CN110229143A - Salt, polymorph and its pharmaceutical composition, the preparation method and application of a kind of pyrimidine compound - Google Patents

Salt, polymorph and its pharmaceutical composition, the preparation method and application of a kind of pyrimidine compound Download PDF

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CN110229143A
CN110229143A CN201910544016.1A CN201910544016A CN110229143A CN 110229143 A CN110229143 A CN 110229143A CN 201910544016 A CN201910544016 A CN 201910544016A CN 110229143 A CN110229143 A CN 110229143A
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compound
crystal form
angle angle
ray powder
powder diffraction
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代星
江岳恒
刘艳琴
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Yi Fang Biotechnology (shanghai) Co Ltd
Zhejiang Beta Pharma Inc
Betta Pharmaceuticals Co Ltd
Inventisbio Co Ltd China
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Yi Fang Biotechnology (shanghai) Co Ltd
Zhejiang Beta Pharma Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to the salt of compound 1, and its polymorph, and the pharmaceutical composition comprising them, wherein, the salt is preferably hydrobromate, succinate, maleate, fumarate, phosphate, mesylate, Pfansteihl salt, oxalates, malate, benzene sulfonate, hydrochloride, tosilate, sulfate etc..Pharmaceutical preparation the invention further relates to the method for preparing above-mentioned substance, their purposes and comprising these salt and crystal form.

Description

Salt, polymorph and its pharmaceutical composition of a kind of pyrimidine compound, preparation method and Using
Technical field
The present invention relates to a kind of salt of pyrimidine compound and polymorphs, and comprising their pharmaceutical composition, are used for Prepare various salt and polymorphous method and its purposes in preparation pharmaceutical composition.
Background of invention
EGF-R ELISA (EGFR) is a kind of receptor tyrosine protein kinase, belongs to one in erbB receptor family Kind transmembrane protein.
EGFR has regulated and controled the proliferation of cell, survival, adhesion, migration and differentiation, its overactivity in kinds of tumor cells Or continuous activation, such as lung cancer, breast cancer, in the cells such as prostate cancer.Conversion and growth of the abnormal activation of EGFR in tumour In play critical effect.Block EGFR activation be clinically proven for effective targeting therapy on tumor cellular processes it One.EGFR has expression in 50% NSCLC (non-compactness cell lung cancer) case.This becomes EGFR and its family member The leading candidate of targeted therapy.Gefitinib (gefitinib) and Tarceva (erlotinib) are that the first generation of EGFR is small Molecule inhibitor is mainly used for treating the drug of advanced NSCLC.Clinical effectiveness shows Gefitinib or Tarceva to about The asian ancestry NSCLC patient of 10% white man NSCLC and about 35% is effective in cure.Analysis shows majority has EGFR Activating mutations NSCLC patient is significantly higher than the NSCLC patient of EGFR wild type to the reactivity of EGFR- tyrosine kinase inhibitor (TKI).
But clinical research show many patients quickly (12-14 month) just to the micromolecular inhibitor drug of these EGFR Produce drug resistance, i.e. acquired resistance.Residue (gatekeeper residue) T790M that guards the gate mutation is aobvious outside EGFR20 A catastrophe point in son, is to cause one of drug resistant main mechanism.For the inhibitor of new generation research of these EGFR mutation Coming in be successful.Afatinib (afatinib) is EGFR and human epidermal growth factor receptor 2 (HER2) junket Potent, the irreversible double inhibitor of histidine kinase.Other similar multiple target points, high activity, irreversible inhibitor, example Such as, Canertinib (canertinib) replaces Buddhist nun (dacomitinib) also just in later phase clinical test up to gram.These are novel The irreversible inhibitor of the second generation has very strong inhibiting effect to the EGFR that L858R and T790M is mutated, to Gefitinib or strategic point There is significant curative effect in Lip river for the cancer patient that Buddhist nun has developed drug resistance.But these second generations EGFR mutant inhibitor pair Wild type EGFR (WT-EGFR) similarly has extremely strong inhibition.The verified inhibition to Wild type EGFR of clinical research It will lead to drug toxicity and side effect with most of patient, for example show as fash or diarrhea in human body.
Overcome the Side effect of second generation EGFR inhibitor, must just reduce to Wild type EGFR (WT-EGFR) Inhibiting effect.The EGFR inhibitor of a new generation should keep prominent to EGFR L858R activated mutant body, Exon19 missing activation Variant and T790M resistant mutants have stronger inhibition, while showing phase to WT-EGFR and other receptor tyrosine kinases To lower inhibiting effect.Such compound, which can be used for treating, EGFR L858R activated mutant body, Exon19 missing activation The treatment of the cancer patient of mutant, and to first generation EGFR inhibitor such as Gefitinib, Tarceva or Conmana The treatment of cancer patient through the EGFR-T790M resistant mutants that develop drug resistance, and do not have to worry the suppression of second generation EGFR mutant Preparation side effect as brought by Afatinib.
Chinese patent application CN105085489A is related to a kind of pyrimidine or pyridine compounds and its pharmaceutically acceptable Salt, stereoisomer, prodrug and solvate, preparation method, pharmaceutical composition and medical usage.This application is shown perhaps Multipair EGFR mutant (it is one or more as EGFR L858R activated mutant bodies, Exon19 missing activated mutant body and/or T790M resistant mutants) there is high inhibitory activity, but there was only the pyrimidine or pyridine of relatively low inhibition to Wild type EGFR Compound.
Compound described in CN105085489A, compound 1 (referring to CN105085489A embodiment 40) as follows, has Preferable bioactivity and safe toxicity parameter.Such compound is prominent in the drug resistance for having EGFR activated mutant body and/or EGFR Preferable effect is had in the treatment of cancer of change.CN105085489A describes the synthesis of compound 1 and its mesylate.In order to The physicochemical properties of compound 1, such as stability, hygroscopicity are further increased, solubility, etc. can be conducive to its production, system It is standby, synthesis and/or pharmaceutical applications property, the present inventor to the new salt form and its polymorphic of compound 1 done deeper into grind Study carefully.
Summary of the invention
An object of the present invention is to provide a kind of salt form of pyrimidine compound 1, preferably its hydrobromate, succinic acid Salt, maleate, fumarate, phosphate, mesylate, Pfansteihl salt, oxalates, malate, benzene sulfonate, hydrochloric acid Salt, tosilate or sulfate, for example, salt form prepared by embodiment 1-13 and/or its crystal form.
Compound 1 described herein refers to the following compound of structure:
" salt " described herein, including pharmaceutically acceptable salt and the unacceptable salt of pharmacy.Not preferably to patient Using the unacceptable salt of pharmacy, but the salt can be used for providing pharmaceutical intermediate and bulk drug form.
As described herein, some salt form of compound 1 such as, hydrobromate, succinate, maleate, fumarate, Phosphate, mesylate, Pfansteihl salt, oxalates, malate, benzene sulfonate, hydrochloride, tosilate or sulfuric acid Salt improves the water solubility of compound 1, and some polymorphics (especially fourth two of these salt form to varying degrees Hydrochlorate crystal form I, maleate crystal form I, fumarate crystal form I, malate crystal form I and Pfansteihl salt crystal form I) etc.) have height Stability, the features such as low wettability are conducive to the production and preparation of compound 1, significant to its final marketization.
In some embodiments, the present invention provides a kind of succinate of compound 1, the preferably fourth two of compound 1 The crystal form I of hydrochlorate.Herein, the crystal form I of the succinate of compound 1 refers to the crystalline substance with following one or more features Type: 1) its X-ray powder diffraction collection is at least at one that 2 θ angles are 10.82,21.66,22.39 and 26.76, ± 0.2 ° Or 4) (1,2,3 or there are diffraction maximum in many places；2) its DSC map is to have heat absorption peak at 177.91 DEG C ± 5 DEG C in initial temperature, In the crystal form I of the succinate of compound 1, the molar ratio of compound 1 and succinic acid is about 1:1.In some embodiments, The X-ray powder diffraction collection of the crystal form I of the succinate of compound 1 has 6 or more (such as 10,16 or 20) X-ray diffraction peak as in the table below:
Angle Angle Angle Angle Angle Angle Angle Angle
2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ°
6.9 15.355 18.494 21.66 24.278 28.452 31.715 36.143
8.173 15.743 19.681 22.011 24.604 28.871 32.12 37.785
8.648 16.171 19.918 22.391 25.026 29.377 32.602 38.924
10.821 16.669 20.278 22.776 25.46 29.95 34.576 39.643
11.811 17.083 20.568 23.652 26.185 30.777 35.35
13.842 17.536 21.031 24.074 26.758 31.199 35.835
It is highly preferred that it is 10.82,17.54,21.66,22.39 Hes that its X-ray powder diffraction collection, which has 2 θ angles, For simplicity, when describing 2 θ angle, symbol " ° " can omit 26.76, ± 0.2 ° of diffraction maximum herein sometimes.
In some embodiments, the X-ray powder diffraction pattern of the succinate crystal form I of compound 1 has in Fig. 7 Main peaks, i.e., have a peak at angle ± 0.2 ° corresponding 2 θ, but intensity can with it is different shown in Fig. 7.X-ray powder diffraction figure Spectrum main peaks in this article refer in an X-ray powder diffraction pattern that relative intensity is at 20% or more peak, for example, relatively Intensity 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or more, or 100% peak, preferably 30% or more, more preferably 50% or more.
In some embodiments, the X-ray powder diffraction pattern of the succinate crystal form I of compound 1 and Fig. 7 basic one It causes.The almost the same 2 θ angle bases in experimental error for referring to the diffraction maximum in two maps of X-ray powder diffraction pattern This is consistent, but intensity can be different.Preferably, the DSC map of the salt is also almost the same with Fig. 8.DSC map is almost the same Refer to the heat absorption peak in two maps, such as its initial temperature, it is almost the same in experimental error.
In some embodiments, the present invention provides a kind of succinate crystal form I of the compound 1 of high-purity, for example, In some embodiments, compound 1 is main in the high purity substance (for example, about 80wt%, about 90wt%, about 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of it is to succinate crystal form I.
The succinate crystal form I of compound 1 can usually be obtained with following methods: by compound 1 and succinic acid by about The molar ratio of 1:1 mixes in appropriate solvent, and then the succinate crystal form I of compound 1 is precipitated.In some embodiments In, the molar ratio of compound 1 and succinic acid can be slightly less than 1:1 (excessive acid), for example, about 1:1.1；About 1:1.15；Greatly About 1:1.2.Selecting for solvent can be one or more organic solvents, for example, methanol, ethyl alcohol, ethyl acetate.In some implementations In scheme, salt-forming reaction and crystallization can carry out under stirring at room temperature.Embodiment 2 has described in detail one and has typically prepared chemical combination The method of the succinate crystal form I of object 1.
The succinate crystal form I of compound 1 usually can form one with pharmaceutically acceptable carrier or diluent together Kind pharmaceutical composition.Preferably, compound 1 is main in the pharmaceutical composition (for example, about 80wt%, about 90wt%, greatly About 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its succinate crystal form I. Sometimes, compound 1 is the sole active agent in the pharmaceutical composition.Sometimes, treatment or prevention are contained in the pharmaceutical composition A effective amount of compound 1, such as to non-small cell lung cancer or other EGFR described herein obstacle mediated or disease.
In some embodiments, the present invention provides a kind of maleate of compound 1, the preferably Malaysia of compound 1 Hydrochlorate crystal form I.Herein, the maleate crystal form I of compound 1 refers to the crystal form with following one or more features: 1) Its X-ray powder diffraction collection at least 2 θ angles be 6.50 °, 13.11 °, ± 0.2 ° 1 at or 2 at have diffraction maximum；2) its DSC map is to have heat absorption peak in the maleate crystal form I of compound 1 at 166.84 DEG C ± 5 DEG C in initial temperature, chemical combination The molar ratio of object 1 and maleic acid is about 1:1.In some embodiments, the X-ray of the maleate crystal form I of compound 1 The X-ray diffraction peak that powder diffraction spectrum has 6 or more (such as 10,16 or 20) as in the table below:
Angle Angle Angle Angle Angle Angle Angle Angle
2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ°
6.132 13.113 16.252 19.126 22.344 25.814 30.281 35.919
6.501 13.746 16.815 19.902 22.961 26.572 31.784 38.842
8.455 14.304 17.724 20.654 23.313 26.985 32.866
9.499 15.025 18.178 21.314 23.903 28.558 33.59
11.802 15.473 18.495 21.945 25.184 28.832 33.858
In some preferred embodiments, the X-ray powder diffraction collection of the maleate crystal form I of compound 1 has 2 θ The diffraction maximum that angle is 6.50,13.11,15.05 and 25.18 ± 0.2.
In some embodiments, the X-ray powder diffraction collection of the maleate crystal form I of compound 1 has in Figure 12 Main peaks, i.e., have peak at angle ± 0.2 ° corresponding 2 θ, but intensity can with it is different shown in Figure 12, for example, relatively strong Degree at 20% or more peak, for example, relative intensity 30% or more, 40% or more, 50% or more, 60% or with On, 80% or more, 90% or more or 100% peak, preferably 30% or more, more preferably 50% or more.
In some embodiments, the X-ray powder diffraction pattern of the maleate crystal form I of compound 1 and Figure 12 are basic Unanimously.Preferably, the DSC map of the crystal form is also almost the same with Figure 13.
In some embodiments, the present invention provides a kind of maleate crystal form I of the compound 1 of high-purity, for example, In some embodiments, compound 1 is main in the high purity substance (for example, about 80wt%, about 90wt%, about 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its maleate crystal form I.
The maleate crystal form I of compound 1 can usually be obtained with following methods: by compound 1 and maleic acid by about The molar ratio of 1:1 mixes in appropriate solvent, then crystallizes the maleate crystal form I of compound 1 and is precipitated.In some embodiment party In case, the molar ratio of compound 1 and maleic acid can be slightly less than 1:1 (excessive acid), for example, about 1:1.1；About 1:1.15； About 1:1.2.Selecting for solvent can be one or more organic solvents, for example, isopropanol.In some embodiments, at Reactant salt and crystallization can carry out under stirring at room temperature.In some embodiments, salt-forming reaction and crystallization solvent for use can be with It is different.Embodiment 3 has described in detail the maleate crystal form I method of a typical prepare compound 1.
The maleate crystal form I of compound 1 usually can form one with pharmaceutically acceptable carrier or diluent together Kind pharmaceutical composition.Preferably, compound 1 is main in the pharmaceutical composition (for example, about 80wt%, about 90wt%, greatly About 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its maleate crystal form I. Sometimes, compound 1 is the sole active agent in the pharmaceutical composition.Sometimes, treatment or prevention are contained in the pharmaceutical composition A effective amount of compound 1, such as to non-small cell lung cancer or other EGFR described herein obstacle mediated or disease.
In some embodiments, the present invention provides a kind of fumarate of compound 1, the preferably rich horse of compound 1 Hydrochlorate crystal form I.Herein, the fumarate crystal form I of compound 1 refers to the crystal form with following one or more features: 1) Its X-ray powder diffraction collection at least 2 θ angles be 5.71 °, 16.97 °, 22.02 °, ± 0.2 ° 1 at or many places (1,2, Or 3, at preferably 3) there is diffraction maximum；2) its DSC map is to have heat absorption peak in chemical combination at 233.34 DEG C ± 5 DEG C in initial temperature In the fumarate crystal form I of object 1, the molar ratio of compound 1 and fumaric acid is about 1:1.In some embodiments, compound The X-ray powder diffraction collection of 1 fumarate crystal form I is with 6 or more (such as 10,16 or 20) such as following table institute The X-ray diffraction peak stated:
Angle Angle Angle Angle Angle Angle Angle Angle Angle Angle
2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ°
5.705 12.835 16.968 19.426 21.809 24.252 27.519 30.314 34.815 37.761
10.024 14.057 17.279 19.798 22.021 24.574 28.436 30.587 35.433 39.841
10.307 15.017 17.79 20.241 22.766 25.233 28.97 31.043 36.043
11.465 15.431 18.264 20.676 23.139 25.739 29.35 31.879 36.39
11.951 16.529 19.159 21.473 23.501 27.04 29.946 32.959 37.035
In some preferred embodiments, the X-ray powder diffraction collection of the fumarate crystal form I of compound 1 has 2 θ The diffraction maximum that angle is 5.71,16.97,19.16,22.02,25.23 and 27.04, ± 0.2 °.
In some embodiments, the X-ray powder diffraction collection of the fumarate crystal form I of compound 1 has in Figure 17 Main peaks, i.e., have peak at angle ± 0.2 ° corresponding 2 θ, but intensity can with it is different shown in Figure 17, for example, relatively strong Degree at 20% or more peak, for example, relative intensity 30% or more, 40% or more, 50% or more, 60% or with On, 80% or more, 90% or more or 100% peak, preferably 30% or more, more preferably 50% or more.
In some embodiments, the X-ray powder diffraction pattern of the fumarate crystal form I of compound 1 and Figure 17 are basic Unanimously.Preferably, the DSC map of the crystal form is also almost the same with Figure 18.
In some embodiments, the present invention provides a kind of fumarate crystal form I of the compound 1 of high-purity, for example, In some embodiments, compound 1 is main in the high purity substance (for example, about 80wt%, about 90wt%, about 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its fumarate crystal form I.
The fumarate crystal form I of compound 1 can usually be obtained with following methods: by compound 1 and fumaric acid by about The molar ratio of 1:1 mixes in appropriate solvent, then crystallizes the fumarate crystal form I of compound 1 and is precipitated.In some embodiment party In case, the molar ratio of compound 1 and fumaric acid can be slightly less than 1:1 (excessive acid), for example, about 1:1.1；About 1:1.15； About 1:1.2.Selecting for solvent can be one or more organic solvents, for example, isopropanol.In some embodiments, at Reactant salt and crystallization can carry out under stirring at room temperature.In some embodiments, salt-forming reaction and crystallization solvent for use can be with It is different.Embodiment 4 has described in detail the fumarate crystal form I method of a typical prepare compound 1.
The fumarate crystal form I of compound 1 usually can form one with pharmaceutically acceptable carrier or diluent together Kind pharmaceutical composition.Preferably, compound 1 is main in the pharmaceutical composition (for example, about 80wt%, about 90wt%, greatly About 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its fumarate crystal form I. Sometimes, compound 1 is the sole active agent in the pharmaceutical composition.Sometimes, treatment or prevention are contained in the pharmaceutical composition A effective amount of compound 1, such as to non-small cell lung cancer or other EGFR described herein obstacle mediated or disease.
In some embodiments, the present invention provides a kind of phosphate of compound 1, the preferably phosphate of compound 1 Crystal form I.
Herein, the phosphate crystal form I of compound 1 refers to the crystal form with following one or more features: 1) its X- Ray powder diffraction is at least to have diffraction maximum at 7.01 ° ± 0.2 ° in 2 θ angles；2) its DSC map is in initial temperature There is heat absorption peak at 149.14 DEG C ± 5 DEG C.In the phosphate crystal form I of compound 1, the molar ratio of compound 1 and phosphoric acid is big About 1:1.In some embodiments, the X-ray powder diffraction collection of the phosphate crystal form I of compound 1 has 6 or more (such as 6,8 or 10) X-ray diffraction peak as in the table below:
Angle Angle Angle Angle Angle Angle Angle Angle
2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ°
6.132 9.236 12.043 14.078 15.103 18.794 21.26 23.247
7.012 11.269 12.776 13.123 16.128 19.733 21.75 23.667
In some preferred embodiments, the X-ray powder diffraction collection of the phosphate crystal form I of compound 1 has 2 angles θ Degree is 7.01 ° and 9.24, ± 0.2 ° of diffraction maximum.
In some embodiments, the X-ray powder diffraction collection of the phosphate crystal form I of compound 1 has in Figure 22 Main peaks, i.e., have a peak at angle ± 0.2 ° corresponding 2 θ, but intensity can with it is different shown in Figure 22, for example, relative intensity At 20% or more peak, for example, relative intensity is 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or more or 100% peak, preferably 30% or more, more preferably 50% or more.
In some embodiments, the X-ray powder diffraction pattern of the phosphate crystal form I of compound 1 and Figure 22 basic one It causes.Preferably, the DSC map of the crystal form is also almost the same with Figure 23.
In some embodiments, the present invention provides a kind of phosphate crystal form I of the compound 1 of high-purity, for example, In some embodiments, compound 1 is main in the high purity substance (for example, about 80wt%, about 90wt%, about 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its phosphate crystal form I.
The phosphate crystal form I of compound 1 can usually be obtained with following methods: by compound 1 and phosphoric acid by about 1:1's Molar ratio mixes in appropriate solvent, then crystallizes the phosphate crystal form I of compound 1 and is precipitated.In some embodiments, change The molar ratio for closing object 1 and phosphoric acid can be slightly less than 1:1 (excessive acid), for example, about 1:1.1；About 1:1.15；About 1:1.2. Selecting for solvent can be one or more organic solvents, for example, methanol.In some embodiments, salt-forming reaction and crystallization It can carry out under stirring at room temperature.In some embodiments, salt-forming reaction and crystallization solvent for use can be different.Embodiment 5 have described in detail the phosphate crystal form I method of a typical prepare compound 1.
The phosphate crystal form I of compound 1 usually can form one kind with pharmaceutically acceptable carrier or diluent together Pharmaceutical composition.Preferably, compound 1 is main in the pharmaceutical composition (for example, about 80wt%, about 90wt%, about 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its phosphate crystal form I.Sometimes, Compound 1 is the sole active agent in the pharmaceutical composition.Sometimes, treatment or prevention effective quantity is contained in the pharmaceutical composition Compound 1, such as to non-small cell lung cancer or other the EGFR described herein obstacle mediated or disease.
In some embodiments, the present invention provides a kind of mesylate of compound 1, the preferably methylsulphur of compound 1 Hydrochlorate crystal form I.Herein, the Mesylate Form I of compound 1 refers to the crystal form with following one or more features: 1) Its X-ray powder diffraction collection at least 2 θ angles be 21.81 ° and 24.23 °, ± 0.2 ° one at or two at have diffraction maximum； 2) its DSC map is to have heat absorption peak at 236.36 DEG C ± 5 DEG C in initial temperature.In the Mesylate Form I of compound 1, The molar ratio of compound 1 and methanesulfonic acid is about 1:1.In some embodiments, the X- of the Mesylate Form I of compound 1 The X-ray diffraction peak that ray powder diffraction has 8 or more (such as 10,16 or 20) as in the table below:
In some preferred embodiments, the X-ray powder diffraction collection of the Mesylate Form I of compound 1 has 2 θ Angle is 15.15,15.80,18.37,21.8 and 24.23 °, ± 0.2 ° of diffraction maximum.
In some embodiments, the X-ray powder diffraction collection of the Mesylate Form I of compound 1 has in Figure 25 Main peaks, i.e., have peak at angle ± 0.2 ° corresponding 2 θ, but intensity can with it is different shown in Figure 25, for example, relatively strong Degree at 20% or more peak, for example, relative intensity 30% or more, 40% or more, 50% or more, 60% or with On, 80% or more, 90% or more or 100% peak, preferably 30% or more, more preferably 50% or more.
In some embodiments, the X-ray powder diffraction pattern of the Mesylate Form I of compound 1 and Figure 25 are basic Unanimously.Preferably, the DSC map of the crystal form is also almost the same with Figure 26.
In some embodiments, the present invention provides a kind of Mesylate Form I of the compound 1 of high-purity, for example, In some embodiments, compound 1 is main in the high purity substance (for example, about 80wt%, about 90wt%, about 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its Mesylate Form I.
The Mesylate Form I of compound 1 can usually be obtained with following methods: by compound 1 and methanesulfonic acid by about The molar ratio of 1:1 mixes in appropriate solvent, then crystallizes the Mesylate Form I of compound 1 and is precipitated.In some embodiment party In case, the molar ratio of compound 1 and methanesulfonic acid can be slightly less than 1:1 (excessive acid), for example, about 1:1.1；About 1:1.15； About 1:1.2.Selecting for solvent can be one or more organic solvents, for example, acetone.In some embodiments, at salt Reaction and crystallization can carry out under stirring at room temperature.In some embodiments, salt-forming reaction and crystallization solvent for use can not Equally.Embodiment 6 has described in detail the Mesylate Form I method of a typical prepare compound 1.
The Mesylate Form I of compound 1 usually can form one with pharmaceutically acceptable carrier or diluent together Kind pharmaceutical composition.Preferably, compound 1 is main in the pharmaceutical composition (for example, about 80wt%, about 90wt%, greatly About 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its Mesylate Form I. Sometimes, compound 1 is the sole active agent in the pharmaceutical composition.Sometimes, treatment or prevention are contained in the pharmaceutical composition A effective amount of compound 1, such as to non-small cell lung cancer or other EGFR described herein obstacle mediated or disease.
In some embodiments, the present invention provides a kind of Pfansteihl salt of compound 1, preferably the L- cream of compound 1 Hydrochlorate crystal form I.Herein, the Pfansteihl salt crystal form I of compound 1 refers to the crystal form with following one or more features: 1) Its X-ray powder diffraction collection at least 2 θ angles be 10.60 °, 14.87 °, 17.77 °, 18.23 °, 21.27 °, 21.81 °, 23.25 °, 23.85 ° and 26.80 °, one or more of ± 0.2 ° have diffraction maximum (at 1,2,3,4,5,6,7,8 or 9)；2) its DSC map is to have heat absorption peak in the Pfansteihl salt crystal form I of compound 1 at 190.50 DEG C ± 5 DEG C in initial temperature, chemical combination The molar ratio of object 1 and Pfansteihl is about 1:1.In some embodiments, the X-ray of the Pfansteihl salt crystal form I of compound 1 The X-ray diffraction peak that powder diffraction spectrum has 10 or more (e.g., 10 or 20) as in the table below:
Angle Angle Angle Angle Angle Angle Angle
2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ°
7.914 13.533 18.227 22.138 28.053 32.768 39.396
8.947 14.869 18.911 23.247 28.798 33.417
9.458 15.875 19.971 23.845 29.695 34.393
9.982 16.468 20.459 24.5 30.37 35.853
10.595 16.985 21.266 26.13 31.03 36.882
11.036 17.774 21.811 26.797 32.077 38.12
In some preferred embodiments, the X-ray powder diffraction collection of the Pfansteihl salt crystal form I of compound 1 has 2 θ Angle be 7.91 °, 8.95 °, 9.98 °, 10.60 °, 14.87 °, 17.77 °, 18.23 °, 18.91 °, 21.27 °, 21.81 °, 22.14 °, 23.25 °, 23.85 °, 24.5 ° and 26.80 °, ± 0.2 ° of diffraction maximum.
In some embodiments, the X-ray powder diffraction collection of the Pfansteihl salt crystal form I of compound 1 has in Figure 28 Main peaks, i.e., have peak at angle ± 0.2 ° corresponding 2 θ, but intensity can with it is different shown in Figure 28, for example, relatively strong Degree at 20% or more peak, for example, relative intensity 30% or more, 40% or more, 50% or more, 60% or with On, 80% or more, 90% or more or 100% peak, preferably 30% or more, more preferably 50% or more.
In some embodiments, the X-ray powder diffraction pattern of the Pfansteihl salt crystal form I of compound 1 and Figure 28 are basic Unanimously.Preferably, the DSC map of the crystal form is also almost the same with Figure 29.
In some embodiments, the present invention provides a kind of Pfansteihl salt crystal form I of the compound 1 of high-purity, for example, In some embodiments, compound 1 is main in the high purity substance (for example, about 80wt%, about 90wt%, about 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its Pfansteihl salt crystal form I.
The Pfansteihl salt crystal form I of compound 1 can usually be obtained with following methods: by compound 1 and Pfansteihl by about The molar ratio of 1:1 mixes in appropriate solvent, then crystallizes the Pfansteihl salt crystal form I of compound 1 and is precipitated.In some embodiment party In case, the molar ratio of compound 1 and Pfansteihl can be slightly less than 1:1 (excessive acid), for example, about 1:1.1；About 1:1.15； About 1:1.2.Selecting for solvent can be one or more organic solvents, for example, isopropanol.In some embodiments, at Reactant salt and crystallization can carry out under stirring at room temperature.In some embodiments, salt-forming reaction and crystallization solvent for use can be with It is different.As embodiment 7 has described in detail the Pfansteihl salt crystal form I method of a typical prepare compound 1.
The Pfansteihl salt crystal form I of compound 1 usually can form one with pharmaceutically acceptable carrier or diluent together Kind pharmaceutical composition.Preferably, compound 1 is main in the pharmaceutical composition (for example, about 80wt%, about 90wt%, greatly About 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its Pfansteihl salt crystal form I. Sometimes, compound 1 is the sole active agent in the pharmaceutical composition.Sometimes, treatment or prevention are contained in the pharmaceutical composition A effective amount of compound 1, such as to non-small cell lung cancer or other EGFR described herein obstacle mediated or disease.
In some embodiments, the present invention provides a kind of oxalates of compound 1, the preferably oxalates of compound 1 Crystal form I.Herein, the Crystal form of oxalate I of compound 1 refers to the crystal form with following one or more features: 1) its X- is penetrated Line powder diffraction spectrum at least 2 θ angles be 6.83 ° and 24.77 °, ± 0.2 ° one at or 2 at have diffraction maximum；2) its DSC schemes Spectrum is to have heat absorption peak at 216.47 DEG C ± 5 DEG C in initial temperature.In the Crystal form of oxalate I of compound 1, compound 1 and grass The molar ratio of acid is about 1:1.In some embodiments, the X-ray powder diffraction collection of the Crystal form of oxalate I of compound 1 With 4 or more (such as 6,10 or 20) X-ray diffraction peak as in the table below:
In some preferred embodiments, the X-ray powder diffraction collection of the Crystal form of oxalate I of compound 1 has 2 angles θ The diffraction maximum that degree is 6.83,12.48,15.99,16.50,17.82,20.76,24.77 and 27.67, ± 0.2 °.
In some embodiments, the X-ray powder diffraction collection of the Crystal form of oxalate I of compound 1 has in Figure 33 Main peaks, i.e., have a peak at angle ± 0.2 ° corresponding 2 θ, but intensity can with it is different shown in Figure 33, for example, relative intensity At 20% or more peak, for example, relative intensity is 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or more or 100% peak, preferably 30% or more, more preferably 50% or more.
In some embodiments, the X-ray powder diffraction pattern of the Crystal form of oxalate I of compound 1 and Figure 33 basic one It causes.Preferably, the DSC map of the crystal form is also almost the same with Figure 34.
In some embodiments, the present invention provides a kind of Crystal form of oxalate I of the compound 1 of high-purity, for example, In some embodiments, compound 1 is main in the high purity substance (for example, about 80wt%, about 90wt%, about 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its Crystal form of oxalate I.
The Crystal form of oxalate I of compound 1 can usually be obtained with following methods: by compound 1 and oxalic acid by about 1:1's Molar ratio mixes in appropriate solvent, then crystallizes the Crystal form of oxalate I of compound 1 and is precipitated.In some embodiments, change The molar ratio for closing object 1 and oxalic acid can be slightly less than 1:1 (excessive acid), for example, about 1:1.1；About 1:1.15；About 1:1.2. Selecting for solvent can be one or more organic solvents, for example, acetone.In some embodiments, salt-forming reaction and crystallization It can carry out under stirring at room temperature.In some embodiments, salt-forming reaction and crystallization solvent for use can be different.As implemented Example 8 has described in detail the Crystal form of oxalate I method of a typical prepare compound 1.
The Crystal form of oxalate I of compound 1 usually can form one kind with pharmaceutically acceptable carrier or diluent together Pharmaceutical composition.Preferably, compound 1 is main in the pharmaceutical composition (for example, about 80wt%, about 90wt%, about 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its Crystal form of oxalate I.Sometimes, Compound 1 is the sole active agent in the pharmaceutical composition.Sometimes, treatment or prevention effective quantity is contained in the pharmaceutical composition Compound 1, such as to non-small cell lung cancer or other the EGFR described herein obstacle mediated or disease.
In some embodiments, the present invention provides a kind of malate of compound 1, such as the malic acid of compound 1 Salt crystal form I.Herein, the malate crystal form I of compound 1 refers to the crystal form with following one or more features: 1) its X-ray powder diffraction collection at least 2 θ angles be 10.62 °, 17.04 °, 17.39 ° and 21.29 °, ± 0.2 ° one at or it is more There is diffraction maximum at place (at 1,2,3 or 4)；2) its DSC map is to have heat absorption peak at 153.85 DEG C ± 5 DEG C in initial temperature.Changing In the malate crystal form I for closing object 1, the molar ratio of compound 1 and malic acid is about 1:1.In some embodiments, chemical combination The X-ray powder diffraction collection of the malate crystal form I of object 1 has 4 or more (such as 6,10 or 20) such as following table The X-ray diffraction peak:
Angle Angle Angle Angle Angle Angle Angle
2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ°
8.397 14.874 19.334 23.809 26.442 30.715 33.975
9.614 15.6 20.61 24.048 27.858 31.134 34.847
10.619 15.98 20.816 24.777 28.968 31.439 35.991
11.834 17.044 21.292 25.153 29.37 31.972 36.85
13.249 17.386 22.35 25.746 29.815 32.13 38.085
13.857 18.289 22.937 26.088 30.332 32.287 38.833
In some preferred embodiments, the X-ray powder diffraction collection of the malate crystal form I of compound 1 has 2 θ Angle is 10.62 °, 17.04 °, 17.39 °, 20.61 °, 20.82 ° ± 0.2 °, 21.29 °, 22.35 ° and 26.44 °, ± 0.2 ° Diffraction maximum.
In some embodiments, the X-ray powder diffraction collection of the malate crystal form I of compound 1 has in Figure 36 Main peaks, i.e., have peak at angle ± 0.2 ° corresponding 2 θ, but intensity can with it is different shown in Figure 36, for example, relatively strong Degree at 20% or more peak, for example, relative intensity 30% or more, 40% or more, 50% or more, 60% or with On, 80% or more, 90% or more or 100% peak, preferably 30% or more, more preferably 50% or more.
In some embodiments, the X-ray powder diffraction pattern of the malate crystal form I of compound 1 and Figure 36 are basic Unanimously.Preferably, the DSC map of the crystal form is also almost the same with Figure 37.
In some embodiments, the present invention provides a kind of malate crystal form I of the compound 1 of high-purity, for example, In some embodiments, compound 1 is main in the high purity substance (for example, about 80wt%, about 90wt%, about 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its malate crystal form I.
The malate crystal form I of compound 1 can usually be obtained with following methods: by compound 1 and malic acid by about The molar ratio of 1:1 mixes in appropriate solvent, then crystallizes the malate crystal form I of compound 1 and is precipitated.In some embodiment party In case, the molar ratio of compound 1 and malic acid can be slightly less than 1:1 (excessive acid), for example, about 1:1.1；About 1:1.15； About 1:1.2.Selecting for solvent can be one or more organic solvents, for example, acetone.In some embodiments, at salt Reaction and crystallization can carry out under stirring at room temperature.In some embodiments, salt-forming reaction and crystallization solvent for use can not Equally.Embodiment 9 has described in detail the malate crystal form I method of a typical prepare compound 1.
The malate crystal form I of compound 1 usually can form one with pharmaceutically acceptable carrier or diluent together Kind pharmaceutical composition.Preferably, compound 1 is main in the pharmaceutical composition (for example, about 80wt%, about 90wt%, greatly About 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its malate crystal form I. Sometimes, compound 1 is the sole active agent in the pharmaceutical composition.Sometimes, treatment or prevention are contained in the pharmaceutical composition A effective amount of compound 1, such as to non-small cell lung cancer or other EGFR described herein obstacle mediated or disease.
In some embodiments, the present invention provides a kind of benzene sulfonate of compound 1, preferably benzene sulfonate crystal form I.? Herein, the benzene sulfonate crystal form I of compound 1 refers to the crystal form with following one or more features: 1) its X-ray powder Diffracting spectrum at least 2 θ angles be 11.55 °, 16.47 °, 19.45 °, 20.14 °, 20.98 ° and 24.80 °, ± 0.2 ° one at Or many places (at such as 1,2,3,4,5 or 6) has diffraction maximum；2) its DSC map is to have hot suction at 207.71 DEG C ± 5 DEG C in initial temperature Receive peak.In the benzene sulfonate crystal form I of compound 1, the molar ratio of compound 1 and benzene sulfonic acid is about 1:1.In some embodiment party In case, the X-ray powder diffraction collection of the benzene sulfonate crystal form I of compound 1 has 6 or more (such as 8,12 or 20 It is a) X-ray diffraction peak as in the table below:
In some preferred embodiments, the X-ray powder diffraction collection of the benzene sulfonate crystal form I of compound 1 has 2 θ Angle be 7.21 °, 8.16 °, 8.67 °, 10.90 °, 11.55 °, 12.34 °, 13.26 °, 14.25 °, 16.46 °, 17.45 °, 18.57 °, 19.45 °, 20.14 °, 20.98 °, 24.80 ° and 26.75 °, ± 0.2 ° of diffraction maximum.
In some embodiments, the X-ray powder diffraction collection of the benzene sulfonate crystal form I of compound 1 has in Figure 41 Main peaks, i.e., have peak at angle ± 0.2 ° corresponding 2 θ, but intensity can with it is different shown in Figure 41, for example, relatively strong Degree at 20% or more peak, for example, relative intensity 30% or more, 40% or more, 50% or more, 60% or with On, 80% or more, 90% or more or 100% peak, preferably 30% or more, more preferably 50% or more.
In some embodiments, the X-ray powder diffraction pattern of the benzene sulfonate crystal form I of compound 1 and Figure 41 are basic Unanimously.Preferably, the DSC map of the crystal form is also almost the same with Figure 42.
In some embodiments, the present invention provides a kind of benzene sulfonate crystal form I of the compound 1 of high-purity, for example, In some embodiments, compound 1 is main in the high purity substance (for example, about 80wt%, about 90wt%, about 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its benzene sulfonate crystal form I.
The benzene sulfonate crystal form I of compound 1 can usually be obtained with following methods: by compound 1 and benzene sulfonic acid by about The molar ratio of 1:1 mixes in appropriate solvent, then crystallizes the benzene sulfonate crystal form I of compound 1 and is precipitated.The selection of solvent can One or more organic solvents are thought, for example, isopropanol.In some embodiments, salt-forming reaction and crystallization can be in room temperatures Stirring is lower to be carried out.In some embodiments, salt-forming reaction and crystallization solvent for use can be different.Embodiment 10 describes in detail The benzene sulfonate crystal form I method of one typical prepare compound 1.
The benzene sulfonate crystal form I of compound 1 usually can form one with pharmaceutically acceptable carrier or diluent together Kind pharmaceutical composition.Preferably, compound 1 is main in the pharmaceutical composition (for example, about 80wt%, about 90wt%, greatly About 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its benzene sulfonate crystal form I. Sometimes, compound 1 is the sole active agent in the pharmaceutical composition.Sometimes, treatment or prevention are contained in the pharmaceutical composition A effective amount of compound 1, such as to non-small cell lung cancer or other EGFR described herein obstacle mediated or disease.
In some embodiments, the present invention provides a kind of hydrochloride of compound 1, the preferably hydrochloride of compound 1 Crystal form I.Herein, the hydrochloride Form I of compound 1 refers to the crystal form with following one or more features: 1) its X- is penetrated Line powder diffraction spectrum at least 2 θ angles be 7.79 ° and 9.71 °, ± 0.2 ° 1 at or 2 at there is diffraction maximum to have diffraction maximum；2) Its DSC map has heat absorption peak at 106 DEG C, 170 DEG C and 209 DEG C ± 5 DEG C, in the hydrochloride Form I of compound 1, chemical combination The molar ratio of object 1 and hydrochloric acid is about 1:1.In some embodiments, the X-ray powder of the hydrochloride Form I of compound 1 The X-ray diffraction peak that diffracting spectrum has 6 or more (such as 10,16 or 20) as in the table below:
Angle Angle Angle Angle Angle Angle
2θ° 2θ° 2θ° 2θ° 2θ° 2θ°
3.649 9.705 13.888 16.758 23.728 26.732
4.742 11.197 14.858 18.091 25.188 27.9
7.109 12.572 15.343 21.783 25.634
7.794 13.419 15.833 23.225 25.817
It is highly preferred that its X-ray powder diffraction collection have 2 θ angles be 3.65 °, 4.74 °, 7.11 °, 7.79 °, 9.71 ° and 11.20 °, ± 0.2 ° of diffraction maximum.
In some embodiments, the X-ray powder diffraction pattern of the hydrochloride Form I of compound 1 has in Figure 44 Main peaks, i.e., have a peak at angle ± 0.2 ° corresponding 2 θ, but intensity can with it is different shown in Figure 44.X-ray powder diffraction Map main peaks in this article refer in an X-ray powder diffraction pattern that relative intensity is at 20% or more peak, for example, phase To intensity 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or more, or 100% peak, preferably 30% or more, more preferably 50% or more.
In some embodiments, the X-ray powder diffraction pattern of the hydrochloride Form I of compound 1 and Figure 44 basic one It causes.The almost the same 2 θ angle bases in experimental error for referring to the diffraction maximum in two maps of X-ray powder diffraction pattern This is consistent, but intensity can be different.Preferably, the DSC map of the salt is also almost the same with Figure 45.DSC map basic one It causes to refer to the heat absorption peak in two maps, such as its initial temperature, it is almost the same in experimental error.
In some embodiments, the present invention provides a kind of hydrochloride Form I of the compound 1 of high-purity, for example, In some embodiments, compound 1 is main in the high purity substance (for example, about 80wt%, about 90wt%, about 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of it is to hydrochloride Form I.
The hydrochloride Form I of compound 1 can usually be obtained with following methods: by compound 1 and hydrochloric acid by about 1:1's Molar ratio mixes in appropriate solvent, and then the hydrochloride Form I of compound 1 is precipitated.In some embodiments, compound 1 and the molar ratio of hydrochloric acid can be slightly less than 1:1 (excessive acid), for example, about 1:1.1；About 1:1.15；About 1:1.2.Solvent Select to be one or more organic solvents, for example, the mixing of methylene chloride and methanol.In some embodiments, at Reactant salt and crystallization can carry out under stirring at room temperature.Embodiment 11 has described in detail the salt of a typical prepare compound 1 The method of hydrochlorate crystal form I.
The hydrochloride Form I of compound 1 usually can form one kind with pharmaceutically acceptable carrier or diluent together Pharmaceutical composition.Preferably, compound 1 is main in the pharmaceutical composition (for example, about 80wt%, about 90wt%, about 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its hydrochloride Form I.Sometimes, Compound 1 is the sole active agent in the pharmaceutical composition.Sometimes, treatment or prevention effective quantity is contained in the pharmaceutical composition Compound 1, such as to non-small cell lung cancer or other the EGFR described herein obstacle mediated or disease.
In some embodiments, the present invention provides a kind of hydrochloride Form II of compound 1.Herein, compound 1 Hydrochloride Form II refer to the crystal form with following one or more features: 1) its X-ray powder diffraction collection is at least in 2 θ Angle is to have diffraction maximum at 10.88 ° ± 0.2 °；2) its DSC map has heat absorption at 123 DEG C, 160 DEG C and 180 DEG C ± 5 DEG C Peak, in the hydrochloride Form II of compound 1, the molar ratio of compound 1 and hydrochloric acid is about 1:1.In some embodiments, The X-ray powder diffraction collection of the hydrochloride Form II of compound 1 have 6 or more (such as 10,16 or 20) such as X-ray diffraction peak described in following table:
Angle Angle Angle Angle Angle Angle Angle Angle
2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ°
3.607 10.876 15.542 19.649 22.976 26.418 31.436 37.175
7.268 12.429 18.252 21.397 23.392 26.846 33.536
9.813 13.384 19.307 21.903 24.987 27.767 37.073
It is highly preferred that it is 3.61 °, 9.81 ° and 10.88 °, ± 0.2 ° that its X-ray powder diffraction collection, which has 2 θ angles, Diffraction maximum.
In some embodiments, the X-ray powder diffraction pattern of the hydrochloride Form II of compound 1 has in Figure 47 Main peaks, i.e., have a peak at angle ± 0.2 ° corresponding 2 θ, but intensity can with it is different shown in Figure 47.X-ray powder diffraction Map main peaks in this article refer in an X-ray powder diffraction pattern that relative intensity is at 20% or more peak, for example, phase To intensity 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or more, or 100% peak, preferably 30% or more, more preferably 50% or more.
In some embodiments, the X-ray powder diffraction pattern of the hydrochloride Form II of compound 1 and Figure 47 basic one It causes.The almost the same 2 θ angle bases in experimental error for referring to the diffraction maximum in two maps of X-ray powder diffraction pattern This is consistent, but intensity can be different.Preferably, the DSC map of the salt is also almost the same with Figure 48.DSC map basic one It causes to refer to the heat absorption peak in two maps, such as its initial temperature, it is almost the same in experimental error.
In some embodiments, the present invention provides a kind of hydrochloride Form II of the compound 1 of high-purity, for example, In some embodiments, compound 1 is main in the high purity substance (for example, about 80wt%, about 90wt%, about 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its hydrochloride Form II.
The hydrochloride Form II of compound 1 can usually be obtained with following methods: compound 1 and hydrochloric acid are pressed about 1:1 Molar ratio mixed in appropriate solvent, then the hydrochloride Form II of compound 1 is precipitated.In some embodiments, change The molar ratio for closing object 1 and hydrochloric acid can be slightly less than 1:1 (excessive acid), for example, about 1:1.1；About 1:1.15；About 1:1.2. Selecting for solvent can be one or more organic solvents, for example, the mixing of methylene chloride and isopropanol.In some embodiments In, salt-forming reaction and crystallization can carry out under stirring at room temperature.Embodiment 11 has described in detail a typical prepare compound 1 Hydrochloride Form II method.
