叔-正丁基-[(2S)-1-羟丙烷-2-基]氨基甲酸酯

反应条件: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 120 ml of a ca 1.6 M solution of n-butyllithium in n-hexane was added with stirring during 15 min. to a solution of 17.5 g (S)-N-BOC-alaninol in 120 ml tetrahydrofuran at −78° C. The mixture was then stirred at −15° C. for 45 min. The mixture was then cooled to −78° C. and a solution of 7.3 mL thionyl chloride in 50 mL THF, cooled to −78° C. in a jacketed dropping funnel, was added at once with vigorous stirring. The temperature rose to ca −38° C. The mixture was then stirred at −15° C. for 1 h. The reaction mixture was distributed between 10% citric acid and ethyl acetate. The phases separated, the organic phase was washed with 10% sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The residue was taken up in 150 mL ethyl acetate and a solution of 35 g sodium metaperiodate was added at 0° C. 0.20 g ruthenium dioxide hydrate was added to the well stirred mixture. The mixture was stirred at room temperature for 1.5 h. The phases were separated. The organic phase was purified by chromatography on silica gel with ethyl acetate: hexane=2: 1 to yield 13.79 g (S)-4-Methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester as white crystals melting at 121.1-121.8° C. after recrystallisation from t-butylmethylether. The mixture was then cooled to −78° C. was added at once with vigorous stirring rose to ca −38° C The mixture was then stirred at −15° C. for 1 h The phases separated the organic phase was washed with 10% sodium bicarbonate and brine dried over magnesium sulfate evaporated a solution of 35 g sodium metaperiodate was added at 0° C 0.20 g ruthenium dioxide hydrate was added to the well stirred mixture The mixture was stirred at room temperature for 1.5 h The phases were separated The organic phase was purified by chromatography on silica gel with ethyl acetate

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cooled (0° C.), stirred solution of (S)-2-(N-tert-butoxycarbonylamino)-1-propanol (6.74 g, 0.04 mol), benzyl 4-hydroxybenzoate (8.78 g, 0.04 mol), and Ph3P (15.13 g, 0.06 mol) in THF (100 ml) was added DIAD (11.4 ml, 0.06 mol), and the reaction mixture was heated under reflux overnight. The solution was evaporated and the residue was dissolved in CH2Cl2 (30 ml) and TFA (30 ml). The solution was stirred at room temperature for 30 min. and the solution was concentrated in vacuo. The residue was dissolved in CHCl3, washed with sat. NaRCO3, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3 to CHCl3—MeOH (9:1, v/v) as eluent to give benzyl (S)-4-(2-amino-1-propoxy)benzoate (6.63 g, 2 steps, 60%) as a yellow oil. 1H-NMR (CDCl3) δ1.18 (d, J=6.3 Hz, 3 H), 3,35-3.39 (m, 1 H), 3.71-3.75 (m, 1 H), 3.90-3.93 (m, 1 H), 5.34 (s, 2 H), 6.90-6.93 (m, 2H), 7.32-7.46 (M, 5H), 8.01-8.04 (m, 2H). the reaction mixture was heated under reflux overnight The solution was evaporated the residue was dissolved in CH2Cl2 (30 ml) the solution was concentrated in vacuo The residue was dissolved in CHCl3 washed with sat. NaRCO3 dried over Na2SO4 evaporated The residue was purified by column chromatography on silica-gel with CHCl3 to CHCl3—MeOH (9:1

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred and cooled (0° C.) solution of (S)-2-(N-tert-butoxycarbonylamino)-1-propanol (6.74 g, 0.04 mol), benzyl 4-hydroxybenzoate (8.78 g, 0.04 mol), and Ph3P (15.13 g, 0.06 mol) in THF (100 mL) was added diisopropyl azodicarboxylate (DIAD) (11.4 mL, 0.06 mol), and the resulting mixture was heated under reflux overnight. The solution was evaporated and the residue was dissolved in CH2Cl2 (30 mL) and TFA (30 mL). The resulting solution was stirred at room temp for 30 min., and the solution was evaporated in vacuo. The residue was dissolved in CHCl3, washed with sat. NaHCO3, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3 to CHCl3:MeOH (9:1, v/v) as eluent to give 6.63 g (2 steps, 60%) benzyl (S)-4-(2-amino-1-propoxy)benzoate as a yellow oil. 1H-NMR (CDCl3) δ1.18 (d, J=6.3 Hz, 3 H), 3.35-3.39 (m, 1 H), 3.71-3.75 (m, 1 H), 3.90-3.93 (m, 1 H), 5.34 (s, 2 H), 6.90-6.93 (m, 2 H), 7.32-7.46 (m, 5 H), 8.01-8.04 (m, 2 H). the resulting mixture was heated under reflux overnight The solution was evaporated the residue was dissolved in CH2Cl2 (30 mL) The resulting solution was stirred at room temp for 30 min. the solution was evaporated in vacuo The residue was dissolved in CHCl3 washed with sat. NaHCO3 dried over Na2SO4 evaporated The residue was purified by column chromatography on silica-gel with CHCl3 to CHCl3:MeOH (9:1

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of (S)-2-(N-tert-butoxycarbonylamino)-1-propanol (0.90 g, 5.13 mmol), methyl 4-hydroxy-3-nitrobenzoate (1.01 g, 5.12 mmol), and Ph3P (1.75 g, 6.67 mmol) in THF (15 mL) was added diisopropyl azodicarboxylate (DIAD) (1.31 mL, 6.65 mmol) at room temp, and the resulting mixture was heated under reflux overnight. The solution was evaporated and the residue was dissolved in CH2Cl2 (20 mL) and TFA (10 mL). The mixture was stirred at room temp for 3 hr. The mixture was concentrated in vacuo. The residue was dissolved in CHCl3, washed with sat. NaHCO3, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with 5% MeOH in CHCl3 as eluent to give 313 mg (24%) methyl(S)-3-nitro-4-(2-amino-1-propoxy)benzoate as a pale yellow oil: 1H-NMR (CDCl3) δ1.22 (d, 3 H, J=6.8 Hz), 3.43-3.48 (m, 1 H), 3.69-3.87 (m, 2 H), 3.89 (x 3 H), 6.93-6.95 (m, 1H), 7.99-8.02 (m, 1 H), 8.18-8.21 (m, 1 H). the resulting mixture was heated under reflux overnight The solution was evaporated the residue was dissolved in CH2Cl2 (20 mL) The mixture was concentrated in vacuo The residue was dissolved in CHCl3 washed with sat. NaHCO3, brine dried over Na2SO4 evaporated The residue was purified by column chromatography on silica-gel with 5% MeOH in CHCl3 as eluent

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cooled (0° C.) solution of (S)-2-(N-tert-butoxycarbonylamino)-1-propanol (1.05 g, 5.99 mmol), methyl 3-chloro-4-hydroxybenzoate (1.12 g, 6.00 mmol), and PhP (2.36 g, 9.00 mmol) in THF (20 mL) was added diisopropyl azodicarboxylate (DIAD) (1.77 mL, 8.99 mmol), and the resulting mixture was heated under reflux for 2 days. The solution was evaporated off and the residue was dissolved in CH2Cl2 (20 mL) and TFA (10 mL). The resulting mixture was stirred at room temp for 1.5 hr. The solution was concentrated in vacuo, and the residue was dissolved in CHCl3. The mixture was extracted with H2O, and the aqueous layer was made basic by the addition of sat. NaHCO3. This basic aqueous layer was extracted with CHCl3. The extract was washed with brine, dried over Na2SO4 and evaporated to give 660 mg (2 steps, 32%) methyl (S)-3-chloro-4-(2-amino-1-propoxy)benzoate as a colorless oil. 1H-NMR (CDCl3) δ1.21 (d, 3 H, J=6.4 Hz), 3.41-3.48 (m, 1 H), 3.77-3.81 (m, 1 H), 3.89 (s, 3 H), 3.98-4.01 (m, 1 H), 6.91-6.94 (m, 1 H), 7.90-7.93 (m, 1 H), 8.05-8.06 (m, 1 H). the resulting mixture was heated under reflux for 2 days The solution was evaporated off the residue was dissolved in CH2Cl2 (20 mL) The solution was concentrated in vacuo the residue was dissolved in CHCl3 The mixture was extracted with H2O the aqueous layer was made basic by the addition of sat. NaHCO3 This basic aqueous layer was extracted with CHCl3 The extract was washed with brine dried over Na2SO4 evaporated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cooled (0° C.) solution of (S)-2-(N-tert-butoxycarbonylamino)-1-propanol (1.02 g, 5.82 mmol), methyl 4-hydroxybenzoate (0.89 g, 5.85 mmol), and Ph3P (1.98 g, 7.55 mmol) in THF (20 mL) was added diisopropyl azodicarboxylate (DIAD) (1.49 mL, 7.57 mmol), and the resulting mixture was heated under reflux overnight. The solution was evaporated and the residue was dissolved in CH2Cl2 (20 mL) and TFA (10 mL). The mixture was stirred at room temp for 1.5 hr. The solution was concentrated in vacuo and the residue was treated with sat. NaHCO3. The mixture was extracted with CHCl3, washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHC3:MeOH (50:1, v/v) to give 480 mg (2 steps 39%) methyl (S)-4-(2-amino-1-propoxy)benzoate as a pale yellow oil. 1H-NMR (CDCl3) δ1.19 (d, 3 H, J=6.4 Hz), 3.35-3.39 (m, 1 H), 3.72-3.76 (m, 1 H), 3.89 (s, 3 H), 3.90-3.94 (m, 1 H), 6.92 (d, 2 H, J=8.8 Hz), 7.99 (d, 2 H, J=8.8 Hz). the resulting mixture was heated under reflux overnight The solution was evaporated the residue was dissolved in CH2Cl2 (20 mL) The solution was concentrated in vacuo the residue was treated with sat. NaHCO3 The mixture was extracted with CHCl3 washed with brine dried over Na2SO4 evaporated The residue was purified by column chromatography on silica-gel with CHC3

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cooled (0° C.), stirred solution of (S)-2-(N-tert-butoxycarbonylamino)-1-propanol (6.74 g, 0.04 mol), benzyl 4-hydroxybenzoate (8.78 g, 0.04 mol), and Ph3P (15.13 g, 0.06 mol) in THF (100 ml) was added DIAD (11.4 ml, 0.06 mol), and the reaction mixture was heated under reflux overnight. The solution was evaporated and the residue was dissolved in CH2Cl2 (30 ml) and TFA (30 ml). The solution was stirred at room temperature for 30 min. and the solution was concentrated in vacuo. The residue was dissolved in CHCl3, washed with sat. NaHCO3, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3 to CHCl3-MeOH (9:1, v/v) as eluent to give benzyl (S)-4-(2-amino-1-propoxy)benzoate (6.63 g, 2 steps, 60%) as a yellow oil. 1H-NMR (CDCl3) δ 1.18 (d, J=6.3 Hz, 3 H), 3.35–3.39 (m, 1 H), 3.71–3.75 (m, 1 H), 3.90–3.93 (m, 1 H), 5.34 (s, 2 H), 6.90–6.93 (m, 2H), 7.32–7.46 (m, 5H), 8.01–8.04 (m, 2H). the reaction mixture was heated under reflux overnight The solution was evaporated the residue was dissolved in CH2Cl2 (30 ml) the solution was concentrated in vacuo The residue was dissolved in CHCl3 washed with sat. NaHCO3 dried over Na2SO4 evaporated The residue was purified by column chromatography on silica-gel with CHCl3 to CHCl3-MeOH (9:1

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of (S)-2-(N-tert-butoxycarbonylamino)-1-propanol (0.90 g, 5.13 mmol), methyl 4-hydroxy-3-nitrobenzoate (1.01 g, 5.12 mmol), and Ph3P (1.75 g, 6.67 mmol) in THF (15 mL) was added diisopropyl azodicarboxylate (DIAD) (1.31 mL, 6.65 mmol) at room temp, and the resulting mixture was heated under reflux overnight. The solution was evaporated and the residue was dissolved in CH2Cl2 (20 mL) and TFA (10 mL). The mixture was stirred at room temp for 3 hr. The mixture was concentrated in vacuo. The residue was dissolved in CHCl3, washed with sat. NaHCO3, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with 5% MeOH in CHCl3 as eluent to give 313 mg (24%) methyl(S)-3-nitro-4-(2-amino-1-propoxy)benzoate as a pale yellow oil. 1H-NMR (CDCl3) δ 1.22 (d, 3 H, J=6.8 Hz), 3.43–3.48 (m, 1 H), 3.69–3.87 (m, 2 H), 3.89 (s, 3 H), 6.93–6.95 (m, 1 H), 7.99–8.02 (m, 1 H), 8.18–8.21 (m, 1 H). the resulting mixture was heated under reflux overnight The solution was evaporated the residue was dissolved in CH2Cl2 (20 mL) The mixture was concentrated in vacuo The residue was dissolved in CHCl3 washed with sat. NaHCO3, brine dried over Na2SO4 evaporated The residue was purified by column chromatography on silica-gel with 5% MeOH in CHCl3 as eluent

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cooled (0° C.) solution of (S)-2-(N-tert-butoxycarbonylamino)-1-propanol (1.05 g, 5.99 mmol), methyl 3-chloro-4-hydroxybenzoate (1.12 g, 6.00 mmol), and Ph3P (2.36 g, 9.00 mmol) in THF (20 mL) was added diisopropyl azodicarboxylate (DIAD) (1.77 mL, 8.99 mmol), and the resulting mixture was heated under reflux for 2 days. The solution was evaporated off and the residue was dissolved in CH2Cl2 (20 mL) and TFA (10 mL). The resulting mixture was stirred at room temp for 1.5 hr. The solution was concentrated in vacuo, and the residue was dissolved in CHCl3. The mixture was extracted with H2O, and the aqueous layer was made basic by the addition of sat. NaHCO3. This basic aqueous layer was extracted with CHCl3. The extract was washed with brine, dried over Na2SO4 and evaporated to give 660 mg (2 steps, 32%) methyl (S)-3-chloro-4-(2-amino-1-propoxy)benzoate as a colorless oil. 1H-NMR (CDCl3) δ 1.21 (d, 3 H, J=6.4 Hz), 3.41–3.48 (m, 1 H), 3.77–3.81 (m, 1 H), 3.89 (s, 3 H), 3.98–4.01 (m, 1 H), 6.91–6.94 (m, 1 H), 7.90–7.93 (m, 1 H), 8.05–8.06 (m, 1 H). the resulting mixture was heated under reflux for 2 days The solution was evaporated off the residue was dissolved in CH2Cl2 (20 mL) The solution was concentrated in vacuo the residue was dissolved in CHCl3 The mixture was extracted with H2O the aqueous layer was made basic by the addition of sat. NaHCO3 This basic aqueous layer was extracted with CHCl3 The extract was washed with brine dried over Na2SO4 evaporated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (S)-(−)-2-(tert-Butoxycarbonylamino)-1-propanol (523 mg, 2.98 mmol, 1.0 equiv.) was dissolved in 45 mL methylene chloride in a 100 mL r.b. flask with a magnetic stir bar. To this clear homogeneous solution, Dess-Martin periodinane (1.523 g, 3.591 mmol, 1.2 equiv.) was added in one part and the cloudy white reaction mixture was allowed to stir at room temperature for 2 h. Thin-layer chromotography monitored the reaction to completion. The reaction mixture was diluted with 100 mL ethyl acetate. Sodium bisulfite solution (2 M, 20 mL) was added to the reaction mixture and the organic layer was separated. The aqueous layer was washed with 3×30 mL EtOAc. The combined organic layers were washed with 50 mL 1 M NaOH, followed by saturated NaCl (30 mL) and dried over MgSO4. Filtration and rotary evaporation produced the desired product as a yellow oil (475 mg, 92% yield, Rf=0.63, 1:1 hexanes/ethyl acetate). Step B: Preparation of [2-(4-methoxy-phenylamino)-(1S)-methyl-ethyl]-carbamic acid tert-butyl ester. (S)-2-(tert-Butoxycarbonylamino)-propionaldehyde (473 mg, 2.74 mmol) and p-anisidine (1.031 g, 8.371 mmol, 3.0 equiv.) was dissolved in 45 mL of MeOH at 0° C. in a 100 mL r.b. flask with a magnetic stir bar. Optionally, acetic acid (469 μL, 8.21 mmol, 3.0 equiv.) can be added via syringe to assist in the reaction. To the stirring dark colored solution was added sodium cyanoborohydride (326 mg, 5.82 mmol, 1.89 equiv.). Gas evolution and disappearance of color were observed. The reaction was allowed to slowly warm to room temperature with stirring over 30 minutes and the reaction was monitored by LC/MS. At the completion of the reaction, the mixture was quenched with 1 M NaOH, and extracted 3×50 mL ethyl acetate. The resulting organics were washed with 50 mL saturated NaHCO3, 40 mL saturated NaCl, and dried over MgSO4. Evaporation of ethyl acetate provided 728 mg of a brown oil. Purification by automated ISCO chromatography provided a clear oil of [2-(4-methoxy-phenylamino)-(1S)-methyl-ethyl]-carbamic acid tert-butyl ester (583 mg, 2.079 mmol, 76% yield). HPLC-MS calcd. for C15H24N2O3 (M+H+) 281.2. found 281.5. 1H NMR (CDCl3, 400 MHz) δ 1.21 (d, 6H, J=6.6 Hz), 1.47 (s, 9H), 3.05 (dd, 1H, J=12.2, 7.3 Hz), 3.13 (dd, 1H, J=12.2, 4.6 Hz), 3.76 (s, 3H), 3.93 (broad s, 1H), 4.62 (broad s, 1H), 6.60 (d, 2H, J=6.8 Hz), 6.80 (2H, d, J=6.8 Hz). Step C: [2-(4-Methoxy-phenylamino)-(1S)-methyl-ethyl]-carbamic acid tert-butyl ester (383 mg, 1.37 mmol) was added to 10 mL of a trifluroacetic acid solution (10 v/v % in methylene chloride) at room temperature in a 25 mL r.b. flask with a magnetic stirbar. The reaction turns dark purple/black in color after 5 minutes. The reaction is allowed to stir at room temperature until the reaction is judged complete by HPLC/MS. The solvent is removed by evaporation and to provide 2-(4-Methoxy-phenylamino)-(1S)-methyl-ethyl-ammonium trifluoroacetate salt as a brown oil (394 mg, 1.34 mmol, 98% yield) and used directly in the next reaction. HPLC-MS calcd. for C10H16N2O (M+H+) 181.1. found 181.5. the reaction to completion the organic layer was separated The aqueous layer was washed with 3×30 mL EtOAc The combined organic layers were washed with 50 mL 1 M NaOH dried over MgSO4 Filtration and rotary evaporation

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate 57 (4.03 g, 23.0 mmol), N-hydroxyphthalimide (5.63 g, 34.5 mmol) and triphenylphosphine (9.05 g, 34.5 mmol) in anhydrous THF (172 mL) at 0° C. under nitrogen was added DIAD (6.69 mL, 34.5 mmol) in anhydrous THF (40 mL) over 15 minutes. The mixture was stirred at 0° C. for 30 min and at room temperature for 2.5 h. Solvent was evaporated off and the residue was subjected to chromatography to give a white solid 58 (7.38 g). Solvent was evaporated off

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Diethylazodicarboxylate (349 μL, 2.22 mmol) in THF (1 mL) was added slowly to a solution of 2,6-difluoro-3-nitrophenol (260 mg, 1.48 mmol), ((S)-2-hydroxy-1-methylethyl)carbamic acid tert-butyl ester (312 mg, 1.78 mmol) and triphenylphosphine (582 mg, 2.22 mmol) in THF (10 mL) at 0° C. The solution was stirred for 30 min at 0° C., and then concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, gradient 0-30% EtOAc in cyclohexane) to afford the title compound as a pale yellow oil (340 mg, 69%). 1H NMR (CDCl3, 300 MHz): δ 7.82 (1H, ddd, J=13.0, 9.5, 5.3 Hz), 7.04 (1H, app. td, J=9.4, 2.1 Hz), 4.75 (1H, br s), 4.24-4.12 (2H, m), 4.00 (1H, br s), 1.44 (9H, s), 1.34 (3H, d, J=6.9 Hz) concentrated in vacuo The residue was purified by flash chromatography (Si—PPC, gradient 0-30% EtOAc in cyclohexane)