Patent Application
20070247585
The starting substances can be obtained in accordance with generally accessible literature procedures or are commercially available. The reactions described are known from the literature.
270.2 g (1.70 mol) of 2,3-difluoroethoxybenzene are initially introduced in 1200 ml of THF, and 1100 ml (1.75 mol) of n-BuLi (15% soln. in hexane) are added at −70° C. After 1 h at this temperature, a solution of 270.2 g (1.70 mol) of 1,4-cyclohexanedione monoethylene ketal in 800 ml of THF is metered in, and the batch is stirred for 1 h. The reaction mixture is warmed to 0° C. and hydrolysed using 4 N HCl. The solution is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The crude product remaining after removal of the solvents under reduced pressure (609.8 g of red-brown oil) is used directly for the next reaction.
609 g (about 1.94 mol) of crude 8-(4-ethoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]decan-7-ol in 2000 ml of toluene are heated on a water separator for 2 h together with 220 ml (3.93 mol) of ethylene glycol with addition of 36.1 g (0.19 mol) of p-toluenesulfonic acid monohydrate. After cooling, the batch is washed successively with water, sat. sodium hydrogencarbonate solution and sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. The crude product (507 g of orange oil) is crystallised from ethanol at −20° C., giving 8-(4-ethoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene as yellow solid.
1400 ml (1.40 mol) of borane/THF complex (1 M solution) are added at −7° C. to a solution of 320.0 g (1.08 mol) of 8-(4-ethoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene in 3000 ml of THF, and the reaction mixture is stirred at room temperature for 3 h. 262 ml (4.50 mol) of ethanol, 650 ml (2.6 mol) of aqueous sodium hydroxide solution (4 M) and 360 ml (4.11 mol) of aqueous hydrogen peroxide soln. (35%) are added successively to the batch, during which the internal temperature does not exceed 47° C. (ice bath). When the addition is complete, the mixture is refluxed for 2 h, and the solution is cooled, added to water and stirred vigorously. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The solution is concentrated to dryness, and the crude product (336 g of yellow oil) is purified by column chromatography (SiO2, dichloromethane: MTBE=8:2), giving 8-(4-ethoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]decan-7-ol as pale-yellow oil.
50.0 g (1.25 mol) of sodium hydride (60% suspension in mineral oil) are washed repeatedly with n-pentane and suspended in 3000 ml of toluene. The suspension is heated to 90° C., and a solution of 145.0 g (0.46 mol) of 8-(4-ethoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]decan-7-ol in 700 ml of DMF is slowly metered in. The batch is stirred at 90° C. for 30 h, cooled and hydrolysed using water. The mixture is neutralised by addition of 2 N hydrochloric acid, and the organic phase is separated off. The aqueous phase is extracted with toluene, and the combined organic phases are washed with sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness under reduced pressure. The crude product obtained is recrystallised from ethanol at 5° C., giving (±)-(4aR*, 9bS*)-7-ethoxy-6-fluoro-1,4,4a,9b-tetrahydro-2H-spiro-[dibenzo[b,d]-furan-3,2′-1,3-dioxolane] as colourless solid.
135.0 g (459 mmol) of (±)-(4aR*, 9bS*)-7-ethoxy-6-fluoro-1,4,4a,9b-tetrahydro-2H-spiro[dibenzo[b,d]furan-3,2′-1,3-dioxolane] are dissolved in 1800 ml of toluene and stirred vigorously together with 550 ml (14.6 mol) of formic acid with addition of 10.0 ml (0.56 mol) of water. After 18 h, the organic phase is separated off, and the formic acid is extracted with toluene. The combined organic phases are washed successively with water, sat. sodium hydrogencarbonate solution and sat. sodium chloride solution and dried using sodium sulfate. The crude product remaining after removal of the solvent is purified by column chromatography (SiO2, toluene:ethyl acetate=4:1), giving (±)-(4aR*, 9bS*)-7-ethoxy-6-fluoro-1,4,4a,9b-tetrahydro-2H-dibenzofuran-3-one as colourless solid.
58.3 g (170 mmol) of methoxymethyltriphenylphosphonium chloride are initially introduced in 500 ml of THF, and a solution of 19.1 g (170 mmol) of potassium tert-butoxide in 200 ml of THF is added at 0° C. After 30 min at this temperature, 7-ethoxy-6-fluoro-1,4,4a,9b-tetrahydro-2H-dibenzofuran-3-one as a solution in 300 ml of THF is added, and the batch is stirred at room temperature for 17 h. Water is added at 0° C., and the mixture is acidified using 2 N hydrochloric acid. The batch is extracted with MTBE, and the combined extracts are washed with sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. Purification of the crude product by column chromatography (SiO2, toluene) gives (±)-(4aR*, 9bS*)-7-ethoxy-6-fluoro-3-[1-methoxy-methylidene]-1,2,3,4,4a,9b-hexahydrodibenzofuran as colourless solid.
8.0 g (28.7 mmol) of (±)-(4aR*, 9bS*)-7-ethoxy-6-fluoro-3-[1-methoxy-methylidene]-1,2,3,4,4a,9b-hexahydrodibenzofuran are dissolved in 200 ml of toluene and stirred vigorously at room temperature for 18 h together with 30 ml (0.80 mol) of formic acid and 0.5 ml (27.8 mmol) of water. The organic phase is separated off and washed successively with water, sat. sodium hydrogencarbonate solution and sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. Purification by column chromatography (SiO2, toluene:ethyl acetate=99:1) gives a mixture (64:36) of (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran-3-carbaldehyde and (±)-(3S*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran-3-carbaldehyde.
6.70 g (25.2 mmol) of a mixture (64:36) of (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran-3-carbaldehyde and (±)-(3S*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran-3-carbaldehyde are dissolved in 170 ml of methanol/THF mixture (5:2), and 0.37 ml (2.50 mmol) of aqueous sodium hydroxide solution (20%) is added dropwise. After 1 h at room temperature, the solution is added to water and acidified using 2 N hydrochloric acid. The batch is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. The crude product from the reaction is used directly for the following steps.
10.0 g (27.0 mmol) of ethyltriphenylphosphonium bromide are initially introduced in 100 ml of THF, and 2.98 g (26.0 mmol) of potassium tert-butoxide in 40 ml of THF are added at −5° C. After 1 h at this temperature, 6.50 g (24.6 mmol) of (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran-3-carbaldehyde as a solution in 60 ml of THF are added dropwise, and the batch is stirred at room temperature for 2 h. The reaction solution is hydrolysed using water and acidified using 2 N HCl. The mixture is extracted with MTBE, and the combined organic phases are dried using sodium sulfate. The crude product remaining after removal of the solvents is filtered adsorptively (SiO2, toluene), and the filtrate is concentrated to dryness. Recrystallisation of the residue from methanol gives (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-3-propenyl)-1,2,3,4,4a,9b-hexahydrodibenzofuran as E/Z isomer mixture.
3.50 g (12.7 mmol) of (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-3-propenyl-1,2,3,4,4a,9b-hexahydrodibenzofuran in THF are hydrogenated for 23 h in a hydrogen atmosphere with addition of 1.8 g of Pd/C. After completion of the uptake of hydrogen, the reaction solution is filtered and concentrated to dryness. The residue is filtered adsorptively (SiO2, toluene:n-heptane=1:1), and the beige solid obtained is recrystallised repeatedly from isopropanol at room temperature, giving (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-3-propyl-1,2,3,4,4a,9b-hexahydrodibenzofuran as colourless solid (melting point 128° C.).
Δε=−6.0
Δn=0.102
γ1=127 mPa·s
1H-NMR (500 MHz, CHCl3): δ=6.73 (d, 1H, J=8.0 Hz, 9-H), 6.45 (dd, 1H, J=8.0 Hz, J=6.8 Hz, 8-H), 4.06 (dq, 2H, J=7.0 Hz, J=1.5 Hz, OCH2CH3), 3.95 (ddd, 1H, J=12.6 Hz, J=11.5 Hz, J=3.5 Hz, 4a-H), 2.74 (ddd, 1H, J=12.6 Hz, J=12.6 Hz, J=2.8 Hz, 9b-H), 2.41-2.37 (m, 1H, 4-H), 2.30-2.26 (m, 1H, 1-H), 1.89 (dd, 1H, J=13.8 Hz, J=2.7 Hz, 2-H), 1.58-1.45 (m, 2H, 1-H, 3-H), 1.42 (t, 3H, J=7.0 Hz, OCH2CH3), 1.39-1.29 (m, 5H, 4-H, CH2CH2CH3), 1.06 (ddd, 1H, J=13.8 Hz, J=12.9 Hz, J=4.0 Hz, 2-H), 0.91 (t, 3H, J=6.9 Hz, CH2CH2CH3).
19F-NMR (235 MHz, CHCl3): δ=−157.9 (d, 1 F, 4J=6.8 Hz).
MS: m/e (%)=278 (100, M+), 235 ([M-Pr]+, 49).
7.94 g (50.2 mmol) of 2,3-difluoroethoxybenzene are initially introduced in 50 ml of THF, and 30.5 ml (48.8 mol) of n-BuLi (15% soln. in hexane) are added at −70° C. After 1 h at this temperature, a solution of 10.0 g (40.0 mmol) of (±)-(4aR*, 9bS*)-7-ethoxy-6-fluoro-1,4,4a,9b-tetrahydro-2H-dibenzofuran-3-one in 150 ml of THF is metered in. After 4 h, the batch is hydrolysed using water and acidified using 4 N HCl. The solution is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The crude product remaining after removal of the solvents under reduced pressure is digested in 500 ml of ethanol at 40° C. Filtration gives (±)-(4aR*, 9bS*)-7-ethoxy-3-(4-ethoxy-2,3-difluorophenyl)-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran-3-ol as colourless solid.
8.5 g (20.8 mmol) of (±)-(4aR*, 9bS*)-7-ethoxy-3-(4-ethoxy-2,3-difluorophenyl)-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran-3-ol in 200 ml of toluene are heated on a water separator for 30 min together with 396 mg (2.08 mmol) of p-toluenesulfonic acid monohydrate. After cooling, the batch is filtered adsorptively (SiO2, ethyl acetate:n-heptane=4:1), and the filtrate is concentrated to dryness. The product mixture obtained in this way can be used directly for the following reaction.
7.4 g (about 19.0 mmol) of a mixture of (±)-(4aR*, 9bS*)-7-ethoxy-3-(4-ethoxy-2,3-difluorophenyl)-6-fluoro-1,2,4a,9b-tetrahydrodibenzofuran and (±)-(4aR*, 9bS*)-7-ethoxy-3-(4-ethoxy-2,3-difluorophenyl)-6-fluoro-1,4,4a,9b-tetrahydrodibenzofuran in 160 ml of ethyl acetate/ethanol mixture (3:1) are hydrogenated at 80° C. in the presence of 3.70 g of Raney nickel and 1.50 g of ion exchanger (weakly H-acidic) under hydrogen pressure (4.4 bar). After 18 h, the catalyst is filtered off, and the filtrate is concentrated to dryness. The crude product is recrystallised successively from isopropanol, n-heptane and ethanol, giving (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-3-(4-ethoxy-2,3-difluorophenyl)-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran as colourless solid (melting point 126° C.).
Δε=−12.0
Δn=0.138
1H-NMR (250 MHz, CHCl3): δ=6.94-6.87 (m, 1H, Harom.), 6.78 (dm, 1H, J=8.0 Hz, Harom.), 6.75-6.67 (m, 1H, Harom.), 6.49 (dd, 1H, J=8.0 Hz, J=7.0 Hz, Harom.), 4.17-4.04 (m, 5H, OCH2CH3, 4a-H, OCH2CH3), 3.11-2.86 (m, 2H, 9b-H, 3-H), 2.54-2.37 (m, 2H, Haliph.), 2.20-1.96 (m, 2H, Haliph.), 1.63-1.55 (m, 2H, Haliph.), 1.44 (t, 3H, J=7.0 Hz, OCH2CH3), 1.43 (t, 3H, J=7.0 Hz, OCH2CH3).
19F-NMR (235 MHz, CHCl3): δ=−142.9 (ddd, 1F, J=13.5 Hz, J=7.4 Hz, J=1.2 Hz), −159.2 (ddd, 1F, J=13.5 Hz, J=7.4 Hz, J=1.2 Hz), −159.8 (d, 1 F, J=6.8 Hz).
MS (EI): m/e (%)=392 (39, M+), 234 (100).
3. (±)-(3R*,4aR*,9bS*)-7-Ethoxy-6-fluoro-3-vinyl-1,2,3,4,4a,9b-hexahydrodibenzofuran
5.0 g (14.0 mmol) of methyltriphenylphosphonium bromide are initially introduced in 50 ml of THF, and 1.60 g (14.3 mmol) of potassium tert-butoxide in 20 ml of THF are added at −5° C. After 1 h at this temperature, 3.40 g (12.9 mmol) of (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran-3-carbaldehyde as a solution in 30 ml of THF are added dropwise, and the batch is stirred at room temperature for 16 h. The reaction solution is hydrolysed using water and acidified using 2 N HCl. The mixture is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The crude product remaining after removal of the solvents is purified by column chromatography (SiO2, toluene). Further purification was carried out by repeated recrystallisation from isopropanol, giving (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-3-vinyl-1,2,3,4,4a,9b-hexahydrodibenzofuran as colourless solid (melting point 141° C.).
1H-NMR (250 MHz, CHCl3): δ=6.75 (dm, 1H, J=8.0 Hz, 9-H), 6.46 (dd, 1H, J=8.0 Hz, J=7.0 Hz, 8-H), 5.92-5.78 (m, 1H, Hvinyl) 5.11-4.97 (m, 2H, Hvinyl), 4.07 (d, 2H, J=7.0 Hz, OCH2CH3), 4.05-3.95 (m, 1H, 4a-H), 2.83-2.72 (m, 1H, 9b-H), 2.47-2.18 (m, 3H, Haliph.), 1.97-1.87 (m, 1H, Haliph.), 1.80-1.67 (m, 1H, Haliph.), 1.53-1.18 (m, 5H, J=7.0 Hz, Haliph., OCH2CH3).
19F-NMR (235 MHz, CHCl3): δ=−157.6 (d, 1 F, 4J=6.8 Hz).
MS (EI): m/e (%)=262 (81, M+), 206 (100, [M-Et-Vn]+).
6.0 g (about 21.7 mmol) of (E/Z) isomer mixture of (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-3-propenyl-1,2,3,4,4a,9b-hexahydrodibenzofuran (see 1.9) are refluxed in 60 ml of toluene together with 1.15 g (7.0 mmol) of benzene-sulfinic acid sodium salt and 21.4 ml of 1 N hydrochloric acid. After 1 h, the mixture is added to water, and the organic phase is separated off. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. Repeated recrystallisation from isopropanol gives (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-3-((E)-propenyl)-1,2,3,4,4a,9b-hexahydrodibenzofuran as colourless solid (melting point 145° C.).
Δε=−6.0
Δn=0.110
1H-NMR (250 MHz, CHCl3): δ=6.74 (dm, 1H, J=8.0 Hz, 9-H), 6.46 (dd, 1H, J=8.0 Hz, J=7.0 Hz, 8-H), 5.54-5.38 (m, 2H, Hvinyl), 4.07 (q, 2H, J=7.0 Hz, OCH2CH3), 4.04-3.92 (m, 1H, 4a-H), 2.81-2.70 (m, 1H, 9b-H), 2.42-2.11 (m, 3H, Haliph.), 1.91-1.82 (m, 1H, Haliph.), 1.76-1.62 (m, 4H, J=4.8 Hz, Haliph., CH═CHCH3), 1.52-1.14 (m, 5H, J=7.0 Hz, Haliph., OCH2CH3).
19F-NMR (235 MHz, CHCl3): δ=−159.1 (d, 1F, 4J=6.8 Hz).
MS (EI): m/e (%)=276 (72, M+), 206 (100, [M-Et-C3H5]+).
8.98 g (22.5 mmol) of butyltriphenylphosphonium bromide are initially introduced in 100 ml of THF, and 2.58 g (23.0 mmol) of potassium tert-butoxide in 40 ml of THF are added at −5° C. After 1 h at this temperature, 5.50 g (20.8 mmol) of (±)-(3R*, 4aR*, 9bS-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran-3-carbaldehyde as a solution in 60 ml of THF are added dropwise, and the batch is stirred at room temperature for 2 h. The reaction solution is hydrolysed using water and acidified using 2 N HCl. The mixture is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The crude product remaining after removal of the solvents is purified by column chromatography (SiO2, toluene). The E/Z isomer mixture obtained in this way can be used directly for the following reaction.
5.1 g (about 10.7 mmol) of (E/Z) isomer mixture of (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-3-pent-1-enyl-1,2,3,4,4a,9b-hexahydrodibenzofuran in 50 ml of THF are hydrogenated in a hydrogen atmosphere with addition of 5.0 g of Pd/C (5% Pd). After completion of the uptake of hydrogen (37 h), the reaction solution is filtered and concentrated to dryness. The residue is filtered adsorptively (SiO2, toluene), and the beige solid obtained is re-crystallised repeatedly from isopropanol at room temperature, giving (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-3-pentyl-1,2,3,4,4a,9b-hexahydro-dibenzofuran as colourless solid (melting point 118° C.).
Δε=−5.4
Δn=0.104
γ1=172 mPa·s
1H-NMR (250 MHz, CHCl3): δ=6.74 (dm, 1H, J=8.0 Hz, 9-H), 6.45 (dd, 1H, J=8.0 Hz, J=7.0 Hz, 8-H), 4.07 (q, 2H, J=7.0 Hz, OCH2CH3), 4.01-3.90 (m, 1H, 4a-H), 2.80-2.69 (m, 1H, 9b-H), 2.43-2.36 (m, 1H, Haliph.), 2.29 (dm, 1H, J=12.5 Hz, Haliph.), 1.90 (dd, 1H, J=13.1 Hz, J=2.7 Hz, Haliph.), 1.50-1.20 (m, 14H, Haliph.), 1.16-0.98 (m, 1H, Haliph.), 0.90 (t, 3H, J=7.0 Hz, OCH2CH3).
19F-NMR (235 MHz, CHCl3): δ=−160.1 (d, 1F, 4J=7.1 Hz).
MS (EI): m/e (%)=306 (100, M+), 235 (100, [M-C5H11]+).
31.0 g (0.17 mol) of 1-butoxy-2,3-difluorobenzene are initially introduced in 200 ml of THF, and 100 ml (0.16 mol) of n-BuLi (15% soln. in hexane) are added at −70° C. After 2 h at this temperature, a solution of 35.6 g (0.16 mol) of 4′-propylbicyclohexyl-4-one in 200 ml of THF is metered in, and the batch is stirred for 2.5 h. The reaction mixture is hydrolysed with ice-cooling and acidified using 2 N HCl. The solution is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The solution is concentrated to dryness, and the crude product (66.3 g of yellow solid) is used directly for the following reaction. 6.2 4-(4-Butoxy-2,3-difluorophenyl)-4′-propylbicyclohexyl-3-ene
66.3 g (about 0.16 mol) of crude 4-(4-butoxy-2,3-difluorophenyl)-4′-propylbicyclohexyl-4-ol in 200 ml of toluene are heated on a water separator for 2 h together with 3.04 g (16.0 mmol) of p-toluenesulfonic acid monohydrate. After cooling, the batch is washed successively with water, sat. sodium hydrogencarbonate solution and sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. The crude product (60.7 g of orange oil) is crystallised from ethanol, giving 4-(4-butoxy-2,3-difluorophenyl)-4′-propylbicyclohexyl-3-ene as yellow solid.
