Method of obtaining 2-amino-6-alkyl-amino-4,5,6,7-tetrahydrobenzothiazoles
View Patent ↗The present invention relates to a process for preparing 2-amino-6-alkyl-amino-4,5,6,7-tetrahydrobenzothiazoles (I) wherein the asterisk (*) represents an asymmetric carbon and R 1 is C 1 -C 6 alkyl; their enantiomers or mixtures thereof, their solvates, hydrates or pharmaceutically acceptable salts, comprising: (a) reacting a compound (II) with a secondary amine, optionally in the presence of an acid and a solvent 1, to form an enamine; (b) optionally removing said acid and said solvent 1, and then reacting said enamine with sulfur in the presence of a solvent 2; and (c) reacting the previously obtained compound with cyanamide to obtain the compound (I). Pramipexole, a compound with dopamine D-2 agonist activity, is among the compounds (I) and is useful for the treatment of Parkinson's disease and schizophrenia.
1. A compound of formula (III):
wherein:
the asterisk (*) indicates the presence of an asymmetric carbon;
R 1 is a linear or branched C 1 -C 6 alkyl group; and
R 2 and R 3 are, independently of one another, C 1 -C 3 alkyl groups, or R 2 and R 3 together form a divalent C 4 -C 5 radical, or a —CH 2 CH 2 OCH 2 CH 2 — radical, forming a cycle with the nitrogen atom to which it is attached.
2. A compound according to claim 1 , wherein R 1 is n-propyl and R 2 and R 3 together form a divalent linear C 4 radical forming a cycle with the nitrogen to which they are attached.
3. A compound of formula (IV)
wherein:
the asterisk (*) indicates the presence of an asymmetric carbon; and
R 1 is a linear or branched C 1 -C 6 alkyl group.
4. A compound according to claim 3 , wherein R 1 is an n-propyl group.
5. A process for forming an enamine of formula (III)
comprising reacting a compound of formula (II)
with a secondary amine of formula NHR 2 R 3 ,
wherein:
the asterisk (*) indicates the presence of an asymmetric carbon;
R 1 is a linear or branched C 1 -C 6 alkyl group; and
R 2 and R 3 are, independently of one another, C 1 -C 3 alkyl groups, or R 2 and R 3 together form a divalent C 4 -C 5 radical, or a —CH 2 CH 2 OCH 2 CH 2 — radical, forming a cycle with the nitrogen atom to which it is attached.