Nothing Special   »   [go: up one dir, main page]

WO2016101912A1 - Crystal form of salt of epidermal growth factor receptor kinase inhibitor and preparation method thereof - Google Patents

Crystal form of salt of epidermal growth factor receptor kinase inhibitor and preparation method thereof Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
salt
crystalline form
hydrobromide salt
Prior art date
Application number
PCT/CN2015/098901
Other languages
French (fr)
Chinese (zh)
Inventor
陈敏华
张炎锋
刘凯
张晓宇
Original Assignee
苏州晶云药物科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN201410821405.1A external-priority patent/CN104961688A/en
Priority claimed from CN201510019173.2A external-priority patent/CN105837518A/en
Application filed by 苏州晶云药物科技有限公司 filed Critical 苏州晶云药物科技有限公司
Publication of WO2016101912A1 publication Critical patent/WO2016101912A1/en

Links

Images

Classifications

    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Disclosed are a crystal form of a salt of an epidermal growth factor receptor kinase inhibitor and a preparation method thereof, and in particular, the crystal forms of a hydrobromide and a phosphate of a compound of formula (I).

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Crystal form of salt of epidermal growth factor receptor kinase inhibitor and preparation method thereof 技术领域Technical field
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。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.
背景技术Background technique
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：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. On May 20, 2014, the FDA has awarded the experimental drug CO1686 breakthrough therapy as a monotherapy for the treatment of T790M's second-line EGFR-mutant non-small cell lung cancer (NSCLC). CO1686 is currently in clinical phase III and its structure is shown in formula (I):
Figure PCTCN2015098901-appb-000001
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。The study found that the early study used the free base form of CO1686, but because of its hydrobromide form, it can improve drug utilization and reduce variability. In August 2013, it switched to its hydrobromide clinically, but its dosage is still Continue to climb.
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。At present, the 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.
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。Therefore, only 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 .
发明内容Summary of the invention
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。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 new form of hydrobromide, as well as the new phosphate form. Moreover, 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.
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。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.
Figure PCTCN2015098901-appb-000002
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。In a first aspect, 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.
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。The hydrobromide salt form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2theta (2θ) values of 8.9 ° ± 0.2 °, 18.1 ° ± 0.2 °, and 20.7 ° ± 0.2 °.
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。Further, the hydrobromide crystal form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2θ values of 11.4°±0.2°, 18.5°±0.2°, and 25.2°±0.2°.
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。Further, the hydrobromide salt form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2θ values of 24.5°±0.2°, 26.1°±0.2°, and 31.1°±0.2°.
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。 In a preferred embodiment, the hydrobromide salt form A provided by the present invention has an X-ray powder diffraction pattern with a 2θ 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°.
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。In a more specific embodiment, the present invention provides Form A with an X-ray powder diffraction pattern substantially as shown in FIG.
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。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.
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。In the above production method, the alcohol solvent is preferably an alcohol, and the halogenated hydrocarbon is preferably chloroform.
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。In a second aspect, 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.
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。The hydrobromide salt form B provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2θ values of 8.2 ° ± 0.2 °, 15.9 ° ± 0.2 °, and 22.2 ° ± 0.2 °.
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。Further, the hydrobromide salt form B provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2θ values of 10.1±0.2°, 18.2°±0.2°, and 23.1°±0.2°.
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。Further, the hydrobromide salt form B provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2θ values of 21.2°±0.2°, 24.7°±0.2°, and 27.3°±0.2°.
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。In a preferred embodiment, the hydrobromide salt form B provided by the present invention has an X-ray powder diffraction pattern with a 2θ 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°.
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。In a more specific embodiment, the hydrobromide salt form B provided by the present invention has an X-ray powder diffraction pattern substantially as shown in FIG.
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。In another more specific embodiment, 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.
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。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.
