* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
10.00 g (65.29 mmol) 4-fluoro-3-methyl-benzoic acid amide are stirred together with 50 ml phosphorus oxychloride for 4 hours at 60° C. and then evaporated down i. vac. The residue is poured into ice water, the resulting precipitate is filtered off and washed with water. After being taken up in ethyl acetate the organic phase is washed with sat. potassium carbonate solution, dried over sodium sulphate and evaporated down completely i. vac. Yield: 8.00 g (91percent) C8H6FN (135.14) Rf value: 0.84 (silica gel; dichloromethane)
7.00 g (51.8 mmol) <strong>[185147-08-4]4-fluoro-3-methyl-benzonitrile</strong> are heated to 110° C. together with 1-N-methyl-[1,4]diazepan for 1 week with stirring. After evaporation i. vac. the residue is separated on aluminium oxide (eluant: dichloromethane) and the corresponding fractions are again purified on silica gel (eluting gradient: dichloromethane/methanol 100:1->9:1). Yield: 1.70 g (14percent) C14H19N3 (229.33) Mass spectrum: (M+H)+=230 Rf value: 0.25 (silica gel; dichloromethane/methanol=9:1)
With caesium carbonate; In N,N-dimethyl acetamide; at 150℃; for 5.0h;
INTERMEDIATE 2 (132 mg, 0.5 mmol) was combined with 3-methyl-4-bromobenzonitrile (100 mg, 0.5 mmol) and Cs2CO3 (1.65 g, 5 mmol) in 5 mL of N,N-dimethylacetamide. The reaction mixture was EPO <DP n="72"/>stirred at 150 0C for 5 h, then was dumped into water and acidified with 2N aq. HCl to pH <2. The resulting solid precipitate was extracted with ethyl acetate and washed with water followed by brine, dried over anhydrous Na2SO4, filtered, and concentrated. Purification by Combi-Flash (silica, 5-30percent ethyl acetate/hexane gradient) gave the product. LC-MS calc. for C21H18N2O3S: 378; Found: 379 (M+H).
With caesium carbonate; In N,N-dimethyl acetamide; at 150℃; for 5.0h;
INTERMEDIATE 1 (200 mg, 0.80 mmol) was combined with 3-methyl-4-bromobenzonitrile (160 mg, 0.55 mmol) and Cs2CO3 (1.65 g, 5 mmol) in 5 mL of N,N-dimethylacetamide. The reaction mixture was stirred at 150 0C for 5 h, then was dumped into water and acidified with 2N aq. HCl to pH <2. The resulting solid precipitate was extracted with ethyl acetate and washed with water followed by brine, dried over anhydrous Na2SO4, filtered, and concentrated. Purification by Combi-Flash (silica, 5-30percent ethyl acetate/hexane gradient) gave the product. LC-MS calc. for C20H16N2O3S: 364; Found: 365 (M+H).
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 120℃;
To a solution of 19 (3.0 g, 14.0 mmol) in NMP (20 mL) was added K2CO3 (5.80 g, 41.9 mmol) and <strong>[185147-08-4]4-fluoro-3-methyl-benzonitrile</strong> (28, 1.89 g, 14.0 mmol). The reaction was heated to 120° C. overnight. The reaction mixture was cooled to RT, diluted with H2O and extracted 3 times with EtOAc. The combined extracts were washed with H2O and brine, dried (Na2SO4), filtered and evaporated in vacuo to afford 29 which was used in subsequent steps without further purification.
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 0.5h;Heating / reflux; Irradiation;
3-(bromomethyl)-4-fluorobenzonitrileTo a solution of <strong>[185147-08-4]4-fluoro-3-methylbenzonitrile</strong> (15.0 g, 111 mmol), in CCl4 (600 mL) was added N-bromosuccinimide (23.7 g, 133 mmol), and benzoyl perioxide (5.38 g, 22.2 mol). The mixture was irradiated with a sunlamp (250 W) to create a gentle reflux. After 0.5 hours of exposure the reaction was complete by TLC. The reaction mixture was cooled and filtered through celite. The filtrate was condensed in vacou to yield brown oil. The crude residue was purified via silica gel column chromatography (hexanes/ethyl acetate) to yield 17.7 g of the desired product. 1HNMR(CDCl3) delta : 7.78 (d, IH), 7.65 (m, IH), 7.20 (t, IH), 4.48 (s, 2H).