(R)-(+)-2-氨基-3-苄氧基-1-丙醇

反应条件: temp:78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (R)-2-amino-3-benzyloxy-1-propanol (698.4 g, 3.931 mol) in EtOH (3.6 L) was added Et3N (1.27 L, 9.11 mol) in portions over 10 min. Then a solution of 2-chloro-6-methoxy-3-nitropyridine (672.7 g, 3.567 mol) in EtOH (0.6 L) was added in portions over 10 min. The mixture was heated at 78° C. for 2 h. The reaction mixture was cooled to room temperature and added to stirred ice/H2O (8.4 L). The mixture was extracted with EtOAc (9+6+3 L). The extracts were washed with brine (6 L), dried over MgSO4 (˜900 g), filtered and evaporated to give (2R)-2-{[6-(methyloxy)-3-nitro-2-pyridinyl]amino}-3-[(phenylmethyl)oxy]-1-propanol (1373.1 g, 115%) as an orange oil. The reaction mixture was cooled to room temperature added The mixture was extracted with EtOAc (9+6+3 L) The extracts were washed with brine (6 L) dried over MgSO4 (˜900 g) filtered evaporated

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

实验步骤: A solution of (R)-2-amino-3-benzyloxy-1-propanol (5 g, 27.6 mmol) in CH2Cl2 (250 mL) was treated with allyl chloroformate (3.2 mL, 30 mmol) and saturated aqueous NaHCO3 (250 mL) for 18 h. The organic layer was separated and concentrated in vacuo. Purification by chromatography eluting with 30% EtOAc/hexanes afforded 6.9 g (94%) of (R)-2-(allyloxycarbonylamino)-3-benzyloxy-1-propanol as an amorphous solid: 1H NMR (CDCl3) δ 2.56 (br s, 1H), 3.69 (m, 3H), 3 88 (m, 2H), 4.54 (s, 2H), 4.58 (d, 2H, J=5.6 Hz), 5.23 (dd, 1H, J=10.4, 1.1 Hz), 5.33 (dd, 1H, J=17.1, 1.1 Hz), 5.42 (m, 1H), 5.93 (m, 1H), 7.35 (m, 5H). The organic layer was separated concentrated in vacuo Purification by chromatography eluting with 30% EtOAc/hexanes

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

实验步骤: A solution of (R)-2-amino-3-benzyloxy-1-propanol (0.46 g, 2.33 mmol) and (R)-3-tetradecanoyloxytetradecanoic acid (1.29 g, 2.83 mmol) in CH2Cl2 (20 mL) was treated with EDC·MeI (0.78 g, 2.79 mmol) and stirred for 16 h at room temperature. The reaction mixture was filtered through a short pad of Celite® and concentrated. Flash chromatography on silica gel with 45% EtOAc-hexanes afforded 1.1 g (69%) of 3-benzyloxy-(R)-2-[(R)-3-tetradecanoyloxytetradecanoylamino]propanol as a colorless solid: mp 42-44.5° C.; 1H NMR δ 0.88 (t, 6H, J=6.5 Hz), 1.0-1.7 (m, 42 H), 2.50 (t, 2H, J=7.5 Hz), 2.46 (m, 2H), 3.56 (br s, 1H), 3.5-3.75 (m, 3H), 3.78 (dd, 1H, J=11, 4 Hz), 4.08 (m, 1H), 4.51 (s, 2H), 5.17 (m, 1H), 6.36 (d, 1H, J=7.8 Hz), 7.2-7.4 (m, 5H). The reaction mixture was filtered through a short pad of Celite® concentrated

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

实验步骤: A solution of (R)-2-amino-3-benzyloxy-1-propanol (5 g, 27.6 mmol) in CH2Cl2 (250 mL) was treated with allyl chloroformate (3.2 mL, 30 mmol) and saturated aqueous NaHCO3 (250 mL) for 18 h. The organic layer was separated and concentrated in vacuo. Purification by chromatography eluting with 30% EtOAc/hexanes afforded 6.9 g (94%) of (R)-2-(allyloxycarbonylamino)-3-benzyloxy-1-propanol as an amorphous solid: 1H NMR (CDCl3) δ 2.56 (br s, 1 H), 3.69 (m, 3 H), 3 88 (m, 2 H), 4.54 (s, 2 H), 4.58 (d, 2 H, J=5.6 Hz), 5.23 (dd, 1 H, J=10.4, 1.1 Hz), 5.33 (dd, 1 H, J=17.1, 1.1 Hz), 5.42 (m, 1 H), 5.93 (m, 1 H), 7.35 (m, 5 H). The organic layer was separated concentrated in vacuo Purification by chromatography eluting with 30% EtOAc/hexanes

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

实验步骤: A solution of (R)-2-amino-3-benzyloxy-1-propanol (5 g, 27.6 mmol) in CH2Cl2 (250 mL) was treated with allyl chloroformate (3.2 mL, 30 mmol) and saturated aqueous NaHCO3 (250 mL) for 18 h. The organic layer was separated and concentrated in vacuo. Purification by chromatography eluting with 30% EtOAc/hexanes afforded 6.9 g (94%) of (R)-2-(allyloxycarbonylamino)-3-benzyloxy-1-propanol as an amorphous solid: 1H NMR (CDCl3) δ 2.56 (br s, 1 H), 3.69 (m, 3 H), 3 88 (m, 2 H), 4.54 (s, 2 H), 4.58 (d, 2 H, J=5.6 Hz), 5.23 (dd, 1 H, J=10.4, 1.1 Hz), 5.33 (dd, 1 H, J=17.1, 1.1 Hz), 5.42 (m, 1 H), 5.93 (m, 1 H), 7.35 (m, 5 H). The organic layer was separated concentrated in vacuo Purification by chromatography eluting with 30% EtOAc/hexanes

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

实验步骤: A solution of (R)-2-amino-3-benzyloxy-1-propanol (0.46 g, 2.33 mmol) and (R)-3-tetradecanoyloxytetradecanoic acid (1.29 g, 2.83 mmol) in CH2Cl2 (20 mL) was treated with EDC.MeI (0.78 g, 2.79 mmol) and stirred for 16 h at room temperature. The reaction mixture was filtered through a short pad of Celite® and concentrated. Flash chromatography on silica gel with 45% EtOAc-hexanes afforded 1.1 g (69%) of 3-benzyloxy-(R)-2-[(R)-3-tetradecanoyloxytetradecanoylamino]propanol as a colorless solid: mp 42-44.5° C.; 1H NMR δ 0.88 (t, 6 H, J=˜6.5 Hz), 1.0-1.7 (m, 42 H), 2.50 (t, 2 H, J=7.5 Hz), 2.46 (m, 2 H), 3.56 (br s, 1 H), 3.5-3.75 (m, 3 H), 3.78 (dd, 1 H, J=11, 4 Hz), 4.08 (m, 1 H), 4.51 (s, 2 H), 5.17 (m, 1 H), 6.36 (d, 1 H, J=7.8 Hz), 7.2-7.4 (m, 5 H). The reaction mixture was filtered through a short pad of Celite® concentrated

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

实验步骤: A solution of (R)-2-amino-3-benzyloxy-1-propanol (0.46 g, 2.33 mmol) and (R)-3-tetradecanoyloxytetradecanoic acid (1.29 g, 2.83 mmol) in CH2Cl2 (20 mL) was treated with EDC.MeI (0.78 g, 2.79 mmol) and stirred for 16 h at room temperature. The reaction mixture was filtered through a short pad of Celite® and concentrated. Flash chromatography on silica gel with 45% EtOAc-hexanes afforded 1.1 g (69%) of 3-benzyloxy-(R)-2-[(R)-3-tetradecanoyloxytetradecanoylamino]propanol as a colorless solid: mp 42-44.5° C.; 1H NMR δ 0.88 (t, 6 H, J=˜6.5 Hz), 1.0-1.7 (m, 42 H), 2.50 (t, 2 H, J=7.5 Hz), 2.46 (m, 2 H), 3.56 (br s, 1 H), 3.5-3.75 (m, 3 H), 3.78 (dd, 1 H, J=11, 4 Hz), 4.08 (m, 1 H), 4.51 (s, 2 H), 5.17 (m, 1 H), 6.36 (d, 1 H, J=7.8 Hz), 7.2-7.4 (m, 5 H). The reaction mixture was filtered through a short pad of Celite® concentrated

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

实验步骤: A mixture of O-(phenylmethyl)-L-serine (commercial product) (139.0 g; 0.712 mol) and NaBH4 (96%; 75 g; 1.9 mol) in dry THF (700 mL, distilled on sodium/benzophenone), under N2 atmosphere, was slowly added (1.5 hours) with a solution of I2 (181.0 g; 0.713 mol) in dry THF (350 mL) at a temperature of 0 to 15° C. When the addition was completed and the dark color had disappeared, the mixture was refluxed for 18 hours, then cooled at 0° C. and the NaBH4 excess was destroyed with cold water (30 mL), followed by 15N KOH (320 mL). When bubble evolution was no longer observed, the mixture was heated, distilling most of the organic solvent (THF). The aqueous mixture was refluxed for 6 hours, then stirred at r.t. for a further 18 hours. CHCl3 (700 mL) and Et2O (300 mL) were added thereto under strong stirring; after 15 minutes the diphasic mixture was filtered through Celite® and the separated solid was repeatedly washed with CHCl3/Et2O 3:1 (4 L). The filtered solution was concentrated, removing water by repeated azeotropical distillations with CH3CN. The crude oil (130 g) was purified twice by flash chromatography (CH2Cl2/CH3OH/NH4OH 25% (w/w) 54:40:6 to 90:9:1), thereby obtaining the desired compound (92.63 g; 0.511 mol). Yield: 72%. When the addition the mixture was refluxed for 18 hours the NaBH4 excess was destroyed with cold water (30 mL) When bubble evolution the mixture was heated distilling most of the organic solvent (THF) The aqueous mixture was refluxed for 6 hours CHCl3 (700 mL) and Et2O (300 mL) were added after 15 minutes the diphasic mixture was filtered through Celite® the separated solid was repeatedly washed with CHCl3/Et2O 3:1 (4 L) The filtered solution was concentrated removing water The crude oil (130 g) was purified twice by flash chromatography (CH2Cl2/CH3OH/NH4OH 25% (w/w) 54:40:6 to 90:9:1)

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

实验步骤: A mixture of O-(phenylmethyl)-L-serine (commercial product) (139.0 g; 0.712 mol) and NaBH4 (96%; 75 g; 1.9 mol) in dry THF (700 mL, distilled on sodium/benzophenone), under N2 atmosphere, was slowly added (1.5 hours) with a solution of I2 (181.0 g; 0.713 mol) in dry THF (350 mL) at a temperature of 0 to 15° C. When the addition was completed and the dark color had disappeared, the mixture was refluxed for 18 hours, then cooled at 0° C. and the NaBH4 excess was destroyed with cold water (30 mL), followed by 15N KOH (320 mL). When bubble evolution was no longer observed, the mixture was heated, distilling most of the organic solvent (THF). The aqueous mixture was refluxed for 6 hours, then stirred at r.t. for a further 18 hours. CHCl3 (700 mL) and Et2O (300 mL) were added thereto under strong stirring; after 15 minutes the diphasic mixture was filtered through Celite® and the separated solid was repeatedly washed with CHCl3/Et2O 3:1 (4 L). The filtered solution was concentrated, removing water by repeated azeotropical distillations with CH3CN. The crude oil (130 g) was purified twice by flash chromatography (CH2Cl2/CH3OH/NH4OH 25% (w/w) 54:40:6 to 90:9:1), thereby obtaining the desired compound (92.63 g; 0.511 mol). Yield: 72%. When the addition the mixture was refluxed for 18 hours the NaBH4 excess was destroyed with cold water (30 mL) When bubble evolution the mixture was heated distilling most of the organic solvent (THF) The aqueous mixture was refluxed for 6 hours CHCl3 (700 mL) and Et2O (300 mL) were added after 15 minutes the diphasic mixture was filtered through Celite® the separated solid was repeatedly washed with CHCl3/Et2O 3:1 (4 L) The filtered solution was concentrated removing water The crude oil (130 g) was purified twice by flash chromatography (CH2Cl2/CH3OH/NH4OH 25% (w/w) 54:40:6 to 90:9:1)

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

实验步骤: Chloroacetyl chloride (0.242 mL) was added to a mixed solution of (R)-(+)-2-amino-3-benzyloxy-1-propanol (500 g) in toluene (7 mL) and a 2 N sodium hydroxide solution (7 mL) under ice-cooling. The reaction solution was stirred at room temperature for one hour. Then, THF and brine were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Sodium iodide (82.7 mg) and potassium tert-butoxide (681 mg) were added to a solution of the resulting residue in THF (15 mL) under ice-cooling. The reaction solution was stirred at room temperature for one hour. Then, a saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: heptane-ethyl acetate system) to obtain 387 mg of the title compound. The property values of the compound are as follows. the organic layer was separated The resulting organic layer was washed with brine dried over anhydrous magnesium sulfate concentrated under reduced pressure Sodium iodide (82.7 mg) and potassium tert-butoxide (681 mg) were added to a solution of the resulting residue in THF (15 mL) under ice- cooling The reaction solution was stirred at room temperature for one hour Then, a saturated ammonium chloride solution and ethyl acetate were added to the reaction solution the organic layer was separated The resulting organic layer was washed with brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (eluent solvent: heptane-ethyl acetate system)

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

实验步骤: Bromoacetyl chloride (5.06 mL) was added to a mixed solution of (R)-(+)-2-amino-3-benzyloxy-1-propanol (10 g) in toluene (100 mL) and a 2 N sodium hydroxide solution (100 mL) under ice-cooling. The reaction solution was stirred at 0° C. for 30 minutes and then at 60° C. for one hour. The reaction solution was returned to room temperature. Then, a toluene-THF (1:1) mixed solution was added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.36 g of the title compound. The property values of the compound are as follows. at 60° C. for one hour was returned to room temperature was added to the reaction solution the organic layer was separated The resulting organic layer was dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system)

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

实验步骤: A mixture of O-(phenylmethyl)-L-serine (commercial product) (139.0 g; 0.712 mol) and NaBH4 (96%; 75 g; 1.9 mol) in dry THF (700 mL, distilled on sodium/benzophenone), under N2 atmosphere, was slowly added (1.5 hours) with a solution of I2 (181.0 g; 0.713 mol) in dry THF (350 mL) at a temperature of 0 to 15° C. When the addition was completed and the dark color had disappeared, the mixture was refluxed for 18 hours, then cooled at 0° C. and the NaBH4 excess was destroyed with cold water (30 mL), followed by 15N KOH (320 mL). When bubble evolution was no longer observed, the mixture was heated, distilling most of the organic solvent (THF). The aqueous mixture was refluxed for 6 hours, then stirred at r.t. for a further 18 hours. CHCl3 (700 mL) and Et2O (300 mL) were added thereto under strong stirring; after 15 minutes the diphasic mixture was filtered through Celite® and the separated solid was repeatedly washed with CHCl3/Et2O 3:1 (4 L). The filtered solution was concentrated, removing water by repeated azeotropical distillations with CH3CN. The crude oil (130 g) was purified twice by flash chromatography (CH2Cl2/CH3OH/NH4OH 25% (wlw) 54:40:6 to 90:9:1), thereby obtaining the desired compound (92.63 g; 0.511 mol). When the addition the mixture was refluxed for 18 hours the NaBH4 excess was destroyed with cold water (30 mL) When bubble evolution the mixture was heated distilling most of the organic solvent (THF) The aqueous mixture was refluxed for 6 hours CHCl3 (700 mL) and Et2O (300 mL) were added after 15 minutes the diphasic mixture was filtered through Celite® the separated solid was repeatedly washed with CHCl3/Et2O 3:1 (4 L) The filtered solution was concentrated removing water The crude oil (130 g) was purified twice by flash chromatography (CH2Cl2/CH3OH/NH4OH 25% (wlw) 54:40:6 to 90:9:1)