丙二酸单乙酯钾盐

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To an oven-dried flask was added potassium ethyl malonate (3.66 g, 21.5 mmol) and freshly distilled acetonitrile (70 mL). The mixture was cooled to 10° C. to 15° C. and stirred under an atmosphere of nitrogen and to it added anhydrous magnesium chloride (2.44 g, 25.7 mmol) and triethylamine (2.05 g, 20.3 mmol). The mixture was then stirred at room temperature under nitrogen for 2.5 hours. The resultant white slurry was recooled to 0° C. and 2,4,5-trifluorobenzoyl chloride was added over a period of 15 minutes, followed by more triethylamine (0.23 g, 2.3 mmol). The mixture was then stirred at room temperature overnight under nitrogen. Acetonitrile was then removed in vacuo and toluene (30 mL) was added. The mixture was reconcentrated and more toluene (60 mL) then added. Hydrochloric acid (1.5 M, 40 mL) was cautiously added, ensuring that the temperature did not exceed 25° C., and the aqueous layer separated. The organic fraction was washed with 1.5 M HCl (2×25 mL) and water (2×25 mL), dried over MgSO4, and solvent removed in vacuo to afford 3-oxo-3-(2,4,5-trifluoro-phenyl-propionic acid ethyl ester as a pale orange solid (2.35 g, 9.55 mmol, 94%). Rf 0.55 (CH2C2), mp 57-59° C. FTIR, νmax/cm −1 3088, 2990, 1735, 1687, 1514, 1429, 1321, 1205, 1140, 1055, 897, 807. 1 H NMR (CDCl3, 250 MHz), δ/ppm [12.69 (s), 5.81 (s) and 3.92 (d, J=3.9 Hz)] (2 H, keto-enol tautomers); 7.74 (1 H, m, Ar H); 6.98 (1 H, m, Ar H); 4.24 and 4.17 (2 H, both q, 3J=7.1 Hz); 1.31 and 1.24 (3 H, both t, 3J=7.1 Hz). 13C{1 H}NMR (CDCl3, 63 MHz), δ/ppm 187.8 (C=O); 173.0 (—HC=C); 166.9 (CO2Et); 163.7, 159.8, 155.9, 151.8, 149.0, 145.3, 120.9 (quat. Ar C); 118.7, 106.6 (Ar C—H); 92.9 (HC=C); 61.4 and 60.6 (—OCH2); 49.4 (—OCCH2CO—); 14.0 (—CH3). 19FNMR (CDCl3, 235 MHz) δ/ppm −110.6 and −111.7 (m, Ar F); −123.5 and −129.0 (m, Ar F); −140.5 and −141.7 (m, Ar F). λmax/nm (δ/dm3mol−1cm−1) 295 (4781), 281 (3962), 240 (5191). HRMS (EI), M+/z C11H9F3O3 (M−) requires 246.0504; found 246.0514. The mixture was cooled to 10° C. to 15° C. The mixture was then stirred at room temperature under nitrogen for 2.5 hours was recooled to 0° C. The mixture was then stirred at room temperature overnight under nitrogen Acetonitrile was then removed in vacuo and toluene (30 mL) was added more toluene (60 mL) then added Hydrochloric acid (1.5 M, 40 mL) was cautiously added did not exceed 25° C. the aqueous layer separated The organic fraction was washed with 1.5 M HCl (2×25 mL) and water (2×25 mL) dried over MgSO4, and solvent removed in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Triethylamine (9.71 g) and magnesium chloride (7.61 g) were successively added to a suspension of potassium ethyl malonate (10.8 g) in tetrahydrofuran with stirring at room temperature. After stirring at 60-70° C. for 1.5 hr, a solution of 5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl chloride prepared in Step V in toluene was added dropwise, and the mixture was further stirred for 30 min. After cooling, toluene (50 ml) and 2N hydrochloric acid (60 ml) were added to the reaction mixture, and the mixture was stirred for 1 hr. The organic layer was washed successively with water (50 ml), 5% sodium hydrogencarbonate (50 ml, twice), and water (50 ml) again, and the organic layer was concentrated under reduced pressure. Toluene (50 ml) was added to the residue, and the mixture was concentrated under reduced pressure. The residue was dissolved in toluene (50 ml) to give a solution of 3-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxyphenyl)-3-oxopropionic acid ethyl ester in toluene. This was identified as the title compound by HPLC. After stirring at 60-70° C. for 1.5 hr the mixture was further stirred for 30 min After cooling the