Salt of quinazoline derivative, preparation method therefor and application thereof
10870627 ยท 2020-12-22
Assignee
Inventors
- Guangxin Xia (Shanghai, CN)
- Di Li (Shanghai, CN)
- Ning Zhou (Shanghai, CN)
- Ao Chen (Shanghai, CN)
- Liang Zhao (Shanghai, CN)
- Jiansheng Han (Shanghai, CN)
- Yanjun Liu (Shanghai, CN)
Cpc classification
C07F9/6512
CHEMISTRY; METALLURGY
A61K31/517
HUMAN NECESSITIES
A61K31/5377
HUMAN NECESSITIES
A61P35/00
HUMAN NECESSITIES
C07C309/05
CHEMISTRY; METALLURGY
C07C309/29
CHEMISTRY; METALLURGY
C07D405/12
CHEMISTRY; METALLURGY
C07C309/39
CHEMISTRY; METALLURGY
C07F9/6558
CHEMISTRY; METALLURGY
C07D403/12
CHEMISTRY; METALLURGY
C07D401/12
CHEMISTRY; METALLURGY
C07C59/105
CHEMISTRY; METALLURGY
C07D307/06
CHEMISTRY; METALLURGY
C07D413/12
CHEMISTRY; METALLURGY
C07C59/305
CHEMISTRY; METALLURGY
International classification
C07C309/05
CHEMISTRY; METALLURGY
C07D307/06
CHEMISTRY; METALLURGY
C07F9/6512
CHEMISTRY; METALLURGY
A61P35/00
HUMAN NECESSITIES
C07C309/29
CHEMISTRY; METALLURGY
C07C59/105
CHEMISTRY; METALLURGY
C07C65/11
CHEMISTRY; METALLURGY
A61K31/517
HUMAN NECESSITIES
C07D413/12
CHEMISTRY; METALLURGY
C07D405/12
CHEMISTRY; METALLURGY
C07D401/12
CHEMISTRY; METALLURGY
C07C309/39
CHEMISTRY; METALLURGY
C07C59/305
CHEMISTRY; METALLURGY
A61K31/5377
HUMAN NECESSITIES
C07F9/6558
CHEMISTRY; METALLURGY
C07D403/12
CHEMISTRY; METALLURGY
Abstract
A salt of a quinazoline derivative (N-[4-(3-chlorine-4-fluoroanilino)]-7-(3-morpholinepropanol)-6-(2-fluoroacrylamide)-quinazoline, the structure thereof is as represented by formula I). Compared with a known quinazoline derivative, the salt of the quinazoline derivative has one or more improved properties and at least has better water solubility, wherein a citrate, a benzene sulfonate, and an ethanedisulphonate thereof further have better crystallinity and are not easy to absorb moisture. ##STR00001##
Claims
1. A crystal form 1 of the monocitrate represented by formula 2, wherein the crystal form 1 has an X-ray powder diffraction pattern comprising characteristic peaks at diffraction angle 2 of 8.2800.2, 8.7200.2, 16.9620.2, 19.1240.2, 19.7420.2 and 25.2220.2 ##STR00016##
2. The crystal form 1 of the monocitrate represented by formula 2 according to claim 1, wherein the crystal form 1 has an X-ray powder diffraction pattern comprising characteristic peaks at diffraction angle 2 of 8.2800.2, 8.7200.2, 13.6210.2, 14.0430.2, 16.5220.2, 16.9620.2, 19.1240.2, 19.7420.2, 21.3670.2, 23.4390.2, 25.2220.2 and 26.8420.2.
3. The crystal form 1 of the monocitrate represented by formula 2 according to claim 1, wherein the crystal form 1 has an X-ray powder diffraction pattern comprising characteristic peaks at diffraction angle 2 of 5.2780.2, 8.2800.2, 8.7200.2, 9.8620.2, 10.7400.2, 11.5640.2, 13.6210.2, 14.0430.2, 14.8530.2, 16.5220.2, 16.9620.2, 19.1240.2, 19.7420.2, 20.5010.2, 20.8020.2, 21.3670.2, 23.4390.2, 23.7990.2, 25.2220.2, 26.3590.2, 26.8420.2, 27.4940.2, 28.9190.2, 32.3830.2 and 32.7640.2.
4. The crystal form 1 of the monocitrate represented by formula 2 according to claim 1, wherein the crystal form 1 has an X-ray powder diffraction pattern comprising characteristic peaks at diffraction angle 2 of 8.2800.2, 8.7200.2, 9.8620.2, 10.7400.2, 11.5640.2, 13.6210.2, 14.0430.2, 16.5220.2, 16.9620.2, 19.1240.2, 19.7420.2, 20.8020.2, 21.3670.2, 23.4390.2 and 25.2220.2.
5. The crystal form 1 of the monocitrate represented by formula 2 according to claim 1, wherein the crystal form 1 has one or more of the parameters as follows: the XRPD pattern shown as
6. The crystal form 1 of the monocitrate represented by formula 2 according to claim 1, wherein the melting point of the crystal form 1 is 165-169 C.; or, the water absorption of the crystal form 1 in a relative humidity range of 20-80% is 0.21%.
7. A preparation method for the crystal form 1 of the monocitrate represented by formula 2 according to claim 1, comprising the following procedure: carrying out a salt formation reaction on the quinazoline derivative and the citric acid in tetrahydrofuran to give the crystal form 1 of the monocitrate represented by formula 2 wherein, the structure of the quinazoline derivative is represented by formula ##STR00017##
8. The preparation method according to claim 7, wherein, the volume/mass ratio of the tetrahydrofuran to the quinazoline derivative is 25-50 mL/g; or, the molar ratio of the citric acid to the quinazoline derivative is 1-1.5; or, the temperature of the salt formation is 10-30 C.; or, the duration of the salt formation is 0.5-24 hours; or, the operation of the salt formation reaction is mixing the solution of citric acid in tetrahydrofuran with the solution of the quinazoline derivative in tetrahydrofuran; or, the post-treatment of the salt formation reaction is filtration and drying; or, the method comprises the following procedure: mixing the solution of citric acid in tetrahydrofuran with the solution of the quinazoline derivative in tetrahydrofuran, reacting, followed by the isolation of the precipitated solids and drying to give the product.
9. The preparation method according to claim 8, wherein, the volume/mass ratio of the tetrahydrofuran to the quinazoline derivative is 26-48 mL/g; or, the operation of the salt formation reaction is that adding the solution of citric acid in tetrahydrofuran into the solution of the quinazoline derivative in tetrahydrofuran; the concentration of the quinazoline derivative solution in tetrahydrofuran is 25-50 mg/mL; the concentration of the citric acid solution in tetrahydrofuran is 50-100 mg/mL; or, the post-treatment of the salt formation reaction is filtration and drying; or, the method comprises the following procedure: mixing the solution of citric acid in tetrahydrofuran with the solution of the quinazoline derivative in tetrahydrofuran, reacting, followed by the isolation of the precipitated solids and drying to give the product; the temperature for the drying is 40-45 C.; the drying is vacuum drying.
10. A pharmaceutical composition, comprising a therapeutically and/or prophylactically effective dose of the salt of the crystal form 1 of the monocitrate represented by formula 2 according to claim 1, and at least one kind of pharmaceutically acceptable excipient.
11. A method for treating tumor diseases in a subject in need thereof, comprising: administering an effective amount of the crystal form 1 of the monocitrate represented by formula 2 according to claim 1 to the subject.
12. A method for treating a patient in need of a medicament for EGFR tyrosine kinase inhibitor HER2 tyrosine kinase inhibitor or HER4 tyrosine kinase inhibitor comprising: administering an effective amount of the crystal form 1 of the monocitrate represented by formula 2 according to claim 1 to the patient.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
(101) The following embodiments further illustrate the present invention, but the present invention is not limited thereto. The experimental methods that do not specify the specific conditions in the following embodiments are selected according to conventional methods and conditions, or according to the description of the product.
