CN107955019A - A kind of salt form of EGFR inhibitor, crystal form and preparation method thereof - Google Patents

A kind of salt form of EGFR inhibitor, crystal form and preparation method thereof Download PDF

Info

Publication number
CN107955019A
CN107955019A CN201710968068.2A CN201710968068A CN107955019A CN 107955019 A CN107955019 A CN 107955019A CN 201710968068 A CN201710968068 A CN 201710968068A CN 107955019 A CN107955019 A CN 107955019A
Authority
CN
China
Prior art keywords
compound
crystal form
formula
crystal forms
crystal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201710968068.2A
Other languages
Chinese (zh)
Other versions
CN107955019B (en
Inventor
丁照中
陈曙辉
胡利红
刘希乐
张路
李卫东
郭慎慎
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangdong Zhongsheng Pharmaceutical Co Ltd
Original Assignee
Guangdong Zhongsheng Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangdong Zhongsheng Pharmaceutical Co Ltd filed Critical Guangdong Zhongsheng Pharmaceutical Co Ltd
Publication of CN107955019A publication Critical patent/CN107955019A/en
Application granted granted Critical
Publication of CN107955019B publication Critical patent/CN107955019B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a kind of salt form of EGFR inhibitor, crystal form and preparation method thereof, further includes the salt form and crystal form and is preparing the application in treating non-small cell lung cancer drug.

Description

A kind of salt form of EGFR inhibitor, crystal form and preparation method thereof
Technical field
Salt form, crystal form the present invention relates to a kind of EGFR inhibitor of T790M mutation and preparation method thereof, further include described The application of salt form and crystal form in non-small cell lung cancer drug is treated.
Background technology
Protein tyrosine kinase is that phosphate group of a kind of catalysis on protein substrate is transferred to junket from ATP or GTP The enzyme of histidine residue.Receptor tyrosine kinase from extracellularly phosphorylation is caused to intracellular delivery signal by activating secondary letter Number path.Various kinds of cell process is utilized by these signals-modulatings, including propagation, carbohydrate, protein synthesis, blood vessel Generation, cell growth and cell survival.In addition, many diseases or illness are active not normal with one or more kinases, it is abnormal Or imbalance is related.
EGF-R ELISA belongs to transmembrane tyrosine kinase acceptor ErbB families, which includes EGFR (also referred to as ErbB or HER1), (HER2 the or neu genes) of ErbB2, (HER3) and ErbB4 (HER4) of ErbB3.In addition to HER3, With tyrosine kinase activity.EGFR/ErbB families tyrosine kinase receptor has in cell Proliferation, differentiation and apoptosis Indispensable effect, and therefore become the effective target for being used for preventing growth and metastasis of tumours.The epidermal growth factor of the first generation Sub- receptor tyrosine kinase inhibitors (in EGFR-TKI), including Gefitinib (J Med 2004；350:2129-39) and Lip river in distress For Buddhist nun (Lancet Oncol 2011；12:735-42), they are had been demonstrated in the advanced NSCLC with body cell Activating mutations It is effective in patient.These are mutated the kinase domain in encoding EGFR, as 19 extra of polynucleotides is shown The leucine of 858 on the in-frame deletion and 21 exons of son is replaced into arginic point mutation (L858R) (Nat Rev Cancer 2007；7:169-81).However, patient eventually causes to swell after first generation EGFR-TKIs is received due to drug resistance Knurl produces secondary growth.The secondary mutation that the threonine of No. 790 positions is replaced into methionine (T790M) most generally believes Resistance mechanism.This mutation is detected (N Engl in the tumour cell that the patient being in progress occurs in 50%~60% disease J Med 2005；353:207-8).Second generation EGFR-TKIs, such as Afatinib (Lancet Oncol 2014；15:213-22) With dacomitinib (Cancer 2014；120:Exploitation 1145-54) to overcome generation TKIs produce drug resistance.They Can be with the cysteine of irreversible upper 797 of covalent bond EGFR.Covalent mechanism is believed to overcome double-mutant to be increased The affinity of the ATP added.But cysteine -797 is present in the EGFR of form of ownership.Therefore the chemical combination of these second generations Thing, it is not only active to the EGFR of Activating mutations and secondary mutation but also also active to the EGFR of wild type.To wild type The suppression of EGFR is not believed to be helpful in its clinical efficacy, but can cause the side effect of fash and diarrhea (Curr.Med.Chem.2006,13,3483-3492)。
Therefore third generation EGFR-TKIs, including AZD9291 (Cancer Discov 2014；4:1046-61),CO-1686 (Cancer Res.2013；19:2240-2247) with HM61713 (US 2013011213), they are oral irreversible tools There is the EGFR-TKIs of Catastrophic selection, T790M mutation can be suppressed and traditional EGFR is mutated, and do not have to Wild type EGFR Effect.They have efficiently in T790M positive tumors, but they still have certain toxicity, as can still produce diarrhea, skin Rash, nausea even clinical side effects ((the J Clin Oncol 2014 such as hyperglycaemia；32:abstr 8009；J Clin Oncol 2014；32:abstr 8010).It will be apparent that a compound with more high activity and hypotoxicity can bring bigger benefit.
AstraZeneca AZD9291 is a kind of oral small molecule third generation epidermal growth factor tyrosine kinase inhibitor, AZD9291 is stronger for the specific binding capacity of medicament-resistant mutation T790M and sensitizing mutation site (19Del and L858R), therefore Drug resistant Patients with Non-small-cell Lung has good therapeutic effect after being treated for a line TKI, but since it is wild to EGFR Type also has certain suppression, therefore can clinically produce the side effects such as diarrhea, fash.
CO1686 is a kind of new, oral, selective depressant for treating EGFR saltant type Patients with Non-small-cell Lung, it It can suppress crucial activation and T790M medicament-resistant mutations, it makes Wild type EGFR signal leave unused, and has good tolerance, The metabolin that CO1686 is produced has inhibitory action to two targets of IGF1R and INSR, thus clinically side effect shows as high blood Sugar.
The content of the invention
Offer formula (II) compound of the present invention.
The present invention also provides the A crystal forms of formula (II) compound, it is characterised in that its X-ray powder diffraction pattern is in following 2 θ There is characteristic diffraction peak at angle：4.55 ± 0.2 °, 13.84 ± 0.2 °, 15.97 ± 0.2 °, 18.91 ± 0.2 °.
In some schemes of the present invention, the X-ray powder diffraction pattern of above-mentioned A crystal forms has feature at following 2 θ angles Diffraction maximum：4.55 ± 0.2 °, 10.21 ± 0.2 °, 11.35 ± 0.2 °, 13.84 ± 0.2 °, 15.97 ± 0.2 °, 17.22 ± 0.2 °, 18.91 ± 0.2 °, 22.54 ± 0.2 °.
In some schemes of the present invention, the X-ray powder diffraction pattern of above-mentioned A crystal forms has feature at following 2 θ angles Diffraction maximum：4.55 ± 0.2 °, 9.27 ± 0.2 °, 10.21 ± 0.2 °, 11.35 ± 0.2 °, 13.84 ± 0.2 °, 14.45 ± 0.2 °, 15.97 ± 0.2 °, 16.58 ± 0.2 °, 17.22 ± 0.2 °, 18.91 ± 0.2 °, 22.54 ± 0.2 °, 23.67 ± 0.2 °.
In some schemes of the present invention, the A crystal forms of above-mentioned A crystal forms, its XRPD collection of illustrative plates is as shown in Figure 1.
In some schemes of the present invention, the XRPD spectrum analysis data of above-mentioned A crystal forms are as shown in table 1：
Table 1
In some schemes of the present invention, the differential scanning calorimetric curves of above-mentioned A crystal forms at 71.51 DEG C ± 3 DEG C and There is endothermic peak at 154.71 DEG C ± 3 DEG C.
In some schemes of the present invention, the DSC collection of illustrative plates of above-mentioned A crystal forms is as shown in Figure 2.
In some schemes of the present invention, the thermal gravimetric analysis curves of the above-mentioned A crystal forms weightlessness at 126.44 DEG C ± 3 DEG C reaches 2.676%, at 172.01 DEG C ± 3 DEG C, weightlessness is up to 2.9411%.
In some schemes of the present invention, the TGA collection of illustrative plates of above-mentioned A crystal forms is as shown in Figure 3.
The present invention also provides the preparation method of formula (II) compound A crystal forms, including：
(a) formula (I) compound is added in solvent and dissolved；
(b) it is added slowly with stirring the mixed solution of methanesulfonic acid and solvent；
(c) when stirring 8~16 is small at 20~30 DEG C；
(d) when drying 8~16 is small after centrifuging；
Wherein, the solvent is tetrahydrofuran, and the volume ratio of methanesulfonic acid and solvent is 1 in the mixed solution:9.