110 ml (0.11 mol) of borane/THF complex (1 M solution) are added at −5° C. to a solution of 31.4 g (80.4 mmol) of 4-(4-butoxy-2,3-difluorophenyl)-4′-propylbicyclohexyl-3-ene in 320 ml of THF, and the reaction mixture is stirred at room temperature for 3 h. 20 ml (0.35 mol) of ethanol, 50 ml (0.2 mol) of aqueous sodium hydroxide solution (4 M) and 28 ml (0.32 mol) of aqueous hydrogen peroxide soln. (35%) are added successively to the batch, during which the internal temperature does not exceed 47° C. (ice bath). When the addition is complete, the mixture is refluxed for 2 h, and the solution is cooled, added to water and stirred vigorously. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The solution is concentrated to dryness, and the crude product (32 g) is purified by column chromatography (SiO2, toluene → toluene:ethyl acetate=8:2), giving 4-(4-butoxy-2,3-difluorophenyl)-4′-propylbicyclohexyl-3-ol as colourless solid.
5.40 g (135 mmol) of sodium hydride (60% suspension in mineral oil) are washed repeatedly with n-pentane and suspended in 400 ml of toluene. The suspension is heated to 90° C., and a solution of 17.5 g (42.8 mmol) of 4-(4-butoxy-2,3-difluorophenyl)-4′-propylbicyclohexyl-3-ol in 100 ml of DMF is metered in slowly. The batch is stirred at 90° C. for 20 h, cooled and hydrolysed using water. The mixture is neutralised by addition of 2 N hydrochloric acid, and the organic phase is separated off. The aqueous phase is extracted with toluene, and the combined organic phases are washed with sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness under reduced pressure. The crude product obtained is recrystallised from ethanol at 5° C., giving (±)-(3R*, 4aR*, 9bS*-7-butoxy-6-fluoro-3-(4-propylcyclohexyl)-1,2,3,4,4a,9b-hexahydrodibenzofuran as colourless solid (melting point 105° C.).
Δε=−5.6
Δn=0.114
γ1=974 mPa·s
1H-NMR (250 MHz, CHCl3): δ=6.73 (dm, 1H, J=8.0 Hz, 9-H), 6.45 (dd, 1H, J=8.0 Hz, J=7.0 Hz, 8-H), 3.99 (t, 3H, J=6.9 Hz, OCH2CH2), 3.98-3.88 (m, 1H, 4a-H), 2.77-2.66 (m, 1H, Haliph.), 2.40-2.26 (m, 2H, Haliph.), 1.90-1.69 (m, 9H, Haliph.), 1.65-1.02 (m, 13H, Haliph.), 0.96 (t, 3H, J=7.4 Hz, Me), 0.88 (t, 3H, J=7.2 Hz, Me).
19F-NMR (235 MHz, CHCl3): δ=158.2 (d, 1 F, j=6.8 Hz).
MS (EI): m/e (%)=388 (100, M+).
99.5 g (0.63 mol) of 2,3-difluoroethoxybenzene are initially introduced in 800 ml of THF, and 384 ml (0.63 mol) of n-BuLi (15% soln. in hexane) are added at −70° C. After 30 min at this temperature, a solution of 150 g (0.63 mol) of 4-(1,4-dioxaspiro[4.5]dec-8-yl)cyclohexanone in 700 ml of THF is metered in, and the batch is stirred for 30 min. The reaction mixture is warmed to 0° C. and hydrolysed using 2 N HCl. The solution is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The crude product remaining after removal of the solvents under reduced pressure is used directly for the next reaction.
250 g of crude 4-(1,4-dioxaspiro[4.5]dec-8-yl)-1-(4-ethoxy-2,3-difluorophenyl)cyclohexanol in 1000 ml of toluene are heated on a water separator for 3 h together with 80.0 ml (1.43 mol) of ethylene glycol with addition of 12.0 g (0.06 mol) of p-toluenesulfonic acid monohydrate. After cooling, the batch is washed successively with water, sat. sodium hydrogencarbonate solution and sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is crystallised from acetonitrile, giving 8-[4-(4-ethoxy-2,3-difluorophenyl)cyclohex-3-enyl]-1,4-dioxaspiro[4.5]decane as colourless solid.
550 ml (0.55 mol) of borane/THF complex (1 M solution) are added at −5° C. to a solution of 154.0 g (0.41 mol) of 8-[4-(4-ethoxy-2,3-difluorophenyl)-cyclohex-3-enyl]-1,4-dioxaspiro[4.5]decane in 1500 ml of THF, and the reaction mixture is stirred at room temperature for 3 h. 99 ml (1.7 mol) of ethanol, 250 ml (1.0 mol) of aqueous sodium hydroxide solution (16%) and 140 ml (1.6 mol) of aqueous hydrogen peroxide soln. (35%) are added successively to the batch, during which the internal temperature does not exceed 46° C. (ice bath). When the addition is complete, the mixture is refluxed for 2 h, and the solution is cooled, added to water and stirred vigorously. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The solution is concentrated to dryness, and the crude product is purified by column chromatography (SiO2, toluene:ethyl acetate=8:2), giving 5-(1,4-dioxaspiro[4.5]dec-8-yl)-2-(4-ethoxy-2,3-difluorophenyl)cyclohexanol as colourless, viscous oil.
30.0 g (0.75 mol) of sodium hydride (60% suspension in mineral oil) are washed repeatedly with n-pentane and suspended in 2500 ml of toluene. The suspension is heated to 90° C., and a solution of 101.5 g (0.26 mol) of 5-(1,4-dioxaspiro[4.5]dec-8-yl)-2-(4-ethoxy-2,3-difluorophenyl)cyclohexanol in 500 ml of DMF is metered in slowly. The batch is stirred at 90° C. for 20 h, cooled and hydrolysed using water. The mixture is neutralised by addition of 2 N hydrochloric acid, and the organic phase is separated off. The aqueous phase is extracted with toluene, and the combined organic phases are washed with sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness under reduced pressure. The crude product obtained is firstly purified by column chromatography (SiO2, toluene:ethyl acetate=8:2) and then recrystallised successively from toluene and toluene:ethanol (3:1), giving (±)-(3R*,4aR*,9bS*)-3-(1,4-dioxaspiro[4.5]dec-8-yl)-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran as colourless, crystalline solid.
13.3 g (35.3 mmol) of (±)-(3R*,4aR*,9bS*)-3-(1,4-dioxaspiro[4.5]dec-8-yl)-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran are dissolved in 200 ml of toluene and stirred vigorously together with 40 ml (1.06 mol) of formic acid with addition of 1.0 ml (55.6 mmol) of water. After 18 h, the organic phase is separated off, and the formic acid is extracted with toluene. The combined organic phases are washed successively with water, sat. sodium hydrogencarbonate solution and sat. sodium chloride solution and dried using sodium sulfate. The crude product remaining after removal of the solvent is purified by column chromatography (SiO2, toluene:ethyl acetate=4:1), giving (±)-4-((3R*,4aR*,9bS*)-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran-3-yl)cyclohexanone as colourless solid.
14.1 g (41.3 mmol) of methoxymethyltriphenylphosphonium chloride are initially introduced in 250 ml of THF, and a solution of 4.6 g (41.0 mmol) of potassium tert-butoxide in 100 ml of THF is added at 0° C. After 30 min at this temperature, (±)-4-((3R*,4aR*,9bS*)-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran-3-yl)cyclohexanone as a solution in 150 ml of THF is added, and the batch is stirred at room temperature for 17 h. The mixture is treated with water at 0° C. and acidified using 2 N hydrochloric acid. The batch is extracted with MTBE, and the combined extracts are washed with sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. Purification of the crude product by column chromatography (SiO2, toluene:ethyl acetate=95:5) gives (±)-(3R*,4aR*,9bS*)-7-ethoxy-6-fluoro-3-(4-methoxymethylene-cyclohexyl)-1,2,3,4,4a,9b-hexahydrodibenzofuran as colourless solid.
10.0 g (27.7 mmol) of (±)-(3R*,4aR*,9bS*)-7-ethoxy-6-fluoro-3-(4-methoxy-methylenecyclohexyl)-1,2,3,4,4a,9b-hexahydrodibenzofuran are dissolved in 400 ml of toluene and stirred vigorously at room temperature for 18 h together with 30 ml (0.80 mol) of formic acid and 1.0 ml (55.6 mmol) of water. The organic phase is separated off and washed successively with water, sat. sodium hydrogencarbonate solution and sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness.
The residue is dissolved in 250 ml of methanol/THF mixture (5:2), and 0.44 ml (3.0 mmol) of aqueous sodium hydroxide solution (20%) is added dropwise. After 3 h at room temperature, the solution is added to water and acidified using 2 N hydrochloric acid. The batch is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. The crude product from the reaction is used directly for the following steps.
9.65 g (27.0 mmol) of methyltriphenylphosphonium bromide are initially introduced in 100 ml of THF, and 3.09 g (27.0 mmol) of potassium tert-butoxide in 60 ml of THF are added at −5° C. After 1 h at this temperature, 8.40 g (about 24 mmol) of crude (±)-4-((3R*,4aR*,9bS*)-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran-3-yl)cyclohexanecarbaldehyde as a solution in 90 ml of THF are added dropwise, and the batch is stirred at room temperature for 3 h. The reaction solution is hydrolysed using water and acidified using 2 N HCl. The mixture is extracted with MTBE, and the combined organic phases are dried using sodium sulfate. The crude product remaining after removal of the solvents is filtered adsorptively (SiO2, toluene), and the filtrate is concentrated to dryness. Repeated recrystallisation of the residue from ethanol gives (±)-(3R*,4aR*,9bS*)-7-ethoxy-6-fluoro-3-(4-vinylcyclohexyl)-1,2,3,4,4a,9b-hexahydrodibenzofuran as colourless solid (m.p. 132° C.).
Δε=−6.7
Δn=0.121
γ1=911 mPa·s
1H-NMR (250 MHz, CHCl3): δ=6.74 (dm, 1H, J=7.8 Hz, 9-H), 6.45 (dd, 1H, J=8.0 Hz, J=7.0 Hz, 8-H), 5.84-5.71 (m, 1H, Hvinyl.), 5.00-4.86 (m, 2H, Hvinyl.), 4.07 (q, 2H, J=7.0 Hz, OCH2CH3), 4.00-3.89 (m, 1H, 4a-H), 2.78-2.67 (m, 1H, Haliph.), 2.41-2.27 (m, 2H, Haliph.), 1.91-1.74 (m, 7H, Haliph.), 1.67-1.63 (m, 1H, Haliph.), 1.42 (t, 3H, J=7.0 Hz, OCH2CH3), 1.36-1.06 (m, 7H, Haliph.)
MS (EI): m/e (%)=344 (100, M+).
The following compounds are obtained analogously to the examples indicated using the corresponding precursors (Examples 1-1014; Tables 1 to 4, data Table 5):
Analogously to Example 1: Examples 8 to 62:
Analogously to Example 1: Examples 63 to 117:
Analogously to Examples 3, 4 and 5: Examples 118 to 173:
Analogously to Examples 3, 4 and 5: Examples 173 to 227:
Analogously to Example 2: Examples 228 to 282:
Analogously to Example 2: Examples 283 to 337:
Analogously to Example 2: Examples 338 to 392:
Analogously to Example 2: Examples 393 to 447:
Analogously to Example 2: Examples 448 to 502:
Analogously to Example 2: Examples 503 to 557:
Analogously to Example 2: Examples 558 to 612:
Analogously to Example 2: Examples 613 to 667:
Analogously to Example 2: Examples 668 to 715:
Analogously to Example 2: Examples 716 to 767:
Analogously to Example 2: Examples 768 to 815:
Analogously to Example 2: Examples 816 to 863:
Analogously to Example 2: Examples 864 to 911:
Analogously to Example 2: Examples 912 to 959:
Analogously to Example 6: Examples 960 to 1014:
Analogously to Example 6: Examples 1015 to 1069:
Analogously to Example 7: Examples 1070 to 1124:
Analogously to Example 7: Examples 1125 to 1179:
Values for individual compounds from all of Tables 1-4:
The entire disclosure[s] of all applications, patents and publications, cited herein and of corresponding DE 10 2006 019 045.9, filed Apr. 25, 2006, are incorporated by reference herein.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10 2006 019 045.9 | Apr 2006 | DE | national |
