3,5-DIFLUORO-4-FORMYLBENZONITRILE, 97%

ft-BuLi (2.5 M, 4.4 mL) was added to a stirred solution of DIPEA (1.1, 11 mmol) in dry THF (100 mL) at -78°C under a nitrogen atmosphere then warmed to at 0°C and stirred for 1 h. The solution was cooled to -78°C and 3, 5-difluorobenzonitrile (1.39 g, 10 mmol) was added. The mixture was stirred at -78°C for 1 h then DMF (877 mg, 12 mmol) was added and the reaction continued for a further 0.5 h before addition of 10percent v/v aqueous acetic acid (20 mL). The mixture was warmed to room temperature, extracted with ethyl acetate and then concentrated in vacuo to afford 3, 5-difluoro-4-formylbenzonitrile (1.29 g, 77percent) as a yellow solidStep a: Synthesis of 3, 5-difluoro-4-formylbenzonitrileTo a solution of 3, 5-difluorobenzonitrile (1 gm, 7.1 mmol) in dry tetrahydrofuran (20 mL), lithium diisopropylamide (0.769 gm, 7.1 mmol) was added at -78 °C. The resulting reaction mixture was stirred for about 1 hour. Dimethylformamide (0.62 g, 8.5 mmol) was added dropwise to the reaction mixture and stirring was continued for about 45 minutes. Acetic acid (1 .5 mL) and water (40 mL) were added to the cold solution of reaction mixture. The aquoeus phase was extracted with diethyl ether (4x50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel (100-200) column chromatography using hexane and ethyl acetate as gradient system to afford pure 3, 5-difluoro-4-formylbenzonitrile (0.5 gm, 31 .25percent ).To a solution of 3, 5-difluorobenzonitrile (1 gm, 7.1 mmol) in dry tetrahydrofuran (20 mL), lithium diisopropylamide (0.769 gm, 7.1 mmol) was added at -78° C. The resulting reaction mixture was stirred for about 1 hour. Dimethylformamide (0.62 g, 8.5 mmol) was added dropwise to the reaction mixture and stirring was continued for about 45 minutes. Acetic acid (1.5 mL) and water (40 mL) were added to the cold solution of reaction mixture. The aquoeus phase was extracted with diethyl ether (4*50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel (100-200) column chromatography using hexane and ethyl acetate as gradient system to afford pure 3, 5-difluoro-4-formylbenzonitrile (0.5 gm, 31.25percent). 2, 6-Difluoro-4 [ (methylsulfinyl) (methylthio) methyl] benzonitrile (2.17 g, 8.32 mmol; see step (i) above) was dissolved in 90 mL of THF and 3.5 mL of concentrated sulfuric acid was added. The mixture was left at room temperature for 3 days and subsequently poured into 450 mL of water. Extraction three times with EtOAc followed and the combined ethereal phase was washed twice with aqueous sodium bicarbonate and with brine, dried [(NA2SO4)] and evaporated. Yield: 1.36 g [(98percent).] The position of the formyl group was established by 13C NMR. The signal from the fluorinated carbons at 162.7 ppm exhibited the expected coupling pattern with two coupling constants in the order of 260 Hz and 6.3 Hz respectively corresponding to an ipso and a meta coupling from the fluorine atoms. 'H NMR (400 MHz, [CDC13)] [8] 10.35 (s, 1H), 7.33 (m, 2H)2, 6-Difluoro-4 [(methylsulfonyl)(methylthio)methyl] benzonitrile (2.17 g, 8.32 mmol ; see step (i) above) was dissolved in 90 mL of THF and 3.5 mL of concentrated sulfuric acid was added. The mixture was left at room temperature for 3 days and subsequently poured into 450 mL of water. Extraction three times with EtOAc followed and the combined ethereal phase was washed twice with aqueous sodium bicarbonate and with brine, dried (Na2SO4) and evaporated. Yield: 1.36 g (98percent). The position of the formyl group was established [BYAPOS;3C] NMR. The signal from the fluorinated carbons at 162.7 ppm exhibited the expected coupling pattern with two coupling constants in the order of 260 Hz and 6.3 Hz respectively corresponding to an ipso and a meta coupling from the fluorine atoms. 