CN106459111B - A kind of crystal form of anticancer compound and its preparation method and application - Google Patents
A kind of crystal form of anticancer compound and its preparation method and application Download PDFInfo
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- 239000013078 crystal Substances 0.000 title claims abstract description 80
- 150000001875 compounds Chemical class 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 230000001093 anti-cancer Effects 0.000 title abstract description 5
- 238000003756 stirring Methods 0.000 claims description 18
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 17
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 15
- 201000005202 lung cancer Diseases 0.000 claims description 15
- 208000020816 lung neoplasm Diseases 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 14
- 238000001291 vacuum drying Methods 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 9
- 230000008025 crystallization Effects 0.000 claims description 9
- 239000012296 anti-solvent Substances 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000004090 dissolution Methods 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 239000003560 cancer drug Substances 0.000 claims 1
- 229910052801 chlorine Chemical group 0.000 claims 1
- 239000000460 chlorine Chemical group 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- -1 chloro- 3- fluorophenyl Chemical group 0.000 abstract description 7
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 abstract description 5
- 239000001301 oxygen Substances 0.000 abstract description 5
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 18
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 14
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 14
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 12
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 12
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 11
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- 229940049068 xalkori Drugs 0.000 description 10
- 206010028980 Neoplasm Diseases 0.000 description 7
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- 239000000523 sample Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000012827 research and development Methods 0.000 description 3
- 208000000649 small cell carcinoma Diseases 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
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- 229960005061 crizotinib Drugs 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
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- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 108010079505 Endostatins Proteins 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 238000002619 cancer immunotherapy Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229940082789 erbitux Drugs 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 238000011354 first-line chemotherapy Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000007901 in situ hybridization Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 229940084651 iressa Drugs 0.000 description 1
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- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
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- 238000011275 oncology therapy Methods 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
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- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
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- 230000019491 signal transduction Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000003319 supportive effect Effects 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of anticancer compound (R) -3- [1- (2, the chloro- 3- fluorophenyl of 6- bis-) ethyoxyl] -5- [3- fluorophenyl -1- dimethyl phosphine acyl-oxygen -4- base] pyridine -2- amine crystal form and preparation method, structural formula is as shown in formula I.Stability of crystal form of the present invention is good, low in hygroscopicity, good fluidity, meets pharmaceutical preparation application demand.
Description
Technical field
The present invention relates to a kind of anticancer compound (R) -3- [1- (2,6- bis- chloro- 3- fluorophenyl) ethyoxyl] -5- [3- fluorobenzene
Base -1- dimethyl phosphine acyl-oxygen -4- base] pyridine -2- amine crystal form and preparation method thereof.
Background technique
Lung cancer is most common lung's primary malignant tumor, is generally divided into non-small cell lung cancer (NSCLC) and cellule
Lung cancer (SCLC).Lung cancer is the highest cancer of morbidity and mortality, and non-small cell lung cancer account for lung cancer sum 80%~
85%, the death rate is up to 80%~90%.According to the statistics of the World Health Organization (WHO), global lung cancer neopathy in 2002
Example 1332132, the 12.4% of whole new cancer cases sums is accounted for, occupies first, the Ministry of Public Health, China public affairs on April 29th, 2008
The Third National coroner's inquest main result of cloth shows that Past 30 Years China lung cancer mortality rises 465%, at present lung cancer
Liver cancer has been substituted as China first place Death Cause for Malignant Tumors, has accounted for the 22.7% of mortality of malignant tumors.
5 years survival rates about 10%~15% of developed country's lung cancer are then lower in China.If advanced NSCLC is not treated,
Median survival interval about 4~5 months, survival rate was lower than 10% within 1 year, and the standard First-line chemotherapy scheme of advanced NSCLC is equivalent to most preferably
Supportive treatment can effectively extend median survival interval, improve 1 year survival rate.But the curative effect of current chemotherapy seems that reaching one puts down
Platform, objective effective percentage about 30%, median survival interval 8~9 months, 1 year survival rate 30%~40%.Therefore, finding more has
The treatment means of effect and safety become a hot spot of current lung cancer research.Tumor cells targeted therapy is for other biological
The treatment means of approach.Currently, the target therapeutic agent of NSCLC mainly has the inhibition of EGF-R ELISA (EGFR) family
Agent, angiogenesis inhibitors, multiple target point inhibitor, signal transduction inhibitor, inducer of apoptosis etc..Chinese Anti-Cancer Association's clinic is swollen
Tumor cooperation Professional Committee (CSCO) executive committee General Board, famous clinical tumor expert professor Ma Jun point out: " by
There is concealment in early stage, most of Patients with Non-small-cell Lung have been Locally Advanceds when finding or have shifted, and are more than half
Patients with lung cancer can miss operative chance.Traditional chemicotherapy offer limited effectiveness, and with insufferable drug toxicity, usually
The number of chemicotherapy failure is more, and the effect of successive treatment is poorer.But the appearance of targeted drug provides one kind to lung cancer is conquered
Newly may."
Pfizer announced that XALKORI (crizotinib) capsule of the said firm obtains U.S.'s food on August 26th, 2011
Product drug administration FDA approval, this is first drug that targeted therapy is carried out to anaplastic lymphoma kinase (ALK), is used for
Treatment is diagnosed as the Locally Advanced of the ALK positive or the non-small cell lung cancer of transfer by the detection method that FDA ratifies.XALKORI
Curative effect system be based on objective remission rate (ORR).XALKORI is while acquisition FDA quickly ratifies, after Pfizer is being listed
Clinical test, it is intended to which further assessment is done to the clinical efficacy of XALKORI.According to FDA about targeted therapy and with diagnosis
Newest instruction, Pfizer have carried out hand-in-glove with FDA and molecular diagnosis business department, Abbott Laboratories in clinical test, it is ensured that
The diagnosis detection technique of XALKORI and Abbott Laboratories is evaluated and is ratified simultaneously.The latter, that is, molecular diagnosis business department, Abbott Laboratories
Vysis ALK Break Apart FISH (fluorescence in situ hybridization) probe reagent box, to find ALK fusion gene.
XALKORI and the ALK FISH kit of molecular diagnosis business department, Abbott Laboratories are granted simultaneously, also indicate the tumour medicine of Pfizer
Or cancer immunotherapies for the first time with diagnosis detection scheme together with carry out exploitation and it is granted." by the driving base for really understanding NSCLC
Cause, such as ALK, we can choose out the most possibly patient to therapeutic response.XALKORI, which is that we provide one, to be explored not
Carry out the brand-new road of medicament research and development and treatment of cancer, " the responsible person Paul of cancer research department, UNIVERSITY OF COLORADO AT DENVER
Bunn professor and James Dudley chief physician point out." XALKORI is first treatment lung cancer for carrying out FDA approval 6 years more
New drug represents Treatment for Non-small Cell Lung Mode change, we are diverted through biology from machine-made therapeutic scheme
The treatment mode of marker decision." in XALKORI clinical test, testing program requires the biomarker ALK of patient tumors
Fusion testing result is the positive, to improve a possibility that making a response to treatment.It is used for this inspection of lung cancer therapy for the first time
Survey method can make researcher observe good therapeutic effect in the patients screened in advance.Preliminary epidemiology is ground
Study carefully and show that ALK positive rate is about 3-5% in non-small cell lung cancer, it is meant that every year in the U.S. about 6 500 to 11
The Patients with Non-small-cell Lung of 000 ALK positive.The targeted therapy of clinical test is registered by XALKORI, late ALK sun
Property Patients with Non-small-cell Lung in, objective remission rate be 50 to 61%.
In the scholarly forecast 2008-2013 term, Chinese non-small cell lung cancer (NSCLC) treatment market will double with
On, from 3.07 hundred million dollars to 6.48 hundred million dollar.The increase of colorectal cancer case treatment will accelerate this growth.Urbanization and population
During aging will lead to 2008-2018, Chinese non-small cell lung cancer morbidity case increases by 47%, from 36.15 ten thousand to 53.13
Ten thousand.Most apparent increase will occur in city, and following 10 years non-small cell lung cancer morbidity cases will increase by 72% herein, with
This is on the contrary, rural area only has 8% growth.Gefitinib (Iressa of AstraZeneca), Erlotinib (special sieve of Roche
It is triumphant) and the targeted therapies such as Endostatin (rhEndostatin of Jiangsu first sign medicine company) it is increasingly widespread, and new target therapeutic agent pushes away
--- bevacizumab (Avastin of Roche) and cetuximab (Erbitux of Merck) --- is during being 2008-2013 out
Push the main power in Chinese non-small cell lung cancer market.The market share of China, trans-corporation Treatment for Non-small Cell Lung will be from
34% in 2008 rises to 47% in 2013.This growth will mainly be increased by the introducing of targeted drug and be driven.Due to
Low-price competition is fierce, and the chemotherapeutics of trans-corporation will lose in the market of China.Therefore, as " the me of Crizotinib
Too " drug, compound of formula I will have wide market potential.
Drug crystal forms research and the research and development of drug solid-state have very important meaning in pharmacy industry.Drug molecule usually has not
Same solid forms, including salt, polycrystalline, eutectic is amorphous, hydrate and solvate；The not isomorphous of same drug molecule
Type, in crystal structure, stability, the properties such as productibility and bioavilability might have significant difference, thus directly
Influence the curative effect and exploitability of drug.Therefore, any one drug research and development requires to carry out comprehensive and systematic polymorphic sieve
Choosing, finds crystal form as much as possible, then in-depth study is carried out to these crystal forms using various solid-state approach, to find most
It is suitble to the crystal form of exploitation.
Summary of the invention
The purpose of the present invention is to provide a kind of crystal forms of formula (I) compound
Preferably, the crystal form is crystal form A, XRPD map 20 (± 0.2 °) for 7.86,9.60,11.76,12.37,
14.68, there is diffraction maximum at 19.61,20.02,21.19,23.76,24.89.
It is furthermore preferred that the XRPD map of the crystal form A is as shown in Figure 1.
Another object of the present invention also resides in the method for providing and preparing the formula (I) compound crystal form A, including with organic molten
Agent A dissolves formula (I) compound, stirs cooling crystallization, filters to obtain target crystal form.
Another object of the present invention also resides in a kind of method for preparing the formula (I) compound crystal form A of substitution that provides, packet
It includes and dissolves formula (I) compound with organic solvent B, anti-solvent A stirring and crystallizing is added, filters to obtain target crystal form.
Preferably, the organic solvent A is selected from tetrahydrofuran and/or acetone.
Preferably, the organic solvent B is selected from methylene chloride and/or chloroform, and the anti-solvent A is selected from isopropyl ether, positive heptan
Alkane and/or n-hexane.
Another object of the present invention also resides in the crystal form B of offer formula (I) compound, and the crystal form is crystal form B, XRPD figure
Spectrum is to have diffraction at 6.82,10.14,11.25,12.55,13.50,14.90,16.27,19.78,25.21 at (± 0.2 °) of 2 θ
Peak.
Preferably, the XRPD map of the crystal form B is as shown in Figure 2.
The object of the invention is also to provide a kind of methods for preparing the formula (I) compound crystal form B, including with organic molten
Agent C dissolves compound of formula I, stirs cooling crystallization, filters to obtain target crystal form, optional, it also include vacuum drying step after filtering.
Another object of the present invention also resides in the method for the preparation formula (I) compound crystal form B of a kind of substitution that provides, including with
Organic solvent D dissolves compound of formula I, and anti-solvent B crystallization is added, filters to obtain target crystal form, optional, it also include vacuum after filtering
Drying steps.
Preferably, the vacuum drying temperature is 20-40 DEG C, more preferable 20-30 DEG C, most preferably 25 DEG C.
Preferably, the organic solvent C is selected from isopropanol and/or n-butanol.
Preferably, the organic solvent D is selected from isopropanol, acetone and/or 2- butanone, and the anti-solvent B is selected from and is positive heptan
Alkane or n-hexane.
Another object of the present invention, which also resides in, provides a kind of pharmaceutical composition, the crystal form and medicine comprising therapeutically effective amount
Acceptable carrier on.
Another object of the present invention also resides in the above-mentioned crystal form of offer or pharmaceutical composition is used to prepare the work of anti-tumor drug
With, it is preferred that the application being used to prepare in treatment lung-cancer medicament.
Crystal form purity provided by the present invention is high, and stability is good, low in hygroscopicity, good fluidity, and pharmaceutical preparation is suitble to need.
Detailed description of the invention
Fig. 1 is (R) -3- [1- (2,6- bis- chloro- 3- fluorophenyl) ethyoxyl] -5- [3- fluorophenyl -1- dimethyl phosphine acyl-oxygen -
4- yl] pyridine -2- amine crystal form A XRPD map；
Fig. 2 is (R) -3- [1- (2,6- bis- chloro- 3- fluorophenyl) ethyoxyl] -5- [3- fluorophenyl -1- dimethyl phosphine acyl-oxygen -
4- yl] pyridine -2- amine crystal form B XRPD map.
Specific embodiment
Embodiment 1
Compound of formula I crude product 5.0g is put into acetone 42ml, 60 DEG C of stirring in water bath dissolutions, then natural cooling stirring analysis
Brilliant 2h.Filtering, 25 DEG C of vacuum drying obtain target crystal form A 4.1g.Through detecting, XRPD map is as shown in Figure 1.
Embodiment 2
Compound of formula I crude product 5.0g is put into tetrahydrofuran 150ml, 60 DEG C of stirring in water bath dissolutions, then natural cooling
Stirring and crystallizing 2h.Filtering, 25 DEG C of vacuum drying obtain target crystal form A3.6g.Through detecting, XRPD map coincide with Fig. 1 substantially,
All characteristic peaks are in error range.
Embodiment 3
Compound of formula I crude product 5.0g is put into methylene chloride 30ml, stirring and dissolving, isopropyl ether 100ml is then added and stirs
Mix crystallization 2h.Filtering, 25 DEG C of vacuum drying obtain target crystal form A4.4g.Through detecting, XRPD map coincide with Fig. 1 substantially, institute
There is characteristic peak in error range.
Embodiment 4
Compound of formula I crude product 5.0g is put into methylene chloride 30ml, stirring and dissolving, normal heptane 100ml is then added and stirs
Mix crystallization 2h.Filtering, 25 DEG C of vacuum drying obtain target crystal form A4.5g.Through detecting, XRPD map coincide with Fig. 1 substantially, institute
There is characteristic peak in error range.
Embodiment 5
Compound of formula I crude product 5.0g is put into isopropanol 30ml, 60 DEG C of stirring in water bath dissolutions, then natural cooling stirs
Crystallization 2h.Filtering, 25 DEG C of vacuum drying obtain target crystal form B4.3g.Through detecting, XRPD map is as shown in Figure 2.
Embodiment 6
Compound of formula I crude product 5.0g is put into isopropanol 50ml, normal heptane 150ml stirring and crystallizing 2h is then added.It crosses
Filter, 25 DEG C of vacuum drying obtain target crystal form B 4.3g.Through detecting, XRPD map coincide with Fig. 2 substantially, and all characteristic peaks are equal
In error range.
Embodiment 7
Compound of formula I crude product 5.0g is put into acetone 150ml, then normal heptane is added in 40 DEG C of stirring in water bath dissolutions
1200ml stirring and crystallizing 2h.Filtering, 25 DEG C of vacuum drying obtain target crystal form B 4.4g.Through detecting, XRPD map substantially with
Fig. 2 coincide, and all characteristic peaks are in error range.
Experimental example one, crystal form A stability study
Using crystal form prepared by the embodiment of the present invention 1 as sample, the stability of crystal form, knot are detected under condition of different temperatures
Fruit is as shown in table 1
Table 1
| Temperature | 25℃ | 45℃ | 60℃ |
| Crystal form | A | A | A |
As seen from the above table, crystal form A has good stability under the conditions of 25 DEG C -60 DEG C
Experimental example two, crystal form B stability study
Using crystal form prepared by the embodiment of the present invention 5 as sample, the stability of crystal form, knot are detected under condition of different temperatures
Fruit is as shown in table 2
Table 2
| Temperature | 20℃ | 30℃ | 50℃ |
| Crystal form | B | B | B |
As seen from the above table, crystal form B has good stability under the conditions of 20 DEG C -50 DEG C
Experimental example three, draw it is moist
Draw according to " drug draws moist test guideline " (2010 editions two annex XI X J of Chinese Pharmacopoeia) moist
Test.Take dry stuffed glass weighing bottle (outer diameter 50mm, a height of 15mm), be placed in test the previous day suitable 25 DEG C ±
In 1 DEG C of thermostatic drier (placing ammonium chloride saturated solution in lower part), accurately weighed weight (ml)；Take it is appropriate for crystal form of the present invention,
It is laid in above-mentioned weighing bottle, the thickness of test sample is typically about 1mm, accurately weighed weight (m2)；By weighing bottle opening, and with
Bottle cap is placed 24 hours under the conditions of being placed in above-mentioned constant temperature and humidity together；Cover weighing bottle lid, precise weighing (m3).
Percentage weight increase
Draws moist test judgment criteria is as follows:
It deliquesces: absorbing enough moisture and form liquid
According to above method, (R) -3- of the invention [1- (2,6- bis- chloro- 3- fluorophenyl) ethyoxyl] -5- [3- fluorine is measured
Phenyl -1- dimethyl phosphine acyl-oxygen -4- base] pyridine -2- amine crystal form A compound percentage weight increase be 0.3%, crystal form B compound
Percentage weight increase be 1.0%, it is moist to show that crystal form A and crystal form B of the present invention slightly draw, is hardly influenced and damp by high humility
Solution.
Example IV, mobility
Appropriate crystal form A and crystal form B of the present invention are taken, angle of repose measurement is carried out.
Fixed funnel method measures angle of repose.Funnel is fixed on certain altitude H, powder is placed in funnel, is nature stream
Under it is in heaps, until the top of cone has just released until hopper outlet, measure the radius r of circular cone bottom surface, calculate angle of repose.Stop
Angle=arc tg (H/r).Measurement result arranges in table 3.
| Crystal form | Angle of repose (°) |
| Crystal form A | 26.4 |
| Crystal form B | 23.6 |
The result shows that crystal form crystal form A of the present invention, crystal form B have lesser angle of repose, illustrate the mobility of crystal form of the present invention
It is higher.
Claims (18)
- The crystal form of formula 1. (I) compound,It is characterized in that, the crystal form is crystal form A, XRPD map (± 0.2 °) of 2 θ for 7.86,9.60,11.76,12.37, 14.68, there is diffraction maximum at 19.61,20.02,21.19,23.76,24.89.
- 2. the crystal form of formula (I) compound according to claim 1, which is characterized in that the XRPD map of the crystal form A is as schemed Shown in 1.
- 3. the method for preparing formula described in claim 1 (I) compound crystal form A, including with organic solvent A dissolution type (I) chemical combination Object stirs cooling crystallization, filters to obtain target crystal form.
- 4. preparation method according to claim 3, which is characterized in that the organic solvent A is selected from tetrahydrofuran and/or third Ketone.
- 5. the method for preparing formula described in claim 1 (I) compound crystal form A, including with organic solvent B dissolution type (I) chemical combination Object is added anti-solvent A stirring and crystallizing, filters to obtain target crystal form.
- 6. preparation method according to claim 5, which is characterized in that the organic solvent B is selected from methylene chloride and/or chlorine Imitative, the anti-solvent A is selected from isopropyl ether, normal heptane and/or n-hexane.
- The crystal form of formula 7. (I) compound,It is characterized in that, the crystal form is crystal form B, XRPD map (± 0.2 °) of 2 θ for 6.82,10.14,11.25, 12.55, there is diffraction maximum at 13.50,14.90,16.27,19.78,25.21.
- 8. the crystal form of formula (I) compound according to claim 7, which is characterized in that the XRPD map of the crystal form B is as schemed Shown in 2.
- 9. the method for preparing formula (I) compound crystal form B described in claim 7 or 8 any one, including it is molten with organic solvent C Type I compound is solved, cooling crystallization is stirred, filters to obtain target crystal form, optional, it also include vacuum drying step after filtering.
- 10. preparation method according to claim 9, which is characterized in that the organic solvent C is selected from isopropanol and/or just Butanol.
- 11. the method for preparing formula (I) compound crystal form B described in claim 7 or 8 any one, including it is molten with organic solvent D Type I compound is solved, anti-solvent B crystallization is added, filters to obtain target crystal form, optional, it also include vacuum drying step after filtering.
- 12. preparation method according to claim 11, which is characterized in that the organic solvent D is selected from isopropanol, acetone And/or 2- butanone, it is normal heptane or n-hexane that the anti-solvent B, which is selected from,.
- 13. the preparation method according to claim 9 or 11, which is characterized in that the vacuum drying temperature is 20-40 ℃。
- 14. preparation method according to claim 13, which is characterized in that the vacuum drying temperature is 20-30 DEG C.
- 15. preparation method according to claim 13, which is characterized in that the vacuum drying temperature is 25 DEG C.
- 16. described in a kind of pharmaceutical composition, the claim 1-2 comprising therapeutically effective amount or claim 7-8 any one Crystal form and pharmaceutically acceptable carrier.
- 17. crystal form described in claim 1-2 or claim 7-8 any one or claim 16 described pharmaceutical composition are used for Prepare the effect of anti-tumor drug.
- 18. the effect for being used to prepare anti-tumor drug described in claim 17, which is characterized in that be used to prepare treatment lung Cancer drug.
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| CN1777427A (en) * | 2003-02-26 | 2006-05-24 | 苏根公司 | Aminoheteroaryl compounds as protein kinase inhibitors |
| CN102105150A (en) * | 2008-05-21 | 2011-06-22 | 阿里亚德医药股份有限公司 | Phosphorous derivatives as kinase inhibitors |
| CN103826641A (en) * | 2011-02-24 | 2014-05-28 | 江苏豪森药业股份有限公司 | Phosphorus containing compounds as protein kinase inhibitors |
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| CN102105150A (en) * | 2008-05-21 | 2011-06-22 | 阿里亚德医药股份有限公司 | Phosphorous derivatives as kinase inhibitors |
| CN103826641A (en) * | 2011-02-24 | 2014-05-28 | 江苏豪森药业股份有限公司 | Phosphorus containing compounds as protein kinase inhibitors |
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