Granted Patent B2

US 12,269,840 · App. 17/299,087 · Granted Apr 8, 2025

Inventors: Michael Anthony Schmidt (Cranbury, NJ); Bin Zheng (Kendall Park, NJ); Benjamin M. Cohen (Cranford, NJ); Amanda J. Rogers (Asbury, NJ); Changxia Yuan (Warren, NJ); Jason J. Zhu (East Brunswick, NJ); Chao Hang (Monmouth Junction, NJ); Daniel S. Treitler (Cranford, NJ); Adam Joseph Freitag (Hopewell, NJ); Geoffrey Eugene Purdum (Freehold, NJ); Miao Yu (Malvern, PA); Melda Sezen Edmonds (Princeton, NJ); Siwei Guo (Vacaville, CA)

Assignee: BRISTOL-MYERS SQUIBB COMPANY

C07H21/00C07H1/00C07H19/16C07H19/20

Abstract

Claims (29)

1. A process for the preparation of Compound I having the formula

comprising the steps of

a) reacting Compound 1 with TBSCl and Et 3 N

to afford Compound 2;

b) reacting Compound 2 with a phosphorus (V) compound consisting of Compound A to afford Compound 3

c) reacting Compound 3 and Compound 9

to afford Compound 4;

d) reacting Compound 4 in a solvent, and then adding a base, followed by the addition of a phosphorus (V) compound consisting of Compound B

 to afford Compound 5 having the formula

e) selectively deprotecting Compound 5 to afford Compound 6 having the formula

f) the Compound 6 is cyclized in a suitable solvent under basic conditions to afford Compound 7 having the formula

g) the Compound 7 is subsequently mixed in a suitable base, stirred and concentrated to afford Compound 8 having the formula

and h) the Compound 8 is subsequently deprotected to afford Compound I.

2. The process according to claim 1 , wherein step b) further comprises a base selected from imidazole, DBU, diisopropylethylamine, triazole, tetrazole, metal alkoxide bases, lithium diisopropylamide, sodium bis(trimethysiliyl)amide or other amide bases.

3. The process according to claim 2 , wherein the base is imidazole.

4. The process according to claim 1 , wherein step c) further comprises a solvent selected from THF, MeCN or DMF.

5. The process according to claim 4 , wherein the solvent is THF.

6. The process according to claim 1 , wherein step c) further comprises a base selected from lithium diisopropylamide, sodium bis(trimethysiliyl)amide, other amide bases, potassium t-butoxide, DBU or other alkoxide bases.

7. The process according to claim 6 , wherein the base in step c) is sodium tert-pentoxide or sodium t-amylate.

8. The process according to claim 1 , wherein the solvent in step d) is THF, 2-MeTHF, MeCN or DMF.

9. The process according to claim 8 , wherein the solvent in step d) is 2-MeTHF.

10. The process according to claim 1 , wherein the base in step d) is imidazole, DBU, triazole, tetrazole, diisopropylethylamine or other t-butoxides.

11. The process according to claim 10 , wherein the base in step d) is imidazole.

12. The process according to claim 1 , wherein the solvent in step f) is THF, MeCN, NMP or DMF or mixtures thereof.

13. The process according to claim 12 , wherein the solvent in step f) is a mixture of THF and NMP.

14. The process according to claim 1 , wherein the base in step f) is lithium diisopropylamide, potassium bis(trimethylsilyl)amide, other amide bases, potassium t-butoxide, DBU, other alkoxide bases, NaHMDS or other alkylsilylamines.

15. The process according to claim 14 , wherein the base in step f) is lithium t-butoxide.

16. The process according to claim 1 , wherein the base in step g) is methylamine, ammonium or other alkylamine bases.

17. The process according to claim 16 , wherein the base in step g) is methylamine.

Continuity (2)

References Cited (9)