Method for producing heterocyclic compound

A method of producing 4-fluoro-3-hydroxy-5-methyl-6-[4-(1H-pyrazol-1-yl)benzyl]-2-benzofuran-1(3H)-one or a salt thereof, 3-fluoro-2-formyl-4-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]benzoic acid or a salt thereof, or a mixture thereof, which comprises subjecting a compound represented by the formula (I)

• wherein
• R1 and R2 are each independently a hydrogen atom or an optionally substituted hydrocarbon group, or
• R1 and R2 form, together with the adjacent nitrogen atom, a 3- to 8-membered monocyclic nitrogen-containing non-aromatic heterocycle,
• or a salt thereof, to a hydrolysis reaction.

A method of producing a compound represented by the formula (I)

• wherein
• R1 and R2 are each independently a hydrogen atom or an optionally substituted hydrocarbon group, or
• R1 and R2 form, together with the adjacent nitrogen atom, a 3- to 8-membered monocyclic nitrogen-containing non-aromatic heterocycle,
• or a salt thereof, which comprises subjecting a compound represented by the formula (II)
• wherein each symbol is as defined above,
• or a salt thereof, to a formylation reaction.

A method of producing 4-fluoro-3-hydroxy-5-methyl-6-[4-(1H-pyrazol-1-yl)benzyl]-2-benzofuran-1(3H)-one or a salt thereof, 3-fluoro-2-formyl-4-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]benzoic acid or a salt thereof, or a mixture thereof, which comprises Step (i):

• a step of subjecting a compound represented by the formula (II)
• wherein
• R1 and R2 are each independently a hydrogen atom or an optionally substituted hydrocarbon group, or
• R1 and R2 form, together with the adjacent nitrogen atom, a 3- to 8-membered monocyclic nitrogen-containing non-aromatic heterocycle,
• or a salt thereof, to a formylation reaction to obtain a compound represented by the formula (I)
• wherein each symbol is as defined above,
• or a salt thereof, and
• Step (ii):
• a step of subjecting the compound represented by the formula (I) or a salt thereof, to a hydrolysis reaction.

A method of producing 1,5-anhydro-2,4-dideoxy-2-(4-fluoro-5-methyl-1-oxo-6-(4-(1H-pyrazol-1-yl)benzyl)-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitol or a salt thereof, which comprises

• Step (i):
• a step of subjecting a compound represented by the formula (II)
• wherein
• R1 and R2 are each independently a hydrogen atom or an optionally substituted hydrocarbon group, or
• R1 and R2 form, together with the adjacent nitrogen atom, a 3- to 8-membered monocyclic nitrogen-containing non-aromatic heterocycle,
• or a salt thereof, to a formylation reaction to obtain a compound represented by the formula (I)
• wherein each symbol is as defined above,
• or a salt thereof,
• Step (ii):
• a step of subjecting the compound represented by the formula (I) or a salt thereof to a hydrolysis reaction to obtain 4-fluoro-3-hydroxy-5-methyl-6-[4-(1H-pyrazol-1-yl)benzyl]-2-benzofuran-1(3H)-one or a salt thereof, 3-fluoro-2-formyl-4-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]benzoic acid or a salt thereof, or a mixture thereof, and
• Step (iii):
• a step of reacting the obtained 4-fluoro-3-hydroxy-5-methyl-6-[4-(1H-pyrazol-1-yl)benzyl]-2-benzofuran-1 (3H)-one or a salt thereof, 3-fluoro-2-formyl-4-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]benzoic acid or a salt thereof, or a mixture thereof with 2-amino-1,5-anhydro-2,4-dideoxy-L-threo-pentitol.

A method of producing a compound represented by the formula (VIII)

• wherein R6 is a hydrogen atom or an optionally substituted C1-6 alkyl group,
• or a salt thereof, which comprises subjecting a compound represented by the formula (IX)
• wherein
• R6 is as defined above, and
• R7 is a protecting group,
• or a salt thereof, to a reduction reaction.

A method of producing a compound represented by the formula (IX)

• wherein
• R6 is a hydrogen atom or an optionally substituted C1-6 alkyl group, and
• R7 is a protecting group,
• or a salt thereof, which comprises subjecting a compound represented by the formula (X)
• wherein R6 is as defined above,
• or a salt thereof, to a protection reaction of the hydroxy group.

A method of producing a compound represented by the formula (X)

• wherein R6 is a hydrogen atom or an optionally substituted C1-6 alkyl group,
• or a salt thereof, which comprises reacting a compound represented by the formula (XI)
• wherein the symbol is as defined above,
• or a salt thereof, with 4-(1H-pyrazol-1-yl)benzaldehyde.

A method of producing a compound represented by the formula (IX)

• wherein
• R6 is a hydrogen atom or an optionally substituted C1-6 alkyl group, and
• R7 is a protecting group,
• or a salt thereof, which comprises
• Step (i):
• a step comprising reacting a compound represented by the formula (XI)
• wherein R6 is as defined above,
• or a salt thereof, with 4-(1H-pyrazol-1-yl)benzaldehyde to obtain a compound represented by the formula (X)
• wherein the symbol is as defined above,
• or a salt thereof, and
• Step (ii):
• a step of subjecting the compound represented by the formula (X) or a salt thereof, to a protection reaction of the hydroxy group.

A method of producing a compound represented by the formula (VIII)

• wherein R6 is a hydrogen atom or an optionally substituted C1-6 alkyl group,
• or a salt thereof, which comprises
• Step (i):
• a step of reacting a compound represented by the formula (XI)
• wherein R6 is as defined above,
• or a salt thereof, with 4-(1H-pyrazol-1-yl)benzaldehyde to obtain a compound represented by the formula (X)
• wherein the symbol is as defined above,
• or a salt thereof,
• Step (ii):
• a step of subjecting the compound represented by the formula (X) or a salt thereof to a protection reaction of the hydroxy group to obtain a compound represented by the formula (IX)
• wherein
• R6 is as defined above, and
• R7 is a protecting group,
• or a salt thereof, and
• Step (iii):
• a step of subjecting the compound represented by the formula (IX) or a salt thereof, to a reduction reaction.

A method of producing 4-fluoro-3-hydroxy-5-methyl-6-[4-(1H-pyrazol-1-yl)benzyl]-2-benzofuran-1(3H)-one or a salt thereof, 3-fluoro-2-formyl-4-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]benzoic acid or a salt thereof, or a mixture thereof, which comprises

• Step (i):
• a step of reacting a compound represented by the formula (XI)
• wherein R6 is a hydrogen atom or an optionally substituted C1-6 alkyl group,
• or a salt thereof, with 4-(1H-pyrazol-1-yl)benzaldehyde to obtain a compound represented by the formula (X)
• wherein the symbol is as defined above,
• or a salt thereof,
• Step (ii):
• a step of subjecting the compound represented by the formula (X) or a salt thereof to a protection reaction of the hydroxy group to obtain a compound represented by the formula (IX)
• wherein
• R6 is as defined above, and
• R7 is a protecting group,
• or a salt thereof,
• Step (iii):
• a step of subjecting the compound represented by the formula (IX) or a salt thereof to a reduction reaction to obtain a compound represented by the formula (VIII)
• wherein the symbol is as defined above,
• or a salt thereof, and
• Step (iv):
• a step of subjecting the compound represented by the formula (VIII) or a salt thereof to a formylation reaction, and then a hydrolysis reaction, if desired.

A method of producing 1,5-anhydro-2,4-dideoxy-2-(4-fluoro-5-methyl-1-oxo-6-(4-(1H-pyrazol-1-yl)benzyl)-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitol or a salt thereof, which comprises

• Step (i):
• a step comprising reacting a compound represented by the formula (XI)
• wherein R6 is a hydrogen atom or an optionally substituted C1-6 alkyl group,
• or a salt thereof, with 4-(1H-pyrazol-1-yl)benzaldehyde to obtain a compound represented by the formula (X)
• wherein the symbol is as defined above,
• or a salt thereof,
• Step (ii):
• a step of subjecting the compound represented by the formula (X) or a salt thereof to a protection reaction of the hydroxy group to obtain a compound represented by the formula (IX)
• wherein
• to R6 is as defined above, and
• R7 is a protecting group,
• or a salt thereof,
• Step (iii):
• a step of subjecting the compound represented by the formula (IX) or a salt thereof to a reduction reaction to obtain a compound represented by the formula (VIII)
• wherein the symbol is as defined above,
• or a salt thereof,
• Step (iv):
• a step of subjecting the compound represented by the formula (VIII) or a salt thereof to a formylation reaction, and then a hydrolysis reaction, if desired, to obtain 4-fluoro-3-hydroxy-5-methyl-6-[4-(1H-pyrazol-1-yl)benzyl]-2-benzofuran-1(3H)-one or a salt thereof, 3-fluoro-2-formyl-4-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]benzoic acid or a salt thereof, or a mixture thereof, and
• Step (v):
• a step of reacting 4-fluoro-3-hydroxy-5-methyl-6-[4-(1H-pyrazol-1-yl)benzyl]-2-benzofuran-1(3H)-one or a salt thereof, 3-fluoro-2-formyl-4-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]benzoic acid or a salt thereof, or a mixture thereof with 2-amino-1,5-anhydro-2,4-dideoxy-L-threo-pentitol.