WO2015035531A1 - Crystal form of regorafenib salt and preparation method and application thereof - Google Patents

Abstract

This application relates to a novel regorafenib salt and a crystal form thereof. Compared with an existing regorafenib monohydrate and a crystal form thereof, the regorafenib salt and the crystal form thereof in this application have one or more modification features. This application further relates to preparation methods of the regorafenib salt and the crystal form thereof, a pharmaceutical composition thereof, and application thereof in preparing medicine for treating metastatic colorectal cancer.

Description

 Regefenib salt crystal form, preparation method and use thereof

 This application relates to the field of medicinal chemical crystallization technology. In particular, it relates to a rifafenib salt and a crystalline form thereof, and to a process for the preparation of the regorafenib salt and a crystalline form thereof, a pharmaceutical composition thereof and use thereof. Background technique

 Regfinini is an anti-cancer drug approved by the FDA on September 27, 2012. Regfinib is a multi-targeted tyrosine kinase inhibitor for the treatment of metastatic colorectal cancer. The developer is Bayer Healthcare Pharmaceuticals. The trade name is Stivarga, which is marketed as a monohydrate of regorafenib free base.

The English name of Regigerin is Regorafenib, also known as BAY73-4506; the chemical name is 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluoro Phenoxyl-pyridine-2-carboxylic acid amide having a molecular formula of C ₂₁ H ₁₅ C1F ₄ N40 ₃ ; molecular weight 482.8; chemical structural formula is as follows:

Patent document WO 2005/009961 discloses regorafenib and its salts, processes for their preparation and uses. Specifically, Example 1 discloses regorafenib and its preparation method, and discloses its iH NMR and MS (HPLC/ES) data. Examples 2 to 4 disclose the hydrochloride, hydrazine sulfonate and benzenesulfonate of regorafenib and a process for the preparation thereof, and the melting points of the three salts are disclosed.

Patent document WO2008/043446 discloses resveripin monohydrate and its preparation method, and discloses its X-ray diffraction pattern (XRD), thermogravimetric analysis/difference scanning analysis (TGA/DSC), Raman spectroscopy, Characterization data of infrared optical (IR), near-infrared (NIR), far-infrared (FI) and 13C-solid-state nuclear magnetic resonance ( ¹³ C-NMR), the compound has a water content of 3.6% (weight) ). Riegenil monohydrate exhibits high stability in the preparation of pharmaceutical compositions.

Patent document WO2008/058644 discloses crystal form II of regorafenib and a preparation method thereof, the melting point of which is 181 ° C, TGA shows weight loss < 0.4%, and the advantage of crystal form II is that it is regia in water and organic solvent. Non-Nickel Form I, which has a melting point of 186 to 206 ° C, and TGA shows a weight loss of < 0.4%. The document is also open Characterization data of XRD, TGA/DSC, Raman spectroscopy, IR, NIR, FIR and ¹³ C-NMR of Regefenib Form II and Form I.

Patent document WO2008/055629 discloses crystal form III of regorafenib and a preparation method thereof, which has a melting point of 141 ° C, TGA shows a weight loss of < 0.4%, and discloses XRD, TGA/DSC, Raman spectroscopy of Form III. Characterization data of IR, NIR, FIR and ¹³ C-NMR. The advantage of crystalline germanium is high solubility in water and organic solvents. In addition, this patent document also discloses the manner in which rifafenib monohydrate is converted to Form III.

 Patent document WO 2013/000917 discloses the use of regorafenib and its hydrates, solvates and pharmaceutically acceptable salts or crystal forms thereof for the preparation of a medicament for the treatment of ophthalmic diseases, but does not disclose its pharmaceutically acceptable Preparation of salts or crystal forms or their characterization data.

 The present inventors have found that the crystal forms of crystal form I, crystal form II, crystal form III and regorafenil monohydrate of rifafenib free base are both hydrophobic and have very poor solubility in water; Nitrobenzene sulfonate has poor solubilization effect in water; Reigefinoxime sulfonate has a weight change of about 7.2% in the range of 20%~80% relative humidity, and is easy to absorb water; Regafinil hydrochloride does not absorb at high temperature Stable, after desolvation at 140 ° C, it will be converted to rifafenib free base.

 Therefore, there is still a need in the art to develop new regorafenib salts and their crystalline forms. Summary of the invention

 The present application provides a rifafenib salt and a crystal form thereof, including regorafenib p-nonylbenzenesulfonate, regorafenib p-chlorobenzenesulfonate, regorafenib 1,5-naphthalene disulfonate , Regafinibethane disulfonate, regorafenib hydrobromide, regorafenibethane, regorafenil 2-naphthalene sulfonate and crystalline forms of these salts.

 The novel regorafenib salt and its crystalline form provided by the present application have one or more superior properties compared to known rifafenib salts and their crystalline forms. Specific improved properties include, for example, higher crystallinity, solubility, dissolution rate, lower hygroscopicity, and better storage stability; in particular, the crystalline form of the regorafenib salt of the present application has favorable non-hygroscopicity. , solubility, good thermal stability and good storage stability.

 Accordingly, one of the contents of the present application is to provide rifafenib p-nonylbenzenesulfonate and its crystal form, and a process for the preparation thereof.

The rifafenib-p-nonylbenzenesulfonate provided by the present application is a compound formed by a 1:1 molar ratio of regorafenib and p-nonylbenzenesulfonic acid, and has the following structural formula: o

 Cl, F, 'CL meaning

The present application provides a method for preparing rifafenib-p-nonylbenzenesulfonate, the method comprising: respectively forming a solution system of regorafenib and p-nonylbenzenesulfonic acid in a soluble solvent, regorafenib and The molar ratio of p-nonylbenzenesulfonic acid is 1:1~1:2, and the two systems are mixed to form a suspension, and the solvent is removed to obtain the reggfenibene p-nonylbenzenesulfonate; The solvent is an alcohol, an ester, a ketone, an ether or an alkane; preferably, the soluble NH solvent is removed by filtration.

 The present application provides a crystalline form T of rifafenib-p-nonylbenzenesulfonate having an X-ray powder diffraction pattern of 4.5 ± 0.2 at 2 Torr. 13.4 ± 0.2. 18.1 ± 0.2. 20.8 ± 0.2. 21.9 ± 0.2. And 23.0 ± 0.2. There is a characteristic peak; further, its X-ray powder diffraction pattern is 4.5 ± 0.2 at 2 。. , 11.0 ± 0.2. , 11.5 ± 0.2. 13.4 ± 0.2°, 14.8 ± 0.2°, 16.6 ± 0.2°, 18.1 ± 0.2°, 2N0 '. 4 ± 0.2°, 20.8 ± 0.2°, 21.9 ± 0.2°, 23.0 ± 0.2. And 25.0 ± 0.2. There are characteristic peaks; further, the 2Θ characteristic peak of NH X-ray powder diffraction pattern and its relative intensity are:

 Diffraction angle 2Θ relatively strong

 4.5 ± 0.2. 38.0

 11.0 ± 0.2 ° 13.6

 11.5±0.2° 15.9

 13.4 ± 0.2 ° 42.2

 14.8 ± 0.2 ° 29.8

 16.6 ± 0.2 ° 29.9

 18.1 ± 0.2° 50.6

 19.3±0.2° 11.3

 20.4 ± 0.2 ° 42.1

 20.8 ± 0.2° 71.4

 21.9 ± 0.2° 100.0

 23.0 ± 0.2° 77.7

 24.0±0.2° 11.5

 25.0 士 0.2° 23.2

 26.1 ± 0.2° 18.5

 27.1±0.2° 19.5

 28.8 ± 0.2° 11.4

 29.0 ± 0.2° 14.3

 29.6 ± 0.2° 12.8

 33.7±0.2° 10.4

The present application also provides a method for preparing the crystal form T of rifignin, p-nonylbenzenesulfonate, the method package Included: a solution system of rifignin and p-nonylbenzenesulfonic acid in a soluble solvent, respectively, the molar ratio of regorafenib to p-nonylbenzenesulfonic acid is 1: 1~1:2, mixing two The system forms a suspension which is crystallized at a temperature of from -10 ° C to 50 ° C to obtain the crystal form T. The soluble solvent is preferably CH alcohol, C ₄ -C ₅ ester, C ₃ -C ₄ ketone, decyl tert-butyl ether or n-heptane; the concentration of the solution in the soluble solvent of regorafenib is preferably The solubility in the soluble solvent is 0.1 to 1 times, more preferably 0.5 to 1 times at the crystallization temperature; the concentration of the soluble solvent solution of the nonylbenzenesulfonic acid is preferably such that it is soluble at the crystallization temperature. The solubility in the solvent is 0.5 to 1 times; the molar ratio of regorafenib to p-nonylbenzenesulfonic acid is preferably 1:1 to 1:1.5; preferably, the crystallization temperature is room temperature, and the crystallization time is 1 to 48 hours. More preferably, it is 1 to 10 hours.

 Compared with the prior art, in particular with the Regfinibine p-nonylbenzenesulfonate and its crystalline form T of the present application, one or more improved properties, such as: better solubility, dissolution rate, lower Hygroscopicity, higher decomposition temperature and better storage stability.

 The regorafenib has the following beneficial effects on the mercaptobenzenesulfonate crystal form T:

 1 The crystal form T weighs 0.04% in the range of 20% to 80% relative humidity, and the weight change is about 0.11 with respect to the regorafenib monohydrate and its crystal form (in the range of 20% to 80% relative humidity) %) is less hygroscopic;

 2 has a higher decomposition temperature than the regorafenib monohydrate and its crystal form;

3 In the presence of sodium dodecyl sulfate (SDS), it has a better solubilizing effect relative to rifafinib monohydrate and its crystal form.

 4 The crystal form T is a flaky particle, which is larger than the regagirine monohydrate and its crystalline particles, and has good fluidity;

 5 Stable at room temperature, placed at room temperature for 6 months, the crystal form and melting point unchanged.

 A second aspect of the present application is to provide rifafenib p-chlorobenzenesulfonate and its crystal form, and a process for the preparation thereof.

 The rifafenib p-chlorobenzene sulfonate provided by the present application is regignon and p-chlorobenzene sulfonic acid.

A compound formed by a molar ratio of 1 : 1 has the following structural formula:

The present application provides a method for preparing rifafenib p-chlorobenzenesulfonate, the method comprising: separately forming a solution system of regorafenib and p-chlorobenzenesulfonic acid in a soluble solvent, regorafenib and p-chloro Benzenesulfonic acid The molar ratio is 1:1~1:2, the two systems are mixed to form a suspension, and the solvent is removed to obtain the reggfene-p-chlorobenzenesulfonate; preferably, the soluble solvent is an alcohol or an ester. , ketones, ethers and alkanes; preferably, the soluble solvent is removed by filtration.

 The present application provides a crystalline form C of rifafenib p-chlorobenzenesulfonate having an X-ray powder diffraction pattern of 9.0 ± 0.2 at 2 Torr. 9.9 士 0.2. 18.2 ± 0.2. , 19.9 ± 0.2. , 23. 1 ± 0.2. And 27.4 ± 0.2. There is a characteristic peak; further, the X-ray powder diffraction pattern is 9.0 ± 0.2° and 9.9 ± 0.2 at 2Θ. 12.4 ± 0.2. , 15.7 ± 0.2 °, 18.2 ° ± 0.2, 19.9 ± 0.2 °, 21.9 ± 0.2 °, 23.1 ± 0.2 °, 24.1 ± 0.2 °, 25. 2 ± 0.2 °, 25.5 ± 0.2. And 27.4 ± 0.2. There are characteristic peaks; further, the 2Θ characteristic peaks of the X-ray powder diffraction pattern and their relative intensities are:

 Diffraction angle 2Θ relative intensity%

 9.0 士 0.2° 53.0

 9.9 士 0.2° 37.9

 12.4±0.2° 17.3

 15.7 士 0.2° 35.8

 18.2 ± 0.2 ° 82.4

 18.7 ± 0.2 ° 1 1.7

 19.9 士 0.2° 60.1

 20.5 ± 0.2 ° 13.6

 21.9 ± 0.2° 14.6

 23. 1 ± 0.2 ° 63.3

 24. 1 ± 0.2 ° 27.6

 25.2 ± 0.2° 39.9

 25.5 ± 0.2 ° 34.2

 27.4 ± 0.2° 100.0

 28.5 ± 0.2° 17.9

 29.0 ± 0.2 ° 12.0

 29.8 ± 0.2° 15.9

 30. 1 ± 0.2 ° 12.3

The present application also provides a method for preparing the crystal form C of the rifafenib p-chlorobenzenesulfonate, the method comprising: respectively forming a solution system of regorafenib and p-chlorobenzenesulfonic acid in a soluble solvent, The molar ratio of gefenib and p-chlorobenzenesulfonic acid is 1:1~1:2, and the two systems are mixed to form a suspension, which is crystallized at a temperature of from -10 ° C to 50 ° C to obtain the crystal form C. . The soluble solvent is preferably a C ^ CA alcohols, C ₄ ~C ₅ esters, C ₃ ~C _4-one, Yue tert-butyl ether or n-heptane; concentration of soluble solvent solution is preferably regorafenib The solubility in the soluble solvent is 0.1 to 1 times, more preferably 0.5 to 1 time at the crystallization temperature; the concentration of the soluble solvent solution of p-chlorobenzenesulfonic acid is preferably the soluble solvent at the crystallization temperature The medium solubility is 0.5 to 1 times; the molar ratio of regorafenib to p-chlorobenzenesulfonic acid is preferably 1: 1 to 1: 1.5; preferably, the crystallization temperature is room temperature, and the crystallization time is 1 to 48 hours, It is preferably 1 to 10 hours. Compared with the prior art, especially in comparison with the known regorafenib monohydrate and its crystal form, the reggfenfenib p-chlorobenzene sulfonate and its crystal form C of the present application have one or more improvements. Characteristics such as higher solubility, dissolution rate, higher decomposition temperature and better storage stability.

 The rifafenib p-chlorobenzene sulfonate crystal form C has the following beneficial effects:

 1 stable at room temperature, placed at room temperature for 6 months, the crystal form and melting point unchanged;

 2 has a higher decomposition temperature than the regorafenib monohydrate and its crystal form;

3 In the presence of sodium dodecyl sulfate (SDS), it has a better solubilizing effect relative to rifafinib monohydrate and its crystal form.

 A third aspect of the present application is to provide rifafenib 1,5-naphthalene disulfonate and a crystalline form thereof, and a process for the preparation thereof.

 The regorafenib 1,5-naphthalenedisulfonate provided by the present application is a compound formed by a 2:1 molar ratio of regorafenib and 1,5-naphthalenedisulfonate, and has the following structural formula:

 The present application provides a method for preparing the regorafenib 1,5-naphthalene disulfonate, comprising the steps of: respectively forming a solution system of regorafenib and 1,5-naphthalenedisulfonic acid in a soluble solvent; The molar ratio of reguginib to 1,5-naphthalenedisulfonic acid is 1:1 to 2:1. The two systems are mixed to form a suspension, and the solvent is removed to obtain the regorafenib 1,5-naphthalene disulfide. Preferably, the soluble solvent is an alcohol, an ester, a ketone, an ether or an alkane; preferably, the soluble solvent is removed by filtration.

The present application provides a crystalline form N of rifafenib 1,5-naphthalene disulfonate having an X-ray powder diffraction pattern of 7.3 ± 0.2 °, 10.3 ± 0.2 °, 12.8 ± 0.2 °, 15.1 ± 0.2 °, 18.8 at 2 Torr. Characteristic peaks at 0.2° and 26.1 ± 0.2°; further, the X-ray powder diffraction pattern is 7.3 ± 0.2 at 2 Torr. , 8.3 ± 0.2. , 9.6 ± 0.2. , 10.3 ± 0.2 °, 11.6 ± 0.2 °, 12.8 ± 0.2 °, 13.7 ± 0.2 °, 15.1 ± 0.2 °, 16.5 ± 0.2 °, 18.8 ± 0.2 °, 19.8 ± 0.2. 21.1 ± 0.2. And 26.1 ± 0.2. There is a characteristic peak; further, its X-ray powder diffraction pattern is basically 2Θ characteristic peak and its relative intensity is as follows:

 Diffraction angle 2Θ relative intensity%

 7.3 ± 0.2 ° 99.5

 8.3±0.2° 19.3

 9.6 ± 0.2° 14.8

 10.3 ± 0.2 ° 27.3

 11.6 ± 0.2 ° 21.8

 12.8±0.2° 46.0

 13.7 ± 0.2° 16.3

 15.1 ± 0.2 ° 37.8

 15.9 士 0.2° 11.7

 16.5 ± 0.2 ° 28.1

 17.8 ± 0.2° 12.6

 18.8 ± 0.2° 39.9

 19.8 ± 0.2. 35.2

 21.1 ± 0.2 ° 23.4

 21.5±0.2° 10.2

 23.2 ± 0.2 ° 12.7

 24.8 ± 0.2. 18.0

 26.1 ± 0.2° 100.0

 26.6 ± 0.2 ° 11.0

The present application also provides a method for preparing the crystal form N of the rifafenib 1,5-naphthalene disulfonate, the method comprising: respectively forming a regent solvent of regorafenib and 1,5-naphthalenedisulfonic acid In the solution system, the molar ratio of regorafenib to 1,5-naphthalenedisulfonic acid is 1: 1~2: 1, mixing two systems to form a suspension, at a temperature of -10 ° C to 50 ° C Crystallization is carried out to obtain the crystal form N. The soluble solvent is preferably CH ^ alcohol, C ₄ ~ C ₅ ester, C K ₄ ketone, decyl tert-butyl ether or n-heptane; the concentration of the soluble solvent solution of regorafenib is preferably The concentration of the soluble solvent solution in the soluble solvent at a crystallization temperature of 0.1 to 1 times, more preferably 0.5 to 1 times, of the 1,5-naphthalenedisulfonic acid is preferably at a crystallization temperature in a soluble solvent. 0.5 to 1 times the solubility; the molar ratio of regorafenib to 1,5-naphthalene disulfonic acid is preferably 2: 1.5 to 2: 1; preferably, the crystallization temperature is room temperature, and the crystallization time is 1 to 48. Hour, more preferably 1 to 10 hours.

 Compared with the prior art, in particular, compared with the known regorafenib monohydrate and its crystal form, the reggfenfenil 1,5-naphthalene disulfonate and its crystal form N of the present application have one or A variety of improved properties such as: higher solubility, dissolution rate, higher decomposition temperature and better storage stability.

 The crystal form N of the Rifafenib 1,5-naphthalene disulfonate has the following beneficial effects:

 1 stable at room temperature, placed at room temperature for 6 months, the crystal form and melting point unchanged;

2 has a higher decomposition temperature than the reggfinib monohydrate and its crystal form; 3 In the presence of sodium dodecyl sulfate (SDS), it has a better solubilizing effect relative to regorafenib monohydrate and its crystal form.

 The fourth content of the present application is to provide rifafenib ethanedisulfonate and its crystal form, and a preparation method thereof. The retic ethanedisulfonate provided by the present application is a compound formed by a 2:1 molar ratio of regorafenib and ethanedisulfonate, and its structural formula

 The present application provides a method for preparing the regorafenib sulphonate, comprising the steps of: respectively forming a solution system of regorafenib and ethanedisulfonic acid in a soluble solvent, regorafenib and ethanedisulfonate The molar ratio of the acid is 1:1 to 2:1, and the two systems are mixed to form a suspension, and the solvent is removed to obtain the reggfenibene ethanedisulfonate; preferably, the soluble solvent is an alcohol or an ester. , ketones, ethers or alkanes; preferably, the soluble solvent is removed by filtration.

 The present application provides crystal form E of rifafenibethane disulfonate having an X-ray powder diffraction pattern of 10.6 ± 0.2 at 2 Torr. 12.1 ± 0.2. , 17.0 ± 0.2. 18.1 ± 0.2. 22.7 ± 0.2. And 23.6. ± 0.2. There is a characteristic peak; further, its X-ray powder diffraction pattern is 10.6 ± 0.2 at 2 。. 12.1 ± 0.2. 14.1 ± 0.2. 15.8 士 0.2. 17.0 ± 0.2. 18.1 ± 0.2 °, 20.1 ± 0.2 °, 21.3 ± 0.2 °, 22.7 ± 0.2 °, 23.6 ± 0.2. 24.3 ± 0.2. And 27.8 ± 0.2. There are characteristic peaks; further, the X-ray powder diffraction pattern is basically 2 Θ characteristic peaks and their relative intensities are as follows:

 Diffraction angle 2Θ relative intensity%

 10.6 ± 0.2 34.8

 12.1 ± 0.2 47.7

 14.1 ± 0.2 18.4

 15.8 ± 0.2 23.2

 17.0 ± 0.2 43.5

 17.4士 0.2 1 1.3

 17.9士 0.2 37.3

 18.1±0.2 58.4

 20.1 ± 0.2 30.4

20.5 ± 0.2 14.7 21.0 ± 0.2 ° 26.6

 21.3±0.2° 44.0

 21.7 ± 0.2 ° 16.0

 22.7±0.2° 100.0

 23.6 ± 0.2 ° 86.9

 24.3±0.2° 44.7

 24.5 ± 0.2 ° 18.4

 25.1 ± 0.2 ° 1 1.6

 26.2 ± 0.2° 15.3

 27.2 ± 0.2 ° 15.0

 27.8 ± 0.2° 33.3

 28.5 ± 0.2° 10.5

 28.9 ± 0.2° 18.3

The present application also provides a method for preparing the crystal form E of regorafenib sulphonate, the method comprising: respectively forming a solution system of regorafenib and ethanedisulfonic acid in a soluble solvent, Regigo The molar ratio of nitrite to ethanedisulfonic acid is 1:1 to 2:1, and the two systems are mixed to form a suspension, which is crystallized at a temperature of -10 ° C to 50 ° C to obtain the crystal form E. The soluble solvent is preferably a C ^ CA alcohols, C ₄ ~C ₅ esters, C ₃ ~C _4-one, Yue tert-butyl ether or n-heptane; concentration of soluble solvent solution is preferably regorafenib The solubility in the soluble solvent is 0.1 to 1 times, more preferably 0.5 to 1 time at the crystallization temperature; the concentration of the soluble solvent solution of ethanedisulfonic acid is preferably in the soluble solvent at the crystallization temperature 0.5 to 1 times the solubility, the molar ratio of regorafenib to ethanedisulfonic acid is preferably 2: 1.5 to 2: 1; preferably, the crystallization temperature is room temperature, and the crystallization time is 1 to 48 hours, more preferably 1 ~10 hours.

 Compared with the prior art, especially the known regorafenib monohydrate and its crystal form, the regefefenil disulfonate and its crystal form E of the present application have one or more improvements. Properties such as: higher solubility, dissolution rate, higher decomposition temperature and better storage stability.

 The crystal form N of regorafenibethane disulfonate has the following beneficial effects:

 1 stable at room temperature, placed at room temperature for 6 months, the crystal form and melting point unchanged;

 2 has a higher decomposition temperature than the regorafenib monohydrate and its crystal form;

3 In the presence of sodium dodecyl sulfate (SDS), it has a better solubilizing effect relative to rifafinib monohydrate and its crystal form.

A fifth aspect of the present application is to provide a reggfinib hydrobromide salt and a crystal form thereof, and a process for the preparation thereof. The regorafenib hydrobromide provided by the present application is a compound formed by the ratio of regorafenib and hydrobromide in a molar ratio of 1:1, and the structural formula is as follows:

The present application provides a preparation method of the reggfenfen hydrobromide, comprising the following steps: respectively forming a solution system of regorafenib and hydrobromic acid in a soluble solvent, and a molar ratio of regorafenib and hydrobromic acid The ratio is 1:1 to 1:2, and the two systems are mixed to form a suspension, and the solvent is removed to obtain the reggfenibine hydrobromide; preferably, the soluble solvent is an alcohol, a ketone or an alkane; The soluble solvent is removed by filtration.

 The present application provides rifafenib hydrobromide crystal form HI having an X-ray powder diffraction pattern of 5.1 ± 0.2 °, 10.1 ± 0.2 °, 15.1 ± 0.2 °, 18.2 ± 0.2 °, 19.5 ± 0.2 ° and 24.8. The characteristic peak at 0.2°; further, the X-ray powder diffraction pattern is 5.1 ± 0.2 at 2 。. 10.1. ± 0.2, 15.1 ± 0.2. , 18.2 ± 0.2 °, 19.5 ± 0.2 °, 20.3 ± 0.2 °, 23.2 ± 0.2 °, 24.8 ± 0.2 °, 25.2 ± 0.2 °, and 30.0 ± 0.2 ° with characteristic peaks; further, its X-ray powder diffraction pattern Basically 2Θ characteristic peaks and their relative intensities are as follows:

 Diffraction angle 2Θ relative intensity%

 5.1 士 0.2° 100.0

 10.1±0.2° 60.0

 15.1 ± 0.2° 24.1

 18.2 ± 0.2 ° 13.6

 19.5±0.2° 10.8

 20.3 ± 0.2. 8.6

 23.2 ± 0.2. 14.5

 24.8 ± 0.2 ° 20.3

 25.2±0.2° 12.2

 30.0±0.2° 18.5

 35.0 ± 0.2° 12.4

The present application also provides a method for preparing the regentifene hydrobromide crystal form HI, the method comprising: respectively forming a solution system of regorafenib and hydrobromic acid in a soluble solvent, regorafenib and The molar ratio of hydrobromic acid is 1:1 to 1:2, and the two systems are mixed to form a suspension, which is crystallized at a temperature of -10 ° C to 50 ° C to obtain the crystal form H1. The soluble solvent is preferably a Cr^C alcohol, a C ₃ -C ₄ ketone or n-heptane; a degree of 0.1 to 1 times, more preferably 0.5 to 1 times; a concentration of a soluble solvent solution of hydrobromic acid is preferably It has a solubility of 0.5 to 1 times in a soluble solvent at a crystallization temperature; a molar ratio of regorafenib to hydrobromide is preferred The ratio is 1:1 to 1:1.5; preferably, the crystallization temperature is room temperature, and the crystallization time is 1 to 48 hours, more preferably 1 to 10 hours.

 Compared with the prior art, in particular, the reggfenfen hydrobromide and its crystalline form m of the present application have one or more improved properties compared to the known regorafenib monohydrate and its crystalline form. For example: higher solubility, dissolution rate and better storage stability.

 The regorafenib hydrobromide crystal form HI has the following beneficial effects:

 1 stable at room temperature, placed at room temperature for 6 months, the crystal form and melting point unchanged;

 2 has a higher decomposition temperature than the regorafenib monohydrate and its crystal form;

3 In the presence of sodium dodecyl sulfate (SDS), it has a better solubilizing effect relative to rifafinib monohydrate and its crystal form.

 The present application provides a regent feneride hydrobromide crystal form H2 having an X-ray powder diffraction pattern of 20.6 ± 0.2°, 12.0 ± 0.2°, 16.8 ± 0.2°, 19.2 ± 0.2°, 21.3 ± 0.2° and 24.4. The characteristic peak at 0.2°; further, the X-ray powder diffraction pattern is 10.6 ± 0.2 at 2 。. , 12.0 ± 0.2. , 16.8 ± 0.2. 17.0 ± 0.2. , 18.9 ± 0.2. 19.2 ± 0.2. 20.2 ± 0.2°, 20.5 ± 0.2. 21.3 ± 0.2°, 24.1 ± 0.2. 24.4 ± 0.2. , 25.7 ± 0.2. And 26.5 ± 0.2. There is a characteristic peak; further, its X-ray powder diffraction pattern is basically 2Θ characteristic peak and its relative intensity is as follows:

 Diffraction angle 2Θ relative intensity%

 7.4±0.2° 15.6

 10.3±0.2° 14.3

 10.6 ± 0.2. 29.2

 12.0±0.2° 25.8

 16.8 ± 0.2 ° 50.8

 17.0±0.2° 27.1

 18.9 ± 0.2° 35.7

 19.2±0.2° 66.4

 19.6±0.2° 18.2

 20.2 ± 0.2. 32.6

 20.5 ± 0.2. 33.1

 21.3±0.2° 52.9

 24.2±0.2° 43.8

 24.4±0.2° 100.0

 24.7 ± 0.2 ° 32.3

 25.7 ± 0.2 ° 48.2

 26.5±0.2° 51.0

 27.5 ± 0.2. 15.9

 28.2±0.2° 30.5

 29.5 ± 0.2. 14.6

30.8±0.2° 17.7 31.9±0.2 14.1

 32.7±0.2 20.8

 34.3±0.2 15.6

 The present application provides a method for preparing the reggaefenic acid hydrobromide crystal form H2, the method comprising: forming a suspension of the ragefibrin hydrobromide crystal form m in a solvent, the suspension Crystallization was carried out at a temperature of -io °c ~ 50 °c to obtain the crystal form H2. Wherein the solvent is selected from the group consisting of ethyl acetate, mercapto tert-butyl ether or a mixture thereof; the amount of the rigafibrin hydrobromide crystal form HI is preferably 1.1 of its solubility in the solvent system at the crystallization temperature. It is preferably 20 times, more preferably 1.5 to 10 times; preferably, the crystallization temperature is room temperature, and the crystallization time is 1 to 72 hours, more preferably 1 to 10 hours.

 Compared with the prior art, in particular, the reggfenfen hydrobromide and its crystalline form H2 of the present application have one or more improved properties compared to the known regorafenib monohydrate and its crystalline form. For example: higher solubility, dissolution rate and better storage stability.

 The Reggfenibine ethyl sulfonate form H2 has the following beneficial effects:

 The sigroginib hydrobromide crystal form H2 is a homomorphic crystal of the sigroginib hydrobromide crystal form HI, the properties of which are substantially the same, have a higher decomposition temperature, in the dodecyl group In the presence of sodium sulphate (SDS), it has a better solubilizing effect relative to rifafinib monohydrate and its crystal form.

A sixth aspect of the present application is to provide rifafenibethane sulfonate and a crystalline form thereof, and a process for the preparation thereof. The rifafenibethane sulfonate provided by the present application is a compound formed by a 1:1 molar ratio of regorafenib and ethanesulfonate.

The present application provides a method for preparing the regorafenic acid ethyl sulfonate, comprising the steps of: respectively forming a solution system of regorafenib and ethanesulfonic acid in a soluble solvent, and a molar ratio of regorafenib and ethanesulfonic acid The ratio is 1:1~1:2, the two systems are mixed to form a suspension, and the solvent is removed to obtain the reggfenibine sulfonate; preferably, the soluble solvent is an ester, an alcohol or a ketone; Preferably, the soluble solvent is removed by filtration.

 The present application provides a crystalline form of rifafenibethane sulfonate Etl having an X-ray powder diffraction pattern of 8.2 ± 0.2 at 2 Torr. , 8.9 ± 0.2. , 13.0 ± 0.2. 18.8 ± 0.2. 23.6 ± 0.2. And 24.6 ± 0.2. Further, the X-ray powder diffraction pattern is 8.2 ± 0.2 °, 8.9 ± 0.2 °, 12.2 ± 0.2 °, 13.0 ± 0.2 °, 14.4 ± 0.2 °, 16.2 ± 0.2 °, 17.9 ± 0.2 °, 18.8 ± 0.2 °, 20.1 ± 0.2 °, 22.0 ± 0.2. 23.6 ± 0.2. And 24.6 ± 0.2. There are characteristic peaks; further, the 2Θ characteristic peaks of the X-ray powder diffraction pattern and their relative intensities are as follows:

Diffraction angle 2Θ relative intensity% 8.2 ± 0.2 ° 18.3

 8.9 ± 0.2° 22.9

 12.2 ± 0.2. 19.0

 13.0±0.2° 22.7

 14.4±0.2° 20.3

 16.2±0.2° 14.1

 17.9±0.2° 24.9

 18.8±0.2° 33.8

 20.1 ± 0.2. 21.2

 20.4 ± 0.2. 19.9

 22.0±0.2° 28.3

 23.4 ± 0.2. 47.9

 23.6 ± 0.2. 73.5

 24.6 ± 0.2 ° 100.0

 25.9 ± 0.2 ° 13.3

 26.2±0.2° 11.6

 28.3±0.2° 15.0

 30.6 ± 0.2. 12.0

 32.3 ± 0.2 ° 11.0

The present application also provides a method for preparing the regentinilethane sulfonate crystal form Etl, the method comprising: respectively forming a solution system of regorafenib and ethanesulfonic acid in a soluble solvent, regorafenib and The molar ratio of ethanesulfonic acid was 1:1 to 1:2, and the two systems were mixed to form a suspension, which was subjected to crystallization at a temperature of -10 ° C to 50 ° C to obtain the crystal form Etl. The soluble solvent is preferably a Cr^C alcohol, a C ₃ ～C ₄ ketone or a C ₄ ～C ₅ ester; the concentration of the soluble solvent solution of regorafenib is preferably at a crystallization temperature in a soluble solvent. The solubility is 0.1 to 1 times, more preferably 0.5 to 1 time; the concentration of the soluble solvent solution of ethanesulfonic acid is preferably 0.5 to 1 times the solubility in a soluble solvent at the crystallization temperature; The molar ratio of ethanesulfonic acid is preferably 1:1 to 1:1.5; preferably, the crystallization temperature is room temperature, and the crystallization time is from 1 to 48 hours, more preferably from 1 to 10 hours.

 Compared with the prior art, in particular, compared with the known regorafenib monohydrate and its crystal form, the reggfenfenate salt of the present application and its crystal form Etl have one or more improved properties. For example, higher solubility, dissolution rate, higher decomposition temperature and better storage stability.

 The reggfene ethanesulfonate crystal form Etl has the following beneficial effects:

 1 stable at room temperature, placed at room temperature for 6 months, the crystal form and melting point unchanged;

 2 has a higher decomposition temperature than the regorafenib monohydrate and its crystal form;

3 In the presence of sodium dodecyl sulfate (SDS), it has a better solubilizing effect relative to rifafinib monohydrate and its crystal form. The present application also provides regium fentanyl ethyl sulfonate crystal form Et2, the X-ray powder diffraction pattern of which is 12.3 ± 0.2 °, 13.6 ± 0.2 °, 16.0 ± 0.2 °, 20.5 ± 0.2 °, 24.3 ± 0.2 ° and There is a characteristic peak at 24.5 ± 0.2°; further, its X-ray powder diffraction pattern is 7.4 ± 0.2 at 2 。. , 8.2 ± 0.2. 12.3 ± 0.2. 13.6 ± 0.2°, 16.0 ± 0.2°, 16.9 ± 0.2°, 18.5 ± 0.2°, 20.5 ± 0.2°, 20.9 ± 0.2°, 22.1 ± 0.2. , 24.3 ± 0.2. And 24.5 ± 0.2. There are characteristic peaks; further, the characteristic peaks of the X-ray powder diffraction pattern and their relative intensities are as follows:

 Diffraction angle 2Θ relative

 7.4±0.2° 20.7

 8.2 ± 0.2 ° 23.9

 8.4 ± 0.2° 23.1

 12.3±0.2° 100.0

 13.6 ± 0.2 ° 35. .9

 16.0 ± 0.2. 32. .3

 16.9 ± 0.2. 22. .3

 18.2±0.2° 23. .9

 18.5 ± 0.2 ° 28. .3

 18.9 ± 0.2. 24. .3

 19.2±0.2° 12. .7

 20.1 ± 0.2. 30. .7

 20.5 ± 0.2. 46. .6

 20.9 ± 0.2. 29.9

 21.8±0.2° 28. .3

 22.1±0.2° 31. .5

 23.4 ± 0.2. 19. .5

 23.7 ± 0.2. 19. .5

 24.3±0.2° 77. .7

 24.5±0.2° 73. .3

 26.4 ± 0.2 ° 16. .3

 27.3 ± 0.2. 23. .1

 28.5±0.2° 27. .5

 28.7±0.2° 31. .5

 29.3 ± 0.2. 19. .5

The present application provides a method for preparing the Riegfried Ethylsulfonate crystal form Et2, the method comprising: forming a suspension of the Reggfenibine ethyl sulfonate form Etl in a solvent, the suspension Crystallization was carried out at -10 ° C to 50 ° C to obtain the crystal form Et 2 . Wherein the solvent is selected from the group consisting of mercapto tert-butyl ether, n-heptane or a mixture thereof; the amount of the reggfenibene ethyl sulfonate crystal form Etl is preferably 1.1 of the solubility in the solvent system at the crystallization temperature. It is preferably 20 times, more preferably 1.5 to 10 times; preferably, the crystallization temperature is room temperature, and the crystallization time is 1 to 72 hours, more preferably 1 to 10 hours. Compared with the prior art, especially the known regorafenib monohydrate and its crystal form, the reggfenfen hydrobromide and its crystal Et2 of the present application have one or more improved properties, For example: higher solubility, dissolution rate and better storage stability.

 The reggfene ethanesulfonate crystal form Et2 has the following beneficial effects:

 The sigroginib hydrobromide crystal form Et2 is a homomorphic crystal of the Reggfenib hydrobromide crystal form Etl, and the properties of the two are substantially the same, and have a higher decomposition temperature in the dodecyl group. In the presence of sodium sulphate (SDS), it has a better solubilizing effect relative to rifafinib monohydrate and its crystal form.

 Seventh of the content of the present application is to provide regosiniline 2-naphthalenesulfonate and its crystal form, and a preparation method thereof. The present application provides Regafinil 2-naphthalenesulfonate, which is formed by a ratio of 1 : 1 of regorafenib and 2-naphthalenesulfonic acid.

 The crystal form of the Regfini-N-naphthalene sulfonate salt Na has an X-ray powder diffraction pattern of 4.7 ± 0.2 at 2 Torr. , 13.7 ± 0.2. , 16.4 ± 0.2. , 18.0 ± 0.2. 20.2 ± 0.2. And 21.9 ± 0.2. The characteristic peak is further characterized by an X-ray powder diffraction pattern of 4.7 ± 0.2 at 2 Torr. , 10.5 ± 0.2. 1, 1 ± 0.2 ° 13.7 ± 0.2 °, 14.3 ± 0.2 °, 16.4 ± 0.2 °, 18.0 ± 0.2 °, 20.2 ± 0.2 °, 21.5 ± 0.2 °, 21.9 ± 0.2 °, 22.5 ± 0.2. And 24.0 ± 0.2. There are characteristic peaks; further, the characteristic peaks of the X-ray powder diffraction pattern and their relative intensities are as follows:

 Diffraction angle 2Θ relative intensity%

 4.7 ± 0.2° 100.0

 10.5 ± 0.2. 13.7

 1 1.1±0.2° 1 1.0

 13.7±0.2° 48.4

 14.3±0.2° 25.9

 16.4 ± 0.2° 37.4

 18.0 ± 0.2° 69.6

 18.4 ± 0.2° 13.5

 20.2 ± 0.2. 88.3

 21.5±0.2° 23.1

 21.9±0.2° 45.7

 22.5±0.2° 19.5

 23.4 ± 0.2. 13.1

 24.0±0.2° 28.3

 25.3 ± 0.2 ° 22.5

26.0 ± 0.2. 17.8 26.6±0.2° 19.9

 29.9 ± 0.2 ° 12.8.

The present application provides a method for preparing the Rifafinib 2-naphthalene sulfonate crystalline form Na, the method comprising: respectively forming a solution system of regorafenib and 2-naphthalenesulfonic acid in a soluble solvent, Regal The molar ratio of fenidazole to 2-naphthalenesulfonic acid is 1:1~1:2, the two systems are mixed, and the mixture is stirred at -10 ° C to 50 ° C to remove the soluble solvent, and the positive glucan is added. The alkane forms a suspension, and the suspension is crystallized at -10 ° C to 50 ° C to obtain the crystalline form Na. The soluble solvent is preferably CH ^ alcohol, C ₄ ~ C ₅ ester, C ₃ ~ C ₄ ketone or decyl tert-butyl ether; the amount of regorafenib is preferably in a soluble solvent at the crystallization temperature Solubility

0.1 to 1 times, more preferably 0.5 to 1 time; n-heptane is preferably used in an amount of 0.1 to 0.5 times that of the Regginib soluble solvent; 2-naphthalenesulfonic acid is preferably used in the crystallization temperature. The solubility in the solvent is 0.5 to 1 times; the molar ratio of regorafenib to 2-naphthalenesulfonic acid is preferably 1:1 to 1:1.5; and the mixture is preferably stirred at room temperature for 1 minute to 48 hours, more preferably 1 to 10 hours; the suspension is preferably stirred at room temperature for 1 to 48 hours, more preferably 1 to 10 hours.

 Compared with the prior art, in particular, the Riegfried 2-naphthalene sulfonate crystalline form Na of the present application has one or more improved properties compared to the known regorafenib monohydrate and its crystalline form. For example: higher solubility, dissolution rate, higher decomposition temperature and better storage stability.

 The crystal form Na of the Regfinene 2-naphthalene sulfonate has the following beneficial effects:

 1 stable at room temperature, placed at room temperature for 6 months, the crystal form and melting point unchanged;

 2 has a higher decomposition temperature than the regorafenib monohydrate and its crystal form;

3 In the presence of sodium dodecyl sulfate (SDS), it has a better solubilizing effect relative to rifafinib monohydrate and its crystal form.

 In any of the above preparation methods of the present application:

 Unless otherwise specified, "room temperature" means a temperature of about 10 to 30 °C.

 The stirring can be carried out by a conventional method in the art, such as magnetic stirring, mechanical stirring, etc., and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.

The removal of the solvent can be accomplished by conventional techniques in the art, such as filtration, centrifugation or evaporation. The filtration is generally carried out at room temperature under a pressure of less than atmospheric pressure, preferably at a pressure of less than 0.09 MPa. The specific operation of the centrifugation is as follows: The sample to be separated is placed in a centrifuge tube and centrifuged at a rate of 6000 rpm until the solids all sink to the bottom of the centrifuge tube. The evaporation can be carried out at about 20 to 40 ° C under atmospheric pressure or under vacuum, or by evaporation with an inert gas stream. When the solvent removal step is carried out for suspension agitation, the solvent is preferably removed by filtration. The various crystal forms obtained in the above methods can be further dried. The drying can be carried out by conventional techniques in the art, such as drying at room temperature, drying by air or drying under reduced pressure, in a fume hood, a blast oven or a vacuum oven; it can be carried out under reduced pressure or without decompression, Preferably the pressure is less than

0.09 MPa; drying temperature is about 30 to 50 ° C; drying time is 10 to 72 hours, preferably 10 to 48 hours, more preferably 10 to 24 hours.

 The volatilization is a crystallization mode used in the present application, and a solid is obtained by removing the solvent. The evaporation apparatus used is, for example, a rotary evaporator, an evacuated evaporation system, a nitrogen-blowing type evaporation system, or a vortex vacuum evaporation system.

 The ultrasound can promote dissolution of the sample by: placing the container containing the sample suspension in an ultrasonic cleaner, sonicating at a power of 20 Khz to 40 Khz for 1 to 30 minutes, preferably at 40 Khz for 5 minutes.

 The starting material, regorafenide free base in the present application can be prepared by the method described in Example 1 of the patent document WO2005/009961, which is incorporated herein by reference.

 The present application provides a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more of the Regafinil salts and crystalline forms thereof, and at least one pharmaceutically acceptable Accepted carrier. Wherein the regorafenib salt and its crystal form are selected from the group consisting of rifafenib-p-nonylbenzenesulfonate, rifafenib-p-nonylbenzenesulfonate crystal form T, regorafenib p-chlorobenzenesulfonate Acid salt, rifafenib p-chlorobenzene sulfonate crystal form (, regorafenib 1,5-naphthalene disulfonate, regorafenib 1,5-naphthalene disulfonate crystal form N, Regal Non-niobetic acid disulfonate, rifafenib ethyl disulfonate crystalline ruthenium, regorafenib hydrobromide, regorafenib hydrobromide crystal form Η1, regomafenil hydrobromide Form H2, Regafinilethane sulfonate, Reggfenibine ethyl sulfonate crystal form Etl, Reggfenibine ethyl sulfonate crystal form Et2, Regafinil 2-naphthalene sulfonate or Regal The non-N-naphthalene sulfonate salt form Na. Further, the pharmaceutical composition may further comprise a crystalline form or amorphous form of other pharmaceutically acceptable reggfenib or a salt thereof; optionally, the pharmaceutical composition One or more other pharmaceutically acceptable pharmaceutically active components may also be included.

The carrier in the pharmaceutical composition includes sugars, cellulose and derivatives thereof, starch or modified starch, solid inorganic substances such as calcium phosphate, dicalcium phosphate, hydroxyl tracheite, calcium sulfate, calcium carbonate, semi-solid Such as lipid or paraffin, binders such as microcrystalline cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl decyl cellulose, hydroxyethyl cellulose, glidants such as colloidal silica, Light anhydrous silicic acid, crystalline cellulose, talc or magnesium stearate, disintegrating agents such as sodium starch glycolate, crospovidone, croscarmellose, sodium carboxymethyl cellulose, dried corn Starch, lubricants such as stearic acid, magnesium stearate, sodium stearyl fumarate, polyethylene glycol. The pharmaceutically acceptable carrier in the pharmaceutical composition includes, but is not limited to, a diluent such as starch, modified starch, lactose, powdered cellulose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, tricalcium phosphate, Mannitol, sorbitol, sugar, etc.; binders such as acacia, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, copolyvidone, etc. a disintegrating agent, such as starch, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silica, etc.; lubricant, such as hard a fatty acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate, etc.; a glidant such as colloidal silica; a complex forming agent such as various grades of cyclodextrin and a resin; A speed controlling agent such as hydroxypropylcellulose, hydroxydecylcellulose, hydroxypropylmethylcellulose, ethylcellulose, decylcellulose, decyl decyl acrylate, wax, and the like. Other pharmaceutically acceptable carriers that may be used include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, viscosity modifiers, preservatives, antioxidants, and the like.

 The pharmaceutical composition may be in a solid or liquid form, such as a solid oral dosage form, including tablets, granules, powders, pills, and capsules; liquid oral dosage forms, including solutions, syrups, suspensions, dispersions, and emulsions. Injectable preparations, including solutions, dispersions, and lyophilizates. The formulation may be adapted for rapid release, delayed release or modified release of the active ingredient. It may be a conventional, dispersible, chewable, orally dissolved or rapidly melted formulation. The administration route includes oral, intravenous, subcutaneous injection, transdermal administration, rectal administration, intranasal administration, sublingual administration and the like. Ready. In preparing a pharmaceutical composition, one or more of the Regfininines salts or crystalline forms thereof of the present application are mixed with one or more pharmaceutically acceptable carriers, optionally with one or more The other pharmaceutically active ingredients are mixed. The solid preparation can be prepared by a process such as direct mixing, granulation, or the like.

The present application provides a reggfenibine salt of the present application or a crystalline form thereof, or a pharmaceutical composition comprising the above-described regorafenib salt or a crystalline form thereof, for the preparation of a medicament for the treatment and/or prevention of a hyperproliferative disorder Use, wherein the hyperproliferative disorder is selected from the group consisting of a solid tumor, a lymphoma, a sarcoma, a leukemia, a breast cancer, a respiratory cancer, a brain cancer, a genital cancer, a digestive tract cancer, a urinary tract cancer, an eye cancer, a liver cancer, a skin cancer, Head and neck cancer, squamous adenocarcinoma and/or parasitic adenocarcinoma, especially metastatic colorectal cancer. Wherein the regorafenib salt and its crystal form are regorafenib-p-nonylbenzenesulfonate, regorafenib-p-nonylbenzenesulfonate crystal form T, regorafenib p-chlorobenzenesulfonate , regium fentanyl p-chlorobenzene sulfonate crystal form C, regorafenib 1,5-naphthalene disulfonate, regorafenib 1,5-naphthalene disulfonate N, regorafenib Sulfonate, regorafenib ethanesulfonate E, regorafenib hydrobromide, rigaginib hydrobromide Hl, reguginib hydrobromide H2, reguginib hydrobromide Acid salt, reguginibethane sulfonate, rifafenibine sulphonate crystal form Etl, regorafenib ethane sulfonate crystal form Et2, reguginib 2-naphthalene sulfonate or reggae 2-naphthalene sulfonate crystal form Na.

 Further, the present application provides a method of treating a hyperproliferative disorder comprising administering to a patient a therapeutically and/or prophylactically effective amount of one or more of the Regafinil salts of the present application or a crystalline form thereof or the foregoing comprising the present application a pharmaceutical composition of the gefini salt or a crystalline form thereof, wherein the reggfenibine salt and its crystalline form include, but are not limited to, regorafenib p-nonylbenzenesulfonate, regorafenib p-nonylbenzenesulfonate Acid crystal form T, regorafenib p-chlorobenzene sulfonate, regorafenib p-chlorobenzene sulfonate crystal form C, regorafenib 1,5-naphthalene disulfonate, regorafenil 1 , 5-naphthalenedisulfonate N, regorafenib ethanesulfonate, regorafenib ethanesulfonate E, regorafenib hydrobromide, regorafenib hydrobromide HI, Regafinil Hydrobromide H2, Regafinil Hydrobromide, Regafinib Ethylsulfonate, Reggfenibine Ethyl Form Etl, Reggfenibine Ethyl Form Et2, regorafenib 2-naphthalene sulfonate, regorafenib 2-naphthalene sulfonate crystalline form Na, wherein the hyperproliferative disorders include, but are not limited to, solid tumors, lymphomas, sarcomas, leukemias , breast cancer, respiratory cancer, brain cancer, genital cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, squamous adenocarcinoma and/or parathyroid carcinoma, especially metastatic colon Rectal cancer, wherein the patient is a mammal including a human. DRAWINGS

 BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an XRPD pattern of regorafenib prepared according to Example 1 of WO2005/009961.

 Figure 2 is an XRPD pattern of the crystalline form of regorafenib monohydrate.

 Figure 3 is a PLM diagram of the crystalline form of regorafenib monohydrate.

 Figure 4 is a TGA diagram of the crystalline form of regorafenib monohydrate.

 Figure 5 is a DSC chart of the crystalline form of regorafenib monohydrate.

 Figure 6 is an isothermal adsorption curve of the crystalline form of regorafenib monohydrate.

 Figure 7 is an XRPD pattern of rifafenib versus mercaptobenzenesulfonate Form T.

 Figure 8 is a PLM diagram of the crystal form T of rifigninib versus mercaptobenzenesulfonate.

 Figure 9 is a TGA diagram of the crystal form T of rifigninib versus mercaptobenzenesulfonate.

 Figure 10 is a DSC chart of the crystal form T of rifigninib versus mercaptobenzenesulfonate.

 Figure 11 is an isotherm adsorption curve of rifafenib for the mercaptobenzene sulfonate form T.

 Figure 12 is an XRPD pattern of rifafenib p-chlorobenzenesulfonate Form C.

 Figure 13 is a PLM diagram of the crystal form C of rifafenib p-chlorobenzenesulfonate.

 Figure 14 is a TGA diagram of the crystal form C of rifafenib p-chlorobenzenesulfonate.

 Figure 15 is a DSC chart of the crystal form C of rifafenib p-chlorobenzenesulfonate.

Figure 16 is an isotherm adsorption curve of rifafenib p-chlorobenzenesulfonate crystal form C. Figure 17 is an XRPD pattern of crystalline form N of 1,5-naphthalene disulfonate of regorafenib.

 Figure 18 is a PLM diagram of the crystalline form N of 1,5-naphthalene disulfonate of regorafenib.

 Figure 19 is a TGA diagram of crystal form N of 1,5-naphthalene disulfonate of regorafenib.

 Figure 20 is a DSC chart of the crystalline form N of 1,5-naphthalene disulfonate of regorafenib.

 Figure 21 is an isotherm adsorption curve of the crystalline form N of 1,5-naphthalene disulfonate of regorafenib.

 Figure 22 is an XRPD pattern of the crystal form E of rifafenib ethylene disulfonate.

 Figure 23 is a PLM diagram of crystal form E of regorafenibethane disulfonate.

 Figure 24 is a TGA diagram of crystal form E of regorafenibethane disulfonate.

 Figure 25 is a DSC chart of crystal form E of regorafenibethane disulfonate.

 Figure 26 is an isotherm adsorption curve of crystal form E of regorafenibethane disulfonate.

 Figure 27 is an XRPD pattern of the ergfinib hydrobromide crystal form HI.

 Figure 28 is a PLM diagram of rifafenib hydrobromide crystal form HI.

 Figure 29 is a TGA diagram of the geigerfinil hydrobromide crystal form HI.

 Figure 30 is a DSC chart of the ergfinib hydrobromide crystal form HI.

 Figure 31 is an isotherm adsorption curve for the HI of the rifafenib hydrobromide crystal form.

 Figure 32 is an XRPD pattern of the Reggfenib Hydrobromide Form H2.

 Figure 33 is an XRPD pattern of the rifafenibine salt form Etl.

 Figure 34 is a PLM diagram of the rifafenibine salt form Etl.

 Figure 35 is a TGA diagram of the rifafenibine salt form Etl.

 Figure 36 is a DSC chart of the crystal form Erl of the rifafenibine sulfonate.

 Figure 37 is an isotherm adsorption curve of the crystal form Etl of the rifafenibine sulfonate.

 Figure 38 is an XRPD pattern of the rifafenibine salt form Et2.

 Figure 39 is an XRPD pattern of the crystalline form Na of 2-naphthylsulfonate of regorafenib.

 Figure 40 is a PLM diagram of the crystalline form Na of 2-naphthylsulfonate of regorafenib.

 Figure 41 is a TGA diagram of the crystalline form Na of 2-naphthylsulfonate of regorafenib.

 Figure 42 is a DSC chart of the crystalline form Na of 2-naphthylsulfonate of regorafenib.

 Figure 43 is an isotherm adsorption curve of the crystalline form Na of 2-naphthylsulfonate of regorafenib. detailed description

The examples describe in detail the crystalline forms of the present application, methods for their preparation, and uses. It will be apparent to those skilled in the art that many changes in the materials and methods can be practiced without departing from the inventive concept. Instruments and methods used to collect data:

 X-ray powder diffraction ( XPRD ) The instrument used was a Bruker D8 Advance diffractometer with a Ka X-ray with a copper target wavelength of 1.54 nm, a 40 kV and 40 mA operating condition, a Θ-2Θ goniometer, Mo single. Colorimeter, Lynxeye detector. The instrument was tested with diamond sand before use. The collection software is a Diffrac Plus XRD Commanded sample that is tested at room temperature and the sample to be tested is placed on a non-reflective sheet. Detailed test conditions are as follows, angle range: 3-40 ° 2θ, step size: 0.02 ° 2 Θ, speed: 0.2 sec / step. Samples were not ground prior to testing unless otherwise stated.

 The Polarized Light Microscope (PLM) spectrum is derived from a ΧΡ-500Ε polarized light microscope (Shanghai Changfang Optical Instrument Co., Ltd.). Take a small amount of powder sample on the glass slide, add a small amount of mineral oil to better disperse the powder sample, cover the cover glass, and then place the sample on a ΧΡ-500Ε polarized light microscope (Shanghai Changfang Optical Instrument Co., Ltd.) On the stage, select the appropriate magnification to observe the shape of the sample and take a picture.

The differential thermal analysis (DSC) data is from the TA Instruments Q200 MDSC, the instrument control software is Thermal Advantage, and the analysis software is Universal Analysis. Usually take 1 - 10 mg of the sample and place it in an aluminum crucible with a punched hole (unless otherwise specified). The sample is raised from room temperature to a temperature of 10 ° C / min under the protection of 50 ml / min dry N ₂ . At 200 °C or 300 °C, the TA software records the change in heat during the temperature rise of the sample. In the present invention, the melting point is reported as the starting temperature.

The thermogravimetric analysis (TGA) data is from the TA Instruments Q500 TGA, the instrument control software is Thermal Advantage, and the analysis software is Universal Analysis. Usually 5-15 mg of the sample is placed in a platinum crucible, and the sample is lifted from room temperature to a temperature of 10 ° C / min under the protection of 50 ml / min dry N ₂ at a temperature increase rate of 10 ° C / min. At 300 °C, the TA software records the change in weight of the sample during the heating process.

 The dynamic moisture adsorption analysis (DVS) data is from the TA Instruments Q5000 TGA, the instrument control software is Thermal Advantage, and the analysis software is Universal Analysis. Usually, 1-10 mg of the sample is placed in the platinum crucible, usually the TA software records the sample. The isothermal adsorption curve is plotted for the change in weight during the change in relative humidity from 0% to 80% to 0%. Depending on the sample, different adsorption and desorption steps are applied to the sample.

Nuclear magnetic analysis (ifiNMR) data was obtained from Bruker Ascend Tm 500. Usually use full frequency excitation, 30PPM, single pulse, 30. Angle excitation, scanning 16 times, digital orthogonal detection, temperature control 298K:. The HPLC analysis data is from the Agilent 1260, the instrument control software is Agilent ChemStation B.04 online, and the analysis software is Agilent ChemStation B.04 offline.釆C18 column, 150mm*4.6mm, column temperature 25 °C, wavelength 220nm, flow rate 1.3ml/min, injection volume 5ul, running time 15min. Mobile phase A is water with 0.05% TFA and mobile phase B is acetonitrile. The gradient is as follows:

 The various reagents used in the examples were commercially available unless otherwise specified.

 The temperature in the examples is room temperature unless otherwise specified.

 The ultrasonic operation in the examples was carried out for 5 minutes at a power of 40 kHz. Example 1

 For the preparation of rifafenib free base, reference is made to the method described in Example 1 of WO2005/009961. Specifically:

Add 4-chloro-3-(trifluoro) to a solution of 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid amide (1.42 g, 5.46 mmol) in benzene (3 mL) Mercapto)phenylisocyanate (1.2 g, 5.46 mmol). The mixture was stirred at room temperature for 48 hours. The resulting solid was filtered under reduced pressure, dried for 4 hours at room temperature in vacuo to give the compound (1.1 ⁴ g, ^2.3 5 mmoles; yield ^43% :).

 The X-ray powder diffraction pattern is shown in Figure 1. Show: Example 1 The prepared sample was substantially identical to the X-ray powder diffraction pattern of Reggfenib Form I disclosed in WO2008/058644.

 Ifi-NMR (DMSO-6) 2.80 (d, J=4.5, 3H), 7.07-7.10 (m, 1H), 7.19 (dd, J=3.0, 6.0, 1H), 7.35 (dd, J=2.5, 1 1.5, 1H), 7.43 (d, J=2.5, 1H), 7.64 (s, 2H), 8.13-8.19 (m, 2H), 8.50 (d, J=5.5, 1H), 8.75 (s, lH), 8.79-8.81 (m, 1H), 9.54 (s, 1H); MS (HPLC/ES) 483.06 m/z = (M+1). Show: The sample prepared in Example 1 is identical to the Reggezini free base prepared in Example 1 of WO2005/009961.

Example 2

Weighed 1 g of Regagene prepared in Example 1 in a 250 ml round bottom flask, added 24 ml of acetone, and then ultrasonically dissolved; under stirring, 120 ml of water was added to the acetone solution of regorafenib. A white solid precipitated during the dropwise addition, and the mixture was filtered under reduced pressure and dried in vacuo at 40 ° C overnight to give 0.92 g of sig.

 The X-ray powder diffraction pattern is shown in Figure 2. The X-ray powder diffraction pattern of the regorafenib monohydrate disclosed in WO 2008/043446 is substantially the same.

 The PLM map is shown in Figure 3. Display: Small rod crystals.

 The TGA map is shown in Figure 4. Display: 4.3% weight loss before 150 °C, decomposition temperature is 211 °C.

The DSC spectrum is shown in Figure 5. Display: Melt decomposition begins at 182 °C.

 The isothermal adsorption curve is shown in Figure 6. Display: 20% RH~80% RH weight change is 0.11%. Example 3

 Weighed 1.OOg of the regorafenib prepared in Example 1 in a 250 ml round bottom flask, and added 180 ml of isopropanol to dissolve ultrasonically; weigh 0.36 g of p-nonylbenzenesulfonic acid in another 5 ml glass vial, After adding 4 ml of isopropanol, it was sonicated; under stirring, an isopropanol solution of nonylbenzenesulfonic acid was added dropwise to a solution of regorafenib in isopropanol, and after stirring at room temperature for 7 hours, a white solid precipitated. After stirring for 1 hour, it was filtered, washed three times with isopropyl alcohol, and dried under vacuum at 40 ° C for 10 hours to obtain 1.21 g of a white solid.

 The X-ray powder diffraction pattern is shown in Fig. 7. Display: Reggfenib p-mercaptobenzenesulfonate crystal form T. The PLM map is shown in Figure 8. Display: flaky crystals.

 The TGA map is shown in Figure 9. Display: Form T decomposition temperature is 238 °C.

 The DSC spectrum is shown in Figure 10. Display: Form T begins to melt and decompose at 237 °C.

 The isothermal adsorption curve is shown in Figure 11. Display: 20% RH~80% RH weight change is 0.04%.

HPLC characterization showed that regorafenib and p-nonylbenzenesulfonic acid were salted at a molar ratio of 1:1.

 The above test results show that: the crystal form T is very stable at high temperature, is not easy to absorb moisture, and has a good morphology.

Example 4

 Weighed 1.OOg of the rifafinib prepared in Example 1 in a 250 ml round bottom flask, and dissolved in 180 ml of isopropanol, sonicated; weigh 0.36 g of p-nonylbenzenesulfonic acid in a 500 ml flask, and add 8 ml. After isopropanol, the solution was sonicated; under stirring, a solution of regorafenib in isopropanol was added dropwise to a solution of p-nonylbenzenesulfonic acid in isopropanol. After stirring at room temperature for 6 hours, a white solid precipitated and continued. After stirring for 1 hour, it was filtered, washed three times with isopropyl alcohol, and dried under vacuum at 50 ° C for 10 hours to obtain 1.20 g of rifafinib p-nonylbenzenesulfonate crystal form T, yield 88.5%.

Example 5

Weigh l.Olg The regorafenide prepared in Example 1 was placed in a 50 ml glass bottle, and 28 ml of hydrazine was added. Ultrasonic dissolution after alcohol; weigh 0.45g p-nonylbenzenesulfonic acid in another 20ml glass bottle, add 6ml sterol and ultrasonically dissolve; add decyl benzenesulfonic acid sterol solution to the mixture under stirring After stirring at room temperature for 1 hour, a white solid was precipitated and filtered, decyl alcohol was washed three times, and vacuum dried at 50 ° C for 10 hours to obtain a crystal form of rifafenib-nonylbenzenesulfonate. T. The yield was 1.24 g and the yield was 90.5%.

Example 6

 Weigh 1.03 g of the regorafenib prepared in Example 1 in a 500 ml round bottom flask, add 215 ml of n-butanol, and dissolve ultrasonically; weigh 0.48 g of p-nonylbenzenesulfonic acid in another 20 ml glass vial, add After 10 ml of n-butanol, it was sonicated; under stirring, a solution of p-nonylbenzenesulfonic acid in n-butanol was added dropwise to a solution of regorafenib in n-butanol. After stirring at 50 ° C for 10 hours, a white solid precipitated. After filtration, the n-butanol was washed three times, and dried under vacuum at 40 ° C for 10 hours to obtain a crystal form T of rifignin-p-nonylbenzenesulfonate. The yield was 1.22 g, and the yield was 87.3%.

Example 7

 1. OOg of the rifafinib prepared in Example 1 was placed in a 250 ml round bottom flask, and 120 ml of ethyl acetate was added thereto, followed by ultrasonic dissolution; 0.54 g of p-nonylbenzenesulfonic acid was weighed into another 20 ml glass vial, After adding 10 ml of ethyl acetate, the solution was sonicated; under stirring, the ethyl acetate solution of p-nonylbenzenesulfonic acid was added to the solution of rigaginib in ethyl acetate, and after stirring at room temperature for 5 hours, a white solid precipitated. After stirring for 1 hour, the mixture was filtered, washed with ethyl acetate three times, and dried under vacuum at 40 ° C for 10 hours to obtain the crystal form T of sigroginib p-nonylbenzenesulfonate. The yield was 1.23 g, and the yield was 90.7%.

Example 8

 1. llg The reggfene prepared in Example 1 was placed in a 250 ml round bottom flask, and 162 ml of isopropyl acetate was added and ultrasonically dissolved; 0.72 g of p-nonylbenzenesulfonic acid was weighed into another 20 ml glass vial. After adding 8 ml of isopropyl acetate, ultrasonically dissolve; under stirring, add isopropyl acetate solution of nonylbenzenesulfonic acid to isopropylprednisolone isopropyl acetate solution, and stir at -10 °C. After a few hours, a white solid precipitated, stirring was continued for 32 hours, then filtered, washed with isopropyl acetate three times, and dried under vacuum at 40 ° C for 15 hours to obtain the crystal form T of sigroginib p-nonylbenzenesulfonate. The yield was 1.20 g, and the yield was 87.6%.

Example 9

Weigh 1.02 g of rifafinib prepared in Example 1 in a 1 L round bottom flask, add 600 ml of acetone and dissolve ultrasonically; weigh 0.37 g of p-nonylbenzenesulfonic acid in another 20 ml glass vial and add 8 ml of acetone. After sonication; under stirring, the acetone solution of p-nonylbenzenesulfonic acid was added dropwise to the acetone solution of regorafenib. After stirring at room temperature for 1 hour, a white solid was precipitated, filtered, and washed three times with acetone, 30°. C was vacuum dried for 10 hours to obtain the crystal form T of rifafenib-p-nonylbenzenesulfonate. Yield 0.98g, The yield was 70.8%.

Example 10

 Weigh l.Olg prepared in Example 1 in a 250 ml round bottom flask, add 150 ml of butanone and dissolve ultrasonically; weigh 0.36 g of p-nonylbenzenesulfonic acid in another 20 ml glass vial, add After 9 ml of methyl ethyl ketone, the solution was sonicated; under stirring, the butanone solution of nonylbenzenesulfonic acid was added dropwise to the solution of rifafenib in methyl ethyl ketone. After stirring at -10 ° C for 13 hours, a white solid precipitated and continued. After stirring for 35 hours, it was filtered, butanone was washed three times, and vacuum-dried at 30 ° C for 24 hours to obtain a crystal form T of rifignin-p-nonylbenzenesulfonate. Yield l.l lg, yield 81.0%.

Example 11

 Weigh 1.02 g of rifafinib prepared in Example 1 in a 1 L round bottom flask, add 450 ml of decyl tert-butyl acid, and dissolve ultrasonically; weigh 0.37 g of p-nonylbenzenesulfonic acid in another 20 ml glass vial. Adding 7ml of decyl tert-butyl ether and ultrasonically dissolving; adding a solution of nonylbenzenesulfonic acid in decyl tert-butyl ether to the solution of sigroginib in decyl tert-butyl ether under stirring After stirring at -10 ° C for 1 hour, a white solid precipitated, which was filtered, washed three times with decyl-tert-butyl ether, and dried under vacuum at 30 ° C for 48 hours to obtain a crystal form T of sigroginib p-nonylbenzenesulfonate. The yield was 0.99 g, and the yield was 71.6%.

Example 12

 1.00 g of the Riegfried prepared in Example 1 in a 1 L round bottom flask, after adding 600 ml of n-heptane, ultrasonically dissolved; weigh 0.36 g of p-nonylbenzenesulfonic acid in another 20 ml glass vial, After adding 10 ml of n-heptane, the solution was sonicated; and the n-heptane solution of p-nonylbenzenesulfonic acid was added dropwise to the n-heptane solution of regorafenib under stirring, stirred at room temperature for 3 hours, filtered, and washed with n-heptane. Three times, vacuum drying at 50 ° C for 10 hours gave Regentinil p-nonylbenzenesulfonate crystal form T. The yield was 0.87 g, and the yield was 64.1%.

Example 13

 Weigh 1.50 g of the regorafenib prepared in Example 1 in a 50 ml glass bottle, add 15 ml of ethanol, and stir to dissolve at 40 ° C; weigh 0.60 g of p-chlorobenzenesulfonic acid in another 50 ml glass bottle, add 1 ml After ethanol, the solution was sonicated; under stirring, the ethanol solution of regorafenib was added dropwise to the ethanol solution of p-chlorobenzenesulfonic acid, and after stirring at 40 ° C for 11 hours, a white solid precipitated, and the mixture was stirred at room temperature for 37 hours and then filtered. The ethanol was washed three times and dried under vacuum at 40 ° C for 72 hours to obtain a yield of 95 g of p-chlorobenzenesulfonate of 95.3%.

 HPLC characterization showed that regorafenib and p-chlorobenzenesulfonic acid were salted at a molar ratio of 1:1.

Example 14 1.70 g of the Riegfried prepared in Example 1 was weighed into a 100 ml round bottom flask, and dissolved by adding 60 ml of sec-butanol at 50 ° C; 0.68 g of p-chlorobenzenesulfonic acid was weighed into another 100 ml flask, and added. 2 ml of sec-butanol was sonicated; after stirring, a solution of sigroginib in sec-butanol was added dropwise to a solution of p-chlorobenzenesulfonic acid in sec-butanol, and after stirring at 50 ° C for 1 hour, a white solid precipitated. After stirring at room temperature for 4 hours, it was filtered, sec-butyl alcohol was washed three times, and vacuum dried at 50 ° C for 16 hours to obtain a yield of 1.96 g of p-chlorobenzenesulfonate 82.4%.

 HPLC characterization showed that regorafenib and p-chlorobenzenesulfonic acid were salted at a molar ratio of 1:1.

Example 15

 Weigh 1 g of Regagene prepared in Example 1 in a 250 ml round bottom flask, add 180 ml of isopropanol to dissolve; weigh 0.41 g of p-chlorobenzenesulfonic acid in another 250 ml flask, add 4 ml of isopropyl After alcohol, the solution was sonicated; under stirring, the solution of regorafenib in isopropanol was added dropwise to a solution of p-chlorobenzenesulfonic acid in isopropanol. After stirring at 50 ° C for 1 hour, a white solid precipitated and stirring was continued. After an hour, it was filtered, washed with isopropyl alcohol three times, and dried under vacuum at 40 ° C for 10 hours to give 1.29 g of white solid.

 The X-ray powder diffraction pattern is shown in Fig. 12. Display: Regefenib p-chlorobenzenesulfonate crystal form C. The PLM map is shown in Figure 13. Display: Small particle crystals.

 The TGA map is shown in Figure 14. Display: Form C has a weight loss of 7.98% before 150 °C and a decomposition temperature of 230 °C.

 The DSC spectrum is shown in Figure 15. Display: Form C begins to melt and decompose at 186 °C.

 The isothermal adsorption curve is shown in Figure 16. Display: 20% RH~80% RH weight change is 0.38%. HPLC characterization showed that regorafenib and p-chlorobenzenesulfonic acid were salted at a molar ratio of 1:1.

 The above test results show that the crystal form C is stable at high temperatures and is not easily hygroscopic.

Example 16

 Weigh l.Olg prepared in Example 1 in a 250 ml round bottom flask, add 180 ml of isopropanol to dissolve; weigh 0.41 g of p-chlorobenzenesulfonic acid in another 250 ml flask, add 8 ml of isopropyl After alcohol, the solution was sonicated; under stirring, the solution of regorafenib in isopropanol was added dropwise to a solution of p-chlorobenzenesulfonic acid in isopropanol. After stirring at 50 ° C for 5 hours, a white solid precipitated and stirring was continued. After an hour, it was filtered, washed three times with isopropyl alcohol, and dried under vacuum at 50 ° C for 10 hours to obtain 1.22 g of yelfinidin p-chlorobenzenesulfonate crystal form C, yield 86.3%.

Example 17

Weigh 1.03 g of the regorafenib prepared in Example 1 in a 500 ml round bottom flask, and add 220 ml of decyl alcohol to dissolve; weigh 0.83 g of p-chlorobenzenesulfonic acid in another 500 ml of the fire, and add 2 ml of sterol after ultrasonication. Dissolving; adding a stilfuryl sterol solution to a decyl alcohol solution of p-chlorobenzenesulfonic acid under stirring After stirring at room temperature for 5 hours, a white solid precipitated, stirring was continued for 4 hours, and then filtered, and the decyl alcohol was washed three times, and dried under vacuum at 40 ° C for 16 hours to obtain a crystal form C of rifafenib p-chlorobenzenesulfonate. The yield was 1.20 g, and the yield was 83.3%.

Example 18

 Weighed 1.OOg of the rifafinib prepared in Example 1 in a 500 ml round bottom flask, and dissolved in 215 ml of n-butanol; weighed 0.60 g of p-chlorobenzenesulfonic acid in another 500 ml flask, and added 4 ml of n-butyl After alcohol, the solution was sonicated; under stirring, the n-butanol solution of regorafenil was added dropwise to the n-butanol solution of p-chlorobenzenesulfonic acid, and after stirring at -10 ° C for 10 hours, a white solid precipitated and stirring was continued. After 38 hours, it was filtered, n-butanol was washed three times, and vacuum-dried at 30 ° C for 10 hours to obtain a crystal form C of rifafenib p-chlorobenzenesulfonate. The yield was 1.27 g, and the yield was 90.8%.

Example 19

 Weigh 1 g of the rifafinib prepared in Example 1 in a 1 L round bottom flask, and dissolve it by adding 600 ml of ethyl acetate; weigh 0.53 g of p-chlorobenzenesulfonic acid in another 1 L flask, and add 8 ml of acetic acid. After esterification, the solution was sonicated; the ethyl acetate solution of regorafenib was added dropwise to a solution of p-chlorobenzenesulfonic acid in ethyl acetate under stirring, and after stirring at -10 ° C for 1 hour, a white solid precipitated and was filtered. The ethyl acetate was washed three times and dried under vacuum at 40 ° C for 10 hours to obtain the crystal form C of the sigroginib p-chlorobenzenesulfonate. The yield was 1.21 g, and the yield was 85.6%.

Example 20

 Weigh 1.02 g of the regorafenib prepared in Example 1 in a 250 ml round bottom flask, and add 203 ml of isopropyl acetate to dissolve; weigh 0.41 g of p-chlorobenzenesulfonic acid in another 250 ml flask, and add 9 ml of acetic acid. After propyl ester, the solution was sonicated; under stirring, the isopropylprene isopropyl acetate solution was added dropwise to a solution of p-chlorobenzenesulfonic acid in isopropyl acetate. After stirring at room temperature for 6 hours, a white solid precipitated and continued. After stirring for 4 hours, it was filtered, washed with isopropyl acetate three times, and dried under vacuum at 40 ° C for 48 hours to obtain the crystal form C of rifafenib p-chlorobenzenesulfonate. Yield 1.17 g, yield 82.0%.

Example 21

 Weigh 1.02 g of the regorafenib prepared in Example 1 in a 150 ml round bottom flask, dissolved in 60 ml of acetone; weigh 0.62 g of p-chlorobenzenesulfonic acid in another 150 ml flask, add 15 ml of acetone, and dissolve ultrasonically; Under stirring, the acetone solution of regorafenib was added dropwise to the acetone solution of p-chlorobenzenesulfonic acid. After stirring at room temperature for 1 hour, a white solid precipitated. After stirring for 6 hours, it was filtered, and acetone was washed three times, 30 °. C was vacuum dried for 72 hours to obtain the crystal form C of rifafenib p-chlorobenzenesulfonate. The yield was 1.29 g, and the yield was 90.4%.

Example 22 Weighed 1.OOg of the rifafinib prepared in Example 1 in a 150 ml round bottom flask, and dissolved in 75 ml of butanone; weighed 0.40 g of p-chlorobenzenesulfonic acid in another 150 ml flask, and added 6 ml of methyl ethyl ketone. Ultrasonic solution; Under stirring, the solution of rifafenib in methyl ethyl ketone was added dropwise to the solution of p-chlorobenzenesulfonic acid in methyl ethyl ketone. After stirring at -10 ° C for 7 hours, a white solid precipitated and stirring was continued for 41 hours. The butanone was washed three times and dried under vacuum at 30 ° C for 24 hours to obtain a crystal form C of rifafenib p-chlorobenzenesulfonate. The yield was 1.30 g, and the yield was 92.9%.

Example 23

 Weigh 1 g of the rifafinib prepared in Example 1 in a 1 L round bottom flask, add 450 ml of decyl tert-butyl ether to dissolve; weigh 0.41 g of p-chlorobenzenesulfonic acid in another 1 L flask, add After 10 ml of decyl tert-butyl ether, it was sonicated; under stirring, a solution of sigroginib in decyl tert-butyl ether was added dropwise to a solution of p-chlorobenzenesulfonic acid in decyl tert-butyl ether, and stirred at room temperature for 4 hours. After the system was clarified, after stirring for 5 hours, a white solid was precipitated, stirring was continued for 16 hours, and then filtered, and the mixture was washed three times with decyl-tert-butyl ether, and dried under vacuum at 30 ° C for 10 hours to obtain rifafenib p-chlorobenzenesulfonate. Form C. The yield was 1.09 g, and the yield was 77.1%.

Example 24

 Weigh 1 g of Regagene prepared in Example 1 in a 1 L round bottom flask, add 600 ml of n-heptane to dissolve; weigh 0.41 g of p-chlorobenzenesulfonic acid in another 1 L glass vial, add 10 ml positive After heptane, the solution was sonicated; the n-heptane solution of regorafenib was added dropwise to the n-heptane solution of p-chlorobenzenesulfonic acid under stirring, and stirred at room temperature for 10 hours, and a white solid was precipitated and filtered, n-heptane. It was washed three times and dried under vacuum at 30 ° C for 10 hours to obtain a crystal form C of rifafenib p-chlorobenzenesulfonate. The yield was 0.95g and the yield was 67.2%.

Example 25

 Weigh 1.50 g of the regorafenib prepared in Example 1 in a 50 ml glass bottle, add 15 ml of ethanol, and stir to dissolve at 40 ° C; weigh 0.45 g, 5-naphthalene disulfonic acid in another 5 ml glass vial, After adding 4 ml of ethanol, it was sonicated; under stirring, the ethanol solution of 1,5-naphthalene disulfonic acid was added dropwise to the ethanol solution of regorafenib, and after stirring at 40 ° C for 1 hour, a white solid precipitated and was transferred to room temperature. After stirring for 4 hours, it was filtered, washed three times with ethanol, and dried under vacuum at 40 ° C for 16 hours to obtain 1.86 g of a 5-naphthalene disulfonate yield of 95.5%.

 HPLC characterization showed that regorafenib and 1,5-naphthalenedisulfonic acid were salted in a 2:1 molar ratio.

Example 26

Weigh 1.80 g of the regorafenib prepared in Example 1 in a 100 ml glass vial, add 64 ml of sec-butanol, and stir to dissolve at 50 ° C; weigh 0.54 g, 5-naphthalene disulfonic acid in another 5 ml glass vial Medium, plus After injecting 4 ml of sec-butanol, it was sonicated; under stirring, a solution of 1,5-naphthalene disulfonic acid in sec-butanol was added dropwise to the solution of sigfurfurin in sec-butanol, and after stirring at 40 ° C for 1 hour, The white solid was precipitated, stirred at room temperature for 4 hours, filtered, washed with sec-butyl alcohol three times, and dried under vacuum at 40 ° C for 48 hours to give 2.09 g of a 5-naphthalene disulfonate yield of 89.4%.

 HPLC characterization showed that regorafenib and 1,5-naphthalenedisulfonic acid were salted in a 2:1 molar ratio.

Example 27

 Weighed 1.OOg of the regorafenib prepared in Example 1 in a 250 ml round bottom flask, dissolved in 120 ml of ethyl acetate; and weighed 0.60 g of 1,5-naphthalenedisulfonic acid in another 20 ml glass vial. After adding 5 ml of ethyl acetate, the solution was sonicated; and the ethyl acetate solution of 1,5-naphthalenedisulfonic acid was added dropwise to the ethyl acetate solution of regorafenib under stirring, and stirred at room temperature for 5 hours, and there was a white solid. After the mixture was stirred for 1 hour, it was filtered, and the mixture was washed three times with ethyl acetate, and dried under vacuum at 40 ° C for 10 hours to give 1.19 g of a white solid.

 The X-ray powder diffraction pattern is shown in Fig. 17. Display: Regentinol 1,5-naphthalene disulfonate crystal form ^ PLM map shown in Figure 18. Display: Small particle crystals.

 The TGA map is shown in Figure 19. Display: Form N loses 2.0% at 150 °C and has a decomposition temperature of 240 °C.

 The DSC spectrum is shown in Figure 20. Display: Form N begins to melt and decompose at 238 °C.

 The isothermal adsorption curve is shown in Figure 21. Display: 20% RH~80% RH weight change is 3.77%. HPLC characterization showed that regorafenib and 1,5-naphthalenedisulfonic acid were salted in a 2:1 molar ratio.

 The above test results show that the crystal form N is stable at a high temperature.

Example 28

 Weighed 1.OOg of the rifafinib prepared in Example 1 in a 250 ml round bottom flask, dissolved in 150 ml of ethyl acetate; weigh 0.30 g of 1,5-naphthalene disulfonic acid in another 250 ml flask, add After 10 ml of ethyl acetate, the solution was sonicated; the ethyl acetate solution of regorafenib was added dropwise to a solution of 1,5-naphthalenedisulfonic acid in ethyl acetate under stirring, and after stirring at room temperature for 6 hours, a white solid precipitated. After further stirring for 1 hour, it was filtered, washed with ethyl acetate three times, and dried under vacuum at 30 ° C for 10 hours to obtain 1.16 g of sig-fifene 1,5-naphthalene disulfonate crystal form N, yield 89.3%.

Example 29

Weigh l.Olg prepared in Example 1 in a 250 ml round bottom flask, add 220 ml of decyl alcohol to dissolve; weigh 0.45 g of 1,5-naphthalene disulfonic acid in another 5 ml glass vial, add 4 ml of decyl alcohol was dissolved by ultrasonication; under stirring, a solution of 1,5-naphthalene disulfonic acid in sterol was added dropwise to a solution of sigroginib in methanol, and after stirring at 50 ° C for 10 hours, a white solid precipitated. Continue stirring for 38 hours and filter. The decyl alcohol was washed three times and dried under vacuum at 40 ° C for 16 hours to obtain a crystal form N of repaginib 1,5-naphthalene disulfonate. The yield was 1.09 g, and the yield was 83.1%.

Example 30

 Weigh 1.03 g of the regorafenib prepared in Example 1 in a 500 ml round bottom flask, add 360 ml of isopropanol to dissolve; weigh 0.34 g of 1,5-naphthalene disulfonic acid in another 5 ml glass vial, add 4ml of isopropanol was sonicated; after stirring, the isopropanol solution of 1,5-naphthalenedisulfonic acid was added dropwise to the isopropyl alcohol solution of rifafenib, and stirred at 50 ° C for 10 hours, there was white The solid was precipitated, and the mixture was further stirred for 1 hour, filtered, washed three times with isopropyl alcohol, and vacuum-dried at 50 ° C for 10 hours to obtain a crystal form N of repaginib 1,5-naphthalene disulfonate. Yield 1.18 g, yield 88.2%.

Example 31

 Weigh 1.02 g of rifafinib prepared in Example 1 in a 500 ml round bottom flask, add 215 ml of n-butanol to dissolve; weigh 0.34 gl, 5-naphthalene disulfonic acid in another 20 ml glass vial, add 6 ml After n-butanol was ultrasonically dissolved; under stirring, a solution of 1,5-naphthalene disulfonic acid in n-butanol was added dropwise to a solution of regorafenib in n-butanol, and after stirring at room temperature for 1 hour, a white solid precipitated. Filtration, n-butanol was washed three times, and dried under vacuum at 40 ° C for 24 hours to obtain Regentinil 1,5-naphthalene disulfonate crystal form N. The yield was 1.20 g, and the yield was 90.6%.

Example 32

 Weigh 1.02 g of the regorafenib prepared in Example 1 in a 250 ml round bottom flask, add 180 ml of isopropyl acetate to dissolve; weigh 0.40 g of 1,5-naphthalene disulfonic acid in another 20 ml glass vial, After adding 8 ml of isopropyl acetate, the solution was sonicated; and the isopropyl acetate solution of 1,5-naphthalenedisulfonic acid was added dropwise to the isopropylprednione isopropyl acetate solution under stirring, and stirred at room temperature for 5 hours. A white solid precipitated, and the mixture was further stirred for 5 hours, filtered, washed with isopropyl acetate three times, and dried under vacuum at 40 ° C for 72 hours to obtain Regentinil 1,5-naphthalene disulfonate crystal form N. The yield was 1.15 g, and the yield was 86.8%.

Example 33

 Weighed 1.OOg of the regorafenib prepared in Example 1 in a 250 ml round bottom flask, dissolved in 60 ml of acetone; weigh 0.30 g of 1,5-naphthalene disulfonic acid in another 20 ml glass vial, add 6 ml After acetone, the solution was sonicated; under stirring, the acetone solution of 1,5-naphthalene disulfonic acid was added dropwise to the acetone solution of regorafenib. After stirring at room temperature for 10 hours, a white solid was precipitated, filtered, and washed with acetone three times. Drying at 40 ° C for 48 hours under vacuum gave Reggfenib 1,5-naphthalene disulfonate Form N. The yield was 1.21 g, and the yield was 93.2%. Example 34

Weighed 1.OOg of the rifafinib prepared in Example 1 in a 250 ml round bottom flask, dissolved in 75 ml of butanone; weighed 0.30 g of 1,5-naphthalenedisulfonic acid in another 20 ml glass vial, added 7ml Ding After ketone, the solution was sonicated; under stirring, a solution of 1,5-naphthalenedisulfonic acid and methyl ethyl ketone was added dropwise to the solution of rifafenib in methyl ethyl ketone. After stirring at -10 ° C for 10 hours, a white solid precipitated and continued. After stirring for 38 hours, it was filtered, butanone was washed three times, and dried under vacuum at 40 ° C for 16 hours to obtain Regentinil 1,5-naphthalene disulfonate crystal form N. The yield was 1.19 g, and the yield was 91.6%.

Example 35

 Weigh 1.02 g of the rifafinib prepared in Example 1 in a 1 L round bottom flask, and dissolve it by adding 450 ml of decyl tert-butyl ether; weigh 0.31 gl, 5-naphthalene disulfonic acid in another 20 ml glass vial. After adding 10 ml of decyl tert-butyl ether, it was sonicated; and a solution of 1,5-naphthalenedisulfonic acid in decyl tert-butyl ether was added dropwise to the solution of sigroginib in decyl tert-butyl ether under stirring. After stirring at -10 ° C for 10 hours, a white solid precipitated. After further stirring for 1 hour, it was filtered, washed with decyl-tert-butyl ether three times, and dried under vacuum at 30 ° C for 10 hours to obtain reguginib 1,5-naphthalene. Sulfonate crystal form N. The yield was 0.95 g, and the yield was 71.7%.

Example 36

 Weighed 1.OOg of the rifafinib prepared in Example 1 in a 1 L round bottom flask, and dissolved in 600 ml of n-heptane; 0.60 g of 1,5-naphthalene disulfonic acid was weighed into another 5 ml glass vial, After adding 4 ml of n-heptane, it was sonicated; under stirring, the n-heptane solution of 1,5-naphthalene disulfonic acid was added dropwise to the n-heptane solution of regorafenib, and after stirring at room temperature for 1 hour, there was a white solid. The precipitate was filtered, washed with n-heptane three times, and dried under vacuum at 40 ° C for 72 hours to obtain Regentinil 1,5-naphthalene disulfonate crystal form N. The yield was 0.88 g, and the yield was 67.8%.

Example 37

 Weigh 1.30 g of rifafinib prepared in Example 1 in a 50 ml glass bottle, add 13 ml of ethanol, and stir to dissolve at 40 ° C; weigh 0.26 g of ethanedisulfonic acid in another 5 ml glass vial, add 2 ml of ethanol After sonication; under stirring, the ethanol solution of ethanedisulfonic acid was added dropwise to the ethanol solution of rifafenib. After stirring at 40 ° C for 1 hour, a white solid precipitated, and stirred at room temperature for 4 hours, then filtered. It was washed three times and dried under vacuum at 40 ° C for 16 hours to obtain a yield of 1.51 g of ethanedisulfonate of 97.0%.

 HPLC characterization showed that regorafenib and ethanedisulfonic acid were salted at a molar ratio of 2:1.

Example 38

 1.50 g of the rifafinib prepared in Example 1 was placed in a 100 ml round bottom flask, 64 ml of sec-butanol was added, and dissolved by stirring at 50 ° C; 0.30 g of ethanedisulfonic acid was weighed into another 5 ml glass vial, After adding 3 ml of sec-butanol, it was sonicated; under stirring, a solution of sec-butanol of ethanedisulfonic acid was added dropwise to a solution of sigrenibine in sec-butanol, and after stirring at 50 ° C for 1 hour, a white solid precipitated. After filtration, the sec-butanol was washed three times, and dried under vacuum at 30 ° C for 10 hours to obtain a yield of 1.48 g of ethanedisulfonate of 82.4%.

HPLC characterization showed that regorafenib and ethanedisulfonic acid were salted in a 2:1 molar ratio. Example 39

 Weighed 1.OOg of the rifafinib prepared in Example 1 in a 500 ml round bottom flask, and dissolved in 225 ml of isopropanol; weighed 0.40 g of ethanedisulfonic acid in another 5 ml glass vial, and added 3 ml of isopropyl After alcohol, the solution was sonicated; under stirring, an isopropyl alcohol solution of ethanedisulfonic acid was added to a solution of regorafenib in isopropanol. After stirring at room temperature for 1 hour, a white solid was precipitated, filtered, and washed with isopropyl alcohol three times. Drying at 40 ° C for 10 hours under vacuum gave 1.12 g of a white solid.

 The X-ray powder diffraction pattern is shown in Fig. 22. Display: Regefenibethane disulfonate crystal form E.

The PLM map is shown in Figure 23. Display: Small particle crystals.

 The TGA map is shown in Figure 24. Display: Form E loses 1.12% before 150 °C and decomposes at 234 °C.

 The DSC spectrum is shown in Figure 25. Display: Form E begins to melt and decompose at 235 °C.

 The isothermal adsorption curve is shown in Fig. 26. Display: 20% RH~80% RH weight change is 0.89%.

HPLC characterization showed that regorafenib and ethanedisulfonic acid were salted at a molar ratio of 2:1.

 The above test results show that: the crystal form E is stable at high temperature and is not easy to absorb moisture.

Example 40

 Weighed 1.OOg of the regorafenib prepared in Example 1 in a 250 ml round bottom flask, and dissolved in 180 ml of isopropanol; weighed 0.20 g of ethanedisulfonic acid in another 250 ml flask, and added 6 ml of isopropanol. After sonication, the isopropyl alcohol solution of regorafenib was added dropwise to the isopropyl alcohol solution in isopropyl disulfide under stirring. After stirring at room temperature for 1 hour, a white solid was precipitated, and stirring was continued for 3 hours, followed by filtration. The propanol was washed three times and dried under vacuum at 40 ° C for 24 hours to obtain 1.10 g of rifafinibethane disulfonate crystal form E in a yield of 91.9%.

Example 41

 Weighed 1.OOg of the rifafinib prepared in Example 1 in a 100 ml round bottom flask, and dissolved in 44 ml of decyl alcohol; weighed 0.24 g of ethanedisulfonic acid in another 5 ml glass vial and added 4 ml of decyl alcohol. Ultrasonic dissolution; Under stirring, the decyl alcohol solution of ethanedisulfonic acid was added to the stilfuryl alcohol solution. After stirring at 50 ° C for 1 hour, a white solid was precipitated. After stirring for 1 hour, it was filtered, and the sterol was washed three times. It was dried under vacuum at 40 ° C for 48 hours to obtain the crystal form E of rifafinib ethylene disulfonate. The yield was 1.13 g, and the yield was 94.4%.

Example 42

Weigh 1.04 g of rifafenib prepared in Example 1 in a 500 ml round bottom flask, add 215 ml of n-butanol to dissolve; weigh 0.21 g of ethanedisulfonic acid in another 5 ml glass vial, and add 4 ml of n-butanol. After sonication, the n-butanol solution of ethanedisulfonic acid was added to the n-butanol solution of rifafenib under stirring. After stirring at room temperature for 3 hours, a white solid was precipitated, stirring was continued for 45 hours, and then filtered. The alcohol was washed three times and dried under vacuum at 50 ° C for 10 hours to obtain a crystal form E of rifafinib ethylene disulfonate. The yield was 1.17 g, and the yield was 94.0%.

Example 43

 Weigh 1.03 g of the regorafenib prepared in Example 1 in a 250 ml round bottom flask, add 134 ml of ethyl acetate to dissolve; weigh 0.31 g of ethanedisulfonic acid in another 5 ml glass vial, and add 4 ml of ethyl acetate. After sonication, the ethyl acetate solution of ethanedisulfonic acid was added to the ethyl acetate solution of rifafenib under stirring. After stirring at room temperature for 10 hours, a white solid was precipitated, filtered, and washed three times with ethyl acetate. Drying under vacuum at °C for 72 hours gave Regentinibethanedisulfonate Form E. The yield was 1.15 g, and the yield was 93.3%.

Example 44

 Weigh l.Olg The regorafenide prepared in Example 1 was dissolved in a 250 ml round bottom flask, and 162 ml of isopropyl acetate was added. Weigh 0.20 g of ethanedisulfonic acid in another 20 ml glass vial, and add 5 ml of acetic acid. After isopropyl ester, the solution was sonicated; under stirring, isopropyl disulfonic acid in isopropyl acetate solution was added to the isopropylprednione isopropyl acetate solution. After stirring at -10 ° C for 1 hour, a white solid was precipitated and stirring was continued. After 38 hours, it was filtered, washed with isopropyl acetate three times, and dried under vacuum at 30 ° C for 10 hours to obtain the crystal form E of sigroginibethane disulfonate. Yield 1.10 g, yield 91.0%.

Example 45

 Weighed l.Olg The regorafenide prepared in Example 1 was dissolved in a 150 ml round bottom flask and dissolved in 60 ml of acetone; 0.26 g of ethanedisulfonic acid was weighed into another 20 ml glass vial, and 8 ml of acetone was added for ultrasonic dissolution. Under stirring, the acetone solution of ethanedisulfonic acid was added to the acetone solution of rifafenib. After stirring at room temperature for 1 hour, a white solid was precipitated. After stirring for 1 hour, it was filtered, washed three times with acetone, and dried at 40 ° C under vacuum. After 16 hours, the form E of rifafenibethane disulfonate was obtained. The yield was 1.15 g, and the yield was 95.1%.

Example 46

Weigh 1.02 g of rifafenib prepared in Example 1 in a 1 L round bottom flask, add 750 ml of butanone to dissolve; weigh 0.2 g of ethanedisulfonic acid in another 20 ml glass vial, and add 7 ml of butanone after ultrasonication. Dissolved; a solution of butyl sulfonic acid in methyl ethyl sulfonate was added to the solution of rifafenib in methyl ethyl ketone. After stirring at -10 ° C for 8 hours, a white solid was precipitated. After stirring for 40 hours, it was filtered, and the butanone was washed three times. , 40 °C Drying in vacuum for 10 hours gave Regentinibethanedisulfonate Form E. Yield 1.0 g of white solid, yield 81.9%.

Example 47

 Weigh l.Olg The regorafenide prepared in Example 1 was dissolved in a 1 L round bottom flask, and 450 ml of decyl tert-butyl ether was added to dissolve; 0.20 g of ethanedisulfonic acid was weighed into another 20 ml glass vial, and added. 6ml of decyl-tert-butyl ether was sonicated; after stirring, the solution of decyl-tert-butyl ether of ethanedisulfonic acid was added to the solution of sagel tert-butyl ether of regorafenib, and stirred at -10 °C. After a few hours, a white solid precipitated, which was filtered, washed three times with decyl-tert-butyl ether, and dried under vacuum at 40 ° C for 24 hours to obtain a crystal form of sigroginibethane disulfonate. Yield 0.91g, yield 75.3%

Example 48

 Weigh 1.02 g of rifafinib prepared in Example 1 in a 1 L round bottom flask, add 600 ml of n-heptane to dissolve; weigh 0.20 g of ethanedisulfonic acid in another 20 ml glass vial, and add 10 ml of n-heptane. After sonication, the n-heptane solution of ethanedisulfonic acid was added to the n-heptane solution of rifafenib under stirring. After stirring at room temperature for 3 hours, a white solid was precipitated and stirring was continued for 5 hours, followed by filtration, n-heptane. It was washed three times and dried under vacuum at 40 ° C for 10 hours to obtain Regentinyl Ethanedisulfonate Form E. The yield was 0.83 g, and the yield was 68.0%.

Example 49

 Weighed 1.OOg of the regegeinib prepared in Example 1 was placed in a 250 ml round bottom flask, and ultrasonically dissolved after adding 200 ml of isopropyl alcohol; 0.42 g (concentration of 40% by weight) hydrobromic acid was weighed into another In a 5 ml glass vial, 4 ml of isopropanol was added and ultrasonically dissolved; under stirring, an isopropanol solution of hydrobromic acid was added dropwise to a solution of regorafenib in isopropanol, and stirred at 50 ° C for 1 hour. The white solid was stirred at room temperature for 10 hours, filtered, washed with EtOAc EtOAc EtOAc EtOAc.

 The X-ray powder diffraction pattern is shown in Fig. 27. Display: Regafinib hydrobromide crystal form Hl.

 The PLM map is shown in Figure 28. Display: Small particle crystals.

 The TGA graphic is shown in Figure 29. Display: Crystal form HI loses 10.47% before 150 °C, and the decomposition temperature is 216 °C.

 The DSC spectrum is shown in Figure 30. Display: Form HI begins to melt and decompose at 172 °C.

 The isothermal adsorption curve is shown in Figure 31. Display: 20% RH~80% RH weight change is 1.57%. HPLC characterization showed that regorafenib and hydrobromic acid were salted at a molar ratio of 1:1.

 The above test results show that the crystal form HI is stable at a high temperature.

