CN104610364A - Novel crystal form of phosphorus-containing substituted quinazoline derivative as well as preparation method and application of novel crystal form - Google Patents
Novel crystal form of phosphorus-containing substituted quinazoline derivative as well as preparation method and application of novel crystal form Download PDFInfo
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Abstract
The invention relates to the field of preparation of compounds and particularly relates to a novel crystal form of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(3-(4-methyl-1,4-azaphosphine-1-yl)propyl-1-alkynyl)quinazoline-4-amine p-toluene sulfonate as well as a preparation method and application of the novel crystal form. According to the preparation method, a transition crystal form is obtained by crystallizing or carrying out grinding physical crystal transformation on a mixed solvent of water, methanol, ethanol, n-propanol, isopropanol, acetone, acetonitrile, tetrahydrofuran or dioxane at different proportions and is further converted under special environmental conditions to obtain the novel crystal form of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(3-(4-methyl-1,4-azaphosphine-1-yl)prop-1-alkynyl)quinazoline-4-amine p-toluene sulfonate which has better treatment effect on treatment of hyperproliferative diseases. The drug activity is improved, the bioavailability of the crystal form is improved and the crystal form fills the gap in research on drugs containing the crystal form.
Description
Technical field
The present invention relates to crystal-form compound technical field, be specifically related to new crystal of the quinazoline derivant of phosphorous replacement and its preparation method and application.
Background technology
N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate, it is the quinazoline derivant of phosphorous replacement, its structural formula is as follows, it is the medicine of the overmedication proliferative disease researched and developed by NewGen Therapeutics, Inc., this compound is I receptor kinases inhibitor, can be used for treating relevant disease abnormal to protein kinase activity in Mammals, such as cancer and inflammation.
Chinese patent CN102711472A discloses a kind of phosphorous quinazoline derivant and using method thereof, comprising N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate, this patent describes various phosphorous quinazoline derivant preparation method and its function and efficacy in excess proliferative disease in detail.
Crystal formation is the solid matter state that medicine exists, drug crystal forms research is exactly the research to medicine basis state of matter, only have and had relatively more abundant and comprehensive understanding to chemicals crystal form state, just likely find the drug crystal forms solid matter being more appropriate to disease therapy.Drug crystal forms can affect the physico-chemical property of medicine, directly affects the basis that clinical drug plays disease therapy effect.Therefore, the important component part of drug substance fundamental research is carried out when drug crystal forms being studied.But at present, not yet have N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) relevant report of quinazoline-4-amine tosilate drug crystal forms, the fundamental research of this medicine is occurred blank.And, N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) in drug metabolism, also there is certain deficiency in quinazoline-4-amine tosilate, and bioavailability is not high.
Summary of the invention
In view of this, the object of the present invention is to provide a kind of N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) new crystal and its preparation method and application of quinazoline-4-amine tosilate, can improve pharmaceutical activity and improve drug bioavailability.
In order to realize foregoing invention object, the invention provides following technical scheme:
N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) crystal formation of quinazoline-4-amine tosilate, its x-ray diffractogram of powder substantially as shown in Figure 1, uses CuK
αradiation, the powder x-ray diffraction represented with 2 θ angles is 5.64 ± 1.00, 7.68 ± 1.00, 8.48 ± 1.00, 11.32 ± 1.00, 11.84 ± 1.00, 13.00 ± 1.00, 14.24 ± 1.00, 14.50 ± 1.00, 14.96 ± 1.00, 15.56 ± 1.00, 16.50 ± 1.00, 17.10 ± 1.00, 17.98 ± 1.00, 19.22 ± 1.00, 20.24 ± 1.00, 21.24 ± 1.00, 21.78 ± 1.00, 22.32 ± 1.00, 23.10 ± 1.00, 23.42 ± 1.00, 23.88 ± 1.00, 24.34 ± 1.00, 24.86 ± 1.00, 25.54 ± 1.00, 26.28 ± 1.00, 26.81 ± 1.00, 27.34 ± 1.00, 27.74 ± 1.00, 28.76 ± 1.00, 29.45 ± 1.00, 30.24 ± 1.00, 31.74 ± 1.00, 33.92 ± 1.00, 34.86 ± 1.00, 35.40 ± 1.00, 36.16 ± 1.00, 37.30 ± 1.00, 38.82 ± 1.00, 39.60 ± 1.00, 41.42 ± 1.00, 43.16 ± 1.00, 43.96 ± 1.00, 45.12 ± 1.00, 46.99 ± 1.00, 48.52 ± 1.00 have diffraction peak.
Wherein, described N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate is open at Chinese patent CN102711472A.
The each detailed powder x-ray diffraction parameter of new crystal of the present invention, in table 1, shows as diffraction peak position: 2-Theta value (°) or d value (
); Diffraction peak relative intensity: peak height value (Height%) or peak area value (Area%).
The powder x-ray diffraction peak value of table 1 new crystal of the present invention
Should be appreciated that, the 2 θ values of X-ray powder diffraction figure slightly can change between machine or between sample, its numerical value may differ about 1 unit, or differ about 0.8 unit, or differ about 0.5 unit, or differ about 0.2 unit, or differ about 0.1 unit, therefore quoted numerical value can not be interpreted as absolute value.Should be appreciated that equally, the relative intensity at peak can change according to the orientation of sample in test, its numerical value may differ about 1 unit equally, or differ about 0.8 unit, or differ about 0.5 unit, or differ about 0.2 unit, or differ about 0.1 unit, therefore XRPD trace (trace) intensity be included in the present invention is illustrative, and is not intended to for definitely comparing.
As preferably, the invention provides N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) crystal formation of quinazoline-4-amine tosilate, use CuK
αradiation, the powder x-ray diffraction represented with 2 θ angles is 5.64 ± 0.80, 7.68 ± 0.80, 8.48 ± 0.80, 11.32 ± 0.80, 11.84 ± 0.80, 13.00 ± 0.80, 14.24 ± 0.80, 14.50 ± 0.80, 14.96 ± 0.80, 15.56 ± 0.80, 16.50 ± 0.80, 17.10 ± 0.80, 17.98 ± 0.80, 19.22 ± 0.80, 20.24 ± 0.80, 21.24 ± 0.80, 21.78 ± 0.80, 22.32 ± 0.80, 23.10 ± 0.80, 23.42 ± 0.80, 23.88 ± 0.80, 24.34 ± 0.80, 24.86 ± 0.80, 25.54 ± 0.80, 26.28 ± 0.80, 26.81 ± 0.80, 27.34 ± 0.80, 27.74 ± 0.80, 28.76 ± 0.80, 29.45 ± 0.80, 30.24 ± 0.80, 31.74 ± 0.80, 33.92 ± 0.80, 34.86 ± 0.80, 35.40 ± 0.80, 36.16 ± 0.80, 37.30 ± 0.80, 38.82 ± 0.80, 39.60 ± 0.80, 41.42 ± 0.80, 43.16 ± 0.80, 43.96 ± 0.80, 45.12 ± 0.80, 46.99 ± 0.80, 48.52 ± 0.80 have diffraction peak.
As preferably, the invention provides N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) crystal formation of quinazoline-4-amine tosilate, use CuK
αradiation, the powder x-ray diffraction represented with 2 θ angles is 5.64 ± 0.50, 7.68 ± 0.50, 8.48 ± 0.50, 11.32 ± 0.50, 11.84 ± 0.50, 13.00 ± 0.50, 14.24 ± 0.50, 14.50 ± 0.50, 14.96 ± 0.50, 15.56 ± 0.50, 16.50 ± 0.50, 17.10 ± 0.50, 17.98 ± 0.50, 19.22 ± 0.50, 20.24 ± 0.50, 21.24 ± 0.50, 21.78 ± 0.50, 22.32 ± 0.50, 23.10 ± 0.50, 23.42 ± 0.50, 23.88 ± 0.50, 24.34 ± 0.50, 24.86 ± 0.50, 25.54 ± 0.50, 26.28 ± 0.50, 26.81 ± 0.50, 27.34 ± 0.50, 27.74 ± 0.50, 28.76 ± 0.50, 29.45 ± 0.50, 30.24 ± 0.50, 31.74 ± 0.50, 33.92 ± 0.50, 34.86 ± 0.50, 35.40 ± 0.50, 36.16 ± 0.50, 37.30 ± 0.50, 38.82 ± 0.50, 39.60 ± 0.50, 41.42 ± 0.50, 43.16 ± 0.50, 43.96 ± 0.50, 45.12 ± 0.50, 46.99 ± 0.50, 48.52 ± 0.50 have diffraction peak.
As preferably, the invention provides N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) crystal formation of quinazoline-4-amine tosilate, use CuK
αradiation, the powder x-ray diffraction represented with 2 θ angles is 5.64 ± 0.20, 7.68 ± 0.20, 8.48 ± 0.20, 11.32 ± 0.20, 11.84 ± 0.20, 13.00 ± 0.20, 14.24 ± 0.20, 14.50 ± 0.20, 14.96 ± 0.20, 15.56 ± 0.20, 16.50 ± 0.20, 17.10 ± 0.20, 17.98 ± 0.20, 19.22 ± 0.20, 20.24 ± 0.20, 21.24 ± 0.20, 21.78 ± 0.20, 22.32 ± 0.20, 23.10 ± 0.20, 23.42 ± 0.20, 23.88 ± 0.20, 24.34 ± 0.20, 24.86 ± 0.20, 25.54 ± 0.20, 26.28 ± 0.20, 26.81 ± 0.20, 27.34 ± 0.20, 27.74 ± 0.20, 28.76 ± 0.20, 29.45 ± 0.20, 30.24 ± 0.20, 31.74 ± 0.20, 33.92 ± 0.20, 34.86 ± 0.20, 35.40 ± 0.20, 36.16 ± 0.20, 37.30 ± 0.20, 38.82 ± 0.20, 39.60 ± 0.20, 41.42 ± 0.20, 43.16 ± 0.20, 43.96 ± 0.20, 45.12 ± 0.20, 46.99 ± 0.20, 48.52 ± 0.20 have diffraction peak.
As preferably, the invention provides N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) crystal formation of quinazoline-4-amine tosilate, use CuK
αradiation, the powder x-ray diffraction represented with 2 θ angles is 5.64 ± 0.10, 7.68 ± 0.10, 8.48 ± 0.10, 11.32 ± 0.10, 11.84 ± 0.10, 13.00 ± 0.10, 14.24 ± 0.10, 14.50 ± 0.10, 14.96 ± 0.10, 15.56 ± 0.10, 16.50 ± 0.10, 17.10 ± 0.10, 17.98 ± 0.10, 19.22 ± 0.10, 20.24 ± 0.10, 21.24 ± 0.10, 21.78 ± 0.10, 22.32 ± 0.10, 23.10 ± 0.10, 23.42 ± 0.10, 23.88 ± 0.10, 24.34 ± 0.10, 24.86 ± 0.10, 25.54 ± 0.10, 26.28 ± 0.10, 26.81 ± 0.10, 27.34 ± 0.10, 27.74 ± 0.10, 28.76 ± 0.10, 29.45 ± 0.10, 30.24 ± 0.10, 31.74 ± 0.10, 33.92 ± 0.10, 34.86 ± 0.10, 35.40 ± 0.10, 36.16 ± 0.10, 37.30 ± 0.10, 38.82 ± 0.10, 39.60 ± 0.10, 41.42 ± 0.10, 43.16 ± 0.10, 43.96 ± 0.10, 45.12 ± 0.10, 46.99 ± 0.10, 48.52 ± 0.10 have diffraction peak.
In addition, the present invention is also analyzed described new crystal by infrared spectra and differential canning calorimetry, wherein use infrared spectra when analyzing 3297,2995,2937,2691,2583,1639,1613,1581,1557,1532,1497,1446,1403,1372,1338,1292,1275,1248,1191,1163,1152,1120,1076,1065,1031,1008,957,925,893,860,843,814,795,774,746,711,679cm
-1there is diffuse reflectance infrared spectroscopy peak in place, the permissible variation at its mid-infrared spectral behavior peak is ± 2cm
-1, infrared spectrogram substantially as shown in Figure 2;
When using differential canning calorimetry to analyze, showing as temperature rise rate is there are 4 endotherm(ic)peaks in the DSC collection of illustrative plates of per minute 10 DEG C respectively at 86 DEG C ± 3 DEG C, 108 DEG C ± 3 DEG C, 159 ± 3 DEG C and 177 ± 3 DEG C of places, and its spectrogram substantially as shown in Figure 3;
When using thermogravimetric technical Analysis, show as when temperature rise rate is there is the weightless step of 2 molecular water compositions in the TG collection of illustrative plates of per minute 5 DEG C in 50 ~ 140 DEG C of temperature ranges, weightless ratio is 7% ± 2%, and its spectrogram substantially as shown in Figure 4.
Should be appreciated that deviation may be had to have similar situation with X-ray powder diffraction figure numerical value, the numerical value that infrared spectra, differential canning calorimetry and thermogravimetric technology are quoted can not be interpreted as absolute value.
Present invention also offers a kind of N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate mixing crystal formation, comprise the new crystal of the present invention of arbitrary proportion.
New crystal of the present invention with lapatinibditosylate in the test of the Proliferation Ability of different people tumor cell line, its IC
50all will lower than the IC of lapatinibditosylate
50, show that the pharmaceutical activity of new crystal of the present invention is more excellent.Simultaneously, the present invention is to N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate and crystal formation of the present invention carry out pharmacokinetic trial, result shows, crystal formation of the present invention is obviously better than existing compound reaching in peak concentration and area under the drug-time curve, shows that crystal formation of the present invention has better bioavailability.
Based on this, the invention provides described N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate crystal formation or its mixing crystal formation preparing the application in overmedication proliferative disease medicine.
As preferably, described excess proliferative disease is cancer or inflammation.Preferred, described cancer is mammary cancer, cancer of the stomach, colorectal carcinoma, lung cancer, cortical carcinoma or ovarian cancer.
The present invention also provides a kind of overmedication proliferative disease medicine, includes the crystal formation of the present invention of effective amount or described mixing crystal formation, and pharmaceutically acceptable vehicle.
Significant quantity of the present invention refers to the pharmacologic agent dosage that can reach therapeutic action; Described vehicle refers to the annexation in pharmaceutical preparation except main ingredient, also can be described as auxiliary material.As the tamanori in tablet, weighting agent, disintegrating agent, lubricant, wine in medicine pill, vinegar, concoction etc., base portion in semi-solid preparation ointment, creme, sanitas in liquid preparation, oxidation inhibitor, correctives, perfume compound, solubility promoter, emulsifying agent, solubilizing agent, osmotic pressure regulator, tinting materials etc. all can be described as vehicle, as preferably, vehicle of the present invention is wetting agent, dispersion agent, pH adjusting agent, oxidation inhibitor, weighting agent, thinner, solubilizing agent, suspending agent, correctives, tackiness agent, disintegrating agent, osmotic pressure regulator, flocculation agent, antisticking agent, suspending agent, one or more in emulsifying agent and sanitas, more preferably, be specially lactose, starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose, talcum powder, Magnesium Stearate, sodium cellulose glycolate, or be lactose, starch, Microcrystalline Cellulose, Magnesium Stearate, sodium cellulose glycolate.
As preferably, described excess proliferative disease is cancer or inflammation.Preferred, described cancer is mammary cancer, cancer of the stomach, colorectal carcinoma, lung cancer, cortical carcinoma or ovarian cancer.
As preferably, excess proliferative disease medicine of the present invention is tablet, capsule, pill, injection, sustained release preparation medicine or controlled release preparation medicine, is more preferably tablet or capsule.
Present invention also offers the preparation method of described new crystal, use water and methanol mixed solvent, water and alcohol mixed solvent, water and n-propyl alcohol mixed solvent, water and isopropyl alcohol mixed solvent 3, water and acetone mixed solvent, water and acetonitrile mixed solvent, water and tetrahydrofuran (THF) mixed solvent, water and dioxane mixed solvent any one at 15 DEG C ~ 60 DEG C temperature by N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) after quinazoline-4-amine tosilate sample dissolves completely, remove mixed solvent with Rotary Evaporators and obtain transition crystal formation, described transition crystal formation is envrionment temperature 0 DEG C ~ 40 DEG C, ambient relative humidity is placed more than 1 day for 50% ~ 100% time, obtain described crystal formation,
Described transition crystal formation uses CuK
αradiation, diffraction peak is had 19.78 ± 1 with the powder x-ray diffraction that 2 θ angles represent, preferably there is diffraction peak 19.78 ± 0.8, preferably there is diffraction peak 19.78 ± 0.5, preferably have diffraction peak 19.78 ± 0.2, preferably have diffraction peak 19.78 ± 0.1, its x-ray diffractogram of powder substantially as shown in Figure 5,, each detailed powder x-ray diffraction parameter, in table 2, shows as diffraction peak position: 2-Theta value (°) or d value (
); Diffraction peak relative intensity: peak height value (Height%) or peak area value (Area%).In addition, described transition crystal formation infrared spectra 3407,2961,2916,2869,2566,1618,1591,1578,1561,1531,1497,1446,1396,1374,1338,1302,1255,1214,1157,1120,1077,1060,1031,1008,951,925,894,814,784,749,710,680cm
-1there is diffuse reflectance infrared spectroscopy peak in place, the permissible variation at its mid-infrared spectral behavior peak is ± 2cm
-1, infrared spectrogram substantially as shown in Figure 6.
The powder x-ray diffraction peak value of table 2 transition crystal formation of the present invention
As preferably, the pressure of described Rotary Evaporators is-0.01Mpa; As preferably, the rotating speed of described Rotary Evaporators is 90rpm; As preferably, the working hour of described Rotary Evaporators is 30min; Further preferably, the pressure of described Rotary Evaporators is-0.01Mpa, rotating speed is 90rpm, the working hour is 30min.
As preferably, the mass volume ratio of described N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate sample and mixed solvent is 100mg:4mL-8mL.
As preferably, described envrionment temperature is 10-25 DEG C; As preferably, described ambient relative humidity is 75-90%, and as preferably, described storage period is 1-3 days.Further preferably, described envrionment temperature is 10-25 DEG C, and described ambient relative humidity is 75-90%, and described storage period is 1-3 days.
As preferably, the preparation method of described new crystal uses volume ratio water: methyl alcohol is 1:1, water: ethanol is 1:2, water: n-propyl alcohol is 2:3, water: Virahol is 1:3, water: acetone is 1:1, water: acetonitrile is 1:2, water: tetrahydrofuran (THF) is 1:3 or water: dioxane be the mixed solvent of 1:4 at 15 DEG C ~ 60 DEG C temperature by N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) after quinazoline-4-amine tosilate sample dissolves completely, remove mixed solvent with Rotary Evaporators and obtain transition crystal formation, described transition crystal formation is envrionment temperature 0 DEG C ~ 40 DEG C, ambient relative humidity is placed more than 1 day for 50% ~ 100% time, obtain described crystal formation.
Present invention also offers the preparation method of new crystal described in another, by N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate sample employing grinding physics rotating crystal method acquisition transition crystal formation, described transition crystal formation is placed more than 1 day for 50% ~ 100% time at envrionment temperature 0 DEG C ~ 40 DEG C, ambient relative humidity, obtains described crystal formation; Wherein, the ratio of grinding media to material of described grinding physics rotating crystal method is 1:10-30:1, and grinding rotating speed is 50-800r/min, and milling time is no less than 0.5h;
Described transition crystal formation uses CuK
αradiation, diffraction peak is had 19.78 ± 1 with the powder x-ray diffraction that 2 θ angles represent, preferably there is diffraction peak 19.78 ± 0.8, preferably there is diffraction peak 19.78 ± 0.5, preferably have diffraction peak 19.78 ± 0.2, preferably have diffraction peak 19.78 ± 0.1, its x-ray diffractogram of powder substantially as shown in Figure 5,, each detailed powder x-ray diffraction parameter, in table 2, shows as diffraction peak position: 2-Theta value (°) or d value (
); Diffraction peak relative intensity: peak height value (Height%) or peak area value (Area%).In addition, described transition crystal formation infrared spectra 3407,2961,2916,2869,2566,1618,1591,1578,1561,1531,1497,1446,1396,1374,1338,1302,1255,1214,1157,1120,1077,1060,1031,1008,951,925,894,814,784,749,710,680cm
-1there is diffuse reflectance infrared spectroscopy peak in place, the permissible variation at its mid-infrared spectral behavior peak is ± 2cm
-1, infrared spectrogram substantially as shown in Figure 6.
