* 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.
With sodium borohydrid; triethylamine In methanol; water; acetone; toluene; Petroleum ether
1. Preparation of 2,3-Dichlorophenylacetonitrile To a suspension of 2,3-dichlorobenzaldehyde (40 kg, 228.6 mole) in toluene (254 liters) and methanol (40 liters), was added sodium borohydride (2.59 kg, 68.6 mole) portionwise over a period of 1 hour. The mixture was stirred for a period of 30 minutes prior to treatment with acetone (20 liters). On decomposition of the excess borohydride, water (80 liters) was added. Toluene (54 liters) was added to the toluene phase and the suspension was warmed to 42° C.+-2° C. to attain a solution prior to separation. The organic phase was distilled to remove 54 liters of azeotrope and so effect the removal of water, acetone, and isopropyl alcohol. The resulting toluene solution of 2,3-dichlorobenzyl alcohol was cooled. To the resulting suspension was added triethylamine (27.8 kg, 274.3 mole) followed by methanesulphonyl chloride (31.4 kg, 274.3 mole) over a period of 11/2 hours so as to maintain the temperature at 0° C.+-2° C. The mixture was stirred for 1 hour then water (,100 liters) was charged to the suspension and the mixture was stirred vigorously prior to separation. To the methanesulphonate in the toluene phase was added tetrabutylammonium hydrogen sulphate (15.6 kg, 45.8 mole) and aqueous potassium cyanide solution (22.4 kg, 342.8 mole) in water (70 liters) over a period of 40 minutes. The two phase mixture was stirred overnight, separated and the organic phase was washed with water (70 liters). The toluene phase was distilled to remove 130 kg of toluene in the presence of charcoal (2.8 kg) and dicalite (2.8 kg). Petroleum ether 60/80 (300 liters) was charged to the residue, the mixture was filtered hot and crystallized under vacuum to afford 2,3-dichlorophenylacetonitrile (30 kg, 72percent yield).
Reference：
[1] Patent: US6124308, 2000, A,
2
[ 38594-42-2 ]
[ 124-63-0 ]
[ 3218-45-9 ]
Yield
Reaction Conditions
Operation in experiment
83%
With 2-(Dimethylamino)pyridine; triethylamine In water; toluene; Petroleum ether
2. Preparation of 2,3-Dichlorophenylacetonitrile To the 2,3-dichlorobenzyl alcohol (470.5 g, 2.658 mole) in toluene (1.97 liters) was added triethylamine (322.8E g, 3.19 mole) and dimethylaminopyridine (16.23 g, 0.13 mole). Methanesulphonyl chloride (365.4 g, 3.19 mole) was added over a period of 1 hour. After 2 hours the toluene solution was washed with water. To the methanesulphonate in toluene was added a solution of tetrabutylammonium hydrogen sulphate (180.5 g, 0.53 mole) in water (641 ml) followed by aqueous potassium cyanide solution (259.6 g 3.987 mole) in water (712 ml). The two phase reaction mixture was stirred overnight, separated and the organic phase was washed with water (1069 ml). The toluene was removed under vacuum and the product was precipitated from petroleum ether 60/80 (1069 ml), filtered and washed with petroleum ether 60/80 (356 ml) to give the crude 2,3-dichlorophenylacetonitrile (406 g, 83percent yield).
(i) 2,,3-Dichlorophenylacetic acid Concentrated hydrochloric acid (100ml) was poured onto crushed ice (150ml), the solution added to <strong>[3218-45-9]2,3-dichlorophenylacetonitrile</strong> (30.6gms), and the mixture refluxed for 3 hours. After cooling, the mixture was diluted with water (500ml), extracted with EtOAc (600ml) and the organic phase washed with brine before drying over MgSO4. Evaporation of the solvent left a white solid, 31.3gms.
With potassium hydroxide; water; In ethanol;Heating / reflux;
A solution of 24.23 g of KOH in 74 ml of water is added to a solution of 17.17 g of the compound obtained in the preceding step in 188 ml of EtOH, and then the mixture is heated overnight under reflux. It is concentrated under vacuum, the residue is taken up in 100 ml of water, the aqueous phase is washed three times with ether, the aqueous phase is acidified to pH=1 by adding a concentrated HCl solution, and allowed to crystallize, with stirring, by cooling in an ice bath. The precipitate formed is drained, washed with water and dried under vacuum at 40 C. 17.17 g of the expected product are obtained.
To a suspension of 2,3-dichiorophenyiacetonitriie {45 kg, 241 .9 mole) in methanol litres) was charged 30% w/w sodium methoxide in methanol solution ( 1 13.5 kg, 630.6 mole) then ethyifluoroacetate (29.7 kg, 280.1 mole). The reaction mixture was stirred overni°hi and the product was precipitated from aqueous hydrochloric acid (63.7 kg, 648 mole) in water (350 litres). The slurry was filtered and the solid was dissolved in ethyl acetate and washed with brine solution. Ethyl acetate (100 litres) was removed by <n="21"/>vacuum distillation. DMF (70 litres) was added and the distillation continued to remove the remaining ethyl acetate.To the resulting enol in DMF was added potassium carbonate (20 kg. 145 mole) over a period of 10 minutes. Aikyiation of the potassium enoiale was achieved using ethyl iodide (37.7kg, 24^ .9 mole) at 70'C for VA hours. The reaction mixture was partitioned between toluene (140 litres) and water (75 litres) and the toluene chase was washed with water (50 litres). Toluene (75 iitres) was removed by distillation to afford the crude product as a toluene solution.
10.1 g of potassium cyanide at 97% are added to a solution of 29.25 g of the compound obtained in the preceding step in 200 ml of EtOH and 50 ml of water and the mixture is heated under reflux for 2 hours. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed four times with water, with a saturated solution of NaCl, dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is taken up in 200 ml of pentane and the medium is allowed to crystallize overnight, with stirring. The precipitate formed is drained and dried under vacuum. 17.17 g of the expected product are obtained.
With sodium borohydrid; triethylamine;pyrographite; In methanol; water; acetone; toluene; Petroleum ether;
1. Preparation of 2,3-Dichlorophenylacetonitrile To a suspension of 2,3-dichlorobenzaldehyde (40 kg, 228.6 mole) in toluene (254 liters) and methanol (40 liters), was added sodium borohydride (2.59 kg, 68.6 mole) portionwise over a period of 1 hour. The mixture was stirred for a period of 30 minutes prior to treatment with acetone (20 liters). On decomposition of the excess borohydride, water (80 liters) was added. Toluene (54 liters) was added to the toluene phase and the suspension was warmed to 42 C.+-2 C. to attain a solution prior to separation. The organic phase was distilled to remove 54 liters of azeotrope and so effect the removal of water, acetone, and isopropyl alcohol. The resulting toluene solution of 2,3-dichlorobenzyl alcohol was cooled. To the resulting suspension was added triethylamine (27.8 kg, 274.3 mole) followed by methanesulphonyl chloride (31.4 kg, 274.3 mole) over a period of 11/2 hours so as to maintain the temperature at 0 C.+-2 C. The mixture was stirred for 1 hour then water (,100 liters) was charged to the suspension and the mixture was stirred vigorously prior to separation. To the methanesulphonate in the toluene phase was added tetrabutylammonium hydrogen sulphate (15.6 kg, 45.8 mole) and aqueous potassium cyanide solution (22.4 kg, 342.8 mole) in water (70 liters) over a period of 40 minutes. The two phase mixture was stirred overnight, separated and the organic phase was washed with water (70 liters). The toluene phase was distilled to remove 130 kg of toluene in the presence of charcoal (2.8 kg) and dicalite (2.8 kg). Petroleum ether 60/80 (300 liters) was charged to the residue, the mixture was filtered hot and crystallized under vacuum to afford 2,3-dichlorophenylacetonitrile (30 kg, 72% yield).
With 2-(Dimethylamino)pyridine; triethylamine; In water; toluene; Petroleum ether;
2. Preparation of 2,3-Dichlorophenylacetonitrile To the 2,3-dichlorobenzyl alcohol (470.5 g, 2.658 mole) in toluene (1.97 liters) was added triethylamine (322.8E g, 3.19 mole) and dimethylaminopyridine (16.23 g, 0.13 mole). Methanesulphonyl chloride (365.4 g, 3.19 mole) was added over a period of 1 hour. After 2 hours the toluene solution was washed with water. To the methanesulphonate in toluene was added a solution of tetrabutylammonium hydrogen sulphate (180.5 g, 0.53 mole) in water (641 ml) followed by aqueous potassium cyanide solution (259.6 g 3.987 mole) in water (712 ml). The two phase reaction mixture was stirred overnight, separated and the organic phase was washed with water (1069 ml). The toluene was removed under vacuum and the product was precipitated from petroleum ether 60/80 (1069 ml), filtered and washed with petroleum ether 60/80 (356 ml) to give the crude 2,3-dichlorophenylacetonitrile (406 g, 83% yield).
