JP2006348034A - Method for producing mek inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a MEK(mitogen-activated protein kinase extracellular regulated kinase) inhibitor, N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzamide, useful for treating diseases mediated by MEK activity in mammals. <P>SOLUTION: The method for producing the MEK inhibitor comprises the following process: Using [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol as starting raw material, a benzamide derivative is formed via a methanesulfonate salt of the starting material, (R)-2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-isoindole-1,3-dione, and the corresponding hydroxylamine derivative, which is then deprotonation. This method is safe, effective and economical when performed on a commercial scale. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  This application claims the benefit of priority based on US Provisional Patent Application No. 60 / 690,620, filed June 14, 2005, the contents of which are hereby incorporated by reference in their entirety. Insist.

  The present invention relates to a MEK inhibitor, N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-, useful for treating diseases mediated by MEK activity in mammals. It relates to a process for the preparation of fluoro-4-iodo-phenylamino) -benzamide.

によって表される化合物、N-［（R）−２，３−ジヒドロキシ−プロポキシ］−３，４−ジフルオロ−２−（２−フルオロ−４−ヨード−フェニルアミノ）−ベンズアミドは、MEK-1及びMEK-2の特異性の高い非−ATP−競合的阻害剤である。式１の化合物は、その開示が参考文献として本明細書中に全体として援用されている、PCT国際特許出願公開第WO02/06213号：同第WO04/045617号；同第WO2005/040098号；ヨーロッパ特許第EP1262176号；米国特許出願公開第2003/0055095A1号；同第2004/0054172A1号；同第2004/0147478A1号；及び米国特許出願第10/969,681号中に記載されている。 The following formula 1:

N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is represented by MEK-1 and It is a highly specific non-ATP-competitive inhibitor of MEK-2. Compounds of Formula 1 are disclosed in PCT International Patent Application Publication Nos. WO02 / 06213: WO04 / 045617; WO2005 / 040098; Europe, the disclosure of which is incorporated herein by reference in its entirety. US Patent Publication No. EP1262176; US Patent Application Publication No. 2003 / 0055095A1; 2004 / 0054172A1; 2004 / 0147478A1; and US Patent Application No. 10 / 969,681.

A number of mitogen-activated protein kinase (MAPK) signaling cascades are involved in the regulation of cellular processes including proliferation, differentiation, apoptosis, and stress responses. Each MAPK module consists of three cytoplasmic kinases: mitogen activated protein kinase (MAPK), mitogen activated protein kinase kinase (MAPKK), and mitogen activated protein kinase kinase kinase (MAPKKK). MEK occupies a strategic downstream position in this intracellular signaling cascade and catalyzes the phosphorylation of the MAP kinase substrates, ERK1 and ERK2. Anderson et al. "Requirement for integration of signals from two distinct phosphorylation pathways for activation of MAP kinase" Nature 1990, v.343, pp.651-653. In the ERK pathway, MAPKK corresponds to MEK (M AP kinase E RK K inase), MAPK corresponds to ERK (E xtracellular R egulated K inase ). No MEK substrates other than ERK1 and ERK2 have been found. Seger et al. "Purification and characterization of mitogen-activated protein kinase activator (s) from epidermal growth factor-stimulated A431 cells" J. Biol. Chem., 1992, v.267, pp. 14373-14381. In addition to its unique ability to act as a kinase with dual specificity, this strict selectivity is consistent with MEK's central role in the accumulation of signals in the MAPK pathway. 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 drive tumor growth, progression and metastasis. With a central role in mediating growth-promoting signaling from multiple growth factor receptors, the Ras-MAP kinase cascade offers a potentially broad therapeutic application for molecular targets.

One method of synthesizing Compound I is disclosed in the above-mentioned PCT International Patent Application Publication No. WO02 / 06213 and US Patent Application Publication No. 2004 / 0054172A1. This method begins with the reaction of 2-fluoro-4-iodo-phenylamine with 2,3,4-trifluoro-benzoic acid in the presence of an organic base such as lithium diisopropylamide, and 3,4-difluoro -2- (2-fluoro-4-iodo-phenylamino) -benzoic acid, which is composed of a peptide coupling agent (such as diphenylphosphine chloride) and a tertiary amine base (such as diisopropylethylamine). It is reacted with (R) -O- (2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -hydroxylamine in the presence. The resulting product is hydrolyzed under standard acidic hydrolysis conditions (such as p-toluenesulfonic acid in methanol) to provide compound I. (R) -O- (2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -hydroxylamine is prepared by [[4S) -2, in the presence of Ph ₃ P and diethylazodicarboxylate. 2-dimethyl-1,3-dioxolan-4-yl] methanol and N-hydroxyphthalimide.

  Another method for preparing Compound I, disclosed in the above-cited US patent application Ser. No. 10 / 969,681, is 3,4-difluoro-2- (2) in the presence of N, N′-carbonyldiimidazole. Reaction of -fluoro-4-iodo-phenylamino) -benzoic acid with (R) -O- (2,2-dimethyl [1,3] dioxolan-4-ylmethyl) -hydroxylamine. The resulting product is hydrolyzed with an aqueous acid and crystallized to provide polymorph Form IV of Compound I.

  Despite the fact that the above method is an effective synthetic route for the small scale synthesis of Compound I, there is a need for a new synthetic route that is safe, effective and economical when carried out on a commercial scale. It still remains.

