Method of obtaining 2-amino-6-alkyl-amino-4,5,6,7-tetrahydro-benzothiazoles
View Patent ↗A process for preparing 2-amino-6-alkyl-amino-4,5,6,7-tetrahydrobenzothiazoles of formula (I) wherein the asterisk (*) represents an asymmetric carbon and R 1 is C 1 -C 6 alkyl; and enantiomers and mixtures thereof, and their solvates, hydrates and pharmaceutically acceptable salts. The process involves (a) reacting with a secondary amine, optionally in the presence of an acid and a first solvent, to form an enamine; (b) optionally removing the acid and first solvent, and then reacting the enamine with sulfur in the presence of a second solvent; and (c) reacting the previously obtained compound with cyanamide to obtain the formula (I) compound. Pramipexole, a dopamine D-2 agonist, can be made by such process, and is useful for the treatment of Parkinson's disease and schizophrenia.
1. A process for preparing 2-amino-6-alkyl-amino-4,5,6,7-tetrahydrobenzothiazoles of formula (I)
wherein the asterisk (*) indicates the presence of an asymmetric carbon and R 1 is a linear or branched C 1 -C 6 alkyl group; their enantiomers or mixtures thereof, hydrates of pramipexole or pharmaceutically acceptable salts, comprising the following steps:
(a) reacting a compound of formula (II)
wherein the asterisk (*) and R 1 have the previously mentioned meanings, with a secondary amine of formula
NHR 2 R 3
wherein 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;
optionally in the presence of an acid and a solvent 1, to form an enamine of formula (III)
wherein the asterisk (*), R 1 , R 2 and R 3 have the previously mentioned meanings;
(b) optionally removing said acid and said solvent 1, and then reacting the compound of formula (III) with sulfur in the presence of a solvent 2 to obtain the compound of formula (IV)
wherein the asterisk (*) and R 1 have the previously mentioned meanings, and finally
(c) reacting the compound of formula (IV) with cyanamide to obtain the compound of formula (I).
2. A process for preparing 2-amino-6-alkyl-amino-4,5,6,7-tetrahydrobenzothiazoles of formula (I)
wherein the asterisk (*) indicates the presence of an asymmetric carbon and R 1 is a linear or branched C 1 -C 6 alkyl group; their enantiomers or mixtures thereof, hydrates of pramipexole or pharmaceutically acceptable salts,
comprising reacting a compound of formula (II)
wherein the asterisk (*) and R 1 have the previously mentioned meanings,
with sulfur and cyanamide in the presence of a solvent 2 and a secondary amine of formula NHR 2 R 3 wherein 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.
3. A process according to claim 1 , wherein the solvent 2 comprises an alcohol.
4. A process according to claim 2 , wherein said secondary amine of formula NHR 2 R 3 is substituted by said compound of formula (II).
5. A process according to claim 1 , comprising the additional step of separating the mixture of enantiomers.
6. A process according to claim 1 , comprising the additional step of converting the compound of formula (I) into a pharmaceutically acceptable salt thereof.
7. A process according to claim 1 , wherein the compound of formula (II) is prepared by eliminating the carbonyl-protecting group from a compound of formula (IIb)
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 5 and R 6 form a carbonyl-protecting group.
8. A process according to claim 7 , comprising preparing the compound of formula (IIb) by reductive amination of a compound of formula (IIa)
wherein R 5 and R 6 form a carbonyl-protecting group.
9. A process according to claim 1 , wherein R 1 is n-propyl.
10. A process according to claim 9 , wherein the compound of formula (I) is pramipexole or, hydrates of pramipexole or pharmaceutically acceptable salts.
11. A process for preparing 2-amino-6-alkyl-amino-4,5,6,7-tetrahydrobenzothiazoles of formula (I)
wherein the asterisk (*) indicates the presence of an asymmetric carbon and R 1 is a linear or branched C 1 -C 6 alkyl group; their enantiomers or mixtures thereof, hydrates of pramipexole or pharmaceutically acceptable salts, comprising reacting a compound of formula (IV)
wherein the asterisk (*) and R 1 have the previously mentioned meanings, with cyanamide to obtain the compound of formula (I).
12. A process according to claim 1 , wherein the solvent 2 comprises methanol.
13. A process according to claim 2 , comprising the additional step of separating the mixture of enantiomers.
14. A process according to claim 2 , comprising the additional step of converting the compound of formula (I) into a pharmaceutically acceptable salt thereof.
15. A process according to claim 2 , wherein the compound of formula (II) is prepared by eliminating the carbonyl-protecting group from a compound of formula (IIb).
16. A process according to claim 2 , wherein R 1 is n-propyl.