3S,4S-4-aminomethyl-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of intermediate (1-e) (0.087 mol) and intermediate (3-a) (0.087 mol) in acetonitrile (600 ml) was stirred and refluxed for 90 min. The reaction mixture was cooled, and the solvent was evaporated. The residue was partitioned between DCM and water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was suspended in DIPE with a drop of ACN, filtered off and dried (vacuum, 40° C.), yielding 30.3 g (80%) of (±)-1,1-dimethylethyl trans-4-[[(4-amino-5-chloro-2,3-dimethoxybenzoyl)amino]methyl]-3-hydroxy-1-piperidinecarboxylate (interm. 4). refluxed for 90 min The reaction mixture was cooled the solvent was evaporated The residue was partitioned between DCM and water The organic layer was separated dried filtered the solvent was evaporated filtered off dried (vacuum, 40° C.)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of intermediate (1-d) (max. 0.023 mol crude residue) in methanol (100 ml) was hydrogenated with palladium-on-carbon (10%, 1 g) as a catalyst. After uptake of H2 (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was solidified in DIPE+ACN, filtered off and dried (vacuum, 40° C.), yielding 4 g (76%) of 1,1-dimethylethyl (trans)-4-(aminomethyl)-3-hydroxy-1-piperidinecarboxylate (intermediate 1-e, mp. 178° C.). In an analogous way, but starting from cis-3-hydroxy-4-piperidinemethanol (described in J. Org. Chem., 34, pp. 3674-3676 (1969)), 1,1-dimethylethyl (cis)-4-(aminomethyl)-3-hydroxy-1-piperidinecarboxylate (interm. 1-f) was prepared. After uptake of H2 (1 equivalent), the catalyst was filtered off the filtrate was evaporated filtered off dried (vacuum, 40° C.)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of intermediate (25) (0.56 mol) in methanol (700 ml) was hydrogenated at 50° C. with palladium-on-carbon (5 g; 10%) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was solidified in DIPE, filtered off and dried, yielding 119 g (100%) of (+)-1,1-dimethylethyl (trans)-4-(aminomethyl)-3-hydroxy-1-piperidinecarboxylate (intermediate 2-g; [α]D20=+2.43° (c=24.70 mg/5 ml in CH3OH)). the filtrate was evaporated filtered off dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of intermediate (1-d) (max. 0.023 mol crude residue) in methanol (100 ml) was hydrogenated with palladium-on-carbon (10%, 1 g) as a catalyst. After uptake of H2 (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was solidified in DIPE+ACN, filtered off and dried (vacuum, 40° C.), yielding 4 g (76%) of 1,1-dimethylethyl (trans)-4-(aminomethyl)-3-hydroxy-1-piperidine-carboxylate (intermediate 1-e, mp. 178° C.). After uptake of H2 (1 equivalent), the catalyst was filtered off the filtrate was evaporated filtered off dried (vacuum, 40° C.)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of intermediate (1-d) (max. 0.023 mol crude residue) in methanol (100 ml) was hydrogenated with palladium-on-carbon (10%, 1 g) as a catalyst. After uptake of H2 (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was solidified in DIPE+ACN, filtered off and dried (vacuum, 40° C.), yielding 4 g (76%) of 1,1-dimethylethyl (trans)-4-(aminomethyl)-3-hydroxy-1-piperidine-carboxylate (intermediate 1-e, mp. 178° C.). After uptake of H2 (1 equivalent), the catalyst was filtered off the filtrate was evaporated filtered off dried (vacuum, 40° C.)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of intermediate (25) (0.56 mol) in methanol (700 ml) was hydrogenated at 50° C. with palladium-on-carbon (5 g; 10%) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was solidified in DIPE, filtered off and dried, yielding 119 g (100%) of (+)-1,1-dimethylethyl (trans)-4-(aminomethyl)-3-hydroxy-1-piperidinecarboxylate=+2.43° (c=24.70 mg/5 ml in CH3OH)). the filtrate was evaporated filtered off dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of intermediate (25) (0.56 mol) in methanol (700 ml) was hydrogenated at 50° C. with palladium-on-carbon (5 g; 10%) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was solidified in DIPE, filtered off and dried, yielding 119 g (100%) of (+)-1,1-dimethylethyl (trans)-4-(aminomethyl)-3-hydroxy-1-piperidinecarboxylate=+2.43° (c=24.70 mg/5 ml in CH3OH)). the filtrate was evaporated filtered off dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of intermediate (1-d) (max. 0.023 mol crude residue) in methanol (100 ml) was hydrogenated with palladium-on-carbon (10%, 1 g) as a catalyst. After uptake of H2 (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was solidified in DIPE+ACN, filtered off and dried (vacuum, 40° C.), yielding 4 g (76%) of 1,1-dimethylethyl (trans)-4-(aminomethyl)-3-hydroxy-1-piperidinecarboxylate (intermediate 1-e, mp. 178° C.). After uptake of H2 (1 equivalent), the catalyst was filtered off the filtrate was evaporated filtered off dried (vacuum, 40° C.)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of intermediate (1-d) (max. 0.023 mol crude residue) in methanol (100 ml) was hydrogenated with palladium-on-carbon (10%, 1 g) as a catalyst. After uptake of H2 (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was solidified in DIPE+ACN, filtered off and dried (vacuum, 40° C.), yielding 4 g (76%) of 1,1-dimethylethyl (trans)-4-(aminomethyl)-3-hydroxy-1-piperidinecarboxylate (intermediate 1-e, mp. 178° C.). After uptake of H2 (1 equivalent), the catalyst was filtered off the filtrate was evaporated filtered off dried (vacuum, 40° C.)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of intermediate (1-e) (0.087 mol) and intermediate (3-a) (0.087 mol) in acetonitrile (600 ml) was stirred and refluxed for 90 min. The reaction mixture was cooled, and the solvent was evaporated. The residue was partitioned between DCM and water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was suspended in DIPE with a drop of ACN, filtered off and dried (vacuum, 40° C.), yielding 30.3 g (80%) of (±)-1,1-dimethylethyl trans-4-[[(4-amino-5-chloro-2,3-dimethoxybenzoyl)amino]methyl]-3-hydroxy-1-piperidinecarboxylate (interm. 4). refluxed for 90 min The reaction mixture was cooled the solvent was evaporated The residue was partitioned between DCM and water The organic layer was separated dried filtered the solvent was evaporated filtered off dried (vacuum, 40° C.)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of intermediate (1-e) (0.087 mol) and intermediate (3-a) (0.087 mol) in acetonitrile (600 ml) was stirred and refluxed for 90 min. The reaction mixture was cooled, and the solvent was evaporated. The residue was partitioned between DCM and water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was suspended in DIPE with a drop of ACN, filtered off and dried (vacuum, 40° C.), yielding 30.3 g (80%) of (±)-1,1-dimethylethyl trans-4-[[(4-amino-5-chloro-2,3-dimethoxybenzoyl)amino]methyl]-3-hydroxy-1-piperidinecarboxylate (interm. 4). refluxed for 90 min The reaction mixture was cooled the solvent was evaporated The residue was partitioned between DCM and water The organic layer was separated dried filtered the solvent was evaporated filtered off dried (vacuum, 40° C.)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of intermediate (1-d) (max. 0.023 mol crude residue) in methanol (100 ml) was hydrogenated with palladium-on-carbon (10%, 1 g) as a catalyst. After uptake of H2 (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was solidified in DIPE+ACN, filtered off and dried (vacuum, 40° C.), yielding 4 g (76%) of 1,1-dimethylethyl (trans)-4-(aminomethyl)-3-hydroxy-1-piperidinecarboxylate (intermediate 1-e, mp. 178° C.). In an analogous way, but starting from cis-3-hydroxy-4-piperidinemethanol (described in J. Org. Chem., 34, pp. 3674-3676 (1969)), 1,1-dimethylethyl (cis)-4-(aminomethyl)-3-hydroxy-1-piperidinecarboxylate (interm. 1-f) was prepared. After uptake of H2 (1 equivalent), the catalyst was filtered off the filtrate was evaporated filtered off dried (vacuum, 40° C.)