Methods for preparing oxazolidinones and compositions containing them
View Patent ↗Methods of preparing a class of oxazolidinones useful to impede bacterial growth are disclosed.
1. A method of synthesizing a compound of the structure
wherein
R is H,
R 1 a and R 1 b are independently selected from H and F, provided that at least one of R 1 a and R 1 b is F,
Het is tetrazolyl optionally-substituted with methyl;
comprising treating a compound having the structure
wherein R 2 is selected from the group consisting of optionally substituted benzyl and optionally substituted C 1 -C 6 alkyl, with glycidyl ester in the presence of a strong base or an organolitihium salt under conditions to make
wherein the optionally-substituted benzyl and the optionally-substituted C 1 -C 6 alkyl are independently unsubstituted or substituted with halogen or C 1 -C 4 alkyloxy.
2. The method of claim 1 further comprising
reacting
with POCl 3 , POCl(OBn) 2 , or P(N-iPr 2 )(O-tBu) 2 under conditions form
wherein R′ is PO(OH) 2 .
3. The method of claim 2 further comprising
treating the compound of the structure
where R′ is PO(OH) 2 with a base under conditions to form the compound of the structure
wherein R″ is a pharmaceutically acceptable salt of PO(OH) 2 .
4. The method of claim 1 further comprising before said treating step:
coupling a first intermediate of the structure
wherein X is a leaving group, with a second intermediate of the structure
wherein Y is selected from the group consisting of ZnCl 2 , BF 3 , and BR 3 R 4 , wherein R 3 and R 4 are independently selected from the group consisting of OH and optionally-substituted C 1 -C 6 mono and dihydric alcohols, and wherein R 3 and R 4 together may form a ring,
under conditions to produce the compound of the structure
5. The method of claim 4 further comprising before said coupling step:
a) treating an aryl halide of structure 5a
wherein X 1 is leaving group, with a second strong base and then reacting a resulting anion with ZnCl 2 or a trialkylboric acid ester under conditions to form structure 6
or
b) treating the aryl halide of structure 5a with a palladium catalyst and a diester of diboronic acid under conditions to form structure 6
6. The method of claim 5 ,
wherein the second strong base is n-butyl lithium, or the strong base or organolitihium salt is n-butyl lithium; or
wherein the palladium catalyst is PdCl 2 (dppf) 2 .
7. A method of synthesizing a compound of the structure
wherein:
R 2 is selected from the group consisting of optionally substituted benzyl and optionally substituted C 1 -C 6 alkyl wherein the optionally-substituted benzyl and the optionally-substituted C 1 -C 6 alkyl are independently unsubstituted or substituted with halogen or C 1 -C 4 alkyloxy,
R 1 a and R 1 b are independently selected from H and F, provided that at least one of R 1 a and R 1 b is F, and
Het is tetrazolyl optionally-substituted with methyl comprising:
coupling a first intermediate of the structure
wherein X is a leaving group, with a second intermediate of the structure
wherein
Y is selected from the group consisting of ZnCl 2 , BF 3 , and BR 3 R 4 , wherein R 3 and R 4 are independently selected from the group consisting of OH and optionally-substituted C 1 -C 6 mono and dihydric alcohols, and wherein R 3 and R 4 together may form a ring
under conditions to produce the compound of the structure
8. A method of making the second intermediate of the structure
wherein
R 2 is selected from the group consisting of optionally substituted benzyl and optionally substituted C 1 -C 6 alkyl,
R 1 a and R 1 b are independently selected from H and F, provided that at least one of R 1 a and R 1 b is F, and
Y is selected from the group consisting of ZnCl 2 , BF 3 , and BR 3 R 4 , wherein R 3 and R 4 are independently selected from the group consisting of OH and optionally-substituted C 1 -C 6 mono and dihydric alcohols, and wherein R 3 and R 4 together may form a ring;
comprising:
a) treating an aryl halide of structure 5a and
wherein X 1 is leaving group, with a strong base and then reacting a resulting anion with ZnCl 2 or a trialkylboric acid ester under conditions to form structure 6
or
b) treating the aryl halide of structure 5a with a palladium catalyst and a diester of diboronic acid under conditions to form structure 6
9. The method of claim 8 ,
wherein the strong base is n-butyl lithium; or
wherein the palladium catalyst is PdCl 2 (dppf) 2 .
10. The method of claim 1
wherein the treating step is performed in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.
11. The method of claim 4 , wherein X is selected from the group consisting of Cl, Br, I, and trifluoromethanesulfonate.
12. The method of claim 7 wherein the coupling is carried out in the presence of a palladium complex.
13. The method of claim 12 , wherein the palladium complex is a phosphine ligand bound to palladium.
14. The method of claim 13 , wherein the palladium complex is selected from the group consisting of dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0), and Pd 2 (dba) 3 .
15. The method of claim 14 , wherein the palladium complex is Pd 2 (dba) 3 .
16. The method of claim 5 , wherein Y is selected from the group consisting of B(OH) 2 , BF 3 , and
17. The method of claim 16 , wherein Y is B(OH) 2 .
18. The method of claim 1 wherein Het is 2-methyl-tetrazol-5-yl.
19. The method of claim 4 wherein Het is 2-methyl-tetrazol-5-yl and X is Br.
20. The method of claim 3 ,
wherein the base is a sodium base and wherein R″ is PO 3 Na 2 .
21. The method of claim 7 , further comprising treating the compound of the structure
with a glycidyl ester.
22. The method of claim 1 , wherein the glycidyl ester is glycidyl butyrate.
23. The method of claim 1 wherein the glycidyl ester has R stereochemistry.
24. The method of claim 1 , wherein the glycidyl ester is R-(−)-glycidyl butyrate.
25. The method of claim 1 , wherein the treating of the compound of the structure
with a glycidyl ester is carried out in the presence of lithium hexamethyldisilazide.
26. The method of claim 1 , wherein the compound of the structure
is
27. The method of claim 2 , wherein the compound of the structure
28. The method of claim 3 , wherein the compound of the structure
29. The process of claim 1 further comprising
recrystallizing a mixture comprising palladium and
before said treating step to reduce the palladium level.
30. The process of claim 18 further comprising
recrystallizing a mixture comprising palladium and
before said treating step to reduce the palladium level.
31. A method of synthesizing a compound of the structure
wherein
R is H,
R 1 a is F and R 1 b is H, and
Het is 2-methyl-tetrazol-5-yl,
comprising recrystallizing a mixture comprising palladium and
to reduce the palladium level, wherein R 2 is selected from the group consisting of optionally substituted benzyl and optionally substituted C 1 -C 6 alkyl, and
treating the recrystallized compound having the structure
with glycidyl ester in the presence of a strong base or an organolitihium salt under conditions to make
wherein the optionally-substituted benzyl and the optionally-substituted C 1 -C 6 alkyl are independently unsubstituted or substituted with halogen or C 1 -C 4 alkyloxy.
32. The method of claim 31 ,
wherein R 2 is benzyl;
wherein the strong base or the organolitihium salt is n-butyl lithium;
wherein the palladium catalyst is Pd 2 (dba) 3 ; and
wherein the glycidyl ester is R-(−)-glycidyl butyrate.
33. The method of claim 4 , wherein the coupling is carried out in the presence of a palladium complex.
34. The method of claim 33 , wherein the palladium complex complex is a phosphine ligand bound to palladium.
35. The method of claim 34 wherein the palladium complex is selected from the group consisting of dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0), and Pd 2 (dba) 3 .
36. The method of claim 35 , wherein the palladium complex is Pd 2 (dba) 3 .