WO2022160737A1 - Crystal form of tetrahydropyran ring compound and preparation method therefor - Google Patents

Crystal form of tetrahydropyran ring compound and preparation method therefor Download PDF

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WO2022160737A1
WO2022160737A1 PCT/CN2021/118616 CN2021118616W WO2022160737A1 WO 2022160737 A1 WO2022160737 A1 WO 2022160737A1 CN 2021118616 W CN2021118616 W CN 2021118616W WO 2022160737 A1 WO2022160737 A1 WO 2022160737A1
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crystal form
compound
angles
pattern
ray powder
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PCT/CN2021/118616
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French (fr)
Chinese (zh)
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林昊
毛庆华
姚婷
谭焱
于涛
吴成德
陈曙辉
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东宝紫星(杭州)生物医药有限公司
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Publication of WO2022160737A1 publication Critical patent/WO2022160737A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/04—Carbocyclic radicals

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  • the present invention relates to a crystal form of tetrahydropyran ring compounds and a preparation method thereof, and specifically discloses the polymorphic form of the compound represented by formula (I) and a preparation method thereof.
  • Diabetes is a metabolic disease characterized by hyperglycemia.
  • hypoglycemic drugs for clinical treatment include biguanides, sulfonylureas, insulin resistance improvers, glinides, ⁇ -glucosidase inhibitors and dipeptidyl peptidase-IV inhibitors.
  • SGLTs Sodium-glucose cotransporters
  • the family members mainly include SGLT1 and SGLT2 proteins. Transmembrane transport of glucose in the gut and kidneys plays a key role in maintaining blood sugar stability in humans.
  • SGLTs inhibitor drugs such as Dapagliflozin, Canagliflozin, Empagliflozin and Sotagliflozin have been approved for the treatment of diabetes.
  • Dipeptidyl peptidase-IV is a cell surface serine protease that inactivates various glucagon-like peptide-1 (GLP-1) and glucose-dependent Glucose-dependent insulinotropic polypeptide (GIP).
  • GLP-1 glucagon-like peptide-1
  • GIP glucose-dependent Glucose-dependent insulinotropic polypeptide
  • DPP-4 inhibitors can inactivate DPP-4, thereby not decomposing GLP-1, and exerting the effect of controlling blood sugar by increasing the level of GLP-1.
  • DPP-4 inhibitors such as sitagliptin, vildagliptin, saxagliptin, and linagliptin have been widely used in the clinical treatment of diabetes.
  • the synergistic effect of SGLT1 and DPP4 target inhibition can promote and prolong the secretion and concentration of endogenous GLP-1, stimulate the secretion of endogenous insulin and improve the application of overall glucose energy in the body.
  • Glucose excretion under the condition of blood sugar level thus running through the overall pathway of glucose absorption, metabolism and excretion in the body, reducing blood sugar level in an all-round way and not easily causing the risk of hypoglycemia.
  • the present invention provides Form A of the compound of formula (I), whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 6.13 ⁇ 0.20°, 15.99 ⁇ 0.20° and 21.04 ⁇ 0.20°:
  • the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 6.13 ⁇ 0.20°, 8.21 ⁇ 0.20°, 10.63 ⁇ 0.20°, 15.99 ⁇ 0.20°, 17.21 ⁇ 0.20 °, 21.04 ⁇ 0.20°, 21.53 ⁇ 0.20° and 22.47 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.13 ⁇ 0.20°, 15.99 ⁇ 0.20°, and/or 21.04 ⁇ 0.20°, and/or 8.21 ⁇ 0.20°, and/or 10.63 ⁇ 0.20°, and/or 12.08 ⁇ 0.20°, and/or 14.40 ⁇ 0.20°, and/or 17.21 ⁇ 0.20°, and/or 21.53 ⁇ 0.20°, and/or 22.47 ⁇ 0.20°, and/or 26.47 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form A is shown in FIG. 1 .
  • the differential scanning calorimetry curve of the above-mentioned Form A has endothermic peaks at 73.5 ⁇ 3°C and 109.1 ⁇ 3°C.
  • the DSC spectrum of the above-mentioned A crystal form is shown in FIG. 2 .
  • the present invention provides the B crystal form of the compound of formula (I), whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 10.64 ⁇ 0.20°, 15.59 ⁇ 0.20° and 20.65 ⁇ 0.20°:
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 5.24 ⁇ 0.20°, 6.17 ⁇ 0.20°, 10.64 ⁇ 0.20°, 13.87 ⁇ 0.20°, 15.59 ⁇ 0.20 °, 16.58 ⁇ 0.20°, 20.65 ⁇ 0.20° and 21.75 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 5.24°, 6.17°, 7.00°, 8.12°, 10.64°, 11.69°, 12.18°, 12.55° , 13.87°, 15.59°, 16.58°, 18.06°, 18.45°, 20.27°, 20.65°, 21.31°, 21.75°, 22.67°, 24.66°, 25.38°, 26.26°, 27.18°, 28.40°, 31.12°, 32.14 °, 33.38°, 36.61°, 37.27° and 38.83°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 10.64 ⁇ 0.20°, 15.59 ⁇ 0.20°, and/or 20.65 ⁇ 0.20°, and/or 5.24 ⁇ 0.20°, and/or 6.17 ⁇ 0.20°, and/or 13.87 ⁇ 0.20°, and/or 16.58 ⁇ 0.20°, and/or 21.75 ⁇ 0.20°, and/or 7.00 ⁇ 0.20°, and/or 8.12 ⁇ 0.20° , and/or 11.69 ⁇ 0.20°, and/or 12.18 ⁇ 0.20°, and/or 12.55 ⁇ 0.20°, and/or 18.06 ⁇ 0.20°, and/or 18.45 ⁇ 0.20°, and/or 20.27 ⁇ 0.20°, and /or 21.31 ⁇ 0.20°, and/or 22.67 ⁇ 0.20°, and/or 24.66 ⁇ 0.20°, and/or 25.38 ⁇ 0.20°, and/or 26.26
  • the XRPD pattern of the above-mentioned crystal form B is shown in FIG. 3 .
  • the differential scanning calorimetry curve of the above-mentioned Form B has an onset of an endothermic peak at 104.1 ⁇ 3°C.
  • the DSC spectrum of the above-mentioned crystal form B is shown in FIG. 4 .
  • thermogravimetric analysis curve of the above-mentioned crystal form B loses 1.98% of the weight at 100°C, and loses 0.54% of the weight at 130°C.
  • the TGA spectrum of the above-mentioned B crystal form is shown in FIG. 5 .
  • the present invention provides the C crystal form of the compound of formula (I), whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 12.00 ⁇ 0.20°, 17.01 ⁇ 0.20° and 18.01 ⁇ 0.20°:
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 5.05 ⁇ 0.20°, 8.65 ⁇ 0.20°, 12.00 ⁇ 0.20°, 17.01 ⁇ 0.20°, 17.60 ⁇ 0.20 °, 18.01 ⁇ 0.20°, 18.44 ⁇ 0.20° and 20.89 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 5.05 ⁇ 0.20°, 6.00 ⁇ 0.20°, 8.65 ⁇ 0.20°, 12.00 ⁇ 0.20°, 17.01 ⁇ 0.20 °, 17.60 ⁇ 0.20°, 18.01 ⁇ 0.20°, 18.44 ⁇ 0.20°, 20.89 ⁇ 0.20° and 22.93 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 4.36°, 5.05°, 6.00°, 8.19°, 8.65°, 9.95°, 12.00°, 12.30° , 13.57°, 14.07°, 15.02°, 15.62°, 16.50°, 17.01°, 17.60°, 18.01°, 18.44°, 19.04°, 19.40°, 19.87°, 20.36°, 20.89°, 22.27°, 22.93°, 23.35 °, 24.48°, 25.14°, 25.49°, 26.97°, 28.88°, 29.24°, 32.83° and 36.94°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 12.00 ⁇ 0.20°, 17.01 ⁇ 0.20°, and/or 5.05 ⁇ 0.20°, and/or 6.00 ⁇ 0.20° 0.20°, and/or 8.65 ⁇ 0.20°, and/or 17.60 ⁇ 0.20°, and/or 18.01 ⁇ 0.20°, and/or 18.44 ⁇ 0.20°, and/or 20.89 ⁇ 0.20°, and/or 22.93 ⁇ 0.20° , and/or 4.36 ⁇ 0.20°, and/or 8.19 ⁇ 0.20°, and/or 9.95 ⁇ 0.20°, and/or 12.30 ⁇ 0.20°, and/or 13.57 ⁇ 0.20°, and/or 14.07 ⁇ 0.20°, and /or 15.02 ⁇ 0.20°, and/or 15.62 ⁇ 0.20°, and/or 16.50 ⁇ 0.20°, and/or 19.04 ⁇ 0.20°, and/or 19.40 ⁇ 0.20
  • the XRPD pattern of the above-mentioned crystal form C is shown in FIG. 6 .
  • thermogravimetric analysis curve of the above-mentioned crystal form C has a weight loss of 3.41% at 100 ⁇ 3°C.
  • the TGA spectrum of the above-mentioned C crystal form is shown in FIG. 7 .
  • the present invention provides the D crystal form of the compound of formula (I), whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 4.81 ⁇ 0.20°, 15.74 ⁇ 0.20° and 17.09 ⁇ 0.20°:
  • the X-ray powder diffraction pattern of the above crystal form D has characteristic diffraction peaks at the following 2 ⁇ angles: 4.81 ⁇ 0.20°, 9.60 ⁇ 0.20°, 14.58 ⁇ 0.20°, 15.74 ⁇ 0.20°, 17.09 ⁇ 0.20 °, 19.86 ⁇ 0.20°, 22.46 ⁇ 0.20° and 23.85 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form D has characteristic diffraction peaks at the following 2 ⁇ angles: 4.81°, 9.60°, 10.60°, 11.51°, 13.05°, 14.58°, 15.74°, 17.09° , 18.11°, 19.86°, 22.46°, 23.85° and 27.16°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form D has characteristic diffraction peaks at the following 2 ⁇ angles: 4.81 ⁇ 0.20°, 15.74 ⁇ 0.20°, and/or 17.09 ⁇ 0.20°, and/or 9.60 ⁇ 0.20° 0.20°, and/or 14.58 ⁇ 0.20°, and/or 19.86 ⁇ 0.20°, and/or 22.46 ⁇ 0.20°, and/or 23.85 ⁇ 0.20°, and/or 10.60 ⁇ 0.20°, and/or 11.51 ⁇ 0.20° , and/or 13.05 ⁇ 0.20°, and/or 18.11 ⁇ 0.20°, and/or 27.16 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned D crystal form is shown in FIG. 8 .
  • the differential scanning calorimetry curve of the above-mentioned crystal form D has an onset of an endothermic peak at 92.5 ⁇ 3°C.
  • the DSC spectrum of the above-mentioned D crystal form is shown in FIG. 9 .
  • thermogravimetric analysis curve of the above-mentioned crystal form D loses weight up to 4.49% at 60 ⁇ 3°C, and loses another 2.48% at 100 ⁇ 3°C.
  • the TGA spectrum of the above-mentioned D crystal form is shown in FIG. 10 .
  • the present invention also provides compounds of formula (II):
  • n is 0 to 5; preferably 0.5 to 1.5; more preferably 0.75 or 0.86.
  • the present invention provides the E crystal form of the compound of formula (II), whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 19.36 ⁇ 0.20°, 20.98 ⁇ 0.20° and 21.44 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction pattern of the above-mentioned crystal form E has characteristic diffraction peaks at the following 2 ⁇ angles: 3.92 ⁇ 0.20°, 15.24 ⁇ 0.20°, 19.36 ⁇ 0.20°, 19.88 ⁇ 0.20°, 20.32 ⁇ 0.20 °, 20.98 ⁇ 0.20°, 21.44 ⁇ 0.20° and 23.68 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form E has characteristic diffraction peaks at the following 2 ⁇ angles: 3.92 ⁇ 0.20°, 14.54 ⁇ 0.20°, 15.24 ⁇ 0.20°, 19.36 ⁇ 0.20°, 19.88 ⁇ 0.20 °, 20.32 ⁇ 0.20°, 20.98 ⁇ 0.20°, 21.44 ⁇ 0.20°, 22.98 ⁇ 0.20° and 23.68 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form E has characteristic diffraction peaks at the following 2 ⁇ angles: 3.92°, 7.12°, 8.68°, 9.54°, 10.52°, 11.38°, 12.39°, 13.40° , 14.54°, 15.24°, 16.50°, 17.20°, 18.50°, 19.36°, 19.88°, 20.32°, 20.98°, 21.44°, 22.14°, 22.98°, 23.68°, 24.00°, 25.70°, 24.00°, 25.70 °, 26.20°, 26.92°, 27.96°, 29.30°, 30.48°, 31.08°, 31.82°, 33.91°, 34.84°, 36.38° and 38.08°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form E has characteristic diffraction peaks at the following 2 ⁇ angles: 19.36 ⁇ 0.20°, 20.98 ⁇ 0.20°, and/or 21.44 ⁇ 0.20°, and/or 3.92 ⁇ 0.20°, and/or 15.24 ⁇ 0.20°, and/or 19.88 ⁇ 0.20°, and/or 20.32 ⁇ 0.20°, and/or 23.68 ⁇ 0.20°, and/or 22.98 ⁇ 0.20°, and/or 7.12 ⁇ 0.20° , and/or 8.68 ⁇ 0.20°, and/or 9.54 ⁇ 0.20°, and/or 10.52 ⁇ 0.20°, and/or 11.38 ⁇ 0.20°, and/or 12.39 ⁇ 0.20°, and/or 13.40 ⁇ 0.20°, and /or 14.54 ⁇ 0.20°, and/or 16.50 ⁇ 0.20°, and/or 17.20 ⁇ 0.20°, and/or 18.50 ⁇ 0.20°, and/or 22.14 ⁇ 0.2
  • the XRPD pattern of the above-mentioned crystal form E is shown in FIG. 11 .
  • the differential scanning calorimetry curve of the above-mentioned Form E has an endothermic peak at 161.6 ⁇ 3°C.
  • the DSC spectrum of the above-mentioned E crystal form is shown in FIG. 12 .
  • thermogravimetric analysis curve of the above-mentioned crystal form E has a weight loss of 2.2714% at 200 ⁇ 3°C.
  • the TGA spectrum of the above-mentioned E crystal form is shown in FIG. 13 .
  • the crystalline forms of the compound of formula (I) of the present invention are stable, less affected by light, heat and humidity, and have good drug efficacy in vivo, and have broad prospects for finished medicines.
  • the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • SXRD single crystal X-ray diffraction method
  • the cultured single crystal is collected by Bruker D8 venture diffractometer
  • the light source is CuK ⁇ radiation
  • the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • the solvent used in the present invention is commercially available.
  • the present invention adopts the following abbreviations: EtOH stands for ethanol; MeOH stands for methanol; TFA stands for trifluoroacetic acid; TsOH stands for p-toluenesulfonic acid; mp stands for melting point; EtSO3H stands for ethanesulfonic acid ; THF stands for tetrahydrofuran; EtOAc stands for ethyl acetate.
  • the XRPD pattern was collected on a PANalytical X-ray powder diffraction analyzer, and the scanning parameters are shown in Table 6.
  • TGA and DSC graphs were acquired on a TAQ5000/Discovery TGA 5500 Thermogravimetric Analyzer or a Mettler TGA2SF/1100 Thermogravimetric Analyzer and a TAQ 2000/Discovery DSC 2500 Differential Scanning Calorimeter, respectively, and the test parameters are listed in Table 7 .
  • Figure 14 The molecular structure ellipsoid diagram of the compound of formula (I);
  • Figure 15 Amorphous XRPD pattern of the compound of formula (I).
  • the organic phase was dried over anhydrous sodium sulfate, the solid was filtered off, and then concentrated under reduced pressure to obtain the crude product.
  • the crude product was slurried with ethanol (80 mL), the solid was collected by filtration and the filter cake was washed with ethanol (10 mL ⁇ 3).
  • the filter cake was dissolved in a mixed solvent of dichloromethane (50 mL) and ethanol (100 mL), and stirred with a water pump under reduced pressure until the volume was concentrated to 100 mL.
  • the solid was collected by filtration and the filter cake was washed with ethanol (10 mL x 3).
  • the filter cake was concentrated under reduced pressure to obtain compound K.
  • the crude product was used in the next reaction without further purification.
  • Table 9 Atomic coordinates(x 10 ⁇ 4) and equivalent isotropic displacement parameters(A ⁇ 2x 10 ⁇ 3).
  • amorphous compound of formula (I) drop into a mixed solvent of 36mL of ethanol and 72mL of n-heptane at 20°C, heat to 48°C under stirring, keep stirring slowly for 4 hours, filter and collect the filter cake and place it in a vacuum oven Dry at 50°C for 48 hours to obtain the C crystal form of the compound of formula (I).
  • amorphous compound of formula (I) disperse it with 8L ultrapure water to form a suspension, and transfer it into 4L ultrapure water under nitrogen protection and stirring at 100rpm. Under stirring at 200 rpm, the temperature was slowly raised to 40 ⁇ 5° C., and the temperature was kept stirring for 16 hours. After filtration, the filter cake was washed three times with ultrapure water, 1L each time. The filter cake was then dispersed with 8L of ultrapure water to form a suspension, which was transferred into 4L of ultrapure water under nitrogen protection with stirring at 100rpm. Under stirring at 200 rpm, the temperature was slowly raised to 40 ⁇ 5° C., and the temperature was kept stirring for 16 hours.
  • the filter cake was washed three times with ultrapure water, 1L each time. Under the temperature of 40 ⁇ 5°C, P ⁇ -0.08MPa, the filter cake is decompressed and rotary evaporated to remove water, and the water content is less than 20% detected by infrared drying and weight loss method.
  • the obtained solid was pulverized with a high-speed pulverizer and passed through a 40-mesh sieve.
  • the obtained powder is put into a vacuum drying box, and dried under vacuum at a temperature of 40 ⁇ 5° C. and P ⁇ -0.08MPa to a moisture content of less than 2%.
  • the dried solid is placed in an environment of relative humidity of 92.5% (saturated potassium nitrate solution, temperature 25° C.), sealed and placed for 3 days to obtain the E crystal form of the compound of formula (I).
  • Example 3 Stability test of formula (I) compound B crystal form, D crystal form and E crystal form
  • Crystal form B was kept closed for 10 days under the condition of 60°C and kept closed for a certain period of time under the condition of light, and the crystal form did not change;
  • Crystal form D was kept closed for 2 weeks at 60°C, 2 weeks at 92.5% RH, and kept closed for a certain period of time under light conditions, and the crystal form did not change.
  • a single dose can downregulate blood glucose levels in healthy rats after oral glucose
  • the compound E crystal form of formula (I) can effectively reduce and significantly reduce the AUC level of blood glucose in animals within 2 hours, and the hypoglycemic effect is better than the same dose of Canagliflozin.

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Abstract

The present invention relates to a crystal form of a tetrahydropyran ring compound and a preparation method therefor. Specifically disclosed are the polymorphism of the compound represented by formula (I), and a preparation method for the compound.

Description

四氢吡喃环类化合物的晶型及其制备方法Crystal form of tetrahydropyran ring compounds and preparation method thereof
本申请主张如下优先权This application claims the following priority
CN202110104069.9，申请日：2021年01月26日。CN202110104069.9, application date: January 26, 2021.
技术领域technical field
本发明涉及四氢吡喃环类化合物的晶型及其制备方法，具体公开了式(Ⅰ)所示化合物的多晶型及其制备方法。The present invention relates to a crystal form of tetrahydropyran ring compounds and a preparation method thereof, and specifically discloses the polymorphic form of the compound represented by formula (I) and a preparation method thereof.
背景技术Background technique
糖尿病是一种以高血糖为特征的代谢性疾病。目前，临床治疗用降糖药物包括双胍类、磺酰脲类、胰岛素耐受改善剂、格列奈类、α-葡萄糖苷酶抑制剂和二肽基肽酶-IV抑制剂等。这些药物长期治疗仍存在安全性问题，因此，迫切需要开发出一种更安全、优效的新型降糖药物满足糖尿病的治疗需要。Diabetes is a metabolic disease characterized by hyperglycemia. At present, hypoglycemic drugs for clinical treatment include biguanides, sulfonylureas, insulin resistance improvers, glinides, α-glucosidase inhibitors and dipeptidyl peptidase-IV inhibitors. There are still safety problems in the long-term treatment of these drugs. Therefore, there is an urgent need to develop a newer, safer and more effective hypoglycemic drug to meet the needs of diabetes treatment.
钠-葡萄糖共转运蛋白(sodium-glucose cotransporters,SGLTs)是一类在小肠黏膜和肾近曲小管中发现的葡萄糖转运蛋白家族，家族成员主要包括SGLT1蛋白和SGLT2蛋白两类，其功能是介导肠道和肾脏中葡萄糖的跨膜转运，在维持人体血糖稳定中起着关键作用。达格列净(Dapagliflozin)，卡格列净(Canagliflozin)，恩格列净(Empagliflozin)和索格列净(Sotagliflozin)等SGLTs抑制剂药物先后被批准用于治疗糖尿病。Sodium-glucose cotransporters (SGLTs) are a family of glucose transporters found in the small intestinal mucosa and proximal renal tubules. The family members mainly include SGLT1 and SGLT2 proteins. Transmembrane transport of glucose in the gut and kidneys plays a key role in maintaining blood sugar stability in humans. SGLTs inhibitor drugs such as Dapagliflozin, Canagliflozin, Empagliflozin and Sotagliflozin have been approved for the treatment of diabetes.
二肽基肽酶-IV(Dipeptidyl peptidase 4)是一种细胞表面的丝氨酸蛋白酶，可以灭活多种胰高血糖素样肽-1(glucagon-like peptide-1，GLP-1)和葡萄糖依赖性促胰岛素分泌多肽(glucose-dependent insulinotropic polypeptide，GIP)。DPP-4抑制剂可以使DPP-4失活，从而不分解GLP-1，通过提高GLP-1的水平，发挥控制血糖的作用。西格列汀(sitagliptin)、维格列汀(vildagliptin)、沙格列汀(saxagliptin)、利格列汀(linagliptin)等DPP-4抑制剂已经广泛用于糖尿病的临床治疗。Dipeptidyl peptidase-IV (Dipeptidyl peptidase 4) is a cell surface serine protease that inactivates various glucagon-like peptide-1 (GLP-1) and glucose-dependent Glucose-dependent insulinotropic polypeptide (GIP). DPP-4 inhibitors can inactivate DPP-4, thereby not decomposing GLP-1, and exerting the effect of controlling blood sugar by increasing the level of GLP-1. DPP-4 inhibitors such as sitagliptin, vildagliptin, saxagliptin, and linagliptin have been widely used in the clinical treatment of diabetes.
SGLT1和DPP4靶点抑制协同作用，可促进和延长内源性GLP-1的分泌和浓度，刺激内源性胰岛素的分泌而提高体内整体糖能量的应用，再加上SGLT2靶点抑制，加快高血糖水平条件下葡萄糖的排泄，从而贯穿葡萄糖在体内的吸收，代谢和排泄整体途径，全方位降低血糖水平且不易引发低血糖风险。The synergistic effect of SGLT1 and DPP4 target inhibition can promote and prolong the secretion and concentration of endogenous GLP-1, stimulate the secretion of endogenous insulin and improve the application of overall glucose energy in the body. Glucose excretion under the condition of blood sugar level, thus running through the overall pathway of glucose absorption, metabolism and excretion in the body, reducing blood sugar level in an all-round way and not easily causing the risk of hypoglycemia.
综上所述，SGLT1/SGLT2/DPP4三重抑制剂有着良好的开发前景。In conclusion, the triple inhibitor of SGLT1/SGLT2/DPP4 has good development prospects.
发明内容SUMMARY OF THE INVENTION
本发明提供了式(Ⅰ)化合物的A晶型，其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：6.13±0.20°、15.99±0.20°和21.04±0.20°：The present invention provides Form A of the compound of formula (I), whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2θ angles: 6.13±0.20°, 15.99±0.20° and 21.04±0.20°:
Figure PCTCN2021118616-appb-000001
Figure PCTCN2021118616-appb-000001
本发明的一些方案中，上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.13±0.20°、8.21±0.20°、10.63±0.20°、15.99±0.20°、17.21±0.20°、21.04±0.20°、21.53±0.20°和22.47±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles: 6.13±0.20°, 8.21±0.20°, 10.63±0.20°, 15.99±0.20°, 17.21±0.20 °, 21.04±0.20°, 21.53±0.20° and 22.47±0.20°.
在本发明的一些技术方案中，上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.13±0.20°，15.99±0.20°，和/或21.04±0.20°，和/或8.21±0.20°，和/或10.63±0.20°，和/或12.08±0.20°，和/或14.40±0.20°，和/或17.21±0.20°，和/或21.53±0.20°，和/或22.47±0.20°，和/或26.47±0.20°。In some technical solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 6.13±0.20°, 15.99±0.20°, and/or 21.04±0.20°, and/or 8.21±0.20°, and/or 10.63±0.20°, and/or 12.08±0.20°, and/or 14.40±0.20°, and/or 17.21±0.20°, and/or 21.53±0.20°, and/or 22.47± 0.20°, and/or 26.47±0.20°.
本发明的一些方案中，上述A晶型，其XRPD图谱如附图1所示。In some solutions of the present invention, the XRPD pattern of the above-mentioned crystal form A is shown in FIG. 1 .
本发明的一些方案中，上述A晶型的XRPD图谱解析数据如表1所示：In some schemes of the present invention, the XRPD spectrum analysis data of above-mentioned A crystal form is shown in Table 1:
表1式(I)化合物A晶型的XRPD解析数据Table 1 XRPD analysis data of the crystal form of compound A of formula (I)
Figure PCTCN2021118616-appb-000002
Figure PCTCN2021118616-appb-000002
在本发明的一些方案中，上述A晶型的差示扫描量热曲线在73.5±3℃以及109.1±3℃处具有吸热峰的峰值。In some aspects of the present invention, the differential scanning calorimetry curve of the above-mentioned Form A has endothermic peaks at 73.5±3°C and 109.1±3°C.
在本发明的一些方案中，上述A晶型的DSC图谱如图2所示。In some embodiments of the present invention, the DSC spectrum of the above-mentioned A crystal form is shown in FIG. 2 .
本发明提供了式(Ⅰ)化合物的B晶型，其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：10.64±0.20°、15.59±0.20°和20.65±0.20°：The present invention provides the B crystal form of the compound of formula (I), whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2θ angles: 10.64±0.20°, 15.59±0.20° and 20.65±0.20°:
Figure PCTCN2021118616-appb-000003
Figure PCTCN2021118616-appb-000003
本发明的一些方案中，上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.24±0.20°、6.17±0.20°、10.64±0.20°、13.87±0.20°、15.59±0.20°、16.58±0.20°、20.65±0.20°和21.75±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2θ angles: 5.24±0.20°, 6.17±0.20°, 10.64±0.20°, 13.87±0.20°, 15.59±0.20 °, 16.58±0.20°, 20.65±0.20° and 21.75±0.20°.
本发明的一些方案中，上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.24°、6.17°、7.00°、8.12°、10.64°、11.69°、12.18°、12.55°、13.87°、15.59°、16.58°、18.06°、18.45°、20.27°、20.65°、21.31°、21.75°、22.67°、24.66°、25.38°、26.26°、27.18°、28.40°、31.12°、32.14°、33.38°、36.61°、37.27°和38.83°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2θ angles: 5.24°, 6.17°, 7.00°, 8.12°, 10.64°, 11.69°, 12.18°, 12.55° , 13.87°, 15.59°, 16.58°, 18.06°, 18.45°, 20.27°, 20.65°, 21.31°, 21.75°, 22.67°, 24.66°, 25.38°, 26.26°, 27.18°, 28.40°, 31.12°, 32.14 °, 33.38°, 36.61°, 37.27° and 38.83°.
本发明的一些方案中，上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.64±0.20°，15.59±0.20°，和/或20.65±0.20°，和/或5.24±0.20°，和/或6.17±0.20°，和/或13.87±0.20°，和/或16.58±0.20°，和/或21.75±0.20°，和/或7.00±0.20°，和/或8.12±0.20°，和/或11.69±0.20°，和/或12.18±0.20°，和/或12.55±0.20°，和/或18.06±0.20°，和/或18.45±0.20°，和/或20.27±0.20°，和/或21.31±0.20°，和/或22.67±0.20°，和/或24.66±0.20°，和/或25.38±0.20°，和/或26.26±0.20°，和/或27.18±0.20°，和/或28.40±0.20°，和/或31.12±0.20°，和/或32.14±0.20°，和/或33.38±0.20°，和/或36.61±0.20°，和/或37.27±0.20°，和/或38.83±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2θ angles: 10.64±0.20°, 15.59±0.20°, and/or 20.65±0.20°, and/or 5.24± 0.20°, and/or 6.17±0.20°, and/or 13.87±0.20°, and/or 16.58±0.20°, and/or 21.75±0.20°, and/or 7.00±0.20°, and/or 8.12±0.20° , and/or 11.69±0.20°, and/or 12.18±0.20°, and/or 12.55±0.20°, and/or 18.06±0.20°, and/or 18.45±0.20°, and/or 20.27±0.20°, and /or 21.31±0.20°, and/or 22.67±0.20°, and/or 24.66±0.20°, and/or 25.38±0.20°, and/or 26.26±0.20°, and/or 27.18±0.20°, and/or 28.40±0.20°, and/or 31.12±0.20°, and/or 32.14±0.20°, and/or 33.38±0.20°, and/or 36.61±0.20°, and/or 37.27±0.20°, and/or 38.83± 0.20°.
本发明的一些方案中，上述B晶型，其XRPD图谱如附图3所示。In some solutions of the present invention, the XRPD pattern of the above-mentioned crystal form B is shown in FIG. 3 .
本发明的一些方案中，上述B晶型的XRPD图谱解析数据如表2所示：In some schemes of the present invention, the XRPD spectrum analysis data of the above-mentioned B crystal form are shown in Table 2:
表2式(I)化合物B晶型的XRPD解析数据Table 2 XRPD analysis data of compound B crystal form of formula (I)
Figure PCTCN2021118616-appb-000004
Figure PCTCN2021118616-appb-000004
在本发明的一些方案中，上述B晶型的差示扫描量热曲线在104.1±3℃处具有吸热峰的起始点。In some aspects of the present invention, the differential scanning calorimetry curve of the above-mentioned Form B has an onset of an endothermic peak at 104.1±3°C.
在本发明的一些方案中，上述B晶型的DSC图谱如图4所示。In some embodiments of the present invention, the DSC spectrum of the above-mentioned crystal form B is shown in FIG. 4 .
在本发明的一些方案中，上述B晶型的热重分析曲线在100℃处失重达1.98％，至130℃处又失重0.54％。In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form B loses 1.98% of the weight at 100°C, and loses 0.54% of the weight at 130°C.
在本发明的一些方案中，上述B晶型的TGA图谱如图5所示。In some embodiments of the present invention, the TGA spectrum of the above-mentioned B crystal form is shown in FIG. 5 .
本发明提供了式(Ⅰ)化合物的C晶型，其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：12.00±0.20°、17.01±0.20°和18.01±0.20°：The present invention provides the C crystal form of the compound of formula (I), whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2θ angles: 12.00±0.20°, 17.01±0.20° and 18.01±0.20°:
Figure PCTCN2021118616-appb-000005
Figure PCTCN2021118616-appb-000005
本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.05±0.20°、8.65±0.20°、12.00±0.20°、17.01±0.20°、17.60±0.20°、18.01±0.20°、18.44±0.20°和20.89±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2θ angles: 5.05±0.20°, 8.65±0.20°, 12.00±0.20°, 17.01±0.20°, 17.60±0.20 °, 18.01±0.20°, 18.44±0.20° and 20.89±0.20°.
本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.05±0.20°、6.00±0.20°、8.65±0.20°、12.00±0.20°、17.01±0.20°、17.60±0.20°、18.01±0.20°、18.44±0.20°、20.89±0.20°和22.93±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form C has characteristic diffraction peaks at the following 2θ angles: 5.05±0.20°, 6.00±0.20°, 8.65±0.20°, 12.00±0.20°, 17.01±0.20 °, 17.60±0.20°, 18.01±0.20°, 18.44±0.20°, 20.89±0.20° and 22.93±0.20°.
本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.36°、5.05°、6.00°、8.19°、8.65°、9.95°、12.00°、12.30°、13.57°、14.07°、15.02°、15.62°、16.50°、17.01°、17.60°、18.01°、18.44°、19.04°、19.40°、19.87°、20.36°、20.89°、22.27°、22.93°、23.35°、24.48°、25.14°、25.49°、26.97°、28.88°、29.24°、32.83°和36.94°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2θ angles: 4.36°, 5.05°, 6.00°, 8.19°, 8.65°, 9.95°, 12.00°, 12.30° , 13.57°, 14.07°, 15.02°, 15.62°, 16.50°, 17.01°, 17.60°, 18.01°, 18.44°, 19.04°, 19.40°, 19.87°, 20.36°, 20.89°, 22.27°, 22.93°, 23.35 °, 24.48°, 25.14°, 25.49°, 26.97°, 28.88°, 29.24°, 32.83° and 36.94°.
本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.00±0.20°，17.01±0.20°，和/或5.05±0.20°，和/或6.00±0.20°，和/或8.65±0.20°，和/或17.60±0.20°，和/或18.01±0.20°，和/或18.44±0.20°，和/或20.89±0.20°，和/或22.93±0.20°，和/或4.36±0.20°，和/或8.19±0.20°，和/或9.95±0.20°，和/或12.30±0.20°，和/或13.57±0.20°，和/或14.07±0.20°，和/或15.02±0.20°，和/或15.62±0.20°，和/或16.50±0.20°，和/或19.04±0.20°，和/或19.40±0.20°，和/或19.87±0.20°，和/或20.36±0.20°，和/或22.27±0.20°，和/或23.35±0.20°，和/或24.48±0.20°，和/或25.14±0.20°，和/或25.49±0.20°，和/或26.97±0.20°，和/或28.88±0.20°，和/或29.24±0.20°，和/或32.83±0.20°，和/或36.94±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form C has characteristic diffraction peaks at the following 2θ angles: 12.00±0.20°, 17.01±0.20°, and/or 5.05±0.20°, and/or 6.00±0.20° 0.20°, and/or 8.65±0.20°, and/or 17.60±0.20°, and/or 18.01±0.20°, and/or 18.44±0.20°, and/or 20.89±0.20°, and/or 22.93±0.20° , and/or 4.36±0.20°, and/or 8.19±0.20°, and/or 9.95±0.20°, and/or 12.30±0.20°, and/or 13.57±0.20°, and/or 14.07±0.20°, and /or 15.02±0.20°, and/or 15.62±0.20°, and/or 16.50±0.20°, and/or 19.04±0.20°, and/or 19.40±0.20°, and/or 19.87±0.20°, and/or 20.36±0.20°, and/or 22.27±0.20°, and/or 23.35±0.20°, and/or 24.48±0.20°, and/or 25.14±0.20°, and/or 25.49±0.20°, and/or 26.97± 0.20°, and/or 28.88±0.20°, and/or 29.24±0.20°, and/or 32.83±0.20°, and/or 36.94±0.20°.
本发明的一些方案中，上述C晶型，其XRPD图谱如附图6所示。In some solutions of the present invention, the XRPD pattern of the above-mentioned crystal form C is shown in FIG. 6 .
本发明的一些方案中，上述C晶型的XRPD图谱解析数据如表3所示：In some schemes of the present invention, the XRPD spectrum analysis data of above-mentioned C crystal form is shown in Table 3:
表3式(I)化合物C晶型的XRPD解析数据Table 3 XRPD analysis data of compound C crystal form of formula (I)
Figure PCTCN2021118616-appb-000006
Figure PCTCN2021118616-appb-000006
Figure PCTCN2021118616-appb-000007
Figure PCTCN2021118616-appb-000007
在本发明的一些方案中，上述C晶型的热重分析曲线在100±3℃处失重达3.41％。In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form C has a weight loss of 3.41% at 100±3°C.
在本发明的一些方案中，上述C晶型的TGA图谱如图7所示。In some embodiments of the present invention, the TGA spectrum of the above-mentioned C crystal form is shown in FIG. 7 .
本发明提供了式(Ⅰ)化合物的D晶型，其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：4.81±0.20°、15.74±0.20°和17.09±0.20°：The present invention provides the D crystal form of the compound of formula (I), whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2θ angles: 4.81±0.20°, 15.74±0.20° and 17.09±0.20°:
Figure PCTCN2021118616-appb-000008
Figure PCTCN2021118616-appb-000008
本发明的一些方案中，上述D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.81±0.20°、9.60±0.20°、14.58±0.20°、15.74±0.20°、17.09±0.20°、19.86±0.20°、22.46±0.20°和23.85±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the above crystal form D has characteristic diffraction peaks at the following 2θ angles: 4.81±0.20°, 9.60±0.20°, 14.58±0.20°, 15.74±0.20°, 17.09±0.20 °, 19.86±0.20°, 22.46±0.20° and 23.85±0.20°.
本发明的一些方案中，上述D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.81°、9.60°、10.60°、11.51°、13.05°、14.58°、15.74°、17.09°、18.11°、19.86°、22.46°、23.85°和27.16°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the above crystal form D has characteristic diffraction peaks at the following 2θ angles: 4.81°, 9.60°, 10.60°, 11.51°, 13.05°, 14.58°, 15.74°, 17.09° , 18.11°, 19.86°, 22.46°, 23.85° and 27.16°.
本发明的一些方案中，上述D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.81±0.20°，15.74±0.20°，和/或17.09±0.20°，和/或9.60±0.20°，和/或14.58±0.20°，和/或19.86±0.20°，和/或22.46±0.20°，和/或23.85±0.20°，和/或10.60±0.20°，和/或11.51±0.20°，和/或13.05±0.20°，和/或18.11±0.20°，和/或27.16±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form D has characteristic diffraction peaks at the following 2θ angles: 4.81±0.20°, 15.74±0.20°, and/or 17.09±0.20°, and/or 9.60±0.20° 0.20°, and/or 14.58±0.20°, and/or 19.86±0.20°, and/or 22.46±0.20°, and/or 23.85±0.20°, and/or 10.60±0.20°, and/or 11.51±0.20° , and/or 13.05±0.20°, and/or 18.11±0.20°, and/or 27.16±0.20°.
本发明的一些方案中，上述D晶型，其XRPD图谱如附图8所示。In some solutions of the present invention, the XRPD pattern of the above-mentioned D crystal form is shown in FIG. 8 .
本发明的一些方案中，上述D晶型的XRPD图谱解析数据如表4所示：In some schemes of the present invention, the XRPD spectrum analysis data of above-mentioned D crystal form is shown in Table 4:
表4式(I)化合物D晶型的XRPD解析数据Table 4 XRPD analysis data of compound D crystal form of formula (I)
Figure PCTCN2021118616-appb-000009
Figure PCTCN2021118616-appb-000009
在本发明的一些方案中，上述D晶型的差示扫描量热曲线在92.5±3℃处具有吸热峰的起始点。In some aspects of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form D has an onset of an endothermic peak at 92.5±3°C.
在本发明的一些方案中，上述D晶型的DSC图谱如图9所示。In some embodiments of the present invention, the DSC spectrum of the above-mentioned D crystal form is shown in FIG. 9 .
在本发明的一些方案中，上述D晶型的热重分析曲线在60±3℃处失重达4.49％，至100±3℃处又失重2.48％。In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form D loses weight up to 4.49% at 60±3°C, and loses another 2.48% at 100±3°C.
在本发明的一些方案中，上述D晶型的TGA图谱如图10所示。In some embodiments of the present invention, the TGA spectrum of the above-mentioned D crystal form is shown in FIG. 10 .
本发明还提供了式(Ⅱ)化合物：The present invention also provides compounds of formula (II):
Figure PCTCN2021118616-appb-000010
Figure PCTCN2021118616-appb-000010
其中，in,
n为0～5；优选为0.5～1.5；更优选为0.75或0.86。n is 0 to 5; preferably 0.5 to 1.5; more preferably 0.75 or 0.86.
本发明提供了式(Ⅱ)化合物的E晶型，其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：19.36±0.20°、20.98±0.20°和21.44±0.20°。The present invention provides the E crystal form of the compound of formula (II), whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2θ angles: 19.36±0.20°, 20.98±0.20° and 21.44±0.20°.
本发明的一些方案中，上述E晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.92±0.20°、15.24±0.20°、19.36±0.20°、19.88±0.20°、20.32±0.20°、20.98±0.20°、21.44±0.20°和23.68±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form E has characteristic diffraction peaks at the following 2θ angles: 3.92±0.20°, 15.24±0.20°, 19.36±0.20°, 19.88±0.20°, 20.32±0.20 °, 20.98±0.20°, 21.44±0.20° and 23.68±0.20°.
本发明的一些方案中，上述E晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.92±0.20°、14.54±0.20°、15.24±0.20°、19.36±0.20°、19.88±0.20°、20.32±0.20°、20.98±0.20°、21.44±0.20°、22.98±0.20°和23.68±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form E has characteristic diffraction peaks at the following 2θ angles: 3.92±0.20°, 14.54±0.20°, 15.24±0.20°, 19.36±0.20°, 19.88±0.20 °, 20.32±0.20°, 20.98±0.20°, 21.44±0.20°, 22.98±0.20° and 23.68±0.20°.
本发明的一些方案中，上述E晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.92°、 7.12°、8.68°、9.54°、10.52°、11.38°、12.39°、13.40°、14.54°、15.24°、16.50°、17.20°、18.50°、19.36°、19.88°、20.32°、20.98°、21.44°、22.14°、22.98°、23.68°、24.00°、25.70°、24.00°、25.70°、26.20°、26.92°、27.96°、29.30°、30.48°、31.08°、31.82°、33.91°、34.84°、36.38°和38.08°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form E has characteristic diffraction peaks at the following 2θ angles: 3.92°, 7.12°, 8.68°, 9.54°, 10.52°, 11.38°, 12.39°, 13.40° , 14.54°, 15.24°, 16.50°, 17.20°, 18.50°, 19.36°, 19.88°, 20.32°, 20.98°, 21.44°, 22.14°, 22.98°, 23.68°, 24.00°, 25.70°, 24.00°, 25.70 °, 26.20°, 26.92°, 27.96°, 29.30°, 30.48°, 31.08°, 31.82°, 33.91°, 34.84°, 36.38° and 38.08°.
本发明的一些方案中，上述E晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：19.36±0.20°，20.98±0.20°，和/或21.44±0.20°，和/或3.92±0.20°，和/或15.24±0.20°，和/或19.88±0.20°，和/或20.32±0.20°，和/或23.68±0.20°，和/或22.98±0.20°，和/或7.12±0.20°，和/或8.68±0.20°，和/或9.54±0.20°，和/或10.52±0.20°，和/或11.38±0.20°，和/或12.39±0.20°，和/或13.40±0.20°，和/或14.54±0.20°，和/或16.50±0.20°，和/或17.20±0.20°，和/或18.50±0.20°，和/或22.14±0.20°，和/或24.00±0.20°，和/或25.70±0.20°，和/或24.00±0.20°，和/或25.70±0.20°，和/或26.20±0.20°，和/或26.92±0.20°，和/或27.96±0.20°，和/或29.30±0.20°，和/或30.48±0.20°，和/或31.08±0.20°，和/或31.82±0.20°，和/或33.91±0.20°，和/或34.84±0.20°，和/或36.38±0.20°，和/或38.08±0.20°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form E has characteristic diffraction peaks at the following 2θ angles: 19.36±0.20°, 20.98±0.20°, and/or 21.44±0.20°, and/or 3.92± 0.20°, and/or 15.24±0.20°, and/or 19.88±0.20°, and/or 20.32±0.20°, and/or 23.68±0.20°, and/or 22.98±0.20°, and/or 7.12±0.20° , and/or 8.68±0.20°, and/or 9.54±0.20°, and/or 10.52±0.20°, and/or 11.38±0.20°, and/or 12.39±0.20°, and/or 13.40±0.20°, and /or 14.54±0.20°, and/or 16.50±0.20°, and/or 17.20±0.20°, and/or 18.50±0.20°, and/or 22.14±0.20°, and/or 24.00±0.20°, and/or 25.70±0.20°, and/or 24.00±0.20°, and/or 25.70±0.20°, and/or 26.20±0.20°, and/or 26.92±0.20°, and/or 27.96±0.20°, and/or 29.30± 0.20°, and/or 30.48±0.20°, and/or 31.08±0.20°, and/or 31.82±0.20°, and/or 33.91±0.20°, and/or 34.84±0.20°, and/or 36.38±0.20° , and/or 38.08±0.20°.
本发明的一些方案中，上述E晶型，其XRPD图谱如附图11所示。In some solutions of the present invention, the XRPD pattern of the above-mentioned crystal form E is shown in FIG. 11 .
本发明的一些方案中，上述E晶型的XRPD图谱解析数据如表5所示：In some schemes of the present invention, the XRPD spectrum analysis data of above-mentioned E crystal form are as shown in Table 5:
表5式(Ⅱ)化合物E晶型的XRPD解析数据Table 5 XRPD analysis data of compound E crystal form of formula (II)
Figure PCTCN2021118616-appb-000011
Figure PCTCN2021118616-appb-000011
在本发明的一些方案中，上述E晶型的差示扫描量热曲线在161.6±3℃处具有吸热峰的峰值。In some aspects of the present invention, the differential scanning calorimetry curve of the above-mentioned Form E has an endothermic peak at 161.6±3°C.
在本发明的一些方案中，上述E晶型的DSC图谱如图12所示。In some embodiments of the present invention, the DSC spectrum of the above-mentioned E crystal form is shown in FIG. 12 .
在本发明的一些方案中，上述E晶型的热重分析曲线在200±3℃处失重达2.2714％。In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form E has a weight loss of 2.2714% at 200±3°C.
在本发明的一些方案中，上述E晶型的TGA图谱如图13所示。In some embodiments of the present invention, the TGA spectrum of the above-mentioned E crystal form is shown in FIG. 13 .
技术效果technical effect
本发明式(Ⅰ)化合物的各晶型稳定、受光热湿度影响小且具有良好的体内给药药效，成药前景广阔。The crystalline forms of the compound of formula (I) of the present invention are stable, less affected by light, heat and humidity, and have good drug efficacy in vivo, and have broad prospects for finished medicines.
定义和说明Definition and Explanation
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered indeterminate or unclear without a specific definition, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient.
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those skilled in the art. Well-known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reactions of specific embodiments of the present invention are carried out in suitable solvents suitable for the chemical changes of the present invention and their required reagents and materials. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthetic steps or reaction schemes on the basis of the existing embodiments.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2021118616-appb-000012
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。 The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode is:
Figure PCTCN2021118616-appb-000012
After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。The present invention will be specifically described below through examples, which do not imply any limitation to the present invention.
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。All solvents used in the present invention are commercially available and used without further purification.
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：EtOH代表乙醇；MeOH代表甲醇；TFA代表三氟乙酸；TsOH代表对甲苯磺酸；mp代表熔点；EtSO 3H代表乙磺酸；MeSO 3H代表甲磺酸；THF代表四氢呋喃；EtOAc代表乙酸乙酯。 The solvent used in the present invention is commercially available. The present invention adopts the following abbreviations: EtOH stands for ethanol; MeOH stands for methanol; TFA stands for trifluoroacetic acid; TsOH stands for p-toluenesulfonic acid; mp stands for melting point; EtSO3H stands for ethanesulfonic acid ; THF stands for tetrahydrofuran; EtOAc stands for ethyl acetate.
仪器参数Instrument parameters
本发明粉末X-射线衍射(X-ray powder diffractometer,XRPD)方法The powder X-ray diffraction (X-ray powder diffractometer, XRPD) method of the present invention
XRPD图在PANalytical X射线粉末衍射分析仪上采集，扫描参数如表6所示。The XRPD pattern was collected on a PANalytical X-ray powder diffraction analyzer, and the scanning parameters are shown in Table 6.
表6 XRPD测试参数Table 6 XRPD test parameters
Figure PCTCN2021118616-appb-000013
Figure PCTCN2021118616-appb-000013
Figure PCTCN2021118616-appb-000014
Figure PCTCN2021118616-appb-000014
本发明差热分析(Differential Scanning Calorimeter,DSC)方法Differential Thermal Analysis (Differential Scanning Calorimeter, DSC) method of the present invention
TGA和DSC图分别在TAQ5000/Discovery TGA 5500型热重分析仪或Mettler TGA2SF/1100型热重分析仪和TAQ 2000/Discovery DSC 2500型差示扫描量热仪上采集，表7列出了测试参数。TGA and DSC graphs were acquired on a TAQ5000/Discovery TGA 5500 Thermogravimetric Analyzer or a Mettler TGA2SF/1100 Thermogravimetric Analyzer and a TAQ 2000/Discovery DSC 2500 Differential Scanning Calorimeter, respectively, and the test parameters are listed in Table 7 .
