Process for the purification of cabozantinib

Abstract

The present invention relates to a process for the purification of Cabozantinib in free base form.

Description

[0001] “PROCESS FOR THE PURIFICATION OF CABOZANTINIB”

[0002] ****

[0003] Summary of the invention

[0004] The present invention relates to a process for the purification of Cabozantinib in free base form.

[0005] Technical background

[0006] Cabozantinib is an anticancer drug used in the treatment of medullary thyroid cancer and renal cell or liver cell carcinoma. In particular, it acts by inhibiting specific receptors, and their kinase portion, linked to growth factors, such as, for example, VEGFR-2 (vascular endothelial growth factor receptor 2).

[0007] It has been approved by various regulatory agencies and is marketed under different names and formulations depending on the type of tumor they are targeted toward.

[0008] Its structure formula is the following Formula (I)

[0009] (i);

[0010] International common name: Cabozantinib; brute formula: C28H24FN3O5; CAS: 849217-68- 1.

[0011] Cabozantinib was first described and is the subject of Patent W02005030140 in the name of Exelixis, relating to a class of compounds that can modulate kinase receptor activity.

[0012] The purification of this product, upon completion of its synthesis in its free base form, can be carried out by some classical pathways that use different solvents in which making the recrystallization of the compound of interest to occur. Said solvents can be, for example but not limited to, mixtures of dimethyl sulfoxide (DMSO), acetonitrile and water, in different proportions, or else dioxane or a mixture of dichloromethane, methanol and hexane.

[0013] The purity of the free base of Cabozantinib obtained by these processes is around 95%, with yields ranging from 75 to 90%. Some impurities are therefore not removed, thus resulting in the product remaining out of specification with respect to the stringent requirements determined by its use in the pharmaceutical field. Furthermore, the known purification processes, carried out by solvent crystallization, are found to be poorly reproducible and therefore not at all reliable from the industrial point of view.

[0014] In document WO2018104954, regarding a new crystalline form of the Cabozantinib malate salt, the possibility of purifying also by salification the free base of Cabozantinib is hypothesized. The salts considered appropriate for this process are both inorganic salts and organic salts and are reported in a long list without any exemplification or experimental data about them.

[0015] Therefore, based on the state of the art, it can be stated that there is still a need to provide alternative purification pathways for Cabozantinib that are industrially applicable and can give a highly pure product in free base form with high yields, low cost, and that is easy to implement.

[0016] Aims of the invention

[0017] An aim of the present invention is to provide an alternative purification pathway to those known, for obtaining Cabozantinib in free base form, that enables the isolation with high yields of a product with a high purity degree that complies with the regulations on the pharmaceutical active ingredients.

[0018] These and other aims will be set forth in the following description relating to an alternative purification pathway for the free base of Cabozantinib.

[0019] Description of the invention

[0020] Object of the present invention is a process for the purification of the compound Cabozantinib, directly resulting from its synthesis process, of Formula (I) comprising the following steps: i) dissolving Cabozantinib, directly resulting from its synthesis process, of Formula (I) in at least one organic solvent; ii) adding an organic acid selected from maleic acid of Formula (II) (CAS: 110-16-7) and fumaric acid of Formula (III) (CAS: 110-17-8) iii) precipitating Cabozantinib in salt form, maleate salt or fumarate salt, respectively, by addition of water, preferably double-distilled water, and separating the wet solid precipitate, preferably by filtration; iv) re-suspending Cabozantinib in salt form, obtained in step (iii), in at least one organic solvent and adding an aqueous solution of an inorganic base to let the de-salting process take place and obtaining Cabozantinib of Formula (I) in purified free base form; v) separating, from the suspension of step (iv), the solid Cabozantinib of Formula (I) in purified free base form, preferably by filtration; vi) optionally washing with water, preferably double-distilled water.

[0021] In other words, object of the present invention is a process for the purification of the compound Cabozantinib, directly resulting from its synthesis process, of Formula (I) comprising, after dissolution of the starting Cabozantinib, a first salification step and a second de-salification step, and which uses, as the acid compound for the first salification step, an organic acid selected from maleic acid of Formula (II) (CAS: 110-16-7) and fumaric acid of Formula (III) (CAS: 110-17-8) According to the present invention, when referring to Cabozantinib ’’directly resulting from its synthesis process”, it is intended what, in chemical jargon, is referred to as "reaction crude", i.e., the product obtained from the organic synthesis with its impurities resulting from the solvents and reagents used, as well as by the reaction byproducts. In particular, with regard to the specific product of Formula (I), Cabozantinib reaction crude, resulting from any synthetic route known to the skilled in the art, contains varying amounts of impurities with values ranging from 2 to 3% (purity of the crude product from 97% to 98%). Some of the known impurities that are found in the Cabozantinib reaction crude product are synthesis intermediates and process impurities; for example, but not limited to: (6,7-dimethoxy-4-(4- nitrophenoxy) quinoline); 4-(6,7-dimethoxy-quinoline-4-yloxy) phenylamine); (l-[(4- fluorophenyl) carbamoxyl] cyclopropane) carboxylic acid; (l,l-N,N'-[4-( 4-fluorophenyl)]- 1 -cyclopropane- 1 , 1 -dicarboxy amide).

[0022] According to a preferred aspect of the present invention, the at least one organic solvent, in which Cabozantinib in step (i) is brought into solution, is a mixture of DMSO and acetonitrile. Preferably, in said mixture, DMSO and acetonitrile are in a 1 :2 v / v ratio with each other. According to a preferred aspect of the present invention, the concentration of Cabozantinib inside the solution of step (i) ranges from 0. IM to 0.2M, preferably it is 0.13M. Preferably, according to the invention, once Cabozantinib has been dissolved in an appropriate organic solvent in step (i), preferably a DMSO and acetonitrile mixture, an organic acid selected from maleic acid and fumaric acid is added in step (ii) in an amount of 1.0 equivalents to 1.3 equivalents, preferably in an amount of 1.19 to 1.21 equivalents.

[0023] According to a preferred aspect, in case the organic acid is maleic acid, it is added solid together with the Cabozantinib reaction crude in step (i) and the solubilization of the two compounds in the organic solvent, preferably in the DMSO and acetonitrile mixture, occurs simultaneously. In case the organic acid is fumaric acid, the addition to the organic solution is done after complete solubilization of the Cabozantinib reaction crude, i.e., at the end of step (i).

[0024] Next, in step (iii), water, preferably double-distilled water, is dripped in order to maintain a temperature from 20°C to 25°C inside the reaction solution. The addition of water leads to precipitation of Cabozantinib maleate or fumarate, i.e., the salified form of Cabozantinib with maleic acid or fumaric acid, respectively, depending on the acid used in step (ii). According to a preferred embodiment of the invention, in step (iii) an amount of water is added in a range of 1 to 3 times (volume / volume) to the amount of organic solvent, preferably an amount of 2 times (volume / volume) to the organic solvent.

[0025] Surprisingly, the precipitation of Cabozantinib in the form of maleate or fumarate salt, which takes place in step (iii) according to the purification process of the present invention, turns out to be selective toward the compound Cabozantinib of Formula (I) only, whereas the impurities resulting from its synthesis process are not salified and thus remain in the organic mother liquors.

[0026] Cabozantinib maleate or fumarate salt according to step (iii) of the purification process of the present invention is recovered by a simple vacuum filtration step, for example, by passing the suspension of step (iii) through an appropriate filter system known to the skilled in the art and sized to the equipment and the amount of product obtained, for example, but not limited to, a cellulose filter or a polypropylene fabric filter. The wet solid thus recovered, also named "cake" or "panel," is pressed so as to eliminate the presence of liquid as much as possible and, without further purification steps, undergoes the basic de-salting treatment of step (iv).

[0027] Preferably, said de-salting step, step (iv), occurs in-situ directly by a basic treatment on the wet solid precipitate obtained by filtration (wet de-salting).

[0028] According to a particularly preferred aspect of the invention, said basic treatment of step (iv) consists of re-suspension of the Cabozantinib salt, obtained after filtration in step (iii), in at least one organic solvent, preferably in a mixture of DMSO and acetonitrile, and pf the subsequent addition of an aqueous solution of an inorganic base, preferably a weak base, for example a < 5% weight / volume Na2CCh, NaHCOs or K2CO3 aqueous solution, even more preferably is a 5% weight / volume NaHCOs aqueous solution. Said aqueous solution is added in an amount of 3.0 v / v to 6.0 v / v to the organic solvent used, preferably in an amount of 4.0 v / v to 5.0 v / v to the organic solvent.

[0029] Preferably, once the solid free base of Cabozantinib is obtained again in step (iv), we proceed to its separation by filtration (step (v)). Preferably, a final washing with water (step (vi)), preferably double-distilled water, is carried out, even more preferably said washing with double-distilled water is carried out at a temperature of 40°C to 45°C.

[0030] As will be demonstrated in the experimental section that follows, the purification process of the free base of Cabozantinib according to the present invention from its reaction crude, enables yielding a final product with a purity degree higher than 99%, preferably with a purity degree higher than 99.8%, even more preferably higher than 99.9%.