(102) Measurement instruments and methods:
(103) The instrument used for X-ray powder diffraction (XRPD) measurement was Bruker D8 Advance Diffractometer equipped with a -2 goniometer, a Mo monochromator, and a Lynxeye detector. The software for acquisition was Diffrac Plus XRD Commander and the software for analysis was MDI Jade 5.0. The instrument was calibrated with the standard sample (generally, corundum) supplied by the instrument before use. The measurement conditions were: 2 scanning angle with a range of 340; step size: 0.02; speed: 0.2 seconds/step. Measurement process: The Ka X-ray generated by a copper target with a wavelength of 1.54 nm was used. Under an operating conditions of 40 kV and 40 mA, the samples were measured at room temperature, and the samples to be measured were placed on a non-reflecting plate. Unless otherwise specified, the samples were unground before measurement.
(104) The differential thermal analysis (DSC) data was collected from TA Instruments Q200 MDSC. The software for instrument control was Thermal Advantage and the software for analysis was Universal Analysis. Generally, 1-10 mg of the sample was placed in an uncovered (unless otherwise specified) aluminum crucible, and the temperature was raised from room temperature to 250 C. with a heating rate of 10 C./min under the protection of 40 ml/min dry N.sub.2 gas. At the same time, the heat change of the sample during the heating process was recorded by the TA software.
(105) Thermogravimetric analysis (TGA) data was collected from TA Instruments Q500 TGA. The software for instrument control was Thermal Advantage and software for analysis was Universal Analysis. Generally, 5-15 mg of the sample was placed in a platinum crucible, and the temperature was raised from room temperature to 300 C. with a heating rate of 10 C./min under the protection of 40 ml/min dry N.sub.2 gas. At the same time, the weight change of the sample during the heating process was recorded by the TA software.
(106) The isothermal absorption analysis (DVS) data was collected from TA Instruments Q5000 TGA. The software for instrument control was Thermal Advantage and software for analysis was Universal Analysis. 1-10 mg of the sample was generally placed in a platinum crucible, and the weight change of the sample during the relative humidity changing from 20% to 80% was recorded by the TA software. Depending on the specifics of the sample, different steps of sample adsorption and desorption were also involved.
(107) Bruker Ascend TM500 was used for 41 NMR measurement, generally using full-frequency excitation, single pulse, excitation angle of 30, 16-times scanning, digital orthogonal detection, temperature control at 298K, DMSO as deuterated reagent.
(108) The HPLC measurement conditions are as follows:
(109) Mobile phase A, formic acid:water=0.1:99.9;
(110) Mobile phase B, formic acid:acetonitrile=0.1:99.9;
(111) Elution gradient:
(112) 0 min 10% B;
(113) 0.5 min 10% B;
(114) 4 min 80% B;
(115) 4.5 min 80% B;
(116) 6 min 10% B;
(117) 6.5 min 10% B;
(118) Flow rate: 0.3 mL/min; column: Eclipse Plus-C18 2.1 mm*50.0 mm*1.8 m; column temperature: 40 C.; wavelength: 254 nm.
(119) Unless otherwise specified, the embodiments were all operated at room temperature.
(120) Unless otherwise specified, the various reagents used in the embodiments are commercially available.
(121) In the following examples, the quinazoline derivative (i.e., the compound represented by formula 1) used was given according to the method described in CN102898386. The mixing and the reaction were accompanied by stirring, and the stirring rate was generally 50-1800 RPM. The duration of overnight was generally 12-24 hours.
Embodiment 1: Synthesis of the Crystal Form 1 of the Monocitrate of the Quinazoline Derivative
(122) 2 g of the compound represented by formula 1 was dissolved in 80 mL of tetrahydrofuran and 0.762 g of citric acid was dissolved in 15 mL of tetrahydrofuran, and the acid solution was added dropwise to the alkali solution. The mixture was stirred at room temperature for 0.5 hour to precipitate a solid, stirred overnight, filtered, and dried in a vacuum oven at 45 C. 2.466 g of the crystal form 1 of the monocitrate of the quinazoline derivative was given in a yield of 89.3%.
(123) The XRPD pattern is shown in
(124) As the TGA pattern shown in
(125) As the DSC pattern shown in
(126) As the DVS pattern shown in
(127) 4 g of the compound represented by formula 1 was dissolved in 80 mL of tetrahydrofuran, 2.288 g of citric acid was dissolved in 22.5 mL of tetrahydrofuran, and the other conditions remained the same, and the given product was still the crystal form 1.
Embodiment 2: Synthesis of the Crystal Form 5 of the Monocitrate Dihydrate of the Quinazoline Derivative
(128) 30 mg of the crystal form 1 prepared in embodiment 1 was taken and 2 mL of water was added thereto, followed by crystallization at 60 C. for 16 hours, centrifugation, and vacuum drying at room temperature. 26 mg of the crystal form 5 of the monocitrate dihydrate of the quinazoline derivative was given in a molar yield of 82.4%.
(129) The XRPD pattern was shown in
(130) As the TGA pattern shown in
(131) As the DSC pattern shown in
(132) As the DVS pattern shown in
Embodiment 3: Synthesis of the Crystal Form 5 of the Monocitrate Dihydrate of the Quinazoline Derivative
(133) 30 mg of the crystal form 1 prepared in embodiment 1 was taken and 3 mL of n-butanol was added thereto, followed by crystallization at room temperature for 16 hours, centrifugation, and vacuum drying at room temperature. 24 mg of the crystal form 5 of the dihydrate was given in a molar yield of 76.1%.
Embodiment 4: Synthesis of the Crystal Form 5 of the Monocitrate Dihydrate of the Quinazoline Derivative
(134) 10 mg of the crystal form 1 prepared in embodiment 1 was taken and 1 mL of water and 1 mL of methanol was added thereto, followed by uncovered evaporation of the solvent to dry at room temperature. 7 mg of the crystal form 5 of the dihydrate was given in a molar yield of 66.7%.
(135) 100 mg of the crystal form 1 prepared in embodiment 1 was taken and 1 mL of water and 1 mL of methanol was added thereto, wherein other conditions remained the same. The given product was still the crystal form 5 of the dihydrate.
Embodiment 5: Synthesis of the Crystal Form 5 of the Monocitrate Dihydrate of the Quinazoline Derivative
(136) The methanol in embodiment 4 was replaced with the ethanol, and the other operations remained the same as that in embodiment 4 to give the crystal form 5 of the dihydrate.
Embodiment 6: Synthesis of the Crystal Form 5 of the Monocitrate Dihydrate of the Quinazoline Derivative
(137) The methanol in embodiment 4 was replaced with the isopropanol, and the other operations remained the same as that in embodiment 4 to give the crystal form 5 of the dihydrate.
Embodiment 7: Synthesis of the Crystal Form 5 of the Monocitrate Dihydrate of the Quinazoline Derivative
(138) 10 mg of the crystal form 1 prepared in embodiment 1 was taken and 1 mL of water and 1 mL of methanol was added thereto, followed by uncovered evaporation of the solvent to dry at 60 C. 8 mg of the crystal form 5 of the dihydrate was given in a molar yield of 76.1%.
Embodiment 8: Synthesis of the Crystal Form 5 of the Monocitrate Dihydrate of the Quinazoline Derivative
(139) The methanol in embodiment 7 was replaced with the ethanol, and the other operations remained the same as that in embodiment 7 to give the crystal form 5 of the dihydrate.
Embodiment 9: Synthesis of the Crystal Form 5 of the Monocitrate Dihydrate of the Quinazoline Derivative
(140) The methanol in embodiment 7 was replaced with the isopropanol, and the other operations remained the same as that in embodiment 7 to give the crystal form 5 of the dihydrate.
Embodiment 10: Synthesis of the Crystal Form 5 of the Monocitrate Dihydrate of the Quinazoline Derivative
(141) 10 mg of the crystal form 1 prepared in embodiment 1 was taken and 1 mL of methanol and 1 mL of acetone was added thereto, followed by stirring in water bath at 60 C. for 5 minutes to keep the solution clear and naturally cooling to room temperature. The precipitated solids were centrifuged and dried in vacuum at room temperature. 6 mg of the crystal form 5 of the dihydrate was given in a molar yield of 57.0%.
