剂B中，有固体析出；
III-c)滴毕，任选地降温至0-10℃，继续搅拌1-3小时；
III-d)过滤，干燥，从而得到瑞卢戈利晶型APTI-III。
进一步地，步骤III-a所述溶剂A为DMSO、DMF、NMP、DMAC中的一种或几种组合。有机溶剂B选自醇类(含有1-6个碳原子的脂肪醇)溶剂，其中醇类溶剂优选甲醇、乙醇、异丙醇、正丙醇或正丁醇。
步骤a III-中所述原料瑞卢戈利与有机溶剂的重量体积比为1：1-10；和/或
步骤III-b中所述原料瑞卢戈利与溶剂B的重量体积比为1：3-20。
原料和通用方法：
1、实施例中所用原料为瑞卢戈利无定型参考WO2004067535制备得到，纯度为96.1％。
2、XRPD图谱测定方法
X-射线粉末衍射仪器：BRUKER AXS D2 PHASER X-射线粉末衍射仪；辐射源：
Figure PCTCN2021107493-appb-000008
强度比α1/α2为0.5；发生器(Generator)kv：30.0kv；发生器(Generator)mA：10.0mA；起始的2θ：2.000°，扫描范围：2.0000～40.000°。
3.DSC测定方法
METTLEER DSC1差式扫描量热仪升温程序：25℃～210℃每分钟升温10℃。
4.TGA测定方法
仪器型号：METTLEER TGA/DSC1热重分析仪升温程序：25℃～400℃每分钟升温10℃。
5.红外吸收测定方法
仪器型号：PerkinElmer Spectrun Two傅里叶变换红外光谱仪溴化钾压片扫描范围4400-450cm-1分辨率为4cm-1扫描4次。
6.HPLC检测条件：
仪器：Agilent 1260 series HPLC.
色谱柱：Waters XSelect CSH C18,4.6mm×250mm,5μm
柱温:10℃
样品室温度:5℃
流动相A:pH＝2的磷酸盐缓冲液
流动相B:色谱纯乙腈
时间(min) ％流动相A ％流动相B
0 78 22
20 76 24
49 58 42
55 30 70
58.5 30 70
58.6 78 22
68 78 22
流速：1.0毫升/分钟
测定时间：68分钟
检测波长：230纳米。
本发明的主要优点包括：
(1)晶型APTI-II和晶型APTI-III除杂效果好，可以很容易将产品纯度由96％提高到99.5％以上。
(2)三种新晶型的制备方法均操作简便，易于工业化生产。
(3)本发明的晶型和溶剂合物(如晶型APTI-II)可有效地除去瑞卢戈利中杂质如RS-1、RS2、RS-3和杂质k。
(4)本发明的晶型(如晶型APTI-II)和溶剂合物易于转化为药用晶型，从而可以得到高纯度的药用晶型。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
实施例1：制备瑞卢戈利的晶型APTI-I
取瑞卢戈利固体无定型30.0g于15-25℃溶解于80ml的DMSO中，加入60ml乙醇，降温0-10℃向溶液中滴加80ml水，滴毕，0-10℃搅拌2小时过滤，滤饼干燥得到固体24.6g， HPLC检测纯度96.62％，收率82.0％。
对得到的固体进行XRPD测试，其X-射线粉末衍射数据如表1所示，其X-射线粉末衍射图如图1所示；进行DSC测试，其谱图如图2所示；进行IR测试，其谱图如图3所示；进行TGA测试，其谱图如图4所示；进行H NMR测试，其谱图如图5所示，为瑞卢戈利晶型APTI-I。
实施例2：制备瑞卢戈利的晶型APTI-I
取瑞卢戈利无定型1.0g于15-25℃溶解于2ml的DMSO和0.5ml的异丙醇中，控温0-10℃向溶液中滴加5ml水，滴毕，0-10℃搅拌2小时，过滤，滤饼干燥得到固体0.89g，HPLC检测纯度96.34％，收率89.0％。
对得到的固体进行XRPD测试，其X-射线粉末衍射图如图1所示；进行DSC测试，其谱图如图2所示；进行IR测试，其谱图如图3所示；进行TGA测试，其谱图如图4所示；进行H NMR测试，其谱图如图5所示，该固体为瑞卢戈利的晶型APTI-I。
实施例3：制备瑞卢戈利的晶型APTI-I
取瑞卢戈利无定型1.0g于15-25℃溶解于2ml的DMF中，控温15-25℃向溶液中滴加10ml水，滴毕，15-25℃搅拌2小时，过滤，滤饼干燥得到固体0.92g，HPLC检测纯度96.10％，收率92.0％。
对得到的固体进行XRPD测试，其X-射线粉末衍射图如图1所示；进行DSC测试，其谱图如图2所示；进行IR测试，其谱图如图3所示；进行TGA测试，其谱图如图4所示；进行H NMR测试，其谱图如图5所示，该固体为瑞卢戈利晶型APTI-I。
实施例4：制备瑞卢戈利的晶型APTI-II
取实施例1得到的晶型APTI-I 15.0g(含水30％)，加入120ml的丙酮中，于35-40℃打浆2小时，降温25℃过滤，T<40℃干燥得到固体9.6g，HPLC检测纯度99.71％，收率91.4％。
对得到的固体进行XRPD测试，其X-射线粉末衍射数据如表2所示，其X-射线粉末衍射图如图1所示；进行DSC测试，其谱图如图7所示；进行IR测试，其谱图如图8所示；进行TGA测试，其谱图如图9所示；进行H NMR测试，其谱图如图10所示，该固体为瑞卢戈利的晶型APTI-II。
实施例5：制备瑞卢戈利的晶型APTI-II
取瑞卢戈利无定型1.0g，加入10ml的丙酮中，于30-35℃打浆1.5小时，降温15℃过滤，T<40℃干燥得到固体0.90g，HPLC检测纯度99.67％，收率90％。
对得到的固体进行XRPD测试，其X-射线粉末衍射图如图1所示；进行DSC测试，其谱图如图7所示；进行IR测试，其谱图如图8所示；进行TGA测试，其谱图如图9所示；进行H NMR测试，其谱图如图10所示，该固体为瑞卢戈利的晶型APTI-II。
实施例6：制备瑞卢戈利的晶型APTI-II
取瑞卢戈利无定型6.0g，加入50ml的丙酮中于35-40℃打浆2小时，降温20℃过滤，T<40℃干燥得到固体5.5g，HPLC检测纯度99.64％，收率91.7％。
对得到的固体进行XRPD测试，其X-射线粉末衍射图如图1所示；进行DSC测试，其谱图如图7所示；进行IR测试，其谱图如图8所示；进行TGA测试，其谱图如图9所示；进行H NMR测试，其谱图如图10所示，该固体为瑞卢戈利的晶型APTI-II。
实施例7：制备瑞卢戈利的晶型APTI-III
取瑞卢戈利无定型2.0g，加入4ml的DMSO中，于30-40℃溶解后滴加入15毫升的乙醇中，30-40℃保温2小时，降温5℃过滤，干燥得到固体1.81g，HPLC检测纯度99.68％，收率90.5％。
对得到的固体进行XRPD测试，其X-射线粉末衍射数据如表3所示，其X-射线粉末衍射图如图11所示；进行DSC测试，其谱图如图12所示；进行IR测试，其谱图如图13所示；进行TGA测试，其谱图如图14所示；进行H NMR测试，其谱图如图15所示，该固体为瑞卢戈利的晶型APTI-III。
实施例8：制备瑞卢戈利的专利晶型I
控温30-40℃，向瑞卢戈利(实施例6得到的APTI-II 5.0g)的7.5ml DMSO溶液中滴加30毫升乙醇，滴毕30-40℃保温2小时，降温5℃过滤，干燥得到固体4.39g，HPLC检测纯度99.88％，收率92.0％。
对得到的固体进行XRPD测试，其X-射线粉末衍射数据与文献WO2014051164中晶型I吻合。
可见，以本申请的晶型APTI-II为原料可以方便的转化为药用制剂晶型(即晶型I)。
对比例9：无定型粗品在乙酸乙酯中打浆纯化
取瑞卢戈利无定型2.0g分别在10ml乙酸乙酯中45-60℃打浆2小时，降温25℃过滤，T<40℃干燥得到固体1.90g，HPLC检测纯度97.14％，收率95％。
