(2S)-4-amino-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (˜15° C.) water/MeOH (12 mL each) solution of (S)-4-amino-2-(tert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HCl until its pH reached ˜1.0 and then heated for 2 hr at 40° C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with DOWEX® 50WX8-100 ion-exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g). the cooling bath was removed the reaction was stirred for 20.5 hr Most of the MeOH component was removed in vacuo the remaining mixture was treated with concentrated HCl until its pH The volatile component was removed in vacuo the residue was treated with 4 M HCl/dioxane (20 mL) stirred at ambient condition for 7.5 hr The volatile component was removed in vacuo the residue was purified with DOWEX® 50WX8-100 ion-exchange resin (column was washed with water the compound was eluted with dilute NH4OH prepared from 18 ml of NH4OH and 282 ml of water)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (˜15° C.) water/MeOH (12 mL each) solution of (S)-4-amino-2-(tert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HCl until its pH reached ˜1.0 and then heated for 2 hr at 40° C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with Dowex® 50WX8-100 ion-exchange resin (column was washed with water and the compound was elated with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g). the cooling bath was removed the reaction was stirred for 20.5 hr Most of the MeOH component was removed in vacuo the remaining mixture was treated with concentrated HCl until its pH The volatile component was removed in vacuo the residue was treated with 4 M HCl/dioxane (20 mL) stirred at ambient condition for 7.5 hr The volatile component was removed in vacuo the residue was purified with Dowex® 50WX8-100 ion-exchange resin (column was washed with water prepared from 18 ml of NH4OH and 282 ml of water)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (−15° C.) water/MeOH (12 mL each) solution of (S)-4-amino-2-(tert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HCl until its pH reached ˜1.0 and then heated for 2 hr at 40° C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with DOWEX® 50WX8-100 ion-exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (5)-2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g). the cooling bath was removed the reaction was stirred for 20.5 hr Most of the MeOH component was removed in vacuo the remaining mixture was treated with concentrated HCl until its pH The volatile component was removed in vacuo the residue was treated with 4 M HCl/dioxane (20 mL) stirred at ambient condition for 7.5 hr The volatile component was removed in vacuo the residue was purified with DOWEX® 50WX8-100 ion-exchange resin (column was washed with water the compound was eluted with dilute NH4OH prepared from 18 ml of NH4OH and 282 ml of water)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (˜15° C.) water/MeOH (12 mL each) solution of (S)-4-amino-2-(tert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HCl until its pH reached ˜1.0 and then heated for 2 hr at 40° C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with Dowex® 50WX8-100 ion-exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g). the cooling bath was removed the reaction was stirred for 20.5 hr Most of the MeOH component was removed in vacuo the remaining mixture was treated with concentrated HCl until its pH The volatile component was removed in vacuo the residue was treated with 4 M HCl/dioxane (20 mL) stirred at ambient condition for 7.5 hr The volatile component was removed in vacuo the residue was purified with Dowex® 50WX8-100 ion-exchange resin (column was washed with water the compound was eluted with dilute NH4OH prepared from 18 ml of NH4OH and 282 ml of water)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (˜15° C.) water/MeOH (12 mL each) solution of (S)-4-amino-2-(tert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HCl until its pH reached ˜1.0 and then heated for 2 hr at 40° C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with Dowex® 50WX8-100 ion-exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g). the cooling bath was removed the reaction was stirred for 20.5 hr Most of the MeOH component was removed in vacuo the remaining mixture was treated with concentrated HCl until its pH The volatile component was removed in vacuo the residue was treated with 4 M HCl/dioxane (20 mL) stirred at ambient condition for 7.5 hr The volatile component was removed in vacuo the residue was purified with Dowex® 50WX8-100 ion-exchange resin (column was washed with water the compound was eluted with dilute NH4OH prepared from 18 ml of NH4OH and 282 ml of water)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (˜15° C.) water/MeOH (12 mL each) solution of (S)-4-amino-2-(tert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HCl until its pH reached ˜1.0 and then heated for 2 hr at 40° C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with Dowex® 50WX8-100 ion-exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g). the cooling bath was removed the reaction was stirred for 20.5 hr Most of the MeOH component was removed in vacuo the remaining mixture was treated with concentrated HCl until its pH The volatile component was removed in vacuo the residue was treated with 4 M HCl/dioxane (20 mL) stirred at ambient condition for 7.5 hr The volatile component was removed in vacuo the residue was purified with Dowex® 50WX8-100 ion-exchange resin (column was washed with water the compound was eluted with dilute NH4OH prepared from 18 ml of NH4OH and 282 ml of water)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (˜15° C.) water/MeOH (12 mL each) solution of (S)-4-amino-2-(tert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HCl until its pH reached ˜1.0 and then heated for 2 hr at 40° C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with DOWEX® 50WX8-100 ion-exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g). the cooling bath was removed the reaction was stirred for 20.5 hr Most of the MeOH component was removed in vacuo the remaining mixture was treated with concentrated HCl until its pH The volatile component was removed in vacuo the residue was treated with 4 M HCl/dioxane (20 mL) stirred at ambient condition for 7.5 hr The volatile component was removed in vacuo the residue was purified with DOWEX® 50WX8-100 ion-exchange resin (column was washed with water the compound was eluted with dilute NH4OH prepared from 18 ml of NH4OH and 282 ml of water)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (˜15° C.) water/MeOH (12 mL each) solution of (S)-4-amino-2-(tert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HCl until its pH reached ˜1.0 and then heated for 2 hr at 40° C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with DOWEX® 50WX8-100 ion-exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g). the cooling bath was removed the reaction was stirred for 20.5 hr Most of the MeOH component was removed in vacuo the remaining mixture was treated with concentrated HCl until its pH The volatile component was removed in vacuo the residue was treated with 4 M HCl/dioxane (20 mL) stirred at ambient condition for 7.5 hr The volatile component was removed in vacuo the residue was purified with DOWEX® 50WX8-100 ion-exchange resin (column was washed with water the compound was eluted with dilute NH4OH prepared from 18 ml of NH4OH and 282 ml of water)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (˜15° C.) water/MeOH (12 mL each) solution of (S)-4-amino-2-(tert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HCl until its pH reached ˜1.0 and then heated for 2 hr at 40° C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with DOWEX® 50WX8-100 ion-exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g). the cooling bath was removed the reaction was stirred for 20.5 hr Most of the MeOH component was removed in vacuo the remaining mixture was treated with concentrated HCl until its pH The volatile component was removed in vacuo the residue was treated with 4 M HCl/dioxane (20 mL) stirred at ambient condition for 7.5 hr The volatile component was removed in vacuo the residue was purified with DOWEX® 50WX8-100 ion-exchange resin (column was washed with water the compound was eluted with dilute NH4OH prepared from 18 ml of NH4OH and 282 ml of water)

