methyl 2-(3,5-difluorophenyl)-2-hydroxyacetate

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

実験手順: Methyl 3,5-difluoromandelate was prepared following General Procedure G below and using commerically available 3,5-difluoromandelic acid. The resultant α-hydroxy methyl ester was fluorinated according to the general procedure described in W. J. Middleton, et al., Org. Synth. CoL Vol. VI, 835. Specifically, a solution of diethylaminosulfur trifluoride (1.1 eq) in CH2Cl2 was cooled to 0° C. and treated with methyl 3,5-difluoromandelate (1.0 eq) as a solution in CH2Cl2. After 10 min. the cooling bath was removed and the reaction was stirred at ambient temperature for 30 min. The reaction was monitored by tlc (Rf=0.65, 1:1 ethyl acetate/hexanes). The mixture was then poured onto ice and the layers separated. The organic phase was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo, The product was purified by LC2000 chromatograpy (180 mL/min) using 10% EtoAc/hexanes as the eluent. The resulting methyl 3,5-difluorophenyl-α-fluoroacetate was hydrolyzed by dissolving the ester in 70% aqueous dioxane and treating with lithium hydroxide (2.0 eq.). No starting material remained by tlc after 2 h. The dioxane was removed via rotary evaporation. The aqueous mixture was first washed with ethyl acetate and then acidified with 0.01 N HCl. The aqueous layer was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude solid was recrystallized from ethyl acetate/hexanes affording 3,5-difluorophenyl-α-fluoroacetic acid as a white solid having a melting point of 90-110° C. After 10 min. the cooling bath was removed The mixture was then poured onto ice the layers separated The organic phase was washed with saturated aqueous NaHCO3 and brine The organic layer was dried over Na2SO4 filtered concentrated in vacuo The product was purified by LC2000 chromatograpy (180 mL/min) by dissolving the ester in 70% aqueous dioxane tlc after 2 h The dioxane was removed via rotary evaporation The aqueous mixture was first washed with ethyl acetate The aqueous layer was extracted with ethyl acetate The organic phase was washed with brine dried over Na2SO4 filtered concentrated The crude solid was recrystallized from ethyl acetate/hexanes

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

実験手順: 25.0 g of 3,5-difluorophenylhydroxyacetic acid (D2) are dissolved in 325 ml of methanol. 3.9 g of boric acid are subsequently added, and the reaction mixture is stirred at room temperature for 18 hours. The resultant solution is then evaporated to dryness. The residue is extracted using 100 ml of ethyl acetate and 100 ml of water. The aqueous phase is subsequently extracted twice with 50 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulfate and filtered. The filtrate is evaporated to dryness in vacuo, giving 25.5 g of the title compound as crude product. Recrystallisation from 17 ml of ethyl acetate and 170 ml of cyclohexane give 23.5 g of the pure compound C2 having a melting point of 61.8° C. (MS 201.9 (M+)). The resultant solution is then evaporated to dryness The residue is extracted The aqueous phase is subsequently extracted twice with 50 ml of ethyl acetate each time The combined organic phases are dried over sodium sulfate filtered The filtrate is evaporated to dryness in vacuo

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

実験手順: 25.0 g of 3,5-difluorophenylhydroxyacetic acid (D2) are dissolved in 325 ml of methanol. 3.9 g of boric acid are subsequently added, and the reaction mixture is stirred at room temperature for 18 hours. The resultant solution is then evaporated to dryness. The residue is extracted using 100 ml of ethyl acetate and 100 ml of water. The aqueous phase is subsequently extracted twice with 50 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulfate and filtered. The filtrate is evaporated to dryness in vacuo, giving 25.5 g of the title compound as crude product. Recrystallisation from 17 ml of ethyl acetate and 170 ml of cyclohexane give 23.5 g of the pure compound C2 having a melting point of 61.8° C. (MS 201.9 (M+)). The resultant solution is then evaporated to dryness The residue is extracted The aqueous phase is subsequently extracted twice with 50 ml of ethyl acetate each time The combined organic phases are dried over sodium sulfate filtered The filtrate is evaporated to dryness in vacuo

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

実験手順: 5.0 g of methyl 3,5-difluorophenylhydroxyacetate (C2) are dissolved in 45.0 ml of 2-propanol. 1.32 ml of hydrazine hydrate are then added dropwise, and the reaction mixture is kept under reflux for 18 hours. The solution is subsequently evaporated to dryness, and the resultant residue is purified by flash chromatography on silica gel (gradient for elution: ethyl acetate/0-20.0% by vol. of methanol), giving 3.70 g of the title compound as colourless solid having a melting point of 119.3° C. (MS: 202.8 (MH+)). under reflux for 18 hours The solution is subsequently evaporated to dryness the resultant residue is purified by flash chromatography on silica gel (gradient for elution: ethyl acetate/0-20.0% by vol. of methanol)

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

実験手順: Methyl 3,5-difluoromandelate was prepared following General Procedure G below and using commmerically available 3,5-difluoromandelic acid. The resultant α-hydroxy methyl ester was fluorinated according to the general procedure described in W. J. Middleton, et al., Org. Synth. Col. Vol. VI, 835. Specifically, a solution of diethylaminosulfur trifluoride (1.1 eq) in CH2Cl2 was cooled to 0° C. and treated with methyl 3,5-difluoromandelate (1.0 eq) as a solution in CH2Cl2. After 10 min. the cooling bath was removed and the reaction was stirred at ambient temperature for 30 min. The reaction was monitored by tic (Rf=0.65, 1:1 ethyl acetate/hexanes). The mixture was then poured onto ice and the layers separated. The organic phase was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by LC2000 chromatograpy (180 mL/min) using 10% EtoAc/hexanes as the eluent. The resulting methyl 3,5-difluorophenyl-α-fluoroacetate was hydrolyzed by dissolving the ester in 70% aqueous dioxane and treating with lithium hydroxide (2.0 eq.). No starting material remained by tic after 2 h. The dioxane was removed via rotary evaporation. The aqueous mixture was first washed with ethyl acetate and then acidified with 0.01 N HCl. The aqueous layer was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude solid was recrystallized from ethyl acetate/hexanes affording 3,5-difluorophenyl-α-fluoroacetic acid as a white solid having a melting point of 90-110° C. C8H5F3O2 (MW=190.1); mass spectroscopy: 190.1. After 10 min. the cooling bath was removed The mixture was then poured onto ice the layers separated The organic phase was washed with saturated aqueous NaHCO3 and brine The organic layer was dried over Na2SO4 filtered concentrated in vacuo The product was purified by LC2000 chromatograpy (180 mL/min) by dissolving the ester in 70% aqueous dioxane tic after 2 h The dioxane was removed via rotary evaporation The aqueous mixture was first washed with ethyl acetate The aqueous layer was extracted with ethyl acetate The organic phase was washed with brine dried over Na2SO4 filtered concentrated The crude solid was recrystallized from ethyl acetate/hexanes

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

実験手順: Methyl 3,5-difluoromandelate was prepared following General Procedure G below and using commmerically available 3,5-difluoromandelic acid. The resultant α-hydroxy methyl ester was fluorinated according to the general procedure described in W. J. Middleton, et al., Org. Synth. Col. Vol. VI, 835. Specifically, a solution of diethylaminosulfur trifluoride (1.1 eq) in CH2Cl2 was cooled to 0° C. and treated with methyl 3,5-difluoromandelate (1.0 eq) as a solution in CH2Cl2. After 10 min. the cooling bath was removed and the reaction was stirred at ambient temperature for 30 min. The reaction was monitored by tic (Rf=0.65, 1:1 ethyl acetate/hexanes). The mixture was then poured onto ice and the layers separated. The organic phase was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by LC2000 chromatograpy (180 mL/min) using 10% EtoAc/hexanes as the eluent. The resulting methyl 3,5-difluorophenyl-α-fluoroacetate was hydrolyzed by dissolving the ester in 70% aqueous dioxane and treating with lithium hydroxide (2.0 eq.). No starting material remained by tic after 2 h. The dioxane was removed via rotary evaporation. The aqueous mixture was first washed with ethyl acetate and then acidified with 0.01 N HCl. The aqueous layer was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude solid was recrystallized from ethyl acetate/hexanes affording 3,5-difluorophenyl-α-fluoroacetic acid as a white solid having a melting point of 90-110° C. C8H5F3O2 (MW=190.1); mass spectroscopy: 190.1. After 10 min. the cooling bath was removed The mixture was then poured onto ice the layers separated The organic phase was washed with saturated aqueous NaHCO3 and brine The organic layer was dried over Na2SO4 filtered concentrated in vacuo The product was purified by LC2000 chromatograpy (180 mL/min) by dissolving the ester in 70% aqueous dioxane tic after 2 h The dioxane was removed via rotary evaporation The aqueous mixture was first washed with ethyl acetate The aqueous layer was extracted with ethyl acetate The organic phase was washed with brine dried over Na2SO4 filtered concentrated The crude solid was recrystallized from ethyl acetate/hexanes

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

実験手順: Methyl 3,5-difluoromandelate was prepared following General Procedure G below and using commmerically available 3,5-difluoromandelic acid. The resultant α-hydroxy methyl ester was fluorinated according to the general procedure described in W. J. Middleton, et al., Org. Synth. Col. Vol. VI, 835. Specifically, a solution of diethylaminosulfur trifluoride (1.1 eq) in CH2Cl2 was cooled to 0° C. and treated with methyl 3,5-difluoromandelate (1.0 eq) as a solution in CH2Cl2. After 10 min. the cooling bath was removed and the reaction was stirred at ambient temperature for 30 min. The reaction was monitored by tlc (Rf=0.65, 1:1 ethyl acetate/hexanes). The mixture was then poured onto ice and the layers separated. The organic phase was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by LC2000 chromatograpy (180 mL/min) using 10% EtoAc/hexanes as the eluent. The resulting methyl 3,5-difluorophenyl-α-fluoroacetate was hydrolyzed by dissolving the ester in 70% aqueous dioxane and treating with lithium hydroxide (2.0 eq.). No starting material remained by tlc after 2 h. The dioxane was removed via rotary evaporation. The aqueous mixture was first washed with ethyl acetate and then acidified with 0.01 N HCl. The aqueous layer was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated: The crude solid was recrystallized from ethyl acetate/hexanes affording 3,5-difluorophenyl-α-fluoroacetic acid as a white solid having a melting point of 90-110° C. After 10 min. the cooling bath was removed The mixture was then poured onto ice the layers separated The organic phase was washed with saturated aqueous NaHCO3 and brine The organic layer was dried over Na2SO4 filtered concentrated in vacuo The product was purified by LC2000 chromatograpy (180 mL/min) by dissolving the ester in 70% aqueous dioxane tlc after 2 h The dioxane was removed via rotary evaporation The aqueous mixture was first washed with ethyl acetate The aqueous layer was extracted with ethyl acetate The organic phase was washed with brine dried over Na2SO4 filtered concentrated The crude solid was recrystallized from ethyl acetate/hexanes

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

実験手順: Methyl 3,5-difluoromandelate was prepared following General Procedure G below and using commmerically available 3,5-difluoromandelic acid. The resultant α-hydroxy methyl ester was fluorinated according to the general procedure described in W. J. Middleton, et al., Org. Synth. Col. Vol. VI, 835. Specifically, a solution of diethylaminosulfur trifluoride (1.1 eq) in CH2Cl2 was cooled to 0° C. and treated with methyl 3,5-difluoromandelate (1.0 eq) as a solution in CH2Cl2. After 10 min. the cooling bath was removed and the reaction was stirred at ambient temperature for 30 min. The reaction was monitored by tlc (Rf=0.65, 1:1 ethyl acetate/hexanes). The mixture was then poured onto ice and the layers separated. The organic phase was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by LC2000 chromatography (180 mL/min) using 10% EtoAc/hexanes as the eluent. The resulting methyl 3,5-difluorophenyl-α-fluoroacetate was hydrolyzed by dissolving the ester in 70% aqueous dioxane and treating with lithium hydroxide (2.0 eq.). No starting material remained by tlc after 2 h. The dioxane was removed via rotary evaporation. The aqueous mixture was first washed with ethyl acetate and then acidified with 0.01 N HCl. The aqueous layer was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude solid was recrystallized from ethyl acetate/hexanes affording 3,5-difluorophenyl-α-fluoroacetic acid as a white solid having a melting point of 90-110° C. After 10 min. the cooling bath was removed The mixture was then poured onto ice the layers separated The organic phase was washed with saturated aqueous NaHCO3 and brine The organic layer was dried over Na2SO4 filtered concentrated in vacuo The product was purified by LC2000 chromatography (180 mL/min) by dissolving the ester in 70% aqueous dioxane tlc after 2 h The dioxane was removed via rotary evaporation The aqueous mixture was first washed with ethyl acetate The aqueous layer was extracted with ethyl acetate The organic phase was washed with brine dried over Na2SO4 filtered concentrated The crude solid was recrystallized from ethyl acetate/hexanes

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

実験手順: Methyl 3,5-difluoromandelate was prepared following General Procedure G below and using commerically available 3,5-difluoromandelic acid. The resultant α-hydroxy methyl ester was fluorinated according to the general procedure described in W. J. Middleton, et al., Org. Synth. CoL Vol. VI, 835. Specifically, a solution of diethylaminosulfur trifluoride (1.1 eq) in CH2Cl2 was cooled to 0° C. and treated with methyl 3,5-difluoromandelate (1.0 eq) as a solution in CH2Cl2. After 10 min. the cooling bath was removed and the reaction was stirred at ambient temperature for 30 min. The reaction was monitored by tlc (Rf=0.65, 1:1 ethyl acetate/hexanes). The mixture was then poured onto ice and the layers separated. The organic phase was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo, The product was purified by LC2000 chromatograpy (180 mL/min) using 10% EtoAc/hexanes as the eluent. The resulting methyl 3,5-difluorophenyl-α-fluoroacetate was hydrolyzed by dissolving the ester in 70% aqueous dioxane and treating with lithium hydroxide (2.0 eq.). No starting material remained by tlc after 2 h. The dioxane was removed via rotary evaporation. The aqueous mixture was first washed with ethyl acetate and then acidified with 0.01 N HCl. The aqueous layer was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude solid was recrystallized from ethyl acetate/hexanes affording 3,5-difluorophenyl-α-fluoroacetic acid as a white solid having a melting point of 90-110° C. After 10 min. the cooling bath was removed The mixture was then poured onto ice the layers separated The organic phase was washed with saturated aqueous NaHCO3 and brine The organic layer was dried over Na2SO4 filtered concentrated in vacuo The product was purified by LC2000 chromatograpy (180 mL/min) by dissolving the ester in 70% aqueous dioxane tlc after 2 h The dioxane was removed via rotary evaporation The aqueous mixture was first washed with ethyl acetate The aqueous layer was extracted with ethyl acetate The organic phase was washed with brine dried over Na2SO4 filtered concentrated The crude solid was recrystallized from ethyl acetate/hexanes

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

実験手順: Methyl 3,5-difluoromandelate was prepared following General Procedure G below and using commerically available 3,5-difluoromandelic acid. The resultant α-hydroxy methyl ester was fluorinated according to the general procedure described in W. J. Middleton, et al., Org. Synth. CoL Vol. VI, 835. Specifically, a solution of diethylaminosulfur trifluoride (1.1 eq) in CH2Cl2 was cooled to 0° C. and treated with methyl 3,5-difluoromandelate (1.0 eq) as a solution in CH2Cl2. After 10 min. the cooling bath was removed and the reaction was stirred at ambient temperature for 30 min. The reaction was monitored by tlc (Rf=0.65, 1:1 ethyl acetate/hexanes). The mixture was then poured onto ice and the layers separated. The organic phase was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo, The product was purified by LC2000 chromatograpy (180 mL/min) using 10% EtoAc/hexanes as the eluent. The resulting methyl 3,5-difluorophenyl-α-fluoroacetate was hydrolyzed by dissolving the ester in 70% aqueous dioxane and treating with lithium hydroxide (2.0 eq.). No starting material remained by tlc after 2 h. The dioxane was removed via rotary evaporation. The aqueous mixture was first washed with ethyl acetate and then acidified with 0.01 N HCl. The aqueous layer was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude solid was recrystallized from ethyl acetate/hexanes affording 3,5-difluorophenyl-α-fluoroacetic acid as a white solid having a melting point of 90-110° C. After 10 min. the cooling bath was removed The mixture was then poured onto ice the layers separated The organic phase was washed with saturated aqueous NaHCO3 and brine The organic layer was dried over Na2SO4 filtered concentrated in vacuo The product was purified by LC2000 chromatograpy (180 mL/min) by dissolving the ester in 70% aqueous dioxane tlc after 2 h The dioxane was removed via rotary evaporation The aqueous mixture was first washed with ethyl acetate The aqueous layer was extracted with ethyl acetate The organic phase was washed with brine dried over Na2SO4 filtered concentrated The crude solid was recrystallized from ethyl acetate/hexanes

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

実験手順: A solution of diethylaminosulfur trifluoride (DAST) (1.1 eq) in methylene chloride was cooled to 0° C. and a pre-cooled solution of methyl 3,5-difluoromandelate (1 eq) in methylene chloride was added. The transfer flask was rinsed with a small portion of methylene chloride. After 15 minutes, the cooling bath was removed and the reaction mixture was stirred an additional 40 minutes at ambient temperature. The mixture was poured over ice and the layers separated. The organic phase was washed with saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified via HPLC eluting with 7% ethyl acetate/hexanes providing the title intermediate as a yellow oil. The transfer flask was rinsed with a small portion of methylene chloride the cooling bath was removed The mixture was poured over ice the layers separated The organic phase was washed with saturated NaHCO3 and brine The organic layer was dried over Na2SO4 filtered concentrated The residue was purified via HPLC eluting with 7% ethyl acetate/hexanes providing the title intermediate as a yellow oil

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

実験手順: A solution of diethylaminosulfur trifluoride (DAST) (1.1 eq) in methylene chloride was cooled to 0° C. and a pre-cooled solution of methyl 3,5-difluoromandelate (1 eq) in methylene chloride was added. The transfer flask was rinsed with a small portion of methylene chloride. After 15 minutes, the cooling bath was removed and the reaction mixture was stirred an additional 40 minutes at ambient temperature. The mixture was poured over ice and the layers separated. The organic phase was washed with saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified via HPLC eluting with 7% ethyl acetate/hexanes providing the title intermediate as a yellow oil. The transfer flask was rinsed with a small portion of methylene chloride the cooling bath was removed The mixture was poured over ice the layers separated The organic phase was washed with saturated NaHCO3 and brine The organic layer was dried over Na2SO4 filtered concentrated The residue was purified via HPLC eluting with 7% ethyl acetate/hexanes providing the title intermediate as a yellow oil