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。In the above production method, the alcohol solvent is preferably methanol, and the ether solvent is preferably methyl tert-butyl ether.
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。In a third aspect, 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.
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。The hydrobromide salt form C provided by the invention has an X-ray powder diffraction pattern with a 2θ value of 8.1°±0.2°, There are characteristic peaks at 16.1 ° ± 0.2 °, 24.8 ° ± 0.2 °.
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。Further, the hydrobromide salt form C provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2θ values of 10.4°±0.2°, 20.3°±0.2°, and 23.3°±0.2°.
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。Further, the hydrobromide salt form C provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2θ values of 13.3°±0.2°, 14.7°±0.2°, and 16.2°±0.2°.
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。In a preferred embodiment, the hydrobromide salt form C provided by the present invention has an X-ray powder diffraction pattern with a 2θ 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°.
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。In a more specific embodiment, the hydrobromide salt form C provided by the present invention has an X-ray powder diffraction pattern substantially as shown in FIG.
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。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.
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。In the above production method, the alcohol solvent is preferably methanol, and the ester solvent is preferably ethyl acetate.
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。In a fourth aspect, 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.
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。The hydrobromide salt form D provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2θ values of 20.0°±0.2°, 22.8°±0.2°, and 24.5°±0.2°.
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。Further, the hydrobromide salt form D provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2θ values of 21.8°±0.2°, 26.7°±0.2°, and 7.8°±0.2°.
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。Further, the hydrobromide salt form D provided by the present invention has an X-ray powder diffraction pattern having a characteristic peak at a 2θ value of 11.7°±0.2° and 12.6°±0.2°.
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。In a preferred embodiment, the hydrobromide salt form D provided by the present invention has an X-ray powder diffraction pattern with 2θ 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°.
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。In a more specific embodiment, the hydrobromide salt form D provided by the present invention has an X-ray powder diffraction pattern substantially as shown in FIG.
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。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.
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。In the above preparation method, the reaction molar ratio of the compound of the formula (I) to hydrobromic acid is 1:1 to 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。In a fifth aspect, 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.
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。The hydrobromide salt form E provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2θ values of 7.2 ° ± 0.2 °, 12.2 ° ± 0.2 °, and 21.7 ° ± 0.2 °.
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。Further, the hydrobromide salt form E provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2θ values of 14.5°±0.2°, 23.1°±0.2°, and 27.5°±0.2°.
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。Further, the hydrobromide salt form E provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2θ values of 13.9°±0.2°, 19.3°±0.2°, and 25.6°±0.2°.
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。In a preferred embodiment, the hydrobromide salt form E provided by the present invention has an X-ray powder diffraction pattern with a 2θ 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°.
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。In a more specific embodiment, the hydrobromide salt form E provided by the present invention has an X-ray powder diffraction pattern substantially as shown in FIG.
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。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.
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。In the above preparation method, the reaction molar ratio of the compound of the formula (I) to hydrobromic acid is 1:1 to 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。 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.
Figure PCTCN2015098901-appb-000003
Figure PCTCN2015098901-appb-000003
一方面，本发明提供了式(Ⅰ)化合物的磷酸盐。In one aspect, the invention provides a phosphate of a compound of formula (I).
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。On the other hand, in a preferred aspect, 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.
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。The phosphate crystal form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2θ values of 7.9 ° ± 0.2 °, 22.4 ° ± 0.2 °, and 25.6 ° ± 0.2 °.
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。Further, the phosphate crystal form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2θ values of 12.7°±0.2°, 15.4°±0.2°, and 21.3°±0.2°.
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。Further, the phosphate crystal form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2θ values of 18.3°±0.2°, 20.8°±0.2°, and 21.7°±0.2°.
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。In a preferred embodiment, the present invention provides a phosphate crystal form A having an X-ray powder diffraction pattern having a 2θ 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°.
