2-isocyanatopropan-2-ylbenzene

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a benzene (2 mL) solution of cumylamine (1.80 g, 13.3 mmol) and triethylamine (1.86 mL, 13.3 mmol) was added a 20% toluene solution of phosgene (17.5 mL, 33.3 mmol) dropwise. After completion, the reaction mixture was heated to 60° C. for 2 hours. It was then cooled to room temperature, charged with diethyl ether (20 mL), and filtered. Concentration of the filtrate in vacuo afforded the title compound. This crude product was used in the subsequent step without further purification. It was then cooled to room temperature filtered

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 0.365 grams of dry hydrogen chloride (0.010 mole) was introduced into a solution of 0.43 grams of isocyanic acid (0.010 mole) in 3.44 grams of toluene at 0° under a nitrogen atmosphere. 1.18 gram of α-methylstyrene (0.010 mole) was added to the resultant carbamoyl chloride solution over a period of ten minutes while maintaining the temperature at 0° C. After fifteen minutes, cumyl chloride was present in 75% yield. 11.5 ml of 20.4% isocyanic acid in toluene (0.050 mole) was then added at 0° C. followed by addition of 0.50 ml of 1 M zinc chloride (0.00050 mole) in diisobutyl ketone over a period of 2 minutes at 0° C. After 5 minutes, cumyl isocyanate (b.p 50° C./1 mm was formed in 75% yield based α-methylstyrene. After fifteen minutes

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: To a suspension of (S)-(−)-3-aminoquinculidine dihydrochloride (120 mg, 0.603 mmol) and triethylamine (168 uL, 1.21 mmol) in THF (2 mL) at room temperature was added 3-isopropenyl-□,□-dimethylbenzyl-isocyanate (121 mg, 0.601 mmol). The reaction mixture was stirred for 18 hr and then washed with saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The crude material was purified on a combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH) to afford the title compound (29 mg, 47%) as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 7.51 (dt, J=2.5, 1.2 Hz, 1H), 7.41-7.14 (m, 3H), 5.32 (dd, J=1.6, 0.8 Hz, 1H), 5.06 (s, 1H), 3.74-3.60 (m, 1H), 3.31-3.29 (m, 2H), 3.19 (ddd, J=13.7, 9.5, 1.6 Hz, 1H), 2.88-2.50 (m, 4H), 2.37 (ddd, J=14.0, 4.9, 2.2 Hz, 1H), 2.14 (ddd, J=2.3, 1.8, 1.0 Hz, 3H), 1.81-1.63 (m, 4H), 1.62 (d, J=6.2 Hz, 6H), 1.55-1.38 (m, 1H) ppm. 13C NMR (100 MHz, CD3OD) δ 158.4, 148.4, 144.0, 141.3, 128.0, 124.1, 123.3, 121.9, 111.4, 55.7, 54.7, 46.7, 46.4, 46.0, 29.6, 29.4, 28.4, 26.1, 25.1, 21.0, 19.4 ppm. Purity: >96% UPLCMS (210 nm); retention time 0.81 min; (M+1) 329.5. washed with saturated aqueous NaHCO3 The organic phase was dried over Na2SO4 concentrated The crude material was purified on a combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH)

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

実験手順: To a suspension of (S)-(−)-3-aminoquinculidine dihydrochloride (120 mg, 0.603 mmol) and triethylamine (168 uL, 1.21 mmol) in THF (2 mL) at room temperature was added 3-isopropenyl-□,□-dimethylbenzyl-isocyanate (121 mg, 0.601 mmol). The reaction mixture was stirred for 18 hr and then washed with saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The crude material was purified on a combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH) to afford the title compound (29 mg, 47%) as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 7.51 (dt, J=2.5, 1.2 Hz, 1H), 7.41-7.14 (m, 3H), 5.32 (dd, J=1.6, 0.8 Hz, 1H), 5.06 (s, 1H), 3.74-3.60 (m, 1H), 3.31-3.29 (m, 2H), 3.19 (ddd, J=13.7, 9.5, 1.6 Hz, 1H), 2.88-2.50 (m, 4H), 2.37 (ddd, J=14.0, 4.9, 2.2 Hz, 1H), 2.14 (ddd, J=2.3, 1.8, 1.0 Hz, 3H), 1.81-1.63 (m, 4H), 1.62 (d, J=6.2 Hz, 6H), 1.55-1.38 (m, 1H) ppm. 13C NMR (100 MHz, CD3OD) δ 158.4, 148.4, 144.0, 141.3, 128.0, 124.1, 123.3, 121.9, 111.4, 55.7, 54.7, 46.7, 46.4, 46.0, 29.6, 29.4, 28.4, 26.1, 25.1, 21.0, 19.4 ppm. Purity: >96% UPLCMS (210 nm); retention time 0.81 min; (M+1) 329.5. washed with saturated aqueous NaHCO3 The organic phase was dried over Na2SO4 concentrated The crude material was purified on a combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH)

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

実験手順: To a suspension of (S)-(−)-3-aminoquinculidine dihydrochloride (120 mg, 0.603 mmol) and triethylamine (168 uL, 1.21 mmol) in THF (2 mL) at room temperature was added 3-isopropenyl-, -dimethylbenzyl-isocyanate (121 mg, 0.601 mmol). The reaction mixture was stirred for 18 hr and then washed with saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The crude material was purified on a combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH) to afford the title compound (29 mg, 47%) as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 7.51 (dt, J=2.5, 1.2 Hz, 1H), 7.41-7.14 (m, 3H), 5.32 (dd, J=1.6, 0.8 Hz, 1H), 5.06 (s, 1H), 3.74-3.60 (m, 1H), 3.31-3.29 (m, 2H), 3.19 (ddd, J=13.7, 9.5, 1.6 Hz, 1H), 2.88-2.50 (m, 4H), 2.37 (ddd, J=14.0, 4.9, 2.2 Hz, 1H), 2.14 (ddd, J=2.3, 1.8, 1.0 Hz, 3H), 1.81-1.63 (m, 4H), 1.62 (d, J=6.2 Hz, 6H), 1.55-1.38 (m, 1H) ppm. 13C NMR (100 MHz, CD3OD) δ 158.4, 148.4, 144.0, 141.3, 128.0, 124.1, 123.3, 121.9, 111.4, 55.7, 54.7, 46.7, 46.4, 46.0, 29.6, 29.4, 28.4, 26.1, 25.1, 21.0, 19.4 ppm. Purity: >96% UPLCMS (210 nm); retention time 0.81 min; (M+1) 329.5. was added 3-isopropenyl- washed with saturated aqueous NaHCO3 The organic phase was dried over Na2SO4 concentrated The crude material was purified on a combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH)

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

実験手順: Crude 3-(n-Butyl)-5,5-dimethyl-4-phenyl-4,5-dihydropyrazole (Intermediate IV-1) (1.03 gram, 4.48 mmol maximally) was dissolved in toluene (10 ml) and treated with 1-methyl-1-phenyl-ethylisocyanate (Intermediate VII-2) (0.72 g, 4.48 mmol) and 2 drops of triethylamine and the resulting solution was stirred at room temperature for 16 hours. The solution was concentrated and purified using Sepacore equipment: (petroleum ether/diethyl ether=85/15 (v/v)) to give N-(1-methyl-1-phenyl-ethyl)-3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1H)-pyrazole-1-carbox-amide as a colorless oil (0.97 gram, 55% yield). Rf (petroleum ether/diethyl ether=4/1 (v/v))˜0.3. 1H-NMR (400 MHz, CDCl3) δ 0.88 (t, J=7, 3H), 1.08 (s, 3H), 1.26-1.39 (m, 2H), 1.44 (s, 3H), 1.45-1.56 (m, 2H), 1.70 (s, 3H), 1.76 (s, 3H), 2.09-2.18 (m, 1H), 2.25-2.35 (m, 1H), 3.70 (s, 1H), 6.59 (br s, 1H), 7.03 (br d, J˜8 Hz, 2H), 7.20 (br t, J˜8 Hz, 1H), 7.26-7.36 (m, 5H), 7.44 (br d, J˜8 Hz, 2H). The solution was concentrated purified

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

実験手順: A mixture consisting of 18.1 g of α,α-dimethylbenzyl-isocyanate and 14.2 g of 2-chlorobenzylamine was allowed to stand for 2 hours at room temperature. The white deposit formed was then filtered off. Washing with n-hexane and recrystallization from ethanol gave 28.5 g of colorless crystal product, m.p. 165°-166° C. The white deposit formed was then filtered off Washing with n-hexane and recrystallization from ethanol