tert-butyl N-[(1S)-1-[(2S)-oxiran-2-yl]-2-phenylethyl]carbamate

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane obtained in the same manner as in Reference Example 2 (2.75 g) was added ethanol (27.5 ml). 6.8% Aqueous citric acid solution (29.5 g) was then added thereto, and the mixture was stirred at 70° C. for 2 hr. After cooling to room temperature, ethanol was removed under reduced pressure. The residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Further, a mixed solvent of hexane (2.5 ml) and ethyl acetate (2.5 ml) was added to allow precipitation of the crystals. The crystals were collected by filtration and washed twice with a mixed solvent of hexane/ethyl acetate (1/1). The obtained crystals were dried to give the objective (4S,5R)-4-benzyl-5-hydroxymethyloxazolidin-2-one (1.79 g) in a yield of 80%. After cooling to room temperature ethanol was removed under reduced pressure The residue was extracted with ethyl acetate dried over anhydrous sodium sulfate concentrated under reduced pressure Further, a mixed solvent of hexane (2.5 ml) and ethyl acetate (2.5 ml) was added precipitation of the crystals The crystals were collected by filtration washed twice with a mixed solvent of hexane/ethyl acetate (1/1) The obtained crystals were dried

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

Procedure: A stirred mixture of tert-butyl (1S)-1-[(2S)-oxiranyl]-2-phenylethylcarbamate (V, 247 mg, 0.939 mmol), sodium carbonate (299 mg, 2.82 mmol), and 3-(2,4-dimethylphenyl)propylamine (VI, 628 mg, 2.82 mmol) is heated at reflux overnight. The reaction mixture is cooled to 20–25 degrees C. and concentrated under reduced pressure. Purification by flash column chromatography (silica; methylene chloride/methanol/ammonium hydroxide, 98/2/1) gives tert-butyl (1S,2R)-1-benzyl-3-{[3-(2,4-dimethylphenyl)propyl]amino}-2-hydroxypropylcarbamate (VII), NMR (300 MHz, CD3OD): δ 7.22–7.16, 3.81, 3.18, 2.77, 2.54, 2.15, 2.13, 1.89 and 1.23. is heated at reflux overnight The reaction mixture is cooled to 20–25 degrees C and concentrated under reduced pressure Purification by flash column chromatography (silica; methylene chloride/methanol/ammonium hydroxide, 98/2/1)

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Propanol (2.4 ml) was added to (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (300 mg). After cooling to 4° C., 4 mol/l aqueous sodium hydroxide solution (0.375 ml) and water (0.225 ml) were added to the obtained mixture, and they were stirred at 4° C. for 7 hours. 13.7% aqueous citric acid solution (695 mg) was added to the reaction mixture. After the extraction with tert-butyl methyl ether, the obtained organic layer was washed with water and analyzed by HPLC to find that intended (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (230 mg)was obtained in an yield of 87%. After the extraction with tert-butyl methyl ether the obtained organic layer was washed with water was obtained in an yield of 87%

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

Procedure: A mixture of (4S)-6-bromo-2-methyl-2-(trifluoromethyl)chroman-4-amine (179 mg, 577 μmol) and tert-butyl(S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (198 mg, 750 μmol) in ethanol was heated at reflux for 16 h. At this point, there was still the starting amine left. An additional 1.3 eq of epoxide was added to the reaction, and continued to reflux for 6 h. The resulted mixture was concentrated and purified on Shimadzu HPLC to afford the title compound as a TFA salt. MS m/z: 573, 575. was heated at reflux for 16 h left to reflux for 6 h The resulted mixture was concentrated purified on Shimadzu HPLC

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

Procedure: ((S)-(S)-1-Oxiranyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (D101) (10 g, 38 mmol, 1 equiv) [Chirex 1819W94 Lot#9924382] was dissolved in EtOH (100 ml) and cyclohexylamine (13 ml, 114 mmol, 3 equiv) was added. The resulting mixture was heated, under an atmosphere of nitrogen, for 12 h at reflux temperature. The mixture was cooled and the solvent was removed by evaporation in vacuo. The resulting white solid was washed with H2O and then with Et2O before drying in vacuo to give ((1S,2R)-1-benzyl-3-cyclohexylamino-2-hydroxy-propyl)-carbamic acid tert-butyl ester (H1) (9.0 g, 66%). [M+H]+=363.2 The resulting mixture was heated, under an atmosphere of nitrogen, for 12 h at reflux temperature The mixture was cooled the solvent was removed by evaporation in vacuo The resulting white solid was washed with H2O with Et2O before drying in vacuo

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

Procedure: To a solution of ((S)-(S)-1-oxiranyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (D101) (25 g, 95.1 mmol, 1 equiv)) in MeOH (350 ml) was added aqueous ammonia (32% w/w, 180 ml, 3.2 mol, 3.3 equiv). The resulting mixture was stirred at room temperature for 16 h then concentrated in vacuo to give ((1S,2R)-3-amino-1-benzyl-2-hydroxy-propyl)-carbamic acid tert-butyl ester (D102) (25.2 g, 95%) as a white solid. then concentrated in vacuo

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

Procedure: Into a 100 mL flask was placed (5) (1.0 g, 3.34 mmol), (6) (2S,3S)-1,2-epoxy-3-(Boc-amino)-4-phenylbutane (2.78 g, 10.5 mmol, 3.16 equivalents), and 2-propanol (15 mL). The reaction was heated to reflux. After approximately 61 hours of refluxing, the heat was removed, and the mixture cooled to room temperature. To the cooled mixture was added water/ice (50 mL). To the aqueous mixture was added dichloromethane (50 mL) and then transferred to a separatory funnel. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organics were washed with water, then saturated sodium chloride, and then dried over sodium sulfate. The dried organic solution was filtered, and the filtrate was concentrated under reduced pressure, and then dried under high vacuum overnight. The yellow foam was purified by Biotage chromatography (40+M cartridge; 0 to 5% methanol/dichloromethane over 25 CV) to give 1.24 g (66%) of (7) as a white solid. TLC Rf (hexane/ethyl acetate, 1:2)=0.45; 1H NMR (CD3OD) δ 8.60 (d, 1H), 7.88 (m 4H), 7.50 (d, 2H), 7.36 (m, 1H), 7.25 (m, 4H), 7.18 (m, 1H), 3.93 (m, 2H), 3.70 (m, 2H), 3.0-2.6 (m, 4H), 1.33 (s, 9H), 1.30 (s, 9H); MS (M)+=563; HPLC tR 9.6 minutes. Into a 100 mL flask was placed The reaction was heated to reflux After approximately 61 hours of refluxing the heat was removed To the cooled mixture was added water/ice (50 mL) To the aqueous mixture was added dichloromethane (50 mL) transferred to a separatory funnel The aqueous layer was extracted with dichloromethane (3×50 mL) The combined organics were washed with water saturated sodium chloride, and then dried over sodium sulfate The dried organic solution was filtered the filtrate was concentrated under reduced pressure dried under high vacuum overnight The yellow foam was purified by Biotage chromatography (40+M cartridge; 0 to 5% methanol/dichloromethane over 25 CV)

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

Procedure: Into a 100 mL flask was placed (5) (1.0 g, 3.34 mmol), (6) (2S,3S)-1,2-epoxy-3-(Boc-amino)-4-phenylbutane (2.78 g, 10.5 mmol, 3.16 equivalents), and 2-propanol (15 mL). The reaction was heated to reflux. After approximately 61 hours of refluxing, the heat was removed, and the mixture cooled to room temperature. To the cooled mixture was added water/ice (50 mL). To the aqueous mixture was added dichloromethane (50 mL) and then transferred to a separatory funnel. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organics were washed with water, then saturated sodium chloride, and then dried over sodium sulfate. The dried organic solution was filtered, and the filtrate was concentrated under reduced pressure, and then dried under high vacuum overnight. The yellow foam was purified by Biotage chromatography (40+M cartridge; 0 to 5% methanol/dichloromethane over 25 CV) to give 1.24 g (66%) of (7) as a white solid. TLC Rf (hexane/ethyl acetate, 1:2)=0.45; 1H NMR (CD3OD) δ 8.60 (d, 1H), 7.88 (m 4H), 7.50 (d, 2H), 7.36 (m, 1H), 7.25 (m, 4H), 7.18 (m, 1H), 3.93 (m, 2H), 3.70 (m, 2H), 3.0-2.6 (m, 4H), 1.33 (s, 9H), 1.30 (s, 9H); MS (M)+=563; HPLC tR 9.6 minutes. Into a 100 mL flask was placed The reaction was heated to reflux After approximately 61 hours of refluxing the heat was removed To the cooled mixture was added water/ice (50 mL) To the aqueous mixture was added dichloromethane (50 mL) transferred to a separatory funnel The aqueous layer was extracted with dichloromethane (3×50 mL) The combined organics were washed with water saturated sodium chloride, and then dried over sodium sulfate The dried organic solution was filtered the filtrate was concentrated under reduced pressure dried under high vacuum overnight The yellow foam was purified by Biotage chromatography (40+M cartridge; 0 to 5% methanol/dichloromethane over 25 CV)

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

Procedure: Step BK (3): The product from Step BK (2) was reacted with tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (271 mg, 1.03 mmol) following a procedure analogous to Step AW (1) to afford 415 mg (86% yield) of tert-butyl (2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methyl-2,3-dihydro-1H-inden-1-ylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate. LC-MS (M+H)+=467.29; 1H NMR (500 MHz, CDCl3) δ ppm 7.39-7.16 (m, 7H) 5.93-5.87 (m, 1H) 5.33-4.60 (m, 8H) 4.08 (d, 2H) 3.94 (m, 1H) 3.62 (m, 1H) 3.46 (d, 1H) 3.10-3.06 (m, 2H) 3.6 (m, 1H) 2.59-2.54 (m, 2H) 2.37 (s, 3H) 1.25 (s, 9H).

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

Procedure: Step BK (3): The product from Step BK (2) was reacted with tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (271 mg, 1.03 mmol) following a procedure analogous to Step AW (1) to afford 415 mg (86% yield) of tert-butyl (2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methyl-2,3-dihydro-1H-inden-1-ylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate. LC-MS (M+H)+=467.29; 1H NMR (500 MHz, CDCl3) δ ppm 7.39-7.16 (m, 7H) 5.93-5.87 (m, 1H) 5.33-4.60 (m, 8H) 4.08 (d, 2H) 3.94 (m, 1H) 3.62 (m, 1H) 3.46 (d, 1H) 3.10-3.06 (m, 2H) 3.6 (m, 1H) 2.59-2.54 (m, 2H) 2.37 (s, 3H) 1.25 (s, 9H).

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

Procedure: Step BD (1). (1S,3R)-3-(Allyloxy)-6-bromo-2,3-dihydro-1H-inden-1-amine from Step Z(1) was reacted with tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (Aldrich) according to the procedures described in Step V (1) to afford, after purification, 275 mg (82% yield) of tert-butyl (2S,3R)-4-((1S,3R)-3-(allyloxy)-6-bromo-2,3-dihydro-1H-inden-1-ylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate. MS (M+H)+ 531.43. 1H NMR (500 MHz, CDCl3) δ ppm 1.36 (s, 9H) 1.82 (ddd, J=12.67, 6.26, 6.10 Hz, 1H) 2.69-2.79 (m, 3H) 2.87 (dd, J=13.89, 8.09 Hz, 1H) 3.03 (dd, J=14.04, 4.58 Hz, 1H) 3.38-3.46 (m, 1H) 3.79 (s, 1H) 4.01-4.05 (m, 2H) 4.06-4.15 (m, 2H) 4.54 (d, J=9.16 Hz, 1H) 4.75 (t, J=6.10 Hz, 1H) 5.19 (dd, J=10.38, 1.53 Hz, 1H) 5.31 (ddd, J=17.24, 3.20, 1.53 Hz, 1H) 5.94 (ddd, J=22.74, 10.53, 5.49 Hz, 1H) 7.18-7.32 (m, 7H) 7.40 (d, J=8.24 Hz, 1H) 7.50 (s, 1H). to afford

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Step AS (5). A mixture of 2-allyloxy-5-methoxybenzylamine (375 mg, 1.94 mmol), (2S,3S)-1,2-epoxy-3-(BOC-amino)-4-phenylbutane (818 mg, 3.1 mmol), and lithium perchlorate (514 mg, 4.85 mmol) in acetonitrile (6 mL) was stirred at 60° C. for 2.5 h. The reaction was concentrated and the residue was purified by silica gel chromatography, eluting with a mixture of 5% 2N ammonia in methanol and 95% EtOAc to yield 0.8 g of tert-butyl (2S,3R)-4-(2-(allyloxy)-5-methoxybenzylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate. The BOC-protected amine was dissolved in 10 mL 10% TFA/DCM and stirred at rt for 3 h. The reaction was concentrated under vacuum and the residue purified by reverse phase prep-HPLC to yield the titled compound as the ditrifluoroacetic acid salt (440 mg, 39%). LC-MS (M+H)+=357; 1H NMR (400 MHz, CD3OD) δ 7.30 (m, 5H) 7.00 (m, 3H) 6.10 (m, 1H) 5.40 (m, 1H) 5.30 (m, 1H) 4.61 (m, 2H) 4.22 (m, 3H) 3.76 (s, 3H) 3.66 (m, 1H) 3.18 (m, 1H) 2.90 (m, 3H). The reaction was concentrated the residue was purified by silica gel chromatography eluting with a mixture of 5% 2N ammonia in methanol and 95% EtOAc