Granted Patent B2

US 12,466,825 · App. 17/776,948 · Granted Nov 11, 2025

Inventors: Andrew T. Parsons (Cambridge, MA); Matthew Beaver (Natick, MA)

Assignee: AMGEN INC.

C07D471/04C07F5/05

Abstract

Claims (58)

1 . A compound of Formula 6A:

2 . A composition, the composition comprising a compound of Formula 6A:

3 . A method of making a compound of Formula 6A:

the method comprising reacting a mixture comprising a compound having the structure:

 with an acid with at least one solvent.

4 . The method of claim 3 , wherein the acid is BBr 3 .

5 . The method of claim 3 , wherein the at least one solvent is dichloromethane.

6 . The method of claim 3 , wherein the at least one solvent is heptane.

7 . The method of claim 3 , wherein the mixture is cooled to approximately −20° C.

8 . The method of claim 3 , wherein the method of making a compound of the structure:

comprises mixing a compound having the structure:

with a reagent, a first base, a secondary amine base, a catalyst, and an acid.

9 . The method of claim 8 , wherein the first base in n-Butyl lithium.

10 . The method of claim 8 , wherein the secondary amine base is diisopropylamine.

11 . The method of claim 8 , wherein the catalyst is triethylamine hydrochloride.

12 . The method of claim 8 , wherein the reagent is triethyl borate.

13 . The method of claim 8 , wherein the acid is HCl.

14 . The method of claim 3 , wherein the compound of Formula 6A is used to generate a compound having the Formula 7:

15 . The method of claim 14 ,

comprising the steps of reacting a compound of Formula 6A,

with a compound of Formula 6,

 in the presence of dichlorobis(diphenylphosphinophenyl)ether palladium (II) (Pd(dpePhos)Cl 2 ), and potassium acetate (KOAc).

16 . The method of claim 3 , wherein the compound of Formula 6A is used to generate a compound having the Formula 9:

17 . The method of claim 16 , wherein the method further comprises mixing the compound of Formula 9 with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.

18 . A process of preparing a compound of Formula 6A:

comprising admixing (2-fluoro-6-methoxyphenyl) boronic acid with BBr 3 in at least one solvent to provide the compound of Formula 6A.

19 . The process of claim 18 , wherein 1.0 molar equivalents of the (2-fluoro-6-methoxyphenyl) boronic acid are admixed with 1.2 molar equivalents of the BBr 3 .

20 . The process of claim 18 , comprising preparing a first mixture of the BBr 3 in the at least one solvent before admixing the (2-fluoro-6-methoxyphenyl) boronic acid and the BBr 3 .

21 . The process of claim 20 , comprising preparing a second mixture of the (2-fluoro-6-methoxyphenyl) boronic acid in the at least one solvent before admixing the (2-fluoro-6-methoxyphenyl) boronic acid and the BBr 3 .

22 . The process of claim 21 , comprising adding the second mixture to the first mixture while maintaining the temperature of the at least one solvent in the first mixture between −15° C. and −25° C.

23 . The process of claim 22 , wherein the (2-fluoro-6-methoxyphenyl) boronic acid and the BBr 3 are maintained in the combined first and second mixture for approximately 2 hours.

24 . The process of claim 18 , wherein the at least one solvent is dichloromethane.

25 . The process of claim 18 , wherein the process further comprises a process of making (2-fluoro-6-methoxyphenyl) boronic acid, comprising:

(a) a first step of admixing a first base, a secondary amine base and a catalyst in a solvent to prepare a first mixture;

(b) a second step of admixing 3-fluoroanisole to the first mixture to prepare a second mixture; and

(c) a third step of admixing a reagent to the second mixture to form the (2-fluoro-6-methoxyphenyl) boronic acid.

26 . The process of claim 25 , wherein the first base is n-butyl lithium.

27 . The process of claim 26 , wherein the secondary amine base is diisopropylamine.

28 . The process of claim 27 , wherein the catalyst is triethylamine hydrochloride.

29 . The process of claim 28 , wherein the reagent is triethyl borate.

30 . The process of claim 29 , wherein the first, second and third steps are conducted at −70° C.

31 . A process of preparing a compound of Formula 7

comprising admixing a compound of Formula 6A:

with a compound of Formula 6:

in the presence of a catalyst and potassium acetate to form the compound of Formula (7).

32 . The process of claim 31 , wherein the catalyst is dichlorobis(diphenylphosphinophenyl)ether palladium (II) (Pd(dpePhos)Cl 2 ).

33 . The process of claim 32 , wherein 1.0 molar equivalents of the compound of Formula (6) are admixed with 0.5 molar equivalents of the compound of Formula (6A).

34 . The process of claim 33 , wherein 1.0 molar equivalents of the compound of Formula (7) are admixed with 0.003 molar equivalents of Pd(dpePhos)Cl 2 .

35 . The process of claim 34 , wherein 1.0 molar equivalents of the compound of Formula (7) are admixed with 2.0 molar equivalents of potassium acetate.

36 . The process of claim 32 , wherein the compound of Formula (7), the compound of Formula (6A), the Pd(dpePhos)Cl 2 , and the potassium acetate are admixed in a solvent, wherein the solvent comprises 2-methyl tetrahydrofuran.

37 . The process of claim 36 , wherein the solvent further comprises water.

38 . The process of claim 37 , wherein the solvent is maintained at 75±5° C.

39 . A process of preparing a compound of Formula 9:

or a pharmaceutically acceptable salt thereof, comprising the process of claim 18 .

40 . A process of preparing a compound of Formula 9:

or a pharmaceutically acceptable salt thereof, comprising the process of claim 31 .

41 . The process of claim 40 , further comprising admixing the compound of Formula 7 with trifluoroacetic acid to provide a compound of Formula 8:

42 . The process of claim 41 , further comprising admixing the compound of Formula 8 with acryloyl chloride to afford the compound of Formula 9.

Assignments (1)

Continuity (2)

References Cited (213)

Cited By (2)

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