WO2011004200A1

WO2011004200A1 - Novel pyrrole derivatives

Info

Publication number: WO2011004200A1
Application number: PCT/GB2010/051134
Authority: WO
Inventors: Vinayak Govind Gore; Laxmikant Patkar; Mahesh Gorakhnath Hublikar; Hemant Mande; Kiran Shivaji Pokharkar; Prakash Bansode
Original assignee: Generics [Uk] Limited; Mylan India Private Limited
Priority date: 2009-07-10
Filing date: 2010-07-09
Publication date: 2011-01-13

Abstract

The present invention relates to novel salts of pyrrole derivatives, their preparation and their use in the preparation of sunitinib salts, in particular sunitinib malate (IIa), and sunitinib base. The invention also relates to compositions comprising sunitinib salts or sunitinib base and the use of these compositions in the treatment of cancer.

Description

Novel Pyrrole Derivatives

Field of the invention The present invention relates to novel salts of pyrrole derivatives, their preparation and their use in the preparation of sunitinib salts, in particular sunitinib malate (Ha), and sunitinib base. The invention also relates to compositions comprising sunitinib salts or sunitinib base and the use of these compositions in the treatment of cancer.

Background of the invention

Sunitinib is a multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved as the malate salt by the FDA for the treatment of renal cell carcinoma (RCC) and imatinib- resistant gastrointestinal stromal tumour (GIST). Consequently, there is considerable interest in the development of new processes for its preparation. New processes should be advantageous in terms of cost, operability in manufacturing and high purity of the sunitinib product.

There are several processes disclosed in the prior art for the preparation of sunitinib base and its malate salt. These processes involve the condensation of a formyl pyrrole derivative and 5-fiuoro-2-oxindole 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 6,573,293, US 2006/0009510 and J. Org. Chem., 2003, 68(16), 6447-6450 describe condensation of the pyrrole derivative 1 (R⁶ = NHCH₂CH₂NEt₂) with 5- fiuoro-2-oxindole 2 in the presence of pyrrolidine or potassium hydroxide as a base to afford sunitinib free base (see scheme 1).

2. WO 03/070725 and US 7,119,209 describe a three component condensation, comprising reacting the pyrrole derivative 1 (R⁶ = OH) with 5-fluoro-2-oxindole 2 and the additional step of reacting an amine (H₂NCH₂CH₂NEt₂) with the pyrrole substituted indolinone to form sunitinib free base (scheme 2).

3. US 7,125,905 and US 7,435,832 describe a process for the preparation of sunitinib malate from sunitinib free base and malic acid.

scheme 1: R > 6^b _ = NHCH₂CH₂NEt₂

scheme 2: R⁶ = OH

any group

NR_:

acid

Schemes 1 and 2 There are also several patents describing various approaches to synthesizing the pyrrole derivative key fragment 1. However, all of the above processes suffer from the drawback that the pyrrole derivatives utilised in the prior art processes have low purity. The API obtained utilising these derivatives often requires additional purification steps to meet the quality specifications required for health authority approval. AU the processes described above also use the base form of the pyrrole derivative, nowhere is it mentioned that other forms of the pyrrole derivative may be used. The prior art processes also all require that sunitinib base is first prepared and subsequently converted to the salt of choice. This of course means that the additional step of salt formation is required. Many of the prior art processes also require that either the sunitinib base and/or the subsequent sunitinib salt be further purified for use as an active pharmaceutical ingredient.

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

Summary of the invention

In order to overcome the problems associated with the prior art, the inventors have found that when an acid addition salt form of the pyrrole derivative (I) is used as opposed to the base 1 used in the prior art (see schemes 1 and 2), the resulting sunitinib salt had surprisingly high purity and high quantitative yield. It was also surprisingly found that the use of the salt form of the pyrrole derivative (I) meant subsequent purification was reduced or not needed at all. The inventors also surprisingly found that a sunitinib salt could be prepared directly from the combination of the corresponding salt form of the pyrrole derivative (I) and a 5-fluoro-2-oxindole (III) without the need for first preparing the base (II) and then subsequently converting the base (II) to the desired salt as is the case in the prior art preparation of sunitinib salts. The process of the invention utilizing acid addition salts of pyrrole derivatives (I) resulted in a more simple and cost effective process for the - A - preparation of sunitinib salts. Accordingly there is provided in a first aspect of the invention a process for the preparation of an acid addition salt of a pyrrole substituted indolinone, comprising:

(i) mixing the corresponding acid addition salt of a pyrrole derivative with a 2- oxindole derivative to form a reaction mixture; and

(ii) adding a base to the reaction mixture.

A preferred embodiment of the present invention provides a process for the preparation of an acid addition salt of a pyrrole substituted indolinone (C)

, comprising:

(i) mixing the corresponding acid addition salt of a pyrrole derivative (A) with a 2- oxindole derivative (B) to form a reaction mixture

(ii) adding a base to the reaction mixture,

wherein

R¹ and R² are independently any atom or group,

m is O, 1, 2, 3 or 4,

n is 0, 1, 2, 3, 4 or 5, and

one of R⁸ or R⁸a is a formyl group and the other is H.

