非布司他杂质79

反应条件: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a round-bottomed flask, 2-bromoacetophenone (520 mg, 2.61 mmol) and 4-hydroxy-thiobenzamide (400 mg, 2.61 mmol) were dissolved in ethanol (10 ml), and the resulting solution was heated to reflux. After about one hour, the reaction was cooled to about 35° C. and was allowed to stir for about an additional twelve hours. The reaction mixture was then concentrated in vacuo to an oil, the residue redissolved in ethyl acetate and methylene chloride, and extracted with saturated aqueous sodium bicarbonate. The combined extracts were then extracted with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. The crude product was purified by column chromatography (silica gel; methylene chloride to 2% methanol/methylene chloride). The title product was isolated as a white solid (516 mg, 78% yield). LRMS ([M+H]+)=254.1. the resulting solution was heated to reflux The reaction mixture was then concentrated in vacuo to an oil the residue redissolved in ethyl acetate methylene chloride, and extracted with saturated aqueous sodium bicarbonate The combined extracts were then extracted with brine dried over magnesium sulfate filtered concentrated in vacuo to an oil The crude product was purified by column chromatography (silica gel; methylene chloride to 2% methanol/methylene chloride)

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a round bottomed flask, 4-hydroxybenzonitrile (5.00 g, 41.9 mmol), diethylthiophosphoric acid (7.02 g, 41.9 mmol), and water (8 ml) were heated with stirring to about 80° C. for about thirty minutes. An additional 10 ml of water was then added to the suspension, and the reaction was heated for about another one hour. The mixture was then allowed to stir for about sixteen hours at room temperature and was then extracted with water and 1:1 ether/ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was purified by column chromatography (silica gel; hexanes to ethyl acetate). The product was isolated as a yellow solid (5.54 g, 87% yield). 1H NMR (CD3OD): δ6.74 (d, 2H, J=9.1 Hz), 7.83 (d, 2H, J=8.7 Hz). the reaction was heated for about another one hour to stir for about sixteen hours at room temperature was then extracted with water and 1:1 ether/ethyl acetate The combined organic extracts were dried over magnesium sulfate filtered concentrated in vacuo The resulting solid was purified by column chromatography (silica gel; hexanes to ethyl acetate)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a round-bottomed flask, bromoacetaldehyde dimethoxyacetal (123 μl, 1.04 mmol), p-toluenesulfonic acid (199 mg, 1.04 mmol), and 4-hydroxy-thiobenzamide (160 mg, 1.04 mmol) were dissolved in ethanol (10 ml) and the resulting solution was heated to reflux for about twenty-four hours. The reaction mixture was then concentrated to an oil which was redissolved in ethyl acetate, and extracted with saturated aqueous sodium carbonate. The combined organic extracts were then washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. The crude product was purified by column chromatography (hexanes to 10% ethyl acetate/hexanes) to furnish the title compound as a white solid (113 mg, 61% yield). LRMS ([M+H+])=177.8. Preparation of Intermediate 1-(4-Methoxy-phenyl)-1H-pyrazole: the resulting solution was heated to reflux for about twenty-four hours The reaction mixture was then concentrated to an oil which was redissolved in ethyl acetate extracted with saturated aqueous sodium carbonate The combined organic extracts were then washed with brine dried over magnesium sulfate filtered concentrated in vacuo to an oil The crude product was purified by column chromatography (hexanes to 10% ethyl acetate/hexanes)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a round-bottomed flask, bromoacetaldehyde dimethoxyacetal (123 μl, 1.04 mmol), p-toluenesulfonic acid (199 mg, 1.04 mmol), and 4-hydroxy-thiobenzamide (160 mg, 1.04 mmol) were dissolved in ethanol (10 ml) and the resulting solution was heated to reflux for about twenty-four hours. The reaction mixture was then concentrated to an oil which was redissolved in ethyl acetate, and extracted with saturated aqueous sodium carbonate. The combined organic extracts were then washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. The crude product was purified by column chromatography (hexanes to 10% ethyl acetate/hexanes) to furnish the title compound as a white solid (113 mg, 61% yield). LRMS ([M+H+])=177.8. Preparation of Intermediate 1-(4-Methoxy-phenyl)-1H-pyrazole: the resulting solution was heated to reflux for about twenty-four hours The reaction mixture was then concentrated to an oil which was redissolved in ethyl acetate extracted with saturated aqueous sodium carbonate The combined organic extracts were then washed with brine dried over magnesium sulfate filtered concentrated in vacuo to an oil The crude product was purified by column chromatography (hexanes to 10% ethyl acetate/hexanes)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-Bromo-3-(4-chlorobenzoyl)propionate acid and an equimolar amount of 4-hydroxythio-benzamide are stirred in isopropyl alcohol solvent containing sodium carbonate to give 4-(4-chlorophenyl)-4-hydroxy-2-(4-hydroxyphenyl)-2-thiazolin-5-acetic acid. This compound is dehydrated by heating to give the title compound.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-Bromo-3-(4-chlorobenzoyl)propionate acid and an equimolar amount of 4-hydroxythio-benzamide are stirred in isopropyl alcohol solvent containing sodium carbonate to give 4-(4-chlorophenyl)-4-hydroxy-2-(4-hydroxyphenyl)-2-thiazolin-5-acetic acid. This compound is dehydrated by heating to give the title compound.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: By a process analogous to Example 2, methyl-3-bromo-3-(4-chlorobenzoyl)propionate and 4-hydroxy-thiobenzamide are reacted to give methyl 4-(4-chlorophenyl)-2-(4-hydroxyphenyl)thiazole-5-acetate. This compound is hydrolysed using 2 N sodium hydroxide to give the title compound.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: By a process analogous to Example 2, methyl-3-bromo-3-(4-chlorobenzoyl)propionate and 4-hydroxy-thiobenzamide are reacted to give methyl 4-(4-chlorophenyl)-2-(4-hydroxyphenyl)thiazole-5-acetate. This compound is hydrolysed using 2 N sodium hydroxide to give the title compound.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-Bromo-3-(4-chlorobenzoyl)propionic acid (27 g), and 4-hydroxy-thiobenzamide (14.6 g) were heated to 80° in dimethylformamide (50 ml). The reactants were kept at this temperature for 1 hour, cooled and poured onto ice. The resulting gum solidified, and was filtered, and washed with water, to give 31.6 g of powder, m.p. 184°-194° C. (decomp.). This was recrystallised from aqueous isopropanol affording 25.4 g of the title compound, hemihydrate, m.p. 192°-194° (d). cooled poured onto ice was filtered washed with water

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-Hydroxybenzenecarbothioamide (1.53 g, 10 mmol) and potassium hydroxide (1.50 g, 26.8 mmol) were dissolved in a mixture of 60 ml of water and 15 ml of methanol. A solution of bromopyruvic acid (1.67 g, 10 mmol) in 10 ml of methanol was added dropwise at room temperature. The resulting mixture was heated to reflux for 1.5 h, cooled to room temperature, poured into 100 ml of water and adjusted with 0.2N HCl solution to pH2. The mixture was placed in a refrigerator for 15 h. The title compound was obtained by filtration as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.82 (d, 2H), 7.78 (d, 2H), 8.37 (s, 1H), 10.05 (s, 1H), 13.00 (s, 1H). The resulting mixture was heated to reflux for 1.5 h

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: At a temperature and in the manner as described in Example 1, 69 g of potassium thiocyanate (0.7 mol) and 52 g of phenol (0.55 mol) are stirred with 0.5 l of 98% hydrofluoric acid, and subsequently, the mixture is stirred for 3 days at room temperature. 0.3 l of hydrofluoric acid are then distilled off at normal pressure and a bath temperature of up to 60° C, the remainder is cooled and the residue is stirred with ice and water. The crude product precipitated is suction-filtered and may be purified by dissolving in dilute soda solution at room temperature, clarifying the solution and subsequent precipitation of the product with mineral acid or by recrystallization from water. The 4-hydroxy-thiobenzamide so obtained has a melting point of 192° - 193° C. The yield is 85% of the theoretical yield, relative to the phenol used. 0.3 l of hydrofluoric acid are then distilled off at normal pressure and a bath temperature of up to 60° C the remainder is cooled the residue is stirred with ice and water The crude product precipitated is suction-filtered may be purified by dissolving in dilute soda solution at room temperature the solution and subsequent precipitation of the product with mineral acid by recrystallization from water

反应条件: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a round-bottomed flask, 2-bromoacetophenone (520 mg, 2.61 mmol) and 4-hydroxy-thiobenzamide (400 mg, 2.61 mmol) were dissolved in ethanol (10 ml), and the resulting solution was heated to reflux. After about one hour, the reaction was cooled to about 35° C. and was allowed to stir for about an additional twelve hours. The reaction mixture was then concentrated in vacuo to an oil, the residue redissolved in ethyl acetate and methylene chloride, and extracted with saturated aqueous sodium bicarbonate. The combined extracts were then extracted with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. The crude product was purified by column chromatography (silica gel; methylene chloride to 2% methanol/methylene chloride). The title product was isolated as a white solid (516 mg, 78% yield). LRMS ([M+H]+)=254.1. the resulting solution was heated to reflux The reaction mixture was then concentrated in vacuo to an oil the residue redissolved in ethyl acetate methylene chloride, and extracted with saturated aqueous sodium bicarbonate The combined extracts were then extracted with brine dried over magnesium sulfate filtered concentrated in vacuo to an oil The crude product was purified by column chromatography (silica gel; methylene chloride to 2% methanol/methylene chloride)