As preferably, the ratio of grinding media to material of described grinding physics rotating crystal method is 3:1-10:1; As preferably, grinding rotating speed is 200-400r/min; As preferably, milling time is 1-8h.Further preferably, the ratio of grinding media to material of described grinding physics rotating crystal method is 3:1-10:1, and grinding rotating speed is 200-400r/min, and milling time is 1-8h.
As preferably, often rotating 15min when grinding, stopping 2min.
As preferably, described envrionment temperature is 10-25 DEG C; As preferably, described ambient relative humidity is 75-90%, and as preferably, described storage period is 1-3 days.Further preferably, described envrionment temperature is 10-25 DEG C, and described ambient relative humidity is 75-90%, and described storage period is 1-3 days.
From above technical scheme, the present invention is by water and methyl alcohol, ethanol, n-propyl alcohol, Virahol, acetone, acetonitrile, the mixed solvent crystallization that tetrahydrofuran (THF) or dioxane are made by different ratio or adopt grinding physics rotating crystal method to obtain transition crystal formation, and then conversion obtains better N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(the 4-methyl isophthalic acid of overmedication proliferative disease effect under special environment condition, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate new crystal, not only increase the pharmaceutical activity of the quinazoline derivant of this phosphorous replacement, and improve its bioavailability, compensate for the blank of its crystal formation drug research.
Accompanying drawing explanation
Fig. 1 shows the X-ray powder diffraction figure of N-of the present invention (3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate crystal formation;
Fig. 2 shows the infrared spectrogram of N-of the present invention (3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate crystal formation;
Fig. 3 shows the Differential Scanning Calorimetry of N-of the present invention (3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate crystal formation;
Fig. 4 shows the thermogravimetric spectrogram of N-of the present invention (3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate crystal formation;
Fig. 5 shows the X-ray powder diffraction figure of transition crystal formation of the present invention;
Fig. 6 shows the infrared spectrogram of transition crystal formation of the present invention.
Embodiment
The invention discloses new crystal of the quinazoline derivant of phosphorous replacement and its preparation method and application, those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.New crystal of the present invention, preparation method and application are described by preferred embodiment, related personnel obviously can not depart from content of the present invention, spirit and scope methods and applications as herein described are changed or suitably change with combination, realize and apply the technology of the present invention.
In N-provided by the invention (3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate crystal formation and preparation method thereof, agents useful for same all can be buied by market.
Wherein, N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(the 4-methyl isophthalic acid used, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate can buy from NewGen Therapeutics, Inc., also prepare by following methods:
By 450g (0.823mol) compound N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine is (shown in I, purchased from NewGen Therapeutics, Inc.), p-methyl benzenesulfonic acid 298g (1.731mol), add in solvent 4500ml (Virahol: water=10:1), mechanical stirring is heated to backflow, react 10 hours, naturally cooling is lowered the temperature, solid is separated out, after filtration, filter cake adds the making beating of 2000ml methyl alcohol, constant weight is dried to after filtration, obtain yellow solid N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate.
Below in conjunction with embodiment, set forth the present invention further.
Embodiment 1: prepare N-of the present invention (3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate crystal formation
By 100mgN-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate sample dissolution (water: methyl alcohol volume ratio 1:1) in 6.0mL mixed solvent, solvent is removed with Rotary Evaporators, pressure is-0.01Mpa, rotating speed 90rpm, time is that 30min obtains 83mg transition crystal formation, powder x-ray diffraction analysis is carried out to the transition crystal formation obtained, as shown in Figure 5, infrared spectra as shown in Figure 6 for its diffracting spectrum.
Transition crystal form samples described in 100mg is laid in culture dish, through envrionment temperature be 10 DEG C, ambient relative humidity is 90%, place and obtain described new crystal in 1 day, powder x-ray diffraction analysis is carried out to the new crystal sample obtained, its diffracting spectrum as shown in Figure 1, as shown in Figure 2, as shown in Figure 3, thermogravimetric spectrogram as shown in Figure 4 for Differential Scanning Calorimetry for infrared spectra.
Embodiment 2: prepare N-of the present invention (3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate crystal formation
By 100mgN-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate sample dissolution (water: ethanol contend is than 1:2) in 8.0mL mixed solvent, solvent is removed with Rotary Evaporators, pressure is-0.01Mpa, rotating speed 90rpm, time is that 30min obtains 85mg transition crystal formation, powder x-ray diffraction analysis is carried out to the transition crystal formation obtained, its diffracting spectrum substantially as shown in Figure 5, infrared spectra substantially as shown in Figure 6, consistent with the qualification result of embodiment 1.
Transition crystal form samples described in 100mg is laid in culture dish, through envrionment temperature be 20 DEG C, ambient relative humidity is 75%, place and obtain described new crystal in 2 days, powder x-ray diffraction analysis is carried out to the new crystal sample obtained, substantially as shown in Figure 1, substantially as shown in Figure 2, Differential Scanning Calorimetry substantially as shown in Figure 3 for infrared spectra for its diffracting spectrum, thermogravimetric spectrogram is substantially as shown in Figure 4, consistent with the qualification result of embodiment 1.
Embodiment 3: prepare N-of the present invention (3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate crystal formation
By 100mgN-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate sample dissolution (water: Virahol volume ratio 1:3) in 4.0mL mixed solvent, solvent is removed with Rotary Evaporators, pressure is-0.01Mpa, rotating speed 90rpm, time is that 30min obtains 82mg transition crystal formation, powder x-ray diffraction analysis is carried out to the transition crystal formation obtained, its diffracting spectrum substantially as shown in Figure 5, infrared spectra substantially as shown in Figure 6, consistent with the qualification result of embodiment 1.
Transition crystal form samples described in 100mg is laid in culture dish, through envrionment temperature be 25 DEG C, ambient relative humidity is 90%, place and obtain described new crystal in 3 days, powder x-ray diffraction analysis is carried out to the new crystal sample obtained, substantially as shown in Figure 1, substantially as shown in Figure 2, Differential Scanning Calorimetry substantially as shown in Figure 3 for infrared spectra for its diffracting spectrum, thermogravimetric spectrogram is substantially as shown in Figure 4, consistent with the qualification result of embodiment 1.
Embodiment 4: prepare N-of the present invention (3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate crystal formation
By 100mgN-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate sample dissolution (water: n-propyl alcohol volume ratio 2:3) in 8.0mL mixed solvent, solvent is removed with Rotary Evaporators, pressure is-0.01Mpa, rotating speed 90rpm, time is that 30min obtains 77mg transition crystal formation, powder x-ray diffraction analysis is carried out to the transition crystal formation obtained, its diffracting spectrum substantially as shown in Figure 5, infrared spectra substantially as shown in Figure 6, consistent with the qualification result of embodiment 1.
Transition crystal form samples described in 100mg is laid in culture dish, through envrionment temperature be 0 DEG C, ambient relative humidity is 50%, place and obtain described new crystal in 5 days, powder x-ray diffraction analysis is carried out to the new crystal sample obtained, substantially as shown in Figure 1, substantially as shown in Figure 2, Differential Scanning Calorimetry substantially as shown in Figure 3 for infrared spectra for its diffracting spectrum, thermogravimetric spectrogram is substantially as shown in Figure 4, consistent with the qualification result of embodiment 1.
Embodiment 5: prepare N-of the present invention (3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate crystal formation
By 100mgN-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate sample dissolution (water: acetone volume ratio 1:1) in 6.0mL mixed solvent, solvent is removed with Rotary Evaporators, pressure is-0.01Mpa, rotating speed 90rpm, time is that 30min obtains 78mg transition crystal formation, powder x-ray diffraction analysis is carried out to the transition crystal formation obtained, its diffracting spectrum substantially as shown in Figure 5, infrared spectra substantially as shown in Figure 6, consistent with the qualification result of embodiment 1.
Transition crystal form samples described in 100mg is laid in culture dish, through envrionment temperature be 5 DEG C, ambient relative humidity is 60%, place and obtain described new crystal in 4 days, powder x-ray diffraction analysis is carried out to the new crystal sample obtained, substantially as shown in Figure 1, substantially as shown in Figure 2, Differential Scanning Calorimetry substantially as shown in Figure 3 for infrared spectra for its diffracting spectrum, thermogravimetric spectrogram is substantially as shown in Figure 4, consistent with the qualification result of embodiment 1.
Embodiment 6: prepare N-of the present invention (3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate crystal formation
By 100mgN-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate sample dissolution (water: acetonitrile volume ratio 1:2) in 7.0mL mixed solvent, solvent is removed with Rotary Evaporators, pressure is-0.01Mpa, rotating speed 90rpm, time is that 30min obtains 83mg transition crystal formation, powder x-ray diffraction analysis is carried out to the transition crystal formation obtained, its diffracting spectrum substantially as shown in Figure 5, infrared spectra substantially as shown in Figure 6, consistent with the qualification result of embodiment 1.
Transition crystal form samples described in 100mg is laid in culture dish, through envrionment temperature be 30 DEG C, ambient relative humidity is 70%, place and obtain described new crystal in 1 day, powder x-ray diffraction analysis is carried out to the new crystal sample obtained, substantially as shown in Figure 1, substantially as shown in Figure 2, Differential Scanning Calorimetry substantially as shown in Figure 3 for infrared spectra for its diffracting spectrum, thermogravimetric spectrogram is substantially as shown in Figure 4, consistent with the qualification result of embodiment 1.
Embodiment 7: prepare N-of the present invention (3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate crystal formation
By 100mgN-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate sample dissolution (water: dioxane volume ratio 1:4) in 6.0mL mixed solvent, solvent is removed with Rotary Evaporators, pressure is-0.01Mpa, rotating speed 90rpm, time is that 30min obtains 81mg transition crystal formation, powder x-ray diffraction analysis is carried out to the transition crystal formation obtained, its diffracting spectrum substantially as shown in Figure 5, infrared spectra substantially as shown in Figure 6, consistent with the qualification result of embodiment 1.
Transition crystal form samples described in 100mg is laid in culture dish, through envrionment temperature be 35 DEG C, ambient relative humidity is 80%, place and obtain described new crystal in 1 day, powder x-ray diffraction analysis is carried out to the new crystal sample obtained, substantially as shown in Figure 1, substantially as shown in Figure 2, Differential Scanning Calorimetry substantially as shown in Figure 3 for infrared spectra for its diffracting spectrum, thermogravimetric spectrogram is substantially as shown in Figure 4, consistent with the qualification result of embodiment 1.
Embodiment 8: prepare N-of the present invention (3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate crystal formation
By 100mgN-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate sample dissolution (water: tetrahydrofuran (THF) volume ratio 1:3) in 6.0mL mixed solvent, solvent is removed with Rotary Evaporators, pressure is-0.01Mpa, rotating speed 90rpm, time is that 30min obtains 85mg transition crystal formation, powder x-ray diffraction analysis is carried out to the transition crystal formation obtained, its diffracting spectrum substantially as shown in Figure 5, infrared spectra substantially as shown in Figure 6, consistent with the qualification result of embodiment 1.
Transition crystal form samples described in 100mg is laid in culture dish, through envrionment temperature be 40 DEG C, ambient relative humidity is 85%, place and obtain described new crystal in 3 days, powder x-ray diffraction analysis is carried out to the new crystal sample obtained, substantially as shown in Figure 1, substantially as shown in Figure 2, Differential Scanning Calorimetry substantially as shown in Figure 3 for infrared spectra for its diffracting spectrum, thermogravimetric spectrogram is substantially as shown in Figure 4, consistent with the qualification result of embodiment 1.
Embodiment 9: prepare N-of the present invention (3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate crystal formation
Take 5g N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate sample is placed in ball mill agate mortar, agate ball quality 30g, ratio of grinding media to material is about 6:1.Drum's speed of rotation is 400r/min, turns 15min and stops 2min, obtains 3.8g transition crystal formation in 120min sampling, powder x-ray diffraction analysis is carried out to the transition crystal formation obtained, substantially as shown in Figure 5, infrared spectra is substantially as shown in Figure 6, consistent with the qualification result of embodiment 1 for its diffracting spectrum.
Transition crystal form samples described in 100mg is laid in culture dish, through envrionment temperature be 15 DEG C, ambient relative humidity is 95%, place and obtain described new crystal in 2 days, powder x-ray diffraction analysis is carried out to the new crystal sample obtained, substantially as shown in Figure 1, substantially as shown in Figure 2, Differential Scanning Calorimetry substantially as shown in Figure 3 for infrared spectra for its diffracting spectrum, thermogravimetric spectrogram is substantially as shown in Figure 4, consistent with the qualification result of embodiment 1.
Embodiment 10:N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate crystal formation is to the inhibited proliferation of different people tumor cell line
Get and be in one bottle, cell in good condition exponential phase of growth, add 0.05% tryptic digestive juice, digestion makes attached cell come off, counting 2 ~ 4 × 10
4individual/ml, makes cell suspension; Obtained cell suspension is inoculated on 96 orifice plates, and 180 μ l/ holes, put constant temperature CO
2cultivate 24 hours in incubator; Add the test medicine of different concns, 20 μ l/ holes, cultivate 72h; Add after detection reagent (CCK-8) hatches 1-2h and detect; With the light absorption value of enzyme-linked immunosorbent assay instrument in every hole, wavelength 450nm place, and by following formulae discovery cell inhibitory rate.IC is calculated after obtaining inhibiting rate
50.Test medicine is N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate crystal formation, contrast medicine is lapatinibditosylate (Lapatinib) and N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosic acid salt compound (being called for short KU004 tosilate), respectively process different tumour cell IC
50value the results are shown in Table 3.
The each test medicine of table 3 is to the IC of different people tumour cell
50value
As seen from the above table, new crystal of the present invention is to the IC50 value of different tumour cell all lower than the lapatinibditosylate of contrast, and the structure of visible new crystal improves the pharmaceutical activity of this compound, and is better than the effect of similar drugs on the market.
Embodiment 11: pharmacokinetic trial
With N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate and crystal formation of the present invention be that detected object carries out pharmacokinetic trial, the results are shown in Table 4.
Table 4 pharmacokinetic trial result
| Cmax(μg/mL) | Tmax | AUC | |
| Former compound | 5.878 | 6 | 65.335 |
| Crystal formation of the present invention | 10.493 | 6 | 118.889 |
As shown in Table 4, the Plasma Concentration of crystal formation of the present invention can maintain the long period relative to former compound, and area under the drug-time curve is obviously better than original compound, and bioavailability is higher.
Embodiment 12: the medicine (tablet) of overmedication proliferative disease of the present invention
Use described new crystal sterling prepared by embodiment 1, add lactose, starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose, talcum powder, Magnesium Stearate, sodium cellulose glycolate as the adjunct ingredient preparing tablet, proportioning makes the tablet of every sheet content of dispersion at 100 ~ 500mg according to a certain percentage, and tablet formulation ratio is in table 5;
The preparation formula of table 5 tablet
Lactose, starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose are mixed with new crystal sterling bulk drug, adds 1% sodium cellulose glycolate solution in right amount, make soft material, sieve granulation, wet grain is dried, and sieve whole grain, add Magnesium Stearate and talcum powder mixes, compressing tablet, to obtain final product.
