CN110776495A - Crystal form of kinase inhibitor and preparation method and application thereof - Google Patents
Crystal form of kinase inhibitor and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses crystal forms of a compound shown as a formula (I), a preparation method thereof and application of a pharmaceutical composition compound containing the crystal forms in production of a medicament for treating cancers.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to two crystal forms of a kinase inhibitor shown as a formula (I), a preparation method thereof and application of the crystal forms in production of medicaments for treating cancers. The compounds of formula (I) are represented by the following structure:
background
A2- (2, 4, 5-substituted aniline) pyrimidine derivative, the chemical name: 2- ((5-acrylamido-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylic acid isopropyl ester; CAS: 1847461-43-1, the structural formula is shown in formula (I):
patents WO2015/195228a1, CN106559991A, US20170197962a1 disclose preparation methods and potential tumor inhibitory activities of compounds of formula (I), but neither describe nor suggest the presence of crystals. The compound belongs to a compound which is difficult to dissolve in water, and is used in a solid form in a preparation, so that the research on the crystal form of the compound has very important significance.
Through crystal form research on the compound shown in the formula (I), two crystal forms with obvious X-ray powder diffraction pattern characteristics are found, and the crystal forms are simple in preparation method, convenient to store and suitable for preparing various preparations.
Disclosure of Invention
The invention aims to provide a crystal form of the compound and a preparation method thereof.
Another object of the present invention is to provide pharmaceutical compositions containing the crystalline forms of the compound.
It is a further object of the present invention to provide the use of this crystalline form of the compound for the manufacture of a medicament for the treatment of cancer.
The above object of the present invention is achieved by the following means:
according to the object of the present invention, there is first provided a compound of formula (I) in a crystalline state.
Further, the present invention provides crystalline form a, form B of the compound of formula (I).
Crystal form A of a compound of formula (I)
The X-ray powder diffraction pattern (using CuKa source) of the crystal form A of the compound shown in the formula (I) is characterized in that: characteristic diffraction peaks are correspondingly arranged at the positions of 9.6 +/-0.2 degrees, 10.9 +/-0.2 degrees, 12.5 +/-0.2 degrees, 13.0 +/-0.2 degrees, 14.9 +/-0.2 degrees, 15.5 +/-0.2 degrees, 18.2 +/-0.2 degrees, 19.4 +/-0.2 degrees, 21.5 +/-0.2 degrees, 23.7 +/-0.2 degrees, 31.7 +/-0.2 degrees and the like of the 2 theta.
In a particular embodiment, the present invention provides a compound of formula (I) having the form a characterized by an X-ray powder diffraction pattern (using a CuKa source): characteristic diffraction peaks are correspondingly arranged at the positions of 7.0 +/-0.2 degrees, 9.6 +/-0.2 degrees, 10.9 +/-0.2 degrees, 12.5 +/-0.2 degrees, 13.0 +/-0.2 degrees, 14.9 +/-0.2 degrees, 15.3 +/-0.2 degrees, 15.5 +/-0.2 degrees, 18.2 +/-0.2 degrees, 19.4 +/-0.2 degrees, 20.4 +/-0.2 degrees, 21.5 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.4 +/-0.2 degrees, 23.8 +/-0.2 degrees, 24.5 +/-0.2 degrees, 26.0 +/-0.2 degrees, 27.2 +/-0.2 degrees, 31.4 +/-0.2 degrees, 31.7 +/-0.2 degrees and the like of 2 theta.
Further, the X-ray powder diffraction pattern of the crystal form A of the compound shown in the formula (I) has the following characteristic diffraction peaks, d values and relative intensities.
In a particular embodiment, the present invention provides form a of the compound of formula (I) having substantially the same X-ray powder diffraction pattern (XRPD) as shown in figure 1.
The crystalline form A of the compound of formula (I) according to the invention can be obtained by the following process.
(1) Dissolving a compound shown as a formula (I) in isopropanol;
(2) crystallizing;
(3) separating out solids;
(4) optionally, the isolated solid is dried.
In the step (1), the volume-to-mass ratio of the solvent to the compound shown in the formula (I) is 50: 1 to 70: 1; and (3) dissolving by adopting a heating mode, wherein the temperature is 50-80 ℃.
In the step (2), the crystallization is carried out under stirring or standing; the crystallization method is a method which is conventional in the technical field, such as cooling, distilling part of the solvent, adding seed crystal, adding poor solvent and the like.
In the above step (3), the separation may be carried out by a conventional method in the art such as filtration, and optionally, the separated solid may be washed with a suitable solvent.
In the step (4), the drying temperature is generally 30-120 ℃, preferably 40-70 ℃, and the drying can be carried out under normal pressure or reduced pressure.
Crystal form B of a compound of formula (I)
The X-ray powder diffraction pattern (using CuKa source) of the crystal form B of the compound shown in the formula (I) is characterized in that: characteristic diffraction peaks are correspondingly arranged at the positions of 6.0 +/-0.2 degrees, 8.5 +/-0.2 degrees, 12.5 +/-0.2 degrees, 15.4 +/-0.2 degrees, 21.9 +/-0.2 degrees, 25.7 +/-0.2 degrees and the like of 2 theta.
In a particular embodiment, the present invention provides a compound of formula (I) having the form a characterized by an X-ray powder diffraction pattern (using a CuKa source): characteristic diffraction peaks are correspondingly arranged at the positions of 6.0 +/-0.2 degrees, 8.5 +/-0.2 degrees, 12.1 +/-0.2 degrees, 12.5 +/-0.2 degrees, 15.4 +/-0.2 degrees, 15.9 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.9 +/-0.2 degrees, 22.7 +/-0.2 degrees, 25.2 +/-0.2 degrees, 25.7 +/-0.2 degrees, 26.1 +/-0.2 degrees and the like of 2 theta.
Further, the X-ray powder diffraction pattern of the compound shown in the formula (I) in the crystal form B has the following characteristic diffraction peaks, d values and relative intensities.
In a particular embodiment, the present invention provides crystalline form B of the compound of formula (I) having an X-ray powder diffraction pattern (XRPD) substantially the same as shown in figure 2.
The crystalline form B of the compound of formula (I) according to the invention can be obtained by the following process.
(1) Dissolving a compound shown as a formula (I) in acetone;
(2) crystallizing;
(3) separating out solids;
(4) optionally, the isolated solid is dried.
In the step (1), the volume-to-mass ratio of the solvent to the compound shown in the formula (I) is 20: 1 to 40: 1; dissolving by adopting a heating mode, wherein the temperature is 40-53 ℃.
In the step (2), the crystallization is carried out under stirring or standing; the crystallization method is a method which is conventional in the technical field, such as cooling, distilling part of the solvent, adding seed crystal, adding poor solvent and the like.
In the above step (3), the separation may be carried out by a conventional method in the art such as filtration, and optionally, the separated solid may be washed with a suitable solvent.
In the step (4), the drying temperature is generally 30-120 ℃, preferably 40-70 ℃, and the drying can be carried out under normal pressure or reduced pressure.
The compound of formula (I) of the present invention can be prepared by the methods disclosed in WO2015/195228A1, CN106559991A, US20170197962A1 and the like; can also be prepared by the following preparation method.
Step 1 (preparation of Compound 1)
N can be prepared by the reaction of 4-fluoro-2-methoxy-5-nitrobenzene and N, N, N' -trimethylethylenediamine
1- (2- (dimethylamino) ethyl) -5-methoxy-N
1-methyl-2-nitrobenzene-1, 4-diamine (compound 1). The reaction is carried out in an organic solvent (for example, acetonitrile, dioxane, ethylene glycol dimethyl ether or a mixed solvent thereof) in the presence of a base. The amount of N, N, N' -trimethylethylenediamine used is, for example, preferably in the range of 1 to 1.5 times by mole, more preferably 1.05 to 1.1 times by mole, based on 4-fluoro-2-methoxy-5-nitrobenzene. Examples of the base to be used include sodium hydrogencarbonate, potassium carbonate, sodium carbonate, cesium carbonate and a mixed base thereof. The amount of the base to be used is, for example, preferably in the range of 2 to 5 times by mole, more preferably 2.5 to 3.5 times by mole, based on 4-fluoro-2-methoxy-5-nitrobenzene. The reaction temperature varies depending on the kinds of the raw materials and the base used, and is usually in the range of 70 ℃ to 90 ℃. The reaction time varies depending on the kind of the raw material and the base used and the reaction temperature, and is usually preferably in the range of 2 to 4 hours.
Step 2 (preparation of Compound 2)
Isopropyl 2-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate (compound 2) is prepared by reacting isopropyl 2, 4-dichloropyrimidine-5-carboxylate with N-methylindole. The reaction is carried out in an organic solvent (e.g., dichloroethane, nitromethane, nitrobenzene, tetrahydrofuran, or a mixed solvent thereof) in the presence of a lewis acid. Examples of the Lewis acid to be used include iron trichloride, aluminum trichloride, boron trifluoride diethyl etherate and a mixed acid thereof. The amount of N-methylindole to be used is, for example, preferably in the range of 1.0 to 1.8 times by mole, more preferably 1.05 to 1.2 times by mole, based on isopropyl 2, 4-dichloropyrimidine-5-carboxylate. The amount of the Lewis acid to be used is, for example, preferably in the range of 1.0 to 3.0 times by mole, more preferably 1.1 to 1.5 times by mole, based on isopropyl 2, 4-dichloropyrimidine-5-carboxylate. The reaction temperature varies depending on the kinds of the raw materials and Lewis acid used, and is usually in the range of 40 ℃ to 80 ℃. The reaction time varies depending on the kind of the raw material and Lewis acid used and the reaction temperature, and is usually preferably within a range of from 3 hours to 10 hours.
Step 3 (preparation of Compound 3)
By reacting isopropyl 2-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate with N
1- (2- (dimethylamino) ethyl) -5-methoxy-N
12- ((4(2 (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylic acid isopropyl ester (Compound 3) can be prepared by reacting-methyl-2-nitrobenzene-1, 4-diamine. The reaction is carried out in an organic solvent (e.g., acetonitrile, dioxane, ethylene glycol dimethyl ether, n-butanol, isopropanol or a mixed solvent thereof) in the presence of an acid. Examples of the acid to be used include methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid and mixed acids thereof. As N
1- (2- (dimethylamino) ethyl) -5-methoxy-N
1The amount of (E) -methyl-2-nitrophenyl-1, 4-diamine used is, for example, preferably in the range of 1.0 to 1.8 times by mole, more preferably 1.2 to 1.3 times by mole, based on isopropyl 2-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate. The amount of the acid to be used is, for example, preferably in the range of 3.0 to 7.0 times by mole, more preferably 4.0 to 5.5 times by mole, based on 2-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylic acid isopropyl ester. The reaction temperature varies depending on the kind of the raw material and the acid used, and is usually in the range of 70 ℃ to 90 ℃. The reaction time is determined by the kind of the raw material and acid used, and the reaction temperatureIn contrast, it is generally preferred that the reaction time is in the range of 8 hours to 24 hours.
Step 4 (preparation of Compound 4)
Isopropyl 2- (5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate (compound 4) was prepared by reacting isopropyl 2- ((4(2 (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate with zinc dust. The reaction is carried out in an organic solvent (acetonitrile, acetone, tetrahydrofuran, ethylene glycol dimethyl ether or a mixed solvent thereof) in the presence of an acidic medium. As the acidic medium used, ammonium chloride is generally used. The amount of zinc powder to be used is, for example, preferably in the range of 3.0 to 10.0 times by mole, more preferably 4.0 to 6.0 times by mole, based on isopropyl 2- ((4(2 (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate. The amount of ammonium chloride to be used is, for example, preferably in the range of 8.0 to 20.0 times by mole, more preferably 10.0 to 12.0 times by mole, based on isopropyl 2- ((4(2 (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate. The reaction temperature is usually in the range of 10 to 40 ℃. The reaction time is usually preferably in the range of 0.5 to 3 hours.
Step 5 (preparation of Compound represented by formula (I))
Isopropyl 2- ((5-acrylamido-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate can be prepared by reacting isopropyl 2- (5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate with acrylic acid (compound of formula (I)). The reaction is carried out in the presence of a condensing agent in an organic solvent (dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran or a mixed solvent thereof). Examples of the condensing agent to be used include Dicyclohexylcarbodiimide (DCC), Diisopropylcarbodiimide (DIC), 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (EDCI), and a mixture thereof. Examples of the condensation activator of the reaction include 1-hydroxybenzotriazole (HOBt), 4-Dimethylaminopyridine (DMAP), 4-pyrrolidinylpyridine (4-PPY), 1-hydroxy-7-azobenzotriazol (HOAT), Diisopropyltriethylamine (DIPEA), and a mixture thereof. The amount of acrylic acid used is, for example, preferably in the range of 1.0 to 2.0 times by mole, more preferably 1.05 to 1.2 times by mole, based on isopropyl 2- (5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate. The amount of the condensing agent to be used is, for example, preferably in the range of 1.0 to 4.0 times by mole, preferably 1.5 to 2.5 times by mole, based on isopropyl 2- (5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate. The amount of the condensation activator to be used is, for example, preferably in the range of 1.0 to 4.0 times by mole, preferably 1.5 to 2.5 times by mole, relative to isopropyl 2- (5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate. The amount of acrylic acid used is, for example, preferably in the range of 1.0 to 4.0 times by mole, more preferably 1.5 to 2.5 times by mole, based on isopropyl 2- (5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate. The reaction temperature varies depending on the kind of the raw material and the condensing agent used, and is usually in the range of 10 to 30 ℃. The reaction time varies depending on the kind of the raw material and the condensing agent used and the reaction temperature, and is usually preferably in the range of 2 hours to 12 hours.
In the production method of the compound represented by the above formula (I), each compound used as a raw material is a known compound, or can be produced according to a known method.
The X-ray powder diffraction analysis is completed by CuKa source determination of Shimadzu XRD-6100X-ray powder diffractometer under the environment temperature and the environment humidity. The "ambient temperature" is generally 0 to 40 ℃; the ambient humidity is typically 30% to 80% relative humidity.
The X-ray powder diffraction pattern of the crystal form A, B of the compound shown in the formula (I) provided by the invention is shown in attached figures 1 and 2. The 'representative X-ray powder diffraction pattern' refers to that the X-ray powder diffraction characteristics of the crystal form accord with the overall appearance displayed by the pattern, and it can be understood that in the test process, the peak-appearing positions or peak intensities of the X-ray powder diffraction patterns measured by the same crystal form have certain differences due to the influence of various factors (such as the granularity of a test sample, a sample processing method, an instrument, test parameters, test operation and the like in the test process). In general, the experimental error of the 2 θ values of diffraction peaks in the X-ray powder diffraction pattern may be. + -. 0.2 °, preferably. + -. 0.2 °.
It is a further object of the present invention to provide a pharmaceutical composition comprising the above crystalline form of the compound of formula (I) and the use of the above crystalline form of the compound of formula (I) for the manufacture of a medicament for the treatment of cancer. .
To achieve the object, in one aspect the present invention provides a pharmaceutical composition or formulation comprising a therapeutically effective amount of a compound of formula (I) in crystalline form, a compound of formula (I) in crystalline form a, in crystalline form B and a pharmaceutically acceptable adjuvant.
In another aspect, the present invention provides the use of a crystalline compound of formula (I), form a of a compound of formula (I), form B for the manufacture of a medicament for the treatment of cancer. .
The pharmaceutical composition or preparation can be prepared according to conventional production methods in the pharmaceutical field, for example, one or more of the compound shown in the formula (I) in a crystalline state, the crystal form A of the compound shown in the formula (I) and the crystal form B of the compound shown in the formula (I) are mixed with one or more carriers and then are prepared into a required dosage form. In one embodiment, the particle size distribution of the compound of formula (I), form A, form B in crystalline form is controlled to be less than 100 μm, preferably less than 50 μm, more preferably less than 10 μm.
The above condition can be selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, melanoma, and mesothelioma.
The dosage form of the pharmaceutical composition or the preparation comprises: tablet, capsule, pill, granule, powder, aerosol, powder spray, spray gel, implant, membrane, cream, ointment, paste, patch, etc. They are administered by oral, sublingual, injection, via the buccal route, pulmonary/tracheal or transdermal routes, etc., depending on the characteristics of the respective dosage form.
The dosage of the above pharmaceutical composition or preparation is adjusted according to the nature and severity of the patient's condition, the route of administration and the age, weight, etc. of the patient, and is generally between 1mg and 500mg, preferably between 20mg and 400mg, more preferably between 50mg and 200mg per day; the administration may be once or more daily.
In some embodiments, the pharmaceutical compositions provided herein are oral solid formulations, preferably capsules or tablets. The oral solid preparation contains a pharmaceutical adjuvant besides the compound shown as the active ingredient crystalline formula (I), wherein the pharmaceutical adjuvant is conventional in the field and comprises a filling agent, a disintegrating agent, a binding agent or a wetting agent, a lubricating agent, a surfactant and the like. The filler generally includes lactose, microcrystalline cellulose, mannitol, pregelatinized starch, sucrose, dextrin, sorbitol, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, calcium hydrogen carbonate, sodium carbonate, hydroxypropyl cellulose, ethyl cellulose, aluminum hydroxide, and the like. These may be used alone or in combination, and among them, lactose, microcrystalline cellulose, mannitol, pregelatinized starch, or calcium hydrogen phosphate is preferable. The disintegrant generally comprises starch, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch and the like. They may be used alone or in combination, and among them, crospovidone, croscarmellose sodium, low-substituted hydroxypropylcellulose or sodium carboxymethyl starch are preferable. The binder generally includes povidone (polyvinylpyrrolidone), hydroxypropylmethylcellulose, microcrystalline cellulose, hydroxypropylcellulose, ethylcellulose, polyethylene glycol, starch slurry, gum arabic, and the like. They may be used alone or in combination, among which povidone (polyvinylpyrrolidone), microcrystalline cellulose or hydroxypropyl cellulose is preferable. Such lubricants typically include zinc stearate, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, sucrose esters of fatty acids, aerosil (including light, hydrated and colloidal silica), stearic acid, palmitic acid, aluminum silicate, and solid polyethylene glycols, and the like. They may be used alone or in admixture thereof, with magnesium stearate, colloidal silica or talc being preferred. The surfactant generally comprises sodium dodecyl sulfate, Tween-80, poloxamer, sodium lauryl sulfate and the like. They may be used alone or in combination. Among them, sodium lauryl sulfate or Tween-80 is preferable.
If necessary, other adjuvants such as sweetening agent (such as aspartame, steviosin, etc.), colorant (such as yellow iron oxide, red iron oxide, etc.), stabilizer (such as citric acid, lactic acid, malic acid, glycine, etc.), pH regulator (such as calcium carbonate, sodium bicarbonate, tartaric acid, fumaric acid, citric acid, etc.) can also be added into the above composition or preparation.
The preparation of the oral solid preparation can be carried out according to the conventional method for preparing the oral solid preparation in the field, for example, capsules can be prepared by adopting the common dry granulation and capsule filling mode; the tablet can be prepared by wet granulation and tabletting. When the oral solid preparation is a capsule, a gastric soluble capsule, an enteric soluble capsule and the like can be prepared according to requirements.
Experiments prove that the compound shown in the crystalline formula (I), the crystal form A of the compound shown in the formula (I) and the crystal form B of the compound shown in the formula (I) have simple and convenient preparation methods: has the advantages of good stability and preparation adaptability, etc. These advantages facilitate their formulation into corresponding formulations, e.g. their formulations have good stability and effectiveness in preparation and storage.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of a crystal form A of a compound shown as a formula (I).
FIG. 2 is an X-ray powder diffraction pattern of a crystal form B of the compound shown in the formula (I).
Detailed Description
The present invention will be described in further detail with reference to the following examples. This should not be construed as limiting the scope of the above-described subject matter of the invention to the following examples. Various substitutions and alterations according to the general knowledge and conventional practice in the art are intended to be included within the scope of the present invention without departing from the spirit of the present invention as described above.
Example 1: preparation of isopropyl 2- ((5-acrylamido-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate (compound of formula (I))
(1)N
1- (2- (dimethylamino) ethyl) -5-methoxy-N
1Preparation of (E) -methyl-2-nitrophenyl-1, 4-diamine (Compound 1)
N, N, N' -trimethylethylenediamine (7.0g, 69mmol) was added to a mixture of 4-fluoro-2-methoxy-5-nitrobenzene (10g, 54mmol) and potassium carbonate (15.0g) in acetonitrile (100ml), the temperature was raised to 80 ℃ to react for 2 hours, the potassium carbonate was removed by filtration, and the filtrate was concentrated under reduced pressure to give N as a brownish red oil
1- (2- (dimethylamino) ethyl) -5-methoxy-N
1Methyl-2-nitrophenyl-1, 4-diamine, which was used in the next reaction without further purification.
(2) Preparation of isopropyl 2-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate (Compound 2)
A solution of isopropyl 2, 4-dichloropyrimidine-5-carboxylate (10.0g, 43mmol) in tetrahydrofuran (100ml) was cooled to below 10 ℃, anhydrous ferric trichloride (8.3g, 51mmol) was added, the mixture was stirred and dispersed uniformly, and N-methylindole (6.7g, 51mmol) was added. The reaction was stirred at 45 ℃ for 4 hours and cooled. The reaction was quenched by the addition of isopropanol (20ml) and water (20 ml). After stirring and reacting for 20 minutes, filtering the reaction solution by using kieselguhr, adding 100ml of water and 100ml of dichloromethane into the filtrate, and separating the solution; the aqueous phase was extracted with 300ml of dichloromethane, the organic phases were combined, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a solid. Adding isopropanol, beating, filtering and drying to obtain solid 2-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylic acid isopropyl ester 9.8 g.
(3) Preparation of isopropyl 2- ((4(2 (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate (Compound 3)
Will N
1- (2- (dimethylamino) ethyl) -5-methoxy-N
1A mixture of-methyl-2-nitrophenyl-1, 4-diamine (10.0g, 37mmol) in isopropanol (200ml) was cooled to below 10 deg.C, trifluoroacetic acid (17.9g, 157mmol) was added, stirring was continued, isopropyl 2-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate (10.0g, 30mmol) was added, and the mixture was heated to reflux for 36 hours. And cooling, and slowly pouring the reaction liquid into a sodium bicarbonate ice-water mixed liquid to precipitate a solid. The mixture was filtered, the filter cake was dissolved in dichloromethane, magnesium sulfate was added to dry the mixture, the mixture was concentrated to dryness under reduced pressure, isopropanol 30ml was added to the mixture to slurry the mixture, the solid was collected by filtration and recrystallized from acetone to obtain 11.2g of isopropyl 2- ((4(2 (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate as a brownish red solid.
(4) Preparation of isopropyl 2- (5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate (Compound 4)
A mixture of isopropyl 2- ((4(2 (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate (5.6g, 10mmol) in acetone (200ml) was cooled to below 10 ℃, zinc powder (3.9g, 60mmol) and saturated aqueous ammonium chloride were added, the reaction was stirred at room temperature for 30 minutes, the mixture was filtered through a pad of celite, the filter cake was washed with isopropanol, and the filtrates were combined. The filtrate was concentrated under reduced pressure to give isopropyl 2- (5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate.
(5) Preparation of Compounds of formula (I)
A mixture of isopropyl 2- (5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino-4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate (5.3g, 10mmol) in 100ml of methylene chloride was cooled to 10 ℃ or lower, EDCI (3.8g, 20mmol), DIPEA (5.2g, 40mmol) and acrylic acid (0.7g, 10mmol) were added in this order, and the reaction was stirred at room temperature for 30 minutes. The reaction was concentrated under reduced pressure and the resulting oil was purified by preparative TLC (5% methanol/DCM) to give 3.6g of orange yellow solid isopropyl 2- ((5-acrylamido-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -4- (1-methyl-1H-indol-3-yl) pyrimidine-5-carboxylate.
ESI-MS m/z：586.4[M+H]
+
Example 2: preparation of form A
Dissolving 2.0g of the compound shown in the formula (I) in 120ml of isopropanol at 80 ℃, slowly cooling at room temperature, stirring for crystallization for 5-15 hours, filtering, and drying the obtained yellow solid at 50 ℃ under reduced pressure to obtain the compound A type crystal shown in the formula (I).
The measured X-ray diffraction pattern of the powder is shown in figure 1, and the measured values are as follows (the measured values corresponding to diffraction peaks with relative intensity of more than 5% in the range of 2 theta angles of 4-50 degrees are taken):
example 3: preparation of form B
Adding 2.0g of the compound shown in the formula (I) into 50ml of acetone, heating, refluxing, dissolving and clearing, cooling to below 10 ℃, stirring, crystallizing, filtering and separating out solids, and drying a filter cake at 50 ℃ under reduced pressure to obtain a compound B type crystal shown in the formula (I) and a light yellow solid.
The measured X-ray powder diffraction pattern is shown in figure 2, and the measured values are as follows (the measured value corresponding to the diffraction peak with the relative intensity of more than 5 percent in the range of 2 theta angle from 4 degrees to 50 degrees is taken):
example 4: capsule containing 40mg of compound of formula (I) and preparation thereof
Prescription
| Components | Content (wt.) |
| Compound of formula (I) crystalline form A (prepared as in example 2) | 40mg |
| Microcrystalline cellulose | 95.4mg |
| Lactose | 27mg |
| Magnesium stearate | 0.6mg |
| 163mg |
Preparation: after the compound crystal form A shown in the formula (I) in the components in the table above, microcrystalline cellulose and lactose are uniformly mixed, magnesium stearate is added and the mixture is uniformly mixed. The powder is filled into capsule shells.
Example 5: capsule containing 80mg of compound of formula (I) and preparation thereof
Prescription
| Components | Content (wt.) |
| Compound of formula (I) in crystalline form B (prepared as in example 3) | 80mg |
| Microcrystalline cellulose | 95.4mg |
| Lactose | 18mg |
| Magnesium stearate | 0.6mg |
| 194mg |
Preparation: after the compound crystal form B shown in the formula (I) in the components in the table above, microcrystalline cellulose and lactose are uniformly mixed, magnesium stearate is added and the mixture is uniformly mixed. The powder is filled into capsule shells.
Example 6: stability test of Crystal forms
The compound shown as the formula (I) in the crystal form A, B is placed under the conditions of 40 ℃ and 75% RH to examine the stability of the crystal form, and an X-ray powder diffraction pattern is tested after one week.
The X-ray powder diffraction pattern of the crystal form A, B is basically the same as that of the attached drawings 1 and 2 respectively.
Claims (6)
1. A compound of formula (I) in a crystalline state:
2. a crystalline form a of a compound of formula (I) characterized by: characteristic diffraction peaks are correspondingly arranged at the positions of 9.6 +/-0.2 degrees, 10.9 +/-0.2 degrees, 12.5 +/-0.2 degrees, 13.0 +/-0.2 degrees, 14.9 +/-0.2 degrees, 15.5 +/-0.2 degrees, 18.2 +/-0.2 degrees, 19.4 +/-0.2 degrees, 21.5 +/-0.2 degrees, 23.7 +/-0.2 degrees, 31.7 +/-0.2 degrees and the like of the 2 theta.
3. Form a according to claim 2, wherein the crystalline form has an X-ray powder diffraction pattern (XRPD) substantially the same as shown in figure 1.
4. A crystalline form B of a compound of formula (I) characterized by: characteristic diffraction peaks are correspondingly arranged at the positions of 6.0 +/-0.2 degrees, 8.6 +/-0.2 degrees, 12.5 +/-0.2 degrees, 15.4 +/-0.2 degrees, 21.9 +/-0.2 degrees, 25.7 +/-0.2 degrees and the like of 2 theta.
5. The crystalline form B according to claim 4, wherein the crystalline form has an X-ray powder diffraction pattern (XRPD) substantially the same as shown in figure 2.
6. Use of a crystalline form of a compound of formula (I) as claimed in any one of claims 1 to 5 for the manufacture of a medicament for the treatment of cancer.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111303125A (en) * | 2020-04-10 | 2020-06-19 | 天津法莫西医药科技有限公司 | Methoxy-substituted indole-pyrimidine compound and preparation method thereof |
| CN112292378A (en) * | 2019-05-22 | 2021-01-29 | 上海翰森生物医药科技有限公司 | Indole derivative-containing inhibitor, preparation method and application thereof |
| CN112645934A (en) * | 2020-12-25 | 2021-04-13 | 中山奕安泰医药科技有限公司 | Ostinib intermediate and refining method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106559991A (en) * | 2014-06-19 | 2017-04-05 | 阿里亚德医药股份有限公司 | For the heteroaryl compound of kinase inhibition |
| CN107043368A (en) * | 2016-02-05 | 2017-08-15 | 齐鲁制药有限公司 | The crystallization of arylamine pyrimidine compound and its salt |
| CN108047205A (en) * | 2016-12-14 | 2018-05-18 | 河南美泰宝生物制药有限公司 | 2- (2,4,5- substitution phenylamino) pyrimidine derivatives, its preparation method and its application in antitumor drug is prepared |
-
2018
- 2018-07-30 CN CN201810853582.6A patent/CN110776495A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106559991A (en) * | 2014-06-19 | 2017-04-05 | 阿里亚德医药股份有限公司 | For the heteroaryl compound of kinase inhibition |
| CN107043368A (en) * | 2016-02-05 | 2017-08-15 | 齐鲁制药有限公司 | The crystallization of arylamine pyrimidine compound and its salt |
| CN108047205A (en) * | 2016-12-14 | 2018-05-18 | 河南美泰宝生物制药有限公司 | 2- (2,4,5- substitution phenylamino) pyrimidine derivatives, its preparation method and its application in antitumor drug is prepared |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112292378A (en) * | 2019-05-22 | 2021-01-29 | 上海翰森生物医药科技有限公司 | Indole derivative-containing inhibitor, preparation method and application thereof |
| CN112292378B (en) * | 2019-05-22 | 2024-02-06 | 上海翰森生物医药科技有限公司 | Indole derivative-containing inhibitor, preparation method and application thereof |
| CN111303125A (en) * | 2020-04-10 | 2020-06-19 | 天津法莫西医药科技有限公司 | Methoxy-substituted indole-pyrimidine compound and preparation method thereof |
| CN112645934A (en) * | 2020-12-25 | 2021-04-13 | 中山奕安泰医药科技有限公司 | Ostinib intermediate and refining method thereof |
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