Synthesis of 1,2,5-tri-o-benzoyl-3-dibenzylamino-3-deoxyribose as intermediate for producing 3′-amino-3′-deoxyadenosine and 3′-amino-3′-deoxyguanosine and the protected derivatives thereof

Patent metadata

Field	Value
Publication number	US-12060384-B2
Application number	US-202017428548-A
Country	US
Kind code	B2
Filing date	Feb 5, 2020
Priority date	Feb 5, 2019
Publication date	Aug 13, 2024
Grant date	Aug 13, 2024

Abstract

The invention generally relates to improved processes for the preparation of intermediates of a cyclic dinucleotide which is useful as a STING agonist.

First claim

We claim:

1. A process for preparing Compound 8 of the formula:

comprising the steps of
a) reacting Compound 1 in a benzoyl protection reaction

 to afford Compound 2;
b) reacting Compound 2 in an oxidation reaction to afford Compound 3;

c) which is subsequently reacted in a reductive amination

 to afford Compound 4;
d) Compound 4 is reacted in a protection step using a benzyl protecting agent and base in a solvent at a temperature of about 70° C. to afford Compound 5 of the formula

e) which is subsequently reacted in a deprotection step with an acid in a common organic solvent to afford Compounds 6 and 7 of the formula

f) and reacting Compounds 6 and 7 with a benzoyl protecting reagent and a base in an organic solvent to afford Compound 8.

2. The process according to claim 1 wherein the protecting group in step a) is benzyl chloride.

3. The process according to claim 1 wherein the oxidation group in step b) is TEMPO.

4. The process according to claim 1 wherein the reducing group in step c) is BnNH 2 .

5. The process according to claim 1 wherein the protecting group in step d) is BnBr.

6. The process according to claim 1 wherein the base in step d) is a Hunig's base.

7. The process according to claim 1 wherein the deprotecting agent in step e) is TsOH.

8. The process according to claim 1 wherein the protecting group in step f) is Bz 2 O.

9. A process for preparing Compound 15 of the formula

a) which comprises reacting Compound 8 using Vorbrüggen chemistry to afford Compound 9

b) which is subsequently deprotected to afford Compound 10 of the formula

c) which is then subsequently protected to afford Compounds 11 and 12 of the formula

d) which are reacted with a benzoyl protecting reagent to afford Compound 13 of the formula

e) Compound 13 is then reacted with ammonia to afford Compound 14 of the formula

f) which is subsequently hydrogenated to afford intermediate Compound 15 or Compound 15a

10. The process according to claim 9 wherein the Vorbruggen chemistry reagent in step a) is HA BZ .

11. The process according to claim 9 wherein the deprotecting agent in step b) is KOH.

12. The process according to claim 9 wherein the protecting group in step c) is TSCl.

13. The process according to claim 9 wherein the benzyl protecting group in step d) is BzCl.

14. The process according to claim 9 wherein the hydrogenation reagent in step f) is PdCl 2 or Pd/C.

15. A process for preparing Compound 22 of the formula

which comprises
a) reacting Compound 8 using Vorbrüggen chemistry to afford Compound 16 of the formula

b) which is hydrolyzed to afford Compound 17;

c) which is subsequently deprotected to afford Compound 18 of the formula

d) which is then protected to afford Compound 19 of the formula,

e) which is further protected using an isobutyryl containing reagent to afford Compound 20 of the formula,

or alternatively, Compound 19 is reacted to afford Compound 23 which is further protected using an isobutyryl containing reagent to afford Compound 20

f) which is deprotected under acidic conditions to afford Compound 21 of the formula

g) which is then hydrogenated to afford Compound 22.

16. The process according to claim 15 wherein the Vorbruggen chemistry reagent in step a) is HG CL .

17. The process according to claim 15 wherein the hydrolyzing agent in step b) is TsOH.

18. The process according to claim 15 wherein the deprotecting agent in step c) is KOH.

19. The process according to claim 15 wherein the protecting agent in step d) is TBSCl.

20. The process according to claim 15 wherein the isobutyl protecting group in step e) is iBuCOCl.

21. The process according to claim 15 wherein the deprotecting agent in step f) is TsOH.

22. The process according to claim 15 wherein the hydrogenation reagent in step g) is Pd/C.

23. A compound selected from the following

Assignees

• Bristol Myers Squibb Co

Inventors

• Yuan Changxia
• Schmidt Michael Anthony
• Ortiz Adrian
• Rogers Amanda J
• Zhu Jason J
• Xu Zhongmin
• Yu Miao
• Simmons Eric M
• Wu Shulin

Classifications

• C07H5/06

  Aminosugars · CPC title

• C07H1/00 Primary

  Processes for the preparation of sugar derivatives · CPC title

• C07H19/167 Primary

  with ribosyl as the saccharide radical · CPC title

• C07H5/04 Primary

  to nitrogen · CPC title