2-(4-bromophenyl)propan-2-amine

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

実験手順: 1-(4-Bromophenyl)-1-methyl-ethylamine (1 g, 4.67 mmol) and epichlorohydrin (439 μl, 5.6 mmol) in EtOH (15 mL) were heated at 70° C. for 18 h. The reaction mixture was concentrated in vacuo and purified by reverse phase preparative HPLC-MS to obtain 1-[1-(4-bromo-phenyl)-1-methyl-ethyl]-azetidin-3-ol as a white solid (489 mg, 38%). The reaction mixture was concentrated in vacuo purified by reverse phase preparative HPLC-MS

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

実験手順: To a solution of 1-(4-bromo-phenyl)-1-methyl-ethylamine (400 mg, 1.84 mmol) in diisopropylethylamine (4 mL) was added N,N-bis(2-chloroethyl)-4-methylbenzene sulphonamide (500 mg, 1.68 mmol) and the reaction subjected to microwave irradiation at 150° C. for 9 h afterwhich time the reaction was concentrated in vacuo and the crude residue purified by reverse phase preparative HPLC-MS to afford 1-[1-(4-bromo-phenyl)-1-methyl-ethyl]-4-(toluene-4-sulfonyl)-piperazine as a peach solid (375 mg, 47%). irradiation at 150° C. for 9 h afterwhich time the reaction was concentrated in vacuo the crude residue purified by reverse phase preparative HPLC-MS

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-(quinuclidin-3-yl)acetic acid hydrochloride (0.97 g, 4.7 mmol) in DMF (30 mL) was added HATU (1.79 g, 4.72 mmol), 2-(4-bromophenyl)propan-2-amine (1.0 g, 4.7 mmol), and triethylamine (3.9 mL, 28 mmol). The resulting mixture was stirred at 60° C. for 16 h. The mixture was concentrated in vacuo, diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4 and evaporated to afford crude product, which was purified by silica gel column chromatography (EtOAc/methanol 50/1 to 3/1) to obtain N-(2-(4-bromophenyl)propan-2-yl)-2-(quinuclidin-3-yl)acetamide as a yellow solid (1.3 g, 76%). The mixture was concentrated in vacuo diluted with EtOAc washed with brine The organic layer was dried over Na2SO4 evaporated to afford crude product, which was purified by silica gel column chromatography (EtOAc/methanol 50/1 to 3/1)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-(quinuclidin-3-yl)acetic acid hydrochloride (0.97 g, 4.7 mmol) in DMF (30 mL) was added HATU (1.79 g, 4.72 mmol), 2-(4-bromophenyl)propan-2-amine (1.0 g, 4.7 mmol), and triethylamine (3.9 mL, 28 mmol). The resulting mixture was stirred at 60° C. for 16 h. The mixture was concentrated in vacuo, diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4 and evaporated to afford crude product, which was purified by silica gel column chromatography (EtOAc/methanol 50/1 to 3/1) to obtain N-(2-(4-bromophenyl)propan-2-yl)-2-(quinuclidin-3-yl)acetamide as a yellow solid (1.3 g, 76%). The mixture was concentrated in vacuo diluted with EtOAc washed with brine The organic layer was dried over Na2SO4 evaporated to afford crude product, which was purified by silica gel column chromatography (EtOAc/methanol 50/1 to 3/1)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-(quinuclidin-3-yl)acetic acid hydrochloride (0.97 g, 4.7 mmol) in DMF (30 mL) was added HATU (1.79 g, 4.72 mmol), 2-(4-bromophenyl)propan-2-amine (1.0 g, 4.7 mmol), and triethylamine (3.9 mL, 28 mmol). The resulting mixture was stirred at 60° C. for 16 h. The mixture was concentrated in vacuo, diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4 and evaporated to afford crude product, which was purified by silica gel column chromatography (EtOAc/methanol 50/1 to 3/1) to obtain N-(2-(4-bromophenyl)propan-2-yl)-2-(quinuclidin-3-yl)acetamide as a yellow solid (1.3 g, 76%). The mixture was concentrated in vacuo diluted with EtOAc washed with brine The organic layer was dried over Na2SO4 evaporated to afford crude product, which was purified by silica gel column chromatography (EtOAc/methanol 50/1 to 3/1)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-(quinuclidin-3-yl)acetic acid hydrochloride (0.97 g, 4.7 mmol) in DMF (30 mL) was added HATU (1.79 g, 4.72 mmol), 2-(4-bromophenyl)propan-2-amine (1.0 g, 4.7 mmol), and triethylamine (3.9 mL, 28 mmol). The resulting mixture was stirred at 60° C. for 16 h. The mixture was concentrated in vacuo, diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4 and evaporated to afford crude product, which was purified by silica gel column chromatography (EtOAc/methanol 50/1 to 3/1) to obtain N-(2-(4-bromophenyl)propan-2-yl)-2-(quinuclidin-3-yl)acetamide as a yellow solid (1.3 g, 76%). The mixture was concentrated in vacuo diluted with EtOAc washed with brine The organic layer was dried over Na2SO4 evaporated to afford crude product, which was purified by silica gel column chromatography (EtOAc/methanol 50/1 to 3/1)

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

実験手順: The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the 2-(4-bromophenyl)propan-2-amine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 595/597 [M+H]+.

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

実験手順: N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide (1.00 g, 2.75 mmol), 4-bromocumylamine (0.770 g, 3.60 mmol), N-methylmorpholine (0.310 g, 3.06 mmol), and benzene (15 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(4-bromocumyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.515 g, 32.4% yield). After completion of the reaction the solvent was distilled off under reduced pressure the precipitated crystals were isolated by filtration The crystals were washed with hexane dried

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

実験手順: To a solution of 2-(4-bromophenyl)propan-2-amine, hydrochloric acid (1.0 g, 4.0 mmol, AKOS) in DCM (30 mL) at about 0° C. was added TEA (1.11 mL, 7.98 mmol). A solution of BOC2O (1.623 ml, 7.01 mmol) in DCM (10 mL) was added dropwise over about 10 min. After about 30 min, the ice bath was removed and the mixture was stirred overnight at rt. The mixture was diluted with water (30 mL) and extracted with DCM (2×30 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatograph (40 g silica gel column, 0-40% EtOAc/Heptane) to give tert-butyl 2-(4-bromophenyl)propan-2-ylcarbamate the title compound (1.13 g, 90%): LC/MS (Table 2, Method b) Rt=2.66 min.; MS m/z: 315 (M+H)+. the ice bath was removed The mixture was diluted with water (30 mL) extracted with DCM (2×30 mL) dried over MgSO4 filtered concentrated in vacuo The crude material was purified by flash chromatograph (40 g silica gel column, 0-40% EtOAc/Heptane)

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

実験手順: The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and 1-(4-bromo-phenyl)-1-methyl-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 75% of theory; LC (method 5): tR=1.12 min; Mass spectrum (ESI+): m/z=440/442 (Br) [M+H]+.

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

実験手順: A mixture of 4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxylic acid, 30-ie, (110 mg, 0.5 mmol), 2-(4-bromophenyl)propan-2-amine, 36-b, (70 mg, 0.32 mmol), HATU (290 mg, 0.76 mmol) and DIEA (82 mg, 0.64 mmol) in DMF (3 mL) was stirred at room temperature overnight. The mixture was washed with aqueous NH4Cl (15 mL) and extracted with EtOAc (30 mL). The organic layers were dried and concentrated in vacuo. The residue was washed with hexane to afford compound 36-c (80 mg, 57%). 1H NMR (300 MHz, CDCl3) δ11.62 (s, 1H), 9.55 (s, 1H), 9.41 (dd, J=1.5, 4.8 Hz, 1H), 9.00 (d, J=4.2 Hz, 1H), 8.63 (dd, J=1.5, 8.1 Hz, 1H), 7.78 (dd, J=5.1, 8.4 Hz, 1H)), 7.43 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 1.78 (s, 6H). LC-MS: (M+H)+ 414. The mixture was washed with aqueous NH4Cl (15 mL) extracted with EtOAc (30 mL) The organic layers were dried concentrated in vacuo The residue was washed with hexane

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

実験手順: 1-(4-Bromophenyl)-1-methyl-ethylamine (1 g, 4.67 mmol) and epichlorohydrin (439 μl, 5.6 mmol) in EtOH (15 mL) were heated at 70° C. for 18 h. The reaction mixture was concentrated in vacuo and purified by reverse phase preparative HPLC-MS to obtain 1-[1-(4-bromo-phenyl)-1-methyl-ethyl]-azetidin-3-ol as a white solid (489 mg, 38%). The reaction mixture was concentrated in vacuo purified by reverse phase preparative HPLC-MS