Method for the resolution of 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazol and intermediate compounds
The invention relates to a novel method for the resolution of the racemic mixture of compound (R,S)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole, or the enrichment of same with in one of its enantiomers, and to intermediate compounds which can be used to perform said method.
1. A process for the resolution into one of the enantiomers of the racemate of the compound of formula (I)
or for the enrichment of a mixture with any enantiomeric excess of said compound of formula (I), comprising the following steps:
a) reacting said racemate, or said mixture with any enantiomeric excess of the compound of formula (I), with any of the enantiomers of a chiral acid of formula (IV):
wherein R is monosubstituted phenyl or alkylphenyl,
in a polar aprotic solvent and water mixture where said solvent is dimethylformamide; and
b) obtaining, by means of crystallization or fractionated crystallization of the reaction mixture of step a), an optically pure diastereoisomeric mono-salt of general formula (V) or a mono-salt enriched in any of its two possible diastereoisomeric forms of general formula (V):
wherein X is the anion of the salt of the chiral acid of formula (IV).
2. The process according to claim 1 , wherein the chiral acid of formula (IV) is (+)-di-p-toluyl-D-tartaric acid.
3. The process according to claim 1 , wherein the chiral acid of formula (IV) is (−)-di-p-toluyl-L-tartaric acid.
4. The process according to claim 1 , for the isolation of a solid enriched in the (R)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole (+)-di-p-toluyl-D-tartrate diastereoisomeric salt (+,+), wherein the compound of formula (IV) is (+)-di-p-toluyl-D-tartaric acid and the solvent and water mixture water content is less than 5% (v/v).
5. The process according to claim 1 , for the isolation of a solid enriched in the (S)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole (+)-di-p-toluyl-D-tartrate diastereoisomeric salt (−,+), wherein the compound of formula (IV) is (+)-di-p-toluyl-D-tartaric acid and the solvent and water mixture water content is greater than 5% and less than 40% (v/v).
6. The process according to claim 1 , for the isolation of a solid enriched in the (R)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole (−)-di-p-toluyl-L-tartrate diastereoisomeric salt (+,−), wherein the compound of formula (IV) is (−)-di-p-toluyl-L-tartaric acid and the solvent and water mixture water content is less than 20% (v/v).
7. The process according to claim 1 , for the isolation of a solid enriched in the (S)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole (−)-di-p-toluyl-L-tartrate diastereoisomeric salt (−,−), wherein the compound of formula (IV) is (−)-di-p-toluyl-L-tartaric acid and the solvent and water mixture water content is greater than 40% and less than 55% (v/v).
8. The process according to claim 1 , comprising an additional isolation step of isolating the other optically pure diastereoisomeric mono-salt of general formula (V), or of a mono-salt enriched in the other diastereoisomeric form of general formula (V):
wherein X is the anion of the salt of the chiral acid of formula (IV).
9. The process according to claim 8 , wherein the additional isolation step of the other mono-salt comprises the addition of water to the mother liquor generated upon isolating the first mono-salt of general formula (V), so as to cause precipitation of the said other mono-salt of general formula (V).