对比例10：无定型粗品在乙醇中打浆纯化
取瑞卢戈利无定型2.0g分别在10ml乙醇中45-60℃打浆2小时，降温25℃过滤，T<40℃干燥得到固体1.78g，HPLC检测纯度96.67％，收率89％。
对比例11：无定型粗品在甲醇中打浆纯化
取瑞卢戈利无定型2.0g分别在10ml甲醇中45-60℃打浆2小时，降温25℃过滤，T<40℃干燥得到固体1.72g，HPLC检测纯度96.85％，收率86％。
对比例12：无定型粗品在乙腈中打浆纯化
取瑞卢戈利无定型2.0g分别在10ml乙腈中45-60℃打浆2小时，降温25℃过滤，T<40℃干燥得到固体1.76g，HPLC检测纯度99.01％，收率88％。
对比例13：无定型粗品在甲基叔丁基醚中打浆纯化
取瑞卢戈利无定型2.0g分别在10ml甲基叔丁基醚中35-45℃打浆2小时，降温25℃过滤，T<40℃干燥得到固体1.90g，HPLC检测纯度97.03％，收率95％。
对比例14：无定型粗品在甲基异丁基酮中打浆纯化
取瑞卢戈利无定型2.0g分别在10ml甲基异丁基酮中35-45℃打浆2小时，降温25℃过滤，T<40℃干燥得到固体1.80g，HPLC检测纯度98.23％，收率90％。
对比例15：无定型粗品在二氯甲烷/乙酸乙酯中打浆纯化
取瑞卢戈利无定型2.0g分别在10ml二氯甲烷/乙酸乙酯(体积比7/3)中35-45℃打浆2小时，降温25℃过滤，T<40℃干燥得到固体1.72g，HPLC检测纯度99.01％，收率86％。
另外实验发现，在乙酸乙酯，乙腈，甲基叔丁基醚，甲基异丁基酮中得到都是相应的溶剂合物；二氯甲烷/乙酸乙酯得到乙酸乙酯溶剂合物，并且试图将溶剂合物转为专利晶型I过程中乙酸乙酯不能去除。
HPLC测定实施例1-15所获得的每种晶体中的式I化合物和相关物质的含量，结果示于表4中。
表4
样品 式I化合物(％) RS-1(％) RS2(％) RS-3(％) 杂质k
原料无定型 96.18 0.63 0.86 0.28 0.13
实施例1晶型APTI-I 96.62 0.55 0.80 0.12 0.13
实施例2晶型APTI-I 96.34 0.60 0.81 0.22 0.13
实施例3晶型APTI-I 96.10 0.61 0.82 0.25 0.12
实施例4晶型APTI-II 99.71 0.04 0.05 0.07 0.04
实施例5晶型APTI-II 99.67 N.D. 0.08 0.06 0.05
实施例6晶型APTI-II 99.64 N.D. 0.05 0.06 0.04
实施例7晶型APTI-III 99.68 0.03 0.12 0.08 0.05
实施例8晶型I 99.88 N.D. 0.03 0.04 0.03
对比例9 97.14 0.45 0.60 0.13 0.11
对比例10 96.67 0.50 0.62 0.11 0.12
对比例11 96.85 0.51 0.58 0.20 0.12
对比例12 99.01 0.12 0.25 0.13 0.08
对比例13 97.03 0.48 0.46 0.12 0.12
对比例14 98.23 0.25 0.35 0.14 0.09
对比例15 99.01 0.10 0.23 0.05 0.12
由表5可知，本发明的晶型APTI-II和晶型APTI-III的除杂效果很好，尤其晶型APTI-II除杂效果优异，杂质RS-1、杂质RS-2、杂质RS-3，杂质k均可降低至0.1％以下。此外，由本发明的晶型制得的晶型I的纯度高达99.88％且各杂质含量均在0.05％以下。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种式I化合物的晶型，
    Figure PCTCN2021107493-appb-100001
    其特征在于，所述的晶型为晶型APTI-II；
    并且所述晶型APTI-II的X射线粉末衍射图在2θ值为7.0°±0.2°、9.5°±0.2°、10.6°±0.2°、15.7°±0.2°和20.7°±0.2°中的一处或多处有特征峰。
  2. 如权利要求1所述的晶型，其特征在于，所述晶型APTI-II为式I化合物的半丙酮合物晶型。
  3. 如权利要求1所述的晶型，其特征在于，所述晶型APTI-II的X射线粉末衍射图还在2θ值为4.7±0.2°、5.7±0.2°、8.8±0.2°、11.1±0.2°、12.3±0.2°、13.0±0.2°、14.1±0.2°、17.8±0.2°、19.1±0.2°、和20.0±0.2°中的任意一处或多处具有特征峰。
  4. 如权利要求1所述的晶型，其特征在于，所述晶型APTI-II还具有下述一个或多个特征：
    a.所述晶型APTI-II的X射线粉末衍射图基本如图6所示；
    b.所述的晶型APTI-II的差示扫描量热分析图(DSC图)在178℃～195℃范围内有一个吸热峰；
    c.所述晶型APTI-II的差示扫描量热分析图(DSC图)的起始值为180.8±2℃、和/或峰值为190.23±2℃；
    d.所述晶型APTI-II的差示扫描量热分析图(DSC)基本如图7所示；
    e.所述晶型APTI-II的红外吸收谱图在3250±10、3211±10、3055±10、2978±10、1717±10、1678±10、和1526±10cm -1处有吸收峰；
    f.所述晶型APTI-II的红外吸收谱图基本如图8所示；
    g.所述晶型APTI-II热重分析图(TGA图)在0℃至60±3℃范围内有约0.15±0.2％的失重；
    e.所述晶型APTI-II的热重分析图(TGA图)基本如图9所示。
  5. 如权利要求1所述的晶型的制备方法，其特征在于，所述的制备方法包 括步骤：
    II-a)提供式I化合物原料于丙酮中的混合物；
    II-b)搅拌步骤II-a)的混合物；和
    II-c)收集所述混合物中的固体，干燥，从而得到晶型APTI-II。
  6. 一种式I化合物的溶剂合物，
    Figure PCTCN2021107493-appb-100002
    其特征在于，所述的溶剂合物为式I化合物的半丙酮合物。
  7. 一种如权利要求6所述的溶剂合物的制备方法，其特征在于，包括步骤：
    S-a)提供式I化合物原料于丙酮中的混合物；
    S-b)搅拌步骤S-a)的混合物；和
    S-c)收集所述混合物中的固体，干燥，从而得到式I化合物的半丙酮合物。
  8. 一种式I化合物的晶型，
    Figure PCTCN2021107493-appb-100003
    其特征在于，所述的晶型为晶型APTI-III；
    并且所述晶型APTI-III的X射线粉末衍射图在2θ值为7.2°±0.2°、9.7°±0.2°、10.7°±0.2°、13.1°±0.2°、15.8°±0.2°和19.0°±0.2°处有特征峰。
  9. 如权利要求8所述的晶型的制备方法，其特征在于，包括步骤：
    III-a)提供式I化合物原料于溶剂A中的溶液a；
    III-b)将步骤3a)溶液a加入至溶剂B中；
    III-c)任选地降温至0～10℃并搅拌；和
    III-d)收集析出固体，干燥，从而得到所述的晶型APTI-III。
  10. 一种如权利要求1所述的晶型、如权利要求6所述的溶剂合物或如权利要求8所述的晶型在制备高纯度的式I化合物的药用晶型中的用途。
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