(9H-fluoren-9-yl)methyl piperidine-1-carboxylate

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

実験手順: To (S)-(9H-fluoren-9-yl)methyl (2-((di-tert-butoxyphosphoryl)oxy)-1-(3-fluoro-5-iodophenyl)ethyl)carbamate (6450 mg, 9.27 mmol) was added DMF (Volume: 90 mL) followed by piperidine (25 mL, 253 mmol) and stirred at room temperature for 30 minutes, followed by LCMS. To the crude reaction mixture was added 750 ml of ethyl acetate, washed with saturated sodium bicarbonate (2×), water (5×), saturated salt solution, dried sodium sulfate, and filtered. The solvent was concentrated off to constant mass under high vacuum to give the desire crude product which includes FMOC piperidine impurity, used as is. LCMS (m/z): 474.2 (MH+), 0.80 min. To the crude reaction mixture washed with saturated sodium bicarbonate (2×), water (5×), saturated salt solution, dried sodium sulfate filtered The solvent was concentrated off to constant mass under high vacuum to give the desire crude product which 474.2 (MH+), 0.80 min.

反応条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: THF (15 ml) was added to 2-Chlorotrityl chloride resin (4.0 g, 1.2 mmol/g) and the mixture was agitated for 25 min. FmocN(Bn)CH2CH2OCH2CH2OH (6.1 g, 14.7 mmol) in THF (25 ml) was added followed by pyridine (850 μl, 10.5 mmol) and the mixture was heated to 65° C. for 15 h. MeOH (5 ml) was added and heating was continued for 35 min. The resin was filtered, washed with DMF (3×), CH2Cl2 (3×). MeOH (3×) and Et2O (3×) to give 5.0 g. A small sample was dried carefully and deprotected with DCM/piperidine (1:1) for 30 min. Photometric determination of the resulting Fmoc-piperidine adduct (absorption at 301 nm) gave a resin loading of 0.45 mmol/g. heating was continued for 35 min The resin was filtered washed with DMF (3×), CH2Cl2 (3×) MeOH (3×) and Et2O (3×) to give 5.0 g A small sample was dried carefully deprotected with DCM/piperidine (1:1) for 30 min

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

実験手順: The resin was deprotected using a 20% solution of piperidine in DMF (1×3 min, 1×7 min, 20 ml each) and subsequently washed with DMF (1×20 ml). Acylation was carried out by addition of FmocMetOH (2.4 g, 3 eq), DMF (10 ml), HOBt (990 mg, 3 eq), and DIC (1.01 ml, 3 eq) and DMAP (260 mg, 0.1 eq). The coupling was left for 4 h and the resin was washed with DMF (7×20 ml). A small sample was dried carefully and deprotected with DCM/piperidine (1:1) for 30 min. Photometric determination of the resulting Fmoc-piperidine adduct (absorption at 301 nm) gave a resin loading of 0.43 m mol/g. The remaining resin was capped using a solution of acetic anhydride (2 M) and DMAP (0.1 M) in DMF (20 ml, 1×10 min) and subsequently washed with DMF (12×20 ml), methanol (3×40 ml) and diethyl ether (3×40 ml), and dried in vacuo to yield 3.9 g FmocMet-Rinkamide resin. subsequently washed with DMF (1×20 ml) the resin was washed with DMF (7×20 ml) A small sample was dried carefully deprotected with DCM/piperidine (1:1) for 30 min

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

実験手順: A solution of 7.4 g Fmoc-βPhPro-OH in 120 ml dry DCM was added to 12.0 g 2-chlorotrityl chloride resin (0.83 mmol/g, Novabiochem). DIPEA (3.0 ml) was added and the mixture was shaken for 10 min. Additional 4.5 ml DIPEA were added and shaking was continued for 145 min. Methanol (10 ml) was added the mixture was shaken for another 25 min. The resin was filtered off, washed with DCM (5×100 ml), methanol (2×100 ml) and DCM (4×100 ml). A small sample was dried carefully and deprotected with DCM/piperidine (1:1) for 30 min. Photometric determination of the resulting Fmoc-piperidine adduct (absorption at 301 nm) gave a resin loading of 0.54 mmol/g. The remaining resin was treated with 100 ml DCM and 80 ml piperidine at r.t. for 160 min, washed with DCM (10×100 ml) and diethyl ether (4×80 ml) and dried in vacuo to give 14.37 g HβPhPro-2-chlorotrityl resin. shaking was continued for 145 min was shaken for another 25 min The resin was filtered off washed with DCM (5×100 ml), methanol (2×100 ml) and DCM (4×100 ml) A small sample was dried carefully deprotected with DCM/piperidine (1:1) for 30 min

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

実験手順: To (S)-(9H-fluoren-9-yl)methyl (2-((di-tert-butoxyphosphoryl)oxy)-1-(3-fluoro-5-iodophenyl)ethyl)carbamate (6450 mg, 9.27 mmol) was added DMF (Volume: 90 mL) followed by piperidine (25 mL, 253 mmol) and stirred at room temperature for 30 minutes, followed by LCMS. To the crude reaction mixture was added 750 ml of ethyl acetate, washed with saturated sodium bicarbonate (2×), water (5×), saturated salt solution, dried sodium sulfate, and filtered. The solvent was concentrated off to constant mass under high vacuum to give the desire crude product which includes FMOC piperidine impurity, used as is. LCMS (m/z): 474.2 (MH+), 0.80 min. To the crude reaction mixture washed with saturated sodium bicarbonate (2×), water (5×), saturated salt solution, dried sodium sulfate filtered The solvent was concentrated off to constant mass under high vacuum to give the desire crude product which 474.2 (MH+), 0.80 min.