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。In a more specific embodiment, the phosphate crystal form A provided by the present invention has an X-ray powder diffraction pattern substantially as shown in FIG.
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。In another more specific embodiment, 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.
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。In another more specific embodiment, 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.
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。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.
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。In the above production method, the ketone solvent is preferably acetone, and the ether solvent is preferably tetrahydrofuran.
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。 Further, the reaction molar ratio of the compound of the formula (I) to phosphoric acid is 1:0.8 to 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。A third object of the present invention is to provide 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.
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。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.
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：The above various crystalline forms of the hydrobromide salt of the compound of the formula (I) provided by the present invention, that is, the hydrobromide crystal forms A, B, C, D, E have the following advantages:
(1)具有较好的稳定性，适合长期储存；(1) It has good stability and is suitable for long-term storage;
(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；(2) a significant increase in solubility compared to the known hydrobromide crystal form disclosed in WO2013138502;
(3)制备工艺简单，易于工业化生产。(3) The preparation process is simple and easy to industrialize.
本发明提供的式(I)化合物的磷酸盐晶型A具有如下优点：The phosphate crystal form A of the compound of formula (I) provided by the present invention has the following advantages:
(1)本发明的磷酸盐晶型A具有良好的稳定性；(1) The phosphate crystal form A of the present invention has good stability;
(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；(2) It has low moisture absorbing property, no special drying conditions are needed in the preparation process, simplifies the preparation and post-treatment process of the drug, and is easy for industrial production;
(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。(3) Compared with the known hydrobromide salt form I disclosed in the patent WO2013138502, 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.
附图说明DRAWINGS
图1为式(Ⅰ)化合物氢溴酸盐晶型A的XRPD图。BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an XRPD pattern of the hydrobromide salt form A of the compound of formula (I).
图2为式(Ⅰ)化合物氢溴酸盐晶型B的XRPD图。Figure 2 is an XRPD pattern of the hydrobromide salt form B of the compound of formula (I).
图3为式(Ⅰ)化合物氢溴酸盐晶型B的DSC图。Figure 3 is a DSC chart of the hydrobromide salt form B of the compound of formula (I).
图4为式(Ⅰ)化合物氢溴酸盐晶型C的XRPD图。Figure 4 is an XRPD pattern of the hydrobromide salt form C of the compound of formula (I).
图5为式(Ⅰ)化合物氢溴酸盐晶型D的XRPD图。Figure 5 is an XRPD pattern of the hydrobromide salt form D of the compound of formula (I).
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。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.
图7为式(Ⅰ)化合物氢溴酸盐晶型E的XRPD图。 Figure 7 is an XRPD pattern of the hydrobromide salt form E of the compound of formula (I).
图8为式(Ⅰ)化合物磷酸盐晶型A的XRPD图。Figure 8 is an XRPD pattern of the crystalline form A of the compound of formula (I).
图9为式(Ⅰ)化合物磷酸盐晶型A的DSC图。Figure 9 is a DSC chart of the crystalline form A of the compound of formula (I).
图10为式(Ⅰ)化合物磷酸盐晶型A的TGA图。Figure 10 is a TGA diagram of the crystalline form A of the compound of formula (I).
图11为式(Ⅰ)化合物磷酸盐晶型A的1H NMR图。Figure 11 is a 1 H NMR chart of the crystalline form A of the compound of the formula (I).
图12为式(Ⅰ)化合物磷酸盐晶型A的DVS图。Figure 12 is a DVS diagram of the crystalline form A of the compound of formula (I).
图13为WO2013138502氢溴酸盐形式I的DVS图。Figure 13 is a DVS diagram of WO2013138502 hydrobromide salt form I.
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。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.
具体实施方式detailed description
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。The invention is further illustrated by the following examples, but is not intended to limit the scope of the invention. Improvements in the method of preparation and use of the apparatus may be made by those skilled in the art within the scope of the claims, and such modifications are also considered to be within the scope of the invention. Therefore, the scope of the invention should be determined by the appended claims.
本发明中所用到的缩写的解释如下：The abbreviations used in the present invention are explained as follows:
XRPD：X射线粉末衍射XRPD: X-ray powder diffraction
DSC：差示扫描量热分析DSC: Differential Scanning Calorimetry
TGA：热重分析TGA: Thermogravimetric analysis
DVS：动态水分吸附DVS: Dynamic moisture adsorption
1H NMR：核磁共振氢谱 1 H NMR: Nuclear Magnetic Resonance Spectroscopy
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：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:
X射线反射参数：Cu,Kα辐射X-ray reflection parameters: Cu, Kα radiation
Figure PCTCN2015098901-appb-000004
1.540598；
Figure PCTCN2015098901-appb-000005
1.544426
Figure PCTCN2015098901-appb-000004
1.540598;
Figure PCTCN2015098901-appb-000005
1.544426
Kα2/Kα1强度比例：0.50Kα2/Kα1 intensity ratio: 0.50
电压：45仟伏特(kV)Voltage: 45 volts (kV)
电流：40毫安培(mA)Current: 40 milliamps (mA)
扫描范围：自3.0至40.0度Scan range: from 3.0 to 40.0 degrees
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：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:
扫描速率：10℃/minScan rate: 10 ° C / min
保护气体：氮气Protective gas: nitrogen
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：The 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:
扫描速率：10℃/minScan rate: 10 ° C / min
保护气体：氮气Protective gas: nitrogen
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：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:
温度：25℃Temperature: 25 ° C
载气，流速：N2，200毫升/分钟Carrier gas, flow rate: N 2 , 200 ml / min
单位时间质量变化：0.002％/分钟Unit time quality change: 0.002% / minute
相对湿度范围：0％RH-95％RHRelative humidity range: 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。The materials used in the present invention are commercially available unless otherwise specified. Here, the hydrobromic acid solution refers to a hydrobromic acid aqueous solution having a mass concentration of 40% obtained by a commercially available method.
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。The hydrobromide salt of the compound of the formula (I) is prepared by the method of Example 7 of the patent WO2013138502.
制备例1Preparation Example 1
式(I)化合物的氢溴酸盐的制备Preparation of hydrobromide salt of compound of formula (I)
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。Referring to Example 7 of the patent WO2013138502, 1051.6 mg of the compound of the formula (I) was added with 5.0 mL of a mixed solvent of acetonitrile:water=5:1 (volume ratio); 250 μL of a 40% hydrobromic acid solution was added dropwise to the above solution. After the addition, 3.0 ml of acetonitrile: water = 5:1 (volume ratio) of the mixed solvent is added, and the reaction is stirred at 5 ° C for 24 hours, and the mixture is vacuum dried. The obtained solid is the hydrobromide salt of the sample of the patent WO2013138502. s solid type.
实施例1Example 1
式(Ⅰ)化合物氢溴酸盐晶型A的制备Preparation of Hydrobromide Salt Form A of Compound of Formula (I)
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。 8.0 mg of the hydrobromide salt of the compound of the formula (I) was added to 0.9 mL of a mixed solvent of methanol and chloroform in a volume ratio of 3:50, stirred at room temperature for 48 hours, and the obtained solid was centrifuged to obtain hydrobromic acid. Crystal form A of the salt.
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。The X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 1. Its XRPD diagram is shown in Figure 1.
表1Table 1
2θ2θ d间隔d interval 强度％strength%
6.706.70 13.1913.19 26.7126.71
8.938.93 9.909.90 100.00100.00
9.229.22 9.599.59 44.4944.49
11.4011.40 7.767.76 42.8642.86
12.9212.92 6.856.85 13.5413.54
13.3013.30 6.666.66 18.8718.87
16.2616.26 5.455.45 6.396.39
17.2417.24 5.155.15 31.1531.15
18.1218.12 4.904.90 39.0339.03
18.5318.53 4.794.79 23.8623.86
20.6520.65 4.304.30 49.8749.87
21.2821.28 4.184.18 27.2027.20
21.7021.70 4.104.10 56.3756.37
22.9722.97 3.873.87 4.794.79
23.7323.73 3.753.75 11.0011.00
24.5224.52 3.633.63 21.4821.48
25.2225.22 3.533.53 49.9349.93
25.6925.69 3.473.47 13.4713.47
26.1126.11 3.413.41 24.3124.31
26.5826.58 3.353.35 9.339.33
26.8926.89 3.323.32 9.509.50
27.3127.31 3.273.27 7.877.87
28.0928.09 3.183.18 10.3410.34
29.3129.31 3.053.05 9.579.57
31.0631.06 2.882.88 14.4614.46
33.1533.15 2.702.70 3.983.98
36.6836.68 2.452.45 5.505.50
实施例2Example 2
式(Ⅰ)化合物氢溴酸盐晶型A的制备Preparation of Hydrobromide Salt Form A of Compound of Formula (I)
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。8.0 mg of the hydrobromide salt of the compound of the formula (I) was added to 0.9 mL of a mixed solvent of methanol and chloroform in a volume ratio of 3:50, stirred at 50 ° C for 48 hours, and the obtained solid was centrifuged to obtain a hydrobromine. Form A of the acid salt.
本实施例得到的晶型的X射线粉末衍射数据如表2所示。The X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 2.
表2Table 2
Figure PCTCN2015098901-appb-000006
Figure PCTCN2015098901-appb-000006
Figure PCTCN2015098901-appb-000007
Figure PCTCN2015098901-appb-000007
实施例3Example 3
式(Ⅰ)化合物氢溴酸盐晶型B的制备Preparation of Hydrobromide Salt Form B of Compound of Formula (I)
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。8.2 mg of the hydrobromide salt of the compound of the formula (I) was added to 0.9 mL of a mixed solvent of methanol and methyl tert-butyl ether in a volume ratio of 3:25, stirred at room temperature for 48 hours, and the obtained solid was centrifuged and tested. It is the crystalline form B of the hydrobromide salt.
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。The X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 3. Its XRPD diagram is shown in Figure 2, and its DSC diagram is shown in Figure 3.
表3table 3
Figure PCTCN2015098901-appb-000008
Figure PCTCN2015098901-appb-000008
Figure PCTCN2015098901-appb-000009
Figure PCTCN2015098901-appb-000009
实施例4Example 4
式(Ⅰ)化合物氢溴酸盐晶型C的制备Preparation of Hydrobromide Salt Form C of Compound of Formula (I)
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。8.0 mg of the hydrobromide salt of the compound of the formula (I) was added to 0.9 mL of a mixed solvent of methanol and ethyl acetate in a volume ratio of 3:25, stirred at room temperature for 48 hours, and the obtained solid was centrifuged to be detected as hydrobromine. Form C of the acid salt.
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。The X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 4. Its XRPD diagram is shown in Figure 4.
表4Table 4
Figure PCTCN2015098901-appb-000010
Figure PCTCN2015098901-appb-000010
Figure PCTCN2015098901-appb-000011
Figure PCTCN2015098901-appb-000011
Figure PCTCN2015098901-appb-000012
Figure PCTCN2015098901-appb-000012
实施例5Example 5
式(Ⅰ)化合物氢溴酸盐晶型D的制备Preparation of Hydrobromide Salt Form D of Compound of Formula (I)
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。10.2 mg of the compound of the formula (I) was added to 0.2 mL of pure water, and 1 equivalent of a 40% hydrobromic acid solution was slowly added thereto, and the mixture was stirred at 5 ° C for 12 hours. The supernatant was removed by centrifugation and dried at room temperature.
本实施例得到的晶型的X射线粉末衍射数据如表5所示。The X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 5.
表5table 5
Figure PCTCN2015098901-appb-000013
Figure PCTCN2015098901-appb-000013
Figure PCTCN2015098901-appb-000014
Figure PCTCN2015098901-appb-000014
实施例6Example 6
式(Ⅰ)化合物氢溴酸盐晶型D的制备Preparation of Hydrobromide Salt Form D of Compound of Formula (I)
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。101.8 mg of the compound of the formula (I) was added to 2 mL of pure water, and 1 equivalent of a 40% hydrobromic acid solution was slowly added thereto, and the mixture was stirred at 5 ° C for 12 hours. The supernatant was removed by centrifugation and dried at room temperature to obtain crystal form D of the hydrobromide salt.
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。The X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 6. Its XRPD diagram is shown in Figure 5.
表6Table 6
Figure PCTCN2015098901-appb-000015
Figure PCTCN2015098901-appb-000015
Figure PCTCN2015098901-appb-000016
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。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.
对比实验1 Comparative experiment 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1) Hydrobromide salt form D and hydrobromide form I and form VIII disclosed in WO2013138495 (simple 称已知形式I、已知形式VIII)的溶解度对比研究：A comparative study of the solubility of known Form I, known Form VIII):
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。 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. 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. The experimental results are shown in Tables 7 and 8.
表7Table 7
Figure PCTCN2015098901-appb-000017
Figure PCTCN2015098901-appb-000017
表8Table 8
Figure PCTCN2015098901-appb-000018
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。As can be seen from Tables 7 and 8, 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.
实施例7Example 7
式(Ⅰ)化合物氢溴酸盐晶型E的制备Preparation of Hydrobromide Salt Form E of Compound of Formula (I)
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。10.2 mg of the compound of the formula (I) was added to 0.2 mL of pure water, and 1 equivalent of a 40% by mass hydrobromic acid solution was slowly added thereto, and the mixture was stirred at 5 ° C for 12 hours, and the solid was collected by centrifugation without drying. Formed as crystal form E of the hydrobromide salt.
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。The X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 9. Its XRPD diagram is shown in Figure 7.
表9Table 9
Figure PCTCN2015098901-appb-000019
Figure PCTCN2015098901-appb-000019
Figure PCTCN2015098901-appb-000020
Figure PCTCN2015098901-appb-000020
实施例8Example 8
式(Ⅰ)化合物磷酸盐的制备Preparation of phosphate of compound of formula (I)
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。10.2 mg of the compound of the formula (I) was dissolved in 0.9 mL of acetone, 0.09 mL of a 0.2 mol/L phosphoric acid solution was added dropwise, and the reaction was stirred at 50 ° C for 24 hours, and obtained by centrifugal drying.
上述方法制备得到的磷酸盐产品，其1H NMR鉴定数据如下：The phosphate product prepared by the above method has the following 1 H NMR identification data as follows:
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). 1 H 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, 8.3 Hz, 2H), 7.26 (t, J = 8.1 Hz, 2H), 6.61 (d, J = 2.0 Hz, 1H), 6.44 (dd, J = 17.0, 10.1 Hz, 1H), 6.26 (dd , J = 17.0, 1.8 Hz, 2H), 5.76 (dd, J = 10.1, 1.9 Hz, 1H), 3.77 (s, 3H), 3.56 (d, J = 4.7 Hz, 4H), 3.03 (d, J = 25.7 Hz, 4H), 2.07 (d, J = 15.7 Hz, 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。Upon examination, 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.
表10Table 10
Figure PCTCN2015098901-appb-000021
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。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.
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。In Fig. 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.
结果表明，本发明的磷酸盐晶型A具有良好的稳定性。The results show that the phosphate crystal form A of the present invention has good stability.
实施例9Example 9
式(Ⅰ)化合物磷酸盐的制备Preparation of phosphate of compound of formula (I)
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。10.2 mg of the compound of the formula (I) was obtained by dissolving the free base in 0.9 mL of tetrahydrofuran, adding 0.09 mL of a 0.2 mol/L phosphoric acid solution dropwise, stirring the reaction at 50 ° C for 24 hours, and drying the solid by centrifugation.
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。Upon examination, the solid obtained in this example was a phosphate crystal form A, and its X-ray powder diffraction data is shown in Table 11.
表11Table 11
Figure PCTCN2015098901-appb-000022
Figure PCTCN2015098901-appb-000022
Figure PCTCN2015098901-appb-000023
Figure PCTCN2015098901-appb-000023
实施例10Example 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Phosphate of the compound of the formula (I) of the present invention and the hydrobromide of the compound of the formula (I) disclosed in the patent WO2013138502 酸盐溶解度对比研究：Acid solubility comparison study:
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。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.
表12Table 12
Figure PCTCN2015098901-appb-000024
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。From the above comparison results, it can be seen that the 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.
实施例11Example 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The phosphate crystal form A of the compound of the formula (I) of the present invention is combined with the formula (I) disclosed in the patent WO2013138502 物氢溴酸盐形式I引湿性对比研究：Comparative study on the hygroscopicity of hydrobromide salt form I:
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。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.
实验结果如表13所示。The experimental results are shown in Table 13.
表13 Table 13
Figure PCTCN2015098901-appb-000025
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。 The results show that the phosphate form A of the present invention has significantly lower wettability at 80% and 95% humidity than the known hydrobromide form I.

