Nucleosides and process

• US 4,423,212 A
• Filed: 12/18/1980
• Issued: 12/27/1983
• Est. Priority Date: 12/18/1980
• Status: Expired due to Fees

• Current Assignee: The Upjohn Company (Pharmacia Corp.)
• Original Assignee: The Upjohn Company (Pharmacia Corp.)
• Inventors: Skulnick, Harvey I.
• Primary Examiner(s): HAZEL, BLONDEL
• Application Number:
  US06/217,935
• Time in Patent Office: 1,104 Days
• Field of Search: 536/23, 536/29
• US Class Current: 536/28.3
• CPC Class Codes: C07D 251/12 having three double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 251/16 to only one ring carbon atom
• CPC Class Codes: C07D 251/20 with no nitrogen atoms directly attached to a ring carbon atom
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• CPC Class Codes: C07H 13/08 having the esterifying carboxyl radicals directly attached to carbocyclic rings
• CPC Class Codes: C07H 19/12 Triazine radicals

Abstract

Novel 5,6-dihydro-syn(s)-triazine nucleosides and nucleotides and a novel process for preparing the same. The novel nucleosides and nucleotides are disclosed as active in vitro and/or in vivo against susceptible DNA viruses.

Claims

1. The chemical process which comprises reacting a monosilyl compound of the formula:

##STR11## wherein R is selected from the group consisting of hydrogen, lower alkyl of 1 through 4 carbon atoms, and cyclopropyl and R'"'"' is selected from the group consisting of hydrogen and lower alkyl of 1 through 4 carbon atoms;

with a 2-deoxy-3,5-blocked-D-pentofuranosyl halide in the presence of a Lewis acid and a solvent selected from the group consisting of acetonitrile or nitromethane at a temperature of about minus (-) 25°

C. with subsequent warming to about 25°

C.;

to form a 1-(2-deoxy-3,5-di-O-blocked-D-pentofuranosyl)-5-R-6-R'"'"'-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione.

2. The process according to claim 1, wherein the monosilyl compound is reacted with a 2-deoxy-3,5-blocked-D-pentofuranosyl chloride in the presence of stannic chloride.

3. The process according to claim 2, wherein the 2-deoxy-3,5-blocked-D-pentofuranosyl chloride is a 2-deoxy-3,5-blocked-D-ribofuranosyl chloride.

4. The process according to claim 3, wherein the monosilyl compound is 5-ethyl-5,6-dihydro-2-O-trimethylsilyl-s-triazine-4-(3H)-one.

5. The process according to claim 4, wherein the 2-deoxy-3,5-blocked-D-ribofuranosyl chloride is selected from the group consisting of 2-deoxy-3,5-di-O-acetyl-D-ribofuranosyl chloride, a 2-deoxy-3,5-di-O-benzoyl-D-ribofuranosyl chloride, a 2-deoxy-3,5-di-O-toluoyl-D-ribofuranosyl chloride, and a 2-deoxy-3,5-di-O-p-nitrobenzoyl-D-ribofuranosyl chloride.

6. The process according to claim 3 wherein the monosilyl compound is 5-methyl-5,6-dihydro-2-O-trimethyl-silyl-4-(3H)-one.

7. The process according to claim 6, wherein the 2-deoxy-3,5-blocked-D-ribofuranosyl chloride is selected from the group consisting of 2-deoxy-3,5-di-O-acetyl-D-ribofuranosyl chloride, a 2-deoxy-3,5-di-O-benzoyl-D-ribofuranosyl chloride, a 2-deoxy-3,5-di-O-toluoyl-D-ribofuranosyl chloride, and a 2-deoxy-3,5-di-O-p-nitrobenzoyl-D-ribofuranosyl chloride.

8. The chemical process which comprises reacting a 2,4-bis-silyl compound of the formula:

##STR12## wherein R is selected from the group consisting of hydrogen, lower alkyl of 1 through 4 carbon atoms, and cyclopropyl and R'"'"' is selected from the group consisting of hydrogen and lower alkyl of 1 through 4 carbon atoms;

with a 2-deoxy-3,5-blocked-D-pentofuranosyl halide in the presence of a Lewis acid and a solvent selected from the group consisting of acetonitrile or nitromethane at a temperature of about minus (-) 25°

C. with subsequent warming to about 25°

C.;

to form a 1-(2-deoxy-3,5-di-O-blocked-β

-D-pentofuranosyl)-5-R-6-R'"'"'-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione.

9. The process according to claim 8, wherein the bis-silyl compound is reacted with a 2-deoxy-3,5-di-blocked-D-pentofuranosyl chloride in the presence of stannic chloride.

10. The process according to claim 9, wherein the 2-deoxy-3,5-blocked-D-pentofuranosyl chloride is a 2-deoxy-3,5-blocked-D-ribofuranosyl chloride.

11. The process according to claim 10, wherein the bis-silyl compound is 5-ethyl-5,6-dihydro-2,4-bis-O-trimethylsilyl-s-triazine.

12. The process according to claim 11, wherein the 2-deoxy-3,5-blocked-D-ribofuranosyl chloride is selected from the group consisting of 2-deoxy-3,5-di-O-acetyl-D-ribofuranosyl chloride, a 2-deoxy-3,5-di-O-acetyl-D-ribofuranosyl chloride, and a 2-deoxy-3,5-di-O-toluoyl-D-ribofuranosyl chloride, and a 2-deoxy-3,5-di-O-p-nitrobenzoyl-D-ribofuranosyl chloride.

13. The process according to claim 10, wherein the bis-silyl compound is 5-methyl-5,6-dihydro-2,4-bis-O-trimethylsilyl-s-triazine.

14. The process according to claim 13, wherein the 2-deoxy-3,5-blocked-D-ribofuranosyl chloride is selected from the group consisting of 2-deoxy-3,5-di-O-acetyl-D-ribofuranosyl chloride, and a 2-deoxy-3,5-di-O-toluoyl-D-ribofuranosyl chloride.

15. The chemical process which comprises reacting a monosilyl compound of the formula:

##STR13## wherein R is selected from the group consisting of hydrogen, lower alkyl of 1 through 4 carbon atoms, and cyclopropyl and R'"'"' is selected from the group consisting of hydrogen and lower alkyl of 1 through 4 carbon atoms;

with a 2-deoxy-3,5-blocked-D-pentofuranosyl halide in the presence of a Lewis acid and acetonitrile at a temperature of about minus (-) 25°

C. with subsequent warming to about 25°

C.;

to form a 1-(2-deoxy-3,5-di-O-blocked-β

-D-pentofuranosyl)-5-R-6-R'"'"'-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione.

16. The process according to claim 15, wherein the monosilyl compound is reacted with a 2-deoxy-3,5-blocked-D-pentofuranosyl chloride in the presence of stannic chloride.

17. The process according to claim 16, wherein the 2-deoxy-3,5-blocked-D-pentofuranosyl chloride is a 2-deoxy-3,5-blocked-D-ribofuranosyl chloride.

18. The process according to claim 17, wherein the monosilyl compound is 5-ethyl-5,6-dihydro-2-O-trimethylsilyl-s-triazine-4-(3H)-one.

19. The process according to claim 18, wherein the 2-deoxy-3,5-blocked-D-ribofuranosyl chloride is selected from the group consisting of 2-deoxy-3,5-di-O-acetyl-D-ribofuranosyl chloride, a 2-deoxy-3,5-di-O-benzoyl-D-ribofuranosyl chloride, a 2-deoxy-3,5-di-O-toluoyl-D-ribofuranosyl chloride, and a 2-deoxy-3,5-di-O-p-nitrobenzoyl-D-ribofuranosyl chloride.

20. The process according to claim 17 wherein the monosilyl compound is 5-methyl-5,6-dihydro-2-O-trimethyl-silyl-4-(3H)-one.

21. The process according to claim 20, wherein the 2-deoxy-3,5-blocked-D-ribofuranosyl chloride is selected from the group consisting of 2-deoxy-3,5-di-O-acetyl-D-ribofuranosyl chloride, a 2-deoxy-3,5-di-O-benzoyl-D-ribofuranosyl chloride, a 2-deoxy-3,5-di-O-toluoyl-D-ribofuranosyl chloride, and a 2-deoxy-3,5-di-O-p-nitrobenzoyl-D-ribofuranosyl chloride.

22. The chemical process which comprises reacting a 2,4-bis-silyl compound of the formula:

##STR14## wherein R is selected from the group consisting of hydrogen, lower alkyl of 1 through 4 carbon atoms, and cyclopropyl and R'"'"' is selected from the group consisting of hydrogen and lower alkyl of 1 through 4 carbon atoms;

with a 2-deoxy-3,5-blocked-D-pentofuranosyl halide in the presence of a Lewis acid and acetonitrile at a temperature of about minus (-) 25°

C. with subsequent warming to about 25°

C.;

to form a 1-(2-deoxy-3,5-di-O-blocked-β

-D-pentofuranosyl)-5-R-6-R'"'"'-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione.

23. The process according to claim 22, wherein the bis-silyl compound is reacted with a 2-deoxy-3,5-di-blocked-D-pentofuranosyl chloride in the presence of stannic chloride.

24. The process according to claim 23, wherein the 2-deoxy-3,5-blocked-D-pentofuranosyl chloride is a 2-deoxy-3,5-blocked-D-ribofuranosyl chloride.

25. The process according to claim 24, wherein the bis-silyl compound is 5-ethyl-5,6-dihydro-2,4-bis-O-trimethylsilyl-s-triazine.

26. The process according to claim 25, wherein the 2-deoxy-3,5-blocked-D-ribofuranosyl chloride is selected from the group consisting of 2-deoxy-3,5-di-O-acetyl-D-ribofuranosyl chloride, a 2-deoxy-3,5-di-O-benzoyl-D-ribofuranosyl chloride, a 2-deoxy-3,5-di-O-toluoyl-D-ribofuranosyl chloride, and a 2-deoxy-3,5-di-O-p-nitrobenzoyl-D-ribofuranosyl chloride.

27. The process according to claim 24, wherein the bis-silyl compound is 5-methyl-5,6-dihydro-2,4-bis-O-trimethylsilyl-s-triazine.

28. The process according to claim 27, wherein the 2-deoxy-3,5-blocked-D-ribofuranosyl chloride is selected from the group consisting of 2-deoxy-3,5-di-O-acetyl-D-ribofuranosyl chloride, and a 2-deoxy-3,5-di-O-toluoyl-D-ribofuranosyl chloride.

29. The chemical process which comprises reacting a monosilyl compound of the formula:

##STR15## wherein R is selected from the group consisting of hydrogen, lower alkyl of 1 through 4 carbon atoms, and cyclopropyl and R'"'"' is selected from the group consisting of hydrogen and lower alkyl of 1 through 4 carbon atoms;

with a 2-deoxy-3,5-blocked-D-pentofuranosyl halide that has been dissolved in ethylene dichloride, in the presence of stannic chloride and acetonitrile at a temperature of about minus (-) 25°

C. with subsequent warming to about 25°

C.;

to form a 1-(2-deoxy-3,5-di-O-blocked-β

-D-pentofuranosyl)-5-R-6-R'"'"'-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione.

30. The process according to claim 29, wherein the 2-deoxy-3,5-blocked-D-pentofuranosyl chloride is 2-deoxy-3,5-blocked-D-ribofuranosyl chloride.

31. The process according to claim 30, wherein the monosilyl compound is selected from the group consisting of 5-ethyl-5,6-dihydro-2-O-trimethylsilyl-s-triazine-4-(3H)-one or 5-methyl-5,6-dihydro-2-O-trimethylsilyl-4-(3H)-one.

32. The chemical process which comprises reacting a 2,4-bis-silyl compound of the formula:

##STR16## wherein R is selected from the group consisting of hydrogen, lower alkyl of 1 through 4 carbon atoms, and cyclopropyl and R'"'"' is selected from the group consisting of hydrogen and lower alkyl of 1 through 4 carbon atoms;

with a 2-deoxy-3,5-blocked-D-pentofuranosyl halide that has been dissolved in ethylene dichloride, in the presence of stannic chloride and acetonitrile at a temperature of about minus (-) 25°

C. with subsequent warming to about 25°

C.;

to form a 1-(2-deoxy-3,5-di-O-blocked-β

-D-pentofuranosyl)-5-R-6-R'"'"'-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione.

33. The process according to claim 32, wherein the 2-deoxy-3,5-blocked-D-pentofuranosyl chloride is 2-deoxy-3,5-blocked-D-ribofuranosyl chloride.

34. The process according to claim 33, wherein the bis-silyl compound is selected from the group consisting of 5-ethyl-5,6-dihydro-2,4-bis-O-trimethylsilyl-s-triazine-4-(3H)-one or 5-methyl-5,6-dihydro-2,4-bis-O-trimethylsilyl-4-(3H)-one.