3,5-DICHLOROTHIOPHENOL

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:

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:

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3,5-dichlorothiophenol (1.67 g, 9.34 mmol) in MeCN (120 mL) and DMF (80 mL), 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (4.0 g, 8.49 mmol) was added, followed by K2CO3 (3.52 g, 25.48 mmol). The reaction mixture was stirred at 80° C. overnight. At this time, after cooling, the reaction was diluted with EtOAc (300 mL), washed with water (twice with 150 mL) and brine, and dried over Na2SO4. Concentration under reduced pressure provided an oil. A sample (2.73 g) was purified by FCC (10% EtOAc/Hex) provide a pure sample (1.20 g) of 4-[3-[6-(3,5-Dichloro-phenylsulfanyl)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester. 1H NMR (CDCl3): δ 7.26 (s, 1H), 7.12 (s, 2H), 7.09 (dd, 1H), 6.75 (d, 1H), 6.69 (d, 1H), 4.14 (m, 4H), 3.99 (t, 2H), 2.98-2.89 (m, 4H), 2.64-2.46 (m, 6H), 2.13 (m, 2H), 1.67-1.39 (m, 8H), 1.27 (m, 6H). At this time, after cooling washed with water (twice with 150 mL) and brine dried over Na2SO4 Concentration under reduced pressure provided an oil A sample (2.73 g) was purified by FCC (10% EtOAc/Hex)

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

Procedure: A solution of ethyl 3-chloro-2,4-dioxohexanoate (EP117082 A2) (7.10 g, 34.4 mmol) in acetone (175 ml) was treated with 3,5-dichlorothiophenol (6.16 g, 34.4 mmol), potassium carbonate (5.22 g, 37.8 mmol) and sodium iodide (5.16 g, 34.4 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (70 ml) and concentrated under reduced pressure. The residue was diluted with 2M aqueous hydrochloric acid (70 ml) and extracted with dichloromethane (3×150 ml). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with a solvent gradient of cyclohexane:ethyl acetate (3:1, by volume) gradually changing to cyclohexane:ethyl acetate (1:1, by volume) to afford the title compound (12.3 g) as a red oil. concentrated under reduced pressure The residue was diluted with 2M aqueous hydrochloric acid (70 ml) extracted with dichloromethane (3×150 ml) The combined organic extracts were dried over anhydrous magnesium sulphate filtered concentrated under reduced pressure The crude product was purified by flash chromatography on silica gel eluting with a solvent gradient of cyclohexane:ethyl acetate (3:1, by volume)

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

Procedure: 3-Chloro-2,4-pentanedione (723 μL, 6.07 mmol) and then sodium iodide (910 mg, 6.07 mmol) were added to a stirred suspension of 3,5-dichlorothiophenol (1.09 g, 6.07 mmol) and potassium carbonate (923 mg, 6.68 mmol) in acetone (30 ml), at room temperature, in a flask equipped with a calcium chloride drying tube. The mixture became yellow, then orange and finally red accompanied by a slight exotherm and was stirred for 23 hours at room temperature. The mixture was diluted with water (20 ml) and concentrated under reduced pressure in a fumehood (Caution: possible residual lachrymator) to remove acetone. The residue was diluted with 2M hydrochloric acid (20 ml) and extracted with dichloromethane (1×40 ml, 2×20 ml). The combined organic phases were washed with brine (20 ml), dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to leave an orange solid (1.66 g). The crude product was purified by flash chromatography on silica gel eluting with pentane:diethyl ether (99:1, by volume) to give the title compound (807 mg) as a yellow solid m.p. 79-81° C. equipped with a calcium chloride drying tube concentrated under reduced pressure in a fumehood (Caution: possible residual lachrymator) to remove acetone The residue was diluted with 2M hydrochloric acid (20 ml) extracted with dichloromethane (1×40 ml, 2×20 ml) The combined organic phases were washed with brine (20 ml) dried over anhydrous magnesium sulphate filtered evaporated under reduced pressure

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 9.2 g of 5-chloro-1-ethyl-3-methyl-1H-pyrazole-4-carbaldehyde, 14.3 g of 3,5-dichlorothiophenol and 11.8 g of potassium carbonate in 40 ml of anhydrous N,N-dimethylformamide was stirred under nitrogen at 100° C. for 18 hours. Water (200 ml) was added and the mixture was extracted three times with 100 ml of dichloromethane. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane/petroleum ether (bp 40–60° C.) for the elution to give 12.2 g of 5-(3,5-dichloro-phenylsulphanyl)-1-ethyl-3-methyl-1H-pyrazole-4-carbaldehyde as an orange solid. Mass spectrum (ES) m/z 356 [M+CH3CH+H]+. the mixture was extracted three times with 100 ml of dichloromethane The combined extracts were dried over magnesium sulphate filtered evaporated The residue was purified by flash chromatography on silica gel for the elution