4-chloro-2-methoxyphenol

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

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 mixture of (±)-4-(4-chlorobenzyl)-2-chloromethyimorphoiine (10.0 g 38.5 mmol), 4-chloro-2-methoxyphenol (9.0 g, 58 mmol), potassium ethoxide (6.5 g, 77 mmol), and 18-crown-6 (10.2 g, 38.5) was refluxed in toluene (100 ml) for 34 h. Water (200 ml) was added and the phases were separated. Drying and evaporation of the toluene phase was followed by column chromatography on silica gel with 3% ethanol in dichloromethane as eluent. The free base was dissolved in ether and precipitated with oxalic acid to give the title compound. Yield 10.3 g, 57%, mp 133-139° C. the phases were separated Drying evaporation of the toluene phase The free base was dissolved in ether precipitated with oxalic acid

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

Procedure: A mixture of (±)-4-(4-chlorobenzyl)-2-chloromethyimorphoiine (10.0 g 38.5 mmol), 4-chloro-2-methoxyphenol (9.0 g, 58 mmol), potassium ethoxide (6.5 g, 77 mmol), and 18-crown-6 (10.2 g, 38.5) was refluxed in toluene (100 ml) for 34 h. Water (200 ml) was added and the phases were separated. Drying and evaporation of the toluene phase was followed by column chromatography on silica gel with 3% ethanol in dichloromethane as eluent. The free base was dissolved in ether and precipitated with oxalic acid to give the title compound. Yield 10.3 g, 57%, mp 133-139° C. the phases were separated Drying evaporation of the toluene phase The free base was dissolved in ether precipitated with oxalic acid

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

Procedure: To a solution of ethyl 6-chloro-2-(chloromethyl)-4-phenylquinoline-3-carboxylate (718 mg, 2.0 mmol) in dry N,N-dimethylformamide (3.0 ml) at room temperature was added 4-chloro-2-methoxyphenol (0.301 ml, 2.2 mmol) followed by sodium hydride (88.0 mg of a 60% oil dispersion, 2.2 mol). The mixture was stirred at room temperature for 18 hours, then the reaction mixture was diluted with ethyl acetate and poured into a separatory funnel. The organic phase was washed with saturated sodium bicarbonate and water (2×), then brine. The organic phase was separated, and the solvent removed under reduced pressure to provide a viscous oil. Upon sitting at room temperature overnight a solid formed, to which a mixture of 10% ethyl acetate/hexanes was added, and the resulting solid filtered off. The solid was washed with 20% ethyl acetate/hexanes and dried under reduced pressure to provide ethyl 6-chloro-2-((4-chloro-2-methoxyphenoxy)methyl)-4-phenylquinoline-3-carboxylate then provided PT-011 (558 mg, 58%) as a light yellow powder. TLC Rf=0.38 in 30% ethyl cetate:hexanes on a glass backed silica gel plate. 1H NMR (CDCl3, 400 MHz) δ 8.08 (d, 1H, J=8.9 Hz); 7.69 (dd, 1H, J=8.9, 2.3 Hz); 7.58 (d, 1H, J=2.3 Hz); 7.48-7.52 (m, 3H); 7.36-7.30 (m, 2H); 6.95-6.92 (app d, 1H, J=8.6 Hz); 6.75 (s, 1H); 6.78-6.70 (m, 1H); 5.50 (s, 2H); 3.90 (q, 2H, J=7.0 Hz); 3.80 (s, 3H); 0.82 (t, 3H, J=7.0 Hz). LC MS (CI) shows M+H 482. poured into a separatory funnel The organic phase was washed with saturated sodium bicarbonate and water (2×) The organic phase was separated the solvent removed under reduced pressure to provide a viscous oil Upon sitting at room temperature overnight a solid formed, to which was added the resulting solid filtered off The solid was washed with 20% ethyl acetate/hexanes dried under reduced pressure

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

Procedure: To a solution of ethyl 6-chloro-2-(chloromethyl)-4-phenylquinoline-3-carboxylate (718 mg, 2.0 mmol) in dry N,N-dimethylformamide (3.0 ml) at room temperature was added 4-chloro-2-methoxyphenol (0.301 ml, 2.2 mmol) followed by sodium hydride (88.0 mg of a 60% oil dispersion, 2.2 mol). The mixture was stirred at room temperature for 18 hours, then the reaction mixture was diluted with ethyl acetate and poured into a separatory funnel. The organic phase was washed with saturated sodium bicarbonate and water (2×), then brine. The organic phase was separated, and the solvent removed under reduced pressure to provide a viscous oil. Upon sitting at room temperature overnight a solid formed, to which a mixture of 10% ethyl acetate/hexanes was added, and the resulting solid filtered off. The solid was washed with 20% ethyl acetate/hexanes and dried under reduced pressure to provide ethyl 6-chloro-2-((4-chloro-2-methoxyphenoxy)methyl)-4-phenylquinoline-3-carboxylate then provided PT-011 (558 mg, 58%) as a light yellow powder. TLC Rf=0.38 in 30% ethyl cetate:hexanes on a glass backed silica gel plate. 1H NMR (CDCl3, 400 MHz) δ 8.08 (d, 1H, J=8.9 Hz); 7.69 (dd, 1H, J=8.9, 2.3 Hz); 7.58 (d, 1H, J=2.3 Hz); 7.48-7.52 (m, 3H); 7.36-7.30 (m, 2H); 6.95-6.92 (app d, 1H, J=8.6 Hz); 6.75 (s, 1H); 6.78-6.70 (m, 1H); 5.50 (s, 2H); 3.90 (q, 2H, J=7.0 Hz); 3.80 (s, 3H); 0.82 (t, 3H, J=7.0 Hz). LC MS (CI) shows M+H 482. poured into a separatory funnel The organic phase was washed with saturated sodium bicarbonate and water (2×) The organic phase was separated the solvent removed under reduced pressure to provide a viscous oil Upon sitting at room temperature overnight a solid formed, to which was added the resulting solid filtered off The solid was washed with 20% ethyl acetate/hexanes dried under reduced pressure

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 4-[(4,5-dichloro-2-fluoro-benzoyl)amino]benzoate (34.21 mg, 0.1 mmol), 4-chloro-2-methoxyphenol (12.16 μl, 0.1 mmol), potassium carbonate 13.82 mg, 0.1 mmol) and N-methylpyrrolidinone (1 mL) were heated at 80° C. for 2.5 hours. Methanol (100 μL) and sodium hydroxide (3M, 100 μL, 0.3 mmol) were added and the reaction was stirred at 50° C. for 2 hours. An additional 100 μL of MeOH and 100 μL of 3M NaOH were added and the reactions were heated for another hour. The reaction mixture was filtered and purified by reverse phase preparative chromatography utilizing a gradient of 10-99% acetonitrile in water containing HCl as a modifier to yield 4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamido)benzoic acid (18) (11.78 mg, 25%). ESI-MS m/z calc. 464.99, found 466.3 (M+1)+; Retention time: 2.20 minutes (3 minutes run). the reactions were heated for another hour The reaction mixture was filtered purified by reverse phase preparative chromatography containing HCl as a modifier

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of sodium hydroxide (6.6 g, 160 mmol) in water (45 mL) was added 4-chloro-2-methoxy-phenol (2.0 mL, 16 mmol) and chloroacetic acid (7.7 g, 81 mmol). The resulting mixture was heated to 95° C. and stirred for three hours. The reaction was allowed to cool to ambient temperature and slowly acidified with concentrated hydrochloric acid (10 mL) until the mixture became a solution and then extracted with diethyl ether. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (4.16 g). to cool to ambient temperature extracted with diethyl ether The organic layer was dried over magnesium 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: