1,3-dibromopropan-2-one

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

Procedure: One equivalent of 5-(3-chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-1-methylethyl)-2-oxazolidinone, prepared by the procedure of U.S. Pat. No. 5,061,727 Example 1, is treated with one equivalent of 1,3-dibromoacetone and excess potassium carbonate in acetonitrile. The mixture is stirred at room temperature for 18 hours, filtered and evaporated in vacuo to give 7-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,5-dioxabenzocycloheptan-3-one. One equivalent of this ketone is reduced, at room temperature for one hour, with excess sodium borohydride in methyl alcohol. The reaction mixture is poured into water, made acidic with 1N hydrochloric acid and extracted with methylene chloride. The organic extracts are dried and evaporated in vacuo to give 7-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl-1,5-dioxabenzocycloheptan-3-ol. Hydrolysis with 2.5N sodium hydroxide gives the title compound. filtered evaporated in vacuo

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

Procedure: 1,3-Dibromoacetone (15 g, 52 mmol) and thiourea (4.05 g, 53.2 mmol, 1.02 equiv.) in methanol were refluxed overnight. The reaction mixture was diluted with water and the pH was adjusted to 1 with HCl 25%, followed by extraction with ethyl acetate. The pH of the aqueous layer was adjusted to 8-9 using solid sodium carbonate. The aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over magnesiumsulfat dihydrate, filtered and evaporated. The crude product was purified on silica-gel (NH2-modified) with ethyl acetate/n-heptane as eluent yielding a white solid: 340 mg. MS (ES) m/e 145 (M+H) followed by extraction with ethyl acetate The aqueous layer was extracted with ethyl acetate the combined organic extracts were washed with brine dried over magnesiumsulfat dihydrate filtered evaporated The crude product was purified on silica-gel (NH2-modified) with ethyl acetate/n-heptane as eluent yielding a white solid

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

Procedure: 1,3-Dibromoacetone (15 g, 52 mmol) and thiourea (4.05 g, 53.2 mmol, 1.02 equiv.) in methanol were refluxed overnight. The reaction mixture was diluted with water and the pH was adjusted to 1 with HCl 25%, followed by extraction with ethyl acetate. The pH of the aqueous layer was adjusted to 8-9 using solid sodium carbonate. The aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over magnesiumsulfat dihydrate, filtered and evaporated. The crude product was purified on silica-gel (NH2-modified) with ethyl acetate/n-heptane as eluent yielding a white solid: 340 mg. MS (ES) m/e 145 (M+H) followed by extraction with ethyl acetate The aqueous layer was extracted with ethyl acetate the combined organic extracts were washed with brine dried over magnesiumsulfat dihydrate filtered evaporated The crude product was purified on silica-gel (NH2-modified) with ethyl acetate/n-heptane as eluent yielding a white solid

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

Procedure: 1,3-Dibromo-propan-2-one (9 g, 42 mmol) was dissolved in methanol. (90 mL) followed by the addition of thiourea (3.2 g, 42.5 mmol) and the dark colored mixture was refluxed overnight. The solvent was then removed under reduced pressure and the remaining oil was dissolved in an ethyl acetate/water. The mixture was acidified with 1N HCl to pH 1 and extracted with three portions of ethyl acetate. The aqueous layer was then treated with solid sodium carbonate to pH 8 and again extracted with three portions of ethyl acetate. The combined, organic extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product. After purification on silica gel (NH2-modified) with ethyl acetate/n-hepatane as eluents, the desired fractions were combined and concentrated under reduced pressure to yield a solid which was stirred in diethyl ether, filtered and dried to give the title compound as a light brown solid. (0.53 g, 9% yield) MS (ISP): m/e 145.1 (M−H)+ the dark colored mixture was refluxed overnight The solvent was then removed under reduced pressure the remaining oil was dissolved in an ethyl acetate/water extracted with three portions of ethyl acetate The aqueous layer was then treated with solid sodium carbonate to pH 8 again extracted with three portions of ethyl acetate organic extracts were washed with water and brine dried over magnesium sulfate filtered concentrated under reduced pressure to give the crude product After purification on silica gel (NH2-modified) with ethyl acetate/n-hepatane as eluents concentrated under reduced pressure to yield a solid which filtered dried

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (1S,2R)-1-(2-amino-thiazol-5-sulfonylamino)-2-methyl-2-phenyl-cyclopropanecarboxylic acid methyl ester (0.21 g, 0.58 mmol) in ethyl acetate (6.4 mL) was added 1,3-dibromoacetone (0.18 mL, 0.87 mmol), and the mixture was stirred at 60° C. for 18 hours. After cooling to room temperature, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and dried over sodium sulfate. After filtration and evaporation, the obtained residue was separated and purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (68 mg, yield 24%) as a pale-yellow solid. After cooling to room temperature the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution dried over sodium sulfate After filtration and evaporation the obtained residue was separated purified by silica gel chromatography (hexane:ethyl acetate=1:1)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (1S,2R)-1-(2-amino-thiazol-5-sulfonylamino)-2-methyl-2-phenyl-cyclopropanecarboxylic acid methyl ester (0.21 g, 0.58 mmol) in ethyl acetate (6.4 mL) was added 1,3-dibromoacetone (0.18 mL, 0.87 mmol), and the mixture was stirred at 60° C. for 18 hours. After cooling to room temperature, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and dried over sodium sulfate. After filtration and evaporation, the obtained residue was separated and purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (68 mg, yield 24%) as a pale-yellow solid. After cooling to room temperature the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution dried over sodium sulfate After filtration and evaporation the obtained residue was separated purified by silica gel chromatography (hexane:ethyl acetate=1:1)

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

Procedure: The bromomethylketone derivative (4.36 g) and 2,6-dichlorobenzoic acid (2.28 g, 1.1 eq) were dissolved in dimethylformamide (18 mL), KF (1.58 g, 2.5 eq) was added thereto, and the mixture was stirred for 2 h at room temperature. The residue obtained by concentration under reduced pressure was extracted with ethyl acetate, washed with water, twice with saturated aqueous sodium hydrogen carbonate solution, and aqueous sodium chloride solution, dried (anhydrous Na2SO4), and concentrated under reduced pressure to give the 2,6-dichlorobenzoxymethylketone derivative. This compound was dissolved in methanol (20 mL), and reacted by adding NaBH4 (412 mg)-methanol solution (40 mL). The reaction mixture was slowly warmed to room temperature for 2 h. The reaction was stopped by acetic acid. The reaction mixture was distilled under reduced pressure to remove methanol, extracted with ethyl acetate (50 mL×2), washed with water and aqueous sodium chloride solution, dried (anhydrous Na2SO4), concentrated under reduced pressure, and separated by column chromatography (ethyl acetate-hexane, 1:5) to give 4.80 g (86%) of the title compound. The residue obtained by concentration under reduced pressure was extracted with ethyl acetate washed with water, twice with saturated aqueous sodium hydrogen carbonate solution, and aqueous sodium chloride solution dried (anhydrous Na2SO4) concentrated under reduced pressure

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

Procedure: The bromomethylketone derivative (4.36 g) and 2,6-dichlorobenzoic acid (2.28 g, 1.1 eq) were dissolved in dimethylformamide (18 mL), KF (1.58 g, 2.5 eq) was added thereto, and the mixture was stirred for 2 h at room temperature. The residue obtained by concentration under reduced pressure was extracted with ethyl acetate, washed with water, twice with saturated aqueous sodium hydrogen carbonate solution, and aqueous sodium chloride solution, dried (anhydrous Na2SO4), and concentrated under reduced pressure to give the 2,6-dichlorobenzoxymethylketone derivative. This compound was dissolved in methanol (20 mL), and reacted by adding NaBH4 (412 mg)-methanol solution (40 mL). The reaction mixture was slowly warmed to room temperature for 2 h. The reaction was stopped by acetic acid. The reaction mixture was distilled under reduced pressure to remove methanol, extracted with ethyl acetate (50 mL×2), washed with water and aqueous sodium chloride solution, dried (anhydrous Na2SO4), concentrated under reduced pressure, and separated by column chromatography (ethyl acetate-hexane, 1:5) to give 4.80 g (86%) of the title compound. The residue obtained by concentration under reduced pressure was extracted with ethyl acetate washed with water, twice with saturated aqueous sodium hydrogen carbonate solution, and aqueous sodium chloride solution dried (anhydrous Na2SO4) concentrated under reduced pressure

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

Procedure: In the manner given in Example 1, 7-chloro-2-hydrazino-5-(o-fluorophenyl)-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1,3-dibromopropanone under nitrogen to give 7-chloro-2-[[2-bromo-1-(bromomethyl)ethylidene]hydrazino]-5-(o-fluorophenyl)-3H-1,4-benzodiazepine.

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

Procedure: One equivalent of 5-(3-chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-1-methylethyl)-2-oxazolidinone, prepared by the procedure of U.S. Pat. No. 5,061,727 Example 1, is treated with one equivalent of 1,3-dibromoacetone and excess potassium carbonate in acetonitrile. The mixture is stirred at room temperature for 18 hours, filtered and evaporated in vacuo to give 7-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,5-dioxabenzocycloheptan-3-one. One equivalent of this ketone is reduced, at room temperature for one hour, with excess sodium borohydride in methyl alcohol. The reaction mixture is poured into water, made acidic with 1N hydrochloric acid and extracted with methylene chloride. The organic extracts are dried and evaporated in vacuo to give 7-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl-1,5-dioxabenzocycloheptan-3-ol. Hydrolysis with 2.5N sodium hydroxide gives the title compound. filtered evaporated in vacuo

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

Procedure: One equivalent of 5-(3-chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-1-methylethyl)-2-oxazolidinone, prepared by the procedure of U.S. Pat. No. 5,061,727 Example 1, is treated with one equivalent of 1,3-dibromoacetone and excess potassium carbonate in acetonitrile. The mixture is stirred at room temperature for 18 hours, filtered and evaporated in vacuo to give 7-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,5-dioxabenzocycloheptan-3-one. One equivalent of this ketone is reduced, at room temperature for one hour, with excess sodium borohydride in methyl alcohol. The reaction mixture is poured into water, made acidic with 1N hydrochloric acid and extracted with methylene chloride. The organic extracts are dried and evaporated in vacuo to give 7-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl-1,5-dioxabenzocycloheptan-3-ol. Hydrolysis with 2.5N sodium hydroxide gives the title compound. filtered evaporated in vacuo

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

Procedure: 1,3-Dibromoacetone (15 g, 52 mmol) and thiourea (4.05 g, 53.2 mmol, 1.02 equiv.) in methanol were refluxed overnight. The reaction mixture was diluted with water and the pH was adjusted to 1 with HCl 25%, followed by extraction with ethyl acetate. The pH of the aqueous layer was adjusted to 8-9 using solid sodium carbonate. The aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over magnesiumsulfat dihydrate, filtered and evaporated. The crude product was purified on silica-gel (NH2-modified) with ethyl acetate/n-heptane as eluent yielding a white solid: 340 mg. MS (ES) m/e 145 (M+H) followed by extraction with ethyl acetate The aqueous layer was extracted with ethyl acetate the combined organic extracts were washed with brine dried over magnesiumsulfat dihydrate filtered evaporated The crude product was purified on silica-gel (NH2-modified) with ethyl acetate/n-heptane as eluent yielding a white solid