2,4-dichlorobenzonitrile

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:230.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The reaction was performed as in Example 1. The following reactants were charged to the reactor: 2,4-DCBTC (132.8 g, 0.5 mol), ammonium chloride (28.1 g, 1.05 eq), and 2,4-dichlorobenzoyl chloride (13.3 g). The mixture was heated at 230° C. for 14 h. Distillation of the reaction mixture gave pure 2,4-dichlorobenzonitrile (2,4-DCBN) (76.4 g, 89% yield, melting point: 59°-60° C.). The following reactants were charged to the reactor Distillation of the reaction mixture

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Anhydrous p-toluene sulfonic acid (20.99 g, 110.04 mmol) was melted at 120° C. and 3-amino-4-methoxy benzoic acid methyl ester (10 g, 55.20 mmol) obtained in step 1 of Preparation Example 1 and 2,4-dichlorobenzonitrile (18.99 g, 110.04 mol) were added thereto and stirred at 180° C. for 6 hours. The resulting solution was cooled to room temperature and the reaction was stopped by adding NaHCO3 thereto. The resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO4 and concentrated under a reduced pressure. The concentrate was dissolved in 50% methanol and 5% NaOCl (30 ml, 20.64 mmol) was added dropwise thereto. After 5 min, the resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent—MeOH:CDCl3=5:95, Merck, Silicagel 60) to obtain the title compound (18 g, 10.32 mmol) in a yield of 84%. were added The resulting solution was cooled to room temperature The resulting mixture was extracted with ethyl acetate the extract was dried over MgSO4 concentrated under a reduced pressure The concentrate was dissolved in 50% methanol After 5 min the resulting mixture was extracted with ethyl acetate the extract was dried over MgSO4 concentrated under a reduced pressure The resulting residue was purified by silica gel column chromatography (eluent—MeOH:CDCl3=5:95, Merck, Silicagel 60)

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

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

Procedure: Under argon, 4-chloroaniline (6.67 g, 52.5 mmol) was slowly added to EtMgBr (52 mL, 1 M in THF, 52 mmol) portion wise. After the solution was stirred for 0.5 h, 2,4-dichlorobenzonitrile (9.03 g, 52.5 mmol) was added. The resulting solution was stirred at rt overnight. The reaction mixture was carefully quenched with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated. Crude product (16.26 g,) was obtained as a sticky brown foam which was used without purification for the next step. LC-MS m/z 299.3 (MH+), retention time 1.75 min (MDLC 1); 1H NMR (300 MHz, CDCl3) δ 4.92 (2H, br), 7.09-7.51 (7H, m). The resulting solution was stirred at rt overnight The reaction mixture was carefully quenched with water extracted with ethyl acetate The organic layer was dried over MgSO4 filtered concentrated

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

Procedure: Under argon, 4-chloroaniline (6.67 g, 52.5 mmol) was slowly added to EtMgBr (52 mL, 1 M in THF, 52 mmol) portion wise. After the solution was stirred for 0.5 h, 2,4-dichlorobenzonitrile (9.03 g, 52.5 mmol) was added. The resulting solution was stirred at rt overnight. The reaction mixture was carefully quenched with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated. Crude product (16.26 g,) was obtained as a sticky brown foam which was used without purification for the next step. LC-MS m/z 299.3 (MH+), retention time 1.75 min (MDLC 1); 1H NMR (300 MHz, CDCl3) δ 4.92 (2H, br), 7.09-7.51 (7H, m). The resulting solution was stirred at rt overnight The reaction mixture was carefully quenched with water extracted with ethyl acetate The organic layer was dried over MgSO4 filtered concentrated

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an oven-dried three-neck round bottom flask fitted with a condenser and addition funnel charged flushed with nitrogen was added magnesium (2.82 g; 116 mmol) and anhydrous ether (100 mL). A solution of 4-methylbenzyl bromide (12.91 g; 69.7 mmol) in ether (50 mL) was added dropwise via the addition funnel at room temperature. After the addition, the reaction mixture was heated at 40° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and was cannulated to another dried flask charged with a solution of 2,4-dichlorobenzonitrile (10.0 g; 58.0 mmol) in ether (150 mL) under a nitrogen atmosphere. The resulting reaction mixture was stirred at 40° C. for 6 hours. The reaction was cooled to room temperature and quenched slowly with 2N aq. HCl. Partitioned between ethyl acetate and 2N aq. HCl. The organic portion was washed with 2N aq. HCl, water, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was filtered through a silica gel plug (eluted with 20% ethyl acetate/hexane), and recrystallized from hexane to afford product: m/e=279 (M+1). To an oven-dried three-neck round bottom flask fitted with a condenser and addition funnel charged flushed with nitrogen After the addition to cool to room temperature was cannulated to another dried flask The resulting reaction mixture The reaction was cooled to room temperature quenched slowly with 2N aq. HCl Partitioned between ethyl acetate and 2N aq. HCl The organic portion was washed with 2N aq. HCl, water, brine dried (Na2SO4) filtered concentrated in vacuo The crude product was filtered through a silica gel plug (eluted with 20% ethyl acetate/hexane) recrystallized from hexane to afford product