Example 50 Weighed 1.OOg Example 1 prepared rifafinib in a 250 ml round bottom flask, added 180 ml of isopropanol and sonicated; weighed 0.42 g of hydrobromic acid (concentration of 40% by weight) to another In a 250 ml flask, 8 ml of isopropanol was added and ultrasonically dissolved; under stirring, a solution of regorafenib in isopropanol was added dropwise to a solution of hydrobromic acid in isopropanol, and stirred at 50 ° C for 1 hour to precipitate white. The solid was filtered, washed with isopropyl alcohol three times, and dried under vacuum at 30 ° C for 72 hours to obtain 1.07 g of sig-fibene hydrogen bromide crystal form HI with a yield of 91.6%.

Example 51

 Weigh 1.02 g of Regfininib prepared in Example 1 in a 50 ml glass vial, add 22 ml of sterol and dissolve ultrasonically; weigh 0.42 g of hydrobromic acid (concentration of 40% by weight) in another 5 ml of glass In a vial, 3 ml of sterol was added and ultrasonically dissolved; under stirring, a solution of hydrobromide in sterol was added dropwise to a solution of sigroginib in sterol, and after stirring at -10 ° C for 1 hour, a white solid was precipitated and filtered. The decyl alcohol was washed three times and dried under vacuum at 40 ° C for 10 hours to obtain a reggectin hydrobromide crystal form H1. Yield 1.04 g of white solid, yield 87.3%.

Example 52

 Weigh 1.02g of the rifafinib prepared in Example 1 in a 500ml round bottom flask, add

After 269 ml of n-butanol, ultrasonically dissolve; weigh 0.64 g (concentration of 40% by weight) hydrobromic acid in another 5 ml glass vial, add 4 ml of n-butanol and dissolve ultrasonically; under stirring, hydrobromic acid The n-butanol solution was added dropwise to the n-butanol solution of rifafenib. After stirring at room temperature for 10 hours, a white solid precipitated, which was filtered, washed three times with n-butanol, and dried under vacuum at 50 ° C for 10 hours to obtain reggectin hydrogen. Bromate crystal form Hl. The yield was 1.07 g, and the yield was 89.8%.

Example 53

 Weigh 1.03 g of Regfinib prepared in Example 1 and place it in a 250 ml round bottom flask, and dissolve it by ultrasonication after adding 120 ml of acetone; weigh 0.55 g (concentration of 40% by weight) of hydrobromic acid to another 20 ml of glass. In a vial, 7 ml of acetone was added and ultrasonically dissolved; under stirring, a solution of hydrobromic acid in acetone was added dropwise to the acetone solution of regorafenib, and after stirring at -10 ° C for 1 hour, a white solid was precipitated, filtered, and washed three times with acetone. It was dried under vacuum at 40 ° C for 24 hours to obtain a reggectin hydrobromide crystal form H1. The yield was 1.08 g, and the yield was 89.8%.

Example 54

Weigh 1.04 g of rifafinib prepared in Example 1 in a 1 L round bottom flask, and ultrasonically dissolve after adding 750 ml of butanone; weigh 0.44 g of hydrobromic acid (concentration of 40% by weight) to another 20 ml. In a glass vial, after adding 8 ml of methyl ethyl ketone, the solution was sonicated; under stirring, a solution of hydrobutyric acid and methyl ethyl ketone was added dropwise to the solution of rifafenib in methyl ethyl ketone. After stirring at room temperature for 1 hour, a white solid was precipitated and filtered. The ketone was washed three times and dried under vacuum at 40 ° C for 48 hours to obtain a reggectin hydrobromide crystal form H1. The yield was 0.97 g, and the yield was 79.9%.

Example 55

 Weigh 1.02 g of Regfinib prepared in Example 1 in a 1 L round bottom flask, ultrasonically dissolved after adding 600 ml of n-heptane; weigh 0.42 g of hydrobromic acid (concentration of 40% by weight) to another 20 ml In a glass vial, 10 ml of n-heptane was added and ultrasonically dissolved; under stirring, a solution of hydrobromic acid in n-heptane was added dropwise to the n-heptane solution of regorafenib, and stirred at 50 ° C for 10 hours. The solid was precipitated, and after stirring for further 38 hours, it was filtered, washed three times with n-heptane, and dried under vacuum at 50 ° C for 10 hours to obtain a sig-fibene hydrogen bromide crystal form H1. The yield was 0.80 g, and the yield was 67.2%.

Example 56

 0.3 g of rigaginib hydrobromide crystal form HI prepared in Example 49 was placed in a 50 ml glass vial, and 20 ml of ethyl acetate was added. After stirring at room temperature for 72 hours, filtration and vacuum drying at 40 ° C for 10 hours, 0.30 g of a white solid was obtained with a yield of 96.8%.

 The X-ray powder diffraction pattern is shown in Fig. 32. Display: Regafinil hydrobromide crystal form H2.

Example 57

 The ethyl acetate in Example 56 was replaced with mercapto tert-butyl ether, and the other operation was the same as in Example 56 to obtain the crystals of the sig-fibene hydrogen bromide, H2, yield 0.29 g, yield 93.5%.

Example 58

 Weigh 1.60 g of rifafinib prepared in Example 1 in a 50 ml glass bottle, add 13 ml of ethanol, and stir to dissolve at 40 ° C; weigh 0.37 g of ethanesulfonic acid in another 5 ml glass vial, add 2 ml of ethanol. Ultrasonic dissolution; Under stirring, the ethanol solution of ethanesulfonic acid was added dropwise to the ethanol solution of regorafenib. After stirring at 40 ° C for 1 hour, a white solid was precipitated, stirred at room temperature for 4 hours, filtered, and washed three times with ethanol. It was dried under vacuum at 30 ° C for 24 hours to obtain a yield of 96.7% of 1.9 g of ethanesulfonate.

 HPLC characterization showed that regorafenib and ethanesulfonic acid were salted at a molar ratio of 1:1.

Example 59

 1.30 g of the rigagene prepared in Example 1 in a 1 L round bottom flask, dissolved in 450 ml of decyl tert-butyl ether; 0.30 g of ethanesulfonic acid was weighed into another 20 ml glass vial, and 10 ml of thiol was added. After tert-butyl ether, ultrasonically dissolve; under stirring, a solution of decyl-tert-butyl ether of ethanesulfonic acid was added dropwise to a solution of sigroginib in decyl tert-butyl ether. After stirring at room temperature for 10 hours, there was a white solid. The mixture was further stirred for 1 hour, filtered, and washed with decyl-tert-butyl ether three times, and vacuum-dried at 40 ° C for 10 hours to obtain a yield of 1.12 g of repellamide, and a yield of 70.2%.

HPLC characterization showed that regorafenib and ethanesulfonic acid were salted at a molar ratio of 1:1. Example 60

 Weigh 1.00 g of the regorafenide free base prepared in Example 1 in a 250 ml round bottom flask, add 134 ml of ethyl acetate and dissolve ultrasonically; weigh 0.23 g of ethanesulfonic acid into another 5 ml glass vial. Adding 3 ml of ethyl acetate to dissolve in the ultrasonic solution; adding ethyl acetate solution of ethanesulfonic acid to the ethyl acetate solution of rifafenib under stirring, and stirring at 50 ° C for 5 hours, a white solid precipitated, continue After stirring for 43 hours, it was filtered, washed with ethyl acetate threetimes, and dried under vacuum at 50 ° C for 16 hours to give 1.18 g of white solid.

 The X-ray powder diffraction pattern is shown in Fig. 33. Display: Regoginis ethyl sulfonate crystal form Etl. The PLM map is shown in Figure 34. Display: Small particle crystals.

 The TGA graphic is shown in Figure 35. Display: Form Etl loses 0.45% before 150 °C and decomposes at 224 °C.

 The DSC spectrum is shown in Figure 36. Display: Form Etl begins to melt and decompose at 201 °C.

 The isothermal adsorption curve is shown in Figure 37. Display: 20% RH~80% RH weight change is 0.54%. HPLC characterization showed that regorafenib and ethanesulfonic acid were salted at a molar ratio of 1:1.

 The above test results show that: the crystal form Etl is stable at a high temperature and is not easily hygroscopic.

Example 61

 Weighed 1.OOg The regorafenide free base prepared in Example 1 was placed in a 250 ml round bottom flask, and dissolved in 120 ml of ethyl acetate, and sonicated; 0.23 g of ethanesulfonic acid was weighed into another 250 ml flask. Add 6ml of ethyl acetate to dissolve in the ultrasonic solution; add the effluentil ethyl acetate solution to the ethyl acetate lysate of ethanesulfonic acid under stirring, stir at 50 ° C for 5 hours, precipitate a white solid, continue to stir 5 After an hour, it was filtered, washed with ethyl acetate three times, and dried under vacuum at 40 ° C for 24 hours to obtain 1.04 g of sigphimamine sulphate crystal form Etl with a yield of 84.7%.

Example 62

 Weighing l.Olg The regorafenide free base prepared in Example 1 was placed in a 50 ml round bottom flask, and ultrasonically dissolved after adding 25 ml of ethanol; 0.46 g of ethanesulfonic acid was weighed into another 5 ml glass vial, and added. 2ml ethanol was sonicated; under stirring, the ethanol solution of ethanesulfonic acid was added dropwise to the ethanol solution of rifafenib. After stirring at room temperature for 5 hours, a white solid precipitated. After stirring for 1 hour, it was filtered and washed three times with ethanol. Drying at 40 ° C for 72 hours under vacuum gave a regentinil ethyl sulfonate crystal form Etl. The yield was 1.19 g, and the yield was 95.9%.

Example 63

Weigh 1.02 g of the Riegfried free base prepared in Example 1 in a 250 ml round bottom flask, add 180 ml of isopropanol and dissolve ultrasonically; weigh 0.28 g of ethanesulfonic acid into another 5 ml glass vial. Add 3 ml of isopropanol to dissolve in the ultrasonic solution; add isopropyl sulfonic acid in isopropyl alcohol solution to the isopropyl alcohol solution in isopropyl alcohol, and stir at room temperature for 1 hour. White solid precipitates, filtered, isopropyl The alcohol was washed three times and dried under vacuum at 40 ° C for 10 hours to obtain a regentinilethane sulfonate crystal form Etl. The yield was 1.18 g, and the yield was 94.2%.

Example 64

 Weighed 1.OOg The regorafenide free base prepared in Example 1 was placed in a 500 ml round bottom flask, and ultrasonically dissolved after adding 215 ml of n-butanol; 0.35 g of ethanesulfonic acid was weighed into another 5 ml glass vial. Add 3 ml of n-butanol to dissolve ultrasonically; add n-butanol solution of ethanesulfonic acid to the n-butanol solution of rifafenib under stirring, and stir at 50 ° C for 15 hours to precipitate a white solid. Continue After stirring for 33 hours, it was filtered, washed three times with n-butanol, and vacuum dried at 40 ° C for 48 hours to obtain a crystal form of reggfene ethanesulfonate. Yield 1.13 g, yield 92.0%.

Example 65

 Weighed l.Olg The regorafenide free base prepared in Example 1 was placed in a 250 ml round bottom flask, and dissolved in 120 ml of acetone, and sonicated; 0.24 g of ethanesulfonic acid was weighed into another 5 ml glass vial, and added. 4ml acetone was sonicated; under stirring, the acetone solution of ethanesulfonic acid was added dropwise to the acetone solution of rifafenib, and stirred at -10 °C for 2 hours, and a white solid was precipitated. After stirring for 46 hours, the mixture was filtered. The mixture was washed three times and dried under vacuum at 40 ° C for 10 hours to obtain a crystal form of reggfene ethanesulfonate. The yield was 1.15 g, and the yield was 92.7%.

Example 66

 Weighing l.OOg The regagifin free base prepared in Example 1 was placed in a 1 L round bottom flask and added.

After 750 ml of methyl ethyl ketone, the solution was sonicated; 0.46 g of ethanesulfonic acid was weighed into another 5 ml glass vial, and 4 ml of methyl ethyl ketone was added to dissolve ultrasonically; and the butanone solution of ethanesulfonic acid was added dropwise to regagineril under stirring. The butanone solution was stirred at room temperature for 10 hours, and a white solid was precipitated, filtered, washed with n-butyl ketone three times, and dried under vacuum at 40 ° C for 24 hours to obtain a crystal form of reggfinibethanesulfonate. The yield was 0.98 g, and the yield was 79.8%. Example 67

 0.33 g of the Reggezinilethane salt form Etl prepared in Example 60 was placed in a 50 ml vial, and 20 ml of decyl tert-butyl acid was added. After stirring at room temperature for 72 hours, filtration and vacuum drying at 40 ° C for 10 hours, 0.32 g of a white solid was obtained with a yield of 97.0%.

 The X-ray powder diffraction pattern is shown in Fig. 38. Display: Regoginisulfate salt form Et2. Example 68

The mercapto tert-butyl ether of Example 67 was replaced with n-heptane, and the other operation was the same as that of Example 67 to obtain the crystals of the sig-fibene dimethanesulfonate form Et2, yield 0.31 g, yield 93.9%. Example 69

 Weighed 1.OOg of the regorafenide free base prepared in Example 1 was placed in a 250 ml round bottom flask and dissolved in 180 ml of isopropanol; 0.44 g of 2-naphthalenesulfonic acid was weighed into another 5 ml glass vial. Add 4ml of isopropanol to dissolve ultrasonically; add 2-naphthalenesulfonic acid in isopropanol solution to the solution of rifafenib in isopropanol, stir at room temperature for 2 hours, remove the solvent by evaporation, add 50ml positive The white solid was immediately precipitated by heptane, stirred at room temperature for 1 hour, filtered, washed three times with isopropyl alcohol, and dried under vacuum at 30 ° C for 24 hours to give 1.30 g of a white solid.

 The X-ray powder diffraction pattern is shown in Figure 39. Display: Rifafenib 2-naphthalene sulfonate crystal form Na. The PLM map is shown in Figure 40. Display: Small particle crystals.

 The TGA map is shown in Figure 41. Display: Form Na is at a decomposition temperature of 235 °C.

 The DSC spectrum is shown in Figure 42. Display: Form Na begins to melt and decompose at 193 °C.

 The isothermal adsorption curve is shown in Figure 43. Display: 20% RH~80% RH weight change is 0.26%. HPLC characterization showed that regorafenib and 2-naphthalenesulfonic acid were salted at a molar ratio of 1:1.

 The above test results show that the crystalline form Na is stable at high temperatures and is not easily hygroscopic.

Example 70

 Weighed 1.OOg of the Riegfried free base prepared in Example 1 was placed in a 500 ml round bottom flask, and 225 ml of isopropanol was added; 0.44 g of 2-naphthalenesulfonic acid was weighed into another 500 ml flask, and added. 8ml isopropanol was sonicated; add repigfidil in isopropanol solution to 2-naphthalenesulfonic acid in isopropanol solution, stir at 50 °C for 2 hours, remove the solvent by evaporation, add 25ml of n-glycan The white solid was immediately precipitated by alkane sonication, stirred at room temperature for 10 hours, filtered, washed three times with isopropyl alcohol, and dried under vacuum at 40 ° C for 10 hours to obtain 1.36 g of yelfinidin 2-naphthalenesulfonate salt Na, yield 95.0. %.

Example 71

 Weighing l.Olg The regorafenide free base prepared in Example 1 was placed in a 500 ml round bottom flask and dissolved in 220 ml of decyl alcohol; 0.88 g of 2-naphthalenesulfonic acid was weighed into another 5 ml glass vial. Add 4ml of sterol to dissolve ultrasonically; add 2-naphthenesulfonic acid sterol solution to the sterol fentanol solution, stir at room temperature for 2 hours, remove the solvent by evaporation, add 110ml of n-heptane ultrasonically The white solid was precipitated, stirred at -10 ° C for 1 hour, filtered, washed with decyl alcohol three times, and vacuum dried at 50 ° C for 10 hours to obtain a crystalline form Na of 2-naphthalenesulfonate of rifafenib, yield 1.23 g, yield 85.1 %.

Example 72

Weighed 1.OOg of the Riegfried free base prepared in Example 1 was placed in a 500 ml round bottom flask, and dissolved in 215 ml of n-butanol; 0.53 g of 2-naphthalenesulfonic acid was weighed into another 5 ml glass vial. Add 4ml of n-butanol to dissolve ultrasonically; add n-butanol solution of 2-naphthalenesulfonic acid to the n-butyl of Riegfried The alcohol solution was stirred at room temperature for 1 hour, and the solvent was quickly evaporated. The white solid was immediately precipitated by adding 50 ml of n-heptane. The mixture was stirred at 50 ° C for 1 hour, filtered, washed three times with n-butanol, and vacuum dried at 40 ° C. In an hour, the crystalline form Na of 2-naphthylsulfonate of rifafenib was obtained, and the yield was 1.28 g, and the yield was 89.4%. Example 73

 Weigh 1.02 g of the regorafenide free base prepared in Example 1 in a round-bottomed flask of mllOOml, dissolved in 67 ml of acetone; weigh 0.66 g of 2-naphthalenesulfonic acid into another 5 ml glass vial, add 4 ml Acetone was dissolved in acetone; the acetone solution of 2-naphthalenesulfonic acid was added dropwise to the acetone solution of regorafenib, stirred at room temperature for 2 hours, the solvent was evaporated, and 34 ml of n-heptane was added to immediately precipitate a white solid. After stirring at 10 ° C for 48 hours, it was filtered, washed three times with acetone, and dried under vacuum at 40 ° C for 16 hours to obtain Na-naphthalenesulfonate salt Na of rifafinib to give 1.27 g, yield: 87.0%.

Example 74

 Weighing l.Olg The regorafenide free base prepared in Example 1 was placed in a 500 ml round bottom flask, and dissolved in 360 ml of methyl ethyl ketone; 0.44 g of 2-naphthalenesulfonic acid was weighed into another 5 ml glass vial. Add 4ml of methyl ethyl ketone to dissolve ultrasonically; add 2-butanesulfonic acid and methyl ethyl ketone solution to the butanone solution of rifafenib, stir at 50 ° C for 48 hours, quickly evaporate and remove the solvent, add 180ml of ng The white solid was immediately precipitated by alkane ultrasonication, stirred at -10 ° C for 4 hours, filtered, washed three times with methyl ethyl ketone, and dried under vacuum at 30 ° C for 10 hours to obtain a crystalline form Na of 2-naphthalenesulfonate of rifafenib, which gave 1.24 g. The yield was 85.8%.

Example 75

 Weighing l.Olg The regorafenide free base prepared in Example 1 was placed in a 250 ml round bottom flask and dissolved in 120 ml of ethyl acetate; 0.44 g of 2-naphthalenesulfonic acid was weighed into another 5 ml glass vial. Add 4ml of ethyl acetate to dissolve in the ultrasonic solution; add 2-ethyl naphthalenesulfonic acid in ethyl acetate solution to the ethyl acetate solution of regorafenib, stir at -10 ° C for 1 hour, and quickly evaporate and remove the solvent. The white solid was immediately precipitated by adding 24 ml of n-heptane, and the mixture was stirred at room temperature for 1 hour, filtered, washed three times with ethyl acetate, and dried under vacuum at 40 ° C for 72 hours to obtain the Na-naphthalenesulfonate salt Na of rifafinib. The yield was 1.28 g, and the yield was 88.5%.

Example 76

Weigh 1.02 g of the Riegfried free base prepared in Example 1 in a 250 ml round bottom flask, and dissolve in 162 ml of isopropyl acetate; weigh 0.44 g of 2-naphthalenesulfonic acid into another 5 ml glass vial. Add 4ml of isopropyl acetate to dissolve ultrasonically; add 2-naphthalenesulfonic acid isopropyl acetate solution to the isopropylprednisolone isopropyl acetate solution, stir at room temperature for 2 hours, and quickly evaporate and remove the solvent. Immediately, a white solid was precipitated by adding 17 ml of n-heptane, and the mixture was stirred at room temperature for 10 hours, filtered, washed three times with isopropyl acetate, and dried under vacuum at 50 ° C for 10 hours to obtain a Na-naphthalenesulfonate salt of Nagfinib. , The yield was 1.29 g, and the yield was 88.4%.

