Processes for preparing quinoline compounds and pharmaceutical compositions containing such compounds
The present invention is directed to processes for making and compositions containing quinolines such as formula I or pharmaceutically acceptable salts thereof wherein: X1 is H, Br, Cl, or X2 is H, Br, Cl, or n1 is 1-2; and n2 is 1-2.
1. A process for preparing a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X 1 is H, Br, Cl, or F;
X 2 is Br, Cl, or F;
n1 is 1-2; and
n2 is 1-2;
the process comprising:
reacting a compound of formula f(1) with a reactant y(1) in the presence of a non-nucleophilic base which is an alkali metal alkoxide to yield the compound of formula g(1):
wherein LG represents a leaving group; and
contacting a compound of formula g(1) with a reactant z(1) to yield the compound of formula I:
2. The process according to claim 1 , wherein the compound of formula f(1) is made by converting a compound of formula e(1) to the compound of formula f(1):
wherein LG represents a leaving group.
3. The process according to claim 1 , wherein reactant z(1) is made by reacting a reactant z(1a) with a chlorinating agent to yield the reactant z(1):
wherein X 1 is Br, Cl, or F; and n1 is 1-2.
4. The process according to claim 1 , wherein the compound of formula I is a compound of formula IA-1:
or a pharmaceutically acceptable salt thereof, wherein:
X 1 is H, Cl, Br, or F; and
X 2 is Cl, Br, or F.
5. The process according to claim 1 , wherein the compound of formula f(1) is the compound f(2):
the reactant y(1) is a reactant (y)(2):
wherein X 2 is fluoro; and
the compound of formula g(1) is a compound of formula g(2):
6. The process according to claim 1 , wherein the reaction is carried out in a polar solvent.
7. The process according to claim 6 , wherein the alkali metal alkoxide is sodium tert-butoxide and the polar solvent is DMA.
8. The process according to claim 6 , wherein the alkali metal alkoxide is sodium tert-pentoxide, and the polar solvent is DMA.
9. The process according to claim 1 , wherein the reaction is carried out in the presence of an inorganic base.
10. The process according to claim 9 , wherein the inorganic base is K 2 CO 3 , and the reaction is carried out in a solvent comprising a combination of THF and H 2 O.
11. A process for preparing a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X 1 is H, Br or Cl;
X 2 is H;
n1 is 1-2; and
n2 is 1-2;
the process comprising:
reacting a compound of formula f(1) with a reactant y(1) in the presence of a non-nucleophilic base which is an alkali metal alkoxide to yield the compound of formula g(1):
wherein LG represents a leaving group; and
contacting a compound of formula g(1) with a reactant z(1) to yield the compound of formula I:
12. The process according to claim 11 , wherein the compound of formula f(1) is made by converting a compound of formula e(1) to the compound of formula f(1):
wherein LG represents a leaving group.
13. The process according to claim 11 , wherein reactant z(1) is made by reacting a reactant z(1a) with a chlorinating agent to yield the reactant z(1):
wherein X 1 is H, Br or Cl; and n1 is 1-2.
14. The process according to claim 11 , wherein the compound of formula I is a compound of formula IA-1:
or a pharmaceutically acceptable salt thereof, wherein:
X 1 is H, Cl or Br; and
X 2 is H.
15. The process according to claim 11 , wherein
the compound of formula f(1)
the reactant y(1) is a reactant (y)(2):
wherein X 2 is hydrogen; and
the compound of formula g(1) is a compound of formula g(2):
16. The process according to claim 11 , wherein the reaction is carried out in a polar solvent.
17. The process according to claim 16 , wherein the alkali metal alkoxide is sodium tert-butoxide or sodium tert-pentoxide, and the polar solvent is DMA.
18. The process according to claim 11 , wherein the reaction is carried out in the presence of an inorganic base.
19. The process according to claim 18 , wherein the inorganic base is K 2 CO 3 , and the reaction is carried out in a solvent comprising a combination of THF and H 2 O.
20. A process for preparing a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X 1 is F;
X 2 is H; and
n1 is 2;
the process comprising:
reacting a compound of formula f(1) with a reactant y(1) in the presence of a non-nucleophilic base which is an alkali metal alkoxide to yield the compound of formula g(1):
wherein LG represents a leaving group; and
contacting a compound of formula g(1) with a reactant z(1) to yield the compound of formula I: