methyl 3,5-dichloro-2-hydroxybenzoate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 1 liter Parr autoclave was charged with 221 g. (1 mole) -dichlorophenyl)- of methyl 3,5-dichlorosalicylate and 140 g. (8 moles) of anhydrous ammonia. The mixture was stirred at 25° C for 24 hours. After venting excess ammonia, the product was ground to a fine powder and triturated with boiling chloroform. The mixture was filtered while hot and the residue weighed 153 g. Analysis by infrared, gas chromatography, and nuclear magnetic resonance confirmed that the product was 3,5-dichlorosalicylamide. A 1 liter Parr autoclave was charged with 221 g triturated with boiling chloroform The mixture was filtered while hot and the residue

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

実験手順: A 5 liter flask fitted with a sealed agitator, a condenser and a thermometer is used. 320 g of methyl 3,5-dichlorosalicylate (1.45 mole), 1,280 ml of methyl-ethyl-ketone and 177 g of propargyl bromide (1.45 mole+3% excess) are placed in it, then 200 g of potassium carbonate (1.45 mole) and 21.5 g of sodium iodide (0.145 mole). A thick pulp is obtained, which becomes fluid when brought to reflux. The reflux is maintained for 8 hours. A 5 liter flask fitted with a sealed agitator, a condenser A thick pulp is obtained to reflux The reflux is maintained for 8 hours

反応条件: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl-3,5-dichlorosalicylate (prepared according to Ahmed et al., Medicinal Chemistry 2008, 4, 298-308, which is expressly incorporated by reference herein; 2.0 g, 9.0 mmol) was dissolved in dry THF (30 mL), cooled to −40° C. and treated in portions with isopropyl magnesium chloride, 2.0 M in THF; 10 mL, 20 mmol). The mixture was stirred at −20 to −40° C. for 45 min, warmed to 25° C. and stirred for 4 h. The excess reagent was quenched by addition of satd NH4Cl (10 mL). The mixture was diluted with EtOAc (50 mL) and the pH was adjusted to ˜1 by addition of 1 M HCl. The organic phase was washed with satd NaCl solution (20 mL), dried (Na2SO4) and evaporated. The residue was purified by reverse-phase high-performance liquid chromatography (RP-HPLC) with 70% acetonitrile to give the purified ketone (1.1 g): mp: 102-104° C. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=2.5 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H), 3.54 (dt, J=13.6, 6.8 Hz, 1H), 1.26 (d, J=6.8 Hz, 6H); EIMS m/z 232. warmed to 25° C. stirred for 4 h The excess reagent was quenched by addition of satd NH4Cl (10 mL) The mixture was diluted with EtOAc (50 mL) the pH was adjusted to ˜1 by addition of 1 M HCl The organic phase was washed with satd NaCl solution (20 mL) dried (Na2SO4) evaporated The residue was purified by reverse-phase high-performance liquid chromatography (RP-HPLC) with 70% acetonitrile

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 1 liter Parr autoclave was charged with 221 g. (1 mole) -dichlorophenyl)- of methyl 3,5-dichlorosalicylate and 140 g. (8 moles) of anhydrous ammonia. The mixture was stirred at 25° C for 24 hours. After venting excess ammonia, the product was ground to a fine powder and triturated with boiling chloroform. The mixture was filtered while hot and the residue weighed 153 g. Analysis by infrared, gas chromatography, and nuclear magnetic resonance confirmed that the product was 3,5-dichlorosalicylamide. A 1 liter Parr autoclave was charged with 221 g triturated with boiling chloroform The mixture was filtered while hot and the residue

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 1 liter Parr autoclave was charged with 221 g. (1 mole) -dichlorophenyl)- of methyl 3,5-dichlorosalicylate and 140 g. (8 moles) of anhydrous ammonia. The mixture was stirred at 25° C for 24 hours. After venting excess ammonia, the product was ground to a fine powder and triturated with boiling chloroform. The mixture was filtered while hot and the residue weighed 153 g. Analysis by infrared, gas chromatography, and nuclear magnetic resonance confirmed that the product was 3,5-dichlorosalicylamide. A 1 liter Parr autoclave was charged with 221 g triturated with boiling chloroform The mixture was filtered while hot and the residue

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: A 5 liter flask fitted with a sealed agitator, a condenser and a thermometer is used. 320 g of methyl 3,5-dichlorosalicylate (1.45 mole), 1,280 ml of methyl-ethyl-ketone and 177 g of propargyl bromide (1.45 mole+3% excess) are placed in it, then 200 g of potassium carbonate (1.45 mole) and 21.5 g of sodium iodide (0.145 mole). A thick pulp is obtained, which becomes fluid when brought to reflux. The reflux is maintained for 8 hours. A 5 liter flask fitted with a sealed agitator, a condenser A thick pulp is obtained to reflux The reflux is maintained for 8 hours

反応条件: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl-3,5-dichlorosalicylate (prepared according to Ahmed et al., Medicinal Chemistry 2008, 4, 298-308, which is expressly incorporated by reference herein; 2.0 g, 9.0 mmol) was dissolved in dry THF (30 mL), cooled to −40° C. and treated in portions with isopropyl magnesium chloride, 2.0 M in THF; 10 mL, 20 mmol). The mixture was stirred at −20 to −40° C. for 45 min, warmed to 25° C. and stirred for 4 h. The excess reagent was quenched by addition of satd NH4Cl (10 mL). The mixture was diluted with EtOAc (50 mL) and the pH was adjusted to ˜1 by addition of 1 M HCl. The organic phase was washed with satd NaCl solution (20 mL), dried (Na2SO4) and evaporated. The residue was purified by reverse-phase high-performance liquid chromatography (RP-HPLC) with 70% acetonitrile to give the purified ketone (1.1 g): mp: 102-104° C. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=2.5 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H), 3.54 (dt, J=13.6, 6.8 Hz, 1H), 1.26 (d, J=6.8 Hz, 6H); EIMS m/z 232. warmed to 25° C. stirred for 4 h The excess reagent was quenched by addition of satd NH4Cl (10 mL) The mixture was diluted with EtOAc (50 mL) the pH was adjusted to ˜1 by addition of 1 M HCl The organic phase was washed with satd NaCl solution (20 mL) dried (Na2SO4) evaporated The residue was purified by reverse-phase high-performance liquid chromatography (RP-HPLC) with 70% acetonitrile

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 1 liter Parr autoclave was charged with 221 g. (1 mole) -dichlorophenyl)- of methyl 3,5-dichlorosalicylate and 140 g. (8 moles) of anhydrous ammonia. The mixture was stirred at 25° C for 24 hours. After venting excess ammonia, the product was ground to a fine powder and triturated with boiling chloroform. The mixture was filtered while hot and the residue weighed 153 g. Analysis by infrared, gas chromatography, and nuclear magnetic resonance confirmed that the product was 3,5-dichlorosalicylamide. A 1 liter Parr autoclave was charged with 221 g triturated with boiling chloroform The mixture was filtered while hot and the residue