methyl 2-(3-fluoro-4-methoxyphenyl)acetate

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

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of freshly prepared lithium diisopropylamide (21.6 mL of 0.31M stock solution, 6.69 mmol) cooled to −78° C. was treated with a solution of (3-fluoro-4-methoxy-phenyl)-acetic acid methyl ester (1.26 g, 6.38 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (16 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.47 g, 7.02 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was warmed to 25° C. and stirred at 25° C. for 48 h. The reaction mixture was then quenched by the slow addition of a saturated aqueous ammonium chloride solution (10 mL). The reaction mixture was then poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-propionic acid methyl ester (1.50 g, 83.8%) as a clear oil: EI-HRMS m/e calcd for C16H21FO3(M+) 280.1477 found 280.1474. The reaction mixture was stirred at −78° C. for 4 h The reaction was warmed to 25° C. stirred at 25° C. for 48 h The reaction mixture was then quenched by the slow addition of a saturated aqueous ammonium chloride solution (10 mL) The reaction mixture was then poured into water (100 mL) extracted with ethyl acetate (3×50 mL) The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×50 mL) dried over sodium sulfate filtered concentrated in vacuo

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of freshly prepared lithium diisopropylamide (21.6 mL of 0.31M stock solution, 6.69 mmol) cooled to −78° C. was treated with a solution of (3-fluoro-4-methoxy-phenyl)-acetic acid methyl ester (1.26 g, 6.38 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (16 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.47 g, 7.02 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was warmed to 25° C. and stirred at 25° C. for 48 h. The reaction mixture was then quenched by the slow addition of a saturated aqueous ammonium chloride solution (10 mL). The reaction mixture was then poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-propionic acid methyl ester (1.50 g, 83.8%) as a clear oil: EI-HRMS m/e calcd for C16H21FO3(M+) 280.1477 found 280.1474. The reaction mixture was stirred at −78° C. for 4 h The reaction was warmed to 25° C. stirred at 25° C. for 48 h The reaction mixture was then quenched by the slow addition of a saturated aqueous ammonium chloride solution (10 mL) The reaction mixture was then poured into water (100 mL) extracted with ethyl acetate (3×50 mL) The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×50 mL) dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: The (3-fluoro-4-methoxyphenyl)acetic acid methyl ester (5.16 g, 26.0 mmol) is dissolved in carbon tetrachloride (300 mL) along with NBS (5.56 g, 31.3 mmol) and benzoyl peroxide (0.63 g, 2.60 mmol) and refluxed for 2 h. The solution is then allowed to cool to room temperature and is filtered. The filtrate is evaporated and the residue purified via flash column chromatography (EtOAc/hexanes 5:95→EtOAc/hexanes 2:8) to give bromo-(3-fluoro-4-methoxyphenyl)acetic acid methyl ester as a yellow oil. 1H NMR (CDCl3) δ 7.37 (d, J=12 Hz, 1H), 7.26-7.23 (m, 1H), 6.93 (t, J=8 Hz, 1H), 5.31 (s, 1H), 3.91 (s, 3H), 3.81 s, 3H). refluxed for 2 h is filtered The filtrate is evaporated the residue purified via flash column chromatography (EtOAc/hexanes 5:95→EtOAc/hexanes 2:8)

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

Procedure: (3-Fluoro-4-methoxyphenyl)acetic acid (5.0 g, 27.1 mmol) is dissolved in MeOH (100 mL). To it is added concentrated H2SO4 (5 mL) and the solution it warmed to reflux for 2 h. At that point, the solution is evaporated to dryness and taken up in EtOAc. The solution is washed with saturated aqueous NaHCO3, dried (Na2SO4) and evaporated to give (3-fluoro-4-methoxyphenyl)acetic acid methyl ester (cas#588-14-7) as a yellow oil. MS (ESI) m/z 199.3 (M+H). the solution it warmed to reflux for 2 h At that point, the solution is evaporated to dryness The solution is washed with saturated aqueous NaHCO3 dried (Na2SO4) evaporated

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

Procedure: (3-Fluoro-4-methoxyphenyl)acetic acid (5.0 g, 27.1 mmol) is dissolved in MeOH (100 mL). To it is added concentrated H2SO4 (5 mL) and the solution it warmed to reflux for 2 h. At that point, the solution is evaporated to dryness and taken up in EtOAc. The solution is washed with saturated aqueous NaHCO3, dried (Na2SO4) and evaporated to give (3-fluoro-4-methoxyphenyl)acetic acid methyl ester (cas#588-14-7) as a yellow oil. MS (ESI) m/z 199.3 (M+H). the solution it warmed to reflux for 2 h At that point, the solution is evaporated to dryness The solution is washed with saturated aqueous NaHCO3 dried (Na2SO4) evaporated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of freshly prepared lithium diisopropylamide (21.6 mL of 0.31M stock solution, 6.69 mmol) cooled to −78° C. was treated with a solution of (3-fluoro-4-methoxy-phenyl)-acetic acid methyl ester (1.26 g, 6.38 mmol) in tetrahydrofuran/l,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (16 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.47 g, 7.02 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was warmed to 25° C. and stirred at 25° C. for 48 h. The reaction mixture was then quenched by the slow addition of a saturated aqueous ammonium chloride solution (10 mL). The reaction mixture was then poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The organics were washed with a saturated aqueous lithium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-propionic acid methyl ester (1.50 g, 83.8%) as a clear oil: EI-HRMS m/e calcd for C16H21FO3(M+) 280.1477 found 280.1474. The reaction mixture was stirred at −78° C. for 4 h The reaction was warmed to 25° C. stirred at 25° C. for 48 h The reaction mixture was then quenched by the slow addition of a saturated aqueous ammonium chloride solution (10 mL) The reaction mixture was then poured into water (100 mL) extracted with ethyl acetate (3×50 mL) The organics were washed with a saturated aqueous lithium chloride solution (1×50 mL) dried over sodium sulfate filtered concentrated in vacuo

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of freshly prepared lithium diisopropylamide (21.6 mL of 0.31M stock solution, 6.69 mmol) cooled to −78° C. was treated with a solution of (3-fluoro-4-methoxy-phenyl)-acetic acid methyl ester (1.26 g, 6.38 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (16 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.47 g, 7.02 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was warmed to 25° C. and stirred at 25° C. for 48 h. The reaction mixture was then quenched by the slow addition of a saturated aqueous ammonium chloride solution (10 mL). The reaction mixture was then poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-propionic acid methyl ester (1.50 g, 83.8%) as a clear oil: EI-HRMS m/e calcd for C16H21FO3(M+) 280.1477 found 280.1474. The reaction mixture was stirred at −78° C. for 4 h The reaction was warmed to 25° C. stirred at 25° C. for 48 h The reaction mixture was then quenched by the slow addition of a saturated aqueous ammonium chloride solution (10 mL) The reaction mixture was then poured into water (100 mL) extracted with ethyl acetate (3×50 mL) The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×50 mL) dried over sodium sulfate filtered concentrated in vacuo

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: A 500 mL 24/40 round bottomed flask equipped with a stirring bar was charged with (3-fluoro-4-methoxyphenyl)acetic acid methyl ester (4.17 g) and dissolved in anhydrous carbon tetrachloride (200 mL). N-Bromosuccinimide (“NBS”) (4.89 g) was added, followed by benzoyl peroxide (“BPO”) (550 mg). The flask was equipped with a water cooled condenser and placed in a pre-heated 100° C. oil bath. After refluxing for 17.5 hours, the flask was removed from the oil bath, cooled to room temperature and filtered. The filtrate was analyzed by LCMS and TLC. Since the starting material and both products did not ionize well, TLC (40% ethyl acetate/heptane) was used to determine conversion of starting material to product. TLC indicated the starting material had been completely consumed. The filtrate was concentrated to a residue, dissolved in a minimal amount of DCM and adsorbed onto a silica pre-column. After ISCO purification (80 g column, 0-100% ethyl acetate/heptane over 25 column volumes) fractions for the major uv product (30-40% ethyl acetate) were combined and concentrated to yield methyl 2-bromo-2-(3-fluoro-4-methoxyphenyl)acetate (4.73 g). The NMR in CDCl3 was consistent with methyl 2-bromo-2-(3-fluoro-4-methoxyphenyl)acetate and matched that reported in WO 2007/024945. The fractions for a second minor uv active product (50-60% ethyl acetate) were combined and concentrated. NMR indicated the di-brominated compound methyl 2,2-dibromo-2-(3-fluoro-4-methoxyphenyl)acetate (0.539 g, 6.7%). The flask was equipped with a water cooled condenser placed in a pre-heated 100° C. After refluxing for 17.5 hours the flask was removed from the oil bath filtered had been completely consumed The filtrate was concentrated to a residue dissolved in a minimal amount of DCM After ISCO purification (80 g column, 0-100% ethyl acetate/heptane over 25 column volumes) fractions for the major uv product (30-40% ethyl acetate) concentrated