Methods of preparing hydroxylamine derivatives useful in the preparation of anti-infective agents

1. A process for preparing a compound of Formula I, or a salt thereof:

which comprises a reduce/couple sequence or a couple/reduce sequence,

wherein:

the reduce/couple sequence comprises

(E1) reducing a compound of Formula V

 or an acidic or basic salt thereof,

to obtain a compound of Formula VI

 or an acidic or basic salt thereof; and

(F1) coupling the compound of Formula VI, or an acidic or basic salt thereof, with a compound of formula VII

 or a salt thereof;

to form the compound of Formula I, or a salt thereof;

the couple/reduce sequence comprises

(E2) coupling a compound of Formula V:

 or an acidic or basic salt thereof,

with a compound of Formula VII

 or a salt thereof,

to obtain a compound of Formula VIII

 or a salt thereof; and

(F2) reducing the compound of Formula VIII, or a salt there, to form the compound of Formula I, or a salt thereof;

PG 1 is an amine protecting group which forms with the amino nitrogen to which it is attached a carbamate, a benzylamine, or a sulfonamide; and

PG 2 is an oxygen protecting group selected from acetyl (Ac), benzyl (Bn), 4-MeOBn, benzoyl (Bz), and tert-Butyldimethylsilyl ether (TBS).

2. The process according to claim 1 , wherein the reduction step in step E1 or F2 is conducted with a mono or bidentate phosphine in the presence of 1) a transition metal in a polar solvent or 2) a borohydride reagent and a protic or Lewis acid in a suitable solvent.

3. The process according to claim 2 , wherein the phosphine is bis(dicyclohexylphosphino)-ferrocene, triphenylphosphine, tricyclohexylphosphine, or 1,1′-Bis(diphenylphosphino)ferrocene.

4. The process according to claim 2 , wherein the reaction is conducted in the presence of a transition metal in a polar solvent and the transition metal is Rh(I), Ru, Pd, Ni, or Cu.

5. The process according to claim 4 , wherein the transition metal is Rh(I) in the form of bis(norbornadiene)rhodium(I) tetrafluoroborate.

6. The process according to claim 2 , wherein the reaction is conducted in the presence of a borohydride reagent, and an acid in a suitable solvent including water, the borohydride reagent is NaBH 4 , the suitable solvent is ethanol or an ethanol/triglyme mixture, the acid is a Lewis acid selected from a Fe(III) halide or a Fe(III) salt, wherein the water can be in the form of a hydrate salt of Fe(III) halide or Fe(III) salt.

7. The process according to claim 2 , wherein the reaction is conducted in the presence of a borohydride reagent and a protic acid in a polar solvent, the borohydride reagent is a carboxylic acid modified NaBH 4 , the polar solvent is acetonitrile or ethyl acetate, and the protic acid is H 2 SO 4 .

8. The process according to claim 1 , wherein the coupling step in step E2 or F1 is conducted in the presence of a coupling reagent in a non-nucleophilic solvent system and optionally a peptide coupling additive and optionally an acid or a base additive.

9. The process according to claim 8 , wherein the coupling reagent is 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (EDC.HCl).

10. The process of claim 8 wherein the non-nucleophilic solvent system comprises one or more of CH 3 CN, NMP, toluene or DMF.

11. The process of claim 8 wherein the peptide coupling additive is HOPO.

12. The process of claim 8 wherein the additive is CF 3 CO 2 Na.

13. The process of claim 8 wherein the base additive is lutidine.

14. The process of any one of claims 1 to 13 , wherein PG 1 is Boc and PG 2 is benzyl.

15. The process according to claim 1 , which further comprises preparing a compound of Formula V

 or an acidic or basic salt thereof,

by Step C1 followed by Step D1

(C1) cyclizing a halooxime of Formula III:

 or an acidic or basic salt thereof, wherein X is bromo or chloro,

by addition of a base in a solvent to obtain a compound of Formula IV

 or an acidic or basic salt thereof; and

(D1) deprotecting the compound of Formula IV, or a salt thereof, to form a compound of Formula V, or an acidic or basic salt thereof.

16. The process of claim 15 , wherein the base is KOtBu.

17. The process of claim 15 , wherein the solvent is THF, DMF, or toluene.

18. The process of claim 15 , wherein the deprotection step is conducted with a protic acid, Lewis acid or nucleophilic base in a solvent.

19. The process of claim 18 , wherein the deprotection step is conducted with a Lewis acid, and optionally BSA, in a solvent, wherein the Lewis acid is TMSBr or TMSI.

20. The process according to claim 1 , which further comprises preparing a compound of Formula V

 or an acidic or basic salt thereof,

by Step C2 followed by Step D2

(C2) deprotecting a compound of Formula III in a strong acid in a non-nucleophilic solvent:

 or a salt thereof

to obtain a compound of Formula IX

 or an acidic or basic salt thereof; and

(D2) cyclizing the compound of Formula IX, or an acidic or basic salt thereof, with a base to form a compound of Formula V, or an acidic or basic salt thereof;

wherein X is bromo or chloro.

21. The process of claim 20 , wherein the acid is MsOH.

22. The process of claim 20 , wherein the solvent is CH 2 Cl 2 .

23. The process of claim 20 , wherein the base is NaOH.

24. The process of claim 20 , wherein the solvent is CH 2 Cl 2 /H 2 O.

25. The process according to claim 1 or 2 , which further comprises preparing a compound of Formula III

 or a salt thereof, wherein X is bromo or chloro,

through Steps A and B below:

(A) reacting SM of Formula

 or a salt thereof,

with a sulfur reagent to obtain a sulfur ylide compound of Formula II

 or a salt thereof;

(B) reacting the compound of Formula II, or a salt thereof, with a halide source to form a halooxime compound of Formula III, or a salt thereof.

26. The process of claim 22 , wherein the sulfur reagent is Me 3 SOI and the non-nucleophilic base is KOtBu.

27. The process of claim 22 , wherein the solvent in step (A) is a mixture of THF and DMF.

28. The process of claim 22 , wherein the halide source is LiCl and the acid is chloroacetic acid or cyanoacetic acid.

29. The process of claim 22 , wherein the solvent in step (B) is a mixture of THF, DMF and DMSO.