2-bromo-1-(2-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: To a solution of 2-bromo-1-(2-fluorophenyl)ethanone (10.0 g, 46.1 mmol) in ethanol (460.8 mL) is added drop wise diallyamine (9.4 g, 96.8 mmol) in ethanol (460.8 mL). The reaction is stirred for 2 hr. Pyridine is then added to the reaction (11.2 mL, 138.2 mmol) followed by the addition of hydroxylamine hydrochloride (4.8 g, 69.1 mmol). The reaction is refluxed for 4 hr and then concentrated to dryness. The residue is dissolved in toluene (230.4 mL) and is refluxed for 8 hr. The mixture is cooled to room temperature and extracted with saturated sodium bicarbonate solution. The aqueous phase is then extracted with DCM. The organic phase is concentrated and the mixture purified by silica gel chromatography eluting with hexane to 1:1 hexane/ethyl acetate to give the title compound (6.6 g, 58%). ES/MS (m/e): 248 (M+H). The reaction is refluxed for 4 hr concentrated to dryness The residue is dissolved in toluene (230.4 mL) is refluxed for 8 hr extracted with saturated sodium bicarbonate solution The aqueous phase is then extracted with DCM The organic phase is concentrated the mixture purified by silica gel chromatography eluting with hexane to 1:1 hexane/ethyl acetate

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2′-fluoroacetophenone (28.6 g) in ethyl acetate (400 mL) was added copper (II) bromide (92.6 g), and the mixture was heated under reflux for 4 hr. The reaction mixture was allowed to cool to room temperature and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give crude 2-bromo-1-(2-fluorophenyl)ethanone (yield 90.5 g) as an oil. Potassium carbonate (88 g) was added to ethyl cyanoacetate (168 g), and the mixture was stirred at 45° C. for 1 hr. A solution (360 mL) of crude 2-bromo-1-(2-fluorophenyl)ethanone (90.5 g) in acetone was added dropwise over 20 min. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hr. Water (300 mL) and ethyl acetate (300 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 10% aqueous sodium dihydrogen phosphate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=20:1→4:1) to give the title compound as an oil (yield 64.0 g, about 100%). After completion of the dropwise addition the mixture was stirred at the same temperature for 1 hr the mixture was extracted with ethyl acetate The extract was washed with 10% aqueous sodium dihydrogen phosphate solution and saturated brine dried over anhydrous sodium sulfate concentrated under reduced pressure was evaporated under reduced pressure the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=20:1→4:1)

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

Procedure: Compound C1 (11.4 g, 65.8 mmol), 2-bromo-1-(2-fluorophenyl)ethanone (13.0 g, 59.9 mmol) and N,N-diisopropylethylamine (23.0 mL, 132 mmol) were combined in a mixture of acetonitrile (100 mL) and 2-methyltetrahydrofuran (300 mL) and heated at reflux for 18 hours. After cooling, the reaction mixture was concentrated in vacuo; the residue was mixed with ethyl acetate, then washed sequentially with saturated aqueous ammonium chloride solution and with saturated aqueous sodium bicarbonate solution. The combined aqueous layers were extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide the product as a pale brown foam. Yield: 18.1 g, assumed quantitative. LCMS m/z 292.4 [M+H]+. 1H NMR (500 MHz, CDCl3), presumed to be a mixture of rotamers: δ 8.15 (v br s, 1H), 8.03-8.07 (m, 1H), 7.30 and 7.31 (2 s, 1H), 7.13-7.20 (m, 2H), 7.02-7.08 (m, 1H), 2.31 (s, 3H), 1.49 (br s, 9H). heated at reflux for 18 hours After cooling the reaction mixture was concentrated in vacuo the residue was mixed with ethyl acetate washed sequentially with saturated aqueous ammonium chloride solution and with saturated aqueous sodium bicarbonate solution The combined aqueous layers were extracted with ethyl acetate the combined organic layers were dried over magnesium sulfate filtered concentrated under reduced pressure

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

Procedure: To a solution of 37 mg (0.13 mmol) 1-Dimethylaminomethylene-3-(3-methanesulfonyl-phenyl)-thiourea in 0.33 ml DMF was added 28 mg (0.13 mmol) 2-Fluorophenacyl bromide and the mixture was allowed to stir at room temperature for 16 h. 17 mg (0.13 mmol) diisopropylethylamine was added and the mixture was subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient to yield 38.5 mg (79%) of the title compound after evaporation of the product fractions. HPLC separation on reversed phase eluting with an acetonitrile/water gradient

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

Procedure: To a solution of 37 mg (0.13 mmol) 1-Dimethylaminomethylene-3-(3-methanesulfonyl-phenyl)-thiourea in 0.33 ml DMF was added 28 mg (0.13 mmol) 2-Fluorophenacyl bromide and the mixture was allowed to stir at room temperature for 16 h. 17 mg (0.13 mmol) diisopropylethylamine was added and the mixture was subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient to yield 38.5 mg (79%) of the title compound after evaporation of the product fractions. HPLC separation on reversed phase eluting with an acetonitrile/water gradient

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

Procedure: A solution of 4-Amino-6-carboethoxy-5,6,7,8-tetrahydro-2(1H)-quinazolinone (262 mg) and 2'-fluoro-bromoacetophenone (217 mg) in dry DMF (10 mL) was refluxed under nitrogen for 1.5 h. The solution was cooled and 40 mL water is added. The precipitate was collected and washed successively with 10 mL of methanol and 20 mL hot ethyl acetate to yield 9-Carboethoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (Compound 1), m.p. 257-277° C. The solution was cooled The precipitate was collected washed successively with 10 mL of methanol and 20 mL hot ethyl acetate

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

Procedure: A solution of 4-Amino-6-carboethoxy-5,6,7,8-tetrahydro-2(1H)-quinazolinone (262 mg) and 2'-fluoro-bromoacetophenone (217 mg) in dry DMF (10 mL) was refluxed under nitrogen for 1.5 h. The solution was cooled and 40 mL water is added. The precipitate was collected and washed successively with 10 mL of methanol and 20 mL hot ethyl acetate to yield 9-Carboethoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (Compound 1), m.p. 257-277° C. The solution was cooled The precipitate was collected washed successively with 10 mL of methanol and 20 mL hot ethyl acetate

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

Procedure: The title compound was prepared in analogy to example 1 step e) from 72 mg (0.33 mmol) 2-fluorophenacylbromide and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude product was purified through stirring with methylene chloride at room temperature yielding 121 mg (99%) [4-(2-fluoro-phenyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a light green solid. MS ISP (m/e): 381.3 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.77 (s, 1H), 9.29 (s, 1H), 8.12 (t, 1H), 8.02 (s, 1H), 7.69 (s, 1H), 7.53 (d, 1H), 7.38-7.29 (m, 5H), 3.92 (s, 3H), 2.35 (s, 3H). The crude product was purified

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

Procedure: The title compound was prepared according to the general procedure described in example 125 using 0.25 g of resin (0.5 mmol/g). Attachment of the 2-amino-indane-2-carboxylic acid moiety to the resin was followed by acylation with 3-hydroxy-4-methoxy-benzoic acid and treatment with 50% piperidine in DMF for 2 h. After extensive washing with DMF and DCM the resin was reacted with 2-bromo-1-(2-fluoro-phenyl)-ethanone (3 equivalents) in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 3 equivalents) in 3 ml of DCM overnight at room temperature. The compound was cleaved from the resin with neat TFA for 2 h, and TFA was evaporated in vacuo. The crude intermediate product was dissolved in 4 ml of THF, 10 mg of lithium borohydride were added and the reaction mixture was shaken for 3 h. Then the reaction mixture was quenched with acetic acid, evaporated to dryness, and the residue was purified by preparative RP HPLC (water/ACN gradient). Yield: 3.7 mg. After extensive washing with DMF and DCM the resin TFA was evaporated in vacuo The crude intermediate product was dissolved in 4 ml of THF 10 mg of lithium borohydride were added Then the reaction mixture was quenched with acetic acid evaporated to dryness the residue was purified by preparative RP HPLC (water/ACN gradient)