methyl 3-(4-fluorophenyl)-3-oxopropanoate

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

実験手順: 31 g (0.25 mol) of p-fluorobenzaldehyde, 49 g (0.25 mol) of methyl 4-fluorobenzoylacetate and 39.25 g (0.25 mol) of ethyl 3-amino-4-methyl-pent-2-enoate are boiled under reflux for 18 hours in 150 ml of ethylene glycol at a bath temperature of 130° C. The mixture is cooled to room temperature, extracted three times using 300 ml of diethyl ether, the combined ether phases are concentrated, and the residue is dissolved in 100 ml of toluene and chromatographed on 700 ml of silica gel (0.04-0.063 mm) using toluene as an eluent. extracted three times the combined ether phases are concentrated the residue is dissolved in 100 ml of toluene chromatographed on 700 ml of silica gel (0.04-0.063 mm)

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

実験手順: A solution of methyl 4-fluorobenzoylacetate (20.03 g, 97 mmoles), mesityl oxide (14.58 g, 0.145 moles) and borontrifluoride etherate (13.77 g, 97 mmoles) was kept at 0° C. for 3 days and diluted with ether and saturated NaHCO3. The organic layer was washed with brine and dried (MgSO4). Removal of the volatiles in vacuo provided a residue which was diluted with 200 ml anhydrous methanol and 20 ml of Triton-B. The mixture was heated at reflux 2 hours, cooled, acidified with aqueous HCl and extracted with ether. The organic layers were washed with aqueous HCl, water and brine and dried (MgSO4). Removal of the volatiles in vacuo provided a residue which was purified by HPLC using 8% ethyl acetate in hexanes as the eluent. Concentration in vacuo of the product-rich fractions provided 14.9 g of the oily product. The organic layer was washed with brine dried (MgSO4) Removal of the volatiles in vacuo provided a residue which The mixture was heated at reflux 2 hours cooled extracted with ether The organic layers were washed with aqueous HCl, water and brine dried (MgSO4) Removal of the volatiles in vacuo provided a residue which was purified by HPLC Concentration in vacuo of the product-rich fractions

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

実験手順: A solution of methyl 4-fluorobenzoylacetate (20.03 g, 97 mmoles), mesityl oxide (14.58 g, 0.145 moles) and borontrifluoride etherate (13.77 g, 97 mmoles) was kept at 0° C. for 3 days and diluted with ether and saturated NaHCO3. The organic layer was washed with brine and dried (MgSO4). Removal of the volatiles in vacuo provided a residue which was diluted with 200 ml anhydrous methanol and 20 ml of Triton-B. The mixture was heated at reflux 2 hours, cooled, acidified with aqueous HCl and extracted with ether. The organic layers were washed with aqueous HCl, water and brine and dried (MgSO4). Removal of the volatiles in vacuo provided a residue which was purified by HPLC using 8% ethyl acetate in hexanes as the eluent. Concentration in vacuo of the product-rich fractions provided 14.9 g of the oily product. The organic layer was washed with brine dried (MgSO4) Removal of the volatiles in vacuo provided a residue which The mixture was heated at reflux 2 hours cooled extracted with ether The organic layers were washed with aqueous HCl, water and brine dried (MgSO4) Removal of the volatiles in vacuo provided a residue which was purified by HPLC Concentration in vacuo of the product-rich fractions

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

実験手順: 5-(4-Fluoro-phenyl)-1H-pyrazol-3-ol (7.67 g, 84%) was prepared as a white solid from 3-(4-Fluoro-phenyl)-3-oxo-propionic acid methyl ester (10.0 g, 51.0 mmol) and hydrazine (4.76 mL, 153 mmol) by a procedure analogous to Example 22. C9H7FN2O: 1H NMR (d6-DMSO): δ 7.66 (dd, 2H, JCH—CF=11.7 Hz, JCH—CH=8.7 Hz), 7.21 (d, 2H, J=8.7 Hz), 5.83 (s, 1H) ppm.

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

実験手順: 5-(4-Fluoro-phenyl)-1H-pyrazol-3-ol (7.67 g, 84%) was prepared as a white solid from 3-(4-Fluoro-phenyl)-3-oxo-propionic acid methyl ester (10.0 g, 51.0 mmol) and hydrazine (4.76 mL, 153 mmol) by a procedure analogous to Example 22. C9H7FN2O: 1H NMR (d6-DMSO): δ 7.66 (dd, 2H, JCH—CF=11.7 Hz, JCH—CH=8.7 Hz), 7.21 (d, 2H, J=8.7 Hz), 5.83 (s, 1H) ppm.

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

実験手順: 31 g (0.25 mol) of p-fluorobenzaldehyde, 49 g (0.25 mol) of methyl 4-fluorobenzoylacetate and 39.25 g (0.25 mol) of ethyl 3-amino-4-methyl-pent-2-enoate are boiled under reflux for 18 hours in 150 ml of ethylene glycol at a bath temperature of 130° C. The mixture is cooled to room temperature, extracted three times using 300 ml of diethyl ether, the combined ether phases are concentrated, and the residue is dissolved in 100 ml of toluene and chromatographed on 700 ml of silica gel (0.04-0.063 mm) using toluene as an eluent. extracted three times the combined ether phases are concentrated the residue is dissolved in 100 ml of toluene chromatographed on 700 ml of silica gel (0.04-0.063 mm)

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

実験手順: A mixture of methyl 3-(4-fluorophenyl)-3-oxopropanoate (10.0 g, 0.051 mol) and hydrazine hydrate (1.1 eq, 2.8 g, 0.056 mol) in 20 mL glacial acetic acid is heated 3 h under reflux. The resulting suspension is cooled down and 10 mL diethyl ether is added. The precipitate is filtered off, dried in vacuo and 9 g (100%) of 3-(4-fluorophenyl)-1H-pyrazol-5-ol are obtained as white solid. is heated 3 h under reflux The resulting suspension is cooled down The precipitate is filtered off dried in vacuo and 9 g (100%) of 3-(4-fluorophenyl)-1H-pyrazol-5-ol are obtained as white solid

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

実験手順: 31 g (0.25 mol) of p-fluorobenzaldehyde, 49 g (0.25 mol) of methyl 4-fluorobenzoylacetate and 39.25 g (0.25 mol) of ethyl 3-amino-4-methyl-pent-2-enoate are boiled under reflux for 18 hours in 150 ml of ethylene glycol at a bath temperature of 130° C. The mixture is cooled to room temperature, extracted three times using 300 ml of diethyl ether, the combined ether phases are concentrated, and the residue is dissolved in 100 ml of toluene and chromatographed on 700 ml of silica gel (0.04-0.063 mm) using toluene as an eluent. extracted three times the combined ether phases are concentrated the residue is dissolved in 100 ml of toluene chromatographed on 700 ml of silica gel (0.04-0.063 mm)

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

実験手順: 31 g (0.25 mol) of p-fluorobenzaldehyde, 49 g (0.25 mol) of methyl 4-fluorobenzoylacetate and 39.25 g (0.25 mol) of ethyl 3-amino-4-methyl-pent-2-enoate are boiled under reflux for 18 hours in 150 ml of ethylene glycol at a bath temperature of 130° C. The mixture is cooled to room temperature, extracted three times using 300 ml of diethyl ether, the combined ether phases are concentrated, and the residue is dissolved in 100 ml of toluene and chromatographed on 700 ml of silica gel (0.04-0.063 mm) using toluene as an eluent. extracted three times the combined ether phases are concentrated the residue is dissolved in 100 ml of toluene chromatographed on 700 ml of silica gel (0.04-0.063 mm)

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 39.2 g of methyl 4-fluorobenzoylacetate (0.20 mmol) and 16.8 g of isobutyronitrile (0.24 mol, concentration >99%) were dissolved in 200 ml of toluene and treated with 57.9 g of tin tetrachloride (0.22 mmol, concentration >99%) at room temperature after the course of 10 minutes. After 30 min at room temperature, the mixture was heated to 80° C. After 8 h, the suspension was again cooled to room temperature and treated with 200 ml of water. The mixture was diluted with 200 ml of ethyl acetate and the phases were separated. The organic phase was washed twice with 40 ml of 1N sodium hydroxide solution and concentrated in vacuo (40° C./25 mbar) after drying over magnesium sulphate. 50.9 g of crude product were obtained in the form of a yellow oil. After chromatography of 12.0 g of crude product on silica gel (eluent: hexane/isopropanol 90:10), 10.08 g of methyl 3-amino-2-[1-(4-fluorophenyl)methanoyl]-4-methylpent-2-enoate were obtained in the form of a yellowish oil. After 8 h the suspension was again cooled to room temperature the phases were separated The organic phase was washed twice with 40 ml of 1N sodium hydroxide solution concentrated in vacuo (40° C./25 mbar) after drying over magnesium sulphate 50.9 g of crude product were obtained in the form of a yellow oil

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 5.00 g of methyl 4-fluorobenzoylacetate (24.2 mmol, concentration 95%) and 1.69 g of isobutyronitrile (24.2 mmol, concentration 98%) were dissolved in 25 ml of toluene and treated with 7.01 g of tin tetrachloride (26.6 mmol, concentration >99%) at room temperature after the course of 10 minutes. After 3 h at room temperature, the mixture was heated to 80° C. After 11.5 h, the suspension was again cooled to room temperature and treated with 25 ml of water. The mixture was diluted with 10 ml of ethyl acetate and the phases were separated. The organic phase was washed twice with 10 ml of 1N sodium hydroxide solution and concentrated in vacuo (40° C./25 mbar) after drying over magnesium sulphate. 6.18 g of crude product were obtained in the form of a yellow oil. After chromatography on silica gel (eluent: hexane/ethyl acetate 1.5:1), 3.84 g of methyl 3-amino-2-[1-(4-fluorophenyl)methanoyl]-4-methylpent-2-enoate were obtained in the form of an oil. After 11.5 h the suspension was again cooled to room temperature the phases were separated The organic phase was washed twice with 10 ml of 1N sodium hydroxide solution concentrated in vacuo (40° C./25 mbar) after drying over magnesium sulphate 6.18 g of crude product were obtained in the form of a yellow oil

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

実験手順: A mixture of methyl 4-fluorobenzoylacetate (3.92 g), p-toluenesulfonyl azide (4.00 g), triethylamine (2.02 g) and acetonitrile (30 ml) was stirred at 0° C. for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give a yellow oil. The Lawesson's reagent (8.10 g) and tetrahydrofuran (50 ml) were added to this yellow oil and the mixture was heated under reflux for 16 hrs. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography to give methyl 5-(4-fluorophenyl)-1,2,3-thiadiazole-4-carboxylate (1.95 g, yield 41%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, v/v). extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate concentrated to give a yellow oil the mixture was heated under reflux for 16 hrs The reaction mixture was concentrated the residue was purified by silica gel column chromatography