Claims (22)

  1. 一种式(Ⅰ)化合物的盐的晶型，a crystalline form of a salt of a compound of formula (I),
    Figure PCTCN2015098901-appb-100001
    Figure PCTCN2015098901-appb-100001
    其特征在于，所述盐为氢溴酸盐或磷酸盐。Characterized in that the salt is a hydrobromide or a phosphate.
  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。A crystalline form of a salt of a compound of formula (I) according to claim 1 wherein said crystalline form is a hydrobromide salt form A of a compound of formula (I) having an X-ray powder diffraction pattern at a 2theta value There are characteristic peaks at 8.9 ° ± 0.2 °, 20.7 ° ± 0.2 °, 18.1 ° ± 0.2 °, 11.4 ° ± 0.2 °, 18.5 ° ± 0.2 °, 25.2 ° ± 0.2 °.
  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。A crystalline form of a salt of a compound of formula (I) according to claim 2, characterized in that the X-ray powder diffraction pattern of the hydrobromide salt form A of the compound of formula (I) is also 2theta value of 24.5° There are characteristic peaks at ±0.2°, 26.1°±0.2°, and 31.1°±0.2°.
  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。A crystalline form of a salt of a compound of formula (I) according to claim 1 wherein the crystalline form is a hydrobromide salt form B of a compound of formula (I) having an X-ray powder diffraction pattern at a 2theta value It has characteristic peaks at 8.2 ° ± 0.2 °, 15.9 ° ± 0.2 °, 22.2 ° ± 0.2 °, 10.1 ° ± 0.2 °, 18.2 ° ± 0.2 °, 23.1 ° ± 0.2 °.
  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。A crystalline form of a salt of a compound of formula (I) according to claim 4, characterized in that the X-ray powder diffraction pattern of the hydrobromide salt form B of the compound of formula (I) is also 2theta value of 21.2° There are characteristic peaks at ±0.2°, 24.7°±0.2°, and 27.3°±0.2°.
  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。A crystalline form of a salt of a compound of formula (I) according to claim 1 wherein said crystalline form is a hydrobromide salt form C of a compound of formula (I) having an X-ray powder diffraction pattern at a 2theta value It has characteristic peaks at 8.1 ° ± 0.2 °, 16.1 ° ± 0.2 °, 24.8 ° ± 0.2 °, 10.4 ° ± 0.2 °, 20.3 ° ± 0.2 °, and 23.3 ° ± 0.2 °.
  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。A crystalline form of a salt of a compound of formula (I) according to claim 6, characterized in that the X-ray powder diffraction pattern of the hydrobromide salt form C of the compound of formula (I) is also at a 2theta value of 13.3°. There are characteristic peaks at ±0.2°, 14.7°±0.2°, and 16.2°±0.2°.
  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。A crystalline form of a salt of a compound of formula (I) according to claim 1 wherein said crystalline form is The hydrobromide salt form D of the compound of formula (I) has an X-ray powder diffraction pattern at 2theta values of 20.0 ° ± 0.2 °, 22.8 ° ± 0.2 °, 24.5 ° ± 0.2 °, 21.8 ° ± 0.2 °, 26.7 ° There are characteristic peaks at ±0.2° and 7.8°±0.2°.
  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。A crystalline form of a salt of a compound of formula (I) according to claim 8, characterized in that the X-ray powder diffraction pattern of the hydrobromide salt form D of the compound of formula (I) is also at a 2theta value of 11.7°. ±0.2°, 12.6°±0.2°. There are characteristic peaks.
  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。A crystalline form of a salt of a compound of formula (I) according to claim 1 wherein the crystalline form is a hydrobromide salt form E of a compound of formula (I) having an X-ray powder diffraction pattern at 2theta There are characteristic peaks at 7.2 ° ± 0.2 °, 12.2 ° ± 0.2 °, 21.7 ° ± 0.2 °, 14.5 ° ± 0.2 °, 23.1 ° ± 0.2 °, 27.5 ° ± 0.2 °.
  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。A crystalline form of a salt of a compound of formula (I) according to claim 10, characterized in that the X-ray powder diffraction pattern of the hydrobromide salt form E of the compound of formula (I) is also 2theta value of 13.9 ° There are characteristic peaks at ±0.2°, 19.3°±0.2°, and 25.6°±0.2°.
  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。A crystalline form of a salt of a compound of formula (I) according to claim 1 wherein the crystalline form is a phosphate crystal form A of a compound of formula (I) having an X-ray powder diffraction pattern at a 2theta value of 7.9. Characteristic peaks are found at °±0.2°, 22.4°±0.2°, and 25.6°±0.2°.
  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。A crystalline form of a salt of a compound of formula (I) according to claim 12, characterized in that the X-ray powder diffraction pattern of the phosphate crystal form A of the compound of formula (I) is also 2theta value of 12.7 ° ± 0.2 Characteristic peaks at °, 15.4 ° ± 0.2 °, 21.3 ° ± 0.2 °.
  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。A crystalline form of a salt of a compound of formula (I) according to claim 13, characterized in that the X-ray powder diffraction pattern of the phosphate crystal form A of the compound of formula (I) is also at a 2theta value of 18.3 ° ± 0.2 Characteristic peaks at °, 20.8 ° ± 0.2 °, 21.7 ° ± 0.2 °.
  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。A process for the preparation of a hydrobromide salt form A of a compound of formula (I) according to any one of claims 2-3, which comprises hydrobromide salt of a compound of formula (I) in an alcohol The mixture is stirred and crystallized in a mixed solvent of a halogenated hydrocarbon to obtain a solid; the alcohol solvent is methanol, and the halogenated hydrocarbon solvent is chloroform.
  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。A process for the preparation of a hydrobromide salt form B of a compound of formula (I) according to any one of claims 4 to 5, which comprises hydrobromide salt of a compound of formula (I) in an alcohol The mixture is stirred and crystallized in a mixed solvent of an ether to obtain a solid; the alcohol solvent is methanol, and the ether solvent is methyl tert-butyl ether.
  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。A process for the preparation of a hydrobromide salt form C of a compound of formula (I) according to any one of claims 6 to 7, which comprises hydrobromide salt of a compound of formula (I) in an alcohol The mixture is stirred and crystallized in a mixed solvent of an ester to obtain a solid; the alcohol solvent is methanol, and the ester solvent is ethyl acetate.
  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。A process for the preparation of a hydrobromide salt form D of a compound of formula (I) according to any one of claims 8-9, The method comprises the steps of: crystallization of a compound of the formula (I) and a hydrobromic acid solution in a molar ratio of a certain molar ratio in a pure water, collecting and drying the solid; wherein the compound of the formula (I) and the hydrobromide are obtained. The molar ratio of acid is 1:1 to 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。A process for the preparation of a hydrobromide salt form E of a compound of formula (I) according to any one of claims 10-11, characterized in that it comprises a solution of a compound of formula (I) and a hydrobromic acid solution in a molar amount The ratio of the ratio is crystallized by stirring at a low temperature in pure water to obtain a solid; wherein the molar ratio of the compound of the formula (I) to hydrobromic acid is 1:1 to 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。A process for the preparation of a phosphate form A of a compound of the formula (I) according to any one of claims 12 to 14, characterized in that it comprises reacting a compound of the formula (I) with phosphoric acid in a ketone or ether solvent The reaction is stirred and crystallized; the ketone solvent is acetone, and the ether solvent is tetrahydrofuran; and the molar ratio of the compound of the formula (I) to phosphoric acid is 1:0.8 to 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。A pharmaceutical composition comprising a crystalline form of a salt of a compound of formula (I) according to any one of claims 1-14 and a pharmaceutically acceptable carrier.
  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。 Use of a crystalline form of a salt of a compound of formula (I) according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 21 for the manufacture of a medicament for the treatment of cancer.
PCT/CN2015/098901 2014-12-25 2015-12-25 Crystal form of salt of epidermal growth factor receptor kinase inhibitor and preparation method thereof WO2016101912A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201410821405.1 2014-12-25
CN201410821405.1A CN104961688A (en) 2014-12-25 2014-12-25 Phosphate of epidermal growth factor receptor kinase inhibitor and preparation method thereof
CN201510019173.2 2015-01-14
CN201510019173.2A CN105837518A (en) 2015-01-14 2015-01-14 Epidermal growth factor receptor inhibitor hydrobromide novel crystal form and preparation method thereof

Publications (1)

Publication Number Publication Date
WO2016101912A1 true WO2016101912A1 (en) 2016-06-30

Family

ID=56149292

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/098901 WO2016101912A1 (en) 2014-12-25 2015-12-25 Crystal form of salt of epidermal growth factor receptor kinase inhibitor and preparation method thereof

Country Status (1)

Country Link
WO (1) WO2016101912A1 (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013138495A1 (en) * 2012-03-15 2013-09-19 Celgene Avilomics Research, Inc. Solid forms of an epidermal growth factor receptor kinase inhibitor
WO2013138502A1 (en) * 2012-03-15 2013-09-19 Celgene Avilomics Research, Inc. Salts of an epidermal growth factor receptor kinase inhibitor

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013138495A1 (en) * 2012-03-15 2013-09-19 Celgene Avilomics Research, Inc. Solid forms of an epidermal growth factor receptor kinase inhibitor
WO2013138502A1 (en) * 2012-03-15 2013-09-19 Celgene Avilomics Research, Inc. Salts of an epidermal growth factor receptor kinase inhibitor

Similar Documents

Publication Publication Date Title
WO2016124137A1 (en) Phosphate of epidermal growth factor receptor inhibitor, crystalline form of phosphate, and preparation method
JP5261487B2 (en) Crystal forms of dihydropteridinone derivatives
CN101970425B (en) Crystalline forms and two solvated forms of 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1h-benzimidazol-2-yl]quinolin-2(1h)-one lactic acid salts
JP2017206516A (en) Novel polymorphic form of pridopidine hydrochloride
WO2016165650A1 (en) Co-crystal of olaparib and urea and preparation method therefor
WO2016091221A1 (en) Salt of pyrrolo[2,3-d]pyrimidine compound and novel polymorph of salt
CN113527203A (en) Novel crystal form of lenvatinib mesylate and preparation method and application thereof
AU2015330554B2 (en) Crystal form of bisulfate of JAK inhibitor and preparation method therefor
US10208065B2 (en) Crystalline free bases of C-Met inhibitor or crystalline acid salts thereof, and preparation methods and uses thereof
JP2018501289A (en) Novel crystal form of neratinib maleate and process for producing the same
WO2017107972A1 (en) Novel crystalline form of selective s1p1 receptor agonist and method for preparing same
CN104470920A (en) Solid state form of vemurafenib choline salt
WO2016090257A1 (en) Salts and crystalline forms of 6-acetyl-8-cyclopentyl-5-methyl-2((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d] pyrimidin-7(8h)-one (palbociclib)
CN113840604A (en) Crystalline forms of a JAK2 inhibitor
KR20230048089A (en) solid form of the compound
WO2016155670A1 (en) Cdk inhibitor, eutectic crystal of mek inhibitor, and preparation method therefor
WO2016078587A1 (en) Lu ae58054 hydrochloride crystalline form a, and preparation method and application thereof
WO2019134455A1 (en) Novel crystal form of acalabrutinib and preparation method and use thereof
AU2011324253A1 (en) Hydrate of 1-{(2S)-2-amino-4-[2,4-bis(trifluoromethyl)-5,8-di- hydropyrido(3,4-d]pyrimidin-7(6H)-yl]-4-oxobutyl}-5,5-difluoro-piperidin-2-one tartrate
WO2016101912A1 (en) Crystal form of salt of epidermal growth factor receptor kinase inhibitor and preparation method thereof
WO2022072470A1 (en) Crystalline form of tegavivint, method of preparation, and use thereof
WO2017028802A1 (en) Crystal form of 5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine dihydrochloride and preparation method thereof
TW201811326A (en) Salt forms of 4-cyano-N-(2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)pyridin-3-yl)-1H-imidazole-2-carboxamide
CN106065016A (en) A kind of crystal form of cyclin dependent kinase inhibitor and preparation method thereof
WO2017152858A1 (en) Crystal form of ceritinib and preparation method thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15871980

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15871980

Country of ref document: EP

Kind code of ref document: A1