Diastereoselective synthesis of phosphate derivatives
The present invention provides a method for the preparation of intermediates useful in the synthesis of gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate. It also provides a method of preparing gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate.
1. A process for the preparation of gemcitabine-[phenyl (benzoxy-L-alaninyl)] phosphate (Formula I):
having a diastereomeric purity of greater than about 95%;
wherein:
R 1 is an electron-withdrawing group;
a is an integer between 1 and 5; and
P 1 group is selected from —C(O)C 1 -C 6 alkyl, —C(O)aryl, —C(O)OC 1 -C 6 alkyl, and —C(O)OCH 2 -aryl;
the process comprising the steps of:
a) suspending or dissolving the (R)-diastereomer of a compound of Formula II:
or a mixture of the (R)- and (S)-diastereomers of the compound of Formula II in a solvent (S2);
b) treating the solution or suspension with a base (B2) to obtain the (S)-diastereomer having a diastereomeric purity of greater than about 95%;
c) isolating the (S)-diastereomer of Formula II, having a diastereomeric purity of greater than about 95%;
d) reacting the compound of Formula II, having a diastereomeric purity of greater than about 95% with a compound of Formula III:
in the presence of a base (B1) to provide the (S)-diastereomer of a compound of Formula IV:
having a diastereomeric purity of greater than about 95%; and
e) removing the P 1 group from the compound of Formula IV to provide gemcitabine-[phenyl (benzoxy-L-alaninyl)] phosphate (Formula I) having a diastereomeric purity of greater than about 95%.
2. The process of claim 1 , wherein R 1 is selected from fluoro, chloro, cyano, trifluoromethyl, and nitro.
3. The process of claim 1 , wherein R 1 is fluoro and a is 5.
4. The process of claim 1 , wherein R 1 is fluoro and a is 2.
5. The process of claim 1 , wherein R 1 is chloro and a is 5.
6. The process of claim 1 , wherein R 1 is chloro and a is 2.
7. The process of claim 1 , wherein R 1 is selected from trifluromethyl, nitro, or cyano and a is 1.
8. The process of claim 1 , wherein P 1 is —C(O)OC 1 -C 6 alkyl.
9. The process of claim 8 , wherein P 1 is —C(O)O-tBu.
10. The process of claim 1 , wherein P 1 is —C(O)OCH 2 -aryl.
11. The process of claim 1 , wherein P 1 is —C(O)C 1 -C 6 alkyl or —C(O)aryl.
12. The process of claim 1 , wherein P 1 is —C(O)CH 3 .
13. The process of claim 1 , wherein S2 is a mixture comprising a hydrocarbon.
14. The process of claim 13 , wherein S2 is a mixture of hexane or heptane and a polar organic solvent.
15. The process of claim 14 , wherein S2 is a mixture of heptane and ethyl acetate.
16. The process of claim 1 , wherein B2 is a tertiary amine.
17. The process of claim 16 , wherein B2 is triethylamine.
18. The process of claim 1 , wherein step b) comprises stirring the compound of Formula II and B2 for up to 32 hours.
19. The process of claim 1 , wherein B1 is tBuMgCl or tBuMgBr.
20. The process of claim 1 , wherein step d) is conducted in THF.
21. The process of claim 1 , wherein step e) is conducted in a mixture of C 1-4 -alcohol and water.
22. The process of claim 1 , wherein the diastereomeric purity of the gemcitabine-[phenyl (benzoxy-L-alaninyl)] phosphate (Formula I) is greater than about 98%.
23. The process of claim 1 , wherein the diastereomeric purity of the gemcitabine-[phenyl (benzoxy-L-alaninyl)] phosphate (Formula I) is greater than about 99%.