mixture was stirred for 1 hr The organic layer was washed successively with water (50 ml), 5% sodium hydrogencarbonate (50 ml twice), and water (50 ml) again, and the organic layer was concentrated under reduced pressure Toluene (50 ml) was added to the residue the mixture was concentrated under reduced pressure The residue was dissolved in toluene (50 ml)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: As an alternative to the quinolone synthesis outlined above, the quinolone nucleus may be formed using the route illustrated in Scheme II. Similar methodology for the preparation of quinolones was first described in German patent application DE3142854. Starting from a 4-bromo-3-fluoro-benzoyl chloride, condensation with malonic acid monoethyl ester monopotassium salt gives a benzoyl acetate that is subsequently reacted with triethyl orthoformate. The resulting ethoxymethylene derivative is reacted with a primary amine and cyclized to the quinolone. ##STR38## may be formed

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution containing 1.0 g (6.9 mmol) of (2R,3R)-2,3-dimethyl-hexanoic acid in 10 mL of dichloromethane was added 1.1 g of chloromethylene dimethyl-ammonium chloride (8.3 mmol). The resulting solution was stirred under nitrogen for 1.5 hours. The solvent was subsequently evaporated to give (2R,3R)-2,3-dimethyl-hexanoyl chloride. To a solution containing 2.5 g (14.6 mmol) of potassium monoethyl malonate in 50 mL of acetonitrile was added 1.7 g (17.3 mmol) of magnesium chloride and 1.2 g (11.4 mmol) of triethylamine. The resulting mixture was stirred at room temperature for 2.5 hours. The reaction was cooled to 0° C. and a solution of the (2R,3R)-2,3-dimethyl-hexanoyl chloride in acetonitrile (20 mL) was slowly added followed by the addition of triethylamine (0.4 g, 0.4 mmol). The reaction was heated to 40° C. and stirred at that temperature for 6 hours. The reaction mixture was cooled to 25° C., quenched with a saturated solution of ammonium chloride and extracted into ethyl acetate. The solution was washed with brine, dried over MgSO4 and concentrated. The resulting residue was filtered through a silica plug, eluting with 60/40 solution of hexane/ethyl acetate to afford 1.3 g (87.8% yield) of the titled compound as an oil. The reaction was cooled to 0° C. The reaction was heated to 40° C. stirred at that temperature for 6 hours The reaction mixture was cooled to 25° C. quenched with a saturated solution of ammonium chloride extracted into ethyl acetate The solution was washed with brine dried over MgSO4 concentrated The resulting residue was filtered through a silica plug eluting with 60/40 solution of hexane/ethyl acetate

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 5 L 3-neck round bottom flask, equipped with a reflux condenser, mechanical stirrer, nitrogen inlet, and thermometer, was charged with 1390 mL of dry THF and 389.3 g of potassium ethyl malonate. MgCl2 (217.8 g) was added in three equal portions so that the internal temperature was less than 50° C. The resulting grey slurry was heated to 55° C. to 60° C. using a temperature controlled heating mantle. The mixture was stirred at 55° C. to 60° C. for 5 hours. A 2 L 3-neck round bottom flask, equipped with a 500 mL addition funnel, mechanical stirrer, nitrogen inlet, and thermometer, was charged with 680 mL of dry THF and 286.8 g of 1,1′-carbonyldiimidazole (CDI). The addition funnel was charged portion-wise with a solution of 219.9 g of (2R,3R)-2,3-dimethyl-hexanoic acid in 350 mL of dry THF. The entire dimethyl-hexanoic acid acid/THF solution was added dropwise to the stirred CDI/THF suspension at such a rate so as to control the evolution of CO2 and to maintain the reaction at a temperature of 20° C. to 25° C. Following the addition, the