The present invention also provides the B crystal form of formula (II) compound, it is characterised in that its X-ray powder diffraction pattern is in following 2 θ There is characteristic diffraction peak at angle：9.89 ± 0.2 °, 15.46 ± 0.2 °, 19.60 ± 0.2 °, 21.44 ± 0.2 ° of
In some schemes of the present invention, the X-ray powder diffraction pattern of above-mentioned B crystal form has feature at following 2 θ angles Diffraction maximum：5.00 ± 0.2 °, 9.89 ± 0.2 °, 14.86 ± 0.2 °, 15.46 ± 0.2 °, 19.60 ± 0.2 °, 21.44 ± 0.2 °, 24.64±0.2°。
In some schemes of the present invention, the X-ray powder diffraction pattern of above-mentioned B crystal form has feature at following 2 θ angles Diffraction maximum：5.00 ± 0.2 °, 9.89 ± 0.2 °, 12.00 ± 0.2 °, 14.86 ± 0.2 °, 15.46 ± 0.2 °, 19.60 ± 0.2 °, 20.11 ± 0.2 °, 21.44 ± 0.2 °, 24.05 ± 0.2 °, 24.64 ± 0.2 °.
In some schemes of the present invention, the XRPD collection of illustrative plates of above-mentioned B crystal form is as shown in Figure 5.
In some schemes of the present invention, the XRPD spectrum analysis data of above-mentioned B crystal form are as shown in table 2：
Table 2
In some schemes of the present invention, the differential scanning calorimetric curve of above-mentioned B crystal form has at 199.07 DEG C ± 3 DEG C Endothermic peak.
In some schemes of the present invention, the DSC collection of illustrative plates of above-mentioned B crystal form is as shown in Figure 6.
In some schemes of the present invention, its thermal gravimetric analysis curve of the thermal gravimetric analysis curve of above-mentioned B crystal form is at 173.87 DEG C Weightlessness is up to 0.1283% at ± 3 DEG C, and at 212.74 DEG C ± 3 DEG C, weightlessness is up to 0.9514%.
In some schemes of the present invention, the TGA collection of illustrative plates of above-mentioned B crystal form is as shown in Figure 7.
The present invention also provides the preparation method of formula (II) compound B crystal form, including：
(a) adding formula (II) compound in solvent makes it into suspension；
(b) when stirring 8~16 is small at 35~45 DEG C of suspension；
(c) when drying 8~16 is small after centrifuging；
Wherein, the solvent is selected from acetone, isopropanol, ethyl acetate and 2- methyltetrahydrofurans.
The present invention also provides above-claimed cpd or A crystal forms or B crystal form answering in treatment non-small cell lung cancer drug is prepared With.
Technique effect
The present invention has compound preferable PK properties and oral absorption rate, its stable crystal form, draw moist good, light Heat affecting is small.
The compounds of this invention shows excellent work to the EGFR (sensitive and T790M drug resistances) of sensitizing mutation and double mutation Property, and have Wild type EGFR compared with high selectivity.Their caused diseases of exception to the enzyme by EGF-R ELISA It is likely to provide more effective treatment.
Definition and explanation
Unless otherwise indicated, following term used herein and phrase are intended to containing following meanings.One specific phrase Or term it is especially define in the case of should not be considered as it is uncertain or unclear, and should be according to common Implication goes to understand.When occurring trade name herein, it is intended to refer to its corresponding commodity or its active ingredient.
The midbody compound of the present invention can be prepared by a variety of synthetic methods well-known to those skilled in the art, The embodiment and ability formed including the embodiment that is set forth below, the combination of itself and other chemical synthesis process Equivalent substitution mode on field technique known to personnel, preferred embodiment include but not limited to the embodiment of the present invention.
The chemical reaction of the specific embodiment of the invention is completed in a suitable solvent, and the solvent must be suitable for The chemical change and its required reagent and material of the present invention.In order to obtain the compound of the present invention, it is sometimes desirable to this area skill Art personnel modify or select to synthesis step or reaction process on the basis of existing embodiment.
The present invention can be specifically described by embodiment below, these embodiments are not meant to any limit to the present invention System.
All solvents used in the present invention are commercially available, and can be used without being further purified.
The present invention uses following initialisms：R.t. room temperature is represented；THF represents tetrahydrofuran；NMP represents N- crassitudes Ketone；MeSO3H represents Loprazolam；DME represents glycol dimethyl ether；DCM represents dichloromethane；Xphos represents 2- dicyclohexyls 4 ' the 6 '-tri isopropyl biphenyl of phosphine -2 '；EtOAc represents ethyl acetate；MeOH represents methanol；Acetone represents acetone；2-Me- THF represents 2- methyltetrahydrofurans；IPA represents isopropanol.
Compound manually orSoftware is named, and commercial compound uses supplier's directory name.
Powder x-ray diffraction (X-ray powder diffractometer, XRPD) method of the present invention
Instrument model：Brooker D8advance x-ray diffractometers
Test method：About 10~20mg samples are detected for XRPD.
Detailed XRPD parameters are as follows：
Light pipe：Cu,kα,
Light pipe voltage：40kV, tube current：40mA
Divergent slit：0.60mm
Detector slit：10.50mm
Antiscatter slits：7.10mm
Scanning range：4-40deg
Walk footpath：0.02deg
Step-length：0.12 second
Sample disk rotating speed：15rpm
Differential thermal analysis (Differential Scanning Calorimeter, DSC) method of the present invention
Instrument model：TA Q2000 differential scanning calorimeters
Test method：Take sample (~1mg) to be placed in DSC aluminum pots to be tested, in 50mL/min N2Under the conditions of, with 10 DEG C/heating rate of min, heating sample from 30 DEG C (room temperature) to 300 DEG C (or 350 DEG C).
Thermogravimetric analysis (Thermal Gravimetric Analyzer, TGA) method of the present invention
Instrument model：TA Q5000IR thermogravimetric analyzers
Test method：Take sample (2~5mg) to be placed in TGA platinum pots to be tested, in 25mL/min N2Under the conditions of, with The heating rate of 10 DEG C/min, heating sample from room temperature to 350 DEG C or weightlessness 20%.
Dynamic vapor sorption of the present invention analyzes (Dynamic Vapor Sorption, DVS) method
Instrument model：SMS DVS Advantage dynamic vapor sorption instrument
Test condition：Take sample (10~15mg) to be placed in DVS sample discs to be tested.
Detailed DVS parameters are as follows：
Temperature：25℃
Balance：Dm/dt=0.01%/min is (most short：10min, it is most long：180min)
It is dry：Dry 120min under 0%RH
RH (%) tests step：10%
RH (%) tests step scope：0%-90%-0%
It is as follows to draw moist classification of assessment：
Hygroscopicity is classified Δ W%
Deliquescence Absorb enough moisture and form liquid
Great hygroscopicity Δ W% >=15%
There is hygroscopicity 15%>Δ W% >=2%
Slightly hygroscopicity 2%>Δ W% >=0.2%
Nothing or almost no hygroscopicity Δ W%<0.2%
Note：Δ W% represents to be increased weight by moisture absorption of the test product under 25 ± 1 DEG C and 80 ± 2%RH.
Brief description of the drawings
Fig. 1 is the alpha-emitting XRPD spectrograms of Cu-K of (II) compound A crystal forms；
Fig. 2 is the DSC spectrograms of (II) compound A crystal forms；
Fig. 3 is the TGA spectrograms of (II) compound A crystal forms；
Fig. 4 is the DVS spectrograms of (II) compound A crystal forms；
Fig. 5 is that the Cu-K α of (II) compound B crystal form radiate XRPD spectrograms；
