tert-butyl N-[(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiran-2-yl]ethyl]carbamate

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

Procedure: tert-Butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiran-2-yl]ethylcarbamate (2.0 g, 6.7 mmol) and 3-isopropylbenzylamine hydrochloride (2.5 g, 13.5 mmol) in isopropanol (60 mL) are refluxed 3 h. The reaction is cooled and stirred 16 h. The solution is concentrated under reduced pressure, redissolved in chloroform, washed with 1N hydrochloric acid, saturated sodium bicarbonate, brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. Purification by flash chromatography (silica, 7% methanol/chloroform) gives the title compound in pure form. ESI MS m/z 449.3 [M+H]+. The reaction is cooled The solution is concentrated under reduced pressure redissolved in chloroform washed with 1N hydrochloric acid, saturated sodium bicarbonate, brine dried (sodium sulfate) filtered concentrated under reduced pressure Purification by flash chromatography (silica, 7% methanol/chloroform)

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

Procedure: N1-Isobutyl-L-alaninamide (3.8 g, 26 mmol) and tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiran-2-yl]ethylcarbamate prepared by the method in EXAMPLE S-3 (3.1 g, 10.4 mmol) in isopropanol (50 mL) are refluxed 4 h. The reaction is cooled and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/chloroform) gives the title compound. ESI MS m/z 444.1 [M+H]+. are refluxed 4 h The reaction is cooled concentrated under reduced pressure Purification by flash column chromatography (silica, 8% methanol/chloroform)

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

Procedure: Following the general procedure of EXAMPLEs 4 and 14–164 and making non-critical variations and reacting tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE 3) with (2S)-2-amino-N-ethylpropanamide (VI), the title compound is obtained.

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

Procedure: Sodium azide (0.22 g, 4 mmole) and ammonium chloride (2 eq) are added to tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE 3, 0.6 g, 2 mmole). The reaction is heated to 75–80 degrees C. and stirred for 16 hours. The reaction is monitored by TLC to insure completion. The solvent is removed under reduced pressure. The concentrate is partitioned between ethyl acetate and water, the phases are separated and the organic phase is washed with bicarbonate and saline, dried over anhydrous sodium sulfate and concentrated to give the title compound, TLC (ethyl acetate/hexane) Rf=0.45; (MH+)=343. The reaction is heated to 75–80 degrees C The solvent is removed under reduced pressure The concentrate is partitioned between ethyl acetate and water the phases are separated the organic phase is washed with bicarbonate and saline dried over anhydrous sodium sulfate concentrated

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE 3, 245 mg, 0.82 mmol) is suspended in isopropyl alcohol (6 mL) and 3-methoxybenzylamine (160 microL, 1.22 mmol) is added with stirring at 20–25 degrees C. This mixture is heated to gentle reflux (bath temp 85 degrees C.) under nitrogen for 2 hours, whereupon the resulting mixture is concentrated under reduced pressure to give the title compound. The title compound is purified by flash chromatography (2–5% methanol/methylene chloride; gradient elution) to give purified title compound. This mixture is heated whereupon the resulting mixture is concentrated under reduced pressure

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

Procedure: tert-Butyl (1S,2S)-3-bromo-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate (IV, EXAMPLE 2) is dissolved in absolute alcohol (150 mL) and ethyl acetate (100 mL) and potassium hydroxide (2.3 g, 34.9 mmole, 1.1 eq.) in ethyl alcohol (85%, 5 mL) is added at −20 degrees C. The cold bath is then removed and the mixture stirred for 0.5 hour. The reaction is monitored by TLC (ethyl acetate/hexane, 20/80). When the reaction is complete, it is diluted with dichloromethane and extracted, washed with water, saline, dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The crude material is purified by flash chromatography on silica gel to give the title compound, TLC (ethyl acetate/hexane, 20/80) Rf=0.3; MS (MH+)=300.4. The cold bath is then removed it is diluted with dichloromethane extracted washed with water, saline dried over anhydrous sodium sulfate the solvent removed under reduced pressure The crude material is purified by flash chromatography on silica gel

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

Procedure: An isopropyl alcohol (25 ml) solution of tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiran-2-yl]ethylcarbamate (2.2 g, 7.2 mmol) and 6-Iodo-chroman-4-ylamine (3.0 g, 10.9 mmol) was stirred at 75° C. for 0 h. The IPA was removed in vacuo and the resulting residue dissolved in EtOAc (200 ml). The organic layer was washed with 1 N HCl (4×50 ml), followed by NaHCO3 (2×50 ml), and brine (1×50 ml). The organic layer was dried over Na2SO4 and concentrated in vacuo to yield 3.5 g (85%) of the title compound as an off white solid. MS (ESI+) for C24H29F2IN2O4 m/z 574.8 (M+H)+. The IPA was removed in vacuo the resulting residue dissolved in EtOAc (200 ml) The organic layer was washed with 1 N HCl (4×50 ml) The organic layer was dried over Na2SO4 concentrated in vacuo

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

Procedure: An isopropyl alcohol (25 ml) solution of tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiran-2-yl]ethylcarbamate (2.2 g, 7.2 mmol) and 6-Iodo-chroman-4-ylamine (3.0 g, 10.9 mmol) was stirred at 75° C. for 0 h. The IPA was removed in vacuo and the resulting residue dissolved in EtOAc (200 ml). The organic layer was washed with 1 N HCl (4×50 ml), followed by NaHCO3 (2×50 ml), and brine (1×50 ml). The organic layer was dried over Na2SO4 and concentrated in vacuo to yield 3.5 g (85%) of the title compound as an off white solid. MS (ESI+) for C24H29F2IN2O4 m/z 574.8 (M+H)+. The IPA was removed in vacuo the resulting residue dissolved in EtOAc (200 ml) The organic layer was washed with 1 N HCl (4×50 ml) The organic layer was dried over Na2SO4 concentrated in vacuo

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

Procedure: A mixture of tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiran-2-yl]ethylcarbamate (1.0 g, 3.3 mmol) and 3-methoxybenzylamine (1.8 g, 13.3 mmol) in isopropyl alcohol (30 ml) was stirred at room temperature for 6.5 h. The reaction mixture was diluted with EtOAc (100 ml) and washed with 1 N HCl (3×30 ml), sat'd aq. NaHCO3 (1×50 ml) and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield an off white solid. The residue was dissolved in THF (20 ml) and chilled to 0° C. followed by the addition of Et3N (0.6 ml, 4.4 mmol) and benzylchloroformate (0.5 ml, 3.6 mmol). The reaction mixture was warmed spontaneously for 3 h. The reaction mixture was diluted with EtOAc, washed with 1N HCl, NaHCO3, and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. Flash chromatography 30% EtOAC/Heptanes yields 1.3 g (70%) of [3-tert-butoxycarbonylamino-4-(3,5-difluoro-phenyl)-2-hydroxy-butyl]-(3-methoxybenzyl)-carbamic acid benzyl ester. MS (ESI+) for C31H36F2N2O6 m/z 570.8 (M+H)+. washed with 1 N HCl (3×30 ml) The organic layer was dried over Na2SO4 concentrated in vacuo to yield an off white solid chilled to 0° C. The reaction mixture was warmed spontaneously for 3 h washed with 1N HCl, NaHCO3, and brine The organic layer was dried over Na2SO4 concentrated in vacuo

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

Procedure: tert-Butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, PREPARATION 3, 1.75 g, 5.8 mmole) is mixed with isopropanol (30 ml). The reaction flask is charged with 3-iodobenzylamine (VI). The reaction mixture is heated to reflux for 45 minutes, HPLC analysis indicates complete disappearance of the epoxide (V). The reaction mixture is concentrated under reduced pressure and the residue is partitioned between ethyl acetate (150 ml) and aqueous hydrochloric acid (3%, 35 ml). The organic phase is separated and washed with aqueous hydrochloric acid (3%, 20 ml), bicarbonate, saline and dried over sodium sulfate. Concentration under reduced pressure gives the title compound, M+H=535. The reaction mixture is heated to reflux for 45 minutes The reaction mixture is concentrated under reduced pressure the residue is partitioned between ethyl acetate (150 ml) and aqueous hydrochloric acid (3%, 35 ml) The organic phase is separated washed with aqueous hydrochloric acid (3%, 20 ml), bicarbonate, saline dried over sodium sulfate Concentration under reduced pressure

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

Procedure: tert-Butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, PREPARATION 3, 1.75 g, 5.8 mmole) is mixed with isopropanol (30 ml). The reaction flask is charged with 3-iodobenzylamine (VI). The reaction mixture is heated to reflux for 45 minutes, HPLC analysis indicates complete disappearance of the epoxide (V). The reaction mixture is concentrated under reduced pressure and the residue is partitioned between ethyl acetate (150 ml) and aqueous hydrochloric acid (3%, 35 ml). The organic phase is separated and washed with aqueous hydrochloric acid (3%, 20 ml), bicarbonate, saline and dried over sodium sulfate. Concentration under reduced pressure gives the title compound, M+H=535. The reaction mixture is heated to reflux for 45 minutes The reaction mixture is concentrated under reduced pressure the residue is partitioned between ethyl acetate (150 ml) and aqueous hydrochloric acid (3%, 35 ml) The organic phase is separated washed with aqueous hydrochloric acid (3%, 20 ml), bicarbonate, saline dried over sodium sulfate Concentration under reduced pressure

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

Procedure: tert-Butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, PREPARATION 3, 245 mg, 0.82 mmol) is suspended in isopropyl alcohol (6 mL) and 3-methoxybenzylamine (160 μL, 1.22 mmol) is added with stirring at 20–25°. This mixture is heated to gentle reflux (bath temp 85°) under nitrogen for 2 hr, whereupon the resulting mixture is concentrated under reduced pressure to give the title compound. The title compound is purified by flash chromatography (2–5% methanol/methylene chloride; gradient elution) to give purified title compound. This mixture is heated to gentle reflux (bath temp 85°) under nitrogen for 2 hr whereupon the resulting mixture is concentrated under reduced pressure