Process for the production of ethyl 3-amino-1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxylate through chiral separation of a racemic mixture
A process for chiral separation of ethyl 3-amino-1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxylate (VI) from the racemic mixture of ethyl 3-amino-1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxylate and ethyl 3-amino-1-[(3S,4R)-4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxylate (V).
1. A process of producing a compound of Formula VI
from a mixture of enantiomers comprising separating the enantiomers of a racemic mixture of Formula V
by chiral chromatography using an eluent and a chiral stationary phase selected from amylose tris(3-chloro-4-methylphenylcarbamate) and amylose tris(3-chloro-5-methylphenylcarbamate) wherein the eluent is acetonitrile.
2. The process of claim 1 , wherein productivity of the process is greater than 2.0 KKD.
3. The process of claim 1 , wherein the chiral stationary phase is amylose tris(3-chloro-5-methylphenylcarbamate) immobilized on silica gel.
4. The process of claim 1 , wherein the chiral stationary phase is amylose tris(3-chloro-4-methylphenylcarbamate) coated on silica gel.
5. The process of claim 1 , wherein the productivity of the process is in the range of about 2.0 to about 6.0 KKD.
6. The process of claim 1 , wherein the selectivity of the process is the range of about 1.0 to about 4.0.
7. The process of claim 1 , wherein the process is conducted at a temperature between about 20° C. to about 40° C.
8. The process of claim 1 , wherein the process has a concentration of the racemic mixture (V) from about 100 g/L to about 300 g/L.
9. A method of isolating ethyl 3-amino-1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxylate (VI), substantially free of ethyl 3-amino-1-[(3S,4R)-4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxylate, said method comprising
a) absorbing a racemic mixture of ethyl 3-amino-1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxylate and ethyl 3-amino-1-[(3S,4R)-4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxylate (V) onto a chiral separation medium;
b) passing a solvent system through the chiral separation medium in an amount sufficient to elute ethyl 3-amino-1-[4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxylate enantiomers from the separation medium;
c) isolating ethyl 3-amino-1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxylate (VI), substantially free of ethyl 3-amino-1-[(3S,4R)-4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxylate;
wherein said chiral separation medium is amylose tris(3-chloro-5-methylphenylcarbamate) immobilized on silica gel or
amylose tris(3-chloro-4-methylphenylcarbamate) coated on silica gel.
10. The method of claim 9 , wherein the chiral separation medium is amylose tris(3-chloro-5-methylphenylcarbamate) immobilized on silica gel.
11. The method of claim 9 , wherein the chiral separation medium is amylose tris(3-chloro-4-methylphenylcarbamate) coated on silica gel.
12. The method of claim 9 , wherein the solvent system comprises is acetonitrile.
13. The method of claim 9 , wherein the process has a productivity of in the range of about 2.0 to about 6.0 KKD.
14. The method of claim 9 , wherein the selectivity of the process is the range of about 1.0 to about 4.0.
15. The method of claim 9 , wherein the temperature is between about 20° C. to about 40° C.
16. The method of claim 9 , wherein the concentration of the racemic mixture (V) is about 100 g/L to about 300 g/L.
17. The method of claim 5 , wherein the productivity of the process is in the range of about 3.0 to about 5.0 KKD.
18. The method of claim 6 , wherein the selectivity of the process is the range of about 1.5 to about 3.5.
19. The method of claim 7 , wherein the process is conducted at a temperature between about 25° C. to about 35° C.
20. The method of claim 8 , wherein the process has a concentration of the racemic mixture (V) of about 200 g/L.