tert-butyl N-[(2S)-1-hydroxy-3-methylbutan-2-yl]carbamate

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

Procedure: To 5 g (0.023 mol) of Boc-Valine dissolved in THF (30 mL) at −10° C. under N2 are added NMM (2.5 mL 0.023 mol) and IBCF (3 mL, 0.023 mol). The reaction mixture is stirred 15 minutes and filtered. The filtrate is added slowly to an ice-cold solution of NaBH4 (2.3 g, 0.061 mol) in H2O (10 mL) and stirred 1 hour at ice-bath temperature then 1 hour at room temperature. The reaction mixture is cooled to 0° C. and treated with saturated NaHCO3 solution, extracted with EtOAc, washed with 1M HCl saturated with NaHCO3, dried over anhydrous MgSO4, and evaporated to dryness. The crude Boc-ValCH2OH product is purified over a silica gel column eluted with 95:5 EtOAc/MeOH. filtered stirred 1 hour at ice-bath temperature 1 hour at room temperature extracted with EtOAc washed with 1M HCl saturated with NaHCO3 dried over anhydrous MgSO4 evaporated to dryness The crude Boc-ValCH2OH product is purified over a silica gel column eluted with 95:5 EtOAc/MeOH

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

Procedure: To 5 g (0.023 mol) of Boc-Valine dissolved in THF (30 mL) at −10° C. under N2 are added NMM (2.5 mL 0.023 mol) and IBCF (3 mL, 0.023 mol). The reaction mixture is stirred 15 minutes and filtered. The filtrate is added slowly to an ice-cold solution of NaBH4 (2.3 g, 0.061 mol) in H2O (10 mL) and stirred 1 hour at ice-bath temperature then 1 hour at room temperature. The reaction mixture is cooled to 0° C. and treated with saturated NaHCO3 solution, extracted with EtOAc, washed with 1M HCl saturated with NaHCO3, dried over anhydrous MgSO4, and evaporated to dryness. The crude Boc-ValCH2OH product is purified over a silica gel column eluted with 95:5 EtOAc/MeOH. filtered stirred 1 hour at ice-bath temperature 1 hour at room temperature extracted with EtOAc washed with 1M HCl saturated with NaHCO3 dried over anhydrous MgSO4 evaporated to dryness The crude Boc-ValCH2OH product is purified over a silica gel column eluted with 95:5 EtOAc/MeOH

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

Procedure: To a solution of ((1S)-1-hydroxymethyl-2-methylpropyl)carbamic acid t-butyl ester (3.00 g, 14.8 mmol) (obtained as described in Reference Example 61(1)) in tetrahydrofuran (150 ml) were added diphenylphosphoryl azide (4.78 ml, 22.2 mmol), triphenylphosphine (5.82 g, 22.2 mmol) and a 40% solution of diethylazodicarboxylate in toluene (9.67 g, 22.2 mmol) in an ice bath under an atmosphere of nitrogen, and the mixture was stirred for 2 hours under the same conditions. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (9:1) as the eluant to afford ((1S)-1-azidomethyl-2-methylpropyl)carbamic acid t-butyl ester (3.26 g, yield 90%) as a colorless oil. the completion of the reaction the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution The organic layer was dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The obtained residue was purified by chromatography on a silica gel column

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

Procedure: This compound was prepared in 81% yield from the ester 4b (9.28 g, 40 mmol) by reduction with lithium borohydride in dry DME following the procedure that has been described earlier1,2. TLC Rf 0.47 (eluent MeOH/CHCl3,7/93). 1H NMR (CDCl3) δ 0.91 and 0.98 (dd, J=2 Hz, 6H, CH3CHCH3), 1.44 (s, 9H, t-Bu), 1.45-1.97 (m, 1H, CH3CHCH3), 2.15 (s, 1H, OH), 3.24-3.49 (m, 1H, CHCH2), 3.53-3.72 (m, 2H, CH2OH), 4.36-4.77 (m, 1H, NH). CI MS, m/e 204 (M+ +1).

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

Procedure: In 5 ml of 1,2-dimethoxyethane (DME), 1.086 g of Boc-Val-OH was dissolved and 550 μl of N-methylmorpholine and 650 μl of isobutyl chloroformate were successively added dropwise at −15° C. After stirring for 1 min, N-methylmorpholine hydrochloride was filtered off and washed twice with 2.5 ml each of DME. The filtrate and washings were combined and a solution of 284 mg of sodium borohydride in 2.5 ml of water was added in one portion. After 30 sec, 125 ml of water was added and the mixture was extracted with 25 ml of ethyl acetate and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure to give 879 mg of the title compound. N-methylmorpholine hydrochloride was filtered off washed twice with 2.5 ml each of DME a solution of 284 mg of sodium borohydride in 2.5 ml of water was added in one portion After 30 sec 125 ml of water was added the mixture was extracted with 25 ml of ethyl acetate dried over anhydrous sodium sulfate The dried solution was evaporated under reduced pressure

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

Procedure: To 5 g (0.023 mol) of Boc-Valine dissolved in THF (30 mL) at −10° C. under N2 are added NMM (2.5 mL 0.023 mol) and IBCF (3 mL, 0.023 mol). The reaction mixture is stirred 15 minutes and filtered. The filtrate is added slowly to an ice-cold solution of NaBH4 (2.3 g, 0.061 mol) in H2O (10 mL) and stirred 1 hour at ice-bath temperature then 1 hour at room temperature. The reaction mixture is cooled to 0° C. and treated with saturated NaHCO3 solution, extracted with EtOAc, washed with 1M HCl saturated with NaHCO3, dried over anhydrous MgSO4, and evaporated to dryness. The crude Boc-ValCH2OH product is purified over a silica gel column eluted with 95:5 EtOAc/MeOH. filtered stirred 1 hour at ice-bath temperature 1 hour at room temperature extracted with EtOAc washed with 1M HCl saturated with NaHCO3 dried over anhydrous MgSO4 evaporated to dryness The crude Boc-ValCH2OH product is purified over a silica gel column eluted with 95:5 EtOAc/MeOH

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

Procedure: To 5 g (0.023 mol) of Boc-Valine dissolved in THF (30 mL) at −10° C. under N2 are added NMM (2.5 mL 0.023 mol) and IBCF (3 mL, 0.023 mol). The reaction mixture is stirred 15 minutes and filtered. The filtrate is added slowly to an ice-cold solution of NaBH4 (2.3 g, 0.061 mol) in H2O (10 mL) and stirred 1 hour at ice-bath temperature then 1 hour at room temperature. The reaction mixture is cooled to 0° C. and treated with saturated NaHCO3 solution, extracted with EtOAc, washed with 1M HCl saturated with NaHCO3, dried over anhydrous MgSO4, and evaporated to dryness. The crude Boc-ValCH2OH product is purified over a silica gel column eluted with 95:5 EtOAc/MeOH. filtered stirred 1 hour at ice-bath temperature 1 hour at room temperature extracted with EtOAc washed with 1M HCl saturated with NaHCO3 dried over anhydrous MgSO4 evaporated to dryness The crude Boc-ValCH2OH product is purified over a silica gel column eluted with 95:5 EtOAc/MeOH

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

Procedure: To a solution of Dess-Martin periodinane (3.12 g, 0.0073 mol, 1.5 eq) in dichloromethane (25 mL) was added a solution of N-Boc-L-valinol (1 g, 0.0049 mol, 1 eq) in dichloromethane (25 mL). The reaction mixture was stirred at room temperature for 3 h and was diluted with diethyl ether (50 mL). The mixture was poured into an aqueous saturated solution of sodium bicarbonate (100 mL) containing sodium thiosulfate (8.16 g, 10.5 eq). The mixture was stirred for 30 min and the layers were separated. The ether layer was washed with an aqueous saturated solution of sodium bicarbonate (50 mL), water (50 mL), dried (sodium sulfate) and filtered. The filtrate was concentrated to give the crude (1-formyl-2-methyl-propyl)-carbamic acid tert-butyl ester used for the next step without further purification. The mixture was stirred for 30 min the layers were separated The ether layer was washed with an aqueous saturated solution of sodium bicarbonate (50 mL), water (50 mL) dried (sodium sulfate) filtered The filtrate was concentrated

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

Procedure: To a solution of Dess-Martin periodinane (3.12 g, 0.0073 mol, 1.5 eq) in dichloromethane (25 mL) was added a solution of N-Boc-L-valinol (1 g, 0.0049 mol, 1 eq) in dichloromethane (25 mL). The reaction mixture was stirred at room temperature for 3 h and was diluted with diethyl ether (50 mL). The mixture was poured into an aqueous saturated solution of sodium bicarbonate (100 mL) containing sodium thiosulfate (8.16 g, 10.5 eq). The mixture was stirred for 30 min and the layers were separated. The ether layer was washed with an aqueous saturated solution of sodium bicarbonate (50 mL), water (50 mL), dried (sodium sulfate) and filtered. The filtrate was concentrated to give the crude (1-formyl-2-methyl-propyl)-carbamic acid tert-butyl ester used for the next step without further purification. The mixture was stirred for 30 min the layers were separated The ether layer was washed with an aqueous saturated solution of sodium bicarbonate (50 mL), water (50 mL) dried (sodium sulfate) filtered The filtrate was concentrated

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

Procedure: In 5 ml of 1,2-dimethoxyethane (DME), 1.086 g of Boc-Val-OH was dissolved and 550 μl of N-methylmorpholine and 650 μl of isobutyl chloroformate were successively added dropwise at −15° C. After stirring for 1 min, N-methylmorpholine hydrochloride was filtered off and washed twice with 2.5 ml each of DME. The filtrate and washings were combined and a solution of 284 mg of sodium borohydride in 2.5 ml of water was added in one portion. After 30 sec, 125 ml of water was added and the mixture was extracted with 25 ml of ethyl acetate and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure to give 879 mg of the title compound. N-methylmorpholine hydrochloride was filtered off washed twice with 2.5 ml each of DME a solution of 284 mg of sodium borohydride in 2.5 ml of water was added in one portion After 30 sec 125 ml of water was added the mixture was extracted with 25 ml of ethyl acetate dried over anhydrous sodium sulfate The dried solution was evaporated under reduced pressure

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

Procedure: To a solution of Dess-Martin periodinane (3.12 g, 0.0073 mol, 1.5 eq) in dichloromethane (25 mL) was added a solution of N-Boc-L-valinol (1 g, 0.0049 mol, 1 eq) in dichloromethane (25 mL). The reaction mixture was stirred at room temperature for 3 h and was diluted with diethyl ether (50 mL). The mixture was poured into an aqueous saturated solution of sodium bicarbonate (100 mL) containing sodium thiosulfate (8.16 g, 10.5 eq). The mixture was stirred for 30 min and the layers were separated. The ether layer was washed with an aqueous saturated solution of sodium bicarbonate (50 mL), water (50 mL), dried (sodium sulfate) and filtered. The filtrate was concentrated to give the crude (1-formyl-2-methyl-propyl)-carbamic acid tert-butyl ester used for the next step without further purification. The mixture was stirred for 30 min the layers were separated The ether layer was washed with an aqueous saturated solution of sodium bicarbonate (50 mL), water (50 mL) dried (sodium sulfate) filtered The filtrate was concentrated

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

Procedure: To a solution of Dess-Martin periodinane (3.12 g, 0.0073 mol, 1.5 eq) in dichloromethane (25 mL) was added a solution of N-Boc-L-valinol (1 g, 0.0049 mol, 1 eq) in dichloromethane (25 mL). The reaction mixture was stirred at room temperature for 3 h and was diluted with diethyl ether (50 mL). The mixture was poured into an aqueous saturated solution of sodium bicarbonate (100 mL) containing sodium thiosulfate (8.16 g, 10.5 eq). The mixture was stirred for 30 min and the layers were separated. The ether layer was washed with an aqueous saturated solution of sodium bicarbonate (50 mL), water (50 mL), dried (sodium sulfate) and filtered. The filtrate was concentrated to give the crude (1-formyl-2-methyl-propyl)-carbamic acid tert-butyl ester used for the next step without further purification. The mixture was stirred for 30 min the layers were separated The ether layer was washed with an aqueous saturated solution of sodium bicarbonate (50 mL), water (50 mL) dried (sodium sulfate) filtered The filtrate was concentrated