methyl 2-[4-(bromomethyl)phenyl]acetate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Carbazole (1.0 g, 6.0 mmol) and sodium hydride (60 wt. % in mineral oil, 0.14 g, 6.0 mmol) were placed under argon and dissolved in DMF (5 mL). The mixture was stirred at room temperature for 30 min, followed by treatment with (4-bromomethylphenyl)acetic acid methyl ester (1.5 g, 6.0 mmol) and 5 mg of potassium iodide. The reaction was heated to 80° C. for 2 h. The reaction was then diluted with ethyl acetate (30 mL) and water (30 mL). The organic layer was isolated and the aqueous layer extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water (2×20 mL), brine (15 mL), dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (0-80% gradient of ethyl acetate in hexane) afforded the title compound (0.71 g, 36%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.20 (d, 2H, J=7.7 Hz), 7.49 (m, 2H), 7.40 (d, 2H, J=8.1 Hz), 7.32 (m, 2H), 7.17 (d, 2H, J=8.1 Hz), 7.12 (d, 2H, J=8.1 Hz), 5.52 (s, 2H), 3.71 (s, 3H), 3.61 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 171.6, 140.3, 135.7, 132.8, 129.3, 126.5, 125.5, 122.8, 120.1, 118.9, 108.5, 51.7, 45.9, 40.4. ESI-HRMS (m/z): [M+H]+ calcd. for C22H19NO2, 330.1489. found, 330.1494. The reaction was heated to 80° C. for 2 h The organic layer was isolated the aqueous layer extracted with ethyl acetate (2×10 mL) The combined organic layers were washed with water (2×20 mL), brine (15 mL) dried (Na2SO4) concentrated in vacuo Purification by column chromatography (0-80% gradient of ethyl acetate in hexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of N-methylmorpholine-N-oxide (63.9 g, 545 mmol) in MeCN (848 g) and toluene (742 g), was added a solution of methyl [4-(bromomethyl)phenyl]acetate (53.0 g) in toluene (212 g) at 0 to 25° C. After stirring for 5 hr, water (106 g) was added to the reaction mixture. The aqueous layer was removed and remaining MeCN in the organic layer was removed under reduced pressure. The remaining toluene solution was washed with water twice (530 g×2), and concentrated under reduced pressure at a temperature below 40° C. until the weight of the solution was 233 g. An activated charcoal (3 g) was added to the solution and removed by filtration. To the solution was added 2,6-dibutyl-4-hydroxytoluene (152 mg), and concentrated under reduced pressure to give the subtitle compound. Yield 30.9 g, 79% from methyl [4-(bromomethyl)phenyl]acetate; 1H NMR (DMSO-d6) δ 9.99 (s, 1H), 7.87 (d, 2H), 7.86 (d, 2H), 3.83 (s, 2H), 3.63 (s, 3H) The aqueous layer was removed was removed under reduced pressure The remaining toluene solution was washed with water twice (530 g×2) concentrated under reduced pressure at a temperature below 40° C. until the weight of the solution An activated charcoal (3 g) was added to the solution removed by filtration To the solution was added 2,6-dibutyl-4-hydroxytoluene (152 mg) concentrated under reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of p-bromomethylphenylacetic acid (50.0 g, 218 mmol) in MeOH (125 g) and toluene (250 g), was added thionyl chloride (15.6 g) dropwise at 0° C. and stirred for 3 hr. Separately NaHCO3 (33 g, 393 mmol) was dissolved in water (540 g), mixed with toluene (200 g) and cooled to 0° C. The reaction solution described above was added dropwise to the mixture and stirred for 1 hr. The aqueous layer was removed and the organic layer washed with water. The solution was then concentrated under reduced pressure at a temperature below 40° C. to give the subtitle compound as a crude product (58.9 g) used directly in the following reaction. 1H NMR (DMSO-d6) δ 7.37 (d, 2H), 7.34 (d, 2H), 4.62 (s, 2H), 3.73 (s, 2H), 3.63 (s, 3H) above was added dropwise to the mixture stirred for 1 hr The aqueous layer was removed the organic layer washed with water The solution was then concentrated under reduced pressure at a temperature below 40° C.

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In analogy to Example 140, step 6, 3-chloro-4-(3,3,3-trifluoro-2-hydroxy-2-isoquinolin-5-yl-1-methyl-propyl)-phenol (Example 147, step 5) was reacted with (4-bromomethyl-phenyl)-acetic acid methyl ester to give {4-[3-chloro-4-(3,3,3-trifluoro-2-hydroxy-2-isoquinolin-5-yl-1-methyl-propyl)-phenoxymethyl]-phenyl}-acetic acid methyl ester. This compound was hydrolyzed in analogy to Example 141 to give the title compound as an off-white solid. MS (m/e, ISP neg. ion)=528.0 [M-−H+].