WO2011104555A2

WO2011104555A2 - Novel process

Info

Publication number: WO2011104555A2
Application number: PCT/GB2011/050369
Authority: WO
Inventors: Vinayak Govind Gore; Laxmikant Narahari Patkar; Kiran Shivaji Pokharkar; Mahesh Gorakhnath Hublikar; Prakash Vishnu Bansode
Original assignee: Generics [Uk] Limited; Mylan India Private Limited
Priority date: 2010-02-25
Filing date: 2011-02-24
Publication date: 2011-09-01
Also published as: WO2011104555A3

Abstract

The present invention relates to an improved process for preparing acid addition salts of sunitinib, in particular sunitinib (2S)-2-hydroxybutanedioate (I). The invention also relates to compositions comprising sunitinib acid addition salts such as sunitinib (2S)-2- hydroxybutanedioate (I) and to the use of said compositions in the treatment of disease.

Description

Novel Process

Field of the invention The present invention relates to an improved process for preparing acid addition salts of sumtinib, in particular sumtinib (2S)-2-hydroxybutanedioate (I). The invention also relates to compositions comprising sumtinib acid addition salts such as sunitinib (2S)-2- hydroxybutanedioate (I) and to the use of said compositions in the treatment of disease.

N- [2- (diethylam o) ethyl] ^

2,4-dimethyl-lH-pyriOle-3-carboxamide (sunitinib) is a multi-targeted receptor tyrosine kinase (RTK) inhibitor that is approved as the malate salt (I) by the FDA for die treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST).

Background of the invention

There are several processes disclosed in the prior art for the preparation of sunitinib base and its malate salt. These processes generally involve the condensation of a pyrrole derivative and an oxindole derivative in the presence of a base to form sunitinib free base. The free base is then converted into the malate salt by treating the free base with malic acid. (1) US 6573293, US 2006/0009510 and J. Org. Chem., 2003, vol. 68(16), pages 6447- 6450 describe the condensation of a pyrrole derivative and an oxindole derivative in the presence of pyrrolidine or potassium hydroxide as a base to afford sunitinib free base.

(2) WO 03/070725 and US 7119209 describe a three component condensation, comprising preparing a pyrrole derivative, reacting it with an oxindole derivative and the additional step of reacting an amine with the pyrrole substituted indolinone to form sunitinib free base.

(3) US 7125905 and US 7435832 describe a process for the preparation of sunitinib malate from free base and malic acid.

(4) Another approach for the preparation of sunitinib base has been described in WO 2010/001167. Again a pyrrole derivative and an oxindole derivative are condensed, this time in the presence of an acid catalyst.

All of the above processes involve the preparation and then isolation of sunitinib base, before conversion to die desired sunitinib salts, particularly sunitinib malate. The inventors have found several drawbacks in working with sunitinib base:

(1) Due to die low solubility profile of sunitinib base in a significant number of typically used organic solvents, large amounts of solvent and high temperatures are required for purification of the sunitinib base. This is particularly disadvantageous on an industrial scale, where the base may requite several purification steps to meet the quality specifications required for human consumption.

(2) Typically sunitinib base is a powder having a very fine particle nature. This makes processing such a powder difficult, particularly in industrial settings.

(3) Conversion of sunitinib base to sunitinib malate involves the addition of a solution comprising malic acid to sunitinib base. The aforementioned problems of solubility of the base in common solvents mean that the initial reaction mass is a suspension. Sunitinib malate salt also has very poor solubility in common solvents. However, compared to sunitinib base, the corresponding malate salt is much easier to filter and amenable to purification. Thus, the complete formation of the sunitinib malate salt during this step is difficult to judge due to the heterogeneous nature of the reaction mass from start to end.

WO 2009/150523 describes a process for the direct preparation of sunitinib malate involving the condensation of the malate salt of 5-formyl-2,4-dimethyl-lH-pyrrole-3- carboxylic acid (2-diemylaminoethyl) amide, with 5-fluoro-l,3-dihydroindol-2-one in the presence of an organic amine. The amine is present in catalytic amounts and is present to aid in the reaction process. All the specific embodiments described in WO 2009/150523 require reaction temperatures of greater than about 70°C and typically between about 90°C and 100°C. Reactions at these temperatures require large amounts of energy to maintain and thus increase the cost of such processes. The use of the malate salt of the 5-formyl-2,4- dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide also means that said malate salt has to be prepared and isolated, or requires an extra step of first preparing the malate salt and then adding the remaining reactants to prepare sunitinib malate.

In view of the importance of sunitinib salts for the treatment of cancer, there is a great need for developing an alternative and commercially feasible process for their synthesis with commercially acceptable yield and high purity.

Summary of the invention

There is thus required an elegant, one pot process suitable for preparing acid addition salts of sunitinib on an industrial scale and in high purity.

Accordingly, in a first aspect according to the invention, there is provided a process for preparing an acid addition salt of sunitinib comprising: reacting a pyrrole derivative (III)

(ii) with a 5-fluoiO-2-oxindole derivative (II) to form a reaction mixture

(iii) adding an amine derived or ammonium derived salt of the acid to the reaction mixture; and

(iv) isolating the sunitinib salt; wherein one of R₈ or R₈a is a formyl group and the other is H.

In a preferred embodiment of a process according to the first aspect of the invention the acid is an inorganic acid selected from the group comprising HC1, HBr, HN0₃, H₃P0₄, H₂S0₄ and HC10₄. In an alternative embodiment the acid is an organic acid, preferably the organic moiety of the organic acid is hydrogen, or a straight or branched chain, substituted or unsubstituted alkyl, alkenyl, allyl, aryl or arylalkyl group, or a heteroatom-substituted straight or branched chain alkyl or aryl group. Preferably the organic moiety of the organic acid is a straight or branched chain, substituted or unsubstituted alkyl, alkenyl, allyl, aryl or arylalkyl group, or a heteroatom-substituted straight or branched chain alkyl or aryl group.

An example of an organic acid, wherein the organic moiety of the organic acid is hydrogen, is formic acid. Examples of organic acids, wherein the organic moiety of the organic acid is a straight or branched chain, substituted or unsubstituted alkyl group, are acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, malic acid, tartaric acid, citric acid, methane sulfonic acid, ethane sulfonic acid, trifluoroacetic acid, chloroacetic acid, glycine, pyruvic acid, thioglycolic acid, histidine, phenylalanine and thioacetic acid. Examples of organic acids, wherein the organic moiety of the organic acid is a straight or branched chain, substituted or unsubstituted alkenyl group, are maleic acid and fumaric acid. Examples of organic acids, wherein the organic moiety of the organic acid is a straight or branched chain, substituted or unsubstituted allyl group, are acrylic acid and methacrylic acid. Examples of organic acids, wherein the organic moiety of the organic acid is a straight or branched chain, substituted or unsubstituted aryl group, are benzoic acid, p-toluene sulfonic acid, salicylic acid, 3-pyridine-acetic acid and pyrazole-3-carboxylic acid. Examples of organic acids, wherein the organic moiety of the organic acid is a straight or branched chain, substituted or unsubstituted arylalkyl group, are phenyl acetic acid and 4-hydroxy phenyl acetic acid. Examples of organic acids, wherein the organic moiety of the organic acid is a heteroatom-substituted straight or branched chain alkyl group, are oxalic acid, malonic acid, succinic acid, malic acid, tartaric acid, citric acid, trifluoroacetic acid, chloroacetic acid, glycine, pyruvic acid, thioglycolic acid, histidine and phenylalanine. Examples of organic acids, wherein die organic moiety of the organic acid is a heteroatom- substituted straight or branched chain aryl group, are salicylic acid, 3-pyridine-acetic acid and pyrazole-3-carboxylic acid.

In particularly preferred embodiments the organic acid is selected from the group comprising sulfonic acids, and mono-, di- and tri-carboxylic acids. In particularly preferred embodiments the organic acid is selected from the group comprising acetic acid, formic acid, oxalic acid, D-malic acid, L-malic acid, DL-malic acid, maleic acid, methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid and malonic acid.

In a further embodiment of a process according to the first aspect of the invention the amine or ammonium moiety is selected from the group comprising primary amines and secondary amines, preferably selected from d e group comprising cyclic amines, allyl amines, arylalkyl amines, heteroalkyl amines, alkyl amines, alkenyl amines, alkynyl amines and aryl amines.

In further preferred embodiments of a process according to the first aspect of the invention, about 1 to about 3 equivalents of the amine derived or ammonium derived salt of the acid are used with respect to the pyrrole derivative (III) and/or the 5-fluoro-2- oxindole derivative (II) in the preparation of the sunitinib salt. More preferably the stoichiometry is about 1 to about 2 equivalents. In a further preferred embodiment the reaction is carried out at between about 0°C to about 50°C, more preferably at between about 20°C to about 40°C, and most preferably at between about 25°C to about 35°C. Preferably, the sunitinib salt is obtained in a yield of 60% or more, preferably 70% or more, preferably 80% or more, from the pyrrole derivative (III) and/ or the 5-fiuoro-2-oxindole derivative (II).

Preferably, the sunitinib salt is obtained on a commercial scale, preferably in batches of 0.5kg or more, 1kg or more, 10kg or more, 100kg or more, 500kg or more, or 1000kg or more.

The inventors have found that the process according to the first aspect of the present invention is particularly amenable to preparing high purity sunitinib malate. Accordingly, there is provided in a second aspect of the invention a process for the preparation of sunitinib malate comprising: reacting a pyrrole derivative (III)

(ϋ) with a 5-fiuoro-2-oxindole derivative (II) to form a reaction mixture

(iii) adding an amine derived or ammonium derived malate salt to the reaction mixture and isolating the sunitinib malate salt; wherein one of R₈ or R₈a is a formyl group and the other is H.

In one embodiment of a process according to the second aspect of the invention, the process is carried out in an organic solvent system, preferably the organic solvent system comprises acetonitrile and methanol. In particularly preferred embodiments the v/v ratio of acetonitrile to methanol is 5:1 to 1:5, most preferably the v/v ratio of acetonitrile to methanol is about 3:2. The inventors have found that a solvent system comprising acetonitrile and methanol in a ratio of about 3:2 results in a particularly pure sunitinib malate product.

In a further preferred embodiment of a process according to the second aspect of the invention the amine or ammonium moiety is selected from the group comprising primary amines and secondary amines, preferably selected from the group comprising cyclic amines, allyl airlines, arylalkyl amines, heteroalkyl amines, alkyl amines, alkenyl amines, alkynyl amines and aryl amines. Most preferably the amine derived or ammonium derived malate salt is selected from die group comprising 2-(N,N-diethylamino)ethyl ammonium malate, 2-(N,N-diethylamino)ethyl ammonium dimalate, diammonium malate, dipyrrolidine malate, di-n-propyl ammonium malate, and di-diisopropyl ammonium malate. A particularly preferred embodiment of a process according to the second aspect is provided wherein the malic acid is L-malic acid.

In further preferred embodiments of a process according to the second aspect of the invention, about 1 to about 3 equivalents of the amine derived or ammonium derived malate salt are used with respect to the pyrrole derivative (III) and/or the 5-fluoro-2- oxindole derivative (II) in the preparation of sunitinib malate. More preferably the stoichiometry is about 1 to about 2 equivalents.

In a further preferred embodiment the reaction is carried out at between about 0°C to about 50°C, more preferably at between about 20°C to about 40°C, and most preferably at between about 25°C to about 35°C. Preferably, the sunitinib malate is obtained in a yield of 60% or more, preferably 70% or more, preferably 80% or more, from the pyrrole derivative (III) and/or the 5-fluoro-2- oxindole derivative (II). Preferably, the sunitinib malate is obtained on a commercial scale, preferably in batches of 0.5kg or more, 1kg or more, 10kg or more, 100kg or more, 500kg or more, or 1000kg or more.

A third aspect according to the invention provides the use of an amine derived or ammonium derived malate salt as a reagent in the preparation of sunitinib malate.

A fourth aspect of the invention provides sunitinib malate prepared by a process according to the second aspect of the invention having a purity as determined by HPLC of at least 97%, preferably at least 99%, most preferably at least 99.8%.

Preferably the sumtinib malate according to the fourth aspect or prepared by a process according to the second aspect of the present invention has a polymorphic purity of at least 97%, preferably at least 99%, most preferably at least 99.8%, preferably as determined by XRPD.

Preferably the sunitinib malate according to the fourth aspect or prepared by a process according to the second aspect of the present invention is suitable for use in medicine, preferably for treating a protein kinase mediated disorder. Preferably the disorder is a cell proliferative disorder, most preferably the disorder is one of advanced renal cell carcinoma (RCC) or gastrointestinal stromal tumor (GIST).

A fifth aspect of the invention provides a pharmaceutical composition comprising sunitinib malate according to the fourth aspect or prepared by a process according to the second aspect of the present invention and one or more pharmaceutically acceptable excipients. Preferably the pharmaceutical composition is suitable for treating a protein kinase mediated disorder. Preferably the disorder is a cell proliferative disorder, most preferably the disorder- is one of advanced renal cell carcinoma (RCC) or gastrointestinal stromal tumor (GIST). A sixth aspect of the invention provides a use of sunitinib malate according to the fourth aspect or prepared by a process according to the second aspect of the present invention in the manufacture of a medicament for the treatment of a protein kinase mediated disorder. Preferably the disorder is a cell proliferative disorder, most preferably the disorder is one of advanced renal cell carcinoma (RCC) or gastrointestinal stromal tumor (GIST).

A seventh aspect of die invention provides a method of treating a protein kinase mediated disorder, comprising administering to a patient in need thereof a therapeutically effective amount of sunitinib malate according to the fourth aspect or prepared by a process according to the second aspect of the present invention. Preferably the disorder is a cell proliferative disorder, most preferably the disorder is one of advanced renal cell carcinoma (RCC) or gastrointestinal stromal tumor (GIST). Preferably the patient is a mammal, preferably a human. An eighth aspect according to the invention provides the use of an amine derived or ammonium derived acid addition salt as a reagent in the preparation of the corresponding acid addition salt of sunitinib.

A ninth aspect of the invention provides an acid addition salt of sunitinib prepared by a process according to the first aspect of the invention having a purity as determined by HPLC of at least 97%, preferably at least 99%, most preferably at least 99.8%.

Preferably die acid addition salt of sunitinib according to the ninth aspect or prepared by a process according to the first aspect of the present invention has a polymorphic purity of at least 97%, preferably at least 99%, most preferably at least 99.8%, preferably as determined by XRPD.

Preferably the acid addition salt of sunitinib according to the ninth aspect or prepared by a process according to the first aspect of the present invention is suitable for use in medicine, preferably for treating a protein kinase mediated disorder. Preferably the disorder is a cell proliferative disorder, most preferably the disorder is one of advanced renal cell carcinoma (RCC) or gastrointestinal stromal tumor (GIST). A tenth aspect of the invention provides a pharmaceutical composition comprising an acid addition salt of sumtinib according to the ninth aspect or prepared by a process according to the first aspect of the present invention and one or more pharmaceutically acceptable excipients. Preferably the pharmaceutical composition is suitable for treating a protein kinase mediated disorder. Preferably the disorder is a cell proliferative disorder, most preferably the disorder is one of advanced renal cell carcinoma (RCC) or gastrointestinal stromal tumor (GIST).

An eleventh aspect of the invention provides a use of an acid addition salt of sumtinib according to the ninth aspect or prepared by a process according to the first aspect of the present invention in the manufacture of a medicament for the treatment of a protein kinase mediated disorder. Preferably the disorder is a cell proliferative disorder, most preferably the disorder is one of advanced renal cell carcinoma (RCC) or gastrointestinal stromal tumor (GIST).

A twelfth aspect of the invention provides a method of treating a protein kinase mediated disorder, comprising administering to a patient in need thereof a therapeutically effective amount of an acid addition salt of sumtinib according to the ninth aspect or prepared by a process according to the first aspect of the present invention. Preferably the disorder is a cell proliferative disorder, most preferably the disorder is one of advanced renal cell carcinoma (RCC) or gastrointestinal stromal tumor (GIST). Preferably the patient is a mammal, preferably a human.

Brief description of the drawings

Figure 1 shows a XRP diffractogram of sumtinib L-malate in polymorphic form I as disclosed in US 7435832. Sumtinib L-malate in polymorphic form I has an X-ray diffraction pattern comprising peaks at 13.2, 19.4, 24.2 and 25.5 ± 0.2 degrees 2-theta. Preferably sumtinib L-malate in polymorphic form I has an X-ray diffraction pattern comprising peaks at 13.2, 19.4, 21.3, 22.1, 24.2 and 25.5 ± 0.2 degrees 2-theta. Detailed description of the invention

For the purposes of the present invention, an "alkyl" group is defined as a monovalent saturated hydrocarbon, which may be straight-chained or branched, or be or include cyclic groups. An alkyl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton. Examples of alkyl groups are methyl, ethyl, //-propyl, /^'-propyl, //-butyl, i- butyl, /-butyl and s-pentyl groups. Preferably an alkyl group is straight-chained or branched, and does not include any heteroatoms in its carbon skeleton. Preferably an alkyl group is a C_rC₁₂ alkyl group, preferably a Q-Q alkyl group. An "alkylene" group is similarly defined as a divalent alkyl group.

An "alkenyl" group is defined as a monovalent hydrocarbon, which comprises at least one carbon-carbon double bond, which may be straight-chained or branched, or be or include cyclic groups. An alkenyl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton. Examples of alkenyl groups are vinyl, allyl, but-l-enyl and but-2-enyl groups. Preferably an alkenyl group is straight-chained or branched, and does not include any heteroatoms in its carbon skeleton. Preferably an alkenyl group is a C₂-C₁₂ alkenyl group, preferably a C₂-C₆ alkenyl group. An "alkenylene" group is similarly defined as a divalent alkenyl group.

An "alkynyl" group is defined as a monovalent hydrocarbon, which comprises at least one carbon-carbon triple bond, which may be straight-chained or branched, or be or include cyclic groups. An alkynyl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton. Examples of alkynyl groups are ethynyl, propargyl, but-l-ynyl and but-2-ynyl groups. Preferably an alkynyl group is straight-chained or branched, and does not include any heteroatoms in its carbon skeleton. Preferably an alkynyl group is a C₂-C₁₂ alkynyl group, preferably a C₂-C_c alkynyl group. An "alkynylene" group is similarly defined as a divalent alkynyl group. An "aryl" group is defined as a monovalent aromatic hydrocarbon. An aryl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton. Examples of aryl groups are phenyl, naphthyl, anfhracenyl and phenanthrenyl groups. Preferably an aryl group does not include any heteroatoms in its carbon skeleton. Preferably an aryl group is a C₄-C₁₄ aiyl group, preferably a C₆-C_w aryl group. An "aiylene" group is similarly defined as a divalent aryl group.

For the purposes of the present invention, a "heteroatom" is defined as N, O, S, F, CI, Br or I, preferably as N, O or S.

For the purposes of the present invention, where a combination of groups is referred to as one moiety, for example, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule. Preferably the groups, where a combination of groups is referred to as one moiety, comprise 4-18 carbon atoms. A typical example of an arylalkyl group is benzyl.

For the purposes of this invention, an optionally substituted group may be substituted with one or more of -F, -CI, -Br, -I, -CF₃, -CC1₃, -CBr₃, -CI₃, -OH, -SH, -NH₂, -CN, -N0₂, -COOH, -R^x-0-R^y, -R^x-S-R^y, -R^x-SO-R^y, -R^x-S0₂-R^y, -R^x-S0₂-OR^y, -RO-S0₂-R^y, -R^x-S0₂-N(R)₂, -R^x-NR^'-S0₂-R^y, -RO-S0₂-OR^', -RO-S0₂-N(R^J)₂, -R^x-NR^y-S0₂-OR^y, -R^x-NR^'-S0₂-N(R% -R^X- (R^})₂, -R^X-N(R>)₃ ⁺, -R^X-P(R% -R^x-Si(R)₃, -R^x-CO-R^y, -R^x-CO-OR^y, -R^xO-CO-R^y, -R^x-CO-N(R^y)₂, -R^x-NR^'-CO-R^y, -RO-CO-OR^y, -RO-CO-N(R -R^x-NR^y-CO-OR^y, -R^x-NR^y-CO-N(R^s)₂, -R^x-CS-R^y, -R^x-CS-OR^y, -R^xO-CS-R^y, -R^X-CS-N(R^!)₂, -R^x-NR^'-CS-R^y, -RO-CS-OR^', -RO-C8-N(R)₂, -R^x-NR^'-CS-OR^y, -R^X-NR^'-CS-N(R)₂ or -R^y, or a bridging substituent such as -0-, -S-, -NR^y- or -R^x-, or a π-bonded substituent such as =0, =S or =NR^y. In this context, -R^x- is independently a chemical bond, a C_j-Ci₀ allcylene, C₂-C₁₀ alkenylene or C₂-C₁₀ alkynylene group. -R^y is independently hydrogen, unsubstituted C_rC₆ allcyl or unsubstituted C₄-C₁₀ aryl. Optional substituent(s) are not taken into account when calculating the total number of carbon atoms in die parent group substituted with the optional substituent(s). Preferably a substituted group comprises 1, 2 or 3 substituents, preferably 1 or 2 substituents, preferably 1 substituent.

Any optional substituent may be protected. Suitable protecting groups for protecting optional substituents are known in the art, for example from "Protective Groups in Organic Synthesis" by T.W. Greene and P.G.M. Wuts (Wiley-Interscience, 3^rd edition,

1999).

As used herein the term "solvent system" should be taken to mean one of the following possibilities:

CO a single organic solvent

(2) a combination of two or more organic solvents in various proportions

(3) a combination of water and one or more organic solvents in various proportions

The inventors have found that when an acid addition salt derived from an organic amine or ammonium or derivatives thereof and an organic or inorganic acid is added to a reaction mass containing pyrrole derivative 1 and 2-oxindole derivative 2, the resulting corresponding sunitinib salt is obtained wherein the salt moiety is obtained from the acid of the initial organic amine or ammonium salt. The resulting sunitinib salt has surprisingly high purity and high quantitative yield. The reaction requires relatively reduced reaction times and most surprisingly the reaction can be carried out at ambient temperatures. This aspect is not taught or even suggested in the prior art, which teaches reaction temperatures of greater than about 70°C. The process of the invention utilising salts derived from organic amines or ammonium and carboxylic acid derivatives results in a simpler, more cost effective, one pot process for the preparation of sunitinib salts, in particular sunitinib malate.

The inventors have surprisingly found that a Knoevenagel type of condensation reaction between pyrrole derivative 1 and 2-oxindole derivative 2 proceeds advantageously in the presence of an organic amine or ammonium derived salt of the acid to directly afford a pure sunitinib acid addition salt. A generalized example of this type of reaction according to the invention is shown in scheme 1 below wherein the acid is a carboxylic acid.

sunitinib carboxylate salt

Scheme 1

(wherein R, Ri and R2 are each independendy hydrogen, or a straight or branched chain, substituted or unsubstituted alkyl, alkenyl, allyl, aryl or arylalkyl group, or a heteroatom-substituted straight or branched chain alkyl or aryl group)

Accordingly, in a first aspect according to the invention, there

preparing an acid addition salt of sunitinib comprising:

(i) reacting a pyrrole derivative III)

(ii) with a 5-fluoro-2-oxindole derivative (II) to form a reaction mixture

The pyrrole derivative (III) is used in its free base form, not as a salt. Similarly, the 5- fiuoro-2-oxindole derivative (II) is preferably used in its free base form, not as a salt.

In a preferred embodiment the reaction is carried out at between about 0°C to about 50°C, more preferably at between about 20°C to about 40°C, and most preferably at between about 25°C to about 35°C. In a further embodiment the reaction time varies from between about 0.5 hour to about 24 hours. One skilled in die art of synthesis will realize that the reaction times are indicative and do not limit the scope of the invention in any way. In further alternative embodiments the reaction mass is acidic in nature. This condition is in contrast to the prior art reports where an organic or inorganic base is required to effect the condensation of the pyrrole intermediate and the oxindole derivative. Advantageously, the processes of the invention do not require the extra basification step.

In one embodiment of a process according to the first aspect of the invention the acid is an inorganic acid selected from the group comprising HCl, HBr, HN0₃, H₃P0₄, H₂S0₄ and HC10₄. In a preferred alternative embodiment the acid is an organic acid, preferably the organic moiety of the organic acid is hydrogen, or a straight or branched chain, substituted or unsubstituted alkyl, alkenyl, allyl, aryl or arylalkyl group, or a heteroatom-substituted straight or branched chain alkyl or aryl group. In particularly preferred embodiments the organic acid is selected from the group comprising sulfonic acids, and mono-, di-, and tricarboxylic acids. In further particularly preferred embodiments the organic acid is selected from the group comprising acetic acid, formic acid, oxalic acid, D-malic acid, L-malic acid, DL-malic acid, maleic acid, methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid and malonic acid. In one embodiment of a process according to the first aspect of the invention the process is carried out in an organic solvent system, in this regard the solvents may be chosen in preferred embodiments from acetone, methanol, ethanol, butanol, acetonitrile and mixtures thereof. The use of these solvent systems in any ratio all result in pure products, however it is within the skill set of the skilled person to determine the ratios of the solvents in combination that result in a particularly pure product of greater than 97% chemical purity as determined by HPLC.

In a further embodiment of a process according to the first aspect of the invention the amine or ammonium moiety is selected from the group comprising primary amines and secondary amines, preferably selected from the group comprising cyclic amines, allyl amines, arylalkyl amines, heteroalkyl amines, alkyl amines, alkenyl amines, alkynyl amines and aryl amines. In a further embodiment of a process according to the first aspect of the invention the amine or ammonium moiety is selected from the group comprising primary amines such as alkyl and aryl amines for example ethyl amine; secondary amines such as dimethyl amine, diethyl amine, dipropyl amine, dibutyl amine and dicyclohexyl amine; cyclic amines such as pyrrolidine and piperidine; arylalkyl amines such as alkyl arylalkyl amines such as N-methyl benzyl amine; heteroalkyl amines such as 2-amino-pyrrolidine and N,N-dimethyl ethylene diamine; allyl amines; alkyl amines; alkenyl amines; alkynyl amines; and aryl amines.

The amine derived or ammonium derived salt of the acid can be prepared by simply mixing die appropriate organic amine or ammonia or derivatives thereof and the appropriate acid in a solvent system and isolating the resulting solid either by filtration or by evaporation of the solvent system. The isolated salts were characterized by spectroscopic techniques to confirm that salts were actually prepared and the solution was not just a physical mixture of the organic amine or ammonia or derivatives thereof and the acid. The amine derived salt of the acid or the ammonium derived salt of the acid are most preferably prepared using equimolar stoichiometry of the acid and the amine or ammonium moiety. Alternatively the acid and the amine or ammonium moiety may be used in a ratio of from about 1 :2 to about 2:1. The amine or ammonium moieties and the acid moieties are preferably combined in a Q-C₅ alcoholic solvent. Most preferably the alcoholic solvents are selected from the group comprising methanol, ethanol, propanol, isopropanol, butanol, pentanol and mixtures thereof. In preferred embodiments the reaction proceeds at a temperature of between about 10°C to about 80°C, preferably between about 20°C to about 50°C, and most preferably between about 25°C to about 35°C.

In certain embodiments of a process according to the first aspect of the invention the sunitinib salt may be isolated in step (iv) by any means known to the skilled person. In particularly preferred embodiments the sunitinib salt may be isolated either by evaporation of the solvent system or by filtration and drying.

In further embodiments the isolated sunitinib salt may be subjected to further purification by crystallization from a solvent system, preferably a solvent system comprising a C C₅ alcoholic solvent. Accordingly, in further preferred embodiments the solvent system comprises butanol and water, most preferably in a ratio of between about 1:10 to about 10:1. The most preferred ratio of about 4:1 has been found to afford a particularly pure product wherein the presence of contaminant polymorphic forms is below detection limits.

An eighth aspect according to the invention provides the use of an amine derived or ammonium derived acid addition salt as a reagent in the preparation of the corresponding acid addition salt of sunitinib.

A ninth aspect of the invention provides an acid addition salt of sunitinib prepared by a process according to die first aspect of the invention having a HPLC purity of at least 97%, preferably at least 99%, most preferably having a HPLC purity of at least 99.8%.

A tenth aspect of the invention provides a pharmaceutical composition comprising an acid addition salt of sunitinib according to the ninth aspect or prepared by a process according to the first aspect of the invention and one or more pharmaceutically acceptable excipients. A pharmaceutically acceptable excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples of excipients without limitation include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

The inventors have found that the process according to the first aspect is particularly amenable to preparing high purity sumtinib malate. Accordingly there is provided in a second aspect of the invention a process for the preparation of sumtinib malate comprising: reacting a pyrrole derivative III)

with a 5-fluoro-2-oxindole derivative (II) to form a reaction mixture;

adding an amine derived or ammonium derived malate salt to die reaction mixture; and isolating the sumtinib malate salt; wherein one of R₈ or R₈a is a formyl group and the other

The pyrrole derivative (III) is used in its free base form, not as a salt. Similarly, the 5- fluoro-2-oxindole derivative (II) is preferably used in its free base form, not as a salt. In one embodiment of a process according to the second aspect of the invention, the process is carried out in an organic solvent system, preferably the organic solvent system is acetonitrile : methanol, preferably the v/v ratio of acetonitrile to methanol is from about 5:1 to about 1:5, most preferably the v/v ratio of acetonitrile to methanol is about 3:2. The inventors have found that when the v/v ratio of acetonitrile to methanol is about 3:2, a particularly pure sunitinib malate is formed and advantageously the impurity having the characteristic RRT of approximately 0.97 is controlled to within accepted ICH Guidelines. The reason for this is thought to be due to a particularly advantageous solubility profile of this solvent system. Other preferred solvent systems comprise acetone, methanol, ethanol, butanol, acetonitrile and mixtures thereof. The use of these solvent systems in any ratio results in pure products, however it is within the skill set of the skilled person to determine the ratios of the solvents in combination that result in a particularly pure product of greater than 97% chemical purity as determined by HPLC.

In a further preferred embodiment the reaction is carried out at between about 0°C to about 50°C, more preferably the reaction is carried out at between about 20°C to about 40°C, most preferably at between about 25°C and about 35°C. The inventors have found that contrary to the teachings in the prior art die reactions according to the second aspect of the invention, wherein in the desired sunitinib malate the malate counterion is provided by the malate moiety in the amine derived or ammonium derived malate salt, are characterized by the process according to step (iii) of a process according to the invention. Surprisingly, the sunitinib malate obtained has a particularly advantageous purity profile.

In a further preferred embodiment of a process according to the second aspect of the invention the amine or ammonium derived malate salt is selected from the group comprising primary amines and secondary amines, preferably selected from the group comprising cyclic amines, allyl amines, arylalkyl amines, heteroalkyl amines, alkyl amines, alkenyl amines, alkynyl amines and aryl amines. Primary as well as secondary amines have been employed in the present disclosure.

The inventors have found that the most preferred amine or ammonium derived malate salt is selected from the group comprising 2-( ,N-diethylamino)ethyl ammonium malate, 2- (N,N-diethylarnino)ethyl ammonium dimalate, diammonium malate, dipyrrolidine malate, di-n-propyl ammonium malate, and di-diisopropyl ammonium malate. In further preferred embodiments of a process according to the second aspect of the invention, 1 to 3 equivalents of the amine derived or ammonium derived malate salt are used with respect to compound (II) and/ or compound (III) in the preparation of sunitinib malate. More preferably the stoichiometiy is about 1 to 2 equivalents and the most preferred stoichiometiy is about 1.5 equivalents of the amine derived or ammonium derived malate salt.

A particularly preferred embodiment of a process according to the second aspect of the invention is provided wherein the malic acid is L-malic acid, resulting in sunitinib malate wherein die malate counterion is in the L configuration.

The amine derived or ammonium derived malate salt can be prepared by simply mixing the appropriate organic amine or ammonia or derivatives thereof and malic acid in a solvent system and isolating the resulting malate salt either by filtration or by evaporation of the solvent system. The isolated malate salts were characterized by spectroscopic techniques to confirm that the salts were actually prepared and the solution was not just a physical mixture of the organic amine or ammonia or derivatives thereof and the malic acid. The amine derived or the ammonium derived malate salts are most preferably prepared using equimolar stoichiometiy of the acid and the amine or ammonium moiety. Alternatively the acid and the amine or ammonium moiety may be used in a ratio of from about 1 :2 to about 2:1. The amine or ammonium moieties and the malic acid are preferably combined in a C C₅ alcoholic solvent. Most preferably the alcoholic solvents are selected from the group comprising methanol, ethanol, propanol, isopropanol, butanol, pentanol and mixtures thereof. In preferred embodiments the reaction proceeds at a temperature of between about 10°C to about 80°C, preferably between about 20°C to about 50°C, and most preferably between about 25°C to about 35°C.

It should be noted that in the preparation of the amine derived or ammonium derived malate salts the different stoichiometiy of the organic amine or ammonium moieties and the acid moieties results in the preparation of different salts. For example, 1 mol equivalent of 2-(N,N-diemylamino)ethyl amine reacted with 1 mol equivalent of malic acid results in 2-(N,N-c emylamino)ethyl ammonium malate, whereas 2-( ,N-diethylamino)ethyl ammonium dimalate is obtained when 1 mol equivalent of 2-(N,N-died ylamino)ethyl amine is reacted with 2 mol equivalents of malic acid. Both of these salts, when employed in the process according the invention, afford sunitinib malate. All the salts have an acidic pH. In certain embodiments of a process according to the second aspect of the invention the sunitinib malate may be isolated in step (iv) by any means known to the skilled person. In particularly preferred embodiments the sunitinib malate may be isolated either by evaporation of the solvent system or by filtration and drying. In further embodiments the isolated sunitinib malate salt may be subjected to further purification by crystallization from a solvent system, preferably a solvent system comprising a C_rC₅ alcoholic solvent. Accordingly, in further preferred embodiments the solvent system comprises butanol and water, most preferably in a ratio of between about 1:10 to about 10:1. The most preferred ratio of about 4:1 has been found to afford a particularly pure product wherein the presence of contaminant polymorphic forms is below detection limits.

The process according to the second aspect of the invention provides sunitinib malate having a polymorphic purity such that the presence of other polymorphic forms is undetectable. Accordingly there is provided in further preferred embodiments sunitinib malate having a polymorphic purity of greater than 97%, more preferably greater than 99%, most preferably greater than 99.8%, preferably as determined by XRPD.

A third aspect according to the invention provides the use of an amine derived or ammonium derived malate salt as a reagent in the preparation of the corresponding sunitinib malate salt.

A fourth aspect of the invention provides sunitinib malate prepared by a process according to the second aspect of the invention having a HPLC purity of at least 97%, preferably at least 99%, most preferably having a HPLC purity of at least 99.8%. A fifth aspect of the invention provides a pharmaceutical composition comprising sunitinib malate according to the fourth aspect or prepared by a process according to the second aspect of the invention and one or more pharmaceutically acceptable excipients. A pharmaceutically acceptable excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples of excipients without limitation include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

Examples

The preparation of sunitinib malate is a very good example of the practical application of the invention, as in this case it was easy to measure the chemical and polymorphic purity of the final sunitinib malate salt and the residual amount of base (organic amine) as a determination of purity. Unless otherwise specified references in the description and the following examples to HPLC purity were determined by:

HPLC Machine: Waters

Column: Inertsil ODS 3V (250 x 4.6mm), 5 μηι

Mobile Phase: 0.05 M ammonium acetate : methanol + 0.05% acetic acid

Diluent: buffer : methanol (60:40 v/v)

Flow Rate: 1.0 ml/min

Wavelength: 235 nm

Auto-Sampler Temperature: 15 ± 2°C

In the following examples the pyrrole derivative (III) is N-[2-(diemylamino)ethyl]-5-formyl- 2,4-dimethyl-lH-pyrrole-3-carboxamide wherein R₈ is a formyl group and the 5-fluoro-2- oxindole derivative (II) is 5-fluoro-2-oxindole wherein R₈a is hydrogen. Example 1: Preparation of 2-(N,N-diethylamino)ethyl ammonium dimalate

Into 10ml of methanol at 25-30°C, 2-(N,N-diethylan ino)ethyl amine (2g, 1 mol equivalent) was added followed by the addition of L-malic acid (4.62g, 2 mol equivalent) under stirring. A clear solution was observed. After stirring for 1 hour, the solvent was removed under vacuum on a rotary evaporator to afford a dark yellow oil.

Yield = 6.5g (98%)

NMR (solvent: DMSO-d₆): 0.98 (t, 6H), 2.33 (dd, 2H), 2.40-2.67 (m, 8H), 2.65 (t, 2H), 4.04 (dd, 2H)

Example 2: Preparation of sunitinib malate from 2-(N,N-<iiemylamino)ethyl ammonium dimalate

2-( ,N-Diemylamino)ethyl ammonium dimalate (4.3g, 1.5 mol equivalent), N-[2- (diemylammo)emyl]-5-formyl-2,4-dimemyl-lH-pyrrole-3-carboxamide (2g, 1 mol equivalent) and 5-fiuoro-2-oxindole (1.13g, 1 mol equivalent) were added to 20ml of acetonitrile : methanol (3:2) at 25-30°C to obtain a clear solution. After 3 hours stirring at 25-30°C, a yellow solid progressively precipitated out of the solution. The yellow solid was isolated by filtration, washed with methanol (10ml) and dried under vacuum at 55-60°C for 3-4 hours.

Yield = 3.2g (80%)

Chemical Purity (HPLC) > 98%

This solid was further purified by dissolving in butanol : water (4:1, 20 volumes) at 60- 65°C, cooling to 25-30°C, and filtering and drying the precipitated sunitinib malate.

Yield = 80%

Chemical Purity (HPLC) > 99.7%

Polymorphic Purity (XRPD) > 99% (other polymorphic forms below detection limit) The structure of sunitinib malate was confirmed by NMR and HPLC retention time with standard sample. XRPD analysis indicated polymorphic form I as shown in Figure 1. Sunitinib malate polymorphic form I was obtained before and after recrystallisation.

Example 3: Preparation of 2-(N,N-diemylamino)ethyl ammonium malate

Into 10ml of methanol at 25-30°C, 2-( ,N-diethylamino)ethyl amine (2g, 1 mol equivalent) was added followed by the addition of L-malic acid (2.31g, 1 mol equivalent) under stirring. A clear solution was observed. After stirring for 1 hour, the solvent was removed under vacuum on a rotary evaporator to afford a dark yellow oil. Yield = 4.1g (95%)

NMR (solvent: DMSO-d₆): 0.98 (t, 6H), 2.27 (t, 1H), 2.30-2.54 (m, 7H), 2.83 (t, 2H), 3.86 (dd, 1H) Example 4: Preparation of sunitinib malate from 2-(N,N-diemylamino)ethyl ammonium malate

Into 20ml of acetonitrile : methanol (3:2), 2-(N,N-cHethylamino)ethyl ammonium malate (2.83g, 1.5 mol equivalent), N-[2-(diemylamino)emyl]-5-formyl-2,4-dimemyl-lH-pyrrole-3- carboxamide (2g, 1 mol equivalent) and 5-fiuoro-2-oxindole (1.13g, 1 mol equivalent) were added at 25-30°C to obtain a clear solution within 15 minutes. After 3 hours stirring at 25- 30°C, a yellow solid progressively precipitated out of the solution. The yellow solid was isolated by filtration, washed with methanol (10ml) and dried under vacuum at 55-60°C for 3-4 hours.

Yield = 2.9g (72%)

Chemical Purity (HPLC) > 98.77%

Yield = 80%

Chemical Purity (HPLC) > 99.76%

Polymorphic Purity (XRPD) > 99% (other polymorphic forms below detection limit)

The structure of sumtinib malate was confirmed by NMR and HPLC retention time with standard sample. XRPD analysis indicated polymorphic form I as shown in Figure 1. Sunitinib malate polymorphic form I was obtained before and after recrystallisation.

Example 5: Preparation of diammonium malate

Into 10ml of methanol at 25-30°C, ammonia (10% methanoHc solution 5ml, 2 mol equivalent) was added followed by the addition of L-malic acid (2g, 1 mol equivalent). A clear solution was observed. A white solid progressively precipitated out. The solution was stirred for 1 hour and the white solid filtered and dried under vacuum on a rotary evaporator.

Yield = 2.4g (96%) NMR (solvent: DMSO-d₆): 2.27 (dd, IH), 2.48-2.54 (m, IH), 3.86 (dd, H)

Example 6: Prepar tion of sunitinib malate from diammonium malate

Into 20ml of acetonitrile : methanol (3:2), diammonium malate (1.9g, 1.5 mol equivalent), N-[2-(diemylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxam^ (2g, 1 mol equivalent) and 5-fluoro-2-oxindole (1.13g, 1 mol equivalent) were added at 25-30°C to obtain a clear solution. After 3 hours stirring at 25-30°C, an orange solid progressively precipitated out of the solution. The orange solid was isolated by filtration, washed with methanol (10ml) and dried under vacuum at 60-65°C for 3-4 hours.

Yield = 3g (75%)

Chemical Purity (HPLC) > 98.51%

Yield = 50%

Chemical Purity (HPLC) > 99.49%

Polymorphic Purity (XRPD) > 99% (other polymorphic forms below detection limit)

The structure of sunitinib malate was confirmed by NMR and HPLC retention time with standard sample. XRPD analysis indicated polymorphic form I as shown in Figure 1. Sumtinib malate polymorphic form I was obtained before and after recrystallisation.

Example 7: Preparation of di-diisopropyl ammonium malate

Into 10ml of methanol at 25-30°C, diisopropyl amine (3g, 2 mol equivalent) was added followed by the addition of L-malic acid (2g, 1 mol equivalent). A clear solution was observed. After stirring for 1 hour, the solvent was removed under vacuum on a rotary evaporator to afford a dark yellow oil.

Yield = 4.9g (98%)

NMR (solvent: DMSO-d₆): 1.07 (d, 12H), 1.09 (d, 12H), 2.30 (dd, IH), 2.65 (dd, IH), 3.05- 3.13 (m, 4H), 3.80-3.84 (dd, IH) Example 8: Preparation of sunitinib malate from di-diisopropyl ammonium malate

Into 20ml of acetonitrile : methanol (3:2), di-diisopropyl ammonium malate (1.9g, 1.5 mol equivalent), N-[2-(<diethylamino)emyl]-5-formyl-2,4-dimemyl-lH-pyrrole-3-carboxami (2g, 1 mol equivalent) and 5-fluoro-2-oxindole (1.13g, 1 mol equivalent) were added at 25- 30°C to obtain a clear solution. After stirring for 3 hours at 25-30°C, a yellow solid progressively precipitated out of the solution. The yellow solid was isolated by filtration, washed with methanol (10ml) and dried in a vacuum oven at 60-65°C for 3-4 hours.

Yield = 2.9g (72.5%)

Chemical Purity (HPLC) > 97.84%

Yield = 70%

Chemical Purity (HPLC) > 98.77%

Polymorphic Purity (XRPD) > 99% (other polymorphic forms below detection limit)

The structure of sunitinib malate was confirmed by NMR and HPLC retention time with standard sample. XRPD analysis indicated polymorphic form I as shown in Figure 1. Sunitinib malate polymorphic form I was obtained before and after recrystallisation.

Example 9: Preparation of dipyrrolidine malate

Into 10ml of methanol at 25-30°C, pyrrolidine (2.1g, 2 mol equivalent) was added followed by the addition of L-malic acid (2g, 1 mol equivalent). A clear solution was observed after 15 minutes. After stirring for 1 hour, the solvent was removed under vacuum on a rotary evaporator to afford a light yellow oil.

Yield = 4g (98%)

NMR (solvent: DMSO-d₆): 1.78 (t, 8H), 2.01-2.09 (dd, IH), 2.37-2.43 (dd, IH), 3.01-3.16 (t, 8H), 3.87-3.91 (m, IH) Example 10: Preparation of sunitinib malate from dipyrrolidine malate

Into 20ml of acetonitrile : methanol (3:2), dipyrrolidine malate (3.1g, 1.5 mol equivalent), N-[2-(diethylamino)ediyl]-5-foimyl-2,4-dimemyl-lH-pyrrole-3-carboxamide (2g, 1 mol equivalent) and 5-fiuoro-2-oxindole (l-13g, 1 mol equivalent) were added at 25-30°C to obtain a clear solution. After 3 hours stirring at 25-30°C, a yellow solid progressively precipitated out of the solution. The yellow solid was isolated by filtration, washed with methanol (10ml) and dried under vacuum at 60-65°C for 3-4 hours.

Yield = 1.3g (32%)

Chemical Purity (HPLC) > 97.87%

Polymorphic Purity (XRPD) > 95%

The structure of sunitinib malate was confirmed by NMR and HPLC retention time with standard sample. XRPD analysis indicated polymorphic form I as shown in Figure 1.

Example 11: Preparation of di-n-propyl ammonium malate

Into 10ml of methanol at 25-30°C, n-propyl amine (1.76g, 2 mol equivalent) was added followed by the addition of L-malic acid (2g, 1 mol equivalent). A clear solution was observed. After stirring for 1 hour, the solvent was removed under vacuum on a rotary evaporator to afford a light yellow oil.

Yield = 3.5g (95%)

NMR (solvent: DMSO-d₆): 0.85-0.90 (t, 6H), 1.47-1.55 (m, 4H), 2.05-2.13 (dd, 1H), 2.39- 2.46 (dd, 1H), 2.63-2.68 (t, 4H), 3.84-3.89 (t, 1H) Example 12: Preparation of sunitinib malate from di-n-propyl ammonium malate

Into 20ml of acetonitrile : methanol (3:2), di-n-propyl ammonium malate (2.85g, 1.5 mol equivalent), N-[2-(diemylammo)emyl]-5-formyl-2,4-dimemyl-lH-pyrrole-3-carboxami (2g, 1 mol equivalent) and 5-fluoro-2-oxindole (1.13g, 1 mol equivalent) were added at 25- 30°C to obtain a clear solution. After 3 hours stirring at 25-30°C, a yellow solid progressively precipitated out of the solution. The yellow solid was isolated by filtration, washed with methanol (10ml) and dried under vacuum at 60-65°C for 3-4 hours.

Yield = 3g (75%)

Chemical Purity (HPLC) > 98.39%

Polymorphic Purity (XRPD) > 95%

The structure of sunitinib malate was confirmed by NMR and HPLC retention time with standard sample. XRPD analysis indicated polymorphic form I as shown in Figure 1. The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof.

Claims

1. A process for preparing an acid addition salt of sunitinib comprising: reacting a pyrrole derivative III)

with a 5-fluoro-2-oxindole derivative II) to form a reaction mixture

2. A process according to claim 1 , wherein the acid is an inorganic acid selected from the group comprising HC1, HBt, HN0₃, H₃P0₄, H₂S0₄ and HC10₄.

3. A process according to claim 1, wherein the acid is an organic acid.

4. A process according to claim 3, wherein the organic moiety of the organic acid is hydrogen, or a straight or branched chain, substituted or unsubstituted alkyl, alkenyl, allyl, aryl or arylalkyl group, or a heteroatom-substituted straight or branched chain alkyl or aryl group.

5. A process according to claim 3 or 4, wherein the organic acid is selected from the group comprising acetic acid, formic acid, oxalic acid, D-malic acid, L-malic acid, DL-malic acid, maleic acid, methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid and malonic acid.

6. A process according to any one of claims 1 to 5, wherein the amine or ammonium moiety is selected from the group comprising primary amines and secondary amines.

7. A process according to claim 6, wherein the amine or ammonium moiety is selected from the group comprising cyclic amines, allyl amines, arylalkyl amines, heteroalkyl amines, alkyl amines, alkenyl amines, alkynyl amines and aryl amines.

8. A process according to any one of claims 1 to 7, wherein the reaction is carried out at between about 0°C to about 50°C.

9. A process for the preparation of sunitinib malate comprising: (i) reacting a pyrrole derivative (III)

(ii) with a 5-fiuoro-2-oxindole derivative II) to form a reaction mixture

adding an amine derived or ammonium derived malate salt to the reaction mixture and

(iv) isolating the sunitinib malate salt; wherein one of R₈ or R₈a is a formyl group and the other is H.

10. A process according to claim 9, wherein the process is carried out in an organic solvent system.

11. A process according to claim 10, wherein the organic solvent system is acetonitrile : methanol.

12. A process according to claim 11, wherein the v/v ratio of acetonitrile to methanol is about 5:1 to about 1:5.

13. A process according to claim 12, wherein the v/v ratio of acetonitrile to methanol is about 3:2.

14. A process according to any one of claims 9 to 13, wherein the malic acid is L-malic acid.

15. A process according to any one of claims 9 to 14, wherein the amine or ammonium moiety is selected from the group comprising primary amines and secondary amines.

16. A process according to claim 15, wherein the amine or ammonium moiety is selected from the group comprising cyclic amines, allyl amines, arylalkyl amines, heteroalkyl amines, alkyl amines, alkenyl amines, aLkynyl amines and aryl amines.

17. A process according to claim 9, wherein the amine derived or ammonium derived malate salt is selected from the group comprising 2-(N,N-diemylamino)ethyl ammonium malate, 2-(N,N-die ylamino)ethyl ammonium dimalate, diammonium malate, dipyrrolidine malate, di-n-propyl ammonium malate, and di-diisopropyl ammonium malate.

18. A process according to any one of claims 9 to 17, wherein the reaction is carried out at: © between about 0°C to about 50°C; and/or

(ϋ) between about 20°C to about 40°C; and/ or

(iii) between about 25°C to about 35°C.

19. An amine derived or ammonium derived malate salt for use in the preparation of su tinib malate.

20. Sunitinib malate prepared by a process according to any one of claims 9 to 18, having a purity as determined by HPLC of:

(i) at least 97%; or

(ii) at least 99%; or

(iii) at least 99.8%.

21. Sunitinib malate having a purity as determined by HPLC of:

(i) at least 97%; or

(ii) at least 99%; or

(iii) at least 99.8%.

22. Sunitinib malate according to claim 20 or 21, for:

(i) use in medicine; and/ or

(ii) treating a protein kinase mediated disorder; and/ or

(iii) treating a cell proliferative disorder; and/ or

(iv) treating advanced renal cell carcinoma (RCC) or gastrointestinal stromal tumor (GIST).

23. A pharmaceutical composition comprising sunitinib malate according to any one of claims 20 to 22, or prepared by a process according to any one of claims 9 to 18, and one or more pharmaceutically acceptable excipients.

24. A pharmaceutical composition according to claim 23, for use in the treatment of:

(i) a protein kinase mediated disorder; and/ or

(ii) a cell proliferative disorder; and/ or

(iii) advanced renal cell carcinoma (RCC) or gastrointestinal stromal tumor (GIST).

25. Use of sunitinib malate according to any one of claims 20 to 22, or prepared by a process according to any one of claims 9 to 18, in the manufacture of a medicament for the treatment of:

(i) a protein Idnase mediated disorder; and/ or

(ii) a cell proliferative disorder; and/ or

26. A method of treating a protein Idnase mediated disorder, comprising administering to a patient in need thereof a therapeutically effective amount of sunitinib malate according to any one of claims 20 to 22, or prepared by a process according to any one of claims 9 to 18.

27. A method according to claim 26, wherein the disorder is:

(i) a cell proliferative disorder; and/ or

advanced renal cell carcinoma (RCC) or gastrointestinal stromal tumor (GIST).

28. An amine derived or ammonium derived acid addition salt for use in the preparation of the corresponding acid addition salt of sunitinib.

29. An acid addition salt of sunitinib prepared by a process according to any one of claims 1 to 8, having a purity as determined by HPLC of:

(l) at least 97%; or

(ii) at least 99%; or

(iii) at least 99.8%.

30. An acid addition salt of sunitinib having a purity as determined by HPLC of:

(i) at least 97%; or

(ii) at least 99%; or

(iii) at least 99.8%.

31. An acid addition salt of sunitinib according to claim 29 or 30, for:

® use in medicine; and/ or (ii) treating a protein kinase mediated disorder; and/or

(iii) treating a cell proliferative disorder; and/ or

32. A pharmaceutical composition comprising an acid addition salt of sunitinib according to any one of claims 29 to 31, or prepared by a process according to any one of claims 1 to 8, and one or more pharmaceutically acceptable excipients.

A pharmaceutical composition according to claim 32, for use in the treatment of: a protein kinase mediated disorder; and/ or

a cell proliferative disorder; and/ or

advanced renal cell carcinoma (RCC) or gastrointestinal stromal tumor (GIST).

34. Use of an acid addition salt of sunitinib according to any one of claims 29 to 31, or prepared by a process according to any one of claims 1 to 8, in the manufacture of a medicament for the treatment of:

(i) a protein kinase mediated disorder; and/ or

(ii) a cell proliferative disorder; and/ or

35. A method of treating a protein kinase mediated disorder, comprising administering to a patient in need thereof a therapeutically effective amount of an acid addition salt of sunitinib according to any one of claims 29 to 31, or prepared by a process according to any one of claims 1 to 8.

36. A method according to claim 35, wherein the disorder is:

(i) a cell proliferative disorder; and/ or

(ii) advanced renal cell carcinoma (RCC) or gastrointestinal stromal tumor (GIST).