Process for the preparation of macrolide antibacterial agents
Described herein are processes for the preparation of compounds of formula (I): and pharmaceutically acceptable salts, solvates, and hydrates thereof.
1. A process comprising (g) reacting a compound of formula (VI)
with a C-substituted alkyne to obtain a compound of formula (VII)
wherein C is selected from the group consisting of hydrogen, alkyl, heteroalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl, each of which is optionally substituted; and R 1b is a saccharide that includes a 2′-hydroxyl group acylated with R 1a , and R 1a is a sterically hindered acyl group; or a salt thereof, wherein
A is CH 2 , C(O), C(O)O, C(O)NH, S(O) 2 , S(O) 2 NH, C(O)NHS(O) 2 ;
B is (CH 2 ) n where n is an integer ranging from 0-10, or B is an unsaturated carbon chain of 2-10 carbons;
V is C(O), C(═NR 11 ), CH(NR 12 R 13 ), or N(R 14 )CH 2 ; where R 11 is hydroxy or alkoxy, each of R 12 and R 13 is independently hydrogen, hydroxy, alkyl, arylalkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl; dimethylaminoalkyl, acyl, sulfonyl, ureyl, and carbamoyl; R 14 is hydrogen, hydroxy, alkyl, arylalkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, dimethylaminoalkyl, acyl, sulfonyl, ureyl, or carbamoyl;
W is hydrogen, F, Cl, Br, I, or OH; and
X is hydrogen; and Y is OR 7 ; where R 7 is hydrogen, a monosaccharide, a disaccharide, alkyl, aryl, heteroaryl, acyl, or C(O)NR 8 R 9 , where each of R 8 and R 9 is independently hydrogen, hydroxy, alkyl, arylalkyl, alkylaryl, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, alkoxy, dimethylaminoalkyl, acyl, sulfonyl, ureyl, or carbamoyl; or X and Y are taken together with the attached carbon to form C═O.
2. The process of claim 1 further comprising (h) contacting the compound of formula (VII) with a composition comprising an alcohol to prepare a compound of formula (I)
or a salt, solvate, or hydrate thereof; wherein
C is selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroalkyl, aryl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted; and
R 1 is a saccharide that includes a 2′-hydroxy group.
3. The process of claim 1 wherein A-B is alkylene.
4. The process claim 1 wherein A-B is (CH 2 ) 4 .
5. The process of claim 1 wherein W is F.
6. The process of claim 1 wherein C is optionally substituted aryl or optionally substituted heteroaryl.
7. The process of claim 1 wherein C is alkylaryl, aminoaryl, or alkylaminoaryl.
8. The process of claim 1 wherein C is alkylphenyl, aminophenyl, or alkylaminophenyl.
9. The process of claim 1 wherein C is aminophenyl.
10. The process of claim 1 wherein C is 3-aminophenyl.
11. The process of claim 1 wherein the compound of formula (VI) is
wherein A-B is (CH 2 ) 4 .
12. The process of claim 1 wherein the compound of formula (VI) is
wherein A-B is (CH 2 ) 4 .
13. The process of claim 1 wherein the compound of formula (VII) is
wherein A-B is (CH 2 ) 4 .
14. The process of claim 2 wherein the compound of formula (I) is
wherein A-B is (CH 2 ) 4 .
15. A compound of the formula
wherein A is CH 2 and B is (CH 2 ) 3 ;
W is hydrogen or F; and
R 1a is optionally substituted benzoyl.
16. The compound of claim 15 wherein W is hydrogen.
17. The compound of claim 15 wherein W is F.
18. The compound of claim 15 where R 1a is benzoyl.
19. A composition comprising a compound of the formula
in greater than about 98%; wherein
A is CH 2 and B is (CH 2 ) 3 .
20. The composition of claim 19 comprising the compound in greater than about 99%.
21. A composition comprising a compound of the formula
wherein
A is CH 2 and B is (CH 2 ) 3 and optionally a pharmaceutically acceptable carrier, wherein the composition comprises less than about 1.0% by weight of 3-aminophenylethyne compared to the compound.
22. The composition of claim 21 , wherein the composition comprises less than about 0.1% by weight of the 3-aminophenylethyne compared to the compound.
23. The composition of claim 21 , wherein the composition is substantially free of the 3-aminophenylethyne.
24. The process of claim 1 where R 1a is optionally substituted benzoyl.
25. The composition of claim 21 , wherein the composition comprises less than about 0.5% by weight of the 3-aminophenylethyne compared to the compound.
26. The composition of claim 21 , wherein the composition comprises less than about 0.15% by weight of the 3-aminophenylethyne compared to the compound.