4-O-tert-butyl 1-O-(2,5-dioxopyrrolidin-1-yl) (2S)-2-(phenylmethoxycarbonylamino)butanedioate

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

Procedure: A solution of Z-Asp(OtBu)-OSu (115.6 g; 0.275 mol) in DMF (1.16 L) was stirred at 0° in a 3 L, 3-necked round bottom flask fitted with a mechanical stirrer and thermometer. The H-Leu-Lys(Boc)-OH (89.86 g; 0.250 mol) was added followed by Et3N (35.2 mL; 0.25 mol). The reaction mixture was stirred at 0° for 0.5 h and at 25° for 1.5 h. Additional Et3N (17 mL) was added (to maintain pH 8) and the reaction mixture stirred at 25° for 20 h. The reaction mixture was evaporated, dissolved in EtOAc (3 L), washed with 1M citric acid (3×1 L), H2O (3×1 L), dried (MgSO4) and evaporated in vacuo. The residual paste was dissolved in anhydrous ether (5 L) and stirred magnetically while DCHA (53.5 mL; 0.268 mol) was added slowly. After standing in the cold room (20 h) the white salt was collected and washed with anhydrous ether (2×0.5 L) and petroleum ether (2×0.5 L). Yield: 177 g (84%); m.p. 173°-174°; [α]D25 -12.57° (c 1, MeOH). fitted with a mechanical stirrer (to maintain pH 8) the reaction mixture stirred at 25° for 20 h The reaction mixture was evaporated dissolved in EtOAc (3 L) washed with 1M citric acid (3×1 L), H2O (3×1 L) dried (MgSO4) evaporated in vacuo The residual paste was dissolved in anhydrous ether (5 L) was added slowly After standing in the cold room (20 h) was collected washed with anhydrous ether (2×0.5 L) and petroleum ether (2×0.5 L)

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

Procedure: A solution of Z-Asp(OtBu)-OSu (115.6 g; 0.275 mol) in DMF (1.16 L) was stirred at 0° in a 3 L, 3-necked round bottom flask fitted with a mechanical stirrer and thermometer. The H-Leu-Lys(Boc)-OH (89.86 g; 0.250 mol) was added followed by Et3N (35.2 mL; 0.25 mol). The reaction mixture was stirred at 0° for 0.5 h and at 25° for 1.5 h. Additional Et3N (17 mL) was added (to maintain pH 8) and the reaction mixture stirred at 25° for 20 h. The reaction mixture was evaporated, dissolved in EtOAc (3 L), washed with 1M citric acid (3×1 L), H2O (3×1 L), dried (MgSO4) and evaporated in vacuo. The residual paste was dissolved in anhydrous ether (5 L) and stirred magnetically while DCHA (53.5 mL; 0.268 mol) was added slowly. After standing in the cold room (20 h) the white salt was collected and washed with anhydrous ether (2×0.5 L) and petroleum ether (2×0.5 L). Yield: 177 g (84%); m.p. 173°-174°; [α]D25 -12.57° (c 1, MeOH). fitted with a mechanical stirrer (to maintain pH 8) the reaction mixture stirred at 25° for 20 h The reaction mixture was evaporated dissolved in EtOAc (3 L) washed with 1M citric acid (3×1 L), H2O (3×1 L) dried (MgSO4) evaporated in vacuo The residual paste was dissolved in anhydrous ether (5 L) was added slowly After standing in the cold room (20 h) was collected washed with anhydrous ether (2×0.5 L) and petroleum ether (2×0.5 L)

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

Procedure: 1.68 ml (12.0 mmol) of triethylamine are added to a suspension containing 2.58 g (12.0 mmol) of H-Val-OtBu.HCl and 4.62 g (11.0 mmol) of Z-Asp(OtBu)-OSu in 25 ml of dimethylformamide (DMF). The reaction mixture is left to stand overnight, then evaporated under reduced pressure. The residue is mixed with 50 ml of ethyl acetate and the suspension obtained is successively washed with 25 ml of water, 3 times with 25 ml of 1 mol/liter hydrochloric acid each, 3 times with 25 ml of 5% aqueous sodium hydrogenocarbonate each and finally with 25 ml of water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain 4.3 g (81.7%) of oily Z-Asp(OtBu)-Val-OtBu protected dipeptide, Rf1 =0.85. The reaction mixture is left evaporated under reduced pressure The residue is mixed with 50 ml of ethyl acetate the suspension obtained is successively washed with 25 ml of water, 3 times with 25 ml of 1 mol/liter hydrochloric acid each, 3 times with 25 ml of 5% aqueous sodium dried over anhydrous sodium sulfate evaporated under reduced pressure

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

Procedure: A solution of Z-Asp(OtBu)-OSu (115.6 g; 0.275 mol) in DMF (1.16 L) was stirred at 0° in a 3 L, 3-necked round bottom flask fitted with a mechanical stirrer and thermometer. The H-Leu-Lys(Boc)-OH (89.86 g; 0.250 mol) was added followed by Et3N (35.2 mL; 0.25 mol). The reaction mixture was stirred at 0° for 0.5 h and at 25° for 1.5 h. Additional Et3N (17 mL) was added (to maintain pH 8) and the reaction mixture stirred at 25° for 20 H. The reaction mixture was evaporated, dissolved in EtOAc (3 L), washed with 1M citric acid (3×1 L), H2O (3×1 L), dried (MgSO4) and evaporated in vacuo. The residual paste was dissolved in anhydrous ether (5 L) and stirred magnetically while DCHA (53.5 mL; 0.268 mol) was added slowly. After standing in the cold room (20 h) the white salt was collected and washed with anhydrous ether (2×0.5 L) and petroleum ether (2×0.5 L). Yield: 177 g (84%); m.p. 173°-174°; [α]D25 -12.57° (c 1, MeOH). fitted with a mechanical stirrer (to maintain pH 8) the reaction mixture stirred at 25° for 20 H The reaction mixture was evaporated dissolved in EtOAc (3 L) washed with 1M citric acid (3×1 L), H2O (3×1 L) dried (MgSO4) evaporated in vacuo The residual paste was dissolved in anhydrous ether (5 L) was added slowly After standing in the cold room (20 h) was collected washed with anhydrous ether (2×0.5 L) and petroleum ether (2×0.5 L)

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

Procedure: A solution of Z-Asp(OtBu)-OSu (115.6 g; 0.275 mol) in DMF (1.16 L) was stirred at 0° in a 3 L, 3-necked round bottom flask fitted with a mechanical stirrer and thermometer. The H-Leu-Lys(Boc)-OH (89.86 g; 0.250 mol) was added followed by Et3N (35.2 mL; 0.25 mol). The reaction mixture was stirred at 0° for 0.5 h and at 25° for 1.5 h. Additional Et3N (17 mL) was added (to maintain pH 8) and the reaction mixture stirred at 25° for 20 h. The reaction mixture was evaporated, dissolved in EtOAc (3 L), washed with 1M citric acid (3×1 L), H2O (3×1 L), dried (MgSO4) and evaporated in vacuo. The residual paste was dissolved in anhydrous ether (5 L) and stirred magnetically while DCHA (53.5 mL; 0.268 mol) was added slowly. After standing in the cold room (20 h) the white salt was collected and washed with anhydrous ether (2×0.5 L) and petroleum ether (2×0.5 L). Yield: 177 g (84%); m.p. 173°-174°; [α]D25 -12.57° (c 1, MeOH). fitted with a mechanical stirrer (to maintain pH 8) the reaction mixture stirred at 25° for 20 h The reaction mixture was evaporated dissolved in EtOAc (3 L) washed with 1M citric acid (3×1 L), H2O (3×1 L) dried (MgSO4) evaporated in vacuo The residual paste was dissolved in anhydrous ether (5 L) was added slowly After standing in the cold room (20 h) was collected washed with anhydrous ether (2×0.5 L) and petroleum ether (2×0.5 L)