WO2022078122A1 - New crystal forms of acalabrutinib and preparation method therefor - Google Patents

New crystal forms of acalabrutinib and preparation method therefor Download PDF

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WO2022078122A1
WO2022078122A1 PCT/CN2021/117369 CN2021117369W WO2022078122A1 WO 2022078122 A1 WO2022078122 A1 WO 2022078122A1 CN 2021117369 W CN2021117369 W CN 2021117369W WO 2022078122 A1 WO2022078122 A1 WO 2022078122A1
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apti
crystal form
acaltinib
new crystal
iii
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PCT/CN2021/117369
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French (fr)
Chinese (zh)
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张靖达
黄培晨
郭万成
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奥锐特药业(天津)有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • the invention belongs to the technical field of compound synthesis, in particular to a new crystal form of acaltinib and a preparation method thereof.
  • Acalabrutinib (trade name: Calquence) is a new drug approved by the FDA in October 2017 from AstraZeneca for the treatment of mantle cell lymphoma (MCL).
  • Acalabrutinib is a second-generation BTK inhibitor with higher drug selectivity and lower side effects than the first-generation BTK inhibitor Ibrutinib.
  • WO2017002095A1 discloses 8 crystal forms of acalabrutinib, and it is reported in the text that crystal form I to crystal form V are all free bases, wherein crystal form I is an anhydrate, crystal form II is a trihydrate, with poor fluidity and uneven particle size, The water content is different under different conditions, and the water content can reach up to 10%; the crystal form III is a dihydrate, the crystal form is unstable, and the water content changes with the change of conditions, and the highest water content can reach 8%; Form V is an anhydrate, obtained by dehydration of crystal form II under low humidity conditions and dehydration under heating conditions, respectively; crystal form VI and crystal form VII are methanol solvates; crystal form VIII is acetic acid solvate.
  • crystal form I is difficult to separate out from the solution, the preparation is difficult, and the crystal form II, crystal form III, crystal form IV and crystal form V have poor stability; crystal form VI, crystal form VII, crystal form VII are solvates, in The advantages of using formulations are not obvious.
  • the present invention provides four new crystal forms of acaltinib, all of which have been confirmed by PXRD, DSC, HNMR, IR, and TGA detection, APTI-I, APTI-II (co-crystal of acaltinib and maltitol), APTI-III (co-crystal of acaltinib and ethyl maltol), APTI-IV (co-crystal of acaltinib and succinic acid)
  • the preparation of crystals) is simple in operation, low in cost, easy to scale up production, and provides a new option for formulation research and development.
  • the first new crystal form APTI-I of acaltinib uses Cu-K ⁇ radiation, and its X-ray powder diffraction diffraction angles 2 ⁇ are: 6.2° ⁇ 0.2°, 6.5° ⁇ 0.2°, 10.2° ⁇ 0.2°, 10.8° ⁇ 0.2°, 11.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, 14.4° ⁇ 0.2°, 15.0° ⁇ 0.2°, 16.2° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.6° ⁇ 0.2° a one or more characteristic peaks.
  • Acatinib crystal form APTI-I using amorphous solid or crystal form III solid as raw material, in ethanol, acetone or a mixed solvent of acetone/ethanol/n-heptane, the free base crystal form APTI of acatinib can be obtained -I, changing the type of solvent is not conducive to obtaining the new crystal form of the free base of acaltinib.
  • the volume of the reaction solvent is preferably 3-6 volumes; the reaction temperature is preferably 50-60° C.; and the stirring time is preferably 1-3 hours.
  • acaltinib solid (amorphous or crystal form III)
  • 3-50 volumes of ethanol heat up to 5-80 °C for 0.5 hours, cool to 0-30 °C and let stand for 3-10 days until a large amount of solid is precipitated. , filtered to obtain acaltinib crystal form APTI-I.
  • the volume of the reaction solvent is preferably 3-8 volumes; the reaction temperature is preferably 50-60° C.; the cooling temperature is preferably 15-25° C.; and the standing time is preferably 3-7 days.
  • the volume of the reaction solvent acetone is preferably 3-6 volumes, the volume of the solvent ethanol is preferably 1-2 volumes, and the volume of n-heptane is preferably 0.5-1 volumes;
  • the reaction temperature is preferably 50-60 ° C;
  • the room temperature is preferably 15-25 °C;
  • the stirring time is preferably 1-3 hours.
  • the crystal form has good stability: the crystal form of APTI-I does not change at 50°C for 7 days, the crystal form does not change at high temperature of 80°C for 8 hours, and the crystal form does not change at 25°C and 80% RH for 48 hours.
  • the changes show that the crystal form has good stability and provides a new option for formulation development.
  • the second new crystal form APTI-II of acaltinib uses Cu-K ⁇ radiation, and the diffraction angles 2 ⁇ of X-ray powder diffraction of the crystal form APTI-II are: 5.0° ⁇ 0.2°, 5.7° ⁇ 0.2°, 9.1° ⁇ 0.2°, 10.1° ⁇ 0.2°, 10.4° ⁇ 0.2°, 11.3° ⁇ 0.2°, 12.9° ⁇ 0.2°, 14.5° ⁇ 0.2°, 15.1° ⁇ 0.2°, 16.0° ⁇ 0.2 °, 16.4° ⁇ 0.2°, 17.8° ⁇ 0.2°, 18.3° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.1° ⁇ 0.2°, 20.3° ⁇ 0.2°, 20.6° ⁇ 0.2°, 21.1° ⁇ 0.2°, 21.9° ⁇ 0.2°, 22.4° ⁇ 0.2°, 23.5° ⁇ 0.2°, 24.2° ⁇ 0.2°, 24.9° ⁇ 0.2°, 25.8° ⁇ 0.2°, 27.7° ⁇ 0.2°, 28.6° ⁇ 0.2° or multiple characteristic peaks.
  • the new crystal form APTI-II is a co-crystal of acalatinib and maltitol, using the amorphous solid or crystal form III of acaltinib as raw material, in ethanol, isopropanol, n-propanol, n-butanol, Ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone, acetone solvent or any two or more mixed solvents thereof are heated to 50-60° C., malt alcohol is added, the temperature is maintained and the temperature is lowered to obtain the eutectic APTI-II.
  • Acatinib solid (amorphous or crystalline form III) with 3-10 volumes of ethanol, isopropanol, n-propanol, n-butanol, ethyl acetate, butanone, methyl isobutyl ketone, acetone solvent Or dissolve in any two or more mixed solvents, add 0.9-2 equivalent of malt alcohol at 5-80 ° C, stir until there is solid precipitation, cool down to room temperature and filter to obtain acatinib crystal form APTI- II.
  • the volume of the reaction solvent is preferably 5-8 volumes, the reaction temperature is preferably 50-60°C, the maltol equivalent is preferably 0.9-1.2 equivalent, and the room temperature is preferably 15-25°C.
  • the crystal form has good stability: the crystal form of APTI-II does not change at 50°C for 7 days, the crystal form does not change at high temperature at 80°C for 8 hours, and the crystal form does not change at 25°C and 80% RH for 48 hours.
  • the changes show that the crystal form has good stability and provides a new option for formulation development.
  • the third new crystal form APTI-III of acaltinib uses Cu-K ⁇ radiation, and the diffraction angle 2 ⁇ of X-ray powder diffraction of the crystal form APTI-III is: 5.0° ⁇ 0.2°, 5.7° ⁇ 0.2°, 7.2° ⁇ 0.2°, 9.1° ⁇ 0.2°, 10.1° ⁇ 0.2°, 10.3° ⁇ 0.2°, 11.3° ⁇ 0.2°, 12.8° ⁇ 0.2°, 15.1° ⁇ 0.2°, 15.7° ⁇ 0.2 °, 16.0° ⁇ 0.2°, 16.3° ⁇ 0.2°, 17.8° ⁇ 0.2°, 18.4° ⁇ 0.2°, 19.2° ⁇ 0.2°, 20.0° ⁇ 0.2°, 20.5° ⁇ 0.2°, 21.1° ⁇ 0.2°, 21.8° ⁇ 0.2°, 22.4° ⁇ 0.2°, 23.4° ⁇ 0.2°, 24.1° ⁇ 0.2°, 24.8° ⁇ 0.2°, 25.1° ⁇ 0.2°, 25.7° ⁇ 0.2°, 28.3° ⁇ 0.2° or multiple characteristic peaks.
  • the new crystal form APTI-III is a co-crystal of acaltinib and ethyl maltol.
  • the amorphous solid or crystal form III of acaltinib is used as the raw material, and the temperature is raised to 50-60 °C in n-propanol or acetone solvent. °C, the system is clarified, add ethyl maltol, keep warm and cool to obtain.
  • acaltinib solid amorphous or crystal form III
  • 3-50 volumes of n-propanol (or acetone) add 0.9-2 equivalents of ethyl maltol at 5-80 °C, and stir until there is a solid Precipitation, cooled to room temperature and filtered to obtain the crystalline form APTI-III of acaltinib.
  • the volume of the reaction solvent is preferably 5-8 volumes, the reaction temperature is preferably 50-60°C, the equivalent of ethyl maltol is preferably 0.9-1.2 equivalent, and the room temperature is preferably 15-25°C.
  • the crystal form has good stability: the crystal form of APTI-III does not change at 50°C for 7 days, the crystal form does not change at high temperature at 80°C for 8 hours, and the crystal form does not change at 25°C and 80%RH high humidity for 48 hours The changes show that the crystal form has good stability and provides a new option for formulation development.
  • the fourth new crystal form APTI-IV of acaltinib uses Cu-K ⁇ radiation, and the diffraction angle 2 ⁇ of X-ray powder diffraction of the crystal form APTI-IV is: 5.2° ⁇ 0.2°, 8.9° ⁇ 0.2°, 9.3° ⁇ 0.2°, 10.2° ⁇ 0.2°, 11.5° ⁇ 0.2°, 12.5° ⁇ 0.2°, 13.4° ⁇ 0.2°, 15.2° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.6° ⁇ 0.2 °, 18.3° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.4° ⁇ 0.2°, 23.0° ⁇ 0.2°, 24.2° ⁇ 0.2°, 24.7° ⁇ 0.2°, 25.3° ⁇ 0.2°, 26.0° ⁇ 0.2°, One or more characteristic peaks at 27.1° ⁇ 0.2°.
  • the new crystal form APTI-IV is a co-crystal of acaltinib and succinic acid.
  • the amorphous solid or crystal form III of acaltinib is used as the raw material, and the temperature is raised to 50-60 in ethanol (or butanone) solvent. °C, add succinic acid, keep warm and cool to obtain eutectic APTI-IV.
  • acaltinib solid amorphous or crystal form III
  • 3-50 volumes of ethanol (or butanone) add 0.4-1 equivalent of succinic acid at 5-70 ° C, and stir until a solid is precipitated, It was cooled to room temperature and filtered to obtain the crystalline form APTI-IV of acaltinib.
  • the volume of the reaction solvent is preferably 5-8 volumes, the reaction temperature is preferably 50-60°C, the equivalent of succinic acid is preferably 0.5-0.6 equivalent, and the room temperature is preferably 15-25°C.
  • the crystal form has good stability: the crystal form of APTI-IV does not change at 50°C for 7 days, the crystal form does not change at 80°C for 8 hours, and the crystal form does not change at 25°C and 80% RH for 48 hours.
  • the changes show that the crystal form has good stability and provides a new option for formulation development.
  • the present invention also provides a composition comprising one or two, three or four of the new crystal forms of acaltinib, APTI-I, APTI-II, APTI-III and APTI-IV.
  • the present invention also provides a pharmaceutical composition for treating mantle cell lymphoma, comprising an effective dose of one of the new crystal forms APTI-I, APTI-II, APTI-III and APTI-IV of acaltinib or Two or three or four.
  • compositions may also contain pharmaceutically acceptable carriers, diluents or excipients.
  • Fig. 1 is the PXRD pattern of the typical example of described crystal form APTI-I;
  • Fig. 2 is the DSC spectrum of described crystal form APTI-I
  • Fig. 3 is the HNMR spectrum of described crystal form APTI-I
  • Fig. 4 is the IR spectrum of described crystal form APTI-I
  • Fig. 5 is the TGA spectrum of described crystal form APTI-I
  • Fig. 6 is the PXRD pattern of the typical example of described crystal form APTI-II;
  • Fig. 7 is the DSC spectrum of described crystal form APTI-II;
  • Fig. 8 is the HNMR spectrum of described crystal form APTI-II;
  • Fig. 9 is the IR spectrum of described crystal form APTI-II;
  • Fig. 10 is the TGA spectrum of described crystal form APTI-II;
  • Fig. 11 is the PXRD pattern of the typical example of described crystal form APTI-III;
  • Figure 12 is the DSC spectrum of the described crystal form APTI-III
  • Fig. 13 is the HNMR spectrum of described crystal form APTI-III;
  • Figure 14 is the IR spectrum of the described crystal form APTI-III;
  • Fig. 15 is the TGA spectrum of described crystal form APTI-III;
  • Fig. 16 is the PXRD pattern of the typical example of described crystal form APTI-IV;
  • Figure 17 is the DSC spectrum of the described crystal form APTI-IV;
  • Fig. 18 is the HNMR spectrum of described crystal form APTI-IV;
  • Figure 19 is the IR spectrum of the described crystal form APTI-IV.
  • Figure 20 is the TGA spectrum of the crystalline form APTI-IV.
  • the new crystalline form APTI-I of acaltinib, using Cu-K ⁇ radiation, its X-ray powder diffraction at diffraction angles 2 ⁇ are: 6.2° ⁇ 0.2°, 6.5° ⁇ 0.2°, 10.2° ⁇ 0.2°, 10.8° ⁇ 0.2°, 11.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, 14.4° ⁇ 0.2°, 15.0° ⁇ 0.2°, 16.2° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.6° ⁇ 0.2° , 20.6° ⁇ 0.2°, 21.6° ⁇ 0.2°, 22.1° ⁇ 0.2°, 24.0° ⁇ 0.2°, 25.6° ⁇ 0.2°, 26.1° ⁇ 0.2°, 27.7° ⁇ 0.2° one or more characteristic peaks .
  • the preparation method is as follows:
  • the new crystalline form APTI-II of acaltinib, using Cu-K ⁇ radiation, its X-ray powder diffraction at diffraction angles 2 ⁇ are: 5.0° ⁇ 0.2°, 5.7° ⁇ 0.2°, 9.1° ⁇ 0.2°, 10.1° ⁇ 0.2°, 10.4° ⁇ 0.2°, 11.3° ⁇ 0.2°, 12.9° ⁇ 0.2°, 14.5° ⁇ 0.2°, 15.1° ⁇ 0.2°, 16.0° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.8° ⁇ 0.2° , 18.3° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.1° ⁇ 0.2°, 20.3° ⁇ 0.2°, 20.6° ⁇ 0.2°, 21.1° ⁇ 0.2°, 21.9° ⁇ 0.2°, 22.4° ⁇ 0.2°, 23.5 ° ⁇ 0.2°, 24.2° ⁇ 0.2°, 24.9° ⁇ 0.2°, 25.8° ⁇ 0.2°, 27.7° ⁇ 0.2°, 28.6° ⁇ 0.2° one or more characteristic peaks.
  • the preparation method is as follows:
  • acalatinib Take 0.3 g of acalatinib, add 2.4 mL of a preferred solvent, heat up to 50-60 °C until the system is clear, add 1.1 equivalents of maltitol, keep at 50-60 °C for 1 hour, cool down to room temperature, keep stirring at room temperature for 1 hour, Suction filtration, the filter cake is rinsed with the preferred solvent used and then dried in vacuo at 40 °C to obtain acatinib crystal form APTI-II, the preferred solvent and the weight of the obtained acatinib crystal form APTI-II are shown in the following table:
  • the third new crystal form APTI-III of acaltinib uses Cu-K ⁇ radiation.
  • the diffraction angles 2 ⁇ of X-ray powder diffraction of the crystal form APTI-III are: 5.0° ⁇ 0.2°, 5.7° ⁇ 0.2° , 7.2° ⁇ 0.2°, 9.1° ⁇ 0.2°, 10.1° ⁇ 0.2°, 10.3° ⁇ 0.2°, 11.3° ⁇ 0.2°, 12.8° ⁇ 0.2°, 15.1° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.0 ° ⁇ 0.2°, 16.3° ⁇ 0.2°, 17.8° ⁇ 0.2°, 18.4° ⁇ 0.2°, 19.2° ⁇ 0.2°, 20.0° ⁇ 0.2°, 20.5° ⁇ 0.2°, 21.1° ⁇ 0.2°, 21.8° ⁇ One or more of 0.2°, 22.4° ⁇ 0.2°, 23.4° ⁇ 0.2°, 24.1° ⁇ 0.2°, 24.8° ⁇ 0.2°, 25.1° ⁇ 0.2°, 25.7° ⁇ 0.2°, 28.3° ⁇ 0.2° Characteristic peaks.
  • the preparation method is as follows:
  • the fourth new crystal form APTI-IV of acaltinib using Cu-K ⁇ radiation, the diffraction angles 2 ⁇ of X-ray powder diffraction of the crystal form APTI-IV are: 5.2° ⁇ 0.2°, 8.9° ⁇ 0.2° , 9.3° ⁇ 0.2°, 10.2° ⁇ 0.2°, 11.5° ⁇ 0.2°, 12.5° ⁇ 0.2°, 13.4° ⁇ 0.2°, 15.2° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.6° ⁇ 0.2°, 18.3 ° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.4° ⁇ 0.2°, 23.0° ⁇ 0.2°, 24.2° ⁇ 0.2°, 24.7° ⁇ 0.2°, 25.3° ⁇ 0.2°, 26.0° ⁇ 0.2°, 27.1° ⁇ One or more characteristic peaks at 0.2°.
  • the preparation method is as follows:

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Abstract

Disclosed are four crystal forms of acalabrutinib, namely APTI-I, a cocrystal APTI-II of acalabrutinib and maltitol, a cocrystal APTI-III of acalabrutinib and ethyl maltol, and a cocrystal APTI-IV of acalabrutinib and succinic acid. These crystal forms have good stability and provide options for development of preparations.

Description

阿卡替尼的新晶型及其制备方法New crystal form of acalatinib and preparation method thereof
本申请要求申请日为2020年10月14日的中国专利申请CN202011096217.9的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of Chinese patent application CN202011096217.9 with an application date of October 14, 2020. This application cites the full text of the above Chinese patent application.
技术领域technical field
本发明属于化合物合成技术领域，具体说是阿卡替尼的新晶型及其制备方法。The invention belongs to the technical field of compound synthesis, in particular to a new crystal form of acaltinib and a preparation method thereof.
背景技术Background technique
阿卡替尼(Acalabrutinib，商品名：Calquence)是FDA于2017年10月批准的来自阿斯利康制药的一款用于治疗套细胞淋巴瘤(MCL)的新药。阿卡替尼(Acalabrutinib)是第二代BTK抑制剂，相比于第一代的BTK抑制剂Ibrutinib，药物选择性更高，副作用更低。Acalabrutinib (trade name: Calquence) is a new drug approved by the FDA in October 2017 from AstraZeneca for the treatment of mantle cell lymphoma (MCL). Acalabrutinib is a second-generation BTK inhibitor with higher drug selectivity and lower side effects than the first-generation BTK inhibitor Ibrutinib.
WO2017002095A1公开了Acalabrutinib的8个晶型，文中报道晶型I至晶型V均为游离碱，其中晶型I为无水合物、晶型II为三水合物，流动性较差，粒度不均一，不同的条件下含水量不同，含水量最高可达10％；晶型III为二水合物，晶型不稳定，含水量随条件变化而变化，最高含水量可达8％；晶型IV、晶型V为无水合物，分别由晶型II在低湿度条件下脱水和加热条件下脱水得到；晶型VI与晶型VII为甲醇溶剂合物；晶型VIII为乙酸溶剂合物。晶型I难于从溶液中析出，制备难度大，晶型II、晶型III、晶型IV、晶型V稳定性较差；晶型VI、晶型VII、晶型VII为溶剂合物，在制剂方面使用优势不明显。WO2017002095A1 discloses 8 crystal forms of acalabrutinib, and it is reported in the text that crystal form I to crystal form V are all free bases, wherein crystal form I is an anhydrate, crystal form II is a trihydrate, with poor fluidity and uneven particle size, The water content is different under different conditions, and the water content can reach up to 10%; the crystal form III is a dihydrate, the crystal form is unstable, and the water content changes with the change of conditions, and the highest water content can reach 8%; Form V is an anhydrate, obtained by dehydration of crystal form II under low humidity conditions and dehydration under heating conditions, respectively; crystal form VI and crystal form VII are methanol solvates; crystal form VIII is acetic acid solvate. The crystal form I is difficult to separate out from the solution, the preparation is difficult, and the crystal form II, crystal form III, crystal form IV and crystal form V have poor stability; crystal form VI, crystal form VII, crystal form VII are solvates, in The advantages of using formulations are not obvious.
发明内容SUMMARY OF THE INVENTION
为了克服现有的阿卡替尼的晶型所存在的上述不足，本发明提供四种阿 卡替尼的新晶型，均经过PXRD、DSC、HNMR、IR、TGA检测确认，APTI-I、APTI-II(阿卡替尼与麦芽醇的共晶物)、APTI-III(阿卡替尼与乙基麦芽酚的共晶物)、APTI-IV(阿卡替尼与丁二酸的共晶物)的制备操作简单，成本低，易于放大生产，为制剂研发提供新的选择。In order to overcome the above-mentioned deficiencies of the existing crystal forms of acaltinib, the present invention provides four new crystal forms of acaltinib, all of which have been confirmed by PXRD, DSC, HNMR, IR, and TGA detection, APTI-I, APTI-II (co-crystal of acaltinib and maltitol), APTI-III (co-crystal of acaltinib and ethyl maltol), APTI-IV (co-crystal of acaltinib and succinic acid) The preparation of crystals) is simple in operation, low in cost, easy to scale up production, and provides a new option for formulation research and development.
本发明提供的阿卡替尼第一种新晶型APTI-I，使用Cu-Kα辐射，其X射线粉末衍射的衍射角2θ为：6.2°±0.2°，6.5°±0.2°，10.2°±0.2°，10.8°±0.2°，11.6°±0.2°，13.0°±0.2°，14.4°±0.2°，15.0°±0.2°，16.2°±0.2°，17.5°±0.2°，18.6°±0.2°，19.6°±0.2°，20.6°±0.2°，21.6°±0.2°，22.1°±0.2°，24.0°±0.2°，25.6°±0.2°，26.1°±0.2°，27.7°±0.2°的一处或多处特征峰。The first new crystal form APTI-I of acaltinib provided by the present invention uses Cu-Kα radiation, and its X-ray powder diffraction diffraction angles 2θ are: 6.2°±0.2°, 6.5°±0.2°, 10.2°± 0.2°, 10.8°±0.2°, 11.6°±0.2°, 13.0°±0.2°, 14.4°±0.2°, 15.0°±0.2°, 16.2°±0.2°, 17.5°±0.2°, 18.6°±0.2° a one or more characteristic peaks.
此产物经核磁确认结构为阿卡替尼的游离碱，PXRD显示此结构和专利公开报道的均不同。The structure of this product was confirmed by NMR to be the free base of acaltinib, and PXRD showed that the structure was different from that reported in the patent publication.
阿卡替尼晶型APTI-I，以无定形固体或晶型III固体为原料，在乙醇、丙酮或丙酮/乙醇/正庚烷的混合溶剂中可以获得阿卡替尼的游离碱晶型APTI-I，改变溶剂种类不利于获得阿卡替尼的游离碱新晶型。Acatinib crystal form APTI-I, using amorphous solid or crystal form III solid as raw material, in ethanol, acetone or a mixed solvent of acetone/ethanol/n-heptane, the free base crystal form APTI of acatinib can be obtained -I, changing the type of solvent is not conducive to obtaining the new crystal form of the free base of acaltinib.
该制备方法具有如下优点：The preparation method has the following advantages:
(1)纯化效果好，产品纯度高；(1) Good purification effect and high product purity;
(2)制备方法简单，易于生产；(2) the preparation method is simple and easy to produce;
(3)使用单一溶剂丙酮、乙醇即可制备，溶剂回收方便，避免因使用混合溶剂导致溶剂回收成本的增加；(3) It can be prepared by using single solvent acetone and ethanol, the solvent recovery is convenient, and the increase of solvent recovery cost due to the use of mixed solvent is avoided;
阿卡替尼晶型APTI-I制备方法：Preparation method of acaltinib crystal form APTI-I:
方法一：method one:
将阿卡替尼固体(无定形或晶型III)用3-50体积的丙酮溶解，在5-80℃下搅拌0.5-48小时至有固体析出，过滤，得到阿卡替尼的晶型APTI-I。Dissolve acaltinib solid (amorphous or crystal form III) with 3-50 volumes of acetone, stir at 5-80° C. for 0.5-48 hours until a solid is precipitated, and filter to obtain the crystal form APTI of acaltinib -I.
其中所述反应溶剂体积优选3-6体积；反应温度优选为50-60℃；搅拌时间优选为1-3小时。The volume of the reaction solvent is preferably 3-6 volumes; the reaction temperature is preferably 50-60° C.; and the stirring time is preferably 1-3 hours.
方法二：Method Two:
将阿卡替尼固体(无定形或晶型III)用3-50体积的乙醇溶解，升温至5-80℃保温0.5小时，降温至0-30℃静置3-10天至有大量固体析出，过滤，得阿卡替尼晶型APTI-I。Dissolve acaltinib solid (amorphous or crystal form III) with 3-50 volumes of ethanol, heat up to 5-80 °C for 0.5 hours, cool to 0-30 °C and let stand for 3-10 days until a large amount of solid is precipitated. , filtered to obtain acaltinib crystal form APTI-I.
其中所述反应溶剂体积优选3-8体积；所述反应温度优选为50-60℃；降温温度优选为15-25℃；静置时间优选为3-7天。The volume of the reaction solvent is preferably 3-8 volumes; the reaction temperature is preferably 50-60° C.; the cooling temperature is preferably 15-25° C.; and the standing time is preferably 3-7 days.
方法三：Method three:
将阿卡替尼固体(无定形或晶型III)用3-50体积丙酮、1-5体积乙醇溶解，在5-80℃下加入0.5-3体积正庚烷，搅拌至有固体析出，降温至0-30℃，过滤，得阿卡替尼晶型APTI-I。Dissolve acaltinib solid (amorphous or crystal form III) with 3-50 volumes of acetone and 1-5 volumes of ethanol, add 0.5-3 volumes of n-heptane at 5-80°C, stir until a solid is precipitated, and cool down. To 0-30 ℃, filter to obtain acaltinib crystal form APTI-I.
其中所述反应溶剂丙酮体积优选3-6体积，溶剂乙醇体积优选1-2体积，正庚烷体积优选0.5-1体积；所述反应温度优选为50-60℃；室温温度优选为15-25℃；搅拌时间优选为1-3小时。The volume of the reaction solvent acetone is preferably 3-6 volumes, the volume of the solvent ethanol is preferably 1-2 volumes, and the volume of n-heptane is preferably 0.5-1 volumes; the reaction temperature is preferably 50-60 ° C; the room temperature is preferably 15-25 °C; the stirring time is preferably 1-3 hours.
本发明的晶型APTI-I相对于现有技术取得了以下有益效果：The crystal form APTI-I of the present invention has achieved the following beneficial effects with respect to the prior art:
(1)提供了一种制备阿卡替尼游离碱新晶型的制备方法；(1) a preparation method for preparing acaltinib free base new crystal form is provided;
(2)该方法操作简便，易于放大；(2) The method is easy to operate and easy to enlarge;
(3)该晶型稳定性好：APTI-I在50℃放置7天晶型没有变化，高温80℃8小时晶型没有变化，在25℃，80％RH高湿条件下48小时晶型没有变化，显示该晶型具有良好的稳定性，为制剂开发提供了新的选择。(3) The crystal form has good stability: the crystal form of APTI-I does not change at 50°C for 7 days, the crystal form does not change at high temperature of 80°C for 8 hours, and the crystal form does not change at 25°C and 80% RH for 48 hours. The changes show that the crystal form has good stability and provides a new option for formulation development.
本发明提供的阿卡替尼第二种新晶型APTI-II，使用Cu-Kα辐射，所述晶型APTI-II的X射线粉末衍射的衍射角2θ为：5.0°±0.2°，5.7°±0.2°，9.1°±0.2°，10.1°±0.2°，10.4°±0.2°，11.3°±0.2°，12.9°±0.2°，14.5°±0.2°,15.1°±0.2°，16.0°±0.2°，16.4°±0.2°，17.8°±0.2°，18.3°±0.2°，18.7°±0.2°，19.1°±0.2°，20.3°±0.2°，20.6°±0.2°，21.1°±0.2°，21.9°±0.2°，22.4°±0.2°，23.5°±0.2°，24.2°±0.2°，24.9°±0.2°，25.8°±0.2°，27.7°±0.2°，28.6°±0.2°的一处或多处特征峰。The second new crystal form APTI-II of acaltinib provided by the present invention uses Cu-Kα radiation, and the diffraction angles 2θ of X-ray powder diffraction of the crystal form APTI-II are: 5.0°±0.2°, 5.7° ±0.2°, 9.1°±0.2°, 10.1°±0.2°, 10.4°±0.2°, 11.3°±0.2°, 12.9°±0.2°, 14.5°±0.2°, 15.1°±0.2°, 16.0°±0.2 °, 16.4°±0.2°, 17.8°±0.2°, 18.3°±0.2°, 18.7°±0.2°, 19.1°±0.2°, 20.3°±0.2°, 20.6°±0.2°, 21.1°±0.2°, 21.9°±0.2°, 22.4°±0.2°, 23.5°±0.2°, 24.2°±0.2°, 24.9°±0.2°, 25.8°±0.2°, 27.7°±0.2°, 28.6°±0.2° or multiple characteristic peaks.
此产物经核磁确认结构为阿卡替尼与麦芽醇的共晶物，核磁显示阿卡替 尼与麦芽醇的摩尔比为1：1，PXRD显示此结构和专利公开报道的均不同。The structure of this product was confirmed by nuclear magnetic resonance to be a co-crystal of acaltinib and maltitol, and nuclear magnetic resonance showed that the molar ratio of acaltinib and maltitol was 1:1, and PXRD showed that this structure was different from that reported in the patent publication.
新晶型APTI-II是阿卡替尼与麦芽醇的共晶物，以阿卡替尼的无定形固体或晶型III为原料，在乙醇、异丙醇、正丙醇、正丁醇、乙酸乙酯、丁酮、甲基异丁基酮、丙酮溶剂或其中的任意两种或多种混合溶剂中升温至50-60℃，加入麦芽醇，保温、降温得到共晶物APTI-II。The new crystal form APTI-II is a co-crystal of acalatinib and maltitol, using the amorphous solid or crystal form III of acaltinib as raw material, in ethanol, isopropanol, n-propanol, n-butanol, Ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone, acetone solvent or any two or more mixed solvents thereof are heated to 50-60° C., malt alcohol is added, the temperature is maintained and the temperature is lowered to obtain the eutectic APTI-II.
阿卡替尼晶型APTI-II制备方法：Preparation method of acaltinib crystal form APTI-II:
将阿卡替尼固体(无定形或晶型III)用3-10体积的乙醇、异丙醇、正丙醇、正丁醇、乙酸乙酯、丁酮、甲基异丁基酮、丙酮溶剂或其中的任意两种或多种混合溶剂中溶解，在5-80℃下加入0.9-2当量的麦芽醇，搅拌至有固体析出，降至室温过滤，得到阿卡替尼的晶型APTI-II。其中所述反应溶剂体积优选5-8体积，所述反应温度优选为50-60℃，麦芽醇当量优选0.9-1.2当量，室温温度优选为15-25℃。Acatinib solid (amorphous or crystalline form III) with 3-10 volumes of ethanol, isopropanol, n-propanol, n-butanol, ethyl acetate, butanone, methyl isobutyl ketone, acetone solvent Or dissolve in any two or more mixed solvents, add 0.9-2 equivalent of malt alcohol at 5-80 ° C, stir until there is solid precipitation, cool down to room temperature and filter to obtain acatinib crystal form APTI- II. The volume of the reaction solvent is preferably 5-8 volumes, the reaction temperature is preferably 50-60°C, the maltol equivalent is preferably 0.9-1.2 equivalent, and the room temperature is preferably 15-25°C.
本发明的新晶型APTI-II相对于现有技术取得了以下有益效果：The new crystal form APTI-II of the present invention has achieved the following beneficial effects with respect to the prior art:
(1)提供了一种制备阿卡替尼麦芽醇共晶物的制备方法；(1) a preparation method for preparing acaltinib-maltitol co-crystal is provided;
(2)该方法操作简便，易于放大；(2) The method is easy to operate and easy to enlarge;
(3)该晶型稳定性好：APTI-II在50℃放置7天晶型没有变化，高温80℃8小时晶型没有变化，在25℃，80％RH高湿条件下48小时晶型没有变化，显示该晶型具有良好的稳定性，为制剂开发提供了新的选择。(3) The crystal form has good stability: the crystal form of APTI-II does not change at 50°C for 7 days, the crystal form does not change at high temperature at 80°C for 8 hours, and the crystal form does not change at 25°C and 80% RH for 48 hours. The changes show that the crystal form has good stability and provides a new option for formulation development.
本发明提供的阿卡替尼第三种新晶型APTI-III，使用Cu-Kα辐射，所述晶型APTI-III的X射线粉末衍射的衍射角2θ为：5.0°±0.2°，5.7°±0.2°，7.2°±0.2°，9.1°±0.2°，10.1°±0.2°，10.3°±0.2°，11.3°±0.2°，12.8°±0.2°,15.1°±0.2°，15.7°±0.2°，16.0°±0.2°，16.3°±0.2°，17.8°±0.2°，18.4°±0.2°，19.2°±0.2°，20.0°±0.2°，20.5°±0.2°，21.1°±0.2°，21.8°±0.2°，22.4°±0.2°，23.4°±0.2°，24.1°±0.2°，24.8°±0.2°，25.1°±0.2°，25.7°±0.2°，28.3°±0.2°的一处或多处特征峰。The third new crystal form APTI-III of acaltinib provided by the present invention uses Cu-Kα radiation, and the diffraction angle 2θ of X-ray powder diffraction of the crystal form APTI-III is: 5.0°±0.2°, 5.7° ±0.2°, 7.2°±0.2°, 9.1°±0.2°, 10.1°±0.2°, 10.3°±0.2°, 11.3°±0.2°, 12.8°±0.2°, 15.1°±0.2°, 15.7°±0.2 °, 16.0°±0.2°, 16.3°±0.2°, 17.8°±0.2°, 18.4°±0.2°, 19.2°±0.2°, 20.0°±0.2°, 20.5°±0.2°, 21.1°±0.2°, 21.8°±0.2°, 22.4°±0.2°, 23.4°±0.2°, 24.1°±0.2°, 24.8°±0.2°, 25.1°±0.2°, 25.7°±0.2°, 28.3°±0.2° or multiple characteristic peaks.
此产物经核磁确认结构为阿卡替尼与乙基麦芽酚的共晶物，核磁显示阿 卡替尼与乙基麦芽酚的摩尔比为1：1，PXRD显示此结构和专利公开报道的均不同。The structure of this product was confirmed by NMR to be a co-crystal of acalatinib and ethyl maltol. NMR showed that the molar ratio of acaltinib and ethyl maltol was 1:1. different.
新晶型APTI-III是阿卡替尼与乙基麦芽酚的共晶物，以阿卡替尼的无定形固体或晶型III为原料，在正丙醇或丙酮溶剂中升温至50-60℃，体系澄清，加入乙基麦芽酚，保温、降温得到。The new crystal form APTI-III is a co-crystal of acaltinib and ethyl maltol. The amorphous solid or crystal form III of acaltinib is used as the raw material, and the temperature is raised to 50-60 °C in n-propanol or acetone solvent. ℃, the system is clarified, add ethyl maltol, keep warm and cool to obtain.
阿卡替尼晶型APTI-III制备方法：Preparation method of acatinib crystal form APTI-III:
将阿卡替尼固体(无定形或晶型III)用3-50体积的正丙醇(或丙酮)溶解，在5-80℃下加入0.9-2当量的乙基麦芽酚，搅拌至有固体析出，降至室温过滤，得到阿卡替尼的晶型APTI-III。其中所述反应溶剂体积优选5-8体积，所述反应温度优选为50-60℃，乙基麦芽酚当量优选0.9-1.2当量，室温温度优选为15-25℃。Dissolve acaltinib solid (amorphous or crystal form III) with 3-50 volumes of n-propanol (or acetone), add 0.9-2 equivalents of ethyl maltol at 5-80 °C, and stir until there is a solid Precipitation, cooled to room temperature and filtered to obtain the crystalline form APTI-III of acaltinib. The volume of the reaction solvent is preferably 5-8 volumes, the reaction temperature is preferably 50-60°C, the equivalent of ethyl maltol is preferably 0.9-1.2 equivalent, and the room temperature is preferably 15-25°C.
本发明的新晶型APTI-III相对于现有技术取得了以下有益效果：The new crystal form APTI-III of the present invention has achieved the following beneficial effects with respect to the prior art:
(1)提供了一种制备阿卡替尼乙基麦芽酚共晶物的制备方法；(1) a preparation method for preparing acaltinib ethyl maltol co-crystal is provided;
(2)该方法操作简便，易于放大；(2) The method is easy to operate and easy to enlarge;
(3)该晶型稳定性好：APTI-III在50℃放置7天晶型没有变化，高温80℃8小时晶型没有变化，在25℃，80％RH高湿条件下48小时晶型没有变化，显示该晶型具有良好的稳定性，为制剂开发提供了新的选择。(3) The crystal form has good stability: the crystal form of APTI-III does not change at 50°C for 7 days, the crystal form does not change at high temperature at 80°C for 8 hours, and the crystal form does not change at 25°C and 80%RH high humidity for 48 hours The changes show that the crystal form has good stability and provides a new option for formulation development.
本发明提供的阿卡替尼第四种新晶型APTI-IV，使用Cu-Kα辐射，所述晶型APTI-IV的X射线粉末衍射的衍射角2θ为：5.2°±0.2°，8.9°±0.2°，9.3°±0.2°，10.2°±0.2°，11.5°±0.2°，12.5°±0.2°，13.4°±0.2°，15.2°±0.2°，15.9°±0.2°，16.6°±0.2°,18.3°±0.2°，18.7°±0.2°，19.4°±0.2°，23.0°±0.2°，24.2°±0.2°，24.7°±0.2°，25.3°±0.2°，26.0°±0.2°，27.1°±0.2°的一处或多处特征峰。The fourth new crystal form APTI-IV of acaltinib provided by the present invention uses Cu-Kα radiation, and the diffraction angle 2θ of X-ray powder diffraction of the crystal form APTI-IV is: 5.2°±0.2°, 8.9° ±0.2°, 9.3°±0.2°, 10.2°±0.2°, 11.5°±0.2°, 12.5°±0.2°, 13.4°±0.2°, 15.2°±0.2°, 15.9°±0.2°, 16.6°±0.2 °, 18.3°±0.2°, 18.7°±0.2°, 19.4°±0.2°, 23.0°±0.2°, 24.2°±0.2°, 24.7°±0.2°, 25.3°±0.2°, 26.0°±0.2°, One or more characteristic peaks at 27.1°±0.2°.
此产物经核磁确认结构为阿卡替尼与丁二酸的共晶物，核磁显示阿卡替尼与丁二酸的摩尔比为1：0.5，PXRD显示此结构和专利公开报道的均不同。The structure of this product was confirmed by NMR to be a co-crystal of acaltinib and succinic acid. NMR showed that the molar ratio of acaltinib to succinic acid was 1:0.5. PXRD showed that the structure was different from that reported in the patent publication.
新晶型APTI-IV是阿卡替尼与丁二酸的共晶物，以阿卡替尼的无定形固 体或晶型III为原料，在乙醇(或丁酮)溶剂中升温至50-60℃，加入丁二酸，保温、降温得到共晶物APTI-IV。The new crystal form APTI-IV is a co-crystal of acaltinib and succinic acid. The amorphous solid or crystal form III of acaltinib is used as the raw material, and the temperature is raised to 50-60 in ethanol (or butanone) solvent. ℃, add succinic acid, keep warm and cool to obtain eutectic APTI-IV.
阿卡替尼晶型APTI-IV制备方法：Preparation method of acaltinib crystal form APTI-IV:
将阿卡替尼固体(无定形或晶型III)用3-50体积的乙醇(或丁酮)溶解，在5-70℃下加入0.4-1当量的丁二酸，搅拌至有固体析出，降至室温过滤，得到阿卡替尼的晶型APTI-IV。其中所述反应溶剂体积优选5-8体积，所述反应温度优选为50-60℃，丁二酸当量优选0.5-0.6当量，室温温度优选为15-25℃。Dissolve acaltinib solid (amorphous or crystal form III) with 3-50 volumes of ethanol (or butanone), add 0.4-1 equivalent of succinic acid at 5-70 ° C, and stir until a solid is precipitated, It was cooled to room temperature and filtered to obtain the crystalline form APTI-IV of acaltinib. The volume of the reaction solvent is preferably 5-8 volumes, the reaction temperature is preferably 50-60°C, the equivalent of succinic acid is preferably 0.5-0.6 equivalent, and the room temperature is preferably 15-25°C.
本发明的新晶型APTI-IV相对于现有技术取得了以下有益效果：The new crystal form APTI-IV of the present invention has achieved the following beneficial effects with respect to the prior art:
(1)提供了一种制备阿卡替尼丁二酸共晶物的制备方法；(1) a preparation method for preparing acatinib succinic acid co-crystal is provided;
(2)该方法操作简便，易于放大；(2) The method is easy to operate and easy to enlarge;
(3)该晶型稳定性好：APTI-IV在50℃放置7天晶型没有变化，高温80℃8小时晶型没有变化，在25℃，80％RH高湿条件下48小时晶型没有变化，显示该晶型具有良好的稳定性，为制剂开发提供了新的选择。(3) The crystal form has good stability: the crystal form of APTI-IV does not change at 50°C for 7 days, the crystal form does not change at 80°C for 8 hours, and the crystal form does not change at 25°C and 80% RH for 48 hours. The changes show that the crystal form has good stability and provides a new option for formulation development.
本发明还提供一种组合物，含有阿卡替尼的新晶型APTI-I、APTI-II、APTI-III、APTI-IV中的一种或两种或三种或四种。The present invention also provides a composition comprising one or two, three or four of the new crystal forms of acaltinib, APTI-I, APTI-II, APTI-III and APTI-IV.
本发明还提供一种用于治疗套细胞淋巴瘤的药物组合物，含有有效剂量的阿卡替尼的新晶型APTI-I、APTI-II、APTI-III、APTI-IV中的一种或两种或三种或四种。The present invention also provides a pharmaceutical composition for treating mantle cell lymphoma, comprising an effective dose of one of the new crystal forms APTI-I, APTI-II, APTI-III and APTI-IV of acaltinib or Two or three or four.
上述药物组合物还可以包含药学上可接受的载体、稀释剂或赋形剂。The above-mentioned pharmaceutical compositions may also contain pharmaceutically acceptable carriers, diluents or excipients.
附图说明Description of drawings
图1为所述的晶型APTI-I的典型实例的PXRD图谱；Fig. 1 is the PXRD pattern of the typical example of described crystal form APTI-I;
图2为所述的晶型APTI-I的DSC图谱；Fig. 2 is the DSC spectrum of described crystal form APTI-I;
图3为所述的晶型APTI-I的HNMR图谱；Fig. 3 is the HNMR spectrum of described crystal form APTI-I;
图4为所述的晶型APTI-I的IR图谱；Fig. 4 is the IR spectrum of described crystal form APTI-I;
图5为所述的晶型APTI-I的TGA图谱；Fig. 5 is the TGA spectrum of described crystal form APTI-I;
图6为所述的晶型APTI-II的典型实例的PXRD图谱；Fig. 6 is the PXRD pattern of the typical example of described crystal form APTI-II;
图7为所述的晶型APTI-II的DSC图谱；Fig. 7 is the DSC spectrum of described crystal form APTI-II;
图8为所述的晶型APTI-II的HNMR图谱；Fig. 8 is the HNMR spectrum of described crystal form APTI-II;
图9为所述的晶型APTI-II的IR图谱；Fig. 9 is the IR spectrum of described crystal form APTI-II;
图10为所述的晶型APTI-II的TGA图谱；Fig. 10 is the TGA spectrum of described crystal form APTI-II;
图11为所述的晶型APTI-III的典型实例的PXRD图谱；Fig. 11 is the PXRD pattern of the typical example of described crystal form APTI-III;
图12为所述的晶型APTI-III的DSC图谱；Figure 12 is the DSC spectrum of the described crystal form APTI-III;
图13为所述的晶型APTI-III的HNMR图谱；Fig. 13 is the HNMR spectrum of described crystal form APTI-III;
图14为所述的晶型APTI-III的IR图谱；Figure 14 is the IR spectrum of the described crystal form APTI-III;
图15为所述的晶型APTI-III的TGA图谱；Fig. 15 is the TGA spectrum of described crystal form APTI-III;
图16为所述的晶型APTI-IV的典型实例的PXRD图谱；Fig. 16 is the PXRD pattern of the typical example of described crystal form APTI-IV;
图17为所述的晶型APTI-IV的DSC图谱；Figure 17 is the DSC spectrum of the described crystal form APTI-IV;
图18为所述的晶型APTI-IV的HNMR图谱；Fig. 18 is the HNMR spectrum of described crystal form APTI-IV;
图19为所述的晶型APTI-IV的IR图谱；Figure 19 is the IR spectrum of the described crystal form APTI-IV;
图20为所述的晶型APTI-IV的TGA图谱。Figure 20 is the TGA spectrum of the crystalline form APTI-IV.
具体实施方式Detailed ways
结合以下具体实施，对本发明作进一步的详细说明，本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括于本发明中，并且以所附的权利要求书保护范围为准。实施本发明的过程、条件、试剂、实验方法等，除以下专门提及的内容外，均为本领域的普遍知识和公知常识，本发明没有特别限制内容。In conjunction with the following specific implementation, the present invention will be further described in detail, and the protection content of the present invention is not limited to the following examples. Variations and advantages that can occur to those skilled in the art without departing from the spirit and scope of the inventive concept are all included in the present invention, and are subject to the protection scope of the appended claims. The processes, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are general knowledge and common knowledge in the field, and the present invention has no special limited contents.
实施例1：Example 1:
阿卡替尼的新晶型APTI-I，使用Cu-Kα辐射，其X射线粉末衍射在衍射角2θ为：6.2°±0.2°，6.5°±0.2°，10.2°±0.2°，10.8°±0.2°， 11.6°±0.2°，13.0°±0.2°，14.4°±0.2°，15.0°±0.2°，16.2°±0.2°，17.5°±0.2°，18.6°±0.2°，19.6°±0.2°，20.6°±0.2°，21.6°±0.2°，22.1°±0.2°，24.0°±0.2°，25.6°±0.2°，26.1°±0.2°，27.7°±0.2°的一处或多处特征峰。制备方法如下：The new crystalline form APTI-I of acaltinib, using Cu-Kα radiation, its X-ray powder diffraction at diffraction angles 2θ are: 6.2°±0.2°, 6.5°±0.2°, 10.2°±0.2°, 10.8°± 0.2°, 11.6°±0.2°, 13.0°±0.2°, 14.4°±0.2°, 15.0°±0.2°, 16.2°±0.2°, 17.5°±0.2°, 18.6°±0.2°, 19.6°±0.2° , 20.6°±0.2°, 21.6°±0.2°, 22.1°±0.2°, 24.0°±0.2°, 25.6°±0.2°, 26.1°±0.2°, 27.7°±0.2° one or more characteristic peaks . The preparation method is as follows:
取阿卡替尼16.0g于15-30℃溶解于64mL的丙酮中，升温至50-60℃，保温搅拌2小时，降温至室温，保温搅拌2小时，过滤，滤饼于40℃真空干燥后得到阿卡替尼晶型APTI-I 9.5g，纯度为99.3％。Dissolve 16.0 g of acaltinib in 64 mL of acetone at 15-30 °C, heat up to 50-60 °C, keep stirring for 2 hours, cool down to room temperature, keep stirring for 2 hours, filter, and vacuum dry the filter cake at 40 °C Acaltinib crystal form APTI-I 9.5g was obtained with a purity of 99.3%.
实施例2：Example 2:
阿卡替尼的新晶型APTI-I的制备方法：The preparation method of the new crystal form APTI-I of acaltinib:
取阿卡替尼0.3g加入2.4mL的乙醇中，升温至50-60℃并保温0.5小时，降至室温，静置析晶3-5天，过滤，滤饼于40℃真空干燥后得到阿卡替尼晶型APTI-I 0.16g。Take 0.3 g of acalatinib and add it to 2.4 mL of ethanol, heat it up to 50-60 °C and keep it for 0.5 hours, then drop to room temperature, stand for crystallization for 3-5 days, filter, and vacuum dry the filter cake at 40 °C to obtain acatinib. Catinib crystal form APTI-I 0.16g.
实施例3：Example 3:
阿卡替尼的新晶型APTI-I的制备方法：The preparation method of the new crystal form APTI-I of acaltinib:
取阿卡替尼0.3g加入0.9mL的丙酮，加入0.3mL乙醇，升温至50-60℃，滴加0.3mL正庚烷，保温0.5小时，降至室温，搅拌2小时，过滤，滤饼于40℃真空干燥后得到阿卡替尼晶型APTI-I 0.16g，纯度为99.7％。Take 0.3 g of acalatinib, add 0.9 mL of acetone, add 0.3 mL of ethanol, raise the temperature to 50-60 °C, add 0.3 mL of n-heptane dropwise, keep the temperature for 0.5 hours, cool down to room temperature, stir for 2 hours, filter, and filter the filter cake in After vacuum drying at 40°C, 0.16 g of acaltinib crystal form APTI-I was obtained with a purity of 99.7%.
实施例4：Example 4:
阿卡替尼的新晶型APTI-II，使用Cu-Kα辐射，其X射线粉末衍射在衍射角2θ为：5.0°±0.2°，5.7°±0.2°，9.1°±0.2°，10.1°±0.2°，10.4°±0.2°，11.3°±0.2°，12.9°±0.2°，14.5°±0.2°,15.1°±0.2°，16.0°±0.2°，16.4°±0.2°，17.8°±0.2°，18.3°±0.2°，18.7°±0.2°，19.1°±0.2°，20.3°±0.2°，20.6°±0.2°，21.1°±0.2°，21.9°±0.2°，22.4°±0.2°，23.5°±0.2°，24.2°±0.2°，24.9°±0.2°，25.8°±0.2°，27.7°±0.2°，28.6°±0.2°的一处或多处特征峰。The new crystalline form APTI-II of acaltinib, using Cu-Kα radiation, its X-ray powder diffraction at diffraction angles 2θ are: 5.0°±0.2°, 5.7°±0.2°, 9.1°±0.2°, 10.1°± 0.2°, 10.4°±0.2°, 11.3°±0.2°, 12.9°±0.2°, 14.5°±0.2°, 15.1°±0.2°, 16.0°±0.2°, 16.4°±0.2°, 17.8°±0.2° , 18.3°±0.2°, 18.7°±0.2°, 19.1°±0.2°, 20.3°±0.2°, 20.6°±0.2°, 21.1°±0.2°, 21.9°±0.2°, 22.4°±0.2°, 23.5 °±0.2°, 24.2°±0.2°, 24.9°±0.2°, 25.8°±0.2°, 27.7°±0.2°, 28.6°±0.2° one or more characteristic peaks.
制备方法如下：The preparation method is as follows:
取阿卡替尼10.0g，加入60mL丙酮，升温至50-60℃至体系澄清，加入 1.1当量麦芽醇，于50-60℃保温1小时，降温至室温，于室温保温搅拌2小时，抽滤，滤饼用丙酮淋洗后于40℃真空干燥后得到阿卡替尼晶型APTI-II10.3g。Take 10.0 g of acalatinib, add 60 mL of acetone, heat up to 50-60 °C until the system is clear, add 1.1 equivalent of maltitol, keep at 50-60 °C for 1 hour, cool down to room temperature, keep stirring at room temperature for 2 hours, suction filtration , the filter cake was rinsed with acetone and then dried under vacuum at 40°C to obtain 10.3 g of acaltinib crystal form APTI-II.
实施例5：Example 5:
阿卡替尼的新晶型APTI-II的另一制备方法：Another preparation method of the new crystal form APTI-II of acaltinib:
取阿卡替尼0.3g，加入2.4mL优选溶剂，升温至50-60℃至体系澄清，加入1.1当量麦芽醇，于50-60℃保温1h小时，降温至室温，于室温保温搅拌1小时，抽滤，滤饼用所用优选溶剂淋洗后于40℃真空干燥后得到阿卡替尼晶型APTI-II，优选溶剂及得到阿卡替尼晶型APTI-II的重量如下表所示：Take 0.3 g of acalatinib, add 2.4 mL of a preferred solvent, heat up to 50-60 °C until the system is clear, add 1.1 equivalents of maltitol, keep at 50-60 °C for 1 hour, cool down to room temperature, keep stirring at room temperature for 1 hour, Suction filtration, the filter cake is rinsed with the preferred solvent used and then dried in vacuo at 40 °C to obtain acatinib crystal form APTI-II, the preferred solvent and the weight of the obtained acatinib crystal form APTI-II are shown in the following table:
Figure PCTCN2021117369-appb-000001
Figure PCTCN2021117369-appb-000001
实施例6：Example 6:
阿卡替尼的第三种新晶型APTI-III，使用Cu-Kα辐射，所述晶型APTI-III的X射线粉末衍射的衍射角2θ为：5.0°±0.2°，5.7°±0.2°，7.2°±0.2°，9.1°±0.2°，10.1°±0.2°，10.3°±0.2°，11.3°±0.2°，12.8°±0.2°,15.1°±0.2°，15.7°±0.2°，16.0°±0.2°，16.3°±0.2°，17.8°±0.2°，18.4°±0.2°，19.2°±0.2°，20.0°±0.2°，20.5°±0.2°，21.1°±0.2°，21.8°±0.2°，22.4°±0.2°，23.4°±0.2°，24.1°±0.2°，24.8°±0.2°，25.1°±0.2°，25.7°±0.2°，28.3°±0.2°的一处或多处特征峰。The third new crystal form APTI-III of acaltinib uses Cu-Kα radiation. The diffraction angles 2θ of X-ray powder diffraction of the crystal form APTI-III are: 5.0°±0.2°, 5.7°±0.2° , 7.2°±0.2°, 9.1°±0.2°, 10.1°±0.2°, 10.3°±0.2°, 11.3°±0.2°, 12.8°±0.2°, 15.1°±0.2°, 15.7°±0.2°, 16.0 °±0.2°, 16.3°±0.2°, 17.8°±0.2°, 18.4°±0.2°, 19.2°±0.2°, 20.0°±0.2°, 20.5°±0.2°, 21.1°±0.2°, 21.8°± One or more of 0.2°, 22.4°±0.2°, 23.4°±0.2°, 24.1°±0.2°, 24.8°±0.2°, 25.1°±0.2°, 25.7°±0.2°, 28.3°±0.2° Characteristic peaks.
制备方法如下：The preparation method is as follows:
取阿卡替尼10.0g，加入60mL丙酮，升温至50-60℃至体系澄清，加入1.1当量乙基麦芽酚，于50-60℃保温1小时，降温至室温，于室温保温搅拌2小时，抽滤，滤饼用丙酮淋洗后于40℃真空干燥后得到阿卡替尼晶型APTI-III 10.1g。Take 10.0 g of acalatinib, add 60 mL of acetone, heat up to 50-60 °C until the system is clear, add 1.1 equivalents of ethyl maltol, keep at 50-60 °C for 1 hour, cool down to room temperature, keep stirring at room temperature for 2 hours, Suction filtration, the filter cake was rinsed with acetone and then dried under vacuum at 40 °C to obtain 10.1 g of acaltinib crystal form APTI-III.
实施例7：Example 7:
阿卡替尼的第三种新晶型APTI-III的另一制备方法如下：Another preparation method of the third new crystal form APTI-III of acaltinib is as follows:
取阿卡替尼0.3g，加入2.4mL正丙醇，升温至50-60℃至体系澄清，加入1.1当量乙基麦芽酚，于50-60℃保温1小时，降温至室温，于室温保温搅拌2小时，抽滤，滤饼用正丙醇淋洗后于40℃真空干燥后得到阿卡替尼晶型APTI-III 0.23g。Take 0.3 g of acalatinib, add 2.4 mL of n-propanol, heat up to 50-60 °C until the system is clear, add 1.1 equivalents of ethyl maltol, keep at 50-60 °C for 1 hour, cool down to room temperature, keep stirring at room temperature After 2 hours, suction filtration, the filter cake was rinsed with n-propanol and then dried under vacuum at 40 °C to obtain 0.23 g of acaltinib crystal form APTI-III.
实施例8：Example 8:
阿卡替尼的第四种新晶型APTI-IV，使用Cu-Kα辐射，所述晶型APTI-IV的X射线粉末衍射的衍射角2θ为：5.2°±0.2°，8.9°±0.2°，9.3°±0.2°，10.2°±0.2°，11.5°±0.2°，12.5°±0.2°，13.4°±0.2°，15.2°±0.2°，15.9°±0.2°，16.6°±0.2°,18.3°±0.2°，18.7°±0.2°，19.4°±0.2°，23.0°±0.2°，24.2°±0.2°，24.7°±0.2°，25.3°±0.2°，26.0°±0.2°，27.1°±0.2°的一处或多处特征峰。The fourth new crystal form APTI-IV of acaltinib, using Cu-Kα radiation, the diffraction angles 2θ of X-ray powder diffraction of the crystal form APTI-IV are: 5.2°±0.2°, 8.9°±0.2° , 9.3°±0.2°, 10.2°±0.2°, 11.5°±0.2°, 12.5°±0.2°, 13.4°±0.2°, 15.2°±0.2°, 15.9°±0.2°, 16.6°±0.2°, 18.3 °±0.2°, 18.7°±0.2°, 19.4°±0.2°, 23.0°±0.2°, 24.2°±0.2°, 24.7°±0.2°, 25.3°±0.2°, 26.0°±0.2°, 27.1°± One or more characteristic peaks at 0.2°.
制备方法如下：The preparation method is as follows:
取阿卡替尼12.5g，加入100mL乙醇，升温至50-60℃至体系澄清，加入0.6当量丁二酸，于50-60℃保温1小时，降温至室温，于室温保温搅拌2小时，抽滤，滤饼用乙醇淋洗后于40℃真空干燥后得到阿卡替尼晶型APTI-IV 11.6g。Take 12.5 g of acalatinib, add 100 mL of ethanol, heat up to 50-60 °C until the system is clear, add 0.6 equivalent of succinic acid, keep at 50-60 °C for 1 hour, cool down to room temperature, keep stirring at room temperature for 2 hours, extract Filtration, the filter cake was rinsed with ethanol and then dried under vacuum at 40 °C to obtain 11.6 g of acaltinib crystal form APTI-IV.
实施例9：Example 9:
阿卡替尼的第四种新晶型APTI-IV的另一制备方法如下：Another preparation method of the fourth new crystal form APTI-IV of acaltinib is as follows:
取阿卡替尼0.3g，加入2.4mL丁酮，升温至50-60℃至体系澄清，加入0.6当量丁二酸，于50-60℃保温1小时，降温至室温，于室温保温搅拌2小时，抽滤，滤饼用丁酮淋洗后于40℃真空干燥后得到阿卡替尼晶型APTI-IV0.23g。Take 0.3 g of acalatinib, add 2.4 mL of butanone, heat up to 50-60 °C until the system is clear, add 0.6 equivalent of succinic acid, keep at 50-60 °C for 1 hour, cool down to room temperature, and keep stirring at room temperature for 2 hours , suction filtration, the filter cake is rinsed with butanone and then dried under vacuum at 40°C to obtain 0.23 g of acaltinib crystal form APTI-IV.
对比例1：改变溶剂制备APTI-IComparative Example 1: Preparation of APTI-I by changing the solvent
取阿卡替尼0.3g，加入1.5mL所选溶剂，升温至50-60℃至体系澄清，于50-60℃保温1小时，降温至室温，于室温保温搅拌1小时，抽滤，滤饼用所选溶剂淋洗后于40℃真空干燥后得到。所选溶剂及结果如下表所示：Take 0.3 g of acalatinib, add 1.5 mL of the selected solvent, heat up to 50-60 °C until the system is clear, keep at 50-60 °C for 1 hour, cool down to room temperature, keep stirring at room temperature for 1 hour, suction filtration, filter cake It is obtained after rinsing with the selected solvent and drying under vacuum at 40°C. The selected solvents and results are shown in the table below:
溶剂solvent 甲醇methanol 异丙醇isopropyl alcohol 正丙醇n-Propanol 四氢呋喃tetrahydrofuran 甲醇/水＝1/1Methanol/Water = 1/1 丁酮Butanone
结果result 无固体析出No solid precipitation 粘稠物sticky 无固体析出No solid precipitation 无固体析出No solid precipitation 晶型IIIForm III 无固体析出No solid precipitation
对比例2：改变溶剂制备APTI-IComparative Example 2: Preparation of APTI-I by changing the solvent
取阿卡替尼0.3g，加入1.5mL所选良溶剂，升温至50-60℃至体系澄清，于50-60℃滴加0.3mL所选不良溶剂，保温1小时，降温至室温，于室温保温搅拌1小时，降温至0-10℃保温0.5小时。所选溶剂及结果如下表所示：Take 0.3 g of acalatinib, add 1.5 mL of the selected good solvent, raise the temperature to 50-60 °C until the system is clear, add 0.3 mL of the selected poor solvent dropwise at 50-60 °C, keep it for 1 hour, cool down to room temperature, and keep it at room temperature. Keep stirring for 1 hour, then cool to 0-10°C and keep warm for 0.5 hours. The selected solvents and results are shown in the table below:
良溶剂good solvent 甲醇methanol 甲酸乙酯Ethyl formate 四氢呋喃tetrahydrofuran 二氯甲烷Dichloromethane 正丙醇n-Propanol
不良溶剂poor solvent MTBEMTBE 正庚烷n-heptane 正庚烷n-heptane 正庚烷n-heptane MTBEMTBE
结果result 粘稠物sticky 粘稠物sticky 粘稠物sticky 无固体析出No solid precipitation 粘稠物sticky
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes may be made to these embodiments without departing from the principle and essence of the present invention. Revise. Accordingly, the scope of protection of the present invention is defined by the appended claims.

Claims (13)

  1. 阿卡替尼的新晶型APTI-I，其特征在于，其X射线粉末衍射在衍射角2θ为：6.2°±0.2°，6.5°±0.2°，10.2°±0.2°，10.8°±0.2°，11.6°±0.2°，13.0°±0.2°，14.4°±0.2°，15.0°±0.2°，16.2°±0.2°，17.5°±0.2°，18.6°±0.2°，19.6°±0.2°，20.6°±0.2°，21.6°±0.2°，22.1°±0.2°，24.0°±0.2°，25.6°±0.2°，26.1°±0.2°，27.7°±0.2°的一处或多处特征峰。The new crystal form APTI-I of acaltinib is characterized in that its X-ray powder diffraction at diffraction angles 2θ are: 6.2°±0.2°, 6.5°±0.2°, 10.2°±0.2°, 10.8°±0.2° , 11.6°±0.2°, 13.0°±0.2°, 14.4°±0.2°, 15.0°±0.2°, 16.2°±0.2°, 17.5°±0.2°, 18.6°±0.2°, 19.6°±0.2°, 20.6 °±0.2°, 21.6°±0.2°, 22.1°±0.2°, 24.0°±0.2°, 25.6°±0.2°, 26.1°±0.2°, 27.7°±0.2° one or more characteristic peaks.
  2. 根据权利要求1所述的阿卡替尼的新晶型APTI-I的制备方法，其特征在于，以无定形固体或晶型III固体为原料，在乙醇、丙酮或丙酮/乙醇/正庚烷的溶剂中获得阿卡替尼的游离碱晶型APTI-I。The preparation method of the new crystal form APTI-I of acaltinib according to claim 1, is characterized in that, with amorphous solid or crystal form III solid as raw material, in ethanol, acetone or acetone/ethanol/n-heptane The free base crystalline form APTI-I of acaltinib was obtained in the solvent of .
  3. 阿卡替尼的新晶型APTI-II，其特征在于，其X射线粉末衍射在衍射角2θ为：5.0°±0.2°，5.7°±0.2°，9.1°±0.2°，10.1°±0.2°，10.4°±0.2°，11.3°±0.2°，12.9°±0.2°，14.5°±0.2°,15.1°±0.2°，16.0°±0.2°，16.4°±0.2°，17.8°±0.2°，18.3°±0.2°，18.7°±0.2°，19.1°±0.2°，20.3°±0.2°，20.6°±0.2°，21.1°±0.2°，21.9°±0.2°，22.4°±0.2°，23.5°±0.2°，24.2°±0.2°，24.9°±0.2°，25.8°±0.2°，27.7°±0.2°，28.6°±0.2°的一处或多处特征峰。The new crystal form APTI-II of acaltinib is characterized in that its X-ray powder diffraction at diffraction angles 2θ are: 5.0°±0.2°, 5.7°±0.2°, 9.1°±0.2°, 10.1°±0.2° , 10.4°±0.2°, 11.3°±0.2°, 12.9°±0.2°, 14.5°±0.2°, 15.1°±0.2°, 16.0°±0.2°, 16.4°±0.2°, 17.8°±0.2°, 18.3 °±0.2°, 18.7°±0.2°, 19.1°±0.2°, 20.3°±0.2°, 20.6°±0.2°, 21.1°±0.2°, 21.9°±0.2°, 22.4°±0.2°, 23.5°± One or more characteristic peaks at 0.2°, 24.2°±0.2°, 24.9°±0.2°, 25.8°±0.2°, 27.7°±0.2°, 28.6°±0.2°.
  4. 根据权利要求3所述的阿卡替尼的新晶型APTI-II，其特征在于，新晶型APTI-II为阿卡替尼与麦芽醇的共晶物。The new crystal form APTI-II of acaltinib according to claim 3, wherein the new crystal form APTI-II is a co-crystal of acaltinib and maltitol.
  5. 根据权利要求4所述的阿卡替尼的新晶型APTI-II的制备方法，其特征在于，以阿卡替尼的无定形固体或晶型III为原料，在乙醇、异丙醇、正丙醇、正丁醇、乙酸乙酯、丁酮、甲基异丁基酮、丙酮溶剂或其中的任意两种或多种混合溶剂中升温至50-60℃，加入麦芽醇，保温、降温得到新晶型APTI-II。The preparation method of the new crystal form APTI-II of acaltinib according to claim 4, is characterized in that, using the amorphous solid or crystal form III of acaltinib as raw material, in ethanol, isopropanol, normal Propanol, n-butanol, ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone, acetone solvent or any two or more mixed solvents thereof are heated to 50-60 ℃, add malt alcohol, keep warm and cool to obtain New crystal form APTI-II.
  6. 阿卡替尼的新晶型APTI-III，其特征在于，其X射线粉末衍射在衍射角2θ为：5.0°±0.2°，5.7°±0.2°，7.2°±0.2°，9.1°±0.2°，10.1°±0.2°，10.3°±0.2°，11.3°±0.2°，12.8°±0.2°,15.1°±0.2°，15.7°±0.2°，16.0°±0.2°，16.3°±0.2°，17.8°±0.2°，18.4°±0.2°，19.2°±0.2°，20.0°±0.2°，20.5°±0.2°，21.1°±0.2°， 21.8°±0.2°，22.4°±0.2°，23.4°±0.2°，24.1°±0.2°，24.8°±0.2°，25.1°±0.2°，25.7°±0.2°，28.3°±0.2°的一处或多处特征峰。The new crystal form APTI-III of acaltinib is characterized in that its X-ray powder diffraction at diffraction angles 2θ are: 5.0°±0.2°, 5.7°±0.2°, 7.2°±0.2°, 9.1°±0.2° , 10.1°±0.2°, 10.3°±0.2°, 11.3°±0.2°, 12.8°±0.2°, 15.1°±0.2°, 15.7°±0.2°, 16.0°±0.2°, 16.3°±0.2°, 17.8 °±0.2°, 18.4°±0.2°, 19.2°±0.2°, 20.0°±0.2°, 20.5°±0.2°, 21.1°±0.2°, 21.8°±0.2°, 22.4°±0.2°, 23.4°± One or more characteristic peaks at 0.2°, 24.1°±0.2°, 24.8°±0.2°, 25.1°±0.2°, 25.7°±0.2°, 28.3°±0.2°.
  7. 根据权利要求6所述的阿卡替尼的新晶型APTI-III，其特征在于，新晶型APTI-III为阿卡替尼与乙基麦芽酚的共晶物。The new crystal form APTI-III of acaltinib according to claim 6, wherein the new crystal form APTI-III is a co-crystal of acaltinib and ethyl maltol.
  8. 根据权利要求7所述的阿卡替尼的新晶型APTI-III的制备方法，其特征在于，以阿卡替尼的无定形固体或晶型III为原料，在正丙醇或丙酮溶剂中升温至50-60℃，加入乙基麦芽酚，保温、降温得到新晶型APTI-III。The preparation method of the new crystal form APTI-III of acaltinib according to claim 7, is characterized in that, with the amorphous solid or crystal form III of acaltinib as raw material, in n-propanol or acetone solvent The temperature is raised to 50-60° C., ethyl maltol is added, the temperature is maintained, and the temperature is lowered to obtain a new crystal form APTI-III.
  9. 阿卡替尼的新晶型APTI-IV，其特征在于，其X射线粉末衍射在衍射角2θ为：5.2°±0.2°，8.9°±0.2°，9.3°±0.2°，10.2°±0.2°，11.5°±0.2°，12.5°±0.2°，13.4°±0.2°，15.2°±0.2°，15.9°±0.2°，16.6°±0.2°,18.3°±0.2°，18.7°±0.2°，19.4°±0.2°，23.0°±0.2°，24.2°±0.2°，24.7°±0.2°，25.3°±0.2°，26.0°±0.2°，27.1°±0.2°的一处或多处特征峰。The new crystal form APTI-IV of acaltinib is characterized in that its X-ray powder diffraction at diffraction angles 2θ are: 5.2°±0.2°, 8.9°±0.2°, 9.3°±0.2°, 10.2°±0.2° , 11.5°±0.2°, 12.5°±0.2°, 13.4°±0.2°, 15.2°±0.2°, 15.9°±0.2°, 16.6°±0.2°, 18.3°±0.2°, 18.7°±0.2°, 19.4 °±0.2°, 23.0°±0.2°, 24.2°±0.2°, 24.7°±0.2°, 25.3°±0.2°, 26.0°±0.2°, 27.1°±0.2° one or more characteristic peaks.
  10. 根据权利要求6所述的阿卡替尼的新晶型APTI-IV，其特征在于，新晶型APTI-IV为阿卡替尼与丁二酸的共晶物。The new crystal form APTI-IV of acaltinib according to claim 6, wherein the new crystal form APTI-IV is a co-crystal of acaltinib and succinic acid.
  11. 根据权利要求7所述的阿卡替尼的新晶型APTI-IV的制备方法，其特征在于，以阿卡替尼的无定形固体或晶型III为原料，在乙醇、丁酮溶剂中升温至50-60℃，加入丁二酸，保温、降温得到新晶型APTI-IV。The preparation method of the new crystal form APTI-IV of acaltinib according to claim 7, it is characterized in that, take the amorphous solid of acaltinib or crystal form III as raw material, heat up in ethanol, butanone solvent To 50-60 ℃, add succinic acid, keep warm and cool to obtain a new crystal form APTI-IV.
  12. 一种组合物，其特征在于，含有阿卡替尼的新晶型APTI-I、APTI-II、APTI-III、APTI-IV中的一种或两种或三种或四种。A composition, characterized in that it contains one or two or three or four of the new crystal forms APTI-I, APTI-II, APTI-III and APTI-IV of acaltinib.
  13. 一种用于治疗套细胞淋巴瘤的药物组合物，其特征在于，含有有效剂量的阿卡替尼的新晶型APTI-I、APTI-II、APTI-III、APTI-IV中的一种或两种或三种或四种。A pharmaceutical composition for the treatment of mantle cell lymphoma, characterized in that one of the new crystal forms APTI-I, APTI-II, APTI-III, APTI-IV of acaltinib containing an effective dose or Two or three or four.
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