Preparation of N-substituted 2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amides
View Patent ↗From compounds of formula II wherein R 1 and R 2 are independently of one another H, C 1 –C 6 alkyl, C 1 –C 6 halogenalkyl, C 1 –C 6 alkoxy, C 1 –C 6 alkoxy-C 1 –C 6 alkyl, or C 1 –C 6 alkoxy-C 1 –C 6 alkyloxy, R 3 is C 1 –C 6 alkyl, R 4 is C 1 –C 6 alkyl, and R 5 is C 1 –C 6 alkyl, C 1 –C 6 hydroxyalkyl, C 1 –C 6 alkoxy-C 1 –C 6 -alkyl, C 1 –C 6 alkanoyloxy-C 1 –C 6 alkyl, C 1 –C 6 aminoalkyl, C 1 –C 6 alkylamino-C 1 –C 6 -alkyl, C 1 –C 6 -dialkylamino-C 1 –C 6 -alkyl, C 1 –C 6 -alkanoylamido-C 1 –C 6 -alkyl, HO(O)C—C 1 –C 6 -alkyl, C 1 –C 6 alkyl-O—(O)C—C 1 –C 6 alkyl, H 2 N—C(O)—C 1 –C 6 alkyl, C 1 –C 6 alkyl-HN—C(O)—C 1 –C 6 alkyl or (C 1 –C 6 alkyl) 2 N—C(O)—C 1 –C 6 -alkyl, R 6 is C 1 –C 6 alkyl, R 7 is C 1 –C 6 alkyl or C 1 –C 6 alkoxy, or R 6 and R 7 together are tetramethylene, pentamethylene, 3-oxa-1,5-pentylene or —CH 2 CH 2 O— substituted, if necessary, with C 1 –C 4 -Alkyl, phenyl or benzyl, it is possible—through halolactonization, azidation of the halogen group, ring opening with an amine R 5 —NH 2 , and reduction of the azide group to form the amino group—to prepare compounds of formula I wherein R 5 is C 1 –C 6 alkyl, C 1 –C 6 hydroxyalkyl, C 1 –C 6 alkoxy-C 1 –C 6 alkyl, C 1 –C 6 alkanoyloxy-C 1 –C 6 alkyl, C 1 –C 6 aminoalkyl, C 1 –C 6 alkylamino-C 1 –C 6 alkyl, C 1 –C 6 dialkylamino-C 1 –C 6 -alkyl, C 1 –C 6 alkanoylamido-C 1 –C 6 alkyl, HO(O)C—C 1 –C 6 alkyl, C 1 –C 6 alkyl-O—(O)C—C 1 –C 6 alkyl, H 2 N—C(O)—C 1 –C 6 alkyl, C 1 –C 6 alkyl-HN—C(O)—C 1 –C 6 alkyl or (C 1 –C 6 alkyl) 2 —N—C(O)—C 1 –C 6 alkyl. If 2(S),7(R)-diastereomer of formula II is used, the 2(S),4(S),5(S),7(S)-diastereomer of formula Ia is obtained in a high degree of purity.
1. A compound of formula II
wherein R 1 and R 2 are independently of one another H, C 1 –C 6 alkyl, C 1 –C 6 halogenalkyl, C 1 –C 6 alkyloxy, C 1 –C 6 alkoxy-C 1 –C 6 alkyl or C 1 –C 6 alkoxy-C 1 –C 6 alkyloxy, R 3 is C 1 –C 6 alkyl, R 4 is C 1 –C 6 alkyl, R 6 is C 1 –C 6 alkyl, and R 7 is C 1 –C 6 alkyl or C 1 –C 6 alkoxy, or R 6 and R 7 together are tetramethylene, pentamethylene, 3-oxa-1,5-pentylene or —CH 2 CH 2 O—C(O)— optionally substituted with C 1 –C 4 alkyl, phenyl or benzyl.
2. A compound according to claim 1 , wherein R 1 is 1-methoxyprop-3-yloxy, R 2 is methoxy, R 3 and R 4 are isopropyl and R 6 is methyl or ethyl, R 7 is methyl, ethyl or methoxy, or R 6 and R 7 together are tetramethylene, pentamethylene or —CH(CH 2 C 6 H 5 )CH 2 —O—C(O)—.
3. A compound according to claim 1 , that corresponds to formula IIa
wherein R 1 and R 2 are independently of one another H, C 1 –C 6 alkyl, C 1 –C 6 halogenalkyl, C 1 –C 6 alkoxy, C 1 –C 6 alkoxy-C 1 –C 6 alkyl, or C 1 –C 6 alkoxy-C 1 –C 6 alkyloxy, R 3 is C 1 –C 6 alkyl, R 4 is C 1 –C 6 alkyl, R 6 is C 1 –C 6 alkyl and R 7 is C 1 –C 6 alkyl or C 1 –C 6 alkoxy, or R 6 and R 7 together are tetramethylene, pentamethylene, 3-oxa-1,5-pentylene or —CH 2 CH 2 O—C(O)— optionally substituted with C 1 –C 4 alkyl, phenyl or benzyl.
4. A compound of formula III
wherein R 1 and R 2 are independently of one another H, C 1 –C 6 alkyl, C 1 –C 6 halogenalkyl, C 1 –C 6 alkoxy, C 1 –C 6 alkoxy-C 1 –C 6 alkyl, or C 1 –C 6 alkoxy-C 1 –C 6 alkyloxy, R 3 is C 1 –C 6 alkyl R 4 is C 1 –C 6 alkyl, and X is Cl, Br, I or N 3 .
5. A compound according to claim 4 wherein R 1 is 1-methoxyprop-3-yloxy, R 2 is methoxy, R 3 and R 4 are isopropyl and X is Cl, Br, I or N 3 .
6. A compound according to claim 5 , that corresponds to formula IIIa
wherein R 1 and R 2 are independently of one another H, C 1 –C 6 alkyl, C 1 –C 6 halogenalkyl, C 1 –C 6 alkoxy, C 1 –C 6 alkoxy-C 1 –C 6 alkyl, or C 1 –C 6 alkoxy-C 1 –C 6 alkyloxy, R 3 is C 1 –C 6 alkyl, R 4 is C 1 –C 6 alkyl, and X is Cl, Br, I or N 3 .
7. A compound of formula VII in the form of its racemate or enantiomer
wherein R 4 is C 1 –C 6 alkyl, R 6 is C 1 –C 6 alkyl, and R 7 is C 1 –C 6 alkyl or C 1 –C 6 alkoxy, or R 6 and R 7 together are tetramethylene, pentamethylene, 3-oxa-1,5-pentylene or —CH 2 CH 2 O—C(O)— optionally substituted with C 1 –C 4 alkyl, phenyl or benzyl, and Z is Cl, Br or I.
8. A compound according to claim 7 , wherein R 4 is 1-methyl ethyl, Z is Cl, and R 6 is methyl or ethyl, R 7 is methyl, ethyl or methoxy, or R 6 and R 7 together are tetramethylene, pentamethylene or —CH(CH 2 C 6 H 5 )CH 2 —O—CO—.
9. A compound according to claim 7 , that corresponds to formula VIIa
wherein R 4 is C 1 –C 6 alkyl, R 6 is C 1 –C 6 alkyl, and R 7 is C 1 –C 6 alkoxy, or R 6 and R 7 together are tetramethylene, pentamethylene, 3-oxa-1,5-pentylene or —CH 2 CH 2 O—C(O)— optionally substituted with C 1 –C 4 alkyl, phenyl or benzyl, and Z is Cl, Br or I.
10. A compound according to claim 2 , that corresponds to formula IIa
wherein R 1 and R 2 are independently of one another H, C 1 –C 6 alkyl, C 1 –C 6 halogenalkyl, C 1 –C 6 alkoxy, C 1 –C 6 alkoxy-C 1 –C 6 alkyl, or C 1 –C 6 alkoxy-C 1 –C 6 alkyloxy, R 3 is C 1 –C 6 alkyl, R 4 is C 1 –C 6 alkyl, R 6 is C 1 –C 6 alkyl, and R 7 is C 1 –C 6 alkyl or C 1 –C 6 alkoxy, or R 6 and R 7 together are tetramethylene, pentamethylene, 3-oxa-1,5-pentylene or —CH 2 CH 2 O—C(O)— optionally substituted with C 1 –C 4 alkyl, phenyl or benzyl.