Process for the preparation of macrolide antibacterial agents
View Patent ↗Described herein are processes for the preparation of compounds of formula (I): and pharmaceutically acceptable salts, solvates, and hydrates thereof.
1. A process comprising (c) reacting a compound of formula (V)
with a compound of formula N 3 —B—A—NH 2 to obtain a compound of formula (VI)
wherein:
R 1b is a monosaccharide or disaccharide that includes a 2′-hydroxy group acylated with R 1a wherein R 1a is a sterically hindered acyl group; and L is a leaving group;
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, R 12 and R 13 are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, dimethylaminoalkyl, acyl, sulfonyl, ureyl, and carbamoyl; R 14 is hydrogen, hydroxy, alkyl, aralkyl, 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 R 8 and R 9 are each independently selected from hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, alkoxy, dimethylaminoalkyl, acyl, sulfonyl, ureyl, or carbamoyl; or X and Y taken together with the attached carbon to form C═O; and pharmaceutically acceptable salts, solvates, and hydrates thereof.
2. A process of claim 1 , wherein V is C═O.
3. The process of claim 2 wherein -A-B— is alkylene.
4. The process of claim 2 wherein R 1b is desosamine.
5. The process of claim 2 wherein R 1a is selected from the group consisting of branched alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl acyl groups, each of which is optionally substituted.
6. The process of claim 4 wherein R 1a is optionally substituted benzoyl.
7. The process of claim 2 wherein W is hydrogen or F.
8. The process of claim 2 wherein X is hydrogen; and Y is OR 7 , where R 7 is cladinose.
9. The process of claim 1 wherein X and Y are taken together with the attached carbon to form C═O.
10. The process of claim 2 wherein R 1a is benzoyl.
11. The process of claim 1 wherein R 1a a is optionally substituted benzoyl, and further comprising converting the compound of formula (VI) into a compound of formula (I)
wherein
R 1 is a monosaccharide or disaccharide; and
C represents 1 or 2 substituents independently selected in each instance from the group consisting of hydrogen, halogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, aminoaryl, alkylaminoaryl, acyl, acyloxy, sulfonyl, ureyl, and carbamoyl, each of which is optionally substituted.
12. The process of claim 11 wherein the compound of formula (I) is of the formula
or a pharmaceutically acceptable salt thereof; where A is CH2; and B is (CH2) n , and n is 3.
13. The process of claim 11 wherein V is C═O.
14. The process of claim 11 wherein X and Y are taken together with the attached carbon to form C═O.
15. The process of claim 11 wherein W is hydrogen or F.
16. The process of claim 11 wherein W is F.
17. The process of claim 11 wherein -A-B— is alkylene.
18. The process of claim 11 wherein C is optionally substituted aryl or optionally substituted heteroaryl.
19. The process of claim 11 wherein C is optionally substituted aryl.
20. The process of claim 11 wherein R 1 is a monosaccharide that includes a 2′-hydroxyl group acylated with R 1a .
21. The process of claim 20 wherein R 1a is benzoyl.
22. The process of any one of claims 11 to 21 wherein R 1 is desosamine.
23. The process of claim 11 wherein the compound of formula (I) is of the formula
where A is CH 2 ; B is (CH 2 ) 3 ; and HX is an acid.
24. The process of claim 11 wherein the compound of formula (I) is of the formula
where A is CH 2 ; and B is (CH 2 ) 3 .
25. The process of claim 11 wherein the compound of formula (I) is of the formula
where A is CH 2; and B is (CH 2 ) 3 .