Method for the production of bicyclic aromatic amino acids and intermediate products thereof

Process for the preparation of compounds of the formula I

• in which
• R1 denotes H, alkyl having 1, 2, 3, 4, 5 or 6 C atoms or benzyl,
• R2 denotes R10, CO—R10, COOR6, COOR10, CONHR10, SO2R6 or SO2R10,
• R3 denotes H or alkyl having 1-6 C atoms,
• R4 denotes H, Hal, OA, NHR10, N(R1)2, —NH-acyl, —O-acyl, CN, NO2, OR10, SR10, R2 or CONHR0,
• R5 denotes NH2, H2N—C(═NH) or H2N—(C═NH)—NH, where the primary amino groups may also be provided with conventional amino-protecting groups, or may be mono-, di- or trisubstituted by R10, CO—R10, COOR10 or SO2R10,
• or R6,
• X is absent or denotes NH,
• R6 denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by Hal, A, —CO-A, OA, CN, COOH, COOA, CONHA, NO2, ═NH or ═O,
• R9 denotes H, Hal, OA, NHA, NAA′, NHacyl, Oacyl, CN, NO, SA, SOA, SO2A, SO2Ph or SO3H,
• R10 denotes H, A, Ar or aralkylene having 7-14 C atoms,
• A, A′ each, independently of one another, denote H or alkyl or cycloalkyl having 1-15 C atoms, each of which is unsubstituted or mono-, di- or trisubstituted by R9 and in which one, two or three methylene groups may be replaced by N, O and/or S,
• Ar denotes mono- or bicyclic aromatic ring system having 0, 1, 2, 3 or 4 N, O and/or S atoms which is unsubstituted or mono-, di- or trisubstituted by A and/or R9,
• Ph denotes phenyl which is unsubstituted or mono-, di- or trisubstituted by A,
• Hal denotes F, Cl, Br or I and,
• and pharmaceutically usable derivatives, solvates and stereoisomers thereof,
• where
• a) 5-oxotetrahydrofuran-2-carboxylic acid is reacted with a compound of the formula II
• R7—L II
• in which
• R7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms and
• L denotes Cl, Br, I or a free or reactively functionally modified OH group,
• to give a compound of the formula III
• in which
• R7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms,
• b) then a compound of the formula III is reacted with a compound of the formula IV
• R8—L IV
• in which
• R8 denotes alkylsulfonyl having 1-6 C atoms or arylsulfonyl having 6-10 C atoms and
• L denotes Cl, Br, I or a free or reactively functionally modified OH group,
• to give a compound of the formula V
• in which
• R7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms and
• R8 denotes alkylsulfonyl having 1-6 C atoms or arylsulfonyl having 6-10 C atoms,
• c) then a compound of the formula III or V is reacted with a compound of the formula VI
• in which
• R1 denotes H, alkyl having 1, 2, 3, 4, 5 or 6 C atoms or benzyl,
• R2 denotes R10, CO—R10, COOR6, COOR10, CONHR10, SO2R6 or SO2R10,
• R3 denotes H or alkyl having 1-6 C atoms,
• R4 denotes H, Hal, OA, NHR10, N(R10)2, —NH-acyl, —O-acyl, CN, NO2, OR10, SR1, R2 or CONHR10,
• R6 denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by Hal, A, —CO-A, OA, CN, COOH, COOA, CONHA, NO2, ═NH or ═O,
• R9 denotes H, Hal, OA, NHA, NAA′, NHacyl, Oacyl, CN, NO2, SA, SOA, SO2A, SO2Ph or SO3H,
• R10 denotes H, A, Ar or aralkylene having 7-14 C atoms,
• A, A′ each, independently of one another, denote H or alkyl or cycloalkyl having 1-15 C atoms, each of which is unsubstituted or mono-, di- or trisubstituted by R9 and in which one, two or three methylene groups may be replaced by N, O and/or S,
• Ar denotes mono- or bicyclic aromatic ring system having 0, 1, 2, 3 or 4 N, O and/or S atoms which is unsubstituted or mono-, di- or trisubstituted by A and/or R9,
• Ph denotes phenyl which is unsubstituted or mono-, di- or trisubstituted by A,
• Hal denotes F, Cl, Br or I,
• to give a compound of the formula VII
• in which
• R1 denotes H, alkyl having 1, 2, 3, 4, 5 or 6 C atoms or benzyl,
• R2 denotes R10, CO—R10, COOR6, COOR10, CONHR10, SO2R6 or SO2R10,
• R3 denotes H or alkyl having 1-6 C atoms,
• R4 denotes H, Hal, OA, NHR10, N(R10)2, —NH-acyl, —O-acyl, CN, NO2, OR10, SR10, R2 or CONHR10,
• R6 denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by Hal, A, —CO-A, OA, CN, COOH, COOA, CONHA, NO2, ═NH or ═O,
• R7 denotes benzyl or alkyl having 1, 2, 3, 4, 5 or 6 C atoms,
• R9 denotes H, Hal, OA, NHA, NAA′, NHacyl, Oacyl, CN, NO2, SA, SOA, SO2A, SO2Ph or SO3H,
• R10 denotes H, A, Ar or aralkylene having 7-14 C atoms,
• A, A′ each, independently of one another, denote H or alkyl or cycloalkyl having 1-15 C atoms, each of which is unsubstituted or mono-, di- or trisubstituted by R9 and in which one, two or three methylene groups may be replaced by N, O and/or S,
• Ar denotes mono- or bicyclic aromatic ring system having 0, 1, 2, 3 or 4 N, O and/or S atoms which is unsubstituted or mono-, di- or trisubstituted by A and/or R9,
• Ph denotes phenyl which is unsubstituted or mono-, di- or trisubstituted by A,
• Hal denotes F, Cl, Br or I,
• d) then a compound of the formula VII is converted into a compound of the formula VIII
• in which
• R1 denotes H, alkyl having 1, 2, 3, 4, 5 or 6 C atoms or benzyl,
• R2 denotes R10, CO—R10, COOR6, COOR10, CONHR10, SO2R6 or SO2R10,
• R3 denotes H or alkyl having 1-6 C atoms,
• R4 denotes H, Hal, OA, NHR10, N(R10)2, —NH-acyl, —O-acyl, CN, NO2, OR10, SR10R2 or CONHR10,
• R6 denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by Hal, A, —CO-A, OA, CN, COOH, COOA, CONHA, NO2, ═NH or ═O,
• R9 denotes H, Hal, OA, NHA, NAA′, NHacyl, Oacyl, CN, NO2, SA, SOA, SO2A, SO2Ph or SO3H,
• R10 denotes H, A, Ar or aralkylene having 7-14 C atoms,
• A, A′ each, independently of one another, denote H or alkyl or cycloalkyl having 1-15 C atoms, each of which is unsubstituted or mono-, di- or trisubstituted by R9 and in which one, two or three methylene groups may be replaced by N, O and/or S,
• Ar denotes mono- or bicyclic aromatic ring system having 0, 1, 2, 3 or 4 N, O and/or S atoms which is unsubstituted or mono-, di- or trisubstituted by A and/or R9,
• Ph denotes phenyl which is unsubstituted or mono-, di- or trisubstituted by A,
• Hal denotes F, Cl, Br or I,
• e) subsequently, if desired, a compound of the formula VIII is converted into a compound of the formula VIIIa
• in which
• R1, R2, R3 and R4 have the meanings indicated under d) and
• L denotes Cl, Br, I or a reactively functionally modified OH group,
• e) then a compound of the formula VIII or a compound of the formula VIIIa is reacted
• e) i) with a compound of the formula IX
• R5—H IX
• in which
• R5 denotes NH2, H2N—C(═NH) or H2N—(C═NH)—NH, where the primary amino groups may also be provided with conventional amino-protecting groups, or may be mono-, di- or trisubstituted by R10, CO—R10, COOR10 or SO2R10,
• in which R10 has the meanings indicated for the formula I,
• or is reacted
• e) ii) with a compound of the formula X
• R6—NH2 X
• in which
• R6 denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by Hal, A, —CO-A, OA, CN, COOH, COOA, CONHA, NO2, ═NH or ═O,
• to give a compound of the formula I,
• subsequently, if desired, a radical R2 is converted into another radical R2 by reacting a compound of the formula I in which R2 denotes H with a compound selected from the group
• L-R10, L-CO—R10, L-COOR6, L-COOR10, R10′—N═C═O, R6—SO2L, R10—SO2L,
• in which
• R10 denotes A, Ar or aralkylene having 7-14 C atoms and
• L denotes Cl, Br, I or a free or reactively functionally modified OH group,
• and/or a base or acid of the formula I is converted into one of its salts.