Fig. 6 is the DSC spectrograms of (II) compound B crystal form；
Fig. 7 is the TGA spectrograms of (II) compound B crystal form；
Fig. 8 is the DVS spectrograms of (II) compound B crystal form.
Embodiment
In order to be better understood from present disclosure, it is described further with reference to specific embodiment, but specifically Embodiment be not the limitation done to present disclosure.
Embodiment 1：The preparation of formula (I) compound
Step 1：
N2Under protection, dichloromethane (20L) solution of pyridine (1.74Kg, 22.01mol, 1.10 equivalent) is cooled to -20 DEG C, Trifluoromethanesulfonic anhydride (5.87Kg, 20.81mol, 1.04 equivalent) is slowly added dropwise, is added dropwise, reaction system is at -20 DEG C And stir 0.5 it is small when, then ethylene bromohyrin (2.50Kg, 20.01mol, 1.0 equivalent) is slowly added dropwise, reaction temperature maintain 0 DEG C with Descend and stir 1.0 it is small when, TLC (petroleum ethers:Ethyl acetate=5:1) display reaction is completed.Reaction is finished reaction system directly Filtering, filtrate is concentrated, adds petroleum ether (15L), and the solid of precipitation is filtered, and filtrate concentration, obtains compound b (4.80Kg, yield 93.33%) is the grease of buff.1HNMR(400MHz,CDCl3):4.77 (t, J=6.40Hz, 2H), 3.63 (t, J=6.40Hz, 2H)
Step 2：
Compound b (8.5Kg, 33.07mol, 1 equivalent) and diphenyl sulfide (6.78Kg, 36.38mol, 1.10 equivalent) are put In dry toluene (22.0L), reaction mixture under nitrogen protection, be heated to 100 DEG C and stir 6 it is small when.1HNMR is shown instead It should complete.Reaction system is cooled to room temperature, and adds methyl tertiary butyl ether(MTBE) (20L), the solid filtering of precipitation, filter cake is in vacuum 40 DEG C of dryings in drying box, it is brown solid to obtain compound c (7.4Kg, yield 50.48%).1H NMR(400MHz, CDCl3):8.08-8.15(m,4H),7.69-7.83(m,6H),4.85-4.93(m,2H),3.66-3.72(m,2H).
Step 3：
Compound c (7.4Kg, 16.69mol, 1 equivalent) and saleratus (2.01Kg, 20.03mol, 1.20 equivalent) are put In tetrahydrofuran (18.2L) and H2In O (9.1L), reaction mixture is when 15 DEG C of stirrings 3 are small.1HNMR display reactions are completed.Add Enter H2O (10L), water are mutually extracted (10L*4) with DCM, are merged organic phase and are concentrated to give compound d (5.72Kg, yield are 94.57%) it is the grease of buff.1H NMR(400MHz,CDCl3):7.87 (d, J=7.60Hz, 8H), 7.62-7.78 (m, 12H), 7.48 (dd, J=16.00,8.80Hz, 2H), 6.68 (dd, J=8.80,1.60Hz, 2H), 6.53 (dd, J= 16.00,2.20Hz,2H).
Step 4：
Indole-2-carboxylic acid (3Kg, 18.62mol, 1.0 equivalent) is dissolved in THF (15L), starts to be added portionwise at 20 DEG C Lithium Aluminium Hydride (900g, 23.7mol, 1.3 equivalent), temperature programming is to 70 DEG C, after Lithium Aluminium Hydride adds, when stirring 3 is small at 70 DEG C, TLC (petroleum ethers:Ethyl acetate=1:1) the reaction was complete for monitoring, is cooled to 20 DEG C, is slowly added to water (900mL), NaOH (1N, Reaction 900mL) is quenched, after being quenched completely, decompression filters, and filtrate is spin-dried for, and obtains grease russet, grease is dissolved in EA (3L), under stirring, adds petroleum ether (30L), flaxen solid is separated out in solution.Filtering, solid petroleum ether:Acetic acid Ethyl ester=10:1 (15L) is beaten, and decompression filters, and drying to constant weight obtains compound r in 50 DEG C of vacuum drying chambers for solid (2.14kg, yield：74%), it is faint yellow solid1H NMR(400MHz,CDCl3) δ 8.36 (br s, 1H), 7.60 (d, J= 8.0Hz, 1H), 7.35 (d, J=8.0Hz, 1H), 7.20 (dt, J=1.6,8.0Hz, 1H), 7.15-7.09 (m, 1H), 6.42 (d, J=1.6Hz, 1H), 4.83 (s, 2H), 1.93 (br s, 1H)
Step 5：
In N2Under protection, compound r (2.14kg, 14.04mol, 1.0 equivalent) is dissolved in DCM (50L), is cooled to 0 DEG C, Add KOH (1.97Kg, 35.1mol, 2.5 equivalent), at 0 DEG C, stir 30min, by diphenyl (vinyl) sulfonium (6.36Kg, 17.54mol, 1.25 equivalents) DCM (10L) is dissolved in, it is slowly dropped in reaction system, controlling reaction temperature is added dropwise at 0-5 DEG C Finish, be warming up to 30 DEG C, when stirring 5 is small, TLC (petroleum ethers:Ethyl acetate=2:1) the reaction was complete for monitoring, adds water (30L) to be quenched Reaction, liquid separation, organic phase are washed with saline solution (60L), and drying is spin-dried for, and obtain the grease of black, add DME (1.2L) ,- It is stirred overnight at 10 DEG C, separates out the solid of yellow, filtered, solid is beaten with DME (1.2L) at -10 DEG C, is filtered, filter cake stone Oily ether (800mL) is beaten once at normal temperatures, filtering, filter cake vacuum drying chamber drying to constant weight, and it is white to obtain compound e Solid (1.1Kg, yield：44.5%).1HNMR(400MHz,CDCl3) δ 7.63-7.57 (m, 1H), 7.31 (dd, J=0.8, 8.0Hz, 1H), 7.21 (dt, J=0.8,8.0Hz, 1H), 7.18-7.11 (m, 1H), 6.24 (d, J=0.8Hz, 1H), 5.01 (d, J=0.8Hz, 2H), 4.22-4.16 (m, 2H), 4.13-4.07 (m, 2H)
Step 6：
Fluoro- 2, the 4- dichloro pyrimidines of 5- (2.12kg, 12.67mol, 1.05 equivalent) are added into glycol dimethyl ether (10L) In solution, solution is cooled to 0-5 DEG C, N2After alchlor (3.22kg, 24.13mol, 2.0 equivalent) is added portionwise under protection Under reaction solution is stirred at 30 DEG C 1 it is small when.Compound e (3.22kg, 24.13mol, 1.0 equivalent) is slowly added to again above-mentioned In reaction solution, when stirring 15 is small at 20 DEG C, TLC (dichloromethane：Methanol=6:1) the reaction was complete for monitoring.Reaction solution is slowly added Enter in water (40L), there are a large amount of solids to separate out, continue stirring 0.5 it is small when after filter, filter cake is added in methanol (16L), and room temperature is beaten Starch 1 it is small when, filtered after being cooled to room temperature.It is yellow-brown solid that filtration cakes torrefaction, which obtains compound g (3.36kg, 90% yield),.1HNMR(400MHz,CDCl3) δ 8.43-8.42 (d, J=4.0Hz, 1H), 7.98-7.96 (m, 1H), 7.40-7.32 (m, 3H), 5.28(s,2H),4.27-4.22(m,4H)
LCMS(ESI)(20-80AB):m/z:304.1[M+1].
Step 7：
30L Isosorbide-5-Nitraes-dioxane is added to 50L kettles (20 DEG C), (3.0kg, 9.88mol, 1.0 work as by compound (f) Amount), compound (g) (1.93Kg, 10.37mol, 1.05 equivalent), palladium (110.91g, 0.494mol, 0.05 equivalent), XPhos (471g, 0.988mol, 0.1 equivalent), potassium phosphate (4.19Kg, 19.76mol, 2.0 equivalent) are added (20 in reaction kettle DEG C), N2Displacement 3 times.Temperature programming is sampled after the completion of detection reaction is controlled in HPLC, is cooled to room temperature to 100 ± 5 DEG C.Will reaction Liquid is filtered under diminished pressure.Filter cake with 25 ± 5 DEG C of 40L purified waters mashing 2 it is small when.By filter cake with methanol (30L) mashing 1 it is small when, filter cake exists Constant weight is dried under vacuum under the conditions of 50 DEG C.It is yellow solid to obtain compound i (4.18kg, 91.6% yield).1H NMR (400MHz, DMSO-d6) δ 8.89 (d, J=8.0Hz, 1H), 8.59 (d, J=1.92Hz, 1H), 8.50 (s, 1H), 7.78 (dd, J=7.2,3.58Hz, 1H), 7.55 (d, J=8.0Hz, 1H), 7.37 (d, J=13.30Hz, 1H), 7.17-7.29 (m, 2H), 5.11 (s, 2H), 4.21 (br dd, J=12.99,4.83Hz, 4H), 4.02 (s, 3H) .LCMS (ESI) (20-80AB):m/z: 454.2[M+1].
Step 8：
10.4L 1-methyl-2-pyrrolidinones are added to 50L kettles (20 DEG C), by compound (h) (4.15kg, 9.15mol, 1.0 equivalents), N, N, N- trimethyls ethylenediamine (1.12Kg, 10.98mol, 1.2 equivalent), potassium carbonate (2.53Kg, 18.30mol, 2.0 equivalents) add in reaction kettle (20 DEG C).Temperature programming is sampled in HPLC after the completion of control detection reaction, cooling to 100 ± 5 DEG C To 25 ± 5 DEG C.10.4L purified waters are added dropwise in above-mentioned solution, separate out a large amount of red solids.Decompression filters, by filter cake with pure It is colourless to filtrate to change water (20L) washing filter cake, filter cake with 25 ± 5 DEG C of 20L methanol mashing 1 it is small when, decompression filters, and filter cake is at 50 DEG C Under the conditions of be dried under vacuum to constant weight.It is red solid to obtain compound k (4.26kg, 86.4% yield).1H NMR(400MHz, CDCl3) δ 9.06 (s, 1H), 8.35 (d, J=2.89Hz, 1H), 7.91 (br, dd, J=4.96,3.70Hz, 1H), 7.54 (s, 1H), 7.35-7.43 (m, 1H), 7.27-7.33 (m, 3H), 6.69 (s, 1H), 5.29 (s, 2H), 4.30 (t, J=5.08Hz, 2H), 4.22 (t, J=5.14Hz, 2H), 4.00 (s, 3H), 3.28 (t, J=7.15Hz, 2H), 2.89 (s, 3H), 2.57 (t, J =7.15Hz, 2H), 2.28 (s, 6H), 1.69 (s, 3H) .LCMS (ESI) (20-80AB):m/z:536.3[M+1].
Step 9：
NMP (6L) is added in 10L autoclaves (room temperature), 0.75kg compounds (l) are added in reaction kettle (room temperature), N2Bubbling~5min.The wet Pd-C of 75g (50%) are added in reaction solution, use H2Gas is replaced 4 times.Reaction pressure is adjusted to 2.0MPa, Under stirring condition, reaction is warming up to 25 DEG C.At 25 DEG C, stirring 20 (when R1 pressure is less than 1.5MPa, adds H when small2Extremely After 2.0MPa), middle control sampling detection (HPLC), sampling detection (sampling method：0.1mL is taken to be dissolved in 1mL MeOH).Stop reaction, Then autoclave pressure is down to normal pressure；Reaction solution is filtered under diminished pressure by diatomite (750g)；Filter cake is washed 1 time with 6L DCM, Filtrate adjusts pH=1 with Aq.HCl (1M, 0.4L)；DCM (6L x 5) extractions, TLC detection (sampling methods are added into filtrate： Directly fetch water phase 0.1ml；Solvent：DCM/MeOH=10：1, iodine colour developing, is substantially not visible NMP).Water is added NaOH (5M) and adjusts PH to 5 is saved, there is solid precipitation, continues to stir 0.5h.Decompression filters, and filter cake is washed with water, and collects filter cake.Solid is in 50 DEG C of vacuum Drying 48 obtains compound l when small.1HNMR(400MHz,CD3OD):δ, 8.55 (s, 1H), 8.41 (d, J=3.14Hz, 1H), 7.83-7.89 (m, 1H), 7.49 (dd, J=7.22,1.19Hz, 1H), 7.27 (ddd, J=8.82,7.62,1.13Hz, 2H), 7.16(s,1H),5.14(s,2H),4.18-4.30(m,4H),4.04(s,3H),3.37-3.49(m,4H),2.92(s,6H), 2.74(s,3H)LCMS(ESI)(20-80AB):m/z:506.4[M+1].
Step 10：
By 10L purified waters, 458.76g NaHCO3, 15L dichloromethane add in 50L reaction kettles, stir at room temperature to solid Body dissolved clarification.Compound (J) 1.48Kg is slowly added to, after stirring 10min, reaction solution stands 10min layerings.Organic phase dichloromethane Layer uses saturated common salt water washing 2 times (10L x 2).Anhydrous sodium sulfate is dried.Organic layer is spin-dried for, obtains brown solid 1.26Kg. Unhindered amina (1.26Kg, 2.49mol, 1.0 equivalent) is dissolved with 12.6L DME and 1.26L purified waters and is transferred to 50L autoclaves In, -5-0 DEG C are cooled to, chlorpromazine chloride (347.77g, 2.74mol, 1.1 equivalent) is slowly added dropwise into above-mentioned solution, is added dropwise Finish.Continue stirring 0.5 it is small when.LCMS 20-80AB 35MIN monitoring starting material lefts are less than 1%, and reaction is completed.By hydroxide Sodium (398.74g, 9.96mol, 4.0 equivalent) is added in above-mentioned solution, is warming up to 70 DEG C, when stirring 6-8 is small, the reaction was complete.Will Reaction solution is down to room temperature.Reaction solution is poured into 65L purified waters, separates out a large amount of brown solids, and decompression filters, filter cake vacuum drying 24 Hour to constant weight, obtains formula (I) compound brown solid (1.16Kg, yield 78%)1H NMR(400MHz,CDCl3):δ,10.12 (s, 1H), 9.45 (s, 1H), 8.39 (d, J=3.01Hz, 1H), 7.88-7.96 (m, 1H), 7.55 (s, 1H), 7.24-7.40 (m, 4H), 6.81 (s, 1H), 6.25-6.45 (m, 2H), 5.68 (dd, J=9.79,2.01Hz, 1H), 5.31 (s, 2H), 4.14- 4.27(m,4H),3.90(s,3H),2.86-2.92(m,2H),2.73(s,3H),2.25-2.32(m,8H)LCMS(ESI)(20- 80AB):m/z:560.3[M+1].
Embodiment 2：The preparation of formula (II) compound
8L acetone is added into 50L reaction kettles, at room temperature by formula (I) compound (1.10Kg, 1.97mol, 1.0 equivalent) Adding in reaction kettle, stirring to dissolving clarification, thiourea resin (220.44g, 20% mass ratio) is added in above-mentioned reaction solution, 25 DEG C are stirred overnight, and decompression filters, and filter cake is washed with 3L acetone.Merge acetone, solution is transferred in 50L reaction kettles, heat up To 65 DEG C, Loprazolam (185.34g, 1.93mol, 0.98 equivalent) is slowly added dropwise in constant pressure funnel, is added dropwise, solution is clear Clearly.After 30min, solution separates out off-white powder.When insulated and stirred 2 is small, 25 DEG C are cooled to.N2The lower decompression of protection filters, filter cake To constant weight, it is brown solid (965g, yield 73%) to obtain formula (II) compound for vacuum drying chamber drying1H NMR(400MHz, CD3OD):δ, 8.37 (s, 1H), 8.34 (d, J=3.07Hz, 1H), 7.87 (dd, J=7.78,3.14Hz, 1H), 7.44 (d, J =7.91Hz, 1H), 7.15-7.26 (m, 2H), 6.96 (s, 1H), 6.42-6.55 (m, 2H), 5.86 (dd, J=8.72, 3.07Hz, 1H), 5.05 (s, 2H), 4.13-4.22 (m, 4H), 4.00 (s, 3H), 3.49 (t, J=5.65Hz, 2H), 3.28 (t, J=5.71Hz, 2H), 2.87 (s, 6H), 2.72 (d, J=1.51Hz, 6H) .LCMS (ESI) (20-80AB):m/z:560.3[M+ 1].
Embodiment 3：The preparation of formula (II) compound A crystal forms
Formula (I) compound of 120mg is taken, the dissolving of 0.5mL tetrahydrofurans is added, is then added slowly with stirring 0.14mL Methanesulfonic acid-tetrahydrofuran solution (V/V, 1:9).Centrifuged after being stirred overnight at 25 DEG C, residual solids sample is placed in vacuum drying (30 DEG C) are dried overnight in case, obtain the A crystal forms of formula (II) compound.
Embodiment 4：The preparation of formula (II) compound B crystal form
Weigh 50mg formulas (II) compound to be added in 4.0mL vials, adding suitable acetone makes it into suspension. After adding magneton, above-mentioned suspension sample is placed on magnetic force heating stirrer (40 DEG C) and is tested (lucifuge), is stirred at 40 DEG C Centrifuged after mixing overnight, residual solids sample is placed in vacuum drying chamber (30 DEG C) and is dried overnight, and the B for obtaining formula (II) compound is brilliant Type.
Weigh 50mg formulas (II) compound to be added in 4.0mL vials, adding suitable isopropanol makes it into suspended Liquid.After adding magneton, above-mentioned suspension sample is placed on magnetic force heating stirrer (40 DEG C) and is tested (lucifuge), at 40 DEG C Centrifuged after being stirred overnight, residual solids sample is placed in vacuum drying chamber (30 DEG C) and is dried overnight, and the B for obtaining formula (II) compound is brilliant Type.
Weigh 50mg formulas (II) compound to be added in 4.0mL vials, adding suitable ethyl acetate makes it into outstanding Turbid.After adding magneton, above-mentioned suspension sample is placed on magnetic force heating stirrer (40 DEG C) and is tested (lucifuge), 40 DEG C Under be stirred overnight after centrifuge, residual solids sample is placed in vacuum drying chamber (30 DEG C) and is dried overnight, and obtains the B of formula (II) compound Crystal form.
Weigh 50mg formulas (II) compound to be added in 4.0mL vials, adding suitable 2- methyltetrahydrofurans makes It is into suspension.After adding magneton, above-mentioned suspension sample is placed on magnetic force heating stirrer (40 DEG C) and is tested and (kept away Light), centrifuged after being stirred overnight at 40 DEG C, residual solids sample is placed in vacuum drying chamber (30 DEG C) and is dried overnight, and obtains formula (II) The B crystal form of compound.
Under room temperature, formula (II) compound (700g), absolute ethyl alcohol (5.6L) are added in reaction kettle.Stir and rise Temperature is to 85 DEG C to solid whole dissolved clarification.Normal heptane (3.5L) is slowly added into reaction kettle, fraction solids are separated out in solution.Protect When temperature stirring 1 is small, reaction solution is cooled to 25 DEG C.N2The lower decompression of protection filters, solid vacuum drying chamber drying to constant weight.By solid Added with 7L acetone into reaction kettle, stir and be warming up to 60 DEG C of stirring 12-40 of interior temperature it is small when turn crystalline substance, after the completion of turning brilliant, cooling To room temperature.N2The lower decompression of protection filters, and the B crystal form for constant weight, obtaining formula (II) compound is dried in filter cake vacuum drying chamber (530g, yield 75%)1H NMR(400MHz,CD3OD):δ, 8.37 (s, 1H), 8.34 (d, J=3.07Hz, 1H), 7.87 (dd, J=7.78,3.14Hz, 1H), 7.44 (d, J=7.91Hz, 1H), 7.15-7.26 (m, 2H), 6.96 (s, 1H), 6.42- 6.55 (m, 2H), 5.86 (dd, J=8.72,3.07Hz, 1H), 5.05 (s, 2H), 4.13-4.22 (m, 4H), 4.00 (s, 3H), 3.49 (t, J=5.65Hz, 2H), 3.28 (t, J=5.71Hz, 2H), 2.87 (s, 6H), 2.72 (d, J=1.51Hz, 6H) .LCMS(ESI)(20-80AB):m/z:560.3[M+1].
Embodiment 5：The Study on Hygroscopicity of formula (II) compound A crystal forms
Experiment material：
SMS DVS Advantage dynamic vapor sorption instrument
Experimental method：
Take 10~15mg of formula (II) compound A crystal forms to be placed in DVS sample discs to be tested.
Experimental result：
The DVS spectrograms of formula (II) compound A crystal forms are as shown in figure 4, △ W=7.86%.
Experiment conclusion：
Moisture absorption weightening of formula (II) the compound A crystal forms under 25 DEG C and 80%RH is 7.86%, there is hygroscopicity.
Embodiment 6：The Study on Hygroscopicity of formula (II) compound B crystal form
Experiment material：
SMS DVS Advantage dynamic vapor sorption instrument
Experimental method：
Take 10~15mg of formula (II) compound B crystal form to be placed in DVS sample discs to be tested.
Experimental result：
The DVS spectrograms of formula (II) compound B crystal form are as shown in figure 8, △ W=0.830%.
Experiment conclusion：
Moisture absorption weightening of formula (II) the compound B crystal form under 25 DEG C and 80%RH is 0.83%, slightly hygroscopicity.
Embodiment 7：The stability experiment of formula (II) compound B crystal form
Foundation《Bulk pharmaceutical chemicals and preparation stability test direction principle》(four general rules 9001 of Chinese Pharmacopoeia 2015 edition), are investigated Formula (II) compound B crystal form is in high temperature (60 DEG C, open), high humidity (room temperature/relative humidity 92.5%, open) and intense light irradiation Stability under the conditions of (5000lx, closed).
Formula (II) compound B crystal form 15mg is weighed, the bottom of glass sample bottle is placed in, spreads out into thin layer.High temperature and height The sample placed under wet bar part seals bottleneck with aluminium-foil paper, and a little apertures are pricked on aluminium-foil paper, ensures that sample can be filled with surrounding air Tap is touched；The sample placed under high light conditions is sealed with screw cap.The sample placed under different condition was in the 5th day, 10 days Sampling detection (XRPD), compared with the initial detecting result of 0 day, result of the test see the table below shown in 3 testing result：
The stability result of the test of 3 formula of table (II) compound B crystal form
Conclusion：Formula (II) compound B crystal form is with good stability under high temperature, high humidity, high light conditions.
Internal drug efficacy study of formula (II) the compound B crystal form in NCI-H1975 heterografts (CDX) model
Experiment material：
BALB/c nude mices, female, 6-8 weeks, about 18-22 grams of weight, special pathogen-free domestic was maintained at by mouse In environment, and in single ventilated cage (10 mouse are per cage).All cages, place mat and water carry out disinfection before use.Institute Some animals can freely obtain the commercial laboratory diet of standard authentication.Share 100 and be purchased from the small of Beijing dimension tonneau China Mouse is used to study.Every mouse is subcutaneously implanted tumor tissues (20-30 cubic millimeters), the growth for tumour in right flank abdomen.When Mean tumour volume starts to test when reaching about 140-200 cubic millimeters.Experimental method：
It is subcutaneously implanted on heterograft (CDX) the BALB/c nude mouses in NCI-H1975 patients with lung cancer source and carries out internal medicine Effect.Test-compound is administered orally daily for experiment, successive administration 21 days.Gross tumor volume biweekly uses two-dimentional kind of calliper, Volume is measured with cubic millimeter, is calculated by the following formula：V=V=0.5a x b2, wherein a and b are the major diameter of tumour respectively And minor axis.Antitumor drug effect is to increase volume divided by untreated animal by using the average tumor of the processed animal of compound Average tumor increase volume determine.
Experimental result：It is shown in Table 4.
Table 4
Experiment conclusion：
Formula (II) compound B crystal form (12mg/Kg) has suitable with AZD9291 (3mg/Kg), CO1686 (50mg/Kg) Suppress tumor promotion.
Internal drug efficacy study of formula (II) the compound B crystal form in A431 heterografts (CDX) model
Experiment material：
BALB/c nude mices, female, 6-8 weeks, about 18-20 grams of weight, special pathogen-free domestic was maintained at by mouse In environment, and in single ventilated cage (5 mouse are per cage).All cages, place mat and water carry out disinfection before use.It is all Animal can freely obtain the commercial laboratory diet of standard authentication.All laboratory mices are purchased from Shanghai BK The mouse of Laboratory Animal Co., LTD are used to study.Every mouse is subcutaneously implanted tumor tissues (20- in right flank abdomen 30 cubic millimeters), the growth for tumour.Start to test when mean tumour volume reaches about 150-200 cubic millimeters
Experimental method：
Selectivity in vivo is carried out on application on human skin squamous cell A431 heterografts (CDX) BALB/c nude mouses are subcutaneously implanted Experiment.
Successive administration is administered orally 11 days in test compound.Gross tumor volume is biweekly with two-dimentional kind of calliper, volume Measured with cubic millimeter, calculated by the following formula：V=V=0.5a x b2, wherein a and b are the major diameter of tumour respectively and short Footpath.Antitumor drug effect is by using the average tumor increase volume of the processed animal of compound divided by putting down for untreated animal Equal tumour increases volume to determine.
Experimental result：It is shown in Table 5.
Table 5
Experiment conclusion：
Formula (II) compound B crystal form (12mg/Kg) has more preferably more selective than AZD9291 (3mg/Kg).

