CN114853762A

CN114853762A - Solid form of imidazotriazine compound and preparation method and application thereof

Info

Publication number: CN114853762A
Application number: CN202210078555.2A
Authority: CN
Inventors: 易仕东; 石洲; 王天明; 李龙; 陈平运; 孙灏; 骆伟; 谢佳
Original assignee: Sichuan Kelun Pharmaceutical Research Institute Co Ltd
Current assignee: Sichuan Kelun Pharmaceutical Research Institute Co Ltd
Priority date: 2021-02-03
Filing date: 2022-01-24
Publication date: 2022-08-05

Abstract

The application discloses a solid form of 2-fluoro-N-methyl-4- [7- [ (quinoline-6-yl) methyl ] imidazo [1,2-B ] - [1,2,4] triazine-2-yl ] benzamide dihydrochloride, a preparation method thereof, a pharmaceutical composition containing the same and application thereof in preparing a medicament for preventing and/or treating tumor diseases.

Description

Solid form of imidazotriazine compound and preparation method and application thereof

Technical Field

The present invention relates to solid forms of 2-fluoro-N-methyl-4- [7- [ (quinolin-6-yl) methyl ] imidazo [1,2-B ] - [1,2,4] triazin-2-yl ] benzamide dihydrochloride (also known as carbamatinib hydrochloride), processes for preparing said solid forms, pharmaceutical compositions comprising said solid forms, and uses of said solid forms.

Background

Carbamatinib (caplatinib), developed by novartis, switzerland, was approved for sale in the united states at 05 months 2020 for the treatment of METex14 mutant adult metastatic non-small cell lung cancer (NSCLC). The drug is the first selective MET inhibitor approved by FDA, and has the advantages of good curative effect, safety, controllability and the like. The chemical name of the compound is 2-fluoro-N-methyl-4- [7- [ (quinoline-6-yl) methyl ] imidazo [1,2-B ] - [1,2,4] triazine-2-yl ] benzamide, the dihydrochloride monohydrate of the compound is mainly used as an active ingredient of a clinical product, the structure of the compound is shown as follows,

currently, chinese patent CN200980123120.8 discloses a crystal of a dihydrochloride and a crystal of a diphenylsulfonate of carbamtinib. Different crystal forms of the same drug may have obvious differences in the aspects of stability, bioavailability and the like, thereby affecting the curative effect of the drug. Therefore, the development and acquisition of a new stable crystal form of a compound are more beneficial to the processing of drugs and the use in pharmaceutical compositions, and have important significance in providing more qualitative and quantitative information for the curative effect research of solid drugs, and are urgent needs in the drug development process.

Disclosure of Invention

SUMMARY

The present invention provides a solid form of 2-fluoro-N-methyl-4- [7- [ (quinolin-6-yl) methyl ] imidazo [1,2-B ] - [1,2,4] triazin-2-yl ] benzamide dihydrochloride (hereinafter referred to as compound 1).

In one aspect, the present invention provides a crystal I of compound 1 having an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at diffraction angles (2 θ) of 5.18 ± 0.2 °, 7.43 ± 0.2 °, 8.74 ± 0.2 °, 12.56 ± 0.2 °, 15.00 ± 0.2 ° and 16.12 ± 0.2 °.

A second aspect of the present invention provides a crystal II of compound 1 having an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at diffraction angles (2 θ) of 6.62 ± 0.2 °, 7.09 ± 0.2 °, 9.49 ± 0.2 °, 14.32 ± 0.2 °, 15.65 ± 0.2 ° and 25.15 ± 0.2 °.

The third aspect of the present invention provides a crystal III of Compound 1, which has an X-ray powder diffraction pattern comprising characteristic peaks at diffraction angles (2. theta.) of 6.36. + -. 0.2 °, 10.39. + -. 0.2 °, 13.79. + -. 0.2 °, 22.94. + -. 0.2 °, 24.64. + -. 0.2 ° and 28.17. + -. 0.2 °.

In a fourth aspect, the present invention provides a process for preparing crystal I, crystal II and/or crystal III of Compound 1 of the present invention.

In a fifth aspect, the present invention provides a pharmaceutical composition comprising crystalline I, crystalline II and/or crystalline iii of compound 1 of the present invention, and one or more pharmaceutically acceptable carriers.

In a sixth aspect, the present invention provides the use of crystal I, crystal II, crystal iii of compound 1 of the present invention and/or a pharmaceutical composition of the present invention in the manufacture of a medicament for the prevention or treatment of a neoplastic disease.

A seventh aspect of the present invention provides a method for the prevention and/or treatment of a neoplastic disease comprising administering to a subject in need thereof an effective amount of crystalline I, crystalline II, crystalline iii of compound 1 of the present invention and/or a pharmaceutical composition of the present invention.

Detailed Description

Definition of

Unless defined otherwise below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. Reference to the techniques used herein is intended to refer to those techniques commonly understood in the art, including those variations of or alternatives to those techniques that would be apparent to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

As used herein, the terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps, although not necessarily present (i.e., these terms also encompass the terms "consisting essentially of … …" and "consisting of … …").

The word "about" as used herein refers to a value that one of ordinary skill in the art would consider to be within an acceptable standard error of the stated value, e.g., ± 0.05, ± 0.1, ± 0.2, ± 0.3, ± 0.5, ± 1, ± 2 or ± 3, etc.

