FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention: PYRROLE DERIVATIVES
2. Applicant(s):

(a) NAME: MYLAN INDIA PRIVATE LIMITED
(b) NATIONALITY: An Indian Company.
(c) ADDRESS: Plot 1A/2, MIDC. Industrial Estate, Taloja,
Panvel, District Raigad, Maharashtra-410208, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed :

FIELD OF INVENTION
The present invention relates to novel intermediates in the preparation of sunitinib (VII) and salts thereof, in particular sunitinib malate (IV) , to processes for preparing said intermediates, and to suntinib and its salts, in particular sunitinib malate (IV) prepared using said processes. The invention also relates to compositions comprising sunitinib or its pharmaceutically acceptable salts prepared via said novel intermediates.
Sunitinib is a multi-targeted receptor tyrosine kinase (RTK) inhibitor approved as the malate

salt by the FDA for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST).
(IV)
There is thus considerable interest in the development of hew processes for the preparation of sunitinib or its salts. Any new process should be advantageous in terms of cost, operability in manufacturing and result in sunitinb or a salt thereof having high purity.
BACKGROUND OF INVENTION
There are several processes disclosed in the prior art for the preparation of sunitinib base (VII) and its malate salt. These processes generally involve the condensation of a pyrrole derivative and a 2-oxindole derivative in the presence of a base to form sunitinib free base (VII). The free base (VII) is then converted into the malate salt by treating the free base (VII) with malic acid.
1. US 6,573,293 B2, US 2006/0009510 A1 and J. Onj. Chem. 2003, 68(16), 6447-6450 describes condensation of an appropriate pyrrole derivative with a 2-oxindole in the presence of pyrrolidine or potassium hydroxide as a base to afford sunitinib free base.
2. WO 03/070725 and US 7119209 B2 describe a three component condensation, comprising reacting an appropriate pyrrole derivative with a 2-oxindole and the

additional step of reacting an amine with the pyrrole substituted indolinone to form sunitinib free base.
3. US 7,125,905 or US 7,435,832 B2 describes 3 process for the preparation of sunitinib malate from sunitinib free base and malic acid.
4. Another approach for the preparation of sunitinib base has been described in patent application PCT/GB2009/050771 where N-[2-(Diethylamino)ethyl]- 2,4-dimethyMH-pyrrole-3-carboxamide and 5-fluoro 3-formyl 2-oxindole are condensed in the presence of an acid catalyst.
5. An approach for the direct preparation of sunitinib malate is described in WO 2009/150523 and involves condensation of the malic acid salt of N-[2-(Diethylamino)ethyl]-5-forrnyl-2,4-dimethyl-1 H-pyrrole-3-carboxamide and 5-fluoro-2-oxindole (5-fluoro-1,3-dihydroindol-2-one) in presence of organic amine.
There are also several patents and patent applications describing various approaches to synthesizing the key pyrrole derivatives disclosed above.
With the exception of WO 2009/150523, the above prior art processes involve the isolation of sunitinib base before conversion to a salt thereof. However, the inventors have found several drawbacks in working with sunitinib base for the following reasons:
1. the low solubility profile of sunitinib base in a significant number of the 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 require 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 on an industrial scale.
3. conversion of sunitinib base to sunitinib malate involves the addition of a solution comprising malic acid to the sunitinib base. The aforementioned problems of solubility of the base in commonly used solvents means 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 is amenable to purification. Thus, the complete formation of the sunitinib

malate salt during this step is difficult to judge due to the heterogenous nature of the reaction mass from during the reaction.
The only process, described in WO 2009/150523, involving direct isolation of sunitinib malate salt, employs a high temperature of 79°C or above and also requires an organic amine (secondary amine) to effect this transformation.
WO 2009/150523 describes a process for the direct preparation of sunitinib malate involving the condensation of the malate salt of N-[2-(Diethylamino)ethyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide, with 5-fluoro-2-oxindole 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 malic salt of N-[2-(Diethylammo)ethyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide also means that said malate salt has to be prepared and isolated or requires an extra step of first preparing the malate salt then adding the remaining reactants to prepare sunitinb malate.

In view of the importance of pyrrole substituted indolinones such as sunitinib in the treatment of cancer, there is a great need for developing an improved and commercially feasible
The prior art processes all require the presence of a carbonyl group either on the pyrrole derivative or the oxindole derivative. The inventors have found that use of pyrrole intermediates with these carbonyl groups result in unreacted carbonyl pyrrole derivatives (VI and VIM) as contaminants. Scheme 1 shows a generalised scheme for preparing sunitinib malate according to the prior art.

process for the preparation of sunitinib salts. In particular there is a need for a one pot process that results in pure sunitinib, in particular sunitinib malate without the presence of aldehyde contaminants (VI and VIII) or the need for a further purification step and wherein sunitinib base does need to be isolated separately.

SUMMARY OF THE INVENTION
In order to overcome the problems associated with the prior art, in particular handling sunitinib base (VII) and preparing particularly pure sunitinib salts such as sunitib malate, the inventors have found that when a sulphite intermediate of N-[2-(Diethylamino)ethyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (I) is reacted with 5-fluoro-2-oxindole (II) in the presence of an amine derived or ammonium derived salt, particularly pure sunitinib or a salt thereof comprising undetectable amounts of compounds VI and VIM is obtained. Accordingly, there is provided in a first aspect of the invention a process for preparing sunitinib or a salt thereof comprising:
reacting a pyrrole derivative (I)


In preferred embodiments a process for preparing an acid addition salt of sunitinib is provided comprising adding an acid to the mixture. The acid may comprise an inorganic acid for example selected from the group comprising HCI, HBr, HN03, H3PO4, H2S04 and HCIO4 or alternatively the acid may comprise and organic acid, preferably the organic moiety of the organic acid is a straight or branched chain, substituted or unsubstituted alkyl, alkenyl, allyl group, aryl group, aryl alkyl group, hetero atom substituted straight or branched chain alkyl or aryl group. In particularly preferred embodiments the organic acid is selected from the group comprising sulfonic acids, 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. Preferably the acid is L malic acid and the resulting salt is sunitinib L malate.
Alternatively, in particularly preferred embodiments, acid addition salts of sunitinib may be prepared by adding an amine derived or ammonium derived salt of the acid to the reaction

mixture. In a preferred embodiment the acid moiety is an inorganic acid selected from the group comprising HCI, HBr, HN03i H3PO4, H2S04 and HCIO4. In an alternative embodiment the acid is an organic acid, preferably the organic moiety of the organic acid is a straight or branched chain, substituted or unsubstituted alkyl, alkenyl, allyl group, aryl group, aryl alkyl group, hetero atom substituted straight or branched chain alkyl or aryl group. In particularly preferred embodiments the organic acid is selected from the group comprising sulfonic acids, 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. Most advantageously the acid is L-malic acid.
In particularly preferred embodiments when the amine derived or an ammonium derived acid addition salt is added to the reaction mixture the amine moiety is selected from the group comprising primary amines and secondary amines, preferably the amine moiety is selected from the group comprising cyclic amines, allyl amines, arylalkyl amines, heteroalkyl amines, alkyl amines, alkenyl amines, alkynyl amines and aryl amines.
In the most advantageous embodiments the amine derived or ammonium derived acid addition salt is a malate salt preferably selected from the group comprising: 2-(N,N-diethylamino)ethylammonium malate, 2-(N,N-diethylamino)ethylammonium di-malate, ammonium malate, dipyrrolidine malate, n-propylammonium malate, diisopropylammonium malate.
In a preferred embodiment according to the first aspect of the invention X is a metal cation, preferably an alkali metal or an alkaline earth metal, advantageously the metal cation is either sodium or potassium, most advantageously sodium.
A process according to the first aspect of the invention wherein the sunitinib or salt thereof is isolated. In particularly preferred embodiments the sunitinib or salt thereof is further purified by recrystallisation from a C1-C6 alcohol-water mixture, preferably the C1-C6 alcoho!:water mixture has a ratio of 4:1, most preferably the C1-C6 alcohol is n-butanol.

In certain preferred embodiments of a process according to the first aspect of the invention the reaction is carried out at between about 0°C to about 50°C, preferably at between about 20 to about 40°C, most preferably at between about 25°C to about 35DC.
in further preferred embodiments according to the first aspect of a process according to the invention the process is carried out in an organic solvent system, preferably the organic solvent system comprises acetonitrile and methanol. Advantageously the v/v ratio of acetonitrile to methanol is from about 5:1 to about 1:5. Most advantageously the v/v ratio of acetonitrile to methanol is 3:2.
In further advantageous embodiments according to the first aspect of the invention the reaction mixture during stages i) and ii) has a pH of between 4.0 to 7.0, preferably between 4.0 to 6.0, most preferably between 4.0 to 5.0.
A second aspect provides sunitinib or a salt thereof prepared according to the first aspect of the invention having purity as determined by HPLC of at least 97%, preferably 99%, most preferably 99.8%. In particularly preferred embodiments the sunitinib salt is sunitinib malate (IV).
A third aspect of the invention provides a pyrrole derivative (|),

wherein X is a suitable cation and n is 1, 2 or 3.
In a preferred embodiment according to the fourth aspect of the invention X is a metal cation, preferably an alkali metal or an alkaline earth metal, advantageously the metal cation is either sodium or potassium, most advantageously sodium.

In a fourth aspect of the invention a process for preparing a pyrrole derivative (I) is provided comprising
reacting the aldehyde (VI)

(VI) with a bisulphite anion of formula [HS03 ]
Preferably, the bisulphite anion is provided by mixing a metabisulphite salt in the reaction mixture. Alternatively a bisulphite salt could be used. Preferably, an alkali metal or an alkaline earth metal, advantageously the salt is an alkali bisulphite salt, preferably sodium or potassium bisulphite, most preferably the alkali bisulphite is sodium bisulphite NAHSO3
Preferably the metabisulphite salt is a salt of an alkali metal or an alkaline earth metal, advantageously the salt is an alkali metabisulphite salt, preferably sodium or potassium metabisulphite, most preferably the alkali metabisulphite is sodium metabisulphite.
In certain preferred embodiments of a process according to the fourth aspect of the invention the reaction occurs in an aqueous, C1-5 alcohol solvent system, preferably the C1-5 alcohol is ethanol.
In further preferred embodiments the reaction occurs at a temperature in the range of -10°C to reflux of the alcohol. Most preferably the reaction occurs at a temperature in the range of 10°Cto30°C.
In further advantageous embodiments according to the fourth aspect of the invention the reaction mixture has a pH of between 4.0 to 7.0, preferably between 4.0 to 6.0, most preferably between 4.0 to 5.0.
In certain preferred embodiments pyrrole derivative (I) is further isolated preferably by filtration

A fifth aspect provides pyrrole derivative (I) prepared according to the fourth aspect of the invention having purity as determined by HPLC of at least 97%, preferably 99%, most preferably 99.8%. Further particularly preferred embodiments provide pyrrole derivative (I) comprising less than 3% of compounds (VI) and/or (VIII), preferably less than 1%, advantageously less than 0.1%, most advantageously less than 0.01%.
A sixth aspect provides sunitinb or salts thereof comprising less than 3% of compounds (VI) and/or (VIII), preferably less than 1%, advantageously less than 0.1%, most advantageously less than 0.01%.
A seventh aspect provides a composition comprising sunitinib or a salt thereof according to the second or sixth aspect of the invention or prepared according to the first aspect of the invention and one or more pharmaceutically acceptable excipients. Most preferably the sunitinib salt is sunitinib malate (IV). Preferably the composition is for use In the treatment of a protein kinase mediated disorder, in certain embodiments the disorder is a cell proliferative disorder, and in further embodiments the disorder is one of advanced renal cell carcinoma (RCC) or gastrointestinal stromal tumor (GIST).
Scheme 2 shows a generalised scheme for preparing sunitinib or salt thereof via pyrrole derivative (I) according to the invention. Route A relates to preparing sunitinib acid addition salts by adding an amine derived or ammonium derived salt of the acid to the reaction mixture, in this case the acid moiety is a carboxylic acid. Route B relates to the preparation sunitinib acid addition salts by preparing suntinib base (VII) and subsequent in situ addition of the desired acid.

wherein X is a suitable cation and n is 1, 2 or 3
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: XRP Diffractogram of sunitinib malate (IV) as disclosed in US 7,435,832
corresponds to Form I.
DETAILED DESCRIPTION OF THE INVENTION
As used herein the term "solvent system" can be taken to mean one of the following:
1. Single organic solvent
2. Combination of two or more organic solvents in various proportions.
3. Combination of water and organic solvents in various proportions.
The inventors have found that utilising a novel sulphite pyrrole derivative (I) in the condensation reaction with a 2-oxindole, in particular 5-fluoro-2-oxindole (II) provides an alternative route to preparing pure sunitinib or a salt thereof, in particular sunitinib malate (IV). . Accordingly, there is provided in a first aspect of the invention a process for preparing sunitinib or a salt thereof comprising:
reacting a pyrrole derivative (I)


wherein X is a suitable cation and n is 1, 2 or 3.
In a preferred embodiment according to the first aspect of the invention X is a metal cation, preferably an alkali metal or an alkaline earth metal, advantageously the metal cation is either sodium or potassium, most advantageously sodium.
In a preferred embodiment of a process according to the first aspect of the invention when an acid addition salt of sunitinib is prepared the acid moiety is an inorganic acid selected from the group comprising HCI, HBr, HN02 H3P04, H2S04 and HCI04 In an alternative embodiment the acid is an organic acid, preferably the organic moiety of the organic acid is a straight or branched chain, substituted or unsubstituted alkyl, alkenyl, atlyl group, aryl group, aryl alkyl group, hetero atom substituted straight or branched chain alkyl or aryl group. In particularly preferred embodiments the organic acid is selected from the group comprising sulfonic acids, mono, di, and tri carboxylic acids, (n 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.
The inventors have found that when an acid addition salt of an organic amine or ammonia or derivatives thereof and an organic or inorganic acid is added to the reaction mass containing pyrrole derivative (I) and 5-fluoro-2-oxindole derivative (II), the resulting corresponding sunitinib salt is obtained whereby the salt moiety is obtained from the acid of the initial organic amine or ammonia salt added. The resulting sunitinib salt has surprisingly high purity, high quantitative yield, required relatively reduced reaction time and importantly most surprisingly the reaction can be carried out 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 and carboxylic acid derivatives results in a simpler, more cost effective one pot process for the preparation of sunitinb salts. In particular, sunitinb malate. The process may also be used to prepare sunitinib base (VII) by simple condensation of pyrrole derivative (t) and 5-fluoro-2-oxindole derivative (II). The base (VII) may then be utilised conventionally to prepare acid addition

salts such as sunitinib malate (IV) by adding the desired acid, such as malic acid to the reaction mixture.
The inventors have also found that sunitinib or salts thereof prepared using pyrrole derivative (I) do not comprise any detectable by-products normally associated with sunitinib preparation. In particular

The prior art processes at! require the presence of a carbonyi group either on the pyrrole derivative or the oxindole derivative. The inventors have found that use of pyrrole intermediates with these carbonyi groups result in unreacted carbonyi pyrrole derivatives (VI and VIII) as contaminants. The processes of the invention do not require these carbonyi intermediates. Indeed The absence of formyl intermediates (VI) and (VIII) was confirmed by spectroscopic analysis (IR, 1HNMR, HPLC) of the reaction mixture. The compounds (VI) and (VIII) were not detected at any point during the condensation reaction of the sulphite pyrrole derivative (I) and the 5-fluoro-2-oxindole derivative (II).
The preparation of sunitinib base (VII) or sunitinib acid addition salts from the corresponding pyrrole derivative (I) is preferably achieved under the influence of the amine derived or ammonium derived salt of the acid. This salt catalyses the condensation of the pyrrole derivative (I) and 5-fluoro-2-oxindole (II) under acidic pH. Typically, the pH of the reaction is between about 4.0- 7.0, more preferably between 4.0- 5.5.
As the pyrrole derivative (I) is prepared under the same pH conditions, as the amine catalysed condensation reaction, the pyrrole derivative (I) remains intact and does not revert back to the corresponding aldehyde precursor during the reaction.
In a further aspect according to the invention there is provided a process for the preparation of sunitinib malate (IV) comprising:


with 5-fluoro-2-oxindole /ol) was added drop wise to the above solution over a time period of 15 to 20 mins, whilst maintaining the temperature below 20°C. The temperature of the reaction mixture was reduced and maintained at about 10°C and stirred for a further 1 to 2 hours. The resulting precipitate was filtered and washed with ethanol (10ml, 5vol) followed by water (4ml, 2vol). The solid obtained was then dried in a vacuum oven at 40°C to obtain the title compound.
Yield= 2.1g; %Molar Yie)d= 79%. )R {KBr, cmA); 3376 (N-H str.), 3298 {O-H sir.) 2976 & 2943 (ali C-H str.), 1609 (C-O str.), 1533, 1511, 1438, 1381, 1341, 1254, 1171, 1061, 1025, 980, etc. 1H NMR (DMSO-d6): 2.04 (s, 3H, -CH3), 2.28 (s, 3H, -CH3), 2.50 (m, 6H, -CH2-
CH3), 3.34 (m, 8H, -CH2-), 4.87 (d, 1H, >CH-OH), 5.52 (d, 1H, -OH, D20 exch), 6.92 (s, 1H, >NH, D20 exch), 10.07 (bs, 1H, >NH, D20 exch).
Example 3: Preparation of Sunitinib malate (IV) using the sodium salt of pyrrole derivative (I)
Sodium pyrrole derivative N-[-2-(Diethylamino)ethyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (I) (10g, 0.028M), 5-fluoro-2-oxindole (4.3g, 0..028M) and 2-(N,N-diethylamino)ethylammonium-(di)-malate (16.32g, 0-042M) were added to acetonitrile:methanol (6:4 vol), at 25-30°C. A clear solution was obtained within 5 minutes. After stirring for 3hr at 25-30°C a yellow solid progressively precipitated out of the solution. The yeltow solid was isolated by filtration, washed with methanol (5vol, 50ml) and dried under vacuum at 55-60°C for 3-4 hrs.
Yield= 10g; %Molaryield= 66.66%, IR (KBr): 3326 cm"1 (broad, N-H str.), 3231 (broad O-H str.), 3063, 2927, 1671 (>C=0), 1654, 1636, 1577, 1475, etc. 1H NMR (DMSO-d6): 1.12 ppm
(t, 6H, J= 7.14Hz, 2 x - CH2CH.3;), 2.36 (m, 2H, -CH2-COOH), 2.44 (s. 3H, -CH3), 2.46 (s, 3H, -CH3), 2.55 (m, 1H, -CHOH-COOH), 2.92 (m, 6H, 3 x -CHgz), 4.02 (m, 2H, -CHgz), 6.86 (m, 1H, vinyl), 6.94 {t, 1H, J= 10.22Hz, 2H, aromatic ortho position), 7.64 (bs, 1H, -CONH-,

D2O exchangeable), 7.73 (s, 1H, aromatic ortho position), 7.78 (d, 1H, J= 9.42Hz, aromatic meta position), 10.92 (s, 1H, -NH-OH, D20 exchangeable), 13.73 (s, 1H, -NH-pyrrole, D20 exchangeable). 13C NMR (DMSO-d6): 9.69 ppm (2C, 2 x -CH2-CH3 DEPT), 10.68 (1C, CH3 DEPT), 13.46 (1C, CH3 DEPT), 35.01 (1C, CH2 DEPT), 40.89 (1C, CH2i DEPT), 46.81 (2C, 2 x CH2 DEPT), 50.57 (1C, CH2 DEPT), 66.40 (1C, vinyl, DEPT), 106.06 (d, 1C, Ar-C, ortho position, DEPT), 110.08 (d. 1C. Ar-C, ortho position, DEPT), 112.60 (d, 1C, Ar-C, meta position, DEPT), 115.04 (1C, -CHOH-COOH), 124.91 C=0), 1560, 1475, etc. 1H NMR (DMSO-d6): 5 0.97 ppm (t, J= 7.08Hz, 6H, 2 x
-CH2-CH3-), 2.42 (s, 3H, -CH3;), 2.44 (s, 3H, -CH3;), 2.47- 2.56 (m, 6H, >N-CH_2-), 3.25-
3.31 (m, 2H, -CO-NH-CH2), 6.83- 6.87 (m, 1H, vinyl proton), -CO-NH-CH2-, D20
exchangeable), 6.90- 6.94 (t, J= 5.9Hz, 1H, aromatic ortho position), 7.43- 7.47 (t, J= 5.6Hz, 1H, aromatic meta position), 7.74- 7.78 (dd, J= 5.9Hz, 1H, aromatic ortho position), 7.72 (s, 1H, aliphatic amide -NH-, D20 exchangeable), 10.90 (s, 1H, pyrrole -NH-, D20
exchangeable), 13.68 (s, 1H, indole -NH-, D20 exchangeable. "C NMR (DMSO-d6): 6 10.64
ppm (1C, -CH3-, DEPT), 11.92 (2C, 2 x -CH2-CH3 DEPT), 13.38 (1C, -CH3-, DEPT), 37.02
(1C, -CH2-, DEPT), 46.55 (2C. -CH2-, DEPT), 51.69 (1C, -CH2-, DEPT), 105.90 (1C, d,
aromatic ortho position, DEPT), 110.10 90 (1C, d, aromatic meta position, DEPT), 112.45

(1C, d, aromatic meta position, DEPT), 124.94 (1C, vinyl DEPT), (127.22 (1C, d, =C-F, aromatic, DEPT), 114.62- 159.84 (2C-CO-C=C- non aromatic, 6H Ar-C), 164.60 (1C, >CO), 169.63 (1C, >CO). Mass (m/z): (M+1) 399 (100%), [(M+2) +1] 401 (14%).
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.

WE CLAIM
1. A process for preparing sunitinib (VII) or salt thereof comprising: reacting a pyrrole derivative (I)

wherein X is a suitable cation and n is 1, 2 or 3.
2. A process according to claim 1 for preparing an acid addition salt of sunitinib comprising adding an acid to the reaction mixture.
3. A process according to claim 1 for preparing an acid addition salt of sunitinib comprising adding an amine derived or ammonium derived salt of the acid to the reaction mixture.
4. A process according to claim 2 or 3 wherein the acid is an inorganic acid.
5. A process according to claim 4 wherein the inorganic acid is selected from the group comprising HCI, HBr, HN03, H3P04, H2S04 and HCI04,

6. A process according to claim 2 or 3 wherein the acid is an organic acid.
7. A process according to claim 6 wherein tine organic moiety of the organic acid is selected from the group comprising: a straight or branched chain, substituted or unsubstituted alkyl, alkenyl, allyl group, aryl group, aryl alkyl group, hetero atom substituted straight or branched chain alkyl or aryl group.
8. A process according to claim 7 wherein the organic acid is selected from the group comprising sulfonic acids, mono, di, and tri carboxylic acids.
9. A process according to claim 8 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.
10. A process according to claim 9 wherein the acid is L-malic acid.
11. A process according to claim 3 wherein the amine moiety is selected from the group comprising: primary amines and secondary amines.
12. A process according to claim 11 wherein the amine moiety is selected from the group comprising cyclic amines, allyl amines, arylalkyl amines, heteroalkyl amines, alky! amines, alkenyl amines, alkynyl amines and aryl amines.
13. A process according to claim 3 wherein the amine derived or ammonium derived acid addition salt is a malate salt.
14. A process according to claim 13 wherein the amine derived or ammonium derived acid addition salt is a malate salt selected from the group comprising: 2-(N,N-diethylamino)ethylammonium malate, 2-(N,,N)-diethylamino)ethylammonium di-malate, ammonium malate, dipyrrolidine malate, n-propylammonium malate, diisopropytammonium malate.
15. A process according to any preceding claim wherein X is a metal cation.

16. A process according to claim 15 wherein X is an alkali metal or an alkaline earth metal.
17. A process according to claim 16 wherein X is either sodium or potassium.
18. A process according to claim 17 wherein X is sodium.
19. A process according to any preceding claim wherein the sunitinib or salt thereof is isolated.
20. A process according to claim 19 wherein the sunitinib or salt thereof is further purified by recrystallisation from a C1-C6 alcohol-water mixture.
21. A process according to claim 20 wherein the C1-C6 alcohol is n-butanol.
22. A process according to claim 20 or 21 wherein the C1-C6 alcohol:water mixture has a ratio of 4:1.
23. A process according to any preceding claim wherein the reaction is carried out at between about 25°C to about 35°C.
24. A process according to any preceding claim wherein the process is carried out in an organic solvent system.
25. A process according to claim 24 wherein the organic solvent system comprises acetonitrile and methanol.
26. A process according to claim 25 wherein the v/v ratio of acetonitrile to methanol is from about 5:1 to about 1:5.
27. A process according to claim 26 wherein the v/v ratio of acetonitrile to methanol is 3:2.
28. A process according to any preceding claim wherein the reaction mixture has a pH of between 4.0 to 7.0.

29. A process according to claim 28 wherein the reaction mixture has a pH of between 4.0 to 6.0.
30. A process according to claim 29 wherein the reaction mixture has a pH of between 4.0 to 5.0.
31. Sunitinib or a salt thereof prepared according to any of claims 1 to 30 having purity as determined by HPLC of at least 97%.
32. Sunitinib or a salt thereof according to claim 31 having purity as determined by HPLC of at least 99%.
33. Sunitinib or a salt thereof according to claim 32 having purity as determined by HPLC of at least 99.8%.
34. Sunitinib or a salt thereof comprising less than 3% of compounds (VI) and/or (VIII).
35. Sunitinib or a salt thereof comprising less than 1% of compounds (VI) and/or (VIII).
36. Sunitinib or a salt thereof comprising less than 0.01% of compounds (VI) and/or (VIII).
37. A sunitinib salt according to any of claims 31 to 36 wherein the salt is sunitinib malate.
38. A composition comprising sunitinib or a salt thereof according to any of claims 31 to 37 or prepared according any of claims 1 to 30 and one or more pharmaceutically acceptable excipients.
39. A composition according to claim 38 wherein the sunitinib salt is sunitinib malate (IV).
40. A composition according to claim 38 or 39 for use in the treatment of a protein kinase mediated disorder.

41. A pyrrole derivative (I),

(I) wherein X is a suitable cation and n is 1, 2 or 3.
42. A pyrrole derivative (I) according to claim 41 wherein X is a metal cation.
43. A pyrrole derivative (I) according to claim 42 wherein X is an alkali metal or an alkaline earth metal,
44. A pyrrole derivative (I) according to claim 43 wherein X is either sodium or potassium.
45. A pyrrole derivative (I) according to claim 44 wherein X is sodium.
46. A process for preparing a pyrrole derivative (I) comprising:
reacting the aldehyde (VI)

with a bisulphite anion of formula [HS03"], wherein X and n are as hereinbefore defined.
47. A process according to claim 46 wherein the bisulphite anion is provided by mixing a metabisulphite salt in the reaction mixture.

48. A process according to claim 47 wherein the metabisulphite salt is a salt of an alkali metal or an alkaline earth metal.
49. A process according to claim 48 wherein the metabisulphite salt is sodium or potassium metabisulphite.
50. A process according to claim 49 wherein the metabisulphite salt is sodium metabisulphite.
51. A process according to any of claims 46 to 50 wherein the reaction occurs in an aqueous, C1-5 alcohol solvent system.
52. A process according to claim 51 wherein the C1-5 alcohol I is ethanol.
53. A process according to any of claims 46 to 52 wherein the reaction mixture has a pH of between 4.0 to 7.0.
54. A process according to claim 53 wherein the reaction mixture has a pH of between 4.0 to 5.0.
55. A process according to any of claims 46 to 54 wherein the pyrrole derivative (I) is further isolated.
56. A pyrrole derivative (I) having purity as determined by HPLC of at least 97%.
57. A pyrrole derivative (I) according to claim 56 having purity as determined by HPLC of at least 99%.
58. A pyrrole derivative (I) according to claim 57 having purity as determined by HPLC of at least 99.8%.
59. A pyrrole derivative (I) according to claims 41 to 45 comprising less than 3% of compounds (VI) and/or (VIII).

60. A pyrrole derivative (I) according to claim 59 comprising less than 1% of compounds (VI) and/or (VIII).
61. A pyrrole derivative (I) according to claim 60 comprising less than 0.01% of compounds (VI) and/or (VIII).
62. A process for the preparation of sunitinib malate (IV) comprising:
with 5-fluoro-2-oxindole (II)
reacting a pyrrole derivative (I)


(II) in the presence of malic acid or an amine derived or an ammonium derived malic acid salt
and isolating the sunitinib malate (IV)
wherein X is a suitable cation and n is 1, 2 or 3.

63. A process according to claim 62 wherein the amine derived or ammonium derived malic acid salt is selected from the group comprising: 2-(N,N-diethylamino)ethylammonium malate, 2-(N,N) diethylamino)ethylammonium di-malate, ammonium malate, dipyrrolidine malate, n-propylammonium malate, diisopropylammonium malate.
64. A process according to claim 63 wherein the amine derived or an ammonium derived malic acid salt is 2-(N,N) diethylamino)ethylammonium di-malate.
65. A process according to any of claims 62 to 64 wherein the temperature of the reaction is between 25 to 35°C
66. A process according to any of claims 62 to 65 wherein the pH of the reaction mixture is between 4 to 6.
67. A process according to any of claims 62 to 66 wherein X is sodium.