[0031] Compared with the known technique, the process for the purification of Cabozantinib object of the present invention has some advantages.

[0032] In particular, based on the data previously reported, the first advantage of the present invention over other known state-of-the-art purification techniques is immediately apparent. In fact, the latter, as previously referred, enable to obtain the free base of Cabozantinib characterized by a purity degree ranging at about 97%, which is not directly usable in final pharmaceutical applications. In contrast, the process of the present invention allows purity degrees even higher than 99%, such as 99.8-99.9%, to be achieved.

[0033] An additional advantage of the purification process according to the present invention, as demonstrated by the experimental section below, is determined by the high yield of the process, which is around 80% when going through the formation of Cabozantinib fumarate salt whereas it turns out to be more than 90% in the case of using maleic acid for the salification step.

[0034] The purity degree of the final product achieved thanks to the use of the purification process according to the present invention is higher than both that normally obtained by classical purification techniques (extraction / precipitation in solvent) and that which can be obtained through a salification step with a salt other than the preferred ones according to the invention (i.e., maleic acid and fumaric acid). These observations are also confirmed when looking at data on the yield of "classical" purification processes or those employing other salts, as demonstrated by the example relating to purification processes not according to the present invention.

[0035] The invention will be now described in detail by the following examples, by way of illustration and in no way limiting.

[0036] Description of the figures

[0037] Figure 1: ’H-NMR spectrum of free base of Cabozantinib obtained after the purification according to the present invention, Example 1 (instrument: Bruker DRX Advance 400), 400 MHz in CDCh-dl solution.

[0038] Experimental section

[0039] Example 1 : Purification process according to the present invention (maleate salt)

[0040] In a three-necked flask, crude Cabozantinib resulting from the synthesis (crude CBZ, 10 g, 19.95 mmol), maleic acid (2.8 g, 24.12 mmol), DMSO (50 ml, 55 g) and acetonitrile (100 ml, 78.6 g) are loaded, in that order. The mixture is left under stirring at a temperature of 20°C to 25°C for 15-20 minutes, or otherwise until the product is completely solubilized. A solution with a pale yellow / brown color is obtained and left under stirring at a temperature of 20°C to 25°C for 2-3 hours.

[0041] Next, double-distilled water (300 ml) is dripped in a time between 1 and 2 hours so as to maintain a temperature of 20°C to 25°C; if necessary, the dripping time can be lengthened; the reaction is slightly exothermic. Once dripping the double-distilled water is completed, the mixture is left under stirring at a temperature of 20°C to 25°C for 2-3 hours.

[0042] It is vacuum filtered on Buchner with a cellulose filter and the resulting solid is washed with double-distilled water (60 ml) at the end of the filtration process, by pressing it to remove most of the liquid.

[0043] The wet solid is then placed in a flask and DMSO (28 ml, 30.8 g) and acetonitrile (39 ml, 30.7 g) are loaded. The suspension is vigorously stirred and, if necessary, brought to a temperature of 20-25°C. A 5% sodium bicarbonate solution [previously prepared by solubilizing 15 g sodium bicarbonate in 300 ml double-distilled water] is added at a time interval of about 30-70 minutes, at successive aliquots or by dripping. After the addition of the aqueous basic solution is completed, the mixture is left under vigorous stirring at a temperature of 20°C to 25°C, for 18-24 hours. Next, it is vacuum filtered by using a cellulose filter and the resulting solid is washed first with a 5% bicarbonate solution [previously prepared by solubilizing 2 g sodium bicarbonate in 40 ml double-distilled water] and then with double-distilled water only (40 ml), pressing it at the end to remove most of the liquid. The wet solid product thus obtained is loaded into a flask and double-distilled water (300 ml) is added. The mixture is left under vigorous stirring at a temperature of 40°C to 45°C for 3-4 hours. It is vacuum filtered by using a cellulose filter and the resulting solid is washed with double-distilled water (40 ml twice), by pressing it to remove most of the liquid.

[0044] The solid product obtained (free base of Cabozantinib) is dried under vacuum at a temperature of 60°C. Yield: 9.3 g (average 93%; yield range: 88.4^-97.7%).

[0045] The sample was subjected to the following analyses:

[0046] ’H-NMR spectrography (instrument: Bruker DRX Advance 400), 400 MHz in CDCh-dl solution; spectrum depicted in Figure 1; water content, always less than 8%;

[0047] UHPLC (instrument: Waters Acquity Arc) that records a final product purity of 99.9%.

[0048] Example 2: Purification process according to the present invention (fumarate salt)

[0049] In a three-necked flask, crude Cabozantinib resulting from the synthesis (crude CBZ, 10 g, 19.95 mmol), DMSO (50 ml, 55 g) and acetonitrile (100 ml, 78.6 g) are loaded, in that order. Fumaric acid (2.77 g, 23.9 mmol) is added and the mixture is left under stirring at a temperature of 20°C to 25°C for 2-3 hours.

[0050] It is vacuum filtered on Buchner with a cellulose filter and the resulting solid is washed with acetonitrile pre-cooled to a temperature of 0°C to 5°C (10 ml, 7.9 g).

[0051] The wet solid is then placed in a flask and DMSO (28 ml, 30.8 g) and acetonitrile (39 ml, 30.7 g) are loaded. The suspension is vigorously stirred and, if necessary, brought to a temperature of 20-25°C. A 5% sodium bicarbonate solution [previously prepared by solubilizing 15 g sodium bicarbonate in 300 ml double-distilled water] is added at a time interval of about 30-70 minutes, at successive aliquots or by dripping. After the addition of the aqueous basic solution is completed, the mixture is left under vigorous stirring at a temperature of 20°C to 25°C, for 15-24 hours. Next, it is vacuum filtered by using a cellulose filter and the resulting solid is washed first with a 5% bicarbonate solution [previously prepared by solubilizing 2 g sodium bicarbonate in 40 ml double-distilled water] and then with double-distilled water only (40 ml), pressing it at the end to remove most of the liquid. The wet product is loaded into a flask and double-distilled water (300 ml) is added. The mixture is left under vigorous stirring at a temperature of 40°C to 45°C for 3-4 hours. It is vacuum filtered by using a cellulose filter and the resulting solid is washed with doubledistilled water (40 ml twice), by pressing it to remove most of the liquid.

[0052] The solid product obtained (free base of Cabozantinib) is dried under vacuum at a temperature of 60°C. Yield: 7.9 g (79%).

[0053] The sample was subjected to the analysis performed in Example 1, and the purity, measured by UHPLC, was found to be 99.9% also in this case.

[0054] Example 3: Purification process not according to the present invention (phosphate salt)

[0055] In a three-necked flask, crude Cabozantinib resulting from the synthesis (crude CBZ, 10 g, 19.95 mmol), DMSO (50 ml, 55 g) and acetonitrile (100 ml, 78.6 g) are loaded, in that order. The mixture is left under stirring at a temperature of 20°C to 25°C until the starting product is completely solubilized.

[0056] A solution of 85% phosphoric acid [previously prepared by dispersing 2.2 ml (3.7 g) phosphoric acid in 15 ml acetonitrile (11.8 g)] is dripped into the reaction mixture in a time of 10-20 minutes. The mixture is left under stirring for 2-3 hours at a temperature of 20- 25°C. It is vacuum filtered on Buchner by using a cellulose filter and the resulting solid is washed with acetonitrile pre-cooled to a temperature of 0°C to 5°C (20 ml, 15.7 g), by pressing it to remove most of the liquid. The wet solid is then placed in a flask and DMSO (28 ml, 30.8 g) and acetonitrile (39 ml, 30.7 g) are loaded. The suspension is vigorously stirred and, if necessary, brought to a temperature of 20-25°C. A 5% sodium bicarbonate solution [previously prepared by solubilizing 8.35 g sodium bicarbonate in 167 ml double-distilled water] is added at a time interval of about 30-70 minutes, at successive aliquots or by dripping. After the addition of the aqueous basic solution is completed, the mixture is left under vigorous stirring at a temperature of 20°C to 25°C, for 1-2 hours. Next, it is vacuum filtered with a cellulose filter and the resulting solid is washed first with a 5% bicarbonate solution [previously prepared by solubilizing 1.5 g sodium bicarbonate in 30 ml double-distilled water] and then with double-distilled water only (30 ml), by pressing it to remove most of the liquid.

[0057] The solid product obtained (free base of Cabozantinib) is dried under vacuum at a temperature of 50°C. Yield: 8.8 g (88%). The purity measured by UHPLC was found to be: 99.5%. In particular, some specific impurities remain clearly detectable, that maintain a size of the peak area similar to that of the product prior to purification.

[0058] Example 4: Purification process not according to the present invention (hydrochloride salt) In a three-necked flask, crude Cabozantinib resulting from the synthesis (crude CBZ, 10 g, 19.95 mmol), DMSO (50 ml, 55 g) and acetonitrile (100 ml, 78.6 g) are loaded, in that order. The mixture is left under stirring at a temperature of 20°C to 25°C until the starting product is completely solubilized.

[0059] A diluted hydrochloric acid solution [previously prepared by dispersing 3 ml (3.6 g) of 37% hydrochloric acid in 20 ml double-distilled water] is dripped into the reaction mixture in a time of 10-20 minutes. The mixture is left under stirring for 1-2 hours at a temperature of 20-25°C. Next, 100 ml double-distilled water is dripped and after dripping is completed, the mixture is left under agitation for 1-2 hours. It is vacuum filtered on Buchner by using a cellulose filter and the resulting solid is washed with double-distilled water (70 ml), by pressing it to remove most of the liquid.

[0060] The wet solid is then placed in a flask and DMSO (28 ml, 30.8 g) and acetonitrile (39 ml, 30.7 g) are loaded. The suspension is put under vigorous stirring and, if necessary, is brought to a temperature of 20-25°C. A 5% sodium bicarbonate solution [previously prepared by solubilizing 8.35 g sodium bicarbonate in 167 ml double-distilled water] is added at a time interval of about 30-70 minutes, at successive aliquots or by dripping. After the addition of the aqueous basic solution is completed, the mixture is left under vigorous stirring at a temperature of 20°C to 25°C, for 1-2 hours. Next, it is vacuum filtered by using a cellulose filter and the resulting solid is washed first with a 5% bicarbonate solution [previously prepared by solubilizing 1.5 g sodium bicarbonate in 30 ml double-distilled water] and then with double-distilled water only (30 ml), by pressing it to remove most of the liquid.

[0061] The solid product obtained (free base of Cabozantinib) is dried under vacuum at a temperature of 50°C. Yield: 7.8 g (78%). The purity measured by UHPLC was found to be:

[0062] 99.7%. In particular, some specific impurities remain clearly detectable, that maintain a size of the peak area similar to that of the product prior to purification.

[0063] Conclusions

[0064] As can be highlighted from the comparison of the results obtained from the processs not according to the present invention in Examples 3 and 4 with those according to the present invention in Examples 1 and 2, the use of acids other than the maleic and fumaric acids for the salification step of Cabozantinib cannot bring to the desired results, especially with regard to the purity degree, which never succeeds in achieving the desired values. In particular, it was noted that some specific impurities are left, that cannot be effectively reduced / eliminated.

Claims

Claims1. A process for the purification of the compound Cabozantinib, directly resulting from its synthesis process, of Formula (I)comprising the following steps: i) dissolving Cabozantinib, directly resulting from its synthesis process, of Formula (I) in at least one organic solvent; ii) adding an organic acid selected from maleic acid of Formula (II) (CAS: 110-16-7) and fumaric acid of Formula (III) (CAS: 110-17-8)(ill); iii) precipitating Cabozantinib in salt form, maleate salt or fumarate salt, respectively, by addition of water, preferably double-distilled water, and separating the wet solid precipitate, preferably by filtration; iv) re-suspending Cabozantinib in salt form, obtained in step (iii), in at least one organic solvent and adding an aqueous solution of an inorganic base to let the de-salting process take place and obtaining Cabozantinib of Formula (I) in purified free base form; v) separating, from the suspension of step (iv), the solid Cabozantinib of Formula (I) in purified free base form, preferably by filtration; vi) optionally washing with water, preferably double-distilled water.

2. The process according to claim 1, characterized in that said at least one organic solvent of step (i) is a mixture of DMSO and acetonitrile, preferably a mixture of DMSO and acetonitrile in a 1 :2 ratio.

3. The process according to claim 1 or 2, characterized in that said organic acid selected frommaleic acid and fumaric acid of step (ii) is added to the solution of step (i) in an amount of 1.0 to 1.3 equivalents.

4. The process according to any one of claims 1 to 3, characterized in that said water, preferably double-distilled water, added in step (iii) is added in an amount in the range of 1 to 3 times (volume / volume) to the amount of organic solvent of step (i), preferably in an amount of 2 times (volume / volume) to amount of organic solvent of step (i).

5. The process according to any one of claims 1 to 4, characterized in that said at least one organic solvent of step (iv) is a mixture of DMSO and acetonitrile.

6. The process according to any one of claims 1 to 5, characterized in that said aqueous solution of an inorganic base of step (iv) is a 5% weight / volume NaHCOs solution.

7. The process according to claim 6, characterized in that said 5% weight / volume NaHCOs solution of step (iv) is added in an amount of 3.0 v / v to 6.0 v / v to said at least one organic solvent of step (iv).

8. The process according to any one of claims 1 to 7, characterized in that said organic solvent of step (v) is DMSO.

9. Cabozantinib of Formula (I) with a purity degree greater than or equal to 99.8%, obtained by the purification process according to any one of claims 1-8.