Crystal form of monomethanesulfonate of deuterated 3-(4,5-substituted aminopyrimidine)phenyl compound and preparation method therefor
11629144 · 2023-04-18
Assignee
Inventors
- Yongqiang Zhu (Jiangsu, CN)
- Yang Yang (Jiangsu, CN)
- Ou Hai (Jiangsu, CN)
- Zhaogang Liu (Jiangsu, CN)
- Chao Feng (Jiangsu, CN)
Cpc classification
A61K31/506
HUMAN NECESSITIES
International classification
Abstract
Disclosed in the present invention are a crystal form of monomethanesulfonate of a deuterated 3-(4,5-substituted aminopyrimidine)phenyl compound as represented by formula I, and a preparation method therefor. The crystal form is highly stable, can be used for treatment or prevention of diseases or conditions by means of epidermal growth factor receptors (EGFRs) in some mutation forms, can effectively inhibit the growth of a variety of tumor cells, and have an inhibiting effect on other proteases of EGFR and Her families, and thus can be used for preparing antitumor drugs.
Claims
1. 1. A crystal form A of monomethanesulfonate of a deuterated 3-(4,5-substituted aminopyrimidine)phenyl compound as represented by formula I: ##STR00018## wherein in X-ray powder diffraction of the crystal form A, a 2θ diffraction angle has characteristic peaks at 15.42±0.2°, 17.86±0.2°, 20.58±0.2°, 21.58±0.2°, 23.86±0.2°, and 24.96±0.2°.
2. The crystal form A according to claim 1, wherein in the X-ray powder diffraction, the 2θ diffraction angle also has characteristic peaks at 6.34±0.2°, 10.24±0.2°, 10.72±0.2°, 14.94±0.2°, 15.42±0.2°, 16.88±0.2°, 17.86±0.2°, 20.58±0.2°, 21.58±0.2°, 23.86±0.2°, 24.96±0.2°, 26.28±0.2°, and 27.58±0.2°.
3. The crystal form A according to claim 1, having an X-ray powder diffraction pattern as shown in
4. The crystal form A according to claim 1, having a thermogravimetric analysis graph as shown in
5. The crystal form A according to claim 1, having infrared spectra with the following characteristic absorption peaks: 3249 cm.sup.−1, 3019 cm.sup.−1, 1942 cm.sup.−1, 1906 cm.sup.−1, 1672 cm.sup.−1, 1575 cm.sup.−1, 1552 cm.sup.−1, 1411 cm.sup.−1, 1368 cm.sup.−1, 727 cm.sup.−1, 558 .sup.−1, and 522 cm.sup.−1.
6. A crystal form B of monomethanesulfonate of a deuterated 3-(4,5-substituted aminopyrimidine)phenyl compound as represented by formula I: ##STR00019## wherein in X-ray powder diffraction of the crystal form B, a 2θ diffraction angle has characteristic peaks at 10.38±0.2°, 14.9±0.2°, 18.1±0.2°, 22.68±0.2°, and 26.20±0.2°.
7. The crystal form B according to claim 6, wherein in the X-ray powder diffraction of the crystal form B, the 2θ diffraction angle also has characteristic peaks at 7.20±0.2°, 8.00±0.2°, 8.50±0.2°, 10.38±0.2°, 14.9±0.2°, 16.06±0.2°, 18.1±0.2°, 19.28±0.2°, 20.88±0.2°, 21.96±0.2°, 22.68±0.2°, 23.54±0.2°, and 26.20±0.2°.
8. The crystal form B according to claim 6, having an X-ray powder diffraction pattern as shown in
9. The crystal form B according to claim 6, having a thermogravimetric analysis graph as shown in
10. The crystal form B according to claim 6, having infrared spectra with the following characteristic absorption peaks: 3248 cm.sup.−1, 3103 cm.sup.−1, 1906 cm.sup.−1, 1671 cm.sup.−1, 1618 cm.sup.−1, 1575 cm.sup.−1, 1533 cm.sup.−1, 1141 cm.sup.−1, 1235 cm.sup.−1, 1162 cm.sup.−1, and 807 cm.sup.−1.
11. A preparation method of the crystal form B according to claim 6, comprising following steps: 1) mixing the deuterated 3-(4,5-substituted aminopyridine)phenyl compound of formula I with a solvent at the temperature of 50-80° C., and dropwise adding methanesulfonic acid; 2) stirring and crystallizing at the temperature of 0-30° C.; and 3) filtering and drying to obtain the crystal form B.
12. The preparation method according to claim 11, wherein the solvent in step 1) is selected from acetonitrile, acetone or a mixture of acetonitrile and acetone, and the use amount of the solvent is 5-40 times that of deuterated 3-(4,5-substituted aminopyridine)phenyl compound of formula I in mL/g units.
13. The preparation method according to claim 12, wherein the use amount of the solvent in step 1) is 10-20 times that of deuterated 3-(4,5-substituted aminopyridine)phenyl compound of formula I in mL/g units.
14. The preparation method according to claim 11, wherein the molar ratio of methanesulfonic acid to deuterated 3-(4,5-substituted aminopyridine)phenyl compound of formula I in step 1) is (0.1-1):1.
15. A pharmaceutical composition comprising crystal form A according to claim 1 and a pharmaceutically acceptable carrier.
16. A method of treating a human or an animal afflicted with a tumor comprising administering an effective amount of the pharmaceutical composition of claim 15 to the human or animal so as to treat the human or animal.
17. A pharmaceutical composition comprising crystal form B according to claim 6 and a pharmaceutically acceptable carrier.
18. A method of treating a human or an animal afflicted with a tumor comprising administering an effective amount of the pharmaceutical composition of claim 17 to the human or animal so as to treat the human or animal.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
DETAILED DESCRIPTION
(11) The following detailed embodiments describe how to prepare the various compounds and/or perform the various methods of the present invention, and are to be understood as merely illustrative, and not restrictive, of the above disclosure. One skilled in the art will be able to quickly and accurately identify the reactants and variations in reaction conditions and techniques.
Embodiment 1: Preparation of a Compound in Formula I
(12) ##STR00004##
(13) A synthetic mute is as follows:
(14) ##STR00005## ##STR00006##
(15) ##STR00007##
(16) A 250 mL single-neck flask was taken, N-methylethanolamine (10 g, 133.1 mmol), TEA (26.9 g, 266.3 mmol) and acetonitrile (100 mL) were added into the single-neck flask separately, then benzyl chloride (23.9 g, 139.8 mmol) was slowly added dropwise to a reaction solution at 0° C., the mixture was kept stirring for 1 h at room temperature, no raw material remaining was monitored by TLC, a solvent was distilled off under reduced pressure, and the mixture was purified by column chromatography to obtain 21 g of colorless liquid which is the compound 1 with the yield of 95.5%.
(17) ##STR00008##
(18) A 250 mL eggplant-shaped flask was taken, the compound 1 (21 g, 127.1 mmol), TEA (25.7 g, 254.2 mmol) and DCM (100 ml) were added into the eggplant-shaped flask, and then MsCl (14.6 g, 127.1 mmol) was dropwise added at 0° C. A reaction solution was stirred at room temperature for 3 h, no raw material remaining was monitored by TLC, a solvent was distilled off under reduced pressure, and the mixture was purified by column chromatography to obtain 20 g of faint yellow liquid which is the compound 2 with the yield of 85.6%.
(19) ##STR00009##
(20) A 500 mL sealed tube was taken, the compound 2 (20 g, 108.9 mmol) and 215 mL of ammonia water were added in the sealed tube, mixed liquid was stirred overnight at 40° C., no raw material remaining was monitored by TLC, and the mixed liquid was purified by column chromatography to obtain 15 g of colorless liquid which is the compound 3 with the yield of 84%.
(21) ##STR00010##
(22) A 500 mL eggplant-shaped flask was taken, the compound 3 (15 g, 91.3 mmol) and DCM (200 mL) were added in the eggplant-shaped flask, Boc.sub.2O (19.9 g, 91.3 mmol) was slowly dropwise added at room temperature, the mixture was kept stirring for 3 h at room temperature after completion of the addition, no raw material remaining was monitored by TLC, a solvent was distilled off under reduced pressure, and the mixture was purified by column chromatography to obtain 21 g of the compound 4 which is white solid and has the yield of 87%.
(23) ##STR00011##
(24) A 100 mL eggplant-shaped flask was taken, the compound 4 (10 g, 37.8 mmol) and DMF (40 mL) were added to the eggplant-shaped flask, NaH (2.3 g, 56.7 mmol) was added in batches, the mixture was stirred for 30 min, was added with a DMF (10 mL) solution of TsOCD, (7.9 g, 41.6 mmol), and then was stirred at room temperature for 3 h, no raw material remaining was monitored by TLC, the mixture was quenched by addition of 150 mL of H.sub.2O, and was extracted by addition of EA (50 mL*3), organic phases were combined, the mixture was washed with brine, and was dried through anhydrous Na.sub.2SO.sub.4, a solvent was distilled off under reduced pressure, and the mixture was purified by column chromatography to obtain 8.5 g of the compound 5 as a white solid with the yield of 80%.
(25) ##STR00012##
(26) A 250 mL eggplant-shaped flask was taken, the compound 5 (8.5 g, 30.18 mmol) and THF (80 mL) were added into the eggplant-shaped flask, LiAlH.sub.4 (3.4 g, 90.59 mmol) was added in batches under ice bath, then the mixture was heated to 60° C. overnight, no raw material remaining was monitored by TLC, the mixture was quenched by slow addition of Na.sub.2SO.sub.4.Math.10H.sub.2O, solid was removed by filtration, the filtrate was collected, a solvent was distilled off under reduced pressure, and the mixture was purified by column chromatography to obtain 4.5 g of colorless liquid which is the compound 6 and has the yield of 76.3%.
(27) ##STR00013##
(28) A 100 mL eggplant-shaped flask was taken, the compound 6 (4.5 g, 23 mmol), MeOH (50 mL) and Pd(OH).sub.2/C (200 mg) were added into the eggplant-shaped flask respectively, hydrogen was changed for 3 times by vacuum pumping, the mixture was stirred at room temperature overnight, no raw material remaining was monitored by TLC, Pd(OH).sub.2/C was removed by filtration, the pH value of a reaction solution was regulated to acidity, and a solvent was distilled off under reduced pressure to obtain 2.8 g of white solid which is the compound 7 with the yield of 85.9%.
(29) ##STR00014##
(30) A 250 mL eggplant-shaped flask was taken, 2,4-dichloropyrimidine (11.37 g, 76.33 mmol), aluminum trichloride (10.18 g, 76.33 mmol) and 100 mL of ethylene glycol dimethyl ether (DME) were added into the eggplant-shaped flask respectively, and the mixture was stirred at room temperature for 20 minutes. Then a compound II (10.00 g, 63.61 mmol) was added in batches, the temperature rises to 80° C. and reaction was carried out for 6 h. The reaction was stopped and the mixture was cooled to room temperature, 100 mL of water was added, the mixture was stirred for 2 h and was filtered, and solid was washed by ethanol and dried under vacuum to obtain 15.46 g of a red crude product which is a compound III with the yield of 90.1%. 300 mL 1,4-dioxane was added in a 500 mL eggplant-shaped flask, the compound III (20.00 g, 82.07 mmol), a compound 4-fluoro-2-methoxy-5-nitroaniline (16.80 g, 90.28 mmol) and p-toluenesulfonic acid (17.17 g, 90.28 mmol) were added into the eggplant-shaped flask respectively. The temperature rises to 85° C. for reaction for 8 h, the mixture was cooled to room temperature, was added with water for stirring, was dropwise added with 40% sodium hydroxide solution until the pH equals to 9, and was filtered, solid was washed with ethanol and dried under vacuum to obtain 30.00 g of yellow solid which is the compound 8 with the yield of 92.9%.
(31) ##STR00015##
(32) A 120 mL sealed tube was taken, and the compound 8 (2 g, 4.77 mmol), the compound 7 (810 mg, 5.72 mmol), DIPEA (1.23 g, 9.54 mmol) and DMA (10 mL) were added into the sealed tube. The mixture was reacted in the sealed tube at the temperature of 140° C. for 6 h, no raw material remaining was monitored by TLC, a reaction solution was cooled to room temperature, was added with 20 mL of water, and was separated out to obtain solid, the solid was filtered, a filter cake was added into 2 mL of methanol for pulping and washing, and filtering and drying were carried out to obtain 1.7 g of red solid which is the compound 9 with the yield of 70.6%.
(33) ##STR00016##
(34) A 250 mL single-neck flask was taken, the compound 9 (1.7 g, 3.37 mmol), Pd/C (200 mg) and MeOH (100 mL) were added into the single-neck flask, hydrogen is changed for 3 times by vacuum pumping, the mixture was stirred overnight at room temperature, no raw material remaining was monitored by TLC, Pd/C was removed by filtration, a solvent was distilled off under reduced pressure to obtain yellow green solid, and the solid was purified by column chromatography, and was eluted by an eluent (DCM:MeOH:NH.sub.3H.sub.2O=20:1:0.1) to obtain 1.2 g of yellow green solid which is the compound 10 with the yield of 75%.
(35) Compound Shown in Formula I
(36) ##STR00017##
(37) A 20 mL single-neck flask was taken, the compound 10 (500 mg, 1.05 mmol) and DCM (30 mL) were added into the single-neck flask, then 3-chloropropionyl chloride (133.7 mg, 1.05 mmol) was slowly dropwise added into a reaction solution at 0° C., the reaction solution was kept stirring for 30 min at room temperature, no raw material remaining was monitored by TLC, then NaOH (168 mg, 4.2 mmol) was added into the reaction solution, the reaction solution was heated to 65° C. and was stirred overnight, no raw material remaining was monitored by HPLC, a solvent was distilled off under reduced pressure, and the mixture was purified by column chromatography and was eluted by eluent (DCM:MeOH=10:1) to obtain 280 mg of faint yellow solid which is the compound shown in formula I, and the yield of the compound was 50.4%.
(38) .sup.1H NMR (400 MHz, CDCl3) δ 10.19 (s, 1H), 9.88 (s, 1H), 9.12 (s, 1H), 8.39 (d, J=5.3 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.74 (s, 1H), 7.26-7.14 (m, 2H), 7.00 (d, J=7.0 Hz, 1H), 6.82 (s, 1H), 6.49 (dd, J=16.9, 2.2 Hz, 1H), 6.39 (dd, J=16.9, 9.8 Hz, 1H), 5.73 (dd, J=9.8, 2.2 Hz, 1H), 4.49-4.32 (m, 2H), 3.91 (s, 3H), 3.05 (t, J=6.0 Hz, 2H), 2.95-2.87 (m, 2H), 2.73 (s, 3H), 2.39-2.23 (m, 7H), 1.82 (s, 3H). LC-MS [M+H].sup.+ 528.7
Embodiment 2: Preparation of a Crystal Form A of Monomethanesulfonate of a Compound Shown in Formula I
(39) 1.0 g of the compound shown in formula I was added into 15 ml of dichloromethane, the mixture was stirred until the solution is clear, prepared methanesulfonic acid (182 mg of methanesulfonic acid may be dissolved into 5 ml of dichloromethane) was dropwise added at the controlled temperature of 30-50° C., the mixture was cooled to 0-30° C. for stirring and crystallization, was filtered and was dried under vacuum at 50° C. to obtain 1.1 g of the product with the yield of 93.0%, and the X-ray powder diffraction pattern, the infrared spectrogram, the thermogravimetric analysis graph (TG) and the differential scanning calorimetry curve graph (DSC) are respectively shown in
Embodiment 3: Preparation of the Crystal Form A of the Monomethanesulfonate of the Compound Shown in Formula I
(40) 0.5 g of the compound shown in formula I was added into 10 ml of dichloromethane, the mixture was stirred until the solution is clear, prepared methanesulfonic acid (90 mg of methanesulfonic acid may be dissolved into 2.5 ml of dichloromethane) was dropwise added at the controlled temperature of 30-50° C., the mixture was cooled to 0-30° C. for stirring and crystallization, was filtered and was dried under vacuum at 50° C. to obtain 500 mg of the product with the yield of 84.7%, and the X-ray powder diffraction pattern and the infrared spectrogram were within an error range compared to embodiment 2.
Embodiment 4: Preparation of a Crystal Form B of the Monomethanesulfonate of the Compound Shown in Formula I
(41) 20 g of the compound shown in formula I was added into 400 ml of acetone, the mixture was heated until refluxing, methanesulfonic acid (3.6 g of methanesulfonic acid) was dropwise added, the mixture was cooled to 0-30° C., was stirred and crystallized for 4 h at controlled temperature, was filtered, and was dried under vacuum at 50° C. to obtain 21.6 g of the product with the yield of 91.5%. The X-ray powder diffraction pattern, the infrared spectrogram, the thermogravimetric analysis graph (TG) and the differential scanning calorimetrycurve graph (DSC) are respectively shown in
Example 5: Preparation of the Crystal Form B of the Monomethanesulfonate of the Compound Shown in Formula I
(42) 500 g of the compound shown in formula I was added into 10 L of acetone, the mixture was heated until refluxing, methanesulfonic acid (90.9 g of methanesulfonic acid) was dropwise added, the mixture was cooled to 0-30° C., was stirred and crystallized for 4 h at controlled temperature, was filtered, and was dried under vacuum at 50° C. to obtain 550 g of the product with the yield of 93.0%, and the X-ray powder diffraction pattern and the infrared spectrogram were within an error range compared to embodiment 4.
Example 6: Preparation of the Crystal Form B of the Monomethanesulfonate of the Compound Shown in Formula I
(43) 30 g of the compound shown in formula I was added into 300 ml of acetonitrile, the mixture was heated until refluxing, methanesulfonic acid (5.5 g of methanesulfonic acid) was dropwise added, the mixture was cooled to 0-30° C., was stirred and crystallized for 4 h at controlled temperature, was filtered, and was dried under vacuum at 50° C. to obtain 31 g of the product with the yield of 87.3%, and the X-ray powder diffraction pattern and the infrared spectrogram were within an error range compared to embodiment 4.
Effect Embodiment: Properties of the Crystal Forms A and B of the Monomethanesulfonate of the Compound Shown in Formula I
(44) 1. Stability Differential Scanning Calorimetry (DSC) Test
(45) Instrument: NETZSCH DSC 204 type differential thermal analyzer
(46) Rate of temperature rise: 10.00° C./min
(47) The result shows that the crystal forms A and B of the monomethanesulfonate of the compound shown in formula I have DSC graphs basically shown in
(48) 2. Crystal Influence Factor Test
(49) Samples of the crystal forms A and B of the monomethanesulfonate of the compound shown in formula I were exposed to high-temperature, high-humidity and illumination conditions for 15 days respectively, and the results showed that the crystal form A of the monomethanesulfonate was converted to the crystal form B of the monomethanesulfonate at high temperature and high humidity.
(50) 3. Accelerated Lofting Test
(51) A sample of the crystal form B of the monomethanesulfonate of the compound shown in formula I was placed in a petri dish and was sampled and tested at 0 hour, 1 month, 2 months, 3 months, and 6 months respectively at a temperature of 40±2° C. and a relative humidity of 75%±5%, with the results shown in Table 1:
(52) TABLE-US-00001 TABLE 1 Accelerated Lofting Test of the Crystal Form B of Monomethanesulfonate of the Compound Shown in Formula I Investigation Standard Time (month) items limit 0 1 2 3 6 Appearance White to Light Light Light Light Light faint yellow yellow yellow yellow yellow yellow powder powder powder powder powder powder Maximum ≤2.50 1.62 1.87 1.42 1.62 1.61 individual impurity Total impurity ≤4.0% 2.55 3.12 2.72 2.72 2.74 Loss on drying ≤1.0 0.08 0.03 0.03 0.03 0.14 Methane- ≤15.0- 15.5 15.2 15.4 15.4 15.4 sulfonic 15.8% acid (%) Content (%) Should 80.5 82.2 82.3 79.5 80.8 not be less than 78.0%
(53) The above experiments proved that in the accelerated lofting experiment of the crystal form B of the monomethanesulfonate of the compound shown in formula I, all investigation items have no obvious change; and meanwhile, the X-ray powder diffraction pattern (
(54) 4. Long-Term Lofting Experiments
(55) A sample of the crystal form B of the monomethanesulfonate of the compound shown in formula I was placed in a petri dish under the conditions of the temperature being 25±5° C. and the relative humidity being 60%±10% and was sampled and tested at 0 hour, 3 months, and 6 months respectively, with the results shown in Table 2:
(56) TABLE-US-00002 TABLE 2 Long-term Lofting Experiments of the Crystal Form B of Monomethanesulfonate of the Compound Shown in Formula I Time (month) Investigation items Standard limit 0 3 6 Appearance White to faint Yellow Yellow Yellow yellow powder powder powder powder Maximum individual ≤2.50 1.62 1.65 1.48 impurity Total impurity ≤4.0% 2.55 2.78 2.50 Loss on diying ≤1.0 0.08 0.08 0.6 Methanesulfonic acid (%) ≤15.0-15.8% 15.5 15.4 15.4 Content (%) Should not be 80.5 80.0 82.3 less than 78.0%
(57) The above experiments proved that in the long-term lofting experiment of the crystal form B of the monomethanesulfonate of the compound shown in formula I, all investigation items have no obvious change; and meanwhile, the X-ray powder diffraction pattern (
(58) From the above results, it can be seen that in the accelerated lofting test (with the temperature of 40±2° C. and the relative humidity of 75%±5%) and the long-term lofting test (with the temperature of 25±5° C. and the relative humidity of 60%±10%), the crystal form, purity, and relative impurity of the crystal form B of the monomethanesulfonate of the compound shown in formula I involved in the present invention are not changed greatly, indicating the good stability of the crystal form B of the monomethanesulfonate of the compound shown in formula I.