Fruquintinib eutectic crystal, preparation method therefor, composition, and uses thereof

Abstract

Provided are a fruquintinib and a saccharin salt or eutectic crystal, a fruquintinib and a malonic acid eutectic crystal or a fruquintinib and a maleic eutectic crystal, a preparation method therefor, a pharmaceutical composition containing thereof, and uses thereof in preparing drugs for treating and/or preventing diseases related to abnormal angiogenesis, such as cancer, tumors, macular degeneration, chronic inflammation and the like.

Claims

1. Compound A formed by fruquintinib and saccharin having the structure shown below: ##STR00005##

2. Compound A according to claim 1, wherein compound A is a cocrystal or salt.

3. Compound A according to claim 1, wherein the X-ray powder diffraction pattern of the crystalline form of compound A, expressed as 2θ angles, has the following characteristic peaks: 5.0±0.2°, 13.2±0.2°, 15.4±0.2° and 17.0±0.2°.

4. Compound A according to claim 3, wherein the X-ray powder diffraction pattern of the crystalline form of compound A, expressed as 2θ angles, further comprises the following characteristic peaks: 10.8±0.2°, 11.5±0.2, 14.8±0.2°, 23.8±0.2° and 25.4±0.2°.

5. Compound A according to claim 4, wherein the X-ray powder diffraction pattern of the crystalline form of compound A, expressed as 2θ angles, has the following characteristic peaks and relative intensities: TABLE-US-00018 2θ Relative intensity %  5.0 ± 0.2° 100.0  9.8 ± 0.2° 22.4 10.4 ± 0.2° 20.1 10.8 ± 0.2° 35.3 11.5 ± 0.2° 37.9 12.5 ± 0.2° 18.3 13.2 ± 0.2° 54.3 13.7 ± 0.2° 16.0 14.8 ± 0.2° 31.7 15.4 ± 0.2° 74.0 16.1 ± 0.2° 26.3 17.0 ± 0.2° 50.9 17.8 ± 0.2° 21.2 18.3 ± 0.2° 21.9 20.4 ± 0.2° 34.4 20.8 ± 0.2° 16.1 21.6 ± 0.2° 19.2 22.1 ± 0.2° 34.6 22.8 ± 0.2° 33.6 23.1 ± 0.2° 21.6 23.8 ± 0.2° 86.9 25.1 ± 0.2° 21.0 25.4 ± 0.2° 74.2 26.4 ± 0.2° 40.5 26.9 ± 0.2° 27.0 27.8 ± 0.2° 15.6 28.8 ± 0.2° 19.2.

6. Compound A according to claim 3, wherein the Fourier IR spectrum of the crystalline form of compound A has characteristic peaks at wave number of 1650±2 cm.sup.−1, 1507±2 cm.sup.−1, 1422±2 cm.sup.−1, 1395±2 cm.sup.−1, 1371±2 cm.sup.−1, 1274±2 cm.sup.−1, 1252±2 cm.sup.−2, 1226±2 cm.sup.−1, 1145±2 cm.sup.−1, 937±2 cm.sup.−1, 877±2 cm.sup.−1 and 756±2 cm.sup.−1.

7. Compound A according to claim 3, wherein a single crystal of the crystalline form of compound A, measured at 106 K, belongs to the triclinic system with space group P1, and has the following unit cell parameters: a=8.6 ű0.2 Å, b=9.0 ű0.2 Å, c=17.3 ű0.2 Å; and dihedral angles: α=84.0°±0.2°, β=77.4°±0.2°, γ=77.8°±0.2°.

8. A method of preparing compound A according to claim 1, comprising directly reacting fruquintinib with 0.67 to 3 equivalents of saccharin, in an organic solvent or a solvent combination, wherein the organic solvent is a solvent that can dissolve fruquintinib or saccharin.

9. A method of preparing the crystalline form of compound A according to claim 3, comprising any one of the following methods: 1) mixing fruquintinib and saccharin at a molar ratio of 1:0.67 to 1:1.5 in a solvent selected from the group consisting of a C.sub.1 to C.sub.4 alcohol, a C.sub.4 to C.sub.5 ester, a haloalkane, a C.sub.4 to C.sub.6 ether, a C.sub.3 to C.sub.4 ketone, acetonitrile, and any mixture thereof, for reaction, and removing the solvent to obtain the crystalline form of compound A; the operation temperature of the preparation method is from 10 to 50° C.; the crystallization time is from 8 to 48 hours; the weight-to-volume ratio of fruquintinib to the solvent is from 5 mg:1 ml to 50 mg:1 ml; and the weight-to-volume ratio of saccharin to the solvent is from 2 mg:1 ml to 20 mg:1 ml; 2) adding a solvent to the mixture of equal molar ratio of fruquintinib and saccharin, completely wetting the mixture, and grinding it until dry to obtain the crystalline form of compound A, wherein the solvent is selected from the group consisting of water, a C.sub.1 to C.sub.4 alcohol, a C.sub.4 to C.sub.5 ester, an alkane, a C.sub.4 to C.sub.6 ether, a C.sub.3 to C.sub.4 ketone, acetonitrile, and any mixture thereof; the weight-to-volume ratio of the mixture to the solvent is from 20 mg:1 ml to 220 mg:1 ml; and the operation temperature of the preparation method is from 10 to 40° C.; or 3) forming a solution of a mixture of equal molar ratio of fruquintinib and saccharin with mixed organic solvents, wherein the organic solvent is selected from the group consisting of a C.sub.1 to C.sub.4 alcohol, a C.sub.4 to C.sub.5 ether, a C.sub.4 to C.sub.5 ester, a haloalkane, a C.sub.3 to C.sub.4 ketone, acetonitrile, nitromethane, and any mixture thereof, volatilizing naturally for crystallization to obtain compound A crystalline form; the operation temperature of the preparation method is from 10 to 50° C.; and the weight-to-volume ratio of the mixture to the solvent is from 5 mg:1 ml to 50 mg:1 ml.

10. A cocrystal of fruquintinib and malonic acid having the structure shown below: ##STR00006##

11. The cocrystal according to claim 10, wherein the X-ray powder diffraction pattern of the crystalline form of the cocrystal, expressed as 2θ angles, has the following characteristic peaks: 10.9±0.2°, 14.2±0.2°, 16.4±0.2° and 19.9±0.2°.

12. The cocrystal according to claim 11, wherein the X-ray powder diffraction pattern of the crystalline form of the cocrystal, expressed as 2θ angles, further comprises the following characteristic peaks: 9.8±0.2°, 11.6±0.2°, and 14.9±0.2°.

13. The cocrystal according to claim 12, wherein the X-ray powder diffraction pattern of the crystalline form of the cocrystal, expressed as 2θ angles, has the following characteristic peaks and relative intensities: TABLE-US-00019 2θ Relative intensity %  5.3 ± 0.2° 13.0  5.7 ± 0.2° 37.3  9.8 ± 0.2° 56.7 10.9 ± 0.2° 100.0 11.6 ± 0.2° 49.9 14.2 ± 0.2° 62.0 14.9 ± 0.2° 18.8 15.3 ± 0.2° 29.6 16.4 ± 0.2° 69.3 19.9 ± 0.2° 71.7 22.1 ± 0.2° 11.4 23.5 ± 0.2° 10.3 25.0 ± 0.2° 20.6 33.1 ± 0.2° 10.6 37.8 ± 0.2° 10.3.

14. The cocrystal according to claim 11, wherein the Fourier IR spectrum of the crystalline form of the cocrystal has characteristic peaks at wave number of 1741±2 cm.sup.−1, 1663±2 cm.sup.−1, 1609±2 cm.sup.−1, 1509±2 cm.sup.−1, 1421±2 cm.sup.−1, 1390±2 cm.sup.−1, 1227±2 cm.sup.−1, 1122±2 cm.sup.−1, 983±2 cm.sup.−1, 838±2 cm.sup.−1 and 738±2 cm.sup.−1.

15. A method of preparing the cocrystal according to claim 10, comprising directly reacting fruquintinib with 0.5 to 2.5 molar equivalents of malonic acid, in an organic solvent or solvent combination, wherein the organic solvent is a solvent that can dissolve fruquintinib or malonic acid.

16. A method of preparing the crystalline form of the cocrystal according to claim 11, comprising any one of the following preparation methods: 1) mixing fruquintinib and malonic acid at a molar ratio of 1:0.5 to 1:2 in a solvent selected from the group consisting of a C.sub.1 to C.sub.4 alcohol, a haloalkane, a C.sub.4 to C.sub.6 ether, a C.sub.3 to C.sub.4 ketone, acetonitrile, and any mixture thereof, for reaction, and removing the solvent to obtain the crystalline form of the cocrystal of fruquintinib and malonic acid; the operation temperature of the preparation method is from 10 to 50° C.; the crystallization time is from 8 to 48 hours; the weight-to-volume ratio of fruquintinib to the solvent is from 5 mg:1 ml to 50 mg:1 ml; and the weight-to-volume ratio of malonic acid to the solvent is from 1 mg:1 ml to 30 mg:1 ml; 2) adding a solvent to the mixture of equal molar ratio of fruquintinib and malonic acid, completely wetting the mixture, and grinding it until dry to obtain the crystalline form of the cocrystal of fruquintinib and malonic acid, wherein the solvent is selected from the group consisting of water, a C.sub.1 to C.sub.4 alcohol, a C.sub.4 to C.sub.5 ester, an alkane, a C.sub.4 to C.sub.6 ether, a C.sub.3 to C.sub.4 ketone, acetonitrile, and any mixture thereof; the weight-to-volume ratio of the mixture to the solvent is from 20 mg:1 ml to 253 mg:1 ml; and the operation temperature of the preparation method is from 10 to 40° C.; or 3) forming a solution of a mixture of equal molar ration of fruquintinib and malonic acid with mixed organic solvents, wherein the organic solvent is selected from the group consisting of a C.sub.1 to C.sub.4 alcohol, a C.sub.4 to C.sub.6 ether, a haloalkane, a C.sub.3 to C.sub.4 ketone, acetonitrile, and any mixture thereof, volatilizing the solution naturally to crystallize to obtain the crystalline form of the cocrystal of fruquintinib and malonic acid; the operation temperature of the preparation method is from 10 to 50° C.; and the weight-to-volume ratio of the mixture to the solvent is from 1 mg:1 ml to 50 mg:1 ml.

17. A cocrystal of fruquintinib and maleic acid having the structure shown below: ##STR00007##

18. The cocrystal according to claim 17, wherein the X-ray powder diffraction pattern of the crystalline form of the cocrystal, expressed as 2θ angles, has the following characteristic peaks: 3.9±0.2°, 5.6±0.2°, 8.9±0.2° and 15.0±0.2°.

19. The cocrystal according to claim 18, wherein the X-ray powder diffraction pattern of the crystalline form of the cocrystal, expressed as 2θ angles, further comprises the following characteristic peaks: 8.4±0.2°, 11.4±0.2°, 17.6±0.2°, 23.4±0.2° and 27.4±0.2°.

20. The cocrystal according to claim 19, wherein the X-ray powder diffraction pattern of the crystalline form of the cocrystal, expressed as 2θ angles, has the following characteristic peaks and relative intensities: TABLE-US-00020 2θ Relative intensity %  3.9 ± 0.2° 20.9  5.6 ± 0.2° 100.0  7.6 ± 0.2° 13.8  8.4 ± 0.2° 26.9  8.9 ± 0.2° 55.6 10.8 ± 0.2° 12.3 11.4 ± 0.2° 27.7 12.7 ± 0.2° 20.5 15.0 ± 0.2° 60.3 16.2 ± 0.2° 24.3 17.6 ± 0.2° 29.7 23.4 ± 0.2° 23.8 24.2 ± 0.2° 26.5 24.9 ± 0.2° 16.6 26.4 ± 0.2° 23.4 27.4 ± 0.2° 33.2 28.9 ± 0.2° 14.5.

21. The cocrystal according to claim 18, wherein the Fourier IR spectrum of the crystalline form of the cocrystal has characteristic peaks at wave number of 1627±2 cm.sup.−1, 1510±2 cm.sup.−1, 1422±2 cm.sup.−1, 1398±2 cm.sup.−1, 1233±2 cm.sup.−1, 1126±2 cm.sup.−1, 986±2 cm.sup.−1, 861±2 cm.sup.−1, and 650±2 cm.sup.−1.

22. A method of preparing the cocrystal according to claim 17, comprising the method of directly reacting fruquintinib with 0.5 to 3 equivalents of maleic acid, in an organic solvent or solvent combination, wherein the organic solvent is a solvent that can dissolve fruquintinib or maleic acid.

23. A method of preparing the crystalline form of the cocrystal according to claim 18, comprising any one of the following methods: 1) mixing fruquintinib and maleic acid at a molar ratio of 1:0.5 to 1:1.5 in a solvent selected from the group consisting of a C.sub.1 to C.sub.4 alcohol, a haloalkane, a C.sub.3 to C.sub.4 ketone, acetonitrile, and any mixture thereof, for reaction, and removing the solvent to obtain the crystalline form of the cocrystal of fruquintinib and maleic acid; the operation temperature of the preparation method is from 10 to 50° C.; the crystallization time is from 8 to 48 hours; the weight-to-volume ratio of fruquintinib to the solvent is from 5 mg:1 ml to 50 mg:1 ml; and the weight-to-volume ratio of maleic acid to the solvent is from 3 mg:1 ml to 20 mg:1 ml; 2) adding a solvent to the mixture of equal molar ratio of fruquintinib and maleic acid, completely wetting the mixture, and grinding it until dry to obtain the crystalline form of the cocrystal, wherein the solvent is selected from the group consisting of water, a C.sub.1 to C.sub.4 alcohol, a C.sub.4 to C.sub.5 ester, an alkane, a C.sub.4 to C.sub.6 ether, a C.sub.3 to C.sub.4 ketone, acetonitrile, and any mixture thereof; the weight-to-volume ratio of the mixture to the solvent is from 20 mg:1 ml to 205 mg:1 ml; and the operation temperature of the preparation method is from 10 to 50° C.; or 3) forming a solution of a mixture of equal molar ratio of fruquintinib and maleic acid with mixed organic solvents, wherein the organic solvent is selected from the group consisting of a C.sub.1 to C.sub.4 alcohol, a C.sub.3 to C.sub.4 ketone, a cycloether, a haloalkane, acetonitrile, and any mixture thereof, volatilizing naturally for crystallization to obtain the crystalline form of the cocrystal of fruquintinib and maleic acid; the operation temperature of the preparation method is from 10 to 50° C.; and the weight-to-volume ratio of the mixture to the solvent is from 1 mg:1 ml to 50 mg:1 ml.

24. A pharmaceutical composition comprising a therapeutically effective amount of compound A according to claim 1, and at least one pharmaceutically acceptable carrier or excipient.

25. A method for treating a disease in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of compound A according to claim 1, or a pharmaceutical composition thereof, wherein the disease is associated with abnormal angiogenesis in the patient; and wherein the disease is selected from the group consisting of cancer, tumor, macular lesion, and chronic inflammatory disease.

26. A pharmaceutical composition comprising a therapeutically effective amount of the cocrystal of fruquintinib and malonic acid according to claim 10, and at least one pharmaceutically acceptable carrier or excipient.

27. A method for treating a disease in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of the cocrystal of fruquintinib and malonic acid according to claim 10, or a pharmaceutical composition thereof, wherein the disease is associated with abnormal angiogenesis in the patient; and wherein the disease is selected from the group consisting of cancer, tumor, macular lesion, and chronic inflammatory disease.

28. A pharmaceutical composition comprising a therapeutically effective amount of the cocrystal of fruquintinib and maleic acid according to claim 17, and at least one pharmaceutically acceptable carrier or excipient.

29. A method for treating a disease in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of the cocrystal of fruquintinib and maleic acid according to claim 17, or a pharmaceutical composition thereof, wherein the disease is associated with abnormal angiogenesis in the patient; and wherein the disease is selected from the group consisting of cancer, tumor, macular lesion, and chronic inflammatory disease.

Description

DESCRIPTION OF DRAWINGS

(1) FIG. 1 is the .sup.1HNMR spectrum of the known fruquintinib prepared with the method in Example 1 of the patent CN101575333B.

(2) FIG. 2 is the XRPD pattern of the known fruquintinib prepared with the method in Example 1 of the patent CN105461702 Å.

(3) FIG. 3 is the PLM of the known fruquintinib prepared with the method in Example 1 of the patent CN105461702 Å.

(4) FIG. 4 is the XRPD pattern of the Crystalline Form of Compound A of the present invention.

(5) FIG. 5 is the TGA thermogram of the Crystalline Form of Compound A of the present invention.

(6) FIG. 6 is the DSC thermogram of the Crystalline Form of Compound A of the present invention.

(7) FIG. 7 is the IR spectrum of the Crystalline Form of Compound A of the present invention.

(8) FIG. 8 is the PLM of the Crystalline Form of Compound A of the present invention.

(9) FIG. 9 is the .sup.1HNMR spectrum of Compound A of the present invention.

(10) FIG. 10 is the XRPD pattern of the crystalline form of the cocrystal of fruquintinib and malonic acid of the present invention.

(11) FIG. 11 is the TGA thermogram of the crystalline form of the cocrystal of fruquintinib and malonic acid of the present invention.

(12) FIG. 12 is the DSC thermogram of the crystalline form of the cocrystal of fruquintinib and malonic acid of the present invention.

(13) FIG. 13 is the IR spectrum of the crystalline form of the cocrystal of fruquintinib and malonic acid of the present invention.

(14) FIG. 14 is the PLM of the crystalline form of the cocrystal of fruquintinib and malonic acid of the present invention.

(15) FIG. 15 is the .sup.1HNMR spectrum of the crystalline form of the cocrystal of fruquintinib and malonic acid of the present invention.

(16) FIG. 16 is the XRPD pattern of the crystalline form of the cocrystal of fruquintinib and maleic acid of the present invention.

(17) FIG. 17 is the TGA thermogram of the crystalline form of the cocrystal of fruquintinib and maleic acid of the present invention.

(18) FIG. 18 is the DSC thermogram of the crystalline form of the cocrystal of fruquintinib and maleic acid of the present invention.

(19) FIG. 19 is the IR spectrum of the crystalline form of the cocrystal of fruquintinib and maleic acid of the present invention.

(20) FIG. 20 is the PLM of the crystalline form of the cocrystal of fruquintinib and maleic acid of the present invention.

(21) FIG. 21 is the .sup.1HNMR spectrum of the crystalline form of the cocrystal of fruquintinib and maleic acid of the present invention.

SPECIFIC IMPLEMENTATIONS

(22) The following examples help to further understand the present invention, but are not intended to limit the contents of the present invention.

(23) Testing Instruments and Methods:

(24) X-ray powder diffraction (XRPD): performed on Bruker D8 Advance diffractometer. Samples were tested at room temperature. Testing conditions: 2θ scan range 3 to 40°, step size 0.02° and speed 0.2 s/step.

(25) Polarized light microscopy (PLM) pictures were obtained from XP-500 Epolarized light microscope (by Shanghai Changfang Optical Instrument Co., LTD.) with 4× or 10× objective lens and 10× eyepiece, which was used to observe and photograph the morphology of samples.

(26) Thermogravimetric (TGA) analysis data were collected on TA Instruments Q500 TGA. Method: segmented high resolution testing method that a sample was heated at a heating rate of 10° C./min under the protection of dry nitrogen (N.sub.2).

(27) Differential scanning calorimetry (DSC) analysis data were collected on TA Instruments Q200 DSC. Method: A sample was placed in a sealed aluminum pan and was heated at a heating rate of 10° C./min under the protection of dry nitrogen (N.sub.2).

(28) .sup.1H nuclear magnetic resonance (.sup.1H-NMR) data were collected on Bruker Avance II DMX 500 MHZ nuclear magnetic resonance spectrometer and a sample was dissolved with deuterium reagent.

(29) Infrared (IR) analysis data were collected on Bruker Tensor 27 with OPUS software. Generally, data are collected within 600 to 4,000 cm.sup.−1 by ATR means.

(30) High performance liquid chromatography (HPLC) data were collected on Ultimate 3000 and the concentration was tested with the external standard method.

(31) Unless particularly specified, embodiments were operated at room temperature and the solvent ratio was volume ratio.

(32) Unless particularly specified, all reagents used in the embodiments were commercially available.

(33) Ultrasonic operation in the embodiments could promote sample dissolution, and was performed with ultrasonic cleaner for 15 min at 40 kHz power.

Preparation Example 1

(34) Fruquintinib was prepared by referring to the method of Example 1 in the patent CN101575333B.

(35) The .sup.1HNMR spectrum is shown in FIG. 1, indicating that the fruquintinib is consistent with that prepared by referring to the method in Example 1 of the patent CN101575333B.

Preparation Example 2

(36) Fruquintinib Crystalline Form I was prepared by referring to the method of Example 1 in the patent CN105461702 Å.

(37) Its XRPD pattern is shown in FIG. 2, indicating that the fruquintinib Crystalline Form I is consistent with that prepared by referring to the method in Example 1 of the patent CN105461702 Å.

(38) Its PLM is shown in FIG. 3, indicating that fruquintinib Crystalline Form I is in fine needle shape.

(39) Fruquintinib Crystalline Form III, fruquintinib mono acetic acid solvate (Crystalline Form IV) and Crystalline Form VII were prepared by referring to the methods of Example 34, Example 39 and Example 42, respectively in the patent CN105461702 Å.

Example 1

(40) In 50 mg fruquintinib prepared in Preparation Example 1 added 3.5 ml methanol and 69.8 mg saccharin to form a solution, and the solution was stirred at room temperature for 8 hours and then filtrated under vacuum; the filter cake was vacuum dried at 40° C. for 10 hours to obtain 68.9 mg Compound A of the present invention.

(41) Its XRPD pattern is shown in FIG. 4, indicating the compound is the crystalline Compound A.

(42) Its TGA thermogram is shown in FIG. 5.

(43) Its DSC thermogram is shown in FIG. 6.

(44) Its IR spectrum is shown in FIG. 7.

(45) Its PLM is shown in FIG. 8.

(46) Its .sup.1HNMR spectrum is shown in FIG. 9.

Example 2

(47) In 50 mg fruquintinib prepared in Preparation Example 1 added 8.0 ml of methanol and ether mixture (1:1) and 34.9 mg saccharin, stirred at room temperature for 24 hours and then filtrated under vacuum; the filter cake was vacuum dried at 25° C. for 24 hours to obtain 67.3 mg Compound A of the present invention.

Example 3

(48) In 50 mg fruquintinib prepared in Preparation Example 1 added 1.0 ml chloroform and 15.5 mg saccharin, stirred at 40° C. for 24 hours and then filtrated under vacuum; the filter cake was vacuum dried at 30° C. for 20 hours to obtain 42.5 mg Compound A of the present invention.

Example 4

(49) In 50 mg fruquintinib prepared in Preparation Example 1 added 5 ml n-propanol; a saccharin solution (23.3 mg saccharin dissolved in 5.0 ml ethyl acetate) was dripped into the fruquintinib suspension during stirring; stirred at 50° C. for 48 hours and then filtrated under vacuum; the filter cake was vacuum dried at 40° C. for 36 hours to obtain 61.5 mg Compound A of the present invention.

Example 5

(50) Compound A was obtained by replacing the solvent in Example 4 according to the following table.

(51) TABLE-US-00005 No. Solvent Experiment 1 Mixed solvent of n-butanol and dichloromethane Experiment 2 Mixed solvent of isopropyl ether and 1,4-dioxane Experiment 3 Mixed solvent of acetonitrile and butanone Experiment 4 Mixed solvent of acetone and isopropyl acetate

Example 6

(52) Added 0.5 ml acetone into 30 mg fruquintinib prepared in Preparation Example 1 and 14.0 mg saccharin to completely wet the mixture at room temperature, ground the mixture until dry to obtain Compound A of the present invention.

Example 7

(53) Completely wetted 30 mg fruquintinib prepared in Preparation Example 1 and 14.0 mg saccharin using 0.2 mL water at room temperature, ground the mixture until dry to obtain Compound A of the present invention.

Example 8

(54) Completely wetted 30 mg fruquintinib prepared in Preparation Example 1 and 14.0 mg saccharin using 2.2 ml tetrahydrofuran at room temperature, ground the mixture until dry to obtain Compound A of the present invention.

Example 9

(55) Compound A was obtained by replacing the solvent in Example 9 according to the following table.

(56) TABLE-US-00006 No. Solvent Experiment 1 Mixed solventof methanol and isopropyl acetate Experiment 2 Mixed solvent of n-propanol and chloroform Experiment 3 Mixed solvent of acetonitrile and ether Experiment 4 Mixed solvent of ethyl acetate and butanone Experiment 5 Mixed solvent of isopropyl ether and methanol Experiment 6 n-heptane

Example 10

(57) 10 mg fruquintinib prepared in Preparation Example 1 was dissolved in 0.5 ml dichloromethane using ultrasonic; a saccharin solution (4.7 mg saccharin dissolved in 0.1 ml methanol) was dripped into the dichloromethane solution of fruquintinib; volatilized at room temperature to obtain Compound A of the present invention.

Example 11

(58) 10 mg fruquintinib prepared in Preparation Example 1 and 4.7 mg saccharin were dissolved in 2.2 ml tetrahydrofuran using ultrasonic; volatilized at room temperature to obtain Compound A of the present invention.

Example 12

(59) 10 mg fruquintinib prepared in Preparation Example 1 and 4.7 mg saccharin were dissolved in 0.3 ml mixed solvent of trifluoroethanol and methanol (2:1) using ultrasonic, volatilized at 40° C. to obtain Compound A of the present invention.

Example 13

(60) 10 mg fruquintinib prepared in Preparation Example 1 and 4.7 mg saccharin were dissolved in 3.0 ml mixed solvent of nitromethane and isopropanol (2:1) using ultrasonic, itvolatilized at 50° C. to obtain Compound A of the present invention.

Example 14

(61) Compound A was obtained by replacing the solvent in Example 13 according to the following table.

(62) TABLE-US-00007 No. Solvent Experiment 1 Mixed solvent of n-butanol and ether Experiment 2 Mixed solvent of ethyl acetate and 1,4-dioxane Experiment 3 Mixed solvent of isopropyl acetate and chloroform Experiment 4 Mixed solvent of acetone and acetonitrile Experiment 5 Mixed solvent of butanone and isopropyl ether

(63) The samples prepared in Examples 2 to 14 had essentially the same or similar XRPD patterns, DSC thermograms, TGA thermograms, IR spectra (not shown) as those of the sample of Example 1, indicating that the samples of Examples 2 to 14 and Example 1 are the same.

Example 15

(64) In 50 mg fruquintinib prepared in Preparation Example 1 added 1.0 ml tetrahydrofuran and 13.2 mg malonic acid, stirred at room temperature for 24 hours and then filtrated under vacuum; the filter cake was vacuum dried at 25° C. for 24 hours to obtain 59.6 mg cocrystal of fruquintinib and malonic acid of the present invention.

(65) The XRPD pattern is shown in FIG. 10, indicating the compound is the crystalline cocrystal of fruquintinib and malonic acid.

(66) Its TGA thermogram is shown in FIG. 11.

(67) Its DSC thermogram is shown in FIG. 12.

(68) Its IR spectrum is shown in FIG. 13.

(69) Its PLM is shown in FIG. 14.

(70) Its .sup.1HNMR spectrum is shown in FIG. 15.

Example 16

(71) In 50 mg fruquintinib prepared in Preparation Example 1 added 5.3 ml acetone and 26.5 mg malonic acid, then stirred at room temperature for 16 hours and then filtrated under vacuum; the filter cake was vacuum dried at 40° C. for 16 hours to obtain 56.9 mg cocrystal of fruquintinib and malonic acid of the present invention.

Example 17

(72) In 50 mg fruquintinib prepared in Preparation Example 1 added 0.82 ml acetonitrile; a malonic acid solution (33.1 mg malonic acid dissolved in 0.4 ml methanol) was dripped into the fruquintinib suspension during stirring; then stirred at 40° C. for 30 h and then filtrated under vacuum; the filter cake was vacuum dried at 50° C. for 12 hours to obtain 50.8 mg cocrystal of fruquintinib and malonic acid of the present invention.

Example 18

(73) In 50 mg fruquintinib prepared in Preparation Example 1 added 8.2 ml solvent mixture of methyl tert-butyl ether and tetrahydrofuran (1:2); a malonic acid solution (6.6 mg malonic acid dissolved in 1.0 ml solvent mixture of methyl tert-butyl ether and tetrahydrofuran (1:2)) was dripped into the fruquintinib suspension during stirring, then stirred at 50° C. for 42 hours and then filtrated under vacuum; the filter cake was vacuum dried at 45° C. for 20 hours to obtain 33.9 mg cocrystal of fruquintinib and malonic acid of the present invention.

Example 19

(74) The cocrystal of fruquintinib and malonic acid was obtained by replacing the solvent in Example 18 according to the following table.

(75) TABLE-US-00008 No. Solvent Experiment 1 Mixed solvent of isopropanol and ether Experiment 2 Mixed solvent of chloroform and butanone Experiment 3 Mixed solvent of dichloromethane and n-butanol Experiment 4 Mixed solvent of 1,4-dioxane and ethanol

Example 20

(76) In 30 mg fruquintinib prepared in Preparation Example 1 and 7.9 mg malonic acid added 1.9 ml acetonitrile to completely wet the mixture at room temperature, then it was ground until dry to obtain the cocrystal of fruquintinib and malonic acid of the present invention.

Example 21

(77) In 30 mg fruquintinib prepared in Preparation Example 1 and 7.9 mg malonic acid added 0.5 ml methanol to completely wet the mixture at room temperature, it was then ground until dry to obtain the cocrystal of fruquintinib and malonic acid of the present invention.

Example 22

(78) In 30 mg fruquintinib prepared in Preparation Example 1 and 7.9 mg malonic acid added 0.15 ml water to completely wet the mixture at 40° C., it was then ground until dry to obtain the cocrystal of fruquintinib and malonic acid of the present invention.

Example 23

(79) The cocrystal of fruquintinib and malonic acid was obtained by replacing the solvent in Example 22 according to the following table.

(80) TABLE-US-00009 No. Solvent Experiment 1 Mixed solvent of n-propanol and ethyl acetate Experiment 2 Mixed solvent of isopropyl acetate and methyl cyclohexane Experiment 3 Mixed solvent of secondary butanol and butanone Experiment 4 Mixed solvent of acetone and isopropyl ether Experiment 5 Mixed solvent of chloroform and ether

Example 24

(81) 10 mg fruquintinib prepared in Preparation Example 1 was dissolved in 1.0 ml chloroform using ultrasonic; a malonic acid solution (2.6 mg maleic dissolved in 0.1 ml methanol) was dripped into the dichloromethane solution of fruquintinib; the solution was volatilized at room temperature to obtain the cocrystal of fruquintinib and malonic acid of the present invention.

Example 25

(82) 10 mg fruquintinib prepared in Preparation Example 1 and 2.6 mg malonic acid were dissolved in 0.25 ml mixed solvent of acetone and tetrahydrofuran (1:1); after the mixture was dissolved using ultrasonic, it was volatilized at 45° C. to obtain the cocrystal of fruquintinib and malonic acid of the present invention.

Example 26

(83) 10 mg fruquintinib prepared in Preparation Example 1 and 2.6 mg malonic acid were dissolved in 12.5 ml mixed solvent of methanol and diethyl ether (15:2); after the mixture was dissolved using ultrasonic, it was volatilized at room temperature to obtain the cocrystal of fruquintinib and malonic acid of the present invention.

Example 27

(84) The cocrystal of fruquintinib and malonic acid was obtained by replacing the solvent in Example 26 according to the following table.

(85) TABLE-US-00010 No. Solvent Experiment 1 Acetonitrile Experiment 2 Mixed solvent of dichloromethane and n-butanol Experiment 3 Mixed solvent of acetone and 1,4-dioxane Experiment 4 Mixed solvent of tetrahydrofuran and isopropyl ether Experiment 5 Mixed solvent of butanone and dichloromethane

(86) The samples prepared in Examples 16 to 27 have essentially the same or similar XRPD patterns, DSC thermograms, TGA thermograms, IR spectra (not shown) as those of the sample of Example 15, indicating that the samples of Examples 16 to 27 and Example 15 are the same.

Example 28

(87) In 50 mg fruquintinib prepared in Preparation Example 1 was added 2.5 ml acetone; a maleic acid solution (14.8 mg maleic acid dissolved in 0.4 ml acetone) was dripped into the acetone solution of fruquintinib; it was then stirred at room temperature for 16 hours and then filtrated under vacuum; the filter cake was vacuum dried at 40° C. for 16 hours to obtain 61.0 mg cocrystal of fruquintinib and maleic acid of the present invention.

(88) The XRPD pattern is shown in FIG. 16, indicating the compound is the crystalline cocrystal of fruquintinib and maleic acid.

(89) Its TGA thermogram is shown in FIG. 17.

(90) Its DSC thermogram is shown in FIG. 18.

(91) Its IR spectrum is shown in FIG. 19.

(92) Its PLM is shown in FIG. 20.

(93) Its .sup.1HNMR spectrum is shown in FIG. 21.

Example 29

(94) In 50 mg fruquintinib prepared in Preparation Example 1 added 10.0 ml methanol and 29.5 mg maleic acid; it was then stirred at room temperature for 8 hours and then filtrated under vacuum; the filter cake was dried under vacuum at room temperature for 36 hours to obtain 57.6 mg cocrystal of fruquintinib and maleic acid of the present invention.

Example 30

(95) In 50 mg fruquintinib prepared in Preparation Example 1 added 0.8 ml dichloromethane; a maleic acid solution (7.4 mg maleic acid dissolved in 0.2 ml isopropanol) was dripped into the suspension of fruquintinib during stirring; it was then stirred at 45° C. for 30 hours and then filtrated under vacuum; the filter cake was vacuum dried at 60° C. for 12 hours to obtain 47.8 mg cocrystal of fruquintinib and maleic acid of the present invention.

Example 31

(96) In 50 mg fruquintinib prepared in Preparation Example 1 added 1.4 ml solvent mixture of acetonitrile:and methanol (1:1); a maleic acid solution (44.3 mg maleic acid dissolved in 0.8 ml acetonitrile and methanol (1:1)) was dripped into the suspension of fruquintinib during stirring; it was then stirred at 50° C. for 48 hours and then filtrated under vacuum; the filter cake was vacuum dried at 45° C. for 30 hours to obtain 52.4 mg cocrystal of fruquintinib and maleic acid of the present invention.

Example 32

(97) The cocrystal of fruquintinib and maleic acid was obtained by replacing the solvent in Example 31 according to the following table.

(98) TABLE-US-00011 No. Solvent Experiment 1 Acetonitrile Experiment 2 Mixed solvent of secondary butanol and acetone Experiment 3 Mixed solvents of chloroform and butanone Experiment 4 Mixed solvents of dichloromethane and n-butanol

Example 33

(99) In 30 mg fruquintinib prepared in Preparation Example 1 and 8.9 mg maleic acid added 1.0 ml isopropanol to completely wet the mixture at room temperature, it was then ground until dry to obtain the cocrystal of fruquintinib and maleic acid of the present invention.

Example 34

(100) In 30 mg fruquintinib prepared in Preparation Example 1 and 8.9 mg maleic acid added 1.9 ml acetone to completely wet the mixture at room temperature, it was then ground until dry to obtain the cocrystal of fruquintinib and maleic acid of the present invention.

Example 35

(101) In 30 mg fruquintinib prepared in Preparation Example 1 and 8.9 mg maleic acid added 0.19 ml methanol to completely wet the mixture at 40° C., it was then ground until dry to obtain the cocrystal of fruquintinib and maleic acid of the present invention.

Example 36

(102) The cocrystal of fruquintinib and maleic acid was obtained by replacing the solvent in Example 35 according to the following table.

(103) TABLE-US-00012 No. Solvent Experiment 1 Water Experiment 2 N-heptane Experiment 3 Mixed solvent of isopropanol and methyl cyclohexane Experiment 4 Mixed solvents of methanol and tetrahydrofuran Experiment 5 Mixed solvent of n-butanol and ethyl acetate Experiment 6 Mixed solvent of isopropyl acetate and ether Experiment 7 Mixed solvent of isopropyl ether and acetone Experiment 8 Mixed solvent of butanone and acetonitrile

Example 37

(104) 10 mg fruquintinib prepared in Preparation Example 1 was dissolved in 0.8 ml dichloromethane using ultrasound; a maleic acid solution (3.0 mg maleic acid dissolved in 0.2 ml methanol) was dripped into the dichloromethane solution of fruquintinib; it was then volatilized at room temperature to obtain the cocrystal of fruquintinib and maleic acid of the present invention.

Example 38

(105) In 10 mg fruquintinib prepared in Preparation Example 1 and 3.0 mg maleic acid added 13.0 ml mixed solvent of isopropanol and chloroform (1:4); after the mixture was dissolved using ultrasonic, it was volatilized at room temperature to obtain the cocrystal of fruquintinib and maleic acid of the present invention.

Example 39

(106) In 10 mg fruquintinib prepared in Preparation Example 1 and 3.0 mg maleic acid added 0.26 ml mixed solvent of chloroform and tetrahydrofuran (1:1); after the mixture was dissolved using ultrasonic, it was volatilized at 50° C. to obtain the cocrystal of fruquintinib and maleic acid of the present invention.

Example 40

(107) The cocrystal of fruquintinib and maleic acid was obtained by replacing the solvent in Example 39 according to the following table.

(108) TABLE-US-00013 No. Solvent Experiment 1 Isopropyl alcohol Experiment 2 Acetone Experiment 3 Mixed solvent of butanone and tetrahydrofuran Experiment 4 Mixed solvent of 1,4-dioxane and chloroform Experiment 5 Mixed solvent of n-butanol and acetonitrile

(109) The samples prepared in Examples 29 to 40 have essentially the same or similar XRPD patterns, DSC thermograms, TGA thermograms, IR spectra (not shown) as those of the sample of Example 28, indicating that the samples of Examples 29 to 40 and Example 28 are the same.

Example 41

(110) Hard-shell capsule: A large number of capsules was prepared by filling traditional two-piece hard-shell capsules. The dosage unit contains 5 mg active pharmaceutical ingredient (7.3 mg Compound A of the present invention), 150 mg lactose, 50 mg cellulose and 3 mg magnesium stearate.

Example 42

(111) Hard-shell capsule: The amount of the active pharmaceutical ingredient in Example 41 was changed to 4 mg (5.9 mg Compound A of the present invention), and the other operations were the same as those of Example 41.

Example 43

(112) Hard-shell capsule: The amount of the active pharmaceutical ingredient in Example 41 was changed to 1 mg (1.5 mg Compound A of the present invention), and the other operations were the same as those of Example 41.

Examples 44-49

(113) Hard-shell capsule: Compound A in Examples 41 to 43 was respectively replaced by the cocrystal of fruquintinib and malonic acid of the present invention or the cocrystal of fruquintinib and maleic acid of the present invention. The free bases in the formulation of the cocrystal of fruquintinib and malonic acid of the present invention or the cocrystal of fruquintinib and maleic acid of the present invention and in the formulation of Compound A have the same molar amount, and the total amount of the co-crystal and the fillers in these formulations is the same as the total amount in formulation of Compound A, and other preparation steps are the same as those in the Examples 41 to 43.

Exchange 50

(114) Soft gelatin capsule: A mixture of active ingredients was prepared in digestible oil such as soybean oil, cottonseed oil or olive oil and molten gelatin was pumped by active displacement pump to form a soft gelatin capsules containing 5 mg active pharmaceutical ingredient (7.3 mg Compound A of the present invention). The capsule was washed and dried. The active pharmaceutical ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a pharmaceutical mixture able to be mixed with water.

Example 51

(115) Soft gelatin capsule: The amount of the active pharmaceutical ingredient in Example 50 was changed to 4 mg (5.9 mg Compound A of the present invention), and the other operations were the same as those of Example 50.

Example 52

(116) Soft gelatin capsule: The amount of the active pharmaceutical ingredient in Example 50 was changed to 1 mg (1.5 mg Compound A of the present invention), and the other operations were the same as those of Example 50.

Examples 53-58

(117) Hard-shell capsule: Compound A in Examples 50 to 52 was respectively replaced by the cocrystal of fruquintinib and malonic acid of the present invention or the cocrystal of fruquintinib and maleic acid of the present invention. The free bases in the formulation of the cocrystal of fruquintinib and malonic acid of the present invention or the cocrystal of fruquintinib and maleic acid of the present invention and in the formulation of Compound A have the same molar amount, and the total amount of the co-crystal and the fillers in these formulations is the same as the total amount in formulation of Compound A, and other preparation steps are the same as those in the Examples 50 to 52.

Example 59

(118) Tablet: A large number of tablets were prepared by conventional processes such that the dosage unit was 5 mg active pharmaceutical ingredient (7.3 mg Compound A of the present invention), 1 mg colloidal silica, 2 mg magnesium stearate, 100 mg microcrystalline cellulose, 10 mg starch and 50 mg lactose. Appropriate aqueous or non-aqueous coating could be used to improve palatability, improve appearance and stability or delay absorption.

Example 60

(119) Tablet: The amount of the active pharmaceutical ingredient in Example 59 was changed to 4 mg (5.9 mg Compound A of the present invention), and the other operations were the same as those of Example 59.

Example 61

(120) Tablet: The amount of the active pharmaceutical ingredient in Example 59 was changed to 1 mg (1.5 mg Compound A of the present invention), and the other operations were the same as those of Example 59.

Examples 62-67

(121) Tablet: Hard-shell capsule: Compound A in Examples 59 to 61 was respectively replaced by the cocrystal of fruquintinib and malonic acid of the present invention or the cocrystal of fruquintinib and maleic acid of the present invention. The free bases in the formulation of the cocrystal of fruquintinib and malonic acid of the present invention or the cocrystal of fruquintinib and maleic acid of the present invention and in the formulation of Compound A have the same molar amount, and the total amount of the co-crystal and the fillers in these formulations is the same as the total amount in formulation of Compound A, and other preparation steps are the same as those in the Examples 59 to 61.

Example 68

(122) Immediate Release Tablet/Capsule:

(123) This solid oral dosage form was prepared by conventional and new processes. These dosage units are taken orally and rapidly break down. The active pharmaceutical ingredient was mixed with liquids containing such as sugar, gelatin, pectin and sweetener. These liquids were solidified into solid tablets or caplets by freeze-drying and solid extraction techniques. The pharmaceutical compounds can be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent ingredients to produce a porous matrix for rapid release that does not require water. Active pharmaceutical ingredients included the Compounds A, cocrystal of fruquintinib and malonic acid and cocrystal of fruquintinib and maleic acid of the present invention.

Example 69

(124) Sustained Release Tablet/Capsule:

(125) This kind of solid oral dosage form was prepared by conventional and new processes.

(126) These dosage units are taken orally to release slowly and deliver the drug. The active pharmaceutical ingredient was mixed with one or more solids such as starch, sugar or other hygroscopic agent, prepared into solid dispersion by aqueous hypromellose solution or by ethylcellulose ethanol solution, then prepared into solid tablets or caplets by wet granulation. Active pharmaceutical ingredients included the Compounds A, cocrystal of fruquintinib and malonic acid and cocrystal of fruquintinib and maleic acid of the present invention.

Example 70

(127) Sterile IV Solution:

(128) Compound A in the present invention was formulated into a 2.5 mg/ml solution with sterile water for injection, meanwhile 2 wt % of solubilizer Pluronic F-68 was added and the pH value was adjusted as needed. For administration, the above solution was diluted with 5% sterile dextrose to 0.5 to 2.5 mg/ml and administered as an intravenous infusion over 10 to 30 minutes.

Examples 71-72

(129) Sterile IV solution: Compound A in Example 70 was respectively replaced by the cocrystal of fruquintinib and malonic acid of the present invention or the cocrystal of fruquintinib and maleic acid of the present invention. The free bases in the formulation of the cocrystal of fruquintinib and malonic acid of the present invention or the cocrystal of fruquintinib and maleic acid of the present invention and in the formulation of Compound A have the same molar amount, and the total amount of the co-crystal and the fillers in these formulations is the same as the total amount in formulation of Compound A, and other preparation steps are the same as those in Example 70.

Example 73

(130) Lyophilized powder for intravenous administration: (i) 135-1350 mg Compound A of the present invention in the form of lyophilized powder, (ii) 32-327 mg/ml sodium citrate, and (iii) 300-3000 mg dextran 40 could be used to make a sterile preparation. Compound A of the present invention was added with sterile injection water or 5% dextrose to a concentration of 6 to 13 mg/ml, further diluted with saline or 5% dextran to a concentration of 0.1 to 0.6 mg/ml, and was administered by intravenous bolus or intravenous infusion for 10 to 30 minutes.

Examples 74-75

(131) Lyophilized powder for intravenous administration: Compound A in Example 73 was respectively replaced by the cocrystal of fruquintinib and malonic acid of the present invention or the cocrystal of fruquintinib and maleic acid of the present invention. The free bases in the formulation of the cocrystal of fruquintinib and malonic acid of the present invention or the cocrystal of fruquintinib and maleic acid of the present invention and in the formulation of Compound A have the same molar amount, and the total amount of the co-crystal and the fillers in these formulations is the same as the total amount in formulation of Compound A, and other preparation steps are the same as those in Example 73.

Example 76

(132) Intramuscular suspension: For intramuscular injection, the following solutions or suspensions could be prepared:

(133) 1 mg/ml such as Compound A of the present invention (insoluble in water)

(134) 0.5 mg/ml sodium carboxymethylcellulose

(135) 0.1 mg/ml Tween80

(136) 9 mg/ml sodium chloride

(137) 9 mg/ml benzyl alcohol

Examples 77-78

(138) Intramuscular suspension: Compound A in Example 76 was respectively replaced by the cocrystal of fruquintinib and malonic acid of the present invention or the cocrystal of fruquintinib and maleic acid of the present invention. The free bases in the formulation of the cocrystal of fruquintinib and malonic acid of the present invention or the cocrystal of fruquintinib and maleic acid of the present invention and in the formulation of Compound A have the same molar amount, and the total amount of the co-crystal and the fillers in these formulations is the same as the total amount in formulation of Compound A, and other preparation steps are the same as those in Example 76.

Example 79

(139) A proper amount of Compound A of the present invention was dissolved in a mixed solution of tetrahydrofuran and chloroform to form a solution; and the solution was volatized at 40° C. through a small hole to obtain the single crystal of Compound A.

(140) The single crystal parameters are shown in Table 1 and the atomic coordinates are shown in Table 2.

(141) TABLE-US-00014 TABLE 1 Single Crystal Parameters of Compound A Crystal Parameters Molecular component C.sub.21H.sub.19O.sub.5N.sub.3.sup.•C.sub.7H.sub.5O.sub.3NS Molecular weight (g/mol)  576.58 Crystal system Triclinic Space group P1 Temperature/K  106.3 a/Å   8.6146(10) b/Å   8.9574(11) c/Å  17.310(2) α/°  84.030(10) β/°  77.369(10) γ/°  77.771(10) Z   2 V/Å.sup.3 1271.5(3) D.sub.calc/g cm.sup.−3   1.519

(142) In Table 2, a, b and c are for e axis length, α, β and γ are dihedral angle, Z for the number of molecules in unit of C.sub.21H.sub.19O.sub.5N.sub.3.C.sub.7H.sub.5O.sub.3NS in each unit cell, V for cell volume and D.sub.calc for unit cell density.

(143) Single crystal analytical parameters: residual factor R1=0.0702, weighted R value wR.sup.2=0.1282, goodness of fit GooF(S)=1.037, S value close to 1, indicating that single crystal data are reasonable.

(144) TABLE-US-00015 TABLE 2 Atomic Coordinates of Compound A Atom X Y Z S1 6100.9(8)    419.7(7) 2756.2(4) O2  9429(2)    3065(2) 6171.2(11) O6  6049(2)  −2480(2) 4413.6(11) O3  9537(2)  −2321(2) 7420.0(11) O1  8070(2)    3208(2) 4983.8(11) O4  7059(2)  −5470(2) 9582.4(12) N2  8512(3)  −3534(2) 6587.1(13) O7  4897(2)    1813(2) 2760.3(12) O8  7683(2)    510(2) 2275.2(11) N1  7591(3)  −2099(2) 5500.2(12) O5  12063(3)  −8357(3) 9779.7(14) N3  10143(3)  −8958(3) 10805.5(13) C5  7746(3)    570(3) 5194.7(14) C3  8703(3)  −862(3) 6337.2(15) N4  6269(3)  −248(3) 3653.4(13) C12  8130(3)  −3847(3) 8451.1(16) C1  7877(3)  −3388(3) 5941.8(15) C25  4948(3)  −1377(3) 1802.5(17) C4  8003(3)  −795(3) 5671.4(15) C6  8235(3)    1827(3) 5387.4(15) C8  9198(3)    429(3) 6527.6(15) C7  8983(3)    1756(3) 6062.6(15) C23  5332(3)  −2188(3) 3140.5(15) C22  5908(3)  −1646(3) 3795.1(15) C11  9571(3)  −3603(3) 7969.7(15) C2  8884(3)  −2285(3) 6779.5(14) C14  9789(3)  −5924(3) 9138.3(15) C10  10097(3)    3049(3) 6863.5(16) C16  11079(3)  −4444(3) 8050.6(16) C21  11280(4) −10098(3) 11164.3(16) C28   4819(3)  −3542(3) 3114.9(17) C27   4359(3)  −3812(3) 2427.7(18) C13   8307(3)  −5027(3) 9030.2(16) C15  11205(3)  −5626(3) 8636.2(16) C9   7228(3)   3394(3) 4334.0(16) C19  10631(3)  −8145(3) 10138.9(16) C17   9394(3)  −6970(3) 9820.5(16) C24   5383(3)  −1131(3) 2493.8(16) C26   4432(4)  −2749(4) 1782.2(18) C18   7767(4)  −6659(4) 10055.7(18) C20   6565(4)  −7323(5)   10676(2) O9    5056(11)    675(10)    156(5) H1 7130 −2082  5092 H3 9108 −8797 11032 H5 7247 623  4752 H12 7104 −3257  8390 H1A 7610 −4273  5786 H25 4997 −649  1362 H8 9678 380  6977 H10A 9236 3042  7339 H10B 10567 3962  6838 H10C 10942 2131  6886 H16 12029 −4213  7705 H21A 12120 −10619 10747 H21B 10704 −10848 11494 H21C 11785 −9600 11495 H28 4782 −4270  3556 H27 3992 −4729  2400 H15 12234 −6216  8692 H9A 6132 3190  4530 H9B 7821 2675  3931 H9C 7160 4444  4100 H26 4125 −2960  1316 H20A 6477 −6889 11184 H20B 6921 −8436 10728 H20C 5505 −7081 10523

Comparation Example 1

(145) The fruquintinib Crystalline Form I, Crystalline Form III and Crystalline Form VII prepared in Preparation Example 2, as well as the Crystalline Form of Compound A of the present invention, the crystalline form of the cocrystal of fruquintinib and malonic acid of the present invention and the crystalline form of the cocrystal of fruquintinib and maleic acid were respectively dissolved in water for solubility experiment. The specific operation steps: respectively took 10 mg of each of the above samples and put them into a 20 ml glass bottle respectively, added 10 ml deionized water, placed the solution at 25° C. ultrasound for 1 min, then took the samples for filtration and analyzed their concentrations using HPLC; calculated their solubility in water respectively.

(146) TABLE-US-00016 TABLE 3 Solubility in Water Solubility Sample name (ug/mL) Known fruquintinib Crystalline Form I  2.2 Known fruquintinib Crystalline Form III  2.1 Known fruquintinib Crystalline Form VII  2.6 Crystalline Form of Compound A of the  9.9 present invention Crystalline form of the cocrystal of fruquintinib 12.0 and malonic acid of the present invention Crystalline form of the cocrystal of fruquintinib  9.4 and maleic acid of the present invention

(147) According to Table 3, compared with the known fruquintinib Crystalline Form I, Form III and Form VII, Compound A, the cocrystal of fruquintinib and malonic acid and the cocrystal of fruquintinib and maleic acid of the present invention have about 4 to 6 times higher in solubility, indicating that they have better water solubility and thus better bioavailability.

Comparation Example 2

(148) The fruquintinib mono acetic acid solvate (Crystalline Form IV) prepared in Preparation Example 2, as well as the Crystalline Form of Compound A of the present invention, the crystalline form of the cocrystal of fruquintinib and malonic acid of the present invention and the crystalline form of the cocrystal of fruquintinib and maleic acid were respectively stirred in water for crystal slurry experiment. The specific operation steps: respectively took 10 mg of each of the above samples and put them into a 5 ml glass bottle respectively, added 2 ml deionized water, stirred the solution at room temperature for 24 hours, then took the samples for filtration; and analyzed their crystalline forms with XRD.

(149) TABLE-US-00017 TABLE 4 Crystalline Form Stability Sample name XRD test result Known fruquintinib monoacetate Known fruquintinib (Crystalline Form IV) Crystalline Form I Compound A's CrystallineForm Crystalline Form of Compound of the present invention A of the present invention Ccrystalline form of the cocrystal Crystalline form of the cocrystal of fruquintinib and malonic acid of fruquintinib and malonic acid of the present invention of the present invention Ccrystalline form of the cocrystal Crystalline form of the cocrystal of fruquintinib and maleic acid of fruquintinib and maleic acid of the present invention of the present invention

(150) According to Table 4, compared with the Known fruquintinib mono acetic acid solvate (Crystalline Form IV), the Crystalline Form of Compound A, the crystalline form of the cocrystal of fruquintinib and malonic acid and the crystalline form of the cocrystal of fruquintinib and maleic acid of the present invention have better crystalline form stability and thus may have better process operability.

(151) All the patents, patent application disclosures, patent applications and non-patented publications cited in this document are incorporated into this document by citation in full.

(152) The above mentioned are only the embodiments of the present invention, which do not cover the entire protection scope of the present invention. Within the technical scope revealed in the present invention, modifications or replacements made by those skilled in the art without creative labor should all be within the protection scope of the present invention. Therefore, these shall be made within the scope of the present invention defined by the claims.