propan-2-yl 3-oxobutanoate

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:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Ethoxy-6-pentadecyl benzaldehyde (3 g, 8.3 mmol) and isopropyl acetoacetate (1.19 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3 mmol) and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs. Ethyl-3-amino crotonate (1.08 g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was evaporated and reaction mixture was washed with distilled water and extracted with dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound was purified by column chromatography using silica gel (100-200 mesh) with hexane:EtOAc (94:6) solvent system to give ethyl isopropyl 1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate as viscous liquid. refluxed for 10 hrs n-Butanol was evaporated reaction mixture was washed with distilled water extracted with dichloromethane (10 mL) Organic layer was dried over sodium sulfate evaporated compound was purified by column chromatography

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

実験手順: To a solution of dimedone (0.984 g, 4.1 mmole) in hot ethanol (12 ml) was added 3-(4-trifluoromethylphenyl)-4-pyrazolecarboxaldehyde (1.0 g, 4.1 mmole), isopropyl acetoacetate (0.6 ml, 4.1 mmole) and lastly ammonium acetate (0.616 g, 8.0 mmole). The mixture was maintained at reflux for 18 h. No precipitate formed from the reaction. The reaction mixture was stripped of the ethanol in vacuo. The crude material was dissolved in ethyl acetate and washed with water (2×) and the organic phase was separated and stripped in vacuo. The material was then dissolved in ethyl ether and after a few minutes a white precipitate started to form. The white suspension was then filtered over night as it was a slow viscous filtration. The white material was washed with more ether to provide the desired product (1.55 g, 78%) as a white powder. Rf=0.45 in ethyl acetate. 1H NMR (400 MHz; DMSO d6) d 9.14 (bs, 1H); 8.34 (bd, 2H, J=7.4 Hz); 7.8 (bs, 2H); 7.35 (bs, 1H); 5.05 (bs, 1H); 4.65-4.55 (m, 1H); 3.35 (bs, 1H); 2.52 (bs, 1H); 2.46 (d, 1H, J=16.8 Hz); 2.32 (d, 1H, J=16.8 Hz); 2.23 (s, 3H); 2.20 (d, 1H, J=16.0 Hz); 2.04 (d, 1H, J=16.0 Hz); 1.05 (s, 3H); 0.93 (s, 3H); 0.7 (d, 3H, J=6.2 Hz); 0.55 (s, 3H, J=6.2 Hz). LC MS shows MH+ at 488; 2M+H at 975. The mixture was maintained at reflux for 18 h No precipitate formed from the reaction washed with water (2×) the organic phase was separated The material was then dissolved in ethyl ether and after a few minutes a white precipitate to form The white suspension was then filtered over night as it a slow viscous filtration The white material was washed with more ether

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

実験手順: To a solution of dimedone (0.984 g, 4.1 mmole) in hot ethanol (12 ml) was added 3-(4-trifluoromethylphenyl)-4-pyrazolecarboxaldehyde (1.0 g, 4.1 mmole), isopropyl acetoacetate (0.6 ml, 4.1 mmole) and lastly ammonium acetate (0.616 g, 8.0 mmole). The mixture was maintained at reflux for 18 h. No precipitate formed from the reaction. The reaction mixture was stripped of the ethanol in vacuo. The crude material was dissolved in ethyl acetate and washed with water (2×) and the organic phase was separated and stripped in vacuo. The material was then dissolved in ethyl ether and after a few minutes a white precipitate started to form. The white suspension was then filtered over night as it was a slow viscous filtration. The white material was washed with more ether to provide the desired product (1.55 g, 78%) as a white powder. Rf=0.45 in ethyl acetate. 1H NMR (400 MHz; DMSO d6) d 9.14 (bs, 1H); 8.34 (bd, 2H, J=7.4 Hz); 7.8 (bs, 2H); 7.35 (bs, 1H); 5.05 (bs, 1H); 4.65-4.55 (m, 1H); 3.35 (bs, 1H); 2.52 (bs, 1H); 2.46 (d, 1H, J=16.8 Hz); 2.32 (d, 1H, J=16.8 Hz); 2.23 (s, 3H); 2.20 (d, 1H, J=16.0 Hz); 2.04 (d, 1H, J=16.0 Hz); 1.05 (s, 3H); 0.93 (s, 3H); 0.7 (d, 3H, J=6.2 Hz); 0.55 (s, 3H, J=6.2 Hz). LC MS shows MH+ at 488; 2M+H at 975. The mixture was maintained at reflux for 18 h No precipitate formed from the reaction washed with water (2×) the organic phase was separated The material was then dissolved in ethyl ether and after a few minutes a white precipitate to form The white suspension was then filtered over night as it a slow viscous filtration The white material was washed with more ether

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

実験手順: A solution of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (53)70 (74 g, 0.5 mol) and 2-propanol (30 g, 0.5 mol) was heated at 135° C. for 20 h. The acetone formed during the reaction was removed with a rotary evaporator. The residue was distilled to provide 65 g (0.451 mol, 90%) of 54 as a clear, colorless liquid: bp 185°-187° C. was removed with a rotary evaporator The residue was distilled

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

実験手順: A solution of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (53)70 (74 g, 0.5 mol) and 2-propanol (30 g, 0.5 mol) was heated at 135° C. for 20 h. The acetone formed during the reaction was removed with a rotary evaporator. The residue was distilled to provide 65 g (0.451 mol, 90%) of 54 as a clear, colorless liquid: bp 185°-187° C. was removed with a rotary evaporator The residue was distilled

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

実験手順: The ester, 2-methoxyethyl acetoacetate (51), was prepared by the reaction of 2-methoxyethanol with 2,2,6-trimethyl-4H-1,3-dioxin-4-one (53) (eq. 28). (Hyatt, J. A. J. Org. Chem. 1984, 49, 5102. Hyatt, J. A.; Feldman, P. L.; Clemens, R. J. Ibid. 1984, 49, 5105. Kato, T.; Sato, M.; Kanuma, N. Chem. Pharm. Bull. 1982, 30, 1315). The enamine, 1-methylethyl 3-aminocrotonate (52) was prepared by the reaction of ammonia with 1-methylethyl acetoacetate (54) (eq. 29) (Iwanami, J. et al. Chem. Pharm. Bull. 27, 1426 (1979)) which was obtained by the reaction of 2-propanol with 53 (eq. 30) as shown in Schemes IIa, IIb and IIc. ##STR13##

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

実験手順: To a solution of 4.33 g (30 mmol) isopropyl 3-oxobutanoate in 90 ml benzene are added 4.83 g (30 mmol) 3-(trifluoromethyl)aniline and 1.80 g (30 mmol) acetic acid. The mixture is stirred under reflux for four hours using a Dean-Stark trap to remove water. After removal of the solvent in vacuo, the residue is purified by preparative HPLC (column: YMC C18 ODS-AQ 250 mm×30 mm, 11 μm; solvent A: acetonitrile, solvent B: water; gradient: 0 min 10% A, 3 min 10% A, 11 min 90% A, 13 min 90% A, 13.2 min 10% A, 15 min 10% A; wavelength: 220 nm; injection volume: ca. 900 μl ethanol solution; number of injections: 8). The product containing fractions are combined and concentrated in vacuo. under reflux for four hours to remove water After removal of the solvent in vacuo the residue is purified by preparative HPLC (column: YMC C18 ODS-AQ 250 mm×30 mm, 11 μm; solvent A: acetonitrile, solvent B: water; gradient: 0 min 10% A, 3 min 10% A, 11 min 90% A, 13 min 90% A, 13.2 min 10% A, 15 min 10% A; wavelength: 220 nm; injection volume: ca. 900 μl ethanol solution; number of injections: 8) The product containing fractions concentrated in vacuo

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

実験手順: To a solution of 4.33 g (30 mmol) isopropyl 3-oxobutanoate in 90 ml benzene are added 4.83 g (30 mmol) 3-(trifluoromethyl)aniline and 1.80 g (30 mmol) acetic acid. The mixture is stirred under reflux for four hours using a Dean-Stark trap to remove water. After removal of the solvent in vacuo, the residue is purified by preparative HPLC (column: YMC C18 ODS-AQ 250 mm×30 mm, 11 μm; solvent A: acetonitrile, solvent B: water; gradient: 0 min 10% A, 3 min 10% A, 11 min 90% A, 13 min 90% A, 13.2 min 10% A, 15 min 10% A; wavelength: 220 nm; injection volume: ca. 900 μl ethanol solution; number of injections: 8). The product containing fractions are combined and concentrated in vacuo. under reflux for four hours to remove water After removal of the solvent in vacuo the residue is purified by preparative HPLC (column: YMC C18 ODS-AQ 250 mm×30 mm, 11 μm; solvent A: acetonitrile, solvent B: water; gradient: 0 min 10% A, 3 min 10% A, 11 min 90% A, 13 min 90% A, 13.2 min 10% A, 15 min 10% A; wavelength: 220 nm; injection volume: ca. 900 μl ethanol solution; number of injections: 8) The product containing fractions concentrated in vacuo

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

実験手順: 21 mg (0.09 mmol) of 8-formyl-2-methyl-4-oxo-4H-chromene-5-carbonitrile are dissolved with 14 mg (0.09 mmol) of isopropyl acetoacetate, 8 mg (0.09 mmol) of 3-aminocrotononitrile and 6 mg (0.09 mmol) of acetic acid in 2 ml of 2-propanol and heated under reflux under argon for 6 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 8.8 mg (22% of theory) of the title compound are obtained as a yellow solid. heated under reflux under argon for 6 h The solvent is removed in vacuo the residue is purified by preparative HPLC