CN107721987A - The crystal formation of quinazolines tyrosine kinase inhibitor - Google Patents
The crystal formation of quinazolines tyrosine kinase inhibitor Download PDFInfo
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- CN107721987A CN107721987A CN201710686893.3A CN201710686893A CN107721987A CN 107721987 A CN107721987 A CN 107721987A CN 201710686893 A CN201710686893 A CN 201710686893A CN 107721987 A CN107721987 A CN 107721987A
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- 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
- C07D403/12—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 linked by a chain containing hetero atoms as chain links
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Abstract
The invention belongs to field of medicaments, be the crystal formation C, its preparation method, pharmaceutical composition of compound (E) N shown in formula (I) (base of 4 (fluoroanilino of 3 chlorine 4) 7 methoxyquinazoline hydrochloride 6) 4 (base of azaspiro [3.3] heptane 2) 2 crotonamides more particularly to a kind of Pan HER tyrosine kinase inhibitors, and its prepare be used to treat and/or prevent hyperproliferative disease and/or the medicine of chronic obstructive pulmonary disease in application.
Description
1st, technical field
The present invention relates to a kind of crystal formation of quinazolines tyrosine kinase inhibitor and preparation method thereof, pharmaceutical composition,
And its prepare be used for treat and/or prevent excessively proliferative disease and/or the medicine of chronic obstructive pulmonary disease in application.
2nd, background technology
Compound (E)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxyquinazoline hydrochloride -6- bases) -4- (2- azaspiros
Ring [3.3] heptane -2- bases) -2- crotonamides (abbreviation formula (I) compound in specification, in patent application WO2012/159457
In have been described) for Pan-HER can not retroactive inhibition quinazoline derivative species tyrosine kinase inhibitor.Research shows, Pan-
HER tyrosine kinase irreversible inhibitors are also inhibited to HER2/4 in addition to effectively suppressing EGFR, this to HER/
There are the medicine of Irreversible inhibition in ErbB families in addition to pharmaceutical activity is improved, and also reduce the generation of drug resistance, especially
Have to the H1975 cell lines of Erlotinib resistances and significantly inhibit effect, given play to good antitumor activity.
The research of crystal formation plays an important role in drug development process, and the different crystal forms of same medicine are dissolving
Degree, stability, bioavilability etc. are there is significant difference, in order to better control over the quality of medicine, meet preparation,
The requirement of situations such as production, transport, storage, we are studied the crystal formation to formula (I) compound, good to find to have
The crystal formation of property.
3rd, the content of the invention
The present invention relates to (the 4- ((the chloro- 4- fluorophenyls of 3-) of Pan-HER tyrosine kinase inhibitors (E)-N- shown in formula (I)
Amino) -7- methoxyquinazoline hydrochloride -6- bases) -4- (2- azaspiros [3.3] heptane -2- bases) -2- crotonamides crystal formation C,
Its preparation method, the pharmaceutical composition comprising the crystal formation, and these compounds prepare be used for treat excessively proliferative disease and/
Or the application in the medicine of chronic obstructive pulmonary disease.
Specifically, the present invention provides：
(1) the crystal formation C, described crystal formation C of a kind of formula (I) compound have following architectural feature：Radiated using Cu-K α,
The X-ray powder diffraction represented with 2 θ angles, 6.4 ± 0.2 °, 11.0 ± 0.2 °, 14.8 ± 0.2 °, 15.5 ± 0.2 °,
There is characteristic peak at 18.3 ± 0.2 °, 20.7 ± 0.2 °.
(2) the crystal formation C of formula (I) compound described in above-mentioned (1), it has following architectural feature：Radiated using Cu-Ka,
The X-ray powder diffraction represented with 2 θ angles, on the basis of comprising features described above peak, also 6.6 ± 0.2 °, 11.8 ±
There is characteristic peak at 0.2 °, 16.3 ± 0.2 °, 19.1 ± 0.2 °, 22.6 ± 0.2 °.
(3) the crystal formation C of formula (I) compound described in above-mentioned (2), it has following architectural feature：Radiated using Cu-Ka,
The X-ray powder diffraction represented with 2 θ angles, on the basis of comprising features described above peak, also 9.0 ± 0.2 °, 22.0 ±
There is characteristic peak at 0.2 °, 23.6 ± 0.2 °, 24.0 ± 0.2 °, 25.1 ± 0.2 °, 27.2 ± 0.2 °.
(4) the crystal formation C of formula (I) compound described in above-mentioned (3), is radiated, the X-ray represented with 2 θ angles using Cu-Ka
Powder diffraction, its X-ray powder diffraction figure are as shown in Figure 1.
(5) the crystal formation C of formula (I) compound described in above-mentioned (1)~(4), in DSC thermal maps spectrum, temperature is at 110-120 DEG C
There is an endothermic transition peak in place, transition temperature when maximum is absorbed heat, i.e., the temperature at endotherm peak, be 119.6 ± 3 DEG C,
Its dsc analysis figure is as shown in Figure 2.
(6) the crystal formation C of formula (I) compound described in above-mentioned (1)~(4), in TGA collection of illustrative plates, its temperature is less than 210-
230 DEG C, preferably 220 DEG C, its weightlessness are 0-3.2%, and institute's weight loss is impurity, free water and/or the organic solvent in crystal formation, high
When the temperature, degrade, its TGA figures are substantially as shown in Figure 3.
(7) formula (I) compound described in can be prepared by the method disclosed in patent WO2012/159457, its
Compound hydrogen spectrum (1H-NMR) as shown in Figure 4.
(8) present invention also offers the crystal formation C of described formula (I) compound two kinds of preparation methods, wherein the first system
The technical scheme of Preparation Method is as follows：
Formula (I) compound is washed and starched into 50-80h in 30-70 DEG C of solvent, then filtered, dries, produces crystal formation C.
The crystal formation C of described formula (I) compound preparation method, formula (I) compound preferably wash and starch 60- at 40-60 DEG C
80h。
The crystal formation C of described formula (I) compound preparation method, formula (I) compound preferably wash and starch 70- at 45-55 DEG C
75h。
The crystal formation C of described formula (I) compound preparation method, formula (I) compound preferably wash and starch 72h at 50 DEG C.
Described washes and starches what is preferably carried out under air-proof condition, and described drying preferably under vacuum, more preferably exists
16h is dried in vacuo at 45 DEG C.
The crystal formation C of described formula (I) compound preparation method, described solvent include organic solvent, water and organic
The mixed solvent that solvent is formed with water according to special ratios, described organic solvent include one or two kinds of in following solvent
Or the mixed organic solvents that two or more solvents are formed：
Aromatic hydrocarbon solvent, selected from benzene, toluene, ethylbenzene, propyl benzene, ortho-xylene, meta-xylene, paraxylene, 1.3.5-
Trimethylbenzene, 1,2,4- trimethylbenzenes, preferably toluene, ortho-xylene, meta-xylene, paraxylene；
Ether solvent, preferably fatty ethers or cyclic ether solvents, the fatty ether solvent is preferably ether, dipropyl
Ether, diisopropyl ether, methyl tertiary butyl ether(MTBE), ethyl-butyl ether, ethyl tert-butyl ether (ETBE), butyl oxide, more preferably diamyl ether, methyl- tert
Butyl ether, the cyclic ether solvents are preferably oxirane, 1,2- expoxy propane, tetrahydrofuran, 2- methylfurans, dioxolanes
Or Isosorbide-5-Nitrae-dioxane, more preferably Isosorbide-5-Nitrae-dioxane；The preferred cyclic ether solvents of ether solvent.
Sulfoxide type solvents, selected from dimethyl sulfoxide (DMSO), diethyl sulfoxide or benzyl benzene sulfoxide, more preferably dimethyl sulfoxide (DMSO), diethyl
Base sulfoxide.
Listed instantiation is not limited in arene indicated above, ethers and sulfoxide type solvents, it is all
It is the function that the solvent belonged in above-mentioned classification can realize the present invention, that is, the crystal formation C shown in formula (I) is prepared.
Signified " mixed organic solvents " can be being mutually mixed for one species or variety classes solvent, same kind of
Mixed solvent, including but not limited to benzene and toluene, ether and dimethyl ether, ether and Isosorbide-5-Nitrae-dioxane, dimethyl sulfoxide (DMSO) and two
Ethyl-sulfoxide etc.；Different types of mixed solvent, including but not limited to toluene and ether, ether and dimethyl sulfoxide (DMSO), toluene
With dimethyl sulfoxide (DMSO) etc..
Described " mixed solvent that organic solvent is formed with water according to special ratios ", its instantiation includes but is not limited to
It is several below：Arene/water, ether solvent/water, sulfoxide type solvents/water, arene/ethers/water, arene/sulfoxide
Class solvent/water, sulfoxide type solvents/ethers/water, preferably ether solvent/water, sulfoxide type solvents/water, more preferably dimethyl sulfoxide (DMSO)/
Water；Described special ratios are 30:1-1:30, preferably 25:1‐1:25, preferably 20:1‐1:20, preferably 15:1‐1:15, preferably
10:1‐1:10。
(9) the crystal formation C of formula (I) compound of the invention second of preparation method, its technical scheme are as follows：
By formula (I) compound (E)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxyquinazoline hydrochloride -6- bases) -4-
(2- azaspiros [3.3] heptane -2- bases) -2- crotonamides are recrystallized in aromatic hydrocarbon solvent and/or ketones solvent and are prepared into
Arrive, described aromatic hydrocarbon solvent is selected from benzene, toluene, ethylbenzene, propyl benzene, ortho-xylene, meta-xylene, paraxylene, 1.3.5- tri-
Toluene, 1,2,4- trimethylbenzenes；Described ketones solvent is selected from alkanones or ring ketones solvent, the choosing of described alkanones solvent
From MEK, first isopropyl acetone, acetone, espeleton, methylisobutylketone, DIBK, described ring ketones solvent is selected from ring
Acetone, cyclohexanone, isophorone, 1-METHYLPYRROLIDONE.
In crystal formation C of the present invention second of preparation method, its optimal technical scheme is that the aromatic hydrocarbon solvent is selected from benzene, first
Benzene, ortho-xylene, meta-xylene, paraxylene, described ketones solvent are selected from acetone, cyclohexanone, 1-METHYLPYRROLIDONE, virtue
Varsol can form mixed solvent, preferably toluene/1-METHYLPYRROLIDONE mixed solvent with ketones solvent according to special ratios,
Described special ratios are selected from 30:1-1:30, preferably 20:1‐1:20, preferably 10:1‐1:10, preferably 5:1‐1:5.Recrystallizing
In preparation method, described mixed solvent can be the mixed solvent configured in specific proportions in advance or prepare
Process is added in specific proportions in batches.
(10) present invention also provides the crystal formation C and one or more pharmaceutical carriers and/or the medicine of diluent of formula (I) compound
Compositions, the pharmaceutical composition can be prepared into pharmaceutically acceptable any formulation, with oral, parenteral, rectum or transpulmonary
The modes such as administration, which are applied to, needs its patient.During for being administered orally, conventional solid pharmaceutical preparation is can be made into, such as tablet, capsule
Agent, pill, granule etc.；It may be made as oral liquid, such as oral solution, oral suspensions, syrup.Mouth is made
During formulation, suitable filler, adhesive, disintegrant, lubricant etc. can be added.During for parenteral, it can be made into
Injection, including parenteral solution, injection sterile powder and concentrated solution for injection.When injection is made, existing pharmacy can be used to lead
Conventional method production in domain, when preparing injection, can be added without additives, can also be added suitably according to the property of medicine
Additives.During for rectally, suppository etc. can be made into.During for transpulmonary administration, inhalant or spray etc. can be made into.
(11) present invention also provides treatment and/or the method for prevention excessively proliferative disease and/or chronic obstructive pulmonary disease, its
Including to needing patient of this treatment to give (E)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxyl group quinoline azoles of effective dose
Quinoline -6- bases) -4- (2- azaspiros [3.3] heptane -2- bases) -2- crotonamides crystallization C.
The crystal formation C of the invention for also providing formula (I) compound is in preparation treatment and/or prevention excessively proliferative disease and/or slowly
Application in the medicine of property obstructive lung disease.
(12) excessively proliferative disease described in is selected from：Brain tumor, lung cancer, lung cancer in non-cellule type, squamous cell, bladder
Cancer, stomach cancer, oophoroma, peritoneal cancer, cancer of pancreas, breast cancer, head and neck cancer, cervix cancer, carcinoma of endometrium, colorectal cancer, liver cancer,
Kidney, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, solid tumor, NHL, central nerve neuroma (neuroglia
Knurl, glioblastoma multiforme, glioma sarcomatosum), prostate cancer, thyroid cancer, the hyperplasia of prostate of skin or prostate.
(13) present invention also provides the crystal formation C and the treatment preparation of one or more second of formula (I) compound composition, can
These second treatment preparations and the crystal formation C of formula (I) compound are simultaneously or sequentially administered, excessively increased for treating and/or preventing
Raw disease and/or chronic obstructive pulmonary disease.The second therapeutic agent is selected from antimetabolite, including capecitabine, gemcitabine；It is raw
Long factor inhibitors, including pazopanib, Imatinib；Antibody, including Trastuzumab, bevacizumab；Mitotic inhibitor, bag
Include taxol, vinorelbine, docetaxel, Doxorubicin；Antitumor steroids, including Letrozole, tamoxifen, fluorine dimension department
Group；Alkylating agents, including endoxan, BCNU；Metal platinum class, including carboplatin, cis-platinum, oxaliplatin；Topoisomerase
Inhibitor, including Topotecan；Immunosupress class, including everolimus.
The crystal formation C of formula (1) compound major advantage includes：
(1) compound (E)-N- (4- ((the chloro- 4- fluorobenzene of 3-) amino) -7- methoxyquinazoline hydrochlorides -6- provided by the invention
Base) -4- (2- azaspiros [3.3] heptane -2- bases) -2- crotonamides crystal formation C preparation method it is easy to operate, be adapted to industry
Metaplasia is produced；
(2) the crystal formation C provided by the invention has good character, be easy to produce, detect, it is prepared by preparation, transport and
Storage；
(3) purity of the crystal formation C provided by the invention is high, residual solvent is few, and solubility is higher, and stability is good, quality
It is easily-controllable；
(4) the crystal formation C provided by the invention has good inhibitory activity to Pan-Her kinases, in vivo with good
Good exposed amount and/or bioavilability；
(5) the crystal formation C provided by the invention has good antitumous effect, excessive available for treatment and/or prevention
Proliferative disease and/or chronic obstructive pulmonary disease.
4th, illustrate
Fig. 1 is the crystal formation C of formula (I) compound X-ray powder diffraction collection, and ordinate represents diffracted intensity
(intensity), abscissa represents angle of diffraction (2 θ).
Fig. 2 is the crystal formation C of formula (I) compound means of differential scanning calorimetry (DSC) analysis chart, and ordinate represents hot-fluid (W/g),
Abscissa represents temperature T (DEG C).
Fig. 3 is the crystal formation C of formula (I) compound thermogravimetric analysis (TGA) curve and difference quotient thermogravimetric analysis (DTG) curve, horizontal
Coordinate is temperature (DEG C), and left side ordinate represents weight (%), and right side ordinate represents weight loss rate (%) and the relation of temperature.
Fig. 4 is formula (I) compound1H-NMR。
X-ray powder diffraction (X-ray Powder Diffraction, XRPD) refers to that beam of x-rays is irradiated to object
When upper, scattered by atom in object, each atom produces scattered wave, and these ripples interfere with each other, and as a result just produces diffraction.
The result of diffracted wave superposition makes the intensity of ray strengthen in a certain direction, weakens in the other direction.Diffraction patterns are analyzed, just
Crystal structure can be obtained.X-ray diffractometer is to utilize diffraction principle, the accurate crystal structure for determining material, texture and stress, essence
True carry out material phase analysis, qualitative analysis, quantitative analysis.For crystalline material, when crystal to be measured and incident beam are in different angle
When, those meet that the crystal face of Bragg diffraction will be detected, and it is exactly strong with different diffraction to be embodied in XRD spectrum
The diffraction maximum of degree.For amorphous material, because the long-range order of atomic arrangement in crystal structure is not present in its structure, simply exist
There is shortrange order in several atoms ranges, therefore the XRD spectrum of amorphous material is some diffusing scattering steamed bun peaks.
During with X-ray powder diffraction measure crystal formation of the invention, sometimes due to the condition of the instrument of measure or measure, right
Slightly evaluated error, the crystallization of the spectrum peak in error range the crystallization in the present invention can be also covered by for the peak measured
In.Therefore it is determined that during crystalline texture, it should take this error into account, therefore the applicant is it is determined that consider during 2 θ angles
Error range (± 0.2 °).
Differential scanning calorimetry (differential scanning calorimetry, DSC) is a kind of thermal analysis system.
Under programed temperature, measurement is input to relation of the difference power (as in the form of heat) of sample and reference substance with temperature.Difference
The curve that scanning calorimeter instrument recorded claims DSC curve, and it is with hot-fluid (unit W/g, i.e. unit mass sample neither endothermic nor exothermic work(
Rate) it is ordinate, using temperature T or time t as abscissa, a variety of thermodynamics and kineticses parameters can be determined, such as specific heat capacity,
Reaction heat, the heat of transformation, phasor, reaction rate, crystalline rate, superpolymer crystal degree, sample purity etc..The method use temperature range
Wide (- 175~725 DEG C), high resolution, sample dosage are few.
Due to the influence of determining instrument or the condition of measure in DSC curve, can slightly be determined for the peak of measure
Error, the peak figure in error range, during its corresponding crystallization is intended to be included within the scope of the present invention.Therefore, it is determined that crystal knot
During structure, it should take this error into account, therefore the applicant is it is determined that produce maximum rate of heat flow (the i.e. peak at neither endothermic nor exothermic peak
At value) temperature when consider error range (± 3 DEG C).
Thermogravimetric analyzer (Thermogravimetric Analysis, TGA), which refers to measure under programed temperature, to be treated
The quality of test sample product and a kind of thermoanalysis technology of temperature change relation, for studying the heat endurance of material and component.Thermogravimetric
Method be under temperature programmed control, the quality of measurement of species with temperature (or time) variation relation.When measured matter is in heating process
In have distillation, when vaporizing, decompositing gas or lose the crystallization water, tested material mass will change.At this moment thermogravimetric is bent
Line is not just straight line but declined.By analyzing thermogravimetric curve, it is possible to know that measured matter produces change in how many spend
Change, and according to weight loss, can calculate and how many material lost, such as the crystallization water.Help to study crystallographic by TGA experiments
The change of matter, the physical phenomenon such as melt, evaporate, to distil and adsorb material；Also contribute to study the dissociation of material, oxidation,
Reduction, heat endurance, decomposable process, the quantitative analysis of composition, additive and filler influence, moisture content and volatile matter, reaction move
The chemical phenomenon of the materials such as mechanics.Thermogravimetric analysis is commonly divided into two classes：Dynamically (heat up) and static (constant temperature).DTG is tested
Obtained curve is referred to as thermogravimetric curve (TGA curves), and TGA curves make ordinate with quality, represent Mass lost from the top down；With
Temperature (or time) makees abscissa, represents temperature (or time) increase from left to right.
5th, embodiment
The embodiment of form by the following examples, the above of the present invention is made further specifically
It is bright.But the scope that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following examples.It is but above-mentioned interior based on the present invention
Hold realized technology and belong to the scope of the present invention.
Formula (I) compound crystal form of embodiment 1 C preparation (heat washes and starches preparation method)
Formula (I) compound 200mg is added into reaction bulb, listed solvent in 2.0mL tables 1 is then added, sealing, is heated to
50 DEG C of stirring 72h, solid non-dissolved clarification always, filter solid, obtain crystal formation C.
Table 1 prepares crystal formation C solvent for use
| Solvent is numbered | Solvent species |
| 1 | 1,4- dioxane |
| 2 | Toluene |
| 3 | DMSO:Water==1:20 |
Formula (I) compound crystal form of embodiment 2 C preparation (recrystallization preparation method)
In reaction bulb, formula (I) compound 200mg is added, then it is small to put into 115 DEG C of oil baths stirring 1 by addition toluene 2mL
Shi Hou, solid is insoluble, when adding 200 μ L of NMP, dissolved clarification, after stirring 2.0h, starts Temperature fall, white solid is separated out after 22h,
After being again stirring for 5.0h, solid is filtered, obtains crystal formation C.
X-ray powder diffraction determines
Crystal structure of the present invention is not limited to complete with the X-ray powder diffraction figure with being painted in accompanying drawing disclosed in the present application
Exactly the same crystal structure, as long as there is any crystal structure essentially identical with the X-ray powder diffraction figure disclosed in accompanying drawing
It is intended to be included within the scope.
XRPD test conditions：
X ray reflection parameter：Cu, K α；Entrance slit：0.6mm；Divergent slit：1mm；Scan pattern：Continuously；
Scanning range：3.0~45.0 degree；Sampling step length：0.02 degree；Often walk sweep time：19.8s；Probe angle：
2.0 degree.
The crystal formation C of formula (I) compound is shown in Figure 1 in X-ray powder diffraction figure, and the crystal formation is in the following θ angles of diffraction 2
There is peak at place：6.4±0.2°、6.6±0.2°、9.0±0.2°、11.0±0.2°、11.8±0.2°、13.7±0.2°、14.8±
0.2°、15.5±0.2°、16.0±0.2°、16.3±0.2°、18.3±0.2°、19.1±0.2°、19.7±0.2°、20.7±
0.2°、22.0±0.2°、22.6±0.2°、24.0±0.2°、25.1±0.2°、27.2±0.2°、30.3±0.2°、31.5±
0.2°。
Differential scanning calorimetry
The crystal formation C of formula (I) compound solid-state hot property is studied by differential scanning calorimetry (DSC).Crystal formation C DSC
Curve is shown in Fig. 2.
DSC test conditions：Purged with nitrogen with 50mL/min, with the 10 DEG C/min rates of heat addition between 25 DEG C to 250 DEG C
Data are collected, are drawn in the case of endothermic peak is directed downwardly.
Thermogravimetric analysis
TGA test conditions：Purged with nitrogen with 60mL/min, room temperature between 350 DEG C with the 10 DEG C/min rates of heat addition
Collect data.Its TGA curve show with Fig. 3 in.
Nuclear-magnetism detection method
Instrument：Bruker Advance III 400；Solvent：Deuterated DMSO.
The nucleus magnetic hydrogen spectrum of formula (1) compound is shown in Fig. 4.
Formula (I) compound crystal form of embodiment 3 C study on the stability
Test sample：
The crystal formation C of formula (I) compound, prepared according to the method in embodiment.
Formula (I) compound, prepared according to the preparation method disclosed in WO2012/159457 specifications.
Test method：
Hot test：This product is laid in clean surface ware, puts 40 DEG C of ± 2 DEG C of RH75% ± 5%, 60 DEG C of ± 2 DEG C of conditions
Under, the 5 day investigation that carries out character, purity separately sampled in the 5th, 10 day, moisturize within 10 days, XRD is investigated.This product internal layer is used
Medicinal low density polyethylene (LDPE) bag, after overcoat polyester/aluminium/polyvinyl medicine composite packing film packs, in 10 days progressive
The investigation of shape, purity XRD.
Moisture：According to the Coulometric Titration of 0832 the first method of aquametry of Chinese Pharmacopoeia four general rules of version in 2015 2.
XRD：With reference to Chinese Pharmacopoeia four general rule 0451X ray diffraction methods measure of version in 2015.
Purity：Determined according to high performance liquid chromatography Chinese Pharmacopoeia four general rules 0512 of version in 2015.0.3mg/ml is prepared to supply
Test sample solution.Mobile phase A is 0.03mol/L diammonium hydrogen phosphate+0.02mol/L sodium perchlorates (phosphoric acid adjusts pH value to 4.0)-acetonitrile
(90:10), Mobile phase B is 0.03mol/L diammonium hydrogen phosphate+0.02mol/L sodium perchlorates (phosphoric acid adjusts pH value to 4.0) (25:
75)；Carry out linear gradient elution.
Result of the test
The crystal formation C stability results of the formula of table 2. (I) compound
The formula of table 3. (I) compound stability result
RH：Represent humidity.
Conclusion (of pressure testing)
The crystal formation C of formula (I) compound, in 40 DEG C of RH75%, be open or remain silent under the conditions of place 5 to 10 days, it is its character, pure
Degree, moisture, XRD do not have significant change；In 60 DEG C of high temperature, be open or remain silent under the conditions of place 5 to 10 days, its character, purity, water
Divide, XRD does not have significant change.