In one embodiment of the invention, the present invention relates to N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino)- A method for producing benzamide is provided, the method comprising the following steps:
a) [(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methanol was treated with trifluoromethanesulfonic anhydride to give [(4R) -2,2-dimethyl-1,3. -Dioxolan-4-yl] methyl trifluoromethanesulfonate;
b) [(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methyl trifluoromethanesulfonate is reacted with N-hydroxyphthalamide to give (R) -2- (2,2 -Obtaining dimethyl- [1,3] dioxolan-4-ylmethoxy) -isoindole-1,3-dione;
c) (R) -2- (2,2-Dimethyl- [1,3] dioxolan-4-ylmethoxy) -isoindole-1,3-dione as O-{[(4R) -2,2-dimethyl- Converted to 1,3-dioxolan-4-yl] methyl} hydroxylamine;
d) O-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methyl} hydroxylamine and 3,4-difluoro-2- (2) using a carboxylic acid activating reagent. -Fluoro-4-iodophenylamino) -benzoic acid coupled to N-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -3,4-difluoro 2-[(2-fluoro-4-iodophenyl) amino] benzamide is formed; and
e) N-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -3,4-difluoro-2-[(2-fluoro-4-iodophenyl) amino] Benzamide is deprotonated to produce N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) benzamide;
including.

  In another embodiment, the present invention provides the preparation of N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. A method is provided wherein steps a) -c) are performed as a one-pot reaction.

  In another embodiment, the present invention provides the preparation of N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. Wherein step c) comprises (R) -2- (2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -isoindole-1,3-dione as O-{[ Including the use of aqueous ammonia to convert to (4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methyl} hydroxylamine.

｛式中、
Ｘは、ハロゲンである。｝
により表される化合物と２−フルオロ−４−ヨードアニリンをＩ族金属カチオンアミドの存在下でカップリングすることを含む反応によって製造される。 In another embodiment, the present invention provides the preparation of N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. A method is provided wherein 3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -benzoic acid is represented by the following formula 2 :

{Where,
X is a halogen. }
And 2-fluoro-4-iodoaniline in the presence of a Group I metal cation amide.

  In another embodiment, the present invention relates to N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. A manufacturing method is provided, wherein X is fluorine and the Group I metal cation amide is lithium amide.

In another embodiment, the present invention relates to N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. A method of preparation is provided, wherein a small amount of the compound of formula 2 and 2-fluoro-4-iodoaniline are first added to the lithium amide in an aprotic solvent followed by a slow and sustained balance. Is added.

  In another embodiment, the present invention relates to N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. A manufacturing method is provided, wherein the aprotic solvent is tetrahydrofuran.

  In another embodiment, the present invention relates to N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. A manufacturing method is provided, wherein the carboxylic acid activating reagent in step d) is 1,1′-carbonyldiimidazole.

  In another embodiment, the present invention relates to N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. A manufacturing method is provided, wherein the carboxylic acid activating reagent in step d) is thionyl chloride.

  In another embodiment, the present invention relates to N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. Of N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide comprising at least one single phase crystallization A manufacturing method is provided.

  In another embodiment, the present invention relates to N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. A method of preparation is provided, wherein a first of N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. Single phase crystallization of is carried out in toluene containing 1-20% v / v acetonitrile and N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- A second single-phase crystallization of (2-fluoro-4-iodo-phenylamino) -benzamide is carried out in a mixture of ethanol and toluene.

Definitions and abbreviations Compound I is N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

  The phrase “via MEK activity” refers to a biological or molecular process that is regulated, regulated, or inhibited by MEK protein kinase activity. For certain applications, those that inhibit the protein kinase activity associated with the MAPK signaling cascade and inhibit abnormal cell growth or inflammation are preferred.

As used herein, the term “alkyl” is a branched or straight-chain paraffinic hydrocarbon group (saturated aliphatic group) having 1 to 10 carbon atoms in the chain; In general, it means what can be represented by the formula C _k H _{2k + 1} , where k is an integer from 1 to 10. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, n-pentyl, isopentyl, neopentyl, and hexyl, and their simple aliphatic isomers. .

  The term “aryl” means an aromatic monocyclic or fused polycyclic structure containing a total of 4-18, preferably 6-18, ring carbon atoms (no heteroatoms). Exemplary aryl groups include phenyl, naphthyl, anthracenyl and the like.

The phrase “Group I metal cation” means Li ⁺ , Na ⁺ , K ⁺ , Rb ⁺ , Cs ⁺ , or Fr ⁺ .

The phrase “Group II metal cation” means Be ⁺² , MG ⁺² , Ca ⁺² , Sr ⁺² , Ba ⁺² , or Ra ⁺² .

The phrase “Group I metal cation amide” is replaced by a metal cation in which the hydrogen atom on the nitrogen atom of ammonia or amine is Li ⁺ , Na ⁺ , K ⁺ , Rb ⁺ , Cs ⁺ , or Fr ⁺ Means a compound that has been

The phrase “Group II metal cation amide” refers to a hydrogen atom on the nitrogen atom of ammonia or amine in which Be ⁺² , MG ⁺² , Ca ⁺² , Sr ⁺² , Ba ⁺² , or Ra ⁺² Means a compound substituted by a metal cation.

The phrase “Group I metal cation dialkylamide” includes two independent unsubstituted alkyl groups as defined above, wherein the hydrogen atom on the nitrogen from the dialkylamine is Li ⁺ , Na ⁺ , K ⁺ , Rb ^+. , Cs ⁺ , or Fr ⁺ means a compound substituted by a metal cation. Illustrative examples of Group I metal cation dialkylamides include lithium diisopropylamide.

The phrase “Group II metal cation dialkylamide” comprises two independent unsubstituted alkyl groups as defined above, wherein the hydrogen atom on the nitrogen from the dialkylamine is Be ⁺² , Mg ⁺² , Ca ⁺² , Sr ⁺² , Ba ⁺² , or Ra ⁺² means a compound substituted by a metal cation. Illustrative examples of Group II metal cation dialkylamides include magnesium bis (diisopropylamide).

The phrase “Group I metal cation bis (trialkylsilyl) amide” comprises two independent trialkylsilyl groups, wherein each alkyl is independently an unsubstituted alkyl group as defined above, and bis ( By trialkylsilyl) amine is meant a compound in which the hydrogen atom on the nitrogen is replaced by a metal cation which is Li ⁺ , Na ⁺ , K ⁺ , Rb ⁺ , Cs ⁺ , or Fr ⁺ . Illustrative examples of Group I metal cation bis (trialkylsilyl) amides include lithium bis (trimethylsilyl) amide (“LiHDMS” or “lithium hexamethyldisilazane”).

The phrase “Group II metal cation bis (trialkylsilyl) amide” comprises two independent trialkylsilyl groups, wherein each alkyl is independently an unsubstituted alkyl group as defined above, and bis ( Trialkylsilyl) means a compound in which the hydrogen atom on the nitrogen of the amine is replaced by a metal cation which is Be ⁺² , Mg ⁺² , Ca ⁺² , Sr ⁺² , Ba ⁺² , or Ra ⁺² . Illustrative examples of Group II metal cation bis (trialkylsilyl) amides include magnesium di [bis (trimethylsilyl) amide].

The phrase “Group I metal cation alkoxide” includes an unsubstituted alkyl group as defined above, wherein the hydrogen atom on the oxygen of the alcohol is Li ⁺ , Na ⁺ , K ⁺ , Rb ⁺ , Cs ⁺ , or Fr ^+. Means a compound substituted by a metal cation. Illustrative examples of Group I metal cation alkoxides include lithium methoxide, sodium ethoxide, and potassium tert-butoxide.

The phrase “Group II metal cation alkoxide” includes an unsubstituted alkyl group as defined above wherein the hydrogen atom on the oxygen of the alcohol is Be ⁺² , Mg ⁺² , Ca ⁺² , Sr ⁺² , Ba ^{+ 2} or a compound substituted by a metal cation that is Ra ⁺² . Illustrative examples of Group II metal cation alkoxides include magnesium bismethoxide and calcium bisethoxide.

Among the above bases, preferred are bases containing a salt of a Group I metal cation. More preferred are bases including Li ⁺ , Na ⁺ , or K ⁺ salts. Even more preferred are bases including salts of Li ⁺ . However, any base whose pKa of the conjugate acid is 16 or more is suitable for the method of the present invention.

The phrase “carboxylic acid activating reagent” refers to a coupling reaction involving the substitution of —C (═O) OH group, or the corresponding conjugate base (ie, —C (═O) O ⁻ ), respectively, OH or O 2 ^—. Means a reagent that is activated toward. Illustrative examples of carboxylic acid activating reagents include lipase enzymes, mineral acids including HCl and sulfite, boron trifluoride-ether complex, 2,4,6-trichloro-1,3,5-triazine, 3-nitro -2-pyridinesulfenyl chloride, trifluoroacetic anhydride, mesyl chloride, S (O) Cl ₂ , S (O) ₂ Cl ₂ , P (O) Cl ₃ , oxalyl chloride, (phenyl) ₂ P (= O ) Cl (“DPPCl”), 1,1′-carbonyldiimidazole (“CDI”), triphenylphosphine / diethylazodicarboxylate, N, N′-dicyclohexylcarbodiimide (“DCC”), 1- (3- Water-soluble carbodiimide, including 2-dimethyl-1-ethoxycarbonate, containing dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (“EDC”) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide methiodide Rubonyl-1,2-dihydroquinoline (“EEDQ”), benzotriazol-1-yloxy-tris (dimethylamino) -phosphonium hexafluorophosphate (“BOP”), and bromo-tris (pyrrolidino) -phosphonium hexafluorophosphate ( "PyBrOP"). Additional carboxylic acid activating reagents can be found in Comprehensive Organic Transformations, by Richard C. Larock, VCH Publishers, Inc, New York, 1989.

Preferred carboxylic acid activating reagent, the _{following: (COCl) 2, S (} O) Cl 2, S (O) 2 Cl 2, P (O) Cl 3, ( _{phenyl) 2 P (= O) Cl} , 1 , 1′-carbonyldiimidazole, triphenylphosphine / diethylazodicarboxylate, EDC, EDCl, and N, N′-dicyclohexylcarbodiimide.

  The term “hydrazine degradation” refers to chemical methods that use hydrazine or its derivatives to cleave amide bonds.

The phrase “reactive functional group” refers to a group that is expected to react with a given solvent, reagent, catalyst, initiator, reaction intermediate, or reaction product under the particular reaction conditions employed. means. Examples of reactive functional groups include, but are not limited to, including _{NH 2, OH, SH, CO} 2 H, N = C = O, and C (O) Cl.

  The phrase “non-nucleophilic base” means a base that is slow to act as a nucleophile in a substitution reaction such as an aromatic nucleophilic substitution reaction. Examples of non-nucleophilic bases are tertiary organic amines defined below, Group I metal cation hydrides, Group II metal cation hydrides, Group I metal cation dialkylamides, Group II metal cation alkylamides, Group I metals Cation bis (trialkylsilyl) amide, group II metal cation bis (trialkylsilyl) amide, group I metal cation tertiary alkoxide, group II metal cation tertiary alkoxide.

  The phrase “acid catalyst” means a Bronsted or Lewis acid that is present in a catalytic amount, a stoichiometric amount, or an amount that exceeds the stoichiometric amount.

  The phrase “aprotic solvent” means a solvent that does not obtain protons (ie, acts as a Bronsted acid) under the particular conditions employed. This means that the pKa of the aprotic solvent (relative to water or optionally DMSO) is greater than the pKa of the most powerful base conjugate acid employed. Typical aprotic solvents with high pKa (ie, higher than 30) include diethyl ether, tetrahydrofuran, dioxane, dimethyl sulfoxide, hexane, heptane, dimethylformamide, toluene, and benzene. Typical aprotic solvents with lower pKa (ie 19 <pKa <30) include ethyl acetate, acetone, and acetonitrile. Solvents with a pKa lower than 19 such as tert-butyl alcohol are usually not aprotic, even though nitromethane is an aprotic solvent. Solvents containing functional groups selected from OH, NH and SH are typically not aprotic.

  The phrases “protic solvent” or “protic impurity” mean a solvent or impurity that obtains protons under the particular conditions employed, respectively.

The phrase “tertiary organic amine” means that the three substituents are independently selected from C ₁ -C ₁₂ alkyl, C ₃ -C ₁₂ cycloalkyl, and benzyl, or of the three substituents Together with the nitrogen atom to which they are attached form a monocyclic hetero 5- or 6-membered ring containing one nitrogen and carbon atom, and the third substituent is C ₁ -C Selected from ₁₂ alkyl, C ₃ -C ₁₂ cycloalkyl, and benzyl, or the three substituents together with the nitrogen atom to which they are attached, a total of 1 or 2 nitrogen and carbon atoms And a bicyclic hetero 7 to 12 membered ring optionally having a carbon-nitrogen double bond ("C = N"). Illustrative examples of tertiary organic amines are 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.

  The term “purify” means separating the desired compound from the undesired components of a mixture containing both the desired compound and the undesired components, the method comprising distillation, column chromatography, thin layer chromatography Chromatography, including normal phase chromatography, reverse phase chromatography, gas phase chromatography, and ion exchange chromatography, precipitation, extraction, rotary evaporation, with incompatible functional groups including quenching with polymer bound quenching agents Includes chemical trapping by reaction, filtration, centrifugation, physical separation and fractional crystallization.

  The phrase “commercial scale implementation” refers to the process of using more than 1 kilogram of reagent.

  The term “polymorph” means different crystalline forms of the same compound, and hydrates (eg, bound water is present in the crystal structure) and solvates (eg, bound other than water) of the same compound. Other solid state molecular forms including but not limited to (solvent).

  The term “peak intensity” refers to the relative signal intensity within a given X-ray diffraction pattern. Factors that can affect the relative peak intensity are the thickness and preferred orientation of the sample (ie, the crystalline particles are not randomly distributed).

  The term “peak position” as used herein refers to the X-ray reflection position measured and observed in an X-ray powder diffraction experiment. The peak position is directly related to the unit cell dimensions.

  The term “slurry” refers to a solid material suspended in a liquid medium, typically water or an organic solvent.

  The term “separate from” means a step in the synthesis in which the desired material is isolated from other undesired materials, including filtration, washing with excess solvent or water, drying under heat or vacuum, It is not limited to these.

  The term “X-ray powder diffraction pattern” or PXRD refers to experimentally observed diffractograms or parameters derived therefrom. The X-ray powder diffraction pattern is characterized by peak position (horizontal axis) and peak intensity (vertical axis).

  “DSC” as used in this application means differential scanning calorimetry.

  The term “one-pot reaction” (process, procedure, etc.) refers to a reaction or series of reaction steps (process, procedure, etc.) performed without separation of intermediates.

As used in this application, “Et” means ethyl, “Ac” means acetyl, “Me” means methyl, and “Ms” means methanesulfonyl (CH ₃ SO ₂ ). , “IPr” means isopropyl, “Ph” means phenyl, “EtOAc” means ethyl acetate, “HOAc” means acetic acid, “NEt ₃ ” or “Et ₃ N” Means triethylamine, “Tf” means trifluoromethanesulfonyl, “THF” means tetrahydrofuran, “CDI” means 1,1′-carbonyldiimidazole, “HOBt” means hydroxybenzotriazole `` MeOH '' means methanol, `` i-PrOAc '' means isopropyl acetate, `` KOAc '' means potassium acetate, `` DMSO '' means dimethyl sulfoxide, `` AcCl '' is chloride means acetyl, "CDCl _3" means deuterated black Means Holm, "MTBE" means methyl t- butyl ether, "DMF" means dimethylformamide, and "Ac ₂ O" means acetic anhydride.

Detailed Description of the Invention The present invention relates to MEK inhibitors, N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino)- A new synthetic route is provided, including steps I-III to benzamide (compound I).

Step I: Preparation of O-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methyl} hydroxylamine (6) (4S) -2,2-Dimethyl-1,3-dioxolan-4-yl] methanol (1) to [(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methyltrifluoromethane 2-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -1H by formation of sulfonic acid (3) and its coupling with N-hydroxyphthalimide (4) -O-{[(4R) -2,2-dimethyl-1,3 via obtaining isoindole-1,3 (2H) -dione (5) followed by deprotection to give 6. -Dioxolan-4-yl] methyl} hydroxyl Producing emissions (6) comprising the new step I.

  The reaction of trifluoromethanesulfonic anhydride (2) with compound (1) is preferably carried out at a temperature of −50 ° C. to 5 ° C. in an aprotic solvent in the presence of a non-nucleophilic base such as a tertiary organic amine. Is carried out at temperatures below -15 ° C. to form the triflate (3). A preferred tertiary organic amine is triethylamine and a preferred solvent is toluene.

  Treatment of triflate (3) with N-hydroxyphthalimide (4) yields phthalimide (5), which can be separated if desired. However, to minimize processing time and increase the overall yield, O-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methyl} hydroxylamine (6) is It can be produced in a one-pot process without separation of phthalimide (5).

Cleavage of the phthalimide functional group can be accomplished by methods known in the art such as hydrazine degradation. However, it is desirable to use a less toxic aqueous ammonia solution or anhydrous ammonia instead of methyl hydrazine (CH ₃ NHNH ₂ ).

Step II: Preparation of 3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -benzoic acid (9)

The preparation of compound (9) is carried out in the presence of about 1 molar equivalent to about 10 molar equivalents of at least one base at a time and temperature sufficient to obtain compound (9), wherein X Is hydrogen or O—SO ₂ R ¹ or OP (═O) (OR ¹ ) ₂ and R ¹ is alkyl or aryl, optionally by reacting with compound (8) in a solvent. There are the following bases:
Group I metal cation hydride or Group II metal cation hydride comprising lithium hydride, sodium hydride, potassium hydride, and calcium hydride,
A Group I metal cation dialkylamide or a Group II metal cation dialkylamide, including lithium diisopropylamide,
Lithium amide, sodium amide, potassium amide, Group I metal cation amide or Group II metal cation amide,
Group I metal cation alkoxides including sodium ethoxide, potassium tert-butoxide and magnesium ethoxide, Group I metal cation alkoxides, and Group I metal cation hexamethyldisilazides including lithium hexamethyldisilazide;
Chosen from.

  Preferably, the preparation of compound (9) comprises the step of converting compound (7) from about 3 molar equivalents to about 5 molar equivalents of a Group I metal cation in an aprotic solvent, wherein X is halogen, more preferably X is fluorine. The reaction is carried out by reacting with compound (8) in the presence of an amide at a temperature of 20 ° C to 55 ° C, more preferably at a temperature of 45 ° C to 55 ° C. A catalytic amount of a Group I metal cation dialkylamide can be added if desired. A preferred Group I metal cation amide is lithium amide, a preferred Group I metal cation dialkylamide is lithium diisopropylamide, and a preferred solvent is tetrahydrofuran. Preferably, the reaction is carried out by adding a small amount of compound (7) and compound (8) to the lithium amide in tetrahydrofuran followed by the remaining portion slowly and continuously. This procedure minimizes the risk of excessive pressurization of the reaction vessel due to the formation of gaseous by-product (ammonia).

Step III: Preparation of N-((R) -2,3-dihydroxypropoxy) -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide (Compound I) COCl ₂ , S (O) Cl ₂ , S (O) ₂ Cl ₂ , P (O) Cl ₃ , triophenylphosphine / diethylazodicarboxylate, diphenylphosphinic chloride, N, N′-dicyclohexylcarbodiimide, ( Benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate, (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate, N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide hydrochloride Or using a carboxylic acid activating reagent such as 1,1-carbonyldiimidazole (CDI) {[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methyl} hydroxylamine (6) and 3,4-difluoro-2- (2-fluoro-4-iodophenylamino)- It can be obtained by coupling benzoic acid (9).

  A preferred carboxylic acid activating reagent is 1,1'-carbonyldiimidazole (CDI) as shown in Scheme 3. Preparation of the desired polymorph IV CDI of Compound I is described in US patent application Ser. No. 10 / 969,681, cited above.

  In accordance with the present invention, the above method is modified to include an advantageous procedure for product purification and isolation, which procedure is toluene / acetonitrile and a second recycle for initial isolation / crystallization. It is carried out in a single phase system such as ethanol / toluene for crystallization. The water addition performed in the previous procedure was omitted to avoid two-phase crystallization from the immiscible water-toluene system resulting in indefinite product purity. The single phase procedure of the present invention provides consistent control and removal of unreacted starting materials and byproducts.

Alternatively, Compound I can be prepared using O-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methyl} hydroxylamine using thionyl chloride (SOCl ₂ ) as shown in Scheme 4. It can be obtained by coupling (6) and 3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -benzoic acid (9).

  The reagents and reaction conditions described herein are merely illustrative of a wide variety of starting materials, their amounts and conditions that can be suitably employed in the present invention as understood by one of skill in the art, and any It is not intended to be limited by the method.

  HPLC (Condition A): detection at an injection volume of 10 μL, flow rate of 1.0 mL / min and 246 nm on a 150 mm × 4.6 mm × 3.5 μm Agilent Zorbax RX-C18 column at a column temperature of 30 ° C. Mobile phase A (v / v): 25 mM acetate buffer, pH 6.0; mobile phase B (v / v): acetonitrile, and linear gradient table:

サンプル調製：１００μＬの反応混合物を１０mLのアセトニトリルで希釈する。バイアル中でこのサンプル２００μLを３００μLの炭酸緩衝液pH１０．０及び３００μLのアセトニトリル中２−メルカプトピリジン溶液（１８mM）と混合し、バイアルを５０℃で１０分間加熱し、そして移動相A中で１：１の比に希釈する。

Sample preparation: Dilute 100 μL of reaction mixture with 10 mL of acetonitrile. In a vial, 200 μL of this sample is mixed with 300 μL carbonate buffer pH 10.0 and 300 μL 2-mercaptopyridine solution (18 mM) in acetonitrile, the vial is heated at 50 ° C. for 10 minutes, and in mobile phase A 1: Dilute to a ratio of 1.

  GC (Condition B): RTX-5 column (30m x 0.25mm x 2) with an initial oven temperature of 120 ° C for 2 minutes, 15 ° C / min to a final temperature of 250 ° C, and a final time of 2.33 minutes. 0.25 μm); flow rate: 1 mL / min.

  HPLC (Condition C): 5 μL injected onto a 150 mm × 4.6 mm × 3 μm Phenomenex Luna C18 (2) column; flow rate: 10 mL / min; detected at 255 nm; mobile phase A: 0.1% trifluoroacetic acid (TFA) 95/5 v / v water / acetonitrile containing, mobile phase B: 5/95 v / v water / acetonitrile containing 0.1% TFA; Table of linear gradients:

サンプル調製：１ｍLの反応混合物をアセトニトリルで１００ｍLに希釈し、この溶液の１ｍLを、５０：５０の水／アセトニトリルで１０ｍLに希釈する。

Sample preparation: 1 mL of the reaction mixture is diluted to 100 mL with acetonitrile, and 1 mL of this solution is diluted to 10 mL with 50:50 water / acetonitrile.

HPLC (Condition D): Waters SymmetryShield RP 18, 150 mm x 4.6 mm x 3.5 μm, 5 μl is injected; flow rate: 1.0 mL / min; detection at 235 nm; mobile phase A: 25 mM acetic acid adjusted to pH 5.5 Buffer, mobile phase B: acetonitrile;
Linear slope table:

サンプル調製：４０μLの反応混合物を２０ｍLのアセトニトリル中で希釈する。

Sample preparation: Dilute 40 μL of reaction mixture in 20 mL of acetonitrile.

HPLC (Condition E): Inject 10 μL of sample onto YMC ODS-AQ 5 μm, 250 mm × 4.6 mm column; flow rate: 1.0 mL / min; detection at 280 nm; temperature 30 ° C .; mobile phase: 0.1% 75/25 v / v acetonitrile / water containing the formic acid.
Sample preparation: Quench the reaction mixture sample with dipropylamine and stir for about 5 minutes, then dilute further with mobile phase.

  DSC measurements were taken using a Mettler-Toledo DSC 822, temperature range was 25 ° C. to 150 ° C., heating rate 5 ° C./min in a 40 μL aluminum pan.

Experimental conditions for powder X-ray diffraction (PXD) To obtain a powder XRD pattern, a Rigaku Miniflex + X-ray diffractometer was used. The instrument was operated using Cu Kα ₁ emission with a 1.50451 unit nickel filter. The main instrument parameters were set or fixed as follows:

Example 1. Preparation of O-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methyl} hydroxylamine (6) [(4S) -2,2-dimethyl-1,3-dioxolane- 4-yl] methanol (1) (13.54 mL, 0.109 mol) (DAISO Co., Ltd., CAS # 22323-82-6) and 115 mL containing triethylamine (18.2 mL, 0.131 mol) The solution in toluene was cooled to −15 ° C. and then the trifluoromethanesulfonic anhydride (2) (18.34 mL, 30.75 g, 0.109 mol (Aldrich, Catalog # 17,617-6) was added dropwise, after which the mixture was stirred for 2 hours and N-hydroxyphthalimide (4) (18.99 g, 0.116 mol) in 95 mL toluene (Aldrich catalog # H5 370-4) and 18.2 mL (0 13 mol) is transferred to another flask containing a mixture (slurry) of triethylamine, the resulting mixture is warmed to 20-25 ° C. and at least 5 hours or the reaction is complete (determined by HPLC (condition A)) Water (93 mL) was added to quench the reaction mixture, the phases were separated, the bottom aqueous layer was discarded, and the water quench was repeated two more times to give a pale yellow organic layer. The organic layer was heated to 35 ° C. and treated with 36.7 mL of ammonium hydroxide solution (containing about 28-29% wt / wt ammonia) for at least 12 hours or as determined by GC (Condition B). The mixture was stirred until the reaction was deemed complete, and water was removed to about half of the original volume by co-distillation with toluene under reduced pressure at about 35-45 ° C. Toluene ( 70 mL) was added to the concentrated solution, and the distillation was repeated Samples were removed for water content determination by Karl Fischer method (samples injected into pots containing methanol and salicylic acid and EM Science Aquastar AQV- 2000 Titrator) Distillation was repeated when the water content was above 0.1%, the concentrated solution was filtered to remove white by-products and the filtrate was 9.7% w / w in toluene. Was stored as 112 mL (98 g) of product solution containing 6 of compound 6. This solution was ready for use in the final coupling step (Example 3). The overall chemical yield was 59%. A small sample was evaporated to obtain a sample for NMR identification.

Example 2 Preparation of 3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -benzoic acid (9) 2-Fluoro-4-iodoaniline (8) (16.4 g, 0.069 mol) (Aldrich Prepare a 38 mL tetrahydrofuran (THF) solution of catalog # 30,660-6) and 2,3,4-trifluorobenzoic acid (7) (11.98 g, 0.068 mol) (Aldrich catalog # 33,382-4), A portion of this solution (about 5%) was then added to a slurry of lithium amide (5 g, 0.22 mol) in 40 mL of stirring THF at 50-55 ° C. After about 15-30 minutes, gas evolution and color change were observed following the exotherm. The remaining portions of the above solutions (8) and (7) were slowly added over 1-2 hours while maintaining the temperature at 45 ° C to 55 ° C. The mixture was stirred until the reaction was deemed complete (by HPLC (condition C)). The final mixture is cooled to 20-25 ° C. and transferred to another reaction vessel containing 6N hydrochloric acid (47 mL), followed by stirring with 25 mL of acetonitrile and 40 mL of 50% sodium hydroxide solution. After the treatment with, the bottom aqueous layer was discarded. The organic layer was concentrated under reduced pressure and 57 mL of acetone was added. The mixture was warmed to 50 ° C. and stirred, 25 mL of warm (40-50 ° C.) water was added and cooled to 25-30 ° C. to cause crystallization (within 1-4 hours). When crystallization occurred, the mixture was further cooled to 0-5 ° C. and stirred for about 2 hours. The solid product was filtered and the wet cake was dried in a vacuum oven at about 55 ° C. The overall chemical yield was 21.4 g, 80%.

Example 2B. Production of 3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -benzoic acid (9) by solid addition method of lithium amide 2,3,4-trifluorobenzoic acid (13 ) (5.0 g, 28.4 mmol) and 2-fluoro-4-iodoaniline (14) (6.73 g, 28.4 mmol) in MeCN (100 mL) under a nitrogen atmosphere with lithium amide (2. 61 g, 113.6 mmol) was added in small portions. The reaction mixture was heated to reflux for 45 minutes, cooled to ambient temperature, and quenched with 1N HCl and water. The yellowish white precipitate was filtered and washed with water. The solid was triturated in CH ₂ Cl ₂ (30 mL) for 1 hour, filtered, and dried in a vacuum oven at 45 ° C. for 14 hours to give 8.0 g (72%) of compound (9) as an off-white solid. The melting point was 201.5 to 203 ° C.

Example 3 Preparation of N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide (Compound I) in 100 mL acetonitrile 3 , 4-Difluoro-2- (2-fluoro-4-iodophenylamino) -benzoic acid (9) (20 g, 0.051 mol) was converted to 1,1′-carbonyldiimidazole (CDI) (8.66 g, 0.053 mol) (Aldrich catalog # 11,553-3) and stirred at 20-25 ° C. for about 2 hours until the reaction was deemed complete by HPLC (condition D). 9.7% (w / w) O-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methyl} hydroxylamine (6 in 94 mL (84.9 g) of toluene ) And stirred for about 4 hours or until the reaction was deemed complete by HPLC (condition D). To this mixture was added 66 mL of 5.6% hydrochloric acid solution, and after stirring, the bottom aqueous layer was discarded. Again, 66 mL of 5.6% hydrochloric acid solution was added to the organic layer and stirred at 20-25 ° C. for 12-18 hours or until the reaction was deemed complete by HPLC (Condition D). The bottom aqueous layer was discarded, the remaining organic layer was concentrated under reduced pressure to remove about 10-20% solvent, and the volume was adjusted with toluene (80 mL) to about 9-11 mL / g. The crude product was crystallized at 10-15 ° C. The slurry was stirred for about 2 hours and the crude solid product was filtered and dried. The dried crude product was again added to the reactor and dissolved in 150 mL of 5% v / v ethanol / toluene mixture at 55-67 ° C. The solution was then clarified at this temperature through a filter (line filter) to remove any residual particulates. The solution was then slowly cooled to 5 ° C. to crystallize and stirred for at least 2 hours, filtered and dried. The dried solid product was again dissolved in EtOH (60 mL) at 35 ° C. and precipitated by adding water (300 mL) at 35 ° C. followed by cooling to 20 ° C. The slurry was stirred for at least 2 hours to convert the crystals to the desired type IV polymorph as determined by DSC and powder X-ray diffraction pattern (PXRD). The slurry is filtered, dried in a vacuum oven at 70-90 ° C., and the final N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-) An iodo-phenylamino) -benzamide (Compound I) product was obtained. The overall chemical yield was 13 g, 53%.
Melting point (DSC): 112 ± 1 ° C. Appearance: white to off-white crystals.
The PXRD shown in FIG. 1 is consistent with polymorph IV disclosed in the above-mentioned US patent application Ser. No. 10 / 969,681.

Example 4 Preparation of N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide (Compound I) 1 mL of stirred 3,4-Difluoro-2- (2-fluoro-4-iodophenylamino) -benzoic acid (9) (120 g, 0.30 mol) in a mixture of N, N-dimethylformamide and 1000 mL of toluene was added thionyl chloride ( 55 g, 0.462 mol) was added. The mixture was heated to 50-65 ° C. and stirred for 2 hours or until the reaction was deemed complete by HPLC (Condition E). The final reaction mixture was cooled and concentrated in vacuo to a slurry while keeping the temperature below 35 ° C. Toluene (600 mL) was added to dissolve the slurry and the vacuum distillation was repeated. Additional toluene (600 mL) was added to the slurry to dissolve all solids and the surface solution was then cooled to 5-10 ° C. The solution was then added with a solution of O-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methyl} hydroxylamine (6) (63 g, 0.43 mol) in 207 mL of toluene. Treatment was followed by treatment with potassium carbonate (65 g) and water (200 mL) and stirred at 20-25 ° C. for at least 2 hours. Agitation was stopped, the phases were allowed to separate, and the bottom layer was discarded. The remaining organic layer was treated with hydrochloric acid solution (7.4%, 240 mL) until the pH was less than 1 and stirred for 2 hours. The final reaction mixture was slightly concentrated in vacuo, collecting about 100 mL of distillate, cooling the resulting organic solution to 5 ° C. to crystallize the product and filter. The filter cake was washed with toluene (1000 mL) followed by water (100 mL) and the wet cake (crude product Compound I) was returned to the flask. Toluene (100 mL), ethanol (100 mL) and water (100 mL) were then added, stirred at 30-35 ° C. for about 15 minutes, and the bottom aqueous layer was discarded. Water (200 mL) was then added to the organic solution and the mixture was stirred at about 30 ° C. for crystallization. Stirring was continued for 2 hours after crystallization of the product and further cooled to about 0 ° C. and stirred for at least 2 hours. The slurry is filtered and the wet cake is dried under reduced pressure at 55-85 ° C. to give the final product N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2- Fluoro-4-iodo-phenylamino) -benzamide (Compound I) was obtained. The overall chemical yield was 86 g, 58%.

FIG. 1 shows a powder X-ray of polymorph IV of N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. It is a diffraction diagram.

Claims (11)

A process for producing N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide, comprising the following steps:
a) [(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methanol was treated with trifluoromethanesulfonic anhydride to give [(4R) -2,2-dimethyl-1,3. -Dioxolan-4-yl] methyl trifluoromethanesulfonate;
b) [(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methyl trifluoromethanesulfonate is reacted with N-hydroxyphthalamide to give (R) -2- (2,2 -Obtaining dimethyl- [1,3] dioxolan-4-ylmethoxy) -isoindole-1,3-dione;
c) (R) -2- (2,2-Dimethyl- [1,3] dioxolan-4-ylmethoxy) -isoindole-1,3-dione as O-{[(4R) -2,2-dimethyl- Converted to 1,3-dioxolan-4-yl] methyl} hydroxylamine;
d) O-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methyl} hydroxylamine and 3,4-difluoro-2- (2) using a carboxylic acid activating reagent. -Fluoro-4-iodophenylamino) -benzoic acid coupled to form N-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -3,4-difluoro Forming 2- [2-fluoro-4-iodophenyl) amino] benzamide; and
e) N-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -3,4-difluoro-2- [2-fluoro-4-iodophenyl) amino] benzamide Is deprotonated to produce N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) benzamide;
Said method.   The method according to claim 1, wherein steps a) to c) are performed as a one-pot reaction.   Step c) replaces (R) -2- (2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -isoindole-1,3-dione with O-{[(4R) -2,2 The process of claim 1 comprising the use of aqueous ammonia to convert to -dimethyl-1,3-dioxolan-4-yl] methyl} hydroxylamine. 3,4-Difluoro-2- (2-fluoro-4-iodophenylamino) -benzoic acid is represented by the following formula 2 :

{Where,
X is a halogen. }
The process according to claim 1, which is prepared by coupling 2-fluoro-4-iodoaniline with a compound represented by the formula I in the presence of a Group I metal cation amide.   The method of claim 4, wherein X is fluorine and the Group I metal cation is lithium amide. 6. A small amount of the compound of formula 2 and 2-fluoro-4-iodoaniline are first added to the lithium amide in an aprotic solvent, followed by the remaining portion slowly and continuously. The method described.   The method of claim 6, wherein the aprotic solvent is tetrahydrofuran.   The process according to claim 1, wherein the carboxylic acid activating reagent in step d) is 1,1'-carbonyldiimidazole.   The process according to claim 1, wherein the carboxylic acid activating reagent in step d) is thionyl chloride.   Further comprising at least one single phase crystallization of N-[(R) -2,3-dihydroxypropoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. The method of claim 1.   The first single-phase crystallization of N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is 1 to Carried out in toluene with 20% v / v acetonitrile and N-[(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo- The process according to claim 10, wherein the second single-phase crystallization of (phenylamino) -benzamide is carried out in a mixture of 5% (v / v) ethanol and toluene.

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