Process for the preparation of intermediates useful for making (2S,5R)-7-oxo-n-piperidin-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

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

comprising:

A) coupling a pipecolic acid with an azacycloalkylamine in the presence of a first organic solvent, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), 1-hydroxy-2-pyridone (HOPO), and at least one acid to form a compound of formula II

and

B) contacting the compound of formula (II) with a protecting group in the presence of a nucleophilic catalyst and a second organic solvent to form the compound of formula I.

2. The process of claim 1 , wherein in step A) the pipecolic acid is

and the azacycloalkylamine is

3. The process of claim 2 , wherein in step A), the at least one acid is selected from aqueous hydrochloric acid or methanesulfonic acid (MsOH).

4. The process of claim 2 , wherein the first organic solvent is selected from DCM, DMF, AcNMe 2 , THF, MeTHF, EtOAc, i-PrOAc and acetonitrile and mixtures thereof.

5. The process of claim 2 , wherein the second organic solvent is selected from DCM, DMF, AcNMe 2 , THF, MeTHF, EtOAc, i-PrOAc and acetonitrile and mixtures thereof.

6. The process of claim 4 or 5 , wherein the first and second organic solvent is acetonitrile.

7. The process of claim 1 , wherein the nucleophilic catalyst is 4-dimethylaminopyridine (DMAP).

8. The process of claim 7 , wherein the protecting group is chosen from methanesulfonyl chloride, chloromethanesulfonyl chloride, dicloromethanesulfonyl chloride, benzenesulfonyl chloride, p-trifluromethylbenzenesulfonyl chloride, p-toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, p-fluorobenzenesulfonyl chloride, p-methoxybenzenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 2,4-dichlorobenzenesulfonyl chloride, and p-trifluoromethylbenzenesulfonyl chloride.

9. The process of claim 8 , wherein the protecting group is 2-nitrobenzenesulfonyl chloride or 4-nitrobenzenesulfonyl chloride.

10. The process of claim 9 , wherein the compound of Formula (I) is

11. A process for preparing a compound of Formula IV or a pharmaceutically acceptable salt thereof:

comprising:

contacting a hydroxy urea of formula (III);

in the presence of a sulfur trioxide amine selected from sulfur trioxide-triethyl amine,

sulfur trioxide-tripropyl amine, and sulfur trioxide-tributylamine, and at least one solvent

selected from 2-methyltetrahydrofuran and tetrahydrofuran to form a reaction mixture;

adding an aqueous solution of dipotassium phosphate to the reaction mixture; and

adding tetrabutylammonium hydrogensulfate to form a compound (IV) in a biphasic mixture.

12. The process of claim 11 further comprising formation of the compound of formula (V)

comprising:

contacting compound (IV) with trimethylsilyl bromide (TMSBr) in the presence of an organic solvent; and

adding tetrabutylammonium acetate-acetic acid complex in acetonitrile and water to form compound (V).

13. The process of claim 12 , further comprising adding isopropyl alcohol to the reaction mixture containing compound (V) and filtering the resultant mixture.