Example 77

 Weighing l.Olg The regorafenide free base prepared in Example 1 was placed in a 1 L round bottom flask and dissolved in 450 ml of decyl tert-butyl ether; 0.44 g of 2-naphthalenesulfonic acid was weighed into another 5 ml of glass. In a vial, 4 ml of decyl tert-butyl ether was added to dissolve ultrasonically; a solution of 2-naphthylsulfonic acid in decyl tert-butyl ether was added dropwise to the solution of sagel tert-butyl ether in rifafenib, and stirred at room temperature. After 4 hours, the solvent was quickly evaporated, and 90 ml of n-heptane was added to ultrasonically to precipitate a white solid. After stirring at 40 ° C for 1 hour, it was filtered, washed with decyl tert-butyl ether three times, and dried under vacuum at 40 ° C for 10 hours to obtain Regal. The crystalline form of 2-naphthalenesulfonate Na was 0.96 g, and the yield was 66.4%.

Example 78

 Formulation of Sterile IV Solution: The T-form of the invention, the T-form of rifafenib-p-toluenesulfonate, was prepared into a 7 mg/ml solution with sterile water for injection while adding 2% by weight of solubilizer. Pluronic F-68, and adjust the pH as needed (H is adjusted to a small dose between 4-9, the large dose is as close as possible to the pH of normal human blood).

 Dosage of sterile IV solution: Dilute the above sterile IV solution to 2 mg with 5 % sterile dextrose

/ml, and administered with a 60-minute intravenous infusion.

Example 79-86

 Preparation of Sterile Solution: The T crystal form of the Regentinyl p-Amphetylbenzenesulfonate in Example 78 was replaced with the C crystal form of the Rigfidoni p-chlorobenzenesulfonate, N crystal form prepared in the present invention. Regafinil 1,5-naphthalenedisulfonate, E-formed regorafenib disulfonate, HI crystalline rigaginib hydrobromide, H2 crystalline reggfenibine hydrobromide , Etl crystal form of rifafibrinide, Et2 crystal form of regorafenibine crystal form and Na crystal form of regorafenil 2-naphthalene sulfonate, free in various salt forms in the formula The molar amount of the base and the free base in the p-nonylbenzenesulfonate was the same, and the total amount of the filler and the salt form in the various salt formulations was the same as in Example 78, and the same operation as in Example 78.

Example 87

 Preparation of lyophilized powder: (i) 135-1350 mg of the lyophilized powder form of the T crystal form of the regium fentanyl p-nonylbenzene sulfonate, dissolved in an appropriate amount of water for injection, sterile filtration, Packed in amps, sealed after lyophilization, and checked for leaks.

Intravenous administration of lyophilized powder: The lyophilized powder of the above-mentioned T-formed regorafenib-nonylbenzenesulfonate is reconstituted with sterile water for injection or 5% dextrose to a concentration of 21 mg/ml. Further, it was diluted with physiological saline or 5% dextrose into a 0.5 mg/ml solution, and administered by intravenous bolus or intravenous infusion for 15-60 minutes. Example 88-95

 Preparation of lyophilized powder for intravenous administration: The T crystal form of rifafinib in Example 87 was replaced with the thiophenyl sulfonate of Form C, which was prepared in the present invention, respectively. Acid salt, N crystal form of regorafenib 1,5-naphthalene disulfonate, E crystal form of regorafenib disulfonate, HI crystal form of regorafenib hydrobromide, H2 crystal form Regal Finica hydrobromide, Etl crystal form of regorafenibine, Et2 crystal form of regorafenibine and Na crystal form of regorafenil 2-naphthalene sulfonate The molar amount of the free base in the salt form and the free base in the p-nonylbenzenesulfonate is the same, and the total amount of the filler and the salt form in the various salt formulations is the same as in Example 87, and other operations are carried out simultaneously. Example 87.

Example 96

 Preparation of intramuscular suspension:

 50 mg / ml T crystal form of the invention, reguginib p-nonylbenzene sulfonate

 5 mg / ml of sodium decyl cellulose

 4 mg / ml Tween80

 9 mg / ml sodium chloride

 9 mg / ml phenyl mercapto alcohol

 (as follows)

 Dissolve sodium carboxymethyl cellulose first with an appropriate amount of water, and set aside; dissolve Tween80, sodium chloride, and phenylhydranol in an appropriate amount of water, add to the aqueous solution of sodium carboxymethyl cellulose, and mix well; Ni-p-phenylbenzenesulfonate is added to the mixed solution and stirred and dispersed uniformly.

Example 97-105

 Preparation of Intramuscular Suspension: The T crystal form of the Regentinil-p-toluenesulfonate in Example 96 was replaced with the C crystal form of the Rig-Finnish p-chlorobenzenesulfonate, N crystal prepared by the present invention. Rigginib 1,5-naphthalene disulfonate, E crystal form regorafenib disulfonate, HI crystal form regorafenib hydrobromide, H2 crystal form regorafenib hydrobromide Salt, Etl crystal form of regorafenibine, Et2 crystal form of regorafenibine crystal form and Na crystal form of regorafenib 2-naphthalene sulfonate, in various salt forms in the formulation The molar amount of the free base and the free base in the p-nonylbenzenesulfonate was the same, and the total amount of the filler and the salt form in the various salt formulations was the same as in Example 96, and the same operation as in Example 96.

Example 106

Preparation of hard shell gum: The capsule particles were prepared by filling a conventional two-piece hard capsule. 100 mg of the powdered active ingredient regorafenib (ie 135 mg of the T-form of the invention, reguginib-nonylbenzenesulfonate) is mixed with 150 mg of lactose and 50 mg of cellulose, and then 6 mg of hard is added. Magnesium citrate, mixed and filled with capsules, that is. Examples 107-114

 Preparation of hard shell colloid: The T crystal form of rifafifinib in Example 106 was replaced with the C crystal form of rifafenib p-chlorobenzenesulfonate and N crystal prepared by the invention. Rigginib 1,5-naphthalene disulfonate, E crystal form regorafenib disulfonate, HI crystal form regorafenib hydrobromide, H2 crystal form regorafenib hydrobromide Salt, Etl crystal form of regorafenibine, Et2 crystal form of regorafenibine crystal form and Na crystal form of regorafenib 2-naphthalene sulfonate, in various salt forms in the formulation The molar amount of the free base and the free base in the p-nonylbenzenesulfonate was the same, and the total amount of the filler and the salt form in the various salt formulations was the same as in Example 106, and the same operation as in Example 106.

Example 115

 Preparation of soft gelatin capsule: Add gelatin, glycerin, preservative to water, stir and heat to about 80 °C to form a transparent glue. Add a light-proofing agent, coloring agent, etc. to the glue. The glue is kept at 60 ° C, and is ready for use; the T-form of the invention is prepared by adding the T-form of sigroginib to the terpene benzene sulfonate in vegetable oil such as soybean oil, cottonseed oil or olive oil, and uniformly forming the mixture. The content of the suspension active soft gelatin of gramage active ingredient regorafenib (ie 135mgT crystal form reguginib p-nonylbenzene sulfonate); also can be used to convert T crystal form regomafenib to decyl benzene sulfonic acid The salt is dissolved in a water-soluble liquid diluent such as polyethylene glycol to form a transparent water-soluble soft capsule content; the glue and the soft capsule content are input into the soft capsule by a pump to press the soft capsule. After the plastic bottle is dried and cleaned, it can meet the required soft plastic bottle. Example 116-123

 Preparation of soft gelatin capsule: The T crystal form of rifafifinib in Example 115 was replaced with the phthalic acid salt of the invention, which was prepared by the invention. Rigginib 1,5-naphthalene disulfonate, E crystal form regorafenib disulfonate, HI crystal form regorafenib hydrobromide, H2 crystal form regorafenib hydrobromide Salt, Etl crystal form of regorafenibine, Et2 crystal form of regorafenibine crystal form and Na crystal form of regorafenib 2-naphthalene sulfonate, in various salt forms in the formulation The molar amount of the free base and the free base in the p-nonylbenzenesulfonate was the same, and the total amount of the filler and the salt form in the various salt formulations was the same as in Example 115, and the other operation was the same as in Example 115.

Example 124

Preparation of tablets: A large number of tablets were prepared by a conventional process. 100 mg of the active ingredient regorafenib (ie 135 mg of the T-form of the invention, reguginib p-nonylbenzenesulfonate), 98.8 mg of lactose, 11 mg of starch, 2 mg of sodium carboxymethyl starch and 275 mg The microcrystalline cellulose is mixed in a mixer, granulated with water as a wetting agent, the wet granules are dried in an oven to a moisture content below 3%, and 2 mg of sodium carboxymethyl starch and 5 mg of stearin are added to the back dry granules. Magnesium acid, evenly mixed, determine the main drug component in the granules, determine the tablet weight, and compress. Examples 125-132

 Preparation of the tablet: The T crystal form of the Regentinil-p- benzenesulfonate in Example 124 was replaced by the C crystal form of the invention, the sigroginib p-chlorobenzene sulfonate, and the N crystal form. Finnish 1,5-naphthalene disulfonate, E crystal form of regorafenib disulfonate, HI crystal form of regorafenib hydrobromide, H2 crystal form of regorafenib hydrobromide, Etl Crystalline regorafenibine, Et2 crystal form of regorafenibine crystal form and Na crystal form of regorafenib 2-naphthalene sulfonate, free base in various salt forms in the formulation The molar amount of the free base in the nonylbenzenesulfonate was the same, and the total amount of the filler and the salt form in the various salt formulations was the same as in Example 124, and the same operation as in Example 124.

Example 133

 Preparation of immediate release tablets/gels: 100 mg of the active ingredient regorafenib (ie 135 mg of the T-form of the invention, reguginib-nonylbenzenesulfonate) mixed with 162 mg of lactose, 100 mg of microcrystalline cellulose Evenly, add 3mg of magnesium stearate to the above mixed powder and mix it, then add it to the tableting machine to obtain the immediate release tablet; 100 mg of the active ingredient regorafenib (ie 135mgT crystal form of regorafenib) The besylate salt was mixed with 115 mg of pregelatinized starch and added to a plastic bottle filling machine for plastic-filled instant release capsules.

Example 134

 Preparation of the immediate release tablet/gel: The T crystal form of the Regentinil p-nonylbenzenesulfonate in Example 133 was replaced with the C crystal form of the regium-n-p-chlorobenzenesulfonate of the present invention. N-formed regorafenib 1,5-naphthalene disulfonate, E crystal form regorafenib disulfonate, HI crystal form regorafenib hydrobromide, H2 crystal form regomafen hydrogen Bromate, Etl crystal form of regorafenibine, Et2 crystal form of regorafenibine and Na crystal form of regorafenil 2-naphthalene sulfonate, various salt forms in the formula The molar amount of the free base in the free base and the p-nonylbenzenesulfonate was the same, and the total amount of the filler and the salt form in the various salt formulations was the same as in Example 133, and the same operation as in Example 133.

Example 135

 Taking the crystalline form T of p-nonylbenzenesulfonate and the crystal form of p-chlorobenzenesulfonate (1,5-naphthalenedisulfonate crystal form N, ethanedisulfonate) prepared by the present invention, respectively Crystal form, hydrobromide crystal form Hl, hydrobromide crystal form H2, ethanesulfonic acid crystal form Etl, ethanesulfonic acid crystal form Et2, 2-naphthalene sulfonate crystal form Na and regomafenil monohydrate The material was compared for solubility, 20%-80% RH weight change, melting point, decomposition temperature and morphology.

 The weight change in the relative humidity range of 20%-80% RH is obtained by DVS detection.

 Melting point comparison: Obtained by DSC.

Decomposition temperature comparison: Obtained by TGA detection. Morphology comparison: Obtained by PLM detection.

 Solubility comparison: 增 was solubilized with sodium dodecylbenzene sulfonate in combination with HPLC detection. Take lOmg sample and 50mg sodium dodecylbenzene sulfonate in 20ml glass bottle, add 15ml deionized water, 40K z ultrasonic working power ultrasonic for 60min, sample and filter and dilute to 5ml volumetric flask, remove water, use The volume of acetonitrile was adjusted and the concentration was determined by HPLC. The results are shown in Table 1. Table 1 Comparison of performance of different grades of regorafenib

It can be seen from Table 1 that the sigroginib p-nonylbenzenesulfonate crystal form τ, p-chlorobenzene sulfonate crystal form, 1,5-naphthalene disulfonate crystal form N, ethylene II prepared by the present invention Sulfonate crystal form, hydrobromide crystal form Hl, The ethanesulfonic acid crystal form Etl and 2-naphthalene sulfonate crystal form Na have the advantages of high decomposition temperature and good solubilization effect compared with the fergicin monohydrate. The solubilization effect is monohydrate 10 ~ 95 times.

 All of the patents, patent application publications, patent applications and non-patent publications cited in the specification are hereby incorporated by reference in its entirety in its entirety.

 The above description of the invention and the description of the specific embodiments thereof are not to be construed as limiting the invention. In accordance with the disclosure of the present application, those skilled in the art can increase or decrease the disclosed technical features in the above general description or/and specific embodiments (including embodiments) without departing from the inventive constituent elements involved. Or a combination, forming other technical solutions belonging to the invention. The scope of the invention should be determined by the scope of the invention as defined by the appended claims.

Claims

claims

1. Regorafenib p-toluene sulfonate crystal form T, its structural formula is as follows:

It is characterized in that using Cu-Kα radiation, its X-ray powder diffraction pattern at 2Θ is 4.5±0.2. , 13.4±0.2. , 18.1±0.2. , 20.8±0.2. , 21.9±0.2. and 23.0±0.2. There are characteristic peaks.

2. Regorafenib p-toluenesulfonate crystal form T according to claim 1, characterized in that its X-ray powder diffraction pattern at 2Θ is 4.5±0.2. , 11.0±0.2. , 11.5±0.2. , 13.4±0.2. , 14.8±0.2°, 16.6±0.2°, 18.1±0.2°, 20.4±0.2°, 20.8±0.2°, 21.9±0.2°, 23.0±0.2 and 25.0±0.2. There are characteristic peaks.

3. Regorafenib p-toluenesulfonate crystal form T according to claim 2, characterized in that the characteristic peaks and their relative intensities of its X-ray powder diffraction pattern are as follows:

Diffraction angle 2Θ relatively strong

4.5±0.2. 38.0

1 1.0±0.2° 13.6

1 1.5±0.2° 15.9

13.4±0.2° 42.2

14.8±0.2° 29.8

16.6±0.2° 29.9

18.1±0.2° 50.6

19.3±0.2° 1 1.3

20.4±0.2° 42.1

20.8±0.2° 71.4

21.9±0.2° 100.0

23.0±0.2° 77.7

24.0±0.2° 1 1.5

25.0±0.2° 23.2

26.1±0.2° 18.5

27.1±0.2° 19.5

28.8±0.2° 1 1.4

29.0±0.2° 14.3

29.6±0.2° 12.8

33.7±0.2° 10.4

4. Preparation method of regorafenib p-methylbenzene sulfonate crystal form T according to any one of claims 1 to 3 Method, the method includes: respectively forming a solution system of regorafenib and p-methylbenzenesulfonic acid in a soluble solvent, and the molar ratio of regorafenib and p-methylbenzenesulfonic acid is 1:1~1: 2. Mix the two systems to form a suspension, and crystallize at a temperature of -10°C to 50°C to obtain the crystal form T;

The soluble solvent is preferably CH alcohol, C ₄ ~ C ₅ ester, C ₃ ~ C ₄ ketone, methyl tert-butyl ether or n-heptane; the concentration of the soluble solvent solution of regorafenib is preferably: The solubility in the soluble solvent at the crystallization temperature is 0.1 to 1 times, and more preferably 0.5 to 1 times; the concentration of the soluble solvent solution of p-methylbenzenesulfonic acid is preferably such that the solubility in the soluble solvent at the crystallization temperature is 0.5 to 1 times the medium solubility; the molar ratio of regorafenib and p-toluenesulfonic acid is preferably 1: 1 to 1: 1.5; the crystallization temperature is preferably room temperature, and the crystallization time is 1 to 48 hours. More preferably, 1 to 10 hours.

5. Regorafil

H is characterized by having an X-ray powder diffraction pattern of 9.0±0.2 at 2Θ using Cu-Kα radiation. There are characteristic peaks at , 9.9±0.2°, 18.2±0.2°, 19.9±0.2°, 23.1±0.2° and 27.4±0.2°.

6. Regorafenib p-chlorobenzene sulfonate crystal form C according to claim 5, characterized in that its X-ray powder diffraction pattern at 2Θ is 9.0 ± 0.2. , 9.9±0.2. , 12.4±0.2. , 15.7±0.2. , 18.2±0.2. There are characteristic peaks at , 19.9±0.2°, 21.9±0.2°, 23.1±0.2°, 24.1°±0.2°, 25.2±0.2°, 25.5±0.2° and 27.4±0.2°.

7. Regorafenib p-chlorobenzene sulfonate crystal form C according to claim 6, characterized in that the characteristic peaks and relative intensities of its X-ray powder diffraction pattern are as follows:

Diffraction angle 2Θ Relative intensity %

9.0±0.2° 53.0

9.9±0.2° 37.9

12.4±0.2° 17.3

15.7±0.2° 35.8

18.2±0.2° 82.4

18.7±0.2° 1 1.7

19.9±0.2° 60.1

20.5±0.2° 13.6

21.9±0.2° 14.6

23.1±0.2° 63.3

24.1±0.2° 27.6

25.2±0.2° 39.9

25.5±0.2° 34.2

27.4±0.2° 100.0

28.5±0.2° 17.9

29.0±0.2° 12.0

29.8±0.2° 15.9

30.1±0.2° 12.3

8. The preparation method of regorafenib p-chlorobenzene sulfonate crystal form C according to any one of claims 5 to 7, said method comprising: forming regorafenib and p-chlorobenzene sulfonic acid in a soluble solvent respectively The solution system in the solution system, the molar ratio of regorafenib and p-chlorobenzenesulfonic acid is 1:1 1:2, mix the two systems to form a suspension, and crystallize at a temperature of -10°C to 50°C to obtain the result. The crystalline form C;

The soluble solvent is preferably CrC alcohol, C ₄ C ₅ ester, C ₃ C ₄ ketone, methyl tert-butyl ether or n-heptane; the concentration of the soluble solvent solution of regorafenib is preferably at The solubility in the soluble solvent at the crystallization temperature is 0.1 1 times, and more preferably 0.5 1 times; the concentration of the soluble solvent solution of p-chlorobenzene sulfonic acid is preferably 0.5 times the solubility in the soluble solvent at the crystallization temperature. 1 times; the molar ratio of regorafenib and p-chlorobenzenesulfonic acid is preferably 1:1 to 1:1.5; the crystallization temperature is preferably room temperature, and the crystallization time is 1 to 48 hours, more preferably 1 to 10 hours.

9. Regorafenib 1,5-naphthalene disulfonate crystal form N, its structural formula is as follows:

It is characterized by using Cu-Kα radiation and its X-ray powder diffraction pattern at 2Θ is 7.3±0.2. , 10.3±0.2. , 12.8±0.2. , 15.1±0.2. , 18.8±0.2. and 26.1±0.2. There are characteristic peaks.

10. Regorafenib 1,5-naphthalene disulfonate crystal form N according to claim 9, characterized in that its X-ray powder diffraction pattern at 2Θ is 7.3±0.2. , 8.3±0.2. , 9.6±0.2. , 10.3±0.2. , 11.6± 0.2° 12.8± 0.2° 13.7± 0.2° 15.1± 0.2° 16.5± 0.2° 18.8± 0.2° 19.8± 0.2° 21.1±0.2. and 26.1±0.2. There are characteristic peaks.

11. Regorafenib 1,5-naphthalene disulfonate crystal form N according to claim 10, characterized in that the characteristic peaks and relative intensities of its X-ray powder diffraction pattern are as follows: Diffraction angle 2Θ Relative intensity %

7.3±0.2° 99.5

8.3±0.2° 19.3

9.6±0.2° 14.8

10.3±0.2° 27.3

11.6±0.2° 21.8

12.8±0.2° 46.0

13.7±0.2° 16.3

15.1±0.2° 37.8

15.9±0.2° 11.7

16.5±0.2° 28.1

17.8±0.2° 12.6

18.8±0.2° 39.9

19.8±0.2. 35.2

21.1±0.2° 23.4

21.5±0.2° 10.2

23.2±0.2° 12.7

24.8±0.2. 18.0

26.1±0.2° 100.0

26.6±0.2° 11.0

12. The preparation method of regorafenib 1,5-naphthalene disulfonate crystal form N according to any one of claims 9 to 11, the method includes: forming regorafenib and 1,5-naphthalene respectively A solution system of disulfonic acid in a soluble solvent. The molar ratio of regorafenib and 1,5-naphthalenedisulfonic acid is 1:1~2:1. Mix the two systems to form a suspension at -10° Crystallize at a temperature of C~50°C to obtain the crystal form N;

The soluble solvent is preferably C-C alcohol, C ₄ -C ₅ ester, C ₃ - _{C 4} ketone, methyl tert-butyl ether or n-heptane; the concentration of the soluble solvent solution of regorafenib is preferably Its solubility in a soluble solvent at the crystallization temperature is 0.1 to 1 times, more preferably 0.5 to 1 times; the concentration of the soluble solvent solution of 1,5-naphthalene disulfonic acid is preferably 0.1 to 1 times that of the soluble solvent at the crystallization temperature. 0.5 to 1 times the solubility in the soluble solvent; the molar ratio of regorafenib and 1,5-naphthalenedisulfonic acid is preferably 2: 1.5 to 2: 1; the crystallization temperature is preferably room temperature, and the crystallization time is 1 to 48 hours, more preferably 1 to 10 hours.

13. Regorafenib ethanedisulfonate crystal form E, its structural formula is as follows:

It is characterized in that using Cu-Kα radiation, its X-ray powder diffraction pattern has 2Θ of 10.6±0.2°, 12.1±0.2°, 17.0±0.2°, 18.1±0.2°, 22.7±0.2° and 23.6±0.2°. Characteristic peaks.

14. Regorafenib ethylenedisulfonate crystal form E according to claim 13, characterized in that its X-ray powder diffraction pattern at 2Θ is 10.6±0.2°, 12.1±0.2°, 14.1±0.2°, 15.8 ±0.2°, 17.0±0.2°, 18.1±0.2°, 20.1±0.2°, 21.3±0.2°, 22.7±0.2°, 23.6±0.2°, 24.3±0.2° and 27.8±0.2. There are characteristic peaks.

15. Regorafenib ethanedisulfonate crystal form E according to claim 14, characterized in that the characteristic peaks and their relative intensities of its X-ray powder diffraction pattern are as follows:

Diffraction angle 2Θ Relative intensity %

10.6±0.2° 34.8

12.1±0.2° 47.7

14.1±0.2° 18.4

15.8±0.2° 23.2

17.0±0.2° 43.5

17.4±0.2° 1 1.3

17.9±0.2° 37.3

18.1±0.2° 58.4

20.1±0.2° 30.4

20.5±0.2° 14.7

21.0±0.2° 26.6

21.3±0.2° 44.0

21.7±0.2° 16.0

22.7±0.2° 100.0

23.6±0.2° 86.9

24.3±0.2° 44.7

24.5±0.2° 18.4

25.1±0.2° 1 1.6

26.2±0.2° 15.3

27.2±0.2 15.0

27.8±0.2 33.3

28.5±0.2 10.5

28.9±0.2 18.3

16. The preparation method of regorafenib ethylenedisulfonate crystal form E according to any one of claims 13 to 15, the method comprising: separately forming regorafenib and ethylenedisulfonic acid in a soluble solvent The solution system, the molar ratio of regorafenib and ethanedisulfonic acid is 1:1~2:1, mix the two systems to form a suspension, and crystallize at a temperature of -10°C~50°C to obtain The crystalline form E;

The soluble solvent is preferably CH alcohol, C ₄ ~ C ₅ ester, C ₃ ~ C ₄ ketone, methyl tert-butyl ether or n-heptane; the concentration of the soluble solvent solution of regorafenib is preferably: The solubility in the soluble solvent at the crystallization temperature is 0.1 to 1 times, and more preferably 0.5 to 1 times; the concentration of the soluble solvent solution of ethylenedisulfonic acid is preferably the solubility in the soluble solvent at the crystallization temperature. 0.5~1 times; the molar ratio of regorafenib and ethylenedisulfonic acid is preferably 2: 1.5~2: 1; preferably the crystallization temperature is room temperature, and the crystallization time is 1~48 hours, more preferably 1~ 10 hours.

17. Regorafenib hydrobromide crystal form HI, its structural formula is as follows:

It is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is 5.1±0.2 at 2Θ. , 10.1±0.2. , 15.1±0.2. , 18.2±0.2. , 19.5±0.2. and 24.8±0.2. There are characteristic peaks.

18. Regorafenib hydrobromide crystal form HI according to claim 17, characterized in that its X-ray powder diffraction pattern at 2Θ is 5.1 ± 0.2. , 10.1±0.2. , 15.1±0.2. , 18.2±0.2. , 19.5±0.2. , 20.3±0.2. , 23.2±0.2. , 24.8±0.2. , 25.2±0.2. and 30.0±0.2. There are characteristic peaks.

19. Regorafenib hydrobromide crystal form HI according to claim 18, characterized in that the characteristic peaks of its X-ray powder diffraction pattern and their relative intensities are as follows:

Diffraction angle 2Θ Relative intensity %

5.1±0.2° 100.0

10.1±0.2° 60.0

15.1±0.2° 24.1

18.2±0.2° 13.6

19.5±0.2° 10.8

20.3±0.2. 8.6

23.2±0.2. 14.5

24.8±0.2 20.3

25.2±0.2 12.2

30.0±0.2 18.5

35.0±0.2 12.4ο

20. The preparation method of regorafenib hydrobromide crystal form m according to any one of claims 17 to 19, the method comprising: forming a solution of regorafenib and hydrobromic acid in a soluble solvent respectively system, the molar ratio of regorafenib and hydrobromic acid is 1:1~1:2, mix the two systems to form a suspension, and crystallize at a temperature of -10°C~50°C to obtain the crystal Type HI;

The soluble solvent is preferably a C to C alcohol, a C ₃ to _{C 4} ketone or n-heptane; the concentration of the solution of regorafenib in the soluble solvent is preferably equal to its solubility in the soluble solvent at the crystallization temperature 0.1 to 1 times, more preferably 0.5 to 1 times, the concentration of the soluble solvent solution of hydrobromic acid is preferably 0.5 to 1 times its solubility in the soluble solvent at the crystallization temperature; Regorafenib and hydrobromic acid The molar ratio of is preferably 1:1~1:1.5; preferably the crystallization temperature is room temperature, and the crystallization time is 1~48 hours, more preferably 1~10 hours.

21. Regorafenib hydrobromide crystal form H2 is characterized by using Cu-Kα radiation and its X-ray powder diffraction pattern at 2Θ is 10.6±0.2. , 12.0±0.2. , 16.8±0.2. , 19.2±0.2. , 21.3±0.2. and 24.4±0.2. There are characteristic peaks.

22. Regorafenib hydrobromide crystal form H2 according to claim 21, characterized in that its X-ray powder diffraction pattern at 2Θ is 10.6±0.2°, 12.0±0.2°, 16.8±0.2°, 17.0± 0.2°, 18.9±0.2°, 19.2±0.2°, 20.2±0.2°, 20.5±0.2°, 21.3±0.2°, 24.1±0.2°, 24.4±0.2°, 25.7±0.2° and 26.5±0.2. There are characteristic peaks.

23. Regorafenib hydrobromide crystal form H2 according to claim 22, characterized in that the characteristic peaks and their relative intensities of its X-ray powder diffraction pattern are as follows:

Diffraction angle 2Θ Relative intensity %

7.4±0.2° 15.6

10.3±0.2° 14.3

10.6±0.2. 29.2

12.0±0.2° 25.8

16.8±0.2° 50.8

17.0±0.2° 27.1

18.9±0.2° 35.7

19.2±0.2° 66.4

19.6±0.2° 18.2

20.2±0.2. 32.6

20.5±0.2. 33.1

21.3±0.2° 52.9

24.2±0.2° 43.8

24.4±0.2 100.0

24.7±0.2 32.3

25.7±0.2 48.2

26.5±0.2 51.0

27.5±0.2 15.9

28.2±0.2 30.5

29.5±0.2 14.6

30.8±0.2 17.7

3 1.9±0.2 14.1

32.7±0.2 20.8

34.3±0.2 15.6

24. The method for preparing the regorafenib hydrobromide crystal form H2 according to any one of claims 21 to 23, the method comprising: suspending the regorafenib hydrobromide crystal form HI in a solvent. Turbid liquid, the suspension is crystallized at a temperature of -10°C ~ 50°C to obtain the crystal form H2, wherein the solvent is selected from ethyl acetate, methyl tert-butyl ether or a mixture thereof;

The dosage of regorafenib hydrobromide crystal form HI is preferably 1.1 to 20 times its solubility in the solvent system at the crystallization temperature, more preferably 1.5 to 10 times; preferably the crystallization temperature is room temperature. , the crystallization time is 1 to 72 hours, more preferably 1 to 10 hours.

25. Regorafenib ethanesulfonate crystal form Etl, its structural formula is as follows:

It is characterized in that using Cu-Kα radiation, its X-ray powder diffraction pattern at 2Θ is 8.2±0.2. , 8.9±0.2. , 13.0±0.2. , 18.8±0.2. , 23.6±0.2. and 24.6±0.2. There are characteristic peaks.

26. The crystal form Etl of regorafenib ethanesulfonate according to claim 25, characterized in that its X-ray powder diffraction pattern at 2Θ is 8.2±0.2. , 8.9±0.2. , 12.2±0.2. , 13.0±0.2. , 14.4±0.2. , 16.2±0.2°, 17.9±0.2°, 18.8±0.2°, 20.1±0.2°, 22.0±0.2°, 23.6±0.2° and 24.6±0.2. There are characteristic peaks.

27. Regorafenib ethanesulfonate crystal form Etl according to claim 26, characterized in that:

The X-ray powder diffraction pattern basically shows the 2Θ characteristic peaks and their relative intensities as follows:

Diffraction angle 2Θ Relative intensity %

8.2±0.2° 18.3

8.9±0.2° 22.9

12.2±0.2. 19.0

13.0±0.2. 22.7

14.4±0.2. 20.3

16.2±0.2 14.1

17.9±0.2 24.9

18.8±0.2 33.8

20.1±0.2 21.2

20.4±0.2 19.9

22.0±0.2 28.3

23.4±0.2 47.9

23.6±0.2 73.5

24.6±0.2 100.0

25.9±0.2 13.3

26.2±0.2 1 1.6

28.3±0.2 15.0

30.6±0.2 12.0

32.3±0.2 1 1.0

28. The method for preparing the crystalline form Etl of regorafenib ethanesulfonate according to any one of claims 25 to 27, the method comprising: forming a solution of regorafenib and ethanesulfonic acid in a soluble solvent respectively. system, the molar ratio of regorafenib and ethanesulfonic acid is 1:1~1:2, mix the two systems to form a suspension, and crystallize at a temperature of -10°C~50°C to obtain the crystal typeEtl;

The soluble solvent is preferably C-C alcohol, C ₃ ~ C ₄ ketone or C ₄ ~ C ₅ ester; the concentration of the soluble solvent solution of regorafenib is preferably such that it is in the soluble solvent at the crystallization temperature 0.1 to 1 times the solubility, more preferably 0.5 to 1 times; the concentration of the soluble solvent solution of ethanesulfonic acid is preferably 0.5 to 1 times its solubility in the soluble solvent at the crystallization temperature; regorafenib and The molar ratio of ethanesulfonic acid is preferably 1:1~1:1.5; preferably the crystallization temperature is room temperature, and the crystallization time is 1~48 hours, more preferably 1~10 hours.

29. Regorafenib ethanesulfonate crystal form Et2 is characterized by using Cu-Kα radiation and its X-ray powder diffraction pattern at 2Θ is 12.3±0.2. , 13.6±0.2. , 16.0±0.2. , 20.5±0.2. , 24.3±0.2. and 24.5±0.2. There are characteristic peaks.

30. The crystal form Et2 of regorafenib ethanesulfonate according to claim 29, characterized in that its X-ray powder diffraction pattern at 2Θ is 7.4±0.2. , 8.2±0.2. , 12.3±0.2. , 13.6±0.2. , 16.0±0.2. There are characteristic peaks at , 16.9±0.2°, 18.5±0.2°, 20.5±0.2°, 20.9±0.2°, 22.1°±0.2, 24.3±0.2° and 24.5±0.2°.

31. The crystalline form Et2 of regorafenib ethanesulfonate according to claim 30, characterized in that its X-ray powder diffraction pattern basically has 2Θ characteristic peaks and their relative intensities as follows:

Diffraction angle 2Θ Relative intensity %

7.4±0.2° 20.7

8.2±0.2° 23.9

8.4±0.2° 23.1

12.3±0.2. 100.0

13.6±0.2° 35.9

16.0±0.2. 32.3

16.9±0.2. 22.3

18.2±0.2° 23.9

18.5±0.2° 28.3

18.9±0.2. 24.3

19.2±0.2° 12.7

20.1±0.2. 30.7

20.5±0.2. 46.6

20.9±0.2. 29.9

21.8±0.2° 28.3

22.1±0.2° 31.5

23.4±0.2. 19.5

23.7±0.2. 19.5

24.3±0.2° 77.7

24.5±0.2° 73.3

26.4±0.2° 16.3

27.3±0.2. 23.1

28.5±0.2° 27.5

28.7±0.2° 31.5

29.3±0.2. 19.5

32. The method for preparing the regorafenib ethanesulfonate crystal form Et2 according to any one of claims 29 to 31, the method comprising: suspending the regorafenib ethanesulfonate crystal form Et1 in a solvent. Turbid liquid, the suspension is crystallized at -10°C ~ 50°C to obtain the crystal form Et2, wherein the solvent is selected from methyl tert-butyl ether, n-heptane or a mixture thereof;

The dosage of regorafenib ethanesulfonate crystal form Etl is preferably 1.1 to 20 times its solubility in the solvent system at the crystallization temperature, more preferably 1.5 to 10 times; preferably the crystallization temperature is room temperature , the crystallization time is 1 to 72 hours, more preferably 1 to 10 hours.

33.

It is characterized in that using Cu-Kα radiation, its X-ray powder diffraction pattern at 2Θ is 4.7±0.2. , 13.7±0.2. , 16.4±0.2. , 18.0±0.2. , 20.2±0.2. and 21.9±0.2. There are characteristic peaks.

34. Regorafenib 2-naphthalene sulfonate crystal form Na according to claim 33, characterized in that its X-ray powder diffraction pattern at 2Θ is 4.7±0.2. , 10.5±0.2. , 11.1±0.2. , 13.7±0.2. , 14.3±0.2°, 16.4±0.2°, 18.0±0.2°, 20.2±0.2°, 21.5±0.2°, 21.9±0.2°, 22.5±0.2 and 24.0±0.2. There are characteristic peaks.

35. Regorafenib 2-naphthalene sulfonate crystal form Na according to claim 34, characterized in that its X-ray powder diffraction pattern basically has 2Θ characteristic peaks and their relative intensities as follows:

Diffraction angle 2Θ Relative intensity %

4.7±0.2° 100.0

10.5±0.2. 13.7

1 1.1±0.2° 11.0

13.7±0.2° 48.4

14.3±0.2° 25.9

16.4±0.2° 37.4

18.0±0.2. 69.6

18.4±0.2° 13.5

20.2±0.2. 88.3

21.5±0.2° 23.1

21.9±0.2° 45.7

22.5±0.2° 19.5

23.4±0.2. 13.1

24.0±0.2° 28.3

25.3±0.2° 22.5

26.0±0.2. 17.8

26.6±0.2° 19.9

29.9±0.2. 12.8

36. The preparation method of regorafenib 2-naphthalenesulfonate crystal form Na according to any one of claims 33 to 35, the method comprising: forming regorafenib and 2-naphthalenesulfonic acid in soluble In the solution system in the solvent, the molar ratio of regorafenib and 2-naphthalenesulfonic acid is 1:1~1:2. The two systems are mixed, and the resulting mixed solution is stirred at -10°C~50°C and removed. As a soluble solvent, n-heptane is added to form a suspension. The suspension is crystallized at -10°C ~ 50°C to obtain the crystal form Na; the soluble solvent is preferably Cr alcohol, C ₄ ~ C ₅ ester, C ₃ ~ _{C 4} ketone or methyl tert-butyl ether; the dosage of regorafenib is preferably 0.1 to 1 times its solubility in the soluble solvent at the crystallization temperature, and more preferably 0.5 to 1 times; the amount of n-heptane is preferably 0.1 to 0.5 times that of regorafenib in a soluble solvent; the amount of 2-naphthalenesulfonic acid is preferably 0.5 to 1 times its solubility in a soluble solvent at the crystallization temperature times; the molar ratio of regorafenib and 2-naphthalenesulfonic acid is preferably 1: 1 to 1: 1.5; the mixture is preferably stirred at room temperature for 1 minute to 48 hours, more preferably 1 to 10 hours; the suspension The turbid liquid is preferably stirred at room temperature for 1 to 48 hours, more preferably for 1 to 10 hours.

37. A pharmaceutical composition, comprising a therapeutically and/or preventively effective amount of one or more regorafenib p-methylbenzene sulfonate crystal form T, Regorafenib p-chlorobenzene sulfonate crystal Form C according to any one of claims 5 to 7, Regorafenib 1,5-naphthalene disulfonate crystal according to any one of claims 9 to 11 Type N, regorafenib ethanedisulfonate crystal according to any one of claims 13 to 15 Form E, regorafenib hydrobromide crystal form H1 according to any one of claims 17 to 19, regorafenib hydrobromide crystal form H2 according to any one of claims 21 to 23, rights Regorafenib ethanesulfonate crystal form Et1 according to any one of claims 25 to 27, Regorafenib ethanesulfonate crystal form Et2 according to any one of claims 29 to 31, claims 33 to 35 Regorafenib 2-naphthalene sulfonate crystal form Na, and at least one pharmaceutically acceptable carrier.

38. Regorafenib p-methylbenzene sulfonate crystal form T according to any one of claims 1 to 3, regorafenib p-chlorobenzene sulfonate described in any one of claims 5 to 7 Crystal Form C, regorafenib 1,5-naphthalene disulfonate crystal form N according to any one of claims 9 to 11, regorafenib ethyl disulfonate according to any one of claims 13 to 15 Salt crystal form E, regorafenib hydrobromide crystal form HI according to any one of claims 17 to 19, regorafenib hydrobromide crystal form HI according to any one of claims 21 to 23 H2. The regorafenib ethanesulfonate crystal form Et1 described in any one of claims 25 to 27, the regorafenib ethanesulfonate crystal form Et2 described in any one of claims 29 to 31, and the claims The use of the regorafenib 2-naphthalene sulfonate crystal form Na according to any one of 33 to 35 or the pharmaceutical composition according to claim 37 in the preparation of medicines for the treatment and/or prevention of hyperproliferative disorders, The highly proliferative disease is selected from the group consisting of solid tumors, lymphomas, sarcomas, leukemias, breast cancer, respiratory tract cancer, brain cancer, reproductive organ cancer, digestive tract cancer, urethra cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, Thyroid carcinoma and/or parathyroid carcinoma, especially metastatic colorectal cancer.