(2S)-2-amino-3,3-dimethylbutanamide

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

Procedure: Compound 99 was prepared according to the procedure for the synthesis of compound 28 by replacing tert-leucine methylamide with tert-leucine amide.

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

Procedure: Compound 99 was prepared according to the procedure for the synthesis of compound 28 by replacing tert-leucine methylamide with tert-leucine amide.

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

Procedure: To a solution of 1-(3-hydroxy-3-methylbutyl)-1,3-dihydro-2H-benzimidazol-2-one (0.25 g, 1.1 mmol) in 1,2-dichloroethane (30 mL) were added triethylamine (0.52 mL, 3.7 mmol) and 4-nitrophenyl chloroformate (0.27 g, 1.4 mmol) at 0° C. and the mixture was stirred for 4 h at rt. Then to this mixture was added a mixture of L-tert-leucinamide (0.18 g, 1.4 mmol) in 1,2-dichloroethane (5 mL) at 0° C. and stirred at rt. After 14 h, the reaction was quenched by addition of water (50 mL) and filtered and washed with water (30 mL) and dichloromethane (30 mL). The obtained solid was suspended in water (50 mL) and filtered. This procedure was repeated twice followed by recrystallization from methanol. The obtained solid was suspended in water (50 mL) again and filtered and this procedure was repeated twice. Then the solid was dissolved in methanol/dichloromethane and filtered and concentrated in vacuo. The obtained solid was then recrystallized from acetone to give 0.14 g (33%) of the title compound. Then to this mixture was added stirred at rt After 14 h the reaction was quenched by addition of water (50 mL) filtered washed with water (30 mL) and dichloromethane (30 mL) filtered This procedure was repeated twice followed by recrystallization from methanol filtered Then the solid was dissolved in methanol/dichloromethane filtered concentrated in vacuo The obtained solid was then recrystallized from acetone

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

Procedure: To a solution of 1-(3-hydroxy-3-methylbutyl)-1,3-dihydro-2H-benzimidazol-2-one (0.25 g, 1.1 mmol) in 1,2-dichloroethane (30 mL) were added triethylamine (0.52 mL, 3.7 mmol) and 4-nitrophenyl chloroformate (0.27 g, 1.4 mmol) at 0° C. and the mixture was stirred for 4 h at rt. Then to this mixture was added a mixture of L-tert-leucinamide (0.18 g, 1.4 mmol) in 1,2-dichloroethane (5 mL) at 0° C. and stirred at rt. After 14 h, the reaction was quenched by addition of water (50 mL) and filtered and washed with water (30 mL) and dichloromethane (30 mL). The obtained solid was suspended in water (50 mL) and filtered. This procedure was repeated twice followed by recrystallization from methanol. The obtained solid was suspended in water (50 mL) again and filtered and this procedure was repeated twice. Then the solid was dissolved in methanol/dichloromethane and filtered and concentrated in vacuo. The obtained solid was then recrystallized from acetone to give 0.14 g (33%) of the title compound. Then to this mixture was added stirred at rt After 14 h the reaction was quenched by addition of water (50 mL) filtered washed with water (30 mL) and dichloromethane (30 mL) filtered This procedure was repeated twice followed by recrystallization from methanol filtered Then the solid was dissolved in methanol/dichloromethane filtered concentrated in vacuo The obtained solid was then recrystallized from acetone

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

Procedure: To a solution of 1-(3-methylbutyl)1,2-dihydro-2H-benzimidazol-2-one (Step 1, 140 mg, 0.69 mmol) in dichloromethane (2.5 mL) were added triethylamine (0.32 mL, 2.3 mmol) and 4-nitrophenyl chloroformate (150 mg, 0.76 mmol) at 0° C. and the mixture was stirred for 4 h at rt. Then to this mixture was added a solution of L-tert-leucinamide (steps 1 and 2 in example 4, 99 mg, 0.76 mmol) in dichloromethane (2 mL) at 0° C. and stirred rt. After 22 h, the reaction was quenched by addition of water (20 mL) and extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with water (20 mL×3), brine (20 mL) and dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (3/1-1/1) to afford 240 mg (96%) of the titled compound. The obtained product was further purified by recrystallization from hexane/ethyl acetate to give 220 mg of the title compound. stirred rt After 22 h the reaction was quenched by addition of water (20 mL) extracted with ethyl acetate (30 mL×2) The combined organic layers were washed with water (20 mL×3), brine (20 mL) dried over sodium sulfate filtered concentrated The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (3/1-1/1)

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

Procedure: To a solution of 1-(3-methylbutyl)1,2-dihydro-2H-benzimidazol-2-one (Step 1, 140 mg, 0.69 mmol) in dichloromethane (2.5 mL) were added triethylamine (0.32 mL, 2.3 mmol) and 4-nitrophenyl chloroformate (150 mg, 0.76 mmol) at 0° C. and the mixture was stirred for 4 h at rt. Then to this mixture was added a solution of L-tert-leucinamide (steps 1 and 2 in example 4, 99 mg, 0.76 mmol) in dichloromethane (2 mL) at 0° C. and stirred rt. After 22 h, the reaction was quenched by addition of water (20 mL) and extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with water (20 mL×3), brine (20 mL) and dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (3/1-1/1) to afford 240 mg (96%) of the titled compound. The obtained product was further purified by recrystallization from hexane/ethyl acetate to give 220 mg of the title compound. stirred rt After 22 h the reaction was quenched by addition of water (20 mL) extracted with ethyl acetate (30 mL×2) The combined organic layers were washed with water (20 mL×3), brine (20 mL) dried over sodium sulfate filtered concentrated The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (3/1-1/1)

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

Procedure: To a solution of benzyl [(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]carbamate (Step 1, 3.7 g, 14 mmol) in THF (40 mL) was added 10% Pd/C (710 mg). The flask was evacuated and flushed with H2 gas and this process was repeated three times. The flask was filled with H2 gas (4 atm) and stirred for 3 h at rt. Then the reaction mixture was filtered through a pad of Celite and concentrated in vacuo to give the title compound as white solid (crude; 1.8 g) The flask was evacuated flushed with H2 gas The flask was filled with H2 gas (4 atm) Then the reaction mixture was filtered through a pad of Celite concentrated in vacuo

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

Procedure: To a solution of benzyl [(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]carbamate (Step 1, 3.7 g, 14 mmol) in THF (40 mL) was added 10% Pd/C (710 mg). The flask was evacuated and flushed with H2 gas and this process was repeated three times. The flask was filled with H2 gas (4 atm) and stirred for 3 h at rt. Then the reaction mixture was filtered through a pad of Celite and concentrated in vacuo to give the title compound as white solid (crude; 1.8 g) The flask was evacuated flushed with H2 gas The flask was filled with H2 gas (4 atm) Then the reaction mixture was filtered through a pad of Celite concentrated in vacuo

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

Procedure: A solution of 12.0 g (51.7 mmol) of (S)-3,3-dimethyl-2-(1-phenylethylimino)-butyramide in 200 ml of methanol was hydrogenated in a low pressure hydrogenation apparatus in the presence of 2.0 g of 5 percent Pd/C at 40° C. and normal pressure for 6.5 hours. After cooling the catalyst was filtered off and the filtrate was evaporated to dryness: 6.7 g (99.5%) of white crystals containing 90.8% (S)-tert-leucinamide, 97.0% e.e. Recrystallization from 40 ml of cyclohexane yielded 5.3 g (78.5%) of (S)-tert-leucinamide as white crystals, m.p. 104°-105° C., [α]=-23.2 (c=1, CHCl3), 96.9% e.e. After cooling the catalyst was filtered off the filtrate was evaporated to dryness 6.7 g (99.5%) of white crystals containing 90.8% (S)-tert-leucinamide, 97.0% e.e Recrystallization from 40 ml of cyclohexane

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

Procedure: A solution of 12.0 g (51.7 mmol) of (S)-3,3-dimethyl-2-(1-phenylethylimino)-butyramide in 200 ml of methanol was hydrogenated in a low pressure hydrogenation apparatus in the presence of 2.0 g of 5 percent Pd/C at 40° C. and normal pressure for 6.5 hours. After cooling the catalyst was filtered off and the filtrate was evaporated to dryness: 6.7 g (99.5%) of white crystals containing 90.8% (S)-tert-leucinamide, 97.0% e.e. Recrystallization from 40 ml of cyclohexane yielded 5.3 g (78.5%) of (S)-tert-leucinamide as white crystals, m.p. 104°-105° C., [α]=-23.2 (c=1, CHCl3), 96.9% e.e. After cooling the catalyst was filtered off the filtrate was evaporated to dryness 6.7 g (99.5%) of white crystals containing 90.8% (S)-tert-leucinamide, 97.0% e.e Recrystallization from 40 ml of cyclohexane

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

Procedure: Compound 99 was prepared according to the procedure for the synthesis of compound 28 by replacing tert-leucine methylamide with tert-leucine amide.

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

Procedure: In the same way as in example VIII, an incubation was carried out with DL-tertiary leucine amide. Analysis of the remaining reaction mixture after 8 hours showed that both L-tertiary leucine and D-tertiary leucine amide with an e.e. of ≥99% were present in the reaction mixture. Analysis of the remaining reaction mixture after 8 hours