benzyl N-[(3R)-2,5-dioxooxolan-3-yl]carbamate

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of NaBH4 (2.71 g, 71.5 mmol) in THF (50 mL) was cooled to 0° C., treated dropwise with a solution of EXAMPLE 21A (16.21 g, 65.0 mmol) in THF (50 mL), allowed to warm to room temperature, and stirred for 2 hours. The resulting mixture was treated with concentrated HCl (13.1 mL) and ethanol (13.1 mL), heated to reflux for 12 hours, allowed to cool to room temperature, poured into brine (100 mL) and the layers were separated. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was triturated with diethyl ether (50 mL) for 2 hours, cooled overnight, and the solid collected by filtration to provide the desired product (7.81 g, 51%). to warm to room temperature heated to reflux for 12 hours to cool to room temperature the layers were separated The aqueous phase was extracted with ethyl acetate the combined organic layers were washed with water and brine dried (MgSO4) filtered concentrated The concentrate was triturated with diethyl ether (50 mL) for 2 hours cooled overnight the solid collected by filtration

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

Procedure: A stirred suspension of N-(benzyloxycarbonyl)-D-aspartic acid (14.7 g, 55.1 mmol) in ethyl acetate (100 mL) was treated dropwise with thionyl chloride (40 mL, 511 mmol) and the resulting homogeneous mixture was stirred at room temperature for 16 hours, and concentrated. The resulting solid was triturated in 1:1 diethyl ether/hexanes (200 mL) for 2 hours and filtered. The solid was dried to provide the desired product (13.7 g, 99%). concentrated The resulting solid was triturated in 1:1 diethyl ether/hexanes (200 mL) for 2 hours filtered The solid was dried

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

Procedure: A stirred suspension of N-(benzyloxycarbonyl)-D-aspartic acid (14.7 g, 55.1 mmol) in ethyl acetate (100 mL) was treated dropwise with thionyl chloride (40 mL, 511 mmol) and the resulting homogeneous mixture was stirred at room temperature for 16 hours, and concentrated. The resulting solid was triturated in 1:1 diethyl ether/hexanes (200 mL) for 2 hours and filtered. The solid was dried to provide the desired product (13.7 g, 99%). concentrated The resulting solid was triturated in 1:1 diethyl ether/hexanes (200 mL) for 2 hours filtered The solid was dried

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

Procedure: N-(Benzyloxycarbonyl)-D-aspartic anhydride (25) is prepared from N-(benzyloxycarbonyl)-D-aspartic acid (24) by the method of McGarvey et al. (G. J. McGarvey et al., J. Amer. Chem. Soc., 1986, 108, 4943) with an overall yield of 80% with respect to D-aspartic acid (D-23). The melting point is 126-127° C. [α]D+26° (c 1.22, MeOH). Infrared (KBr): 1529, 1697 (O—CO—N), 1781 and 1866 (anhydride).

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Nitrolotrimethanol (5.27 mg, 0.05 mmol) was added to a solution of di-tert-butyl ((R)-(4′-chlorobiphenyl-2-yl)(1-(4-(4-((R)-4-morpholino-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonylcarbamoyl)phenyl)piperidin-4-yl)methoxy)methyl phosphate (EXAMPLE 27, 58.0 mg, 0.05 mmol) in acetone (1.8 ml) and 0.6 ml of pH7.2 buffer (Gibco, Dulbecco's Phosphate Buffered saline 1×). The resulting reaction mixture was stirred at 65° C. for 16 hours. Evaporation of the volatiles under reduced pressure gave a residue which was purified by reverse phase HPLC (Gilson column, eluting with 30→50% H2O with 10 mM NH4OAc/MeCN for 5 minutes) to provide the title product (0.017 g, yield: 19%). The resulting reaction mixture Evaporation of the volatiles under reduced pressure gave a residue which was purified by reverse phase HPLC (Gilson column, eluting with 30→50% H2O with 10 mM NH4OAc/MeCN for 5 minutes)

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

Procedure: A solution of (R)-benzyl 2,5-dioxotetrahydrofuran-3-ylcarbamate (INTERMEDIATE 1, 53.28 g, 213.79 mmol) in THF (330 ml) was added over a 4 hour period using an additional funnel to a mixture of sodium borohydride (8.09 g, 213.79 mmol) in THF (330 ml) at 0° C. After the addition was complete, the mixture was warmed to room temperature and stirred for 2 hours. The solution was then concentrated under reduced pressure to ¼ of the original volume, cooled to 0° C., and carefully quenched by the slow addition of water (400 ml). The mixture was acidified to pH 4 with 1N aqueous hydrochloric acid and extracted with Et2O (5×300 ml). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to provide the title product (45.9 g, yield: 85%). After the addition The solution was then concentrated under reduced pressure cooled to 0° C. carefully quenched by the slow addition of water (400 ml) extracted with Et2O (5×300 ml) The combined organic layers were dried (Na2SO4) concentrated in vacuo

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

Procedure: A mixture of (R)-2-(benzyloxycarbonylamino)succinic acid (Aldrich, 30 g, 112.26 mmol) and acetic anhydride (65.7 ml, 696.02 mmol) was stirred overnight at room temperature during which time the reaction mixture became clear. The volatiles were removed under reduced pressure (water bath temperature 65° C.) and the concentrate was azeotroped with toluene (3×50 ml) and obtained the title product after drying for ˜48 hours at 60° C. under high vacuum pump (28.0 g, yield: almost quantitative). The volatiles were removed under reduced pressure (water bath temperature 65° C.) the concentrate was azeotroped with toluene (3×50 ml)

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

Procedure: A solution of (R)-benzyl 2,5-dioxotetrahydrofuran-3-ylcarbamate (INTERMEDIATE 1, 53.28 g, 213.79 mmol) in THF (330 ml) was added over a 4 hour period using an additional funnel to a mixture of sodium borohydride (8.09 g, 213.79 mmol) in THF (330 ml) at 0° C. After the addition was complete, the mixture was warmed to room temperature and stirred for 2 hours. The solution was then concentrated under reduced pressure to ¼ of the original volume, cooled to 0° C., and carefully quenched by the slow addition of water (400 ml). The mixture was acidified to pH 4 with 1N aqueous hydrochloric acid and extracted with Et2O (5×300 ml). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to provide the title product (45.9 g, yield: 85%). After the addition The solution was then concentrated under reduced pressure cooled to 0° C. carefully quenched by the slow addition of water (400 ml) extracted with Et2O (5×300 ml) The combined organic layers were dried (Na2SO4) concentrated in vacuo

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

Procedure: A mixture of (R)-2-(benzyloxycarbonylamino)succinic acid (Aldrich, 30 g, 112.26 mmol) and acetic anhydride (65.7 ml, 696.02 mmol) was stirred overnight at room temperature during which time the reaction mixture became clear. The volatiles were removed under reduced pressure (water bath temperature 65° C.) and the concentrate was azeotroped with toluene (3×50 ml) and obtained the title product after drying for ˜48 hours at 60° C. under high vacuum pump (28.0 g, yield: almost quantitative). The volatiles were removed under reduced pressure (water bath temperature 65° C.) the concentrate was azeotroped with toluene (3×50 ml)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of NaBH4 (2.71 g, 71.5 mmol) in THF (50 mL) was cooled to 0° C., treated dropwise with a solution of EXAMPLE 21A (16.21 g, 65.0 mmol) in THF (50 mL), allowed to warm to room temperature, and stirred for 2 hours. The resulting mixture was treated with concentrated HCl (13.1 mL) and ethanol (13.1 mL), heated to reflux for 12 hours, allowed to cool to room temperature, poured into brine (100 mL) and the layers were separated. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was triturated with diethyl ether (50 mL) for 2 hours, cooled overnight, and the solid collected by filtration to provide the desired product (7.81 g, 51%). to warm to room temperature heated to reflux for 12 hours to cool to room temperature the layers were separated The aqueous phase was extracted with ethyl acetate the combined organic layers were washed with water and brine dried (MgSO4) filtered concentrated The concentrate was triturated with diethyl ether (50 mL) for 2 hours cooled overnight the solid collected by filtration

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

Procedure: A stirred suspension of N-(benzyloxycarbonyl)-D-aspartic acid (14.7 g, 55.1 mmol) in ethyl acetate (100 mL) was treated dropwise with thionyl chloride (40 mL, 511 mmol) and the resulting homogeneous mixture was stirred at room temperature for 16 hours, and concentrated. The resulting solid was triturated in 1:1 diethyl ether/hexanes (200 mL) for 2 hours and filtered. The solid was dried to provide the desired product (13.7 g, 99%). concentrated The resulting solid was triturated in 1:1 diethyl ether/hexanes (200 mL) for 2 hours filtered The solid was dried

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

Procedure: N-(Benzyloxycarbonyl)-D-aspartic anhydride (25) is prepared from N-(benzyloxycarbonyl)-D-aspartic acid (24) by the method of McGarvey et al. (G. J. McGarvey et al., J. Amer. Chem. Soc., 1986, 108, 4943) with an overall yield of 80% with respect to D-aspartic acid (D-23). The melting point is 126-127° C. [α]D+26° (c 1.22, MeOH). Infrared (KBr): 1529, 1697 (O—CO—N), 1781 and 1866 (anhydride).