'H NMR (400 MHz, [CDC13)] [6] 10.35 (s, 1H), 7.33 (m, 2H)2, 6-Difluoro-4 [ (methylsulfinyl) (methylthio) methyl] benzonitrile (2.17 g, 8.32 mmol; see step (i) above) was dissolved in 90 mL of THF and 3.5 mL of concentrated sulfuric acid was added. The mixture was left at room temperature for 3 days and subsequently poured into 450 mL of water. Extraction three times with EtOAc followed and the combined ethereal phase was washed twice with aqueous sodium bicarbonate and with brine, dried [(NA2SO4)] and evaporated. Yield: 1. [36 G] (98percent). The position of the formyl group was established [BY 13C] NMR. The signal from the fluorinated carbons at 162.7 ppm exhibited the expected coupling pattern with two coupling constants in the order of 260 Hz and 6.3 Hz respectively corresponding to an [IPSO] and a meta coupling from the fluorine atoms. 'H NMR (400 MHz, [CDC13)] 8 10.35 (s, 1H), 7.33 (m, 2H)ft-BuLi (2.5 M, 4.4 mL) was added to a stirred solution of DIPEA (1.1, 11 mmol) in dry THF (100 mL) at -78C under a nitrogen atmosphere then warmed to at 0C and stirred for 1 h. The solution was cooled to -78C and 3, 5-difluorobenzonitrile (1.39 g, 10 mmol) was added. The mixture was stirred at -78C for 1 h then DMF (877 mg, 12 mmol) was added and the reaction continued for a further 0.5 h before addition of 10% v/v aqueous acetic acid (20 mL). The mixture was warmed to room temperature, extracted with ethyl acetate and then concentrated in vacuo to afford Step a: Synthesis of To a solution of 3, 5-difluorobenzonitrile (1 gm, 7.1 mmol) in dry tetrahydrofuran (20 mL), lithium diisopropylamide (0.769 gm, 7.1 mmol) was added at -78 C. The resulting reaction mixture was stirred for about 1 hour. Dimethylformamide (0.62 g, 8.5 mmol) was added dropwise to the reaction mixture and stirring was continued for about 45 minutes. Acetic acid (1.5 mL) and water (40 mL) were added to the cold solution of reaction mixture. The aquoeus phase was extracted with diethyl ether (4*50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel (100-200) column chromatography using hexane and ethyl acetate as gradient system to afford pure To a stirred solution of methoxymethyltriphenylphosphonium chloride (1.47 g, 4.31 mmol) in THF (6 ml), potassium carbonate (0.594 g, 4.31 mmol) was added at 0 deg and stirred for 30 minutes at room temperature. To this 3, 5-Difluoro-4-formylbenzonitrile (200 mg, 1.2 mmol) was dissolved in methanol (3 mL). Then, potassium carbonate (331 mg, 24 mmol) was added thereto at room temperature, and dimethyl(1-diazo-2-oxopropyl)phosphonate (0.22 mL, 1.4 mmol) was added thereto under ice-cooling, followed by stirring under ice-cooling for 30 minutes and at room temperature for additional 2 hours and 30 minutes. The reaction solution was partitioned with the addition of ethyl acetate, a saturated aqueous sodium hydrogen carbonate solution, and water, and the organic layer was washed with saturated saline. After being dried over sodium sulfate, the resulting product was filtered and concentrated, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining methyl 4-ethynyl-3, 5-difluorobenzimidate (172 mg). LCMS (ESI) m/z 196 [M+H]+Step 1: Synthesis of methyl 4-ethynyl-3, 5-difluorobenzimidate (0457) 3, 5-Difluoro-4-formylbenzonitrile (200 mg, 1.2 mmol) was dissolved in methanol (3 mL). Then, potassium carbonate (331 mg, 24 mmol) was added thereto at room temperature, and dimethyl(1-diazo-2-oxopropyl)phosphonate (0.22 mL, 1.4 mmol) was added thereto under ice-cooling, followed by stirring under ice-cooling for 30 minutes and at room temperature for additional 2 hours and 30 minutes. The reaction solution was partitioned with the addition of ethyl acetate, a saturated aqueous sodium hydrogen carbonate solution, and water, and the organic layer was washed with saturated saline. After being dried over sodium sulfate, the resulting product was filtered and concentrated, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane), thereby obtaining methyl 4-ethynyl-3, 5-difluorobenzimidate (172 mg). (0458) LCMS (ESI) m/z 196 [M+H]+To a three-necked flask, 1.0 g (5.984 mmol) of [0192] In a three-necked flask, 1.0 g of

Molecular Weight:167.11
XLogP3:1.3
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:167.01827004
Monoisotopic Mass:167.01827004
Topological Polar Surface Area:40.9
Heavy Atom Count:12
Complexity:210
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes