Pentanoic acid,4-bromo-, ethyl ester

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 4-(4-chloro-2-fluorophenoxy)phenol (2.3 g, 0.0103 mol), ethyl 4-bromopentanoate (2.01 g, 0.0103 mol), and potassium carbonate (1.46 g, 0.105 mol) in DMF (20 ml) was heated in an oil bath at 130° C. for one hour. Additional bromide (0.5 g) and carbonate (0.5 g) were added each hour for the next four hours. At the end of this period, gas chromatography indicated that most of the starting phenol had reacted. After cooling, the reaction mixture was poured into 4N HCl solution (200 ml), and the product extracted into a 1:1 mixture of ether-pentane (2×150 ml). The organic extracts were combined, washed with 10% NaOH solution (200 ml), dried (MgSO4), then the solvent evaporated. The resulting orange oil was purified via preparative HPLC (9:1 hexane/ethyl acetate) with the second peak being collected. Removal of the solvent gave the desired ester as a light yellow oil: RI=1.5344 @ 25° C. Calc: C, 62.21; H, 5.50. Found: C, 62.38; H, 5.33. had reacted After cooling the product extracted into a 1:1 mixture of ether-pentane (2×150 ml) washed with 10% NaOH solution (200 ml) dried (MgSO4) the solvent evaporated The resulting orange oil was purified via preparative HPLC (9:1 hexane/ethyl acetate) with the second peak being collected Removal of the solvent

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 4-(4-chloro-2-fluorophenoxy)phenol (2.3 g, 0.0103 mol), ethyl 4-bromopentanoate (2.01 g, 0.0103 mol), and potassium carbonate (1.46 g, 0.105 mol) in DMF (20 ml) was heated in an oil bath at 130° C. for one hour. Additional bromide (0.5 g) and carbonate (0.5 g) were added each hour for the next four hours. At the end of this period, gas chromatography indicated that most of the starting phenol had reacted. After cooling, the reaction mixture was poured into 4N HCl solution (200 ml), and the product extracted into a 1:1 mixture of ether-pentane (2×150 ml). The organic extracts were combined, washed with 10% NaOH solution (200 ml), dried (MgSO4), then the solvent evaporated. The resulting orange oil was purified via preparative HPLC (9:1 hexane/ethyl acetate) with the second peak being collected. Removal of the solvent gave the desired ester as a light yellow oil. RI=1.5344 @ 25° C. Calc: C, 62.21; H, 5.50. Found: C, 62.38; H, 5.33. had reacted After cooling the product extracted into a 1:1 mixture of ether-pentane (2×150 ml) washed with 10% NaOH solution (200 ml) dried (MgSO4) the solvent evaporated The resulting orange oil was purified via preparative HPLC (9:1 hexane/ethyl acetate) with the second peak being collected Removal of the solvent

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 4-(4-chloro-2-fluorophenoxy)phenol (2.3 g, 0.0103 mol), ethyl 4-bromopentanoate (2.01 g, 0.0103 mol), and potassium carbonate (1.46 g, 0.105 mol) in DMF (20 ml) was heated in an oil bath at 130° C. for one hour. Additional bromide (0.5 g) and carbonate (0.5 g) were added each hour for the next four hours. At the end of this period, gas chromatography indicated that most of the starting phenol had reacted. After cooling, the reaction mixture was poured into 4N HCl solution (200 ml), and the product extracted into a 1:1 mixture of ether-pentane (2×150 ml). The organic extracts were combined, washed with 10% NaOH solution (200 ml), dried (MgSO4), then the solvent evaporated. The resulting orange oil was purified via preparative HPLC (9:1 hexane/ethyl acetate) with the second peak being collected. Removal of the solvent gave the desired ester as a light yellow oil. RI=1.5344 @ 25° C. Calc: C, 62.21; H, 5.50. Found: C, 62.38; H, 5.33. had reacted After cooling the product extracted into a 1:1 mixture of ether-pentane (2×150 ml) washed with 10% NaOH solution (200 ml) dried (MgSO4) the solvent evaporated The resulting orange oil was purified via preparative HPLC (9:1 hexane/ethyl acetate) with the second peak being collected Removal of the solvent

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 4-(4-chloro-2-fluorophenoxy)phenol (2.3 g, 0.0103 mol), ethyl 4-bromopentanoate (2.01 g, 0.0103 mol), and potassium carbonate (1.46 g, 0.105 mol) in DMF (20 ml) was heated in an oil bath at 130° C. for one hour. Additional bromide (0.5 g) and carbonate (0.5 g) were added each hour for the next four hours. At the end of this period, gas chromatography indicated that most of the starting phenol had reacted. After cooling, the reaction mixture was poured into 4N HCl solution (200 ml), and the product extracted into a 1:1 mixture of ether-pentane (2×150 ml). The organic extracts were combined, washed with 10% NaOH solution (200 ml), dried (MgSO4), then the solvent evaporated. The resulting orange oil was purified via preparative HPLC (9:1 hexane/ethyl acetate) with the second peak being collected. Removal of the solvent gave the desired ester as a light yellow oil: RI=1.5344 @ 25° C. Calc: C, 62.21; H, 5.50. Found: C, 62.38; H, 5.33. had reacted After cooling the product extracted into a 1:1 mixture of ether-pentane (2×150 ml) washed with 10% NaOH solution (200 ml) dried (MgSO4) the solvent evaporated The resulting orange oil was purified via preparative HPLC (9:1 hexane/ethyl acetate) with the second peak being collected Removal of the solvent

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 4-(4-chloro-2-fluorophenoxy)phenol (2.3 g, 0.0103 mol), ethyl 4-bromopentanoate (2.01 g, 0.0103 mol), and potassium carbonate (1.46 g, 0.105 mol) in DMF (20 ml) was heated in an oil bath at 130° C. for one hour. Additional bromide (0.5 g) and carbonate (0.5 g) were added each hour for the next four hours. At the end of this period, gas chromatography indicated that most of the starting phenol had reacted. After cooling, the reaction mixture was poured into 4N HCl solution (200 ml), and the product extracted into a 1:1 mixture of ether-pentane (2×150 ml). The organic extracts were combined, washed with 10% NaOH solution (200 ml), dried (MgSO4), then the solvent evaporated. The resulting orange oil was purified via preparative HPLC (9:1 hexane/ethyl acetate) with the second peak being collected. Removal of the solvent gave the desired ester as a light yellow oil: RI=1.5344 @ 25° C. Calc: C, 62.21; H, 5.50. Found: C, 62.38; H, 5.33. had reacted After cooling the product extracted into a 1:1 mixture of ether-pentane (2×150 ml) washed with 10% NaOH solution (200 ml) dried (MgSO4) the solvent evaporated The resulting orange oil was purified via preparative HPLC (9:1 hexane/ethyl acetate) with the second peak being collected Removal of the solvent

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 4-(4-chloro-2-fluorophenoxy)phenol (2.3 g, 0.0103 mol), ethyl 4-bromopentanoate (2.01 g, 0.0103 mol), and potassium carbonate (1.46 g, 0.105 mol) in DMF (20 ml) was heated in an oil bath at 130° C. for one hour. Additional bromide (0.5 g) and carbonate (0.5 g) were added each hour for the next four hours. At the end of this period, gas chromatography indicated that most of the starting phenol had reacted. After cooling, the reaction mixture was poured into 4N HCl solution (200 ml), and the product extracted into a 1:1 mixture of ether-pentane (2×150 ml). The organic extracts were combined, washed with 10% NaOH solution (200 ml), dried (MgSO4), then the solvent evaporated. The resulting orange oil was purified via preparative HPLC (9:1 hexane/ethyl acetate) with the second peak being collected. Removal of the solvent gave the desired ester as a light yellow oil: RI=1.5344 @ 25° C. Calc: C, 62.21; H, 5.50. Found: C, 62.38; H, 5.33. had reacted After cooling the product extracted into a 1:1 mixture of ether-pentane (2×150 ml) washed with 10% NaOH solution (200 ml) dried (MgSO4) the solvent evaporated The resulting orange oil was purified via preparative HPLC (9:1 hexane/ethyl acetate) with the second peak being collected Removal of the solvent

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

Procedure: A mixture of 4-[N-methyl-N-(5-chloro-2-benzoxazolyl)amino]phenol (1.0 g, 0.0039 mole; see Example 7 part (a), ethyl 4-bromovalerate (0.89 g, 0.0043 mole), anhydrous potassium carbonate (0.54 g) and methyl isobutyl ketone (15 ml) was heated under reflux for a period of 30 hours with further portions (0.05 g) of anhydrous potassium carbonate being added at 3 hour intervals. The reaction mixture was cooled, filtered and the filtrate was distilled under reduced pressure to remove the solvent. The residue (a red oil) was distilled under reduced pressure, bp 240°-260° C. at 0.04 mm Hg and the distillate was further purified by preparative thin layer chromatography on silica gel (eluent chloroform/ethanol 15:1) to give the title compound (0.47 g) as a red oil. The pmr and mass spectra of the compound were consistent with the assigned structure. was heated added at 3 hour intervals The reaction mixture was cooled filtered the filtrate was distilled under reduced pressure to remove the solvent The residue (a red oil) was distilled under reduced pressure, bp 240°-260° C. at 0.04 mm Hg the distillate was further purified by preparative thin layer chromatography on silica gel (eluent chloroform/ethanol 15:1)

Conditions: temp:52.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 49 (200 mg, 0.39 mmol, scheme 15) and DIPEA (202 μl, 1.16 mmol) in DMSO (5 ml) at rt under nitrogen was added ethyl 4-bromovalerate (85 μl, 0.58 mmol), and the reaction mixture was heated at 50-55° C. for 1 h, then at rt. The reaction mixture was diluted with AcOEt, and successively washed with water, a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified twice by Biotage (SiliaFlash 25 g cartridge: 2% of ammonium hydroxide in MeOH/DCM: 1/99 to 10/90 over 20 CV, then 10/90 to 15/85 over 10 CV; Snap 25 g cartridge: 2% of ammonium hydroxide in MeOH/DCM: 1/99 to 15/85 over 30 CV) to afford the desired product 517 (94 mg, 0.145 mmol, 37% yield) as a colorless sticky solid. MS (m/z): 647.75 (M+H). at rt successively washed with water a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate filtered concentrated The residue was purified twice by Biotage (SiliaFlash 25 g cartridge

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 4-(4-chloro-2-fluorophenoxy)phenol (2.3 g, 0.0103 mole), ethyl 4-bromopentanoate (2.01 g, 0.103 mole), and potassium carbonate (1.46 g, 0.105 mole) in DMF (20 ml) was heated in an oil bath at 130° C. for one hour. Additional bromide (0.05 g) and carbonate (0.5 g) were added each hour for the next four hours. At the end of this period, gas chromatography indicated that most of the starting phenol had reacted. After cooling, the reaction mixture was poured into 4N HCl solution (200 ml), and the product extracted into a 1:1 mixture of ether-pentane (2×150 ml). The organic extracts were combined, washed with 10% NaOH solution (200 ml), dried (MgSO4), then the solvent evaporated. The resulting orange oil was purified via preparative HPLC (9:1 hexane/ethyl acetate) with the second peak being collected. Removal of the solvent gave the desired ester as a light yellow oil: RI=1.5344@25° C. Calc: C, 62.21; H, 5.50. Found: C, 62.38; H, 5.33. had reacted After cooling the product extracted into a 1:1 mixture of ether-pentane (2×150 ml) washed with 10% NaOH solution (200 ml) dried (MgSO4) the solvent evaporated The resulting orange oil was purified via preparative HPLC (9:1 hexane/ethyl acetate) with the second peak being collected Removal of the solvent

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 4-(4-chloro-2-fluorophenoxy)phenol (2.3 g, 0.0103 mol), ethyl 4-bromopentanoate (2.01 g, 0.0103 mol), and potassium carbonate (1.46 g, 0.105 mol) in DMF (20 ml) was heated in an oil bath at 130° C. for one hour. Additional bromide (0.5 g) and carbonate (0.5 g) were added each hour for the next four hours. At the end of this period, gas chromatography indicated that most of the starting phenol had reacted. After cooling, the reaction mixture was poured into 4N HCl solution (200 ml), and the product extracted into a 1:1 mixture of ether-pentane (2×150 ml). The organic extracts were combined, washed with 10% NaOH solution (200 ml), dried (MgSO4), then the solvent evaporated. The resulting orange oil was purified via preparative HPLC (9:1 hexane/ethyl acetate) with the second peak being collected. Removal of the solvent gave the desired ester as a light yellow oil. RI=1.5344 @ 25° C. Calc: C, 62.21; H, 5.50. Found: C, 62.38; H, 5.33. had reacted After cooling the product extracted into a 1:1 mixture of ether-pentane (2×150 ml) washed with 10% NaOH solution (200 ml) dried (MgSO4) the solvent evaporated The resulting orange oil was purified via preparative HPLC (9:1 hexane/ethyl acetate) with the second peak being collected Removal of the solvent

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 4-(4-chloro-2-fluorophenoxy)phenol (2.3 g, 0.0103 mol), ethyl 4-bromopentanoate (2.01 g, 0.0103 mol), and potassium carbonate (1.46 g, 0.105 mol) in DMF (20 ml) was heated in an oil bath at 130° C. for one hour. Additional bromide (0.5 g) and carbonate (0.5 g) were added each hour for the next four hours. At the end of this period, gas chromatography indicated that most of the starting phenol had reacted. After cooling, the reaction mixture was poured into 4N HCl solution (200 ml), and the product extracted into a 1:1 mixture of ether-pentane (2×150 ml). The organic extracts were combined, washed with 10% NaOH solution (200 ml), dried (MgSO4), then the solvent evaporated. The resulting orange oil was purified via preparative HPLC (9:1 hexane/ethyl acetate) with the second peak being collected. Removal of the solvent gave the desired ester as a light yellow oil: RI=1.5344 @ 25° C. Calc: C, 62.21; H, 5.50. Found: C, 62.38; H, 5.33. had reacted After cooling the product extracted into a 1:1 mixture of ether-pentane (2×150 ml) washed with 10% NaOH solution (200 ml) dried (MgSO4) the solvent evaporated The resulting orange oil was purified via preparative HPLC (9:1 hexane/ethyl acetate) with the second peak being collected Removal of the solvent

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 4-(4-chloro-2-fluorophenoxy)phenol (2.3 g, 0.0103 mol), ethyl 4-bromopentanoate (2.01 g, 0.0103 mol), and potassium carbonate (1.46 g, 0.105 mol) in DMF (20 ml) was heated in an oil bath at 130° C. for one hour. Additional bromide (0.5 g) and carbonate (0.5 g) were added each hour for the next four hours. At the end of this period, gas chromatography indicated that most of the starting phenol had reacted. After cooling, the reaction mixture was poured into 4N HCl solution (200 ml), and the product extracted into a 1:1 mixture of ether-pentane (2×150 ml). The organic extracts were combined, washed with 10% NaOH solution (200 ml), dried (MgSO4), then the solvent evaporated. The resulting orange oil was purified via preparative HPLC (9:1 hexane/ethyl acetate) with the second peak being collected. Removal of the solvent gave the desired ester as a light yellow oil: RI=1.5344 @ 25° C. Calc: C, 62.21; H, 5.50. Found: C, 62.38; H, 5.33. had reacted After cooling the product extracted into a 1:1 mixture of ether-pentane (2×150 ml) washed with 10% NaOH solution (200 ml) dried (MgSO4) the solvent evaporated The resulting orange oil was purified via preparative HPLC (9:1 hexane/ethyl acetate) with the second peak being collected Removal of the solvent