2-CYANO-5-FLUOROBENZYL BROMIDE

1.35 g 2-methyl-4-fluorobenzonitrile (10mmol) was dissolved in 20 mL of carbon tetrachloride, and 0.25g of p-toluene sulfonic acid (0.015 mmol) and 2.15g N-bromo succinimide (NBS) (12mmol) was added. Preparation 7; 2-(bromomethyl)-4-fluorobenzonitrile; A solution of 2-methyl-4-fluoro-benzonitrile (3.5 g, 25.9mmol) in 4OmL of carbon tetrachloride was treated with N-bromosuccinimide (4.6g, 25.9 mmol) and benzoylperoxide (157mg, 0.65 mmol). The mixture was heated to reflux for 3 hours, cooled to room temperature and allowed to stir overnight. The solids were filtered off and washed with carbon tetrachloride. The filtrate was condensed and purified by normal phase flash column chromatography on a 50 g silica gel column (5 - 50percent ethyl acetate/hexanes gradient). Two peaks separated. It was determined that the second eluting peak is the desired product. Pure fractions of this peak were pooled and concentrated in vacuo to yield 2-(bromomethyl)-4- fluorobenzonitrile (1.35g, 0.63 mmol, 25percent yield) as a white solid. 1.35 g 2-methyl-4-fluorobenzonitrile (10mmol) was dissolved in 20 mL of carbon tetrachloride, and 0.25g of p-toluene sulfonic acid (0.015 mmol) and 2.15g N-bromo succinimide (NBS) (12mmol) was added. The reaction was completed after heating for 4 hours, and then cooled to room temperature, filtered, and 20 mL saturated ammonium chloride solution was added and layers were obtained. The organic layer was washed with water and saturated sodium chloride aqueous solution (20 mL * 3) successively to clarification, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure, and the obtained crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain 2-bromomethyl-4-fluoro-benzonitrile (86percent yield). The 2-bromomethyl-4-fluorobenzonitrile (1.0 mmol) and p-toluidine (1.2mmol) was dissolved in 50 mL of tetrahydrofuran, stirred and heated to 60 ° C under reflux, and was added 0.2g sodium ethoxide (3.0mmol) portionwise, and refluxed further 8 hours. After the reaction was confirmed complete by TLC monitoring, the reaction was cooled to room temperature, concentrated, and added 20 mL ethyl acetate, washed with water and saturated sodium chloride solution (20 mL * 3) successively to clarification, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to give the intermediate compound (1.1) 2-(p-methylphenylamino) methyl-4-fluoro-benzonitrile (95percent yield), mass spectrum (ESI +): m/z = 241.4 (M + H) +.Preparation 7; 2-(bromomethyl)-4-fluorobenzonitrile; A solution of 2-methyl-4-fluoro-benzonitrile (3.5 g, 25.9mmol) in 4OmL of carbon tetrachloride was treated with N-bromosuccinimide (4.6g, 25.9 mmol) and benzoylperoxide (157mg, 0.65 mmol). The mixture was heated to reflux for 3 hours, cooled to room temperature and allowed to stir overnight. The solids were filtered off and washed with carbon tetrachloride. The filtrate was condensed and purified by normal phase flash column chromatography on a 50 g silica gel column (5 - 50percent ethyl acetate/hexanes gradient). Two peaks separated. It was determined that the second eluting peak is the desired product. Pure fractions of this peak were pooled and concentrated in vacuo to yield 2-(bromomethyl)-4- fluorobenzonitrile (1.35g, 0.63 mmol, 25percent yield) as a white solid. 1H NMR (400 MHz, DMSO-dbeta) delta ppm 4.79 (s, 2 H), 7.44 (dt, J=8.59, 2.69 Hz, 1 H), 7.68 (dd, J=9.53, 2.55 Hz, 1 H), 8.01 (dd, J=8.59, 5.64 Hz, 1 H).A solution of 18A (4.8 g, 25.4 mmol), NBS (4.5 g, 25.4 mmol) and 100 mg AIBN was refluxed for 2 hours under nitrogen. After cooling to room temperature, the solvent was removed and the residue was purified by column chromatography. 1H NMR (400 MHz, CDCl3): 7.68 (d, J = 5.2, 8.4 Hz, 1H), 7.28 (d, J = 2.4, 8.8 Hz, 1H), 7.10-7.6 (m, 1H), 4.60 (s, 2H).A mixture of 4-fluoro-2-methylbenzonitrile (2 g, 14.8 mmol), NBS (2.64 g, 15 mmol) and AIBN (100 mg) in CCl4 was refluxed under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give crude product as an oil, which was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): delta 7.68 (dd, J= 5.2, 8.4 Hz, 1H), 7.28 (dd, J= 2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).A mixture of 4-fluoro-2-methylbenzonitrile (3) (2 g, 14.8 mmol), NBS (2.64 g, 15 mmol) and AIBN (100 mg) in CCl4 was refluxed under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give crude product as an oil, which was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): delta 7.68 (dd, J= 5.2, 8.4 Hz, IH), 7.28 (dd, J= 2.4, 8.8 Hz, IH), 7.12 (m, IH), 4.6 (s, 2H).2-Bromomethyl-4-fluorobenzonitrile (32). A mixture of 4-fluoro-2-methylbenzonitrile (2 g, 14.8 mmol), NBS (2.64 g, 15 mmol) and AIBN (100 mg) in CCl4 was refluxed under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give crude product as an oil, which was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): delta 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28 (dd, J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).B. Preparation of 2-bromomethyl-4-fluorobenzonitrile (Compound C)[0216] Compound C was prepared by refluxing a mixture of 4-fluoro-2- methylbenzonitrile (Compound B) (2 g, 14.8 mmol), N-bromosuccinimide (NBS) (2.64 g, 15 mmol) and azo-bis-isobutyronitrile (AIBN) (100 mg) in CCl4 under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give the crude product the form of an oil, which was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): delta 7.68 (dd, J= 5.2, 8.4 Hz, IH), 7.28 (dd, J= 2.4, 8.8 Hz, IH), 7.12 (m, IH), 4.6 (s, 2H).2-Bromomethyl-4-fluorobenzonitrile (4) A mixture of 4-fluoro-2-methylbenzonitrile (3) (2 g, 14.8 mmol), NBS (2.64 g, 15 mmol) and AIBN (100 mg) in CCl4 was refluxed under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give crude product as an oil, which was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): delta 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28 (dd, J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).2-methyl-4-fluorophenyl-carbonitrile (2g, 14.8mM, 1.0equiv) in carbon tetrachloride (24mL) was added N- bromosuccinimide (2.64g, 14.8mM, 1.0equiv ), benzoyl peroxide (BPO, 179mg, 0.74mM, 0.05equiv), and heated to reflux for 3h under nitrogen. The reaction was complete by TLC, cooled to room temperature, filtered, washed with carbon tetrachloride, the solvent was concentrated under reduced pressure to give the crude product as a white solid. It was used directly in the next reaction without purification.A solution of compound 2 (20 g, 148 mmol), NBS (26.4 g, 150 mmol) and AIBN (1 g) in CCl4 under nitrogenThe mixture was refluxed for 2 hours and the reaction was cooled to room temperature. The solid was removed by filtration and the organic solution was concentrated to give the crude product as an oilWhich was used in the next step without further purification3.0 g of 4-fluoro-2-methylbenzonitrile was added to 23.7 kg of acetonitrile, Further, 4.0 kg of N-bromosuccinimide was added And 0.15 kg of 2, 2'-azobis(2-methylpropionitrile).The reaction was heated to 70 ° C for 8 hours.The acetonitrile was concentrated under reduced pressure, 25 Kg of methylene chloride was added and stirred, Filtered and the filter cake washed with 12 Kg of dichloromethane.The filtrate was washed three times with 15 kg of 7percent sodium bisulfite solution;The organic phase was concentrated N- methylpyrrolidone was added methylene chloride was removed 15Kg, Further, 3.03 kg of 6-chloro-3-methyluracil and 2.91 kg of potassium carbonate were added.The reaction was heated to 60 ° C for 5 hours.Cooled to 35 ° C, 45 Kg of water was added, After cooling to 10 ° C, filter.The filter cake was added to 19 kg of n-heptane, Stirring, filter, 50 to 55 DEG C to obtain Troglitazone Intermediate II, 4.49 Kg, Yield: 68.9percentHPLC purity 98.2percent.The 4- Fluoro-2-methylbenzonitrile (compound B)(2g, 14.8mmol) , N-Bromosuccinimide(NBS) (2.64g, 15mmol) , AzobisisobutyronitrileAIBN(100mg) dissolved in CCl4 , Under theprotection of nitrogen gas it was heated to reflux for 2 h. Cooled toroom temperature, filtered to remove solids, concentrated to obtain crude oil, Which was used directly in the nextstep without purification.Take 642mg of Take furan-2-yl (piperazin-1-yl) methanone (168mg) in 5mL of acetonitrile, add potassium carbonate (195mg), and stir for a while, then add 4-fluoro-2-bromomethyl-benzonitrile (200mg ), Reaction at room temperature for 3-4 hours. After filtering the reaction solution, the filtrate was evaporated under reduced pressure to remove the solvent.The residue was extracted with ethyl acetate and water. The organic phase was dried, concentrated, dispersed with ether, and filtered to obtain 160 mg of intermediate D12.Dissolve N-Boc-piperazine (500 mg) in dichloromethane (10 mL), add DIPEA (N, N-diisopropylethylamine), and stir well in an ice-water bath.A 3 mL solution of 5-chlorobenzofuran-2-formyl chloride (690 mg) in DCM was slowly added dropwise. The reaction solution was slowly restored to room temperature and stirred for 2 hours.After extraction with water, the organic phase was dried and the solvent was evaporated. The residue was dispersed in ether and filtered to give an off-white solid (720 mg).The above solid was dissolved in methanol, 0.5 mL of concentrated hydrochloric acid solution was added, and the mixture was reacted at room temperature for 4 hours. After the solvent was distilled off, the residue was dispersed with ether. After filtration, a pale yellow solid was obtained. After drying, 200 mg was dissolved in acetonitrile (5 mL). , Anhydrous potassium carbonate (278 mg) and 4-fluoro-2-bromomethylbenzonitrile (150 mg) were added, and the mixture was stirred overnight at room temperature. The reaction solution was filtered the next day. After the solvent was distilled off from the filtrate, ethyl acetate and water were added to extract the organic phase. After drying, the silica gel column was isolated and purified to obtain intermediate D28 (230 mg).

Molecular Weight:214.03
XLogP3:2.3
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:212.95894
Monoisotopic Mass:212.95894
Topological Polar Surface Area:23.8
Heavy Atom Count:11
Complexity:174
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes