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With hydrogenchloride; trifluorormethanesulfonic acid; In methanol; dichloromethane; |
EXAMPLE 12 6-methanesulfonyloxy- 2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride The acid chloride was formed from 2.0 g. of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, as described in Example 9, and was combined with 2 g. of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)benzo[b]thiophene in 50 ml. of dichloromethane. A 2.4 g. portion of trifluoromethanesulfonic acid was added, and the mixture was stirred overnight under reflux. The reaction mixture was then poured over ice and sodium bicarbonate solution, and the organic layer was dried over magnesium sulfate and filtered. The filtrate was evaporated under vacuum to a yellow foam, which was treated with excess 3% hydrogen chloride in anhydrous methanol. The mixture was evaporated to dryness under vacuum to obtain a white foam which was dissolved in 18 ml. of boiling methanol. The solution was cooled to obtain 3.1 g. of the desired product, m.p. 128-130 C., which was identified by nmr analysis. delta1.50-2.00 (6H, m, N-(CH2 CH2)2 CH2); 2.57-3.75 (6H, m, NH(CH2 CH2)2 CH2 and OCH2 CH2 N); 3.36 (3H, s, CH3 SO2); 3.46 (3H, s, CH3 SO2); 4.45 (2H, broad t, J=6 Hz, OCH2 CH2 N); 6.97 (2H, d, J=9 Hz, aromatic o to OCH2); 7.25-7.80 (8H, m, aromatic); 8.25 (1H, d, J=2 Hz, aromatic, o to O and S); 10.70-11.00 (1H, broad s, NH). |
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With hydrogenchloride; trifluorormethanesulfonic acid; In methanol; dichloromethane; |
Preparation 8 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]-thiophene, hydrochloride The acid chloride was formed from 2.0 g. of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, as described in Example 1, and was combined with 2 g. of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-benzo[b]thiophene in 50 ml. of dichloromethane. A 2.4 g. portion of trifluoromethanesulfonic acid was added, and the mixture was stirred overnight under reflux. The reaction mixture was then poured over ice and sodium bicarbonate solution, and the organic layer was dried over magnesium sulfate and filtered. The filtrate was evaporated under vacuum to a yellow foam, which was treated with excess 3% hydrogen chloride in anhydrous methanol. The mixture was evaporated to dryness under vacuum to obtain a white foam which was dissolved in 18 ml. of boiling methanol. The solution was cooled to obtain 3.1 g. of the desired product, m.p. 128-130 C., which was identified by nmr analysis. delta1.50-2.00 (6H, m, N--(CH2 CH2)2 CH2); 2.57-3.75 (6H, m, NH(CH2 CH2)2 CH2 and OCH2 CH2 N); 3.36 (3H, s, CH3 SO2); 3.46 (3H, s, CH3 SO2); 4.45 (2H, broad t, J=6 Hz, OCH2 CH2 N); 6.97 (2H, d, J=9 Hz, aromatic o to OCH2); 7.25-7.80 (8H, m, aromatic); 8.25 (1H, d, J=2 Hz, aromatic, o to O and S); 10.70-11.00 (1H, broad s, NH). |
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With thionyl chloride; In methanol; aluminium trichloride; ice-water; chloroform; toluene; |
EXAMPLE 13 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride The acid chloride was prepared from 19.7 g. of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride in 200 ml. of toluene with 44.9 g. of thionyl chloride, and the acid chloride was used to acylate 20 g. of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)benzo[b]thiophene in the presence of 59.6 g. of aluminum chloride. The aluminum chloride was added portionwise over a period of 30 minutes, and the reaction mixture was then stirred for 16 hours. It was poured over 2 liters of ice-water, and the product was extracted from the aqueous layer with two 200 ml. portions of warm chloroform. The organics were combined, dried and evaporated to obtain an oil, which was crystallized from 350 ml. of methanol to obtain 28 g. of crude product, m.p. 133-135. |
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