2-chloro-6-methylbenzonitrile

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under a nitrogen atmosphere, a stirred solution of aqueous 90% nitric acid was cooled to -35° C., and 40.0 grams (0.264 mole) of 2-chloro-6-methylbenzonitrile was added in one portion. The reaction mixture was then allowed to warm to ambient temperature, where it was stirred for about 18 hours. After this time, the reaction mixture was poured into 3000 mL of ice-water. After the ice melted, the resultant solid was collected by filtration and dried. The NMR spectrum of the solid indicated that it was about 75% pure product. The solid was recrystallized twice from methanol, yielding 13.9 grams of 2-chloro-6-methyl-5-nitrobenzonitrile, mp 85.5°-87.5° C. The NMR spectrum was consistent with the proposed structure. The filtrates from the recrystallizations were combined and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 10% ethyl acetate in petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding an additional 20.4 grams of 2-chloro-6-methyl-5-nitrobenzonitrile, mp 87.5°-89.5° C. The NMR spectrum was consistent with the proposed structure. the resultant solid was collected by filtration dried The solid was recrystallized twice from methanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of 5.7 parts of lithium aluminum hydride in 20 parts of ether is added dropwise a solution of 15 parts of 2-cyano-3-chlorotoluene in 140 parts of ether at reflux temperature. After the addition is complete, stirring at reflux temperature is continued for one hour. The reaction mixture is cooled in an ice-bath and decomposed with 25 parts of water and with a 20% solution of potassium-sodium tartrate (450 parts). The aqueous phase is separated and extracted with ether. The combined ether layers are washed with water, dried, filtered and evaporated. The oily residue is distilled in vacuo, yielding 12 parts of 2-chloro-6-methylbenzylamine; bp. 113° -118° C at 18 mm. pressure. at reflux temperature After the addition at reflux temperature The reaction mixture is cooled in an ice-bath The aqueous phase is separated extracted with ether The combined ether layers are washed with water dried filtered evaporated The oily residue is distilled in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under N2 atmosphere at room temperature to a solution of lithium bis(trimethylsilyl)amide (9.7 mL, 1.0 M solution in THF, 9.7 mmol) was added a solution of 4-bromoaniline (1.67 g, 9.7 mmol) in 10 mL anhydrous THF. After the mixture was stirred at ambient temperature for 40 min, a solution of 2-chloro-6-methylbezonitrile (1.55 mg, 10.2 mmol) in 10 mL anhydrous THF was added. The reaction mixture was stirred at room temperature overnight, and then poured into 300 mL ice water. The orange precipitate was collected by filtration, washed with hexane and air dried to give a light orange solid (2.19 g, 66% yield), which was used directly for the next step without further purification. The reaction mixture was stirred at room temperature overnight The orange precipitate was collected by filtration washed with hexane and air dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under N2 atmosphere at room temperature to a solution of lithium bis(trimethylsilyl)amide (9.7 mL, 1.0 M solution in THF, 9.7 mmol) was added a solution of 4-bromoaniline (1.67 g, 9.7 mmol) in 10 mL anhydrous THF. After the mixture was stirred at ambient temperature for 40 min, a solution of 2-chloro-6-methylbezonitrile (1.55 mg, 10.2 mmol) in 10 mL anhydrous THF was added. The reaction mixture was stirred at room temperature overnight, and then poured into 300 mL ice water. The orange precipitate was collected by filtration, washed with hexane and air dried to give a light orange solid (2.19 g, 66% yield), which was used directly for the next step without further purification. The reaction mixture was stirred at room temperature overnight The orange precipitate was collected by filtration washed with hexane and air dried

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methyl-6-piperidin-1-ylbenzonitrile (1 b) was prepared according to the method described by Grell, W. J. Med. Chem. 1998, 41, 5219. A mixture of 2-chloro-6-methylbenzonitrile (1a, 8.5 g), piperidine (16.6 mL, 3 eq) and N-formyl piperidine (12.5 mL) was heated in an oil bath at 150° C. under N2. After a period of 4 days, HPLC indicated complete conversion of starting materials to product. The reaction mixture was cooled to RT, dissolved in 100 mL of EtOAc, washed with water, 10% HCl, and NaHCO3 (sat), dried over anhydrous MgSO4 and treated with charcoal. The product was concentrated under vacuum to give the crude product (1 b) as pale yellow oil (12.01 g); C18 reversed phase HPLC indicated 88% homogeneity at 220 nm. This crude product was purified by flash column chromatography (hex-EtOAc, 1:0 to 20:1 to 10:1) to afford 2-methyl-6-piperidin-1-ylbenzonitrile (1 b) as colorless oil which solidifies upon standing (˜80% yield). The reaction mixture was cooled to RT washed with water, 10% HCl, and NaHCO3 (sat) dried over anhydrous MgSO4 treated with charcoal The product was concentrated under vacuum to give the crude product (1 b) as pale yellow oil (12.01 g)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: At 0° C., sodium hydride, 60% dispersion in mineral oil, (280 mg, 7 mmol) was added to a solution of ethyl-2-mercaptoacetate (750 μL, 6.8 mmol) in N,N-dimethylformamide (20 mL). After 15 minutes, 2-chloro-6-methylbenzonitrile (1 g, 6.60 mmol) was also added to the mixture which was stirred at room temperature for 2 hours more. The mixture was then concentrated and the residue was diluted with ethyl acetate. The organic layer was washed with water (30 mL), brine (30 mL), dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (cyclohexane/dichloromethane 50/50) to afford the desired benzothiophene (23a) as a white solid (800 mg, 3.40 mmol, 52%). The mixture was then concentrated the residue was diluted with ethyl acetate The organic layer was washed with water (30 mL), brine (30 mL) dried over sodium sulfate filtered evaporated The crude product was purified by flash chromatography on silica gel (cyclohexane/dichloromethane 50/50)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: At 0° C., sodium hydride, 60% dispersion in mineral oil, (280 mg, 7 mmol) was added to a solution of ethyl-2-mercaptoacetate (750 μL, 6.8 mmol) in N,N-dimethylformamide (20 mL). After 15 minutes, 2-chloro-6-methylbenzonitrile (1 g, 6.60 mmol) was also added to the mixture which was stirred at room temperature for 2 hours more. The mixture was then concentrated and the residue was diluted with ethyl acetate. The organic layer was washed with water (30 mL), brine (30 mL), dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (cyclohexane/dichloromethane 50/50) to afford the desired benzothiophene (23a) as a white solid (800 mg, 3.40 mmol, 52%). The mixture was then concentrated the residue was diluted with ethyl acetate The organic layer was washed with water (30 mL), brine (30 mL) dried over sodium sulfate filtered evaporated The crude product was purified by flash chromatography on silica gel (cyclohexane/dichloromethane 50/50)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-chloro-6-methylbenzonitrile (2.0 g) in conc. sulphuric acid (10 mL) was heated at 100° C. for 3-4 h. The reaction mass was quenched in ice-water and the solid obtained was filtered. The precipitate was suck dried to afford 1.5 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.28 (s, 3H), 7.21-7.27 (m, 3H), 7.65 (s, 1H), 7.91 (s, 1H). The reaction mass was quenched in ice-water the solid obtained was filtered dried