4-Fluoro-β-oxobenzenepropanenitrile

White to light brown solid

At -78General procedure: Cyanoacetic acid (1.7 g, 20 mmol, 2 equiv), 0.2 mg MgSOTo a 2 L three-necked round-bottomed flask were added toluene (1050 mL), 60percent NaH (78.20 g, 1.95 mol) and acetonitrile (79.85 g, 1.95 mol), and a solution of methyl fluorobenzoate (150.15 g, 0.96 mol) After heating to 90 ° C, acetonitrile (79.85 g, 1.95 mol) was added after 2 h. After 6.5 h the heating was stopped. After cooling, the filtrate was filtered and the cake was added to water (1650 mL) / L hydrochloric acid adjusted to pH 6 and extracted with dichloromethane (750 mL * 4). The combined methylene chloride layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness to give yellow solid 3 (141.08 g, 93.14percent ).Methyl 4-fluorobenzoate (29.44 kg), toluene (177 L) and acetonitrile (59 L; 5.9 mol equivalents versus methyl 4-fluorobenzoate) were charged to the reactor. The mixture was cooled to a temperature of -5 / 0 ° C. A solution of sodium bis (trimethylsilyl) amide (NaHMDS 40percent in THF) (192 L; 2 mol / mol vs. methyl 4-fluorobenzoate) was added while maintaining the temperature between -5 / + 5 ° C. The addition line was washed off with toluene (9 L). The reaction mixture was quenched by adding dilute hydrochloric acid while maintaining the temperature of -5 / + 25 ° C. The addition of acid was continued until pH <5. The layers separated and the lower aqueous layer was removed. The solvent was removed by vacuum distillation to a small amount. Toluene (59 L) was added and the mixture was heated to 85/90 ° C. to give a solution. The mixture was cooled to T = 50/55 ° C. and n-heptane (29 L) was added to obtain a precipitate. The mixture was further cooled to T = 20/25 ° C. and the solid product was isolated by filtration and washed with n-heptane (59 L). The product in the moist state was dried under vacuum at T = 40/45 ° C. to give 4-fluorobenzoylacetonitrile (26 kg, yield 83percent) of purity 98.7percent Apercent GC. The amount of 4-methoxybenzoylacetonitrile as an impurity was 0.03percent (Apercent GC).Methyl 4-fluorobenzoate (50 g)Was added to a suspension of sodium hydride in methyl-tert-butyl ether (MTBE)(2 eq.) At 90 ° C.4-fluorobenzoylacetonitrile was obtained in about 64percent yield.4-fluorobenzoic acid with a purity of 81percent, 17.5percent4-methoxybenzoylacetonitrile was about 3percentTo a stirred suspension of 2.5 g (11.5 mmol) 2-bromo-l-(4-fiuoro-phenyl) -ethanone in 40 ml ethanol was added a solution of 0.90 g (23 mmol) potassium cyanide in 9 ml water. The mixture was then stirred at RT for 2 h, then acidified to ph=5-6 with aqueous HCl IM and then extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (heptane / ethyl acetate 6:1) afforded 0.11 g (6 percent) 3-(4-fluoro-phenyl)-3-oxo-propionitrile as a yellow solid.To three-necked flask was added potassium tert-butoxide and isopropyl ether, A mixed solution of 68 g of acetonitrile / 8 g of t-butanol / 400 mL of isopropyl ether / 100 g of p-fluorobenzonitrile was added dropwise with stirring, and the temperature of the dropwise addition was controlled within the range of 10 ° C to 25 ° C.After the addition was completed, the temperature of the reaction system was maintained at 27 ° C to 30 ° C for 22 hours.After the reaction of TLC detection raw material was completed, 400 mL of water was added to quench the reaction, and the quenching temperature was controlled below 30 ° C.Then, the isopropyl ether was distilled off under reduced pressure at room temperature, extracted with 600 mL of dichloromethane and separated. The aqueous layer was further extracted with dichloromethane (300 mL × 2). The combined organic phase was ready for further reaction.To the organic phase was added 560mL of 3mol / L hydrochloric acid solution, stirred at room temperature for 3h after stratification.The aqueous layer was extracted with dichloromethane (400 mL x 2). The organic phases were combined, the dichloromethane was evaporated under reduced pressure, 200 mL of isopropanol was added to the residue, and the mixture was stirred at 0 ° C to 10 ° C for 2 hours and then filtered. 100ml isopropanol washing cake, the wet product was dried in vacuo to give p-fluorobenzoyl acetonitrile white crystals 91.9g. Two-step reaction yield 67.7percent, purity 97.50percent.The polyphosphoric acid 300g adding 1L the reaction bottle heating to 120 C, adding compound 3 (100g, 0.61 muM), ring octanone (161.7g, 1 . 28 muM), add 1 - ethyl -3 - methyl imidazole four fluoroborates (30g, 0.15 muM) reaction 1h, after the reaction, by adding 300 ml ice water, 1000 ml ethyl acetate, stirring 30min, then adding NaOH in and to the neutral, separating the organic layer, the organic layer dried with magnesium sulfate, filtered, the filtrate is concentrated to dry, adding isopropanol (300 ml) reflux 30min stirred and cooled to 0 C after, stirring 1h, filtered and dried to obtain white solid 4 (120g, 99.8%), 400 g of phosphorus pentoxide 4000 g of mesyl acid Followed by stirring at 50 C for 3 hours. After cooling to 20-25 C, 118.5 g of cyclooctanone of Formula 2 and 153.3 g of 3- (4-fluorophenyl) -3-oxopropanenitrile(12.0 kg), p-toluenesulfonic acid monohydrate (14.0 kg), Toluene (60 L), cyclooctanone (12 kg), and phosphoric acidThe first part (4.2 kg) of 85% was charged to the reactor.The mixture was heated to reflux and water (from both the reagent and the condensation reaction) was removed by the Dean-Stark apparatus throughout the reaction.Maintaining the reflux state of the mixture while removing water while maintaining the reflux of the mixture, Additional phosphoric acid (2 × 6.4 kg and 4.2 kg) was divided in portions. The mixture was adjusted to T = 80-85 C. and water (48 L) was added.The layers separated and the lower aqueous layer was removed. The organic layer was washed with water (48 L).The organic layer was cooled to T = 70-75 C. and 5% sodium hydroxide solution(21.1 L) was added to bring the pH to> 8. The product starts to precipitate.Toluene (36 L) was added and the mixture was cooled to T = 20-25 C.The solid was isolated by filtration and washed with water and toluene.By drying the moist product under vacuum at T = 50-55 C., 4- (4-fluorophenyl) -5, 6, 7, 8, 9, 10-hexahydrocycloocta [b] pyridin-2 (1 H)one 99.8% A% HPLC (method 1) purity(10.7 kg, yield 54%).Following a procedure described in J.Med.Chem. 2002, 45, 382-389; 0.44 g (2.7 mmol) 3- (4-fluoro-phenyl)-3-oxo-propionitrile (the preparation of which is described in example 17), 0.33 g (2.15 mmol) [l, 4]dithiane -2, 5-diol, 0.16 ml (2.15 mmol) diethyl-amine and 5 ml ethanol were charged in a sealed tube. The reaction mixture was heated at 50 0C for 6 h. The tube was then placed in a fridge (about 4C) for the night, and the product was collected by filtration and dried under vacuum to afford 0.41 g (69%) (2-amino- thiophen-3-yl)-(4-fluoro-phenyl)-methanone as a light brown crystals.Step 1 A mixture of 4-fluorobenzoylacetonitrile (2.84 g), 2, 5-dihydroxy-1, 4-dithian (1.31 g), triethylamine (2.2 ml) and ethanol (15 ml) was stirred for 40 minutes at 50 C. The reaction mixture was cooled to give 2-amino-3-(4-fluorobenzoyl)thiophene as yellow crystals (2.22 g). m.p.178 C. (recrystallized from ethyl ether-hexane) NMR(200 MHz, CDCl3): 6.15(1H, d, J=5.8 Hz), 6.85(1H, d, J=5.8 Hz), 6.94(2H, bs), 7.00-7.20(2H, m), 7.60-7.80(2H, m)To a stirred suspension of 2.5 g (11.5 mmol) 2-bromo-l-(4-fiuoro-phenyl) -ethanone in 40 ml ethanol was added a solution of 0.90 g (23 mmol) potassium cyanide in 9 ml water. The mixture was then stirred at RT for 2 h, then acidified to ph=5-6 with aqueous HCl IM and then extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (heptane / ethyl acetate 6:1) afforded 0.11 g (6 %) To a stirred solution of 0.11 g (0.67 mmol) 3 -(4-fluoro -phenyl)- 3-oxo-propionitrile in 4 ml ethanol was added 0.06 ml (0.67 mmol) cyclopentanone, 22 mg (0.67 mmol) sulfur, and 0.06 ml (0.67 mmol) morpholine. The mixture was heated at 60 0C for 2 h, and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Trituration in ether afforded 0.17 g (98%) (2-amino-5, 6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(4-fluoro- phenyl)-methanone as a red solid. ES-MS m/e (%): 262 (M+H+, 100).

Molecular Weight:163.15
XLogP3:1.1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:163.043341977
Monoisotopic Mass:163.043341977
Topological Polar Surface Area:40.9
Heavy Atom Count:12
Complexity:210
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes