ethyl 2-(4-fluorophenyl)acetate

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

Procedure: 3-(4-Fluorophenyl)-1,4-dihydro-4-oxo-5-(4-chlorophenylamino)-1,6-naphthyridine The title compound was prepared as described in Example 1 above except that ethyl (4-chlorophenyl)acetate was replaced with ethyl (4-fluorophenyl)acetate and phenethylamine was replaced with 4-chloroaniline. MS 366 (M+1)+.

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

Procedure: 1 N Lithium bis(trimethylsilyl)amide (20 mL, 20 mmol) was added dropwise to a solution of ethyl (4-fluorophenyl)acetate prepared according to the method of Example 1A, (3.84 g, 20 mmol) in THF (20 mL) at −78° C. After 15 minutes the mixture was treated dropwise with a suspension of crude 4-(methylthio)benzoyl chloride (3.7 g, 20 mmol) in THF (50 mL), and the resulting mixture was stirred at −78° C. for 60 minutes. The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate. The acetate layer was washed with water, brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was chromatographed (silica gel, 19:1 CH2Cl2-ethyl acetate) to provide the desired product (yield: 4.55 g; 69%). MS (DCI-NH3) m/z 333 (M+H)+, 350 (M+NH4)+; 1H NMR (300 MHz, CDCl3) δ1.25 (m, 3H), 2.50 (s, 3H), 4.20 (m, 2H), 5.53 (s, 1H), 7.03 (t, J=9 Hz, 2H), 7.22 (d, J=9 Hz, 2H), 7.38 (m, 2H), 7.85 (d, J=9 Hz, 2H). prepared The reaction was quenched with saturated NH4Cl extracted with ethyl acetate The acetate layer was washed with water, brine dried over anhydrous MgSO4 concentrated in vacuo The residue was chromatographed (silica gel, 19:1 CH2Cl2-ethyl acetate)

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

Procedure: 1 N Lithium bis(trimethylsilyl)amide (20 mL, 20 mmol) was added dropwise to a solution of ethyl (4-fluorophenyl)acetate prepared according to the method of Example 1A, (3.84 g, 20 mmol) in THF (20 mL) at −78° C. After 15 minutes the mixture was treated dropwise with a suspension of crude 4-(methylthio)benzoyl chloride (3.7 g, 20 mmol) in THF (50 mL), and the resulting mixture was stirred at −78° C. for 60 minutes. The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate. The acetate layer was washed with water, brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was chromatographed (silica gel, 19:1 CH2Cl2-ethyl acetate) to provide the desired product (yield: 4.55 g; 69%). MS (DCI-NH3) m/z 333 (M+H)+, 350 (M+NH4)+; 1H NMR (300 MHz, CDCl3) δ1.25 (m, 3H), 2.50 (s, 3H), 4.20 (m, 2H), 5.53 (s, 1H), 7.03 (t, J=9 Hz, 2H), 7.22 (d, J=9 Hz, 2H), 7.38 (m, 2H), 7.85 (d, J=9 Hz, 2H). prepared The reaction was quenched with saturated NH4Cl extracted with ethyl acetate The acetate layer was washed with water, brine dried over anhydrous MgSO4 concentrated in vacuo The residue was chromatographed (silica gel, 19:1 CH2Cl2-ethyl acetate)

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

Procedure: A mixture of ethyl 2-(4-fluorophenyl)acetate (273 g, 1.5 mol) and 4-cyanopyridine (156.1 g, 1.5 mol) was dissolved in 1.5 L of DMF in a 12 L, 3-necked r.b.flask equipped with a mechanical stir, temperature probe and 1 L addition funnel. 1.5 L of 1.0M tBuOK/tBuOH (1.5 mol) was added into the solution slowly at RT through a 1L addition funnel. The resulting brown solution was stirred at RT for 1 h. A solution of 109.7 g of MeNCS (1.5 mol) in 750 ml DMF was added into the reaction solution slowly at RT. The temperature of the solution was increased from 26° C. to 33° C. The resulting brown solution was stirred for 1 h. The reaction solution was cooled down to ca. 0° C. using ice-water bath and 93 ml of MeI (1.5 mol) was added into the reaction solution through a 125-ml addition funnel. The reaction solution was stirred at RT and a precipitate formed after 30 min. The suspension was stirred at RT overnight. The solid was filtered off and washed with water (2×200 ml) and dried under vacuum at 50° C. overnight. 5-(4-fluorophenyl)-3-methyl-2-methylthio-6-(4-pyridyl)-3H-pyrimidin-4-one was obtained; MS: m/z (M+H)+ 328; C17H14FN3OS requir. 327. equipped with a mechanical stir, temperature probe and 1 L addition funnel The temperature of the solution was increased from 26° C. to 33° C The resulting brown solution was stirred for 1 h The reaction solution was cooled down to ca. 0° C. The reaction solution was stirred at RT a precipitate formed after 30 min The suspension was stirred at RT overnight The solid was filtered off washed with water (2×200 ml) dried under vacuum at 50° C. overnight

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

Procedure: Combined ethyl 2-(4-fluorophenyl)acetate (500 mg, 2.74 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (1.837 mL, 13.72 mmol) and DMF (2 mL) and heated at 100° C. for 5 h. The reaction was then diluted with EtOAc (50 mL), washed with saturated aqueous ammonium chloride (50 mL) and brine, dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was purified on a 30 g NH silica column (Moritex) eluted with 0 to 60% EtOAc in hexanes to give the title compound (223 mg, 34.2% yield) as a clear, colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.1 Hz, 3 H) 2.64 (s, 6 H) 3.98 (q, J=7.1 Hz, 2 H) 7.06-7.15 (m, 4 H) 7.49 (s, 1 H). washed with saturated aqueous ammonium chloride (50 mL) and brine dried over magnesium sulfate concentrated in vacuo to give a yellow oil The oil was purified on a 30 g NH silica column (Moritex) eluted with 0 to 60% EtOAc in hexanes

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

Procedure: Combined ethyl 2-(4-fluorophenyl)acetate (500 mg, 2.74 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (1.837 mL, 13.72 mmol) and DMF (2 mL) and heated at 100° C. for 5 h. The reaction was then diluted with EtOAc (50 mL), washed with saturated aqueous ammonium chloride (50 mL) and brine, dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was purified on a 30 g NH silica column (Moritex) eluted with 0 to 60% EtOAc in hexanes to give the title compound (223 mg, 34.2% yield) as a clear, colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.1 Hz, 3H) 2.64 (s, 6H) 3.98 (q, J=7.1 Hz, 2H) 7.06-7.15 (m, 4H) 7.49 (s, 1H). washed with saturated aqueous ammonium chloride (50 mL) and brine dried over magnesium sulfate concentrated in vacuo to give a yellow oil The oil was purified on a 30 g NH silica column (Moritex) eluted with 0 to 60% EtOAc in hexanes

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

Procedure: Combined ethyl 2-(4-fluorophenyl)acetate (500 mg, 2.74 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (1.837 mL, 13.72 mmol) and DMF (2 mL) and heated at 100° C. for 5 h. The reaction was then diluted with EtOAc (50 mL), washed with saturated aqueous ammonium chloride (50 mL) and brine, dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was purified on a 30 g NH silica column (Moritex) eluted with 0 to 60% EtOAc in hexanes to give the title compound (223 mg, 34.2% yield) as a clear, colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.1 Hz, 3H) 2.64 (s, 6H) 3.98 (q, J=7.1 Hz, 2H) 7.06-7.15 (m, 4H) 7.49 (s, 1H). washed with saturated aqueous ammonium chloride (50 mL) and brine dried over magnesium sulfate concentrated in vacuo to give a yellow oil The oil was purified on a 30 g NH silica column (Moritex) eluted with 0 to 60% EtOAc in hexanes

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

Procedure: A mixture of NaH (1.7 g, 71 mmol) in 100 mL NMP stirred at 0° C., was treated dropwise with a mixture of ethyl 2-(4-fluorophenyl)acetate (5.2 g, 29 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (6.6 g, 29 mmol) in 20 mL ether. The mixture was allowed to warm to room temperature and stirred for 5 hours, M+1=253. The mixture was then carefully quenched with 100 mL H2O, and the pH was adjusted to 5. The mixture was extracted with ether (3×100 mL). The combined organic layers were washed with H2O (3×50 mL) and brine (20 mL). The combined organic layers were then dried over anhydrous Na2SO4 and concentrated in vacuo to give 7.1 g of the crude product as a pale yellow oil. MS (m/z)=253 (M+H)+. to warm to room temperature stirred for 5 hours The mixture was then carefully quenched with 100 mL H2O The mixture was extracted with ether (3×100 mL) The combined organic layers were washed with H2O (3×50 mL) and brine (20 mL) The combined organic layers were then dried over anhydrous Na2SO4 concentrated in vacuo

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

Procedure: A mixture of 2-(4-fluorophenyl)acetic acid (23.5 g, 152 mmol) in thionyl chloride 56 mL, 762 mmol) was refluxed for 2 hours and then concentrated in vacuo. The residue was diluted with 200 mL DCM, and stirred at 0° C. The mixture was treated with EtOH (9.8 mL, 168 mmol) and TEA (26 mL) dropwise. The mixture was then stirred for 2 hours. The mixture was quenched with 20 mL H2O and extracted with DCM (3×50 mL). The combined organics were washed with H2O (3×50 mL) and brine 20 mL, dried over anhydrous Na2SO4, and concentrated in vacuo to give 24.7 g of a pale yellow oil. was refluxed for 2 hours concentrated in vacuo The residue was diluted with 200 mL DCM The mixture was then stirred for 2 hours The mixture was quenched with 20 mL H2O extracted with DCM (3×50 mL) The combined organics were washed with H2O (3×50 mL) and brine 20 mL dried over anhydrous Na2SO4 concentrated in vacuo

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

Procedure: A mixture of NaH (1.7 g, 71 mmol) in 100 mL NMP stirred at 0° C., was treated dropwise with a mixture of ethyl 2-(4-fluorophenyl)acetate (5.2 g, 29 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (6.6 g, 29 mmol) in 20 mL ether. The mixture was allowed to warm to room temperature and stirred for 5 hours, M+1=253. The mixture was then carefully quenched with 100 mL H2O, and the pH was adjusted to 5. The mixture was extracted with ether (3×100 mL). The combined organic layers were washed with H2O (3×50 mL) and brine (20 mL). The combined organic layers were then dried over anhydrous Na2SO4 and concentrated in vacuo to give 7.1 g of the crude product as a pale yellow oil. MS (m/z)=253 (M+H)+. to warm to room temperature stirred for 5 hours The mixture was then carefully quenched with 100 mL H2O The mixture was extracted with ether (3×100 mL) The combined organic layers were washed with H2O (3×50 mL) and brine (20 mL) The combined organic layers were then dried over anhydrous Na2SO4 concentrated in vacuo

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

Procedure: A mixture of 2-(4-fluorophenyl)acetic acid (23.5 g, 152 mmol) in thionyl chloride 56 mL, 762 mmol) was refluxed for 2 hours and then concentrated in vacuo. The residue was diluted with 200 mL DCM, and stirred at 0° C. The mixture was treated with EtOH (9.8 mL, 168 mmol) and TEA (26 mL) dropwise. The mixture was then stirred for 2 hours. The mixture was quenched with 20 mL H2O and extracted with DCM (3×50 mL). The combined organics were washed with H2O (3×50 mL) and brine 20 mL, dried over anhydrous Na2SO4, and concentrated in vacuo to give 24.7 g of a pale yellow oil. was refluxed for 2 hours concentrated in vacuo The residue was diluted with 200 mL DCM The mixture was then stirred for 2 hours The mixture was quenched with 20 mL H2O extracted with DCM (3×50 mL) The combined organics were washed with H2O (3×50 mL) and brine 20 mL dried over anhydrous Na2SO4 concentrated in vacuo

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: p-Fluorotoluene (1.65 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 76 mg ethyl p-fluorophenylacetate was obtained by column chromatography, in a yield of 84%. 1HNMR (400 MHz, CDCl3) δ 1.23 (t, J=7.2 Hz, 3H), 3.58 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 6.98-7.03 (m, 2H), 7.23-7.26 (m, 2H); 13CNMR (100 MHz, CDCl3) δ 14.2, 40.5, 60.9, 115.3, 115.5, 129.8, 129.9, 130.8, 130.9, 160.8, 163.2, 171.5; HRMS (ESI) calcd. for C10H11FNaO2 [M+Na]: 205.0635. found: 205.0634. The ethyl p-fluorophenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 59 mg product p-fluorophenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 91%. was introduced