Formula (I) compound, put 5 to 10 days in 40 DEG C of RH75%, the decentralization of opening condition, purity is down to by 99.0%
81.7%, under the conditions of remaining silent, there is larger improvement, but purity has still declined；5 to 10 are put in 60 DEG C of high temperature, the decentralization of opening condition
My god, purity is down to 89.0% by 99.0%, and purity is down to 77.6% by 99.0% under the conditions of remaining silent.
As a result show, formula (I) compound crystal form A of the present invention shows good stability compared with formula (I) compound, is easy to medicine
The production of product, preparation are prepared, transport and stored, and more conducively ensure validity and security that medicine uses.
Claims (11)
- Compound (E)-N- 1. shown in formula (I) (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxyquinazoline hydrochloride -6- bases) -4- The crystal formation C of (2- azaspiros [3.3] heptane -2- bases) -2- crotonamides, it is characterised in that radiated using Cu-K α, with 2 θ angles The X-ray powder diffraction of expression, 6.4 ± 0.2 °, 11.0 ± 0.2 °, 14.8 ± 0.2 °, 15.5 ± 0.2 °, 18.3 ± 0.2 °, There is characteristic peak at 20.7 ± 0.2 °；It is preferred that also there is characteristic peak at 6.6 ± 0.2 °, 11.8 ± 0.2 °, 16.3 ± 0.2 °, 19.1 ± 0.2 °, 22.6 ± 0.2 °；Further preferably also 9.0 ± 0.2 °, 22.0 ± 0.2 °, 23.6 ± 0.2 °, 24.0 ± 0.2 °, 25.1 ± 0.2 °, 27.2 There is characteristic peak at ± 0.2 °；Still more preferably its X-ray powder diffraction figure is substantially as shown in Figure 1.
- 2. crystal formation C as claimed in claim 1, it is characterised in that in DSC thermal maps spectrum, temperature has one at 110-120 DEG C Individual endothermic transition peak, temperature during maximum rate of heat flow are 119.6 ± 3 DEG C；It is preferred that its DSC collection of illustrative plates is substantially as shown in Figure 2.
- 3. crystal formation C as claimed in claim 1, it is characterised in that in TGA collection of illustrative plates, its temperature is excellent less than 210-230 DEG C 220 DEG C are selected, its weightlessness is 0%-3.2%；Its TGA figures are substantially as shown in Figure 3.
- 4. prepare the method for the crystal formation C described in claim 1, it is characterised in that (((3- is chloro- by 4- by formula (I) compound (E)-N- 4- fluorophenyls) amino) -7- methoxyquinazoline hydrochloride -6- bases) -4- (2- azaspiros [3.3] heptane -2- bases) -2- crotonamides exist 50-80h is washed and starched in 30-70 DEG C of solvent, 60-80h is preferably washed and starched at 40-60 DEG C, 70-75h is preferably washed and starched at 45-55 DEG C, it is excellent It is selected in 50 DEG C and washes and starches 72h, then filter, dries, produce crystal formation C.
- 5. crystal formation C as claimed in claim 4 preparation method, it is characterised in that described solvent include organic solvent, water with And the mixed solvent that organic solvent and water are formed according to special ratios, one kind in following solvent of described organic solvent or The mixed organic solvents that two or more solvent of person is formed：(1) aromatic hydrocarbon solvent, selected from benzene, toluene, ethylbenzene, propyl benzene, ortho-xylene, meta-xylene, paraxylene, 1.3.5- tri- Toluene or 1,2,4- trimethylbenzenes；(2) ether solvent, selected from fatty ethers and cyclic ether solvents, the fatty ether solvent is selected from ether, dipropyl ether, two different Propyl ether, methyl tertiary butyl ether(MTBE), ethyl-butyl ether, ethyl tert-butyl ether (ETBE), butyl oxide or diamyl ether, cyclic ether solvents are selected from epoxy second Alkane, 1,2 epoxy prapane, tetrahydrofuran, 2- methylfurans, dioxolanes or 1,4- dioxane；(3) sulfoxide type solvents, selected from dimethyl sulfoxide (DMSO), diethyl sulfoxide or benzyl benzene sulfoxide.
- 6. crystal formation C as claimed in claim 5 preparation method, it is characterised in that described organic solvent is in following solvent One kind：(1) aromatic hydrocarbon solvent, selected from benzene, toluene, ortho-xylene, meta-xylene or paraxylene；(2) cyclic ether solvents, selected from oxirane, 1,2- expoxy propane, tetrahydrofuran, 2- methylfurans, dioxolanes or 1, 4- dioxane；(3) sulfoxide type solvents, selected from dimethyl sulfoxide (DMSO) or diethyl sulfoxide；Above-mentioned arene, cyclic ethers class, sulfoxide type solvents can with water according to special ratios formed mixed solvent, preferably sulfoxide type with The mixed solvent of the mixed solvent of water, more preferably dimethyl sulfoxide (DMSO) and water；Described special ratios are selected from 30:1-1:30, preferably 25:1‐1:25, preferably 20:1‐1:20.
- 7. prepare the method for the crystal formation C described in claim 1, it is characterised in that (((3- is chloro- by 4- by formula (I) compound (E)-N- 4- fluorophenyls) amino) -7- methoxyquinazoline hydrochloride -6- bases) -4- (2- azaspiros [3.3] heptane -2- bases) -2- crotonamides exist Recrystallization is prepared in aromatic hydrocarbon solvent and/or ketones solvent, and described aromatic hydrocarbon solvent is selected from benzene, toluene, ethylbenzene, third Benzene, ortho-xylene, meta-xylene, paraxylene, 1.3.5- trimethylbenzenes, 1,2,4- trimethylbenzenes；Described ketones solvent is selected from fat Fat ketone or ring ketones solvent, it is different that described alkanones solvent is selected from MEK, first isopropyl acetone, acetone, espeleton, methyl Butanone, DIBK, described ring ketones solvent are selected from cyclopropanone, cyclohexanone, isophorone, 1-METHYLPYRROLIDONE.
- 8. crystal formation C as claimed in claim 7 preparation method, it is characterised in that the aromatic hydrocarbon solvent is selected from toluene, neighbour two Toluene, meta-xylene, paraxylene, described ketones solvent are selected from acetone, cyclohexanone, 1-METHYLPYRROLIDONE, and aromatic hydrocarbons are molten Agent can form mixed solvent, preferably toluene/1-METHYLPYRROLIDONE mixed solvent with ketones solvent according to special ratios, described Special ratios are selected from 30:1-1:30, preferably 20:1‐1:20, preferably 10:1‐1:10, preferably 5:1‐1:5.
- 9. the pharmaceutical composition of the crystal formation C containing formula (I) compound described in claim any one of 1-3, it is characterised in that contain There are one or more pharmaceutical carriers, described pharmaceutical composition can be prepared into pharmaceutically acceptable any formulation.
- 10. the crystal formation C of formula (I) compound described in claim any one of 1-3 is used to treat and/or prevents excessively to increase preparing Application in terms of the medicine of raw disease and/or chronic obstructive pulmonary disease；Described excessively proliferative disease is selected from：It is brain tumor, lung cancer, non- Small cell lung cancer, squamous cell, carcinoma of urinary bladder, stomach cancer, oophoroma, peritoneal cancer, cancer of pancreas, breast cancer, head and neck cancer, uterus Neck cancer, carcinoma of endometrium, colorectal cancer, liver cancer, kidney, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, solid tumor, non-Hodgkin's leaching Bar knurl, central nerve neuroma (glioma, glioblastoma multiforme, glioma sarcomatosum), prostate cancer, thyroid gland The hyperplasia of prostate of cancer, skin or prostate.
- 11. the crystal formation C containing formula (I) compound described in claim any one of 1-3 treats preparation with one or more second Composition, the second therapeutic agent is selected from antimetabolite, including capecitabine, gemcitabine；Growth factor receptor inhibitors, including Pazopanib, Imatinib；Antibody, including Trastuzumab, bevacizumab；Mitotic inhibitor, including taxol, Changchun are auspicious Shore, docetaxel, Doxorubicin；Antitumor steroids, including Letrozole, tamoxifen, fulvestrant；Alkylating agents, including Endoxan, BCNU；Metal platinum class, including carboplatin, cis-platinum, oxaliplatin；Topoisomerase enzyme inhibitor, including topology are special Agree；Immunosupress class, including everolimus.
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