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

Procedure: A solution of (S)-4-amino-2-tert-butyloxycarbonylaminobutyric acid (1.03 g, 4.70 mmol) in acetonitrile (50 ml) was added to a solution of (S)-Boc-serine-β-lactone (0.80 g, 4.27 mmol) in acetonitrile (50 ml) and degassed H2O (50 ml). The pH was maintained at 5.5 by dropwise addition of 1M NaHCO3 with stirring. The mixture was stirred for 5 days at ambient temperature. The pH was controlled by NaHCO3 addition and the reaction monitored by TLC. The solvents were distilled off, the residue triturated with chloroform (5 ml), to which acetic acid was added to give pH 5. The chloroform solution was evaporated and the product isolated after chromatography on silica gel (CHCl3:MeOH 2:1). degassed H2O (50 ml) The pH was maintained at 5.5 by dropwise addition of 1M NaHCO3 The mixture was stirred for 5 days at ambient temperature The pH was controlled by NaHCO3 addition The solvents were distilled off the residue triturated with chloroform (5 ml), to which acetic acid was added to give pH 5 The chloroform solution was evaporated the product isolated after chromatography on silica gel (CHCl3:MeOH 2:1)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaCNBH3 (1.60 g, 24.2 mmol) was added in batches to a chilled (˜15° C.) water/MeOH (12 mL each) solution of (S)-4-amino-2-(tert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HCl until its pH reached ˜1.0 and then heated for 2 hr at 40° C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with Dowex® 50WX8-100 ion-exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g). the cooling bath was removed the reaction was stirred for 20.5 hr Most of the MeOH component was removed in vacuo the remaining mixture was treated with concentrated HCl until its pH The volatile component was removed in vacuo the residue was treated with 4 M HCl/dioxane (20 mL) stirred at ambient condition for 7.5 hr The volatile component was removed in vacuo the residue was purified with Dowex® 50WX8-100 ion-exchange resin (column was washed with water the compound was eluted with dilute NH4OH prepared from 18 ml of NH4OH and 282 ml of water)

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4.0 g (8.22 mmol) of the compound from example 1A was dissolved in 60 ml dichloromethane. 1.795 (8.22 mmol) (2S)-4-Amino-2-[(tert-butoxycarbonyl)amino]butanoic acid and 1.43 ml (8.22 mmol) N,N-diisopropylethylamine were added. The reaction mixture was split into 3 portions. The portions were heated for 30 min in a sealed tube at 75° C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 600 ml silica gel. Solvents used were dichloromethane/ethyl acetate 4/1, dichloromethane/ethyl acetate 1/1, dichloromethane/methanol 4/1 and dichloromethane/methanol 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 4.02 g (6.54 mmol, 80% of theory) of the desired product. The reaction mixture was split into 3 portions From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.) The raw product was dissolved in dichloromethane chromatographed over approx. 600 ml silica gel concentrated to dryness under reduced pressure