Preferably R¹ and R² are independently halo, R³, COR³, CO₂R³ or CON(R³)₂, wherein R³ is independently hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, O or S in its carbon skeleton.

Preferably R¹ is independently alkyl or CONHR³, more preferably R¹ is independently methyl or CO-NH-CH₂CH₂NEt₂.

Preferably R² is independently halo, more preferably R² is fiuoro.

Preferably m is 3.

Preferably n is i.

Another preferred embodiment of the present invention provides a process for the preparation of an acid addition salt of sunitinib (II)

comprising:

(i) mixing the corresponding acid addition salt of a pyrrole derivative (I) with a 5- fluoro-2-oxindole having formula (III) to form a reaction mixture

(ii) adding a base to the reaction mixture,

wherein one of R⁸ or R⁸a is a formyl group and the other is H. Preferably the acid moiety is an organic or inorganic acid. In certain preferred embodiments, the inorganic acid is selected from the group comprising hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid and perchloric acid, most preferably the inorganic acid is hydrochloric acid. In alternative embodiments, the organic acid is selected from the group comprising acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid and malonic acid. Most preferably the acid is (L) malic acid.

The preparation of the (L) malic acid salt of sunitinib (II) is particularly preferred. Accordingly, a particularly preferred embodiment of the present invention provides a process for the preparation of sunitinib malate (Ua)

comprising:

(i) mixing an (L) malic acid salt of a pyrrole derivative (T) with a 5-fluoro-2-oxindole having formula (III) to form a reaction mixture

(ii) adding a base to the reaction mixture,

wherein one of R⁸ or R⁸a is a formyl group and the other is H.

A second aspect of the invention provides acid addition salt forms of a pyrrole derivative having structure (I)

(I)

wherein R⁸ is a formyl group or hydrogen.

In certain embodiments of the present invention, the salt can serve as a means for purification of the pyrrole derivative (T). In further embodiments this salt can be treated with a base to obtain a high purity pyrrole derivative (T), which in further embodiments can then be condensed with a 5-fiuoro-2-oxindole (III) to obtain high purity sunitinib base (II).

A third aspect of the invention provides a process for preparing a salt form according to the second aspect, comprising mixing a pyrrole derivative (I) with an acid. Most preferably the acid is (L) malic acid and in particularly preferred embodiments the process for the preparation of the (L) malic acid salt of the pyrrole derivative (I) comprises:

(i) mixing (L) malic acid and a pyrrole derivative (I) in a solvent system; and

(ii) removing the solvent system.

A fourth aspect of the invention provides a salt form of a pyrrole derivative (I) according to the second aspect of the invention having a purity of at least 95% as measured by HPLC, preferably at least 97%, more preferably at least 99% and most preferably at least 99.7%. The most preferred embodiments comprise the (L) malic acid salt of the pyrrole derivative (I).

A fifth aspect of the invention provides sunitinib (II) or an acid addition salt of sunitinib (II) such as sunitinib malate (Ha), prepared according to the first aspect of the invention, preferably having a purity of at least 97% as measured by HPLC, preferably at least 99%, most preferably having a purity of at least 99.8%.

A sixth aspect of the invention provides sunitinib (II) or an acid addition salt of sunitinib (II) such as sunitinib malate (Ha), having a purity of at least 97% as measured by HPLC, preferably at least 99%, most preferably at least 99.8%. A seventh aspect of the invention provides a composition comprising sunitinib (II) or an acid addition salt of sunitinib (II) such as sunitinib malate (Ha) according to the fifth or sixth aspects of the invention and one or more pharmaceutically acceptable excipients.

An eighth aspect of the invention provides a use of sunitinib (II) or an acid addition salt of sunitinib (II) such as sunitinib malate (Ha) according to the fifth or sixth aspects of the invention, in the manufacture of a medicament for the treatment of a protein kinase mediated disorder. Preferably the disorder is a cell proliferative disorder, more preferably a solid tumour, more preferably advanced renal cell carcinoma (RCC) or gastrointestinal stromal tumour (GIST).

A ninth 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 sunitinib (II) or an acid addition salt of sunitinib (II) such as sunitinib malate (Ha) according to the fifth or sixth aspects of the invention. Preferably the disorder is a cell proliferative disorder, more preferably a solid tumour, more preferably advanced renal cell carcinoma (RCC) or gastrointestinal stromal tumour (GIST). Preferably the patient to be treated is a mammal, preferably a human.

Brief description of the drawings

Figure 1 shows an XRP diffractogram of sunitinib malate form I. Detailed description of the invention

The inventors have surprisingly found that utilising salt forms of pyrrole derivative intermediates, as opposed to utilising the base form of the pyrrole derivative intermediates as disclosed in the prior art, not only serves as a means for purifying the pyrrole derivative per se but, surprisingly, can be condensed efficiently with a 2-oxindole in the presence of a base in a suitable solvent system to directly obtain the corresponding sunitinib salt resulting in a streamlined process. As the pyrrole derivative salt forms are in a purified state, the resulting sunitinib salts surprisingly have an increased purity as measured by HPLC and were prepared in surprisingly high quantitative yield.

The chosen salt may preferably be pharmaceutically acceptable, but this is not necessarily the case. In certain embodiments other salts of pyrrole derivatives (I) and the corresponding salts of sunitinib (II) may be prepared that are not necessarily pharmaceutically acceptable, but may be used as intermediates in the preparation of pharmaceutically acceptable salt forms or the free base of sunitinib (II). Accordingly in a first aspect of the invention a process is provided for preparing an acid addition salt of a pyrrole substituted indolinone (C)

, comprising:

(ii) adding a base to the reaction mixture,

wherein

R¹ and R² are independently any atom or group,

m is O, 1, 2, 3 or 4,

n is 0, 1, 2, 3, 4 or 5, and

one of R⁸ or R⁸a is a formyl group and the other is H.

Preferably R¹ and R² are independently halo, R³, COR³, CO₂R³ or CON(R³)₂, wherein R³ is independently hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, O or S in its carbon skeleton. Preferably R¹ is independently alkyl or CONHR³, more preferably R¹ is independently methyl or CO-NH-CH₂CH₂NEt₂.

Preferably R² is independently halo, more preferably R² is fiuoro. Preferably m is 3. Preferably n is i.

In a preferred embodiment, a process is provided for preparing an acid addition salt of sunitinib having structure (II)

, comprising:

(i) mixing an acid addition salt of a pyrrole derivative (T) with a 5-fluoro-2-oxindole having formula (III) to form a reaction mixture

(ii) adding a base to the reaction mixture,

wherein one of R⁸ or R⁸a is a formyl group and the other is H. As used herein the terms "a 5-fluoro-2-oxindole" and "the 5-fluoro-2-oxindole" can refer to embodiments wherein R⁸a is hydrogen or R⁸a is a formyl group. References to "5-fiuoro- 2-oxindole" refer to those embodiments wherein R⁸a is hydrogen.

Preferably the acid moiety is an organic or inorganic acid. In certain preferred embodiments, the inorganic acid is selected from the group comprising hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid and perchloric acid, most preferably the inorganic acid is hydrochloric acid. In alternative embodiments, the organic acid is selected from the group comprising acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid and malonic acid. Most preferably the acid is (L) malic acid.

Scheme 3 shows a general reaction scheme for a process for the preparation of an acid addition salt of sunitinib (II) according to the invention.

base, solvent

Scheme 3 Sunitinib (II) is marketed as the malic acid salt (Ha). It would thus be advantageous to provide a simple process for preparing sunitinib malate (Ha) of high purity. Accordingly a preferred embodiment of the invention provides a process for the preparation of sunitinib malate having structure (Ha)

comprising:

(i) mixing an (L) malic acid salt of a pyrrole derivative having structure (I) with a 5- fluoro-2-oxindole having formula (III) to form a reaction mixture

(ii) adding a base to the reaction mixture,

wherein one of R⁸ or R⁸a is a formyl group and the other is H.

In particularly preferred embodiments R⁸a is hydrogen and R⁸ is a formyl group or in alternative embodiments R⁸a is a formyl group and R⁸ is hydrogen.

In preferred embodiments of a process according to the first aspect of the invention, steps (i) and (ii) are carried out in a solvent system, preferably the solvent system comprises an organic solvent system. The solvent system may comprise one or more solvents in which the reacting moieties may be dissolved or suspended and further can facilitate the reaction between the pyrrole derivative (I) and the 5-fluoro-2-oxindole (HI). In certain embodiments the solvent system comprises ketone(s) (preferably acetone, MEK), ester (s) (preferably ethyl acetate, isopropyl acetate), acetonitrile, C₁-C₁₀ alcohol(s), dimethylformamide, dimethylacetamide, dimethyl sulfoxide or mixtures thereof. The inventors have found however that most preferably the solvent system comprises a mixture of acetonitrile and methanol.

The term "solvent system" is understood to be one of the following:

(1) a single organic solvent

(2) water as solvent

(3) a combination of more than one organic solvent in various proportions

(4) a combination of water and one or more than one organic solvent in various proportions

The processes of the first aspect of the invention also require a base to be added to the reaction mixture. Any base may be utilized. For example in certain embodiments the base may be an organic base. In preferred embodiments the base is pyrrolidine, but most preferably the base is l,8-diazabicyclo[5.4.0]undec-7-ene (DBU). In particularly preferred embodiments, the molar ratio of the base added with respect to the pyrrole derivative (I) is between 0.1 to 1.2.

In preferred embodiments, the temperature of the reaction is kept at between about 0-85⁰C or in alternative embodiments between 0⁰C and the reflux temperature of the solvent system employed in the reaction. The inventors have found that a reaction temperature around standard room temperature provides excellent reaction conditions without increasing the complexity and the cost of the process according to the invention. Accordingly in particularly preferred embodiments, the reaction is kept between about 20- 30⁰C.

The sunitinib salt may be further isolated by any means available to the skilled person. Certain embodiments involve allowing the solvents to evaporate or drying the sunitinib salt by means of a rotary evaporator or in an oven. Any means may be used that does not cause polymorphic transformation or degradation of the isolated sunitinib salt. Particularly preferred is isolating the sunitinib salt by filtration. It will of course be apparent to the skilled person that sunitinib base (II) may be obtained from the salts of the invention. In one embodiment this may be achieved by adding a base to the salt.

The inventors have found that one or more subsequent washings of the isolated sunitinib salt in the solvent(s) comprising the solvent system is particularly preferable to obtain a particularly pure product. Most preferably the inventors have found that further washing the isolated sunitinib salt (such as sunitinib malate (Ha)) with methanol is particularly advantageous. The process according to the invention provides a product with high purity suitable for use in pharmaceutical compositions and adhering to the strict guidelines on purity imposed by health authorities around the world. However there may be certain instances wherein increased purity is required. In those circumstances further purification can be achieved in certain embodiments by recrystallisation from a C₁-C₆ alcohol-water mixture, preferably the C₁-C₆ alcohol- water mixture has a ratio of about 4:1, and the inventors have found that when the C₁-C₆ alcohol is butanol a particularly pure product having a purity greater than 99.8% is obtained.

Further preferred embodiments of the process provide that the acid addition salt of the pyrrole derivative is prepared in situ and not isolated before reaction with the 2-oxindole derivative (such as the 5-fluoro-2-oxindole (HI)). In alternative embodiments the acid addition salt of the pyrrole derivative is isolated before reaction with the 2-oxindole derivative (such as the 5-fluoro-2-oxindole (IH)). It is always advantageous to prepare a polymorphic form of sunitinib malate that has good bioavailability and processability. When preferred embodiments of the first aspect of the invention are followed, the resulting sunitinib malate has crystalline form I having an XRP diffractogram according to Figure 1. As used herein, sunitinib malate form I is as defined in WO 03/016305, which is hereby incorporated herein in its entirety by reference, i.e. sunitinib malate form I is characterized by an XRPD pattern having peaks at 2Θ values at about 13.2, 19.4, 24.2 and 25.5 °2Θ. In certain embodiments the acid addition salt of sunitinib is subsequently converted to sunitinib base (II), providing particularly pure sunitinib base (II). This base (II) can then be used as an API or converted to a salt, preferably a different salt, for use as an API. It will be apparent to the skilled person that whilst a preferred embodiment of the first aspect of the invention relates to the preparation of sunitinib malate (Ha) by using the (L) malic acid salt of the pyrrole derivative (I), other sunitinib salts may be prepared simply by using the corresponding pyrrole derivative salts and still remain within the scope and spirit of the invention. In these embodiments, the corresponding acid may be any organic or inorganic acid. In a preferred embodiment, organic acids like carboxylic acids, sulfonic acids, phosphorous derived acids and boron derived acids can be used. In a still preferred embodiment, carboxylic acids can be employed.

A more specific process for conversion of the pyrrole derivative acid addition salt to the corresponding sunitinib salt comprises the following steps:

(1) dissolving or suspending one of the pyrrole derivative acid addition salt or the 5- fluoro-2-oxindole component of the reaction in a solvent system;

(2) addition of the other component of the reaction to the reaction mixture;

(3) addition of base to the reaction mixture;

(4) stirring the reaction mixture for a period of time;

(5) isolating the product from the reaction mixture by filtration;

(6) optional purification of the product by recrystallisation;

(7) drying the isolated or recrystallised product, preferably in a vacuum oven at 55- 60⁰C for a period of time.

The inventors have found that the process of using a salt form of the pyrrole intermediate is particularly advantageous in the preparation of sunitinib. Thus in a second aspect of the invention there is provided an acid addition salt form of a pyrrole derivative (I)

wherein R⁸ is either a formyl group or hydrogen.

Preferably the acid moiety is an organic or inorganic acid. In certain preferred embodiments, the inorganic acid is selected from the group comprising hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid and perchloric acid, most preferably the inorganic acid is hydrochloric acid. In alternative embodiments, the organic acid is selected from the group comprising carboxylic acids, sulfonic acids, phosphorous derived acids and boron derived acids. In a still preferred embodiment, carboxylic acids can be employed, preferably acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid. Those familiar with the art can understand that the salt formation is not limited to the acids listed above, but can extend to any organic or inorganic acid.

As used herein, the term "pharmaceutically acceptable salt" refers to those salts, which retain the biological effectiveness and properties of the parent compound. Such salts include acid addition salts which are obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid, malonic acid and the like, preferably hydrochloric acid or (L) malic acid, more preferably (L) malic acid. A particularly preferred pharmaceutically acceptable salt is the (L) malate salt of the pyrrole derivative (I).

In particularly preferred embodiments a salt form is provided comprising the (L) malic acid salt of the pyrrole derivative (I)

(I)

wherein R⁸ is either a formyl group or hydrogen. A third aspect of the invention provides a process for the preparation of a salt form of a pyrrole derivative (I), comprising mixing the pyrrole derivative (I) with an acid.

The inventors have found that a molar ratio of pyrrole derivative (I) to acid in the range of 0.3 to 2 is advantageous. Most preferably the molar ratio is about 1, particularly in those embodiments wherein the (L) malic acid salt is prepared.