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an oven-dried three-neck round bottom flask fitted with a condenser and addition funnel flushed with N2 was added magnesium (4.23 g; 174 mmol) and anhydrous ether (100 mL). A solution of 4-flourobenzyl bromide (8.69 mL; 69.7 mmol) in ether (50 mL) was added dropwise via the addition funnel at room temperature. After the addition, the reaction mixture was heated at 40° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and was cannulated into another dried flask charged with a solution of 2,4-dichlorobenzonitrile (10.0 g; 58.0 mmol) in ether (150 mL) under an N2 atmosphere. The resulting reaction mixture was stirred at 40° C. for 6 hours. The reaction was cooled to room temperature and quenched slowly with 2N aq. HCl, then partitioned between ethyl acetate and 2N aq. HCl. The organic portion was washed with 2N aq. HCl, water, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was filtered through a silica gel plug (eluted with 20% ethyl acetate/hexane), and recrystallized from hexane to afford product: m/e=283 (M+1). To an oven-dried three-neck round bottom flask fitted with a condenser and addition funnel flushed with N2 After the addition to cool to room temperature was cannulated into another dried flask The resulting reaction mixture The reaction was cooled to room temperature quenched slowly with 2N aq. HCl partitioned between ethyl acetate and 2N aq. HCl The organic portion was washed with 2N aq. HCl, water, brine dried (Na2SO4) filtered concentrated in vacuo The crude product was filtered through a silica gel plug (eluted with 20% ethyl acetate/hexane) recrystallized from hexane to afford product

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

Procedure: A solution of 4-chlorobenzyl bromide (Lancaster Chemical) (10.0 g, 48.6 mmol) in 40 mL ether was added under nitrogen to a suspension of magnesium turnings (Alpha Chemical Inc.) in ether (60 mL) over 10 minutes. The suspension was stirred for 2 h and the supernatant was cannulated under nitrogen into another round bottom flask fitted with a magnetic stirrer bar. Then 2,4-dichlorobenzonitrile (7.0 g, 40.5 mmol) in 65 mL ether was slowly added under nitrogen to the Grignard solution and the mixture was stirred over night at room temperature. The imine precipitated out of solution and the mixture was refluxed for 3 h. The reaction mixture was cooled and poured into a flask containing 50 mL ethyl acetate and 50 mL 2N HCl. Stirred vigorously to hydrolyze the imine, separated the organic layer and dried it over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent volume reduced under reduced pressure. The crude product was flash chromatographed on silica gel (92/8 hexanes/ethyl acetate) to give product. 1H NMR 500 MHz (CDCl3): δ 4.40 (s, 2H), 7.2-7.6 (m, 7H). the supernatant was cannulated under nitrogen into another round bottom flask fitted with a magnetic stirrer bar the mixture was stirred over night at room temperature The imine precipitated out of solution the mixture was refluxed for 3 h The reaction mixture was cooled poured into a flask containing 50 mL ethyl acetate and 50 mL 2N HCl Stirred vigorously separated the organic layer dried it over anhydrous magnesium sulfate The desiccant was filtered off chromatographed on silica gel (92/8 hexanes/ethyl acetate) to give product

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

Procedure: A stirred solution of 2,4-dichlorobenzonitrile (51.6 g., 0.03 mole) and the potassium salt of 2,4-dichlorophenol (60.3 g., 0.03 mole) in 250 ml. of dimethyl acetamide was heated for 24 hours at 120° C. The cooled reaction mixture was diluted with 1000 ml. of water and the resultant oil was extracted with ether. Evaporation of the ether solution gave 88.0 g. of brown oil. Analysis by v.p.c. showed a 2:1 mixture of the desired compound and the isomeric 4-chloro-2-(2',4'-dichlorophenoxy) benzonitrile. A series of fractional crystallizations from 60°-110° C. petroleum ether gave the desired 2-chloro-4-(2',4'-dichlorophenoxy)benzonitrile with a melting point of 69°-74° C. The minor isomeric by-product melted at 110°-113° C. The cooled reaction mixture was diluted with 1000 ml of water and the resultant oil was extracted with ether Evaporation of the ether solution gave 88.0 g