WO2016101912A1 - 一种表皮生长因子受体激酶抑制剂的盐的晶型及其制备方法 - Google Patents

一种表皮生长因子受体激酶抑制剂的盐的晶型及其制备方法 Download PDF

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WO2016101912A1
WO2016101912A1 PCT/CN2015/098901 CN2015098901W WO2016101912A1 WO 2016101912 A1 WO2016101912 A1 WO 2016101912A1 CN 2015098901 W CN2015098901 W CN 2015098901W WO 2016101912 A1 WO2016101912 A1 WO 2016101912A1
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formula
compound
salt
crystalline form
hydrobromide salt
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PCT/CN2015/098901
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English (en)
French (fr)
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陈敏华
张炎锋
刘凯
张晓宇
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苏州晶云药物科技有限公司
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Priority claimed from CN201410821405.1A external-priority patent/CN104961688A/zh
Priority claimed from CN201510019173.2A external-priority patent/CN105837518A/zh
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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids

Definitions

  • the present invention relates to the field of chemical and pharmaceutical crystal forms, in particular to N-(3-(2-(4-(4-acetylpiperazin-1-yl)-2-methoxyphenylamino)-5-(three)
  • the crystalline form of the salt of fluoromethyl)pyrimidin-4-ylamino)phenyl)acrylamide more particularly the crystalline form of the hydrobromide and phosphate, and the process for their preparation.
  • N-(3-(2-(4-(4-Acetylpiperazin-1-yl)-2-methoxyphenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)benzene Base acrylamide) (aka CO1686), first developed by Clovis Oncology, is a novel oral, targeted covalent (irreversible) mutant third representative dermal growth factor receptor An inhibitor of (EGFR), capable of inhibiting key activating mutations and T790-resistant mutations, leaving the wild-type EGFR signal idle. This drug was developed for the treatment of patients with NSCLC who initially activated the EGFR mutation and the major resistance mutation T790M.
  • CO1686 is currently in clinical phase III and its structure is shown in formula (I):
  • patent WO2013138495 discloses crystal forms of various free bases of CO1686;
  • patent WO2013138502 discloses various crystalline forms of hydrobromide, wherein the form IV/V/VI/VII is a solvate, which is not suitable for medicinal use;
  • Form II is easily converted to Form I and has poor crystallinity;
  • Form VIII produces a gum after heating,
  • Form III is an unstable, amorphous form, which is readily converted to Form I.
  • Form I of the hydrobromide salt is a crystalline form that can be used for medicinal purposes, but the dose of the hydrobromide crystal form that is used clinically continues to climb, so further research and development is necessary to find a specific hydrobromic acid.
  • Salt form I Better performance, such as higher solubility, better stability, lower moisture leaching, new crystal forms of hydrobromide for storage and industrial production, and new salts and crystal forms to meet the subsequent development needs of the drug .
  • the inventors of the present invention conducted intensive studies and extensive screening of hydrobromide salts and other salts of the compounds of formula (I), and surprisingly, the inventors of the present invention have found compounds of formula (I) which are more suitable for drug development.
  • the novel crystal form of the invention has good stability, simple process, easy operation, suitable for storage and industrial production, and provides a new choice for the subsequent development of the drug.
  • a first object of the present invention is to provide five novel crystal forms of the hydrobromide salt of the compound of formula (I) and a process for the preparation thereof.
  • the present invention provides a novel crystalline form of a hydrobromide salt of a compound of formula (I), designated as hydrobromide crystal form A in the present invention.
  • the hydrobromide salt form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2theta (2 ⁇ ) values of 8.9 ° ⁇ 0.2 °, 18.1 ° ⁇ 0.2 °, and 20.7 ° ⁇ 0.2 °.
  • hydrobromide crystal form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 11.4° ⁇ 0.2°, 18.5° ⁇ 0.2°, and 25.2° ⁇ 0.2°.
  • hydrobromide salt form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 24.5° ⁇ 0.2°, 26.1° ⁇ 0.2°, and 31.1° ⁇ 0.2°.
  • the hydrobromide salt form A provided by the present invention has an X-ray powder diffraction pattern with a 2 ⁇ value of 8.9 ° ⁇ 0.2 °, 11.4 ° ⁇ 0.2 °, 18.1 ° ⁇ 0.2 °, 18.5 ° ⁇ Characteristic peaks are present at 0.2°, 20.7° ⁇ 0.2°, 24.5° ⁇ 0.2°, 25.2° ⁇ 0.2°, 26.1° ⁇ 0.2°, and 31.1° ⁇ 0.2°.
  • the present invention provides Form A with an X-ray powder diffraction pattern substantially as shown in FIG.
  • the invention also provides a preparation method of the hydrobromide salt crystal form A of the compound of the above formula (I), which comprises: hydrobromide salt of the compound of the formula (I) in a mixed solvent of an alcohol and a halogenated hydrocarbon, not higher than The mixture was stirred at 50 ° C and a solid was collected.
  • the alcohol solvent is preferably an alcohol
  • the halogenated hydrocarbon is preferably chloroform
  • the present invention provides another novel crystalline form of the hydrobromide salt of the compound of formula (I), designated as hydrobromide salt form B in the present invention.
  • the hydrobromide salt form B provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 8.2 ° ⁇ 0.2 °, 15.9 ° ⁇ 0.2 °, and 22.2 ° ⁇ 0.2 °.
  • hydrobromide salt form B provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 10.1 ⁇ 0.2°, 18.2° ⁇ 0.2°, and 23.1° ⁇ 0.2°.
  • hydrobromide salt form B provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 21.2° ⁇ 0.2°, 24.7° ⁇ 0.2°, and 27.3° ⁇ 0.2°.
  • the hydrobromide salt form B provided by the present invention has an X-ray powder diffraction pattern with a 2 ⁇ value of 8.2 ° ⁇ 0.2 °, 10.1 ° ⁇ 0.2 °, 15.9 ° ⁇ 0.2 °, 18.2 ° ⁇ There are characteristic peaks at 0.2°, 21.2° ⁇ 0.2°, 22.2° ⁇ 0.2°, 23.1° ⁇ 0.2°, 24.7° ⁇ 0.2°, and 27.3° ⁇ 0.2°.
  • the hydrobromide salt form B provided by the present invention has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the hydrobromide salt form B provided by the present invention begins to have an endothermic peak near heating at 65 ° C, 108 ° C, and 228 ° C, respectively, and the differential scanning calorimetry diagram is substantially as Figure 3 shows.
  • the present invention also provides a process for preparing the hydrobromide salt form B of the compound of the above formula (I), which comprises stirring a hydrobromide salt of the compound of the formula (I) in a mixed solvent of an alcohol and an ether at room temperature. A solid can be obtained.
  • the alcohol solvent is preferably methanol
  • the ether solvent is preferably methyl tert-butyl ether.
  • the present invention provides another novel crystalline form of the hydrobromide salt of the compound of formula (I), which is designated herein as the hydrobromide salt form C.
  • the hydrobromide salt form C provided by the invention has an X-ray powder diffraction pattern with a 2 ⁇ value of 8.1° ⁇ 0.2°, There are characteristic peaks at 16.1 ° ⁇ 0.2 °, 24.8 ° ⁇ 0.2 °.
  • hydrobromide salt form C provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 10.4° ⁇ 0.2°, 20.3° ⁇ 0.2°, and 23.3° ⁇ 0.2°.
  • hydrobromide salt form C provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 13.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, and 16.2° ⁇ 0.2°.
  • the hydrobromide salt form C provided by the present invention has an X-ray powder diffraction pattern with a 2 ⁇ value of 8.1 ° ⁇ 0.2 °, 10.4 ° ⁇ 0.2 °, 13.3 ° ⁇ 0.2 °, and 14.7 ° ⁇ There are characteristic peaks at 0.2°, 16.1° ⁇ 0.2°, 16.2° ⁇ 0.2°, 20.3° ⁇ 0.2°, 23.3° ⁇ 0.2°, and 24.8° ⁇ 0.2°.
  • the hydrobromide salt form C provided by the present invention has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the invention also provides a preparation method of the hydrobromide salt form C of the compound of the formula (I), which comprises stirring the hydrobromide salt of the compound of the formula (I) in a mixed solvent of an alcohol and an ester at room temperature to collect a solid. , can be obtained by drying.
  • the alcohol solvent is preferably methanol
  • the ester solvent is preferably ethyl acetate
  • the present invention provides another novel crystalline form of the hydrobromide salt of the compound of formula (I), which is designated herein as the hydrobromide salt form D.
  • the hydrobromide salt form D provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 20.0° ⁇ 0.2°, 22.8° ⁇ 0.2°, and 24.5° ⁇ 0.2°.
  • hydrobromide salt form D provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 21.8° ⁇ 0.2°, 26.7° ⁇ 0.2°, and 7.8° ⁇ 0.2°.
  • hydrobromide salt form D provided by the present invention has an X-ray powder diffraction pattern having a characteristic peak at a 2 ⁇ value of 11.7° ⁇ 0.2° and 12.6° ⁇ 0.2°.
  • the hydrobromide salt form D provided by the present invention has an X-ray powder diffraction pattern with 2 ⁇ values of 20.0° ⁇ 0.2°, 22.8° ⁇ 0.2°, 24.5° ⁇ 0.2°, 21.8° ⁇ There are characteristic peaks at 0.2°, 26.7° ⁇ 0.2°, 7.8° ⁇ 0.2°, 11.7° ⁇ 0.2°, and 12.6° ⁇ 0.2°.
  • the hydrobromide salt form D provided by the present invention has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the invention also provides a preparation method of the hydrobromide salt form D of the compound of the formula (I), which comprises the formula (I)
  • the compound and the hydrobromic acid solution are stirred and crystallized in a ratio of a certain molar ratio in a pure water at a low temperature of 0 to 10 ° C, and the solid is collected and dried.
  • reaction molar ratio of the compound of the formula (I) to hydrobromic acid is 1:1 to 1:2.
  • the present invention provides another novel crystalline form of the hydrobromide salt of the compound of formula (I), which is designated herein as the hydrobromide salt form E.
  • the hydrobromide salt form E provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 7.2 ° ⁇ 0.2 °, 12.2 ° ⁇ 0.2 °, and 21.7 ° ⁇ 0.2 °.
  • hydrobromide salt form E provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 14.5° ⁇ 0.2°, 23.1° ⁇ 0.2°, and 27.5° ⁇ 0.2°.
  • hydrobromide salt form E provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 13.9° ⁇ 0.2°, 19.3° ⁇ 0.2°, and 25.6° ⁇ 0.2°.
  • the hydrobromide salt form E provided by the present invention has an X-ray powder diffraction pattern with a 2 ⁇ value of 7.2° ⁇ 0.2°, 12.2° ⁇ 0.2°, 13.9° ⁇ 0.2°, 14.5° ⁇ There are characteristic peaks at 0.2°, 19.3° ⁇ 0.2°, 21.7° ⁇ 0.2°, 23.1° ⁇ 0.2°, 25.6° ⁇ 0.2°, and 27.5° ⁇ 0.2°.
  • the hydrobromide salt form E provided by the present invention has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the invention also provides a preparation method of the hydrobromide salt form E of the compound of the formula (I), which comprises the following steps: arranging and dephosphorizing the compound of the formula (I) and the hydrobromic acid solution in a molar ratio at a certain molar ratio; The solid is not dried.
  • reaction molar ratio of the compound of the formula (I) to hydrobromic acid is 1:1 to 1:2.
  • a second object of the present invention is to provide a phosphate, a new crystalline form of a phosphate of the compound of formula (I) and a process for the preparation thereof.
  • the invention provides a phosphate of a compound of formula (I).
  • the phosphate of the compound of the formula (I) provided by the present invention is in a crystalline form, and is referred to as a phosphate crystal form A in the present invention.
  • the phosphate crystal form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 7.9 ° ⁇ 0.2 °, 22.4 ° ⁇ 0.2 °, and 25.6 ° ⁇ 0.2 °.
  • the phosphate crystal form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 12.7° ⁇ 0.2°, 15.4° ⁇ 0.2°, and 21.3° ⁇ 0.2°.
  • the phosphate crystal form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 18.3° ⁇ 0.2°, 20.8° ⁇ 0.2°, and 21.7° ⁇ 0.2°.
  • the present invention provides a phosphate crystal form A having an X-ray powder diffraction pattern having a 2 ⁇ value of 7.9° ⁇ 0.2°, 12.7° ⁇ 0.2°, 15.4° ⁇ 0.2°, and 18.3° ⁇ 0.2°. Characteristic peaks at 20.8° ⁇ 0.2°, 21.3° ⁇ 0.2°, 21.7° ⁇ 0.2°, 22.4° ⁇ 0.2°, and 25.6° ⁇ 0.2°.
  • the phosphate crystal form A provided by the present invention has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the phosphate crystal form A provided by the present invention begins to exhibit an endothermic peak near heating to 192 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG.
  • the present invention provides a crystalline form A of phosphate having a weight loss gradient of about 0.9% when heated to 175 ° C, the thermogravimetric analysis of which is substantially as shown in FIG.
  • the present invention also provides a process for preparing a phosphate of the compound of the above formula (I), which comprises reacting a compound of the formula (I) with phosphoric acid in a ketone or ether solvent, and stirring and crystallization.
  • the ketone solvent is preferably acetone
  • the ether solvent is preferably tetrahydrofuran
  • reaction molar ratio of the compound of the formula (I) to phosphoric acid is 1:0.8 to 1:2.
  • a third object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the phosphate crystal form A of the compound of the formula (I) as an active ingredient or the hydrobromide crystal form A, B, C, D Or one or more of E is an active ingredient, and a pharmaceutically acceptable carrier/excipient.
  • a fourth object of the present invention is to provide a hydrobromide crystal form of the compound of the above formula (I), a phosphate and a crystal form thereof, and a pharmaceutical composition containing the above compound for the preparation of a medicament for treating cancer, particularly non-small cell lung cancer Use in.
  • hydrobromide crystal forms A, B, C, D, E have the following advantages:
  • the phosphate crystal form A of the compound of formula (I) provided by the present invention has the following advantages:
  • the phosphate crystal form A of the present invention has good stability
  • the phosphate form A of the present invention has a higher solubility, which greatly improves the bioavailability and drug efficacy of the drug, and is more suitable for clinical use. It is used in medicine and has a strong economic value.
  • Figure 1 is an XRPD pattern of the hydrobromide salt form A of the compound of formula (I).
  • Figure 2 is an XRPD pattern of the hydrobromide salt form B of the compound of formula (I).
  • Figure 3 is a DSC chart of the hydrobromide salt form B of the compound of formula (I).
  • Figure 4 is an XRPD pattern of the hydrobromide salt form C of the compound of formula (I).
  • Figure 5 is an XRPD pattern of the hydrobromide salt form D of the compound of formula (I).
  • Figure 6 is an XRPD overlay of the hydrobromide salt form D of the compound of formula (I) placed for 2 weeks; a reference chart of Form D from top to bottom, 5 ° C, 25 ° C / 60% RH and 40 ° C / XRPD pattern at 75% RH.
  • Figure 7 is an XRPD pattern of the hydrobromide salt form E of the compound of formula (I).
  • Figure 8 is an XRPD pattern of the crystalline form A of the compound of formula (I).
  • Figure 9 is a DSC chart of the crystalline form A of the compound of formula (I).
  • Figure 10 is a TGA diagram of the crystalline form A of the compound of formula (I).
  • Figure 11 is a 1 H NMR chart of the crystalline form A of the compound of the formula (I).
  • Figure 12 is a DVS diagram of the crystalline form A of the compound of formula (I).
  • Figure 13 is a DVS diagram of WO2013138502 hydrobromide salt form I.
  • Figure 14 is a 3-month stable XRPD stack of the crystalline form A of the compound of formula (I); XRPD reference chart of phosphate form A from top to bottom, phosphate form A at 5 ° C, 25 XRPD pattern at °C/60% RH and 40 °C / 75% RH.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the invention The method parameters of Differential Scanning Calorimetry (DSC) are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • the hydrobromic acid solution refers to a hydrobromic acid aqueous solution having a mass concentration of 40% obtained by a commercially available method.
  • hydrobromide salt of the compound of the formula (I) is prepared by the method of Example 7 of the patent WO2013138502.
  • the hydrobromide salt form D prepared in this example was placed at 5 ° C, 25 ° C / 60% RH, 40 ° C / 75% RH for 2 weeks, focusing on the stability of the crystal form, the test results are shown in Figure 6. (From top to bottom, the crystal form D reference, 5 ° C, 25 ° C / 60% RH, XRPD chart at 40 ° C / 75% RH). The results show that Form D has good stability.
  • the hydrobromide salt form D of the present invention and the sample of the known form VIII are respectively prepared into a saturated solution by using SGF (simulated artificial gastric juice), pH 6.5 FaSSIF (artificial intestinal juice under fasting state) and pure water, and known form I.
  • SGF simulated artificial gastric juice
  • pH 6.5 FaSSIF artificial intestinal juice under fasting state
  • pure water pure water
  • known form I pure water
  • the samples were prepared into a saturated solution by SGF (simulated artificial gastric juice), pH 6.5 FaSSIF (artificial intestinal juice under fasting conditions), and the content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC) after 24 hours.
  • HPLC high performance liquid chromatography
  • the hydrobromide salt form D of the present invention has a higher solubility in SGF, FaSSIF, and pure water for 24 hours than that of the known form VIII.
  • the hydrobromide salt form D of the present invention has a higher 24-hour solubility in SGF and FaSSIF than the known form I.
  • the phosphate product prepared by the above method has the following 1 H NMR identification data as follows:
  • the solid obtained in this example was in the form of a crystal, designated as phosphate crystal form A, and its X-ray powder diffraction data is shown in Table 10. Its XRPD pattern in FIG. 8, DSC thereof is shown in Figure 9, which is a TGA graph in FIG. 10, FIG. 1 H NMR shown in Figure 11.
  • the phosphate crystal form A prepared in this example was placed at 5 ° C, 25 ° C / 60% RH, 40 ° C / 75% RH for 3 months, and the XRPD pattern was measured to investigate the stability of the crystal form. As shown in Figure 14.
  • the XRPD reference chart of the phosphate crystal form A is in order from the top to the bottom, and the phosphate crystal form A XRPD pattern at 5 ° C, 25 ° C / 60% RH, 40 ° C / 75% RH.
  • the solid obtained in this example was a phosphate crystal form A, and its X-ray powder diffraction data is shown in Table 11.
  • the phosphate of the compound of the formula (I) of the present invention (abbreviated as phosphate of the present invention) and the hydrobromide salt (abbreviated as known hydrobromide) disclosed in the patent WO2013138502, respectively, are FeSSIF (artificial intestinal juice under satiety state), water
  • the mixture was formulated into a saturated solution, and the content of the sample in the saturated solution was determined by high performance liquid chromatography after 1 hour and 4 hours.
  • the experimental results are shown in Table 12.
  • solubility of the phosphate of the present invention is significantly higher than that of the known hydrobromide salt after being placed in FeSSIF and water for 1 hour and 4 hours, respectively.
  • a dynamic moisture adsorption (DVS) test was carried out by taking 10 mg of the phosphate crystal form A of the present invention and the hydrobromide salt form I (abbreviated as known form I) disclosed in the patent WO2013138502, respectively.
  • the DVS of the phosphate form A of the present invention is shown in Figure 12, and the DVS of the patented hydrobromide form I is shown in Figure 13.

Abstract

一种表皮生长因子受体激酶抑制剂的盐的晶型及其制备方法，尤其是式（I）化合物的氢溴酸盐和磷酸盐的晶型。

Description

一种表皮生长因子受体激酶抑制剂的盐的晶型及其制备方法 技术领域
本发明涉及化学医药晶型领域，特别是涉及N-(3-(2-(4-(4-乙酰基哌嗪-1-基)-2-甲氧基苯基氨基)-5-(三氟甲基)嘧啶-4-基氨基)苯基)丙烯酰胺)的盐的晶型，更特别涉及氢溴酸盐和磷酸盐的晶型，及其制备方法。
背景技术
N-(3-(2-(4-(4-乙酰基哌嗪-1-基)-2-甲氧基苯基氨基)-5-(三氟甲基)嘧啶-4-基氨基)苯基)丙烯酰胺)(又名CO1686)，由克洛维斯肿瘤公司(Clovis Oncology)首先研发，是一种新颖的口服、靶向共价(不可逆)突变型的第三代表皮生长因子受体(EGFR)抑制剂，能够抑制关键激活突变和T790耐药突变，使野生型EGFR信号闲置。该药开发用于携带初始激活EGFR突变及主要抗性突变T790M的NSCLC患者的治疗。2014年5月20日，FDA已授予实验性药物CO1686突破性疗法认定，作为一种单药疗法，用于携带T790M的二线EGFR突变非小细胞肺癌(NSCLC)的治疗。CO1686目前处在临床III期阶段，其结构如式(Ⅰ)所示：
Figure PCTCN2015098901-appb-000001
研究发现，早期研究使用的是CO1686的游离碱形式，但因其氢溴酸盐形式可提高药物利用性、降低变异性，在2013年8月临床改用其氢溴酸盐，但其剂量仍在继续爬升。
目前，专利WO2013138495公开了CO1686的多种游离碱的晶型；专利WO2013138502公开了氢溴酸盐的多种晶型形式，其中形式IV/V/VI/VII为溶剂合物，不适合药用；形式II易转化成形式I，且结晶度差；形式VIII在加热后会产生胶状物，形式III是不稳定的无水晶型，易转化为形式I。
因此，仅氢溴酸盐的形式I是可用于药用的晶型，但因临床使用的氢溴酸盐晶型的剂量仍在继续爬升，因此，有必要进一步研究开发，找到比氢溴酸盐形式I的 性能更好，比如溶解度更高、稳定性更好、引湿性更低，适合储存和工业化生产的氢溴酸盐的新晶型，以及新的盐及其晶型，从而满足药物的后续开发需要。
发明内容
本发明的发明人对式(Ⅰ)化合物的氢溴酸盐及其它盐进行了深入研究和大量筛选，令人惊奇的是，本发明的发明人找到了更适合药物开发的式(Ⅰ)化合物的氢溴酸盐新晶型，以及新的磷酸盐晶型。并且，本发明的新晶型稳定性好、工艺简单易于操作、适合储存和工业化生产，为药物的后续开发提供了新的选择。
本发明的第一个目的是提供式(Ⅰ)化合物的氢溴酸盐的五种新晶型及其制备方法。
Figure PCTCN2015098901-appb-000002
第一方面，本发明提供了式(Ⅰ)化合物的氢溴酸盐的一种新晶型，本发明中命名为氢溴酸盐晶型A。
本发明提供的氢溴酸盐晶型A，其X射线粉末衍射图在2theta(2θ)值为8.9°±0.2°、18.1°±0.2°、20.7°±0.2°处具有特征峰。
更进一步的，本发明提供的氢溴酸盐晶型A，其X射线粉末衍射图还在2θ值为11.4°±0.2°、18.5°±0.2°、25.2°±0.2°处具有特征峰。
更进一步的，本发明提供的氢溴酸盐晶型A，其X射线粉末衍射图还在2θ值为24.5°±0.2°、26.1°±0.2°、31.1°±0.2°处具有特征峰。
在一个优选实施方案中，本发明提供的氢溴酸盐晶型A，其X射线粉末衍射图在2θ值为8.9°±0.2°、11.4°±0.2°、18.1°±0.2°、18.5°±0.2°、20.7°±0.2°、24.5°±0.2°、25.2°±0.2°、26.1°±0.2°、31.1°±0.2°处具有特征峰。
在一个更具体的实施方案中，本发明提供的晶型A，其X射线粉末衍射图基本如图1所示。
本发明还提供了上述式(Ⅰ)化合物氢溴酸盐晶型A的制备方法，包括：将式(Ⅰ)化合物氢溴酸盐在醇类和卤代烃的混合溶剂中，在不高于50℃的条件下搅拌，收集固体即可得到。
上述制备方法中，所述醇类溶剂优选为醇，所述卤代烃优选为氯仿。
第二方面，本发明提供了式(Ⅰ)化合物的氢溴酸盐的另一种新晶型，本发明中命名为氢溴酸盐晶型B。
本发明提供的氢溴酸盐晶型B，其X射线粉末衍射图在2θ值为8.2°±0.2°、15.9°±0.2°、22.2°±0.2°处具有特征峰。
更进一步的，本发明提供的氢溴酸盐晶型B，其X射线粉末衍射图在2θ值为10.1°±0.2°、18.2°±0.2°、23.1°±0.2°处具有特征峰。
更进一步的，本发明提供的氢溴酸盐晶型B，其X射线粉末衍射图在2θ值为21.2°±0.2°、24.7°±0.2°、27.3°±0.2°处具有特征峰。
在一个优选实施方案中，本发明提供的氢溴酸盐晶型B，其X射线粉末衍射图在2θ值为8.2°±0.2°、10.1°±0.2°、15.9°±0.2°、18.2°±0.2°、21.2°±0.2°、22.2°±0.2°、23.1°±0.2°、24.7°±0.2°、27.3°±0.2°处具有特征峰。
在一个更具体的实施方案中，本发明提供的氢溴酸盐晶型B，其X射线粉末衍射图基本如图2所示。
在另一个更具体的实施方案中，本发明提供的氢溴酸盐晶型B，在加热至65℃、108℃、228℃附近分别开始出现吸热峰，其差示扫描量热图基本如图3所示。
本发明还提供了上述式(Ⅰ)化合物氢溴酸盐晶型B的制备方法，包括将式(Ⅰ)化合物的氢溴酸盐在醇类和醚类的混合溶剂中室温条件下搅拌，收集固体即可得到。
上述制备方法中，所述醇类溶剂优选甲醇，所述醚类溶剂优选甲基叔丁基醚。
第三方面，本发明提供了式(Ⅰ)化合物的氢溴酸盐的另一种新晶型，本发明中命名为氢溴酸盐晶型C。
本发明提供的氢溴酸盐晶型C，其X射线粉末衍射图在2θ值为8.1°±0.2°、 16.1°±0.2°、24.8°±0.2°处具有特征峰。
更进一步的，本发明提供的氢溴酸盐晶型C，其X射线粉末衍射图在2θ值为10.4°±0.2°、20.3°±0.2°、23.3°±0.2°处具有特征峰。
更进一步的，本发明提供的氢溴酸盐晶型C，其X射线粉末衍射图在2θ值为13.3°±0.2°、14.7°±0.2°、16.2°±0.2°处具有特征峰。
在一个优选实施方案中，本发明提供的氢溴酸盐晶型C，其X射线粉末衍射图在2θ值为8.1°±0.2°、10.4°±0.2°、13.3°±0.2°、14.7°±0.2°、16.1°±0.2°、16.2°±0.2°、20.3°±0.2°、23.3°±0.2°、24.8°±0.2°处具有特征峰。
在一个更具体的实施方案中，本发明提供的氢溴酸盐晶型C，其X射线粉末衍射图基本如图4所示。
本发明还提供了式(Ⅰ)化合物氢溴酸盐晶型C的制备方法，包括将式(Ⅰ)化合物的氢溴酸盐在醇类和酯类的混合溶剂中室温条件下搅拌，收集固体，干燥即可得到。
在上述制备方法中，所述醇类溶剂优选为甲醇，所述酯类溶剂优选为乙酸乙酯。
第四方面，本发明提供了式(Ⅰ)化合物的氢溴酸盐的另一种新晶型，本发明中命名为氢溴酸盐晶型D。
本发明提供的氢溴酸盐晶型D，其X射线粉末衍射图在2θ值为20.0°±0.2°、22.8°±0.2°、24.5°±0.2°处具有特征峰。
更进一步的，本发明提供的氢溴酸盐晶型D，其X射线粉末衍射图在2θ值为21.8°±0.2°、26.7°±0.2°、7.8°±0.2°处具有特征峰。
更进一步的，本发明提供的氢溴酸盐晶型D，其X射线粉末衍射图在2θ值为11.7°±0.2°、12.6°±0.2°处具有特征峰。
在一个优选实施方案中，本发明提供的氢溴酸盐晶型D，其X射线粉末衍射图在2θ值为20.0°±0.2°、22.8°±0.2°、24.5°±0.2°、21.8°±0.2°、26.7°±0.2°、7.8°±0.2°、11.7°±0.2°、12.6°±0.2°处具有特征峰。
在一个更具体的实施方案中，本发明提供的氢溴酸盐晶型D，其X射线粉末衍射图基本如图5所示。
本发明还提供了式(Ⅰ)化合物氢溴酸盐晶型D的制备方法，包括将式(Ⅰ) 化合物和氢溴酸溶液以一定摩尔比的配比在纯水中0-10℃的低温条件下搅拌析晶，收集并干燥固体得到。
上述制备方法中，所述式(Ⅰ)化合物与氢溴酸的反应摩尔比为1:1～1:2。
第五方面，本发明提供了式(Ⅰ)化合物的氢溴酸盐的另一种新晶型，本发明中命名为氢溴酸盐晶型E。
本发明提供的氢溴酸盐晶型E，其X射线粉末衍射图在2θ值为7.2°±0.2°、12.2°±0.2°、21.7°±0.2°处具有特征峰。
更进一步的，本发明提供的氢溴酸盐晶型E，其X射线粉末衍射图在2θ值为14.5°±0.2°、23.1°±0.2°、27.5°±0.2°处具有特征峰。
更进一步的，本发明提供的氢溴酸盐晶型E，其X射线粉末衍射图在2θ值为13.9°±0.2°、19.3°±0.2°、25.6°±0.2°处具有特征峰。
在一个优选实施方案中，本发明提供的氢溴酸盐晶型E，其X射线粉末衍射图在2θ值为7.2°±0.2°、12.2°±0.2°、13.9°±0.2°、14.5°±0.2°、19.3°±0.2°、21.7°±0.2°、23.1°±0.2°、25.6°±0.2°、27.5°±0.2°处具有特征峰。
在一个更具体的实施方案中，本发明提供的氢溴酸盐晶型E，其X射线粉末衍射图基本如图7所示。
本发明还提供了式(Ⅰ)化合物氢溴酸盐晶型E的制备方法，包括将式(Ⅰ)化合物和氢溴酸溶液以一定摩尔比的配比在纯水中低温搅拌析晶，收集固体不干燥得到。
上述制备方法中，所述式(Ⅰ)化合物与氢溴酸的反应摩尔比为1:1～1:2。
本发明的第二个目的是提供式(Ⅰ)化合物的磷酸盐，磷酸盐新晶型及其制备方法。
Figure PCTCN2015098901-appb-000003
一方面，本发明提供了式(Ⅰ)化合物的磷酸盐。
另一方面，也是优选的方面，本发明提供的式(Ⅰ)化合物的磷酸盐为结晶形式，本发明中命名为磷酸盐晶型A。
本发明提供的磷酸盐晶型A，其X射线粉末衍射图在2θ值为7.9°±0.2°、22.4°±0.2°、25.6°±0.2°处具有特征峰。
更进一步的，本发明提供的磷酸盐晶型A，其X射线粉末衍射图在2θ值为12.7°±0.2°、15.4°±0.2°、21.3°±0.2°处具有特征峰。
更进一步的，本发明提供的磷酸盐晶型A，其X射线粉末衍射图在2θ值为18.3°±0.2°、20.8°±0.2°、21.7°±0.2°处具有特征峰。
在一个优选实施方案中，本发明提供的磷酸盐晶型A，其X射线粉末衍射图在2θ值为7.9°±0.2°、12.7°±0.2°、15.4°±0.2°、18.3°±0.2°、20.8°±0.2°、21.3°±0.2°、21.7°±0.2°、22.4°±0.2°、25.6°±0.2°处具有特征峰。
在一个更具体的实施方案中，本发明提供的磷酸盐晶型A，其X射线粉末衍射图基本如图8所示。
在另一个更具体的实施方案中，本发明提供的磷酸盐晶型A，在加热至192℃附近开始出现吸热峰，其差示扫描量热分析图基本如图9所示。
在另一个更具体的实施方案中，本发明提供的磷酸盐晶型A，在加热至175℃时，具有约0.9％的重量损失梯度，其热重分析图基本如图10所示。
本发明还提供了上述式(Ⅰ)化合物磷酸盐的制备方法，包括使式(Ⅰ)化合物与磷酸在酮类或醚类溶剂中反应，搅拌析晶得到。
上述制备方法中，所述酮类溶剂优选为丙酮，所述醚类溶剂优选为四氢呋喃。
更进一步的，所述式(Ⅰ)化合物与磷酸的反应摩尔比为1:0.8～1:2。
本发明的第三个目的是提供一种药物组合物，该药物组合物以式(Ⅰ)化合物的磷酸盐晶型A为活性成分，或者以氢溴酸盐晶型A、B、C、D或E的一种或多种为活性成分，以及药学上可接受的载体/辅料。
本发明的第四个目的是提供上述式(I)化合物的氢溴酸盐晶型、磷酸盐及其晶型、及含上述化合物的药物组合物在制备治疗癌症，特别是非小细胞肺癌的药物中的用途。
本发明提供的式(I)化合物的氢溴酸盐的上述多种晶型，即氢溴酸盐晶型A、B、C、D、E具有如下优点：
(1)具有较好的稳定性，适合长期储存；
(2)相比与专利WO2013138502公开的已知氢溴酸盐晶型，溶解度有显著提高；
(3)制备工艺简单，易于工业化生产。
本发明提供的式(I)化合物的磷酸盐晶型A具有如下优点：
(1)本发明的磷酸盐晶型A具有良好的稳定性；
(2)具有较低的引湿性，在制备过程中无需特殊的干燥条件，简化了药品的制备与后处理工艺，易于工业化生产；
(3)与专利WO2013138502公开的已知氢溴酸盐形式I相比，本发明中的磷酸盐的晶型A溶解度更高，大大提高了药物的生物利用度和药物疗效，更适于作为临床药物使用，并具有很强的经济价值。
附图说明
图1为式(Ⅰ)化合物氢溴酸盐晶型A的XRPD图。
图2为式(Ⅰ)化合物氢溴酸盐晶型B的XRPD图。
图3为式(Ⅰ)化合物氢溴酸盐晶型B的DSC图。
图4为式(Ⅰ)化合物氢溴酸盐晶型C的XRPD图。
图5为式(Ⅰ)化合物氢溴酸盐晶型D的XRPD图。
图6为式(Ⅰ)化合物氢溴酸盐晶型D放置2周的XRPD叠图；从上至下依次为晶型D的参比图、5℃，25℃/60％RH和40℃/75％RH下的XRPD图。
图7为式(Ⅰ)化合物氢溴酸盐晶型E的XRPD图。
图8为式(Ⅰ)化合物磷酸盐晶型A的XRPD图。
图9为式(Ⅰ)化合物磷酸盐晶型A的DSC图。
图10为式(Ⅰ)化合物磷酸盐晶型A的TGA图。
图11为式(Ⅰ)化合物磷酸盐晶型A的1H NMR图。
图12为式(Ⅰ)化合物磷酸盐晶型A的DVS图。
图13为WO2013138502氢溴酸盐形式I的DVS图。
图14为式(Ⅰ)化合物磷酸盐晶型A的3个月稳定性XRPD叠图；从上至下依次为磷酸盐晶型A的XRPD参比图，磷酸盐晶型A在5℃，25℃/60％RH和40℃/75％RH下的XRPD图。
具体实施方式
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
DVS：动态水分吸附
1H NMR：核磁共振氢谱
本发明所述的X射线粉末衍射图在Panalytical Empyrean 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射线反射参数：Cu,Kα辐射
Figure PCTCN2015098901-appb-000004
1.540598；
Figure PCTCN2015098901-appb-000005
1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述 的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述的热重分析(TGA)图在TA Q5000上采集。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N2，200毫升/分钟
单位时间质量变化：0.002％/分钟
相对湿度范围：0％RH-95％RH
本发明所使用的原料除非特别说明，均是通过商业购得。其中，所述的氢溴酸溶液是指通过市售方式得到的质量浓度为40％的氢溴酸水溶液。
所述式(I)化合物的氢溴酸盐是参照专利WO2013138502实施例7的方法制备得到的。
制备例1
式(I)化合物的氢溴酸盐的制备
参照专利WO2013138502的实施例7，向1051.6mg式(Ⅰ)化合物中加入5.0mL乙腈：水＝5:1(体积比)的混合溶剂；将250μL 40％的氢溴酸溶液逐滴加入上述溶液中，加完后再补加3.0ml乙腈：水＝5:1(体积比)的混合溶剂，5℃下搅拌反应24小时，过滤真空干燥，所得固体即为专利WO2013138502实施例7中氢溴酸盐的固体。
实施例1
式(Ⅰ)化合物氢溴酸盐晶型A的制备
将8.0mg式(Ⅰ)化合物的氢溴酸盐加入到0.9mL的甲醇与氯仿体积比为3:50的混合溶剂中，室温条件下搅拌48小时，离心干燥所得固体，经检测为氢溴酸盐的晶型A。
本实施例得到的晶型的X射线粉末衍射数据如表1所示。其XRPD图如图1所示。
表1
2θ d间隔 强度％
6.70 13.19 26.71
8.93 9.90 100.00
9.22 9.59 44.49
11.40 7.76 42.86
12.92 6.85 13.54
13.30 6.66 18.87
16.26 5.45 6.39
17.24 5.15 31.15
18.12 4.90 39.03
18.53 4.79 23.86
20.65 4.30 49.87
21.28 4.18 27.20
21.70 4.10 56.37
22.97 3.87 4.79
23.73 3.75 11.00
24.52 3.63 21.48
25.22 3.53 49.93
25.69 3.47 13.47
26.11 3.41 24.31
26.58 3.35 9.33
26.89 3.32 9.50
27.31 3.27 7.87
28.09 3.18 10.34
29.31 3.05 9.57
31.06 2.88 14.46
33.15 2.70 3.98
36.68 2.45 5.50
实施例2
式(Ⅰ)化合物氢溴酸盐晶型A的制备
将8.0mg式(Ⅰ)化合物的氢溴酸盐加入到0.9mL的甲醇与氯仿体积比为3:50的混合溶剂中，50℃条件下搅拌48小时，离心干燥所得固体，经检测为氢溴酸盐的晶型A。
本实施例得到的晶型的X射线粉末衍射数据如表2所示。
表2
Figure PCTCN2015098901-appb-000006
Figure PCTCN2015098901-appb-000007
实施例3
式(Ⅰ)化合物氢溴酸盐晶型B的制备
将8.2mg式(Ⅰ)化合物的氢溴酸盐加入到0.9mL的甲醇与甲基叔丁基醚体积比为3:25的混合溶剂中，室温条件下搅拌48小时，离心所得固体，经检测为氢溴酸盐的晶型B。
本实施例得到的晶型的X射线粉末衍射数据如表3所示。其XRPD图如图2所示，其DSC图如图3所示。
表3
Figure PCTCN2015098901-appb-000008
Figure PCTCN2015098901-appb-000009
实施例4
式(Ⅰ)化合物氢溴酸盐晶型C的制备
将8.0mg式(Ⅰ)化合物的氢溴酸盐加入到0.9mL的甲醇与乙酸乙酯体积比为3:25的混合溶剂中，室温条件下搅拌48小时，离心所得固体，经检测为氢溴酸盐的晶型C。
本实施例得到的晶型的X射线粉末衍射数据如表4所示。其XRPD图如图4所示。
表4
Figure PCTCN2015098901-appb-000010
Figure PCTCN2015098901-appb-000011
Figure PCTCN2015098901-appb-000012
实施例5
式(Ⅰ)化合物氢溴酸盐晶型D的制备
将10.2mg式(Ⅰ)化合物加入到0.2mL的纯水中，缓慢加入1当量质量浓度为40％的氢溴酸溶液，5℃条件下搅拌12小时。离心去除上清液，在室温下干燥即可得到。
本实施例得到的晶型的X射线粉末衍射数据如表5所示。
表5
Figure PCTCN2015098901-appb-000013
Figure PCTCN2015098901-appb-000014
实施例6
式(Ⅰ)化合物氢溴酸盐晶型D的制备
将101.8mg式(Ⅰ)化合物加入到2mL的纯水中，缓慢加入1当量质量浓度为40％的氢溴酸溶液，5℃条件下搅拌12小时。离心去除上清液，在室温下干燥即可得到，经检测为氢溴酸盐的晶型D。
本实施例得到的晶型的X射线粉末衍射数据如表6所示。其XRPD图如图5所示。
表6
Figure PCTCN2015098901-appb-000015
Figure PCTCN2015098901-appb-000016
将本实施例制得的氢溴酸盐晶型D放置于5℃，25℃/60％RH，40℃/75％RH的条件下2周，重点考察晶型稳定性，试验结果如图6(从上至下依次为晶型D参比，5℃，25℃/60％RH，40℃/75％RH下的XRPD图)所示。结果表明，晶型D具有良好的稳定性。
对比实验1
1)氢溴酸盐晶型D与WO2013138495中公开的氢溴酸盐形式I和形式VIII(简 称已知形式I、已知形式VIII)的溶解度对比研究：
将本发明的氢溴酸盐晶型D与已知形式VIII的样品分别用SGF(模拟人工胃液)，pH6.5FaSSIF(空腹状态下人工肠液)和纯水配制成饱和溶液，与已知形式I的样品分别用SGF(模拟人工胃液)，pH6.5FaSSIF(空腹状态下人工肠液)配制成饱和溶液，在24个小时后通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。实验结果如表7和表8所示。
表7
Figure PCTCN2015098901-appb-000017
表8
Figure PCTCN2015098901-appb-000018
由表7和表8可以看出，本发明的氢溴酸盐晶型D在SGF、FaSSIF、纯水中24小时溶解度均高于已知形式VIII。本发明的氢溴酸盐晶型D在SGF、FaSSIF中24小时溶解度均高于已知形式I。
实施例7
式(Ⅰ)化合物氢溴酸盐晶型E的制备
将10.2mg式(Ⅰ)化合物加入到0.2mL的纯水中，缓慢加入1当量的质量浓度为40％的氢溴酸溶液，5℃条件下搅拌12小时，离心收集固体，不干燥，可得到，经检测为氢溴酸盐的晶型E。
本实施例得到的晶型的X射线粉末衍射数据如表9所示。其XRPD图如图7所示。
表9
Figure PCTCN2015098901-appb-000019
Figure PCTCN2015098901-appb-000020
实施例8
式(Ⅰ)化合物磷酸盐的制备
取10.2mg的式(Ⅰ)化合物溶于0.9mL的丙酮中，逐滴加入0.09mL 0.2mol/L的磷酸溶液，50℃条件下搅拌反应24小时，离心干燥即可得到。
上述方法制备得到的磷酸盐产品，其1H NMR鉴定数据如下：
1H NMR(400MHz,DMSO)δ10.17(s,1H),8.67(s,1H),8.28(s,1H),8.10(s,1H),7.74(s,1H),7.51(dd,J＝16.7,8.3Hz,2H),7.26(t,J＝8.1Hz,2H),6.61(d,J＝2.0Hz,1H),6.44(dd,J＝17.0,10.1Hz,1H),6.26(dd,J＝17.0,1.8Hz,2H),5.76(dd,J＝ 10.1,1.9Hz,1H),3.77(s,3H),3.56(d,J＝4.7Hz,4H),3.03(d,J＝25.7Hz,4H),2.07(d,J＝15.7Hz,3H).
经检测，本实施例得到固体为晶体形式，命名为磷酸盐晶型A，其X射线粉末衍射数据如表10所示。其XRPD图如图8，其DSC图如图9，其TGA图如图10，其1H NMR图如图11所示。
表10
Figure PCTCN2015098901-appb-000021
将本实施例制得的磷酸盐晶型A放置于5℃，25℃/60％RH，40℃/75％RH的条件下3个月，测定其XRPD图，考察晶型的稳定性，结果如图14所示。
在图14中，从上至下依次为磷酸盐晶型A的XRPD参比图，磷酸盐晶型A 在5℃，25℃/60％RH，40℃/75％RH下的XRPD图。
结果表明，本发明的磷酸盐晶型A具有良好的稳定性。
实施例9
式(Ⅰ)化合物磷酸盐的制备
取10.2mg的式(Ⅰ)化合物得游离碱溶于0.9mL的四氢呋喃中，逐滴加入0.09mL 0.2mol/L的磷酸溶液，50℃下搅拌反应24小时，离心干燥固体即可得到。
经检测，本实施例得到固体为磷酸盐晶型A，其X射线粉末衍射数据如表11所示。
表11
Figure PCTCN2015098901-appb-000022
Figure PCTCN2015098901-appb-000023
实施例10
本发明的式(I)化合物磷酸盐与专利WO2013138502公开的式(I)化合物氢溴 酸盐溶解度对比研究：
将本发明的式(I)化合物磷酸盐(简称本发明磷酸盐)与专利WO2013138502公开的氢溴酸盐(简称已知氢溴酸盐)样品分别用FeSSIF(饱腹状态下人工肠液)、水配制成饱和溶液，在1个小时、4个小时后通过高效液相色谱测定饱和溶液中样品的含量。实验结果如表12所示。
表12
Figure PCTCN2015098901-appb-000024
通过上述对比结果可以看出，在FeSSIF和水中分别放置1个小时后和4个小时后，本发明的磷酸盐的溶解度均显著高于已知氢溴酸盐。
实施例11
本发明的式(I)化合物磷酸盐晶型A与专利WO2013138502公开的式(I)化合 物氢溴酸盐形式I引湿性对比研究：
分别取10mg本发明的磷酸盐晶型A与专利WO2013138502公开的氢溴酸盐形式I(简称已知晶型I)进行动态水分吸附(DVS)测试。本发明的磷酸盐晶型A的DVS如图12所示，专利氢溴酸盐形式I的DVS如图13所示。
实验结果如表13所示。
表13
Figure PCTCN2015098901-appb-000025
结果表明，本发明的磷酸盐晶型A在80％和95％湿度下引湿性都显著低于已知氢溴酸盐形式I。

Claims (22)

  1. 一种式(Ⅰ)化合物的盐的晶型，
    Figure PCTCN2015098901-appb-100001
    其特征在于，所述盐为氢溴酸盐或磷酸盐。
  2. 根据权利要求1所述的式(Ⅰ)化合物的盐的晶型，其特征在于，所述晶型为式(Ⅰ)化合物的氢溴酸盐晶型A，其X射线粉末衍射图在2theta值为8.9°±0.2°、20.7°±0.2°、18.1°±0.2°、11.4°±0.2°、18.5°±0.2°、25.2°±0.2°处具有特征峰。
  3. 根据权利要求2所述的式(Ⅰ)化合物的盐的晶型，其特征在于，所述式(Ⅰ)化合物的氢溴酸盐晶型A的X射线粉末衍射图还在2theta值为24.5°±0.2°、26.1°±0.2°、31.1°±0.2°处具有特征峰。
  4. 根据权利要求1所述的式(Ⅰ)化合物的盐的晶型，其特征在于，所述晶型为式(Ⅰ)化合物的氢溴酸盐晶型B，其X射线粉末衍射图在2theta值为8.2°±0.2°、15.9°±0.2°、22.2°±0.2°、10.1°±0.2°、18.2°±0.2°、23.1°±0.2°处具有特征峰。
  5. 根据权利要求4所述的式(Ⅰ)化合物的盐的晶型，其特征在于，所述式(Ⅰ)化合物的氢溴酸盐晶型B的X射线粉末衍射图还在2theta值为21.2°±0.2°、24.7°±0.2°、27.3°±0.2°处具有特征峰。
  6. 根据权利要求1所述的式(Ⅰ)化合物的盐的晶型，其特征在于，所述晶型为式(Ⅰ)化合物的氢溴酸盐晶型C，其X射线粉末衍射图在2theta值为8.1°±0.2°、16.1°±0.2°、24.8°±0.2°、10.4°±0.2°、20.3°±0.2°、23.3°±0.2°处具有特征峰。
  7. 根据权利要求6所述的式(Ⅰ)化合物的盐的晶型，其特征在于，所述式(Ⅰ)化合物的氢溴酸盐晶型C的X射线粉末衍射图还在2theta值为13.3°±0.2°、14.7°±0.2°、16.2°±0.2°处具有特征峰。
  8. 根据权利要求1所述的式(Ⅰ)化合物的盐的晶型，其特征在于，所述晶型为 式(Ⅰ)化合物的氢溴酸盐晶型D，其X射线粉末衍射图在2theta值为20.0°±0.2°、22.8°±0.2°、24.5°±0.2°、21.8°±0.2°、26.7°±0.2°、7.8°±0.2°处具有特征峰。
  9. 根据权利要求8所述的式(Ⅰ)化合物的盐的晶型，其特征在于，所述式(Ⅰ)化合物的氢溴酸盐晶型D的X射线粉末衍射图还在2theta值为11.7°±0.2°、12.6°±0.2°。处具有特征峰。
  10. 根据权利要求1所述的式(Ⅰ)化合物的盐的晶型，其特征在于，所述晶型为式(Ⅰ)化合物的氢溴酸盐晶型E，其X射线粉末衍射图在2theta值为7.2°±0.2°、12.2°±0.2°、21.7°±0.2°、14.5°±0.2°、23.1°±0.2°、27.5°±0.2°处具有特征峰。
  11. 根据权利要求10所述的式(Ⅰ)化合物的盐的晶型，其特征在于，所述式(Ⅰ)化合物的氢溴酸盐晶型E的X射线粉末衍射图还在2theta值为13.9°±0.2°、19.3°±0.2°、25.6°±0.2°处具有特征峰。
  12. 根据权利要求1所述的式(Ⅰ)化合物的盐的晶型，其特征在于，所述晶型为式(Ⅰ)化合物的磷酸盐晶型A，其X射线粉末衍射图在2theta值为7.9°±0.2°、22.4°±0.2°、25.6°±0.2°处具有特征峰。
  13. 根据权利要求12所述的式(Ⅰ)化合物的盐的晶型，其特征在于，所述式(Ⅰ)化合物的磷酸盐晶型A的X射线粉末衍射图还在2theta值为12.7°±0.2°、15.4°±0.2°、21.3°±0.2°处具有特征峰。
  14. 根据权利要求13所述的式(Ⅰ)化合物的盐的晶型，其特征在于，所述式(Ⅰ)化合物的磷酸盐晶型A的X射线粉末衍射图还在2theta值为18.3°±0.2°、20.8°±0.2°、21.7°±0.2°处具有特征峰。
  15. 一种制备如权利要求2-3任一项所述的式(Ⅰ)化合物的氢溴酸盐晶型A的方法，其特征在于，包括将式(Ⅰ)化合物的氢溴酸盐在醇类和卤代烃的混合溶剂中搅拌析晶，收集固体得到；所述醇类溶剂为甲醇，所述卤代烃溶剂为氯仿。
  16. 一种制备如权利要求4-5任一项所述的式(Ⅰ)化合物的氢溴酸盐晶型B的方法，其特征在于，包括将式(Ⅰ)化合物的氢溴酸盐在醇类和醚类的混合溶剂中搅拌析晶，收集固体得到；所述醇类溶剂为甲醇，所述醚类溶剂为甲基叔丁基醚。
  17. 一种制备如权利要求6-7任一项所述的式(Ⅰ)化合物的氢溴酸盐晶型C的方法，其特征在于，包括将式(Ⅰ)化合物的氢溴酸盐在醇类和酯类的混合溶剂中搅拌析晶，收集固体得到；所述醇类溶剂为甲醇，所述酯类溶剂为乙酸乙酯。
  18. 一种制备如权利要求8-9任一项所述的式(Ⅰ)化合物的氢溴酸盐晶型D的方法， 其特征在于，包括将式(Ⅰ)化合物和氢溴酸溶液以一定摩尔比的配比在纯水中低温搅拌析晶，收集并干燥固体得到；其中，所述式(Ⅰ)化合物与氢溴酸的摩尔比为1:1～1:2。
  19. 一种制备如权利要求10-11任一项所述的式(Ⅰ)化合物的氢溴酸盐晶型E的方法，其特征在于，包括将式(Ⅰ)化合物和氢溴酸溶液以一定摩尔比的配比在纯水中低温搅拌析晶，收集固体得到；其中，所述式(Ⅰ)化合物与氢溴酸的摩尔比为1:1～1:2。
  20. 一种制备如权利要求12-14任一项所述的式(Ⅰ)化合物的磷酸盐晶型A的方法，其特征在于，包括使式(Ⅰ)化合物与磷酸在酮类或醚类溶剂中反应，搅拌析晶得到；所述酮类溶剂为丙酮，所述醚类溶剂为四氢呋喃；所述式(Ⅰ)化合物与磷酸的摩尔比为1:0.8～1:2。
  21. 一种药物组合物，其含有根据权利要求1-14任意一项所述的式(Ⅰ)化合物的盐的晶型及药学上可接受的载体。
  22. 根据权利要求1至14任意一项所述的式(Ⅰ)化合物的盐的晶型或根据权利要求21所述的药物组合物在制备治疗癌症的药物中的用途。
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* Cited by examiner, † Cited by third party
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WO2013138502A1 (en) * 2012-03-15 2013-09-19 Celgene Avilomics Research, Inc. Salts of an epidermal growth factor receptor kinase inhibitor
WO2013138495A1 (en) * 2012-03-15 2013-09-19 Celgene Avilomics Research, Inc. Solid forms of an epidermal growth factor receptor kinase inhibitor

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013138502A1 (en) * 2012-03-15 2013-09-19 Celgene Avilomics Research, Inc. Salts of an epidermal growth factor receptor kinase inhibitor
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