Ethyl 4-fluoro-β-oxobenzenepropanoate

Colorless liquid

A broad-spectrum antimicrobial fluoroquinolone. The drug strongly inhibits the DNA-supercoiling activity of DNA GYRASE.

(step 1) Diethyl carbonate (130 g, 1.1 mol)was dissolved in a suspension of NaH (60percent in oil, 50.2 g, 1.3 mol) in anhydroustetrahydrofuran (1.5 L), and then compound 2 (150 g, 1.09 mol) was addeddropwise at 70Step 1-Synthesis of ethyl 3-(4-fluorophenyl)-3-oxopropanoate To a solution of 4'-fluoroacetophenone (57.8 g, 0.307 mol) and ethanol (1 ml) in diethyl carbonate (300 ml) was added sodium hydride (24.5 g, 60percent in oil, 0.63 mol) by small portions. Because heat is gradually generated, the mixture was ice-cooled and stirred at room temperature for 2 hrs. To the reaction solution was added 6N hydrochloric acid to quench the reaction. Water (300 ml) was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1-5:1) to give ethyl 3-(4-fluorophenyl)-3-oxopropionate (71.2 g, 89percent). IR ν maxKBrcm-1: 1744, 1696, 1431, 1325, 1202, 1132, 1069, 1017, 853.1H-NMR (CDCl3)δ: 1.28 (3H .x. 0.62, t, J = 7.8 Hz), 1.37 (3H .x. 0.38, t, J = 7.8 Hz), 4.04 (2H .x. 0.62, s), 4.25 (2H .x. 0.62, q, J = 7.8 Hz) , 4.31 (2H .x. 0.38, q, J ' = 7.8 Hz) , 5.75 (1H .x. 0.38, s), 7.28 (1H .x. 0.62, s), 7.70 (2H .x. 0.38, d, J = 8.0 Hz), 7.78 (2H .x. 0.62, d, J-=-8.0 Hz), 7.90 (2H .x. 0.38, d, J = 8.0 Hz), 8.08 (2H .x. 0.62, d, J = 8.0 Hz).Production of intermediates of the formula [XIV] by route (V7):Ethyl 3-(4-fluorophenyl)-3-oxopropanoate [XIV-1]To a mixture of 4-fluoroacetophenone (20.0 g, 0.145 mol), ethanol (lmL) and diethylcarbonate (100 mL) is added sodium hydride (60percent, 12.0 g, 0.29 mol) at 0 °C portionwise over a period of 30 min. Afterwards the reaction mixture is allowed to warm to room temperature and stirred for 3h. Thereafter, the reaction is quenched with aqueous 10percent HC1 and extracted with ethyl acetate (2 x lOOmL). The ethyl acetate layer is dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material is purified by column chromatography using silica gel (230-400 mesh) in ethyl acetate and hexane (1 :99 to 5:95) as eluent and 25g (83percent>) of ethyl 3-(4-fluorophenyl)-3-oxopropanoate are obtained as light yellow liquid.'H-NMR (300MHZ, CDCI3): δ = 7.96-8.01 (m, 1H), 7.10-7.19 (m, 2H), 5.30 (s, 1H), 4.23 (q, 2H), 1.26 (t, 3H) ppmMS (ESI): 209.1 ([M-H]Diethyl carbonate (801 mL, 6.79 mole) was added dropwise over a 30 minute period to a stirring slurry of potassium i-butoxide (609.2 g, 5.43 mole) in toluene (9.5 L) under a nitrogen atmosphere. The reaction mixture was heated to 78 °C and 4-fluoroacetophenone (250 g, 1.81 mole) in toluene (250 mL) was added over a one hour time period. Heating of the reaction mixture was continued overnight. Then the reaction mixture was quenched with 1.5 N HCl(aq) and extracted with ethyl acetate (3>< 1 L). The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo leaving a brown liquid. The liquid was distilled to give the title compound as a colorless liquid (250 g, 79percent). MS m/z 209 (M-H)\General procedure: The substrate b-ketoesters 10 a–n were either purchased or synthesized following published procedures. Some benzoylacetates were commercially available. Ethyl 3-oxo-3-phenyl propanoate (10a) was purchased. The reaction of benzoylacetates 10 b–n was prepared as described in previous reports. 25–27 A solution of a substituted acetophenone 8 a–n (0.05 mol) dissolved in toluene (50 mL) was added dropwise to a solution containing diethyl carbonate (9) (0.10 mol) and sodium hydride (0.15 mol 60percent dispersion in mineral oil). The mixture was stirred at room temperature, and then refluxed for 30 min. The mixture was poured into ice water, acidified with glacial acetic acid, and extracted with EtOAc (3x100 mL). The EtOAc extract was then dried over anhydrous MgSO4. After removal of the solvent in vacuo, the crude products were purified by silica gel column chromatography eluting with dichloromethane to afford benzoylacetates 10 b–n. All synthetic compounds were in agreement with 1H NMR, 13C NMR, IR and mass spectroscopic data.To a stirred solution of potassium-i-butoxide (323 g, 2.89 mol) in toluene (1 L) was added diethyl carbonate (533 g, 4.51 mol) at RT, and the mixture was heated to 80 °C for 1 hr. l-(4-Fluorophenyl)- ethanone (250 g, 1.80 mol) in toluene (2 L) was added to the reaction mixture slowly and stirred at 70 °C for 2 hr, then cooled to RT and stirring was continued for 16 hr. The reaction mixture was quenched with dilute HC1, then diluted with water and extracted with ethyl acetate (EtOAc; 3 X 800 mL). The combined organic layer was washed with brine, dried over NaTo a stirred solution of 4-fluoroacetophenone (20 g, 144 mmol) and diethyl carbonate (85 ml, 720 mmol), sodium hydride (6.9 g, 144 mmol) was added portion wise at temperature (0° C.-5° C.) under nitrogen atmosphere in 1 hour. The reaction mixture was heated to 60° C. and stirred for 30 minutes. The reaction mixture was cooled to 0° C. and was poured into ice cold water (150 ml) and extracted with dichloromethane (2*100 ml). The combined organic layer was dried over sodium sulphate, concentrated under vacuo to give 30 g of the titled product as brown viscous oil. Under nitrogen atmosphere, 30 ML of THF was added to 6.09 g (10 mmol, 1.0 equivalent) of (BrZnCH2COOEt*THF)2.. To a stirred mixture of aryl or heteroaryl halide(Br, I) (0.5 mmol), potassium mono ethyl malonate (0.75 mmol) in THF (10 mL) taken in a 30 mL microwave vial, was added Pd(OAc)To a stirred mixture of aryl or heteroaryl halide(Br, I) (0.5 mmol), potassium mono ethyl malonate (0.75 mmol) in THF (10 mL) taken in a 30 mL microwave vial, was added Pd(OAc)A. To a solution of 4-fluorobenzoyl chloride and 2, 2-dimethyl-1, 3-dioxane-4, 6-dione in dry methylene chloride, addition of 4-(dimethylamino) pyridine was done at about 0 °C and the resulting mixture was stirred at room temperature for one hour. The mixture was washed with water and 1N HCl and then dried by employing anhydrous sodium sulphate. The resulting product was dissolved with ethanol in toluene and heated on reflux condenser at 90 °C for 24 h. Subsequently solvents were allowed to evaporate at room temperature and product formed was recrystallized with ethanol [15]. Ligand ethyl-(4-fluorobenzoyl) acetate (p-EFBA) was obtained with 56percent yield. IR(KBr): cm−1 3670 (b), 2984 (s), 1740 (s), 1692(s), 1648 (s), 1587 (s), 1443 (s), 1412 (s), 1326 (w), 1275 (s), 1217 (s), 1148 (m), 1030 (s), 876 (s), 591 (m); 1H NMR(CDCl3, 400 MHz): δ 12.54 (s, 1H, enolic OH), 7.46 (m, 4H, Ar-H), 5.64 (s, 1H, C = CH), 3.96 (s, 2H keto CH2), 3.67 (q, 2H, OCH2CH3), 1.32 (t, 3H, OCH2CH3) ppm.To a 500 L stainless steel reactor, ethyl malonate potassium salt (31.6 kg, 185.56 mol) and THF (80.0 L) were added with stirring under an atmosphere of nitrogen. Magnesium chloride (16.6 kg, 185.56 mol) was added in portions while maintaining the temperature at 28 – 35 °C. The reaction temperature was raised to 60 – 65 °C and maintained at 60 – 65 °C for 6 h. Next, the reaction temperature was brought back to 25 – 30 °C and the resulting reaction mixture was stirred at 25 – 30 °C for 12 h (RM-1). In another 250 L stainless steel reactor, CDI (27.8 kg, 174.14 mol) and THF (40.0 L) were added with stirring under an atmosphere of nitrogen. Next, a solution of 4-fluorobenzoic acid (20.0 kg, 142.74 mol) in THF (40.0 L) was added at 25 – 30 °C. The resulting clear solution was stirred at 25 – 30 °C for 3 h (RM-2) (Note: RM-2 preparation was started after 9 h stirring of RM-1). Subsequently, RM-2 was added slowly to RM-1 at 25 – 30 °C over a period of 2 h. The resulting slurry was further stirred at 25 – 30 °C for 12 h under an atmosphere of nitrogen, when there was not more than 2.0percent of 2-1 remaining in the reaction mixture, as determined by HPLC analysis. The reaction mixture was cooled to 15 – 20 °C and the pH was adjusted to 6.0 – 6.5 using 4.0 N aq. HCl. The resulting mixture was extracted with ethyl acetate (90.0 L x 3). The organic extracts were combined, dried over anhydrous Na

Molecular Weight:210.20
XLogP3:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:5
Exact Mass:210.06922237
Monoisotopic Mass:210.06922237
Topological Polar Surface Area:43.4
Heavy Atom Count:15
Complexity:232
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes