Preparation method and application of high-purity cabozantinib malate

Abstract

The application provides a preparation method of cabozantinib malate, which comprises the following steps: 1) a required amount of an organic solvent is added into cabozantinib, stirring is conducted at 70-78 DEG C, and a mixed solution is prepared; 2) an aqueous solution of L-malic acid in an organic solvent is added into the mixed solution prepared in the step 1), stirring is conducted, and a reaction solution is prepared; 3) an organic solvent suspension of a cabozantinib malate crystal seed is added into the reaction solution prepared in the step 2), stirring is conducted, cooling is conducted, crystallization is conducted, separation is conducted, and drying is conducted, and cabozantinib malate is obtained. The cabozantinib malate prepared by the preparation method of cabozantinib malate has the advantages of high purity, low residual solvent, low content of genotoxic impurities, simple operation, reduced waste liquid discharge, improved production efficiency, reduced production cost, and suitability for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a preparation method of high-purity cabozantinib malate and application thereof. BACKGROUND

[0002] Cabozantinib (chemical name: N-[4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-N'-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide) can inhibit the growth of tumor cells by inhibiting RET, c-Met and VEGFR2 signaling pathways.

[0003]

[0004] CN102388024A discloses cabozantinib 1:1 malate and N-1 crystal, N-2 crystal thereof and a preparation method thereof, wherein the preparation method of the cabozantinib L-malate N-2 crystal comprises the following steps: first, preparing a crystal seed of the N-2 type, and then using methyl isobutyl ketone and tetrahydrofuran as mixed solvents, and through multiple steps, the cabozantinib L-malate N-2 type crystal is prepared, which takes more than 2 days. This method has defects such as long generation period, high cost, and unqualified solvent residue.

[0005] CN103221035A and CN108341773A disclose a method for preparing cabozantinib L-malate using water and methyl ethyl ketone as solvents, and the post-treatment adopts a large amount of methyl ethyl ketone multiple azeotropic drying or vacuum distillation operation, and the product is obtained by gradually precipitating solid. This method has defects such as complicated operation, many control parameters, much waste liquid, and poor reproducibility. Therefore, there is an urgent need for an improved method for preparing cabozantinib malate with high purity, low impurity content, qualified solvent residue, simple operation. SUMMARY

[0006] One of the purposes of the present application is to provide a preparation method of cabozantinib malate, which comprises the following steps: 1) adding a required amount of an organic solvent into cabozantinib, stirring at 70-78℃, and preparing a mixed solution; 2) adding an organic solvent aqueous solution of L-malic acid into the mixed solution prepared in step 1), stirring, and preparing a reaction liquid; 3) adding an organic solvent suspension of cabozantinib malate crystal seeds into the reaction liquid prepared in step 2), stirring, cooling, crystallizing, separating, and drying, and then the cabozantinib malate is obtained.

[0007] In the preferred technical scheme of the present application, the organic solvent in any one of steps 1) to 3) is selected from any one or combination of linear C1-C5 alcohol, branched C1-C5 alcohol, aliphatic ketone, cyclic ether, ester, preferably any one or combination of methanol, ethanol, acetone, butanone, 1,4-dioxane, tetrahydrofuran, ethyl acetate, 2-butanone.

[0008] In the preferred technical scheme of the present application, the mass-volume ratio (g / ml) of cabozantinib to the organic solvent in step 1) is 1:5-30, preferably 1:10-20, and more preferably 1:19.

[0009] In the preferred technical scheme of the present application, the molar ratio of cabozantinib to malic acid in step 2) is 1:1.0-1.5, preferably any one of 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5.

[0010] In the preferred technical scheme of the present application, the mass-volume ratio (g / ml) of malic acid to the organic solvent in step 2) is 1:1-10, preferably 1:2-8, and more preferably 1:3.1-5.

[0011] In the preferred technical scheme of the present application, the mass-volume ratio (g / ml) of malic acid to water in step 2) is 1:1-10, preferably 1:1-5, and more preferably 1:3.1.

