Therapeutically active compounds and their methods of use

Patent metadata

Field	Value
Publication number	US-9751863-B2
Application number	US-201615229011-A
Country	US
Kind code	B2
Filing date	Aug 4, 2016
Priority date	Aug 5, 2015
Publication date	Sep 5, 2017
Grant date	Sep 5, 2017

Abstract

Provided are compounds useful for treating cancer and methods of making the compounds and intermediates described herein.

First claim

The invention claimed is:

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.

Assignees

• Agios Pharmaceuticals Inc

Inventors

• Zhang Shijie

Classifications

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title