CN111171009A

CN111171009A - Entrictinib crystal form and preparation method thereof

Info

Publication number: CN111171009A
Application number: CN202010028370.1A
Authority: CN
Inventors: 李庆秋; 申淑匣; 张良
Original assignee: Jiangsu Acebright Pharmaceutical Co ltd; Shanghai Acebright Pharmaceuticals Group Co ltd; Anlite Shanghai Pharmaceutical Technology Co ltd
Current assignee: Arizest Shanghai Pharmatech Co ltd; JIANGSU XIDI PHARMACEUTICAL CO Ltd; Shanghai Acebright Pharmaceuticals Group Co ltd
Priority date: 2020-01-10
Filing date: 2020-01-10
Publication date: 2020-05-19
Anticipated expiration: 2040-01-10
Also published as: CN111171009B; WO2021139797A1

Abstract

The invention provides an enretinib crystal form and a preparation method thereof. Specifically, the invention provides a crystal form of a compound shown as a formula I, wherein the crystal form is a crystal form AZT-A, a crystal form AZT-B or a crystal form AZT-E. Compared with the existing crystal form of the enretinib, the crystal form of the invention has the advantages of more excellent solubility, good stability, renewed electrostatic action, simple preparation process, strong operability, high yield, stable quality, short production period and easy realization of large-scale production.

Description

Entrictinib crystal form and preparation method thereof

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to a crystal form of enretinib and a preparation method thereof.

Background

The chemical name of the Entrictinib is Entrectinib: n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4-methylpiperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide with the trade name: rozlytrek, molecular formula: c₃₁H₃₄F₂N₆O₂The molecular weight is: 560.64, CAS number: 1108743-60-7, the chemical structural formula is:

this drug was developed by roche as a treatment for NTRK fusion positive advanced or recurrent solid tumor disease and marketed in japanese application 2019.6.19.

Patent WO2013174876 discloses

crystalline forms

1, 2 and 3 of entitricinib and methods of preparing the same. Wherein the crystal form 1 and the crystal form 2 are anhydrous substances, the crystal form 3 is a solvate of ethyl acetate and n-hexane, the crystal form 2 has good stability, and the crystal form 1 has poor stability and is easy to convert into the crystal form 2.

Patent WO2017202674 discloses an anhydrate form 4 of enretinib which is more thermodynamically stable above 40 ℃.

Obviously, the existing crystal form 1 of the enretinib has the problem of poor crystal form stability, and the

crystal forms

2 and 4 have the problem of poor solubility. Moreover, according to FDA data, emtricinib is a low solubility drug.

In view of the above, there is an urgent need in the art to develop a new crystal form having both good solubility and good crystal form stability to meet the pharmaceutical requirements of the formulation.

Disclosure of Invention

The invention aims to provide a novel crystal form with good solubility and good crystal form stability so as to meet the requirement of medicinal preparation.

In a first aspect of the invention, there is provided a crystalline form of a compound of formula I,

the crystal form is a crystal form AZT-A, a crystal form AZT-B or a crystal form AZT-E.

In another preferred embodiment, the crystalline form is form AZT-a and the XRPD pattern of said crystalline form AZT-a comprises 4 or more 2 Θ values selected from the group consisting of: 7.9 +/-0.2 degrees, 9.4 +/-0.2 degrees, 14.4 +/-0.2 degrees, 15.4 +/-0.2 degrees, 16.0 +/-0.2 degrees and 20.6 +/-0.2 degrees.

In another preferred embodiment, the form AZT-a further comprises an XRPD pattern comprising 1 or more 2 Θ values selected from the group consisting of: 13.1 +/-0.2 degrees, 13.9 +/-0.2 degrees, 15.4 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.6 +/-0.2 degrees, 22.7 +/-0.2 degrees, 23.4 +/-0.2 degrees, 24.1 +/-0.2 degrees and 28.0 +/-0.2 degrees.

In another preferred embodiment, the form AZT-a has an XRPD pattern comprising 6 or more 2 θ values selected from the group consisting of: 7.9 +/-0.2 degrees, 9.4 +/-0.2 degrees, 13.1 +/-0.2 degrees, 13.9 +/-0.2 degrees, 14.4 +/-0.2 degrees, 15.4 +/-0.2 degrees, 16.0 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.6 +/-0.2 degrees, 20.6 +/-0.2 degrees, 22.7 +/-0.2 degrees, 23.4 +/-0.2 degrees, 24.1 +/-0.2 degrees and 28.0 +/-0.2 degrees.

In another preferred embodiment, the crystal form AZT-A loses 0.3 +/-0.1% of weight in the temperature range of 30-150 ℃.

In another preferred embodiment, the crystalline form AZT-A has an endothermic peak at 162.5. + -. 0.5 ℃ and 196.78. + -. 0.5 ℃ respectively.

In another preferred embodiment, the crystalline form AZT-a has an XRPD pattern substantially as shown in figure 1.

In another preferred embodiment, the crystalline form AZT-a has a TGA profile substantially as shown in figure 2.

In another preferred embodiment, the crystalline form AZT-a has a DSC profile substantially as shown in figure 3.

In another preferred embodiment, the crystalline form AZT-A has a structure substantially as shown in figure 4¹H-NMR spectrum.

In another preferred embodiment, the crystalline form is form AZT-B and the XRPD pattern of said crystalline form AZT-B comprises 3 or more 2 Θ values selected from the group consisting of: 7.4 +/-0.2 degrees, 8.1 +/-0.2 degrees, 14.8 +/-0.2 degrees, 17.2 +/-0.2 degrees and 19.9 +/-0.2 degrees.

In another preferred embodiment, the form AZT-B is further characterized by an XRPD pattern comprising 1 or more 2 θ values selected from the group consisting of: 11.4 +/-0.2 degrees, 12.0 +/-0.2 degrees, 20.9 +/-0.2 degrees, 22.3 +/-0.2 degrees, 23.5 +/-0.2 degrees and 24.1 +/-0.2 degrees.

In another preferred embodiment, the form AZT-B has an XRPD pattern comprising 6 or more 2 θ values selected from the group consisting of: 7.4 +/-0.2 degrees, 8.1 +/-0.2 degrees, 11.4 +/-0.2 degrees, 12.0 +/-0.2 degrees, 14.8 +/-0.2 degrees, 17.2 +/-0.2 degrees, 19.9 +/-0.2 degrees, 20.9 +/-0.2 degrees, 22.3 +/-0.2 degrees, 23.5 +/-0.2 degrees and 24.1 +/-0.2 degrees.

In another preferred example, the crystal form AZT-B loses 0.8 +/-0.1 percent of weight within the range of 30-150 ℃;

in another preferred embodiment, the crystal form AZT-B has a melting endothermic peak at 147.3 +/-0.5 ℃.

In another preferred embodiment, the crystalline form AZT-B has an XRPD pattern substantially as shown in figure 5.

In another preferred embodiment, the crystalline form AZT-B has a TGA profile substantially as shown in figure 6.

In another preferred embodiment, the crystalline form AZT-B has a DSC profile substantially as shown in figure 7.

In another preferred embodiment, the crystalline form AZT-B has a 1H-NMR spectrum substantially as shown in figure 8.

In another preferred embodiment, the crystalline form is form AZT-E and the XRPD pattern of said crystalline form AZT-E comprises 3 or more than 3 2 Θ values selected from the group consisting of: 8.9 +/-0.2 degrees, 10.5 +/-0.2 degrees, 16.6 +/-0.2 degrees and 17.2 +/-0.2 degrees.

In another preferred embodiment, the form AZT-E further comprises an XRPD pattern comprising 1 or more 2 Θ values selected from the group consisting of: 15.9 +/-0.2 degrees, 17.0 +/-0.2 degrees, 17.9 +/-0.2 degrees, 22.8 +/-0.2 degrees and 24.7 +/-0.2 degrees.

In another preferred embodiment, the form AZT-E has an XRPD pattern comprising 6 or more 2 θ values selected from the group consisting of: 8.9 +/-0.2 degrees, 10.5 +/-0.2 degrees, 15.9 +/-0.2 degrees, 16.6 +/-0.2 degrees, 17.0 +/-0.2 degrees, 17.2 +/-0.2 degrees, 17.9 +/-0.2 degrees, 22.8 +/-0.2 degrees and 24.7 +/-0.2 degrees.

In another preferred embodiment, the crystal form AZT-E loses weight by about 3.3 +/-0.1 percent in the range of 50-150 ℃;

in another preferred embodiment, the crystal form AZT-E has a dehydration peak at 126.35 +/-0.5 ℃ and a melting endothermic peak at 197.15 +/-0.5 ℃.

In another preferred embodiment, the crystalline form AZT-E has an XRPD pattern substantially as shown in figure 11.

In another preferred embodiment, the crystalline form AZT-E has a TGA profile substantially as shown in figure 12.

In another preferred embodiment, the crystalline form AZT-E has a DSC profile substantially as shown in figure 13.

In another preferred embodiment, the crystalline form AZT-E has a 1H-NMR spectrum substantially as shown in figure 14.

In a second aspect of the invention, there is provided a process for the preparation of the crystalline form of the first aspect;

the method comprises the following steps: (i) providing a solution of an enretinib raw material in a first solvent, precipitating a solid in the solution, and collecting the precipitated solid to obtain the crystal form;

or,

the method comprises the following steps: (ii) providing a mixture of the raw material of the enretinib in a second solvent, processing the mixture, and collecting solid in the mixture, thereby obtaining the crystal form; wherein, the treatment refers to stirring, pulping and/or grinding;

or,

the method comprises the following steps: (iii) treating an enretinib raw material to obtain the crystal form; wherein, the treatment refers to heat treatment and/or drying treatment;

wherein the raw material of the enretinib is an amorphous and/or crystal form of the enretinib.

In another preferred embodiment, in step (i), the solution is seeded to precipitate a solid by adding seed crystals, allowing the solution to cool and/or removing the first solvent.

In another preferred embodiment, the seed crystal is in the form of the first aspect, preferably, in the form of AZT-a.

In another preferred example, in the step (i), the concentration of the entiretiib in the solution is 0.005-1.0 g/mL, preferably 0.01-0.2 g/mL.

In another preferred embodiment, step (i) further comprises an optional drying step after collecting the precipitated solid.

In another preferred embodiment, in step (i), the precipitated solid is collected by filtration.

In another preferred embodiment, in the step (i), when the solution is cooled to precipitate a solid in the solution, the temperature of the solution is 10 to 100 ℃ (preferably 20 to 80 ℃; more preferably 40 to 70 ℃); and/or cooling to less than or equal to 20 deg.C (more preferably less than or equal to 10 deg.C; most preferably less than or equal to 5 deg.C).

In another preferred embodiment, in step (ii), the treatment is carried out at 0 to 70 ℃ (preferably 0 to 50 ℃).

In another preferred example, in the step (ii), the mass-to-volume (mg/ml) ratio of the raw material of the enretinib to the second solvent is (10-500): 1.

In another preferred example, in the step (ii), the treatment time is 1-48 h; preferably, 2-36 h; more preferably, 3-24 h.

In another preferred embodiment, in step (ii), the solid is collected by filtration.

In another preferred embodiment, in step (ii), an optional drying step is further included after collecting the solids therein.

In another preferred embodiment, in step (iii), the heat treatment is heating to 50-100 ℃ and/or holding for 1-5 h.

In another preferred embodiment, the first solvent is selected from: an alcohol solvent, an ester solvent, a ketone solvent, a haloalkane solvent, acetonitrile, an aromatic solvent, or a combination thereof; or, the first solvent is a mixed solvent of water and a solvent selected from the group consisting of: an alcohol solvent, an ester solvent, a ketone solvent, a haloalkane solvent, or a combination thereof.

In another preferred embodiment, the second solvent is selected from: an alcohol solvent, an ester solvent, a ketone solvent, a haloalkane solvent, acetonitrile, an ether solvent, or a combination thereof; or, the first solvent is a mixed solvent of water and a solvent selected from the group consisting of: an alcohol solvent, an ester solvent, a ketone solvent, a haloalkane solvent, acetonitrile, an aromatic solvent, or a combination thereof.

In another preferred embodiment, the ester solvent is a C2-C6 ester solvent; preferably, the ester solvent is selected from: ethyl acetate, isopropyl acetate, ethyl formate, methyl acetate, n-propyl acetate, butyl acetate, or combinations thereof.

In another preferred embodiment, the alcohol solvent is a C1-C4 alcohol solvent; preferably, the alcoholic solvent is selected from: methanol, ethanol, isopropanol, or a combination thereof.

In another preferred embodiment, the halogenated hydrocarbon solvent is a C1-C4 halogenated hydrocarbon solvent; preferably, the halogenated hydrocarbon solvent is dichloromethane.

In another preferred embodiment, the ketone solvent is a C2-C6 ketone solvent; preferably, the ketone solvent is selected from: acetone, MIBK, or combinations thereof.

In another preferred embodiment, the aromatic solvent is a C6-C10 aromatic hydrocarbon; preferably, toluene.

In another preferred example, the ether solvent is a cyclic ether solvent or a chain ether solvent.

In another preferred embodiment, the cyclic ether-based solvent is selected from the group consisting of: 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, or a combination thereof.

In another preferred embodiment, the first solvent is selected from: methanol, ethanol, acetonitrile, toluene, acetone, ethyl acetate, ethyl formate, methyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, dichloromethane, MIBK, or a combination thereof; or, water and a mixed solvent selected from the group consisting of: methanol, ethanol, acetonitrile, toluene, acetone, ethyl acetate, ethyl formate, methyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, methylene chloride, MIBK, or combinations thereof.

In another preferred embodiment, the second solvent is selected from: methanol, ethanol, acetonitrile, toluene, acetone, ethyl acetate, dichloromethane, MIBK, 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran (2-MeTHF), or a combination thereof; or, water and a mixed solvent selected from the group consisting of: methanol, ethanol, acetonitrile, toluene, acetone, ethyl acetate, methylene chloride, MIBK, 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, or a combination thereof.

In another preferred embodiment, when the crystal form is AZT-A, the preparation method is method A1 or method A2.

In another preferred embodiment, the method is method a1, and the method a1 comprises the steps of: providing a solution of an enretinib raw material in a solvent A, cooling and crystallizing, collecting precipitated solid, and drying the obtained solid to obtain the crystal form AZT-A.

In another preferred example, in the method A1, the solvent A is a solvent capable of completely dissolving the raw material of the enretinib at a temperature of 10-150 ℃.

In another preferred embodiment, in method a1, the solvent a is selected from: an alcohol solvent, an ester solvent, a ketone solvent, a haloalkane solvent, acetonitrile, an aromatic solvent, or a combination thereof.

In another preferred example, in method a1, the solvent a is an ester solvent, or a mixed solvent containing an ester solvent; wherein the mixed solvent containing the ester solvent is a mixed solvent composed of the ester solvent and a solvent selected from the following group: an alcohol solvent, a ketone solvent, a halogenated hydrocarbon solvent, or a combination thereof.

In another preferred example, in the method A1, the concentration of the entinostinib in the solution is 0.005-1.0 g/mL, preferably 0.01-0.2 g/mL.

In another preferred example, in the method A1, the temperature of the solution is 10-100 ℃; preferably, 20 to 80 ℃; more preferably, 40 to 70 ℃.

In another preferred example, in the method A1, the crystallization temperature of the cooling crystallization is less than or equal to 20 ℃; more preferably, less than or equal to 10 ℃; most preferably, 5 ℃ or less.

In another preferred example, in the method A1, the crystallization temperature of the cooling crystallization is less than the solution temperature.

In another preferred example, in the method a1, the raw material of the enretinib is amorphous and/or crystalline form of the enretinib.

In another preferred embodiment, the method is method a2, and the method a2 comprises the steps of: the raw material of the enretinib is at T_ATemperature t at temperature_AAnd (4) carrying out the reaction for a while to obtain the crystal form AZT-A.

In another preferred example, in the method a2, the raw material of the enretinib is an amorphous and/or crystalline form of the enretinib; preferably, the crystal form is the crystal form AZT-C of the Entricinib.

In another preferred embodiment, the XRPD pattern of crystalline form AZT-C comprises all 2 Θ values selected from the group consisting of 18.1 ± 0.2 °, 23.1 ± 0.2 °, 25.5 ± 0.2 °.

In another preferred embodiment, in method A2, T_A60-100 ℃ under normal temperature; preferably, T_A＝70～90℃。

In another preferred embodiment, in method A2, t_A1-10 h; preferably, t_A＝3～7h。

In another preferred embodiment, when the crystal form is AZT-B, the preparation method is method B1 or method B2.

In another preferred embodiment, the preparation method is method B1, and the method B1 comprises the steps of: providing a mixture of an enretinib raw material in a solvent B, pulping or stirring, collecting solids in the mixture, and drying the obtained solids to obtain the crystal form AZT-B.

In another preferred embodiment, in the method B1, the mixture is beaten or stirred at 0-70 deg.C (preferably 0-50 deg.C, more preferably 10-40 deg.C).

In another preferred embodiment, in the method B1, the beating or stirring time is 1-24 h; preferably, the time is 2 to 24 hours.

In another preferred example, in the method B1, the mass-to-volume (mg/ml) ratio of the raw material of the emtricinib to the solvent B is (10-500): 1; preferably (10-50): 1 or (150-300): 1.

In another preferred embodiment, the solvent B is selected from: an alcoholic solvent, acetonitrile, or a combination thereof.

In another preferred embodiment, the solvent B is selected from: methanol, ethanol, acetonitrile, toluene, acetone, ethyl acetate, dichloromethane, MIBK, or a combination thereof; preferably, it is selected from: methanol, ethanol, acetonitrile, or combinations thereof.

In another preferred example, in the method B1, the raw material of the enretinib is an amorphous and/or crystalline form of the enretinib.

In another preferred embodiment, the preparation method is method B2, and the method B2 comprises the steps of: the raw material of the enretinib is at T_BDrying at the temperature to obtain a crystal form AZT-B;

in another preferred example, in the method B2, the raw material of the enretinib is an amorphous and/or crystalline form of the enretinib.

In another preferred example, in the method B2, the raw material of the enretinib is crystal form AZT-D of the enretinib.

In another preferred embodiment, the form AZT-D has an XRPD pattern comprising 3 or more 2 θ values selected from 7.1 ± 0.2 °, 7.4 ± 0.2 °, 13.4 ± 0.2 °, 17.6 ± 0.2 °, 19.8 ± 0.2 °, 22.6 ± 0.2 °.

In another preferred embodiment, in method B2, T_BThe temperature is 40-80 ℃; preferably, T_B＝50～60℃。

In another preferred example, in the method B2, the drying time is 1-48 hours; preferably, 2 to 36 hours; more preferably, 12 to 24 hours.

In another preferred embodiment, when the crystal form is AZT-E, the preparation method is method E.

In another preferred embodiment, the method is method E, and the method E comprises the steps of: providing a mixture of an enretinib raw material in a solvent E and water, pulping or stirring, collecting solids in the mixture, and drying the obtained solids to obtain the crystal form AZT-E.

In another preferred embodiment, in method E, at T_E1Beating or stirring at temperature, and T_E10-50 deg.C; preferably, T_E10-40 ℃; more preferably, T _E10 to 5 ℃ or 15 to 30 ℃.

In another preferred embodiment, in the method E, the beating time is t_E1And t is_E1The time is more than or equal to 2 hours; preferably, t_E1≥12h。

In another preferred embodiment, the method E comprises the steps of:

(e1) at T_E2At the temperature, firstly, the raw material of the enretinib is beaten or stirred in a solvent E_E2Adding water to obtain a mixture of the raw material of the enretinib in the solvent E and the water; or

Mixing an enretinib raw material with a mixed solvent of a solvent E and water to obtain a mixture of the enretinib raw material in the solvent E and the water;

(e2) at T_E1Beating or stirring the mixture of the raw material of the enretinib in the solvent E and the water at the temperature_E1Time, collecting a solid from the mixture, and drying the resulting solid to obtain form AZT-E.

In another preferred embodiment, in method E, t_E20.1-1 hour; preferably, t_E20.4-0.6 hours.

In another preferred embodiment, T_E20-50 ℃; preferably, T_E210-40 ℃; more preferably, T_E2＝15～30℃。

In another preferred embodiment, the solvent E is selected from: an alcohol solvent, an ester solvent, a ketone solvent, a haloalkane solvent, acetonitrile, an aromatic solvent, or a combination thereof.

In another preferred embodiment, the solvent E is an alcohol solvent.

In another preferred embodiment, the solvent E is selected from: methanol, ethanol, or a combination thereof.

In another preferred example, in the method E, the volume ratio of the solvent E to the water is (0.1-10): 1; preferably (0.2-5): 1.

In another preferred example, in the method E, the mass-to-volume (g/ml) ratio of the enretinib to the solvent E is (0.05-0.5): 1.

In another preferred example, in the method E, the mass-to-volume (g/ml) ratio of the enretinib to the water is (0.015-1.5): 1.

In another preferred example, in the method E, the raw material of the enretinib is an amorphous and/or crystalline form of the enretinib; preferably, it is selected from: form AZT-A, form AZT-B, form AZT-C, or a combination thereof.

In a third aspect of the invention, there is provided an amorphous form of a compound of formula I,

the amorphous form has an XPRD spectrum substantially as shown in figure 21.

In another preferred example, the amorphous form has a glass transition peak at 80 to 100 ℃ in a DSC chart.

In another preferred embodiment, the amorphous form has a DSC profile substantially as shown in figure 22.

In another preferred embodiment, the amorphous form loses weight by 0.2 ± 0.1% in the range of 15 ℃ to 100 ℃.

In another preferred embodiment, the amorphous form has a TGA profile substantially as shown in figure 23.

In a fourth aspect of the present invention, there is provided a method for producing the amorphous form of the third aspect, comprising the steps of:

1) providing a solution of an enretinib raw material in a solvent 1;

2) adding a solvent 2 into the solution for crystallization, and collecting precipitated solids to obtain amorphous.

In another preferred example, the concentration of the enretinib in the solution is 0.005-1.0 g/mL; preferably, it is 0.01-0.1 g/mL; more preferably, it is 0.01 to 0.02 g/mL.

In another preferred example, the raw material of the enretinib is a crystal form and/or an amorphous form of the enretinib.

In another preferred embodiment, the solvent 1 is selected from the group consisting of: methanol, ethanol, isopropanol, acetonitrile, toluene, acetone, ethyl acetate, dichloromethane, MIBK, toluene, or combinations thereof; and/or

The solvent 2 is selected from the group consisting of: n-heptane, n-hexane, methyl tert-ether, water, anisole, or combinations thereof.

In another preferred embodiment, the solvent 2 is n-hexane.

In a fifth aspect of the invention, there is provided a pharmaceutical composition comprising (i) the crystalline form of the first aspect; and (ii) a pharmaceutically acceptable carrier.

In a sixth aspect of the invention, there is provided a use of the crystalline form according to the first aspect for the preparation of a medicament for the treatment of cancer and/or tumor.

In another preferred embodiment, the cancer is non-small cell lung cancer; more preferably, it is a metastatic ROS1 positive non-small cell lung cancer (NSCLC).

In another preferred embodiment, the tumor is a solid tumor.

In a seventh aspect of the invention, a crystal form of the compound shown in formula I is provided, wherein the crystal form is crystal form AZT-C; and the XRPD pattern of the crystal form AZT-C comprises all 2 theta values selected from the following groups of 18.1 +/-0.2 degrees, 23.1 +/-0.2 degrees and 25.5 +/-0.2 degrees.

In another preferred embodiment, the crystalline form AZT-C is used for preparing the crystalline form AZT-A.

In an eighth aspect of the invention, a crystal form of the compound shown in the formula I is provided, wherein the crystal form is a crystal form AZT-D; and the XRPD pattern of the crystal form AZT-D comprises 3 or more than 3 2 theta values selected from the following group, namely 7.1 +/-0.2 degrees, 7.4 +/-0.2 degrees, 13.4 +/-0.2 degrees, 17.6 +/-0.2 degrees, 19.8 +/-0.2 degrees and 22.6 +/-0.2 degrees.

In another preferred embodiment, the crystalline form AZT-D is used for preparing the crystalline form AZT-B.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Drawings

FIG. 1 is an XRPD spectrum of crystalline form AZT-A of enrotinib according to the invention;

FIG. 2 is a TGA spectrum of crystalline form AZT-A of enrotinib according to the present invention;

FIG. 3 is a DSC spectrum of crystalline form AZT-A of enrotinib in accordance with the present invention;

FIG. 4 shows a crystal form AZT-A of the enrotinib¹H-NMR spectrum;

FIG. 5 is an XRPD spectrum of crystalline form AZT-B of enrofloxacin in accordance with the present invention;

FIG. 6 is a TGA spectrum of crystalline form AZT- -B of enrotinib according to the present invention;

FIG. 7 is a DSC spectrum of crystalline form AZT-B of enrofloxacin in accordance with the present invention;

FIG. 8 shows a crystalline form AZT-B of enretinib according to the invention¹H-NMR spectrum;

FIG. 9 is an XRPD spectrum of crystalline form AZT-C of enrofloxacin in accordance with the present invention;

FIG. 10 is an XRPD spectrum of crystalline form AZT-D of enrofloxacin in accordance with the present invention;

FIG. 11 is an XRPD spectrum of crystalline form AZT-E of enrofloxacin in accordance with the present invention;

FIG. 12 is a TGA spectrum of crystalline form AZT-E of enrotinib in accordance with the present invention;

FIG. 13 is a DSC spectrum of crystalline form AZT-E of enrofloxacin in accordance with the present invention;

FIG. 14 shows crystalline form AZT-E of enretinib in accordance with the present invention¹H-NMR spectrum;

FIG. 15 is an XRPD spectrum of crystalline form AZT-F of enrotinib according to the present invention;

FIG. 16 is an XRPD spectrum of crystalline form AZT-G of enrofloxacin in accordance with the present invention;

FIG. 17 is an XRPD spectrum of crystalline form AZT-H of enrofloxacin in accordance with the present invention;

FIG. 18 is a TGA spectrum of crystalline form AZT-H of enrotinib in accordance with the present invention;

FIG. 19 is an XRPD spectrum of crystalline form AZT-I of enrofloxacin in accordance with the present invention;

FIG. 20 is a TGA spectrum of crystalline form AZT-I of enrotinib according to the present invention;

FIG. 21 is an amorphous XRPD spectrum of enretinib according to the present invention;

FIG. 22 is an amorphous DSC spectrum of enrcotinib of the present invention;

FIG. 23 is an amorphous TGA profile of enretinib according to the present invention.

Detailed Description

The inventors have conducted extensive and intensive studies for a long time. A series of novel crystal forms of entitinib having excellent stability (e.g., high humidity and/or heat, pressure stability, etc.), solubility, were unexpectedly prepared. And the preparation method of the crystal forms is simple and easy for industrialization. The present invention has been completed based on this inventor.

Term(s) for

As used herein, "MIBK" refers to methyl isobutyl ketone.

In this context, each abbreviation is used in the conventional sense understood by those skilled in the art, unless otherwise specified.

As used herein, the term "starting material for enretinib" refers to amorphous forms and/or crystalline forms of enretinib (including the crystalline forms mentioned herein and the crystalline forms or amorphous forms mentioned in various documents or patents (e.g., WO2013174876, WO2017202674) that are amorphous, published or unpublished).

As used herein, "crystalline form of the invention" refers to crystalline form AZT-a, crystalline form AZT-B, crystalline form AZT-C, crystalline form AZT-D, crystalline form AZT-E, crystalline form AZT-F, crystalline form AZT-G, crystalline form AZT-H, and crystalline form AZT-I of entitinib, as described herein, particularly to crystalline form AZT-a, crystalline form AZT-B, and crystalline form AZT-E.

General procedure

All test methods of the invention are general methods, and the test parameters are as follows:

XRPD pattern determination method:

x-ray powder diffraction instrument: bruker D2 Phaser X-ray powder diffractometer; radiation source Cu

Generator (Generator) kv: 30 kv; generator (Generator) mA: 10 mA; initial 2 θ: 2.000 °, scan range: 2.0000-35.000 degree.

TGA profile determination method:

thermogravimetric analysis (TGA) instrument: TGA55 model of TA of USA, with a heating rate of 10 within 20-300 deg.C

The nitrogen flow rate is 40mL/min at C/min.

DSC chart measurement method:

differential Scanning Calorimetry (DSC) instrument: TA Q2000 model of TA company, USA, at 25-300 deg.C, heating rate 10 deg.C/min, nitrogen flow rate 50 mL/min.

Method for measuring 1H-NMR chart:

nuclear magnetic resonance hydrogen spectroscopy (1H-NMR) instrument: (ii) a Frequency: 400 MHz; solvent: DMSO.

In the present invention, the method for drying is a conventional drying method in the art unless otherwise specified, for example, drying in the examples of the present invention means drying in vacuum or drying under normal pressure in a conventional drying oven. Generally, the drying is carried out for 0.1 to 50 hours or 1 to 30 hours.

Crystal form AZT-A of enrotinib and preparation method thereof

In a specific embodiment, the crystalline form of the entiretiib provided by the invention is crystalline form AZT-A.

Preferably, the crystalline form AZT-A is an anhydrate of enretinib.

In a specific embodiment, the crystalline form AZT-a of the present invention has characteristic peaks at 2 θ of 7.9 ± 0.2 °, 9.4 ± 0.2 °, 14.4 ± 0.2 °, 15.4 ± 0.2 °, 16.0 ± 0.2 °, 20.6 ± 0.2 ° under powder X-ray diffraction.

In another preferred embodiment, under powder X-ray diffraction, the crystalline form AZT-a also has characteristic peaks at 2 θ of 13.1 ± 0.2 °, 13.9 ± 0.2 °, 15.4 ± 0.2 °, 16.2 ± 0.2 °, 17.6 ± 0.2 °, 20.6 ± 0.2 °, 22.7 ± 0.2 °, 23.4 ± 0.2 °, 24.1 ± 0.2 °, and/or 28.0 ± 0.2 °.

In another preferred embodiment, under powder X-ray diffraction, the crystalline form AZT-a has characteristic peaks at 2 θ of 7.9 ± 0.2 °, 9.4 ± 0.2 °, 13.1 ± 0.2 °, 13.9 ± 0.2 °, 14.4 ± 0.2 °, 15.4 ± 0.2 °, 16.0 ± 0.2 °, 16.2 ± 0.2 °, 17.6 ± 0.2 °, 20.6 ± 0.2 °, 22.7 ± 0.2 °, 23.4 ± 0.2 °, 24.1 ± 0.2 °, 28.0 ± 0.2 °.

In another preferred embodiment, under the powder X-ray diffraction, the relative intensity of a characteristic peak of the crystal form AZT-A at a2 theta of 22.7 +/-0.2 degrees is more than or equal to 90 percent; more preferably, 95% or more; most preferably, about 100%.

In another preferred embodiment, under the powder X-ray diffraction, the relative intensity of a characteristic peak of the crystal form AZT-A at the 2 theta of 20.6 +/-0.2 degrees is more than or equal to 90 percent; more preferably, the relative intensity of the characteristic peak at 20.6 ± 0.2 ° is < 22.7 ± 0.2 °.

In another preferred embodiment, under the powder X-ray diffraction, the relative intensity of the other characteristic peaks of the crystal form AZT-A except the characteristic peaks at 2.7 +/-0.2 degrees and 20.6 +/-0.2 degrees is less than or equal to 90 percent; preferably, less than or equal to 75%.

More preferably, the crystalline form AZT-a of entitinib of the present invention has the following characteristic peaks and relative intensities under powder X-ray diffraction:

In another preferred example, in a TGA diagram, the AZT-A crystal form loses 0.3 +/-0.1% of weight in the range of 30-150 ℃.

In another preferred embodiment, the AZT-A crystal form has an endothermic peak at 162.5 +/-0.5 ℃ and 196.78 +/-0.5 ℃ respectively in a DSC chart.

In another embodiment, the invention also provides a method for preparing the crystal form of the enrotinib, wherein the crystal form is crystal form AZT-A,

the method (i.e., method a1) includes the steps of:

a1) dissolving an enretinib raw material in a solvent A (preferably, dissolving at 10-100 ℃; preferably, the solution is dissolved at 20-80 ℃; optimally, dissolving at 40-70 ℃) to obtain a solution (clear) of the raw material of the enretinib in the solvent A;

a2) cooling the solution A for crystallization, preferably to a temperature below 20 ℃ (more preferably below 10 ℃; optimally, below 5 ℃) crystallizing, collecting precipitated crystals and drying to obtain a crystal form AZT-A;

alternatively, the method (i.e., method a2) includes the steps of:

mixing Entrictinib raw material (preferably, Entrictinib raw material is AZT-C described herein) at T_ATemperature t at temperature_AAnd (4) carrying out the reaction for a while to obtain the crystal form AZT-A.

In another preferred embodiment, T_A60-100 ℃ under normal temperature; preferably, T_A＝70～90℃。

In another preferred embodiment, t_A1-10 h; preferably, t_A＝3～7h。

In another preferred example, the solvent A is a solvent which can completely dissolve the raw material of the enretinib at the temperature of 10-150 ℃.

In another preferred embodiment, the solvent a is selected from: an alcohol solvent, an ester solvent, a ketone solvent, a haloalkane solvent, acetonitrile, an aromatic solvent, or a combination thereof;

or the solvent A is a mixed solvent consisting of water and a solvent selected from the following group: an alcohol solvent, an ester solvent, a ketone solvent, a haloalkane solvent, or a combination thereof.

In another preferred embodiment, the solvent a is selected from: an alcohol solvent, an ester solvent, a ketone solvent, a haloalkane solvent, acetonitrile, an aromatic solvent, or a combination thereof.

In another preferred example, the solvent a includes: methanol, ethanol, acetonitrile, toluene, acetone, ethyl acetate, isopropyl acetate, ethyl formate, methyl acetate, n-propyl acetate, butyl acetate, methylene chloride, MIBK, or combinations thereof.

In another preferred embodiment, the solvent a is an ester solvent or a mixed solvent containing an ester solvent.

In another preferred example, the mixed solvent containing the ester solvent is a mixed solvent of the ester solvent and a solvent selected from the group consisting of: an alcohol solvent, a ketone solvent, a halogenated hydrocarbon solvent, or a combination thereof.

In another preferred embodiment, the solvent a is selected from: ethyl acetate or a mixed solvent containing ethyl acetate.

In another preferred example, the mixed solvent composed of ethyl acetate is a mixed solvent composed of ethyl acetate and a solvent selected from the group consisting of: methanol, ethanol, acetonitrile, toluene, acetone, dichloromethane, MIBK, or combinations thereof.

In another preferred example, in the step A1), the concentration of the obtained clear solution A can be 0.005-1.0 g/mL, preferably 0.01-0.2 g/mL.

In another preferred example, in the step A1), the dissolving temperature is 10-100 ℃; preferably, 20 to 80 ℃; more preferably, 40 to 70 ℃.

Compared with the prior art, the invention has the following remarkable beneficial effects:

(1) compared with the known anhydrous crystal forms (such as the crystal form 1 and the crystal form 2), the crystal form AZT-A has better solubility and has important significance for the dissolution of subsequent preparations;

(2) the crystal form AZT-A has the advantages of small electrostatic effect on the existing anhydrous substance (experiments show that the crystal form is difficult to be adsorbed on the surface of metal such as a metal scraper due to static electricity compared with the existing anhydrous crystal form), and is suitable for preparation production;

(3) the preparation process of the crystal form AZT-A is simple, strong in operability, high in yield, stable in quality, short in production period and easy to realize large-scale production.

(4) Compared with amorphous AZT-A, the crystal form AZT-A is less prone to dust raising, better in stability under high humidity and/or high temperature, less prone to moisture absorption, good in flowability and suitable for preparation technology.

Crystal form AZT-B of enretinib and preparation method thereof

In a specific embodiment, the crystalline form of the entiretiib provided by the invention is crystalline form AZT-B.

In another preferred embodiment, the crystal form AZT-B is an anhydrate of enrotinib.

In a specific embodiment, crystalline form AZT-B has characteristic peaks at 7.4 ± 0.2 °, 8.1 ± 0.2 °, 14.8 ± 0.2 °, 17.2 ± 0.2 °, 19.9 ± 0.2 ° 2 Θ under powder X-ray diffraction.

In another preferred embodiment, under powder X-ray diffraction, the crystalline form AZT-B also has characteristic peaks at 2 θ of 11.4 ± 0.2 °, 12.0 ± 0.2 °, 20.9 ± 0.2 °, 22.3 ± 0.2 °, 23.5 ± 0.2 °, and/or 24.1 ± 0.2 °.

In another preferred embodiment, the crystalline form AZT-B of entiretinib of the present invention has characteristic peaks at 2 θ of 7.4 ± 0.2 °, 8.1 ± 0.2 °, 11.4 ± 0.2 °, 12.0 ± 0.2 °, 14.8 ± 0.2 °, 17.2 ± 0.2 °, 19.9 ± 0.2 °, 20.9 ± 0.2 °, 22.3 ± 0.2 °, 23.5 ± 0.2 °, and 24.1 ± 0.2 ° under powder X-ray diffraction.

In another preferred embodiment, under the powder X-ray diffraction, the relative intensity of a characteristic peak of the crystal form AZT-B at a2 theta of 14.8 +/-0.2 degrees is more than or equal to 90 percent; more preferably, 95% or more; most preferably, about 100%.

In another preferred embodiment, under the powder X-ray diffraction, the relative intensity of the other characteristic peaks of the crystal form AZT-B except the characteristic peak at 14.8 +/-0.2 degrees is less than or equal to 90 percent; preferably, less than or equal to 75%.

In another preferred embodiment, the crystalline form AZT-B of entiretiib has the following characteristic peaks and relative intensities under powder X-ray diffraction:

2θ/°	relative strength
		7.4±0.2	40％
8.1±0.2	19％
		14.8±0.2	100％
16.7±0.2	16％
		17.2±0.2	62％
19.9±0.2	66％
		22.3±0.2	39％
23.5±0.2	25％
		24.1±0.2	26％

In another preferred embodiment, the crystalline form AZT-B has an XRPD pattern substantially as shown in figure 5;

in another preferred example, in a TGA diagram, the AZT-B crystal form loses 0.8 +/-0.1% of weight in the range of 30-150 ℃.

In another preferred embodiment, the AZT-B crystal form has a melting endothermic peak at 147.3 +/-0.5 ℃ in a DSC chart.

In another preferred embodiment, the crystalline form AZT-B has a DSC profile substantially as shown in figure 7;

in another preferred embodiment, the crystalline form AZT-B has a structure substantially as shown in figure 8¹H-NMR spectrum.

In a specific embodiment, the invention also provides a method for preparing the crystalline form of the entiretiib, wherein the crystalline form is crystalline form AZT-B;

the method (i.e., method B1) includes the steps of:

pulping an enrofloxacin raw material in a solvent B, preferably at a pulping temperature of 0-50 ℃ (preferably 10-40 ℃, such as at room temperature), and drying to obtain a crystal form AZT-B;

alternatively, the method (i.e., method B2) includes the steps of:

the raw material of the enrotinib (preferably, the raw material of the enrotinib is the crystal form AZT-D described in the text) is put in T_BDrying at the temperature to obtain the crystal form AZT-B.

In another preferred example, the solvent B is a solvent which can dissolve the raw material of the enretinib partially at 0-50 ℃.

In another preferred embodiment, the beating time is 1-24h, preferably 2-24 h.

In another preferred example, the mass-volume (mg/ml) ratio of the raw material of the enretinib to the solvent B is (50-500): 1; preferably (150-300): 1.

In another preferred embodiment, the solvent B is selected from: an alcohol solvent, an ester solvent, a ketone solvent, a haloalkane solvent, acetonitrile, an aromatic solvent, or a combination thereof;

or the solvent B is a mixed solvent consisting of water and a solvent selected from the following group: an alcohol solvent, an ester solvent, a ketone solvent, a halogenated hydrocarbon solvent, an aromatic solvent, or a combination thereof.

In another preferred embodiment, the solvent B is selected from: an alcohol solvent, an ester solvent, a ketone solvent, a halogenated hydrocarbon solvent, acetonitrile, an aromatic solvent, or a combination thereof.

In another preferred embodiment, the ester solvent, the alcohol solvent, the aromatic solvent, the halogenated hydrocarbon solvent and the ketone solvent are as defined above.

(1) compared with the known anhydrous crystal forms (such as the crystal form 1 and the crystal form 2), the crystal form AZT-B has better solubility and has important significance for the dissolution of subsequent preparations;

(2) the crystal form AZT-B has the advantages of small electrostatic effect on the existing anhydrous substance (experiments show that the crystal form is difficult to be adsorbed on the surface of metal such as a metal scraper due to static electricity compared with the existing anhydrous crystal form), and suitability for preparation production;

(3) the preparation process of the crystal form AZT-B is simple, strong in operability, high in yield, stable in quality, short in production period and easy to realize large-scale production.

(4) Compared with amorphous AZT-B, the crystal form AZT-B is less prone to dust raising, better in stability under high humidity and/or high temperature, less prone to moisture absorption, good in flowability and suitable for preparation technology.

Crystal form AZT-C of enretinib and preparation method thereof

In a specific embodiment, the crystalline form of the entiretiib provided by the invention is crystalline form AZT-C.

In another preferred embodiment, the crystal form AZT-C has characteristic peaks at 2 theta of 18.1 +/-0.2 degrees, 23.1 +/-0.2 degrees and 25.5 +/-0.2 degrees under powder X-ray diffraction.

In another preferred embodiment, under the powder X-ray diffraction, the crystal form AZT-C has characteristic peaks at 2 theta of 7.6 +/-0.2 degrees, 11.0 +/-0.2 degrees, 13.1 +/-0.2 degrees, 15.3 +/-0.2 degrees, 18.1 +/-0.2 degrees, 18.6 +/-0.2 degrees, 22.4 +/-0.2 degrees, 23.1 +/-0.2 degrees and 25.5 +/-0.2 degrees.

In another preferred embodiment, under the powder X-ray diffraction, the relative intensity of a characteristic peak of the crystal form AZT-C at the 2 theta of 18.1 +/-0.2 degrees is more than or equal to 90 percent; more preferably, 95% or more; most preferably, about 100%.

In another preferred embodiment, under the powder X-ray diffraction, the relative intensity of the other characteristic peaks of the crystal form AZT-C except the characteristic peak at 18.1 +/-0.2 degrees is less than or equal to 80 percent; preferably less than or equal to 60%.

In another preferred embodiment, the crystalline form AZT-C of entiretiib has the following characteristic peaks and relative intensities under powder X-ray diffraction:

2θ/°	relative strength
		7.6±0.2	13％
11.0±0.2	14％
		13.1±0.2	18％
15.3±0.2	12％
		18.1±0.2	100％
18.6±0.2	20％
		22.4±0.2	14％
23.1±0.2	53％
		25.5±0.2	22％

In another preferred embodiment, the crystalline form AZT-C has an XRPD pattern substantially as shown in figure 9;

in another embodiment, the present invention provides a process for preparing the crystalline form of enretinib of the present invention wherein said crystalline form is crystalline form AZT-C, said process (process C) comprising the steps of:

providing a solution of the raw material of the enretinib in the solvent C, crystallizing the solution (preferably, crystallizing the solution by adding a seed crystal), and collecting a precipitated solid to obtain the crystal form AZT-C.

In another preferred embodiment, the crystal seed is AZT-A crystal form.

In another preferred embodiment, the method further comprises the step of beating or stirring before collecting the precipitated solid.

In another preferred embodiment, pulping or stirring is carried out for 1-48 h; preferably, pulping or stirring for 2-30 h; more preferably, 10 to 24 hours.

In another preferred embodiment, the mixture is stirred or beaten at 0 to 50 ℃ (preferably 10 to 40 ℃, more preferably 15 to 30 ℃).

In another preferred embodiment, the method comprises the steps of:

c1) dissolving an enretinib raw material in a solvent C, preferably at a dissolving temperature of 10-100 ℃ (such as 50-70 ℃), thereby obtaining a solution (clear) of the enretinib raw material in the solvent C;

c2) and adding seed crystals into the obtained solution for crystallization, stirring or pulping, and collecting precipitated solids to obtain the crystal form AZT-C.

In another preferred example, the concentration of the solution of the raw material of enretinib in the solvent C may be 0.005-1.0 g/mL, preferably 0.01-0.1 g/mL.

In another preferred example, the solvent C is a solvent which can completely dissolve the raw material of the enretinib at 10-100 ℃.

In another preferred embodiment, the solvent C is selected from: an alcohol solvent, an ester solvent, a ketone solvent, a haloalkane solvent, acetonitrile, an aromatic solvent, or a combination thereof; or the solvent C is a mixed solvent consisting of water and a solvent selected from the following group: an alcohol solvent, an ester solvent, a ketone solvent, an aromatic solvent, a halogenated alkane solvent, or a combination thereof.

In another preferred embodiment, the solvent C is selected from: an alcohol solvent, an ester solvent, a ketone solvent, a haloalkane solvent, acetonitrile, an aromatic solvent, or a combination thereof.

In another preferred embodiment, the ester solvent, the alcohol solvent, the aromatic solvent, the haloalkane solvent and the ketone solvent are as defined above.

In another preferred embodiment, the solvent C is an ester solvent; preferably selected from: ethyl acetate, isopropyl acetate, butyl acetate, or combinations thereof.

Crystal form AZT-D of enretinib and preparation method thereof

In a specific embodiment, the crystalline form of the entiretiib provided by the invention is crystalline form AZT-D.

In another preferred embodiment, under the powder X-ray diffraction, the crystal form AZT-D has characteristic peaks at 2 theta of 7.1 +/-0.2 degrees, 7.4 +/-0.2 degrees, 13.4 +/-0.2 degrees, 17.6 +/-0.2 degrees, 19.8 +/-0.2 degrees and 22.6 +/-0.2 degrees.

In another preferred embodiment, the crystalline form AZT-D of entiretinib of the present invention has characteristic peaks at 2 θ of 7.1 ± 0.2 °, 7.4 ± 0.2 °, 7.6 ± 0.2 °, 12.3 ± 0.2 °, 13.4 ± 0.2 °, 14.4 ± 0.2 °, 15.0 ± 0.2 °, 16.0 ± 0.2 °, 16.7 ± 0.2 °, 17.6 ± 0.2 °, 19.5 ± 0.2 °, 19.8 ± 0.2 °, 20.3 ± 0.2 °, 22.3 ± 0.2 °, 22.6 ± 0.2 ° 24.7 ± 0.2 ° under powder X-ray diffraction.

In another preferred embodiment, under the powder X-ray diffraction, the relative intensity of a characteristic peak of the crystal form AZT-D at a2 theta of 13.4 +/-0.2 degrees is more than or equal to 90 percent; more preferably, 95% or more; most preferably, about 100%.

In another preferred embodiment, under the powder X-ray diffraction, the relative intensity of the other characteristic peaks of the crystal form AZT-D except the characteristic peak at 13.4 +/-0.2 degrees is less than or equal to 80 percent; preferably less than or equal to 50%.

In another preferred embodiment, the crystalline form AZT-D of entiretiib according to the present invention has the following characteristic peaks and relative intensities under powder X-ray diffraction:

2θ/°	relative strength
		7.1±0.2	48％
7.4±0.2	38％
		7.6±0.2	25％
12.3±0.2	21％
		13.4±0.2	100％
14.4±0.2	26％
		16.7±0.2	24％
17.6±0.2	37％
		19.5±0.2	24％
19.8±0.2	40％
		22.3±0.2	24％
22.6±0.2	31％
		24.7±0.2	23％

In another preferred embodiment, the crystalline form AZT-C has an XRPD pattern substantially as shown in figure 10;

in another embodiment, the invention further provides a method for preparing the crystalline form of enretinib of the invention, wherein the crystalline form is crystalline form AZT-D, the method comprising the steps of:

d1) providing a mixture of the raw material of the enretinib in the solvent D, and pulping or stirring (preferably, the pulping or stirring temperature is 0-70 ℃; preferably, 0 to 50 ℃; more preferably, 10-40 ℃; most preferably, 15-30 ℃), collecting the solid therein to obtain form AZT-D.

In another preferred example, the mass-volume (g/ml) ratio of the raw material of the enretinib to the solvent C is (0.01-0.5): 1; preferably, the first and second liquid crystal films are made of a polymer,

(0.02-0.2) 1; more preferably, 1 is (0.05-0.1).

In another preferred example, the solvent D is a solvent which can dissolve part of the raw material of the enretinib at 0-70 ℃.

In another preferable example, the raw material of the enretinib is a crystal form AZT-C.

In another preferred embodiment, the solvent D is selected from: an alcohol solvent, an ester solvent, a ketone solvent, a haloalkane solvent, acetonitrile, an aromatic solvent, or a combination thereof;

or the solvent D is a mixed solvent consisting of water and a solvent selected from the following group: an alcohol solvent, an ester solvent, a ketone solvent, a haloalkane solvent, or a combination thereof.

In another preferred embodiment, the solvent D is selected from: an alcohol solvent, an ester solvent, a ketone solvent, a haloalkane solvent, acetonitrile, an aromatic solvent, or a combination thereof.

In another preferred embodiment, the solvent D is selected from: an alcohol solvent, acetonitrile, or a combination thereof; preferably, solvent D is acetonitrile.

In another preferred example, the step a) is to pulp the raw material of the enretinib in the solvent D, the pulping temperature is 0-70 ℃, and the solid in the solvent is collected, so as to obtain the AZT-D.

Crystal form AZT-E of enretinib and preparation method thereof

In a specific embodiment, the crystalline form of the entiretiib provided by the invention is crystalline form AZT-E.

In another preferred embodiment, the crystal form AZT-E is a monohydrate of the enrofloxacin.

In another preferred embodiment, under the powder X-ray diffraction, the crystal form AZT-E has characteristic peaks at 2 theta of 8.9 +/-0.2 degrees, 10.5 +/-0.2 degrees, 16.6 +/-0.2 degrees and 17.2 +/-0.2 degrees.

In another preferred embodiment, crystalline form AZT-E also has characteristic peaks at 15.9 ± 0.2 °, 17.0 ± 0.2 °, 17.9 ± 0.2 °, 22.8 ± 0.2 °, and/or 24.7 ± 0.2 ° 2 Θ under powder X-ray diffraction.

In another preferred embodiment, under the powder X-ray diffraction, the crystal form AZT-E has characteristic peaks at 2 theta of 8.9 +/-0.2 degrees, 10.5 +/-0.2 degrees, 15.9 +/-0.2 degrees, 16.6 +/-0.2 degrees, 17.0 +/-0.2 degrees, 17.2 +/-0.2 degrees, 17.9 +/-0.2 degrees, 22.8 +/-0.2 degrees and 24.7 +/-0.2 degrees.

In another preferred example, under the powder X-ray diffraction, the relative intensity of the other characteristic peaks of the crystal form AZT-E except the characteristic peaks at 2.7 +/-0.2 degrees and 20.6 +/-0.2 degrees is less than or equal to 80 percent; more preferably, 60% or less; most preferably, less than or equal to 40%.

In another preferred embodiment, the crystalline form AZT-E of entiretiib according to the present invention has the following characteristic peaks and relative intensities under powder X-ray diffraction:

2θ/°	relative strength
		8.9±0.2	100％
10.5±0.2	16.3％
		15.9±0.2°	9.7％
16.6±0.2	30％
		17.0±0.2	21％
17.3±0.2	29％
		18.0±0.2	23％
22.8±0.2	20％
		24.7±0.2	20％

In another embodiment, the invention also provides a method for preparing the crystalline form of the entiretiib, wherein the crystalline form is crystalline form AZT-E;

the method (i.e., method E) includes the steps of:

1) providing a mixture of an enretinib raw material in a solvent E and water, pulping or stirring, and collecting solids in the mixture to obtain the crystal form AZT-E.

In another preferred embodiment, the beating or stirring temperature is T_E1And T_E10-50 deg.C; preferably, T_E10-40 ℃; more preferably, T _E10 to 5 ℃ or 15 to 30 ℃ (e.g., room temperature).

In another preferred embodiment, the time of beating or stirring is t_E1And t is_E1Preferably, t is not less than 2h_E1≥12h。

In another preferred embodiment, step 1) is preceded by the step of: 0) at T_E2At the temperature, firstly pulping the raw material of the enretinib in a solvent E for t_E2Time (preferably, t)_E20.1-1 hour; more preferably, t_E20.4-0.6 hours), adding water to obtain a mixture of the raw material of the enrotinib in a system of the solvent E and the water.

In another preferred example, the raw material of the enretinib is selected from the following group: form AZT-A, form AZT-B, form AZT-C, or a combination thereof.

In another preferred example, the volume ratio of the solvent E to the water is (0.1-10): 1; preferably (0.2-5): 1.

In another preferred example, the mass-to-volume (g/ml) ratio of the enretinib to the solvent E is (0.05-0.5): 1.

In another preferable example, the mass-volume ratio of the enretinib to the water is (0.015-1.5): 1.

In another preferred embodiment, the solvent E is selected from: methanol, ethanol, acetonitrile, toluene, acetone, ethyl acetate, dichloromethane, MIBK, or combinations thereof.

In another preferred embodiment, the solvent E is an alcohol solvent.

In another preferred example, when the solvent E is ethanol, the volume ratio of the solvent E to water is (1-10): 1; preferably (3-5): 1.

In another preferred example, when the solvent E is ethanol, the mass-to-volume (g/ml) ratio of the enretinib to the solvent E is (0.1-0.5): 1.

In another preferred example, when the solvent E is ethanol, the mass-volume ratio of the enretinib to the water is (0.8-1.5): 1.

In another preferred example, when the solvent E is methanol, the volume ratio of the solvent E to water is (0.1-1): 1; preferably (0.2-0.5): 1.

In another preferred example, when the solvent E is methanol, the mass-to-volume (g/ml) ratio of the enretinib to the solvent E is (0.05-0.1): 1.

In another preferred example, when the solvent E is methanol, the mass volume ratio of the enretinib to the water is (0.015-0.05): 1.

(1) compared with various known solvates, the crystal form AZT-E has no problem of solvent toxicity;

(2) the crystal form AZT-E has better thermal stability, high humidity stability and pressure stability, and has important significance for the preparation and storage of subsequent preparations;

(3) the crystal form AZT-E has the advantages of small electrostatic effect (experiments show that compared with the existing anhydrous crystal form, the crystal form is not easy to be adsorbed on the surface of metal such as a metal scraper due to static electricity), and is suitable for preparation production;

(4) the preparation process of the crystal form AZT-E is simple, strong in operability, high in yield, stable in quality, short in production period and easy to realize large-scale production.

(5) Compared with amorphous AZT-E, the crystal form AZT-E is less prone to dust raising, better in stability under high humidity and/or high temperature, less prone to moisture absorption, good in flowability and suitable for preparation technology.

Crystal form AZT-F of enretinib and preparation method thereof

In a specific embodiment, the crystalline form of the entiretiib provided by the invention is crystalline form AZT-F.

In another preferred embodiment, under the powder X-ray diffraction, the crystal form AZT-F has characteristic peaks at 2 theta of 4.8 +/-0.2 degrees, 8.2 +/-0.2 degrees, 10.2 +/-0.2 degrees, 14.3 +/-0.2 degrees, 17.4 +/-0.2 degrees, 18.3 +/-0.2 degrees, 19.2 +/-0.2 degrees, 19.7 +/-0.2 degrees, 20.6 +/-0.2 degrees, 22.0 +/-0.2 degrees, 22.4 +/-0.2 degrees, 22.7 +/-0.2 degrees and 23.5 +/-0.2 degrees.

Preferably, the enretinib crystal form AZT-F provided by the invention has characteristic peaks at 4.8 +/-0.2 °, 8.2 +/-0.2 °, 9.3 +/-0.2 °, 10.2 +/-0.2 °, 13.6 +/-0.2 °, 14.3 +/-0.2 °, 16.5 +/-0.2 °, 17.2 +/-0.2 °, 17.4 +/-0.2 °, 18.3 +/-0.2 °, 19.2 +/-0.2 °, 19.7 +/-0.2 °, 20.6 +/-0.2 °, 22.0 +/-0.2 °, 22.4 +/-0.2 °, 22.7 +/-0.2 °, 23.5 +/-0.2 °, 24.0 +/-0.2 °, 25.3 +/-0.2 ° and 26.4 +/-0.2 ° at 2 θ under powder X-ray diffraction.

In another preferred embodiment, the crystalline form AZT-F of entiretiib has the following characteristic peaks and relative intensities under powder X-ray diffraction:

in another preferred embodiment, the crystalline form AZT-F has an XRPD pattern substantially as shown in figure 15.

In one embodiment, the present invention also provides a process for preparing the crystalline form of emtricinib according to the present invention, wherein the crystalline form is crystalline form AZT-F, the process (process F) comprising the steps of:

providing a solution of an enretinib raw material in a solvent F, concentrating, collecting and precipitating a solid, thereby obtaining the crystal form AZT-F.

In another preferred embodiment, the method comprises the steps of:

d1) dissolving an enretinib raw material in a solvent F, preferably at a dissolving temperature of 10-100 ℃, to obtain a solution (clear) of the enretinib raw material in the solvent F;

d2) concentrating the solution F obtained in the step d1), and collecting precipitated solid to obtain the crystal form AZT-F.

In another preferred example, the solvent F is a solvent which can completely dissolve the raw material of the enretinib at 10-100 ℃.

In another preferred embodiment, solvent F is as defined for solvent C.

In another preferred example, the solvent F includes a solvent such as methanol, DMF, acetonitrile, toluene, acetone, MIBK, and/or toluene. Preferably, the solvent F is toluene.

In another preferred embodiment, the concentration time is less than or equal to 24 hours.

In another preferred embodiment, the concentration temperature is 30-70 ℃; preferably, it is 40 to 60 ℃.

Crystal form AZT-G of enretinib and preparation method thereof

In a specific embodiment, the crystalline form of the entiretiib provided by the invention is crystalline form AZT-G.

In another preferred embodiment, under powder X-ray diffraction, the crystal form AZT-G has characteristic peaks at 2 theta of 8.1 +/-0.2 degrees, 9.3 +/-0.2 degrees, 10.2 +/-0.2 degrees, 14.3 +/-0.2 degrees, 17.2 +/-0.2 degrees, 17.4 +/-0.2 degrees, 18.2 +/-0.2 degrees, 19.1 +/-0.2 degrees, 20.6 +/-0.2 degrees, 22.0 +/-0.2 degrees, 22.4 +/-0.2 degrees and 23.5 +/-0.2 degrees.

In another preferred embodiment, the crystalline form AZT-G of entiretiib according to the present invention has the following characteristic peaks and relative intensities under powder X-ray diffraction:

in another preferred embodiment, the crystalline form AZT-G has an XRPD pattern substantially as shown in figure 16.

In one embodiment, the present invention provides a process for preparing the crystalline form of enretinib of the present invention wherein said crystalline form is crystalline form AZT-G, said process (process G) comprising the steps of:

providing a solution of the raw material of the enretinib in a solvent G, volatilizing the solvent G, collecting and separating out a solid, thereby obtaining the crystal form AZT-G.

In another preferred example, the method comprises the steps of:

g1) dissolving an enretinib raw material in a solvent G, preferably at a dissolving temperature of 10-100 ℃, to obtain a solution (clear) of the enretinib raw material in the solvent G; and

g2) volatilizing the solvent from the solution G obtained in step G1) to obtain AZT-G.

In another preferred example, the solvent G is a solvent which can completely dissolve the raw material of the enretinib at 10-100 ℃.

In another preferred embodiment, solvent G is as defined for solvent C.

In another preferred example, the solvent G includes a solvent such as methanol, isopropanol, toluene, acetone, nitromethane, dichloromethane, and/or MIBK, or the solvent G is a mixed solvent of the above solvent and water.

In another preferred embodiment, the solvent G is toluene.

In another preferred embodiment, the volatilization time is more than or equal to 48 hours; preferably, the time is more than or equal to 96 hours.

In another preferred embodiment, the volatilization temperature is 20-60 ℃; preferably, it is 30 to 50 ℃.

Amorphous form of enretinib and preparation method thereof

In a particular embodiment, the present invention provides an amorphous form of entitinib, said amorphous form having an XPRD spectrum substantially as shown in figure 21.

The preparation method of the amorphous enretinib comprises the following steps:

a) dissolving an enretinib raw material in a solvent 1, preferably at a dissolving temperature of 0-100 ℃, to obtain a clear solution 1;

b) adding a solvent 2 into the solution 1 for crystallization, and collecting precipitated solids to obtain an amorphous form.

In another preferred example, the solvent 1 is a solvent which can completely dissolve the raw material of the enretinib at 10-100 ℃.

In another preferred embodiment, the solvent 1 is selected from: an alcohol solvent, an ester solvent, a ketone solvent, a haloalkane solvent, acetonitrile, an aromatic solvent, or a combination thereof;

or, the solvent 1 is a mixed solvent of water and a solvent selected from the following group: an alcohol solvent, an ester solvent, a ketone solvent, a haloalkane solvent, or a combination thereof.

In another preferred embodiment, the solvent 1 is an ester solvent, an alcohol solvent, or a combination thereof.

In another preferred embodiment, the solvent 1 is selected from: methanol, ethanol, isopropanol, acetonitrile, toluene, acetone, ethyl acetate, dichloromethane, MIBK, toluene, or combinations thereof.

In another preferred embodiment, the solvent 2 is a solvent with poor solubility to the enretinib.

In another preferred embodiment, the solvent 2 is selected from: a saturated hydrocarbon solvent, an ether solvent, water, or a combination thereof.

In another preferred example, the saturated hydrocarbon solvent is C1-C10 aliphatic alkane; preferably, it is selected from the group consisting of: n-heptane, n-hexane, or a combination thereof.

In another preferred example, the ether solvent is a chain ether solvent; preferably, it is selected from the group consisting of: methyl tert-ether, anisole, or combinations thereof.

In another preferred embodiment, the solvent 2 is selected from the group consisting of: n-heptane, n-hexane, methyl tert-ether, water, anisole, and the like, or combinations thereof; preferably, the solvent 2 is selected from: n-hexane, water, or combinations thereof.

Crystal form AZT-H of enretinib and preparation method thereof

In a specific embodiment, the crystal form of the enrotinib provided by the invention is crystal form AZT-H.

In another preferred embodiment, the crystal form AZT-H is 1, 4-dioxane solvate of Entricinib 2 molecule.

In another preferred embodiment, under the powder X-ray diffraction, the crystal form AZT-H has characteristic peaks at 2 theta of 12.5 +/-0.2 degrees, 12.8 +/-0.2 degrees, 16.4 +/-0.2 degrees, 16.8 +/-0.2 degrees, 18.5 +/-0.2 degrees, 19.0 +/-0.2 degrees, 20.1 +/-0.2 degrees, 20.8 +/-0.2 degrees and 21.1 +/-0.2 degrees.

Preferably, the crystalline form AZT-H of entiretiib has the following characteristic peaks and relative intensities under powder X-ray diffraction:

in another preferred embodiment, the crystalline form AZT-H has an XRPD pattern substantially as shown in figure 17.

In another preferred embodiment, the crystalline form AZT-H has a TGA profile substantially as shown in figure 18.

In another embodiment, there is provided a process for preparing a crystalline form of emtricinib of the present invention, wherein the crystalline form is crystalline form AZT-H, the process (process H) steps:

a) stirring or pulping the raw material of the enretinib in an ether solvent (such as 1, 4-dioxane and the like), preferably at the temperature of 0-50 ℃ for 1-24 h;

b) the solid was collected to give crystalline form AZT-H.

In another preferred example, the mass-volume (g: ml) ratio of the raw material of the enretinib to the 1, 4-dioxane is (0.01-0.1): 1; preferably (0.02-0.05): 1.

Crystal form AZT-I of enrotinib and preparation method thereof

In a specific embodiment, the crystalline form of the entiretiib provided by the invention is crystalline form AZT-I.

In another preferred embodiment, under the powder X-ray diffraction, the crystal form AZT-I has characteristic peaks at 2 theta of 8.1 +/-0.2 degrees, 10.1 +/-0.2 degrees, 14.4 +/-0.2 degrees, 17.3 +/-0.2 degrees, 18.1 +/-0.2 degrees, 19.0 +/-0.2 degrees, 20.2 +/-0.2 degrees, 22.0 +/-0.2 degrees and 23.2 +/-0.2 degrees.

In another preferred embodiment, the crystalline form AZT-I of entiretiib has the following characteristic peaks and relative intensities under powder X-ray diffraction:

2θ/°	relative strength
		8.1±0.2	45％
10.1±0.2	23％
		14.4±0.2	21％
17.3±0.2	19％
		18.1±0.2	33％
19.0±0.2	32％
		20.2±0.2	61％
22.1±0.2	100％
		23.2±0.2	48％

In another preferred embodiment, the crystalline form AZT-I has an XRPD pattern substantially as shown in figure 19.

In another preferred embodiment, the crystalline form AZT-I has a TGA profile substantially as shown in figure 20.

In another embodiment, the present invention provides a process for preparing the crystalline form of enrotinib of the present invention, wherein said crystalline form is crystalline form AZT-I, said process (process G) comprising the steps of:

providing a mixture of the raw material of the enrofloxacin in the solvent I, pulping or stirring, and collecting the solid in the mixture, thereby obtaining the crystal form AZT-I.

In another preferred embodiment, the temperature of beating or stirring is 0-50 ℃.

In another preferred embodiment, the time of beating or stirring is 1-24 h.

In another preferred example, the solvent I is a solvent which can not completely dissolve the raw material of the enretinib at 10-100 ℃.

In another preferred example, the solvent I comprises nitromethane, dichloromethane, anisole, 2-MeTHF, or a combination thereof, or the solvent I is a mixed solvent of the above solvents and water.

In another preferred example, the mass volume (g: ml) ratio of the raw material of the enretinib to the solvent I is (0.01-0.1): 1; preferably (0.02-0.05): 1.

The main advantages of the invention include:

(1) the crystal form of the compound shown in the formula I provided by the invention has high standing stability under high-temperature and high-humidity conditions.

(2) The crystal form of the invention also has the advantages of difficult uplifting, difficult moisture absorption, high bioavailability and the like; the preparation method of the crystal form is simple and easy for industrial production.

(3) The solubility of the crystalline forms of the invention is higher than other crystalline forms in the prior art.

(4) The crystal form of the present invention has excellent pressure stability.

Pharmaceutical compositions and methods of administration

Since the crystalline form or amorphous form of the present invention has an excellent therapeutic and prophylactic effect on cancer or tumor, the crystalline form or amorphous form of the present invention and a pharmaceutical composition comprising the crystalline form or amorphous form of the present invention as a main active ingredient can be used for treating and/or preventing cancer or tumor. For example, the crystalline form or amorphous form of the present invention may be used for the preparation of a medicament for the treatment of adult metastatic ROS1 positive non-small cell lung cancer (NSCLC) patients, adult and pediatric patients with solid tumors aged 12 and older, which may be prepared by methods commonly used in the art.

The pharmaceutical composition of the invention comprises the crystal form of the invention and pharmaceutically acceptable excipient or carrier within a safe and effective amount range.

Wherein "safe and effective amount" means: the amount of the compound (or crystalline form) is sufficient to significantly ameliorate the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 to 2000mg of the crystalline form/dosage of the present invention, more preferably, 10 to 200mg of the crystalline form/dosage of the present invention. Preferably, said "dose" is a capsule or tablet.

"pharmaceutically acceptable CarriersThe body "means: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of being combined with the active ingredients of the present invention and with each other without significantly diminishing the efficacy of the active ingredient. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers

Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

The mode of administration of the polymorph or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be delayed in a certain portion of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active ingredient may also be in microencapsulated form with one or more of the above excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.

In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active ingredients, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these materials, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms of the polymorphic forms of the invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.

The crystalline forms of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

When the pharmaceutical composition is used, a safe and effective amount of the polymorphic substance of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1-2000mg, preferably 20-500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.

In the present invention, the crystal water of the crystal form is derived from air or a solvent. The solvents used in the present invention were all analytically pure and had a water content of about 0.1%.

Comparative example 1

Preparation of crystalline form 1 of enretinib

According to the method described in WO2013174876 [0133 ]: suspending 5.5g of dry amorphous N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4-methylpiperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide in 130ml of ethanol and heating at reflux for 10 minutes; about 70ml of ethanol was distilled before cooling to room temperature. Addition of 110ml of water seeding the suspension with 55mg of form 1. The suspension was stirred for about 72 hours and samples were taken to monitor the conversion to form 1 by DSC. Finally, the suspension was filtered and dried to prepare 4.3g of form 1.

Comparative example 2

Preparation of crystalline form 2 of enretinib

According to the method described in WO2013174876 [0134 ]: slurrying dry amorphous N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4-methylpiperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide in 10 volumes of ethanol to enable conversion to the desired crystalline form 2; then 20 volumes of water were added and the suspension was filtered. And finally, drying the product in vacuum to prepare the crystal form 2.

Comparative example 3

Preparation of crystalline form 4 of enretinib

Following the procedure described in example 1 of WO 2017202674: dry amorphous N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4-methylpiperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide was suspended in 10 volumes of ethanol (suspension a). 20ml of suspension A were heated to 60 ℃ to give a solution, which was then cooled to room temperature. To the solution was added 20ml of water to obtain a suspension and the precipitate was filtered. The product was dried under vacuum to prepare form 4.

Example 1

Preparation of enretinib crystal form AZT-A

Examples 1 to 1

Mixing 2g of the Entricinib crystal form 2 with 10ml of ethyl acetate, heating to 50 ℃ for dissolution, cooling to 10 ℃, and drying at room temperature to obtain the crystal form AZT-A. The X-ray powder diffraction pattern is shown in figure 1; TGA test of the obtained solid shows the spectrum of FIG. 2; the obtained solid is subjected to DSC test, and the spectrum of the solid is shown in figure 3; subjecting the obtained solid to¹The spectrum of the H-NMR test is shown in FIG. 4.

Figure 2TGA shows that crystalline form AZT-a lost 0.3% weight at 30 ℃ to 150 ℃ as an anhydrate.

Figure 3DSC shows crystalline AZT-a with the 1 st endotherm at 162.5 ℃ and the 2 nd endotherm at 196.78 ℃.

Examples 1 to 2

Mixing 20mg of the Entricinib crystal form 2 with 0.8ml of isopropyl acetate, heating to 40 ℃ for dissolution, cooling to 20 ℃, and drying at 30 ℃ to obtain the crystal form AZT-A.

Examples 1 to 3

At room temperature, 20mg of enretinib raw material AZT-B (the crystal form AZT-B is mentioned in example 2) is dissolved in 1ml of ethyl acetate/ethanol (1:1) mixed solvent (at 40-50 ℃), cooled to 5 ℃, and dried to obtain the crystal form AZT-A.

Examples 1 to 4

At room temperature, 15mg of enretinib raw material AZT-D is dissolved in 0.7ml of ethyl formate, methyl acetate, n-propyl acetate or butyl acetate at the temperature of 60 ℃, cooled to 10 ℃, and dried to obtain the crystal form AZT-A.

Examples 1 to 5

Heating the Entricinib crystal form AZT-C to 80 ℃, and preserving heat for 5h to obtain the crystal form AZT-A.

Example 2

Preparation of enretinib crystal form AZT-B

Example 2-1

Under the condition of room temperature, pulping 15mg of an enretinib raw material (the crystal form AZT-A is mentioned in the patent) in 0.1ml of ethanol for 24h, and drying to obtain a crystal form AZT-B; the resulting solid was subjected to XRPD testing, and its X-ray powder diffraction pattern is shown in fig. 5; the solid obtained is subjected to TGA test, and the spectrum is shown in figure 6; the obtained solid is subjected to DSC test, and the spectrum of the solid is shown in figure 7; subjecting the obtained solid to¹The spectrum of the H-NMR test is shown in FIG. 8.

Figure 6TGA shows that crystalline form AZT-B lost 0.8% weight at 30 ℃ -150 ℃ as an anhydrate.

Figure 7DSC shows that crystalline AZT-B has a melting endotherm at 147.3 ℃.

Examples 2 to 2

15mg of raw material of the Endotinib (the crystal form 2 in the international patent WO2013174876 application) is pulped in 0.6ml of acetonitrile for 24h at the temperature of 40 ℃, and the crystal form AZT-B is obtained after drying.

Examples 2 to 3

Amorphous 15mg of enretinib in 50 mul of ethanol at room temperature, pulping for 24h at 5 ℃, filtering and drying to obtain the crystal form AZT-B.

Examples 2 to 4

The crystalline form AZT-D (crystalline form obtained in example 4) was dried at 60 ℃ for 24h to obtain crystalline form AZT-B.

Example 3

Preparation of enretinib crystal form AZT-C

At 60 ℃, 20mg of an enretinib raw material (the crystal form 2 named in the international patent WO2013174876 application) is dissolved in 1.5ml of butyl acetate solvent, filtered, added with a small amount of seed crystal AZT-A (the crystal form AZT-A mentioned in example 1) and pulped for 24h at room temperature to obtain the crystal form AZT-C. The resulting solid was subjected to XRPD testing and its X-ray powder diffraction pattern is shown in figure 9.

Example 4

Preparation of enretinib crystal form AZT-D

Pulping 15mg of Entricinib crystal form AZT-C in 0.3ml of acetonitrile for 24h at room temperature to obtain a crystal form AZT-D; the X-ray powder diffraction pattern is shown in FIG. 10.

Example 5

Preparation of enretinib crystal form AZT-E

Example 5-1

Under the condition of room temperature, 0.2g of crystalline form AZT-B of Entricinib is pulped in 1ml of ethanol for 0.5h, then 0.2ml of purified water is added, the mixture is stirred for 24h at the room temperature, the crystalline form AZT-E is obtained by drying, XRPD test is carried out on the obtained solid, and the X-ray powder diffraction pattern is shown in figure 11; TGA testing was performed with the spectrum shown in figure 12; performing DSC test, and the spectrum is shown in figure 13; to carry out¹And H-NMR measurement, and the spectrum is shown in FIG. 14.

KF testing showed a water content of 3.0% (3.1% of theoretical one molecule of water).

Figure 12TGA shows that crystalline form AZT-E loses 3.3% weight at 50 ℃ -150 ℃, consistent with KF moisture, and is identified as enretinib monohydrate.

FIG. 13DSC shows crystalline form AZT-E with a dehydration peak at 126.35 ℃ and a melting endotherm peak at 197.15 ℃.

Examples 5 and 2

Adding 0.3g of raw material AZT-A into 1ml of mixed solvent of ethanol and purified water in a ratio of 3:1 at room temperature, and stirring for 24 hours at 5 ℃ to obtain the crystal form AZT-E.

Examples 5 to 3

And (3) pulping 15mg of raw material AZT-C in 1ml of methanol/water (1:5) for 24 hours at room temperature to obtain the crystal form AZT-E.

Example 6

Preparation of enretinib crystal form AZT-F

Dissolving 15mg of raw Entricinib material (AZT-A crystal form in example 1) in toluene at room temperature, and concentrating at 50 ℃ to obtain solid AZT-F; the X-ray powder diffraction pattern is shown in FIG. 15.

Example 7

Preparation of enretinib crystal form AZT-G

Dissolving 15mg of raw material (the crystal form AZT-A in example 1) of Entricinib in toluene at room temperature, and volatilizing at 40 ℃ for 1 week to obtain solid AZT-G; the X-ray powder diffraction pattern is shown in FIG. 16.

Example 8

Preparation of enretinib crystal form AZT-H

Pulping 15mg of raw Entricinib (the crystal form AZT-A in example 1) in 0.5ml of 1.4-dioxane at room temperature, and drying to obtain solid AZT-H; its X-ray powder diffraction pattern is shown in FIG. 17, and its TGA pattern is shown in FIG. 18.

Figure 18TGA shows that crystalline form AZT-H should have a weight loss of 24.208% at 50-110 ℃ as a2 molecule 1.4-dioxane solvate.

Example 9

Preparation of enretinib crystal form AZT-I

Example 9-1

Pulping 15mg of raw Entricinib (the crystal form AZT-A in example 1) in 0.5ml of 2-MeTHF at room temperature, and drying to obtain solid AZT-I; its X-ray powder diffraction pattern is shown in FIG. 19, and its TGA pattern is shown in FIG. 20.

KF test water content 6.5% (theoretical and molecular water 6.2%)

FIG. 20TGA shows that the crystal form AZT-I has a weight loss of 4.8% at 60-110 ℃ and a weight loss of 2.5% at 110-160 ℃, which is consistent with KF water and is a2 hydrate.

Example 10

Preparation of amorphous enretinib

Example 10-1: preparation of amorphous enretinib

Dissolving 15mg of an enretinib raw material in 1ml of ethyl acetate at room temperature, adding n-hexane at 5 ℃, and drying at room temperature to obtain an amorphous form; an X-ray powder diffraction pattern, a DSC pattern and a TGA pattern are respectively shown in FIG. 21, 22 and 23, respectively.

FIG. 22DSC shows that amorphous form has a glass transition peak at 80-100 ℃;

fig. 23DSC shows that amorphous weight loss is 0.2% from room temperature to 100 degrees.

Example 10-2: preparation of amorphous enretinib

Dissolving 15mg of the raw material of the enretinib in 1.5ml of ethanol at room temperature, quickly adding the solution into 15ml of purified water, and drying at room temperature to obtain amorphous.

Test example 1 stability of Crystal form

Respectively preparing a plurality of samples of the crystal form 1 (comparative example 1), the crystal form 2 (comparative example 2), the crystal form 4 (comparative example 3), the crystal form AZT-A (example 1-1), the crystal form AZT-B (example 2-1), the crystal form AZT-E (example 5-1) and the amorphous form (example 10-1), respectively placing the samples under different conditions (60 ℃, 92.5% RH, 60 ℃ and 92.5% RH and a drier (humidity is 10%) filled with phosphorus pentoxide) for 10 days in an open manner, grinding the samples in a mortar for 5min, sampling the samples, and detecting XRPD and HPLC (X fluorescence detection) to detect whether the crystal form type and the purity of each example are changed. Specific conditions and crystal form changes are shown in tables 1 and 2.

Table 1 stability of the different crystal forms

Crystal form	High temperature of 60 DEG C	High humidity 92.5%	Low humidity 10%	60℃&92.5％	Grinding
						Crystal modification AZT-A (example 1-1)	AZT-A	AZT-A	AZT-A	AZT-A	AZT-A
Crystal form AZT-B (example 2-1)	AZT-B	AZT-B	AZT-B	AZT-B	AZT-B
						Crystal modification AZT-E (example 5-1)	AZT-E	AZT-E	AZT-E	AZT-E	AZT-E
Amorphous form (example 10-1)	Amorphous form	Amorphous form	Amorphous form	-	-
						Crystal form 1 (comparative example 1)	Crystal form 2	Crystal form 1	Crystal form 1	Crystal form 2	Crystal form 2
Crystal form 2 (comparative example 2)	Crystal form 2	Crystal form 2	Crystal form 2	Crystal form 2	Crystal form 2
						Crystal form 4 (comparative example 3)	Crystal form 4	Crystal form 4	Crystal form 4	Crystal form 4	Crystal form 4

Note: '-' represents no detection.

TABLE 2 chemical stability of different crystalline forms

Crystal form	Original purity	High temperature of 60 DEG C	High humidity 92.5%	Low humidity 10%	60℃&92.5％
						Crystal modification AZT-A (example 1-1)	99.85％	99.84％	99.86％	99.85％	99.83％
Crystal form AZT-B (example 2-1)	99.81％	99.81％	99.78％	99.81％	99.80％
						Crystal modification AZT-E (example 5-1)	99.87％	99.85％	99.84％	99.87％	99.86％
Amorphous form (example 10-1)	99.78％	99.73％	99.72％	99.78％	99.70％
						Crystal form 1 (comparative example 1)	94.1％	93.5％	93.4％	94.1％	93.1％
Crystal form 2 (comparative example 2)	95.0％	94.9％	95.0％	95.0％	94.7％
						Crystal form 4 (comparative example 3)	94.8％	94.7％	94.8％	94.8％	94.7％

Note: '-' represents no detection.

As can be seen from Table 1, the crystal forms AZT-A, AZT-B, AZT-E and amorphous crystal forms of the invention have good stability, which is equivalent to that of comparative example 2 and comparative example 3; the crystal form of comparative example 1 is poor in stability and is easily transformed into crystal form 2 under a high temperature condition or after grinding.

As can be seen from Table 2, the crystal forms AZT-A, AZT-B and AZT-E of the invention have good amorphous chemical stability, which is equivalent to that of comparative example 2 and comparative example 3. Comparative example 1 was poor in chemical stability and decreased in purity under high temperature or high humidity conditions.

Test example 2 solubility

4 parts of enrotinib crystal form AZT-A (example 1-1), crystal form AZT-B (example 2-1), crystal form AZT-E (example 5-1), amorphous crystal form (example 10-1), crystal form 1 (comparative example 1), crystal form 2 (comparative example 2) and crystal form 4 (comparative example 3) are weighed respectively, each part is 7mg, purified water, a pH1.2 buffer solution, a pH4.5 buffer solution and a pH6.8 buffer solution are added respectively at 37 ℃ until dissolution is completed, and the results are shown in Table 3.

TABLE 3 solubilities of different crystal modifications

From the data, the solubility of the crystal form AZT-A, the crystal form AZT-B, the crystal form AZT-E and the amorphous form in the buffer solution with the pH value of 1.2 is better than that of the crystal form 1, the crystal form 2 and the crystal form 4 in the comparison ratio.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. A crystal form of a compound shown as a formula I is characterized in that,

the crystal form is a crystal form AZT-A, a crystal form AZT-B or a crystal form AZT-E;

wherein,

the crystalline form is a crystalline form AZT-A, and the XRPD pattern of the crystalline form AZT-A comprises 4 or more than 4 2 theta values selected from the following group: 7.9 +/-0.2 degrees, 9.4 +/-0.2 degrees, 14.4 +/-0.2 degrees, 15.4 +/-0.2 degrees, 16.0 +/-0.2 degrees and 20.6 +/-0.2 degrees;

the crystalline form is a crystalline form AZT-B, and the XRPD pattern of the crystalline form AZT-B comprises 3 or more than 3 2 theta values selected from the group consisting of: 7.4 +/-0.2 degrees, 8.1 +/-0.2 degrees, 14.8 +/-0.2 degrees, 17.2 +/-0.2 degrees and 19.9 +/-0.2 degrees;

the crystalline form is a crystalline form AZT-E, and the XRPD pattern of the crystalline form AZT-E comprises 3 or more than 3 2 theta values selected from the group consisting of: 8.9 +/-0.2 degrees, 10.5 +/-0.2 degrees, 16.6 +/-0.2 degrees and 17.2 +/-0.2 degrees.

2. The crystalline form of claim 1, which is AZT-A crystalline form,

and the crystal form AZT-A also has one or more of the following characteristics:

(1) the crystalline form AZT-a has an XRPD pattern comprising 6 or more than 62 Θ values selected from the group consisting of: 7.9 +/-0.2 °, 9.4 +/-0.2 °, 13.1 +/-0.2 °, 13.9 +/-0.2 °, 14.4 +/-0.2 °, 15.4 +/-0.2 °, 16.0 +/-0.2 °, 16.2 +/-0.2 °, 17.6 +/-0.2 °, 20.6 +/-0.2 °, 22.7 +/-0.2 °, 23.4 +/-0.2 °, 24.1 +/-0.2 ° and 28.0 +/-0.2 °;

(2) the weight loss of the crystal form AZT-A is 0.3 +/-0.1% within the range of 30-150 ℃; and/or

(3) The crystal form AZT-A has an endothermic peak at 162.5 +/-0.5 ℃ and 196.78 +/-0.5 ℃.

3. The crystalline form of claim 1, which is crystalline form AZT-B,

and the crystalline form AZT-B also has one or more of the following characteristics:

(1) the form AZT-B has an XRPD pattern comprising 6 or more than 62 θ values selected from the group consisting of: 7.4 +/-0.2 degrees, 8.1 +/-0.2 degrees, 11.4 +/-0.2 degrees, 12.0 +/-0.2 degrees, 14.8 +/-0.2 degrees, 17.2 +/-0.2 degrees, 19.9 +/-0.2 degrees, 20.9 +/-0.2 degrees, 22.3 +/-0.2 degrees, 23.5 +/-0.2 degrees and 24.1 +/-0.2 degrees;

(2) the weight loss of the crystal form AZT-B is 0.8 +/-0.1% within the range of 30-150 ℃; and/or

(3) The crystal form AZT-B has a melting endothermic peak at 147.3 +/-0.5 ℃.

4. The crystalline form of claim 1, which is crystalline form AZT-E,

and the crystalline form AZT-E also has one or more of the following characteristics:

(1) the form AZT-E has an XRPD pattern comprising 6 or more than 62 θ values selected from the group consisting of: 8.9 +/-0.2 °, 10.5 +/-0.2 °, 15.9 +/-0.2 °, 16.6 +/-0.2 °, 17.0 +/-0.2 °, 17.2 +/-0.2 °, 17.9 +/-0.2 °, 22.8 +/-0.2 ° and 24.7 +/-0.2 °;

(2) the weight loss of the crystal form AZT-E is about 3.3 +/-0.1% within the range of 50-150 ℃; and/or

(3) The crystal form AZT-E has a dehydration peak at 126.35 +/-0.5 ℃ and a melting endothermic peak at 197.15 +/-0.5 ℃.

5. The crystalline form of claim 1,

(i) the crystal form is AZT-A, and the AZT-A has one or more of the following characteristics:

(1) the crystalline form AZT-a has an XRPD pattern substantially as shown in figure 1;

(2) the crystalline form AZT-A has a TGA profile substantially as shown in figure 2; and/or

(3) The crystal form AZT-A has a DSC spectrum basically as shown in figure 3;

or,

(ii) the crystal form is a crystal form AZT-B, and the crystal form AZT-B also has one or more of the following characteristics:

(1) the crystalline form AZT-B has an XRPD pattern substantially as shown in figure 5;

(2) the crystalline form AZT-B has a TGA profile substantially as shown in figure 6; and/or

(3) The crystalline form AZT-B has a DSC spectrum substantially as shown in figure 7;

or,

(iii) the crystal form is AZT-E, and the AZT-E also has one or more of the following characteristics:

(1) the crystalline form AZT-E has an XRPD pattern substantially as shown in figure 11;

(2) the crystalline form AZT-E has a TGA profile substantially as shown in figure 12; and/or

(3) The crystalline form AZT-E has a DSC spectrum substantially as shown in figure 13.

6. A process for preparing the crystalline form of claim 1,

or,

7. An amorphous form of a compound of formula I, wherein,

the amorphous form has an XPRD spectrum substantially as shown in figure 21.

8. A method of preparing the amorphous form of claim 7, comprising the steps of:

1) providing a solution of an enretinib raw material in a solvent 1;

9. A pharmaceutical composition comprising (i) the crystalline form of claim 1; and (ii) a pharmaceutically acceptable carrier.

10. Use of the crystalline form according to claim 1 for the preparation of a medicament for the treatment of cancer and/or tumors.