(2-Chloro-5-iodophenyl)[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methanone

Synthesis of the ketone VII.1To a solution of the fluoride VIII.1 (208kg), tetrahydrofuran (407kg) and (S)-3- hydroxytetrahydrofuran (56kg) is added potassium-terf-butanolate solution (20percent) in tetrahydrofuran (388kg) within 3 hrs at 16 to 25°C temperature. After completion of the addition, the mixture is stirred for 60min at 20°C temperature. Then the conversion is determined via HPLC analysis. Water (355kg) is added within 20 min at a temperature of 21 °C (aqueous quench). The reaction mixture is stirred for 30 min (temperature: 20°C). The stirrer is switched off and the mixture is left stand for 60 min (temperature: 20°C). The phases are separated and solvent is distilled off from the organic phase at 19 to 45°C temperature under reduced pressure. 2- Propanol (703kg) is added to the residue at 40 to 46°C temperature and solvent is distilled off at 41 to 50°C temperature under reduced pressure. 2-Propanol (162kg) is added to the residue at 47°C temperature and solvent is distilled off at 40 to 47°C temperature under reduced pressure. Then the mixture is cooled to 0°C within 1 hr 55 min. The product is collected on a centrifuge, washed with a mixture of 2- propanol (158kg) and subsequently with terf.-butylmethylether (88kg) and dried at 19 to 43°C under reduced pressure. 227kg (91 , 8percent) of product are obtained as colourless solid. The identity of the product is determined via infrared spectrometry.To a solution of the fluoride VIII.1 (208 kg), tetrahydrofuran (407 kg) and (S)-3-hydroxytetrahydrofuran (56 kg) is added potassium-tert-butanolate solution (20percent) in tetrahydrofuran (388 kg) within 3 hrs at 16 to 25° C. temperature. After completion of the addition, the mixture is stirred for 60 min at 20° C. temperature. Then the conversion is determined via HPLC analysis. Water (355 kg) is added within 20 min at a temperature of 21° C. (aqueous quench). The reaction mixture is stirred for 30 min (temperature: 20° C.). The stirrer is switched off and the mixture is left stand for 60 min (temperature: 20° C.). The phases are separated and solvent is distilled off from the organic phase at 19 to 45° C. temperature under reduced pressure. 2-Propanol (703 kg) is added to the residue at 40 to 46° C. temperature and solvent is distilled off at 41 to 50° C. temperature under reduced pressure. 2-Propanol (162 kg) is added to the residue at 47° C. temperature and solvent is distilled off at 40 to 47° C. temperature under reduced pressure. Then the mixture is cooled to 0° C. within 1 hr 55 min. The product is collected on a centrifuge, washed with a mixture of 2-propanol (158 kg) and subsequently with tert.-butylmethylether (88 kg) and dried at 19 to 43° C. under reduced pressure. 227 kg (91.8percent) of product are obtained as colourless solid. The identity of the product is determined via infrared spectrometry.To a solution of the fluoride VIII.1 (208 kg), tetrahydrofuran (407 kg) and (S)-3-hydroxytetrahydrofuran (56 kg) is added potassium-tert-butanolate solution (20percent) in tetrahydrofuran (388 kg) within 3 hrs at 16 to 25° C. temperature. After completion of the addition, the mixture is stirred for 60 min at 20° C. temperature. Then the conversion is determined via HPLC analysis. Water (355 kg) is added within 20 min at a temperature of 21° C. (aqueous quench). The reaction mixture is stirred for 30 min (temperature: 20° C.). The stirrer is switched off and the mixture is left stand for 60 min (temperature: 20° C.). The phases are separated and solvent is distilled off from the organic phase at 19 to 45° C. temperature under reduced pressure. 2-Propanol (703 kg) is added to the residue at 40 to 46° C. temperature and solvent is distilled off at 41 to 50° C. temperature under reduced pressure. 