WO2022012587A1 - 丙烯酮类化合物的丙二酸盐晶型及其制备方法 - Google Patents

丙烯酮类化合物的丙二酸盐晶型及其制备方法 Download PDF

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WO2022012587A1
WO2022012587A1 PCT/CN2021/106233 CN2021106233W WO2022012587A1 WO 2022012587 A1 WO2022012587 A1 WO 2022012587A1 CN 2021106233 W CN2021106233 W CN 2021106233W WO 2022012587 A1 WO2022012587 A1 WO 2022012587A1
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malonate
crystal form
solid
formula
compound
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PCT/CN2021/106233
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French (fr)
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鲁霞
赵晔
张晓宇
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苏州晶云药物科技股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to the field of chemical medicine, in particular to a malonate crystal form of acrylone compounds and a preparation method thereof.
  • JAK3 kinase is a member of the JAK family of cytoplasmic protein tyrosine kinases and plays an important role in the JAK-STAT signaling pathway.
  • a large number of studies have shown that the regulation of JAK3 kinase has important correlations with many diseases, especially autoimmune diseases. Therefore, the development of highly selective JAK3 kinase inhibitors is of great significance for the treatment of various immune diseases.
  • Patent US20170247372A1 discloses the compound of formula (I) and its synthetic route.
  • the disclosed synthetic method requires the use of chiral supercritical fluid chromatography to separate the target compound, the equipment cost is high, and the preparation conditions are harsh, and it is not suitable for large-scale industrial production. There is a need to develop simpler, safer and more productive preparation methods.
  • the present invention provides two crystal forms A and B of the compound malonate of the formula (I), as well as preparation methods and uses thereof.
  • the malonate type A crystal of 2-propen-1-one that is, the malonate crystal form A
  • the 2 ⁇ value has characteristic peaks at 7.9° ⁇ 0.2°, 15.8° ⁇ 0.2° and 19.4° ⁇ 0.2°,
  • the solid compound of formula (I) and malonic acid are slurried in at least one solvent of methyl isobutyl ketone, acetonitrile, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, the solid is collected and stored at room temperature Dry under vacuum to obtain malonate salt form A.
  • the malonate solid of the compound of formula (I) is dissolved in a positive solvent, and an anti-solvent is added after filtration to obtain the malonate crystal form A.
  • the malonate solid of the compound of formula (I) is dissolved in methanol, ethanol/chloroform, filtered and volatilized until a solid is precipitated to obtain the malonate crystal form A.
  • the malonate solid of the compound of formula (I) is dissolved in a positive solvent, and placed in an anti-solvent atmosphere for gas-liquid diffusion for 12 days to obtain the malonate crystal form A.
  • the solid compound of formula (I) was slurried with malonic acid in dichloromethane, and the solid was collected and dried under vacuum at room temperature to give the malonate salt form B.
  • the malonate solid of the compound of formula (I) is dissolved in at least one solvent of acetone, tetrahydrofuran, methanol/dichloromethane, chloroform/isopropanol, acetonitrile/water, and volatilized after filtration until a solid is precipitated to obtain Malonate Form B.
  • a pharmaceutical composition comprising the crystal of any one of 1 and 7 above and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition having JAK3 inhibitory activity comprising the crystal of any one of the above 1 and 7 as an active ingredient.
  • a preventive or therapeutic drug for alopecia areata, rheumatoid arthritis, Crohn's disease, ulcerative colitis, and vitiligo, comprising the crystal according to any one of 1 and 7 above as an active ingredient.
  • the malonate crystal forms A and B of the compound of formula (I) provided by the present invention have the advantages of solubility, melting point, stability, dissolution, hygroscopicity, bioavailability, processing performance, and purification effect.
  • advantages in at least one aspect of preparation production, safety, etc. which provide a new and better choice for the preparation of pharmaceutical preparations containing the compound of formula (I), which is of great significance for drug development.
  • the X-ray powder diffraction of the malonate salt form A has one or both of the 2 ⁇ values of 17.2° ⁇ 0.2°, 14.1° ⁇ 0.2°, 28.7° ⁇ 0.2° There are characteristic peaks at or three places.
  • the X-ray powder diffraction of the malonate crystal form A has characteristic peaks at 2 ⁇ values of 17.2° ⁇ 0.2°, 14.1° ⁇ 0.2°, and 28.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the malonate crystal form A has one or both of the 2 ⁇ values of 10.4° ⁇ 0.2°, 21.0° ⁇ 0.2°, 27.5° ⁇ 0.2° There are characteristic peaks at or three places.
  • the X-ray powder diffraction of the malonate crystal form A has characteristic peaks at 2 ⁇ values of 10.4° ⁇ 0.2°, 21.0° ⁇ 0.2°, and 27.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the malonate crystal form A has 2 ⁇ values of 7.9° ⁇ 0.2°, 10.4° ⁇ 0.2°, 14.1° ⁇ 0.2°, 15.8° ⁇ 0.2° , 17.2° ⁇ 0.2°, 19.4° ⁇ 0.2°, 21.0° ⁇ 0.2°, 27.5° ⁇ 0.2°, 28.7° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8 There are characteristic peaks at or at 9.
  • the X-ray powder diffraction of the malonate crystal form A has 2 ⁇ values of 7.9° ⁇ 0.2°, 10.4° ⁇ 0.2°, 14.1° ⁇ 0.2°, 15.8° ⁇ 0.2° , 17.2° ⁇ 0.2°, 19.4° ⁇ 0.2°, 21.0° ⁇ 0.2°, 27.5° ⁇ 0.2°, 28.7° ⁇ 0.2° have characteristic peaks.
  • the preparation method of described malonate crystal form A is characterized in that,
  • the solid compound of formula (I) and malonic acid are slurried in at least one solvent of methyl isobutyl ketone, acetonitrile, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, the solid is collected and stored at room temperature Dry under vacuum to obtain malonate salt form A.
  • the beating temperature is 20°C to 30°C.
  • the molar ratio of the solid compound of formula (I) to malonic acid is 0.5-1.5:1, for example 1:1.
  • the beating time is 1-10 days, for example, 5 days.
  • the preparation method of described malonate crystal form A is characterized in that,
  • the water content in the ethanol/water mixed solvent is 0-15%.
  • the stirring temperature is 20°C to 30°C.
  • the volatilization temperature is 20°C to 30°C.
  • the preparation method of described malonate crystal form A is characterized in that,
  • the malonate solid of the compound of formula (I) is dissolved in a positive solvent, and an anti-solvent is added after filtration to obtain the malonate crystal form A.
  • the positive solvent is methanol
  • the anti-solvent is selected from at least one of methyl tert-butyl ether and ethyl acetate.
  • the dissolution temperature is 20°C to 30°C.
  • the anti-solvent is added slowly with stirring after filtration.
  • the stirring temperature is 20°C to 30°C.
  • the preparation method of described malonate crystal form A is characterized in that,
  • the malonate solid of the compound of formula (I) is dissolved in methanol, ethanol/chloroform, filtered and volatilized until a solid is precipitated to obtain malonate crystal form A.
  • the volume ratio of ethanol/chloroform is 3-5:1, for example, 4:1.
  • the dissolution temperature is 20°C to 30°C.
  • the volatilization temperature is 20°C to 30°C.
  • the preparation method of described malonate crystal form A is characterized in that,
  • the malonate solid of the compound of formula (I) is dissolved in a positive solvent, and placed in an anti-solvent atmosphere for gas-liquid diffusion for 12 days to obtain the malonate crystal form A.
  • the positive solvent is at least one of methanol, ethanol, acetone and tetrahydrofuran
  • the anti-solvent is selected from 2-methyltetrahydrofuran, methyl tert-butyl ether, isopropyl acetate and at least one of ethyl acetate.
  • the diffusion time is 5 to 20 days, such as 12 days.
  • the diffusion temperature is 5°C to 30°C.
  • the volatilization time of the sample is 5-10 days, for example, 7 days.
  • the X-ray powder diffraction of the malonate crystal form B is at one or both of the 2 ⁇ values of 8.6° ⁇ 0.2°, 28.1 ⁇ 0.2°, 19.3° ⁇ 0.2° or three characteristic peaks.
  • the X-ray powder diffraction of the malonate crystal form B has characteristic peaks at 2 ⁇ values of 8.6° ⁇ 0.2°, 28.1° ⁇ 0.2°, and 19.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the malonate crystal form B has characteristic peaks at one or two of the 2 ⁇ values of 10.6° ⁇ 0.2° and 14.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the malonate crystal form B has characteristic peaks at 2 ⁇ values of 10.6° ⁇ 0.2° and 14.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the malonate crystal form B has 2 ⁇ values of 6.8° ⁇ 0.2°, 8.6° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.6° ⁇ 0.2° , 16.6° ⁇ 0.2°, 19.3° ⁇ 0.2°, 24.6° ⁇ 0.2°, 28.1° ⁇ 0.2° any 4 places, or 5 places, or 6 places, or 7 places, or 8 places have characteristic peaks.
  • the X-ray powder diffraction of the malonate crystal form B has 2 ⁇ values of 6.8° ⁇ 0.2°, 8.6° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.6° ⁇ 0.2° , 16.6° ⁇ 0.2°, 19.3° ⁇ 0.2°, 24.6 ⁇ 0.2°, 28.1° ⁇ 0.2° have characteristic peaks.
  • the preparation method of described malonate crystal form B is characterized in that,
  • the solid compound of formula (I) was slurried with malonic acid in dichloromethane, and the solid was collected and dried under vacuum at room temperature to give the malonate salt form B.
  • the beating temperature is 20°C to 30°C.
  • the molar ratio of the solid compound of formula (I) to malonic acid is 0.5-1.5:1, for example 1:1.
  • the beating time is 3 days.
  • the preparation method of described malonate crystal form B is characterized in that,
  • the malonate solid of the compound of formula (I) is dissolved in at least one solvent of acetone, tetrahydrofuran, methanol/dichloromethane, chloroform/isopropanol, acetonitrile/water, and volatilized after filtration until a solid is precipitated to obtain Malonate Form B.
  • the volume ratio of methanol/dichloromethane is 0.5 ⁇ 2:1, such as 1:1.
  • the volume ratio of chloroform/isopropanol is 3-5:1, for example, 4:1.
  • the volume ratio of acetonitrile/water is 19-9:1, for example, 12.5:1.
  • the dissolution temperature is 20°C to 50°C.
  • the volatilization temperature is 20°C to 30°C.
  • said compound of formula (I) as starting material refers to its solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the compound of formula (I) as starting material is in the form of a solid powder.
  • the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rev/min, wherein the magnetic stirring is 200-1500 rev/min, preferably 300-1000 rev/min , the mechanical stirring is preferably 100 to 300 rpm.
  • the above crystals of the present invention can be used to prepare pharmaceutical compositions, which contain the above crystals of the present invention and a pharmaceutically acceptable carrier.
  • the above crystals of the present invention can be used for the preparation of pharmaceutical compositions having JAK3 inhibitory activity, which comprise the above crystals of the present invention (the propane of the compound of formula (I))
  • the diacid salt crystal form A, B) is used as the active ingredient.
  • the above crystals of the present invention can be used for the preparation of prophylactic or therapeutic drugs for alopecia areata, rheumatoid arthritis, Crohn's disease, ulcerative colitis and vitiligo
  • a medicine comprising the above crystals of the present invention (malonate crystal forms A and B of the compound of formula (I)) as an active ingredient.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising any one of the above-mentioned crystals of the present invention (malonate salt crystal forms A and B of the compound of formula (I)) and a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition with JAK3 inhibitory activity, which contains any one of the above-mentioned crystals of the present invention (malonate crystal forms A and B of the compound of formula (I)) as an active ingredient.
  • the present invention provides a preventive or therapeutic drug for alopecia areata, rheumatoid arthritis, Crohn's disease, ulcerative colitis and vitiligo, which contains any one of the above crystals of the present invention (malonate salt of a compound of formula (I)) Crystal forms A, B) are used as active ingredients.
  • crystalline or “polymorphic form” means as evidenced by the characterization of the X-ray diffraction pattern shown.
  • X-ray diffraction patterns generally vary with the conditions of the instrument.
  • the relative intensities of X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be used as the sole or decisive factor.
  • the relative intensities of the diffraction peaks in the X-ray diffraction pattern are related to the preferred orientation of the crystals, and the peak intensities shown here are illustrative and not for absolute comparison.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall shift of the peak angle will be caused, and a certain shift is usually allowed.
  • the X-ray diffraction pattern of a crystal form in the present invention does not have to be exactly the same as the X-ray diffraction pattern in the examples referred to here, and "the same X-ray diffraction pattern" mentioned herein does not mean absolutely identical, identical peak positions may differ by ⁇ 0.2° and some variability in peak intensity is allowed. Any crystalline form having the same or similar pattern as the characteristic peaks in these patterns is within the scope of the present invention.
  • Those skilled in the art can compare the patterns listed in the present invention with a pattern of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.
  • the malonate salt forms A, B of the present invention are pure, single, substantially free of admixture with any other crystalline forms.
  • substantially free when used to refer to a new crystal form means that the crystal form contains less than 20% by weight of other crystal forms, especially less than 10% by weight of other crystal forms, and even less More than 5% (weight) of other crystal forms, more than 1% (weight) of other crystal forms.
  • numerical values and numerical ranges mentioned in the present invention should not be narrowly construed as numerical values or numerical ranges themselves, and those skilled in the art should understand that they can be based on specific technical environments, without departing from the spirit and scope of the present invention. There are fluctuations around specific numerical values on the basis of principles. In the present invention, such a range of fluctuations that can be foreseen by those skilled in the art is often represented by the term "about”.
  • room temperature usually refers to 20°C to 30°C unless otherwise specified.
  • the X-ray powder diffraction patterns of the present invention were collected on Empyrean and X'Pert 3 X-ray powder diffractometers of Panalytical Corporation.
  • the method parameters of X-ray powder diffraction of the present invention are as follows:
  • the differential scanning calorimetry analysis diagram of the present invention is collected on the Discovery DSC 2500 differential scanning calorimeter of TA company.
  • the method parameters of the differential scanning calorimetry analysis of the present invention are as follows:
  • thermogravimetric analysis diagram of the present invention is collected on the Discovery TGA 5500 type and Q5000 type thermogravimetric analyzer of TA company.
  • the method parameters of thermogravimetric analysis of the present invention are as follows:
  • the hydrogen nuclear magnetic resonance spectrum data ( 1 H NMR) of the present invention was collected from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. Weigh 1-5 mg of the sample, dissolve it with 0.5 mL of deuterated dimethyl sulfoxide, and prepare a solution of 2-10 mg/mL for testing.
  • the dynamic moisture adsorption diagram of the present invention is collected on the Intrinsic type and Intrinsic Plus type dynamic moisture adsorption instrument of SMS company.
  • the method parameters of the dynamic moisture adsorption test of the present invention are as follows:
  • Relative humidity range 0%RH-95%RH-0%RH, room humidity-95%RH-0%RH-95%RH
  • Relative humidity gradient 10% (0%RH-90%RH-0%RH), 5% (90%RH-95%RH and 95%RH-90%RH)
  • the dissolution data described in the present invention are collected on the Agilent 708DS type dissolution apparatus of Agilent Company.
  • the described dissolution test conditions are as follows:
  • the prepared solid is malonate crystal form A, and its X-ray powder diffraction data is shown in Table 1, the diffraction pattern is shown in Figure 1, and the TGA, DSC and 1 H NMR data are shown in Figures 2 to 2, respectively. 4 shown.
  • the solids obtained in this example are all malonate crystal form A.
  • the detailed test conditions involved in this example are shown in Table 2, the X-ray powder diffraction data of the sample of Example 5 is shown in Table 3, and the diffraction pattern is shown in FIG. 5 .
  • the solids obtained in this example are all malonate crystal form A.
  • the detailed test conditions involved in this example are shown in Table 4, the X-ray powder diffraction data of the sample of Example 7 is shown in Table 5, and the diffraction pattern is shown in FIG. 6 .
  • Example 1 An appropriate amount of the solid malonate salt of the compound of formula (I) obtained in Example 1 was weighed at room temperature and placed in a 5 ml glass vial, and a corresponding volume of positive solvent was added to dissolve the solid. Then magnetic stirring (rotation speed is about 1000 rev/min) to obtain a clear solution, to which the corresponding anti-solvent was added dropwise, solid precipitation was observed, and the obtained solid was centrifuged.
  • the solids obtained in this example are all malonate crystal form A.
  • the detailed test conditions involved in this example are shown in Table 6, the X-ray powder diffraction data of the sample of Example 16 is shown in Table 7, and the diffraction pattern is shown in FIG. 7 .
  • Example 1 An appropriate amount of the solid malonate salt of the compound of formula (I) obtained in Example 1 was weighed at room temperature and placed in a 3 ml glass vial, and a corresponding volume of solvent was added to dissolve the solid. Filter the sample solution into a new 3 mL glass vial using a 0.45 micron pore size Teflon filter. After sealing with parafilm, 4 pinholes were made on it, and then it was slowly volatilized at room temperature until a solid was precipitated.
  • the solids obtained in this example are all malonate crystal form A.
  • the detailed test conditions involved in this example are shown in Table 8, the X-ray powder diffraction data of the sample of Example 18 is shown in Table 9, and the diffraction pattern is shown in FIG. 8 .
  • Example 2 Weigh an appropriate amount of the solid malonate of the compound of formula (I) obtained in Example 1 and place it in a 3 ml glass vial, add a corresponding volume of positive solvent to dissolve the solid, and use a 0.45-micron pore size polytetrafluoroethylene
  • the sample solution was filtered through a vinyl filter into a new 3 mL glass vial and placed open into a 20 mL glass vial prefilled with 3 mL of the corresponding antisolvent. After sealing, it was placed at room temperature for gas-liquid permeation for twelve days. The samples without precipitation of solids were transferred to open for evaporation at room temperature for seven days, and the solids were collected.
  • the solids obtained in this example are all malonate crystal form A.
  • the detailed test conditions involved in this example are shown in Table 10, and the X-ray powder diffraction data of the sample of Example 19 are shown in Table 11.
  • the solid obtained in this example is crystal form B, its X-ray powder diffraction data is shown in Table 12, the diffraction pattern is shown in Figure 9, and the TGA, DSC and 1 H NMR data are shown in Figures 10 to 12, respectively. Show.
  • Example 1 An appropriate amount of the solid malonate salt of the compound of formula (I) obtained in Example 1 was weighed at room temperature and placed in a 3 ml glass vial, and a corresponding volume of solvent was added to dissolve the solid. Filter the sample solution into a new 3 ml glass vial using a 0.45 micron pore size Teflon filter. After sealing with parafilm, 4 pinholes were made on it, and then it was slowly volatilized at room temperature until a solid was precipitated.
  • the solids obtained in this example are all malonate crystal form B.
  • the detailed test conditions involved in this example are shown in Table 13, and the X-ray powder diffraction data of the sample of Example 25 are shown in Table 13.
  • a certain quality of the malonate crystal form A of the present invention, the malonate crystal form B and the free base solid of the compound of formula (I) were respectively put into FaSSIF (artificial intestinal juice in an empty stomach) and FeSSIF (a satiety state) at 37° C. After 1 hour, 4 hours and 24 hours of equilibration, the solution was filtered, and the content of the sample in the solution was determined by high performance liquid chromatography (HPLC). During the experiment, the samples of the malonate crystal form A and the malonate crystal form B were equilibrated for 1 hour and dissolved, and the free base sample of the compound of formula (I) remained cloudy all the time.
  • FaSSIF artificial intestinal juice in an empty stomach
  • FeSSIF a satiety state
  • the malonate crystal form A and malonate crystal form B of the present invention were tested for pressure stability by using a manual tablet press, and the crystal form of the present invention was pressed for one minute with a pressure of 650 MPa, and then the tablet was taken out for XPRD test.
  • the XRPD data of the samples before and after the pressure stability of the malonate crystal form A and the malonate crystal form B are shown in Figures 18 and 19. The results show that the crystal form of the present invention is consistent before and after the test, has excellent pressure stability, and can meet the requirements for drug stability during the preparation and tableting process.
  • the malonate crystal form A of the present invention was transferred to a dissolution apparatus to test the dissolution in pH 6.8 phosphate buffer at 37°C.
  • the dissolution profiles of the malonate salt form A, the malonate salt form B and the free base solid of the compound of formula (I) are shown in FIG. 20 .
  • the malonate crystal form A and the malonate crystal form B of the present invention reach the maximum dissolution rate (100%) after 10 minutes and 20 minutes after the start of the dissolution experiment, respectively, and the free base solid of the compound of formula (I) reaches the maximum dissolution rate after 20 minutes.
  • the malonate crystal form A and the malonate crystal form B of the present invention have a faster dissolution rate and a higher dissolution rate in a pH 6.8 phosphate buffer, and can be rapidly dissolved.
  • Biological absorption and utilization can achieve higher bioavailability, and can better meet the requirements for the dissolution performance of raw materials in the development process of drug immediate-release dosage forms.
  • Figures 21 and 22 show the XRPD comparison charts before and after the stability test of the free base of the compound of formula (I), the malonate crystal form A.
  • the HPLC test results of the sample of Example 74 are shown in Table 18.
  • the research data show that the malonic acid crystal form A has good physical and chemical stability. After being stored at 25°C/60% relative humidity or 40°C/75% relative humidity for one week, the crystal form and purity have not changed significantly. The purity of the free base sample was significantly reduced when placed under the same conditions. It shows that, compared with the free base solid disclosed in the prior art, the malonate crystal form A can better meet the stability requirements during drug production and storage.
  • the malonate crystal form A and the malonate crystal form B of the present invention maintain the same crystal form before and after the hygroscopicity study, and have good humidity stability.
  • the malonate crystal form A has a hygroscopic weight gain of 1.1% at 25°C and a relative humidity of 80%. According to the Pharmacopoeia, it is slightly hygroscopic, which can better meet the requirements of the drug's hygroscopicity in the process of drug production and storage.
  • Crystal form B can be kept stable under normal humidity (60% relative humidity), and after dehydration at lower humidity, it can still restore the bound water state after being exposed to conventional humidity conditions, showing good humidity stability, and it is not suitable for raw materials.
  • the requirements for post-treatment processes such as drying in the production process of the drug are low, and the drug can be kept stable under the conventional storage conditions of the drug, and has a good application prospect.
  • Moisture gain is less than 15% but not less than 2%
  • wet weight gain is less than 2% but not less than 0.2%
  • wet weight gain is less than 0.2%

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Abstract

本发明涉及丙烯酮类化合物的晶型及其制备方法。本发明提供了式（I）化合物丙二酸盐两种晶型A、B的制备方法和用途。本发明提供的式（I）化合物的丙二酸盐晶型A、B，在溶解度、熔点、稳定性、溶出度、引湿性、及加工性能、提纯作用、制剂生产、安全性等方面中的至少一方面上存在优势，为含式（I）化合物的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。

Description

丙烯酮类化合物的丙二酸盐晶型及其制备方法 技术领域
本发明涉及化学医药领域，特别是涉及丙烯酮类化合物的丙二酸盐晶型及其制备方法。
背景技术
JAK3激酶是胞质蛋白质酪氨酸激酶JAK家族的一员，在JAK-STAT信号通路中发挥着重要作用。大量研究表明，JAK3激酶的调控与多种疾病，特别是自身免疫系统疾病存在重要的相关性。因此，开发高选择性的JAK3激酶抑制剂对多种免疫疾病的治疗有着重要意义。
1-[(2S，5R)-2-甲基-5(7H-吡咯并[2,3-d]嘧啶-4-基氨基)-1-哌啶基]-2-丙烯-1-酮是一种强效、高选择性的JAK3/TEC双重抑制剂，临床测试结果表明，在治疗斑秃、类风湿性关节炎、克罗恩病以及溃疡性结肠炎等方面具有非常好的应用前景，其结构式如下所示：
Figure PCTCN2021106233-appb-000001
专利US20170247372A1公开了式(I)化合物及其合成路线，公开的合成方法需利用手性超临界流体色谱对目标化合物进行分离，设备成本高，制备条件苛刻，不适用于大规模工业化生产。需开发更为简单、安全且产率高的制备方法。
在US20190060311A1中公开了式(I)化合物的丙二酸盐可作为药物制剂的组成之一，用于白癜风的治疗。
目前，尚无有关式(I)化合物游离碱以及丙二酸盐结晶形态的任何报道。
同一药物的不同晶型在溶解度、熔点、密度、稳定性等方面有显著的差异，从而不同程度地影响药物的稳定性、均一性、生物利用度、疗效和安全性。因此，药物研发中进行全面系统的多晶型筛选，选择最适合开发的晶型，是不可忽视的重要研究内容之一。基于此，有必要对式(I)化合物游离碱以及丙二酸盐进行多晶型筛选，为药物的后续开发提供更多更好的选择。
发明内容
本发明提供了式(I)化合物丙二酸盐的两种晶型A、B及其制备方法和用途。
1.式(I)所示化合物1-[(2S,5R)-2-甲基-5-(7H-吡咯[2,3-d]嘧啶-4-氨基)-1-哌啶基]-2-丙烯-1-酮的丙二酸盐A型晶体、即丙二酸盐晶型A，其特征在于，使用Cu-Kα辐射，所述丙二酸盐晶型A的X射线粉末衍射在2θ值为7.9°±0.2°、15.8°±0.2°和19.4°±0.2°处有特征峰，
Figure PCTCN2021106233-appb-000002
2.上述1所述的丙二酸盐晶型A制备方法，其特征在于，
将式(I)化合物固体与丙二酸在甲基异丁基酮，乙腈，乙酸乙酯，乙酸异丙酯，甲基叔丁基醚中的至少一种溶剂中打浆，收集固体并在室温下真空干燥，得到丙二酸盐晶型A。
3.上述1所述的丙二酸盐晶型A制备方法，其特征在于，
将式(I)化合物固体与丙二酸在甲醇，丙酮，四氢呋喃，2-甲基四氢呋喃，1,4-二氧六环，乙醇，乙醇/水中的至少一种溶剂中溶清，搅拌三天，使用乙酸乙酯进行反溶剂添加，澄清液过滤后挥发直至有固体析出，得到丙二酸盐晶型A。
4.上述1所述的丙二酸盐晶型A制备方法，其特征在于，
将式(I)化合物的丙二酸盐固体溶解于正溶剂中，过滤后加入反溶剂，得到丙二酸盐晶型A。
5.上述1所述的丙二酸盐晶型A制备方法，其特征在于，
将式(I)化合物的丙二酸盐固体溶解于甲醇、乙醇/氯仿，过滤后挥发直至有固体析出，得到丙二酸盐晶型A。
6.上述1所述的丙二酸盐晶型A制备方法，其特征在于，
将式(I)化合物的丙二酸盐固体溶解于正溶剂中，置于反溶剂氛围中气液扩散12天，得到丙二酸盐晶型A。
7.式(I)所示化合物-[(2S,5R)-2-甲基-5-(7H-吡咯[2,3-d]嘧啶-4-氨基)-1-哌啶基]-2-丙烯-1-酮的丙二酸盐B型晶体、即丙二酸盐晶型B，其特征在于，使用Cu-Kα辐射，所述丙二酸盐晶型B的X射线粉末衍射在2θ值为6.8°±0.2°、13.6°±0.2°和16.6°±0.2°处有特征峰，
Figure PCTCN2021106233-appb-000003
8.上述7所述的丙二酸盐晶型B的制备方法，其特征在于，
将式(I)化合物固体与丙二酸在二氯甲烷中打浆，收集固体并在室温下真空干燥，得到丙二酸盐晶型B。
9.上述7所述的丙二酸盐晶型B的制备方法，其特征在于，
将式(I)化合物的丙二酸盐固体在丙酮、四氢呋喃、甲醇/二氯甲烷、氯仿/异丙醇、乙腈/水的至少一种溶剂中溶清，过滤后挥发直至有固体析出，得到丙二酸盐晶型B。
10.药物组合物，其包含上述1和7中任一项所述的晶体和制药学可接受的载体。
11.具有JAK3抑制活性的药物组合物，其含有上述1和7中任一项所述的晶体作为有效成分。
12.斑秃、类风湿性关节炎、克罗恩病、溃疡性结肠炎以及白癜风的预防药或治疗药，其含有上述1和7中任一项所述的晶体作为有效成分。
与现有技术相比，本发明提供的式(I)化合物的丙二酸盐晶型A，B，在溶解度、熔点、稳定性、溶出度、引湿性、生物有效性以及加工性能、提纯作用、制剂生产、安全性等方面中的至少一方面上存在优势，为含式(I)化合物的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。
附图说明
图1实施例1中丙二酸盐晶型A的XRPD图
图2实施例1中丙二酸盐晶型A的TGA图
图3实施例1中丙二酸盐晶型A的DSC图
图4实施例1中丙二酸盐晶型A的 1H NMR图
图5实施例5中丙二酸盐晶型A的XRPD图
图6实施例7中丙二酸盐晶型A的XRPD图
图7实施例16中丙二酸盐晶型A的XRPD图
图8实施例18中丙二酸盐晶型A的XRPD图
图9实施例23中丙二酸盐晶型B的XRPD图
图10实施例23中丙二酸盐晶型B的TGA图
图11实施例23中丙二酸盐晶型B的DSC图
图12实施例23中丙二酸盐晶型B的 1H NMR图
图13实施例24中丙二酸盐晶型B的XRPD图
图14实施例25中丙二酸盐晶型B的XRPD图
图15实施例26中丙二酸盐晶型B的XRPD图
图16实施例30中游离碱、丙二酸盐晶型A、B在FaSSIF(空腹状态下人工肠液)中的动态溶解度
图17实施例30中游离碱、丙二酸盐晶型A、B在FeSSIF(饱食状态下人工肠液)中的动态溶解度
图18实施例31中丙二酸盐晶型A压力稳定性前后的XRPD对比图
图19实施例31中丙二酸盐晶型B压力稳定性前后的XRPD对比图
图20实施例32中游离碱、丙二酸盐晶型A、B在pH6.8的磷酸缓冲液中的溶出曲线图
图21实施例33中稳定性测试前后游离碱的XRPD对比图
图22实施例33中稳定性测试前后丙二酸盐晶型A的XRPD对比图
图23实施例34中丙二酸盐晶型A的DVS图
图24实施例34中DVS测试前后丙二酸盐晶型A的XRPD对比图
图25实施例34中丙二酸盐晶型B的DVS图
图26实施例34中DVS测试前后丙二酸盐晶型B的XRPD对比图
图27实施例35中丙二酸盐晶型A溶液稳定性样品的XRPD图-1
图28实施例35中丙二酸盐晶型A溶液稳定性样品的XRPD图-2
具体实施方式
丙二酸盐晶型A
式(I)所示化合物1-[(2S,5R)-2-甲基-5-(7H-吡咯[2,3-d]嘧啶-4-氨基)-1-哌啶基]-2-丙烯-1-酮的丙二酸盐A型晶体、即丙二酸盐晶型A，其特征在于，使用Cu-Kα辐射，所述丙二酸盐晶型A的X射线粉末衍射在2θ值为7.9°±0.2°、15.8°±0.2°和19.4°±0.2°处有特征峰，
Figure PCTCN2021106233-appb-000004
在本发明的一个实施方式中，所述丙二酸盐晶型A的X射线粉末衍射在2θ值为17.2°±0.2°、14.1°±0.2°、28.7°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述丙二酸盐晶型A的X射线粉末衍射在2θ值为17.2°±0.2°、14.1°±0.2°、28.7°±0.2°处有特征峰。
在本发明的一个实施方式中，所述丙二酸盐晶型A的X射线粉末衍射在2θ值为10.4°±0.2°、21.0°±0.2°、27.5°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述丙二酸盐晶型A的X射线粉末衍射在2θ值为10.4°±0.2°、21.0°±0.2°、27.5°±0.2°处有特征峰。
在本发明的一个实施方式中，所述丙二酸盐晶型A的X射线粉末衍射在2θ值为7.9°±0.2°、10.4°±0.2°、14.1°±0.2°、15.8°±0.2°、17.2°±0.2°、19.4°±0.2°、21.0°±0.2°、27.5°±0.2°、28.7°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。
在本发明的一个实施方式中，所述丙二酸盐晶型A的X射线粉末衍射在2θ值为7.9°±0.2°、10.4°±0.2°、14.1°±0.2°、15.8°±0.2°、17.2°±0.2°、19.4°±0.2°、21.0°±0.2°、27.5°±0.2°、28.7°±0.2°处有特征峰。
所述的丙二酸盐晶型A的制备方法，其特征在于，
将式(I)化合物固体与丙二酸在甲基异丁基酮，乙腈，乙酸乙酯，乙酸异丙酯，甲基叔丁基醚中的至少一种溶剂中打浆，收集固体并在室温下真空干燥，得到丙二酸盐晶型A。
在本发明的一个实施方式中，所述打浆温度为20℃到30℃。
在本发明的一个实施方式中，所述式(I)化合物固体与丙二酸的投料摩尔比为0.5～1.5:1，例如1:1。
在本发明的一个实施方式中，所述打浆时间为1～10天，例如5天。
所述的丙二酸盐晶型A的制备方法，其特征在于，
将式(I)化合物固体与丙二酸在甲醇，丙酮，四氢呋喃，2-甲基四氢呋喃，1,4-二氧六环，乙醇/水中的至少一种溶剂中溶清，搅拌三天，使用乙酸乙酯进行反溶剂添加后，澄清液过滤后挥发直至有固体析出，得到丙二酸盐晶型A。
在本发明的一个实施方式中，所述乙醇/水混合溶剂中水含量为0～15％。
在本发明的一个实施方式中，所述搅拌温度为20℃到30℃。
在本发明的一个实施方式中，所述挥发温度为20℃到30℃。
所述的丙二酸盐晶型A的制备方法，其特征在于，
将式(I)化合物的丙二酸盐固体溶解于正溶剂中，过滤后加入反溶剂，得到丙二酸盐晶型A。
在本发明的一个实施方式中，所述正溶剂为甲醇，所述反溶剂选自甲基叔丁基醚和乙酸乙酯中的至少一种。
在本发明的一个实施方式中，所述溶解温度为20℃到30℃。
在本发明的一个实施方式中，过滤后在搅拌下缓慢加入反溶剂。
在本发明的一个实施方式中，搅拌温度为20℃到30℃。
所述的丙二酸盐晶型A的制备方法，其特征在于，
将式(I)化合物的丙二酸盐固体溶解于甲醇，乙醇/氯仿，过滤后挥发直至有固体析出，得到丙二酸盐晶型A。
在本发明的一个实施方式中，所述乙醇/氯仿的体积比为3～5:1，例如4:1。
在本发明的一个实施方式中，所述溶解温度为20℃到30℃。
在本发明的一个实施方式中，所述挥发温度为20℃到30℃。
所述的丙二酸盐晶型A的制备方法，其特征在于，
将式(I)化合物的丙二酸盐固体溶解于正溶剂中，置于反溶剂氛围中气液扩散12天，得到丙二酸盐晶型A。
在本发明的一个实施方式中，所述正溶剂为甲醇、乙醇、丙酮和四氢呋喃中的至少一种，所述反溶剂选自2-甲基四氢呋喃、甲基叔丁基醚、乙酸异丙酯和乙酸乙酯中的至少一种。
在本发明的一个实施方式中，所述扩散时间为5～20天，例如12天。
在本发明的一个实施方式中，所述扩散温度为5℃到30℃。
在本发明的一个实施方式中，扩散12天后仍未析出固体，将溶液转移至室温下挥发，析出固体，得到丙二酸盐晶型A。
在本发明的一个实施方式中，所述样品的挥发时间为5～10天，例如7天。
丙二酸盐晶型B
式(I)所示化合物1-[(2S,5R)-2-甲基-5-(7H-吡咯[2,3-d]嘧啶-4-氨基)-1-哌啶基]-2-丙烯-1-酮的丙二酸盐B型晶体、即丙二酸盐晶型B，其特征在于，使用Cu-Kα辐射，所述丙二酸盐晶型B的X射线粉末衍射在2θ值为6.8°±0.2°、13.6°±0.2°和16.6°±0.2°处有特征峰，
Figure PCTCN2021106233-appb-000005
在本发明的一个实施方式中，所述丙二酸盐晶型B的X射线粉末衍射在2θ值为8.6°±0.2°、28.1±0.2°、19.3°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述丙二酸盐晶型B的X射线粉末衍射在2θ值为8.6°±0.2°、28.1°±0.2°、19.3°±0.2°处有特征峰。
在本发明的一个实施方式中，所述丙二酸盐晶型B的X射线粉末衍射在2θ值为10.6°±0.2°、14.7°±0.2°中的一处或两处有特征峰。
在本发明的一个实施方式中，所述丙二酸盐晶型B的X射线粉末衍射在2θ值为10.6°±0.2°、14.7°±0.2°处有特征峰。
在本发明的一个实施方式中，所述丙二酸盐晶型B的X射线粉末衍射在2θ值为6.8°±0.2°、8.6°±0.2°、10.6°±0.2°、13.6°±0.2°、16.6°±0.2°、19.3°±0.2°、24.6±0.2°、28.1°±0.2°中的任意4处、或5处、或6处、或7处、或8处有特征峰。
在本发明的一个实施方式中，所述丙二酸盐晶型B的X射线粉末衍射在2θ值为6.8°±0.2°、8.6°±0.2°、10.6°±0.2°、13.6°±0.2°、16.6°±0.2°、19.3°±0.2°、24.6±0.2°、28.1°±0.2°处有特征峰。
所述的丙二酸盐晶型B的制备方法，其特征在于，
将式(I)化合物固体与丙二酸在二氯甲烷中打浆，收集固体并在室温下真空干燥，得到丙二酸盐晶型B。
在本发明的一个实施方式中，所述打浆温度为20℃到30℃。
在本发明的一个实施方式中，所述式(I)化合物固体与丙二酸的投料摩尔比为0.5～1.5:1，例如1:1。
在本发明的一个实施方式中，所述打浆时间为3天。
所述的丙二酸盐晶型B的制备方法，其特征在于，
将式(I)化合物的丙二酸盐固体在丙酮，四氢呋喃、甲醇/二氯甲烷、氯仿/异丙醇、乙腈/水的至少一种溶剂中溶清，过滤后挥发直至有固体析出，得到丙二酸盐晶型B。
在本发明的一个实施方式中，所述甲醇/二氯甲烷的体积比为0.5～2:1，例如1:1。
在本发明的一个实施方式中，所述氯仿/异丙醇的体积比为3～5:1，例如4:1。
在本发明的一个实施方式中，所述乙腈/水的体积比为19～9:1，例如12.5:1。
在本发明的一个实施方式中，所述溶解温度为20℃到50℃。
在本发明的一个实施方式中，所述挥发温度为20℃到30℃。
根据本发明，作为原料的所述式(I)化合物指其固体(晶体或无定形)、半固体、蜡或油形式。优选地，作为原料的式(I)化合物为固体粉末形式。所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50～1800转/分钟，其中，磁力搅拌200～1500转/分钟，优选为300～1000转/分钟，机械搅拌优选为100～300转/分钟。
上述本发明的晶体(式(I)化合物的丙二酸盐晶型A、B)可以用于制备药物组合物，在制备药物组合物时含有上述本发明的晶体和制药学可接受的载体。上述本发明的晶体(式(I)化合物的丙二酸盐晶型A、B)可以用于制备具有JAK3抑制活性的药物组合物，其包含上述本发明的晶体(式(I)化合物的丙二酸盐晶型A、B)作为有效成分。上述本发明的晶体(式(I)化合物的丙二酸盐晶型A、B)可以用于制备斑秃、类风湿性关节炎、克罗恩病、溃疡性结肠炎以及白癜风的预防药或治疗药，其包含上述本发明的晶体(式(I)化合物的丙二酸盐晶型A、B)作为有效成分。
本发明还提供药物组合物，其包含上述本发明的任意一种晶体(式(I)化合物的丙二酸盐晶型A、B)和制药学可接受的载体。
本发明还提供具有JAK3抑制活性的药物组合物，其含有上述本发明的任意一种晶体(式(I)化合物的丙二酸盐晶型A、B)作为有效成分。
本发明提供斑秃、类风湿性关节炎、克罗恩病、溃疡性结肠炎以及白癜风的预防药或治疗药，其含有上述本发明的任意一种晶体(式(I)化合物的丙二酸盐晶型A、B)作为有效成分。
本发明中，“晶体”或“多晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。事实上，X射线衍射图中衍射峰的相对强度与晶体的择优取向有关，本文所示的峰强度为说明性而非用于绝对比较。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品厚度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X射线衍射图不必和这里所指的例子中的X射线衍射图完全一致，本文所述“X射线衍射图相同”并非指绝对相同，相同峰位置可相差±0.2°且峰强度允许一定可变性。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。
在一些实施方案中，本发明的丙二酸盐晶型A、B是纯的、单一的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解 为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。
本发明说明书中记载的数值范围的上限值和下限值可以任意地组合。
实施例
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
本发明中“室温”如果没有特别说明，通常是指20℃到30℃。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
1H NMR：核磁共振氢谱
DVS：动态水分吸附
HPLC：高效液相色谱
本发明所述的X射线粉末衍射图在Panalytical(帕纳科)公司的Empyrean型及X'Pert 3型X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线光源：Cu,Kα
Kα1
Figure PCTCN2021106233-appb-000006
1.54060；Kα2
Figure PCTCN2021106233-appb-000007
1.54443
Kα2/Kα1强度比例：0.50
电压：45千伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度(2θ角)
本发明所述的差示扫描量热分析图在TA公司的Discovery DSC 2500型差示扫描量热仪上采集。本发明所述的差示扫描量热分析的方法参数如下：
扫描速率：10℃/分钟
保护气体：氮气
本发明所述的热重分析图在TA公司的Discovery TGA 5500型及Q5000型热重分析仪上采集。本发明所述的热重分析的方法参数如下：
扫描速率：10℃/分钟
保护气体：氮气
本发明所述的核磁共振氢谱数据( 1H NMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲亚砜溶解，配制成2-10mg/mL的溶液进行测试。
本发明所述的动态水分吸附图在SMS公司的Intrinsic型及Intrinsic Plus型动态水分吸附仪上采集。本发明所述的动态水分吸附测试的方法参数如下：
温度：25℃
保护气体及流量：N 2，200毫升/分钟
dm/dt：0.002％/分钟
最小dm/dt平衡时间：10分钟
最大平衡时间：180分钟
相对湿度范围：0％RH-95％RH-0％RH、室湿-95％RH-0％RH-95％RH
相对湿度梯度：10％(0％RH-90％RH-0％RH)、5％(90％RH-95％RH和95％RH-90％RH)
本发明中所述的溶出数据是在Agilent公司的Agilent 708DS型溶出仪上采集。所述的溶出测试条件如下：
溶出仪 Agilent 708DS
方法 浆法
介质 pH 6.8磷酸盐缓冲液
介质体积 900mL
转速 100rpm
介质温度 37℃
取样点 5,10,15,20,30,45,60,90,120min
补充介质 No
以下实施例中所使用的式(I)化合物游离碱固体可通过商业购买获得。
实施例1：化合物丙二酸盐A的制备
称取2.0g式(I)化合物游离碱固体和749.2mg(摩尔比1:1)的丙二酸于反应器中，加入50mL乙腈后(室温)打浆5天。过滤收集固体，于室温下真空干燥，得到式(I)化合物的丙二酸盐，共2.26g。
经检测，制备得到的固体为丙二酸盐晶型A，其X射线粉末衍射数据如表1所示，衍射图如图1所示，TGA、DSC和 1H NMR数据分别如图2～图4所示。
表1
衍射角2θ d值 强度％
7.89 11.21 100.00
10.42 8.49 10.55
11.40 7.77 0.13
13.05 6.79 0.17
14.12 6.27 19.53
15.72 5.64 39.14
17.29 5.13 8.63
18.10 4.90 2.54
19.40 4.58 18.31
20.95 4.24 5.19
21.87 4.06 3.41
22.11 4.02 3.24
22.61 3.93 0.26
24.16 3.68 3.51
24.61 3.62 4.90
25.89 3.44 1.99
27.52 3.24 14.69
27.84 3.20 9.60
28.65 3.12 8.18
29.78 3.00 0.41
30.83 2.90 1.12
31.77 2.82 2.22
34.04 2.63 0.81
34.94 2.57 0.99
实施例2～6：丙二酸盐晶型A的制备(反应结晶)
室温条件下称取适量的式(I)化合物游离碱固体及一定摩尔比的丙二酸置于1.5毫升玻璃小瓶中，加入相应体积的有机溶剂在室温下打浆3天，收集固体并在室温下真空干燥。
经检测，本实施例得到的固体均为丙二酸盐晶型A。本实施例中所涉详细试验条件如表2所示，实施例5样品的X射线粉末衍射数据如表3所示，衍射图如图5所示。
表2
Figure PCTCN2021106233-appb-000008
表3
衍射角2θ d值 强度％
7.89 11.21 100.00
10.39 8.52 11.66
14.13 6.27 31.47
15.69 5.65 48.50
15.88 5.58 48.09
17.29 5.13 7.87
18.11 4.90 6.35
19.40 4.57 29.58
20.97 4.24 8.18
21.95 4.05 5.43
24.11 3.69 4.53
24.66 3.61 8.21
25.95 3.43 2.68
27.55 3.24 31.38
27.88 3.20 20.74
28.66 3.12 18.44
29.98 2.98 1.08
30.91 2.89 1.09
31.72 2.82 3.19
33.90 2.64 0.36
35.00 2.56 1.27
实施例6～14：丙二酸盐晶型A的制备(反溶剂添加-挥发结晶)
室温条件下称取适量的式(I)化合物游离碱固体及一定摩尔比的丙二酸置于1.5毫升玻璃小瓶中，加入相应体积的有机溶剂在室温下打浆3天，获得澄清液。将所得澄清溶液转移至5毫升玻璃小瓶中，使用乙酸乙酯进行反溶剂添加，未析出固体，而后将澄清液置于室温条件下缓慢挥发，直至有固体析出。
经检测，本实施例得到的固体均为丙二酸盐晶型A。本实施例中所涉详细试验条件如表4所示，实施例7样品的X射线粉末衍射数据如表5所示，衍射图如图6所示。
表4
Figure PCTCN2021106233-appb-000009
表5
衍射角2θ d值 强度％
7.89 11.21 100.00
10.39 8.51 8.92
14.12 6.27 20.09
15.67 5.66 46.26
15.86 5.59 46.57
17.22 5.15 15.55
18.03 4.92 3.97
19.39 4.58 29.39
20.92 4.25 9.69
21.84 4.07 5.59
24.17 3.68 5.89
24.56 3.62 8.41
25.82 3.45 5.72
27.50 3.24 30.00
27.80 3.21 26.93
28.71 3.11 20.39
30.92 2.89 2.46
31.68 2.82 3.80
34.94 2.57 2.59
实施例15～16：丙二酸盐晶型A的制备(反溶剂添加法)
室温条件下称取适量的实施例1得到的式(I)化合物的丙二酸盐固体置于5毫升的玻璃小瓶中，加入相应体积的正溶剂使固体溶清。随后磁力搅拌(转速约为1000转/分钟)得到澄清溶液，并向其中逐滴加入相应反溶剂，观察到有固体析出，离心分离所得固体。
经检测，本实施例得到的固体均为丙二酸盐晶型A。本实施例中所涉详细试验条件如表6所示，实施例16样品的X射线粉末衍射数据如表7所示，衍射图如图7所示。
表6
Figure PCTCN2021106233-appb-000010
表7
衍射角2θ d值 强度％
7.89 11.21 100.00
10.37 8.53 12.91
12.82 6.91 0.69
14.05 6.30 25.73
14.26 6.21 15.67
15.24 5.81 10.00
15.66 5.66 56.02
15.85 5.59 58.11
17.26 5.14 17.01
18.11 4.90 5.63
19.37 4.58 34.82
20.94 4.24 9.30
22.02 4.04 6.36
24.13 3.69 6.76
24.58 3.62 10.52
25.85 3.45 5.18
27.52 3.24 36.35
27.84 3.20 30.88
28.67 3.11 23.06
29.47 3.03 4.11
30.78 2.90 2.93
31.70 2.82 4.69
34.88 2.57 2.60
实施例17～18：丙二酸盐晶型A的制备(缓慢挥发法)
室温条件下称取适量的实施例1得到的式(I)化合物的丙二酸盐固体置于3毫升的玻璃小瓶中，加入相应体积的溶剂以溶解固体。使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至新的3毫升玻璃小瓶中。使用封口膜封口后于其上扎4个针孔，而后置于室温条件下缓慢挥发，直至有固体析出。
经检测，本实施例得到的固体均为丙二酸盐晶型A。本实施例中所涉详细试验条件如表8所示，实施例18样品的X射线粉末衍射数据如表9所示，衍射图如图8所示。
表8
Figure PCTCN2021106233-appb-000011
表9
衍射角2θ d值 强度％
7.89 11.21 100.00
10.43 8.48 15.97
14.13 6.27 34.30
14.28 6.20 24.05
15.23 5.82 9.21
15.76 5.62 59.26
17.30 5.13 10.27
18.22 4.87 5.16
19.44 4.57 37.65
21.00 4.23 9.67
21.93 4.05 6.25
24.22 3.67 6.10
24.66 3.61 13.88
25.90 3.44 4.68
27.58 3.23 39.27
27.88 3.20 32.67
28.70 3.11 25.62
30.15 2.96 1.63
30.87 2.90 3.12
31.68 2.82 2.23
33.03 2.71 0.92
34.01 2.64 1.18
34.93 2.57 1.48
实施例19～22：丙二酸盐晶型A的制备(气液渗透-室温挥发法)
室温条件下称取适量的实施例1得到的式(I)化合物的丙二酸盐固体置于3毫升的玻璃小瓶中，加入相应体积的正溶剂以溶解固体，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至新的3毫升玻璃小瓶中，敞口置于预盛有3毫升相应反溶剂的20毫升玻璃瓶中。封口后置于室温条件下气液渗透十二天时间。未析出固体的样品转移至室温条件下敞口挥发七天，收集固体。
经检测，本实施例得到的固体均为丙二酸盐晶型A。本实施例中所涉详细试验条件如表10所示，实施例19样品的X射线粉末衍射数据如表11所示。
表10
Figure PCTCN2021106233-appb-000012
表11
衍射角2θ d值 强度％
7.89 11.21 100.00
10.39 8.51 11.68
14.10 6.28 32.45
15.69 5.65 56.26
15.84 5.60 51.27
17.22 5.15 12.58
18.09 4.90 8.38
19.39 4.58 36.61
20.96 4.24 10.14
21.97 4.05 6.97
24.13 3.69 6.20
24.60 3.62 10.38
25.86 3.45 6.35
27.51 3.24 43.66
27.84 3.20 35.15
28.71 3.11 28.16
31.73 2.82 5.15
33.92 2.64 1.98
34.93 2.57 3.86
实施例23：丙二酸盐晶型B的制备(反应结晶)
室温条件下称取20.8毫克制备式(I)化合物游离碱固体以及等摩尔比的丙二酸固体置于1.5毫升玻璃小瓶中，加入1.0毫升二氯甲烷，室温条件下磁力搅拌(转速约为1000转/分钟)约3天，离心分离得到固体，室温下真空干燥。
经检测，本实施例得到的固体为晶型B，其X射线粉末衍射数据如表12所示，衍射图如图9所示，TGA、DSC和 1H NMR数据分别如图10～图12所示。
表12
衍射角2θ d值 强度％
6.79 13.02 100.00
8.55 10.34 5.20
10.66 8.30 1.78
13.66 6.48 33.55
15.12 5.86 2.38
16.59 5.34 5.44
17.22 5.15 1.92
19.37 4.58 2.43
20.36 4.36 0.88
21.45 4.14 0.92
23.04 3.86 0.54
24.63 3.61 0.60
27.20 3.28 2.17
28.06 3.18 2.60
30.58 2.92 0.53
实施例24～29：丙二酸盐晶型B的制备(缓慢挥发法)
室温条件下称取适量的实施例1得到的式(I)化合物的丙二酸盐固体置于3毫升的玻璃小瓶中，加入相应体积的溶剂以溶解固体。使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至新的3毫升玻璃小瓶中。使用封口膜封口后于其上扎4个针孔，而后置于室温条件下缓慢挥发，直至有固体析出。
经检测，本实施例得到的固体均为丙二酸盐晶型B。本实施例中所涉详细试验条件如表13所示，实施例25样品的X射线粉末衍射数据如
表14～16所示，实施例24～26的衍射图如图13～15所示。
表13
Figure PCTCN2021106233-appb-000013
表14
衍射角2θ d值 强度％
6.79 13.02 100.00
8.52 10.37 19.38
10.61 8.34 5.77
13.58 6.52 22.03
15.11 5.86 28.05
16.06 5.52 3.71
16.54 5.36 19.61
17.17 5.16 9.90
19.29 4.60 11.77
19.55 4.54 12.67
21.42 4.15 5.78
24.71 3.60 4.83
26.31 3.39 3.20
27.18 3.28 22.15
28.04 3.18 32.30
29.55 3.02 3.32
30.56 2.93 4.38
32.39 2.76 0.60
表15
衍射角2θ d值 强度％
6.79 13.02 100.00
7.85 11.27 4.37
8.58 10.31 17.48
10.67 8.29 9.03
13.64 6.49 25.46
15.13 5.86 14.08
16.59 5.35 15.35
17.23 5.15 8.19
19.39 4.58 8.75
21.45 4.14 3.98
24.68 3.61 2.53
27.21 3.28 11.57
28.06 3.18 15.11
30.55 2.93 2.14
表16
衍射角2θ d值 强度％
6.79 13.02 100.00
8.55 10.34 17.93
10.62 8.33 4.75
13.63 6.50 28.49
14.01 6.32 12.77
15.13 5.85 19.88
16.59 5.34 19.32
17.21 5.15 9.51
19.34 4.59 12.57
21.44 4.14 3.90
24.73 3.60 4.60
27.22 3.28 18.78
28.09 3.18 27.00
29.40 3.04 2.32
30.60 2.92 4.47
实施例30：晶型的溶解度测试
将一定质量的本发明的丙二酸盐晶型A，丙二酸盐晶型B和式(I)化合物游离碱固体分别投入37℃下FaSSIF(空腹状态下人工肠液)、FeSSIF(饱食状态下人工肠液)中进行动态溶解度测试，在1小时、4小时和24小时平衡后，取溶液过滤，通过高效液相色谱法(HPLC)测定溶液中样品的含量。实验过程中，丙二酸盐晶型A，丙二酸盐晶型B样品在平衡1小时后溶清，式(I)化合物游离碱样品始终保持浑浊状态。具体数据如表17所示，绘制丙二酸盐晶型A，丙二酸盐晶型B及式(I)化合物游离碱在不同溶媒中的动态溶解度图如图16、17所示。本发明丙二酸盐晶型A，丙二酸盐晶型B在FaSSIF和FeSSIF中的溶解度明显高于式(I)化合物游离碱。说明，丙二酸盐晶型A、晶型B在生物体内更易被人体消化液溶解，进而更有效的被生物体吸收利用。
表17
Figure PCTCN2021106233-appb-000014
实施例31：晶型的压力稳定性
采用手动压片机对本发明的丙二酸盐晶型A和丙二酸盐晶型B进行压力稳定性测试，采用650MPa压力对本发明晶型压制一分钟，后取出压片进行XPRD测试。丙二酸盐晶型A和丙二酸盐晶型B压力稳定性前后样品的XRPD数据如图18、19所示。结果表明，本发明晶型在测试前后晶型保持一致，具有优异的压力稳定性，能够满足制剂压片工艺过程中对药物稳定性的要求。
实施例32：晶型的溶出度
称取本发明的丙二酸盐晶型A，丙二酸盐晶型B和式(I)化合物游离碱固体各约100mg，倒入压片机模具，在300MPa压力下持续1分钟，取完整压片转移至溶出仪测试37℃下 pH 6.8磷酸缓冲液中的溶出度。丙二酸盐晶型A，丙二酸盐晶型B及式(I)化合物游离碱固体的溶出度图如图20示。本发明丙二酸盐晶型A，丙二酸盐晶型B的分别在溶出实验开始10分钟后与20分钟后达到最大溶出度(100％)，式(I)化合物游离碱固体在实验到达终点(120分钟)时，溶出度未达到20％。与式(I)化合物游离碱相比，本发明丙二酸盐晶型A，丙二酸盐晶型B在pH 6.8磷酸缓冲液中溶出速率更快，溶出度更高，能够更快地被生物体吸收利用，达到更高的生物利用度，能够更好的满足药物速释剂型开发过程中对原料药溶出性能的要求。
实施例33：稳定性研究
称取本发明的丙二酸盐晶型A和式(I)化合物游离碱固体各约15mg，敞口放置于25℃/60％相对湿度和40℃/75％相对湿度条件的稳定箱中，在7天后取样测XRPD和HPLC纯度。本发明的丙二酸盐晶型A在测试条件下的式(I)化合物游离碱固体。
式(I)化合物游离碱，丙二酸盐晶型A稳定验研究前后的XRPD对比图如图21、22所示。实施例74样品的HPLC测试结果如表18所示。
表18
Figure PCTCN2021106233-appb-000015
--：未采集数据。
研究数据表明，丙二酸晶型A具有较好的物理化学稳定性，在25℃/60％相对湿度或40℃/75％相对湿度下保存一周后，晶型与纯度未见明显变化。游离碱样品在相同条件下放置后，纯度显著降低。说明，与现有技术中披露的游离碱固体相比，丙二酸盐晶型A能够更好的满足药物生产以及储存过程中的稳定性要求。
实施例34：引湿性研究
称取本发明的丙二酸盐晶型A和丙二酸盐晶型B各约20mg进行动态水分吸附(DVS)测试，然后取样测XRPD。丙二酸盐晶型A和丙二酸盐晶型B的DVS图和DVS测试前后的XRPD对比图如图23～26所示。
本发明丙二酸盐晶型A和丙二酸盐晶型B在引湿性研究前后晶型保持一致，具有较好的湿度稳定性。丙二酸盐晶型A在25℃，80％相对湿度下吸湿增重1.1％，根据药典规定属于略有引湿性，能够较好的满足药物生产与储存过程中对药物引湿性的要求。晶型B可在常规湿度下(60％相对湿度)保持稳定，在较低湿度下脱水后，仍可在暴露于常规湿度条件后恢复结合水状态，表现出较好的湿度稳定性，对原料药生产过程中干燥等后处理工艺的要求低，可在药物常规储存条件下保持稳定，具有较好的应用前景。
关于引湿性特征描述与引湿性增重的界定(中国药典2010年版附录XIX J药物引湿性试验指导原则)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15％
有引湿性：引湿增重小于15％但不小于2％
略有引湿性：引湿增重小于2％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
实施例35：丙二酸盐晶型A的溶液稳定性测试
为测试晶型A在有机溶剂中的稳定性，室温条件下称取约15mg实施例1得到的式(I)化合物的丙二酸盐晶型A固体于1.5毫升玻璃小瓶中，加入相应体积的溶剂后，在室温下打浆5天，分离固体。本实施例中所涉详细试验条件如表19所示。经检测，本实施例得到的固体均为丙二酸盐晶型A，X射线衍射图如图27、28所示。表明丙二酸盐晶型A在测试溶剂中的稳定性较好，能够满足药物生产过程中合成工艺或结晶工艺对产品稳定性的要求。
表19
Figure PCTCN2021106233-appb-000016
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (12)

  1. 式(I)所示化合物1-[(2S,5R)-2-甲基-5-(7H-吡咯[2,3-d]嘧啶-4-氨基)-1-哌啶基]-2-丙烯-1-酮的丙二酸盐A型晶体、即丙二酸盐晶型A，其特征在于，使用Cu-Kα辐射，所述丙二酸盐晶型A的X射线粉末衍射在2θ值为7.9°±0.2°、15.8°±0.2°和19.4°±0.2°处有特征峰，
    Figure PCTCN2021106233-appb-100001
  2. 权利要求1所述的丙二酸盐晶型A制备方法，其特征在于，
    将式(I)化合物固体与丙二酸在甲基异丁基酮，乙腈，乙酸乙酯，乙酸异丙酯，甲基叔丁基醚中的至少一种溶剂中打浆，收集固体并在室温下真空干燥，得到丙二酸盐晶型A。
  3. 权利要求1所述的丙二酸盐晶型A制备方法，其特征在于，
    将式(I)化合物固体与丙二酸在甲醇，丙酮，四氢呋喃，2-甲基四氢呋喃，1,4-二氧六环，乙醇，乙醇/水中的至少一种溶剂中溶清，搅拌三天，使用乙酸乙酯进行反溶剂添加，澄清液过滤后挥发直至有固体析出，得到丙二酸盐晶型A。
  4. 权利要求1所述的丙二酸盐晶型A制备方法，其特征在于，
    将式(I)化合物的丙二酸盐固体溶解于正溶剂中，过滤后加入反溶剂，得到丙二酸盐晶型A。
  5. 权利要求1所述的丙二酸盐晶型A制备方法，其特征在于，
    将式(I)化合物的丙二酸盐固体溶解于甲醇、乙醇/氯仿，过滤后挥发直至有固体析出，得到丙二酸盐晶型A。
  6. 权利要求1所述的丙二酸盐晶型A制备方法，其特征在于，
    将式(I)化合物的丙二酸盐固体溶解于正溶剂中，置于反溶剂氛围中气液扩散12天，得到丙二酸盐晶型A。
  7. 式(I)所示化合物-[(2S,5R)-2-甲基-5-(7H-吡咯[2,3-d]嘧啶-4-氨基)-1-哌啶基]-2-丙烯-1-酮的丙二酸盐B型晶体、即丙二酸盐晶型B，其特征在于，使用Cu-Kα辐射，所述丙二酸盐晶型B的X射线粉末衍射在2θ值为6.8°±0.2°、13.6°±0.2°和16.6°±0.2°处有特征峰，
    Figure PCTCN2021106233-appb-100002
  8. 权利要求7所述的丙二酸盐晶型B的制备方法，其特征在于，
    将式(I)化合物固体与丙二酸在二氯甲烷中打浆，收集固体并在室温下真空干燥，得到丙二酸盐晶型B。
  9. 权利要求7所述的丙二酸盐晶型B的制备方法，其特征在于，
    将式(I)化合物的丙二酸盐固体在丙酮、四氢呋喃、甲醇/二氯甲烷、氯仿/异丙醇、乙腈/水的至少一种溶剂中溶清，过滤后挥发直至有固体析出，得到丙二酸盐晶型B。
  10. 药物组合物，其包含权利要求1和7中任一项所述的晶体和制药学可接受的载体。
  11. 具有JAK3抑制活性的药物组合物，其含有权利要求1和7中任一项所述的晶体作为有效成分。
  12. 斑秃、类风湿性关节炎、克罗恩病、溃疡性结肠炎以及白癜风的预防药或治疗药，其含有权利要求1和7中任一项所述的晶体作为有效成分。
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