Embodiment 11: Synthesis of the Crystal Form 5 of the Monocitrate Dihydrate of the Quinazoline Derivative
(142) The methanol in embodiment 10 was replaced with the dioxane, and the other operations remained the same as that in embodiment 10 to give the crystal form 5 of the dihydrate.
(143) The XRPD patterns and the DSC patterns of the samples prepared in embodiments 3-11 (not shown) are similar to those of embodiment 2, indicating that the samples prepared in these embodiments are the same as that in embodiment 2.
Embodiment 12: Synthesis of the Crystal Form 13 of the Monocitrate of the Quinazoline Derivative
(144) 10 mg of the crystal form 1 prepared in embodiment 1 was taken and 2.4 mL of n-butanol was added thereto, followed by stirring in water bath at 60 C. for 5 minutes to keep the solution clear and naturally cooling to room temperature. The precipitated solids were centrifuged and dried in vacuum at room temperature. 8 mg of the crystal form 13 was given in a yield of 80%.
(145) The XRPD pattern is shown in
(146) As the TGA pattern shown in
(147) As the DSC pattern shown in
(148) As the DVS pattern shown in
(149) 20 mg of the crystal form 1 prepared in embodiment 1 was taken, and the other conditions remained the same, and the given product was still the crystal form 13.
Embodiment 13: Synthesis of the Crystal Form 13 of the Monocitrate of the Quinazoline Derivative
(150) 10 mg of the crystal form 1 prepared in embodiment 1 was taken and 1 mL of water and 1 mL of acetonitrile was added thereto, followed by uncovered evaporation of the solvent to dry at 60 C. 7 mg of the crystal form 13 was given in a yield of 70%.
(151) The XRPD pattern and the DSC pattern of the sample prepared in embodiment 13 (not shown) are similar to those of embodiment 12, indicating that the sample prepared in the example is the same as that in embodiment 12.
(152) 100 mg of the crystal form 1 prepared in embodiment 1 was taken, and other conditions remained the same. The given product was still the crystal form 13.
Embodiment 14: Synthesis of the Crystal Form 14 of the Monocitrate Hemi(Pentahydrate) of the Quinazoline Derivative
(153) 10 mg of the crystal form 1 prepared in embodiment 1 was taken and 0.05 mL of dimethyl sulfoxide was added thereto with ultrasound to keep the solution clear, followed by rapid addition into a flask with 3 mL of water with stirring for 5 minutes, centrifugation and vacuum drying at room temperature. 8.3 mg of the crystal form 14 of the hemi(pentahydrate) was given in a molar yield of 78.0%.
(154) The XRPD pattern is shown in
(155) As the TGA pattern shown in
(156) As the DSC pattern shown in
(157) As the DVS pattern shown in
(158) 20 mg of the crystal form 1 prepared in embodiment 1 was taken, and the other conditions remained the same, and the given product was still the crystal form 14 of the hemi(pentahydrate).
Embodiment 15: Synthesis of the Crystal Form 14 of the Monocitrate Hemi(Pentahydrate) of the Quinazoline Derivative
(159) 10 mg of the crystal form 1 prepared in embodiment 1 was taken and 1 mL of acetone and 1 mL of water was added thereto, followed by uncovered evaporation of the solvent to dry at 60 C. 8 mg of the crystal form 14 of the hemi(pentahydrate) was given in a yield of 75.1%.
(160) The XRPD pattern and the DSC pattern of the sample prepared in embodiment 15 (not shown) are similar to those of embodiment 14, indicating that the sample prepared in the embodiment is the same as that in embodiment 14.
Embodiment 16: Synthesis of the Crystal Form 7 of the Monocitrate Dihydrate of the Quinazoline Derivative
(161) 10 mg of the crystal form 1 prepared in embodiment 1 was taken and 1 mL of water was added thereto, followed by crystallization at room temperature for 16 hours, centrifugation, and vacuum drying at room temperature. 9 mg of the crystal form 7 of the dihydrate was given in a molar yield of 85.6%.
(162) The XRPD pattern is shown in
(163) As the TGA pattern shown in
(164) As the DSC pattern shown in
(165) As the DVS pattern shown in
Embodiment 17: Synthesis of the Crystal Form 10 of the Monocitrate Trihydrate of the Quinazoline Derivative
(166) 10 mg of the crystal form 1 prepared in embodiment 1 was taken and 2 mL of methanol was added thereto, followed by uncovered evaporation of the solvent to dry at room temperature. 8 mg of the crystal form 10 of the trihydrate was given in a molar yield of 74.2%.
(167) The XRPD pattern is shown in
(168) As the TGA pattern shown in
(169) As the DSC pattern shown in
(170) As the DVS pattern shown in
Embodiment 18: Synthesis of the Crystal Form 10 of the Monocitrate Trihydrate of the Quinazoline Derivative
(171) 10 mg of the crystal form 1 prepared in embodiment 1 was taken and 1 mL of water and 1 mL of n-propanol was added thereto, followed by uncovered evaporation of the solvent to dry at room temperature. 8 mg of the crystal form 10 of the trihydrate was given in a molar yield of 74.2%.
(172) 20 mg of the crystal form 1 prepared in embodiment 1 was taken, and the other conditions remained the same, and the given product was still the crystal form 10 of the trihydrate.
Embodiment 19: Synthesis of the Crystal Form 10 of the Monocitrate Trihydrate of the Quinazoline Derivative
(173) The n-propanol in embodiment 18 was replaced with the tetrahydrofuran, and the other operations remained the same as that in embodiment 18 to give the crystal form 10 of the trihydrate.
Embodiment 20: Synthesis of the Crystal Form 10 of the Monocitrate Trihydrate of the Quinazoline Derivative
(174) The n-propanol in embodiment 18 was replaced with the acetonitrile, and the other operations remained the same as that in embodiment 18 to give the crystal form 10 of the trihydrate.
(175) The XRPD patterns and the DSC patterns of the samples prepared in embodiments 18-20 (not shown) are similar to those of embodiment 17, indicating that the samples prepared in these embodiments are the same as that in embodiment 17.
Embodiment 21: Synthesis of the Crystal Form 11 of the Monocitrate Dihydrate of the Quinazoline Derivative
(176) 10 mg of the crystal form 1 prepared in embodiment 1 was taken and 5 mL of isopropanol was added thereto, followed by stirring in water bath at 60 C. for 5 minutes to keep the solution clear and naturally cooling to room temperature. The precipitated solids were centrifuged and dried in vacuum at room temperature. 7.5 mg of the crystal form 11 of the dihydrate was given in a molar yield of 71.3%.
(177) The XRPD pattern is shown in
(178) As the TGA pattern shown in
(179) As the DSC pattern shown in
(180) As the DVS pattern shown in
Embodiment 22: Synthesis of the Crystal Form 11 of the Monocitrate Dihydrate of the Quinazoline Derivative
(181) The isopropanol in embodiment 21 was replaced with the n-propanol, and the other operations remained the same as that in embodiment 21 to give the crystal form 11 of the dihydrate.
Embodiment 23: Synthesis of the Crystal Form 11 of the Monocitrate Dihydrate of the Quinazoline Derivative
(182) 10 mg of the crystal form 1 prepared in embodiment 1 was taken and 1 mL of methanol and 1 mL of ethanol were added thereto, followed by crystallization at room temperature for 16 hours, centrifugation, and vacuum drying at room temperature. 6.8 mg of the crystal form 11 of the dihydrate was given in a yield of 64.7%.
Embodiment 24: Synthesis of the Crystal Form 11 of the Monocitrate Dihydrate of the Quinazoline Derivative
(183) The methanol in embodiment 23 was replaced with the nitromethane, and the other operations remained the same as that in embodiment 23 to give the crystal form 11 of the dihydrate.
Embodiment 25: Synthesis of the Crystal Form 11 of the Monocitrate Dihydrate of the Quinazoline Derivative
(184) The methanol in embodiment 23 was replaced with the acetonitrile, and the other operations remained the same as that in embodiment 23 to give the crystal form 11 of the dihydrate.
