Synthesis of piperazines, piperidines and related compounds
View Patent ↗Novel methods of synthesizing piperazines, piperidines and related compounds are disclosed, as are compounds useful for their preparation.
1. A method of preparing a compound of formula I:
or a salt thereof, which comprises contacting a compound of formula IV with a compound of formula V:
under conditions sufficient for the formation of the compound of formula I, wherein:
Y-Z is C(O), O, CHOH or CH 2 ;
each E is independently N or CH;
each R 1 is independently fluorine, chlorine or optionally substituted alkyl, aryl, or aralkyl;
R 2 is H or ═O;
each R 3 is independently hydrogen, alkyl, aryl, aralkyl, heterocycle, or heterocycloalkyl;
m is 1, 2 or 3;
n is 1 or 2;
p is 1 or 2; and
q is 1-3.
2. The method of claim 1 , wherein the conditions sufficient for the formation of the compound of formula I are basic conditions.
3. The method of claim 1 , wherein the compound of formula IV is prepared by contacting a compound of formula II and a compound of formula III
with a transition metal catalyst under conditions sufficient for the formation of the compound of formula IV, wherein X is Br or I.
4. The method of claim 3 , wherein the catalyst is a palladium catalyst.
5. The method of claim 4 , wherein the catalyst comprises encapsulated or polymer-bound palladium.
6. The method of claim 4 , wherein the catalyst is bis(triphenylphosphine)palladium(II) dichloride.
7. The method of claim 3 , wherein the catalyst is present in an amount of from about 0.1 to about 7.5 mol percent.
8. The method of claim 1 , wherein Y—Z is C(O).
9. The method of claim 1 , wherein each E is CH.
10. The method of claim 1 , wherein p is 1 and R 1 is chlorine.
11. The method of claim 1 , wherein n and m are both 2.
12. The method of claim 3 , wherein Y—Z is C(O).
13. The method of claim 3 , wherein each E is CH.
14. The method of claim 3 , wherein p is 1 and R 1 is chlorine.
15. The method of claim 3 , wherein n and m are both 2.
16. The method of claim 3 , wherein the compounds of formulae II and III are in solution.
17. The method of claim 16 , wherein the solution comprises an alcohol.
18. The method of claim 3 , wherein the compound of formula IV is extracted using an aqueous acidic solution.
19. The method of claim 18 , wherein the solution comprises lactic acid.
20. The method of claim 3 , wherein the compound of formula IV is isolated as a salt.
21. The method of claim 20 , wherein the salt is a hydrochloride or phosphate salt.
22. A method of preparing (3′-chloro-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-methanone, or a salt thereof, which comprises contacting (3′-chloro-biphenyl-4-yl)-piperidine-4-yl-methanone with 2-chloropyrimidine under conditions sufficient for the formation of (3′-chloro-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-methanone.
23. The method of claim 22 , wherein the conditions sufficient for the formation of (3′-chloro-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-methanone are basic conditions.
24. A method of preparing (3′-chloro-biphenyl-4-yl)-piperidine-4-yl-methanone or a salt thereof, which comprises contacting 3-chlorophenyl boronic acid and (4-bromophenyl)(piperidine-4-yl)methanone with a transition metal catalyst under conditions sufficient for the formation of 3′-chloro-biphenyl-4-yl)-piperidine-4-yl-methanone.
25. The method of claim 24 , wherein the catalyst is a palladium catalyst.
26. The method of claim 25 , wherein the catalyst comprises encapsulated or polymer-bound palladium.
27. The method of claim 25 , wherein the catalyst is bis(triphenylphosphine)palladium(II) dichloride.
28. The method of claim 25 , wherein the catalyst is present in an amount of from about 0.1 to about 7.5 mol percent.
29. The method of claim 28 , wherein the catalyst is present in an amount of about 0.5 mol percent.