WO2006134469A1 - Procedes de preparation d'un inhibiteur de mek - Google Patents

Procedes de preparation d'un inhibiteur de mek Download PDF

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WO2006134469A1
WO2006134469A1 PCT/IB2006/001584 IB2006001584W WO2006134469A1 WO 2006134469 A1 WO2006134469 A1 WO 2006134469A1 IB 2006001584 W IB2006001584 W IB 2006001584W WO 2006134469 A1 WO2006134469 A1 WO 2006134469A1
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Prior art keywords
fluoro
dioxolan
difluoro
dimethyl
benzamide
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PCT/IB2006/001584
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English (en)
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Erwin Ayandra Irdam
Thomas Norman Nanninga
Edward Mark Davis
Howard Isaac Tjiong
Justin Kaine Weaver
Derick Dale Winkle
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Warner-Lambert Company Llc
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Publication of WO2006134469A1 publication Critical patent/WO2006134469A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to methods of preparing MEK inhibitor ⁇ /-[(R)-2,3-dihydroxy-propoxy]-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide that is useful for treating diseases mediated by MEK activity in mammals.
  • Compound I is also known as the compound PD 0325901.
  • Compound I is disclosed in WO 02/06213; WO 04/045617; WO 2005/040098; EP 1262176; U.S. Patent Application Pub. No. 2003/0055095 A1 ; U.S. Patent Application Pub. No. 2004/0054172 A1; U.S. Patent Application Pub. No. 2004/0147478 A1 ; and U.S. Patent Application No. 10/969,681, the disclosures of which are incorporated herein by reference in their entireties.
  • Each MAPK module consists of 3 cytoplasmic kinases: a mitogen-activated protein kinase (MAPK), a mitogen-activated protein kinase kinase (MAPKK), and a mitogen-activated protein kinase kinase (MAPKKK).
  • MEK occupies a strategic downstream position in this intracellular signaling cascade catalyzing the phosphorylation of its MAP kinase substrates, ERK1 and ERK2. Anderson et al.
  • the RAF-MEK-ERK pathway mediates proliferative and anti-apoptotic signaling from growth factors and oncogenic factors such as Ras and Raf mutant phenotypes that promote tumor growth, progression, and metastasis.
  • Ras-MAP kinase cascade provides molecular targets with potentially broad therapeutic applications.
  • Patent Application No. 10/969,681 comprises reaction of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzoic acid with (R)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine in the presence of N 1 N 1 - carbonyldiimidazole.
  • the resulting product is hydrolyzed with aqueous acid and crystallized to provide polymorphic form IV of Compound I.
  • the present invention provides a method of preparing ⁇ /-[(R)-2,3-dihydroxy- propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, the method comprising: a) treating [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol with trifluoromethansulfonic anhydride to form [(4R)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methyl trifluoromethanesulfonate;
  • the present invention provides a method of preparing ⁇ /-[(R)-2,3- dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenyIamino)-benzamide, wherein steps a) through c) are carried out as a one-pot reaction.
  • the present invention provides a method of preparing ⁇ /-[(R)-2,3- dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein step c) comprises use of aqueous ammonia for converting (R)-2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-isoindole-1,3- dione into 0- ⁇ [(4R)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methyl ⁇ hydroxylamine.
  • the present invention provides a method of preparing ⁇ /-[(R)-2,3- dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein 3,4-difluoro-2-(2- fluoro-4-iodophenylamino)-benzoic acid is prepared by a reaction comprising coupling a compound of formula 2
  • the present invention provides a method of preparing ⁇ /-[(R)-2,3- dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein X is fluorine and the Group I metal cation amide is lithium amide.
  • the present invention provides a method of preparing ⁇ /-[(R)-2,3- dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein a small amount of the compound of formula 2 and 2-fluoro-4-iodoaniline is initially added to lithium amide in an aprotic solvent followed by slow continuous addition of a remaining portion.
  • the present invention provides a method of preparing ⁇ /-[(R)-2,3- dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein the aprotic solvent is tetrahydrofuran.
  • the present invention provides a method of preparing ⁇ /-[(R)-2,3- dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein the carboxylic acid activating reagent in step d) is 1 ,1 '-carbonyldiimidazole.
  • the present invention provides a method of preparing ⁇ /-[(R)-2,3- dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein the carboxylic acid activating reagent in step d) is thionyl chloride.
  • the present invention provides a method of preparing /V-[(R)-2,3- dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide comprising at least one single-phase system crystallizing of ⁇ /-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide.
  • the present invention provides a method of preparing ⁇ /-[(R)-2,3- dihydroxy-propoxy]-3,4-difluoro-2-(2-fIuoro-4-iodo-phenylamino)-benzamide, wherein a first single-phase system crystallizing of ⁇ /-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide is carried out in toluene with from 1 to 20 % v/v of acetonitrile and a second single-phase system crystallizing of A/-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide is carried out in a mixture of ethanol and toluene.
  • Compound I is ⁇ /-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide
  • alkyl means a branched- or straight-chained (linear) paraffinic hydrocarbon group (saturated aliphatic group) having from 1 to 10 carbon atoms in its chain, which may be generally represented by the formula C k H 2k+ i, where k is an integer of from 1 to 10.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, n-pentyl, isopentyl, neopentyl, and hexyl, and the simple aliphatic isomers thereof.
  • aryl means an aromatic monocyclic or fused polycyclic ring structure having a total of from 4 to 18, preferably 6 to 18, ring carbon atoms (no heteroatoms).
  • Exemplary aryl groups include phenyl, naphthyl, anthracenyl, and the like.
  • Group I metal cation means Li + , Na + , K + , Rb + , Cs + , or Fr + .
  • Group Il metal cation means Be +2 , Mg +2 , Ca +2 , Sr +2 , Ba +2 , or Ra +2 .
  • Group I metal cation amide means a compound in which a hydrogen atom on nitrogen from ammonia or an amine is replaced by a metal cation which is Li + , Na + , K + , Rb + , Cs + , or Fr + .
  • Group Il metal cation amide means a compound in which a hydrogen atom on nitrogen from ammonia or an amine is replaced by a metal cation which is Be +2 , Mg +2 , Ca +2 , Sr +2 ,
  • Group I metal cation dialkylamide means a compound in which a hydrogen atom on nitrogen from a dialkylamine, which comprises two independent unsubstituted alkyl groups as defined above, is replaced by a metal cation which is Li + , Na + , K + , Rb + , Cs + , or Fr + .
  • Illustrative examples of a Group I metal cation diaikylamide includes lithium diisopropylamide.
  • Group Il metal cation dialkylamide means a compound in which a hydrogen atom on nitrogen from a dialkylamine, which comprises two independent unsubstituted alkyl groups as defined above, is replaced by a metal cation which is Be +2 , Mg +2 , Ca +2 , Sr +2 , Ba +2 , or Ra +2 .
  • a metal cation which is Be +2 , Mg +2 , Ca +2 , Sr +2 , Ba +2 , or Ra +2 .
  • Illustrative examples of a Group Il metal cation dialkylamide includes magnesium bis(diisopropylamide).
  • Group I metal cation bis(trialkylsilyl)amide means a compound in which a hydrogen atom on nitrogen from a bis(trialkylsilyl)amine, which comprises two independent trialkylsilyl groups wherein each alkyl is independently unsubstituted alkyl as defined above, is replaced by a metal cation which is Li + , Na + , K + , Rb + , Cs + , or Fr + .
  • Illustrative examples of a Group I metal cation bis(trialkylsilyl)amide includes lithium bis(trimethylsilyl)amide ("LiHDMS” or "lithium hexamethyldisilazane”).
  • Group Il metal cation bis(trialkylsilyl)amide means a compound in which a hydrogen atom on nitrogen from a bis(trialkylsilyl)amine, which comprises two independent trialkylsilyl groups wherein each alkyl is independently unsubstituted alkyl as defined above, is replaced by a metal cation which is Be +2 , Mg +2 , Ca +2 , Sr +2 , Ba +2 , or Ra +2 .
  • Illustrative examples of a Group Il metal cation bis(trialkylsilyl)amide includes magnesium di[bis(trimethylsilyl)amide].
  • Group I metal cation alkoxide means a compound in which a hydrogen atom on oxygen from an alcohol, which comprises an unsubstituted alkyl group as defined above, is replaced by a metal cation which is Li + , Na + , K + , Rb + , Cs + , or Fr + .
  • Illustrative examples of a Group I metal cation alkoxide includes lithium methoxide, sodium ethoxide, and potassium terf-butoxide.
  • Group Il metal cation alkoxide means a compound in which a hydrogen atom on oxygen from an alcohol, which comprises an unsubstituted alkyl group as defined above, is replaced by a metal cation which is Be +2 , Mg +2 , Ca +2 , Sr +2 , Ba +2 , or Ra +2 .
  • a Group Il metal cation alkoxide includes magnesium bismethoxide and calcium bisethoxide.
  • bases which comprise a salt of a Group I metal cation. More preferred are bases which comprise a salt of Li + , Na + , or K + . Still more preferred are bases which comprise a salt of Li + .
  • any base whereof the conjugate acid has a pKa ⁇ 16 is suitable for the invention process.
  • EDC 1-
  • carboxylic acid activating reagents may be found in Comprehensive Organic Transformations, by Richard C. Larock, VCH Publishers, Inc, New York, 1989.
  • Preferred carboxylic acid activating reagents are selected from: (COCI) 2 , S(O)CI 2 , S(O) 2 CI 2 ,
  • hydrazinolysis means a chemical method that uses hydrazine or its derivatives to cleave amide bonds.
  • reactive functional group means a group that is expected to react with certain solvents, reagents, catalysts, reaction starting materials, reaction intermediates, or reaction products under the particular reaction conditions employed.
  • non-nucleophilic base means a base that is slow to act as a nucleophile in a substitution reaction such as, for example, a nucieophilic aromatic substitution reaction.
  • non- nucleophilic bases include tertiary organic amines, which are defined below, Group I metal cation hydrides, Group Il metal cation hydrides, Group I metal cation dialkylamides, Group Il metal cation dialkylamides, Group I metal cation bis(trialkylsilyl)amides, Group Il metal cation bis(trialkylsilyl)amides, Group I metal cation terf/a/y-alkoxides, and Group Il metal cation terf/a/y-alkoxides.
  • the phrase "acid catalyst” means a Br ⁇ nsted acid or Lewis acid which may be present in catalytic, stoichiometric, or greater than stoichiometric amounts.
  • aprotic solvent means a solvent that does not yield a proton (i.e., acts as a Br ⁇ nsted acid) under the particular conditions employed. This means that the pKa (relative to water or, optionally, DMSO) of an aprotic solvent is greater than the pKa of the conjugate acid of the strongest base employed.
  • Typical aprotic solvents with high pKa's include diethyl ether, tetrahydrofuran, dioxane, dimethylsulfoxide, hexane, heptane, dimethylformamide, toluene, and benzene.
  • Typical aprotic solvents with lower pKa's include ethyl acetate, acetone, and acetonitrile.
  • Solvents with pKa's less than 19 such as, for example, tert-butyl alcohol, usually are not aprotic, although nitromethane is an aprotic solvent.
  • Solvents that contain a functional group selected from OH, NH, and SH are typically not aprotic.
  • protic solvent or “protic contaminant” mean a solvent or contaminant, respectively, that does yield a proton under the particular conditions employed.
  • tertiary organic amine means a trisubstituted nitrogen group wherein the three substituents are independently selected from Ci-Ci 2 alkyl, 03-C-J 2 cycloalkyl, and benzyl, or wherein two of the three substituents are taken together with the nitrogen atom to which they are attached to form a
  • -Ci 2 alkyl, C3-Ci 2 cycloalkyl, and benzyl, or wherein the three substituents are taken together with the nitrogen atom to which they are attached to form a 7-membered to 12-membered bicyclic heterocycle containing 1 or 2 nitrogen atoms total and carbon atoms, and optionally having a carbon-nitrogen double bond ("C N") when 2 nitrogen atoms are present.
  • tertiary organic amine examples include triethylamine, diisopropylethylamine, benzyldiethylamine, dicyclohexyl-methyl-amine, 1,8-diazabicyclo[5.4.0]undec-7-ene (“DBU”), 1,4-diazabicyclo[2.2.2]octane (“TED”), and 1,5-diazabicyclo[4.3.0]non-5-ene.
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • TED 1,4-diazabicyclo[2.2.2]octane
  • 1,5-diazabicyclo[4.3.0]non-5-ene examples include triethylamine, diisopropylethylamine, benzyldiethylamine, dicyclohexyl-methyl-amine, 1,8-diazabicyclo[5.4.0]undec-7-ene (“DBU”), 1,4
  • purifying means separating a desired compound from undesired components of a mixture which contains both by methods which include distillation, chromatography, including column chromatography, thin layer chromatography, normal phase chromatography, reverse phase chromatography, gas phase chromatography, and ion exchange chromatography, precipitation, extraction, rotary evaporation, chemical-based trapping by reaction with an incompatible functional group, including quenching with polymer-bound quenching reagents, filtration, centrifugation, physical separation, and fractional crystallization.
  • the phrase "carried out on a commercial scale" means a process, which employs more than 1 kilogram of a reagent.
  • polymorph refers to different crystalline forms of the same compound and includes, but is not limited to, other solid state molecular forms including hydrates (e.g., bound water present in the crystalline structure) and solvates (e.g., bound solvents other than water) of the same compound.
  • peak intensities refers to relative signal intensities within a given X-ray diffraction pattern. Factors which can affect the relative peak intensities are sample thickness and preferred orientation (i.e. the crystalline particles are not distributed randomly).
  • peak positions refers to X-ray reflection positions as measured and observed in X-ray powder diffraction experiments. Peak positions are directly related to the dimensions of the unit cell.
  • slurry refers to a solid substance suspended in a liquid medium, typically water or an organic solvent.
  • separating from refers to a step in a synthesis in which the desired agent is isolated from other non-desired agents, including, but not limited to any of the following steps: filtering, washing with extra solvent or water, drying with heat and or under vacuum.
  • X-ray powder diffraction pattern or PXRD refers to the experimentally observed diffractogram or parameters derived therefrom. X-Ray powder diffraction patterns are characterized by peak position (abscissa) and peak intensities (ordinate).
  • DSC Differential Scanning Calorimetry
  • one-pot reaction refers to a reaction or series of reaction steps (process, procedure, etc.) carried out with no isolation of intermediates.
  • Et means ethyl
  • Ac means acetyl
  • Me means methyl
  • Ms means methanesulfonyl (CH 3 SO 2 )
  • iPr means isopropyl
  • Ph means phenyl
  • EtOAc means ethyl acetate
  • HAc means acetic acid
  • NEt 3 or “Et 3 N” means triethylamine
  • Tf means trifluoromethanesulfonyl
  • Tf means trifluoromethanesulfonyl
  • THF means tetrahydrofuran
  • GDI means 1,1'-carbonyldiimidazole
  • HBt means hydroxy benzotriazole
  • MeOH means methanol
  • i-PrOAc means isopropyl acetate
  • KOAc means potassium acetate
  • DMSO means dimethylsulfoxide
  • AcCI means acetyl chloride
  • Figure 1 is an X-ray powder diffraction diagram of polymorphic Form IV of ⁇ /-[(R)-2,3-dihydroxy-propoxy]- 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Detailed Description of the Invention
  • the present invention provides a new synthetic route including Steps I through Step III to the MEK inhibitor ⁇ /-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (Compound I).
  • Step I Preparation of 0- ⁇ r(4RV2.2-dimethyl-1.3-dioxolan-4-ynmethyl ⁇ hydroxylan ⁇ ine (6)
  • the method of the present invention comprises a novel Step I of preparing of 0- ⁇ [(4R)-2,2- dimethyl-1 ,3-dioxolan-4-yl]methyl ⁇ hydroxylamine (6) from [(4S)-2,2-dimethyl-1 ,3-dioxoIan-4-yl]methanol (1) through the formation of [(4R)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methyl trifluoromethanesulfonate (3) and its coupling with N-hydroxyphthalimide (4) to afford 2- ⁇ [(4R)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy ⁇ -1 H- isoindole-1 ,3(2H)-dione (5), which is subsequently de-protected to give 6
  • the reaction of compound (1) with trifluoromethanesulfonic anhydride (2) is carried out in the presence of a non-nucleophilic base, such as, for example, a tertiary organic amine, in an aprotic solvent at a temperature of from -5O 0 C to 5 0 C, preferably, at a temperature less than -15 0 C, to form triflate (3).
  • a non-nucleophilic base such as, for example, a tertiary organic amine
  • an aprotic solvent at a temperature of from -5O 0 C to 5 0 C, preferably, at a temperature less than -15 0 C, to form triflate (3).
  • a preferred tertiary organic amine is triethylamine, and a preferred solvent is toluene.
  • Treatment of triflate (3) with N-hydroxyphthalimide (4) furnishes phthalimide (5), which can be isolated if desired.
  • 0- ⁇ [(4R)- 2,2-dimethyl-1,3-dioxolan-4-yl]methyl ⁇ hydroxylamine (6) can be prepared in a one-pot process with no phthalimide (S) isolation. Cleavage of the phthalimide function could be achieved by methods known in the art, for example, by hydrazinolysis. However, the use of less hazardous aqueous or anhydrous ammonia instead of methyl hydrazine (CH 3 NHNH 2 ) is preferred.
  • Step II Preparation of 3.4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) As shown in Scheme 2, Step Il of the method of the present invention provides 3,4-difluoro-2-(2- fluoro-4-iodophenylamino)-benzoic acid (9).
  • Preparation of compound (9) can be carried out by reacting compound (7), wherein X is halogen, or O-SC ⁇ R ⁇ or 0-P( 3 O)(OR ⁇ , wherein R ⁇ is alkyl or aryl, with compound (8) optionally in a solvent, and in the presence of from about 1 mol equivalent to about 10 mol equivalents of at least one base, wherein the base is selected from: a Group I metal cation hydride or a Group 2 metal cation hydride, including lithium hydride, sodium hydride, potassium hydride, and calcium hydride, a Group I metal cation dialkylamide or a Group 2 metal cation dialkylamide, including lithium diisopropylamide, a Group I metal cation amide or a Group 2 metal cation amide, including lithium amide, sodium amide, potassium amide, a Group I metal cation alkoxide or a Group 2 metal cation alkoxide, including sodium ethoxide, potassium
  • preparation of compound (9) is carried out by reacting compound (7), wherein X is halogen, more preferably, X is fluorine, in an aprotic solvent with compound (8) in the presence of from about 3 mol equivalents to about 5 mol equivalents of a Group I metal cation amide at a temperature of from 2O C to 55 ° C, more preferably, at a temperature from 45 ° C to 55 ° C.
  • a catalytic amount of Group I metal cation dialkylamide can be added if necessary.
  • a preferred Group I metal cation amide is lithium amide
  • a preferred Group I metal cation dialkylamide is lithium diisopropylamide
  • a preferred solvent is tetrahydrofuran.
  • the reaction is performed by adding a small amount of compound (7) and compound (8) to lithium amide in tetrahydrofuran followed by slow continuous addition of the remaining portion. This procedure minimizes the risk of reactor over-pressurization due to gas side product (ammonia) generation.
  • Step III Preparation of N-((RV2.3-dihydroxypropoxy)-3.4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide (Compound I)
  • Compound I can be obtained by coupling 0- ⁇ [(4R)-2,2-dimethyl-1,3-dioxolan-4- yl]methyl ⁇ hydroxylamine (6) with 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) using a carboxylic acid activating reagent such as, for example, COCI2, S(O)C ⁇ , S(O)2Cl2, P(O)Cl3, triphenylphosphine/diethylazodicarboxylate, diphenylphosphinic chloride, N, N'-dicyclohexylcarbodiimide, (benzotriazol-1 -yloxy)tripyrolidinophosphonium hexafluorophosphate, (benzotriazol-1 - yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, N-ethyl-N'-(3-
  • a preferred carboxylic acid activating reagent is 1,1'-carbonyldimidazole (CDI) shown in Scheme 3.
  • CDI 1,1'-carbonyldimidazole
  • the method was modified to include the advantageous procedure for product purification and isolation, which procedure is performed in single-phase systems such as, for example, toluene/acetonitrile for the first isolation/crystallization and ethanol/toluene for the second recrystallization.
  • Water addition implemented in the previous procedure, was omitted to avoid the two-phase crystallization from the immiscible water-toluene system that caused inconsistent product purity.
  • the one-phase procedure of the present invention provides consistent control and removal of un- reacted starting material and side products.
  • Compound I can be obtained by coupling 0- ⁇ [(4R)-2,2-dimethyl-1,3-dioxolan-4- yl]methyl ⁇ hydroxylamine (6) with 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) using thionyl chloride (SOCI 2 ) as shown in Scheme 4.
  • HPLC (Conditions A): 10 ⁇ L injection volume onto Agilent Zorbax RX-C18 150 mm x 4.6 mm x 3.5 ⁇ m column at 30 ° C column temperature, 1.0 mL/min flow rate and detection at 246 nm.
  • Mobile phase A (v/v): 25 mM Acetate Buffer, pH 6.0;
  • Mobile phase B (v/v): Acetonitrile, and Linear Gradient Table:
  • Sample Preparation Dilute 100 ⁇ L reaction mixture to 10 mL with acetonitrile. Mix in a vial 200 ⁇ L of this sample solution with 300 ⁇ L carbonate buffer pH 10.0 and 300 ⁇ L solution of 2-mercaptopyridine in acetonitrile (18 mM), heat the vial for 10 minutes at 50 0 C and dilute to 1:1 ratio in mobile phase A.
  • Sample preparation Dilute 1 ml_ reaction mixture to 100 mL with acetonitrile and dilute 1 mL of this solution to 10 mL with 50:50 Water/Acetonitrile.
  • Sample preparation Dilute 40 ⁇ L of reaction mixture in 20 mL acetonitrile.
  • Sample preparation Quench reaction mixture sample with dipropylamine and stir for about 5 minutes before further dilution with mobile phase.
  • a Rigaku Miniflex+ X-ray diffractometer was used for the acquisition of the powder XRD patterns.
  • the instrument operates using the Cu Ka 1 emission with a nickel filter at 1.50451 units.
  • the major instrumental parameters are set or fixed at:
  • Example 2B Preparation of 3.4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) by the solid addition of lithium amide method
  • the final reaction mixture was slightly concentrated under vacuum collecting about 100 mL distillate and the resulting organic solution was cooled to 5 ° C to crystallize the product and filtered.
  • the filter cake was washed with toluene (1000 mL) followed by water (100 mL) and the wet cake (crude product Compound I) was charged back to the flask.
  • Toluene (100 mL), ethanol (100 mL) and water (100 mL) are then added, stirred at 30-35 ° C for about 15 min, and the bottom aqueous phase was discarded. Water (200 mL) was then added to the organic solution and the mixture was stirred at about 3O C to allow for crystallization.

Abstract

L'invention concerne des procédés de préparation d'un inhibiteur de MEK sous la forme d'un N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phénylamino)-benzamide utile pour traiter des maladies médiées par l'activité de MEK chez les mammifères. La présente invention concerne de nouvelles voies de synthèse qui sont sûres, efficaces et économiques lors d'une mise en oeuvre à une échelle commerciale.
PCT/IB2006/001584 2005-06-14 2006-06-01 Procedes de preparation d'un inhibiteur de mek WO2006134469A1 (fr)

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WO2012019113A3 (fr) * 2010-08-05 2012-08-09 Case Western Reserve University Inhibiteurs de l'erk destinés à traiter des troubles du développement de la connectivité neuronale
WO2013107283A1 (fr) 2012-01-17 2013-07-25 Tianjin Binjiang Pharma, Inc. Composés benzohétérocycliques et leur utilisation
US11066358B1 (en) 2021-02-17 2021-07-20 Warner-Lambert Company Llc Compositions of essentially pure form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof
US11084780B1 (en) 2021-02-17 2021-08-10 Springworks Therapeutics, Inc. Crystalline solids of MEK inhibitor N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof
WO2022177556A1 (fr) 2021-02-17 2022-08-25 Warner-Lambert Company Llc Compositions de forme iv essentiellement pure de n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophénylamino)-benzamide et leurs utilisations
WO2022177557A1 (fr) 2021-02-17 2022-08-25 Springworks Therapeutics, Inc. Solides cristallins d'inhibiteur de mek n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophénylamino)-benzamide et utilisations associées
US11571402B2 (en) 2021-02-17 2023-02-07 Springworks Therapeutics, Inc. Dispersible formulations of N-((R)-2,3-dihydroxypropoly)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012019113A3 (fr) * 2010-08-05 2012-08-09 Case Western Reserve University Inhibiteurs de l'erk destinés à traiter des troubles du développement de la connectivité neuronale
CN103221043A (zh) * 2010-08-05 2013-07-24 卡斯西部储备大学 用于治疗神经元连接发育障碍的erk抑制剂
WO2013107283A1 (fr) 2012-01-17 2013-07-25 Tianjin Binjiang Pharma, Inc. Composés benzohétérocycliques et leur utilisation
US9290468B2 (en) 2012-01-17 2016-03-22 Shanghai Kechow Pharma, Inc. Benzoheterocyclic compounds and use thereof
US9937158B2 (en) 2012-01-17 2018-04-10 Shanghai Kechow Pharma, Inc. Benzoheterocyclic compounds and use thereof
US11066358B1 (en) 2021-02-17 2021-07-20 Warner-Lambert Company Llc Compositions of essentially pure form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof
US11084780B1 (en) 2021-02-17 2021-08-10 Springworks Therapeutics, Inc. Crystalline solids of MEK inhibitor N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof
WO2022177556A1 (fr) 2021-02-17 2022-08-25 Warner-Lambert Company Llc Compositions de forme iv essentiellement pure de n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophénylamino)-benzamide et leurs utilisations
WO2022177557A1 (fr) 2021-02-17 2022-08-25 Springworks Therapeutics, Inc. Solides cristallins d'inhibiteur de mek n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophénylamino)-benzamide et utilisations associées
US11427534B1 (en) 2021-02-17 2022-08-30 Springworks Therapeutics, Inc. Solids of MEK inhibitor N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide and uses thereof
US11453641B2 (en) 2021-02-17 2022-09-27 Warner-Lambert Company Llc Methods of treating neurofibromatosis with N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide
US11571402B2 (en) 2021-02-17 2023-02-07 Springworks Therapeutics, Inc. Dispersible formulations of N-((R)-2,3-dihydroxypropoly)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof
US11884610B2 (en) 2021-02-17 2024-01-30 Springworks Therapeutics, Inc. Crystalline solids of mek inhibitor n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof

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