3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carboxamide → 5-benzyloxy-2-[3-(4-cyanophenoxy)-2-hydroxy-3-methylbutyl]pyridine N-oxide

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Reaction Steps

The 5-benzyloxy-2-[3-(4-cyanophenoxy)-3-methyl-1-butenyl]pyridine N-oxide used as the starting material was prepared as follows: (A) 23.8 g of 4-cyanophenol in 150 ml of dimethylformamide were added dropwise to a stirred suspension of 6 g of 80% sodium hydride in 100 ml of dimethylformamide and the mixture was then stirred for a further 1 hour. 39 g of ethyl bromoisobutyrate were added dropwise and the mixture was heated to 100° C. for 76 hours. The solvents were removed by evaporation and the residue was partitioned between diethyl ether and water. The organic phase was washed in succession with 2M sodium hydroxide solution and sodium chloride solution and then evaporated to give 9.4 g of ethyl 2-(4-cyanophenoxy)-2-methylpropionate in the form of a colourless viscous liquid of boiling point 115°-117° C./0.05 mmHg. (B) 5 ml of a 1.2M solution of butyllithium in n-hexane were added to a solution of 0.6 g of diisopropylamine in 10 ml of tetrahydrofuran while stirring at -78° C. under a nitrogen atmosphere. The solution was stirred for a further 15 minutes and then 1.07 g of 5-benzyloxy-2-methylpyridine N-oxide in 10 ml of tetrahydrofuran were added. The mixture was allowed to warm to 20° C, stirred for 30 minutes and then cooled to -78° C. 1.16 g of ethyl 2-(4-cyanophenoxy)-2-methylpropionate were added and the mixture was then allowed to warm to 20° C. and was stirred for 16 hours. The mixture was diluted with 50 ml of ethyl acetate and washed in succession with water and sodium chloride solution. The organic phase was evaporated and the residue was chromatographed on silica gel using dichloromethane/methanol (94:4) for the elution to give 0.46 g of 5-benzyloxy-2-[3-(4-cyanophenoxy)-3-methyl-2-oxobutyl]pyridine N-oxide in the form of a Pale yellow solid of melting point 134°-136° C. (from diethyl ether). (C) 0.46 g of sodium borohydride was added to a stirred solution of 4.53 g of 5-benzyloxy-2-[3-(4-cyanophenoxy)-3-methyl-2-oxobutyl]pyridine N-oxide in 60 ml of ethanol. After 2 hours the solution was diluted with 200 ml of water and extracted with diethyl ether. The organic phase was evaporated to give 3.67 g of 5-benzyloxy-2-[3-(4-cyanophenoxy)-2-hydroxy-3-methylbutyl]pyridine N-oxide of melting point 125° C. after recrystallization from ethanol. (D) 0.7 g of methanesulphonyl chloride was added to a stirred solution of 2.3 g of 5-benzyloxy-2-[3-(4-cyanophenoxy)-2-hydroxy-3-methylbutyl]pyridine N-oxide and 1 ml of 2,6-lutidine in 10 ml of dichloromethane. The mixture was stirred for 4.5 hours and then a further 1 ml of 2,6-lutidine and 0.7 g of methanesulphonyl chloride were added. After 2.5 hours a further 1 ml of 2,6-lutidine and 0.7 g of methanesulphonyl chloride were added and the mixture was stirred for 16 hours. The mixture was then diluted with 50 ml of dichloromethane and washed in succession with 2M hydrochloric acid, water and 10% sodium bicarbonate solution. The organic solution was evaporated and the residue was chromatographed on silica gel using diethyl ether/methanol (9:1) for the elution to give 0.89 g of 5-benzyloxy-2-[3-(4-cyanophenoxy)-3-methyl-2(methylsulphonyloxy)butyl]pyridine N-oxide in the form of a cream solid of melting point 142° C. after recrystallization from ethyl acetate. (E) 1.69 g of 5-benzyloxy-2-[3-(4-Cyanophenoxy)-3-methyl-2-(methylsulphonyloxy)butyl]pyridine N-oxide were added to a solution of 0.14 g of 80% sodium hydride in 15 ml of isopropanol and the solution was stirred at 20° C. for 16 hours. The solvent was then removed by evaporation and the residue was partitioned between ethyl acetate and sodium chloride solution. The organic phase was washed with sodium chloride solution and then evaporated to give 1.64 g of 5-benzyloxy-2-[3-(4 -cyanophenoxy)-3-methyl-1-butenyl]pyridine N-oxide in the form of a pale cream solid of melting point 125° C. after recrystallization from ethyl acetate.

Provenance & Evidence