1-(3-chloro-4-fluorophenyl)ethanone

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 reaction vessel was charged with sodium hydride (as a 60% oil dispersion, 7.2 g, 180 mmol), DME (60 ml) and 2-chloro-5-trifluoromethylpyridine (10 g, 55.1 mmol). 3-Chloro-4-fluoroacetophenone (9.8 g, 56.9 mmol) in DME (20 ml) was added in portions to the mixture under nitrogen at room temperature. The mixture was stirred at ambient temperature for one hour then at 40-45° C. overnight. Upon the completion of the reaction, the mixture was cooled to 5° C. and 10% aqueous sodium hydroxide solution (30 ml) was slowly added to the reaction mixture followed by methanol (60 ml) then hydroxylamine hydrochloride (19.1 g, 357 mmol). The mixture was heated to 72° C. for 4 hours then cooled and diluted with water (1500 ml) with stirring. The resulting solid was removed by filtration and dried under vacuum. It was then slurried in cyclohexane (100 ml) then filtered, washing with further cyclohexane. The crude solid was purified by dissolution in diethylether (50 ml) and passage through silica gel, washing with further diethylether. Concentration of the filtrate afforded 15.56 g (85%) of the title compound. at 40-45° C. overnight Upon the completion of the reaction the mixture was cooled to 5° C. The mixture was heated to 72° C. for 4 hours then cooled with stirring The resulting solid was removed by filtration dried under vacuum then filtered washing with further cyclohexane The crude solid was purified by dissolution in diethylether (50 ml) passage through silica gel, washing with further diethylether

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

Procedure: 1-(3-Chloro-4-fluorophenyl)ethanone (0.86 g, 5.0 mmol), 2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzonitrile (1.37 g, 6.0 mmol) (prepared according to the procedure described in WO 02/74773) and potassium fluoride (0.96 g, 16.5 mmol) were suspended in tetrahydrofuran (20 ml) and the mixture degassed with nitrogen for 30 min. Tris(dibenzylidineacetone)dipalladium(0) (0.14 g, 0.15 mmol) and tri-tert-butylphosphine (0.3M in 1,4-dioxane, 1.0 ml) were added and the mixture stirred at room temperature for 1 h then heated at 50° C. for 18 h. The mixture was allowed to cool to room temperature and then poured into 0.5N sodium hydroxide solution (300 ml) and stirred for 30 min. The solid was filtered, washed with water (50 ml) and isohexane (50 ml) and the brown solid left to air-dry. The solid was purified by flash column chromatography on silica eluting with isohexane on a gradient of ethyl acetate (10-30%). Collecting the appropriate fractions gave 5′-acetyl-2′-fluorobiphenyl-2-carbonitrile (0.31 g, 26%) as a yellow solid: δH(400 MHz, CDCl3) 2.64 (3H, s), 7.31 (1H, t, J 8.8 Hz), 7.52-7.56 (2H, m), 7.68-7.72 (1H, m), 7.81 (1H, dd, J 0.8, 7.4 Hz), 8.04-8.09 (2H, m). the mixture degassed with nitrogen for 30 min then heated at 50° C. for 18 h to cool to room temperature stirred for 30 min The solid was filtered washed with water (50 ml) and isohexane (50 ml) the brown solid left to air-dry The solid was purified by flash column chromatography on silica eluting with isohexane on a gradient of ethyl acetate (10-30%) Collecting the appropriate fractions

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(3-chloro-4-fluorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product. heated for another 10 min the reaction mixture was cooled to 0° C was added dropwise After complete addition extracted in diethyl ether (4×50 mL) dried over Na2SO4 concentrated at 25° C. to obtain the product

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(3-chloro-4-fluorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product. heated for another 10 min the reaction mixture was cooled to 0° C was added dropwise After complete addition extracted in diethyl ether (4×50 mL) dried over Na2SO4 concentrated at 25° C. to obtain the product

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

Procedure: The title compound was prepared by the procedures described in Example 1A substituting 2,4-dichlorothiophenol with 2-chlorothiophenol, and 2-chlorobenzaldehyde with 4′-fluoro-3′-chloroacetophenone.

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

Procedure: To a −78° C. solution of 1-(3-chloro-4-fluorophenyl)ethanone (16.25 g, 94 mmol) and ethyl 2,2-diethoxyacetate (20.73 mL, 113 mmol) in THF (392 mL) was added, dropwise, a solution of LDA (51.8 mL, 104 mmol, 2M in THF). The resultant reaction mixture was gradually allowed to reach room temperature and continued stirring for 16 h. The reaction was carefully quenched with water and diluted with EtOAc. The two layers were separated and the aq. layer was extracted with EtOAc (2×150 mL) The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered and the filtrate was concentrated under reduced pressure to provide a crude oil. It was purified by silica gel chromatography (1500 g Commodity column, eluting with a 10% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate A39A (9.97 g, 35%) as a solid. MS(ES): m/z=257 [M-OEt]+. The resultant reaction mixture to reach room temperature The reaction was carefully quenched with water diluted with EtOAc The two layers were separated the aq. layer was extracted with EtOAc (2×150 mL) The combined organic layer was washed with brine dried over anhydrous MgSO4 filtered the filtrate was concentrated under reduced pressure to provide a crude oil It was purified by silica gel chromatography (1500 g Commodity column eluting with a 10% EtOAc in hexanes) Fractions containing the product evaporated to afford Intermediate A39A (9.97 g, 35%) as a solid

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

Procedure: The 3-chloro-4-fluoroacetophenone is then reacted with an aqueous solution of sodium hypobromite, the aqeuous phase is treated with sodium hydrogensulfite and acidified with hydrochloric acid, and the precipitated product is recrystallized from benzene. 3-Chloro-4-fluorobenzoic acid obtained in a yield of 74%. the precipitated product is recrystallized from benzene

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

Procedure: 3-Chloro-4-fluorobenzoyl chloride is available via a multi-stage synthesis. According to Diep et al., J. Chem. Soc. [1963], 2784-2787, ortho-chlorofluorobenzene is initially reacted with acetyl chloride in the presence of large amounts of aluminum chloride in the presence of carbon disulfide, methylene chloride or tetrachloroethylene, the reaction mixture is decomposed with dilute hydrochloric acid, the organic phase is washed with aqueous sodium hydroxide, then with water, and dried over sodium sulfate, the solvent is evaporated, and the residue is subjected to fractional distillation at reduced pressure. This method gives 3-chloro-4-fluoroacetophenone in a yield of about 80%. the organic phase is washed with aqueous sodium hydroxide with water, and dried over sodium sulfate the solvent is evaporated the residue is subjected to fractional distillation at reduced pressure

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

Procedure: 3-Chloro-4-fluorobenzoyl chloride is available via a multi-stage synthesis. According to Diep et al., J. Chem. Soc. [1963], 2784-2787, ortho-chlorofluorobenzene is initially reacted with acetyl chloride in the presence of large amounts of aluminum chloride in the presence of carbon disulfide, methylene chloride or tetrachloroethylene, the reaction mixture is decomposed with dilute hydrochloric acid, the organic phase is washed with aqueous sodium hydroxide, then with water, and dried over sodium sulfate, the solvent is evaporated, and the residue is subjected to fractional distillation at reduced pressure. This method gives 3-chloro-4-fluoroacetophenone in a yield of about 80%. the organic phase is washed with aqueous sodium hydroxide with water, and dried over sodium sulfate the solvent is evaporated the residue is subjected to fractional distillation at reduced pressure