WO2011104555A2 - Nouveau procédé - Google Patents

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Publication number
WO2011104555A2
WO2011104555A2 PCT/GB2011/050369 GB2011050369W WO2011104555A2 WO 2011104555 A2 WO2011104555 A2 WO 2011104555A2 GB 2011050369 W GB2011050369 W GB 2011050369W WO 2011104555 A2 WO2011104555 A2 WO 2011104555A2
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WIPO (PCT)
Prior art keywords
acid
malate
process according
sunitinib
amines
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PCT/GB2011/050369
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English (en)
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WO2011104555A3 (fr
Inventor
Vinayak Govind Gore
Laxmikant Narahari Patkar
Kiran Shivaji Pokharkar
Mahesh Gorakhnath Hublikar
Prakash Vishnu Bansode
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Generics [Uk] Limited
Mylan India Private Limited
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Application filed by Generics [Uk] Limited, Mylan India Private Limited filed Critical Generics [Uk] Limited
Publication of WO2011104555A2 publication Critical patent/WO2011104555A2/fr
Publication of WO2011104555A3 publication Critical patent/WO2011104555A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • 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.
  • 2,4-dimethyl-lH-pyriOle-3-carboxamide 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).
  • RTK receptor tyrosine kinase
  • 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.
  • sunitinib base All of the above processes involve the preparation and then isolation of sunitinib base, before conversion to die desired sunitinib salts, particularly sunitinib malate.
  • sunitinib base 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:
  • sunitinib base is a powder having a very fine particle nature. This makes processing such a powder difficult, particularly in industrial settings.
  • 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.
  • 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.
  • a process for preparing an acid addition salt of sunitinib comprising: reacting a pyrrole derivative (III)
  • the acid is an inorganic acid selected from the group comprising HC1, HBr, HN0 3 , H 3 P0 4 , H 2 S0 4 and HC10 4 .
  • 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.
  • 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.
  • organic acid wherein the organic moiety of the organic acid is hydrogen
  • organic acids wherein the organic moiety of the organic acid is a straight or branched chain, substituted or unsubstituted alkyl group
  • 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.
  • organic acids wherein the organic moiety of the organic acid is a straight or branched chain, substituted or unsubstituted alkenyl group
  • 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.
  • 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.
  • 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.
  • 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.
  • the organic acid is selected from the group comprising sulfonic acids, and mono-, di- and tri-carboxylic acids.
  • 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 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • a process for the preparation of sunitinib malate comprising: reacting a pyrrole derivative (III)
  • the process is carried out in an organic solvent system, preferably the organic solvent system comprises acetonitrile and methanol.
  • 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.
  • 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.
  • 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.
  • the malic acid is L-malic acid.
  • 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.
  • 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.
  • 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).
  • 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%.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical composition is suitable for treating a protein kinase mediated disorder.
  • 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.
  • 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.
  • the disorder is a cell proliferative disorder, most preferably the disorder is one of advanced renal cell carcinoma (RCC) or gastrointestinal stromal tumor (GIST).
  • RCC advanced renal cell carcinoma
  • GIST gastrointestinal stromal tumor
  • 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%.
  • 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.
  • 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.
  • the disorder is a cell proliferative disorder, most preferably the disorder is one of advanced renal cell carcinoma (RCC) or gastrointestinal stromal tumor (GIST).
  • RCC advanced renal cell carcinoma
  • GIST gastrointestinal stromal tumor
  • 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.
  • the pharmaceutical composition is suitable for treating a protein kinase mediated disorder.
  • 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.
  • 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.
  • the disorder is a cell proliferative disorder, most preferably the disorder is one of advanced renal cell carcinoma (RCC) or gastrointestinal stromal tumor (GIST).
  • RCC advanced renal cell carcinoma
  • GIST gastrointestinal stromal tumor
  • the patient is a mammal, preferably a human.
  • 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.
  • 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.
  • an alkyl group is straight-chained or branched, and does not include any heteroatoms in its carbon skeleton.
  • an alkyl group is a C r C 12 alkyl group, preferably a Q-Q alkyl group.
  • An "alkylene” group is similarly defined as a divalent alkyl group.
  • alkenyl 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.
  • alkenyl groups are vinyl, allyl, but-l-enyl and but-2-enyl groups.
  • an alkenyl group is straight-chained or branched, and does not include any heteroatoms in its carbon skeleton.
  • an alkenyl group is a C 2 -C 12 alkenyl group, preferably a C 2 -C 6 alkenyl group.
  • An "alkenylene” group is similarly defined as a divalent alkenyl group.
  • alkynyl 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.
  • an alkynyl group is straight-chained or branched, and does not include any heteroatoms in its carbon skeleton.
  • an alkynyl group is a C 2 -C 12 alkynyl group, preferably a C 2 -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.
  • an aryl group does not include any heteroatoms in its carbon skeleton.
  • an aryl group is a C 4 -C 14 aiyl group, preferably a C 6 -C w aryl group.
  • An "aiylene” group is similarly defined as a divalent aryl group.
  • heteroatom is defined as N, O, S, F, CI, Br or I, preferably as N, O or S.
  • arylalkyl 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.
  • 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.
  • an optionally substituted group may be substituted with one or more of -F, -CI, -Br, -I, -CF 3 , -CC1 3 , -CBr 3 , -CI 3 , -OH, -SH, -NH 2 , -CN, -N0 2 , -COOH, -R x -0-R y , -R x -S-R y , -R x -SO-R y , -R x -S0 2 -R y , -R x -S0 2 -OR y , -RO-S0 2 -R y , -R x -S0 2 -N(R) 2 , -R x -NR ' -S0 2 -R y , -RO-S0 2 -OR ' , -RO-S0 2 -N(R J )
  • -R x - is independently a chemical bond, a C j -Ci 0 allcylene, C 2 -C 10 alkenylene or C 2 -C 10 alkynylene group.
  • -R y is independently hydrogen, unsubstituted C r C 6 allcyl or unsubstituted C 4 -C 10 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).
  • 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,
  • solvent system should be taken to mean one of the following possibilities:
  • 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.
  • 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)
  • the pyrrole derivative (III) is used in its free base form, not as a salt.
  • the 5- fiuoro-2-oxindole derivative (II) is preferably used in its free base form, not as a salt.
  • 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.
  • the reaction time varies from between about 0.5 hour to about 24 hours.
  • 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.
  • the processes of the invention do not require the extra basification step.
  • the acid is an inorganic acid selected from the group comprising HCl, HBr, HN0 3 , H 3 P0 4 , H 2 S0 4 and HC10 4 .
  • 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.
  • the organic acid is selected from the group comprising sulfonic acids, and mono-, di-, and tricarboxylic acids.
  • 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 process is carried out in an organic solvent system
  • 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.
  • 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.
  • 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.
  • primary amines such as alkyl and aryl amines for example ethyl amine
  • secondary amines such as dimethyl amine, diethyl amine, diprop
  • 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.
  • 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-C 5 alcoholic solvent.
  • the alcoholic solvents are selected from the group comprising methanol, ethanol, propanol, isopropanol, butanol, pentanol and mixtures thereof.
  • 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.
  • the sunitinib salt may be isolated in step (iv) by any means known to the skilled person.
  • the sunitinib salt may be isolated either by evaporation of the solvent system or by filtration and drying.
  • the isolated sunitinib salt may be subjected to further purification by crystallization from a solvent system, preferably a solvent system comprising a C C 5 alcoholic solvent.
  • a solvent system preferably a solvent system comprising a C C 5 alcoholic solvent.
  • 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.
  • a process for the preparation of sumtinib malate comprising: reacting a pyrrole derivative III)
  • the pyrrole derivative (III) is used in its free base form, not as a salt.
  • the 5- fluoro-2-oxindole derivative (II) is preferably used in its free base form, not as a salt.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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 C 5 alcoholic solvent.
  • the alcoholic solvents are selected from the group comprising methanol, ethanol, propanol, isopropanol, butanol, pentanol and mixtures thereof.
  • 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.
  • sunitinib malate When employed in the process according the invention, afford sunitinib malate. All the salts have an acidic pH.
  • 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 r C 5 alcoholic solvent.
  • 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.
  • 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.
  • the pyrrole derivative (III) is N-[2-(diemylamino)ethyl]-5-formyl- 2,4-dimethyl-lH-pyrrole-3-carboxamide wherein R 8 is a formyl group and the 5-fluoro-2- oxindole derivative (II) is 5-fluoro-2-oxindole wherein R 8 a is hydrogen.
  • Example 1 Preparation of 2-(N,N-diethylamino)ethyl ammonium dimalate
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

Abstract

La présente invention concerne un procédé amélioré de préparation des sels d'addition acide du sunitinib, en particulier du (2S)-2-hydroxybutanedioate de sunitinib (I). La présente invention concerne également des compositions comprenant des sels d'addition acide du sunitinib comme le (2S)-2-hydroxybutanedioate (I) de sunitinib et l'emploi desdites compositions dans le traitement de pathologies.
PCT/GB2011/050369 2010-02-25 2011-02-24 Nouveau procédé WO2011104555A2 (fr)

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WO2013190569A2 (fr) * 2012-06-22 2013-12-27 Shilpa Medicare Limited Nouveaux sels de sunitinib et leur préparation
WO2015031604A1 (fr) 2013-08-28 2015-03-05 Crown Bioscience, Inc. Signatures d'expression génique permettant de prédire la réponse d'un sujet à un inhibiteur multikinase et leurs procédés d'utilisation

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WO2013045878A1 (fr) 2011-09-30 2013-04-04 British Telecommunications Plc Attribution de contributions à un encombrement
WO2013190569A2 (fr) * 2012-06-22 2013-12-27 Shilpa Medicare Limited Nouveaux sels de sunitinib et leur préparation
WO2013190569A3 (fr) * 2012-06-22 2014-02-13 Shilpa Medicare Limited Nouveaux sels de sunitinib et leur préparation
WO2015031604A1 (fr) 2013-08-28 2015-03-05 Crown Bioscience, Inc. Signatures d'expression génique permettant de prédire la réponse d'un sujet à un inhibiteur multikinase et leurs procédés d'utilisation

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