Diazonium-free method to make an indazole intermediate in the synthesis of bicyclic 5-(trifluormethoxy)-1h-3-indazolecarboxylic acid amides

A method for preparing compound (I) having the formula:

• wherein R1 is
• wherein
• R2 is H, or C1-4-alkyl (e.g., CH3) which is unsubstituted or substituted one or more by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), NR4R5, or combinations thereof;
• R4 and R5 are each independently H or Ar, Ar—C1-4-alkyl, Het, C1-4-alkyl (e.g., CH3), C3-8-cycloalkyl (e.g., cyclopropyl), or C4-8-cycloalkylalkyl (e.g., cyclopropylmethyl), each of which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), monoalkylamino, dialkylamino (e.g., diethylamino), C3-8-cycloalkyl, or combinations thereof,
• and
• m is 1, 2 or 3;
• or
• R1 is A1, wherein A1 is
• wherein R6 to le are each, independently,
• H,
• C1-4-alkyl (e.g., CH3) which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), Ar (e.g., phenyl) or combinations thereof,
• C3-6-alkenyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), Ar (e.g., phenyl) or combinations thereof,
• C3-6-alkynyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), or Ar (e.g., phenyl) or combinations thereof,
• cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof (e.g., cyclopentyl),
• cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, C1-4-alkyl, C1-4-alkoxy or combinations thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.),
• Ar-alkyl (e.g., benzyl), or
• Het-alkyl (e.g., thienylmethyl);
• wherein
• Ar
• is an aryl group containing 6 to 10 carbon atoms which is unsubstituted or substituted one or more times by
• alkyl having 1 to 8 carbon atoms,
• alkoxy having 1 to 8 carbon atoms,
• halogen (F, Cl, Br, or I, preferably F or Cl),
• amino,
• cyano,
• hydroxyl,
• nitro,
• halogenated alkyl having 1 to 8 carbon atoms,
• halogenated alkoxy having 1 to 8 carbon atoms,
• hydroxyalkyl having 1 to 8 carbon atoms,
• hydroxyalkoxy having 2 to 8 carbon atoms,
• alkenyloxy having 3 to 8 carbon atoms,
• monoalkylamino having 1 to 8 carbon atoms,
• dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms,
• carboxy,
• alkoxycarbonyl,
• alkylaminocarbonyl,
• acylamido (e.g., acetamido),
• acyloxy (e.g., acetoxy),
• alkylthio having 1 to 8 carbon atoms,
• alkylsulphinyl having 1 to 8 carbon atoms,
• alkylsulphonyl having 1 to 8 carbon atoms,
• sulfo,
• sulfonylamino,
• Het,
• cycloalkylamino wherein the cycloalkyl group has 3 to 7 carbon atoms and is optionally substituted by halogen (F, Cl, Br, or I, preferably F or Cl), alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR17, CSR17, cyano, hydroxyl, nitro, oxo, or thio,
• aryloxy wherein the aryl portion contains 6 to 10 carbon atoms (e.g., phenyl, naphthyl, biphenyl) and is optionally substituted by halogen (F, Cl, Br, or I, preferably F or Cl), alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR17, CSR17, cyano, hydroxyl, nitro, oxo, or thio,
• arylthio wherein the aryl portion contains 6 to 10 carbon atoms (e.g., phenyl, naphthyl, biphenyl) and is optionally substituted by halogen (F, Cl, Br, or I, preferably F or Cl), alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR17, CSR17, cyano, hydroxyl, nitro, oxo, or thio, cycloalkyloxy wherein the cycloalkyl group has 3 to 7 carbon atoms and is optionally substituted by halogen (F, Cl, Br, or I, preferably F or Cl), alkyl having 1 to 8 carbon atoms, halogenated
• alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR17, CSR17, cyano, hydroxyl, nitro, oxo, or thio, or
• combinations thereof;
• Ar-alkyl
• is an aryl-alkylene group (e.g., benzyl, phenethyl, phenpropyl) wherein the alkylene portion contains 1 to 4 carbon atoms and is unsubstituted or substituted one or more times by halogen (F, Cl, Br, or I, preferably F or Cl), alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR17, CSR17, cyano, hydroxyl, nitro, oxo, or thio, and the aryl portion is Ar as defined above;
• and
• Het
• is a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by alkyl having 1 to 8 carbon atoms,
• alkoxy having 1 to 8 carbon atoms,
• halogen (F, Cl, Br, or I, preferably F or Cl),
• amino,
• cyano,
• hydroxyl,
• nitro,
• halogenated alkyl having 1 to 8 carbon atoms,
• halogenated alkoxy having 1 to 8 carbon atoms,
• hydroxyalkyl having 1 to 8 carbon atoms,
• hydroxyalkoxy having 2 to 8 carbon atoms,
• alkenyloxy having 3 to 8 carbon atoms,
• monoalkylamino having 1 to 8 carbon atoms,
• dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms,
• carboxy,
• alkoxycarbonyl,
• alkoxycarbonylmethyl,
• alkylaminocarbonyl,
• acylamido (e.g., acetamido),
• acyloxy (e.g., acetoxy),
• alkylthio having 1 to 8 carbon atoms,
• alkylsulphinyl having 1 to 8 carbon atoms,
• alkylsulphonyl having 1 to 8 carbon atoms,
• oxo,
• sulfo,
• sulfonylamino,
• cycloalkylamino wherein the cycloalkyl group has 3 to 7 carbon atoms and is optionally substituted by halogen (F, Cl, Br, or I, preferably F or Cl), alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR17, CSR17, cyano, hydroxyl, nitro, oxo, or thio,
• aryl containing 6 to 10 carbon atoms (e.g., phenyl, naphthyl, biphenyl) and is optionally substituted by halogen (F, Cl, Br, or I, preferably F or Cl), alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR17, CSR17, cyano, hydroxyl, nitro, oxo, or thio,
• aryl-alkylene group (e.g., benzyl, phenethyl, phenpropyl) wherein the aryl portion contains 6 to 10 carbon atoms and the alkylene portion contains 1 to 4 carbon atoms and is unsubstituted or substituted one or more times by halogen (F, Cl, Br, or I, preferably F or Cl), alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR17, CSR17, cyano, hydroxyl, nitro, oxo, or thio,
• aryloxy wherein the aryl portion contains 6 to 10 carbon atoms (e.g., phenyl, naphthyl, biphenyl) and is optionally substituted by halogen (F, Cl, Br, or I, preferably F or Cl), alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 C atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR17, CSR17, cyano, hydroxyl, nitro, oxo, or thio,
• arylthio wherein the aryl portion contains 6 to 10 carbon atoms (e.g., phenyl, naphthyl, biphenyl) and is optionally substituted by halogen (F, Cl, Br, or I, preferably F or Cl), alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR17, CSR17, cyano, hydroxyl, nitro, oxo, or thio,
• cycloalkyloxy wherein the cycloalkyl group has 3 to 7 carbon atoms and is optionally substituted by halogen (F, Cl, Br, or I, preferably F or Cl), alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR17, CSR17, cyano, hydroxyl, nitro, oxo, or thio,
• heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen (F, Cl, Br, or I, preferably F or Cl), alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR17, CSR17, cyano, hydroxyl, nitro, oxo, or thio (e.g., furyl, thienyl, methylthienyl, bithienyl, benzylprazolyl, thiazolyl, imidazolyl, methylimidazolyl, pyrrolidinyl, morpholinyl, thiomorpholinyl),
• heterocyclic-alkyl group, in which the heterocylic portion is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and the alkyl portion is an alkylene group containing 1-4 carbon atoms, wherein said heterocyclic-alkyl group is unsubstituted or substituted one or more times by halogen (F, Cl, Br, or I, preferably F or Cl), alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR17, CSR17, cyano, hydroxyl, nitro, oxo, or thio (e.g., piperidinylethyl), or
• combinations thereof;
• R15 and R16 are each independently
• H,
• Ar,
• Ar-alkyl (e.g., benzyl, fluorobenzyl, methoxybenzyl, phenethyl, phenpropyl),
• Het,
• C1-4-alkyl (e.g., CH3) which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), monoalkylamino, dialkylamino (e.g., diethylamino), C3-8-cycloalkyl, or combinations thereof,
• cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof (e.g., cyclopentyl),
• C3-6-alkenyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), Ar (e.g., phenyl) or combinations thereof, or
• C3-6-alkynyl which is unsubstituted or substituted one or more by F, Cl, Br, I, CN, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), or Ar (e.g., phenyl) or combinations thereof;
• R17 is H,
• C1-6-alkyl (e.g., CH3) which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), NR15R16, SH, SR15, SOR16, C3-8-cycloalkyl, SO2R15, SO2NR15R16, Ar, Het, or combinations thereof,
• C3-6-alkenyl which is unsubstituted or substituted one or more by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), NR15R16, SH, SR15, SOR15, C3-8-cycloalkyl, SO2R15, SO2NR15R16, Ar, Het, or combinations thereof,
• C3-6-alkynyl which is unsubstituted or substituted one or more by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), NR15R16, SH, SR15, SOR15, C3-8-cycloalkyl, SO2R15, SO2NR15R16, Ar, Het, or combinations thereof,
• C3-8-cycloalkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), NR15R16, SH, SR15, SOR15, unsubstituted C3-8-cycloalkyl, SO2R15, SO2NR15R16, Ar, Het, or combinations thereof,
• C4-8-cycloalkylalkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH3), NR15R16, SH, SR15, SOR15, unsubstituted C3-8-cycloalkyl, SO2R15, SO2NR15R16, Ar, Het, or combinations thereof,
• m is as described above;
• and
• o is 1 or 2;
• or
• R1 is
• comprising converting compound (3)
• into its corresponding acid chloride and reacting the acid chloride of (3) with a bicycloamine of formula R1—H in the presence of a peptide coupling reagent, the improvement comprising
• (a) reacting 5-trifluoromethoxyisatin with a ketone-protecting reagent in a solvent to provide a ketone-protected compound;
• (b) treating the ketone-protected compound from step (a) with an electrophilic aminating reagent in an inert solvent to provide an electrophilically aminated compound;
• and
• (c) hydrolyzing the electrophilically aminated compound from step (b) under basic conditions to form a ring opened intermediate and treating the intermediate with aqueous acid to ring close the intermediate and remove the ketone-protecting reagent to provide (3).