In another embodiment there is provided a process wherein the acid and pyrrole derivative (I) are mixed together in a solvent system. In preferred embodiments, the solvent system comprises ketones (preferably acetone, MEK), esters (preferably ethyl acetate, isopropyl acetate), acetonitrile, C₁-C₁₀ alcohols, DCM, dimethylformamide, dimethylacetamide, dimethyl sulfoxide or a mixture thereof.

A preferred process for the preparation of an acid addition salt of a pyrrole derivative (I) comprises:

(i) mixing an acid and a pyrrole derivative (I) in a solvent system; and

(ii) removing the solvent system.

In preferred embodiments, the solvent system comprises ketones (preferably acetone, MEK), esters (preferably ethyl acetate, isopropyl acetate), acetonitrile, C₁-C₁₀ alcohols, DCM, dimethylformamide, dimethylacetamide, dimethyl sulfoxide or a combination thereof.

The term "solvent system" is understood to be one of the following:

(1) a single organic solvent (2) water as solvent

(3) a combination of more than one organic solvent in various proportions

In one embodiment of the process for the preparation of a salt of a pyrrole derivative (T), the pyrrole derivative (I) and the acid may be completely soluble in the solvent system or one component may remain in suspension while the other is completely soluble or both the components may remain in suspension.

Most preferably the acid is (L) malic acid. Thus although the process for preparing a salt form of a pyrrole derivative (I) may be varied within the scope of the appended claims, the inventors have found that the following embodiment is particularly advantageous in preparing a pure (L) malic acid salt of the pyrrole derivative (I). Accordingly a particularly preferred embodiment provides a process comprising:

(a) mixing dichlorome thane (DCM), (L) malic acid and a pyrrole derivative (I);

(b) removing the DCM from the mixture in step (a); and

(c) adding methanol to the mixture from step (b). The (L) malic acid may be mixed with the pyrrole derivative (I) and DCM in any order and in any ratio that allows formation of a stable malate salt. The inventors have found in preferred embodiments that the molar ratio of the pyrrole derivative (T) to (L) malic acid is in the range of 0.3 to 2. A molar ratio of about 1 has been found to be particularly advantageous.

In another embodiment, the mixture from step (a) is stirred at between about 0-100⁰C, preferably for about 15 minutes. The stirring is effected to ensure complete mixing of the reaction mixture and the components therein and thus the timing can be varied within the scope of the appended claims. The temperature of the reaction can also be varied. The inventors found that 20-35⁰C was most advantageous.

In certain embodiments, depending on the relative amounts of the reactants, the reaction mixture may become increasingly viscous. There is thus provided in certain embodiments a process according to the third aspect, comprising at least one further addition and removal of DCM in step (b). The DCM may be removed by evaporation or most preferably by simply decanting the DCM from the reaction mixture and adding fresh DCM. This may be repeated one or more times.

In a particularly advantageous embodiment, the reaction mixture from step (c) completely dissolves in the methanol. This provides a particularly pure product, although it is to be understood that the reaction mixture may be only partially dissolved or suspended in the methanol and provide a product with increased purity.

In another embodiment of the invention, the pyrrole derivative salt can be treated with an excess of base to afford pure pyrrole derivative (I) with a purity of greater than 95%, most preferably greater than 97%, more preferably greater than 99%, and most preferably greater than 99.7% as measured by HPLC. Thus, conversion of the pyrrole derivative (I) to a salt and conversion of said salt back to the pyrrole derivative base (I) provides a method for purifying the pyrrole derivative base (I). The base (I) may then be utilised for the preparation of sunitinib (II) according to the prior art.

The process of the invention and the accompanying embodiments allow for the preparation of sunitinib salts directly without the need to separately isolate the pyrrole derivative salt, thus providing a more simple and cost effective method than previously disclosed in the prior art. However certain embodiments may require isolation of the pyrrole derivative salt. Thus, in those embodiments, the salt is further isolated, preferably by filtration, but it is well within the skill-set of the skilled person to determine a method of isolating the pyrrole derivative salt prepared according to the invention.

In those particularly preferred embodiments wherein the (L) malic acid salt is prepared, it is preferably isolated by allowing the DCM and methanol to evaporate, preferably by rotary evaporation, but any means may be employed. A fourth aspect of the invention provides a salt form of the pyrrole derivative (I) according to the second aspect of the invention or prepared by a process according to the third aspect of the invention, having a purity of at least 95%, preferably at least 97%, more preferably at least 99%, and most preferably at least 99.7% as measured by HPLC. These purity levels ate particularly advantageous when the pyrrole derivative salt is the (L) malic acid salt.

As mentioned previously the use of the (L) malic acid salt of the pyrrole derivative (I) provides a particularly pure sunitinib malate (Ha). Accordingly there is provided in a fifth aspect of the invention sunitinib malate (Ha) prepared by a process according to the first aspect of the invention having a purity of at least 97%, preferably at least 99%, and most preferably at least 99.8% as measured by HPLC.

A sixth aspect of the invention provides sunitinib malate (Ha) having a purity of at least 97%, preferably at least 99%, and most preferably at least 99.8% as measured by HPLC.

The sixth aspect of the invention also provides other acid addition salts of sunitinib (II) having a purity of at least 97%, preferably at least 99%, and most preferably at least 99.8% as measured by HPLC. The sixth aspect of the invention also provides sunitinib (II) having a purity of at least 97%, preferably at least 99%, and most preferably at least 99.8% as measured by HPLC.

A "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein or physiologically/pharmaceutically acceptable salts or prodrugs thereof, with other chemical components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.

A physiologically/pharmaceutically acceptable carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. A physiologically/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.

Accordingly, the invention also provides in a seventh aspect of the invention a composition comprising sunitinib malate (Ha) according to the fifth or sixth aspects of the invention or prepared by a process according to the first aspect of the invention and one or more pharmaceutically acceptable excipients.

The composition according to the seventh aspect may be used in the treatment of a protein kinase mediated disorder. In some embodiments the disorder is a cell proliferative disorder, preferably the disorder is a solid tumour, most preferably the disorder is one of advanced renal cell carcinoma (RCC) or gastrointestinal stromal tumour (GIST).

A further aspect of the invention provides a process for preparing an acid addition salt of sunitinib (II), comprising:

(i) preparing an acid addition salt of a pyrrole derivative (I);

(ii) adding a 5-fluoro-2-oxindole (III) to the reaction mixture from step (i); and

(iii) isolating the desired acid addition salt of sunitinib (II).

In certain embodiments the acid addition salt of pyrrole derivative (I) is isolated before the 5-fluoro-2-oxindole (III) is added.

Examples

In the following examples, the pyrrole derivative is N-[2-(diethylamino)ethyl]-5-formyl-2,4- dimethyl-lH-pyrrole-3-carboxamide wherein R⁸ is a formyl group and the 2-oxindole is 5- fluoro-2-oxindole wherein R⁸a is hydrogen.

Example 1: Conversion of pyrrole derivative (T) (N-[2-(diethylamino)ethyl]-5-formyl-2,4- dimethyl-lH-pyrrole-3-carboxamide) to its malate salt Dichloromethane (30 ml), N-[2-(diethylamino)ethyl]-5-forrnyl-2,4-dirnethyl-lH-pyrrole-3- carboxamide (1O g, 1 equivalent, purity 90-97%) and (L) malic acid (5.04 g, 1 equivalent) were added together and stirred at 25-30⁰C for 15 minutes. A sticky mass was progressively formed. The dichloromethane was decanted and fresh dichloromethane (30 ml) added to the sticky mass, followed by stirring and decantation of the dichloromethane. Methanol (20 ml) was added until the sticky mass completely dissolved. The DCM and methanol solvents were removed by rotary evaporation to obtain a brown coloured sticky mass, which was characterized as the malate salt by NMR.

Yield (w/w) = 13 g (86%)

Purity (HPLC) > 99.0%

Example 2: Conversion of the malate salt of pyrrole derivative (I) (N-[2- (diethylamino)ethyI|-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxamide) to sunitinib malate

Acetonitrile : methanol (1.5:1, 300 ml), malate salt of N-[2-(diethylamino)ethyl]-5-formyl- 2,4-dimethyl-lH-pyrrole-3-carboxamide (15 g, 1 equivalent) and 5-fiuoro-2-oxindole (5.67 g, 1 equivalent) were added at 25-30⁰C to obtain a clear solution within 5 minutes. Pyrrolidine (2.62 g, 1 equivalent) was then added to the reaction mass. After 12 hours stirring at 25-30⁰C, a yellow solid progressively precipitated out of the solution. The yellow solid was isolated by filtration, washed with methanol (105 ml) and dried under vacuum at 55-60⁰C for 3-4 hours to obtain sunitinib malate (Ua) in polymorphic form I having the XRPD shown in Figure 1.

Yield (w/w) = 1O g (67%)

Purity (HPLC) > 97%

This solid may be further purified by dissolving in butanol : water (4:1, 20 volumes) at 50- 60⁰C and cooling to 25-30⁰C to obtain purified sunitinib malate (Ha) in polymorphic form I having the XRPD shown in Figure 1.

Recrystallisation Yield = 80%

Purity (HPLC) > 99.5% Example 3: Conversion of the nialate salt of pyrrole derivative (I) (N-[2- (diethylaniino)ethyl]-5-forrnyl-2,4-diniethyl-lH-pyrrole-3-carboxarnide) to sunitinib nialate

Acetonitrile : methanol (1.5:1, 300 ml), malate salt of N-[2-(diethylamino)ethyl]-5-formyl- 2,4-dimethyl-lH-pyrrole-3-carboxamide (15 g, 1 equivalent) and 5-fluoro-2-oxindole (5.67 g, 1 equivalent) were added at 25-30⁰C to obtain a clear solution within 5 minutes. 1,8- Diazabicyclo[5.4.0]undec-7-ene (2.81 g, 0.5 equivalent) was added to the reaction mass. After 12 hours stirring at 25-30⁰C, a yellow solid progressively precipitated out of the solution. The yellow solid was isolated by filtration, washed with methanol (105 ml) and dried under vacuum at 55-60⁰C for 3-4 hours to obtain sunitinib malate (Ha) in polymorphic form I having the XRPD shown in Figure 1.

Yield (w/w) = 10.7 g (71%)

Purity (HPLC) > 97% This solid may be further purified by dissolving in butanol : water (4:1, 20 volumes) at 50- 60⁰C and cooling to 25-30⁰C to obtain purified sunitinib malate (Ha) in polymorphic form I having the XRPD shown in Figure 1.

Recrystallisation Yield = 80%

Purity (HPLC) > 99.5%

Example 4: Conversion of the malate salt of pyrrole derivative (I) (N-[2- (diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxamide) to sunitinib malate

To a stirring mixture of acetonitrile : methanol (1.5:1, 150 ml), malate salt of N- [2- (diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxamide (7.5 g, 1 equivalent) and 5-fluoro-2-oxindole (2.84 g, 1 equivalent) were added at 25-30⁰C to obtain a clear solution within 5 minutes. l,8-Diazabicyclo[5.4.0]undec-7-ene (1.41 g, 0.5 equivalent) was added to the reaction mass and heated to 45-50⁰C for 2-3 hours. After 3-4 hours stirring at 25-30⁰C, yellow solid progressively precipitated out of the solution. The yellow solid was isolated by filtration, washed with methanol (105 ml) and dried under vacuum at 55-60⁰C for 3-4 hours to obtain sunitinib malate (Ila) in polymorphic form I having the XRPD shown in Figure 1.

Yield (w/w) = 3 g (60%) Purity (HPLC) > 97%

Recrystallisation Yield = 80%

Purity (HPLC) > 99.5%

All XRPDs were recorded on a Bruker AXS D8 Advance Instrument, using Cu KaI radiation as the X-ray source.

It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims only.

Claims

1. A process for the preparation of an acid addition salt of a pyrrole substituted indolinone, comprising:

(ii) adding a base to the reaction mixture.

2. A process for the preparation of an acid addition salt of sunitinib (II)

, comprising:

(i) mixing the corresponding acid addition salt of a pyrrole derivative (I) with a 5- fiuoro-2-oxindole having formula (III) to form a reaction mixture

(ii) adding a base to the reaction mixture,

wherein one of R⁸ or R⁸a is a formyl group and the other is H.

3. A process according to claim 1 or 2, wherein the acid is:

(i) an organic or inorganic acid; and/or

(ii) an inorganic acid selected from the group comprising hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid and perchloric acid; and/or

(iii) hydrochloric acid; and/or (iv) an organic acid selected from the group comprising acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid and malonic acid; and/or

(v) (L) malic acid.

4. A process according to any of the preceding claims, for the preparation of sunitinib malate (Ua)

, comprising:

(i) mixing an (L) malic acid salt of a pyrrole derivative (I) with a 5-fluoro-2-oxindole having formula (III) to form a reaction mixture

(ii) adding a base to the reaction mixture,

wherein one of R⁸ or R⁸a is a formyl group and the other is H.

5. A process according to any of the preceding claims, wherein steps (i) and (ii) are carried out in a solvent system.

6. A process according to claim 5, wherein the solvent system comprises:

(i) an organic solvent system; and/or

(ii) a ketone, an ester, acetonitrile, a C₁-C₁₀ alcohol, dimethylformamide, dimethylacetamide, dimethyl sulfoxide or a mixture thereof; and/or (iii) a mixture of acetonitrile and methanol.

7. A process according to any of the preceding claims, wherein the base is:

(i) an organic base; and/or

(ii) pyrrolidine; and/or

(iii) l,8-diazabicyclo[5.4.0]undec-7-ene.

8. A process according to any of the preceding claims, wherein the molar ratio of the base added with respect to the pyrrole derivative is between 0.1 to 1.2.

9. A process according to any of the preceding claims, wherein the reaction is kept: (i) between about 0-85⁰C; and/or

(ii) between about 20-30⁰C.

10. A process according to any of the preceding claims, wherein the acid addition salt of the pyrrole substituted indolinone (such as the acid addition salt of sunitinib (H)) is: (i) further isolated; and/or

(ii) further isolated by filtration.

11. A process according to claim 10, wherein the isolated salt is further washed with methanol.

12. A process according to claim 10 or 11, wherein the isolated salt is further purified by recrystallisation from:

(i) a C₁-C₆ alcohol-water mixture; and/or

(ii) a C₁-C₆ alcohol-water mixture having a ratio of about 4:1; and/or

(iii) a butanol-water mixture; and/or

(iv) a butanol-water mixture having a ratio of about 4:1.

13. A process according to any of the preceding claims, wherein the acid addition salt of the pyrrole derivative is prepared in situ and not isolated before reaction with the 2- oxindole derivative (such as the 5-fluoro-2-oxindole (HI)).

14. A process according to any of the preceding claims, wherein the acid addition salt prepared is sunitinib malate (Ha) form I having an XRP diffractogram substantially as shown in Figure 1.

15. A process according to any of the preceding claims, wherein the acid addition salt of the pyrrole substituted indolinone (such as the acid addition salt of sunitinib (H)) prepared is subsequently converted to the pyrrole substituted indolinone base (such as sunitinib base (H)).

16. An acid addition salt form of a pyrrole derivative (T)

(I)

wherein R⁸ is either a formyl group or hydrogen.

17. An acid addition salt form of a pyrrole derivative (I) according to claim 16, wherein the acid is:

(i) an organic or inorganic acid; and/or

(iii) hydrochloric acid; and/or

(iv) an organic acid selected from the group comprising acetic acid, oxalic acid, (D) or

(L) malic acid, maleic acid, methanesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid and malonic acid; and/or

(v) (L) malic acid.

18. An acid addition salt form of a pyrrole derivative (I) according to claim 16 or 17, having a purity of:

(i) at least 95% as measured by HPLC; and/or

(ii) at least 97% as measured by HPLC; and/or (iϋ) at least 99% as measured by HPLC; and/or

(iv) at least 99.7% as measured by HPLC.

19. A process for preparing an acid addition salt form of a pyrrole derivative (I) according to any of claims 16 to 18, comprising mixing the pyrrole derivative (T) with the corresponding acid.

20. A process according to claim 19, comprising:

(i) mixing an acid and a pyrrole derivative (I) in a solvent system; and

(ii) removing the solvent system.

21. A process according to claim 20, wherein the solvent system comprises a ketone, an ester, acetonitrile, a C₁-C₁₀ alcohol, DCM, dimethylformamide, dimethylacetamide, dimethyl sulfoxide or a combination thereof.

22. A process according to any of claims 19 to 21, wherein the acid is (L) malic acid.

23. A process according to claim 22, comprising:

(a) mixing dichlorome thane (DCM), (L) malic acid and a pyrrole derivative (I);

(b) removing the DCM from the mixture in step (a); and

(c) adding methanol to the mixture from step (b).

24. A process according to claim 23, wherein the molar ratio of the pyrrole derivative (I) to (L) malic acid is:

(i) in the range of 0.3 to 2; and/or

(ii) about 1.

25. A process according to claim 23 or 24, wherein the mixture from step (a) is stirred at between about 20-35⁰C for about 15 minutes.

26. A process according to any of claims 23 to 25, comprising at least one further addition and removal of DCM in step (b).

27. A process according to any of claims 23 to 26, wherein the DCM from step (b) is removed by decanting.

28. A process according to any of claims 23 to 27, wherein the reaction mixture from step (c) completely dissolves in the methanol.

29. A process according to any of claims 23 to 28, wherein the temperature of the reaction is:

(i) between about 0-100⁰C; and/or

(ii) between about 20-30⁰C.

30. A pyrrole substituted indolinone (such as sunitinib (U)) or an acid addition salt of a pyrrole substituted indolinone (such as an acid addition salt of sunitinib (II), such as sunitinib malate (Ha)), prepared by a process according to any of claims 1 to 15.

31. Sunitinib malate (Ha) prepared by a process according to any of claims 1 to 15.

32. The compound according to claim 30 or 31, having a purity of:

(i) at least 97% as measured by HPLC; and/or

(ii) at least 99% as measured by HPLC; and/or

(iϋ) at least 99.8% as measured by HPLC.

33. A pyrrole substituted indolinone (such as sunitinib (H)) or an acid addition salt of a pyrrole substituted indolinone (such as an acid addition salt of sunitinib (II), such as sunitinib malate (Ha)), having a purity of:

(i) at least 97% as measured by HPLC; and/or

(ii) at least 99% as measured by HPLC; and/or

(iϋ) at least 99.8% as measured by HPLC.

34. The compound according to any of claims 30 to 33, for use in:

(i) medicine; and/or

(ii) the treatment of a protein kinase mediated disorder; and/or

(iϋ) the treatment of a cell proϋferative disorder; and/or (iv) the treatment of a solid tumour; and/or

(v) the treatment of advanced renal cell carcinoma (RCC) or gastrointestinal stromal tumour (GIST).

35. A pharmaceutical composition comprising sunitinib (II) or an acid addition salt of sunitinib (II) (such as sunitinib malate (Ha)) according to any of claims 30 to 34 and one or more pharmaceutically acceptable excipients.

36. A pharmaceutical composition according to claim 35, for use in the treatment of: (i) a protein kinase mediated disorder; and/or

(ii) a cell proliferative disorder; and/or

(iϋ) a solid tumour; and/or

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

37. Use of sunitinib (II) or an acid addition salt of sunitinib (II) (such as sunitinib malate (Ha)) according to any of claims 30 to 34, in the manufacture of a medicament for the treatment of a protein kinase mediated disorder.

38. The use according to claim 37, wherein the disorder is:

(i) a cell proliferative disorder; and/or

(ii) a solid tumour; and/or

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

39. A method of treating a protein kinase mediated disorder comprising administering to a patient in need thereof a therapeutically effective amount of sunitinib (II) or an acid addition salt of sunitinib (II) (such as sunitinib malate (Ha)) according to any of claims 30 to 34.

40. The method according to claim 39, wherein the disorder is:

(i) a cell proliferative disorder; and/or

(ii) a solid tumour; and/or