2-(7-bromoheptoxy)oxane

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

実験手順: 7-Bromoheptanol will be treated with dihydropyrane in the presence of acid to give 1-O-(tetrahydropyran-2-yl)-7-bromoheptanol.

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

実験手順: Oct-1,7-diyne (6.3 g, 59.3 mmol) was alkylated with 2-(7-bromoheptyloxy)tetrahydro-2H-pyran (11 g, 39.56 mmol) as described above to give 2-(pentadeca-8,14-diynyloxy)tetrahydro-2H-pyran (7.82 g, 64%) as a colorless oil. TLC: 10% EtOAc/hexanes, Rf≈0.6; 1H NMR (400 MHz, CDCl3) δ 4.57 (t, J=2.5 Hz, 1H), 3.82-3.87 (m, 1H), 3.70-3.77 (m, 1H), 3.46-3.51 (m, 1H), 3.36-3.42 (m, 1H), 2.14-2.20 (m, 6H), 1.93 (t, J=2.6 Hz, 1H), 1.46-1.72 (m, 20 H)

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

実験手順: 1-O-(Tetrahydropyran-2-yl)-7-bromoheptanol 7-Bromoheptanol will be treated with dihydropyrane in the presence of acid to give 1-O-(tetrahydropyran-2-yl)-7-bromoheptanol.

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

実験手順: Dihydropyran (5.20 g, 6.11 mmol) was added to a stirring 0° C. solution of 7-bromoheptane-1-ol (2) (11.0 g, 56.7 mmol) and a catalytic amount of PTSA in CH2Cl2. After stirring at rt for 12 h, the reaction mixture was diluted with CH2Cl2 (200 mL), washed with water (100 mL×2), brine (100 mL×3), dried over anhydrous sodium sulphate, and evaporated. The residue was purified by silica gel column chromatography using a gradient of 10-20% ethyl acetate/hexane as eluent to give 2-(7-bromoheptyloxy)tetrahydro-2H-pyran (3) (14.50 g, 92%) as a colorless oil. TLC: 10% EtOAc/hexanes, Rf≈0.55; 1H NMR (400 MHz, CDCl3) δ 4.58-4.56 (m, 1H), 3.84-3.88 (m, 1H), 3.68-3.77 (m, 1H), 3.46-3.51 (m, 1H), 3.33-3.43 (m, 3H), 1.80-1.81 (m, 2H), 1.30-1.62 (m, 14H). washed with water (100 mL×2), brine (100 mL×3) dried over anhydrous sodium sulphate evaporated The residue was purified by silica gel column chromatography

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

実験手順: Dihydropyran (5.20 g, 6.11 mmol) was added to a stirring 0° C. solution of 7-bromoheptane-1-ol (2) (11.0 g, 56.7 mmol) and a catalytic amount of PTSA in CH2Cl2. After stirring at rt for 12 h, the reaction mixture was diluted with CH2Cl2 (200 mL), washed with water (100 mL×2), brine (100 mL×3), dried over anhydrous sodium sulphate, and evaporated. The residue was purified by silica gel column chromatography using a gradient of 10-20% ethyl acetate/hexane as eluent to give 2-(7-bromoheptyloxy)tetrahydro-2H-pyran (3) (14.50 g, 92%) as a colorless oil. TLC: 10% EtOAc/hexanes, Rf≈0.55; 1H NMR (400 MHz, CDCl3) δ 4.58-4.56 (m, 1H), 3.84-3.88 (m, 1H), 3.68-3.77 (m, 1H), 3.46-3.51 (m, 1H), 3.33-3.43 (m, 3H), 1.80-1.81 (m, 2H), 1.30-1.62 (m, 14H). washed with water (100 mL×2), brine (100 mL×3) dried over anhydrous sodium sulphate evaporated The residue was purified by silica gel column chromatography

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

実験手順: The title compound, m/e=413.5 ([M−H]−), was produced in analogy with example 54, steps 1 to 6. Thus, 7-bromo-1-heptanol was protected in step 1, leading to 2-(7-bromo-heptyloxy)-tetrahydro-pyran, which was reacted in step 2 with 2-(2,3-difluorophenoxy)-ethanol, affording 2-(7-[2-(2,3-difluoro-phenyl)-ethoxy]-heptyloxy)-tetrahydro-pyran, which after deprotection in step 3 gave 7-[2-(2,3-difluoro-phenyl)-ethoxy]-heptan-1-ol. This was oxidized in step 4 to 7-[2-(2,3-difluoro-phenyl)-ethoxy]-heptanoic acid, which was coupled in step 5 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride, leading to (R)-3-{7-[2-(2,3-difluoro-phenyl)-ethoxy]-heptanoylamino}-4-dimethylamino-butyric acid benzyl ester, which was hydrogenated in step 6.

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

実験手順: Dihydropyran (5.20 g, 6.11 mmol) was added to a stirring 0° C. solution of 7-bromoheptane-1-ol (2) (11.0 g, 56.7 mmol) and a catalytic amount of PTSA in CH2Cl2. After stirring at rt for 12 h, the reaction mixture was diluted with CH2Cl2 (200 mL), washed with water (100 mL×2), brine (100 mL×3), dried over anhydrous sodium sulphate, and evaporated. The residue was purified by silica gel column chromatography using a gradient of 10-20% ethyl acetate/hexane as eluent to give 2-(7-bromoheptyloxyl)tetrahydro-2H-pyran (3) (14.50 g, 92%) as a colorless oil. TLC: 10% EtOAc/hexanes, Rf˜0.55; 1H NMR (400 MHz, CDCl3) δ 4.58-4.56 (m, 1H), 3.84-3.88 (m, 1H), 3.68-3.77 (m, 1H), 3.46-3.51 (m, 1H), 3.33-3.43 (m, 3H), 1.80-1.81 (m, 2H), 1.30-1.62 (m, 14H). washed with water (100 mL×2), brine (100 mL×3) dried over anhydrous sodium sulphate evaporated The residue was purified by silica gel column chromatography

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

実験手順: Dihydropyran (1 mL, 11.0 mmol) and pyridinium p-toluenesulfonate (148 mg, 0.59 mmol) were added to a solution of 7-Bromo-1-heptanol (1.1 g, 5.64 mmol) in CH2Cl2 (22 mL). After stirring overnight, the solution was washed with 1 M HCl (20 mL), saturated NaHCO3 solution (20 mL) and brine (20 mL). The solution was dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel (0%→50% ethyl acetate/hexanes) to give the title compound (1.8 g, >100%). the solution was washed with 1 M HCl (20 mL), saturated NaHCO3 solution (20 mL) and brine (20 mL) The solution was dried (Na2SO4) filtered evaporated The residue was purified by flash chromatography on silica gel (0%→50% ethyl acetate/hexanes)

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

実験手順: 7-Bromoheptanol will be treated with dihydropyrane in the presence of acid to give 1-O-(tetrahydropyran-2-yl)-7-bromoheptanol.

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

実験手順: Oct-1,7-diyne (6.3 g, 59.3 mmol) was alkylated with 2-(7-bromoheptyloxy)tetrahydro-2H-pyran (11 g, 39.56 mmol) as described above to give 2-(pentadeca-8,14-diynyloxy)tetrahydro-2H-pyran (7.82 g, 64%) as a colorless oil. TLC: 10% EtOAc/hexanes, Rf≈0.6; 1H NMR (400 MHz, CDCl3) δ 4.57 (t, J=2.5 Hz, 1H), 3.82-3.87 (m, 1H), 3.70-3.77 (m, 1H), 3.46-3.51 (m, 1H), 3.36-3.42 (m, 1H), 2.14-2.20 (m, 6H), 1.93 (t, J=2.6 Hz, 1H), 1.46-1.72 (m, 20 H)

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

実験手順: 1-O-(Tetrahydropyran-2-yl)-7-bromoheptanol 7-Bromoheptanol will be treated with dihydropyrane in the presence of acid to give 1-O-(tetrahydropyran-2-yl)-7-bromoheptanol.