Embodiment 26: Synthesis of the Crystal Form 11 of the Monocitrate Dihydrate of the Quinazoline Derivative
(185) 10 mg of the crystal form 1 prepared in embodiment 1 was taken and 1 mL of methanol and 1 mL of ethanol were added thereto, followed by stirring in water bath at 60 C. for 5 minutes to keep the solution clear and naturally cooling to room temperature. The precipitated solids were centrifuged and dried in vacuum at room temperature. 7 mg of the crystal form 11 of the dihydrate was given in a molar yield of 66.6%.
Embodiment 27: Synthesis of the Crystal Form 11 of the Monocitrate Dihydrate of the Quinazoline Derivative
(186) The methanol in embodiment 26 was replaced with the nitromethane, and the other operations remained the same as that in embodiment 26 to give the crystal form 11 of the dihydrate.
Embodiment 28: Synthesis of the Crystal Form 11 of the Monocitrate Dihydrate of the Quinazoline Derivative
(187) The methanol in embodiment 26 was replaced with the acetonitrile, and the other operations remained the same as that in embodiment 26 to give the crystal form 11 of the dihydrate.
(188) The XRPD patterns and the DSC patterns of the samples prepared in embodiments 22-28 (not shown) are similar to those of embodiment 21, indicating that the samples prepared in these embodiments are the same as that in embodiment 21.
Embodiment 29: Synthesis of the Crystal Form 2 of the Monocitrate Hemiethanolate of the Quinazoline Derivative
(189) 10 mg of the crystal form 1 prepared in embodiment 1 was taken and 0.4 mL of ethanol was added thereto, followed by stirring at 60 C. for 16 hours, centrifugation and vacuum drying at room temperature. 8 mg of the crystal form 2 of the hemiethanolate was given in a molar yield of 77.4%.
(190) The XRPD pattern is shown in
(191) As the TGA pattern shown in
(192) As the DSC pattern shown in
Embodiment 30: Synthesis of the Crystal Form 2 of the Monocitrate Ditetrahydrofuran Complex of the Quinazoline Derivative
(193) 10 mg of the crystal form 1 prepared in embodiment 1 was taken and 0.4 mL of tetrahydrofuran was added thereto, followed by stirring at room temperature for 16 hours, centrifugation and vacuum drying at room temperature. 9 mg of the crystal form 3 of the ditetrahydrofuran complex was given in a molar yield of 73.7%.
(194) The XRPD pattern is shown in
(195) As the TGA pattern shown in
Embodiment 31: Synthesis of the Crystal Form 2 of the Monocitrate Ditetrahydrofuran Complex of the Quinazoline Derivative
(196) 10 mg of the crystal form 1 prepared in embodiment 1 was taken and 0.4 mL of tetrahydrofuran was added thereto, followed by stirring at 60 C. for 16 hours, centrifugation and vacuum drying at room temperature to give the crystal form 3 of the ditetrahydrofuran complex.
(197) The XRPD patterns and the DSC patterns of the samples prepared in embodiment 31 (not shown) are similar to those of embodiment 30, indicating that the sample prepared in the embodiment are the same as that in embodiment 30.
Embodiment 32: Synthesis of the Crystal Form 2 of the Monocitrate Hemi-1,4-Dioxane Complex of the Quinazoline Derivative
(198) 10 mg of the crystal form 1 prepared in embodiment 1 was taken and 1.2 mL of dioxane was added thereto, followed by stirring in water bath at 60 C. for 5 minutes to keep the solution clear and naturally cooling to room temperature. The precipitated solids were centrifuged and dried in vacuum at room temperature. 6 mg of the crystal form 4 of the hemi-1,4-dioxane compound was given in a molar yield of 56.4%.
(199) The XRPD pattern is shown in
(200) As the TGA pattern shown in
(201) 20 mg of the crystal form 1 prepared in embodiment 1 was taken, followed by the addition of 1.2 mL of dioxane, and the other conditions remained the same, and the given product was still the crystal form 4 of the hemi-1,4-dioxane complex.
Embodiment 33: Synthesis of the Crystal Form 6 of the Monocitrate Hemichloroform Complex of the Quinazoline Derivative
(202) 10 mg of the crystal form 1 prepared in embodiment 1 was taken and 0.4 mL of chloroform was added thereto, followed by stirring at room temperature for 16 hours, centrifugation and vacuum drying at room temperature. 7 mg of the crystal form 6 of the hemichloroform complex was given in a molar yield of 64.4%.
(203) The XRPD pattern is shown in
(204) As the TGA pattern shown in
Embodiment 34: Synthesis of the Monoethanedisulfonate of the Quinazoline Derivative
(205) 10 mg of the compound represented by formula 1 was dissolved in 0.8 mL of tetrahydrofuran and 4.15 mg of ethanedisulfonic acid was dissolved in 0.2 mL of tetrahydrofuran. The solution of ethanedisulfonic acid in tetrahydrofuran was added dropwise to the solution of the compound represented by formula 1 in tetrahydrofuran, accompanied by the precipitation of the solids, followed by stirring overnight, centrifugation, rinsing and drying to give the salt.
(206) The XRPD pattern is shown in
(207) As the TGA pattern shown in
(208) As the DSC pattern shown in
(209) As the DVS pattern shown in
(210) 20 mg of the compound represented by formula 1 was taken, followed by dissolving 16.6 mg of ethanedisulfonic acid in 0.4 mL of tetrahydrofuran, and the other conditions remained the same, and the given product was still the monoethanedisulfonate of the quinazoline derivative with the same XRPD.
Embodiment 35: Synthesis of the Monosulfate of the Quinazoline Derivative
(211) 10 mg of the compound represented by formula 1 was dissolved in 0.8 mL of tetrahydrofuran and the concentrated sulfuric acid containing 1.95 mg of H.sub.2SO.sub.4 was dissolved in 0.2 mL of tetrahydrofuran. The solution of sulfuric acid in tetrahydrofuran was added dropwise to the solution of the compound represented by formula 1 in tetrahydrofuran, accompanied by the turbidity formation, followed by stirring overnight, centrifugation, rinsing and drying to give the salt.
(212) The XRPD pattern is shown in
(213) As the TGA pattern shown in
(214) As the DSC pattern shown in
(215) As the DVS pattern shown in
(216) 20 mg of the compound represented by formula 1 and the concentrated sulfuric acid containing 3.9 mg of H.sub.2SO.sub.4 were taken, and the other conditions remained the same, and the given product was still the monosulfate of the quinazoline derivative with the same XRPD.
(217) 20 mg of the compound represented by formula 1 was taken, followed by dissolving the concentrated sulfuric acid containing 5.06 mg of H.sub.2SO.sub.4 in 0.26 mL of tetrahydrofuran, and the other conditions remained the same, and the given product was still the monosulfate of the quinazoline derivative with the same XRPD.
Embodiment 36: Synthesis of the Disulfate of the Quinazoline Derivative
(218) 10 mg of the compound represented by formula 1 was dissolved in 0.8 mL of tetrahydrofuran and the concentrated sulfuric acid containing 5.85 mg of H.sub.2SO.sub.4 was dissolved in 0.2 mL of tetrahydrofuran. The solution of sulfuric acid in tetrahydrofuran was added dropwise to the solution of the compound represented by formula 1 in tetrahydrofuran, accompanied by the turbidity formation, followed by stirring overnight, centrifugation, rinsing and drying to give the salt.
(219) The XRPD pattern is shown in
(220) As the TGA pattern shown in
(221) As the DSC pattern shown in
(222) As the DVS pattern shown in
(223) 20 mg of the compound represented by formula 1 was taken, followed by dissolving the concentrated sulfuric acid containing 8.56 mg of H.sub.2SO.sub.4 in 0.15 mL of tetrahydrofuran, and the other conditions remained the same, and the given product was still the disulfate of the quinazoline derivative with the same XRPD.
(224) 10 mg of the compound represented by formula 1 was taken, followed by dissolving the concentrated sulfuric acid containing 6.42 mg of H.sub.2SO.sub.4 in 0.2 mL of tetrahydrofuran, and the other conditions remained the same, and the given product was still the disulfate of the quinazoline derivative with the same XRPD.
Embodiment 37: Synthesis of the Monobenzenesulfonate of the Quinazoline Derivative
(225) 10 mg of the compound represented by formula 1 was dissolved in 0.8 mL of tetrahydrofuran and 3.14 mg of the benzenesulfonic acid was dissolved in 0.2 mL of tetrahydrofuran. The solution of benzenesulfonic acid in tetrahydrofuran was added dropwise to the solution of the compound represented by formula 1 in tetrahydrofuran, followed by stirring overnight accompanied by precipitation of the solids, centrifugation, rinsing and drying to give the salt.
(226) The XRPD pattern is shown in
(227) As the TGA pattern shown in
(228) As the DSC pattern shown in
(229) As the DVS pattern shown in
(230) 20 mg of the compound represented by formula 1 and 6.28 mg of the benzenesulfonic acid were taken, and the other conditions remained the same, and the given product was still the monobenzenesulfonate of the quinazoline derivative with the same XRPD.
(231) 20 mg of the compound represented by formula 1 was taken, followed by dissolving 8.17 mg of the benzenesulfonic acid in 0.26 mL of tetrahydrofuran, and the other conditions remained the same, and the given product was still the monobenzenesulfonate of the quinazoline derivative with the same XRPD.
Embodiment 38: Synthesis of the Monohydrochloride Monohydrate of the Quinazoline Derivative
(232) 10 mg of the compound represented by formula 1 was dissolved in 0.8 mL of tetrahydrofuran and the concentrated hydrochloride acid containing 2.2 mg of HCl was dissolved in 0.2 mL of tetrahydrofuran. The solution of hydrochloride acid in tetrahydrofuran was added dropwise to the solution of the compound represented by formula 1 in tetrahydrofuran, accompanied by precipitation of the solids, followed by stirring overnight, centrifugation, rinsing and drying to give the salt.
(233) The XRPD pattern is shown in
(234) As the TGA pattern shown in
(235) As the DSC pattern shown in
(236) As the DVS pattern shown in
(237) 20 mg of the compound represented by formula 1 was taken, followed by dissolving the concentrated hydrochloride acid containing 1.59 mg of HCl in 0.072 mL of tetrahydrofuran, and the other conditions remained the same, and the given product was still the monohydrochloride monohydrate of the quinazoline derivative with the same XRPD.
(238) 10 mg of the compound represented by formula 1 was taken, followed by dissolving the concentrated hydrochloride acid containing 2.39 mg of HCl in 0.21 mL of tetrahydrofuran, and the other conditions remained the same, and the given product was still the monohydrochloride monohydrate of the quinazoline derivative with the same XRPD.
Embodiment 39: Synthesis of the Mono-D-Gluconate Monohydrate of the Quinazoline Derivative
(239) 10 mg of the compound represented by formula 1 was dissolved in 2 mL of dichloromethane and 3.89 mg of the D-gluconic acid was dissolved in 1 mL of dichloromethane. The solution of the compound represented by formula 1 in dichloromethane was added dropwise to the solution of D-gluconic acid in dichloromethane, followed by stirring overnight accompanied by precipitation of the solids, centrifugation, rinsing and drying to give the salt.
(240) The XRPD pattern is shown in
(241) As the TGA pattern shown in
(242) As the DSC pattern shown in
(243) As the DVS pattern shown in
(244) 20 mg of the compound represented by formula 1 was taken, followed by dissolving 23.62 mg of the D-gluconic acid in 7.87 mL of dichloromethane, or in 4.72 mL of dichloromethane to form a suspension, and the other conditions remained the same, and the given product was still the mono-D-gluconate of the quinazoline derivative with the same XRPD.
Embodiment 40: Synthesis of the Mono-L-Tartrate (Crystal Form 15) of the Quinazoline Derivative
(245) 10 mg of the compound represented by formula 1 was dissolved in 0.8 mL of tetrahydrofuran and 2.98 mg of the L-tartaric acid was dissolved in 0.2 mL of tetrahydrofuran. The solution of L-tartaric acid in tetrahydrofuran was added dropwise to the solution of the compound represented by formula 1 in tetrahydrofuran, followed by stirring overnight accompanied by precipitation of the solids, centrifugation, rinsing and drying to give the salt.
(246) The XRPD pattern is shown in
(247) As the TGA pattern shown in
(248) 20 mg of the compound represented by formula 1 and 5.96 mg of the L-tartaric acid were taken, and the other conditions remained the same, and the given product was still the mono-L-tartrate (crystal form 15) of the quinazoline derivative with the same XRPD.
Embodiment 41: Synthesis of the Mono-L-Tartrate Tetrahydrate (Crystal Form 16) Monohydrate of the Quinazoline Derivative
(249) 30 mg of the compound represented by formula 1 was dissolved in 2.5 mL of tetrahydrofuran and 17.87 mg of the L-tartaric was dissolved in 1 mL of tetrahydrofuran. The solution of the compound represented by formula 1 in tetrahydrofuran was added dropwise to the solution of L-tartaric acid in tetrahydrofuran, followed by stirring overnight accompanied by precipitation of the solids, centrifugation and rinsing. Water was added thereto for dissolving and stirred for 6 hours until the complete precipitation of the solids, followed by centrifugation removing the water to give the salt.
(250) The XRPD pattern is shown in
(251) As the TGA pattern shown in
(252) As the DSC pattern shown in
(253) As the DVS pattern shown in
Embodiment 42: Synthesis of the Diphosphonate of the Quinazoline Derivative
(254) 10 mg of the compound represented by formula 1 was dissolved in 0.8 mL of tetrahydrofuran and 4.56 mg of 85% phosphoric acid was dissolved in 0.5 mL of tetrahydrofuran. The solution of phosphoric acid in tetrahydrofuran was added dropwise to the solution of the compound represented by formula 1 in tetrahydrofuran, accompanied by the simultaneous precipitation of the solids, followed by stirring overnight, centrifugation, rinsing and drying to give the salt.
(255) The XRPD pattern is shown in
(256) As the TGA pattern shown in
(257) 20 mg of the compound represented by formula 1 was taken, followed by dissolving 4.28 mg of 85% phosphoric acid in 0.28 mL of tetrahydrofuran, and the other conditions remained the same, and the given product was still the diphosphonate of the quinazoline derivative with the same XRPD.
(258) 10 mg of the compound represented by formula 1 was taken, followed by dissolving 6.42 mg of 85% phosphoric acid in 0.5 mL of tetrahydrofuran, and the other conditions remained the same, and the given product was still the diphosphonate of the quinazoline derivative with the same XRPD.
Embodiment 43: Synthesis of the Monopamoate of the Quinazoline Derivative
(259) 10 mg of the compound represented by formula 1 was dissolved in 0.8 mL of tetrahydrofuran and 7.71 mg of the pamoic acid was dissolved in 0.5 mL of tetrahydrofuran to form a suspension. The solution of the compound represented by formula 1 in tetrahydrofuran was added dropwise to the suspension of pamoic acid in tetrahydrofuran, accompanied by the dissolving of the pamoic acid and the precipitation of the solids after stirring for 1 hour, followed by stirring overnight, centrifugation, rinsing and drying to give the salt.
(260) The XRPD pattern is shown in
(261) 20 mg of the compound represented by formula 1 and 5 mg or 10 mg of pamoic acid were taken, and the other conditions remained the same, and the given product was still the monopamoate of the quinazoline derivative with the same XRPD.
Embodiment 44: Synthesis of the Mono-p-Toluenesulfonate of the Quinazoline Derivative
(262) 10 mg of the compound represented by formula 1 was dissolved in 0.8 mL of chloroform and 4.53 mg of the p-toluenesulfonate monohydrate was dissolved in 0.1 mL of ethanol. The solution of p-toluenesulfonic acid in ethanol was added dropwise to the solution of the compound represented by formula 1 in chloroform, followed by stirring overnight accompanied by the precipitation of the solids, centrifugation, rinsing and drying to give the salt.
(263) The XRPD pattern is shown in
(264) As the TGA pattern shown in
(265) 20 mg of the compound represented by formula 1 and 9.06 mg of the p-toluenesulfonate monohydrate were taken, and the other conditions remained the same, and the given product was still the mono-p-toluenesulfonate of the quinazoline derivative with the same XRPD.
Embodiment 45: Synthesis of the Diglycolate of the Quinazoline Derivative
(266) 10 mg of the compound represented by formula 1 was dissolved in 2 mL of dichloromethane and 3.1 mg of the glycolic acid was added in 0.5 mL of dichloromethane to form a suspension. The solution of the compound represented by formula 1 in dichloromethane was added dropwise to the suspension of glycolic acid in dichloromethane, followed by stirring overnight accompanied by the precipitation of the solids, centrifugation, rinsing and drying to give the salt.
(267) The XRPD pattern is shown in
(268) 20 mg of the compound represented by formula 1 and 2.5 mg or 5 mg of glycolic acid were taken, and the other conditions remained the same, and the given product was still the diglycolate of the quinazoline derivative with the same XRPD.
Embodiment 46: Synthesis of the Monomalonate of the Quinazoline Derivative
(269) 10 mg of the compound represented by formula 1 was dissolved in 2 mL of dichloromethane and 2.06 mg of the malonic acid was added in 0.5 mL of dichloromethane to form a suspension. The solution of the compound represented by formula 1 in dichloromethane was added dropwise to the suspension of malonic acid in dichloromethane, followed by stirring overnight, centrifugation, rinsing and drying to give the salt.
(270) The XRPD pattern is shown in
(271) As the TGA pattern shown in
(272) 20 mg of the compound represented by formula 1 and 1.5 mg or 2.5 mg of the malonic acid were taken, and the other conditions remained the same, and the given product was still the monomalonate of the quinazoline derivative with the same XRPD.
Embodiment 47: Synthesis of the Monosuccinate of the Quinazoline Derivative
(273) 10 mg of the compound represented by formula 1 was dissolved in 2 mL of dichloromethane and 2.34 mg of the succinic acid was added in 0.5 mL of dichloromethane to form a suspension. The solution of the compound represented by formula 1 in dichloromethane was added dropwise to the suspension of succinic acid in dichloromethane, followed by stirring overnight, centrifugation, rinsing and drying to give the salt.
(274) The XRPD pattern is shown in
(275) 20 mg of the compound represented by formula 1 and 1.5 mg or 2.5 mg of the succinic acid were taken, and the other conditions remained the same, and the given product was still the monosuccinate of the quinazoline derivative with the same XRPD.
Embodiment 48: Synthesis of the Mono--Ketoglutarate of the Quinazoline Derivative
(276) 10 mg of the compound represented by formula 1 was dissolved in 0.8 mL of tetrahydrofuran and 3.19 mg of the -ketoglutaric acid was dissolved in 0.2 mL of tetrahydrofuran. The solution of -ketoglutaric acid in tetrahydrofuran was added dropwise to the solution of the compound represented by formula 1 in tetrahydrofuran, accompanied by the simultaneous precipitation of the solids, followed by centrifugation, rinsing and drying to give the salt.
(277) The XRPD pattern is shown in
(278) As the TGA pattern shown in
(279) 20 mg of the compound represented by formula 1 and 6.38 mg of the -ketoglutaric acid were taken, and the other conditions remained the same, and the given product was still the mono--ketoglutarate of the quinazoline derivative with the same XRPD.
Embodiment 49: Synthesis of the Dimaleate of the Quinazoline Derivative
(280) 10 mg of the compound represented by formula 1 was dissolved in 0.8 mL of tetrahydrofuran and 5.06 mg of the maleic acid was dissolved in 0.4 mL of tetrahydrofuran. The solution of maleic acid in tetrahydrofuran was added dropwise to the solution of the compound represented by formula 1 in tetrahydrofuran, accompanied by the simultaneous precipitation of the solids, followed by centrifugation, rinsing and drying to give the salt.
(281) The XRPD pattern is shown in
(282) As the TGA pattern shown in
(283) 20 mg of the compound represented by formula 1 was taken, and the other conditions remained the same, and the given product was still the dimaleate of the quinazoline derivative with the same XRPD.
(284) 10 mg of the compound represented by formula 1 was taken, followed by dissolving 7.59 mg of the maleic acid in 0.3 mL of tetrahydrofuran, and the other conditions remained the same, and the given product was still the dimaleate of the quinazoline derivative with the same XRPD.
Embodiment 50: Synthesis of the Mono-1,5-Naphthalenedisulfonate of the Quinazoline Derivative
(285) 10 mg of the compound represented by formula 1 was dissolved in 0.8 mL of tetrahydrofuran and 7.86 mg of the 1,5-naphthalenedisulfonic acid was dissolved in 0.2 mL of tetrahydrofuran. The solution of 1,5-naphthalenedisulfonic acid in tetrahydrofuran was added dropwise to the solution of the compound represented by formula 1 in tetrahydrofuran, accompanied by the simultaneous precipitation of the solids, followed by stirring overnight, centrifugation, rinsing and drying to give the salt.
(286) The XRPD pattern is shown in
(287) 20 mg of the compound represented by formula 1 and 15.72 mg of the 1,5-naphthalenedisulfonic acid were taken, and the other conditions remained the same, and the given product was still the mono-1,5-naphthalenedisulfonate of the quinazoline derivative with the same XRPD.
Embodiment 51: Synthesis of the Dimalonate of the Quinazoline Derivative
(288) 10 mg of the compound represented by formula 1 was dissolved in 2 mL of dichloromethane and 4.13 mg of the malonic acid was added in 1 mL of dichloromethane to form a suspension. The solution of the compound represented by formula 1 in dichloromethane was added dropwise to the suspension of malonic acid in dichloromethane, followed by stirring overnight, centrifugation, rinsing and drying to give the salt.
(289) The XRPD pattern is shown in
(290) As the TGA pattern shown in
(291) 20 mg of the compound represented by formula 1, and 3 mg/mL or 5 mg/mL of the suspension of malonic acid in dichloromethane were taken, and the molar ratio of the compound represented by formula 1 to the malonic acid in the reaction is 1:2.2. The other conditions remained the same, and the given product was still the dimalonate of the quinazoline derivative with the same XRPD.
Embodiment 52: Synthesis of the Trimalonate of the Quinazoline Derivative
(292) 10 mg of the compound represented by formula 1 was dissolved in 2 mL of dichloromethane and 6.19 mg of the malonic acid was added in 1 mL of dichloromethane to form a suspension. The solution of the compound represented by formula 1 in dichloromethane was added dropwise to the suspension of malonic acid in dichloromethane, followed by stirring overnight, centrifugation, rinsing and drying to give the salt.
(293) The XRPD pattern is shown in
(294) As the TGA pattern shown in
(295) 20 mg of the compound represented by formula 1, and 5 mg/mL or 10 mg/mL of the suspension of malonic acid in dichloromethane were taken, and the molar ratio of the compound represented by formula 1 to the malonic acid in the reaction is 1:3.3. The other conditions remained the same, and the given product was still the trimalonate of the quinazoline derivative with the same XRPD.
Embodiment 53: Synthesis of the Di-1,5-Naphthalenedisulfonate of the Quinazoline Derivative
(296) 10 mg of the compound represented by formula 1 was dissolved in 0.8 mL of tetrahydrofuran and 15.72 mg of the 1,5-naphthalenedisulfonic acid was dissolved in 0.4 mL of tetrahydrofuran. The solution of the compound represented by formula 1 in tetrahydrofuran was added dropwise to the solution of 1,5-naphthalenedisulfonic acid in tetrahydrofuran, accompanied by the simultaneous precipitation of the solids, followed by stirring overnight, centrifugation, rinsing and drying to give the salt.
(297) The XRPD pattern is shown in
(298) As the TGA pattern shown in
(299) 20 mg of the compound represented by formula 1 was taken, followed by dissolving 25.17 mg of the 1,5-naphthalenedisulfonic acid in 0.32 mL of tetrahydrofuran, and the other conditions remained the same, and the given product was still the di-1,5-naphthalenedisulfonate of the quinazoline derivative with the same XRPD.
