Therapeutically active compounds and their methods of use
Provided are compounds useful for treating cancer and methods of making the compounds and intermediates described herein.
1. A method of preparing a compound having the formula (I):
wherein ring A is pyridinyl substituted with trifluoromethyl, comprising reacting a compound of formula (II):
wherein R is alkyl, alkenyl or alkynyl;
with
(biuret) in the presence of a dehydrating agent, wherein the dehydrating agent comprises (i) trimethyl orthoformate and a catalytic amount of trifluoroacetic acid or (ii) titanium(IV) ethoxide.
2. A method of preparing a compound of formula (Ia):
comprising reacting a compound of formula (IIa):
with
with (biuret) in the presence of a dehydrating reagent to provide the compound of formula (Ia), wherein the dehydrating agent comprises (i) trimethyl orthoformate and a catalytic amount of trifluoroacetic acid or (ii) titanium(IV) ethoxide.
3. The method of claim 2 , wherein the reaction is in the presence of a base.
4. The method of claim 3 , wherein the base is sodium ethoxide.
5. The method of claim 1 , wherein the compound of formula (II) is prepared by reacting a compound of formula (III)
with an acid halide and an alcohol.
6. The method of claim 2 , wherein the compound of formula (IIa) is prepared by reacting a compound of formula (IIIa):
with hydrogen chloride and methanol.
7. The method of claim 1 , further comprising halogenating the compound of formula (I) to give a compound of formula (IV)
wherein X is a halogen.
8. The method of claim 2 , further comprising reacting the compound of formula (Ia) with benzyltriethylammonium chloride and POCl 3 to give a compound of formula (IVb)
9. The method of claim 8 , further comprising reacting the compound of formula (IVb) with a compound of formula (Va)
to give a compound of formula (VIb)
10. A method of preparing a compound of formula (VIIIa)
comprising a) reacting compound (Ia)
with benzyltriethylammonium chloride and POCl 3 to obtain compound (IVb)
b) reacting compound (IVb) with 2-(trifluoromethyl)pyridin-4-amine to obtain compound (VIb)
and
c) reacting compound (VIb) with 1-amino-2-methylpropan-2-ol to obtain the compound of formula (VIIIa), wherein compound (Ia) is prepared by reacting
with
in the presence of a dehydrating reagent, wherein the dehydrating agent comprises (i) trimethyl orthoformate and a catalytic amount of trifluoroacetic acid or (ii) titanium(IV) ethoxide.
11. The method of claim 10 , wherein step a) comprises heating to about 95-98° C. for about 18 hours.
12. The method of claim 10 , wherein step b) comprises aging at about 20° C. for about 3 h and then heating to about 60-65° C. for about 15.5 h.
13. The method of claim 10 , wherein step b) is conducted in methyltetrahydrofuran.
14. The method of claim 10 , wherein step c) is conducted at about 20-30° C.
15. The method of claim 10 , wherein step c) is conducted in presence of diisopropylethylamine.
16. The method of claim 10 , wherein the reaction of (IIa) is conducted in the presence of a base.
17. The method of claim 16 , wherein the base is sodium ethoxide.