EP2350056A1

EP2350056A1 - Process for preparing a 3-pyrrole subsituted 2-indolinone malate salt

Info

Publication number: EP2350056A1
Application number: EP09748141A
Authority: EP
Inventors: Bernardino Mangion
Original assignee: Medichem SA
Current assignee: Medichem SA
Priority date: 2008-10-10
Filing date: 2009-10-09
Publication date: 2011-08-03
Also published as: AR073807A1; WO2010041134A1; CN102177155A

Abstract

Disclosed is a process for preparing the malic acid salt of sunitinib comprising reacting malic acid with an acid addition salt of sunitinib, which is a cancer treatment agent, wherein the acid addition salt of sunitinib is an acid weaker than malic acid. Also disclosed are acid addition salts of sunitinib wherein the acid is an acid weaker than malic acid.

Description

PROCESS FOR PREPARING A 3-PYRROLE SUBSTITUTED 2-INDOLINONE

MALATE SALT

CROSS-REFERENCE TO A RELATED APPLICATION

[0001] This patent application claims the benefit of U.S. Provisional Patent Application No. 61/104,344, filed October 10, 2008, the disclosure of which is incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] Sunitinib (Compound I) is the international commonly accepted name for N- [2- (diethylamino)ethyl]-5-[(Z)-(5-fluoro-l,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4- dimethyl-lH-pyrrole-3-carboxamide, and has an empirical formula Of C₂₂H₂₇FN₄O₂, and a molecular weight of 398.47 g/mol. Sunitinib is an active pharmaceutical substance indicated for the treatment of abnormal cell growth, such as cancer, in mammals, particularly in humans.

(Compound I)

[0003] The malic acid salt of sunitinib has been selected for medical purpose and is commercially marketed under the trade name of SUTENT™ for the treatment of renal cell carcinoma and gastrointestinal stromal tumor.

[0004] Sunitinib base and its malate salt are described in U.S. Patent No. 6,573,293 ("the '293 patent"), which is incorporated herein by reference. In particular, Example 80 of the '293 patent describes the preparation of sunitinib base via condensation of N- [2- (diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxamide (compound II), and 5-fluoro-l,3-dihydro-2/f-indol-2-one (compound III) in the presence of ethanol as a solvent, as depicted herein in Scheme 1. According to the '293 patent, the sunitinib base obtained is filtered under vacuum, washed with ethanol, and subsequently dried under vacuum at 54 ⁰C for 130 hours.

Scheme 1

[0005] Example 1 of U.S. Patent Application No. 20070191458A1 ("the '458 publication") describes the preparation of sunitinib malate by reacting sunitinib base with malic acid in the presence of methanol as a solvent. However, no information about the preparation and isolation of the sunitinib base is provided. The '458 publication is incorporated herein by reference.

[0006] Applicants have observed that the purification and isolation of solid sunitinib base is troublesome. For example, solid sunitinib base is difficult to handle since it is a very fine powder which is difficult to filter and isolate. Accordingly, the processing of solid sunitinib base is not desirable for the preparation of sunitinib malate, especially for industrial scale-up. [0007] Thus, there is a need for providing new processes for preparing the malic acid salt of sunitinib which do not require the processing of solid sunitinib base, and which are suitable for industrial implementation.

BRIEF SUMMARY OF THE INVENTION

[0008] The invention provides a process for preparing the malic acid salt of sunitinib comprising first forming an acid addition salt of sunitinib with an acid weaker than malic acid and then reacting the weaker acid addition salt with malic acid. The invention also provides acid addition salts of sunitinib comprising an acid weaker than malic acid.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 is an infrared spectrum of the acetic acid salt of sunitinib. [0010] Figure 2 is an infrared spectrum of the malic acid salt of sunitinib. DETAILED DESCRIPTION OF THE INVENTION

[0011] Applicants have observed that acid addition salts of sunitinib wherein said salts are the salt of an acid weaker than malic acid, can be used for preparing the malic acid salt of sunitinib as an alternative to the processing of sunitinib base. For example, applicants have observed that the acetic acid salt of sunitinib (i.e., sunitinib acetate) can be used successfully for the direct preparation of sunitinib malate by means of treatment with an amount of malic acid sufficient to convert said acetic acid salt to said malic acid salt. Since the acetic acid salt of sunitinib can be prepared easily and rapidly from sunitinib base into the crude reaction solution, the isolation and processing of solid sunitinib base is avoided. Further, sunitinib acetate is a salt-type solid which crystallizes into the organic solvent of the reaction (e.g. n- butanol) and which hence is simple to filter and isolate, introducing thus an additional purification step. Therefore, processes of the invention avoid the isolation and processing of solid sunitinib base, and hence overcome the drawbacks associated with the difficult handling of said sunitinib base. Further, processes of the invention introduce an additional purification step, and so provide the malic acid salt of sunitinib with high purity and high yield. Consequently, processes of the invention are cost-effective and suitable for industrial implementation.

[0012] In an embodiment, the present invention provides a process for preparing the malic acid salt of sunitinib (malic acid salt of compound of Formula I),

said process comprising: (i) providing a solution comprising an acid addition salt of sunitinib in an organic solvent, wherein said salt is the salt of an acid weaker than malic acid; (ii) treating said solution of an acid addition salt of sunitinib with malic acid, to obtain a mixture comprising sunitinib malate; (iii) isolating sunitinib malate from the mixture; and (iv) optionally, purifying said sunitinib malate. "Treating" in step (ii) includes contacting or reacting. The treating can be in any suitable order, i.e., the malic acid can be added to the solution of sunitinib salt or the solution of sunitinib salt can be added to malic acid, as desired. [0013] The organic solvent in accordance with processes of the invention preferably comprises at least one C₁-C₅ alcohol solvent, and more preferably comprises at least n- butanol.

[0014] The malic acid salt of compound (I) obtained according to an embodiment process of the invention has a purity higher than 99.7% as measured by HPLC. [0015] In another embodiment, the invention provides an acid addition salt of sunitinib, wherein said salt is the salt of an acid weaker than malic acid. Preferably, the acid addition salt of the invention is the acetic acid salt of sunitinib (acetic acid salt of compound of formula I). The acid addition salt of sunitinib is a salt other than sunitinib malate. [0016] In another embodiment, the present invention provides a process for preparing an acid addition salt of sunitinib of the invention, said process comprising: (i) providing a solution of sunitinib base in an organic solvent; (ii) treating said solution of sunitinib base with an acid weaker than malic acid, to obtain a mixture comprising the acid addition salt of sunitinib; (iii) optionally, isolating the acid addition salt of sunitinib from the mixture; and (iv) optionally, purifying said acid addition salt of sunitinib. Treating in step (ii) includes contacting or reacting. The treating can be in any suitable order, i.e., the solution of sunitinib base can be added to the weak acid or the weak acid can be added to the sunitinib base solution, as desired.

[0017] For a quick and cost-effective process it is preferable that the crude reaction solution obtained after synthesizing sunitinib base is used directly in step (i) of the process of the invention above. In other words, the acid addition salt of sunitinib of the invention can be prepared easily and rapidly in situ from the crude reaction solution containing the sunitinib base, thereby avoiding the isolation of the sunitinib base. In addition, the synthesis of sunitinib base can be carried out according to any of the methods known in the art. For example, the sunitinib base can be synthesized by reacting JV-[2-(diethylamino)ethyl]-5- formyl-2,4-dimethyl-lH-pyrrole-3-carboxamide (compound II) with 5-fluoro-l,3-dihydro- 2//-indol-2-one (compound III) in an organic solvent.

[0018] The acid weaker than malic acid is preferably an organic acid capable of forming a salt with sunitinib having a pKa greater than the pKa of malic acid, that is, having a pKa greater than 3.40 OpKa₁). For example, the acid weaker than malic acid has a pKa of from about 3.5 to about 6.5, or from about 4 to about 6, or from about 4 to about 5. For example, the pKa of acetic acid is about 4.76. Illustrative organic acids suitable for use in the practice of the invention include acetic acid (pKa about 4.76), formic acid (pKa about 3.75), propanoic acid (pKa about 4.86), 3-hydroxypropanoic acid (pKa about 4.51), succinic acid (pKa about 4.16), butanoic acid (pKa about 4.83), 2 methylpropanoic or isobutyric acid (pKa about 4.88), 3-hydroxybutanoic acid (pKa about 4.70), 4-hydroxybutanoic acid (pKa about 4.72), uric acid (pKa about 3.89), glutaric acid (pKa about 4.31), methylsuccinic acid (pKa about 4.13), pentanoic acid (pKa about 4.84), trimethylacetic acid (pKa about 5.03), ascorbic acid (pKa about 4.10), hexanoic or caproic acid (pKa about 4.85), 4-methylpentanoic acid (pKa about 4.84), benzoic acid (pKa about 4.19), m-hydroxybenzoic acid (pKa about 4.06), p-hydroxybenzoic acid (pKa about 4.48), cyclohexanecarboxylic acid (pKa about 4.90), phenylacetic acid (pKa about 4.28), cis cinnamic acid (pKa about 3.89), trøTK-cinnamic acid (pKa about 4.44), hippuric acid (pKa about 3.55), D-gluconic acid (pKa about 3.76), DL- lactic acid (pKa about 3.86), oleic acid (pKa about 4), 4-acetamidobenzoic acid (pKa about 4.3), adipic acid (pKa about 4.44), sebacic acid (pKa about 4.59), (+)-camphoric acid (pKa about 4.72), nicotinic acid (pKa about 4.85), capric or decanoic acid (pKa about 4.9), lauric acid (pKa about 4.9), palmitic acid (pKa about 4.9), stearic acid (pKa about 4.9), undecylenic acid (pKa about 4.9), caprylic or octanoic acid (pKa about 4.91), orotic acid (pKa about 5.85), and carbonic acid (pka about 6.46), more preferably is acetic acid. [0019] In acids having more than one acid function, e.g., dicarboxylic acids and higher carboxylic acids, which have more than one pKa value, preferably all pKa values are greater than 3.40.

[0020] In preferred embodiments, the acid weaker than malic acid of step (ii) of the process of the invention is acetic acid.

[0021] The solvent of the process above preferably comprises at least one C₁-C₅ alcohol solvent, and more preferably comprises at least π-butanol.

[0022] Isolating the acid addition salt of sunitinib from the mixture of step (iii) of the invention preferably comprises: (i) precipitating said acid addition salt of sunitinib from the mixture thereby obtaining a suspension of said acid addition salt of sunitinib in an organic solvent; and (ii) filtering the suspension.

[0023] In yet another embodiment, the present invention provides a process for preparing the malic acid salt of sunitinib (malic acid salt of compound of Formula I), said process comprising reacting the acid addition salt of sunitinib of the invention with malic acid. [0024] In still yet another embodiment, the present invention relates to the use of the acid addition salt of sunitinib of the invention for preparing the malic acid salt of sunitinib. EXAMPLES

[0025] Fourier transform IR (FTIR) spectra were acquired on a Shimadzu FT-IR 8400S spectrophotometer as KBr discs.

[0026] Differential scanning calorimetry (DSC) measurements were performed in a vented pan at a scan rate of 10 °C/minute from 25 °C to 270 °C under a nitrogen purge using a Mettler-Toledo DSC823.

[0027] High performance liquid chromatography (HPLC) analyses were conducted using a Shimadzu Prominence LC-20 system with the following parameters: column: XTerra MS C18, 5 μm, 4.6 x 150 mm; flow rate: 1 niL/min; detector: UV monitoring 265 nni; mobile phase A: 99.8:0.2 10 mM ammonium bicarbonate, pH 7.5 : triethylamine; mobile phase B: acetonitrile; gradient: 85% A (0 min) - 85% A (6 min) - 70% A (21 min) - 70% A (50 min) - 85% A (55 min) - 85% A (65 min); temperature: ambient; sample: 1.5 mg / mL in 25:75 mobile phase A : mobile phase B; injection volume: 10 μL.

EXAMPLE 1

[0028] This example illustrates a process for preparing the acetic acid salt of sunitinib (acetic acid salt of compound of Formula I) without isolating sunitinib base in accordance with an embodiment of the invention.

[0029] 12.02 g of iV-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3- carboxamide (compound of Formula II), 6.84 g of 5-fluoro-l,3-dihydro-2H-indol-2-one (compound of Formula III) and 230 mL of «-butanol were stirred at room temperature. Pyrrolidine (187 μL) was added and the suspension was heated to reflux. Complete dissolution of the materials was observed at 45 °C. Once at reflux the reaction was monitored by TLC and after 1.5 h the formation of sunitinib base was complete. To the clear red reaction mixture a solution of 3.10 mL glacial acetic acid and 10 mL π-butanol was added dropwise, while maintaining the mixture at reflux. The red clear solution was stirred for 30 minutes at reflux and cooled. At 41 °C crystallization was observed and the mixture was cooled to 0-5 ⁰C and stirred for Ih. The mixture was heated again to dissolution, which took place at 93 °C, and then cooled. Crystallization was observed at 72°C. The mixture was cooled to room temperature and stirred for 15 minutes. The thick orange suspension was filtered and the collected solid was washed with 2 x 24 mL of n-butanol. The solid was dried at 60 ⁰C for 4 h under vacuum to give 15.64 g (75.3 % yield) of a light orange solid. [0030] Analytical data: IR (KBr): Characteristic peaks at (cm^"1): 3452, 3169, 3045, 2991, 2978, 2874, 2810, 2768, 2706, 2100, 1672, 1651, 1620, 1614, 1589, 1576, 1539, 1495, 1477, 1446, 1402, 1396, 1377, 1340, 1325, 1300, 1290, 1279, 1257, 1230, 1196, 1165, 1144, 1115, 1099, 1059, 1040, 1024, 1007, 987, 972, 924, 914, 903, 883, 845, 837, 797, 750, 723, 698, 669, 658, 617, 588, 579, 534, 486, 440, 411. See Figure 1; HPLC: 99.44 % (% area); DSC (openpan) onset: 132.4 °C.

EXAMPLE 2

[0031] This example illustrates a process for preparing the acetic acid salt of sunitinib (acetic acid salt of compound of Formula I) in accordance with an embodiment of the invention.

[0032] 2.04 g of sunitinib base and 15 mL of «-butanol were heated to reflux. At 111 °C a clear red solution was obtained and a solution of 322 μL of glacial acetic acid and 4 mL ra-butanol was added dropwise, maintaining the temperature. Once the addition was complete the solution was stirred for 30 min at 111 ⁰C and cooled to 0-5 ⁰C. Crystallization was observed at 67 ⁰C. The orange suspension was stirred for Ih at 0-5 ⁰C, filtered and the collected solid was washed with 8 mL of n-butanol and dried at 60 °C for 4 h under vacuum to give 2.08 g (88.5 % yield) of a light orange solid.

[0033] Analytical data: IR (KBr): Essentially identical to the IR spectrum shown in Figure 1; HPLC: 99.72 % (% area); DSC (open pan) onset: 132.4 °C.

EXAMPLE 3

[0034] This example illustrates a process for preparing the malic acid salt of sunitinib (malic acid salt of compound of Formula I) from the acetic acid salt of sunitinib in accordance with an embodiment of the invention.

[0035] 4.00 g of sunitinib acetate (prepared as described in Example 1) and 40 mL n-butanol were heated to reflux. At 109 °C a clear red solution was obtained. Once the mixture was at reflux, a solution of 1.29 g L-(-)-malic acid and 6 mL ra-butanol was added dropwise, maintaining the temperature. During the addition an orange solid started to crystallize. The mixture was stirred for 30 minutes at reflux during which time a suspension was obtained. This was cooled to 0-5 °C and stirred for 1 h. The orange suspension was filtered, the collected solid was washed with 2 x 8 mL of rø-butanol and dried at 60 °C for 4 h under vacuum to give 4.45 g (95.7 % yield) of a light orange solid. [0036] 3.51 g of the dry solid obtained above and 17.5 mL of distilled water were heated to dissolution. At 75 ⁰C a clear red solution was obtained. The solution was filtered to remove insoluble particles and the filter was washed with 2.5 mL of water. The filtrate was heated to 75 °C and 26.25 mL 2-propanol were added dropwise, maintaining the temperature of the mixture. Once the addition was complete, the mixture was cooled to room temperature and stirred for 1 h. Crystallization was observed at 30 °C. The orange suspension was cooled to 0-5 °C, stirred for 1 h and filtered. The collected solid was washed with 2 x 7 mL of 2-propanol, and dried at 60 ⁰C for 4 h under vacuum to give 3.31 g (94.3 % yield) of a orange solid.

[0037] Analytical data: Overall yield: 90.24 %; IR (KBr): See Figure 2; HPLC: 99.78 % (% area); Melting range: 188.2 - 189.1 ⁰C.

[0038] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0039] The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0040] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIMS:

1. A process for preparing the malic acid salt of sunitinib of Formula (I):

said process comprising:

(i) providing a solution comprising an acid addition salt of sunitinib in an organic solvent, wherein said salt is the salt of an acid weaker than malic acid;

(ii) treating said solution with malic acid, to obtain a mixture comprising sunitinib malate;

(iii) isolating sunitinib malate from the mixture; and

(iv) optionally, purifying said sunitinib malate.

2. The process of claim 1 , wherein the acid weaker than malic acid is selected from the group consisting of acetic acid, formic acid, propanoic acid, 3-hydroxypropanoic acid, succinic acid, butanoic acid, 2-methylpropanoic acid, 3-hydroxybutanoic acid, 4- hydroxybutanoic acid, uric acid, glutaric acid, methylsuccinic acid, pentanoic acid, trimethylacetic acid, ascorbic acid, hexanoic acid, 4-methylpentanoic acid, benzoic acid, m- hydroxybenzoic acid, p-hydroxybenzoic acid, cyclohexanecarboxylic acid, phenylacetic acid, cis-ciimamic acid, /rαrø-cinnamic acid, hippuric acid, D-gluconic acid, DL-lactic acid, oleic acid, 4-acetamidobenzoic acid, adipic acid, sebacic acid, (+)-camphoric acid, nicotinic acid, capric or decanoic acid, lauric acid, palmitic acid, stearic acid, undecylenic acid, caprylic or octanoic acid, orotic acid, and carbonic acid, preferably acetic acid.

3. The process of claim 1 or 2, wherein the organic solvent comprises at least one C₁-C₅ alcohol solvent.

4. The process of claim 3, wherein the organic solvent comprises at least «-butanol.

5. An acid addition salt of sunitinib, wherein said salt is the salt of an acid weaker than malic acid.

6. The acid addition salt of claim 5, wherein the acid weaker than malic acid is selected from the group consisting of acetic acid, formic acid, propanoic acid, 3- hydroxypropanoic acid, succinic acid, butanoic acid, 2-methylpropanoic acid, 3- hydroxybutanoic acid, 4-hydroxybutanoic acid, uric acid, glutaric acid, methylsuccinic acid, pentanoic acid, trimethylacetic acid, ascorbic acid, hexanoic acid, 4-methylpentanoic acid, benzoic acid, m-hydroxybenzoic acid, j9-hydroxybenzoic acid, cyclohexanecarboxylic acid, phenylacetic acid, c/s-cinnamic acid, trørø-cinnamic acid, hippuric acid, D-gluconic acid, D,L-lactic acid, oleic acid, 4-acetamidobenzoic acid, adipic acid, sebacic acid, (+)-camphoric acid, nicotinic acid, capric or decanoic acid, lauric acid, palmitic acid, stearic acid, undecylenic acid, caprylic or octanoic acid, orotic acid, and carbonic acid, preferably acetic acid.

7. A process for preparing the acid addition salt of sunitinib of claim 5 or 6, said process comprising:

(i) providing a solution of sunitinib base in an organic solvent;

(ii) treating said solution of sunitinib base with an acid weaker than malic acid, to obtain a mixture comprising the acid addition salt of sunitinib;

(iii) optionally, isolating the acid addition salt of sunitinib from the mixture; and

(iv) optionally, purifying said acid addition salt of sunitinib.

8. The process of claim 7, wherein the organic solvent comprises at least one C₁-C₅ alcohol solvent.

9. The process of claim 8, wherein the organic solvent comprises at least n-butanol.

10. The use of the acid addition salt of sunitinib of any one of claims 5 or 6 for preparing the malic acid salt of sunitinib.

11. The process of claim 7, wherein the solution comprising sunitinib base in step (i) is prepared by reacting N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH^"-pyrrole-3- carboxamide with 5-fluoro-l,3-dihydro-2H-indol-2-one in an organic solvent.

12. The process of any one of claims 1 -4 or 7- 11 , wherein the malic acid is L-(-)- malic acid.