5-O-benzyl 1-O-methyl (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanedioate

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

Procedure: To a mixture of (S)-2-tert-butoxycarbonylamino-pentanedioic acid 5-benzyl ester 1-methyl ester (370 mg, 0.70 mmol; 66% purity) described in Manufacturing Example 2-1 and methanol (4 mL) was added palladium-carbon (40 mg, 0.19 mmol; 50% water content) at room temperature, which was stirred for 5 hours at room temperature under a hydrogen atmosphere (1 atm). The reaction mixture was replaced with nitrogen and filtered through a Celite pad. The solvent was evaporated from the filtrate under a reduced pressure, so as to obtain (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-methyl ester (300 mg) in a crude form. The crude product thus obtained was used directly in the next reaction. To a mixture of 3-(3-(4-(pyridin-2-yloxymethyl)-benzyl)-isoxazol-5-yl)-pyridin-2-ylamine (150 mg, 0.42 mmol) described in Reference Example 1 and acetonitrile (3 mL) were added (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-methyl ester (crude, 220 mg), N-methylmorpholine (46 μL, 0.42 mmol), and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (180 mg, 0.46 mmol) in this order at 0° C., which was stirrer overnight at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=4:1), so as to obtain the titled compound (37 mg). filtered through a Celite pad The solvent was evaporated from the filtrate under a reduced pressure

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

Procedure: To a mixture of (S)-2-tert-butoxycarbonylamino-pentanedioic acid 5-benzyl ester (300 mg, 0.89 mmol) and methanol (4 mL) were added benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (390 mg, 0.89 mmol), N-methylmorpholine (98 μL, 0.89 mmol), and acetonitrile (1 mL) at 0° C., which was stirred overnight at room temperature. A 1N sodium hydroxide aqueous solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed first with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, so as to obtain the titled compound (380 mg, purity of 66%) in a crude form. was extracted with ethyl acetate The organic layer was washed first with water with saturated brine, and dried over anhydrous magnesium sulfate The solvent was evaporated under a reduced pressure

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

Procedure: Methyl iodide (1.01 mL, 16.3 mmol) was added dropwise to a solution of (2S)-5-(benzyloxy)-2-{[(tert-butoxy)carbonyl]amino}-5-oxopentanoic acid XII (5.00 g, 14.82 mmol) and K2CO3 (2.25 g, 16.3 mmol) in DMF (25 mL) at r.t. The reaction mixture was stirred about 3 h at r.t. before adding additional methyl iodide (1.01 mL, 16.3 mmol). EtOAc was then added to the reaction and washed 3×10% Na2S2O3 and dried over MgSO4. The solvent was removed under reduced pressure and the crude product was purified on a silica gel column (100:1 and then 50:1 CHCl3/MeOH) to give 5-benzyl 1-methyl (2S)-2-{[(tert-butoxy)carbonyl]amino}pentanedioate XIII (4.20 g, 12.23 mmol, 82% yield). ESIMS found for C18H25NO6 m/z 352 (M+H). washed 3×10% Na2S2O3 dried over MgSO4 The solvent was removed under reduced pressure the crude product was purified on a silica gel column (100:1

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

Procedure: Methyl iodide (1.01 mL, 16.3 mmol) was added dropwise to a solution of (2S)-5-(benzyloxy)-2-{[(tert-butoxy)carbonyl]amino}-5-oxopentanoic acid XII (5.00 g, 14.82 mmol) and K2CO3 (2.25 g, 16.3 mmol) in DMF (25 mL) at room temperature The reaction mixture was stirred about 3 h at room temperature before adding additional methyl iodide (1.01 mL, 16.3 mmol). EtOAc was then added to the reaction and washed 3×10% Na2S2O3 and dried over MgSO4. The solvent was removed under reduced pressure and the crude product was purified on a silica gel column (100:1 and then 50:1 CHCl3/MeOH) to give 5-benzyl 1-methyl (2S)-2-{[(tert-butoxy)carbonyl]amino}pentanedioate XIII (4.20 g, 12.23 mmol, 82% yield). ESIMS found for C18H25NO6 m/z 352 (M+H). washed 3×10% Na2S2O3 dried over MgSO4 The solvent was removed under reduced pressure the crude product was purified on a silica gel column (100:1