Embodiment 13: the medicine (capsule) of overmedication proliferative disease of the present invention
Use described new crystal sterling prepared by embodiment 2, add lactose, starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose, talcum powder, Magnesium Stearate, sodium cellulose glycolate as the adjunct ingredient preparing tablet, proportioning makes the capsule product of each content of dispersion at 100 ~ 500mg according to a certain percentage, and tablet formulation ratio is in table 6;
The preparation formula of table 6 capsule
Lactose, starch, Microcrystalline Cellulose are mixed with new crystal sterling bulk drug, adds 1% sodium cellulose glycolate solution in right amount, make wet grain and dry the whole grain that sieves, add Magnesium Stearate and mix, insert capsule and obtain; Or do not use granulation step, and directly new crystal sterling bulk drug is mixed with excipients, after sieving, directly incapsulate obtained.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1.N-the crystal formation of (3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate, is characterized in that, use CuK
αradiation, the powder x-ray diffraction represented with 2 θ angles is 5.64, 7.68, 8.48, 11.32, 11.84, 13.00, 14.24, 14.50, 14.96, 15.56, 16.50, 17.10, 17.98, 19.22, 20.24, 21.24, 21.78, 22.32, 23.10, 23.42, 23.88, 24.34, 24.86, 25.54, 26.28, 26.81, 27.34, 27.74, 28.76, 29.45, 30.24, 31.74, 33.92, 34.86, 35.40, 36.16, 37.30, 38.82, 39.60, 41.42, 43.16, 43.96, 45.12, 46.99, 48.52 there is diffraction peak.
2. N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate mixing crystal formation, it is characterized in that, crystal formation described in the claim 1 comprising arbitrary proportion.
3. mix crystal formation described in crystal formation described in claim 1 or claim 2 and prepare the application in overmedication proliferative disease medicine.
4. application according to claim 3, is characterized in that, described excess proliferative disease is cancer or inflammation.
5. an overmedication proliferative disease medicine, is characterized in that, mixes crystal formation described in the claim 1 including effective amount described in crystal formation or claim 2, and pharmaceutically acceptable vehicle.
6. overmedication proliferative disease medicine according to claim 5, is characterized in that, described excess proliferative disease is cancer or inflammation.
7. overmedication proliferative disease medicine according to claim 5, is characterized in that, it is tablet, capsule, pill, injection, sustained release preparation medicine or controlled release preparation medicine.
8. overmedication proliferative disease medicine according to claim 5, it is characterized in that, described vehicle is one or more in wetting agent, dispersion agent, pH adjusting agent, oxidation inhibitor, weighting agent, thinner, solubilizing agent, suspending agent, correctives, tackiness agent, disintegrating agent, osmotic pressure regulator, flocculation agent, antisticking agent, suspending agent, lubricant, emulsifying agent and sanitas.
9. the preparation method of crystal formation described in a claim 1, it is characterized in that, use water and methanol mixed solvent, water and alcohol mixed solvent, water and n-propyl alcohol mixed solvent, water and isopropyl alcohol mixed solvent, water and acetone mixed solvent, water and acetonitrile mixed solvent, water and tetrahydrofuran (THF) mixed solvent, water and dioxane mixed solvent any one at 15 DEG C ~ 60 DEG C temperature by N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) after quinazoline-4-amine tosilate sample dissolves completely, remove mixed solvent with Rotary Evaporators and obtain transition crystal formation, described transition crystal formation is envrionment temperature 0 DEG C ~ 40 DEG C, ambient relative humidity is placed more than 1 day for 50% ~ 100% time, obtain described crystal formation,
Wherein, described transition crystal formation uses CuK
αradiation, has diffraction peak with the powder x-ray diffraction that 2 θ angles represent 19.78 ± 1.
10. the preparation method of crystal formation described in a claim 1, it is characterized in that, by N-(3-chloro-4-(3-fluoro Bian oxygen base) phenyl)-6-(3-(4-methyl isophthalic acid, 4 azepine phosphine-1-bases) the third-1-alkynyl) quinazoline-4-amine tosilate sample employing grinding physics rotating crystal method acquisition transition crystal formation, described transition crystal formation is placed more than 1 day for 50% ~ 100% time at envrionment temperature 0 DEG C ~ 40 DEG C, ambient relative humidity, obtains described crystal formation; Wherein, the ratio of grinding media to material of described grinding physics rotating crystal method is 1:10 ~ 30:1, and grinding rotating speed is 50 ~ 800r/min, and milling time is no less than 0.5h;
Described transition crystal formation uses CuK
αradiation, has diffraction peak with the powder x-ray diffraction that 2 θ angles represent 19.78 ± 1.
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| CN105388242A (en) * | 2015-11-11 | 2016-03-09 | 江苏康缘药业股份有限公司 | Detection method of residual solvents in (N-(3-chloro-4-(3-fluorobenzyloxy)phenyl-6-(3-(4-methyl-4-oxo-1-nitrogen-4-phosphorus hetero yclohexane-1-yl)propyl-1-alkynyl)quinazoline-4-amine, bis 4-methyl benzenesulfonate bulk drug |
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