Process for the synthesis of a phosphoinositide 3-kinase inhibitor

1. A process, comprising reacting a compound of Formula (II):

with a compound of Formula (III):

in the presence of a B1, wherein B1 is a base, to afford a compound of Formula (IV):

wherein X 1 is halo.

2. The process of claim 1 , wherein X 1 is chloro.

3. The process of claim 1 , wherein said B1 is an alkali metal bicarbonate base.

4. The process of claim 3 , wherein said alkali metal bicarbonate base is sodium bicarbonate.

5. The process of claim 1 , wherein said reacting is performed in a solvent comprising an alcohol.

6. The process of claim 5 , wherein said alcohol is isopropanol.

7. The process of claim 1 , wherein said reacting is performed at a temperature from 80° C. to 85° C.

8. The process of claim 1 , wherein 1.1 to 1.5 equivalents of the compound of Formula (III) is used based on 1 equivalent of the compound of Formula (II).

9. The process of claim 1 , further comprising deprotecting said compound of Formula (IV) in the presence of A1, wherein A1 is an acid, to afford a deprotected product which is a compound of Formula (I):

or a salt thereof.

10. The process of claim 9 , wherein the deprotected product is a salt having Formula (Ia):

wherein X 2 is halide.

11. The process of claim 10 , wherein X 2 is chloride.

12. The process of claim 9 , wherein said A1 is an aqueous strong acid.

13. The process of claim 12 , wherein said aqueous strong acid is aqueous hydrochloric acid.

14. The process of claim 9 , wherein said deprotecting is performed in a solvent comprising an alcohol.

15. The process of claim 14 , wherein said alcohol of said deprotecting step is isopropanol.

16. The process of claim 9 , wherein said deprotecting is performed at a temperature from 25° C. to 35° C.

17. The process of claim 9 , wherein 2.5 to 3.5 equivalents of A1 is used based on 1 equivalent of the compound of Formula (II).

18. The process of claim 9 , wherein said reacting and deprotecting steps are conducted in the same pot without isolation of the compound of Formula (IV).

19. The process of claim 10 , further comprising treating the salt of Formula (Ia) with B2, wherein B2 is a base, to form a compound of Formula (I):

20. The process of claim 19 , wherein B2 is an alkali metal carbonate base.

21. The process of claim 20 , wherein said alkali metal carbonate base is sodium carbonate.

22. The process of claim 19 , wherein said treating is performed in a solvent comprising water and a halogenated solvent.

23. The process of claim 22 , wherein said halogenated solvent is dichloromethane.

24. The process of claim 19 , wherein 1.5 to 2.5 equivalents of B2 is used based on 1 equivalent of the salt of Formula (Ia).

25. The process of claim 19 , wherein said treating is performed at room temperature.

26. The process of claim 1 , wherein said compound of Formula (II) is prepared by:

(va) reacting a compound of Formula (V):

wherein P 1 is an amine protecting group, with A2, wherein A2 is an acid, followed by

(vb) treating the product of the preceding step (va) with B3, wherein B3 is a base.

27. The process of claim 26 , wherein said amine protecting group is tert-butoxycarbonyl.

28. The process of claim 26 , wherein said A2 is hydrochloric acid.

29. The process of claim 26 , wherein said compound of Formula (V) is prepared by a process comprising:

(iiia) reacting a complex of Formula (VI):

wherein X 3 is halo, with an amine protecting agent in the presence of B4, wherein B4 is a base, followed by:

(iiib) reacting the product of the preceding step (iiia) with (3-fluorophenyl)boronic acid in the presence of a transition metal catalyst.

30. The process of claim 29 , wherein X 3 is bromo.

31. The process of claim 29 , wherein said amine protecting agent is di-tert-butyl dicarbonate.

32. The process of claim 29 , wherein the transition metal catalyst is a palladium catalyst.

33. The process of claim 29 , wherein said complex of Formula (VI) is prepared by reacting a compound of Formula (VII):

with (S)-(+)-mandelic acid.

34. The process of claim 33 , wherein X 3 is bromo.

35. The process of claim 1 , wherein the compound of Formula (III) is prepared by reacting a compound of Formula (VIII):

wherein X 4 is halo, with 3,4-dihydro-2H-pyran in the presence of a A3, wherein A3 is an acid.

36. The process of claim 35 , wherein X 4 is chloro.

37. A process, comprising:

i) reacting a compound of Formula (IX):

with bromine to form a compound of Formula (Xa):

ii) reacting said compound of Formula (Xa) with 4-methylthiazol-2-amine in the presence of polyphosphoric acid to form a compound of Formula (XIa):

iii) reacting said compound of Formula (XIa) with N-bromosuccinimide to form a compound of Formula (XIIa):

iv) reacting said compound of Formula (XIIa) with sodium azide to form a compound of Formula (XIIIa):

v) reacting said compound of Formula (XIIIa) with TMS-Cl in the presence of sodium iodide to form a compound of Formula (VIIa):

vi) reacting said compound of Formula (VIIa) with (S)-(+)-mandelic acid to form a compound of Formula (VIa):

vii) protecting said compound of Formula (VIa) with di-tert-butyl dicarbonate in the presence of sodium carbonate;

viii) reacting the product of step vii) with (3-fluorophenyl)boronic acid in the presence of dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]-phosphoranyl})palladium (Pd-132) to form a compound of Formula (Va):

ix) reacting said compound of Formula (Va) with hydrochloric acid;

x) reacting the product of step ix) with sodium carbonate to form a compound of Formula (II):

xi) reacting said compound of Formula (II) with a compound of Formula (Ma):

in the presence of sodium carbonate to afford a compound of Formula (IV):

xii) deprotecting said compound of Formula (IVa) in the presence of hydrochloric acid to form a salt of Formula (Ib):

and

xiii) reacting said salt of Formula (Ib) with sodium carbonate to form a compound of Formula (I):

38. A process, comprising:

i) reacting a compound of Formula (VIIa)

with (S)-(+)-mandelic acid to form a compound of Formula (VIa)

ii) protecting said compound of Formula (VIa) with di-tert-butyl dicarbonate in the presence of sodium carbonate;

iii) reacting the product of step ii) with (3-fluorophenyl)boronic acid in the presence of dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]-phosphoranyl})palladium (Pd-132) to form a compound of Formula (Va):

iv) reacting said compound of Formula (Va) with hydrochloric acid;

v) reacting the product of step iv) with sodium carbonate to form a compound of Formula (II):

vi) reacting said compound of Formula (II) with a compound of Formula (Ma):

in the presence of sodium carbonate to afford a compound of Formula (IV):

vii) deprotecting said compound of Formula (IV) in the presence of hydrochloric acid to form a salt of Formula (Ib):

viii) reacting said salt of Formula (Ib) with sodium carbonate to form a compound of Formula (I):

39. A compound of Formula (IV):

or a salt thereof.