[0012] In the preferred technical scheme of the present application, the amount of the seed crystal of cabozantinib malate added in step 3) is 0.5-3.0‰ of the weight of cabozantinib, preferably 1.0-2.0‰.

[0013] In the preferred technical scheme of the present application, the seed crystal of cabozantinib malate is dispersed in the organic solvent to prepare a suspension in step 3).

[0014] In the preferred technical scheme of the present application, the organic solvent for preparing the seed crystal suspension of cabozantinib malate is selected from any one or combination of linear C1-C5 alcohol, branched C1-C5 alcohol, aliphatic ketone, cyclic ether, ester, preferably any one or combination of methanol, ethanol, acetone, butanone, 1,4-dioxane, tetrahydrofuran, ethyl acetate, 2-butanone.

[0015] In the preferred technical scheme of the present application, the mass-volume ratio (g / ml) of the seed crystal of cabozantinib malate to the organic solvent in the seed crystal suspension of cabozantinib malate is 1:20-200, preferably 1:50-150, and more preferably 1:80-100.

[0016] In the preferred technical scheme of the present application, the cooling method is selected from any one or combination of natural cooling and forced cooling.

[0017] In the preferred technical scheme of the present application, the forced cooling is achieved by using a cooling medium to realize forced cooling or programmed cooling of the crystallization system.

[0018] In the preferred technical scheme of the present application, the cooling medium is selected from water, ice salt water, dry ice solvent or liquid nitrogen solvent, preferably any one or a combination of condensed water, ice water and ice salt water.

[0019] In the preferred technical scheme of the present application, the crystallization temperature is 0-30℃, preferably 0-20℃, and more preferably 0-10℃.

[0020] In the preferred technical scheme of the present application, the crystallization mode is selected from any one or a combination of static crystallization and stirring crystallization.

[0021] In the preferred technical scheme of the present application, the crystallization time is 1-24h, preferably 10-20h, and more preferably 12-16h.

[0022] In the preferred technical scheme of the present application, the separation is selected from any one or a combination of centrifugation, filtration and membrane treatment.

[0023] In the preferred technical scheme of the present application, the separated and collected cabozantinib malate solid is washed and dried to obtain the product.

[0024] In the preferred technical scheme of the present application, the washing solvent is selected from any one or a combination of linear C1-C5 alcohol, branched C1-C5 alcohol, aliphatic ketone, cyclic ether and ester, preferably any one or a combination of methanol, ethanol, acetone, butanone, 1,4-dioxane, tetrahydrofuran, ethyl acetate and 2-butanone.

[0025] In the preferred technical scheme of the present application, the drying is selected from any one or a combination of vacuum drying, reduced pressure drying, normal pressure drying, spray drying and boiling drying.

[0026] In the preferred technical scheme of the present application, the drying temperature is 40-80℃, preferably 40-60℃, and more preferably 50℃.

[0027] In the preferred technical scheme of the present application, the prepared cabozantinib malate has a purity of not less than 99.5%, wherein the cabozantinib malate is cabozantinib·1.0(L)-malate.

[0028] In the preferred technical scheme of the present application, the prepared cabozantinib malate has a purity of not less than any one of 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 99.91%, 99.92%, 99.93%, 99.94%, 99.95%, 99.96%, 99.97%, 99.98%, 99.99% and 100%.

[0029] In the preferred technical scheme of the present application, the content of L-malic acid in the prepared cabozantinib malate is 18.0%-25.0%, preferably 19.5%-22.5%.

[0030] In the preferred technical scheme of the present application, the content of single impurity in the prepared cabozantinib malate is not more than 0.1%, and the total impurity content is not more than 0.5%.

[0031] In the preferred technical scheme of the present application, the content of genotoxic impurity in the prepared cabozantinib malate is not more than 98.6ppm, wherein the genotoxic impurity is selected from any one or combination of impurity D 【4-(6,7-dimethoxyquinoline-4-oxy)-aniline】, impurity II d (4-fluoroaniline), impurity II b (4-aminophenol).

[0032] In the preferred technical scheme of the present application, the content of genotoxic impurity in the prepared cabozantinib malate is not more than 50ppm.

[0033] In the preferred technical scheme of the present application, the content of genotoxic impurity in the prepared cabozantinib malate is not detected.

[0034] In the preferred technical scheme of the present application, the content of residual solvent in the prepared cabozantinib malate is not more than 0.5%, wherein the residual solvent is selected from any one or combination of methanol, ethanol, acetonitrile, ethyl formate, dichloromethane, methyl ethyl ketone, tetrahydrofuran, triethylamine, N, N-dimethylformamide, N, N-dimethylacetamide.

[0035] In the preferred technical scheme of the present application, the content of residual solvent in the prepared cabozantinib malate is not more than 0.3%, preferably not more than 0.109%.

[0036] In the preferred technical scheme of the present application, the content of methyl ethyl ketone in the prepared cabozantinib malate is not more than 0.05%, preferably not more than 0.011%.

[0037] In the preferred technical scheme of the present application, the content of tetrahydrofuran in the prepared cabozantinib malate is not more than 0.072%, preferably not detected.

[0038] In the preferred technical scheme of the present application, the content of residual solvent in the prepared cabozantinib malate is not more than 0.5%, wherein the residual solvent is selected from any one or combination of methanol, ethanol, acetonitrile, ethyl formate, dichloromethane, methyl ethyl ketone, tetrahydrofuran, triethylamine, N, N-dimethylformamide, N, N-dimethylacetamide.

[0039] In the preferred technical scheme of the present application, the content of cabozantinib malate N-2 crystal form in the prepared cabozantinib malate is not less than 92%, preferably not less than any one of 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%.

[0040] Another object of the present application is to provide a high-purity cabozantinib malate, the purity of which is not less than 99.5%, wherein the cabozantinib malate is cabozantinib·1.0(L)-malate.

[0041] In the preferred technical scheme of the present application, the purity of the cabozantinib malate is not less than 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 99.9%, 99.91%, 99.92%, 99.93%, 99.94%, 99.95%, 99.96%, 99.97%, 99.98%, 99.99%, or 100%.

[0042] In the preferred technical scheme of the present application, the content of L-malic acid in the prepared cabozantinib malate is 18.0%-25.0%, preferably 19.5%-22.5%.

[0043] In the preferred technical scheme of the present application, the content of single impurity in the prepared cabozantinib malate is not more than 0.1%, and the total impurity content is not more than 0.5%.

[0044] In the preferred technical scheme of the present application, the content of genotoxic impurity in the prepared cabozantinib malate is not more than 98.6ppm, wherein the genotoxic impurity is selected from any one or a combination of impurity D, impurity II d, and impurity II b.

[0045] In the preferred technical scheme of the present application, the content of genotoxic impurity in the prepared cabozantinib malate is not more than 50ppm.

[0046] In the preferred technical scheme of the present application, the content of genotoxic impurity in the prepared cabozantinib malate is not detected.

[0047] In the preferred technical scheme of the present application, the amount of residual solvent in the prepared cabozantinib malate is not more than 0.5%, wherein the residual solvent is selected from any one or a combination of methanol, ethanol, acetonitrile, ethyl formate, dichloromethane, methyl ethyl ketone, tetrahydrofuran, triethylamine, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0048] In the preferred technical scheme of the present application, the amount of residual solvent in the prepared cabozantinib malate is not more than 0.3%, preferably not more than 0.109%.

[0049] In the preferred technical scheme of the present application, the amount of methyl ethyl ketone in the prepared cabozantinib malate is not more than 0.05%, preferably not more than 0.011%.

[0050] In the preferred technical scheme of the present application, the amount of tetrahydrofuran in the prepared cabozantinib malate is not more than 0.072%, preferably not detected.

[0051] In the preferred technical scheme of the present application, the amount of the remaining residual solvents other than methyl ethyl ketone in the residual solvent in the prepared cabozantinib malate is not detected.

[0052] In the preferred technical scheme of the present application, the content of the N-2 crystal form of cabozantinib malate in the prepared cabozantinib malate is not less than 92%, preferably not less than 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% in any one of them.

[0053] Another object of the present application is to provide the use of the high-purity cabozantinib malate for preparing a medicament for treating and / or preventing a cell proliferative disease.

[0054] In the preferred technical scheme of the present application, the cell proliferative disease is selected from any one of esophageal cancer, gastric cancer, kidney cancer, thyroid cancer, liver cancer, bone cancer, skin cancer, lymphoma, gliosarcoma, soft tissue sarcoma, non-small cell lung cancer, prostate cancer, breast cancer, ovarian cancer, cervical cancer, intestinal cancer, squamous cell carcinoma, myelocytic leukemia, angioma, melanoma, astrocytoma, Hodgkin's disease, non-Hodgkin's lymphoma and complications thereof.

[0055] Another object of the present application is to provide a pharmaceutical composition containing the high-purity cabozantinib malate of the present application and a pharmaceutically acceptable carrier.

[0056] In the preferred technical scheme of the present application, the weight percentage of the high-purity cabozantinib malate in the pharmaceutical composition is 30%-32%, preferably 31.68%.

[0057] Another object of the present application is to provide a pharmaceutical package containing the high-purity cabozantinib malate of the present application and other drugs.

[0058] In the preferred technical scheme of the present application, the other drug is selected from one or a combination of nivolumab, pembrolizumab, tremelimumab, sintilimab, camrelizumab, tislelizumab, atezolizumab, durvalumab, bevacizumab, pembrolizumab, trastuzumab, cetuximab, erlotinib, gefitinib, imatinib, nilotinib, sunitinib, lapatinib, afatinib, anlotinib, erlotinib, sorafenib, icotinib, crizotinib, and apatinib.

[0059] The purity of cabozantinib malate, related substances, L-malic acid of the present application is detected by high performance liquid chromatography (Chinese Pharmacopoeia 2015 Edition Part 4 General Test 0512) unless otherwise specified. The residual solvent is detected by residual solvent determination method (Chinese Pharmacopoeia 2015 Edition Part 4 General Test 0861). The purity detection method of N-2 crystal form refers to the Raman spectrum analysis described in CN106083714B.

[0060] Unless otherwise specified, when the present application involves percentage between liquids, the percentage is volume / volume percentage; when the present application involves percentage between liquid and solid, the percentage is volume / weight percentage; when the present application involves percentage between solid and liquid, the percentage is weight / volume percentage; and the rest is weight / weight percentage.

[0061] Compared with the prior art, the present application has the following beneficial technical effects:

[0062] 1. The cabozantinib malate prepared by the preparation method of cabozantinib malate of the present application has the advantages of high purity, low residual solvent (such as methanol, ethanol, acetonitrile, ethyl formate, dichloromethane, tetrahydrofuran, triethylamine, N,N-dimethylformamide, N,N-dimethylacetamide, methyl ethyl ketone, etc.), low content of genotoxic impurities

such as 4-(6,7-dimethoxyquinoline-4-oxyl)-aniline, 4-fluoroaniline, 4-aminophenol, etc.

[0063] 2. The preparation method of cabozantinib malate of the present application simplifies the salt formation process, and has the advantages of simple operation, reduction of waste liquid discharge, improvement of production efficiency, reduction of production cost, and suitability for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0064] Figure 1 Experimental HPLC spectrum of the crystalline compound obtained in Example 1 at 25℃.

[0065] Figure 2 Experimental XRPD spectrum of the crystalline compound obtained in Example 1 at 25℃. DETAILED DESCRIPTION

[0066] The above content of the present application is further described in detail by the form of examples below. However, this should not be understood as the scope of the above subject matter of the present application being limited to the following examples.

[0067] Example 1 Preparation of cabozantinib malate

[0068] The preparation of cabozantinib malate comprises the following steps:

[0069] 1) Under the conditions of nitrogen protection and stirring, 100.00 g (0.20 mol, dry weight) of cabozantinib was added to a 3L three-necked flask containing 1.89 L of 2-butanone, and the temperature was raised to 70-78°C, and stirring was performed until dissolution to prepare a mixed solution;

[0070] 2) 200 ml of an aqueous 2-butanone solution containing 32.16 g (0.24 mol) of L-malic acid was added to the mixed solution prepared in step 1), and stirring was performed at 70-78°C for 1 h to prepare a mixed solution, wherein the volume ratio of 2-butanone to water in the aqueous 2-butanone solution was 1:1;

[0071] 3) 10 mL of a 2-butanone suspension containing 0.10 g (0.16 mmol) of cabozantinib malate N-2 crystal form was added to the mixed solution prepared in step 2) to prepare a mixed solution;

[0072] 4) The mixed solution prepared in step 3) was cooled to 0-10°C, and crystallization was performed for 12 h;

[0073] 5) The crystallization solution prepared in step 4) was suction filtered, the filter cake was taken and washed with 300 mL of 2-butanone, and the washed filter cake was dried at 50°C under vacuum for 24 h at a vacuum degree of 0.1 MPa to prepare 108.40 g of a solid, the purity of which was 99.99% (see Figures 1-2 ), impurity D, impurity II d, impurity II b and other impurities were not detected, and residual solvents methanol, ethanol, acetonitrile, ethyl formate, dichloromethane, tetrahydrofuran, triethylamine, N,N-dimethylformamide, N,N-dimethylacetamide were not detected, methyl ethyl ketone was 0.009%, and L-malic acid was 22.17%.

[0074] Preparation of cabozantinib malate

[0075] 1) Under the conditions of nitrogen protection and stirring, 100.00 g (0.20 mol, dry weight) of cabozantinib was added to a 3L three-necked flask containing 1.89 L of 2-butanone, and the temperature was raised to 70-78°C, and stirring was performed until dissolution to prepare a mixed solution;

[0076] 2) 200 ml of an aqueous 2-butanone solution containing 32.16 g (0.24 mol) of L-malic acid was added to the mixed solution prepared in step 1), and stirring was performed at 70-78°C for 1 h to prepare a mixed solution, wherein the volume ratio of 2-butanone to water in the aqueous 2-butanone solution was 1:1;

[0077] 3) 10 mL of a 2-butanone suspension containing 0.10 g (0.16 mmol) of cabozantinib malate N-2 crystal form was added to the mixed solution prepared in step 2) to prepare a mixed solution;

[0078] 4) The mixed solution prepared in step 3) is cooled to 20-30°C, and crystallization is carried out for 12 h.

[0079] 5) The crystallization solution prepared in step 4) is suction filtered, and the filter cake is washed with 300 mL of 2-butanone. The washed filter cake is vacuum dried at 45°C for 24 h at a vacuum degree of 0.1 MPa to obtain a solid 117.23 g, with a purity of 99.96%, no impurity D, impurity II d, impurity II b or other impurities detected, and no residual solvents of methanol, ethanol, acetonitrile, ethyl formate, dichloromethane, tetrahydrofuran, triethylamine, N,N-dimethylformamide, N,N-dimethylacetamide detected, 0.011% of methyl ethyl ketone, and 19.5% of L-malic acid.

[0080] Preparation of cabozantinib malate of Example 3

[0081] 1) Under nitrogen protection and stirring, 100.00 g (0.20 moL, dry weight) of cabozantinib is added to a 3L three-necked flask containing 2.50 L of 2-butanone, and the temperature is raised to 70-78°C, and stirring is carried out until dissolution to prepare a mixed solution;

[0082] 2) 150 ml of a 2-butanone aqueous solution containing 40.20 g (0.3 mol) of L-malic acid is added to the mixed solution prepared in step 1), and stirring is carried out at 70-78°C for 1 h to prepare a mixed solution, wherein the volume ratio of 2-butanone to water in the 2-butanone aqueous solution is 1:1;

[0083] 3) 30 mL of a 2-butanone suspension containing 0.20 g (0.32 mmol) of cabozantinib malate N-2 crystal form is added to the mixed solution prepared in step 2) to prepare a mixed solution;

[0084] 4) The mixed solution prepared in step 3) is cooled to 5-15°C, and crystallization is carried out for 18 h;

[0085] 5) The crystallization solution prepared in step 4) is suction filtered, and the filter cake is washed with 300 mL of 2-butanone. The washed filter cake is vacuum dried at 55°C for 24 h at a vacuum degree of 0.1 MPa to obtain a solid 116.35 g, with a purity of 99.96%, no impurity D, impurity II d, impurity II b or other impurities detected, and no residual solvents of methanol, ethanol, acetonitrile, ethyl formate, dichloromethane, tetrahydrofuran, triethylamine, N,N-dimethylformamide, N,N-dimethylacetamide detected, 0.011% of methyl ethyl ketone, and 19.5% of L-malic acid.

Claims

1. A method for preparing cabozantinib malate, comprising the following steps: 1) Add the required amount of 2-butanone to cabozantinib and stir at 70-78°C to obtain a mixed solution; 2) Add the 2-butanone aqueous solution of L-malic acid to the mixed solution obtained in step 1), stir, and obtain the reaction solution; 3) Add a 2-butanone suspension of cabozantinib malate seed crystals to the reaction solution obtained in step 2), stir, cool, crystallize, separate, and dry to obtain the product. The amount of cabozantinib malate seed crystals added is 0.5-3.0‰ of the weight of cabozantinib.

2. According to the preparation method of claim 1, the mass-to-volume ratio (g / ml) of cabozantinib to organic solvent in step 1) is 1:10-20.

3. According to the preparation method of claim 1, the molar ratio of cabozantinib to malic acid in step 2) is 1:1.0-1.

5.

4. According to the preparation method of claim 1, the mass-volume ratio (g / ml) of malic acid to organic solvent in step 2) is 1:2-8.

5. According to the preparation method of claim 1, the mass-volume ratio (g / ml) of malic acid to water in step 2) is 1:1-5.

6. According to the preparation method of claim 1, in step 3), cabozantinib malate seed crystals are dispersed in 2-butanone to prepare a suspension.

7. According to the preparation method of claim 6, the mass-to-volume ratio (g / ml) of cabozantinib malate seed crystals to 2-butanone in the cabozantinib malate seed suspension is 1:50-150.

8. The preparation method according to claim 1, wherein the cooling method is selected from any one or a combination of natural cooling and forced cooling.

9. The preparation method according to claim 8, wherein the forced cooling is achieved by using a cooling medium to force or program the cooling of the crystallization system.

10. The preparation method according to claim 9, wherein the cooling medium is selected from any one or a combination of water, ice-salt water, dry ice solvent or liquid nitrogen solvent.

11. The preparation method according to claim 9, wherein the crystallization temperature is 0-30℃.

12. The preparation method according to claim 1, wherein the crystallization method is selected from any one or a combination of static crystallization, stirring crystallization, or crystallization.

13. The preparation method according to claim 1, wherein the crystallization time is 10-20 h.

14. The preparation method according to claim 1, wherein the separation is selected from any one or a combination of centrifugation, filtration, membrane treatment.

15. According to the preparation method of claim 1, the separated and collected cabozantinib malate solid is washed and then dried to obtain the product.

16. The preparation method according to claim 15, wherein the washing solvent is selected from 2-butanone.

17. The preparation method according to claim 1, wherein the drying is selected from any one or a combination of vacuum drying, reduced pressure drying, atmospheric pressure drying, spray drying, and fluidized bed drying.

18. The preparation method according to claim 1, wherein the drying temperature is 40-60℃.

Images