tert-butyl (2S)-2-(phenoxymethyl)pyrrolidine-1-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Following the procedure of example 1115 A, N-t-butoxycarbonyl-2-hydroxymethylpyrrolidine (0.80 g, 4.00 mmol) and phenol (1.13 g, 12.00 mmol) provided 0.99 g (89%) of the title compound. MS (DCI, NH3): 278 (MH+).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (S)-(+)-N-Boc-2-phenoxymethylpyrrolidine (0.81 g, 2.9 mmol) in 5 mL of CH2Cl2 at 0° C. was added 5 mL of TFA dropwise over 1 hour. The solution was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was slowly poured into 30 mL of 10% NaOH and extracted thrice with 20 mL of CH2Cl2. The organic layer was then dried over Na2SO4, filtered and concentrated under reduced pressure to give a light yellow oil (0.41 g, 79%). ES (+) MS m/e=178 (M+H). extracted thrice with 20 mL of CH2Cl2 The organic layer was then dried over Na2SO4 filtered concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of phenol (0.40 g, 4.23 mmol) in 10 mL of THF at 0° C. was added sodium hydride (0.226 g, 5.65 mmol), and the mixture was warmed to room temperature. The mixture was stirred 10 minutes (until evolution of hydrogen gas ceased) and cooled to 0° C. A solution of (S)-(+)-N-Boc-2-(4-toluenesulfonyloxymethyl)pyrrolidine (1.0 g, 2.8 mmol) in 2 mL of THF was added dropwise and the resulting mixture was refluxed overnight. To the mixture was added 5 mL of DMF and the mixture was heated at 100° C. overnight. To the mixture was added EtOAc and the organic layer was washed thrice with water, thrice with 1N NaOH, and twice with water. The organic layer was then dried over MgSO4, filtered and concentrated under reduced pressure to give an oil. The oil was purified by silica gel chromatography with 7% EtOAc/Hexanes to give the title compound as a colorless oil (0.55 g, 71%). ES (+) MS m/e=278 (M+H). cooled to 0° C the resulting mixture was refluxed overnight the mixture was heated at 100° C. overnight the organic layer was washed thrice with water, thrice with 1N NaOH The organic layer was then dried over MgSO4 filtered concentrated under reduced pressure to give an oil The oil was purified by silica gel chromatography with 7% EtOAc/Hexanes

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 2.01 g (10 mmol) sample of (S)-1-BOC-2-pyrrolidinemethanol (from Example 1a) and 1.41 g (15 mmol) of phenol (Aldrich) were added to a complex of TPP and DEAD, (prepared as in Example 5b above, 15 mmol of each) in 100 mL of THF. The reaction was stirred for 16 hr, the solvents were removed under vacuum, and the residue was extracted with hexane and chromatographed on silica gel to give 0.7 g of the title compound. the solvents were removed under vacuum the residue was extracted with hexane chromatographed on silica gel

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 2.01 g (10 mmol) sample of (S)-1-BOC-2-pyrrolidinemethanol (from Example 1a) and 1.41 g (15 mmol) of phenol (Aldrich) were added to a complex of TPP and DEAD, (prepared as in Example 5b above, 15 mmol of each) in 100 mL of THF. The reaction was stirred for 16 hr, the solvents were removed under vacuum, and the residue was extracted with hexane and chromatographed on silica gel to give 0.7 g of the title compound. the solvents were removed under vacuum the residue was extracted with hexane chromatographed on silica gel

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-(Pyridin-4-yl-oxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (22) was prepared according to the same procedure for compound 9, except using 4-hydroxypyridine. The crude product was purified with ethyl acetate to afford 1.31 g (47%) of 22 as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.42 (m, 2H), 6.87 (m, 2H), 4.15 (m, 3H), 3.43 (m, 2H), 1.98 (m, 4H), 1.50 (s, 9H). 2-(Pyridin-4-yl-oxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (22) was prepared The crude product was purified with ethyl acetate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-(Pyridin-3-yl-oxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (19) was prepared according to the same procedure for compound 9, except using 3-hydroxypyridine. The crude product was purified with ether to afford 1.70 g (61%) of 19 as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.32 (s, 1H), 8.21 (s, 1H), 7.21 (m, 2H), 4.16 (m, 2H), 3.99-3.86 (m, 1H), 3.38 (m, 2H), 2.05-1.84 (m, 4H), 1.47 (s, 9H). 2-(Pyridin-3-yl-oxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (19) was prepared The crude product was purified with ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (S)-tert-Butyl 2-(phenoxymethyl)azetidine-1-carboxylate (16) was prepared according to the same procedure for compound 9, except using compound 15, and purified with hexanes-ether (2:1) to afford 0.81 g (79%) of 16 as a colorless oil. 1H NMR (300 MHz, CDCl3) δ CDCl3 7.30 (m, 2H), 6.94 (m, 3H), 4.53 (m, 1H), 4.26 (m, 1H), 4.12 (m, 1H), 3.93 (m, 2H), 2.33 (m, 2H), 1.43 (s, 9H). (S)-tert-Butyl 2-(phenoxymethyl)azetidine-1-carboxylate (16) was prepared purified with hexanes-ether (2:1)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 9 (1.46 g, 5.2 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (5 mL) at 0° C. The mixture was stirred at 0° C. for 15 min. After evaporation of the solvent in vacuo, CH2Cl2 (15 mL) and triethylamine (2 mL) were added, then a solution of 6 (1.44 g, 5.9 mmol) in THF (25 mL) was added at 0° C. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated in vacuo, then ethyl acetate (150 mL) was added, washed with water (50 mL×2) and saturated NaCl (50 mL), and dried over Na2SO4. After evaporation of the ethyl acetate, the crude product was purified with ether to afford 1.7 g (84%) of 10 as a yellow solid, mp 204.5-205.9° C. 1H NMR (300 MHz, CDCl3) δ 8.94 (s, 1H), 7.77 (dd, J=8.25 Hz, J=2.1 Hz, 1H), 7.67 (s, 1H), 7.02 (t, J=8.7 Hz, 2H), 6.84 (d, J=8.1 Hz, 1H), 6.69 (t, J=7.2 Hz, 1H), 6.63 (d, J=7.8 Hz, 2H), 3.89 (m, 1H), 3.75-3.66 (m, 2H), 3.23 (m, 1H), 2.96 (m, 1H), 1.72 (m, 2H), 1.54-1.42 (m, 2H). LRMS (FAB) m/e: 387.1 (M+H, 100). Anal. Calcd for C19.N2O5S: C, 59.06, H, 4.70; N, 7.25. Found: C, 58.99, H, 4.74, N, 7.11. After evaporation of the solvent in vacuo, CH2Cl2 (15 mL) and triethylamine (2 mL) were added The reaction mixture was stirred overnight at room temperature The solvent was evaporated in vacuo ethyl acetate (150 mL) was added washed with water (50 mL×2) and saturated NaCl (50 mL) dried over Na2SO4 After evaporation of the ethyl acetate the crude product was purified with ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (S)-(+)-N-Boc-2-phenoxymethylpyrrolidine (0.81 g. 2.9 mmol) in 5 mL of CH2Cl2 in 0° C. was added 5 mL of TFA dropwise over 1 hour. The solution was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was slowly poured into 30 mL of 10% NaOH and extracted thrice with 20 mL CH2Cl2. The organic layer was then dried over Na2SO4, filtered and concentrated under reduced pressure to give a light yellow oil (0.41 g, 79%). ES (+) MS m/e=178 (M+H). extracted thrice with 20 mL CH2Cl2 The organic layer was then dried over Na2SO4 filtered concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of (S)-(−)-1-Boc-2-pyrrolidine methanol (0.267 g, 1.33 mmol), phenol (0.38 g, 4.02 mmol) and triphenylphosphine (0.71 g, 2.71 mmol) in DCM (5 mL) was cooled in an ice-bath and a solution of diisopropyl azodicarboxylate (0.55 g, 2.71 mmol) in toluene (3 mL) was added. The ice-bath was removed and the reaction mixture was stirred at room temperature over the weekend. The mixture was diluted with ether and washed with sodium hydroxide (3 M), then brine, dried over sodium sulfate and evaporated. The resultant solid was suspended in ethyl acetate and cyclohexane and the resultant white crystalline solid was removed by filtration. The filtrate was evaporated and the crude material was purified by column chromatography using a 10 g Si II cartridge eluting with 10% ethyl acetate in cyclohexane to afford (S)-2-phenoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a clear oil (0.22 g). The ice-bath was removed The mixture was diluted with ether washed with sodium hydroxide (3 M) brine, dried over sodium sulfate evaporated cyclohexane and the resultant white crystalline solid was removed by filtration The filtrate was evaporated the crude material was purified by column chromatography eluting with 10% ethyl acetate in cyclohexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of (S)-(−)-1-Boc-2-pyrrolidine methanol (0.267 g, 1.33 mmol), phenol (0.38 g, 4.02 mmol) and triphenylphosphine (0.71 g, 2.71 mmol) in DCM (5 mL) was cooled in an ice-bath and a solution of diisopropyl azodicarboxylate (0.55 g, 2.71 mmol) in toluene (3 mL) was added. The ice-bath was removed and the reaction mixture was stirred at room temperature over the weekend. The mixture was diluted with ether and washed with sodium hydroxide (3 M), then brine, dried over sodium sulfate and evaporated. The resultant solid was suspended in ethyl acetate and cyclohexane and the resultant white crystalline solid was removed by filtration. The filtrate was evaporated and the crude material was purified by column chromatography using a 10 g Si II cartridge eluting with 10% ethyl acetate in cyclohexane to afford (S)-2-phenoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a clear oil (0.22 g). The ice-bath was removed The mixture was diluted with ether washed with sodium hydroxide (3 M) brine, dried over sodium sulfate evaporated cyclohexane and the resultant white crystalline solid was removed by filtration The filtrate was evaporated the crude material was purified by column chromatography eluting with 10% ethyl acetate in cyclohexane