1174020-64-4

1174020-63-3

1174020-64-4

Example 2: Preparation of tert-butyl 4-((1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonylamino)piperidine-1-carboxylate (Compound 1) Tert-butyl 4-[[[(1R,2S,5R)-7-oxo-6-(phenylmethoxy)-1,6-diazabicyclo[3.2.1]octan-2-yl]carbonyl]amino]-1 -piperidinecarboxylate prepared according to the method described in Example 1 was used as starting material for the following hydrodebenzylation reaction. Compound 1 prepared using triphosgene was used as a control. Operating Procedure: 1. To a dry and clean autoclave was added compound 1 (3.0 g) and tetrahydrofuran (THF, 72 mL). 2. Add palladium/carbon catalyst (Pd/C, 10 wt% loading) to the reaction mixture. 3. Adjusted the autoclave internal pressure to 50 psig (total internal pressure). 4. age the reaction mixture for 4 hours at 25°C and 50 psig to ensure complete conversion. 5. Upon completion of the reaction, the reaction was vented and filtered to remove the Pd/C catalyst, and the catalyst was washed with THF (5 x 15 mL). 6. The combined organic phases were concentrated to 1/10 of the original volume, and then the solvent was replaced with isopropyl acetate (IPAc, 45 mL) to give a product slurry. 7. The slurry was continued to be stirred for 4 hours. 8. The reaction mixture was filtered and the solid product was collected and washed with IPAc (9 mL). 9. The resulting white solid was dried under vacuum and purged with nitrogen (N2) to afford the target product tert-butyl 4-((1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (~95% yield, >98% LCAP purity). The spectral data of the product are in agreement with those reported in the literature (see Mangion et al., 2011, Org. Lett. 13: 5480). Table 1 compares the effect of the method employed in the hydroxyl debenzylation reaction of the present invention (i.e., use of silicone-containing compounds and CDI) with that of a previously disclosed method (i.e., use of triphosgene) for the preparation of compound 1.