CN117327055A - Crystal form of EGFR tyrosine kinase inhibitor and preparation method and application thereof - Google Patents
Crystal form of EGFR tyrosine kinase inhibitor and preparation method and application thereof Download PDFInfo
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- CN117327055A CN117327055A CN202210719142.8A CN202210719142A CN117327055A CN 117327055 A CN117327055 A CN 117327055A CN 202210719142 A CN202210719142 A CN 202210719142A CN 117327055 A CN117327055 A CN 117327055A
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Abstract
本发明涉及一种EGFR酪氨酸激酶抑制剂的晶型及其制备方法和用途。具体而言，本发明涉及式(I)所示化合物的A晶型和B晶型，以及它们的制备方法和用途。本发明提供的晶型具有良好的引湿性和稳定性，有利于制备成药物用于临床治疗与EGFR外显子20突变相关的疾病特别是非小细胞肺癌。 The present invention relates to a crystal form of an EGFR tyrosine kinase inhibitor and its preparation method and use. Specifically, the present invention relates to crystal form A and form B of the compound represented by formula (I), as well as their preparation methods and uses. The crystal form provided by the invention has good hygroscopicity and stability, and is beneficial to be prepared into medicine for clinical treatment of diseases related to EGFR exon 20 mutations, especially non-small cell lung cancer.
Description
Technical Field
The invention relates to a novel crystal form of an EGFR tyrosine kinase inhibitor, a preparation method and medical application thereof.
Background
The compound 2- ((5-acrylamido-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -4- (1-methoxy-1H-indol-3-yl) pyrimidine-5-carboxylic acid isopropyl succinate (I) is disclosed in patent application WO2021018017A1 and is a small molecule EGFR/HER2Exon20 insertion mutation inhibitor, and the activation of a downstream signal channel is blocked by inhibiting the activity of EGFR or HER2Exon20 insertion mutants, so that the purpose of inhibiting tumor growth is achieved. The compound serving as a small molecule inhibitor for targeting EGFR/HER2Exon20 insertion mutation has the advantages of definite target mechanism, sufficient preclinical verification, good medicinal property, good safety, low production cost and the like, and is expected to become a new treatment choice for advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR/HER2Exon20 insertion mutation.
Drug polymorphism refers to the presence of two or more different crystal morphologies of the pharmaceutically active ingredient (API). Compared with other states such as amorphous state or liquid state, the crystal has obvious physical and chemical properties and advantages of process treatment, has excellent physical and chemical stability, can effectively remove impurity components, and has excellent processability and flowability. These advantages have a positive impact on both the quality of the drug and the process.
The invention adopts various crystallization means and crystallization conditions to find out the possible polymorphic form of the API, and determines the dominant pharmaceutical crystal form from the aspects of crystallinity, stability, hygroscopicity and processability.
Disclosure of Invention
The invention examines various crystallization conditions of compound 2- ((5-acrylamide-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -4- (1-methoxy-1H-indol-3-yl) pyrimidine-5-carboxylic acid isopropyl succinate (I) to obtain two crystallization products, and X-ray powder diffraction and DSC detection are carried out on the obtained crystallization products, so that novel crystals with good crystallinity, solubility, bioavailability and stability are found.
It is therefore an object of the present invention to provide form A of a compound of formula (I) characterized in that the X-ray powder diffraction pattern obtained using Cu-K alpha radiation comprises characteristic peaks at diffraction angles 2 theta of 5.250 DEG + -0.2 DEG 8.867 DEG + -0.2 DEG 13.077 DEG + -0.2 DEG 14.201 DEG + -0.2 DEG 16.002 DEG + -0.2 DEG 17.612 DEG + -0.2 DEG 19.507 DEG + -0.2 DEG 22.473 DEG + -0.2 DEG,
in a preferred embodiment, form a of the compound of formula (I) is characterized in that the X-ray powder diffraction pattern expressed in terms of 2Θ using Cu-ka radiation comprises characteristic peaks at 2Θ diffraction angles of 5.250 ° ± 0.2 °, 7.932 ° ± 0.2 °, 8.867 ° ± 0.2 °, 10.393 ° ± 0.2 °, 13.077 ° ± 0.2 °, 14.201 ° ± 0.2 °, 16.002 ° ± 0.2 °, 17.612 ° ± 0.2 °, 19.507 ° ± 0.2 °, 19.821 ° ± 0.2 °, 20.021 ° ± 0.2 °, 22.473 ° ± 0.2 °.
In another preferred embodiment, the form A of the compound of formula (I) is characterized in that the X-ray powder diffraction pattern expressed in terms of 2 theta using Cu-K alpha radiation comprises characteristic peaks at 2 theta diffraction angles of 5.250 DEG + -0.2 DEG 7.932 DEG + -0.2 DEG 8.542 DEG + -0.2 DEG 8.867 DEG + -0.2 DEG 10.393 DEG + -0.2 DEG 11.633 DEG + -0.2 DEG 12.106 DEG + -0.2 DEG 13.077 DEG + -0.2 DEG 14.201 DEG + -0.2 DEG 16.002 DEG + -0.2 DEG 17.612 DEG + -0.2 DEG 18.864 DEG + -0.2 DEG 19.507 DEG + -0.2 DEG 19.821 DEG + -0.2 DEG 20.021 DEG + -0.2 DEG 21.042 DEG + -0.2 DEG 22.473 DEG + -0.2 DEG 25.575 DEG + -0.2 DEG 26.390 DEG + -0.2 deg.
In another preferred embodiment, form a of the compound of formula (I) is characterized by the corresponding values of 2θ angle and intensity in the X-ray powder diffraction pattern obtained using Cu-ka radiation as follows:
in another preferred embodiment, form a of the compound of formula (I) is characterized by an X-ray powder diffraction pattern expressed in terms of 2θ using Cu-ka radiation as shown in figure 1.
In another preferred embodiment, the compound of formula (I) in form A is characterized by a DSC profile having an endothermic peak at 144.08.+ -. 3 ℃.
