3-chloro-5-hydroxybenzonitrile

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:

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:

Conditions: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: step 2—A 250 flask was charged with 5-chloro-3-methoxy-benzonitrile (7.0 g, 41.766 mmol) and 2,4,6-collidine (100 mL). The mixture was heated to 170° C. and LiI (16.76 g, 125.298 mmol) was added and the reaction mixture was heated for 4 h. When the methyl ether was consumed the reaction was cooled to RT and quenched with 10% aqueous HCl. The resulting mixture was extracted with EtOAc and washed with water and brine. The EtOAc extract was dried over (Na2SO4) and filtered. The solvent was removed in vacuo to afford a yellow oil which was purified by silica gel chromatography eluting with EtOAc/hexane (10:90) to afford 6.0 g (94%) of 3-chloro-5-hydroxy-benzonitrile. the reaction mixture was heated for 4 h When the methyl ether was consumed the reaction was cooled to RT quenched with 10% aqueous HCl The resulting mixture was extracted with EtOAc washed with water and brine The EtOAc extract was dried over (Na2SO4) filtered The solvent was removed in vacuo to afford a yellow oil which was purified by silica gel chromatography eluting with EtOAc/hexane (10:90)

Conditions: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: step 2—A 250 mL flask was charged with 5-chloro-3-methoxy-benzonitrile (7.0 g, 41.766 mmol) and 2,4,6-collidine (100 mL). The mixture was heated to 170° C. and LiI (16.76 g, 125.298 mmol) was added and the reaction mixture was heated for 4 h. When R-3b was consumed the reaction was cooled to RT and quenched with 10% aqueous HCl. The resulting mixture was extracted with EtOAc and washed with water and brine. The EtOAc extract was dried over (Na2SO4) and filtered. The solvent was removed in vacuo to afford a yellow oil which was purified by silica gel chromatography eluting with EtOAc/hexane (10:90) to afford 6.0 g (94%) of 3-chloro-5-hydroxy-benzonitrile. the reaction mixture was heated for 4 h When R-3b was consumed the reaction was cooled to RT quenched with 10% aqueous HCl The resulting mixture was extracted with EtOAc washed with water and brine The EtOAc extract was dried over (Na2SO4) filtered The solvent was removed in vacuo to afford a yellow oil which was purified by silica gel chromatography eluting with EtOAc/hexane (10:90)

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

Procedure: [3-(3,5-Dicyano-phenoxy)-2-fluoro-4-methoxy-phenyl]-acetic acid (R-45) and [3-(3-cyano-5-difluoromethyl-phenoxy)-2-fluoro-4-methoxy-phenyl]-acetic acid (R-46) can be prepared similarly except R-10 and R-26 respectively are used in place of 3-chloro-5-hydroxy-benzonitrile.

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

Procedure: [3-(3,5-Dicyano-phenoxy)-2-fluoro-4-methoxy-phenyl]-acetic acid (R-45) and [3-(3-cyano-5-difluoromethyl-phenoxy)-2-fluoro-4-methoxy-phenyl]-acetic acid (R-46) can be prepared similarly except R-10 and R-26 respectively are used in place of 3-chloro-5-hydroxy-benzonitrile.