Method for producing 5-(1-piperazinyl) -benzofuran-2-carboxamide by transition metal-catalyzed amination

Process for the preparation of 5-(1-piperazinyl)benzofuran-2-carboxamide, characterized in that

• a) 5-bromosalicylaldehyde is reacted in a one-pot reaction firstly with a compound of the formula I
• L—CH2—COOR1 I
• in which
• L is Cl, Br or I or a reactively esterified OH group, and
• R1 is alkyl having 1-6 carbon atoms or benzyl,
• and subsequently with formamide to give 5-L-benzofuran-2-carboxamide (II), in which L is Cl, Br or I or a reactively esterified OH group,
• (II) is then reacted in a transition metal-catalysed amination with R2-piperazine, in which R2 is H or an amino protecting group, to give the compound of the formula III
• 21
• in which R2 is H or an amino protecting group,
• and subsequently, if R2≠H, R2 is cleaved off,
• or
• b) a compound of the formula IV
• 22
• in which
• L is Cl, Br, I or a reactively esterified OH group,
• R3 is H or CH2R6,
• R4 and R5 are each, independently of one another, OR7, OR8, SR7 or SR8,
• R4 and R5 together are alternatively carbonyl, ═S, ═N—C(R7)2, ═N—C(R8)2, ═N—OH, ═N—OR7, ═N—N[(R7)2], ═N—N[(R8)2] or —O—(CH2)n—O—,
• R6 is CN, COOH, COOR7 or CONH2,
• R7 is alkyl having 1-6 carbon atoms,
• R8 is phenyl which is unsubstituted or mono- or disubstituted by R7, OR7, SR7 or Hal,
• n is 2 or 3,
• is reacted in a transition metal-catalysed amination with R2-piperazine, in which R2 is H or an amino protecting group,
• to give a compound of the formula V
• 23
• in which
• R2 is H or an amino protecting group,
• R3 is H or CH2R6,
• R4 and R5 are each, independently of one another, OR7, OR8, SR7 or SR8,
• R4 and R5 together are alternatively carbonyl, ═S, ═N—C(R7)2, ═N—C(R8)2, ═N—OH, ═N—OR7, ═N—N[(R7)2], ═N—N[(R8)2] or —O—(CH2)n—O—,
• R6 is CN, COOH, COOR7 or CONH2,
• R7 is alkyl having 1-6 carbon atoms,
• R8 is phenyl which is unsubstituted or mono- or disubstituted by R7, OR7, SR7 or Hal,
• n is 2 or 3,
• which is subsequently reacted in a one-pot reaction firstly with a compound of the formula I
• L—CH2—COOR1 I
• in which
• L is Cl, Br, I or a reactively esterified OH group, and
• R1 is alkyl having 1-6 carbon atoms or benzyl,
• and subsequently with formamide to give a compound of the formula III
• 24
• in which R2 is H or an amino protecting group,
• and subsequently, if R2≠H, R2 is cleaved off,
• or
• c) a compound of the formula V
• in which
• R2 is an amino protecting group,
• R3 is H or CH2R6,
• R4 and R5 are each, independently of one another, OR7, OR8, SR7 or SR8,
• R4 and R5 together are alternatively carbonyl, ═S, ═N—C(R7)2, ═N—C(R8)2, ═N—OH, ═N—OR7, ═N—N[(R7)2], ═N—N[(R8)2] or —O—(CH2)n—O—,
• R6 is CN, COOH, COOR7 or CONH2,
• R7 is alkyl having 1-6 carbon atoms,
• R8 is phenyl which is unsubstituted or mono- or disubstituted by R7, OR7, SR7 or Hal,
• n is 2 or 3,
• is reacted with chloroacetamide to give a compound of the formula III
• in which R2 is an amino protecting group,
• and R2 is subsequently cleaved off,
• and/or in that 5-(1-piperazinyl-)benzofuran-2-carboxamide is converted into one of its acid-addition salts by treatment with an acid.