reaction mixture was stirred at 20° C. to 25° C. for 1 hour, during which the slurry became a pale yellow solution. After the 5-hour reaction time, the malonate/MgCl2 reaction mixture was cooled to 20° C. to 25° C. and the condenser was replaced with a 1 L addition funnel. The addition funnel was charged portion-wise with the dimethylhexanoic acid/CDI/THF reaction mixture. This entire reaction mixture was added dropwise to the stirred malonate/MgCl2/THF reaction mixture over about 10 minutes. After the addition was completed, the reaction mixture was heated to 35° C. to 40° C. Some effervescence was noted. The reaction mixture was stirred at 35° C. to 40° C. for 16 hour. The reaction mixture was cooled to 20° C. to 25° C. A 12 L 3-neck round bottom flask, equipped with a mechanical stirrer and thermometer, was charged with 3060 mL of 2N aq. HCl. The reaction mixture (a grey suspension) was added portion-wise to the aq. HCl solution while maintaining an internal temperature of 20° C.–25° C. The reaction temperature was moderated with an ice/water bath; the reaction mixture pH was about 1. Following the addition, the reaction mixture was stirred at 20° C. to 25° C. for 2 hours. The reaction mixture was subsequently charged with 4000 mL of EtOAc and was stirred for 5 minutes. The phases were separated and the aqueous phase was extracted with 2000 mL of EtOAc. The combined organic extract was washed sequentially with: 1N aq. HCl (2×1 500 mL); 1000 mL of water (incomplete phase separation); half saturated aq. Na2CO3 (2×1500 mL); 1000 mL water; and brine (2×1000 mL). (The aqueous base wash removed unreacted malonate ester-acid.) The straw colored organic solution was concentrated under vacuum (35° C.–40° C.) to give a cloudy, pale yellow oil with some white solid present. The oil was redissolved in 1500 mL of n-heptane and was filtered. The filtrate was concentrated under vacuum (40° C.–45° C.) to give 327 g of the titled compound as a pale yellow oil: 1H NMR (400 MHz, CHLOROFORM-D) d ppm 0.82 (t, J=7.1 Hz, 3 H), 0.85 (d, J=6.8 Hz, 3 H), 0.99 (d, J=7.1 Hz, 3 H), 1.20 (t, J=7.3 Hz, 3 H), 2.42–2.49 (m, 1 H), 3.39 (s, 2 H) 4.12 (q, J=7.16 Hz, 3 H). GC Chemical purity: 96.24%. A 5 L 3-neck round bottom flask, equipped with a reflux condenser, mechanical stirrer, nitrogen inlet was less than 50° C The resulting grey slurry was heated to 55° C. to 60° C. controlled heating mantle A 2 L 3-neck round bottom flask, equipped with a 500 mL addition funnel, mechanical stirrer, nitrogen inlet to maintain the reaction at a temperature of 20° C. to 25° C the addition the reaction mixture was stirred at 20° C. to 25° C. for 1 hour, during which the slurry After the 5-hour reaction time was cooled to 20° C. to 25° C. the condenser was replaced with a 1 L addition funnel The addition funnel was charged portion-wise This entire reaction mixture After the addition the reaction mixture was heated to 35° C. to 40° C The reaction mixture was stirred at 35° C. to 40° C. for 16 hour The reaction mixture was cooled to 20° C. to 25° C A 12 L 3-neck round bottom flask, equipped with a mechanical stirrer while maintaining an internal temperature of 20° C.–25° C The reaction temperature was moderated with an ice/water bath the addition the reaction mixture was stirred at 20° C. to 25° C. for 2 hours was stirred for 5 minutes The phases were separated the aqueous phase was extracted with 2000 mL of EtOAc The combined organic extract was washed sequentially with: 1N aq. HCl (2×1 500 mL) (The aqueous base wash removed unreacted malonate ester-acid ) The straw colored organic solution was concentrated under vacuum (35° C.–40° C.) to give a cloudy, pale yellow oil with some white solid present was filtered The filtrate was concentrated under vacuum (40° C.–45° C.)

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a 1 L round bottom flask equipped with a nitrogen inlet was charged 22 g (230 mmol) of magnesium chloride, 39 g (230 mmol) of potassium ethyl malonate and 200 mL of dimethylformamide. The contents of the flask were stirred at 50° C. for 1 hour and then cooled to 35° C. In a separate 500 mL, nitrogen inerted flask was added 200 mL of dimethylformamide, 28.6 g (177 mmol) of carbonyl diimidazole and 20 g of (2R,3R)-2,3-dimethyl-pentanoic acid was dripped in over 30 minutes. When the gas evolution had ceased, the contents of the 500 mL flask were added to the 1 L flask. The reaction was stirred for 2 days at 35° C. The reaction was cooled to room temperature and diluted with 800 mL of 1N HCl. The aqueous solution was extracted 3× with 1 L aliquots of MTBE. The organic extracts were combined and extracted with 200 mL of saturated NaHCO3. The organic layer was dried over MgSO4 and concentrated to give 31.74 g of the titled compound: 1H-NMR (CDCl3) 4.180–4.120 (m, 2H), 3.454 (s, 2H), 2.522–2.453 (q, 1H, J=7.018), 1.738–1.673 (m, 1H), 1.418–1.328 (m, 1H), 1.270–1.217 (m, 3H), 1.113–1.010 (m, 4H), 0.889–0.815 (m, 5H); MS (Ion Mode: APCl) m/z=201 [M+1]+. To a 1 L round bottom flask equipped with a nitrogen inlet cooled to 35° C was dripped in over 30 minutes the contents of the 500 mL flask were added to the 1 L flask The reaction was stirred for 2 days at 35° C The reaction was cooled to room temperature The aqueous solution was extracted 3× with 1 L aliquots of MTBE extracted with 200 mL of saturated NaHCO3 The organic layer was dried over MgSO4 concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 12.34 g (72.5 mmol) of potassium 3-ethoxy-3-oxopropanoate in suspension in 150 ml anhydrous acetonitrile are added at −0° C. under argon 10.11 ml (72.5 mmol) of triethylamine and 8.28 g (87 mmol) of magnesium (II) chloride. The reaction mixture is stirred for 5 h at room temperature, then at 0° C. a solution of 5.47 g (29 mmol) of 2-fluoro-4-methoxybenzoyl chloride dissolved in 30 ml of acetonitrile is added as well as 4.45 ml (31.9 mmol) of triethylamine. The reaction mixture is stirred for 18 h at room temperature then a 1M hydrochloric acid solution is added until the suspension disappears. The product is extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, and concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 85:15) to yield 5.46 g (78%) of ethyl 3-(2-fluoro-4-methoxyphenyl)-3-oxopropanoate in the form of a yellow oil which crystallizes over time. The reaction mixture is stirred for 18 h at room temperature The product is extracted several times with ethyl acetate dried over magnesium sulfate concentrated The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 85:15)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: As an alternative to the quinolone synthesis outlined above, the quinolone nucleus may be formed using the route illustrated in Scheme II. Similar methodology for the preparation of quinolones was first described in German patent application DE3142854. Starting from a 4-bromo-3-fluoro-benzoyl chloride, condensation with malonic acid monoethyl ester monopotassium salt gives a benzoyl acetate that is subsequently reacted with triethyl orthoformate. The resulting ethoxymethylene derivative is reacted with a primary amine and cyclized to the quinolone. may be formed

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: As an alternative to the quinolone synthesis outlined above, the quinolone nucleus may be formed using the route illustrated in Scheme II. Similar methodology for the preparation of quinolones was first described in German patent application DE3142854. Starting from a 4-bromo-3-fluoro-benzoyl chloride, condensation with malonic acid monoethyl ester monopotassium salt gives a benzoyl acetate that is subsequently reacted with triethyl orthoformate. The resulting ethoxymethylene derivative is reacted with a primary amine and cyclized to the quinolone. may be formed

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of ethyl malonate potassium salt (39 g) in acetonitrile (100 mL) was added magnesium chloride (26 g) and triethylamine (48.6 g) and the mixture was stirred at room temperature for 2 hours (solution A). To a solution of 4-chlorophenylacetic acid (18.6 g) in acetonitrile (100 mL) was added carbonyldiimidazole (19.5 g) at room temperature and the mixture was stirred at the same temperature fro 1.5 hours. To the reaction mixture was added the solution A prepared above at room temperature and the mixture was stirred at the same temperature for 30 minutes and at 80° C. for 2 hours. After cooling the reaction mixture to room temperature, thereto was added 2N HCl solution (260 mL) and the mixture was stirred. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and a brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=8/1 to 6/1) to obtain ethyl 4-(4-chlorophenyl)-3-oxobutyrate (25 g, yield: 95%) as a liquid. prepared above at room temperature the mixture was stirred at the same temperature for 30 minutes and at 80° C. for 2 hours the mixture was stirred The organic layer was washed with an aqueous sodium hydrogencarbonate solution a brine, dried over magnesium sulfate filtered The filtrate was concentrated in vacuo the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=8/1 to 6/1)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of ethyl malonate potassium salt (39 g) in acetonitrile (100 mL) was added magnesium chloride (26 g) and triethylamine (48.6 g) and the mixture was stirred at room temperature for 2 hours (solution A). To a solution of 4-chlorophenylacetic acid (18.6 g) in acetonitrile (100 mL) was added carbonyldiimidazole (19.5 g) at room temperature and the mixture was stirred at the same temperature fro 1.5 hours. To the reaction mixture was added the solution A prepared above at room temperature and the mixture was stirred at the same temperature for 30 minutes and at 80° C. for 2 hours. After cooling the reaction mixture to room temperature, thereto was added 2N HCl solution (260 mL) and the mixture was stirred. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and a brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=8/1 to 6/1) to obtain ethyl 4-(4-chlorophenyl)-3-oxobutyrate (25 g, yield: 95%) as a liquid. prepared above at room temperature the mixture was stirred at the same temperature for 30 minutes and at 80° C. for 2 hours the mixture was stirred The organic layer was washed with an aqueous sodium hydrogencarbonate solution a brine, dried over magnesium sulfate filtered The filtrate was concentrated in vacuo the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=8/1 to 6/1)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 2,6-difluorobenzoic acid (15 g, 0.095 mol) and carbonyldiimidazole (18 g, 0.14 mol, 1.5 equiv) in anhydrous tetrahydrofuran (150 mL) was stirred at ambient temperature for 6 hours. In a separate flask, a suspension of anhydrous magnesium(II) chloride (9.0 g, 0.095 mol, 1.0 equiv) and potassium ethyl malonate (22 g, 0.13 mol, 1.4 equiv) in tetrahydrofuran (225 mL) was stirred at 50-60° C. for 6 hours, cooled to ambient temperature, which was then added via syringe to the solution of activated acid, and the mixture was stirred for an additional 18 hours at ambient temperature. The mixture was refluxed for 3 hours, cooled to ambient temperature, poured into water and acidified with hydrochloric acid (12 N aqueous) to pH<2. The aqueous layer was extracted with ethyl acetate and the organic extract was washed with water, dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound. was stirred at 50-60° C. for 6 hours cooled to ambient temperature which was then added via syringe to the solution of activated acid the mixture was stirred for an additional 18 hours at ambient temperature The mixture was refluxed for 3 hours cooled to ambient temperature The aqueous layer was extracted with ethyl acetate the organic extract was washed with water dried with sodium sulfate filtered concentrated in vacuo