The hydrochloride Form II of compound 1 usually can form one kind with pharmaceutically acceptable carrier or diluent together Pharmaceutical composition.Preferably, compound 1 is main in the pharmaceutical composition (for example, about 80wt%, about 90wt%, about 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its hydrochloride Form II.Have When, compound 1 is the sole active agent in the pharmaceutical composition.Sometimes, have in the pharmaceutical composition containing treatment or prevention The compound 1 of effect amount, such as to non-small cell lung cancer or other EGFR described herein obstacle mediated or disease.
In some embodiments, the present invention provides a kind of tosilate of compound 1, preferably compound 1 Tosilate crystal form I.Herein, the tosilate crystal form I of compound 1 refers to following one or more special The crystal form of sign: 1) its X-ray powder diffraction collection at least 2 θ angles be 5.96 °, 6.97 °, 10.02 °, 10.60 °, 19.75 ° and 21.31 °, one or more of ± 0.2 ° have diffraction maximum (at 1,2,3,4,5 or 6)；2) its DSC map is originating Temperature be 131.46 DEG C ± 5 DEG C at have heat absorption peak, in the tosilate crystal form I of compound 1, compound 1 with to first The molar ratio of benzene sulfonic acid is about 1:1.In some embodiments, the X-ray powder of the tosilate crystal form I of compound 1 The X-ray diffraction peak that last diffracting spectrum has 6 or more (such as 10,16 or 20) as in the table below:
Angle Angle Angle Angle Angle Angle Angle Angle
2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ°
5.963 11.867 15.781 19.752 23.359 26.792 30.335 33.438
6.969 13.194 16.182 20.328 23.733 27.586 30.705 35.289
7.474 13.956 16.877 20.821 24.329 28.068 31.435 36.551
10.019 14.325 17.174 21.313 24.859 28.429 32.161 37.978
10.604 14.975 18.712 22.473 25.72 28.94 32.618 38.491
11.593 15.386 19.092 23.047 26.334 29.973 33.037
It is highly preferred that its X-ray powder diffraction collection have 2 θ angles be 5.96 °, 6.97 °, 10.02 °, 10.60 °, 13.96 °, 19.09 °, 19.75 °, 20.33 °, 21.31 °, 23.73 °, 24.86 °, 26.33 ° and 27.59 °, ± 0.2 ° of diffraction Peak.
In some embodiments, the X-ray powder diffraction pattern of the tosilate crystal form I of compound 1 has figure Main peaks in 50, i.e., have a peak at angle ± 0.2 ° corresponding 2 θ, but intensity can with it is different shown in Figure 50.X-ray powder Last diffracting spectrum main peaks in this article refer in an X-ray powder diffraction pattern relative intensity at 20% or more peak, For example, relative intensity 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or More than or 100% peak, preferably 30% or more, more preferably 50% or more.
In some embodiments, the X-ray powder diffraction pattern and Figure 50 of the tosilate crystal form I of compound 1 It is almost the same.The almost the same 2 θ angles for referring to the diffraction maximum in two maps of X-ray powder diffraction pattern are in experimental error model Enclose interior almost the same, but intensity can be different.Preferably, the DSC map of the salt is also almost the same with Figure 51.DSC map The almost the same heat absorption peak referred in two maps, such as its initial temperature, it is almost the same in experimental error.
In some embodiments, the present invention provides a kind of tosilate crystal form I of the compound 1 of high-purity, For example, in some embodiments, compound 1 it is main in the high purity substance (for example, about 80wt%, about 90wt%, About 95wt%, or more or XRPD can't detect the other forms of compound 1) deposited in the form of tosilate crystal form I ?.
The tosilate crystal form I of compound 1 can usually be obtained with following methods: by compound 1 and to toluene sulphur Acid is mixed in appropriate solvent by the molar ratio of about 1:1, and then the tosilate crystal form I of compound 1 is precipitated.Having In a little embodiments, the molar ratio of compound 1 and p-methyl benzenesulfonic acid can be slightly less than 1:1 (excessive acid), for example, about 1:1.1； About 1:1.15；About 1:1.2.Selecting for solvent can be one or more organic solvents, for example, acetone.In some implementations In scheme, salt-forming reaction and crystallization can carry out under stirring at room temperature.Embodiment 12 has described in detail a typical preparationization The method for closing the tosilate crystal form I of object 1.
The tosilate crystal form I of compound 1 usually can be with pharmaceutically acceptable carrier or diluent together group At a kind of pharmaceutical composition.Preferably, compound 1 is main in the pharmaceutical composition (for example, about 80wt%, about 90wt%, about 95wt%, or more or XRPD can't detect the other forms of compound 1) with its tosilate crystal form The form of I exists.Sometimes, compound 1 is the sole active agent in the pharmaceutical composition.Sometimes, contain in the pharmaceutical composition Have and treat or prevent a effective amount of compound 1, such as to non-small cell lung cancer or other EGFR described herein obstacle mediated or disease Disease.
In some embodiments, the present invention provides a kind of tosilate crystal form II of compound 1.Herein, The tosilate crystal form II of compound 1 refers to the crystal form with following one or more features: 1) its X-ray powder spreads out Penetrate map at least 2 θ angles be 7.14 °, 11.39 °, 12.17 °, 14.13 °, 16.23 °, 17.23 °, 18.53 °, 19.18 °, 20.02 °, 20.70 ° and 24.43 °, one or more of ± 0.2 ° have diffraction (at preferably 5 or more, such as 7, at 8,9,10) Peak；2) its DSC map is to have heat absorption peak at 222.17 DEG C ± 5 DEG C in initial temperature, brilliant in the tosilate of compound 1 In type II, the molar ratio of compound 1 and p-methyl benzenesulfonic acid is about 1:1.In some embodiments, compound 1 to toluene The X-ray powder diffraction collection of sulfonate crystal form II have 6 or more (such as 10,16 or 20) it is as in the table below X-ray diffraction peak:
Angle Angle Angle Angle Angle Angle Angle Angle
2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ°
4.088 9.874 12.168 14.928 18.529 20.695 23.959 27.253
7.136 10.334 13.063 15.308 19.18 21.486 24.427 27.686
8.18 10.69 13.288 16.227 19.585 22.119 25.054 28.732
8.598 11.39 14.125 17.233 20.024 23.226 26.305 35.328
It is highly preferred that its X-ray powder diffraction collection have 2 θ angles be 7.14 °, 8.18 °, 8.60 °, 10.69 °, 11.39 °, 12.17 °, 14.13 °, 16.23 °, 17.23 °, 18.53 °, 19.18 °, 19.59 °, 20.02 °, 20.70 °, 21.49 °, 24.43 ° and 26.31 °, ± 0.2 ° of diffraction maximum.
In some embodiments, the X-ray powder diffraction pattern of the tosilate crystal form II of compound 1 has figure Main peaks in 53, i.e., have a peak at angle ± 0.2 ° corresponding 2 θ, but intensity can with it is different shown in Figure 53.X-ray powder Last diffracting spectrum main peaks in this article refer in an X-ray powder diffraction pattern relative intensity at 20% or more peak, For example, relative intensity 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or More than or 100% peak, preferably 30% or more, more preferably 50% or more.
In some embodiments, the X-ray powder diffraction pattern and Figure 53 of the tosilate crystal form II of compound 1 It is almost the same.The almost the same 2 θ angles for referring to the diffraction maximum in two maps of X-ray powder diffraction pattern are in experimental error model Enclose interior almost the same, but intensity can be different.Preferably, the DSC map of the salt is also almost the same with Figure 54.DSC map The almost the same heat absorption peak referred in two maps, such as its initial temperature, it is almost the same in experimental error.
In some embodiments, the present invention provides a kind of tosilate crystal form II of the compound 1 of high-purity, For example, in some embodiments, compound 1 it is main in the high purity substance (for example, about 80wt%, about 90wt%, About 95wt%, or more or XRPD can't detect the other forms of compound 1) with the shape of its tosilate crystal form II Formula exists.
The tosilate crystal form II of compound 1 can usually be obtained with following methods: by compound 1 and to toluene sulphur Acid is mixed in appropriate solvent by the molar ratio of about 1:1, and then the tosilate crystal form II of compound 1 is precipitated.? In some embodiments, the molar ratio of compound 1 and p-methyl benzenesulfonic acid can be slightly less than 1:1 (excessive acid), for example, about 1: 1.1；About 1:1.15；About 1:1.2.Selecting for solvent can be one or more organic solvents, for example, tetrahydrofuran.? In some embodiments, salt-forming reaction and crystallization can carry out under stirring at room temperature.Embodiment 12 has described in detail a typical case Prepare compound 1 tosilate crystal form II method.
The tosilate crystal form II of compound 1 usually can be with pharmaceutically acceptable carrier or diluent together group At a kind of pharmaceutical composition.Preferably, compound 1 is main in the pharmaceutical composition (for example, about 80wt%, about 90wt%, about 95wt%, or more or XRPD can't detect the other forms of compound 1) with its succinate crystal form I's Form exists.Sometimes, compound 1 is the sole active agent in the pharmaceutical composition.Sometimes, contain in the pharmaceutical composition and control The compound 1 for the treatment of or prevention effective dose, such as to non-small cell lung cancer or other EGFR described herein obstacle mediated or disease.
In some embodiments, the present invention provides a kind of sulfate of compound 1, the preferably sulfate of compound 1 Crystal form I.Herein, the sulfate crystal form I of compound 1 refers to the crystal form with following one or more features: 1) its X- is penetrated Line powder diffraction spectrum is at least to have diffraction maximum at 7.39 ° ± 0.2 ° in 2 θ angles；2) its DSC map is in initial temperature There is heat absorption peak at 141.22 DEG C ± 5 DEG C, in the sulfate crystal form I of compound 1, the molar ratio of compound 1 and sulfuric acid is big About 1:1.In some embodiments, the X-ray powder diffraction collection of the sulfate crystal form I of compound 1 has 6 or more (such as 8 or 10) X-ray diffraction peak as in the table below:
Angle Angle Angle Angle Angle Angle Angle
2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ°
7.394 10.538 14.085 16.586 19.008 24.022 39.375
7.887 11.922 14.716 17.868 19.917 24.951
10.055 13.33 15.63 17.929 22.105 26.325
In some embodiments, the X-ray powder diffraction pattern of the sulfate crystal form I of compound 1 has in Figure 56 Main peaks, i.e., have a peak at angle ± 0.2 ° corresponding 2 θ, but intensity can with it is different shown in Figure 56.X-ray powder diffraction Map main peaks in this article refer in an X-ray powder diffraction pattern that relative intensity is at 20% or more peak, for example, phase To intensity 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or more, or 100% peak, preferably 30% or more, more preferably 50% or more.
In some embodiments, the X-ray powder diffraction pattern of the sulfate crystal form I of compound 1 and Figure 56 basic one It causes.The almost the same 2 θ angle bases in experimental error for referring to the diffraction maximum in two maps of X-ray powder diffraction pattern This is consistent, but intensity can be different.Preferably, the DSC map of the salt is also almost the same with Figure 57.DSC map basic one It causes to refer to the heat absorption peak in two maps, such as its initial temperature, it is almost the same in experimental error.
In some embodiments, the present invention provides a kind of sulfate crystal form I of the compound 1 of high-purity, for example, In some embodiments, compound 1 is main in the high purity substance (for example, about 80wt%, about 90wt%, about 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its sulfate crystal form I.
The sulfate crystal form I of compound 1 can usually be obtained with following methods: by compound 1 and sulfuric acid by about 1:1's Molar ratio mixes in appropriate solvent, and then the sulfate crystal form I of compound 1 is precipitated.In some embodiments, compound 1 and the molar ratio of sulfuric acid can be slightly less than 1:1 (excessive acid), for example, about 1:1.1；About 1:1.15；About 1:1.2.Solvent Select to be one or more organic solvents, for example, isopropanol.In some embodiments, salt-forming reaction and crystallization are equal It can carry out under stirring at room temperature.Embodiment 13 has described in detail the side of the sulfate crystal form I of a typical prepare compound 1 Method.
The sulfate crystal form I of compound 1 usually can form one kind with pharmaceutically acceptable carrier or diluent together Pharmaceutical composition.Preferably, compound 1 is main in the pharmaceutical composition (for example, about 80wt%, about 90wt%, about 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its sulfate crystal form I.Sometimes, Compound 1 is the sole active agent in the pharmaceutical composition.Sometimes, treatment or prevention effective quantity is contained in the pharmaceutical composition Compound 1, such as to non-small cell lung cancer or other the EGFR described herein obstacle mediated or disease.
In some embodiments, the present invention provides a kind of hydrobromate of compound 1, preferably the hydrogen bromine of compound 1 Hydrochlorate crystal form I.Herein, the hydrobromate crystal form I of compound 1 refers to the crystal form with following one or more features: 1) Its X-ray powder diffraction collection at least 2 θ angles be 9.93 °, 10.82 °, 14.11 °, 20.42 °, 21.66 °, 25.02 °, 25.89 ° and 26.25 °, one or more of ± 0.2 ° have diffraction maximum (at preferably 5 or more, for example, at 6,7 or 8)；2) its DSC map is to have heat absorption peak at 272.88 DEG C ± 5 DEG C in initial temperature, in the hydrobromate crystal form I of compound 1, chemical combination The molar ratio of object 1 and hydrobromic acid is about 1:1.In some embodiments, the X-ray of the hydrobromate crystal form I of compound 1 The X-ray diffraction peak that powder diffraction spectrum has 6 or more (such as 8,12 or 20) as in the table below:
Angle Angle Angle Angle Angle Angle Angle Angle
2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ°
6.853 12.966 17.358 21.664 25.894 29.161 33.005 38.626
8.385 13.62 18.526 22.506 26.246 29.333 33.429
9.262 14.112 19.024 23.291 26.783 29.888 34.255
9.929 15.469 19.775 23.871 27.319 31.295 35.003
10.815 16.577 20.418 24.324 27.764 31.677 35.777
12.453 17.053 20.821 25.022 28.42 32.593 37.015
It is highly preferred that its X-ray powder diffraction collection have 2 θ angles be 6.85 °, 8.39 °, 9.93 °, 10.82 °, 14.11 °, 19.02 °, 20.42 °, 20.82 °, 21.66 °, 22.51 °, 25.02 °, 25.89 °, 26.25 ° and 27.32 °, ± 0.2 ° Diffraction maximum
In some embodiments, the X-ray powder diffraction pattern of the hydrobromate crystal form I of compound 1 has in Fig. 4 Main peaks, i.e., have a peak at angle ± 0.2 ° corresponding 2 θ, but intensity can with it is different shown in Fig. 4.X-ray powder diffraction figure Spectrum main peaks in this article refer in an X-ray powder diffraction pattern that relative intensity is at 20% or more peak, for example, relatively Intensity 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or more, or 100% peak, preferably 30% or more, more preferably 50% or more.
In some embodiments, the X-ray powder diffraction pattern of the hydrobromate crystal form I of compound 1 and Fig. 4 basic one It causes.The almost the same 2 θ angle bases in experimental error for referring to the diffraction maximum in two maps of X-ray powder diffraction pattern This is consistent, but intensity can be different.Preferably, the DSC map of the salt is also almost the same with Fig. 4.DSC map is almost the same Refer to the heat absorption peak in two maps, such as its initial temperature, it is almost the same in experimental error.
In some embodiments, the present invention provides a kind of hydrobromate crystal form I of the compound 1 of high-purity, for example, In some embodiments, compound 1 is main in the high purity substance (for example, about 80wt%, about 90wt%, about 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its hydrobromate crystal form I.
The hydrobromate crystal form I of compound 1 can usually be obtained with following methods: by compound 1 and hydrobromic acid by about The molar ratio of 1:1 mixes in appropriate solvent, and then the hydrobromate crystal form I of compound 1 is precipitated.In some embodiments In, the molar ratio of compound 1 and hydrobromic acid can be slightly less than 1:1 (excessive acid), for example, about 1:1.1；About 1:1.15；Greatly About 1:1.2.Selecting for solvent can be one or more organic solvents, for example, methanol.In some embodiments, anti-at salt It can should be carried out under stirring at room temperature with crystallization.Embodiment 1 has described in detail the hydrobromate of a typical prepare compound 1 The method of crystal form I.
The hydrobromate crystal form I of compound 1 usually can form one with pharmaceutically acceptable carrier or diluent together Kind pharmaceutical composition.Preferably, compound 1 is main in the pharmaceutical composition (for example, about 80wt%, about 90wt%, greatly About 95wt%, or more or XRPD can't detect the other forms of compound 1) exist in the form of its hydrobromate crystal form I. Sometimes, compound 1 is the sole active agent in the pharmaceutical composition.Sometimes, treatment or prevention are contained in the pharmaceutical composition A effective amount of compound 1, such as to non-small cell lung cancer or other EGFR described herein obstacle mediated or disease.
In some embodiments, the present invention provides a kind of pharmaceutical compositions, and it includes any one or more this paper institutes State salt form or crystal form and pharmaceutically acceptable carrier or diluent.Usually used excipient in field of medicaments, adhesive, Lubricant, disintegrating agent, colorant, flavoring rectify olfactory agent, emulsifier, surfactant, cosolvent, suspending agent, isotonic agent, buffering Agent, preservative, antioxidant, stabilizer, sorbefacient etc., can also as needed it is appropriately combined carry out using.
Pharmaceutical composition of the present invention can be any available dosage form, for example, tablet, capsule etc..When preparing one kind It, can be by main active component and a kind of pharmaceutical carrier, such as starch, lactose, tristearin when the solid composite of tablet form The mixing such as sour magnesium, can wrap up in sugar-coat or other suitable substances to tablet, or be handled so that tablet has extension Or the effect slowed down, and the active constituent for making the tablet discharge predetermined amount in a continuous manner.When preparing a kind of capsule-type When solid composite, active constituent can be mixed with a kind of diluent, and gained mixture is fitted into capsule and obtains one kind Capsule.In some embodiments, pharmaceutical composition of the present invention may be other dosage forms such as granule, powder or The oral administrations such as syrup are administered in such a way that injection, powder-injection, spray or suppository etc. are non-oral.These preparations can pass through Conventional method preparation.
In some embodiments, the salt of compound 1 of the present invention and/or its pharmaceutical composition can be used for preparing It treats or prevents by the EGFR of activation or resistant mutant forms mediation, for example, L858R activated mutant body, Exon19 are lacked What activated mutant body and/or T790M resistant mutants EGFR were mediated, the drug of obstacle or disease.In some embodiments, institute It states obstacle or disease is cancer.In some embodiments, the obstacle or disease include but is not limited to: oophoroma, cervical carcinoma, Colorectal cancer (for example, adenocarcinoma of colon), breast cancer, cancer of pancreas, glioma, glioblastoma, melanoma, prostate Cancer, leukaemia, lymthoma, non-Hodgkin lymphoma, gastric cancer, lung cancer (for example, non-small cell lung cancer), hepatocellular carcinoma, gastrointestinal tract Stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, carcinoma of endometrium, kidney, primary cutaneous type, acute myeloid are white Blood disease (AML), Huppert's disease or celiothelioma.
In the present invention, the EGFR of the activated mutant body or resistant mutant forms can be prominent for such as L858R activation Variant, Exon19 missing activated mutant body and/or T790M resistant mutants.Therefore, by activated mutant body or the resistant mutation bodily form The obstacle or disease that the EGFR of formula is mediated can be lacked for such as L858R activated mutant body, Exon19 activated mutant body and/or The obstacle or disease that T790M resistant mutants are mediated.
The salt of compound 1 of the present invention and/or its pharmaceutical composition are particularly useful for by activated mutant body or resist Property mutant forms EGFR mediate disease prevention or treatment, such as by L858R activated mutant body, Exon19 missing activation The prevention or treatment of disease, obstacle, disorder or the patient's condition that mutant and/or T790M resistant mutants are mediated, for example can use In the prevention or treatment of the cancer patient to have developed drug resistance to Gefitinib, Tarceva or Conmana.
It is yet another aspect of the present invention to provide a kind of cancer combinational therapeutic methods comprising to individual application in need for the treatment of The salt of the compound of the present invention 1 of therapeutically effective amount, crystal form and/or its pharmaceutical composition, while being used in combination conventional Operation or radiotherapy or chemotherapy or immune tumor therapy.The chemotherapy or immune tumor therapy and institute of the present invention The salt for the compound 1 stated, crystal form and/or its pharmaceutical composition can side by side, simultaneously, sequentially or respectively be administered, and And it may include but be not limited to the one or more of following kind of antitumor agent: alkylating agent (such as it is carboplatin, oxaliplatin, suitable Platinum, cyclophosphamide, nitrosoureas, mustargen, melphalan), antimetabolite (such as gemcitabine), and antifol (such as 5- Fluorouracil and Tegafur, Raltitrexed, methopterin, cytarabine, hydroxycarbamide), topoisomerase enzyme inhibitor (such as rely on Moor glycosides, Hycamtin, camptothecine), antimitotic agent (such as vincristine, vincaleukoblastinum, vinorelbine, taxol, Tai Suo Supreme Being), antitumor antibiotics (such as adriamycin, bleomycin, Doxorubicin, daunomycin, mitomycin C, D actinomycin D) resists Estrogenic drug (such as tamoxifen, fulvestrant, Toremifene, Raloxifene, Droloxifene), antiandrogen (such as than Card Shandong amine, Flutamide, Nilutamide), lhrh antagonist or LHRH agonist (such as Goserelin, Leuprorelin and Bu Sherui Woods), aromatase inhibitor (such as Anastrozole, Letrozole), CYP17 lyase inhibitors (such as abiraterone), anti-erbB 2 Antibody trastuzumab [Trastuzumab], anti-egfr antibodies Cetuximab [Erbitux]；Tyrosine kinase, serine/threonine The inhibitor (such as Imatinib and nilotinib, Sorafenib, trametinib, gram azoles replace Buddhist nun) of kinases；Cyclin White dependant kinase inhibitors (such as CDK4 inhibitor palbociclib), anti-human vascular endothelial growth factor antibody shellfish Pearl monoclonal antibody (Avastin) and vegf receptor tyrosine kinase inhibitor (Ah pa replaces Buddhist nun) are cut down, tumor therapeuticing method, example is immunized Such as anti-PD-1 antibody (pembrolizumab, nivolumab), anti-lag-3 antibody, anti-CTLA-4 antibody, resists anti-PD-L1 antibody 4-1BB antibody, anti-GITR antibody, anti-ICOS antibody, interleukin 2.
Detailed description of the invention
Fig. 1 is the XRPD map of compound 1；
Fig. 2 is the TGA and DSC data of compound 1；
Fig. 3 is compound 11H-NMR data；
Fig. 4 is the XRPD map of the hydrobromate crystal form I of compound 1；
Fig. 5 is the TGA and DSC data of the hydrobromate crystal form I of compound 1；
Fig. 6 is the hydrobromate crystal form I's of compound 11H-NMR data；
Fig. 7 is the XRPD map of the succinate crystal form I of compound 1；
Fig. 8 is the TGA and DSC data of the succinate crystal form I of compound 1；
Fig. 9 is the succinate crystal form I's of compound 11H-NMR data；
Figure 10 is the DVS data of the succinate crystal form I of compound 1；
Figure 11 is the XRPD map of the succinate DVS analysis front and back of compound 1；
Figure 12 is the XRPD map of the maleate crystal form I of compound 1；
Figure 13 is the TGA and DSC data of the maleate crystal form I of compound 1；
Figure 14 is the maleate crystal form I's of compound 11H-NMR data；
Figure 15 is the DVS data of the maleate crystal form I of compound 1；
Figure 16 is the XRPD map of the maleate DVS analysis front and back of compound 1；
Figure 17 is the XRPD map of the fumarate crystal form I of compound 1；
Figure 18 is the TGA and DSC data of the fumarate crystal form I of compound 1；
Figure 19 is the fumarate crystal form I's of compound 11H-NMR data；
Figure 20 is the DVS data of the fumarate crystal form I of compound 1；
Figure 21 is the XRPD map of the fumarate DVS test front and back of compound 1；
Figure 22 is the XRPD map of the phosphate crystal form I of compound 1；
Figure 23 is the TGA and DSC data of the phosphate crystal form I of compound 1；
Figure 24 is the phosphate crystal form I's of compound 11H-NMR data；
Figure 25 is the XRPD map of the mesylate (crystal form I) of compound 1；
Figure 26 is the TGA and DSC data of the mesylate (crystal form I) of compound 1；
Figure 27 is the mesylate (crystal form I) of compound 11H-NMR data；
Figure 28 is the XRPD map of the Pfansteihl salt crystal form I of compound 1；
Figure 29 is the TGA and DSC data of the Pfansteihl salt crystal form I of compound 1；
Figure 30 is the Pfansteihl salt crystal form I's of compound 11H-NMR data；
Figure 31 is the DVS data of the Pfansteihl salt crystal form I of compound 1；
Figure 32 is the XRPD map of the Pfansteihl salt DVS analysis front and back of compound 1；
Figure 33 is the XRPD map of the Crystal form of oxalate I of compound 1；
Figure 34 is the TGA and DSC data of the Crystal form of oxalate I of compound 1；
Figure 35 is the Crystal form of oxalate I's of compound 11H-NMR data；
Figure 36 is the XRPD map of the malate crystal form I of compound 1；
Figure 37 is the TGA and DSC data of the malate crystal form I of compound 1；
Figure 38 is the malate crystal form I's of compound 11H-NMR data；
Figure 39 is the DVS data of the malate crystal form I of compound 1；
Figure 40 is the XRPD map of the malate DVS test front and back of compound 1；
Figure 41 is the XRPD map of the benzene sulfonate crystal form I of compound 1；
Figure 42 is the TGA and DSC data of the benzene sulfonate crystal form I of compound 1；
Figure 43 is the benzene sulfonate crystal form I's of compound 11H-NMR data；
Figure 44 is the XRPD map of the hydrochloride Form I of compound 1；
Figure 45 is the TGA and DSC data of the hydrochloride Form I of compound 1；
Figure 46 is the hydrochloride Form I's of compound 11H-NMR data；
Figure 47 is the XRPD map of the hydrochloride Form II of compound 1；
Figure 48 is the TGA and DSC data of the hydrochloride Form II of compound 1；
Figure 49 is the hydrochloride Form II's of compound 11H-NMR data；
Figure 50 is the XRPD map of the tosilate crystal form I of compound 1；
Figure 51 is the TGA and DSC data of the tosilate crystal form I of compound 1；
Figure 52 is the tosilate crystal form I's of compound 11H-NMR data；
Figure 53 is the XRPD map of the tosilate crystal form II of compound 1；
Figure 54 is the TGA and DSC data of the tosilate crystal form II of compound 1；
Figure 55 is the tosilate crystal form II's of compound 11H-NMR data；
Figure 56 is the XRPD map of the sulfate crystal form I of compound 1；
Figure 57 is the TGA and DSC data of the sulfate crystal form I of compound 1；
Figure 58 is the sulfate crystal form I's of compound 11H-NMR data.
Beneficial effect
As described herein, some salt form of compound 1 such as, hydrobromate, succinate, maleate, fumarate, Phosphate, mesylate, Pfansteihl salt, oxalates, malate, benzene sulfonate, hydrochloride, tosilate or sulfuric acid Salt improves the water solubility of compound 1, and some polymorphics (especially fourth two of these salt form to varying degrees Hydrochlorate crystal form I, maleate crystal form I, fumarate crystal form I, malate crystal form I and Pfansteihl salt crystal form I etc.) have height surely Qualitative, the features such as low wettability are conducive to the production and preparation of compound 1, significant to its final marketization.
Specific embodiment
It is further illustrated by the examples that follow the present invention, following embodiment is only used for being more particularly described of the invention preferred Embodiment is not used in and is defined to technical solution of the present invention.
In following each embodiments,
1The instrument that H-NMR analysis uses is equipped with the Bruker Advance of 120 automatic sample handling system of B-ACS 300, use DMSO-d6As deuterated solvent.
Solid sample is analyzed with powder x-ray diffraction analysis instrument (Bruker D8advance).The apparatus preparation LynxEye detector, 2 θ scanning angle ranges of sample are 3 ° to 40 °, and scanning step is 0.02 °.Measure light pipe when sample Voltage and tube current are respectively 40KV and 40mA.
The instrument model of thermogravimetric analysis (TGA) is Discovery TGA 55 (TA Instruments, US).Sample is set In Balanced opening aluminum sample disk, sample size automatic weighing in TGA heating furnace.Sample is added with the rate of 10 DEG C/min Heat is to final temperature.
The instrument model of differential scanning calorimetry (DSC) is TA Instruments Q200 or Discovery DSC 250.Sample records the exact mass of sample through being precisely weighed in the sample disc for being placed on DSC capping punching.Sample is with 10 DEG C/heating rate of min is heated to final temperature.
The instrument model that dynamic water adsorption desorption analyzes (DVS) is DVS Intrinsic (SMS, UK).Sample is placed in instrument It weighs automatically in device sample basket, is then heated to 40 DEG C, dried to dm/dt under nitrogen flowing less than 0.002%, wait be cooled to 25 Start to measure after DEG C, instrument parameter is as follows.
The characterization of compound 1
Initial feed medicine 1 is the good crystal of crystallinity (Fig. 1), and DSC shows that its fusing point is 158 DEG C (Fig. 2).1H-NMR (300MHz) and TGA show sample no solvent residue, and substantially without weightless (Fig. 3) before 200 DEG C, the results showed that sample is anhydrous Crystal form is named as crystal form I.
The preparation of various salt form
Embodiment 1, hydrobromate
50 DEG C, into MeOH (33v) solution of compound 1 (30mg), while stirring be added hydrobromic acid (1.1eq, 40% aq).It is down to room temperature and is stirred overnight, solid is collected by filtration and is dried in vacuo 4 hours at 50 DEG C, finally obtain hydrobromate crystal form I (Fig. 4, table 1), and it is carried out XRPD, TGA, DSC and1H-NMR (400MHz) characterization.
The sample has~0.7% weightlessness between 80 DEG C and 200 DEG C, and fusing point is 274 DEG C (TGA and DSC, Fig. 5).Together When, there are chemical shifts compared with free alkali by NMR, and detect~0.9% MeOH residual (Fig. 6).
So hydrobromate crystal form I is an anhydrous crystal forms.
The XRPD diffraction peak list of 1. hydrobromate crystal form I of table
Embodiment 2, succinate
60 DEG C, into MeOH (16v) solution of compound 1 (24.8mg), the succinic acid methanol of 0.5M is added while stirring Solution (1.1eq.).It is cooled to room temperature, the EtOAc (40v) of 1mL is added, it is small to continue stirring 3.5 for 35 minutes or so precipitation solids Shi Hou is collected by filtration solid, and is dried in vacuum overnight at 50 DEG C.Succinate crystal form I (Fig. 7, table 2) is finally obtained, and to it Carry out XRPD, TGA, DSC,1H-NMR (400MHz) and DVS characterization.
For the sample substantially without weightlessness before decomposition, fusing point is 179 DEG C (TGA and DSC, Fig. 8).Meanwhile NMR and free alkali phase Than there are chemical shifts, and detect that~0.2% EtOAc is remained, and the molar ratio of compound 1 and acid is 1:1 (Fig. 9). DVS analysis shows that, in 80/90%RH the hygroscopic capacity of sample be 0.17%/0.22% (Figure 10), and DVS analysis after sample XRPD map do not change (Figure 11).
So succinate crystal form I is high and low molten residual, the nonhygroscopic anhydrous crystal forms of a fusing point.
The XRPD diffraction peak list of 2. succinate crystal form I of table
Embodiment 3, maleate
60 DEG C, in IPA (27v) solution of compound 1 (25.9mg), the maleic acid IPA solution of 0.5M is added while stirring (~1eq.).After being stirred at room temperature 1 hour, grease is precipitated, continues to become solid after being stirred overnight.50 DEG C of solid is collected by filtration very Sky is dried overnight, and finally obtains maleate crystal form I (table 3), and it is carried out XRPD, TGA, DSC,1H-NMR (400MHz) with And DVS characterization.
For sample without weightlessness before decomposition, fusing point is~169 DEG C (TGA and DSC, Figure 13).Meanwhile NMR shows maleate It is 1:1 into salt, and is tested with~0.3% IPA residual (Figure 14).DVS is analyzed as the result is shown: sample is wet in 80/90%RH Absorb water 0.13%/0.29% (Figure 15) respectively when spending, and the sample crystal form after the completion of analysis does not change (Figure 16).
So maleate crystal form I is a fusing point height, low molten residual, nonhygroscopic anhydrous crystal forms.
The XRPD diffraction peak list of 3. maleate crystal form I of table
Embodiment 4, fumarate
60 DEG C, into IPA (27v) solution of compound 1 (25.9mg), fumaric acid (~1eq.) is added while stirring.Gu Body is precipitated, and is cooled to room temperature after continuing stirring 3.5 hours, solid is collected by filtration and is dried in vacuum overnight at 50 DEG C, finally obtains Fumaric acid crystal form I (Figure 17, table 4), and it is carried out XRPD, TGA, DSC,1H-NMR (400MHz) and DVS analysis.
For sample without weightlessness before decomposition, fusing point is 235 DEG C (TGA and DSC, Figure 18).Meanwhile NMR can be observed~0.2% Residual IPA, and at salt ratio be 1:1 (Figure 19).DVS analysis shows that, sample absorbs water 0.09% in 80/90%RH respectively/ 0.37% (Figure 20), and the XRPD figure for testing front and back sample does not change (Figure 21).
Fumarate crystal form I is anhydrous crystal forms, has acceptable property: high-melting-point, low molten residual, under the conditions of 80%RH not Moisture absorption.
The XRPD diffraction peak list of 4. fumarate crystal form I of table
Angle Intensity Angle Intensity Angle Intensity
2θ° % 2θ° % 2θ° %
5.705 91.2 19.798 23.6 28.97 5.7
10.024 11.5 20.241 9 29.35 6.1
10.307 6.4 20.676 14 29.946 4.8
11.465 4.3 21.473 17.1 30.314 7.6
11.951 7.8 21.809 28.3 30.587 8.5
12.835 23.2 22.021 50.4 31.043 7.1
14.057 4.5 22.766 16.8 31.879 3.8
15.017 7.9 23.139 8.7 32.959 7.1
15.431 6.6 23.501 18.5 34.815 3.6
16.529 13.8 24.252 17.8 35.433 6.8
16.968 100 24.574 9.4 36.043 4.1
17.279 12 25.233 31.4 36.39 3.4
17.79 11.8 25.739 19.8 37.035 3.2
18.264 6.7 27.04 36.3 37.761 3.3
19.159 35.3 27.519 16.1 39.841 3.8
19.426 15 28.436 4.7
Embodiment 5, phosphate
60 DEG C, into MeOH (12v) solution of compound 1 (25.1mg), phosphoric acid (~1eq.) is added while stirring.Cooling When solid be precipitated, after being stirred at room temperature 1 hour, solid is collected by filtration and 50 DEG C are dried in vacuum overnight, finally obtains phosphate crystal form I (Figure 22, table 5), and it is carried out XRPD, TGA, DSC and1H-NMR (400MHz) analysis.
For the sample substantially without weightlessness before decomposition, fusing point is 157 DEG C (TGA and DSC, Figure 23).Meanwhile NMR and free alkali Compared to chemical shift (Figure 24) can be observed.
Phosphate crystal form I is that fusing point is lower, the slightly worse anhydrous crystal forms of crystallinity.
The XRPD diffraction peak list of 5. phosphate crystal form I of table
Angle Intensity Angle Intensity Angle Intensity
2θ° % 2θ° % 2θ° %
6.132 12 13.123 23.1 21.26 24
7.012 100 14.078 22.4 21.75 16.1
9.236 28.7 15.103 8.4 23.247 14.2
11.269 7.3 16.128 10.7 23.667 16.1
12.043 21.2 18.794 15.4
12.776 22 19.733 17.4
Embodiment 6, mesylate
60 DEG C, into acetone (20v) solution of compound 1 (25.8mg), methanesulfonic acid (1.1eq.) is added while stirring.Gu Body is precipitated, and is down to room temperature and stirs 4 hours.Solid is collected by filtration and is dried in vacuum overnight at 50 DEG C, finally obtains methylsulphur acid crystals Type I (Figure 25, table 6), and carry out XRPD, TGA, DSC and1H-NMR (400MHz) analysis.
For sample substantially without weightlessness before decomposition, fusing point is 238 DEG C (TGA and DSC, Figure 26).Meanwhile NMR is in free alkali phase Than there are chemical shifts, and detect~1.2% residual acetone (Figure 27).
So Mesylate Form I is anhydrous crystal forms, but contain more dissolvent residual.
The XRPD diffraction peak list of 6. Mesylate Form I of table
Embodiment 7, Pfansteihl salt
60 DEG C, into IPA (27v) solution of compound 1 (25.5mg), Pfansteihl (1.1eq.) is added while stirring.Analysis Solid out is cooled to room temperature and continues stirring 5 hours.Solid is collected by filtration and is dried in vacuo 2 days at 50 DEG C, finally obtains Pfansteihl Salt crystal form I (Figure 28, table 7), and carry out XRPD, TGA, DSC,1H-NMR (300MHz) and DVS analysis.
For sample substantially without weightlessness before decomposition, fusing point is 192 DEG C (TGA and DSC, Figure 29).Meanwhile NMR as the result is shown at Salt ratio is 1:1 (Figure 30).DVS is analysis shows water absorption of the sample in 80/90%RH is respectively 0.35%/0.71% (figure 31) it, and analyzes the XRPD map of front and back sample and does not change (Figure 32).
Pfansteihl salt crystal form I is anhydrous crystal forms, and has acceptable property: high-melting-point, low molten residual, slight moisture absorption.
The XRPD diffraction peak list of table 7.L- lactate crystal form I
Angle Intensity Angle Intensity Angle Intensity
2θ° % 2θ° % 2θ° %
7.914 33.2 18.911 35.6 29.695 17.3
8.947 45.8 19.971 13.4 30.37 11.1
9.458 13.7 20.459 12.1 31.03 11.6
9.982 32.2 21.266 52.7 32.077 9.6
10.595 99.7 21.811 75.6 32.768 10.7
11.036 15.6 22.138 49.8 33.417 15.3
13.533 12.1 23.247 93 34.393 9.6
14.869 100 23.845 57.9 35.853 9.4
15.875 17.6 24.5 30.8 36.882 13.6
16.468 13.7 26.13 23.9 38.12 10.8
16.985 22.8 26.797 73.8 39.396 10.2
17.774 55.9 28.053 27.2
18.227 53.5 28.798 15.3
Embodiment 8, oxalates
55 DEG C, into acetone (20v) solution of compound 1 (39.8mg), oxalic acid (1.1eq.) is added while stirring.Solid It is precipitated, is cooled to room temperature and continues to be stirred overnight.Solid is collected by filtration, 50 DEG C are dried in vacuo 4 hours, finally obtain Crystal form of oxalate I crystal I (Figure 33, table 8), and carry out XRPD, TGA, DSC and1H-NMR (400MHz) analysis.
For sample without weightlessness before decomposition, fusing point is 218 DEG C (TGA and DSC, Figure 34).Meanwhile NMR is deposited compared with free alkali In chemical shift and~1.2% acetone residue (Figure 35).
Crystal form of oxalate I is anhydrous crystal forms, and containing compared with high solvent residual.
The XRPD diffraction peak list of 8. Crystal form of oxalate I of table
Angle Intensity Angle Intensity Angle Intensity
2θ° % 2θ° % 2θ° %
6.174 8.8 17.824 43.5 27.17 24.1
6.828 80.5 18.639 24 27.673 40.5
7.901 8.3 19.97 9.9 29.121 9.8
10.356 23.8 20.755 37 29.163 9.2
12.205 27.6 21.342 22 29.358 9.9
12.48 42.3 21.878 17.7 29.962 6
13.133 20.7 22.242 15.4 31.803 7.9
13.634 20.5 23.157 14.6 32.228 7.3
14.191 15.7 23.646 11.6 33.001 7.3
15.532 28.8 24.769 100 34.67 6.5
15.989 37.8 25.862 14.4 36.246 9.1
16.503 29.7 26.759 22.4 37.548 6.1
17.051 11.8 26.851 22 38.61 7.8
Embodiment 9, malate
50 DEG C, into acetone (20v) solution of compound 1 (40mg), malic acid (1.1eq.) is added while stirring.Solid It is precipitated, is cooled to room temperature and continues to be stirred overnight.Solid is collected by filtration and is dried in vacuo 4 hours at 50 DEG C.Finally obtain malic acid Salt crystal form I crystal I (Figure 36, table 9), and carry out XRPD, TGA, DSC,1H-NMR (400MHz) and DVS analysis.
For sample without weightlessness before decomposition, fusing point is 157 DEG C (TGA and DSC, Figure 37).NMR shows compound 1 and malic acid 1:1 contains~0.5% acetone residue (Figure 38) at salt, and in sample.DVS analysis detection is to sample in 80/90%RH Water absorption is respectively 0.20%/1.56%, and when being higher than 80%RH, sample is easier to water suction (Figure 39).But sample after DVS test XRPD do not change (Figure 40).
Malate crystal form I is anhydrous crystal forms, and fusing point is high, low molten residual, non-hygroscopic.
The XRPD diffraction peak list of 9. malate crystal form I of table
Angle Intensity Angle Intensity Angle Intensity
2θ° % 2θ° % 2θ° %
8.397 7.6 20.816 41.4 29.815 6.6
9.614 8.7 21.292 100 30.332 8
10.619 69.2 22.35 38.8 30.715 9.8
11.834 28.1 22.937 17.8 31.134 11.7
13.249 7.5 23.809 12.6 31.439 8.7
13.857 5.7 24.048 18.7 31.972 11.1
14.874 18.3 24.777 20.3 32.13 12.8
15.6 11.9 25.153 12.2 32.287 9.9
15.98 16.4 25.746 25 33.975 5.8
17.044 53.7 26.088 29 34.847 9.1
17.386 63.6 26.442 48.4 35.991 7.2
18.289 12.8 27.858 8.4 36.85 5.5
19.334 15.6 28.968 11 38.085 6.5
20.61 33.5 29.37 15.2 38.833 9
Embodiment 10, benzene sulfonate
50 DEG C, into IPA (30v) solution of compound 1 (39.9mg), benzene sulfonic acid (1.1eq.) is added while stirring.Gu Body is precipitated, and is cooled to room temperature and continues to be stirred overnight, and solid is collected by filtration and is dried in vacuo 4 hours at 50 DEG C, finally obtains benzene sulphur Hydrochlorate crystal form I (Figure 41, table 10), and it is carried out XRPD, TGA, DSC and1H-NMR (400MHz) analysis.
Sample weightlessness~0.7% between 100 DEG C and 190 DEG C, fusing point are 217 DEG C (TGA and DSC, Figure 42).Meanwhile with Free alkali is compared to there are chemical shift, the IPA in sample in the presence of~0.8% remains (Figure 43) in NMR.
Benzene sulfonate crystal form I is anhydrous crystal forms, but containing compared with high solvent residual.
The XRPD diffraction peak list of 10. benzene sulfonate crystal form I of table
Angle Intensity Angle Intensity Angle Intensity
2θ° % 2θ° % 2θ° %
7.211 44.1 16.456 73.2 24.801 64
8.164 31.7 17.45 45.9 26.176 19.3
8.666 35.4 17.924 19.9 26.746 34.9
10.435 17.9 18.569 42.6 27.442 15.2
10.898 35.6 19.448 100 28.037 28.4
11.551 63.2 20.135 57.9 29.18 15.1
12.343 37.7 20.979 55.5 29.896 11.1
13.259 38.1 21.782 26 31.66 11.7
14.249 47.7 22.505 27.4 32.659 8.2
14.839 19.8 23.34 23 33.211 13.1
15.4 17.4 24.001 16.1 36.246 9.8
Embodiment 11, hydrochloride
The XRPD formula of two kinds of hydrochlorides is respectively obtained in two kinds of dicyandiamide solutions of DCM/MeOH (1:1) and DCM/IPA (1:1) Sample.
At room temperature, respectively into the solution of two kinds of solvents (33v) of compound 1 (30mg), while stirring be added hydrochloric acid (~ 1eq.).It is precipitated without solid, then 40 DEG C of reduced pressures remove about half solvent.
In DCM/MeOH system, there is solid precipitation after MTBE (17v) is added, continue to be stirred overnight.Solid is collected by filtration And 50 DEG C be dried in vacuo 4 hours, obtain hydrochloride style 1, crystal form I (Figure 44, table 11), and carry out XRPD, TGA, DSC and1H-NMR (300MHz) analysis.
Sample weightlessness~3.8% before 105 DEG C, weightless between 105 DEG C and 175 DEG C~10.3%；DSC 106 DEG C, 170 DEG C and 209 DEG C there are three endothermic peaks, should be desolventizing peak (TGA and DSC, Figure 45).It is residual to can detecte solvent by NMR simultaneously It stays, and there are chemical shift (Figure 46) compared with free alkali.
In DCM/IPA system, solid is precipitated after concentration quickly, is stirred overnight after adding IPA (17v).It is collected by filtration solid Body, and be dried in vacuo 4 hours at 50 DEG C, hydrochloride style 2, crystal form II (Figure 47, table 12) are obtained, and carry out XRPD, TGA, DSC With1H-NMR (300MHz) analysis.
Sample weightlessness~6.4% before 125 DEG C, weightless between 170 DEG C of 125 DEG C~3.5%；DSC is at 123 DEG C, 160 DEG C There are three endothermic peaks with 180 DEG C, should be caused by desolventizing (TGA and DSC, Figure 48).Meanwhile NMR can detect compared with free alkali Chemical shift out, and there are dissolvent residual (Figure 49).
Two batch hydrochlorides may be solvate or hydrate.
The XRPD diffraction peak list of 11. hydrochloride Form I of table
Angle Intensity Angle Intensity Angle Intensity
2θ° % 2θ° % 2θ° %
3.649 100 13.888 20.6 23.728 18.4
4.742 51.3 14.858 16.6 25.188 28
7.109 38.9 15.343 17.9 25.634 29.6
7.794 50.3 15.833 14.6 25.817 30.7
9.705 74.2 16.758 26.3 26.732 32.5
11.197 37 18.091 27.8 27.9 23.6
12.572 16.4 21.783 22.1
13.419 18.1 23.225 20.6
The XRPD diffraction peak list of 12. hydrochloride Form II of table
Angle Intensity Angle Intensity Angle Intensity
2θ° % 2θ° % 2θ° %
3.607 70.9 19.307 18.2 26.846 18
7.268 11.5 19.649 28.6 27.767 24.4
9.813 39.7 21.397 9.1 31.436 6.8
10.876 100 21.903 11.5 33.536 6.8
12.429 12.3 22.976 14.6 37.073 6.2
13.384 19.5 23.392 18.6 37.175 7.1
15.542 19.7 24.987 24.6
18.252 20.1 26.418 13.7
Embodiment 12, tosilate
Two kinds of XRPD styles of tosilate are respectively obtained in acetone and THF.
60 DEG C, into acetone (19v) solution of compound 1 (25.9mg), while stirring be added p-methyl benzenesulfonic acid (~ 1eq.).It is cooled to room temperature, solid is precipitated.After continuing stirring 3 hours, solid is collected by filtration and is dried in vacuum overnight at 50 DEG C, obtains To tosilate style 1, crystal form I (Figure 50, table 13), and it is carried out XRPD, TGA, DSC and1H-NMR (400MHz) points Analysis.Sample weightlessness~7.9% between 100 DEG C to 200 DEG C, this remains opposite with the acetone (1mol) for detecting 7.8% in NMR It answers.DSC detects that 135 DEG C have an endothermic peak, should be desolventizing peak (TGA and DSC, Figure 51；NMR, Figure 52).
Tosilate style 1, crystal form I are acetone solvent compounds, are defined as tosilate crystal form I.
55 DEG C, into THF (20v) solution of compound 1 (39.6mg), while stirring be added p-methyl benzenesulfonic acid (~ 1eq.).It is cooled to room temperature, there is solid precipitation.Continue after being stirred overnight, solid is collected by filtration, and small in 50 DEG C of vacuum drying 4 When, obtain tosilate style 2, crystal form II (Figure 53, table 14), and carry out XRPD, TGA, DSC and1H-NMR(400MHz) Analysis.Sample weightlessness~1% between 100 DEG C to 200 DEG C, fusing point are 228 DEG C (TGA and DSC, Figure 54).Meanwhile NMR and free Alkali compared to there are chemical shifts, and wherein contain~0.9% residual THF (Figure 55).
Tosilate style 2, crystal form II may be solvate or mixing crystal form.
The XRPD diffraction peak list of 13. tosilate crystal form I of table
Angle Intensity Angle Intensity Angle Intensity
2θ° % 2θ° % 2θ° %
5.963 54.7 18.712 10.9 28.068 11.8
6.969 61.4 19.092 39.2 28.429 8.7
7.474 11 19.752 57.6 28.94 9.3
10.019 71.2 20.328 33.5 29.973 8
10.604 100 20.821 16.9 30.335 6.4
11.593 27.1 21.313 90.7 30.705 8.3
11.867 9.1 22.473 24.3 31.435 6
13.194 13.9 23.047 11.8 32.161 8.7
13.956 49.7 23.359 21.4 32.618 7.4
14.325 7.6 23.733 38.7 33.037 7.2
14.975 28.4 24.329 17.5 33.438 7.8
15.386 11.5 24.859 46.5 35.289 6
15.781 9.3 25.72 11.4 36.551 5.1
16.182 18 26.334 48.3 37.978 4.1
16.877 7.6 26.792 27.5 38.491 4.8
17.174 8.3 27.586 34.2
The XRPD diffraction peak list of 14. tosilate crystal form II of table
Angle Intensity Angle Intensity Angle Intensity
2θ° % 2θ° % 2θ° %
4.088 36.1 14.125 50.4 22.119 27.6
7.136 59.2 14.928 17.7 23.226 25.9
8.18 37.5 15.308 20.4 23.959 25.5
8.598 45.5 16.227 100 24.427 69.6
9.874 12.8 17.233 53.4 25.054 22.5
10.334 16.3 18.529 57 26.305 44.1
10.69 33.9 19.18 96.6 27.253 13.4
11.39 75.9 19.585 34.9 27.686 29.7
12.168 53.2 20.024 53.4 28.732 19.3
13.063 21.5 20.695 54.9 35.328 10.1
13.288 23.1 21.486 37
Embodiment 13, sulfate
50 DEG C, into IPA (30v) solution of compound 1 (39.6mg), the IPA of sulfuric acid (~1eq.) is added while stirring Solution (50 μ L).Solid is precipitated, and is cooled to room temperature and is stirred overnight, and solid is collected by filtration and is dried in vacuo 4 hours at 50 DEG C, obtains Sulfate crystal form I (Figure 56, table 15), and carry out XRPD, TGA, DSC and1H-NMR (400MHz) analysis.Sample is in 165 DEG C of slips Weight~5.3% corresponds in NMR~5.2% IPA residual.With the presence of desolventizing peak (TGA and DSC, Figure 57 in DSC；NMR, Figure 58).
Sulfate crystal form I should be the solvated compounds of IPA.
The XRPD diffraction maximum of 15. sulfate crystal form I of table
Angle Intensity Angle Intensity Angle Intensity
2θ° % 2θ° % 2θ° %
7.394 100 14.716 24.8 22.105 24.3
7.887 27.1 15.63 20.3 24.022 25.1
10.055 16.1 16.586 15.6 24.951 25.4
10.538 21 17.868 15.7 26.325 27.3
11.922 18.1 17.929 16.5 39.375 7.4
13.33 20.4 19.008 23.3
14.085 16.5 19.917 24.2

Claims (16)

1. the hydrobromate of compound 1, succinate, maleate, fumarate, phosphate, mesylate, Pfansteihl salt, Oxalates, malate, benzene sulfonate, hydrochloride, tosilate or sulfate:
2. the crystal form I of the succinate of compound 1 described in claim 1, is characterized in that, mole of compound 1 and succinic acid Than for about 1:1, and (a) its X-ray powder diffraction collection is at least 10.82,21.66,22.39 and 26.76 in 2 θ angles, ± 0.2 °, one or more (1,2,3 or 4) have diffraction maximum, and/or (b) its DSC map in initial temperature is 177.91 DEG C There is heat absorption peak at ± 5 DEG C；
Preferably, the X-ray powder diffraction collection of the succinate crystal form I of the compound 1 has 6 or more (such as 10 A, 16 or 20) X-ray diffraction peak as in the table below:
Angle Angle Angle Angle Angle Angle Angle Angle 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 6.9 15.355 18.494 21.66 24.278 28.452 31.715 36.143 8.173 15.743 19.681 22.011 24.604 28.871 32.12 37.785 8.648 16.171 19.918 22.391 25.026 29.377 32.602 38.924 10.821 16.669 20.278 22.776 25.46 29.95 34.576 39.643 11.811 17.083 20.568 23.652 26.185 30.777 35.35 13.842 17.536 21.031 24.074 26.758 31.199 35.835
It is highly preferred that it is 10.82,17.54,21.66,22.39 and 26.76 that its X-ray powder diffraction collection, which has 2 θ angles, ± 0.2 °, diffraction maximum；
It is highly preferred that the crystal form I of the succinate of the compound 1 is shown and Fig. 7 almost the same X-ray powder diffraction figure Spectrum；Preferably, the crystal form I of the succinate is also shown and Fig. 8 almost the same DSC map.
3. the crystal form I of the maleate of compound 1 described in claim 1, is characterized in that, mole of compound 1 and maleic acid Than for about 1:1, and (a) its X-ray powder diffraction collection is at least 6.50 ° in 2 θ angles, 13.11 °, ± 0.2 ° 1 at or There is diffraction maximum at 2, and/or (b) its DSC map has heat absorption peak at initial temperature is 166.84 DEG C ± 5 DEG C；
Preferably, the X-ray powder diffraction collection of the crystal form I of the maleate of the compound 1 have 6 or more (such as 10,16 or 20) X-ray diffraction peak as in the table below:
Angle Angle Angle Angle Angle Angle Angle Angle 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 6.132 13.113 16.252 19.126 22.344 25.814 30.281 35.919 6.501 13.746 16.815 19.902 22.961 26.572 31.784 38.842 8.455 14.304 17.724 20.654 23.313 26.985 32.866 9.499 15.025 18.178 21.314 23.903 28.558 33.59 11.802 15.473 18.495 21.945 25.184 28.832 33.858
It is highly preferred that it is 6.5,13.11,15.03 and 25.18, ± 0.2 ° that its X-ray powder diffraction collection, which has 2 θ angles, Diffraction maximum；
It is highly preferred that the crystal form I of the maleate of the compound 1 is shown and Figure 12 almost the same X-ray powder diffraction Map；It is highly preferred that the crystal form I of the salt is also shown and Figure 13 almost the same DSC map.
4. the crystal form I of the fumarate of compound 1 described in claim 1, is characterized in that, compound 1 rubs with fumarate You are than being about 1:1, and (a) its X-ray powder diffraction collection is at least 5.71 ° in 2 θ angles, 16.97 °, 22.02 °, ± One or more of 0.2 ° have diffraction maximum (at 1,2 or 3, preferably 3), and/or (b) its DSC map initial temperature be 233.34 There is heat absorption peak at DEG C ± 5 DEG C；
Preferably, the X-ray powder diffraction collection of the crystal form I of the fumarate of the compound 1 have 6 or more (such as 10,16 or 20) X-ray diffraction peak as in the table below:
Angle Angle Angle Angle Angle Angle Angle Angle Angle Angle 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 5.705 12.835 16.968 19.426 21.809 24.252 27.519 30.314 34.815 37.761 10.024 14.057 17.279 19.798 22.021 24.574 28.436 30.587 35.433 39.841 10.307 15.017 17.79 20.241 22.766 25.233 28.97 31.043 36.043 11.465 15.431 18.264 20.676 23.139 25.739 29.35 31.879 36.39 11.951 16.529 19.159 21.473 23.501 27.04 29.946 32.959 37.035
It is highly preferred that it is 5.71,16.97,19.16,22.02,25.23 that its X-ray powder diffraction collection, which has 2 θ angles, and 27.04, ± 0.2 °, diffraction maximum；
It is highly preferred that the crystal form I of the fumarate of the compound 1 is shown and Figure 17 almost the same X-ray powder diffraction Map；Preferably, the crystal form I of the salt is also shown and Figure 18 almost the same DSC map.
5. the phosphatic crystal form I of compound 1 described in claim 1, is characterized in that, compound 1 and phosphatic molar ratio It is about 1:1, and (a) its X-ray powder diffraction collection at least has diffraction maximum at 2 θ angles is 7.01 ° ± 0.2 °, and/or (b) its DSC map is to have heat absorption peak at 149.14 DEG C ± 5 DEG C in initial temperature；
Preferably, the X-ray powder diffraction collection of the phosphatic crystal form I of the compound 1 has 6 or more (such as 6 A, 8 or 10) X-ray diffraction peak as in the table below:
Angle Angle Angle Angle Angle Angle Angle Angle 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 6.132 9.236 12.043 14.078 15.103 18.794 21.26 23.247 7.012 11.269 12.776 13.123 16.128 19.733 21.75 23.667
It is highly preferred that it is 7.01 and 9.24 that its X-ray powder diffraction collection, which has 2 θ angles, ± 0.2 ° of diffraction maximum；
It is highly preferred that the phosphatic crystal form I of the compound 1 is shown and Figure 22 almost the same X-ray powder diffraction figure Spectrum；It is highly preferred that the crystal form I of the salt is also shown and Figure 23 almost the same DSC map.
6. the crystal form I of the mesylate of compound 1 described in claim 1, is characterized in that, compound 1 rubs with mesylate You are than being about 1:1, and (a) its X-ray powder diffraction collection is at least 21.81 ° and 24.23 ° in 2 θ angles, ± 0.2 ° There is diffraction maximum at one or at two, and/or (b) its DSC map has heat absorption peak at initial temperature is 236.36 DEG C ± 5 DEG C；
Preferably, the X-ray powder diffraction collection of the crystal form I of the mesylate of the compound 1 have 8 or more (such as 10,16 or 20) X-ray diffraction peak as in the table below:
Angle Angle Angle Angle Angle Angle Angle Angle 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 7.154 11.738 16.459 20.326 24.229 27.775 31.984 36.453 8.459 12.887 16.973 20.972 24.827 28.116 32.888 38.75 8.951 14.042 17.631 21.805 25.694 28.852 33.322 39.306 9.601 14.489 18.37 22.292 25.963 29.24 33.964 10.424 15.152 18.983 22.95 26.467 30.53 34.367 11.508 15.804 19.311 23.825 27.441 31.295 35.621
It is highly preferred that it is 15.15,15.80,18.37,21.81 that its X-ray powder diffraction collection, which has 2 θ angles, and 24.23 °, ± 0.2 ° of diffraction maximum；
It is highly preferred that the crystal form I of the mesylate of the compound 1 is shown and Figure 25 almost the same X-ray powder diffraction Map；It is highly preferred that the crystal form I of the salt is also shown and Figure 26 almost the same DSC map.
7. the crystal form I of the Pfansteihl salt of compound 1 described in claim 1, is characterized in that, mole of compound 1 and Pfansteihl Than for about 1:1, and (a) its X-ray powder diffraction collection is at least 10.60 ° in 2 θ angles, 14.87 °, 17.77 °, 18.23 °, 21.27 °, 21.81 °, 23.25 °, 23.85 ° and 26.80 °, ± 0.2 ° one or more (1,2,3,4,5,6,7, At 8 or 9) there is diffraction maximum, and/or (b) its DSC map has heat absorption peak at initial temperature is 190.50 DEG C ± 5 DEG C；
Preferably, the X-ray powder diffraction collection of the crystal form I of the Pfansteihl salt of the compound 1 has 10 or more (e.g., 10 or 20) X-ray diffraction peak as in the table below:
Angle Angle Angle Angle Angle Angle Angle 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 7.914 13.533 18.227 22.138 28.053 32.768 39.396 8.947 14.869 18.911 23.247 28.798 33.417 9.458 15.875 19.971 23.845 29.695 34.393 9.982 16.468 20.459 24.5 30.37 35.853 10.595 16.985 21.266 26.13 31.03 36.882 11.036 17.774 21.811 26.797 32.077 38.12
It is highly preferred that its X-ray powder diffraction collection have 2 θ angles be 7.91 °, 8.95 °, 9.98 °, 10.60 °, 14.87 °, 17.77 °, 18.23 °, 18.91 °, 21.27 °, 21.81 °, 22.14 °, 23.25 °, 23.85 °, 24.5 ° and 26.80 °, ± 0.2 ° Diffraction maximum；
It is highly preferred that the crystal form I of the Pfansteihl salt of the compound 1 is shown and Figure 28 almost the same X-ray powder diffraction Map；It is highly preferred that the crystal form I of the salt is also shown and Figure 29 almost the same DSC map.
8. the crystal form I of the oxalates of compound 1 described in claim 1, is characterized in that, compound 1 and the molar ratio of oxalic acid are About 1:1, and (a) its X-ray powder diffraction collection at least 2 θ angles be 6.83 ° and 24.77 °, ± 0.2 ° 1 at or 2 at There is diffraction maximum, and/or (b) its DSC map has heat absorption peak at initial temperature is 216.47 DEG C ± 5 DEG C；
Preferably, the X-ray powder diffraction collection of the crystal form I of the oxalates of the compound 1 has 4 or more (such as 6 A, 10 or 20) X-ray diffraction peak as in the table below:
Angle Angle Angle Angle Angle Angle Angle 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 6.174 13.133 17.051 21.878 26.759 29.358 36.246 6.828 13.634 17.824 22.242 26.851 29.962 37.548 7.901 14.191 18.639 23.157 27.17 31.803 38.61 10.356 15.532 19.97 23.646 27.673 32.228 12.205 15.989 20.755 24.769 29.121 33.001 12.48 16.503 21.342 25.862 29.163 34.67
It is highly preferred that it is 6.83,12.48,15.99,16.50,17.82 that its X-ray powder diffraction collection, which has 2 θ angles, 20.76,24.77 and 27.67, ± 0.2 ° of diffraction maximum.
It is highly preferred that the crystal form I of the oxalates of the compound 1 is shown and Figure 33 almost the same X-ray powder diffraction figure Spectrum；It is highly preferred that the crystal form I of the salt is also shown and Figure 34 almost the same DSC map.
9. the crystal form I of the malate of compound 1 described in claim 1, is characterized in that, mole of compound 1 and malic acid Than for about 1:1, and (a) its X-ray powder diffraction collection at least 2 θ angles be 10.62 °, 17.04 °, 17.39 ° and 21.29 °, one or more of ± 0.2 ° have diffraction maximum (at 1,2,3 or 4), and/or (b) its DSC map in initial temperature is There is heat absorption peak at 153.85 DEG C ± 5 DEG C；
Preferably, the crystal form I of the malate of the compound 1, is characterized in that, X-ray powder diffraction collection has 4 A or above (such as 6,10 or 20) X-ray diffraction peak as in the table below:
It is highly preferred that its X-ray powder diffraction collection have 2 θ angles be 10.62 °, 17.04 °, 17.39 °, 20.61, 20.82 °, 21.29 °, 22.35 ° and 26.44 °, ± 0.2 ° of diffraction maximum；
It is highly preferred that the crystal form I of the malate of the compound 1 is shown and Figure 36 almost the same X-ray powder diffraction Map；It is highly preferred that the crystal form I of the salt is also shown and Figure 37 almost the same DSC map.
10. the crystal form I of the benzene sulfonate of compound 1 described in claim 1, is characterized in that, mole of compound 1 and benzene sulfonic acid Than for about 1:1, and (a) its X-ray powder diffraction collection is at least 11.55 ° in 2 θ angles, 16.46 °, 19.45 °, 20.14 °, 20.98 ° and 24.80 °, one or more of ± 0.2 ° have diffraction maximum (at such as 1,2,3,4,5 or 6), and/or (b) its DSC map is to have heat absorption peak at 207.71 DEG C ± 5 DEG C in initial temperature；
Preferably, the X-ray powder diffraction collection of the crystal form I of the benzene sulfonate of the compound 1 have 6 or more (such as 8,12 or 20) X-ray diffraction peak as in the table below:
Angle Angle Angle Angle Angle Angle Angle 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 7.211 11.551 15.4 19.448 23.34 27.442 32.659 8.164 12.343 16.456 20.135 24.001 28.037 33.211 8.666 13.259 17.45 20.979 24.801 29.18 36.246 10.435 14.249 17.924 21.782 26.176 29.896 10.898 14.839 18.569 22.505 26.746 31.66
Preferably, X-ray powder diffraction collection have 2 θ angles be 7.21 °, 8.16 °, 8.67 °, 10.90 °, 11.55 °, 12.34 °, 13.26 °, 14.25 °, 16.46 °, 17.45 °, 18.57 °, 19.45 °, 20.14 °, 20.98 °, 24.80 ° and 26.75 °, ± 0.2 ° of diffraction maximum；
It is highly preferred that the crystal form I of the benzene sulfonate of the compound 1 is shown and Figure 41 almost the same X-ray powder diffraction Map；It is highly preferred that the crystal form I of the salt is also shown and Figure 42 almost the same DSC map.
11. the hydrochloride of compound 1 described in claim 1 is the crystal form I or crystal form of the hydrochloride of the compound 1 II,
Wherein crystal form I is characterized in that, the molar ratio of compound 1 and hydrochloric acid is about 1:1, and (a) its X-ray powder diffraction figure Spectrum at least 2 θ angles be 7.79 ° and 9.71 °, ± 0.2 ° 1 at or 2 at have diffraction maximum, and/or (b) its DSC map 106 DEG C, there is heat absorption peak at 170 DEG C and 209 DEG C ± 5 DEG C；
Preferably, the X-ray powder diffraction collection of the hydrochloride Form I of the compound 1 have 6 or more (such as 8, 12 or 20) X-ray diffraction peak as in the table below:
Angle Angle Angle Angle Angle Angle 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 3.649 9.705 13.888 16.758 23.728 26.732 4.742 11.197 14.858 18.091 25.188 27.9 7.109 12.572 15.343 21.783 25.634 7.794 13.419 15.833 23.225 25.817
It is highly preferred that its X-ray powder diffraction collection have 2 θ angles be 3.65 °, 4.74 °, 7.11 °, 7.79 °, 9.71 °, and 11.20 °, ± 0.2 °, diffraction maximum；
It is highly preferred that the crystal form I of the hydrochloride of the compound 1 is shown and Figure 44 almost the same X-ray powder diffraction figure Spectrum；It is highly preferred that the crystal form I of the salt is also shown and Figure 45 almost the same DSC map；
Wherein the crystal form II of the hydrochloride of the compound 1 is characterized in that, the molar ratio of compound 1 and hydrochloric acid is about 1: 1, and (a) its X-ray powder diffraction collection at least has diffraction maximum at 2 θ angles is 10.88 ° ± 0.2 °, and/or (b) its DSC Map has heat absorption peak at 123 DEG C, 160 DEG C and 180 DEG C ± 5 DEG C；
Preferably, the X-ray powder diffraction collection of the crystal form II of the hydrochloride of the compound 1 has 6 or more (such as 8 A, 12 or 20) X-ray diffraction peak as in the table below:
Angle Angle Angle Angle Angle Angle Angle Angle 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 3.607 10.876 15.542 19.649 22.976 26.418 31.436 37.175 7.268 12.429 18.252 21.397 23.392 26.846 33.536 9.813 13.384 19.307 21.903 24.987 27.767 37.073
It is highly preferred that it is 3.61 °, 9.81 ° and 10.88 ° that its X-ray powder diffraction collection, which has 2 θ angles, ± 0.2 ° is spread out Penetrate peak；
It is highly preferred that the crystal form II of the hydrochloride of the compound 1 is shown and Figure 47 almost the same X-ray powder diffraction figure Spectrum；It is highly preferred that the crystal form II of the salt is also shown and Figure 48 almost the same DSC map.
12. the tosilate of compound 1 described in claim 1 is the crystal form I of the tosilate of compound 1 Or crystal form II,
Wherein, crystal form I is characterized in that, the molar ratio of compound 1 and p-methyl benzenesulfonic acid is about 1:1, and (a) its X-ray powder Last diffracting spectrum at least 2 θ angles be 5.96 °, 6.97 °, 10.02 °, 10.60 °, 19.75 ° and 21.31 °, ± 0.2 ° one at Or many places (at 1,2,3,4,5 or 6) has diffraction maximum, and/or (b) its DSC map has at initial temperature is 131.46 DEG C ± 5 DEG C Heat absorption peak；
Preferably, the X-ray powder diffraction collection of the tosilate crystal form I of the compound 1 has 6 or more (such as 8,12 or 20) X-ray diffraction peak as in the table below:
It is highly preferred that its X-ray powder diffraction collection have 2 θ angles be 5.96 °, 6.97 °, 10.02 °, 10.60 °, 13.96 °, 19.09 °, 19.75 °, 20.33 °, 21.31 °, 23.73 °, 24.86 °, 26.33 ° and 27.59 °, ± 0.2 ° of diffraction Peak；
It is highly preferred that the crystal form I of the tosilate of the compound 1 is shown and Figure 50 almost the same x-ray powder Diffracting spectrum；It is highly preferred that the crystal form I of the salt is also shown and Figure 51 almost the same DSC map.
Wherein the crystal form II of the tosilate of the compound 1 is characterized in that, mole of compound 1 and p-methyl benzenesulfonic acid Than for about 1:1, and (a) its X-ray powder diffraction collection is at least 7.14 ° in 2 θ angles, 11.39 °, 12.17 °, 14.13 °, 16.23 °, 17.23 °, 18.53 °, 19.18 °, 20.02 °, 20.70 ° and 24.43 °, one or more of ± 0.2 ° (at preferably 5 or more, such as 7, at 8,9,10) have diffraction maximum, and/or (b) its DSC map in initial temperature is 222.17 DEG C There is heat absorption peak at ± 5 DEG C；
Preferably, the X-ray powder diffraction collection of the crystal form II of the tosilate of the compound 1 have 6 or with Upper (such as 8,12 or 20) X-ray diffraction peak as in the table below:
Angle Angle Angle Angle Angle Angle Angle Angle 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 4.088 9.874 12.168 14.928 18.529 20.695 23.959 27.253 7.136 10.334 13.063 15.308 19.18 21.486 24.427 27.686 8.18 10.69 13.288 16.227 19.585 22.119 25.054 28.732 8.598 11.39 14.125 17.233 20.024 23.226 26.305 35.328
It is highly preferred that its X-ray powder diffraction collection have 2 θ angles be 7.14 °, 8.18 °, 8.60 °, 10.69 °, 11.39 °, 12.17 °, 14.13 °, 16.23 °, 17.23 °, 18.53 °, 19.18 °, 19.59 °, 20.02 °, 20.70 °, 21.49 °, 24.43 ° ° With 26.31 °, ± 0.2 ° of diffraction maximum；
It is highly preferred that the crystal form II of the tosilate of the compound 1 is shown and Figure 53 almost the same x-ray powder Diffracting spectrum；It is highly preferred that the crystal form II of the salt is also shown and Figure 54 almost the same DSC map.
13. the crystal form I of the sulfate of compound 1 described in claim 1, is characterized in that, compound 1 and the molar ratio of sulfuric acid are About 1:1, and (a) its X-ray powder diffraction collection at least has diffraction maximum at 2 θ angles is 7.39 ° ± 0.2 °, and/or (b) Its DSC map is to have heat absorption peak at 141.22 DEG C ± 5 DEG C in initial temperature；
Preferably, the X-ray powder diffraction collection of the crystal form I of the sulfate of the compound 1 has 6 or more (such as 8 It is a or 10) X-ray diffraction peak as in the table below:
Angle Angle Angle Angle Angle Angle Angle 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 2θ° 7.394 10.538 14.085 16.586 19.008 24.022 39.375 7.887 11.922 14.716 17.868 19.917 24.951 10.055 13.33 15.63 17.929 22.105 26.325
It is highly preferred that the crystal form I of the sulfate of the compound 1 is shown and Figure 56 almost the same X-ray powder diffraction figure Spectrum；It is highly preferred that the crystal form I of the salt is also shown and Figure 57 almost the same DSC map.
14. the crystal form I of the hydrobromate of compound 1 described in claim 1, is characterized in that, mole of compound 1 and hydrobromic acid Than for about 1:1, and (a) its X-ray powder diffraction collection is at least 9.93 ° in 2 θ angles, 10.82 °, 14.11 °, 20.42 °, 21.66 °, 25.02 °, 25.89 ° and 26.25 °, ± 0.2 one or more (at preferably 5 or more, such as 6,7, Or at 8) there is diffraction maximum, and/or (b) its DSC map has heat absorption peak at initial temperature is 272.88 DEG C ± 5 DEG C；
Preferably, the X-ray powder diffraction collection of the crystal form I of the hydrobromate have 6 or more (such as 8,12, or 20) X-ray diffraction peak as in the table below:
It is highly preferred that its X-ray powder diffraction collection have 2 θ angles be 6.85 °, 8.39 °, 9.93 °, 10.82 °, 14.11 °, 19.02 °, 20.42 °, 20.82 °, 21.66 °, 22.51 °, 25.02 °, 25.89 °, 26.25 ° and 27.32 °, ± 0.2 ° of diffraction Peak；
It is highly preferred that the crystal form I of the hydrobromate of the compound 1 is shown and Fig. 4 almost the same X-ray powder diffraction figure Spectrum；It is highly preferred that the crystal form I of the salt is also shown and Fig. 5 almost the same DSC map.
15. a kind of pharmaceutical composition, it includes the salt of compound 1 according to any claim 1-14 and pharmaceutically Acceptable carrier or diluent；Preferably, compound 1 is in the pharmaceutical composition mainly described in claim 2-14 A kind of crystal form exists (for example, about 80wt%, about 90wt%, about 95wt%, or above described in claim 2-14 A kind of crystal form exist or XRPD can't detect the other forms of compound 1).
16. salt described in any one of claim 1-14 or claim 15 described pharmaceutical composition are in preparation treatment or in advance It is anti-by the EGFR of activation or resistant mutant forms mediation, for example, L858R activated mutant body, Exon19 lack activated mutant What body and/or T790M resistant mutants EGFR were mediated, the purposes in the drug of obstacle or disease；
Preferably, the obstacle or disease are selected from one or more of: oophoroma, cervical carcinoma, colorectal cancer are (for example, knot Enteraden cancer), it is breast cancer, cancer of pancreas, glioma, glioblastoma, melanoma, prostate cancer, leukaemia, lymthoma, non- Hodgkin lymphoma, gastric cancer, lung cancer (for example, non-small cell lung cancer), hepatocellular carcinoma, gastrointestinal stromal tumor (GIST), thyroid gland Cancer, cholangiocarcinoma, carcinoma of endometrium, kidney, primary cutaneous type, acute myelocytic leukemia (AML), multiple marrow Tumor or celiothelioma.
CN201910544016.1A 2019-06-21 2019-06-21 Salt, polymorph and its pharmaceutical composition, the preparation method and application of a kind of pyrimidine compound Pending CN110229143A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105085489A (en) * 2014-11-05 2015-11-25 上海页岩科技有限公司 Pyrimidine or pyridine compound, and preparation method and pharmaceutical application thereof
CN106478605A (en) * 2015-09-02 2017-03-08 上海页岩科技有限公司 Pyrimidines, its preparation method and medical usage

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105085489A (en) * 2014-11-05 2015-11-25 上海页岩科技有限公司 Pyrimidine or pyridine compound, and preparation method and pharmaceutical application thereof
CN106478605A (en) * 2015-09-02 2017-03-08 上海页岩科技有限公司 Pyrimidines, its preparation method and medical usage

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