Compositions comprising folic acid derivatives, their preparations and methods of use
Described herein are methods for making folic acid derivatives, intermediates, pharmaceutical compositions and uses thereof.
1. A method for making a compound of formula (V):
the method comprising cyclizing a compound of formula (II) to make a compound of formula (V):
wherein
R 1 and R 2 are each independently selected from H, OH, NH 2 , C 1-6 alkyl or aryl;
R 3 is H, C 1-6 alkyl or aryl;
Y is halo; and
X is Na, K, Mg or Ca.
2. The method of claim 1 , wherein the cyclization step is carried out in the presence of formic acid.
3. The method of claim 2 , further comprising a strong acid.
4. The method of claim 3 , wherein the strong acid is HCl.
5. The method of claim 2 , further comprising a solvent.
6. The method of claim 5 , wherein the solvent is an aqueous solvent.
7. The method of claim 1 , wherein R 1 is NH 2 .
8. The method of claim 1 , wherein R 2 is OH.
9. The method of claim 1 , wherein R 3 is H.
10. The method of claim 1 , wherein X is Ca.
11. The method of claim 1 , wherein Y is Cl.
12. The method of claim 1 , wherein R 1 is NH 2 , R 2 is OH, R 3 is H, X is Ca, and Y is Cl.
13. The method of claim 1 , the method further comprising a reduction of a compound of formula (V) to make a compound of formula (I):