Claims (20)

  1. Formula 1. (II) compound.
  2. The A crystal forms of formula 2. (II) compound, it is characterised in that its X-ray powder diffraction pattern is spread out at following 2 θ angles with feature Penetrate peak：4.55 ± 0.2 °, 13.84 ± 0.2 °, 15.97 ± 0.2 °, 18.91 ± 0.2 °.
  3. 3. A crystal forms according to claim 2, its X-ray powder diffraction pattern has characteristic diffraction peak at following 2 θ angles： 4.55 ± 0.2 °, 10.21 ± 0.2 °, 11.35 ± 0.2 °, 13.84 ± 0.2 °, 15.97 ± 0.2 °, 17.22 ± 0.2 °, 18.91 ± 0.2 °, 22.54 ± 0.2 °.
  4. 4. A crystal forms according to claim 3, its X-ray powder diffraction pattern has characteristic diffraction peak at following 2 θ angles： 4.55 ± 0.2 °, 9.27 ± 0.2 °, 10.21 ± 0.2 °, 11.35 ± 0.2 °, 13.84 ± 0.2 °, 14.45 ± 0.2 °, 15.97 ± 0.2 °, 16.58 ± 0.2 °, 17.22 ± 0.2 °, 18.91 ± 0.2 °, 22.54 ± 0.2 °, 23.67 ± 0.2 °.
  5. 5. A crystal forms according to claim 4, its XRPD collection of illustrative plates is as shown in Figure 1.
  6. 6. A crystal forms according to claims 2 to 5, its differential scanning calorimetric curve is at 71.51 DEG C ± 3 DEG C and 154.71 DEG C There is endothermic peak at ± 3 DEG C.
  7. 7. A crystal forms according to claim 6, its DSC collection of illustrative plates is as shown in Figure 2.
  8. 8. A crystal forms according to claims 2 to 5, its thermal gravimetric analysis curve weightlessness at 126.44 DEG C ± 3 DEG C reaches 2.676%, at 172.01 DEG C ± 3 DEG C, weightlessness is up to 2.9411%.
  9. 9. A crystal forms according to claim 8, its TGA collection of illustrative plates is as shown in Figure 3.
  10. The preparation method of formula 10. (II) compound A crystal forms, including：
    (a) formula (I) compound is added in solvent and dissolved；
    (b) it is added slowly with stirring the mixed solution of methanesulfonic acid and solvent；
    (c) when stirring 8~16 is small at 20~30 DEG C；
    (d) when drying 8~16 is small after centrifuging；
    Wherein, the solvent is tetrahydrofuran, and the volume ratio of methanesulfonic acid and solvent is 1 in the mixed solution:9.
  11. The B crystal form of formula 11. (II) compound, it is characterised in that its X-ray powder diffraction pattern has feature at following 2 θ angles Diffraction maximum：9.89 ± 0.2 °, 15.46 ± 0.2 °, 19.60 ± 0.2 °, 21.44 ± 0.2 °.
  12. 12. B crystal form according to claim 11, its X-ray powder diffraction pattern has feature diffraction at following 2 θ angles Peak：5.00 ± 0.2 °, 9.89 ± 0.2 °, 10.04 ± 0.2 °, 14.86 ± 0.2 °, 15.46 ± 0.2 °, 19.60 ± 0.2 °, 21.44 ± 0.2 °, 24.64 ± 0.2 °.
  13. 13. B crystal form according to claim 12, its X-ray powder diffraction pattern has feature diffraction at following 2 θ angles Peak：5.00 ± 0.2 °, 9.89 ± 0.2 °, 10.04 ± 0.2 °, 12.00 ± 0.2 °, 14.86 ± 0.2 °, 15.46 ± 0.2 °, 19.60 ± 0.2 °, 20.11 ± 0.2 °, 21.44 ± 0.2 °, 24.05 ± 0.2 °, 24.64 ± 0.2 °, 24.82 ± 0.2 °.
  14. 14. B crystal form according to claim 13, its XRPD collection of illustrative plates is as shown in Figure 5.
  15. 15. the B crystal form according to claim 11~14, its differential scanning calorimetric curve has at 199.07 DEG C ± 3 DEG C Endothermic peak.
  16. 16. B crystal form according to claim 15, its DSC collection of illustrative plates is as shown in Figure 6.
  17. 17. the B crystal form according to claim 11~14, its thermal gravimetric analysis curve weightlessness at 173.87 DEG C ± 3 DEG C reaches 0.1283, at 212.74 DEG C ± 3 DEG C, weightlessness is up to 0.9514.
  18. 18. B crystal form according to claim 17, its TGA collection of illustrative plates is as shown in Figure 7.
  19. The preparation method of formula 19. (II) compound B crystal form, including：
    (a) adding formula (II) compound in solvent makes it into suspension；
    (b) when stirring 8~16 is small at 35~45 DEG C of suspension；
    (c) when drying 8~16 is small after centrifuging；
    Wherein, the solvent is selected from acetone, isopropanol, ethyl acetate and 2- methyltetrahydrofurans.
  20. 20. compound or the claim 2~10 A crystal forms or claim 11~19 B are brilliant according to claim 1 Type is preparing the application in treating non-small cell lung cancer drug.
CN201710968068.2A 2016-10-17 2017-10-16 Salt form and crystal form of EGFR inhibitor and preparation method thereof Active CN107955019B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610903608 2016-10-17
CN2016109036084 2016-10-17

Publications (2)

Publication Number Publication Date
CN107955019A true CN107955019A (en) 2018-04-24
CN107955019B CN107955019B (en) 2021-09-14

Family

ID=61963482

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710968068.2A Active CN107955019B (en) 2016-10-17 2017-10-16 Salt form and crystal form of EGFR inhibitor and preparation method thereof

Country Status (1)

Country Link
CN (1) CN107955019B (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108285460A (en) * 2017-01-09 2018-07-17 南京圣和药业股份有限公司 A kind of pharmaceutical salts of EGFR kinase inhibitor and preparation method thereof and purposes
WO2020007219A1 (en) * 2018-07-02 2020-01-09 南京明德新药研发有限公司 Crystalline form of egfr inhibitor and preparation method therefor
CN112292379A (en) * 2018-06-13 2021-01-29 基石药业（苏州）有限公司 Salt form and crystal form of pyridopyridone derivative
CN112912380A (en) * 2018-12-21 2021-06-04 基石药业（苏州）有限公司 Crystal form, amorphous form and application of MEK inhibitor
CN113874362A (en) * 2019-05-13 2021-12-31 罗欣健康科技发展(北京)有限公司 Crystal form of quinazolinone compound and preparation method thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013138495A1 (en) * 2012-03-15 2013-09-19 Celgene Avilomics Research, Inc. Solid forms of an epidermal growth factor receptor kinase inhibitor
CN103748096A (en) * 2012-08-06 2014-04-23 美国艾森生物科学公司 Novel pyrrolopyrimidine compounds as inhibitors of protein kinases
CN105348266A (en) * 2011-07-27 2016-02-24 阿斯利康(瑞典)有限公司 Substituted-3-chlorin-N-[3-(pyrimidine-2-ylamine)phenyl]propanamide or salts thereof
CN105377835A (en) * 2013-07-11 2016-03-02 贝达药业股份有限公司 Protein tyrosine kinase modulators and methods of use

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105348266A (en) * 2011-07-27 2016-02-24 阿斯利康(瑞典)有限公司 Substituted-3-chlorin-N-[3-(pyrimidine-2-ylamine)phenyl]propanamide or salts thereof
WO2013138495A1 (en) * 2012-03-15 2013-09-19 Celgene Avilomics Research, Inc. Solid forms of an epidermal growth factor receptor kinase inhibitor
CN103748096A (en) * 2012-08-06 2014-04-23 美国艾森生物科学公司 Novel pyrrolopyrimidine compounds as inhibitors of protein kinases
CN105377835A (en) * 2013-07-11 2016-03-02 贝达药业股份有限公司 Protein tyrosine kinase modulators and methods of use

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108285460A (en) * 2017-01-09 2018-07-17 南京圣和药业股份有限公司 A kind of pharmaceutical salts of EGFR kinase inhibitor and preparation method thereof and purposes
CN112292379A (en) * 2018-06-13 2021-01-29 基石药业（苏州）有限公司 Salt form and crystal form of pyridopyridone derivative
CN112292379B (en) * 2018-06-13 2022-03-04 基石药业（苏州）有限公司 Salt form and crystal form of pyridopyridone derivative
WO2020007219A1 (en) * 2018-07-02 2020-01-09 南京明德新药研发有限公司 Crystalline form of egfr inhibitor and preparation method therefor
CN112912380A (en) * 2018-12-21 2021-06-04 基石药业（苏州）有限公司 Crystal form, amorphous form and application of MEK inhibitor
CN112912380B (en) * 2018-12-21 2023-08-11 基石药业（苏州）有限公司 Crystal form and amorphous form of MEK inhibitor and application thereof
CN113874362A (en) * 2019-05-13 2021-12-31 罗欣健康科技发展(北京)有限公司 Crystal form of quinazolinone compound and preparation method thereof

Also Published As

Publication number Publication date
CN107955019B (en) 2021-09-14

Similar Documents

Publication Publication Date Title
US11098015B2 (en) Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms thereof for the treatment of cancer
CN107955019A (en) A kind of salt form of EGFR inhibitor, crystal form and preparation method thereof
CN102510855A (en) Crystalline forms of n-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]-quin0lin-4-yl}oxy)phenyl]-n&#39;-(4-fluorophenyl)cyclopropane-1, 1-dicarboxamide
CN108602815B (en) Pyrido [1,2-a ] pyrimidinone analogs, crystalline forms thereof, intermediates thereof, and methods of making the same
WO2018214886A1 (en) Crystal form of deuterated azd9291, preparation method therefor, and use thereof
WO2017107985A1 (en) Crystals of quinazoline derivative and preparation method therefor
CN109689641A (en) A kind of substituted 2- hydrogen-pyrazole derivatives crystal form, salt form and preparation method thereof
CN108047205A (en) 2- (2,4,5- substitution phenylamino) pyrimidine derivatives, its preparation method and its application in antitumor drug is prepared
WO2020061996A1 (en) Novel crystal forms of deuterated azd9291 compound and use thereof
CN107266437B (en) The crystal form of N- phenyl -2- amino-metadiazine compound, salt form and preparation method thereof
WO2020156501A1 (en) Crystals of quinolone derivatives
CN103664890B (en) The crystallization of quinoline and preparation method
US20230322687A1 (en) Salt of arylaminoquinazoline-containing compound, and preparation method therefor and use thereof
CN118561816A (en) Crystal of trifluoroethyl substituted indole aniline pyrimidine compound and salt thereof
TW201829398A (en) Protein tyrosine kinase modulators salt, crystallographic forms, and uses thereof
KR20240045269A (en) FGFR4 inhibitor acid salt and its preparation method and application
CN116063291A (en) Crystal form of heterocyclic compound maleate
CN104470929B (en) The crystal form of Conmana and its application
CN116063288A (en) Crystal form of succinate, preparation method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant