4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)benzenesulfonamide

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

Procedure: 100 mmol (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol in ethyl acetate were added onto 120 mmol of disuccimidylcarbonate (95%) in acetonitrile. Following, a solution of 140 mmol triethylamine in ethylacetate was added and stirred. The mixture was cooled and treated with a suspension of 92 mmol of 4-Amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-(isobutyl)benzene sulfonamide in ethyl acetate. 20 mmol methylamine, 41% aqueous solution in ethanol were added and the mixture was warmed. The reaction was washed twice with 10% Na2CO3-solution and with water. Solvent was evaporated and ethanol was added. Another portion of solvent was distilled off. The temperature was kept around 40-45° C. and crystallization was initiated by seeding. After stirring the mixture was cooled, stirred for another 90 min stirred, cooled and again stirred for 60 min. The precipitate was filtered and washed with ethanol. The wet product was dried in vacuo at 40° C. 43.5 g of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate were suspended in ethanol abs. and dissolved. The clear solution was cooled and seeding was applied. Crystallization occurred while cooling the mixture. Stirring was continued for another 60 min, followed by cooling, stirring and filtering off the product, which was washed with cold ethanol abs. The wet product was dried in vacuo at 40° C. Yield: 42.1 g=71%. The mixture was cooled the mixture was warmed The reaction was washed twice with 10% Na2CO3-solution and with water Solvent was evaporated ethanol was added Another portion of solvent was distilled off was kept around 40-45° C. crystallization After stirring the mixture was cooled stirred for another 90 min stirred cooled again stirred for 60 min The precipitate was filtered washed with ethanol The wet product was dried in vacuo at 40° C and dissolved The clear solution was cooled Crystallization while cooling the mixture Stirring by cooling stirring filtering off the product, which was washed with cold ethanol abs The wet product was dried in vacuo at 40° C

Conditions: temp:6.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The obtained solution was then cooled to 40±3° C. followed by the addition of water. Adjustment of the pH of the solution to around 9.5 with aqueous solution of sodium hydroxide gave crystals 4-Amino-N-(3-amino-2-hydroxy-4-phenyl-butyl)-N-isobutyl-benzenesulfonamide. Additional water was added to this solution to adjust the concentration of 4-Amino-N-(3-amino-2-hydroxy-4-phenyl-butyl)-N-isobutyl-benzenesulfonamide to 5.5-5.8 wt %, and then this solution was cooled to 6±4° C. The resulting crystals were filtered off and washed with a mixed solution composed of water and ethanol and then washed with water. The resulting wet crystals were subjected to vacuum drying to give the product of (2R,3S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-amino-benzenesulfonamide. Yields were 75˜85% based on (1-Benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl)-carbamic acid tert-butyl ester. The resulting crystals were filtered off washed with a mixed solution washed with water drying

Conditions: temp:6.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The obtained solution was then cooled to 40±3° C. followed by the addition of water. Adjustment of the pH of the solution to around 9.5 with aqueous solution of sodium hydroxide gave crystals 4-Amino-N-(3-amino-2-hydroxy-4-phenyl-butyl)-N-isobutyl-benzenesulfonamide. Additional water was added to this solution to adjust the concentration of 4-Amino-N-(3-amino-2-hydroxy-4-phenyl-butyl)-N-isobutyl-benzenesulfonamide to 5.5-5.8 wt %, and then this solution was cooled to 6±4° C. The resulting crystals were filtered off and washed with a mixed solution composed of water and ethanol and then washed with water. The resulting wet crystals were subjected to vacuum drying to give the product of (2R,3S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-amino-benzenesulfonamide. Yields were 75˜85% based on (1-Benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl)-carbamic acid tert-butyl ester. The resulting crystals were filtered off washed with a mixed solution washed with water drying

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

Procedure: The compound of formula 3a (100 g), 10% palladium carbon (10 g) and triethanolamine (2 g) were suspended in methanol and then hydrogenated at 40-45° C. for 2 h. After completion of the reaction (TLC monitoring), filtered the reaction mass to remove palladium carbon. cp. HCl (62 mL) was added to the filtrate, heated to reflux and maintained for 2 h. The reaction mass was cooled to ambient temperature, pH of the reaction mass was adjusted to 6.0-7.0 with 20% sodium hydroxide solution. Methanol was distilled off under vacuum at below 50° C. The resultant residue was dissolved in a mixture of isopropyl alcohol (300 mL) and purified water (600 mL) and pH was further adjusted to 9.0-10.0 with 20% sodium hydroxide solution at ambient temperature. The reaction mass was maintained for 10 h, cooled to 0-5° C., filtered and washed with purified water. The wet cake was suspended in isopropyl alcohol (350 mL), heated to reflux, and maintained for 30 min. The reaction mass was cooled to 2-4° C., maintained for 1 h., filtered and washed with isopropyl alcohol. The wet product was air dried to obtain the compound of formula 4 in 71.3 g (yield-95%) with HPLC purity of 99.76%. After completion of the reaction (TLC monitoring) filtered the reaction mass to remove palladium carbon HCl (62 mL) was added to the filtrate heated to reflux maintained for 2 h Methanol was distilled off under vacuum at below 50° C The resultant residue was dissolved in a mixture of isopropyl alcohol (300 mL) purified water (600 mL) pH was further adjusted to 9.0-10.0 with 20% sodium hydroxide solution at ambient temperature The reaction mass was maintained for 10 h cooled to 0-5° C. filtered washed with purified water heated to reflux maintained for 30 min The reaction mass was cooled to 2-4° C. maintained for 1 h. filtered washed with isopropyl alcohol dried

Conditions: temp:42.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (1S,2R)-{1-benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl}-carbamic acid tert-butyl ester (3, 100 g), 10% palladium carbon (10 gm) and triethanolamine (2 gm) were suspended in isopropyl alcohol. The reaction was heated to 40-45° C. and maintained under 4-6 kg/cm2 of hydrogen pressure for 3 hours. After completion of reaction, the mass was filtered and hydrochloric acid (70 mL) was added to the filtered mass. The solution was heated to reflux and maintained for 2-3 hours. After completion of reaction the mass was cooled to 25-35° C., the reaction mass pH was adjusted to 6.0-7.0 with 20% sodium hydroxide solution and distilled out isopropyl alcohol under vacuum at below 55° C. Ethanol (200 mL) and water (400 mL) was added to the distillate, the mass pH was adjusted to 9.0-10.0 with 20% sodium hydroxide solution at 25-35° C. and maintained the stirring for 2 hours at 25-35° C. The mass was cooled to 0-5° C., filtered and wash with water. The wet product was taken into ethanol (350 mL), maintained the stirring for 30 minutes at reflux temperature. The mass was cooled to 2-4° C., stirred for 2 hours, filtered and washed with ethanol (50 mL). The wet product was dried under normal drying to get title compound 1 (Yield 60 g). After completion of reaction the mass was filtered hydrochloric acid (70 mL) was added to the filtered mass The solution was heated to reflux maintained for 2-3 hours After completion of reaction the mass was cooled to 25-35° C. distilled out isopropyl alcohol under vacuum at below 55° C Ethanol (200 mL) and water (400 mL) was added to the distillate was adjusted to 9.0-10.0 with 20% sodium hydroxide solution at 25-35° C. maintained the stirring for 2 hours at 25-35° C The mass was cooled to 0-5° C. filtered wash with water maintained the stirring for 30 minutes at reflux temperature The mass was cooled to 2-4° C. filtered washed with ethanol (50 mL) The wet product was dried under normal drying

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

Procedure: 100 mmol (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol in ethyl acetate were added onto 120 mmol of disuccimidylcarbonate (95%) in acetonitrile. Following, a solution of 140 mmol triethylamine in ethylacetate was added and stirred. The mixture was cooled and treated with a suspension of 92 mmol of 4-Amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-(isobutyl)benzene sulfonamide in ethyl acetate. 20 mmol methylamine, 41% aqueous solution in ethanol were added and the mixture was warmed. The reaction was washed twice with 10% Na2CO3-solution and with water. Solvent was evaporated and ethanol was added. Another portion of solvent was distilled off. The temperature was kept around 40-45° C. and crystallization was initiated by seeding. After stirring the mixture was cooled, stirred for another 90 min stirred, cooled and again stirred for 60 min. The precipitate was filtered and washed with ethanol. The wet product was dried in vacuo at 40° C. 43.5 g of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate were suspended in ethanol abs. and dissolved. The clear solution was cooled and seeding was applied. Crystallization occurred while cooling the mixture. Stirring was continued for another 60 min, followed by cooling, stirring and filtering off the product, which was washed with cold ethanol abs. The wet product was dried in vacuo at 40° C. Yield: 42.1 g=71%. The mixture was cooled the mixture was warmed The reaction was washed twice with 10% Na2CO3-solution and with water Solvent was evaporated ethanol was added Another portion of solvent was distilled off was kept around 40-45° C. crystallization After stirring the mixture was cooled stirred for another 90 min stirred cooled again stirred for 60 min The precipitate was filtered washed with ethanol The wet product was dried in vacuo at 40° C and dissolved The clear solution was cooled Crystallization while cooling the mixture Stirring by cooling stirring filtering off the product, which was washed with cold ethanol abs The wet product was dried in vacuo at 40° C

Conditions: temp:6.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The obtained solution was then cooled to 40±3° C. followed by the addition of water. Adjustment of the pH of the solution to around 9.5 with aqueous solution of sodium hydroxide gave crystals 4-Amino-N-(3-amino-2-hydroxy-4-phenyl-butyl)-N-isobutyl-benzenesulfonamide. Additional water was added to this solution to adjust the concentration of 4-Amino-N-(3-amino-2-hydroxy-4-phenyl-butyl)-N-isobutyl-benzenesulfonamide to 5.5-5.8 wt %, and then this solution was cooled to 6±4° C. The resulting crystals were filtered off and washed with a mixed solution composed of water and ethanol and then washed with water. The resulting wet crystals were subjected to vacuum drying to give the product of (2R,3S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-amino-benzenesulfonamide. Yields were 75˜85% based on (1-Benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl)-carbamic acid tert-butyl ester. The resulting crystals were filtered off washed with a mixed solution washed with water drying