The term "solid form" as used herein includes all solid state forms of compound 1, e.g. crystalline forms.

The term "crystalline form" or "crystalline" as used herein refers to any solid substance exhibiting a three-dimensional ordering, as opposed to an amorphous solid substance, which results in a characteristic XRPD pattern having well-defined peaks.

The term "X-ray powder diffraction pattern (XRPD pattern)" as used herein refers to an experimentally observed diffraction pattern or a parameter, data or value derived therefrom. XRPD patterns are generally characterized by peak position (abscissa) and/or peak intensity (ordinate).

The term "2 θ" as used herein refers to the peak position in degrees (°) set based on X-ray diffraction experiments, and is typically the abscissa unit in the diffraction pattern. If the reflection is diffracted when the incident beam makes an angle theta with a certain lattice plane, the experimental setup requires recording the reflected beam at an angle of 2 theta. It should be understood that reference herein to particular 2 theta values for particular crystalline forms is intended to refer to 2 theta values (in degrees) measured using the X-ray diffraction experimental conditions described herein.

The term "Differential Scanning Calorimetry (DSC) profile" as used herein refers to the curve recorded by a differential scanning calorimeter.

The term "thermogravimetric analysis (TGA) profile" as used herein refers to the curve recorded by a thermogravimetric analyzer.

As used herein, the term "substantially the same" means that representative peak position and/or intensity variations are taken into account. For example, for X-ray diffraction peaks, one skilled in the art will appreciate that the peak position (2 θ) will show some variation, typically as much as 0.1-0.2 degrees, and that the instruments used to measure diffraction will also cause some variation. In addition, those skilled in the art will appreciate that relative peak intensities will vary due to inter-instrument variation as well as the degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art.

Crystal and preparation method

In a first aspect, the present invention provides a crystal I of compound 1, characterized in that said crystal I has an X-ray powder diffraction pattern comprising characteristic peaks at diffraction angles (2 θ) of 5.18 ± 0.2 °, 7.43 ± 0.2 °, 8.74 ± 0.2 °, 12.56 ± 0.2 °, 15.00 ± 0.2 ° and 16.12 ± 0.2 °;

in some embodiments, the XRPD pattern of crystal I of compound 1 comprises characteristic peaks at diffraction angles (2 θ) of 5.18 ± 0.2 °, 7.43 ± 0.2 °, 8.74 ± 0.2 °, 12.56 ± 0.2 °, 15.00 ± 0.2 °, 15.73 ± 0.2 °, 16.12 ± 0.2 °, 19.70 ± 0.2 °, and 22.52 ± 0.2 °.

In some preferred embodiments, the XRPD pattern for crystal I of Compound 1 includes characteristic peaks at diffraction angles (2 θ) of 5.18 ± 0.2 °, 7.43 ± 0.2 °, 8.74 ± 0.2 °, 12.56 ± 0.2 °, 15.00 ± 0.2 °, 15.73 ± 0.2 °, 16.12 ± 0.2 °, 19.70 ± 0.2 °, 22.52 ± 0.2 °, 26.83 ± 0.2 °, 27.51 ± 0.2 ° and 28.15 ± 0.2 °.

In some preferred embodiments, the XRPD pattern of crystal I of compound 1 comprises characteristic peaks at the following diffraction angles (2 Θ), with 2 Θ values having a range of error of ± 0.2 °:

in a more preferred embodiment, the XRPD pattern of crystal I of compound 1 comprises peaks at diffraction angles (2 θ) substantially the same as shown in figure 1. In a most preferred embodiment, the XRPD pattern of crystal I of compound 1 is as shown in figure 1.

In some embodiments, a Differential Scanning Calorimetry (DSC) pattern of the crystalline I of compound 1 exhibits an endothermic peak at 250 ± 5 ℃ (onset temperature).

In a more preferred embodiment, the DSC profile of said crystal I comprises characteristic peaks at substantially the same temperatures as shown in figure 2.

In a more preferred embodiment, the DSC profile of said crystal I is as shown in figure 2.

In a second aspect, the present invention provides a crystal II of compound 1, characterized in that the X-ray powder diffraction pattern of said crystal II comprises characteristic peaks at diffraction angles (2 θ) of 6.62 ± 0.2 °, 7.09 ± 0.2 °, 9.49 ± 0.2 °, 14.32 ± 0.2 °, 15.65 ± 0.2 ° and 25.15 ± 0.2 °.

In some embodiments, the XRPD pattern of crystal II of compound 1 comprises characteristic peaks at diffraction angles (2 θ) of 6.62 ± 0.2 °, 7.09 ± 0.2 °, 9.49 ± 0.2 °, 11.71 ± 0.2 °, 12.26 ± 0.2 °, 14.32 ± 0.2 °, 15.65 ± 0.2 °, 20.27 ± 0.2 °, and 25.15 ± 0.2 °.

In some preferred embodiments, the XRPD pattern for crystal II of Compound 1 includes characteristic peaks at diffraction angles (2 θ) of 6.62 ± 0.2 °, 7.09 ± 0.2 °, 9.49 ± 0.2 °, 11.71 ± 0.2 °, 12.26 ± 0.2 °, 14.32 ± 0.2 °, 15.65 ± 0.2 °, 20.27 ± 0.2 °, 22.65 ± 0.2 °, 23.15 ± 0.2 °, 25.15 ± 0.2 °, 26.94 ± 0.2 °, 28.00 ± 0.2 ° and 29.11 ± 0.2 °.

In some preferred embodiments, the XRPD pattern of crystal II of compound 1 comprises characteristic peaks at the following diffraction angles (2 Θ), wherein the range of error in 2 Θ values is ± 0.2 °:

2θ(°)±0.2°	strength%	2θ(°)±0.2°	Strength%
				6.62	29.39	24.64	16.61
7.09	12.33	25.15	100.00
				9.49	9.04	25.55	9.58
10.03	5.23	26.19	2.61
				11.71	7.34	26.94	43.79
12.26	11.27	27.65	11.16
				13.63	2.61	28.00	35.05
14.32	63.02	28.97	21.13
				14.87	5.70	29.11	31.45
15.10	7.20	30.13	21.91
				15.43	13.54	30.65	17.97
15.65	52.36	30.95	5.16
				16.08	7.81	31.26	2.19
18.29	8.77	31.57	9.36
				18.45	10.57	32.12	3.92
18.90	2.56	32.71	6.13
				20.27	20.75	33.14	2.65
20.50	5.90	33.98	2.29
				21.10	3.74	34.70	6.32
21.34	6.11	35.17	3.96
				21.69	19.73	35.92	0.96
21.86	17.66	36.55	5.56
				22.30	2.44	37.16	1.59
22.65	19.49	37.54	1.05
				23.15	21.22	38.11	1.45
23.81	4.74	38.61	2.89
				23.99	13.22	39.54	2.24
24.25	4.15	/	/

In a more preferred embodiment, the XRPD pattern of crystal II of compound 1 comprises peaks at diffraction angles (2 θ) substantially the same as shown in figure 3. In a most preferred embodiment, the XRPD pattern of crystal II of compound 1 is shown in figure 3.

In some embodiments, the Differential Scanning Calorimetry (DSC) pattern of the crystalline II of compound 1 exhibits an endothermic peak at 174 ± 5 ℃ (onset temperature).

In a more preferred embodiment, the DSC profile of said crystal II comprises characteristic peaks at substantially the same temperatures as shown in figure 4.

In a more preferred embodiment, the DSC profile of said crystal II is as shown in figure 4.

In a third aspect, the present invention provides a crystal iii of compound 1, characterized in that the crystal iii has an X-ray powder diffraction pattern including characteristic peaks at diffraction angles (2 θ) of 6.36 ± 0.2 °, 10.39 ± 0.2 °, 13.79 ± 0.2 °, 22.94 ± 0.2 °, 24.64 ± 0.2 ° and 28.17 ± 0.2 °.

In some embodiments, the XRPD pattern of crystal iii of compound 1 comprises characteristic peaks at diffraction angles (2 θ) of 6.36 ± 0.2 °, 8.16 ± 0.2 °, 10.39 ± 0.2 °, 13.79 ± 0.2 °, 22.94 ± 0.2 °, 24.15 ± 0.2 °, 24.64 ± 0.2 °, 26.91 ± 0.2 °, and 28.17 ± 0.2 °.

In some preferred embodiments, the XRPD pattern of crystal III of Compound 1 includes characteristic peaks at diffraction angles (2 θ) of 6.36. + -. 0.2 °, 8.16. + -. 0.2 °, 10.39. + -. 0.2 °, 13.50. + -. 0.2 °, 13.79. + -. 0.2 °, 16.48. + -. 0.2 °, 16.66. + -. 0.2 °, 17.89. + -. 0.2 °, 18.25. + -. 0.2 °, 22.94. + -. 0.2 °, 24.15. + -. 0.2 °, 24.64. + -. 0.2 °, 26.91. + -. 0.2 ° and 28.17. + -. 0.2 °.

In some preferred embodiments, the XRPD pattern of crystal iii of compound 1 comprises characteristic peaks at the following diffraction angles (2 Θ), with 2 Θ values having a range of error of ± 0.2 °:

in a more preferred embodiment, the XRPD pattern of crystal iii of compound 1 comprises peaks at diffraction angles (2 θ) substantially the same as shown in figure 5. In a most preferred embodiment, the XRPD pattern of crystal iii of compound 1 is shown in figure 5.

A fourth aspect of the present invention provides a method for producing the crystal I of the above compound 1, comprising the steps of:

putting the compound 1 into a proper solvent 1, heating to a proper temperature for dissolving, then dropwise adding a crystallization solvent, precipitating a solid, centrifuging, and drying to obtain a crystal I of the compound 1.

In some embodiments, the 1 st suitable solvent is selected from: one or more of methanol, ethanol, n-propanol and n-butanol; methanol is preferred.

In some embodiments, the ratio of the amount of the 1 st suitable solvent to the volume (ml) mass (mg) of compound 1 is 2: (80-100).

In some embodiments, the crystallization solvent is selected from one or more of ethyl acetate, acetone, toluene, methyl tert-butyl ether, n-heptane; preferably, the crystallization solvent is selected from ethyl acetate and acetone.

In some embodiments, the crystallization solvent is used in an amount to provide a volume (ml) to mass (mg) ratio of compound 1 of 20: (80-100).

In some embodiments, the heating to a suitable temperature is from 40 to 50 ℃.

In some embodiments, the present invention provides a method for preparing the above-described crystal II of compound 1, comprising the steps of:

and (3) putting the compound 1 into a proper solvent of the No. 2, heating to a proper temperature for dissolving, then adding a crystallization solvent, precipitating a solid, centrifuging, and drying to obtain a crystal II of the compound 1.

In some embodiments, the 2 nd suitable solvent is selected from: one or more of methanol, ethanol, n-propanol, isopropanol, and n-butanol; methanol is preferred.

In some embodiments, the ratio of the amount of the 2 nd suitable solvent to the volume (ml) mass (mg) of compound 1 is 2: (80-100).

In some embodiments, the crystallization solvent is acetonitrile.

In some embodiments, the heating to a suitable temperature is from 40 to 50 ℃; preferably, the heating to a suitable temperature is 45 ℃.

In some embodiments, the present invention provides a method for preparing the above-described crystal iii of compound 1, the method comprising the steps of:

and (3) putting the compound 1 into a proper solvent of the No. 3, heating to a proper temperature for dissolving, then adding a crystallization solvent, precipitating a solid, centrifuging, and drying to obtain a crystal III of the compound 1.

In some embodiments, the 3 rd suitable solvent is selected from: one or more of methanol, ethanol, n-propanol, isopropanol, and n-butanol; methanol is preferred.

In some embodiments, the 3 rd suitable solvent is used in an amount to provide a volume (ml) to mass (mg) ratio of compound 1 of 2: (80-200).

In some embodiments, the crystallization solvent is one or more of toluene, tetrahydrofuran, 1, 4-dioxane, and methanol; preferably, the crystallization solvent is toluene, or a mixed solution of methanol and tetrahydrofuran.

In some embodiments, the crystallization solvent is used in an amount to provide a volume (ml) to mass (mg) ratio of compound 1 of 20: (80-200).

In some embodiments, the heating to a suitable temperature is from 40 to 60 ℃; preferably, heating is to a suitable temperature of 60 ℃.

Pharmaceutical compositions and methods of treatment

In a fifth aspect, the present invention provides a pharmaceutical composition comprising crystalline I, crystalline II and/or crystalline iii of compound 1 of the present invention, together with one or more pharmaceutically acceptable carriers.

The "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic agent is administered and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

The pharmaceutical compositions of the present invention may act systemically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

For these routes of administration, the pharmaceutical compositions of the present invention may be administered in suitable dosage forms.

The dosage form may be a solid, semi-solid, liquid, or gaseous formulation, including, but not limited to, tablets, capsules, powders, granules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, suspensions, elixirs, syrups.

A sixth aspect of the present invention provides the use of crystal I, crystal II, crystal iii of compound 1 and/or a pharmaceutical composition of the present invention in the manufacture of a medicament for the prevention or treatment of a neoplastic disease; preferably, the neoplastic disease includes, but is not limited to, non-small cell lung cancer (NSCLC).

In a seventh aspect, the present invention provides a method for the prevention and/or treatment of a neoplastic disease comprising administering to a subject in need thereof an effective amount of crystal I, crystal II, crystal iii of compound 1 of the present invention and/or a pharmaceutical composition of the present invention. Preferably, the neoplastic disease includes, but is not limited to, non-small cell lung cancer (NSCLC).

The crystal of the compound 1 provided by the invention has excellent effects in preventing and/or treating tumor diseases, and also shows good chemical stability, physical stability and pharmacokinetic properties. For example, the crystal form of the compound 1 of the present invention has better solubility, low hygroscopicity, thermal stability, etc., and thus is more advantageous for the preparation of subsequent formulations, maintaining sufficient biological activity. The reliability in the transportation and storage processes can be kept, so that the quality and the safety of the medicine are effectively ensured; moreover, the composition has good light stability, and does not need special packaging treatment for preventing the influence of illumination, thereby reducing the cost, and improving the safety of the medicine and the effectiveness after long-term storage.

Drawings

FIG. 1: an XRPD pattern of crystal I of compound 1.

FIG. 2: DSC profile of crystal I of compound 1.

FIG. 3: an XRPD pattern of crystal II of compound 1.

FIG. 4: DSC profile of crystal II of compound 1.

FIG. 5: an XRPD pattern of crystal III of compound 1.

Examples

The present invention is further illustrated by the following examples, which are only for illustrating the technical solutions of the present invention and are not intended to limit the scope of the present invention, and those skilled in the art can make some insubstantial modifications and adjustments, and still fall within the scope of the present invention.

Test instrument information and methods used for the experiment:

x-ray powder diffraction (XRPD):

the detection was performed using an Absolute scan at room temperature using an X' Pert3 Powder diffraction instrument irradiated with a Cu target. The detection range was 3.5 ° to 40 °, step size 0.013, dwell time 50s, and scan 1 time.

Differential Scanning Calorimetry (DSC) test instrument is: DSC1(METTLER TOLEDO). The test temperature range is 35 ℃ to 250 ℃, and the heating speed is 10K/min.

Preparation example: preparation of 2-fluoro-N-methyl-4- [7- [ (quinolin-6-yl) methyl ] imidazo [1,2-B ] - [1,2,4] triazin-2-yl ] benzamide dihydrochloride (Compound 1)

The first step is as follows: preparation of 2-fluoro-N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

Adding 11.60g of 4-bromo-2-fluoro-N-methylbenzamide, 15.24g of pinacol diboron and Pd into a reaction bottle ₂ (dba) ₃ 1.10g, tricyclohexylphosphine 0.80g and potassium acetate 14.72g, and then 116ml of 1, 4-dioxane was added to the reaction flask. After three times of nitrogen replacement, the reaction was stirred for 2 hours while heating to 80 ℃ while sampling TLC to monitor the progress of the reaction. When the reaction of the raw materials is monitored to be basically complete, the reaction system is cooled to room temperature, and insoluble impurities are filtered by using kieselguhr. The obtained filtrate was concentrated to dryness under reduced pressure, and after adding 100ml of ethyl acetate to complete dissolution, the organic phase was washed twice with 100ml of purified water, and after separating the liquids, the organic phases were combined and dried over anhydrous sodium sulfate. After the completion of the drying, filtration was carried out, and the obtained filtrate was concentrated to dryness under reduced pressure and then recrystallized from N-hexane to obtain 10.31g of a crude intermediate 2-fluoro-N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzamide in a yield of 73.9%.

The second step: preparation of 4- (3-amino-1, 2, 4-triazin-6-yl) -2-fluoro-N-methylbenzamide

Into a reaction flask were charged 14.37g of crude 2-fluoro-N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide and 74ml of 1, 4-dioxane, and after stirring to dissolve it at room temperature, 6.15g of 3-amino-6-bromo-1, 2, 4-triazine, 6.42 g of an aqueous potassium carbonate solution (19.42g of potassium carbonate in 37ml of water) and PdCl were further added ₂ (dppf) ₂ 0.61 g. After the nitrogen replacement of the reaction system, the temperature is increased to 80 ℃, the reaction is stirred for 2 hours, and during the reaction, a sample is taken for TLC to monitor the reaction process. After the raw materials are basically reacted completely, the reaction system is placed in an ice water bath to be cooled to below 10 ℃, and 117ml of hydrochloric acid aqueous solution is dripped into the reaction system. After the completion of the dropwise addition, the reaction system was warmed to room temperature and stirred for 1 hour, followed by filtration, and the obtained filtrate was washed with ethyl acetate and the aqueous phase was collected. The aqueous phase was placed in an ice-water bath and 120ml of 50% aqueous sodium hydroxide solution was added dropwise to the aqueous phase. After the dropwise addition, a large amount of solid is separated out, the mixture is stirred for 2 hours under the condition of heat preservation, filtered, and a filter cake is washed by purified water. The resulting filter cake was dried to give 6.95g of 4- (3-amino-1, 2, 4-triazin-6-yl) -2-fluoro-N-methylbenzamide in 80.1% yield.

The third step: preparation of 2-fluoro-N-methyl-4- [7- [ (quinolin-6-yl) methyl ] imidazo [1,2-B ] - [1,2,4] triazin-2-yl ] benzamide

To the reaction flask were added 2.80g of 4- (3-amino-1, 2, 4-triazin-6-yl) -2-fluoro-N-methylbenzamide, 4.31g of 1- (2-chloro-1-hydroxy-3- (quinolin-6-yl) propyl) pyrrolidine-2, 5-dione and 28ml of ethylene glycol. After the nitrogen replacement of the reaction system, the temperature is raised to 120 ℃, the reaction is stirred for 2 hours, and during the reaction, the TLC is sampled to monitor the reaction process. When the reaction of the raw materials is basically complete, the reaction system is cooled to room temperature, and then 60ml of purified water is dripped into the reaction system. After the dropwise addition, a large amount of solid is separated out, the mixture is stirred for 0.5h at room temperature under the condition of heat preservation, and then filtered to obtain an orange yellow filter cake. Then the filter cake is placed in a reaction bottle, 60ml of mixed solvent of DMF/MTBE (DMF: MTBE 1:5) is added for reflux pulping for 1h, then the temperature is reduced to room temperature, the filtration is carried out, and the obtained filter cake is washed by MTBE. The resulting filter cake was dried to give 2.97g of 2-fluoro-N-methyl-4- [7- [ (quinolin-6-yl) methyl ] imidazo [1,2-B ] - [1,2,4] triazin-2-yl ] benzamide in a yield of 63.8%.

The fourth step: preparation of 2-fluoro-N-methyl-4- [7- [ (quinolin-6-yl) methyl ] imidazo [1,2-B ] - [1,2,4] triazin-2-yl ] benzamide dihydrochloride

Adding 2-fluoro-N-methyl-4- [7- [ (quinolin-6-yl) methyl group into a reaction flask]Imidazo [1,2-B ] s]-[1,2,4]Triazin-2-yl radical]2.14g of benzamide, 30ml of anhydrous methanol was added, the temperature was raised to 55 ℃ and the mixture was stirred for 0.5 hour, and then 2.1ml of concentrated hydrochloric acid was added to the reaction system. After stirring for 0.5 hour, 30ml of MTBE was added dropwise to the reaction system, followed by stirring with heat preservation for 1 hour. The reaction was slowly cooled to room temperature, filtered, and washed with MTBE. The obtained cake was dried to obtain 2.41g of the objective compound in a yield of 81.1%. ¹ H NMR(400MHz,DMSO-d6)δ9.52(s,1H),9.29-9.27(dd,J＝8,4Hz,1H),9.18-9.15(d,J＝12Hz,1H),8.55-5.54(m,1H),8.52-8.50(d,J＝8Hz,1H),8.38(s,1H),8.30(s,1H),8.27-8.24,(dd,J＝8,4Hz,1H),8.12-8.06(m,3H),7.84-7.80(t,J＝8Hz,1H),4.82(s,2H),2.81-2.80(d,J＝4Hz,3H).

Example 1: preparation of 2-fluoro-N-methyl-4- [7- [ (quinolin-6-yl) methyl ] imidazo [1,2-B ] - [1,2,4] triazin-2-yl ] benzamide dihydrochloride (crystalline I of Compound 1)

100mg of compound 1 was weighed, added to 2mL of methanol, heated to 50 ℃ to dissolve, and then dropped into 20mL of ethyl acetate to precipitate a solid, which was centrifuged after 1 hour and dried at 40 ℃ to obtain a solid. The solid was subjected to XRPD detection, and the resulting XRPD pattern is shown in fig. 1, i.e. crystal i.

Example 2: preparation of 2-fluoro-N-methyl-4- [7- [ (quinolin-6-yl) methyl ] imidazo [1,2-B ] - [1,2,4] triazin-2-yl ] benzamide dihydrochloride (crystalline I of Compound 1)

80mg of compound 1 is weighed, put into 2mL of methanol, heated to 45 ℃ to be dissolved, dropped into 20mL of acetone to precipitate solid, centrifuged after 1h, and dried at 40 ℃ to obtain the solid. And (3) carrying out XRPD detection on the solid, and obtaining an XRPD pattern which is consistent with the pattern shown in figure 1, namely the crystal I.

Example 3: preparation of 2-fluoro-N-methyl-4- [7- [ (quinolin-6-yl) methyl ] imidazo [1,2-B ] - [1,2,4] triazin-2-yl ] benzamide dihydrochloride (crystalline II of Compound 1)

Weighing 100mg of compound 1, putting the compound into 2mL of methanol, heating to 45 ℃ to dissolve the compound, pouring the solution into 20mL of acetonitrile, separating out a solid, centrifuging after 1h, and drying at 40 ℃ to obtain the solid. The solid was subjected to XRPD detection, and the resulting XRPD pattern is shown in fig. 3, i.e. crystal ii.

Example 4: preparation of 2-fluoro-N-methyl-4- [7- [ (quinolin-6-yl) methyl ] imidazo [1,2-B ] - [1,2,4] triazin-2-yl ] benzamide dihydrochloride (Crystal III of Compound 1)

Weighing 100mg of compound 1, putting the compound 1 into 1mL of methanol, heating the mixture to 60 ℃ to dissolve the compound, slowly dropwise adding the mixture into 1mL of mixed solvent (300 microliters of methanol and 700 microliters of tetrahydrofuran) at room temperature to separate out solid, centrifuging the mixture after 1 hour, and drying the solid at 40 ℃ to obtain the solid. The solid was subjected to XRPD detection and the resulting XRPD pattern is shown in figure 5, i.e. crystal iii.

Example 5: preparation of 2-fluoro-N-methyl-4- [7- [ (quinolin-6-yl) methyl ] imidazo [1,2-B ] - [1,2,4] triazin-2-yl ] benzamide dihydrochloride (Crystal III of Compound 1)

Weighing 100mg of compound 1, putting the compound into 1mL of methanol, heating to 60 ℃ to dissolve the compound, pouring the compound into 2mL of toluene, separating out solid, circularly heating and cooling at 20-40 ℃, centrifuging after 4h, and drying at 40 ℃ to obtain the solid. The solid was subjected to XRPD detection and the resulting XRPD pattern is shown in figure 5, i.e. crystal iii.

Example 6: stability study of 2-fluoro-N-methyl-4- [7- [ (quinolin-6-yl) methyl ] imidazo [1,2-B ] - [1,2,4] triazin-2-yl ] benzamide dihydrochloride (Compound 1) in each crystal form

Samples of each crystalline form stored in open-top vials under light (4500lx ± 500lx), 60 ℃ and RH 92.5% conditions were examined and analyzed by XRPD and HPLC for 5 days, 10 days. The results are shown in tables 1 to 3.

Table 1 results of study on illumination stability of crystal form I, crystal form II and crystal form III of compounds

TABLE 2 study results of high temperature 60 deg.C stability of compound crystal I, crystal II and crystal III

TABLE 3 study results of high humidity 92.5% stability of compound crystal I, crystal II and crystal III

Example 7: solubility test of each crystal form of 2-fluoro-N-methyl-4- [7- [ (quinolin-6-yl) methyl ] imidazo [1,2-B ] - [1,2,4] triazin-2-yl ] benzamide dihydrochloride (Compound 1)

And (3) determining the solubility of the crystal form I, the crystal form II and the crystal form III by an HPLC external standard method in different mediums at 25 ℃. The pH7.4 buffer was prepared as follows: taking 1 invitrogen ^TM And dissolving Phosphate Buffer Salin (PBS) to 100ml to obtain the product. The results are shown in Table 4.

TABLE 4 solubility test results for Compound 1 form I, form II and form III

The crystal forms I, II and III have good solubility in the three solvents, and the difference between the solubility in 0.1N HCl aqueous solution and the solubility in pH7.4 buffer solution is small, so that the risk of precipitation of the medicine after entering intestinal juice is avoided, and the bioavailability of the medicine is improved.

Example 8: pharmacological test of each crystal form of 2-fluoro-N-methyl-4- [7- [ (quinolin-6-yl) methyl ] imidazo [1,2-B ] - [1,2,4] triazin-2-yl ] benzamide dihydrochloride (compound 1) in rats

The test method comprises the following steps: the 9 SD rats were randomly divided into 3 groups (n ═ 3) according to body weight, and each group was designated as A, B, C groups, and each of form I, form II, and form III was administered once through oral gavage at a dose of 20mg/kg (0 d when administered). Before administration, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h and 1d (24h) of blood is taken from vein and 0.25ml of blood plasma is separated, and the collected blood plasma is stored in a refrigerator at-80 ℃ for testing. The plasma concentration is measured by LC-MS/MS by adopting a protein precipitation method, a drug time curve is fitted, pharmacokinetic parameters are calculated, and the measurement results are shown in the following table.

From experimental data, the crystal form I, the crystal form II and the crystal form III provided by the application have better pharmacokinetic properties in a rat body after oral gavage administration.

The solid form of compound 1 and the preparation method thereof disclosed in the present application can be implemented by appropriately changing the raw materials, process parameters and the like by referring to the contents in the present application. While the methods and products of the present application have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that the techniques of the present application can be practiced with modification, or with appropriate modification, and combinations of the methods and products described herein without departing from the spirit and scope of the present application. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and content of this application.

Claims

1. Compound 1, crystalline I, characterized in that it has an X-ray powder diffraction pattern comprising characteristic peaks at diffraction angles (2 θ) of 5.18 ± 0.2 °, 7.43 ± 0.2 °, 8.74 ± 0.2 °, 12.56 ± 0.2 °, 15.00 ± 0.2 ° and 16.12 ± 0.2 °,

2. the crystal I according to claim 1, characterized in that the X-ray powder diffraction pattern of the crystal I comprises characteristic peaks at diffraction angles (2 θ) of 5.18 ± 0.2 °, 7.43 ± 0.2 °, 8.74 ± 0.2 °, 12.56 ± 0.2 °, 15.00 ± 0.2 °, 15.73 ± 0.2 °, 16.12 ± 0.2 °, 19.70 ± 0.2 ° and 22.52 ± 0.2 °;

preferably, the X-ray powder diffraction pattern of said crystal I comprises characteristic peaks at diffraction angles (2 θ) of 5.18 ± 0.2 °, 7.43 ± 0.2 °, 8.74 ± 0.2 °, 12.56 ± 0.2 °, 15.00 ± 0.2 °, 15.73 ± 0.2 °, 16.12 ± 0.2 °, 19.70 ± 0.2 °, 22.52 ± 0.2 °, 26.83 ± 0.2 °, 27.51 ± 0.2 ° and 28.15 ± 0.2 °;

preferably, the XRPD pattern of crystal I comprises characteristic peaks at the following diffraction angles (2 θ), wherein the 2 θ values are within ± 0.2 °:

preferably, the XRPD pattern of crystal I comprises a peak at diffraction angle (2 Θ) substantially the same as shown in fig. 1;

preferably, the crystal I has an X-ray powder diffraction pattern as shown in FIG. 1.

3. The crystal I according to claim 1 or 2, characterized in that the DSC pattern of the crystal I shows an endothermic peak at 250 ± 5 ℃;

preferably, the DSC profile of said crystal I comprises characteristic peaks at substantially the same temperatures as shown in figure 2;

preferably, the DSC pattern of said crystal I is shown in figure 2.

4. Compound 1, crystalline form II, characterized in that said crystalline form II has an X-ray powder diffraction pattern comprising characteristic peaks at diffraction angles (2 θ) of 6.62 ± 0.2 °, 7.09 ± 0.2 °, 9.49 ± 0.2 °, 14.32 ± 0.2 °, 15.65 ± 0.2 ° and 25.15 ± 0.2 °.

5. The crystal II according to claim 4, characterized in that the X-ray powder diffraction pattern of the crystal II comprises characteristic peaks at diffraction angles (2 θ) of 6.62 ± 0.2 °, 7.09 ± 0.2 °, 9.49 ± 0.2 °, 11.71 ± 0.2 °, 12.26 ± 0.2 °, 14.32 ± 0.2 °, 15.65 ± 0.2 °, 20.27 ± 0.2 ° and 25.15 ± 0.2 °;

preferably, the X-ray powder diffraction pattern of said crystal II comprises characteristic peaks at diffraction angles (2 θ) of 6.62. + -. 0.2 °, 7.09. + -. 0.2 °, 9.49. + -. 0.2 °, 11.71. + -. 0.2 °, 12.26. + -. 0.2 °, 14.32. + -. 0.2 °, 15.65. + -. 0.2 °, 20.27. + -. 0.2 °, 22.65. + -. 0.2 °, 23.15. + -. 0.2 °, 25.15. + -. 0.2 °, 26.94. + -. 0.2 °, 28.00. + -. 0.2 ° and 29.11. + -. 0.2 °;

preferably, the XRPD pattern of crystal II comprises characteristic peaks at the following diffraction angles (2 Θ), with 2 Θ values having a range of error of ± 0.2 °:

preferably, the XRPD pattern of crystal II comprises a peak at diffraction angle (2 Θ) substantially the same as shown in figure 3;

preferably, the X-ray powder diffraction pattern of the crystal II is shown in figure 3.

6. The crystal II according to claim 4 or 5, characterized in that it has a Differential Scanning Calorimetry (DSC) pattern in which an endothermic peak appears at 174 ± 5 ℃;

preferably, the DSC profile of said crystal II comprises characteristic peaks at substantially the same temperatures as shown in figure 4;

preferably, the DSC pattern of said crystal II is shown in figure 4.

7. Compound 1, crystal III, characterized in that said crystal III has an X-ray powder diffraction pattern comprising characteristic peaks at diffraction angles (2 θ) of 6.36. + -. 0.2 °, 10.39. + -. 0.2 °, 13.79. + -. 0.2 °, 22.94. + -. 0.2 °, 24.64. + -. 0.2 ° and 28.17. + -. 0.2 °.

8. The crystal III according to claim 7, characterized in that the crystal III has an X-ray powder diffraction pattern comprising characteristic peaks at diffraction angles (2 θ) of 6.36 ± 0.2 °, 8.16 ± 0.2 °, 10.39 ± 0.2 °, 13.79 ± 0.2 °, 22.94 ± 0.2 °, 24.15 ± 0.2 °, 24.64 ± 0.2 °, 26.91 ± 0.2 ° and 28.17 ± 0.2 °;

preferably, the XRPD pattern for crystal III includes characteristic peaks at diffraction angles (2 θ) of 6.36 ± 0.2 °, 8.16 ± 0.2 °, 10.39 ± 0.2 °, 13.50 ± 0.2 °, 13.79 ± 0.2 °, 16.48 ± 0.2 °, 16.66 ± 0.2 °, 17.89 ± 0.2 °, 18.25 ± 0.2 °, 22.94 ± 0.2 °, 24.15 ± 0.2 °, 24.64 ± 0.2 °, 26.91 ± 0.2 ° and 28.17 ± 0.2 °;

more preferably, the XRPD pattern of crystal iii comprises characteristic peaks at the following diffraction angles (2 θ), wherein the 2 θ values are within ± 0.2 °:

2θ(°)±0.2° 2θ(°)±0.2° 6.36 25.54 7.59 25.82 8.16 26.32 10.39 26.91 11.78 27.25 12.49 27.58 12.86 28.17 13.50 28.51 13.79 28.90 14.75 29.38 15.28 29.79 15.68 30.56 16.23 31.21 16.48 31.47 16.66 31.77 17.69 31.98 17.89 32.41 18.25 32.73 19.67 32.97 20.39 33.42 20.58 34.38 21.01 34.71 21.24 35.20 21.73 35.98 22.94 36.28 23.50 36.96 24.15 38.41 24.64 38.90

in a more preferred embodiment, the XRPD pattern of crystal iii comprises peaks at diffraction angles (2 θ) substantially the same as shown in figure 5; in a most preferred embodiment, the XRPD pattern of crystal iii is as shown in figure 5.

9. A process for preparing the crystal I of compound 1 according to any one of claims 1 to 3, comprising the steps of:

putting the compound 1 in a proper solvent 1, heating to a proper temperature for dissolving, then dropwise adding a crystallization solvent, separating out a solid, centrifuging, and drying to obtain a crystal I of the compound 1;

the 1 st suitable solvent is selected from: one or more of methanol, ethanol, n-propanol and n-butanol; preferably methanol;

the crystallization solvent is selected from one or more of ethyl acetate, acetone, toluene, methyl tert-butyl ether and n-heptane.

10. A process for preparing the crystalline form II of compound 1 according to any one of claims 4 to 6, comprising the steps of:

putting the compound 1 in a proper solvent of the 2 nd step, heating to a proper temperature for dissolving, then adding a crystallization solvent, separating out a solid, centrifuging, and drying to obtain a crystal II of the compound 1;

the 2 nd suitable solvent is selected from: one or more of methanol, ethanol, n-propanol, isopropanol, and n-butanol; preferably methanol; the crystallization solvent is acetonitrile.

11. A process for preparing a crystal iii of compound 1 according to any one of claims 7 to 8, comprising the steps of:

putting the compound 1 in a proper solvent of the 3 rd step, heating to a proper temperature for dissolving, then adding a crystallization solvent, separating out a solid, centrifuging and drying to obtain a crystal III of the compound 1;

the 3 rd suitable solvent is selected from: one or more of methanol, ethanol, n-propanol, isopropanol, and n-butanol; preferably methanol;

the crystallization solvent is one or more of toluene, tetrahydrofuran, 1, 4-dioxane and methanol; preferably, the crystallization solvent is toluene, or a mixed solution of methanol and tetrahydrofuran.

12. A pharmaceutical composition comprising the crystal I of any one of claims 1 to 3, the crystal II of any one of claims 4 to 6, and/or the crystal iii of any one of claims 7 to 8, and one or more pharmaceutically acceptable carriers.

13. Use of the crystal I of any one of claims 1 to 3, the crystal II of any one of claims 4 to 6, the crystal iii of any one of claims 7 to 8, and/or the pharmaceutical composition of claim 12 for the preparation of a medicament for the prevention or treatment of a neoplastic disease; preferably, the neoplastic disease is non-small cell lung cancer (NSCLC).