N-ethyl-4-fluoroaniline

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Iodoethane (3.6 ml) was added to a mixture of 4-fluoroaniline (4.26 ml) and potassium carbonate (6.9 g) in dry DMF (100 ml). After 18.5 h at 23°, the resulting suspension was poured into water (400 ml) and extracted with EA (400 ml). The organic extract was washed with water (200 ml) then saturated brine (200 ml), dried and evaporated. The residual oil was chromatographed with 2 to 3 to 4% EA in hexane as eluent to give the title compound (3.667 g) as a yellow oil. extracted with EA (400 ml) The organic extract was washed with water (200 ml) saturated brine (200 ml), dried evaporated The residual oil was chromatographed with 2 to 3 to 4% EA in hexane as eluent

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Fluoro-N-ethylaniline [NMR (200 MHz, DMSO-d6): δ1.25 (t, J=7.1 Hz, 3H); 3.12 (q, J=7.1 Hz, 2H); 3.24 (br s, 1H); 6.57 (dd, J1 =4.5 Hz, J2 =9.0 Hz, 2H); 6.90 (t, J=8.9 Hz, 2H)] was prepared from 4-fluoroaniline and acetic anhydride, coupled with 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give (+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-(4-fluorophenyl)benzamide as an off-white powder. NMR (200 MHz, DMSO-d6): δ0.91 (d, J=6.1 Hz, 3H); 0.98 (d, J=6.0 Hz, 3H); 1.08 (t, J=7.0 Hz, 3H); 1.71 (dd, J1 =7.0 Hz, J2 =11.3 Hz, 1H); 2.05 (dd, J1 =7.2 Hz, J2 =10.8 Hz, 1H); 2.31 (d, J=11.4 Hz, 1H) 2.36-2.57 (m, 2H); 2.69 (dd, J1 =2.2 Hz, J2 =10.7 Hz, 1H); 2.85 (dd, J1 =7.0 Hz, J2 =13.9 Hz, 1H); 3.18 (dd, J1 =5.3 Hz, J2 =13.9 Hz, 1H); 3.84 (q, J=7.0 Hz, 2H); 4.78 (s, 1H); 5.11 (d, J=10.0 Hz, 1H); 5.18 (d, J=16.4 Hz, 1H); 5.65-5.88 (m, 1H); 6.46 (d, J=7.4 Hz, 1H); 6.58 (s, 1H); 6.65 (d, J=8.1 Hz, 1H); 7.01-7.27 (m, 9H); 9.33 (s, 1H). Mass spectrum (CI--CH4) m/e: 502 (M+1.90%), 348 (15%), 153 (100%). [α]D20 =6.30° (abs. ethanol, c=1.1) The free amine (0.313 g) was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 3.95 followed by precipitation with diethyl ether from dichloromethane to give 0.263 g of the monohydrochloride salt as a hygroscopic white powder. Calc. for C31H36N3O2F HCl H2O: C, 66.95; H, 7.07; N, 7.56; Cl, 6.38. Found: C, 66.97; H, 7.10; N, 7.47; Cl, 6.41. purified by the methods

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Fluoro-N-ethylaniline [NMR (200 MHz, DMSO-d6): δ1.25 (t, J=7.1 Hz, 3H); 3.12 (q, J=7.1 Hz, 2H); 3.24 (br s, 1H); 6.57 (dd, J1 =4.5 Hz, J2 =9.0 Hz, 2H); 6.90 (t, J=8.9 Hz, 2H)] was prepared from 4-fluoroaniline and acetic anhydride, coupled with 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give (+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-(4-fluorophenyl)benzamide as an off-white powder. NMR (200 MHz, DMSO-d6): δ0.91 (d, J=6.1 Hz, 3H); 0.98 (d, J=6.0 Hz, 3H); 1.08 (t, J=7.0 Hz, 3H); 1.71 (dd, J1 =7.0 Hz, J2 =11.3 Hz, 1H); 2.05 (dd, J1 =7.2 Hz, J2 =10.8 Hz, 1H); 2.31 (d, J=11.4 Hz, 1H) 2.36-2.57 (m, 2H); 2.69 (dd, J1 =2.2 Hz, J2 =10.7 Hz, 1H); 2.85 (dd, J1 =7.0 Hz, J2 =13.9 Hz, 1H); 3.18 (dd, J1 =5.3 Hz, J2 =13.9 Hz, 1H); 3.84 (q, J=7.0 Hz, 2H); 4.78 (s, 1H); 5.11 (d, J=10.0 Hz, 1H); 5.18 (d, J=16.4 Hz, 1H); 5.65-5.88 (m, 1H); 6.46 (d, J=7.4 Hz, 1H); 6.58 (s, 1H); 6.65 (d, J=8.1 Hz, 1H); 7.01-7.27 (m, 9H); 9.33 (s, 1H). Mass spectrum (CI--CH4) m/e: 502 (M+1.90%), 348 (15%), 153 (100%). [α]D20 =6.30° (abs. ethanol, c=1.1) The free amine (0.313 g) was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 3.95 followed by precipitation with diethyl ether from dichloromethane to give 0.263 g of the monohydrochloride salt as a hygroscopic white powder. Calc. for C31H36N3O2F HCl H2O: C, 66.95; H, 7.07; N, 7.56; Cl, 6.38. Found: C, 66.97; H, 7.10; N, 7.47; Cl, 6.41. purified by the methods

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Fluoro-N-ethylaniline [NMR (200 MHz, DMSO-d6): δ 1.25 (t, J=7.1 Hz, 3H); 3.12 (q, J=7.1 Hz, 2H); 3.24 (br s, 1H); 6.57 (dd, J1 =4.5 Hz, J2 =9.0 Hz, 2H); 6.90 (t, J=8.9 Hz, 2H)] was prepared from 4-fluoroaniline and acetic anhydride, coupled with 3-((αR)-α-((2S ,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give (+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-(4-fluorophenyl)benzamide as an off-white powder. NMR (200 MHz, DMSO-d6): δ 0.91 (d, J=6.1 Hz, 3H); 0.98 (d, J=6.0 Hz, 3H); 1.08 (t, J=7.0 Hz, 3H); 1.71 (dd, J1 =7.0 Hz, J2 =11.3 Hz, 1H); 2.05 (dd, J1 =7.2 Hz, J2 =10.8 Hz, 1H); 2.31 (d, J=11.4 Hz, 1H) 2.36-2.57 (m, 2H); 2.69 (dd, J1 =2.2 Hz, J2 =10.7 Hz, 1H); 2.85 (dd, J1 =7.0 Hz, J2 =13.9 Hz, 1H); 3.18 (dd, J1 =5.3 Hz, J2 =13.9 Hz, 1H); 3.84 (q, J=7.0 Hz, 2H); 4.78 (s, 1H); 5.11 (d, J=10.0 Hz, 1H); 5.18 (d, J=16.4 Hz, 1H); 5.65-5.88 (m, 1H); 6.46 (d, J=7.4 Hz, 1H); 6.58 (s, 1H); 6.65 (d, J=8.1 Hz, 1H); 7.01-7.27 (m, 9H); 9.33 (s, 1H). Mass spectrum (CI--CH4) m/e: 502 (M+1, 90%), 348 (15%), 153 (100%). [α]D20 =+6.30° (abs. ethanol, c=1.1) The free amine (0.313 g) was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 3.95 followed by precipitation with diethyl ether from dichloromethane to give 0.263 g of the monohydrochloride salt as a hygroscopic white powder. Calc. for C31H36N3O2F HCl H2O: C, 66.95; H, 7.07; N, 7.56; Cl, 6.38. Found: C, 66.97; H, 7.10; N, 7.47; Cl, 6.41. purified by the methods

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Iodoethane (3.6 ml) was added to a mixture of 4-fluoroaniline (4.26 ml) and potassium carbonate (6.9 g) in dry DMF (100 ml). After 18.5 h at 23°, the resulting suspension was poured into water (400 ml) and extracted with EA (400 ml). The organic extract was washed with water (200 ml) then saturated brine (200 ml), dried and evaporated. The residual oil was chromatographed with 2 to 3 to 4% EA in hexane as eluent to give the title compound (3.667 g) as a yellow oil. extracted with EA (400 ml) The organic extract was washed with water (200 ml) saturated brine (200 ml), dried evaporated The residual oil was chromatographed with 2 to 3 to 4% EA in hexane as eluent

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Fluoro-N-ethylaniline [NMR (200 MHz, DMSO-d6): δ1.25 (t, J=7.1 Hz, 3H); 3.12 (q, J=7.1 Hz, 2H); 3.24 (br s, 1H); 6.57 (dd, J1 =4.5 Hz, J2 =9.0 Hz, 2H); 6.90 (t, J=8.9 Hz, 2H)] was prepared from 4-fluoroaniline and acetic anhydride, coupled with 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give (+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-(4-fluorophenyl)benzamide as an off-white powder. NMR (200 MHz, DMSO-d6): δ0.91 (d, J=6.1 Hz, 3H); 0.98 (d, J=6.0 Hz, 3H); 1.08 (t, J=7.0 Hz, 3H); 1.71 (dd, J1 =7.0 Hz, J2 =11.3 Hz, 1H); 2.05 (dd, J1 =7.2 Hz, J2 =10.8 Hz, 1H); 2.31 (d, J=11.4 Hz, 1H) 2.36-2.57 (m, 2H); 2.69 (dd, J1 =2.2 Hz, J2 =10.7 Hz, 1H); 2.85 (dd, J1 =7.0 Hz, J2 =13.9 Hz, 1H); 3.18 (dd, J1 =5.3 Hz, J2 =13.9 Hz, 1H); 3.84 (q, J=7.0 Hz, 2H); 4.78 (s, 1H); 5.11 (d, J=10.0 Hz, 1H); 5.18 (d, J=16.4 Hz, 1H); 5.65-5.88 (m, 1H); 6.46 (d, J=7.4 Hz, 1H); 6.58 (s, 1H); 6.65 (d, J=8.1 Hz, 1H); 7.01-7.27 (m, 9H); 9.33 (s, 1H). Mass spectrum (CI--CH4) m/e: 502 (M+1.90%), 348 (15%), 153 (100%). [α]D20 =6.30° (abs. ethanol, c=1.1) The free amine (0.313 g) was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 3.95 followed by precipitation with diethyl ether from dichloromethane to give 0.263 g of the monohydrochloride salt as a hygroscopic white powder. Calc. for C31H36N3O2F HCl H2O: C, 66.95; H, 7.07; N, 7.56; Cl, 6.38. Found: C, 66.97; H, 7.10; N, 7.47; Cl, 6.41. purified by the methods