Synthesis of antibacterial aminoglycoside analogs

1. A process for preparing a compound of formula (2), or a salt thereof, or solvate thereof, or an enantiomer thereof, or a diastereomer thereof comprising:

(a) contacting a compound of formula (1):

or an enantiomer thereof, or a diastereomer thereof, with 1-{[(p-nitrobenzyl)oxy]carbonyl}-1H-benzotriazole (PNZ-Bt) to form the compound of formula (2):

or a salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof;

wherein - - - is a single bond or a double bond;

R 1 is H or C 1 -C 3 alkyl;

R 2 is H or C 1 -C 3 alkyl; and

R 3 is H or C 1 -C 3 alkyl.

2. The process of claim 1 , wherein step (a) is performed in the presence of a solvent selected from the group consisting of dichloromethane, methanol, and a combination thereof.

3. The process of claim 1 , further comprising step (b1) or (b2):

(b1) wherein when R 1 , R 2 , and R 3 are H, contacting the compound of formula (2) with a Boc protecting group reagent to yield a compound of formula (3):

or a salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof; or

(b2) wherein when one or more of R 1 , R 2 , or R 3 is independently a C 1 -C 3 alkyl, first removing said C 1 -C 3 alkyl, and then contacting the compound of formula (2), or a salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof, with a Boc protecting group reagent to yield a compound of formula (3):

or a salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof.

4. The process of claim 3 , wherein step (b1) or (b2) is performed in the presence of a Lewis acid.

5. The process of claim 3 , further comprising:

(c) contacting the compound of formula (3), or a salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof, with

 to yield a compound of formula (4):

or a salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof.

6. The process of claim 5 , wherein step (c) is performed in the presence of an activating reagent and a peptide coupling reagent.

7. The process of claim 5 , wherein step (c) is performed in an acidic condition.

8. The process of claim 5 , further comprising preparing a crystalline form of compound of formula (4), or a salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof.

9. The process of claim 5 , further comprising:

(d) contacting the compound of formula (4), or a salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof, with Boc protecting group reagent to yield a compound of formula (5):

or a salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof.

10. The process of claim 9 , wherein step (d) is performed in the presence of an alcohol.

11. The process of claim 9 , further comprising:

(e) contacting the compound of formula (5), or a salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof, with a PNZ deprotecting reagent to yield a compound of formula (6):

or a salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof; and

further comprising preparing a crystalline form of compound of formula (6), or a salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof.

12. The process of claim 11 , further comprising:

(f) contacting the compound of formula (6), or a salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof, with

wherein LG 1 is a leaving group, to yield a compound of formula (7):

or a salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof.

13. The process of claim 12 , further comprising:

(g) contacting the compound of formula (7), or a salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof, with a Boc removing reagent to yield a compound of formula (8):

or a salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof; and

(h) performing a salt formation with an acid to yield a salt of a compound of formula (8), or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof.

14. The process of claim 13 , wherein the Boc removing reagent is TFA, thereby yielding a TFA salt of compound of formula (8), or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof; and

(h) performing a salt formation with an acid to yield a salt of a compound of formula (8), or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof.

15. The process of claim 1 , wherein - - - is a double bond.

16. The process of claim 1 , wherein the stereochemistry at carbon atoms 1, 3, 4, 5, 6, 1′, 2′, 1″, 2″, 3″, and 4″ in formulae (1)-(3) are indicated as in formula (X), wherein indicates a point of attachment to hydrogen or a moiety:

17. The process of claim 14 , wherein the acid in step (h) is sulfuric acid, thereby yielding a sulfate salt of a compound of formula (9):

or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof, wherein x is 1 to 5.