(300) 10 mg of the compound represented by formula 1 was taken, followed by dissolving 18.88 mg of the 1,5-naphthalenedisulfonic acid in 0.32 mL of tetrahydrofuran, and the other conditions remained the same, and the given product was still the di-1,5-naphthalenedisulfonate of the quinazoline derivative with the same XRPD.
Embodiment 54: Synthesis of the Trisuccinate of the Quinazoline Derivative
(301) 10 mg of the compound represented by formula 1 was dissolved in 2 mL of dichloromethane and 7.03 mg of the succinic acid was added in 1 mL of dichloromethane to form a suspension. The solution of the compound represented by formula 1 in dichloromethane was added dropwise to the suspension of succinic acid in dichloromethane, followed by stirring overnight, centrifugation, rinsing and drying to give the salt.
(302) The XRPD pattern is shown in
(303) As the TGA pattern shown in
(304) 20 mg of the compound represented by formula 1, and 5 mg/mL of the suspension of succinic acid in dichloromethane were taken, and the molar ratio of the compound represented by formula 1 to the succinic acid in the reaction is 1:2.2. The other conditions remained the same, and the given product was still the trisuccinate of the quinazoline derivative with the same XRPD.
(305) 10 mg of the compound represented by formula 1, and 10 mg/mL of the suspension of succinic acid in dichloromethane were taken, and the molar ratio of the compound represented by formula 1 to the succinic acid in the reaction is 1:3.3. The other conditions remained the same, and the given product was still the trisuccinate of the quinazoline derivative with the same XRPD.
Embodiment 55: Synthesis of the Di--Ketoglutarate of the Quinazoline Derivative
(306) 10 mg of the compound represented by formula 1 was dissolved in 0.8 mL of tetrahydrofuran and 6.38 mg of the -ketoglutaric acid was dissolved in 0.4 mL of tetrahydrofuran. The solution of the compound represented by formula 1 in tetrahydrofuran was added dropwise to the solution of -ketoglutaric acid in tetrahydrofuran, accompanied by the simultaneous precipitation of the solids, followed by centrifugation, rinsing and drying to give the salt.
(307) The XRPD pattern is shown in
(308) As the TGA pattern shown in
(309) 20 mg of the compound represented by formula 1 was taken, followed by dissolving 19.14 mg of the -ketoglutaric acid in 0.6 mL of tetrahydrofuran, and the other conditions remained the same, and the given product was still the di--ketoglutarate of the quinazoline derivative with the same XRPD.
Embodiment 56: Synthesis of the Mono-p-Chlorobenzenesulfonate of the Quinazoline Derivative
(310) 10 mg of the compound represented by formula 1 was dissolved in 0.8 mL of tetrahydrofuran and 4.2 mg of the p-chlorobenzenesulfonic acid was dissolved in 0.2 mL of tetrahydrofuran. The solution of p-chlorobenzenesulfonic acid in tetrahydrofuran was added dropwise to the solution of the compound represented by formula 1 in tetrahydrofuran, followed by stirring overnight, centrifugation of the precipitated solids, rinsing and drying to give the salt.
(311) The XRPD pattern is shown in
(312) 20 mg of the compound represented by formula 1 and 8.4 mg of the p-chlorobenzenesulfonic acid were taken, and the other conditions remained the same, and the given product was still the mono-p-chlorobenzenesulfonate of the quinazoline derivative with the same XRPD.
Effectiveness Embodiment 1: Solid-State Stability Test
(313) An appropriate amount of the drugs were placed in the surface dish, spread to a thickness of 3-5 mm, and exposed in high temperature, high temperature and high humidity, illumination and oxidation conditions for 10 days respectively, and the solid-state characterization was performed. The purity and the number of impurities 0.05%) of the samples for testing were determined by HPLC, and compared with the samples on day 0. The exposure conditions are:
(314) High temperature (an oven with T=60 C.);
(315) High temperature and high humidity (40 C., a chamber with constant temperature and 75% relative humidity);
(316) Illumination (25 C., a 4500500 lx light incubator);
(317) Oxidation (25 C., a closed container containing urea hydrogen peroxide).
(318) The results are shown in Table 1.
(319) TABLE-US-00001 TABLE 1 High temperature High and high Sample for testing Time and conditions temperature humidity Illumination Oxidation The quinazoline 0 d Purity 99.1% derivative Number of 1 compound impurities represented by 10 d Purity 99.0% 99.0% 99.0% 99.0% formula 1 Number of 2 3 2 3 impurities The monocitrate 0 d Purity 99.2% of the quinazoline Number of 1 derivative impurities (crystal form 1) 10 d Purity 99.1% 99.2% 98.9% 98.9% Number of 1 1 4 3 impurities The 0 d Purity 98.5% monobenzenesulfonate Number of 2 of the quinazoline impurities derivative Purity 98.5% 98.5% 98.5% 98.5% 10 d Number of 2 2 2 2 impurities The 0 d Purity 99.0% monoethanedisulfonate Number of 2 of the quinazoline impurities derivative 10 d Purity 99.0% 99.0% 99.0% 99.0% Number of 2 2 2 2 impurities
Effectiveness Embodiment 2: Solution Stability Test
(320) About 15 mg of the sample was weighed accurately, dissolved with 25 mL of the test solvent (10% aqueous acetone solution, pH=4.0 B-R buffer solution, SGF, SIF) via ultrasound for 20 minutes. The solution was divided into four portions and placed in the clear glass vials, followed by sealing. The samples were exposed in different environments and sampled on day 0 and day 5. The purity of each sample was determined by HPLC, and the number of impurities greater than 0.05% was calculated and compared with the samples on day 0. The exposure environments are:
(321) Room temperature and light-proof test, 25 C.;
(322) High temperature and light-proof test, 60 C.;
(323) Illumination experiment (4500500 lx), 25 C.;
(324) Oxidation experiment (3% v/v hydrogen peroxide), 25 C.
(325) The results are shown in Table 2.
(326) TABLE-US-00002 TABLE 2 High temperature Testing High and high Name Media Time target temperature humidity Illumination Oxidation The quinazoline 10% 0 d Purity 93.4% derivative compound aqueous Number of 2 represented by acetone impurities formula 1 solution 5 d Purity 83.1% 13.3% 61.5% Complete Number of 2 6 4 decomposition impurities B-R Buffer 0 d Purity 99.0% solution Number of 1 impurities 5 d Purity 99.0% 95.0% 99.0% 40.6% Number of 1 4 1 13 impurities SGF 0 d Purity 99.0% Number of 2 impurities 5 d Purity 99.0% 94.2% 99.0% 84.3% Number of 2 4 2 3 impurities SIF 0 d Purity 88.9% Number of 1 impurities 5 d Purity 85.6% 81.9% 50.0% 62.7% Number of 2 4 18 5 impurities The monocitrate of the 10% 0 d Purity 98.6% quinazoline derivative aqueous Number of 1 (crystal form 1) acetone impurities solution 5 d Purity 98.5% 96.8% 98.5% 62.8% Number of 1 2 2 8 impurities B-R Buffer 0 d Purity 98.8% solution Number of 1 impurities 5 d Purity 98.7% 97.0% 98.6% 38.8% Number of 1 4 1 13 impurities SGF 0 d Purity 99.2% Number of 1 impurities 5 d Purity 99.0% 94.6% 99.0% 80.8% Number of 2 2 2 4 impurities SIF 0 d Purity 81.4% Number of 1 impurities 5 d Purity 56.8% 54.0% 24.8% 36.4% Number of 1 6 12 6 impurities The 10% 0 d Purity 98.2% monobenzenesulfonate aqueous Number of 1 of the quinazoline acetone impurities derivative solution 5 d Purity 97.9% 96.8% 97.6% 60.8% Number of 1 3 1 7 impurities B-R 0 d Purity 98.5% Buffer Number of 2 solution impurities 5 d Purity 97.2% 97.2% 98.5% 38.1% Number of 3 3 1 12 impurities SGF 0 d Purity 98.9% Number of 1 impurities 5 d Purity 98.8% 94.4% 98.9% 81.7% Number of 2 2 1 3 impurities SIF 0 d Purity 80.2 Number of 2 impurities 5 d Purity 58.7% 42.0% 10.0% Complete Number of 1 8 9 decomposition impurities The 10% 0 d Purity 99.1% monoethanedisulfonate aqueous Number of 1 of the quinazoline acetone impurities derivative solution 5 d Purity 99.0% 98.1% 99.1% 70.8% Number of 1 3 1 7 impurities B-R 0 d Purity 99.0% Buffer Number of 1 solution impurities 5 d Purity 99.0% 97.7% 99.0% 44.0% Number of 1 3 1 15 impurities SGF 0 d Purity 99.0% Number of 1 impurities 5 d Purity 98.9% 94.5% 98.9% 80.8% Number of 2 2 2 3 impurities SIF 0 d Purity 74.8% Number of 2 impurities 5 d Purity 50.0% 36.5% 25.2% 30.8% Number of 1 6 13 7 impurities
Effectiveness Embodiment 3: .SUP.1.H NMR Measurement of the Salt of the Quinazoline Derivative and Solubility Determination by HPLC Method
(327) The partially salts of the quinazoline derivatives were subjected to .sup.1H NMR measurement and solubility determination by HPLC method.
(328) The solubility was determined as follows: a certain amount of the sample was weighed and the solvent was added thereto in portions with stirring or ultrasonication to accelerate dissolution; the amount of the consumed solvent was recorded once the sample was dissolved. If the sample was still not dissolved at a specific concentration, the solubility thereof was expressed as < such specific concentration; when the solubility of the sample was relatively low, the amount of the solvent could be amplified multiple times, followed by the addition of an excess of sample and stirring overnight. A certain volume of the solution was taken, followed by filtration, concentration, dissolved with a certain volume of other suitable solvents and subjected to HPLC measurement to obtain accurate data of the solubility.
(329) The specific test results are as follows:
(330)
(331)
(332) The water solubility of the monohydrochloride monohydrate of the quinazoline derivative at 20 C. determined by HPLC is 51.5 g/mL.
(333) The water solubility of the mono-D-gluconate of the quinazoline derivative at 20 C. determined by HPLC is 51.4 g/mL.
(334) The water solubility of the diphosphate of the quinazoline derivative at 20 C. determined by HPLC is 25.0 g/mL.
(335)
(336)
(337)
(338)
(339) The water solubility of the dimaleate of the quinazoline derivative at 20 C. determined by HPLC is 25.7 g/mL.
(340)
(341) The water solubility of the trisuccinate of the quinazoline derivative at 20 C. determined by HPLC is 8.6 g/mL.
(342) The solubility of crystal form 1 in different solvents at 20 C. determined by HPLC is shown in Table 3.
(343) TABLE-US-00003 TABLE 3 Abbreviation Solubility mg/mL MeOH 5-12.5 EtOH <1 IPA <1 BtOH <1 H.sub.2O <1 THF <1 Dioxane .sup.1-2.5 ACN <1 CH.sub.2Cl.sub.2 <1 CHCl.sub.3 <1 DMSO 100-200
(344) In addition, the results of the solubility determined by visual inspection are as follows:
(345) (1) The monoethanedisulfonate of the quinazoline derivative: the visual solubility of the salt in water at room temperature of 1-2 mg/mL.
(346) (2) The monosulfate of the quinazoline derivative: the visual solubility of the sample in water at 20 C. is 1-2 mg/mL.
(347) (3) The disulfate of the quinazoline derivative: the visual solubility of the sample in water at 20 C. is 0.91-1 mg/mL.
(348) (4) The mono-L-tartrate tetrahydrate of the quinazoline derivative: the visual solubility of the hydrate in water at room temperature is 0.625-0.667 mg/mL.
(349) (5) The dimalonate of the quinazoline derivative: the visual solubility of the sample in water at room temperature is 2-2.5 mg/mL.
(350) (6) The trimalonate of the quinazoline derivative: the visual solubility of the sample in water at room temperature was 1.67-2 mg/mL.
(351) The above is only the specific embodiments of the present invention, but the scope of the present invention is not limited thereto. Any changes or alternatives made by those skilled in the art according to the technical scope of the present invention without creativity are intended to fall within the scope of the present invention.
Effectiveness Embodiment 4: Comparison of Absorption in Rats after Administration of Free Base and Salt
(352) 21 SD rats were divided into 7 groups, and 20 mol/kg of the free base and 6 salts of the above quinazoline derivative compound represented by formula 1 (8 mL/kg, 2.5 mM) were given by means of intragastric administration (see Table 4). 0.4 mL of blood was taken from the fundus venous plexus of rats before administration and 5, 15, 30, 60, 90, 120, 240, 360, 480, and 1440 minutes after administration, respectively. The blood sample was centrifuged at 8000 RPM for 5 minutes, followed by the isolation of the upper plasma. 200 L of the acetonitrile containing internal standard (Ponatinib, 0.25 M) was added to 50 L of the plasma sample to precipitate the protein, followed by vortexing for 10 minutes and centrifugation at 6000 g for 10 minutes. 200 L of the supernatant was taken and centrifuged again for 10 minutes. 50 L of the supernatant was injected in a 96-well plate. The plasma drug concentration was determined by LC/MS/MS, and the corresponding pharmacokinetic parameters were calculated. See Table 5 and
(353) TABLE-US-00004 TABLE 4 Concen- tration of the Number Preparation Subject dosing Dose of of the test dose solution volume Route of animals/ Compound agents (mol/kg) (mM) (mL/kg) administration gender The CMC-Na 20 2.5 8 Intragastric 3/male monohydrochloride (containing administration monohydrate 0.4% Tween80) mono-D-gluconate CMC-Na 20 2.5 8 Intragastric 3/male (containing administration 0.4% Tween80) The CMC-Na 20 2.5 8 Intragastric 3/male monocitrate (containing administration (crystal form 1) 0.4% Tween80) The CMC-Na 20 2.5 8 Intragastric 3/male monobenzene- (containing administration sulfonate 0.4% Tween80) The CMC-Na 20 2.5 8 Intragastric 3/male monosulfate (containing administration 0.4% Tween80) The CMC-Na 20 2.5 8 Intragastric 3/male monoethane- (containing administration disulfonate 0.4% Tween80) The quinazoline CMC-Na 20 2.5 8 Intragastric 3/male derivative compound (containing administration represented by 0.4% formula 1 Tween80)
(354) TABLE-US-00005 TABLE 5 Dose Cmax Tmax AUC (0-t) MRT (0-T) (mol/kg) (M) (min) (M*min) (min) t1/2 (min) The 20.00 0.98 0.06 70.00 17.32 507.89 66.81 408.76 81.85 270.47 93.62 monohydrochloride monohydrate mono-D-gluconate 20.00 1.12 0.28 80.00 34.64 484.40 201.71 375.68 153.09 213.43 20.92 The monocitrate 20.00 3.35 1.00 100.00 34.64 1894.24 1131.20 359.24 37.56 217.25 91.84 (crystal form 1) The 20.00 2.30 0.47 80.00 34.64 972.26 291.88 357.13 15.20 305.38 127.64 monobenzenesulfonate The monosulfate 20.00 1.66 0.27 70.00 17.32 591.00 29.76 343.51 42.43 230.81 162.24 The 20.00 0.39 0.16 80.00 17.32 195.56 84.51 319.90 59.62 224.64 54.99 monoethanedisulfonate The quinazoline 20.00 0.31 0.07 60.00 122.73 28.00 399.30 91.28 256.89 105.96 derivative compound represented by formula 1
(355) By comparison, the free base and the 6 salts were orally administered to rats at the same dose. It is indicated that the citrate, the monobenzenesulfonate and the monosulfate are better absorbed, while the AUC (0-t) and Cmax of the monohydrochloride monohydrate, the mono-D-gluconate and the monoethanedisulfonate are relatively low. Among them, the citrate has the highest AUC (0-t) and Cmax.
(356) It is to be understood that the foregoing description of the embodiments is intended to be purely illustrative of the principles of the invention, rather than exhaustive thereof, and that changes and variations will be apparent to those skilled in the art, and that the present invention is not intended to be limited other than expressly set forth in the following claims.