[(2S)-oxiran-2-yl]methanol

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

実験手順: A solution of (S)-glycidol (1.00 mL, 15.0 mmol) and morpholine (1.96 mL, 22.5 mmol, 2.5 equiv.) in abs. ethanol was heated in a microwave for 4 min. at 140 0° C., cooled to room temperature and concentrated at 70° C. under a 12 mbar vacuum to afford (2R)-3-(4-morpholinyl)-1,2-propanediol (2.47 g, 102%): 1H NMR (CDCl3) δ 2.37 (dd J=4.0, 12.4 Hz, 1H), 2.40-2.48 (m, 2H), 2.57 (dd, J=9.6, 12.4 Hz, 1H), 2.62-2.71 (m, 2H), 3.50 (dd, J=4.2, 11.4 Hz, 1H), 3.65-3.79 (m, 5H), 3.79-3.88 (m, 1H). concentrated at 70° C. under a 12 mbar vacuum

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

実験手順: (S)-Glycidyl Methanesulfonate was synthesized in an analogous manner to Intermediate F, Step 1, substituting (R)-(+)-glycidol for (S)-(−)-glycidol. This was used in further transformations as a solution of (S)-glycidyl methanesulfonate in DMF, without further purification. This was used in further transformations as a solution of (S)-glycidyl methanesulfonate in DMF, without further purification

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

実験手順: A solution of (S)-(−)-glycidol (8.6 mL, 130 mmol) and triethylamine (36.2 mL, 260 mmol, 2.0 equiv.) in DMF (250 mL) was cooled over an ice bath and methanesulfonyl chloride (10.1 mL, 130 mmol, 1.0 equiv.) was added dropwise. The mixture was stirred for 1.5 hr at room temperature affording a 0.47 M solution of (R)-glycidyl methanesulfonate in DMF, which was used without further purification.

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

実験手順: To a mixture of (2S)-oxiran-2-ylmethanol (296.3 mg, 4.0 mmol), 5-methoxy-2-nitrophenol (676.6 mg, 4.0 mmol) and triphenyl phosphine (1.05 g, 4.0 mmol) in THF (10 mL) was added diethyl azodicarboxylate (DEAD, 704.6 mg, 4.0 mmol) in THF (5 mL) dropwise at room temperature. After addition was completed the reaction mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (040% ethyl acetate in petroleum spirit) to give the subtitled compound (650 mg). After addition The volatiles were removed in vacuo the residue was purified by silica gel flash chromatography (040% ethyl acetate in petroleum spirit)

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

実験手順: To a mixture of (2S)-oxiran-2-ylmethanol (296.3 mg, 4.0 mmol), 5-methoxy-2-nitrophenol (676.6 mg, 4.0 mmol) and triphenyl phosphine (1.05 g, 4.0 mmol) in THF (10 mL) was added diethyl azodicarboxylate (DEAD, 704.6 mg, 4.0 mmol) in THF (5 mL) dropwise at room temperature. After addition was completed the reaction mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (040% ethyl acetate in petroleum spirit) to give the subtitled compound (650 mg). After addition The volatiles were removed in vacuo the residue was purified by silica gel flash chromatography (040% ethyl acetate in petroleum spirit)

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of (S)-(−)-glycidol (0.16 mL, 2.3 mmol) in ethanol (5 mL) was added dropwise to a stirring solution of N-[4-(4-aminophenyl)butyl]carbamic acid benzyl ester (0.59 g, 1.97 mmol) in ethanol (15 mL) at 70° C. The reaction mixture was stirred at 70° C. (oil bath) overnight. The solvent was removed under reduced pressure and the residue was purified by Flash™ (BIOTAGE, Inc) (90 g silica gel cartridge 40M, chloroform/methanol/ammonium hydroxide, 15:1:0.1, v/v) to give 700 (0.29 g, 40%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.51 (m, 4H), 2.48 (t, 2H), 3.07 (m, 1H), 3.26 (t, 2H), 3.30 (m, 1 if), 3.57 (m, 2H), 3.80 (m, 1H), 5.00 (s, 2H), 6.59 (d, 2H), 6.99 (d, 2H), 7.33 (m, 5H). m/z (ESI) 373 [C21H28N2O4+H]+. The solvent was removed under reduced pressure the residue was purified by Flash™ (BIOTAGE, Inc) (90 g silica gel cartridge 40M, chloroform/methanol/ammonium hydroxide, 15:1:0.1

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of (S)-(−)-glycidol (0.16 mL, 2.3 mmol) in ethanol (5 mL) was added dropwise to a stirring solution of N-[4-(4-aminophenyl)butyl]carbamic acid benzyl ester (0.59 g, 1.97 mmol) in ethanol (15 mL) at 70° C. The reaction mixture was stirred at 70° C. (oil bath) overnight. The solvent was removed under reduced pressure and the residue was purified by Flash™ (BIOTAGE, Inc) (90 g silica gel cartridge 40M, chloroform/methanol/ammonium hydroxide, 15:1:0.1, v/v) to give 700 (0.29 g, 40%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.51 (m, 4H), 2.48 (t, 2H), 3.07 (m, 1H), 3.26 (t, 2H), 3.30 (m, 1 if), 3.57 (m, 2H), 3.80 (m, 1H), 5.00 (s, 2H), 6.59 (d, 2H), 6.99 (d, 2H), 7.33 (m, 5H). m/z (ESI) 373 [C21H28N2O4+H]+. The solvent was removed under reduced pressure the residue was purified by Flash™ (BIOTAGE, Inc) (90 g silica gel cartridge 40M, chloroform/methanol/ammonium hydroxide, 15:1:0.1

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

実験手順: In a manner similar to that described for Example 6B, 1-{4-[1-acetyl-4-(4-hydroxy-3-methylphenyl)-piperidin-4-yl]-2-methylphenoxy)-3,3-dimethylbutan-2-one was prepared by using 1 equiv of 1-chloropinacolone and cesium carbonate. 1-{4-[1-Acetyl-4-(4-hydroxy-3-methylphenyl)-piperidin-4-yl]-2-methylphenoxy}-3,3-dimethylbutan-2-one was then alkylated with (S)-glycidol as in Example 1H to yield 1-(4-(1-acetyl-4-[4-(2,3-dihydroxypropoxy)-3-methylphenyl]-piperidin-4-yl}-2-methylphenoxy)-3,3-dimethylbutan-2-one. was prepared

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

実験手順: In a manner similar to that described for Example 6B, 1-{4-[1-acetyl-4-(4-hydroxy-3-methylphenyl)-piperidin-4-yl]-2-methylphenoxy)-3,3-dimethylbutan-2-one was prepared by using 1 equiv of 1-chloropinacolone and cesium carbonate. 1-{4-[1-Acetyl-4-(4-hydroxy-3-methylphenyl)-piperidin-4-yl]-2-methylphenoxy}-3,3-dimethylbutan-2-one was then alkylated with (S)-glycidol as in Example 1H to yield 1-(4-(1-acetyl-4-[4-(2,3-dihydroxypropoxy)-3-methylphenyl]-piperidin-4-yl}-2-methylphenoxy)-3,3-dimethylbutan-2-one. was prepared

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-{1-ethyl-1-[4-(3-hydroxy-3-methylbutyl)-3-methyl-phenyl]propyl}-2-methylphenol (0.14 g, 0.40 mmol) in anhyd DMF (2 mL) was added CsF (67 mg, 0.44 mmol), Cs2CO3 (26 mg, 80 □ mol) and (S)-glycidol (29 μL, 0.44 mmol). The reaction mixture was heated at 80° C. for 4 h. After cooling, the mixture was diluted with DCM (40 mL), washed with H2O (2×40 mL), 1 N HCl (20 mL) and brine, then dried (Na2SO4) and concentrated under reduced pressure. The crude material was chromatographed (silica, EtOAc/DCM, 0:100 to 75:25) to provide the title compound (80 mg, 47%) as a white powdered solid: 1H-NMR (CD2Cl2) δ 7.01 (1H, d, J=8.1), 6.96 (1H, dd, J=2.3, 8.3), 6.88-6.94 (3H, m), 6.73 (1H, d, J=8.3), 3.97-4.11 (3H, m), 3.77-3.84 (1H, m), 3.69-3.76 (1H, m), 2.62 (2H, m), 2.53 (1H, d, J=5.1), 2.24 (3H, s), 2.16 (3H, s), 2.05 (4H, q, J=7.3), 1.99 (1H, t, J=6.1), 1.67 (2H, m), 1.27 (6H, s), 0.58 (6H, t, J=7.3); 13C-NMR (CD2Cl2) δ 155.0, 147.2, 142.0, 138.4, 135.7, 131.2, 130.4, 128.5, 126.9, 126.3, 126.2, 110.9, 71.4, 71.3, 70.1, 64.6, 49.3, 45.2, 29.8, 29.6, 28.3, 20.0, 17.0, 8.9. After cooling washed with H2O (2×40 mL), 1 N HCl (20 mL) and brine dried (Na2SO4) concentrated under reduced pressure The crude material was chromatographed (silica, EtOAc/DCM, 0:100 to 75:25)

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-{1-ethyl-1-[4-(3-hydroxy-3-methylbutyl)-3-methyl-phenyl]propyl}-2-methylphenol (0.14 g, 0.40 mmol) in anhyd DMF (2 mL) was added CsF (67 mg, 0.44 mmol), Cs2CO3 (26 mg, 80 □ mol) and (S)-glycidol (29 μL, 0.44 mmol). The reaction mixture was heated at 80° C. for 4 h. After cooling, the mixture was diluted with DCM (40 mL), washed with H2O (2×40 mL), 1 N HCl (20 mL) and brine, then dried (Na2SO4) and concentrated under reduced pressure. The crude material was chromatographed (silica, EtOAc/DCM, 0:100 to 75:25) to provide the title compound (80 mg, 47%) as a white powdered solid: 1H-NMR (CD2Cl2) δ 7.01 (1H, d, J=8.1), 6.96 (1H, dd, J=2.3, 8.3), 6.88-6.94 (3H, m), 6.73 (1H, d, J=8.3), 3.97-4.11 (3H, m), 3.77-3.84 (1H, m), 3.69-3.76 (1H, m), 2.62 (2H, m), 2.53 (1H, d, J=5.1), 2.24 (3H, s), 2.16 (3H, s), 2.05 (4H, q, J=7.3), 1.99 (1H, t, J=6.1), 1.67 (2H, m), 1.27 (6H, s), 0.58 (6H, t, J=7.3); 13C-NMR (CD2Cl2) δ 155.0, 147.2, 142.0, 138.4, 135.7, 131.2, 130.4, 128.5, 126.9, 126.3, 126.2, 110.9, 71.4, 71.3, 70.1, 64.6, 49.3, 45.2, 29.8, 29.6, 28.3, 20.0, 17.0, 8.9. After cooling washed with H2O (2×40 mL), 1 N HCl (20 mL) and brine dried (Na2SO4) concentrated under reduced pressure The crude material was chromatographed (silica, EtOAc/DCM, 0:100 to 75:25)

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

実験手順: The title compound (R)-HPMPC was prepared from (S)-glycidol (88% ee) and N4 -benzoylcytosine, following the method described for (S)-HPMPC.