表7 TGA和DSC测试参数Table 7 TGA and DSC test parameters
参数parameter TGATGA DSCDSC
方法method 线性升温Linear heating 线性升温Linear heating
样品盘sample tray 铝盘，敞开Aluminium pan, open 铝盘，压盖Aluminium pan, gland
温度范围temperature range 室温-设定温度room temperature - set temperature 室温/25℃-设定温度Room temperature/25℃-set temperature
扫描速率(℃/分钟)Scan rate (℃/min) 1010 1010
保护气体Protective gas 氮气nitrogen 氮气nitrogen
附图说明Description of drawings
图1：式(Ⅰ)化合物的A晶型的XRPD图谱；Figure 1: XRPD pattern of Form A of the compound of formula (I);
图2：式(Ⅰ)化合物的A晶型的DSC图谱；Figure 2: DSC spectrum of the A crystal form of the compound of formula (I);
图3：式(Ⅰ)化合物的B晶型的XRPD图谱；Figure 3: XRPD pattern of the B crystal form of the compound of formula (I);
图4：式(Ⅰ)化合物的B晶型的DSC图谱；Figure 4: DSC spectrum of the B crystal form of the compound of formula (I);
图5：式(Ⅰ)化合物的B晶型的TGA图谱；Figure 5: TGA spectrum of the B crystal form of the compound of formula (I);
图6：式(Ⅰ)化合物的C晶型的XRPD图谱；Figure 6: XRPD pattern of the C crystal form of the compound of formula (I);
图7：式(Ⅰ)化合物的C晶型的TGA图谱；Figure 7: TGA spectrum of the C crystal form of the compound of formula (I);
图8：式(Ⅰ)化合物的D晶型的XRPD图谱；Figure 8: XRPD pattern of the D crystal form of the compound of formula (I);
图9：式(Ⅰ)化合物的D晶型的DSC图谱；Figure 9: DSC spectrum of the D crystal form of the compound of formula (I);
图10：式(Ⅰ)化合物的D晶型的TGA图谱；Figure 10: TGA spectrum of the D crystal form of the compound of formula (I);
图11：式(Ⅱ)化合物的E晶型的XRPD图谱；Figure 11: XRPD pattern of the E crystal form of the compound of formula (II);
图12：式(Ⅱ)化合物的E晶型的DSC图谱；Figure 12: DSC spectrum of the E crystal form of the compound of formula (II);
图13：式(Ⅱ)化合物的E晶型的TGA图谱；Figure 13: TGA spectrum of the E crystal form of the compound of formula (II);
图14：式(Ⅰ)化合物的的分子结构椭球图；Figure 14: The molecular structure ellipsoid diagram of the compound of formula (I);
图15：式(I)化合物的无定形的XRPD图谱。Figure 15: Amorphous XRPD pattern of the compound of formula (I).
具体实施方式Detailed ways
为了更好的理解本发明的内容，下面结合具体实施例来做进一步的说明，但具体的实施方式并不是对本发明的内容所做的限制。In order to better understand the content of the present invention, further description will be given below in conjunction with specific embodiments, but the specific embodiments do not limit the content of the present invention.
实施例1：式(I)化合物的制备Example 1: Preparation of compounds of formula (I)
Figure PCTCN2021118616-appb-000015
Figure PCTCN2021118616-appb-000015
步骤1：化合物B的合成。Step 1: Synthesis of Compound B.
将化合物A(25g，1eq)溶于二氯甲烷(110mL)中，加入三乙胺(27.02g，2eq)，反应降温至0℃于0℃下，将甲烷磺酰氯(15.30g，1eq)逐滴加入反应体系。滴加完毕后，反应由0℃升至15℃，于15℃下搅拌反应3小时。反应完毕后降温至0℃，于0℃下缓慢加入水(100mL)淬灭反应。混合物用二氯甲烷(100mL×2)萃取，合并有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，滤除固体后减压浓缩，得到化合物B。Compound A (25 g, 1 eq) was dissolved in dichloromethane (110 mL), triethylamine (27.02 g, 2 eq) was added, the reaction was cooled to 0 °C at 0 °C, methanesulfonyl chloride (15.30 g, 1 eq) was gradually added Add dropwise to the reaction system. After the dropwise addition, the reaction was increased from 0°C to 15°C, and the reaction was stirred at 15°C for 3 hours. After the reaction was completed, the temperature was lowered to 0°C, and water (100 mL) was slowly added at 0°C to quench the reaction. The mixture was extracted with dichloromethane (100 mL×2), the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered off the solid, and concentrated under reduced pressure to obtain compound B.
步骤2：化合物D的合成。Step 2: Synthesis of Compound D.
将化合物B(6.00g，1eq)，化合物C(3.91g，1eq)，碳酸铯(14.73g，2eq)溶于N,N-二甲基甲酰胺(10.00mL)中，反应体系加热至80℃，于80℃下搅拌反应3小时。反应完毕后，向反应液中加水(50mL)，用乙酸乙酯(30mL×3)萃取，合并有机相依次用水(30mL×3)，饱和食盐水(30mL)洗涤，无水硫酸钠干燥，滤除固体后减压浓缩得粗品。粗品经柱层析纯化得到化合物D。 1H NMR(400MHz，CD 3OD)δ7.41-7.34(m，2H)，6.78-6.74(m，2H)，4.15-4.12(m，1H)，3.64-3.52(m，4H)，2.18-2.07 (m，2H)，1.157(s，9H)。 Compound B (6.00g, 1eq), compound C (3.91g, 1eq), cesium carbonate (14.73g, 2eq) were dissolved in N,N-dimethylformamide (10.00mL), and the reaction system was heated to 80°C , and the reaction was stirred at 80 °C for 3 hours. After the reaction was completed, water (50 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×3), the combined organic phases were washed with water (30 mL×3) and saturated brine (30 mL) in turn, dried over anhydrous sodium sulfate, and filtered. After removing the solid, it was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give compound D. 1 H NMR (400 MHz, CD 3 OD) δ 7.41-7.34 (m, 2H), 6.78-6.74 (m, 2H), 4.15-4.12 (m, 1H), 3.64-3.52 (m, 4H), 2.18- 2.07 (m, 2H), 1.157 (s, 9H).
步骤3：化合物E的合成。Step 3: Synthesis of Compound E.
将化合物D(3.00g，1.00eq)溶于氯化氢的乙酸乙酯溶液(10mL，4M)中，反应在20℃下反应1小时。反应完毕后，反应液加入水(30mL)稀释，混合物用乙酸乙酯(20mL)洗涤。水相用饱和碳酸氢钠水溶液调节至pH＝7。水相用乙酸乙酯(30mL)萃取。有机相用饱和氯化钠水溶液(20mL)洗涤。有机相经无水硫酸钠干燥，滤除固体后减压浓缩，得到化合物E的粗品。该粗品不经进一步纯化直接用于下一步反应。 1H NMR(400MHz，CD 3OD)δ7.39-7.35(m，2H)，6.76-6.74(m，2H)，5.30(m，1H)，3.31-3.13(m，4H)，2.15-2.05(m，2H)。 Compound D (3.00 g, 1.00 eq) was dissolved in an ethyl acetate solution of hydrogen chloride (10 mL, 4 M), and the reaction was carried out at 20° C. for 1 hour. After completion of the reaction, the reaction solution was diluted with water (30 mL), and the mixture was washed with ethyl acetate (20 mL). The aqueous phase was adjusted to pH=7 with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated aqueous sodium chloride solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, and the solid was filtered off and concentrated under reduced pressure to obtain the crude product of compound E. The crude product was used in the next reaction without further purification. 1 H NMR (400 MHz, CD 3 OD) δ 7.39-7.35 (m, 2H), 6.76-6.74 (m, 2H), 5.30 (m, 1H), 3.31-3.13 (m, 4H), 2.15-2.05 ( m, 2H).
步骤4：化合物G的合成。Step 4: Synthesis of Compound G.
将化合物E(2g，1eq)，化合物F(2.58g，1.1eq)，溶于二氯甲烷(20mL)和甲醇(4mL)中，向反应液中加入乙酸(43.11mg，0.1eq)，加入三乙酰氧基硼氢化钠(3.04g，2eq)，反应体系在15℃下反应2小时。反应完毕后，将反应液减压浓缩，向反应液中加水(50mL)洗涤，用二氯甲烷(50mL×2)萃取。合并有机相用饱和食盐水(30mL)洗涤。有机相经无水硫酸钠干燥，滤除固体后减压浓缩得粗品。粗品经柱层析(石油醚/乙酸乙酯＝3/1)分离纯化，得到化合物G。 1H NMR(400MHz，CDCl 3)δ7.37(d，J＝8.8Hz，2H)，7.24-7.17(m，1H)，7.02-6.89(m，2H)，6.74(d，J＝8.8Hz，2H)，4.85-4.74(m，1H)，4.51-4.40(m，1H)，4.31-4.25(m，1H)，4.24-4.18(m，1H)，3.82-3.65(m，1H)，3.45-3.33(m，1H)，3.04-2.83(m，3H)，2.65-2.50(m，2H)，2.50-2.41(m，1H)，2.38-2.23(m，1H)，2.06-1.93(m，1H)，1.26(br s，9H)。 Compound E (2 g, 1 eq), compound F (2.58 g, 1.1 eq) were dissolved in dichloromethane (20 mL) and methanol (4 mL), acetic acid (43.11 mg, 0.1 eq) was added to the reaction solution, and three Sodium acetoxyborohydride (3.04g, 2eq), the reaction system was reacted at 15°C for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, washed with water (50 mL), and extracted with dichloromethane (50 mL×2). The combined organic phases were washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, and the solid was filtered off and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate=3/1) to obtain compound G. 1 H NMR (400 MHz, CDCl 3 ) δ 7.37 (d, J=8.8 Hz, 2H), 7.24-7.17 (m, 1H), 7.02-6.89 (m, 2H), 6.74 (d, J=8.8 Hz, 2H), 4.85-4.74(m, 1H), 4.51-4.40(m, 1H), 4.31-4.25(m, 1H), 4.24-4.18(m, 1H), 3.82-3.65(m, 1H), 3.45- 3.33(m, 1H), 3.04-2.83(m, 3H), 2.65-2.50(m, 2H), 2.50-2.41(m, 1H), 2.38-2.23(m, 1H), 2.06-1.93(m, 1H) ), 1.26 (br s, 9H).
步骤5：化合物I的合成。Step 5: Synthesis of Compound I.
将化合物G(15g，1eq)，化合物H(13.77g，2eq)，乙酸钾(7.98g，3eq)，Pd(dppf)Cl 2(1.98g，0.1eq)溶于无水二氧六环(20mL)中，氮气置换3次，反应加热至90℃，于90℃下反应2小时。反应完毕后，将反应液减压浓缩，向反应液中加水(200mL)稀释，混合物用二氯甲烷(200mL×2)萃取。合并有机相用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，滤除固体后减压浓缩得粗品。粗品经柱层析分离纯化，得到化合物I。 1H NMR(400MHz，CDCl 3)δ7.74(d，J＝8.8Hz，2H)，7.24-7.15(m，1H)，7.01-6.90(m，2H)，6.85(d，J＝8.8Hz，2H)，4.93-4.83(m，1H)，4.46(br d，J＝9.6Hz，1H)，4.27(br d，J＝9.6Hz，1H)，4.24-4.18(m，1H)，3.81-3.68(m，1H)，3.38(br t，J＝10.8Hz，1H)，3.05-2.96(m，1H)，2.93(br d，J＝3.2Hz，2H)，2.63-2.49(m，2H)，2.46(br d，J＝11.6Hz，1H)，2.39-2.27(m，1H)，2.05-1.95(m，1H)，1.51(q，J＝12.0Hz，1H)，1.34(s，12H)，1.26(s，9H)。 Compound G (15g, 1eq), compound H (13.77g, 2eq), potassium acetate (7.98g, 3eq), Pd(dppf)Cl2 (1.98g, 0.1eq ) were dissolved in anhydrous dioxane (20mL) ), nitrogen was replaced three times, the reaction was heated to 90°C, and the reaction was carried out at 90°C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, water (200 mL) was added to the reaction solution to dilute, and the mixture was extracted with dichloromethane (200 mL×2). The combined organic phases were washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered off the solid, and concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by column chromatography to obtain compound I. 1 H NMR (400 MHz, CDCl 3 ) δ 7.74 (d, J=8.8 Hz, 2H), 7.24-7.15 (m, 1H), 7.01-6.90 (m, 2H), 6.85 (d, J=8.8 Hz, 2H), 4.93-4.83 (m, 1H), 4.46 (br d, J=9.6Hz, 1H), 4.27 (br d, J=9.6Hz, 1H), 4.24-4.18 (m, 1H), 3.81-3.68 (m, 1H), 3.38 (br t, J=10.8Hz, 1H), 3.05-2.96 (m, 1H), 2.93 (br d, J=3.2Hz, 2H), 2.63-2.49 (m, 2H), 2.46(br d, J=11.6Hz, 1H), 2.39-2.27(m, 1H), 2.05-1.95(m, 1H), 1.51(q, J=12.0Hz, 1H), 1.34(s, 12H), 1.26(s, 9H).
步骤6：化合物K的合成Step 6: Synthesis of Compound K
将化合物I(3g，1eq)与化合物J(4.29g，1.2eq)以及碳酸钠(1.26g，2eq)与四三苯基磷钯(1.38g，0.2eq)悬浮于甲苯(86mL)与乙醇(21.5mL)以及水(21.5mL)的混合溶剂中。氮气保护下反应于 50℃下搅拌16小时。反应完毕后，反应液浓缩后用二氯甲烷(200mL)稀释，有机相用水(100mL×3)洗涤。有机相经无水硫酸钠干燥后滤除固体后减压浓缩得粗品。粗品用乙醇(80mL)打浆，过滤收集固体并用乙醇(10mL×3)洗涤滤饼。滤饼溶于二氯甲烷(50mL)与乙醇(100mL)的混合溶剂，水泵减压下搅拌至体积浓缩至100mL。过滤收集固体并用乙醇(10mL×3)洗涤滤饼。滤饼减压浓缩，得到化合物K。粗品不经进一步纯化直接用于下一步反应。Compound I (3g, 1eq) and compound J (4.29g, 1.2eq) and sodium carbonate (1.26g, 2eq) and tetrakistriphenylphosphonium palladium (1.38g, 0.2eq) were suspended in toluene (86mL) and ethanol ( 21.5 mL) and water (21.5 mL) in a mixed solvent. The reaction was stirred at 50°C for 16 hours under nitrogen. After the reaction was completed, the reaction solution was concentrated and diluted with dichloromethane (200 mL), and the organic phase was washed with water (100 mL×3). The organic phase was dried over anhydrous sodium sulfate, the solid was filtered off, and then concentrated under reduced pressure to obtain the crude product. The crude product was slurried with ethanol (80 mL), the solid was collected by filtration and the filter cake was washed with ethanol (10 mL×3). The filter cake was dissolved in a mixed solvent of dichloromethane (50 mL) and ethanol (100 mL), and stirred with a water pump under reduced pressure until the volume was concentrated to 100 mL. The solid was collected by filtration and the filter cake was washed with ethanol (10 mL x 3). The filter cake was concentrated under reduced pressure to obtain compound K. The crude product was used in the next reaction without further purification.
步骤7：化合物L的合成Step 7: Synthesis of Compound L
将化合物K(3.3g，1eq)溶于乙酸乙酯(66mL)，加入氯化氢乙酸乙酯溶液(4M，66.00mL，71.76eq)。反应于15℃下搅拌16小时。反应完毕后，将反应液减压浓缩得到化合物L的粗品。粗品不经进一步纯化直接用于下一步反应。Compound K (3.3 g, 1 eq) was dissolved in ethyl acetate (66 mL), and a solution of hydrogen chloride in ethyl acetate (4 M, 66.00 mL, 71.76 eq) was added. The reaction was stirred at 15°C for 16 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product of compound L. The crude product was used in the next reaction without further purification.
步骤8：式(I)化合物的合成Step 8: Synthesis of Compound of Formula (I)
向反应瓶中加入化合物L(760mg，1eq)、甲醇(6mL)和四氢呋喃(3mL)，然后加入一水合氢氧化锂(1.02g，20eq)和水(6mL)，25℃下混合液反应16小时。反应完毕后，反应液用水(10mL)稀释，乙酸乙酯(10mL×3)萃取，有机相用饱和食盐水(30mL)洗涤后用无水硫酸钠干燥，然后在45℃减压浓缩干。用制备高效液相色谱法纯化得到式(I)化合物。 1H NMR(400MHz，CDCl 3)δ7.21(s，2H)，7.17-7.11(m，1H)，7.08–6.94(m，5H)，6.77(d，J＝8.8Hz，2H)，4.87-4.79(m，1H)，4.37(d，J＝9.6Hz，1H)，4.25-4.09(m，3H)，3.95(s，2H)，3.68-3.61(m，1H)，3.55-3.46(m，2H)，3.37(br t，J＝10.0Hz，1H)，3.10(br dd，J＝10.0Hz，J＝6.0Hz，1H)，2.88(q，J＝7.6Hz，1H)，2.75(br d，J＝7.6Hz，2H)，2.69-2.51(m，4H)，2.40(br d，J＝11.6Hz，1H)，2.27(br dd，J＝14.0Hz，J＝7.2Hz，1H)，2.18(s，3H)，2.07-1.95(m，1H)，1.42(q，J＝12.0Hz，1H)，1.15(t，J＝7.6Hz，3H)。 Compound L (760mg, 1eq), methanol (6mL) and tetrahydrofuran (3mL) were added to the reaction flask, then lithium hydroxide monohydrate (1.02g, 20eq) and water (6mL) were added, and the mixture was reacted at 25°C for 16 hours . After completion of the reaction, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL×3), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure at 45°C. Purification by preparative high performance liquid chromatography affords the compound of formula (I). 1 H NMR (400 MHz, CDCl 3 ) δ 7.21 (s, 2H), 7.17-7.11 (m, 1H), 7.08-6.94 (m, 5H), 6.77 (d, J=8.8Hz, 2H), 4.87- 4.79(m, 1H), 4.37(d, J=9.6Hz, 1H), 4.25-4.09(m, 3H), 3.95(s, 2H), 3.68-3.61(m, 1H), 3.55-3.46(m, 2H), 3.37 (br t, J=10.0Hz, 1H), 3.10 (br dd, J=10.0Hz, J=6.0Hz, 1H), 2.88 (q, J=7.6Hz, 1H), 2.75 (br d , J=7.6Hz, 2H), 2.69-2.51 (m, 4H), 2.40 (br d, J=11.6Hz, 1H), 2.27 (br dd, J=14.0Hz, J=7.2Hz, 1H), 2.18 (s, 3H), 2.07-1.95 (m, 1H), 1.42 (q, J=12.0 Hz, 1H), 1.15 (t, J=7.6 Hz, 3H).
实施例2：式(I)化合物的单晶培养实验Example 2: Single crystal cultivation experiment of the compound of formula (I)
15mg式(I)化合物在室温条件下溶解于0.8ml乙醇中，再往溶液中缓慢滴加0.5ml水，将样品溶液用0.45μm微孔滤膜过滤后置于4ml半密封样品瓶中，在室温条件下缓慢挥发。得到的单晶数据如表8～13和图14。15mg of the compound of formula (I) was dissolved in 0.8ml of ethanol at room temperature, 0.5ml of water was slowly added dropwise to the solution, the sample solution was filtered with a 0.45μm microporous membrane and placed in a 4ml semi-sealed sample bottle. It evaporates slowly at room temperature. The obtained single crystal data are shown in Tables 8 to 13 and FIG. 14 .
表8 Summary of X-ray Crystallographic DataTable 8 Summary of X-ray Crystallographic Data
Figure PCTCN2021118616-appb-000016
Figure PCTCN2021118616-appb-000016
Figure PCTCN2021118616-appb-000017
Figure PCTCN2021118616-appb-000017
表9:Atomic coordinates(x 10^4)and equivalent isotropic displacement parameters(A^2x 10^3).Table 9: Atomic coordinates(x 10^4) and equivalent isotropic displacement parameters(A^2x 10^3).
Figure PCTCN2021118616-appb-000018
Figure PCTCN2021118616-appb-000018
Figure PCTCN2021118616-appb-000019
Figure PCTCN2021118616-appb-000019
Figure PCTCN2021118616-appb-000020
Figure PCTCN2021118616-appb-000020
表10:Bond lengths[A]Table 10: Bond lengths[A]
Figure PCTCN2021118616-appb-000021
Figure PCTCN2021118616-appb-000021
Figure PCTCN2021118616-appb-000022
Figure PCTCN2021118616-appb-000022
Figure PCTCN2021118616-appb-000023
Figure PCTCN2021118616-appb-000023
表11:Bond angles[deg].Table 11: Bond angles[deg].
Figure PCTCN2021118616-appb-000024
Figure PCTCN2021118616-appb-000024
Figure PCTCN2021118616-appb-000025
Figure PCTCN2021118616-appb-000025
Figure PCTCN2021118616-appb-000026
Figure PCTCN2021118616-appb-000026
表12:Hydrogen Bonds.Table 12: Hydrogen Bonds.
Figure PCTCN2021118616-appb-000027
Figure PCTCN2021118616-appb-000027
1+X,2+Y,+Z 1 +X, 2+Y,+Z
表13:Torsion angles[deg].Table 13: Torsion angles[deg].
Figure PCTCN2021118616-appb-000028
Figure PCTCN2021118616-appb-000028
Figure PCTCN2021118616-appb-000029
Figure PCTCN2021118616-appb-000029
Figure PCTCN2021118616-appb-000030
Figure PCTCN2021118616-appb-000030
实施例2：无定型式(I)化合物制备Example 2: Preparation of Amorphous Formula (I) Compounds
称取220g式(I)化合物，用880mL二氯甲烷溶解后，于30℃下减压浓缩至体积约为200mL。加入1L甲基叔丁基醚，于30℃下减压浓缩除去溶剂，重复此操作3次后，经鉴定显示得到无定型式(I) 化合物，如图15所示。220 g of the compound of formula (I) was weighed, dissolved in 880 mL of dichloromethane, and concentrated under reduced pressure at 30° C. to a volume of about 200 mL. 1 L of methyl tert-butyl ether was added, and the solvent was concentrated under reduced pressure at 30° C. to remove the solvent. After repeating this operation three times, the identification showed that the compound of amorphous formula (I) was obtained, as shown in FIG. 15 .
实施例3：各晶型的制备方法Example 3: Preparation method of each crystal form
将约100mg无定型的式(I)化合物在3.5mL的ACN中超声约2分钟，分离得到的固体，制备得到式(I)化合物的A晶型。About 100 mg of the amorphous compound of formula (I) was sonicated in 3.5 mL of ACN for about 2 minutes, and the resulting solid was isolated to prepare Form A of the compound of formula (I).
称取15g无定型的式(I)化合物，于20℃，投入525mL乙腈中，搅拌下加热至40℃使固体完全溶解，加入800mL水。继续于40℃搅拌15分钟后，关闭加热继续搅拌12小时，期间自然降至室温。停止搅拌静置2天。过滤收集固体并用母液洗涤滤饼。收集滤饼置于真空烘箱50℃烘干48小时得到式(I)化合物的B晶型。15 g of the amorphous compound of formula (I) was weighed, put into 525 mL of acetonitrile at 20° C., heated to 40° C. with stirring to completely dissolve the solid, and 800 mL of water was added. After continuing to stir at 40° C. for 15 minutes, the heating was turned off and the stirring was continued for 12 hours, during which the temperature was naturally lowered to room temperature. Stop stirring and let stand for 2 days. The solids were collected by filtration and the filter cake was washed with the mother liquor. The filter cake was collected and dried in a vacuum oven at 50° C. for 48 hours to obtain the crystal form B of the compound of formula (I).
称取6g无定型的式(I)化合物，于20℃，投入36mL乙醇与72mL正庚烷的混合溶剂中，搅拌下加热至48℃，保温缓慢搅拌4小时，过滤收集滤饼置于真空烘箱50℃烘干48小时得到式(I)化合物的C晶型。Weigh 6g of amorphous compound of formula (I), drop into a mixed solvent of 36mL of ethanol and 72mL of n-heptane at 20°C, heat to 48°C under stirring, keep stirring slowly for 4 hours, filter and collect the filter cake and place it in a vacuum oven Dry at 50°C for 48 hours to obtain the C crystal form of the compound of formula (I).
称取5g无定型的式(I)化合物，于300rpm搅拌下，投入75mL水中，升温至40℃，于40℃下搅拌66小时。过滤收集固体后，减压浓缩得到式(I)化合物的D晶型。5 g of the amorphous compound of formula (I) was weighed, stirred at 300 rpm, put into 75 mL of water, heated to 40° C., and stirred at 40° C. for 66 hours. After the solid was collected by filtration, it was concentrated under reduced pressure to obtain the D crystal form of the compound of formula (I).
称取780.24g无定型的式(I)化合物，用8L超纯水分散为悬浊液，在氮气保护100rpm搅拌下转入4L超纯水中。200rpm搅拌下，缓慢升温至40±5℃，保温搅拌16小时。过滤，滤饼用超纯水洗涤三次，每次1L。滤饼再用8L超纯水分散为悬浊液，在氮气保护100rpm搅拌下转入4L超纯水中。200rpm搅拌下，缓慢升温至40±5℃，保温搅拌16小时。过滤，滤饼用超纯水洗涤三次，每次1L。滤饼于温度40±5℃，P≤-0.08MPa下减压旋蒸除水至红外线烘干减重法检测含水量<20％。所得固体用高速粉碎机粉碎后，过40目筛。所得粉末放入真空干燥箱，于温度40±5℃，P≤-0.08MPa下真空干燥至含水量<2％。烘干后的固体放入相对湿度92.5％(饱和硝酸钾溶液，温度25℃)环境下，密封放置3天，得到式(I)化合物的E晶型。Weigh 780.24g of amorphous compound of formula (I), disperse it with 8L ultrapure water to form a suspension, and transfer it into 4L ultrapure water under nitrogen protection and stirring at 100rpm. Under stirring at 200 rpm, the temperature was slowly raised to 40±5° C., and the temperature was kept stirring for 16 hours. After filtration, the filter cake was washed three times with ultrapure water, 1L each time. The filter cake was then dispersed with 8L of ultrapure water to form a suspension, which was transferred into 4L of ultrapure water under nitrogen protection with stirring at 100rpm. Under stirring at 200 rpm, the temperature was slowly raised to 40±5° C., and the temperature was kept stirring for 16 hours. After filtration, the filter cake was washed three times with ultrapure water, 1L each time. Under the temperature of 40±5℃, P≤-0.08MPa, the filter cake is decompressed and rotary evaporated to remove water, and the water content is less than 20% detected by infrared drying and weight loss method. The obtained solid was pulverized with a high-speed pulverizer and passed through a 40-mesh sieve. The obtained powder is put into a vacuum drying box, and dried under vacuum at a temperature of 40±5° C. and P≤-0.08MPa to a moisture content of less than 2%. The dried solid is placed in an environment of relative humidity of 92.5% (saturated potassium nitrate solution, temperature 25° C.), sealed and placed for 3 days to obtain the E crystal form of the compound of formula (I).
实施例3：式(I)化合物B晶型，D晶型和E晶型的稳定性试验Example 3: Stability test of formula (I) compound B crystal form, D crystal form and E crystal form
对B晶型及D晶型开展了固体稳定性评估，将样品分别在光照(ICH条件)、60℃条件下闭口放置，在92.5％RH条件下封口膜包裹并扎5个孔后放置，按照计划时间取点后通过XRPD检测晶型是否变化，通过HPLC检测纯度是否变化，具体结果汇总在表14、15和16。The solid stability assessment was carried out for the B crystal form and the D crystal form. The samples were placed under the conditions of light (ICH conditions) and 60 °C, respectively, and were placed under the conditions of 92.5% RH. After the planned time point, XRPD was used to detect whether the crystal form changed, and HPLC was used to detect whether the purity changed. The specific results are summarized in Tables 14, 15 and 16.
B晶型在60℃条件下闭口放置10天、光照条件下闭口放置一定时间后，晶型均未变；Crystal form B was kept closed for 10 days under the condition of 60°C and kept closed for a certain period of time under the condition of light, and the crystal form did not change;
D晶型在60℃条件下闭口放置2周、92.5％RH条件下闭口放置2周、光照条件下闭口放置一定时间后，晶型均未变。Crystal form D was kept closed for 2 weeks at 60°C, 2 weeks at 92.5% RH, and kept closed for a certain period of time under light conditions, and the crystal form did not change.
表14式(I)化合物晶型B与晶型D稳定性测试结果小结Table 14 Summary of the stability test results of compound crystal form B and crystal form D of formula (I)
Figure PCTCN2021118616-appb-000031
Figure PCTCN2021118616-appb-000031
Figure PCTCN2021118616-appb-000032
Figure PCTCN2021118616-appb-000032
*：ICH条件，可见光照度达到1.2E+06 Lux·hrs，紫外光照度达到300W·hrs/m 2。 *: ICH conditions, the visible illuminance reaches 1.2E+06 Lux·hrs, and the UV illuminance reaches 300W·hrs/m 2 .
表15式(I)化合物D晶型稳定性测试HPLC检测结果小结Table 15. Summary of HPLC detection results of compound D crystal form stability test of formula (I)
Figure PCTCN2021118616-appb-000033
Figure PCTCN2021118616-appb-000033
#：RRT＝0.95；#: RRT=0.95;
&：RRT＝1.09。&: RRT=1.09.
表16式(I)化合物E晶型稳定性测试检测结果Table 16 Test results of formula (I) compound E crystal form stability test
Figure PCTCN2021118616-appb-000034
Figure PCTCN2021118616-appb-000034
Figure PCTCN2021118616-appb-000035
Figure PCTCN2021118616-appb-000035
实施例4：式(I)化合物E晶型在大鼠OGTT模型药效研究Example 4: Efficacy study of compound E crystal form of formula (I) in rat OGTT model
实验材料：Experimental Materials:
购自浙江维通利华实验动物技术有限公司的SD大鼠，雄性，7周龄，动物到达后，将其饲养于严格控制环境条件的动物饲养间中，饲养间的温度维持在20～24℃，湿度维持在40～70％。通过温、湿度计对饲养间的温度和湿度进行实时监控，并且每天对温度和湿度记录两次(上午和下午各1次)。动物饲养间的采光由电子定时开灯系统来控制，每天开灯12大时关灯12小时(上午7：00开，下午19：00关)。实验过程中，大鼠单笼饲养，并给每个笼中的大鼠提供玩具。动物适应环境5-7天左右，再开始实验。SD rats, male, 7 weeks old, were purchased from Zhejiang Weitong Lihua Laboratory Animal Technology Co., Ltd. After the animals arrived, they were kept in the animal breeding room with strictly controlled environmental conditions, and the temperature in the breeding room was maintained at 20-24 ℃, the humidity is maintained at 40-70%. The temperature and humidity in the breeding room were monitored in real time by thermometer and hygrometer, and the temperature and humidity were recorded twice a day (once in the morning and once in the afternoon). The lighting in the animal feeding room is controlled by an electronic timing light-on system. The lights are turned on at 12:00 and turned off for 12 hours every day (on at 7:00 in the morning and off at 19:00 in the afternoon). During the experiment, the rats were kept in single cages, and toys were provided to the rats in each cage. Animals adapt to the environment for about 5-7 days before starting the experiment.
实验方法：experimental method:
动物到达一周后，动物称重并禁食16h，测禁食血糖。以禁食血糖为主，体重为辅进行分组，单次口服给予受试药物，随即口服给予2g/kg 50％葡萄糖溶液，将鼠置于代谢笼中。在动物于给糖前0min，给糖后15，30，60，90，120min分别对动物进行血糖检测，根据时间对血糖数据绘制糖耐量曲线，计算曲线下面积(AUC)；在给予初次葡萄糖2h后，给予饲料，自由取食。所有的数据被录入到Excel文档中，并以Mean±SEM的方式表示。数据统计分析使用Graphpad Prism 6.0软件，单因素或双因素方差分析比较方法，以P<0.05作为显著性差异的判断标准。One week after the animals arrived, the animals were weighed and fasted for 16 h, and fasting blood glucose was measured. Fasting blood glucose was the main method, body weight was the supplement, and the test drugs were administered orally in a single dose, followed by oral administration of 2 g/kg 50% glucose solution, and the rats were placed in metabolic cages. The blood glucose of the animals was detected at 0 min before and 15, 30, 60, 90, and 120 min after the glucose administration, and the glucose tolerance curve was drawn according to the time to the blood glucose data, and the area under the curve (AUC) was calculated; After that, they were given feed and free access to food. All data were entered into Excel files and expressed as Mean±SEM. Statistical analysis of data was performed using Graphpad Prism 6.0 software, one-way or two-way ANOVA comparison method, and P<0.05 was used as the criterion for significant differences.
实验结果：见表17，表18。Experimental results: see Table 17, Table 18.
表17.单次给药能够下调健康大鼠口服葡萄糖后的血糖水平Table 17. A single dose can downregulate blood glucose levels in healthy rats after oral glucose
Figure PCTCN2021118616-appb-000036
Figure PCTCN2021118616-appb-000036
Figure PCTCN2021118616-appb-000037
Figure PCTCN2021118616-appb-000037
注：数据以Mean±SEM表示，每组8只大鼠；*P<0.05,**P<0.01,***P<0.001和****P<0.0001vs溶媒对照组， ####P<0.0001vs Canagliflozin组统计方法采用双因素方差分析组间比较。 Note: Data are expressed as Mean±SEM, 8 rats in each group; *P<0.05, **P<0.01, ***P<0.001 and ****P<0.0001 vs vehicle control group, #### P<0.0001vs Canagliflozin group Statistical method used two-way ANOVA to compare between groups.
表18大鼠糖耐受量实验结果Table 18 Rat glucose tolerance test results
组别group 血糖AUC 0-120min(mmol/L*min) Blood glucose AUC 0-120min (mmol/L*min)
溶媒对照组vehicle control group 1101.8±33.80***1101.8±33.80***
阳性化合物Canagliflozin(3mg/Kg)Positive compound Canagliflozin (3mg/Kg) 970.0±22.85****970.0±22.85****
式(I)化合物E晶型(3mg/kg)Formula (I) compound E crystal form (3mg/kg) 768.8±18.49**** #### 768.8±18.49**** ####
式(I)化合物E晶型(10mg/kg)Formula (I) compound E crystal form (10mg/kg) 697.9±10.68****697.9±10.68****
式(I)化合物E晶型(30mg/kg)Formula (I) compound E crystal form (30mg/kg) 661.5±14.11****661.5±14.11****
注：数据以Mean±SEM表示，每组8只大鼠。Note: Data are presented as Mean±SEM, with 8 rats in each group.
***P<0.001,****P<0.0001vs溶媒对照组差异有显著的统计学意义， ####P<0.0001 vs Canagliflozin组差异有显著的统计学意义，统计方法采用单因素方差分析组间比较。 ***P<0.001, ****P<0.0001 vs vehicle control group, there is a statistically significant difference, #### P<0.0001 vs Canagliflozin group, there is a statistically significant difference, the statistical method uses one-way variance Analysis of between-group comparisons.
实验结论：Experimental results:
式(I)化合物E晶型可有效降低显著降低动物2小时内血糖AUC水平，且降糖效果优于同剂量的Canagliflozin。The compound E crystal form of formula (I) can effectively reduce and significantly reduce the AUC level of blood glucose in animals within 2 hours, and the hypoglycemic effect is better than the same dose of Canagliflozin.

Claims (38)

  1. 式(Ⅰ)化合物的A晶型，其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：6.13±0.20°、15.99±0.20°和21.04±0.20°：Form A of the compound of formula (I), its X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2θ angles: 6.13±0.20°, 15.99±0.20° and 21.04±0.20°:
    Figure PCTCN2021118616-appb-100001
    Figure PCTCN2021118616-appb-100001
  2. 根据权利要求1所述的A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.13±0.20°、8.21±0.20°、10.63±0.20°、15.99±0.20°、17.21±0.20°、21.04±0.20°、21.53±0.20°和22.47±0.20°。The crystal form A according to claim 1, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.13±0.20°, 8.21±0.20°, 10.63±0.20°, 15.99±0.20°, 17.21±0.20 °, 21.04±0.20°, 21.53±0.20° and 22.47±0.20°.
  3. 根据权利要求2所述的A晶型，其XRPD图谱基本上如附图1所示。The crystal form A according to claim 2, its XRPD pattern is substantially as shown in FIG. 1 .
  4. 根据权利要求1～3任意一项所述的A晶型，其差示扫描量热曲线在73.5±3℃以及109.1±3℃处具有吸热峰的峰值。The crystal form A according to any one of claims 1 to 3, wherein the differential scanning calorimetry curve has endothermic peaks at 73.5±3°C and 109.1±3°C.
  5. 根据权利要求4所述的A晶型，其DSC图谱基本上如图2所示。Form A according to claim 4, its DSC spectrum is substantially as shown in FIG. 2 .
  6. 式(Ⅰ)化合物的B晶型，其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：10.64±0.20°、15.59±0.20°和20.65±0.20°：Form B of the compound of formula (I), its X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2θ angles: 10.64±0.20°, 15.59±0.20° and 20.65±0.20°:
    Figure PCTCN2021118616-appb-100002
    Figure PCTCN2021118616-appb-100002
  7. 根据权利要求6所述的B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.24±0.20°、6.17±0.20°、10.64±0.20°、13.87±0.20°、15.59±0.20°、16.58±0.20°、20.65±0.20°和21.75±0.20°。The crystal form B according to claim 6, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.24±0.20°, 6.17±0.20°, 10.64±0.20°, 13.87±0.20°, 15.59±0.20 °, 16.58±0.20°, 20.65±0.20° and 21.75±0.20°.
  8. 根据权利要求7所述的B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.24°、6.17°、7.00°、8.12°、10.64°、11.69°、12.18°、12.55°、13.87°、15.59°、16.58°、18.06°、18.45°、20.27°、20.65°、21.31°、21.75°、22.67°、24.66°、25.38°、26.26°、27.18°、28.40°、31.12°、32.14°、33.38°、36.61°、37.27°和38.83°。The crystal form B according to claim 7, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.24°, 6.17°, 7.00°, 8.12°, 10.64°, 11.69°, 12.18°, 12.55° , 13.87°, 15.59°, 16.58°, 18.06°, 18.45°, 20.27°, 20.65°, 21.31°, 21.75°, 22.67°, 24.66°, 25.38°, 26.26°, 27.18°, 28.40°, 31.12°, 32.14 °, 33.38°, 36.61°, 37.27° and 38.83°.
  9. 根据权利要求8所述的B晶型，其XRPD图谱基本上如图3所示。The crystal form B according to claim 8 has an XRPD pattern substantially as shown in FIG. 3 .
  10. 根据权利要求6～9任意一项所述的B晶型，其差示扫描量热曲线在104.1±3℃处具有吸热峰的起始点。The crystal form B according to any one of claims 6 to 9, wherein the differential scanning calorimetry curve has an onset of an endothermic peak at 104.1±3°C.
  11. 根据权利要求10所述的B晶型，其DSC图谱基本上如图4所示。The crystalline form B according to claim 10, the DSC spectrum is substantially as shown in FIG. 4 .
  12. 根据权利要求6～9任意一项所述的B晶型，其热重分析曲线在100℃处失重达1.98％，至130℃处又失重0.54％。According to the crystal form B according to any one of claims 6 to 9, its thermogravimetric analysis curve has a weight loss of 1.98% at 100°C, and a weight loss of 0.54% at 130°C.
  13. 根据权利要求12所述的B晶型，其TGA图谱基本上如图5所示。The crystal form B according to claim 12 , the TGA spectrum of which is substantially as shown in FIG. 5 .
  14. 式(Ⅰ)化合物的C晶型，其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：12.00±0.20°、17.01±0.20°和18.01±0.20°：Form C of the compound of formula (I), its X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2θ angles: 12.00±0.20°, 17.01±0.20° and 18.01±0.20°:
    Figure PCTCN2021118616-appb-100003
    Figure PCTCN2021118616-appb-100003
  15. 根据权利要求14所述的C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.05±0.20°、8.65±0.20°、12.00±0.20°、17.01±0.20°、17.60±0.20°、18.01±0.20°、18.44±0.20°和20.89±0.20°。The crystal form C according to claim 14, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.05±0.20°, 8.65±0.20°, 12.00±0.20°, 17.01±0.20°, 17.60±0.20 °, 18.01±0.20°, 18.44±0.20° and 20.89±0.20°.
  16. 根据权利要求15所述的C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.05±0.20°、6.00±0.20°、8.65±0.20°、12.00±0.20°、17.01±0.20°、17.60±0.20°、18.01±0.20°、18.44±0.20°、20.89±0.20°和22.93±0.20°。The crystal form C according to claim 15, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.05±0.20°, 6.00±0.20°, 8.65±0.20°, 12.00±0.20°, 17.01±0.20 °, 17.60±0.20°, 18.01±0.20°, 18.44±0.20°, 20.89±0.20° and 22.93±0.20°.
  17. 根据权利要求16所述的C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.36°、5.05°、6.00°、8.19°、8.65°、9.95°、12.00°、12.30°、13.57°、14.07°、15.02°、15.62°、16.50°、17.01°、17.60°、18.01°、18.44°、19.04°、19.40°、19.87°、20.36°、20.89°、22.27°、22.93°、23.35°、24.48°、25.14°、25.49°、26.97°、28.88°、29.24°、32.83°和36.94°。The crystal form C according to claim 16, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.36°, 5.05°, 6.00°, 8.19°, 8.65°, 9.95°, 12.00°, 12.30° , 13.57°, 14.07°, 15.02°, 15.62°, 16.50°, 17.01°, 17.60°, 18.01°, 18.44°, 19.04°, 19.40°, 19.87°, 20.36°, 20.89°, 22.27°, 22.93°, 23.35 °, 24.48°, 25.14°, 25.49°, 26.97°, 28.88°, 29.24°, 32.83° and 36.94°.
  18. 根据权利要求17所述的C晶型，其XRPD图谱基本上如图6所示。The crystal form C according to claim 17, its XRPD pattern is substantially as shown in FIG. 6 .
  19. 根据权利要求14～18任意一项所述的C晶型，其热重分析曲线在100℃处失重达3.41％。The crystal form C according to any one of claims 14 to 18, whose thermogravimetric analysis curve has a weight loss of 3.41% at 100°C.
  20. 根据权利要求19所述的B晶型，其TGA图谱基本上如图7所示。The crystal form B according to claim 19, the TGA spectrum of which is substantially as shown in FIG. 7 .
  21. 式(Ⅰ)化合物的D晶型，其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：4.81±0.20°、15.74±0.20°和17.09±0.20°：Form D of the compound of formula (I), its X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2θ angles: 4.81±0.20°, 15.74±0.20° and 17.09±0.20°:
    Figure PCTCN2021118616-appb-100004
    Figure PCTCN2021118616-appb-100004
  22. 根据权利要求21所述的D晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.81±0.20°、9.60±0.20°、14.58±0.20°、15.74±0.20°、17.09±0.20°、19.86±0.20°、22.46±0.20°和23.85±0.20°。The crystal form D according to claim 21, wherein the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.81±0.20°, 9.60±0.20°, 14.58±0.20°, 15.74±0.20°, 17.09±0.20 °, 19.86±0.20°, 22.46±0.20° and 23.85±0.20°.
  23. 根据权利要求22所述的D晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.81°、9.60°、10.60°、11.51°、13.05°、14.58°、15.74°、17.09°、18.11°、19.86°、22.46°、23.85°和27.16°。The crystal form D according to claim 22, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.81°, 9.60°, 10.60°, 11.51°, 13.05°, 14.58°, 15.74°, 17.09° , 18.11°, 19.86°, 22.46°, 23.85° and 27.16°.
  24. 根据权利要求23所述的D晶型，其XRPD图谱基本上如图8所示。The crystal form D according to claim 23, the XRPD pattern thereof is substantially as shown in FIG. 8 .
  25. 根据权利要求21～24任意一项所述的D晶型，其差示扫描量热曲线在92.5±3℃处具有吸热峰的起始点。The crystal form D according to any one of claims 21 to 24, wherein the differential scanning calorimetry curve has an onset of an endothermic peak at 92.5±3°C.
  26. 根据权利要求25所述的D晶型，其DSC图谱基本上如图9所示。The crystalline form D according to claim 25, the DSC spectrum of which is substantially as shown in FIG. 9 .
  27. 根据权利要求21～24任意一项所述的D晶型，其热重分析曲线在60℃处失重达4.49％，在100℃处又失重2.48％。According to the crystal form D according to any one of claims 21 to 24, its thermogravimetric analysis curve has a weight loss of 4.49% at 60°C, and a weight loss of 2.48% at 100°C.
  28. 根据权利要求27所述的D晶型，其TGA图谱基本上如图10所示。The crystal form D according to claim 27, the TGA spectrum of which is substantially as shown in FIG. 10 .
  29. 式(Ⅱ)化合物：Compounds of formula (II):
    Figure PCTCN2021118616-appb-100005
    Figure PCTCN2021118616-appb-100005
    其中，in,
    n为0～5；优选为0.5～1.5；更优选为0.75或0.86。n is 0 to 5; preferably 0.5 to 1.5; more preferably 0.75 or 0.86.
  30. 式(Ⅱ)化合物的E晶型，其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：19.36±0.20°、20.98±0.20°和21.44±0.20°。Form E of the compound of formula (II), its X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2θ angles: 19.36±0.20°, 20.98±0.20° and 21.44±0.20°.
  31. 根据权利要求30所述的E晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.92±0.20°、15.24±0.20°、19.36±0.20°、19.88±0.20°、20.32±0.20°、20.98±0.20°、21.44±0.20°和23.68±0.20°。The crystal form E according to claim 30, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 3.92±0.20°, 15.24±0.20°, 19.36±0.20°, 19.88±0.20°, 20.32±0.20 °, 20.98±0.20°, 21.44±0.20° and 23.68±0.20°.
  32. 根据权利要求31所述的E晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.92±0.20°、14.54±0.20°、15.24±0.20°、19.36±0.20°、19.88±0.20°、20.32±0.20°、20.98±0.20°、21.44±0.20°、22.98±0.20°和23.68±0.20°。The crystal form E according to claim 31, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 3.92±0.20°, 14.54±0.20°, 15.24±0.20°, 19.36±0.20°, 19.88±0.20 °, 20.32±0.20°, 20.98±0.20°, 21.44±0.20°, 22.98±0.20° and 23.68±0.20°.
  33. 根据权利要求32所述的E晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：3.92°、7.12°、8.68°、9.54°、10.52°、11.38°、12.39°、13.40°、14.54°、15.24°、16.50°、17.20°、18.50°、19.36°、19.88°、20.32°、20.98°、21.44°、22.14°、22.98°、23.68°、24.00°、25.70°、24.00°、25.70°、26.20°、26.92°、27.96°、29.30°、30.48°、31.08°、31.82°、33.91°、34.84°、36.38°和38.08°。The crystal form E according to claim 32, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 3.92°, 7.12°, 8.68°, 9.54°, 10.52°, 11.38°, 12.39°, 13.40° , 14.54°, 15.24°, 16.50°, 17.20°, 18.50°, 19.36°, 19.88°, 20.32°, 20.98°, 21.44°, 22.14°, 22.98°, 23.68°, 24.00°, 25.70°, 24.00°, 25.70 °, 26.20°, 26.92°, 27.96°, 29.30°, 30.48°, 31.08°, 31.82°, 33.91°, 34.84°, 36.38° and 38.08°.
  34. 根据权利要求33所述的E晶型，其XRPD图谱基本上如图11所示。The crystal form E according to claim 33, its XRPD pattern is substantially as shown in FIG. 11 .
  35. 根据权利要求31～34任意一项所述的E晶型，其差示扫描量热曲线在161.6±3℃处各具有吸热峰的峰值。The crystal form E according to any one of claims 31 to 34, wherein the differential scanning calorimetry curve each has an endothermic peak at 161.6±3°C.
  36. 根据权利要求35所述的E晶型，其DSC图谱基本上如图12所示。The crystalline form E according to claim 35, the DSC spectrum of which is substantially as shown in FIG. 12 .
  37. 根据权利要求31～34任意一项所述的E晶型，其热重分析曲线在200±3℃处失重达2.2714％。The crystal form E according to any one of claims 31 to 34, whose thermogravimetric analysis curve has a weight loss of 2.2714% at 200±3°C.
  38. 根据权利要求37所述的E晶型，其TGA图谱基本上如图13所示。The crystal form E according to claim 37, the TGA spectrum of which is substantially as shown in FIG. 13 .
PCT/CN2021/118616 2021-01-26 2021-09-15 Crystal form of tetrahydropyran ring compound and preparation method therefor WO2022160737A1 (en)

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