Process for the preparation of a cyclic dinucleotide

Patent metadata

Field	Value
Publication number	US-12269840-B2
Application number	US-201917299087-A
Country	US
Kind code	B2
Filing date	Dec 3, 2019
Priority date	Dec 4, 2018
Publication date	Apr 8, 2025
Grant date	Apr 8, 2025

Abstract

The invention generally relates to an improved processes for the preparation of a cyclic dinucleotide which is useful as a STING agonist of the following formula (I), involving the use of compounds A and B.

First claim

We claim:

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.

Assignees

• Bristol Myers Squibb Co

Inventors

• Schmidt Michael Anthony
• Zheng Bin
• Cohen Benjamin M
• Rogers Amanda J
• Yuan Changxia
• Zhu Jason J
• Hang Chao
• Treitler Daniel S
• Freitag Adam Joseph
• Purdum Geoffrey Eugene
• Yu Miao
• Sezen Edmonds Melda
• Guo Siwei

Classifications

• C07H19/20

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title

• C07H19/16

  Purine radicals · CPC title

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title

• C07H19/167

  with ribosyl as the saccharide radical · CPC title

• C07H21/00 Primary

  Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids · CPC title