Methods of preparing 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds
View Patent ↗Methods useful for preparing compounds of formula I: and salts thereof are disclosed. Also disclosed are intermediates useful in the preparation of such compounds.
1. A method of preparing a compound of formula II(a):
which comprises Noyori hydrogenation of a compound of formula IV:
with a platinum group metal catalyst having a Noyori-type chiral ligand, wherein:
A 1 is pyrazole;
R 1 is chloro; and
m is 1.
2. The method of claim 1 , wherein the chiral ligand is (1R,2R)-(−)-N-(4-toluenesulfonyl)-1,2-diphenylethylenediamine or N-((1R,2R)-2-aminocyclohexyl)-4-methylbenzenesulfonamide).
3. The method of claim 1 , wherein the platinum group metal catalyst is dichloro(pentamethylcyclopentadienyl)iridium (III) dimer.
4. The method of claim 1 , wherein the compound of formula IV is prepared by reacting 1-(2-bromo-5-chlorophenyl)-3-methyl-1H-pyrazole with a trifluoroacetylating agent under transmetalation conditions.
5. The method of claim 4 , wherein the trifluoroacetylating agent is ethyl trifluoroacetate.
6. The method of claim 4 , wherein the transmetalation conditions comprise the use of an alkyllithium or alkylmagnesium reagent.
7. The method of claim 6 , wherein the alkyllithium reagent is n-butyllithium, sec-butyllithium, or t-butyllithium.
8. The method of claim 6 , wherein the alkylmagnesium reagent is isopropyl magnesium chloride or tributylmagnesium chloride.
9. The method of claim 1 , wherein the compound of formula II(a) is crystalline (R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol.