Cyclic phosphate diesters of 1,3-propane-1-aryl diols and their use in preparing prodrugs
View Patent ↗Compounds of Formula I, their preparation and synthetic intermediates, and their use in the synthesis of prodrugs: wherein: V and L are trans relative to one another; V is selected from group consisting of carbocyclic aryl, substituted carbocyclic aryl, heteroaryl, and substituted heteroaryl; and L is a leaving group selected from the group consisting of halogen, alkyl sulfonate, aryloxy optionally substituted with 1-2 substituents, N-containing heteroaryl, and N-hydroxy-nitrogen containing heteroaryl; and salts thereof.
1. A composition comprising a compound of Formula I:
wherein:
V and L are trans relative to one another with a trans/cis ratio of about 85/15 or greater in said composition;
V is selected from the group consisting of substituted carbocyclic aryl, heteroaryl, and substituted heteroaryl;
L is a leaving group selected from the group consisting of halogen, alkyl sulfonate, aryloxy optionally substituted with 1-2 substituents, and imidazolyl;
or a salt thereof.
2. The composition of claim 1
wherein:
V is selected from the group consisting of phenyl substituted with 1-4 substituents and monocyclic heteroaryl optionally substituted with 1-4 substituents; and
L is a leaving group selected from the group consisting of halogen and aryloxy optionally substituted with 1-2 substituents.
3. A composition comprising a compound of Formula I:
wherein:
V and L are trans relative to one another with a trans/cis ratio of about 85/15 or greater in said composition;
V is selected from the group consisting of N-containing heteroaryl optionally substituted with 1-4 substituents and phenyl substituted with 1-4 substituents selected from the group consisting of halo, hydroxy, amino, lower alkoxy and lower perhaloalkyl; and
L is a leaving group selected from the group consisting halogen and aryloxy optionally substituted with 1-2 substituents;
or a salt thereof.
4. The composition of claim 3 wherein V is phenyl substituted with 1-4 substituents selected from the group consisting of halo, hydroxy, amino, lower alkoxy and lower perhaloalkyl.
5. The composition of claim 4 wherein V is selected from the group consisting of 3-chlorophenyl, 3-bromophenyl, 3,5-dichlorophenyl, and 2,4-dichlorophenoxy.
6. The composition of claim 3 wherein V is N-containing heteroaryl optionally substituted with 1-4 substituents.
7. The composition of claim 6 wherein V is selected from the group of 2-pyridyl, 3-pyridyl, and 4-pyridyl.
8. The composition of claim 7 wherein V is 4-pyridyl.
9. The composition of claim 3 wherein L is phenoxy with 1-2 substituents selected from the group consisting of chloro, fluoro, and nitro.
10. The composition of claim 9 wherein L is selected from the group consisting of —OC 6 H 4 NO 2 , —OC 6 H 4 Cl, and —OC 6 H 3 Cl 2 .
11. The composition of claim 10 wherein L is selected from the group consisting of 4-nitrophenoxy, 4-chlorophenoxy, 2,4-dichlorophenoxy, and 3,5-dichlorophenoxy.
12. The composition of claim 11 wherein L is 4-nitrophenoxy.
13. The composition of claim 3 wherein L is halogen.
14. The composition of claim 13 wherein L is selected from the group consisting of Cl and Br.
15. The composition of claim 3 wherein said compound at C′ is the R-enantiomer.
16. The composition of claim 15 wherein V is 4-pyridyl and L is 4-nitrophenoxy.
17. The composition of claim 15 wherein V is 4-pyridyl and L is Cl.
18. The composition of claim 15 wherein V is 3-chlorophenyl and L is 4-nitrophenoxy.
19. The composition of claim 15 wherein V is 3-chlorophenyl and L is Cl.
20. The composition of claim 3 wherein said compound at C′ is the S-enantiomer.
21. The composition of claim 20 wherein V is 4-pyridyl and L is 4-nitrophenoxy.
22. The composition of claim 20 wherein V is 4-pyridyl and L is Cl.
23. The composition of claim 20 wherein V is 3-chlorophenyl and L is 4-nitrophenoxy.
24. The composition of claim 20 wherein V is 3-chlorophenyl and L is Cl.
25. A method for the preparation of composition comprising a compound of Formula I:
wherein
V and L are trans relative to one another with a trans/cis ratio of about 85/15 or greater in said composition;
V is selected from the group consisting of phenyl substituted with 1-4 substituents and monocyclic heteroaryl optionally substituted with 1-4 substituents; and
L is selected from the group consisting of halogen and aryloxy optionally substituted with 1-2 substituents;
or a salt thereof;
comprising:
(a) reacting a 1-(V)-1,3-propane diol or salt thereof with L-P(O)Cl 2 in the presence of a base;
(b) isomerizing the resulting mixture of trans/cis isomers with L − to form the compound of Formula I wherein the ratio of trans/cis is about 85/15 or greater; or
(c) isolating the cis isomer from the resulting mixture; and treating said cis isomer with L − to form a compound of Formula I wherein the ratio of trans/cis is about 85/15 or greater.
26. The method of claim 25 wherein said ratio of trans/cis is at least 85/15.
27. The method of claim 25 wherein said ratio of trans/cis is greater than 85/15.
28. The method of claim 25 wherein L is selected from the group consisting of phenoxy, —OC 6 H 4 NO 2 , —OC 6 H 4 Cl, and —OC 6 H 3 Cl 2 .
29. The method of claim 28 wherein L is selected from the group consisting of 4-nitrophenoxy, 4-chlorophenoxy, 3,5-dichlorophenoxy, and 2,4-dichlorophenoxy.
30. The method of claim 29 wherein L is 4-nitrophenoxy.
31. The method of claim 25 wherein L is a halogen.
32. The method of claim 31 wherein L is selected from the group consisting of Cl and Br.
33. The method of claim 25 wherein said compound at C′ is the R-enantiomer.
34. The method of claim 33 wherein V is 4-pyridyl and L is 4-nitrophenoxy.
35. The method of claim 33 wherein V is 4-pyridyl and L is chloro.
36. The method of claim 33 wherein V is 3-chlorophenyl and L is 4-nitrophenoxy.
37. The method of claim 33 wherein V is 3-chlorophenyl and L is chloro.
38. The method of claim 25 wherein said compound at C′ is the S-enantiomer.
39. The method of claim 38 wherein V is 4-pyridyl and L is 4-nitrophenoxy.
40. The method of claim 38 wherein V is 4-pyridyl and L is chloro.
41. The method of claim 38 wherein V is 3-chlorophenyl and L is 4-nitrophenyl.
42. The method of claim 38 wherein V is 3-chlorophenyl and L is chloro.
43. The method of claim 25 wherein L is aryloxy optionally substituted with 1-2 substituents; and further comprising the use of a solvent system comprising an N-containing heteroaryl solvent.
44. The method of claim 43 wherein said solvent system is used in (a).
45. The method of claim 43 wherein said N-containing heteroaryl solvent is pyridine.
46. The method of claim 25 wherein in a, a salt of the 1-(V)-1,3-propane diol is reacted with L-P(O)Cl 2 in presence of a base.
47. The method of claim 46 wherein said salt is a mineral acid salt.
48. The method of claim 47 wherein said salt is selected from the group consisting of HBr and HCl.
49. The method of claim 48 wherein said salt is HCl salt.
50. The method of claim 25 further comprising isolating the trans isomer of the compound of Formula I.
51. The method of claim 50 wherein V is 4-pyridyl and L is 4-nitrophenyl.
52. The method of claim 50 wherein V is 4-pyridyl and L is chloro.
53. The method of claim 50 wherein V is 3-chlorophenyl and L is 4-nitrophenyl.
54. The method of claim 50 wherein V is 3-chlorophenyl and L is Cl.
55. The method of claim 25 , wherein said 1-(V)-1,3-propane diol is
56. The compound of claim 4 , wherein V is phenyl substituted with 1-4 halo substituents.
57. The compound of claim 56 , wherein said halo substituent is selected from the group consisting of F, Cl, and Br.
58. A composition comprising a compound of Formula I:
wherein:
V and L are trans relative to one another with a trans/cis ratio of about 85/15 or greater in said composition;
V is selected from the group consisting of phenyl substituted with 1-4 substituents and N-containing heteroaryl optionally substituted with 1-4 substituents; and
L is aryloxy optionally substituted with 1-2 substituents;
or a salt thereof.
59. The composition of claim 58 , wherein L is phenoxy with 1-2 substituents selected from the group consisting of chloro, fluoro, and nitro.
60. The composition of claim 59 , wherein L is selected from the group consisting of —OC 6 H 4 NO 2, —OC 6 H 4 Cl, and —OC 6 H 3 Cl 2 .
61. The composition of claim 60 , wherein L is selected from the group consisting of 4-nitrophenoxy, 4-chlorophenoxy, 2,4-dichlorophenoxy, and 3,5-dichlorophenoxy.
62. The composition of claim 61 , wherein L is 4-nitrophenoxy.
63. The composition of claim 62 , wherein V is selected from the group consisting of 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, and 4-(4-chlorophenoxy)phenyl.
64. The composition of claim 62 , wherein V is selected from the group consisting of 3-methylphenyl, 4-methylphenyl, and 3,5-dimethylphenyl.