carbonyl dibromide

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

Procedure: To a mixture of 2-bromo-1-(4-(methylsulfonyl)phenyl) propan-1-one (6.0 g, 20.6 mmol) and thiophenoxyacetic acid (3.8 g, 22.6 mmol) in acetonitrile (60 mL) was added triethylamine (4.0 mL, 28.8 mmol). The mixture was stirred at r.t. for 3 h. T.L.C. showed no bromoketone remaining and DBU (4.0 mL) was added. The mixture was stirred at r.t. for 1 h., then air was bubbled through the mixture for another hour. After dilution with water, the mixture was extracted with EtOAc. The EtOAc extract was washed with 1N aqueous HCl, brine, dried over MgSO4, filtered and the solvent evaporated under vacuum. The residue was swished in Et2O to give the title compound (6.0 g as a pale yellow powder. was added The mixture was stirred at r.t. for 1 h. air was bubbled through the mixture for another hour After dilution with water, the mixture was extracted with EtOAc The EtOAc extract was washed with 1N aqueous HCl, brine dried over MgSO4 filtered the solvent evaporated under vacuum

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

Procedure: The synthesis of bromoketone 2 begins with the Friedel-Crafts reaction between thioanisole and acetyl chloride, to give 4-(methylthio)acetophenone 3 herein referred to as ketosulfide 3).

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

Procedure: To a mixture of 2-bromo-1-(4-(methylsulfonyl)phenyl) propan-1-one (6.0 g, 20.6 mmol) and thiophenoxyacetic acid (3.8 g, 22.6 mmol) in acetonitrile (60 mL) was added triethylamine (4.0 mL, 28.8 mmol). The mixture was stirred at r.t. for 3 h. T.L.C. showed no bromoketone remaining and DBU (4.0 mL) was added. The mixture was stirred at r.t. for 1 h., then air was bubbled through the mixture for another hour. After dilution with water, the mixture was extracted with EtOAc. The EtOAc extract was washed with 1N aquous HCl, brine, dried over MgSO4, filtered and the solvent evaporated under vacuum. The residue was swished in Et2O to give the title compound (6.0 g) as a pale yellow powder. was added The mixture was stirred at r.t. for 1 h. air was bubbled through the mixture for another hour After dilution with water, the mixture was extracted with EtOAc The EtOAc extract was washed with 1N aquous HCl, brine dried over MgSO4 filtered the solvent evaporated under vacuum

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

Procedure: The process which comprises the steps of reacting 4-picoline below about 30° C. with at least three mole equivalents per mole of 4-picoline of an inorganic acid halide selected from phosphorus oxychloride, phosgene, thionyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, carbonyl dibromide or thiophosgene and about five to twenty volumes of dimethylformamide per volume of 4-picoline, adding the reaction mixture to cold water and adjusting the pH to about 8.0 while keeping the temperature below about 30° C., filtering off the precipitated inorganic cationic salt, treating the aqueous filtrate which contains N-[3-dimethylamino-2-(4-pyridinyl)-2-propenylidene]-N-methylmethaniminium salt with at least about 30-35% molar excess of α-cyanoacetamide and at least three mole equivalents of base still keeping the temperature below about 30° C., and then isolating either 5-cyano-[3,4'-bipyridin]-6(1H)-one as its inorganic cationic salt or, after neutralization, in its free base form. the temperature below about 30° C. filtering off the precipitated inorganic cationic salt treating the aqueous filtrate which the temperature below about 30° C.

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

Procedure: The process which comprises the steps of reacting 4-picoline below about 30° C. with at least three mole equivalents per mole of 4-picoline of an inorganic acid halide selected from phosphorus oxychloride, phosgene, thionyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, carbonyl dibromide or thiophosgene and about five to twenty volumes of dimethylformamide per volume of 4-picoline, adding the reaction mixture to cold water and adjusting the pH to about 8.0 while keeping the temperature below about 30° C., filtering off the precipitated inorganic cationic salt, treating the aqueous filtrate which contains N-[3-dimethylamino-2-(4-pyridinyl)-2-propenylidene]-N-methylmethaniminium salt with at least about 30-35% molar excess of α-cyanoacetamide and at least three mole equivalents of base still keeping the temperature below about 30° C., and then isolating either 5-cyano-[3,4'-bipyridin]-6(1H)-one as its inorganic cationic salt or, after neutralization, in its free base form. the temperature below about 30° C. filtering off the precipitated inorganic cationic salt treating the aqueous filtrate which the temperature below about 30° C.

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

Procedure: In scheme II above, the following abbreviations are used: KF is potassium fluoride; DMF is N,N-dimethylformamide; Ar2OH is either 2,3,5,6-tetrafluorophenol, 2,4,6-trifluorophenol or 2,3,6-trifluorophenol; THF is tetahydrofuran; MeOH is methanol. Commercially available bromoketone D is reacted with the appropriately substituted fluorophenol and potassium fluoride to give phenoxy ketone E. The ketone is then reduced with sodium borohydride to give the alcohol F, which is hydrogenated using palladium on carbon as catalyst to give the amino alcohol B′ (Ar2=fluoro-substituted phenyl).

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

Procedure: Cyclohexylacetone (300 mg, 2.14 mmol) in MeOH (5 mL) was treated with pyrrolidone hydrotribromide (1.3 g, 4.28 mmol) and the reaction was stirred at RT overnight. To the resulting solution of crude alpha-bromoketone in MeOH (without workup) was directly added solid sodium bicarbonate to neutralize the acid formed in the bromination step. To this neutralized bromoketone mixture was added 3-[1-(5-ethyl-thiophen-2-ylmethyl)-thioureido]-propionic acid tert-butyl ester (150 mg) in THF (2 mL) and the reaction was stirred for 1 h at RT. The solvent was removed at reduced pressure and the residue was dissolved in water and ethyl acetate. The aq portion was extracted two times with EtOAc, and the combined organic portion was washed with brine and then dried over sodium sulfate. Solvent removal under reduced pressure gave the crude product which was partially purified by silica gel chromatography (eluent: 10:1 hexanes:EtOAc) to give the aminothiazole derivative (300 mg). formed in the bromination step the reaction was stirred for 1 h at RT The solvent was removed at reduced pressure the residue was dissolved in water The aq portion was extracted two times with EtOAc the combined organic portion was washed with brine dried over sodium sulfate Solvent removal under reduced pressure gave the crude product which was partially purified by silica gel chromatography (eluent: 10:1 hexanes:EtOAc)

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

Procedure: Cyclohexylacetone (300 mg, 2.14 mmol) in MeOH (5 mL) was treated with pyrrolidone hydrotribromide (1.3 g, 4.28 mmol) and the reaction was stirred at RT overnight. To the resulting solution of crude alpha-bromoketone in MeOH (without workup) was directly added solid sodium bicarbonate to neutralize the acid formed in the bromination step. To this neutralized bromoketone mixture was added 3-[1-(5-ethyl-thiophen-2-ylmethyl)-thioureido]-propionic acid tert-butyl ester (150 mg) in THF (2 mL) and the reaction was stirred for 1 h at RT. The solvent was removed at reduced pressure and the residue was dissolved in water and ethyl acetate. The aq portion was extracted two times with EtOAc, and the combined organic portion was washed with brine and then dried over sodium sulfate. Solvent removal under reduced pressure gave the crude product which was partially purified by silica gel chromatography (eluent: 10:1 hexanes:EtOAc) to give the aminothiazole derivative (300 mg). formed in the bromination step the reaction was stirred for 1 h at RT The solvent was removed at reduced pressure the residue was dissolved in water The aq portion was extracted two times with EtOAc the combined organic portion was washed with brine dried over sodium sulfate Solvent removal under reduced pressure gave the crude product which was partially purified by silica gel chromatography (eluent: 10:1 hexanes:EtOAc)

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

Procedure: 1-[4-(4-methoxyphenoxy)phenyl]ethan-1-one (1 mmol) was brominated by General Procedure R1. The bromo ketone was condensed with 7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline following general procedure R2. The aminoketone intermediate was treated with n-pentanoyl chloride accoding to General Procedure R3. The product amide was then subjected to imidazole formation employing general procedure R4. The BOC group of the product was removed employing general procedure T1 to afford 7-{2-butyl-4-[4-(4-methoxy-phenoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinoline hydrochloride (yield 135 mg) The BOC group of the product was removed

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

Procedure: 1-[4-(4-methoxyphenoxy)phenyl]ethan-1-one (1 mmol) was brominated by General Procedure R1. The bromo ketone was condensed with 7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline following general procedure R2. The aminoketone intermediate was treated with n-pentanoyl chloride accoding to General Procedure R3. The product amide was then subjected to imidazole formation employing general procedure R4. The BOC group of the product was removed employing general procedure T1 to afford 7-{2-butyl-4-[4-(4-methoxy-phenoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinoline hydrochloride (yield 135 mg) The BOC group of the product was removed

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

Procedure: A 1 L three necked round bottomed flask equipped with reflux condenser, magnetic stir bar, thermometer adapter, and constant pressure addition funnel was charged with the intermediate from Step 2, (55.5 g, 0.21 mol), acetic acid (250 mL) and 33% HBr in acetic acid (120 mL). The solution was stirred and treated with bromine (11.1 mL, 0.21 mol) from the addition funnel at such a rate that the bromine color was discharged rapidly, ca. 15 minutes. After an additional 10 minutes at room temperature, the solution was filtered through a Buchner funnel and the filtrate concentrated in vacuo to give an orange solid. The crude bromoketone was dissolved in dichloromethane and washed with 1N NaHSO3, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 68.8 g of 1-(4-fluorophenyl)-2-(4-methylthiophenyl)-2-bromoethanone as a yellow solid which was used directly without further purification. The crude bromoketone was dissolved in 300 mL acetone and 150 mL of water and heated to reflux for 2.5 hours. The solution was concentrated in vacuo and the residue taken up in dichloromethane, washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and reconcentrated in vacuo to give a light yellow solid that was crystallized from a mixture of dichloromethane and isooctane to provide 37.8 g (65%) of pure 1-(4-fluorophenyl)-2-(4-methylthiophenyl)-2-hydroxy-ethanone: mp 90°-92° C. with reflux condenser, magnetic stir bar, thermometer adapter, and constant pressure addition funnel After an additional 10 minutes at room temperature the solution was filtered through a Buchner funnel the filtrate concentrated in vacuo to give an orange solid washed with 1N NaHSO3 dried over anhydrous MgSO4 filtered concentrated in vacuo

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

Procedure: A solution of 1-(4-Acetyl-phenyl)-ethanone (8.1 g, 5 mmol), in HOAc (50 mL) at 60° C. was treated with bromine (1 eq., 0.26 mL) dropwise over 10 minutes. After 5 more minutes the reaction was cooled, the acetic acid was removed, ethyl acetate (50 mL) was added and then removed to get drive off the remainder of the acetic acid. The crude bromo ketone was then dissolved in ethanol (30 mL) with NaOAc (1.1 g) and thiourea (1 eq., 375 mg) was added. The suspension was stirred at room temperature for 15 hours. The solvents were removed and the resulting mixture was redissolved in 5 ml of 90% DMF, 10% water with 0.1% TFA and purified by reverse phase HPLC to give the product. MS: 219.1 (M+H−). After 5 more minutes the reaction was cooled the acetic acid was removed ethyl acetate (50 mL) was added removed to get was added The solvents were removed the resulting mixture was redissolved in 5 ml of 90% DMF 10% water with 0.1% TFA and purified by reverse phase HPLC to give the product