Process for the preparation of 2-azabicyclo[3.3.0]octane-3-carboxylic Acid Derivatives
View Patent ↗The present invention is aimed at a process for the preparation of compounds of the general formula (I). The objective process is in this case based on the Michael reaction of compounds of the general formula (III) with compounds of the general formula (IV), with subsequent hydrogenation and cyclization of the intermediates of the formula (II) obtained.
1. A process for the preparation of compounds of the general formula (I) or their salts,
wherein:
R 1 is H, (C 1 -C 8 )-alkyl, (C 6 -C 18 )-aryl, (C 7 -C 19 )-aralkyl, (C 1 -C 8 )-alkyl-(C 6 -C 18 )-aryl, (C 3 -C 8 )-cycloalkyl, (C 1 -C 8 )-alkyl-(C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkyl-(C 1 -C 8 )-alkyl,
said process comprising hydrogenating a compound of general formula II in the presence of a catalyst:
wherein
R 1 is as described above and
R 2 is a hydrogenolytically cleavable group.
2. The process of claim 1 , wherein:
R 1 is H or (C 1 -C 8 )-alkyl, and
R 2 is a benzyl that is optionally ring-substituted.
3. The process of claim 1 , wherein the hydrogenation reaction is carried out in an alcohol solvent.
4. The process of claim 2 wherein the hydrogenation reaction is carried out in an alcohol solvent.
5. A compound of the general formula (II) or, if R 1 ═H, its salts
wherein:
R 1 is H, (C 1 -C 8 )-alkyl, (C 6 -C 18 )-aryl, (C 7 -C 19 )-aralkyl, (C 1 -C 8 )-alkyl-(C 6 -C 18 )-aryl, (C 3 -C 8 )-cycloalkyl, (C 1 -C 8 )-alkyl-(C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkyl-(C 1 -C 8 )-alkyl and
R 2 is a hydrogenolytically cleavable group.
6. The compound of claim 5 , wherein R 1 is H.
7. The compound of claim 5 , wherein R 1 is a (C 1 -C 8 )-alkyl.
8. The compound of claim 5 , wherein R 1 is a (C 6 -C 18 )-aryl.
9. The compound of claim 5 , wherein R 1 is a (C 7 -C 19 )-aralkyl.
10. The compound of claim 5 , wherein R 1 is a (C 1 -C 8 )-alkyl-(C 6 -C 18 )-aryl.
11. The compound of claim 5 , wherein R 1 is a (C 3 -C 8 )-cycloalkyl.
12. The compound of claim 5 , wherein R 1 is a (C 1 -C 8 )-alkyl-(C 3 -C 8 )-cycloalkyl.
13. The compound of claim 5 , wherein R 1 is a (C 3 -C 8 )-cycloalkyl-(C 1 -C 8 )-alkyl.
14. A process for the preparation of compounds according to claim 5 , comprising reacting compounds of the general formula (III)
wherein R 1 and R 2 are as defined in claim 5 ,
with enamines of the general formula (IV)
wherein:
R 3 and R 4 independently of one another can be (C 1 -C 8 )-alkyl, (C 6 -C 18 )-aryl, (C 7 -C 19 )-aralkyl, (C 1 -C 8 )-alkyl-(C 6 -C 18 )-aryl, (C 3 -C 8 )-cycloalkyl, (C 1 -C 8 )-alkyl-(C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkyl-(C 1 -C 8 )-alkyl or R 3 and R 4 together form a (C 2 -C 5 )-alkylene bridge.
15. The process of claim 14 , wherein R 1 is H.
16. The process of claim 14 , wherein R 1 is (C 1 -C 8 )-alkyl.
17. The process of claim 14 , wherein either R 3 or R 4 is a (C 1 -C 8 )-alkyl.
18. The process of claim 14 , wherein the reaction is carried out in a halogenated organic solvent.
19. The process of claim 14 , wherein said reaction is carried out at 20-100° C.
20. The process of claim 18 , wherein said reaction is carried out at 20-100° C.