It is another object of the present invention to provide form B of the compound of formula (I) characterized in that the X-ray powder diffraction pattern obtained using Cu-ka radiation comprises characteristic peaks at diffraction angles 2θ of 3.976 ° ± 0.2 °, 7.258 ° ± 0.2 °, 10.007 ° ± 0.2 °, 14.462 ° ± 0.2 °, 15.528 ° ± 0.2 °, 16.192 ° ± 0.2 °, 21.003 ° ± 0.2 ° 24.277 ° ± 0.2 °.
In a preferred embodiment, form B of the compound of formula (I) is characterized in that the X-ray powder diffraction pattern using Cu-ka radiation comprises characteristic peaks at diffraction angles 2θ of 7.258 ° ± 0.2 °, 10.007 ° ± 0.2 °, 10.450 ° ± 0.2 °, 14.462 ° ± 0.2 °, 15.528 ° ± 0.2 °, 16.192 ° ± 0.2 °, 18.651 ° ± 0.2 °, 20.353 ° ± 0.2 °, 21.003 ° ± 0.2 °, 24.277 ° ± 0.2 °.
In another preferred embodiment, form B of the compound of formula (I) is characterized in that the X-ray powder diffraction pattern obtained using Cu-ka radiation comprises characteristic peaks at 2θ diffraction angles of 3.976 ° ± 0.2 °, 7.258 ° ± 0.2 °, 10.007 ° ± 0.2 °, 10.450 ° ± 0.2 °, 14.462 ° ± 0.2 °, 14.891 ° ± 0.2 °, 15.105 ° ± 0.2 °, 15.528 ° ± 0.2 °, 16.192 ° ± 0.2 °, 16.736 ° ± 0.2 °, 18.651 ° ± 0.2 °, 20.353 ° ± 0.2 °, 21.003 ° ± 0.2 °, 21.420 ° ± 0.2 °, 24.277 ° ± 0.2 °, 24.552 ° ± 0.2 °.
In another preferred embodiment, the form B of the compound of formula (I) is characterized by the corresponding values of 2θ angle and intensity in an X-ray powder diffraction pattern using Cu-ka radiation as follows:
in another preferred embodiment, the form B of the compound of formula (I) is characterized by an X-ray powder diffraction pattern in terms of 2θ angles using Cu-ka radiation as shown in fig. 7.
In another preferred embodiment, form B of the compound of formula (I) is characterized by a DSC profile having an endothermic peak at 114.45 ±3 ℃.
The invention also provides a preparation method of the A crystal form of the compound shown in the formula (I), which comprises the following steps:
1) Adding any crystal form or amorphous compound of formula (I) into a good solvent for dissolution;
2) Adding a poor solvent into the solution obtained in the step 1), stirring for crystallization or cooling for crystallization; or, directly cooling and crystallizing the solution obtained in the step 1);
3) And (3) filtering and drying the crystal obtained in the step (2) to obtain the A crystal form.
In a preferred embodiment, the process for the preparation of form a according to the present invention comprises the steps of:
1) Adding any crystal form or amorphous compound of formula (I) into a good solvent for dissolution;
2) Adding a poor solvent into the solution obtained in the step 1), stirring for crystallization or cooling for crystallization
3) And (3) filtering and drying the crystal obtained in the step (2) to obtain the A crystal form.
In another preferred embodiment, the process for the preparation of form a according to the present invention comprises the steps of:
1) Adding any crystal form or amorphous compound of formula (I) into a good solvent for dissolution;
2) Cooling and crystallizing the solution obtained in the step 1);
3) And (3) filtering and drying the crystal obtained in the step (2) to obtain the A crystal form.
In a preferred embodiment, the process for the preparation of form A according to the present invention, wherein the good solvent is selected from the group consisting of alcoholic solvents, ketone solvents and ethereal solvents, preferably C 1 -C 4 Alcohol solvents, more preferably methanol, ethanol, isopropanol, n-butanol, trifluoroethanol; the ketone solvent is preferably acetone and butanone; the ether solvent is preferably 1, 4-dioxane or tetrahydrofuran; preferably, the good solvent is selected from the group consisting of methanol, ethanol, acetone, butanone, tetrahydrofuran, more preferably from the group consisting of ethanol, acetone, and tetrahydrofuran.
In a preferred embodiment, the process for the preparation of form a according to the present invention, wherein the poor solvent is selected from the group consisting of an alkane solvent, an ether solvent, an ester solvent, an aromatic hydrocarbon solvent; the alkane solvent is preferably n-heptane, n-hexane, cyclohexane and methylcyclohexane, the ether solvent is preferably petroleum ether, diethyl ether and methyl tertiary butyl ether, the ester solvent is preferably ethyl acetate, isopropyl acetate and butyl acetate, and the aromatic hydrocarbon solvent is preferably toluene; preferably, the poor solvent is selected from petroleum ether, n-heptane, cyclohexane, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, butyl acetate, more preferably from n-heptane and cyclohexane.
In a preferred embodiment, the process for the preparation of form a according to the present invention, wherein the good solvent is selected from ethanol, acetone and tetrahydrofuran and the poor solvent is selected from n-heptane and cyclohexane.
In another preferred embodiment, the process for preparing form a according to the present invention, wherein the good solvent is ethanol and the poor solvent is n-heptane.
In another preferred embodiment, the process for preparing form a according to the present invention, wherein the good solvent is tetrahydrofuran and the poor solvent is cyclohexane.
In a preferred embodiment, the process for the preparation of form a according to the present invention, wherein the volume ratio of good solvent to poor solvent is from 1:1 to 1:30, preferably from 1:2 to 1:5.
In a preferred embodiment, the process for the preparation of form a according to the present invention, wherein the dissolution in step 1) is carried out at a temperature of 0 to 100 ℃, preferably at a temperature of 20 to 80 ℃, more preferably at a temperature of 60 to 80 ℃.
In a preferred embodiment, the process for the preparation of form a according to the present invention, wherein the crystallization in step 2) is carried out at a temperature of-20 to 40 ℃, preferably at a temperature of 0 to 30 ℃, more preferably at a temperature of 10 to 20 ℃.
The invention also provides a preparation method of the first B crystal form of the compound shown in the formula (I), which comprises the following steps:
1) Adding any crystal form or amorphous compound of formula (I) into a good solvent for dissolution;
2) Adding a poor solvent into the solution obtained in the step 1), and stirring for crystallization;
3) And (3) filtering and drying the crystal obtained in the step (2) to obtain the B crystal form.
The invention also provides a second preparation method of the B crystal form of the compound shown in the formula (I), which comprises the following steps:
1) Adding any crystal form or amorphous compound of formula (I) into a good solvent for pulping;
2) And (3) filtering and drying the crystal obtained in the step (1) to obtain the B crystal form.
In one preferenceIn the first and second preparation methods of form B according to the present invention, wherein the good solvent is a mixed solvent of an organic solvent selected from the group consisting of an alcoholic solvent, an ester solvent, a ketone solvent and a nitrile solvent, and water, and the alcoholic solvent is preferably C 1 -C 4 Alcohol solvents, more preferably methanol, ethanol, isopropanol, n-butanol and trifluoroethanol, ketone solvents, preferably acetone and butanone, nitrile solvents, preferably acetonitrile, and ester solvents, preferably ethyl acetate, isopropyl acetate and butyl acetate; preferably, the organic solvent is selected from methanol, ethanol, acetone, acetonitrile, ethyl acetate.
In a preferred embodiment, the first and second preparation methods of form B according to the present invention, wherein the volume ratio of organic solvent to water in the mixed solvent of organic solvent and water is 100:0.1 to 1:100, preferably 100:1 to 1:10, more preferably 20:1 to 1:10.
In a preferred embodiment, the first process for the preparation of form B according to the present invention, wherein the poor solvent is selected from the group consisting of an alkane solvent, preferably n-heptane, n-hexane, cyclohexane, methylcyclohexane; preferably, the poor solvent is selected from n-heptane.
In a preferred embodiment, the first process for the preparation of form B according to the present invention, wherein the volume ratio of good solvent to poor solvent is from 1:1 to 1:30, preferably from 1:4 to 1:5.
In another preferred embodiment, the first preparation method of form B according to the present invention, wherein the good solvent is C 1 -C 4 A mixed solvent of alcohol and water, preferably a mixed solvent of methanol and water or a mixed solvent of ethanol and water; wherein the volume ratio of the alcohol to the water is preferably 1:5-1:20, preferably 1:7-1:20; the poor solvent is n-heptane; preferably, the volume ratio of the good solvent to the poor solvent is 1:4 to 1:5.
In another preferred embodiment, the first preparation of form B according to the present invention, wherein the dissolution in step 1) is performed at a temperature of 0 to 100 ℃, preferably at a temperature of 20 to 80 ℃, more preferably at a temperature of 20 to 60 ℃.
In another preferred embodiment, the first preparation process of form B according to the present invention, wherein the crystallization in step 2) is performed at a temperature of-20 to 30 ℃, preferably at a temperature of 0 to 20 ℃, more preferably at 10 to 20 ℃.
In another preferred embodiment, the second process for the preparation of form B according to the invention, wherein the beating in step 1) is carried out at a temperature of-20 to 100 ℃, preferably at a temperature of 0 to 20 ℃.
In another preferred embodiment, the second process for preparing form B according to the present invention wherein the good solvent is C 1 -C 4 The mixed solvent of alcohol and water is preferably a mixed solvent of methanol and water or a mixed solvent of ethanol and water, wherein the volume ratio of the alcohol to the water is preferably 1:5-1:20, and preferably 1:7-1:20.
In another preferred embodiment, the second process for preparing form B according to the present invention, wherein the good solvent is water saturated ethyl acetate.
In another preferred embodiment, according to the second preparation method of form B of the present invention, the good solvent is a mixed solvent of acetone and water, wherein the volume ratio of acetone to water is preferably 1:10.
In another preferred embodiment, according to the second preparation method of form B of the present invention, the good solvent is a mixed solvent of acetonitrile and water, wherein the volume ratio of acetonitrile to water is preferably 1:10.
The invention further relates to a pharmaceutical composition which contains the preparation method of the A crystal form of the compound shown in the formula (I) as an active ingredient and a pharmaceutically acceptable carrier.
The invention further relates to a pharmaceutical composition which contains the preparation method of the B crystal form of the compound shown in the formula (I) as an active ingredient and a pharmaceutically acceptable carrier.
The invention further relates to the use of the form a of the compounds of formula (I) according to the invention or of pharmaceutical compositions containing them for the preparation of a medicament for the treatment of diseases associated with mutations in exon20 of EGFR, in particular non-small cell lung cancer.
The invention further relates to the use of the form B of the compounds of formula (I) according to the invention or of pharmaceutical compositions containing them for the preparation of a medicament for the treatment of diseases associated with mutations in exon20 of EGFR, in particular non-small cell lung cancer.
The compounds of formula (I) according to the invention can be synthesized by methods known to the person skilled in the art by means of inverse synthetic analysis and by conventional methods of preparation. See in particular the examples of the invention.
In addition, the compounds of formula (I) used in the present invention may be in any crystalline or amorphous form.
The term "pharmaceutically acceptable" as used herein is useful in preparing a pharmaceutical composition that is generally safe, neither biologically nor otherwise undesirable, and is acceptable for veterinary and human pharmaceutical use.
As used herein, "carrier" refers to a diluent, adjuvant, or excipient with which the compound is administered. Pharmaceutically acceptable carriers can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, rapeseed oil, and the like. Pharmaceutically acceptable carriers may also be physiological saline, gum arabic, gelatin, starch paste, talc, keratin, silica gel, urea, etc. In addition, adjuvants, stabilizers, thickeners, lubricants, colorants, and the like may also be used.
It will be appreciated by those skilled in the art that the pharmaceutical compositions of the present invention may be formulated into various preparation forms well known in the art, such as oral dosage forms (powders, tablets, capsules, soft capsules, liquid medicines, syrups, elixirs, powders, sachets, granules), or topical application preparations (creams, ointments, lotions, gels, balsams, plasters, pastes, sprays, aerosols, etc.), or injection preparations (solutions, suspensions, emulsions), depending on the particular mode of administration. Among the pharmaceutical compositions of the invention, mention may be made in particular of those suitable for oral, parenteral (intravenous or subcutaneous) administration, for example, tablets or dragees, sublingual tablets, gelatine capsules, lozenges, suppositories, creams, ointments, skin gels, injectable preparations, drinkable suspensions and the like.
The pharmaceutical composition according to the present invention may comprise a pharmaceutically acceptable carrier, adjuvant or diluent, for example: fillers, disintegrants, lubricants, suspending agents, binders, sweeteners, flavoring agents, preservatives, matrices, and the like. Fillers such as: starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose, and the like; disintegrants such as: starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, crosslinked sodium carboxymethyl cellulose, and the like; lubricants such as: magnesium stearate, sodium lauryl sulfate, talc, silica, and the like; suspending agents such as: polyvinylpyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methylcellulose, and the like; binders such as starch slurry, polyvinylpyrrolidone, hydroxypropyl methylcellulose, and the like. The compositions of the present invention may be formulated so as to provide quick, sustained or slow release of the active ingredient after administration by the patient by employing any of the methods known in the art.
The pharmaceutical compositions of the invention are administered to an individual animal such as a mammal (rat, mouse, domesticated animal or human) by a variety of routes, all of which are contemplated, e.g., oral, topical, rectal or intravenous, intramuscular, transdermal, intrathecal, epidural or intraventricular injection.
The dosage of the active ingredient of the present invention may vary depending on the individual condition and weight, the nature and severity of the condition, the pharmaceutical form, the route of administration and the period of administration, and may also be selected by those skilled in the art. The dosage may vary between 1-1500 mg/day, and may be administered in a single dose per day or divided doses per day.
By X-ray powder diffraction (XRPD), differential scanning thermal analysis (DSC), hygroscopicity analysis (DVS), infrared spectroscopy (IR) pattern. The various forms described in the present invention were assayed and studied. The crystals of the compound of formula (I) prepared according to the process of the present invention have good stability, solubility and bioavailability and can be advantageously used as pharmaceutically active ingredient.
The present invention will be further elucidated below in connection with the drawings and the specific embodiments, but it will be understood that they are merely illustrative and do not in any way limit the scope of the invention.
Drawings
FIG. 1 is an XRPD pattern for form A of the invention prepared in example 2, with peak numbers 1 to 30 corresponding to the peak numbers in Table 1 in example 2.
FIG. 2 is a TGA spectrum of form A of the present invention prepared in example 2.
FIG. 3 is a DSC chart of form A of the present invention prepared in example 2.
FIG. 4 is a DVS spectrum of form A of the present invention prepared in example 2.
FIG. 5 is an isothermal adsorption curve of form A of the present invention as prepared in example 2.
FIG. 6 is an infrared spectrum of the form A of the present invention prepared in example 2.
Fig. 7 is an XRPD pattern of form B of the invention made in example 5, wherein peak numbers 1 to 38 correspond to peak numbers in table 2 in example 5.
FIG. 8 is a TGA spectrum of form B of the present invention prepared in example 5.
FIG. 9 is a DSC chart of form B of the present invention prepared in example 5.
FIG. 10 is a DVS spectrum of form B of the present invention prepared in example 5.
FIG. 11 is an isothermal adsorption curve of form B of the present invention as prepared in example 5.
FIG. 12 is an infrared spectrum of the B crystal form of the present invention obtained in example 5.
FIG. 13 is a graph comparing the stability XRPD patterns of form B of the invention obtained in test example 2 under normal, long-term and accelerated conditions.
FIG. 14 is a TGA comparison of the stability of form B of the present invention under conventional, long term and accelerated conditions, as prepared in test example 2.
Detailed Description
The present invention will be explained in more detail with reference to the following examples, which are only for illustrating the technical aspects of the present invention and do not limit the spirit and scope of the present invention.
Experimental instrument
1. X-ray powder diffraction (XRPD) method
Instrument model: bruker D2 Phaser/209918
Rays: cu-K alpha (30 kV,10 mA)
Scanning range: 4 ° -50 ° (2θ)
Step size: 0.02 ° (2. Theta.)
Scanning mode: 0.2 seconds/step
2. Differential scanning calorimetric analysis (DSC) method
Instrument model: TA Instruments Q200 DSC/DSC Q2000/2000-3196
Sweep gas: nitrogen gas
Scanning rate: 10 ℃/min, temperature range: 10-200deg.C
Nitrogen flow rate: 50mL/min
3. Thermogravimetric analysis (TGA) method
Instrument model: TA Instruments Q500 TGA/TGA Q50/0050-1847
Sweep gas: nitrogen gas
Scanning rate: 10 ℃/min, temperature range: 0-500 DEG C
Nitrogen flow rate: 40mL/min
4. Dynamic moisture adsorption (DVS) process
Instrument model: TA Instruments Q5000 TGA
Nitrogen flow rate: 10mL/min, humidity: 0 to 90 percent to 0 percent, and the temperature: 25 DEG C
5. Infrared spectroscopy (IR) method
Instrument model: bruker Tensor 27/Thermo IS10
Collection wavelength range: 400cm -1 Up to 4000cm -1
Resolution ratio: 4cm -1 。
The structure of the compound is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS), NMR positionMove by 10 -6 The units of (ppm) are given, NMR was performed using a Bruker dps400 nuclear magnetic instrument with deuterated dimethyl sulfoxide (DMSO-d) 6 ) The internal standard is Tetramethylsilane (TMS).
Mass Spectrometry (MS) was determined using an agilent 1260 lnfinityl/G6125B (ESI) mass spectrometer (manufacturer: agilent).
Example 1: preparation of isopropyl 2- ((5-acrylamido-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -4- (1-methoxy-1H-indol-3-yl) pyrimidine-5-carboxylate succinate (I)
Step 1: preparation of isopropyl 2- ((4-fluoro-2-methoxy-5-nitrophenyl) amino) -4- (1-methoxy-1H-indol-3-yl) pyrimidine-5-carboxylate (b)
Under nitrogen atmosphere, 1, 4-dioxane (480 mL, 10V) was added to the reaction flask, isopropyl 2-chloro-4- (1-methoxy-1H-indol-3-yl) pyrimidine-5-carboxylate (a) (48.00 g,138.8 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (H) (25.87 g,139.0 mmol) were added sequentially under stirring, and after dissolving, tsOH.H was added 2 O (82.81 g,277.63 mmol), was heated to 100deg.C and reacted for 2h. The reaction solution is cooled to room temperature, saturated sodium carbonate aqueous solution is dripped to adjust the pH to 8-9, a large amount of brown solid is precipitated from the solution, the solution is filtered, filter cakes are washed by purified water, the filter cakes are collected and dried to constant weight at the temperature of 40-50 ℃ to obtain 58g of compound b as off-white solid.
Step 2: preparation of isopropyl 2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino) -4- (1-methoxy-1H-indol-3-yl) pyrimidine-5-carboxylate (c)
DMSO (560 mL, 10V) was added to the flask under nitrogen, and compound b (56 g,113.0 mmol), N, N, N' -trimethylethylenediamine (13.86 g,135.6 mmol) and DIPEA (21.91 g,169.5 mmol) were added in this order with stirring, and the temperature was raised to 90℃and the reaction was continued for 2 hours. The reaction solution was cooled to room temperature, purified water (1700 mL, 30V) was added dropwise, a red solid was precipitated, filtered, and the cake was washed with purified water and dried to constant weight at 40-50℃to give 57g of compound c as a red solid.
Step 3: preparation of isopropyl 2- ((5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -4- (1-methoxy-1H-indol-3-yl) pyrimidine-5-carboxylate (d)
Into a reaction flask were added compound c (53 g,26.0 mmol) and methanol (1000 mL, 20V), NH was added with stirring 4 Cl aqueous solution (39.3 g of ammonium chloride is dissolved in 200mL of purified water), the temperature is reduced to-10-0 ℃, 48g of iron powder is added, and the reaction is carried out for 1h at room temperature after the addition. The reaction solution was filtered, the filter cake was washed with methanol, and the filtrate was collected and concentrated under reduced pressure to give 50g of compound d as a brown solid.
Step 4: preparation of isopropyl 2- ((5-acrylamido-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -4- (1-methoxy-1H-indol-3-yl) pyrimidine-5-carboxylate (e)
DCM (1000 mL, 20V) and compound d (50 g,91.3 mmol) were added to the reaction flask, the temperature was reduced to-5-0deg.C, and acryloyl chloride (13.92 g,109.6 mmol) was slowly added dropwise under stirring, and the reaction was carried out at-5-0deg.C for 2h. Sodium trifluoroacetate (6.21 g,45.7 mmol), et were added sequentially 3 N (36.96 g,365.3 mmol) was added, the temperature was raised to 10-15℃and the reaction was continued for 12h. At the end of the reaction, the reaction solution was poured into purified water (3000 mL, 60V) and stirred at 15℃for 30min. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure and dried to constant weight at 40-50℃to give 40g of compound e.
MS-ESI：[M+H] + Calculated values: 602.30, found: 602.20.
1 H-NMR(400MHz,DMSO-d 6 ):δ10.16(s,1H),8.82(s,1H),8.79(s,H),8.72(s,1H),8.45(s,1H),7.73(s,1H),7.51(d,J＝8.0Hz,1H),7.24(t,J＝7.6Hz,1H),7.08～7.05(m,2H),6.46～6.31(m,1H),6.27～6.26(m,1H),5.79～5.76(m,1H),4.98～4.95(m,1H),4.13(s,3H),3.82(s,3H),2.89～2.86(m,2H),2.73(s,3H),2.32～2.29(m,2H),2.20(s,6H),1.11(d,J＝6.0Hz,6H)。
step 5: preparation of isopropyl 2- ((5-acrylamido-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -4- (1-methoxy-1H-indol-3-yl) pyrimidine-5-carboxylate succinate (I)
600mL of the mixed solvent (EtOAc/MeOH=20/1), compound e (40 g,66.5 mmol) were added to the reaction flask, warmed to 70℃and stirred at constant temperature for 0.5h. Succinic acid (8 g,66.5 mmol) was added and the reaction was incubated for 0.5h. Cooling to room temperature, and stirring at room temperature for 12h. The mixture was filtered under reduced pressure, and the filter cake was washed with a mixed solvent (EtOAc/meoh=20/1) and dried under vacuum at 40 ℃ to give 43g of the compound of formula (I).
MS-ESI：[M+H-C 4 H 6 O 4 ] + Calculated values: 602.30, found: 602.20.
1 H-NMR(400MHz,MeOD-d 4 ):δ8.80(s,1H),8.78(s,1H),8.24(s,1H),7.80(d,J＝8.1Hz,1H),7.50(d,J＝8.2Hz,1H),7.25(t,J＝7.3Hz,1H),7.11(t,J＝7.2Hz,1H),6.94(s,1H),6.59～6.39(m,2H),5.83(dd,J＝9.6,2.2Hz,1H),5.07～4.97(m,1H),4.17(s,3H),3.97(s,3H),3.35(t,J＝5.8Hz,2H),3.09(t,J＝5.8Hz,2H),2.72(s,6H),2.68(s,3H),2.52(s,4H),1.12(d,J＝6.3Hz,6H)。
example 2: preparation of form A
120mg of the compound of formula (I) prepared in example 1 is added with 4mL of ethanol, heated to 60 ℃ for dissolution, then 20mL of n-heptane is added dropwise, the temperature is reduced to 10-20 ℃ for stirring for 0.5-1 hour, filtration is carried out, and a filter cake is dried under reduced pressure for 12 hours at 40-50 ℃ to obtain 72mg of white powder with the yield of 60.0%.
The X-ray powder diffraction pattern of the product is shown in figure 1, and the crystal form is defined as a crystal form A. The X-ray diffraction data are shown in table 1 below. TGA shows a decomposition temperature of about 175 ℃ (see fig. 2), DSC shows a melting point of about 144.08 ℃ (see fig. 3), DVS shows a slight hygroscopicity with isothermal adsorption curves (see fig. 4 and 5), IR infrared spectra (see fig. 6).
Table 1 corresponding values of 2θ and intensity for A crystalline forms
Example 3: preparation of form A
60mg of the compound of the formula (I) prepared in example 1 is added with 2mL of acetone, dissolved at 60 ℃, cooled to 10-20 ℃ and stirred for 0.5-1 hour, filtered, and the filter cake is dried for 12 hours at 40-50 ℃ under reduced pressure to obtain 28mg of white powder with the yield of 46.7%.
The X-ray powder diffraction pattern and DSC pattern of the product are compared, and the product is determined to be the A crystal form of the compound of the formula (I).
Example 4: preparation of form A
210mg of the compound of formula (I) obtained in example 1 was added, 10.5ml of tetrahydrofuran was heated to 60℃for dissolution, 21ml of cyclohexane was then added dropwise, the temperature was lowered to 10-20℃for stirring for 0.5-1 hour, filtration was carried out, and the cake was dried under reduced pressure at 40-50℃for 12 hours to obtain 110mg of a white powder in 52.4% yield.
The X-ray powder diffraction pattern and DSC pattern of the product are compared, and the product is determined to be the A crystal form of the compound of the formula (I).
Example 5: preparation of form B
240mg of the compound of formula (I) prepared in example 1 is added with 8mL of ethanol and 0.4mL of water, heated to 60 ℃ for dissolution, then 40mL of n-heptane is added dropwise, the temperature is reduced to 10-20 ℃ for stirring for 0.5-1 hour, filtration and drying of a filter cake at 40-50 ℃ under reduced pressure for 12 hours, thus obtaining 160mg of white powder with a yield of 66.7%.
The X-ray powder diffraction pattern of this product is shown in fig. 7, and this form is defined as form B. The X-ray diffraction data are shown in table 2 below. TGA shows a dehydration temperature of about 70 ℃, a decomposition temperature of 174 ℃ (see fig. 8), DSC shows a melting point of about 114.45 ℃ (see fig. 9), DVS and isothermal adsorption curves show a slight hygroscopicity (see fig. 10 and 11), IR infrared spectra (see fig. 12).
Table 2 corresponding values of 2θ and intensity for crystal form 2B
Example 6: preparation of form B
100mg of the compound of the formula (I) obtained in example 2 was added with 0.6ml of water, 4.2ml of methanol, stirred at room temperature for 5 days, filtered, and the cake was dried under reduced pressure at 40-50℃for 12 hours to obtain 60mg of a white powder with a yield of 60.0%.
The X-ray powder diffraction pattern and DSC pattern of the product are compared, and the compound is determined to be the B crystal form of the compound in the formula (I).
Example 7: preparation of form B
150mg of the compound of formula (I) obtained in example 2 was stirred at room temperature for 3 days by adding 3mL of water-saturated ethyl acetate, and centrifuged, and the obtained solid was dried at room temperature under vacuum overnight to obtain 135mg of white powder in a yield of 90.0%.
The X-ray powder diffraction pattern and DSC pattern of the product are compared, and the compound is determined to be the B crystal form of the compound in the formula (I).
Example 8: preparation of form B
90mg of the compound of formula (I) obtained in example 2 was added to a mixed solvent of 0.6mL of acetone and 6mL of water, stirred at 5℃for 5 days, centrifuged, and the obtained solid was dried at room temperature under vacuum overnight to obtain 20mg of a white powder in 23.3% yield.
The X-ray powder diffraction pattern and DSC pattern of the product are compared, and the compound is determined to be the B crystal form of the compound in the formula (I).
Example 9: preparation of form B
90mg of the compound of formula (I) produced in example 2 was added to a mixed solvent of 0.6mL of acetonitrile and 6mL of water, stirred at room temperature for 5 days, centrifuged, and the obtained solid was dried at room temperature under vacuum overnight to give 40mg of white powder in 44.4% yield.
The X-ray powder diffraction pattern and DSC pattern of the product are compared, and the compound is determined to be the B crystal form of the compound in the formula (I).
Test example 1: adsorption and desorption experiments of moisture
Hygroscopicity is an important physical property of a drug substance, and directly affects the storage stability, processability and technical preparation process of the drug.
The experiment adopts a dynamic moisture adsorption instrument to examine the adsorption and desorption capacities of moisture at the relative humidity of 0-80% at the temperature of 25 ℃ so as to determine the moisture absorption performance of the two crystal forms.
The following table is the definition and scope of hygroscopicity of chinese pharmacopoeia 2020 edition after equilibration of the drug at 25 ℃ ± 1 ℃,80% ± 2% rh.
| Deliquescence of | Absorb sufficient moisture to form a liquid |
| Has very good moisture permeability | The weight gain of the wet-induced hair is not less than 15 percent |
| Having moisture-permeability | The weight gain of the wet-induced weight is less than 15 percent but not less than 2 percent |
| Slightly moisture-absorbing property | The weight gain of the wet-drawing is less than 2 percent but not less than 0.2 percent |
| No or almost no hygroscopicity | The weight gain of the wet-induced weight is less than 0.2 percent |
The hygroscopicity results for form a and form B of the present invention are shown in table 3 below.
TABLE 3 results of hygroscopicity of form A and form B of the present invention
| Crystal form | Melting point DEG C | Moisture permeability |
| A | 141～145 | 80% RH, water absorption 0.27% |
| B | 106～116 | 80% RH, water absorption 0.25% |
The moisture absorption and desorption experiments show that the moisture absorption of the A crystal form and the B crystal form are respectively 0.27% and 0.25%, and the A crystal form and the B crystal form are slightly moisture absorption.
Test example 2: stability test of the B crystal form of the invention for the B crystal form, the stability test of the B crystal form is carried out for 10 days under three conditions of conventional (25 ℃ +/-2 ℃, sealed and light-proof), long-term (25 ℃ +/-2 ℃, 65%RH+/-10%RH, open and light-proof) and acceleration (40 ℃ +/-2 ℃, 75%RH+/-10%RH, open and light-proof). XRPD versus pattern for the three conditions is shown in fig. 13 and tga versus pattern is shown in fig. 14. From the results of the stability test, it was found that,
the crystal form B of the invention has no change of crystal form under three conditions and has excellent stability.
Claims (30)
1. Form A of the compound of formula (I), characterized in that the X-ray powder diffraction pattern obtained using Cu-K alpha radiation comprises characteristic peaks at 2 theta diffraction angles of 5.250 DEG + -0.2 DEG 8.867 DEG + -0.2 DEG 13.077 DEG + -0.2 DEG 14.201 DEG + -0.2 DEG 17.612 DEG + -0.2 DEG 19.507 DEG + -0.2 DEG 22.473 DEG + -0.2 DEG,
2. form a of the compound of formula (I) according to claim 1, characterized in that the X-ray powder diffraction pattern obtained using Cu-ka radiation comprises characteristic peaks at the 2-theta diffraction angles of 5.250 ° ± 0.2 °, 7.932 ° ± 0.2 °, 8.867 ° ± 0.2 °, 10.393 ° ± 0.2 °, 13.077 ° ± 0.2 °, 14.201 ° ± 0.2 °, 16.002 ° ± 0.2 °, 17.612 ° ± 0.2 °, 19.507 ° ± 0.2 °, 19.821 ° ± 0.2 °, 20.021 ° ± 0.2 °, 22.473 ° ± 0.2 °; preferably includes characteristic peaks at 2 theta diffraction angles of 5.250 ° ± 0.2 °, 7.932 ° ± 0.2 °, 8.542 ° ± 0.2 °, 8.867 ° ± 0.2 °, 10.393 ° ± 0.2 °, 11.633 ° ± 0.2 °, 12.106 ° ± 0.2 °, 13.077 ° ± 0.2 °, 14.201 ° ± 0.2 °, 16.002 ° ± 0.2 °, 17.612 ° ± 0.2 °, 18.864 ° ± 0.2 °, 19.507 ° ± 0.2 °, 19.821 ° ± 0.2 °, 20.021 ° ± 0.2 °, 21.042 ° ± 0.2 °, 22.473 ° ± 0.2 °, 25.575 ° ± 0.2 °, 26.390 ° ± 0.2 °.
3. Form a of the compound of formula (I) according to claim 1, characterized in that the X-ray powder diffraction pattern in terms of 2Θ angle obtained using Cu-ka radiation is shown in figure 1.
4. A form a of a compound of formula (I) according to any one of claims 1 to 3, characterized by a DSC profile having an endothermic peak at 144.08 ±3 ℃.
5. Form B of the compound of formula (I), characterized in that the X-ray powder diffraction pattern obtained using Cu-K alpha radiation comprises characteristic peaks at 2 theta diffraction angles of 7.258 DEG + -0.2 DEG, 10.007 DEG + -0.2 DEG, 14.462 DEG + -0.2 DEG, 15.528 DEG + -0.2 DEG, 16.192 DEG + -0.2 DEG, 21.003 DEG + -0.2 DEG, 24.277 DEG + -0.2 DEG,
6. form B of the compound of formula (I) according to claim 5, characterized in that the X-ray powder diffraction pattern obtained using Cu-ka radiation comprises characteristic peaks at the 2-theta diffraction angles of 7.258 ° ± 0.2 °, 10.007 ° ± 0.2 °, 10.450 ° ± 0.2 °, 14.462 ° ± 0.2 °, 15.528 ° ± 0.2 °, 16.192 ° ± 0.2 °, 18.651 ° ± 0.2 °, 20.353 ° ± 0.2 °, 21.003 ° ± 0.2 °, 24.277 ° ± 0.2 °; preferably includes characteristic peaks at 2 theta diffraction angles of 3.976 ° ± 0.2 °, 7.258 ° ± 0.2 °, 10.007 ° ± 0.2 °, 10.450 ° ± 0.2 °, 14.462 ° ± 0.2 °, 14.891 ° ± 0.2 °, 15.105 ° ± 0.2 °, 15.528 ° ± 0.2 °, 16.192 ° ± 0.2 °, 16.736 ° ± 0.2 °, 18.651 ° ± 0.2 °, 20.353 ° ± 0.2 °, 21.003 ° ± 0.2 °, 21.420 ° ± 0.2 °, 24.277 ° ± 0.2 ° and 24.552 ° ± 0.2 °.
7. Form B of the compound of formula (I) according to claim 5, characterized in that the X-ray powder diffraction pattern in terms of 2Θ angle using Cu-ka radiation is shown in fig. 7.
8. Form B of the compound of formula (I) according to any one of claims 5 to 7, characterized by its DSC profile having an endothermic peak at 114.45 ±3 ℃.
9. A process for the preparation of form a of a compound of formula (I) according to any one of claims 1 to 4, comprising the steps of:
1) Adding any crystal form or amorphous compound of formula (I) into a good solvent for dissolution;
2) Adding a poor solvent into the solution obtained in the step 1), stirring for crystallization or cooling for crystallization; or, directly cooling and crystallizing the solution obtained in the step 1);
3) And (3) filtering and drying the crystal obtained in the step (2) to obtain the A crystal form.
10. The production process according to claim 9, wherein the good solvent is selected from the group consisting of an alcoholic solvent, a ketone solvent and an ether solvent, and the alcoholic solvent is preferably C 1 -C 4 Alcohol solvents, more preferably methanol, ethanol, isopropanol, n-butanol, trifluoroethanol; the ketone solvent is preferablyAcetone and butanone; the ether solvent is preferably 1, 4-dioxane or tetrahydrofuran; preferably, the good solvent is selected from the group consisting of methanol, ethanol, acetone, butanone, tetrahydrofuran, more preferably from the group consisting of ethanol, acetone, and tetrahydrofuran.
11. The production process according to claim 9 or 10, wherein the poor solvent is selected from the group consisting of an alkane solvent, an ether solvent, an ester solvent, and an aromatic hydrocarbon solvent; the alkane solvent is preferably n-heptane, n-hexane, cyclohexane and methylcyclohexane, the ether solvent is preferably petroleum ether, diethyl ether and methyl tertiary butyl ether, the ester solvent is preferably ethyl acetate, isopropyl acetate and butyl acetate, and the aromatic hydrocarbon solvent is preferably toluene; preferably, the poor solvent is selected from petroleum ether, n-heptane, cyclohexane, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, butyl acetate, more preferably from n-heptane and cyclohexane.
12. The production method according to any one of claims 9 to 11, wherein the good solvent is selected from ethanol, acetone, and tetrahydrofuran, and the poor solvent is selected from n-heptane and cyclohexane; preferably, the good solvent is ethanol, the poor solvent is n-heptane, or the good solvent is tetrahydrofuran, and the poor solvent is cyclohexane.
13. The production process according to any one of claims 9 to 12, wherein the volume ratio of the good solvent to the poor solvent is 1:1 to 1:30, preferably 1:2 to 1:5.
14. The preparation process according to any one of claims 9 to 13, wherein the dissolution in step 1) is performed at a temperature of 0 to 100 ℃, preferably at a temperature of 20 to 80 ℃, more preferably at a temperature of 60 to 80 ℃.
15. The preparation process according to any one of claims 9 to 14, wherein the crystallization in step 2) is performed at a temperature of-20 to 40 ℃, preferably at a temperature of 0 to 30 ℃, more preferably at a temperature of 10 to 20 ℃.
16. A process for the preparation of form B of a compound of formula (I) according to any one of claims 5 to 8, comprising the steps of:
1) Adding any crystal form or amorphous compound of formula (I) into a good solvent for dissolution;
2) Adding a poor solvent into the solution obtained in the step 1), and stirring for crystallization;
3) And (3) filtering and drying the crystal obtained in the step (2) to obtain the B crystal form.
17. A process for the preparation of form B of a compound of formula (I) according to any one of claims 5 to 8, comprising the steps of:
1) Adding any crystal form or amorphous compound of formula (I) into a good solvent for pulping;
2) And (3) filtering and drying the crystal obtained in the step (1) to obtain the B crystal form.
18. The production process according to claim 16 or 17, wherein the good solvent is a mixed solvent of an organic solvent selected from the group consisting of an alcohol solvent, an ester solvent, a ketone solvent and a nitrile solvent, and water, and the alcohol solvent is preferably C 1 -C 4 Alcohol solvents, more preferably methanol, ethanol, isopropanol, n-butanol and trifluoroethanol, ketone solvents, preferably acetone and butanone, nitrile solvents, preferably acetonitrile, and ester solvents, preferably ethyl acetate, isopropyl acetate and butyl acetate; preferably, the organic solvent is selected from methanol, ethanol, acetone, acetonitrile, ethyl acetate.
19. The production method according to claim 18, wherein the volume ratio of the organic solvent to water in the mixed solvent of the organic solvent and water is 100:0.1 to 1:100, preferably 100:1 to 1:10, more preferably 20:1 to 1:10.
20. The production process according to claim 16, wherein the poor solvent is selected from the group consisting of an alkane solvent, preferably n-heptane, n-hexane, cyclohexane, methylcyclohexane; preferably, the poor solvent is selected from n-heptane.
21. The process of claim 16, wherein the volume ratio of good solvent to poor solvent is from 1:1 to 1:30, preferably from 1:4 to 1:5.
22. The process according to claim 16, wherein the good solvent is C 1 -C 4 A mixed solvent of alcohol and water, preferably a mixed solvent of methanol and water or a mixed solvent of ethanol and water; wherein the volume ratio of the alcohol to the water is preferably 1:5-1:20, preferably 1:7-1:20; the poor solvent is n-heptane; preferably, the volume ratio of the good solvent to the poor solvent is 1:4 to 1:5.
23. The preparation process according to claim 16, wherein the dissolution in step 1) is performed at a temperature of 0 to 100 ℃, preferably at a temperature of 20 to 80 ℃, more preferably at a temperature of 20 to 60 ℃.
24. The preparation process according to claim 17, wherein the beating in step 1) is carried out at a temperature of-20 to 100 ℃, preferably at a temperature of 0 to 20 ℃.
25. The process according to claim 17, wherein the good solvent is C 1 -C 4 A mixed solvent of alcohol and water, preferably a mixed solvent of methanol and water or a mixed solvent of ethanol and water, wherein the volume ratio of the alcohol to the water is preferably 1:5-1:20, preferably 1:7-1:20; or ethyl acetate saturated with water; or a mixed solvent of acetone and water, wherein the volume ratio of the acetone to the water is preferably 1:10; or a mixed solvent of acetonitrile and water, wherein the volume ratio of acetonitrile to water is preferably 1:10.
26. The process according to claim 16, wherein the crystallization in step 2) is carried out at a temperature of-20 to 30 ℃, preferably at a temperature of 0 to 20 ℃, more preferably at 10 to 20 ℃.
27. A pharmaceutical composition comprising as an active ingredient form a of the compound of formula (I) according to any one of claims 1 to 4 together with a pharmaceutically acceptable carrier.
28. A pharmaceutical composition comprising as an active ingredient form B of the compound of formula (I) according to any one of claims 5 to 8, together with a pharmaceutically acceptable carrier.
29. Use of form a of a compound of formula (I) according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 22 for the manufacture of a medicament for the treatment of a disease associated with mutations in exon20 of EGFR, preferably non-small cell lung cancer.
30. Use of form a of the compound of formula (I) according to any one of claims 5 to 8 or of the pharmaceutical composition according to claim 23 for the manufacture of a medicament for the treatment of a disease associated with mutations in exon20 of EGFR, preferably non-small cell lung cancer.
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| CN114057735A (en) * | 2020-08-03 | 2022-02-18 | 江苏恒瑞医药股份有限公司 | Novel crystal form of multi-target tyrosine kinase inhibitor and preparation method thereof |
| CN114539226A (en) * | 2020-11-19 | 2022-05-27 | 上海翰森生物医药科技有限公司 | A kind of crystal form containing free base of indole derivatives and its preparation method and application |
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| CN114057735A (en) * | 2020-08-03 | 2022-02-18 | 江苏恒瑞医药股份有限公司 | Novel crystal form of multi-target tyrosine kinase inhibitor and preparation method thereof |
| CN114539226A (en) * | 2020-11-19 | 2022-05-27 | 上海翰森生物医药科技有限公司 | A kind of crystal form containing free base of indole derivatives and its preparation method and application |
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