2-Propanol (162 kg) is added to the residue at 47° C. temperature and solvent is distilled off at 40 to 47° C. temperature under reduced pressure. Then the mixture is cooled to 0° C. within 1 hr 55 min. The product is collected on a centrifuge, washed with a mixture of 2-propanol (158 kg) and subsequently with tert.-butylmethylether (88 kg) and dried at 19 to 43° C. under reduced pressure. 227 kg (91.8percent) of product are obtained as colourless solid. The identity of the product is determined via infrared spectrometry.Equipped with a thermometer, pressure-equalizing dropping funnel was added 500mL three bottles VII (84.2g, 234mmol), S -3-hydroxytetrahydrofuran (20.6g, 234mmol), was added THF100mL clear solution after stirring, potassium tert-butoxide (34.1 g, 234mmol) was dissolved 150mLTHF added to the system, stirred at room temperature overnight, TLC monitored the reaction was complete, the reaction was quenched with 230 mL of water, spin-out section THF, EA extracted three times, the combined organic phase was washed with water and saturated brine, dried and concentrated to give 120.5 g crude product, after using 170mL of isopropanol + 20mL water crystallized product 75g, purity 98.2percent, yield 75percent.5-Iodo-2-chloro-4'-fluorobenzophenone (V-2) (18.5 g, 0.051 mol) was dissolved in 50 ml of tetrahydrofuran solutionThen, (5)-3_light-based tetrahydrofuran (4.9 g, 0.056 mol) was added and stirred, and finally a solution of potassium t-butoxide (6.9 g, 0.061 mol) dissolved in 30 ml of tetrahydrofuran was added dropwise, and the temperature was controlled at 16-25 ° C. After the addition was completed, the reaction was stirred at 20 ° C for 1 hour, and the reaction was almost complete by TLC, and the purified water was slowly added and stirred for 30 min.The solution was separated and the organic phase was dried. After column chromatography, 14. lg (64.3percent) of solid was obtained.A mixture of formula 7a (100 g, 0.277 mole) and (S)-tetrahydrofuran-3-ol (27.4 g, 0.31 mole) in tetrahydrofuran (260 mL) was prepared. Potassium tert-butoxide (46.5 g, 0.414 mole) in tetrahydrofuran (405 mL) was added to this mixture solution slowly over a period of 90 minutes at 2-6 °C, maintaining the reaction mass at 7-10 °C to complete the reaction. Thereafter, precooled water (285 mL) was added to quench the reaction at 5-18 °C and the product was extracted twice with methyl tert- butyl ether (first with 285 mL, then with 145 mL) at 20-25 °C. Thereafter, the combined organic layers were washed with 10percent aqueous sodium chloride (250mL) solution and concentrated under reduced pressure. The obtained residue was crystallized in isopropyl acetate (150 mL) to result in formula 9a as solid (90 g).A three-necked flask was charged with 2b (35.86 g, 100 mmol)R-3-p-toluenesulfonyloxy tetrahydrofuran 3b (26.65 g, 110 mmol)Potassium carbonate (27.64 g, 200 mmol), Potassium iodide (830 mg, 5 mmol) and acetonitrile (179 mL)Stir well after heating to 50 ~ 55 reaction overnight.The reaction was terminated by direct concentration to remove part of the acetonitrile, Water (179 mL) and dichloromethane (179 mL) were added, The aqueous phase was extracted again with dichloromethane (89 mL)The organic phase saturated brine was washed once (179 mL)Sodium sulfate, After concentration, compound 4b (37.29 g, 87percent) was recrystallized from a petroleum ether ethyl acetate mixed solvent.Potassium carbonate in Example 4 can be replaced with sodium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine or diisopropylethylamine;The reaction solvent acetonitrile may be replaced by N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, 1, 4-dioxane, toluene, isopropanol or acetone.

Molecular Weight:428.6
XLogP3:4.6
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:4
Exact Mass:427.96762
Monoisotopic Mass:427.96762
Topological Polar Surface Area:35.5
Heavy Atom Count:22
Complexity:384
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes