benzyl N-[(5S)-6-hydroxy-5-[(2-methylpropan-2-yl)oxycarbonylamino]hexyl]carbamate

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

Procedure: A solution of sulfur trioxide pyridine complex (53.0 g, 333 mmol) in dimethylsulfoxide (300 mL) was added to a solution of benzyl (5S)-5-{[t-butyloxycarbonyl]amino}-6-hydroxyhexylcarbamate (8.64 g, 34.4 mmol) and triethylamine (14.4 mL, 103 mmol) in dichloromethane (130 mL) at 0° C. The cold bath was removed, and the reaction mixture was stirred for 23 h. It was then poured slowly into a mixture of ice and saturated aqueous sodium chloride (1000 mL). The resulting mixture was extracted with three 600 mL portions of ether. The ether extracts were then combined, washed with three 150 mL portions of saturated aqueous sodium chloride, and concentrated to 1200 mL. The concentrated ether phase was further washed with three 200 mL aliquots of 5% aqueous citric acid, and a 200 mL portion of saturated aqueous sodium chloride. After drying over magnesium sulfate, volatiles were removed under vacuum to afford (2S)-6-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]hexanal (37.58 g. 93%). 1H NMR (300 MHz, DMSO-d6) δ 9.44 (s, 1H), 7.46-7.23 (m, 6H), 5.02 (s, 2H), 3.85-3.75 (m, 1H), 3.07-2.93 (m, 2H), 1.77-1.60 (m, 1H), 1.56-1.23 (m, 5H), 1.41 (s, 9H). The cold bath was removed It was then poured slowly into a mixture of ice and saturated aqueous sodium chloride (1000 mL) The resulting mixture was extracted with three 600 mL portions of ether washed with three 150 mL portions of saturated aqueous sodium chloride concentrated to 1200 mL The concentrated ether phase was further washed with three 200 mL aliquots of 5% aqueous citric acid After drying over magnesium sulfate, volatiles were removed under vacuum

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4 g of benzyl (5S)-5-{[(tert-butyloxy)carbonyl]amino}-6-hydroxyhexylcarbamate, 30 cm3 of trifluoroacetic acid and 20 cm3 of ethanol is stirred at a temperature in the region of 20° C. for 2 hours. After concentration of the reaction medium under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained is taken up in 50 cm3 of water and washed with twice 100 cm3 of diethyl ether. The aqueous phase is separated out after settling has taken place, basified with sodium carbonate to pH 9-10 and then extracted with 3 times 100 cm3 of dichloromethane. The combined extracts are washed with aqueous sodium chloride solution and then dried on magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 2.0 g of benzyl (5S)-5-amino-6-hydroxyhexylcarbamate are obtained in the form of a white solid melting at 82° C. After concentration of the reaction medium under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained washed with twice 100 cm3 of diethyl ether The aqueous phase is separated out after settling extracted with 3 times 100 cm3 of dichloromethane The combined extracts are washed with aqueous sodium chloride solution dried on magnesium sulfate filtered concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4 g of benzyl (5S)-5-{[(tert-butyloxy)carbonyl]amino}-6-hydroxyhexylcarbamate, 30 cm3 of trifluoroacetic acid and 20 cm3 of ethanol is stirred at a temperature in the region of 20° C. for 2 hours. After concentration of the reaction medium under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained is taken up in 50 cm3 of water and washed with twice 100 cm3 of diethyl ether. The aqueous phase is separated out after settling has taken place, basified with sodium carbonate to pH 9-10 and then extracted with 3 times 100 cm3 of dichloromethane. The combined extracts are washed with aqueous sodium chloride solution and then dried on magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 2.0 g of benzyl (5S)-5-amino-6-hydroxyhexylcarbamate are obtained in the form of a white solid melting at 82° C. After concentration of the reaction medium under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained washed with twice 100 cm3 of diethyl ether The aqueous phase is separated out after settling extracted with 3 times 100 cm3 of dichloromethane The combined extracts are washed with aqueous sodium chloride solution dried on magnesium sulfate filtered concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4 g of benzyl (5S)-5-{[(tert-butyloxy)carbonyl]amino}-6-hydroxyhexylcarbamate, 30 cm3 of trifluoroacetic acid and 20 cm3 of ethanol is stirred at a temperature in the region of 20° C. for 2 hours. After concentration of the reaction medium under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained is taken up in 50 cm3 of water and washed with twice 100 cm3 of diethyl ether. The aqueous phase is separated out after settling has taken place, basified with sodium carbonate to pH 9-10 and then extracted with 3 times 100 cm3 of dichloromethane. The combined extracts are washed with aqueous sodium chloride solution and then dried on magnesium sulphate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 2.0 g of benzyl (5S)-5-amino-6-hydroxyhexylcarbamate are obtained in the form of a white solid melting at 82° C. After concentration of the reaction medium under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained washed with twice 100 cm3 of diethyl ether The aqueous phase is separated out after settling extracted with 3 times 100 cm3 of dichloromethane The combined extracts are washed with aqueous sodium chloride solution dried on magnesium sulphate filtered concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C

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

Procedure: A solution of 53.0 g (333 mmol) of sulfur trioxide pyridine complex in 300 mL of dimethylsulfoxide was added to a solution of 8.64 g (34.4 mmol) of benzyl (5S)-5-{[t-butyloxycarbonyl]amino}-6-hydroxyhexylcarbamate and 14.4 mL (103 mmol) of triethylamine in 130 mL of dichloromethane at 0° C. The cold bath was removed, and the reaction mixture was stirred for 23 h. It was then poured slowly into a mixture of ice and 1 L of saturated aqueous sodium chloride. The resulting mixture was extracted with three 600 mL portions of ether. The ether extracts were then combined, washed with three 150 mL portions of saturated aqueous sodium chloride, and concentrated to 1.2 L. The concentrated ether phase was further washed with three 200 mL aliquots of 5% aqueous citric acid, and a 200 mL portion of saturated aqueous sodium chloride. After drying over magnesium sulfate, volatiles were removed under vacuum to afford 37.58 g (93%) of (2S)-6-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]hexanal. 1H NMR (300 MHz, DMSO-d6) δ 9.44 (s, 1H), 7.46-7.23 (m, 6H), 5.02 (s, 2H), 3.85-3.75 (m, 1H), 3.07-2.93 (m, 2H), 1.77-1.60 (m, 1H), 1.56-1.23 (m, 5H), 1.41 (s, 9H). The cold bath was removed It was then poured slowly into a mixture of ice and 1 L of saturated aqueous sodium chloride The resulting mixture was extracted with three 600 mL portions of ether washed with three 150 mL portions of saturated aqueous sodium chloride concentrated to 1.2 L The concentrated ether phase was further washed with three 200 mL aliquots of 5% aqueous citric acid After drying over magnesium sulfate, volatiles were removed under vacuum

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

Procedure: A solution of 150.0 mL (150.0 mmol) of 1 M isopropylchloroformate in toluene was added dropwise to a solution of 20.9 mL (150.0 mmol) of triethylamine and 57.06 g (150.0 mmol) of (2S)-6-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]hexanoic acid in 500 mL of anhydrous tetrahydrofuran at 0° C. After 2 h, the resulting mixture was filtered to remove solids, rinsing with 100 mL of anhydrous tetrahydrofuran. The filtrate was then added dropwise to a stirred solution of 11.35 g (300.0 mmol) of sodium borohydride in 500 mL of 0° C. water. The cold bath was removed, and the resulting mixture was stirred for 18 h. It was then diluted with 800 mL of ethyl acetate and 300 mL of saturated aqueous sodium bicarbonate. The two layers were separated, the aqueous layer was extracted with two 250 mL aliquots of ethyl acetate, and the extracts were combined with the original ethyl acetate layer. The combined ethyl acetate phase was washed with three 100 ml portions of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated under vacuum. The yellow oil was further purified by column chromatography on silica gel, eluting with 4:1 ethyl acetate:hexane to afford 37.70 g (68%) of benzyl (5S)-5-{[t-butyloxycarbonyl]amino}-6-hydroxyhexylcarbamate. 1H NMR (300 MHz, DMSO-d6) δ 7.43-7.30 (m, 5H), 7.25 (t, J=5 Hz, 1H), 6.45 (d, J=8 Hz, 1H), 5.02 (s, 2H), 4.57 (br s, 1H), 3.35-3.29 (m overlapping water peak, 2H), 3.26-3.16 (m, 1H), 3.04-2.93 (m, 2H), 1.39 (s, 9H), 1.57-1.16 (m, 6H). ES-LCMS m/z 389 (M+Na). the resulting mixture was filtered to remove solids rinsing with 100 mL of anhydrous tetrahydrofuran The cold bath was removed It was then diluted with 800 mL of ethyl acetate and 300 mL of saturated aqueous sodium bicarbonate The two layers were separated the aqueous layer was extracted with two 250 mL aliquots of ethyl acetate The combined ethyl acetate phase was washed with three 100 ml portions of saturated aqueous sodium bicarbonate dried over magnesium sulfate concentrated under vacuum The yellow oil was further purified by column chromatography on silica gel eluting with 4:1 ethyl acetate

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

Procedure: A solution of sulfur trioxide pyridine complex (53.0 g, 333 mmol) in dimethylsulfoxide (300 mL) was added to a solution of benzyl (5S)-5-{[t-butyloxycarbonyl]amino}-6-hydroxyhexylcarbamate (8.64 g, 34.4 mmol) and triethylamine (14.4 mL, 103 mmol) in dichloromethane (130 mL) at 0° C. The cold bath was removed, and the reaction mixture was stirred for 23 h. It was then poured slowly into a mixture of ice and saturated aqueous sodium chloride (1000 mL). The resulting mixture was extracted with three 600 mL portions of ether. The ether extracts were then combined, washed with three 150 mL portions of saturated aqueous sodium chloride, and concentrated to 1200 mL. The concentrated ether phase was further washed with three 200 mL aliquots of 5% aqueous citric acid, and a 200 mL portion of saturated aqueous sodium chloride. After drying over magnesium sulfate, volatiles were removed under vacuum to afford (2S)-6-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]hexanal (37.58 g. 93%). 1H NMR (300 MHz, DMSO-d6) δ 9.44 (s, 1H), 7.46-7.23 (m, 6H), 5.02 (s, 2H), 3.85-3.75 (m, 1H), 3.07-2.93 (m, 2H), 1.77-1.60 (m, 1H), 1.56-1.23 (m, 5H), 1.41 (s, 9H). The cold bath was removed It was then poured slowly into a mixture of ice and saturated aqueous sodium chloride (1000 mL) The resulting mixture was extracted with three 600 mL portions of ether washed with three 150 mL portions of saturated aqueous sodium chloride concentrated to 1200 mL The concentrated ether phase was further washed with three 200 mL aliquots of 5% aqueous citric acid After drying over magnesium sulfate, volatiles were removed under vacuum

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4 g of benzyl (5S)-5-{[(tert-butyloxy)carbonyl]amino}-6-hydroxyhexylcarbamate, 30 cm3 of trifluoroacetic acid and 20 cm3 of ethanol is stirred at a temperature in the region of 20° C. for 2 hours. After concentration of the reaction medium under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained is taken up in 50 cm3 of water and washed with twice 100 cm3 of diethyl ether. The aqueous phase is separated out after settling has taken place, basified with sodium carbonate to pH 9-10 and then extracted with 3 times 100 cm3 of dichloromethane. The combined extracts are washed with aqueous sodium chloride solution and then dried on magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 2.0 g of benzyl (5S)-5-amino-6-hydroxyhexylcarbamate are obtained in the form of a white solid melting at 82° C. After concentration of the reaction medium under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained washed with twice 100 cm3 of diethyl ether The aqueous phase is separated out after settling extracted with 3 times 100 cm3 of dichloromethane The combined extracts are washed with aqueous sodium chloride solution dried on magnesium sulfate filtered concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C