WO2011128699A2 - Procédés inédits - Google Patents

Procédés inédits Download PDF

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Publication number
WO2011128699A2
WO2011128699A2 PCT/GB2011/050752 GB2011050752W WO2011128699A2 WO 2011128699 A2 WO2011128699 A2 WO 2011128699A2 GB 2011050752 W GB2011050752 W GB 2011050752W WO 2011128699 A2 WO2011128699 A2 WO 2011128699A2
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WIPO (PCT)
Prior art keywords
acid
salt
process according
sunitinib
malate
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PCT/GB2011/050752
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English (en)
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WO2011128699A3 (fr
Inventor
Vinayak Govind Gore
Laxmikant Narahari Patkar
Bharati Pandit Choudhari
Mahesh Gorakhnath Hublikar
Kiran Shivaji Pokharkar
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 WO2011128699A2 publication Critical patent/WO2011128699A2/fr
Publication of WO2011128699A3 publication Critical patent/WO2011128699A3/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 novel intermediates useful in the preparation of sunitinib (VII) and salts thereof, in particular sunitinib L-malate (IV), to processes for preparing said intermediates, sunitinib (VII) and its salts, and to sunitinib and its salts, in particular sunitinib L-malate (IV), prepared using said processes.
  • the invention also relates to compositions comprising sunitinib (VII) 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).
  • RTK receptor tyrosine kinase
  • WO 03/070725 and US 7119209 describe a three component condensation, comprising reacting an appropriate pyrrole derivative with a 2-oxindole derivative and the additional step of reacting an amine with the pyrrole substituted indolinone to form surntinib free base (VII).
  • sunitinib base is a powder having a very fine particle nature. This makes processing such a powder difficult, particularly on an industrial scale.
  • sunitinib base (VII) Conversion of sunitinib base (VII) to sunitinib malate involves the addition of a solution comprising malic acid to the sunitinib base (VII).
  • the aforementioned problems of solubility of the base (VII) in commonly used solvents mean that the initial reaction mass is a suspension.
  • Sunitinib malate salt also has very poor solubility in common solvents.
  • the corresponding malate salt is much easier to filter and is amenable to purification.
  • the complete formation of the sunitinib malate salt during this step is difficult to judge due to the heterogeneous nature of the reaction mass during the reaction.
  • Scheme 1 shows a generalised scheme for preparing sunitinib malate according to the prior art.
  • X is a suitable cation and n is 1, 2 or 3;
  • X is a suitable cation and n is 1, 2 or 3.
  • Scheme 2 shows a generalised scheme for preparing sunitinib or a salt thereof 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.
  • Route B relates to the preparation of sunitinib acid addition salts by preparing sunitinib base (VII) and subsequent in situ addition of the desired acid.
  • n 1, 2 or 3
  • n 1, 2 or 3
  • the inventors have found that when sulphite intermediate (I) is reacted with 5-fluoto-2-oxindole (II), preferably 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 (VIII) is obtained.
  • a process for preparing sunitinib (VII) or a salt diereof comprising:
  • X is a suitable cation and n is 1, 2 or 3.
  • a process for preparing an acid addition salt of sunitinib comprising adding an acid to the reaction mixture.
  • the acid may comprise an inorganic acid for example selected from the group comprising HC1, HBr, HN0 3 , H 3 P0 4 , H 2 S0 4 and HC10 4 .
  • the acid may comprise an organic acid, preferably the organic moiety of the organic acid is a straight or branched chain, substituted or unsubstituted alkyl, alkenyl, allyl, aryl or arylalkyl group, or a heteroatom-substituted straight or branched chain alkyl or aryl group.
  • the organic acid is selected from the group comprising sulfonic acids, 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 acid is L-malic acid and the resulting salt is sunitinib L-malate (IV).
  • acid addition salts of sunitinib may be prepared by adding an amine derived or ammonium derived salt of the acid to the reaction mixture.
  • the acid moiety is an inorganic acid for example selected from the group comprising HC1, HBr, HN0 3 , H 3 P0 4 , H 2 S0 4 and HC10 4 .
  • the acid moiety is an organic acid, preferably die 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.
  • the organic acid is selected from the group comprising sulfonic acids, 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 acid is L-malic acid.
  • 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 fhioacetic 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 the organic moiety of the organic acid is a heteroatom-substituted straight or blanched chain aryl group are salicylic acid, 3-pyridine-acetic acid and pyrazole-3- carboxylic acid.
  • the amine or ammonium moiety is selected from the group comprising primary amines and secondary amines, preferably the amine or ammonium moiety is selected from the group comprising cyclic amines, allyl amines, arylalkyl amines, heteroalkyl amines, alkyl amines, alkenyl amines, alkynyl amines and aryl amines.
  • Examples of primary amines are alkyl amines and aryl amines.
  • Examples of secondary amines are dialkyl amines, alkyl aryl amines, diaryl amines and alkyl arylalkyl amines.
  • Examples of cyclic amines are pyrrolidine and piperidine.
  • Examples of arylalkyl amines are alkyl arylalkyl amines such as N-methyl benzyl amine.
  • Examples of heteroalkyl amines are 2-amino-pyrrolidine and N,N-dimethyl ethylene diamine.
  • Examples of alkyl amines are ethyl amine, dimethyl amine, diethyl amine, dipropyl amine, dibutyl amine and dicyclohexyl amine.
  • the amine or ammonium derived acid addition salt is a malate salt, preferably selected from the 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.
  • X is a metal cation, preferably an alkali metal or an alkaline earth metal cation.
  • the metal cation is either sodium or potassium, most advantageously sodium.
  • the sunitinib or salt thereof is isolated.
  • the sunitinib or salt thereof is further purified by recrystallisation from a C,-C 6 alcohol : water mixture, preferably the Q-Q alcohol : water mixture has a v/v ratio of about 4:1.
  • the C r C 6 alcohol is n-butanol.
  • the reaction is carried out at a temperature of between about 0°C to about 50°C, preferably at between about 20°C to about 40°C, most preferably at between about 25°C to about 35°C.
  • the process is carried out in an organic solvent system, preferably the organic solvent system comprises acetonitrile and methanol.
  • the organic solvent system comprises acetonitrile and methanol.
  • the v/v ratio of acetonitrile : methanol is from about 5:1 to about 1:5. Most advantageously the v/v ratio of acetonitrile : methanol is about 3:2.
  • 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.
  • the malic acid or malic acid salt used is L- malic acid or an L-malic acid salt, such that the process provides sunitinib L-malate (IV).
  • the amine derived or ammonium derived malic acid salt is selected from the group comprising 2-(N,N-diemylamino)ethyl ammonium malate, 2-( ,N-diemylamino)ethyl ammonium dimalate, diammonium malate, dipyrrolidine malate, di-(n-propyl ammonium) malate, and di-(diisopropyl ammonium) malate.
  • the amine derived or ammonium derived malic acid salt is 2-(N,N- diemylamino) ethyl ammonium dimalate.
  • X is sodium.
  • the sunitinib malate is further purified by recrystallisation from a n-butanol : water mixture having a v/v ratio of about 4:1.
  • the temperature of the reaction is between 25°C to 35°C.
  • the process is carried out in an organic solvent system comprising acetonitrile and methanol having a v/v ratio of acetonitrile : methanol of about 3:2.
  • the pH of the reaction mixture is between 4 to 6.
  • the sumtinib or salt thereof is obtained in a yield of 60% or more, preferably 70% or more, preferably 80% or more, from the pyrrole derivative (I) and/or the 5-fluoro-2-oxindole (II), or from the pyrrole derivative (la) and/or the 5-fiuoro-2-oxindole derivative (Ha).
  • the sunitinib or salt thereof 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 second aspect of the present invention provides sunitinib or a salt thereof prepared by a process according to the first aspect of the present invention, having a purity as determined by HPLC of at least 97%, preferably at least 99%, preferably at least 99.5%, most preferably at least 99.8%.
  • the sunitinib salt is sunitinib malate, preferably sunitinib L-malate (IV).
  • a third aspect of the present invention provides sunitinib or a salt thereof comprising less than 3% of compound (VI) and/ or compound (VIII), preferably less than 1%, advantageously less than 0.1%, most advantageously less than 0.01%.
  • the sunitinib salt is sunitinib malate, preferably sunitinib L-malate (IV).
  • the process according to the first aspect of the invention provides sunitinib or a salt thereof having a polymorphic purity such that the presence of other polymorphic forms is undetectable.
  • the sunitinib or salt thereof according to the second or third aspect of the invention or prepared by a process according to the first aspect of the invention has a polymorphic purity of at least 97%, preferably at least 99%, preferably at least 99.5%, most preferably at least 99.8%, preferably as determined by XRPD.
  • the sunitinib free base (VII) is in polymorphic form I as defined in WO 2010/023473.
  • the sunitinib salt is sunitinib L-malate (IV) in polymorphic form I as defined in US 7435832.
  • the sunitinib or salt thereof according to the second or third aspect of the invention or prepared by a process according to the first aspect of the invention is suitable for use in medicine, preferably for treating a protein kinase mediated disorder, preferably for treating a cell proliferative disorder, preferably for treating renal cell carcinoma (RCC) or gastrointestinal stromal tumor (GIST).
  • a fourth aspect of the present invention provides a pharmaceutical composition comprising sunitinib or a salt thereof according to the second or third aspect of the invention or prepared by a process according to the first aspect of the invention, and one or more pharmaceutically acceptable excipients.
  • the sunitinib salt is sunitinib malate, preferably sunitinib L-malate (IV).
  • 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 renal cell carcinoma (RCC) or gastrointestinal stromal tumor (GIST).
  • RCC renal cell carcinoma
  • GIST gastrointestinal stromal tumor
  • a fifth aspect of the present invention provides use of sunitinib or a salt thereof according to the second or third aspect of the invention or prepared by a process according to the first aspect of the invention, or use of a pharmaceutical composition according to the fourth aspect of the invention, in d e manufacture of a medicament for treating a protein kinase mediated disorder.
  • the medicament is suitable for treating a cell proliferative disorder, preferably renal cell carcinoma (RCC) or gastrointestinal stromal tumor (GIST).
  • RCC renal cell carcinoma
  • GIST gastrointestinal stromal tumor
  • a sixth aspect of the present 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 or a salt thereof according to the second or third aspect of die invention or prepared by a process according to the first aspect of the invention, or a therapeutically effective amount of a pharmaceutical composition according to the fourth aspect of the invention.
  • the method is suitable for treating a cell proliferative disorder, preferably renal cell carcinoma (RCC) or gastrointestinal stromal tumor (GIST).
  • RRCC renal cell carcinoma
  • GIST gastrointestinal stromal tumor
  • the patient is a mammal, preferably a human.
  • a seventh aspect of the invention provides a pyrrole derivative (I)
  • X is a suitable cation and n is 1, 2 or 3.
  • X is a metal cation, preferably an alkali metal or an alkaline earth metal cation.
  • the metal cation is either sodium or potassium, most advantageously sodium.
  • the pyrrole derivative (I) has a purity as determined by HPLC of at least 97%, preferably at least 99%, preferably at least 99.5%, most preferably at least 99.8%.
  • the pyrrole derivative (I) comprises less than 3% of compound (VI) and/or compound (VIII), preferably less than 1%, advantageously less than 0.1%, most advantageously less than 0.01%.
  • An eighth aspect of the invention rovides a process for preparing a pyrrole derivative (I):
  • X is a metal cation, preferably an alkali metal or an alkaline earth metal cation.
  • the metal cation is either sodium or potassium, most advantageously sodium.
  • the bisulphite anion is provided by mixing a metabisulphite salt in the reaction mixture.
  • the metabisulphite salt is a salt of an alkali metal or an alkaline earth metal.
  • the salt is an alkali metal metabisulphite salt, preferably sodium or potassium metabisulphite, most preferably the alkali metal metabisulphite is sodium metabisulphite Na 2 S 2 O s .
  • a bisulphite salt could be used, preferably an alkali metal or alkaline earth metal bisulphite salt.
  • the salt is an alkali metal bisulphite salt, preferably sodium or potassium bisulphite, most preferably the alkali metal bisulphite is sodium bisulphite NaHS0 3 .
  • the bisulphite anion is used in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to the aldehyde (VI).
  • the reaction occurs in an aqueous C r C 5 alcohol solvent system.
  • the Q-C j alcohol is ethanol.
  • 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°C to 30°C.
  • 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.
  • the pyrrole derivative (I) is further isolated, preferably by filtration.
  • die pyrrole derivative (I) is obtained in a yield of 60% or more, preferably 70% or more, preferably 80% or more, from the aldehyde (VI).
  • the pyrrole derivative (I) is obtained on a commercial scale, preferably in batches of 0.1kg or more, 0.5kg or more, 1kg or more, 10kg or more, 100kg or more, 500kg or more, or 1000kg or more.
  • a ninth aspect of the invention rovides a 5-fluoro-2-oxindole derivative (Ila)
  • X is a suitable cation and n is 1, 2 or 3.
  • X is a metal cation, preferably an alkali metal or an alkaline earth metal cation.
  • the metal cation is either sodium or potassium, most advantageously sodium.
  • the 5-fiuoro-2-oxindole derivative (Ila) has a purity as determined by HPLC of at least 97%, preferably at least 99%, preferably at least 99.5%, most preferably at least 99.8%.
  • a tenth aspect of the invention provides a process for preparing a 5-fluoro-2-oxindole derivative (Ila):
  • X is a metal cation, preferably an alkali metal or an alkaline earth metal cation.
  • the metal cation is either sodium or potassium, most advantageously sodium.
  • the bisulphite anion is provided by mixing a metabisulphite salt in the reaction mixture.
  • the metabisulphite salt is a salt of an alkali metal or an alkaline earth metal.
  • the salt is an alkali metal metabisulphite salt, preferably sodium or potassium metabisulphite, most preferably the alkali metal metabisulphite is sodium metabisulphite Na 2 S 2 O s .
  • a bisulphite salt could be used, preferably an alkali metal or alkaline earth metal bisulphite salt.
  • the salt is an alkali metal bisulphite salt, preferably sodium or potassium bisulphite, most preferably the alkali metal bisulphite is sodium bisulphite NaHS0 3 .
  • the bisulphite anion is used in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to the aldehyde (lib).
  • the reaction occurs in an aqueous C,-C 5 alcohol solvent system.
  • the Q-C 5 alcohol is efhanol.
  • 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°C to 30°C.
  • 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.
  • the 5-fiuoro-2-oxindole derivative (Ila) is further isolated, preferably by filtration.
  • the 5-fiuoro-2- oxindole derivative (Ila) is obtained in a yield of 60% or more, preferably 70% or more, preferably 80% or more, from the aldehyde (lib).
  • the 5-fluoro-2- oxindole derivative (Ila) is obtained on a commercial scale, preferably in batches of 0.1kg or more, 0.5kg or more, 1kg or more, 10kg or more, 100kg or more, 500kg or more, or 1000kg or more.
  • Scheme 3 shows a generalised scheme for preparing sunitinib or a salt thereof via pyrrole derivative (I) according to the invention.
  • Route A relates to preparing surtitinib 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 of sunitinib acid addition salts by preparing sunitinib base (VII) and subsequent in situ addition of the desired acid, in this case a carboxylic acid.
  • n 1 2 or 3
  • Figure 1 shows a XRP diffractogram of sunitinib L-malate (TV) in polymorphic form I as disclosed in US 7435832.
  • Sunitinib L-malate (TV) 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.
  • sunitinib L-malate (IV) 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.
  • FIG. 2 shows a differential scanning calorimetry (DSC) trace of sunitinib L-malate (IV) in polymorphic form I as disclosed in US 7435832.
  • Sunitinib L-malate (IV) in polymorphic form I has an endothermic peak at about 198°C ⁇ 2°C, when a rate of heating of 10°C/min is used.
  • FIG. 3 shows a XRP diffractogram of sunitinib free base (VII) in polymorphic form I as disclosed in WO 2010/023473.
  • Sunitinib free base (VII) in polymorphic form I has an X- ray diffraction pattern comprising peaks at 4.48 and 8.88 ⁇ 0.2 degrees 2-theta.
  • suriitinib free base (VII) in polymorphic form I has an X-ray diffraction pattern comprising peaks at 4.48, 7.07, 8.88, 10.57, 11.38, 12.78, 13.51, 14.95, 16.41, 18.86, 19.61, 20.58, 21.59, 22.53, 22.87, 23.09, 25.68, 27.22, 28.07, 29.19, 32.61, 34.09, 36.00, 41.93 and 44.00 ⁇ 0.2 degrees 2-fheta.
  • FIG. 4 shows a differential scanning calorimetry (DSC) trace of sunitinib free base (VII) in polymorphic form I as disclosed in WO 2010/023473.
  • Sunitinib free base (VII) in polymorphic form I has an endothermic peak at about 244°C ⁇ 2°C, when a rate of heating of 10°C/min is used.
  • 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, /- butyl, /-butyl and //-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.
  • An "alkenyl” group is defined as a monovalent hydrocarbon, which comprises at least one carbon-carbon double bond, which may be straight-chained or branched, or be or include cyclic groups.
  • An alkenyl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton. Examples of alkenyl groups are vinyl, allyl, but-l-enyl and but-2-enyl groups.
  • 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 -Q 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 6 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, an hracenyl and phenanthrenyl groups.
  • an aryl group does not include any heteroatoms in its carbon skeleton.
  • an aryl group is a C 4 -C 14 aryl group, preferably a C 6 -C 10 aryl group.
  • An "arylene” group is similarly defined as a divalent aryl group.
  • a "heteroatom” is defined as N, O, S, F, CI, Br or I, preferably as N, O or S.
  • a combination of groups is referred to as one moiety, for example, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaiyl
  • die 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 -SO 2 -N(R 2 , -R x -NR -S0 2 -R y , -RO-S0 2 -OR y , -RO-S0 2 -N(R>) 2 ,
  • -R x - is independently a chemical bond, a C r C 10 alkylene, C 2 -C 10 alkenylene or C 2 -C 10 alkynylene group.
  • -R y is independendy hydrogen, unsubstituted C r C 6 allcyl or unsubstituted C 4 -C 10 aiyl.
  • Optional substituent(s) are not taken into account when calculating the total number of carbon atoms in the 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. uts (Wiley-Interscience, 3 rd edition, 1999). used herein the term “solvent system” should be taken to mean one of the following: a single organic solvent
  • a novel sulphite pyrrole derivative (I) in the condensation reaction witii a 2-oxindole, in particular 5-fiuoro-2-oxindole (II) provides an alternative route to preparing pure sumtinib or a salt thereof, in particular surdtinib L- malate (IV). Accordingly, there is provided in a first aspect of the invention a process for preparing sumtinib or a salt thereof comprising:
  • X is a suitable cation and n is 1, 2 or 3.
  • X is a metal cation, preferably an alkali metal or an alkaline earth metal cation.
  • the metal cation is either sodium or potassium, most advantageously sodium.
  • the acid when an acid addition salt of sunitinib is prepared, the acid may be an inorganic acid, preferably 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 die 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.
  • the organic acid is selected from the group comprising sulfonic acids, 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 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 (I) and 5-fiuoro-2-oxindole derivative (II), the resulting corresponding sumtinib salt is obtained wherein the salt moiety is obtained from the acid of the initial organic amine or ammonium salt.
  • the resulting sumtinib 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 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 sumtinib salts, in particular sunitinib malate.
  • the process of the present invention may also be used to prepare sumtinib base (VII) by simple condensation of pyrrole derivative (I) and 5-fluoro-2-oxindole derivative (II).
  • the base (VII) may then be utilised conventionally to prepare acid addition salts, such as sunitinib L-malate (IV), by adding the desired acid, such as L-malic acid, to the reaction mixture.
  • the acid moiety may be an inorganic acid, preferably selected from the group comprising HC1, HBr, HN0 3 , H 3 P0 4 , H 2 S0 4 and HC10 4 .
  • the acid moiety is an organic acid, preferably the organic moiety of the organic acid is a straight or branched chain, substituted or unsubstituted alkyl, alkenyl, allyl, aryl or arylalkyl group, or a heteroatom-substituted straight or branched chain alkyl or aryl group.
  • the organic acid is selected from the group comprising sulfonic acids, 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, mediane 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 the amine or ammonium moiety is selected from the group comprising cyclic amines, allyl amines, arylalkyl amines, heteroalkyl amines, alkyl amines, alkenyl amines, alkynyl amines and aryl amines.
  • the amine derived or ammonium derived acid addition salt is a malate salt selected from the group comprising 2-(N,N-cHethylamino)ethyl ammonium malate, 2- (N,N-cHemylamino)ethyl ammonium dimalate, diammonium malate, ⁇ pyrrolidine malate, di-(n-propyl ammonium) malate, and di-(diisopropyl ammonium) malate.
  • the amine derived or ammonium derived malate salt is 2-( ,N-cJiethylamino)ethyl ammonium dimalate.
  • the amine derived or ammonium derived salt of the acid can be prepared by simply mixing the appropriate organic amine or ammonia or derivatives thereof and the appropriate acid in a solvent system and isolating the resulting salt either by filtration or by evaporation of the solvent system.
  • the isolated salts were characteri2ed 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 or ammonium derived acid salts are most preferably prepared using equimolar stoichiometry of the acid and the amine or ammonium moiety. Alternatively the acid and the amine or ammonium moiety may be used in a ratio of from about 1:2 to about 2:1.
  • the amine or ammonium moieties and the acid moieties are preferably combined in a Q-C5 alcoholic solvent.
  • 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. It should be noted that in the preparation of the amine or ammonium derived acid salts the different stoichiometry of the organic amine or ammonium moieties and the acid moieties results in the preparation of different salts.
  • the preparation of sunitinib base (VII) or sunitinib acid addition salts from the corresponding pyrrole derivative (I) is preferably achieved under the influence of an amine derived or ammonium derived salt of the acid.
  • This salt catalyses die condensation of the pyrrole derivative (I) and 5-fiuoro-2-oxindole (II) under acidic pH.
  • the pH of the condensation reaction is between about 4.0-7.0, more preferably between about 4.0-5.5.
  • the pyrrole derivative (I) is prepared under the same pH conditions as the condensation reaction, the pyrrole derivative (I) remains intact and does not revert back to the corresponding aldehyde precursor (VI) during the reaction.
  • a most advantageous embodiment of the first aspect of the invention provides a process for the preparation of sunitinib malate, preferably sunitinib L-malate (TV), comprising: reacting a pyrrole derivative (I)
  • sunitinib malate preferably sunitinib L-malate (IV); wherein X is a suitable cation and n is 1, 2 or 3.
  • the resulting sunitinib or salt thereof may be isolated by any means available to the skilled person.
  • the inventors have found filtering the sunitinib or salt thereof to be particularly advantageous.
  • the filtered solid may then be washed with a solvent, preferably an organic solvent.
  • the most advantageous embodiments comprise washing with C r C 6 aliphatic alcohols, such as methanol or ethanol.
  • the washed or unwashed solid may then be allowed to dry or preferably is dried under vacuum.
  • the conditions for drying are easily obtainable by the skilled person, but the inventors have found drying under vacuum at 55-60°C for between about 3 to 4 hours to be particularly advantageous.
  • the isolated sunitinib or salt thereof may be further purified by recrystallisation from an organic solvent and/or water.
  • the inventors have found a mixture of a Q-Q alcohol and water in a v/v ratio of between 1:4 to 4:1, preferably about 4:1, preferably wherein the C r C 6 alcohol is n-butanol, to be particularly advantageous in further purifying the sunitinib or salt thereof.
  • a second aspect of the invention provides sunitinib or a salt thereof prepared by a process according to the invention, having a purity as determined by HPLC of at least 97%, preferably at least 99%, preferably at least 99.5%, most preferably at least 99.8%.
  • the sunitinib or salt thereof does not com rise compound (VI) or compound (VIII):
  • sunitinib L-malate (IV) was preferentially obtained.
  • sunitinib L-malate (IV) was preferentially obtained.
  • a fourth aspect of the present invention provides a pharmaceutical composition comprising sunitinib or a salt thereof 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 seventh aspect of the invention rovides a pyrrole derivative (I)
  • X is a suitable cation and n is 1, 2 or 3.
  • the cation is a metal cation, preferably an alkali metal or an alkaline earth metal cation.
  • the metal cation is either sodium or potassium, most advantageously sodium.
  • the bisulphite anion is provided by mixing a metabisulphite salt in the reaction mixture.
  • the metabisulphite salt is a salt of an alkali metal or an alkaline earth metal.
  • the salt is an alkali metal metabisulphite salt, preferably sodium or potassium metabisulphite, most preferably the alkali metal metabisulphite is sodium metabisulphite Na 2 S 2 O s .
  • a bisulphite salt could be used, preferably an alkali metal or alkaline earth metal bisulphite salt.
  • the salt is an alkali metal bisulphite salt, preferably sodium or potassium bisulphite, most preferably die alkali metal bisulphite is sodium bisulphite NaHS0 3 .
  • the reaction occurs in an aqueous C r C 5 alcohol solvent system, preferably the C r C 5 alcohol is ethanol.
  • the reaction occurs at a temperature in the range of -10°C to reflux of d e alcohol. Most preferably the reaction occurs at a temperature in the range of 10°C to 30°C.
  • 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.
  • the resulting pyrrole derivative (I) may be isolated by any means available to the sldlled person. The inventors have found filtering the pyrrole derivative (I) to be particularly advantageous. The filtered solid may then be washed with a solvent, preferably an organic solvent. The most advantageous embodiments comprise washing with C C 6 aliphatic alcohols, such as methanol or ethanol, and/ or water.
  • the washed or unwashed solid may then be allowed to dry or preferably is dried under vacuum.
  • the conditions for drying are easily obtainable by the sldlled person, but the inventors have found drying under vacuum at between about 30°C to 50°C, most preferably about 40°C, until no weight change is detected, preferably for between about 3 to 4 hours, to be particularly advantageous.
  • Example 3 Preparation of sunitinib L-malate (IV) using the sodium salt of pyrrole derivative (I)
  • This solid was further purified by dissolving in n-butanol : water (4:1, 20vol) at 50-60°C and cooling to 25-30°C.
  • n-propyl amine (1.76g, 2 equivalent) was added followed by the addition of L-malic acid (2g, 1 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.
  • XRPDs were recorded on a Bruker D8 Advance Instrument, using Cu oc-radiation as the X- ray source, with a 2 ⁇ range of from 3 to 50°, a step-size of 0.5° and a time/step of lsec.
  • DSCs were recorded on a Perkin Elmer Pyris 6, with a temperature range of from 25°C to 280°C and a rate of heating of 10°C/min.
  • HPLC purities were determined using:

Abstract

La présente invention concerne des procédés inédits de préparation de sunitinib et de ses sels et, en particulier, du (2S)-2-hydroxybutanedioate de sunitinib. L'invention concerne, en outre, des intermédiaires inédits, leur utilisation dans le cadre de la préparation du sunitinib ou de ses sels et des procédés de préparation desdits intermédiaires. L'invention concerne également des compositions contenant du sunitinib ou ses sels pharmaceutiquement acceptables.
PCT/GB2011/050752 2010-04-16 2011-04-15 Procédés inédits WO2011128699A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103319392A (zh) * 2013-07-10 2013-09-25 张家港市华昌药业有限公司 一种舒尼替尼中间体的制备方法
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

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6573293B2 (en) 2000-02-15 2003-06-03 Sugen, Inc. Pyrrole substituted 2-indolinone protein kinase inhibitors
WO2003070725A2 (fr) 2002-02-15 2003-08-28 Pharmacia & Upjohn Company Procede de preparation de derives de l'indolinone
US20060009510A1 (en) 2004-07-09 2006-01-12 Pharmacia & Upjohn Company Llc Method of synthesizing indolinone compounds
US7435832B2 (en) 2001-08-15 2008-10-14 Pharmacia & Upjohn Company Crystals including a malic acid salt of a 3-pyrrole substituted 2-indolinone, and compositions thereof
WO2009150523A1 (fr) 2008-06-13 2009-12-17 Medichem, S.A. Procédé de préparation d’un sel 2-indolinone malate à substitution 3‑pyrrole
WO2010001167A2 (fr) 2008-07-02 2010-01-07 Generics [Uk] Limited Nouveau processus
WO2010023473A2 (fr) 2008-08-25 2010-03-04 Generics [Uk] Limited Nouvelle forme cristalline et ses procédés de préparation

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6573293B2 (en) 2000-02-15 2003-06-03 Sugen, Inc. Pyrrole substituted 2-indolinone protein kinase inhibitors
US7125905B2 (en) 2000-02-15 2006-10-24 Agouron Pharmaceuticals, Inc. Pyrrole substituted 2-indolinone protein kinase inhibitors
US7435832B2 (en) 2001-08-15 2008-10-14 Pharmacia & Upjohn Company Crystals including a malic acid salt of a 3-pyrrole substituted 2-indolinone, and compositions thereof
WO2003070725A2 (fr) 2002-02-15 2003-08-28 Pharmacia & Upjohn Company Procede de preparation de derives de l'indolinone
US7119209B2 (en) 2002-02-15 2006-10-10 Pharmacia & Upjohn Company Process for preparing indolinone derivatives
US20060009510A1 (en) 2004-07-09 2006-01-12 Pharmacia & Upjohn Company Llc Method of synthesizing indolinone compounds
WO2009150523A1 (fr) 2008-06-13 2009-12-17 Medichem, S.A. Procédé de préparation d’un sel 2-indolinone malate à substitution 3‑pyrrole
WO2010001167A2 (fr) 2008-07-02 2010-01-07 Generics [Uk] Limited Nouveau processus
WO2010023473A2 (fr) 2008-08-25 2010-03-04 Generics [Uk] Limited Nouvelle forme cristalline et ses procédés de préparation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
J. ORG. CHEM., vol. 68, no. 16, 2003, pages 6447 - 6450
T.W. GREENE, P.G.M. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY-INTERSCIENCE

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103319392A (zh) * 2013-07-10 2013-09-25 张家港市华昌药业有限公司 一种舒尼替尼中间体的制备方法
CN103319392B (zh) * 2013-07-10 2015-10-28 张家港市华昌药业有限公司 一种舒尼替尼中间体的制备方法
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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