Convergent processes for preparing macrolide antibacterial agents

1. A process for preparing a compound of formula (I)

or a pharmaceutically acceptable salt thereof; wherein

R 1 is a desosamine or a desosamine derivative;

A is —CH 2 —, —C(O)—, —C(O)O—, —C(O)NH—, —S(O) 2 —, —S(O) 2 NH—, or —C(O)NHS(O) 2 —;

B is saturated C 0 -C 10 ; or B is unsaturated C 2 -C 10 ; or -A-B- taken together is alkylene, alkenylene, cycloalkylene, or arylene;

C represents 2 substituents independently selected in each instance from the group consisting of hydrogen, halogen, hydroxy, acyl, acyloxy, sulfonyl, ureyl, and carbamoyl, and alkyl, alkoxy, heteroalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, each of which is optionally substituted; and

W is hydrogen, F, Cl, Br, I, or OH;

the process comprising (A) contacting a compound of formula

or a salt thereof, where R 100 is a hydroxyl protecting group, and L is a leaving group, with a compound of formula

or a salt thereof, where C is as defined herein, and C P is a protected form of C, and a base, to prepare a compound of formula

or a salt thereof; or

(C) contacting a compound of formula

or a salt thereof, with an acid to prepare a compound of formula

or a salt thereof; or

(E) contacting a compound of formula

or a salt thereof, with an oxidizing agent to prepare a compound of formula

or a salt thereof; or

(F) contacting a compound of formula

or a salt thereof, with a hydroxylating or halogenating agent to prepare a compound of formula

or a salt thereof, wherein W is F, Cl, Br, I, or OH;

any combination of the foregoing.

2. The process of claim 1 comprising

(a) contacting a compound of formula

or a salt thereof, where R 100 is a hydroxyl protecting group, and L is a leaving group, with a compound of formula

or a salt thereof, where N P is a protected amine, and a base; to prepare a compound of formula

or a salt thereof; or

(c) contacting a compound of formula

or a salt thereof, with an acid to prepare a compound of formula

or a salt thereof; or

(e) contacting a compound of formula

or a salt thereof, with an oxidizing agent to prepare a compound of formula

or a salt thereof; or

(g) contacting a compound of formula

or a salt thereof, with a fluorinating agent to prepare a compound of formula

or a salt thereof; or

any combination of the foregoing.

3. The process of claim 2 wherein N P is NHC(O)CF 3 .

4. The process of claim 1 comprising

(a′) contacting a compound of formula

or a salt thereof, where R 100 is a hydroxyl protecting group, and L is a leaving group, with a compound of formula

or a salt thereof, and a base; to prepare a compound of formula

or a salt thereof; or

(b′) contacting a compound of formula

or a salt thereof, with an acid to prepare a compound of formula

or a salt thereof; or

(c′) contacting a compound of formula

or a salt thereof, with an oxidizing agent to prepare a compound of formula

or a salt thereof; or

(d′) contacting a compound of formula

or a salt thereof, with a fluorinating agent to prepare a compound of formula

or a salt thereof; or

any combination of the foregoing.

5. The process of claim 1 wherein the leaving group is halo, pentafluorophenoxy, a sulfonate, a hydroxyamino, or imidazol-1-yl.

6. The process of claim 1 wherein the base is DBU.

7. The process of claim 1 wherein the halogenating agent is NFSI, F-TEDA, or 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate).

8. The process of claim 1 wherein C is aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted.

9. The process of claim 1 wherein A is CH 2 .

10. The process of claim 1 wherein B is (CH 2 ) n and n is an integer from 2 to 6.

11. The process of claim 1 wherein B is (CH 2 ) n , and n is 2, 3, or 4.

12. The process of claim 1 wherein B is (CH 2 ) n , and n is 3.

13. The process of claim 1 wherein R 100 is acyl.

14. The process of claim 1 wherein R 100 is alkylcarbonyl or optionally substituted benzoyl.

15. The process of claim 1 wherein R 100 is acetyl or benzoyl.

16. The process of claim 1 wherein W is H or F.

17. The process of claim 1 wherein W is F.