2-(2,3-Dichlorophenyl)-3,4,4-triethoxy-but-2-enenitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In 1,2-dimethoxyethane;
3. Preparation of 2-(2,3-Dichlorophenyl)-3,4,4-triethoxy-but-2-enenitrile To <strong>[3218-45-9]2,3-dichlorophenylacetonitrile</strong> (100 g, 0.5,1 mole) in dimethoxyethane (750 ml) and ethyl diethoxyacetate (142 g, 0.81 mole) was added potassium-t-butoxide in 1 portion. The mixture was boiled under reflux for 41/2 hours, cooled prior to the addition of ethyl iodide (169.8 g, 1.08 mole) and then heated at 65 C. overnight. The mixture was cooled and concentrated to a residue which was partitioned between water (1.5 liters) and ethyl acetate (1 liter). The aqueous was extracted with ethyl acetate (1 liter) and the combined organic phase was washed with water (500 ml), dried over MgSO4 and evaporated in vacuo to give the desired enol ether as an oil which was used without further purification.
2-(2,3-dichlorophenyl)-3-ethoxy-4-fluoro-2-butenenitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; sodium methylate; potassium carbonate; In methanol; water; ethyl acetate; N,N-dimethyl-formamide;
2. Preparation of 2-(2,3-Dichlorophenyl)-3-ethoxy-4-fluoro-2-butenenitrile To a suspension of <strong>[3218-45-9]2,3-dichlorophenylacetonitrile</strong> (45 kg, 241.9 mole) in methanol (90 liters) was charged 30% w/w sodium methoxide in methanol solution (113.5 kg, 630.6 mole) then ethylfluoroacetate (29.7 kg, 280.1 mole). The reaction mixture was stirred overnight and the product was precipitated from aqueous hydrochloric acid (6:3.7 kg, 648 mole) in water (350 liters). The slurry was filtered and the solid was dissolved in ethyl acetate and washed with brine solution. Ethyl acetate (100 liters) was removed by vacuum distillation. DMF (70 liters) was added and the distillation continued to remove the remaining ethyl acetate. To the resulting enol in DMF was added potassium carbonate (20 kg, 145 mole) over a period of 10 minutes. Alkylation of the potassium enolate was achieved using ethyl iodide (37.7 kg, 241.9 mole) at 70 C. for 11/4 hours. The reaction mixture was partitioned between toluene (140 liters) and water (75 liters) and the toluene phase was washed with water (50 liters). Toluene (75 liters) was removed by distillation to afford the crude product as a toluene solution.
2-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
at 140℃; for 5h;
Procedure B; EXAMPLE 17; 2-(2,3-Dichloro-benzyl)-4,5-dihydro-1H-imidazole; A mixture of 500 mg (2.7 mmol) <strong>[3218-45-9]2,3-dichlorophenylacetonitrile</strong> and 624 mg (2.7 mmol) ethylene diamine p-toluenesulfonic acid mono salt was heated neat to 140 C. and the liquid stirred for 5h at this temperature. Then the cooled reaction mixture was diluted with water and extracted with ethyl acetate, the combined extracts washed with brine, dried over Na2SO4, filtered and evaporated. Trituration of the crude product in tert-butyl methyl ether provided pure 2-(2,3-dichloro-benzyl)-4,5-dihydro-1H-imidazole as colourless crystals: MS (ISP): 231.1 and 229.1 ((M+H)+·).
1. Preparation of 2-(2,3-dichlorophenyl)acetonitrile[00191] 2,3-Dichlorobenzylchloride (5.0 g, 25.5 mmol) was dissolved in 100 ml DMSO. 9.2 g NaCN (188 mmol) were added and the mixture stirred at room temperature for 16 hours. The reaction mixture was diluted with water, and the product extracted with ether. The organic layers were washed with water (2x) and brine, then dried over magnesium sulfate, filtered and concentrated. The product was used as. Crude yield ~ quantitative. An analytical sample was purified by column chromatography on silica, using a gradient from 10% to 75% dichloromethane in hexanes as eluent. The combined aqueous layers and wash liquids were treated with 100 ml bleach to oxidize the excess cyanide to less toxic materials.
With caesium carbonate; In dimethyl sulfoxide; at 20℃; for 96h;
2. Preparation of tert-butyl 4-cyano-4-(2,3- dichlorophenyl)piperidine-l-carboxylate[00192] <strong>[3218-45-9]2-<strong>[3218-45-9](2,3-dichlorophenyl)acetonitrile</strong></strong> (2.49 g crude, est. 83% purity, 11 mmol), 2.70 g tert-butyl bis(2-chloroethyl)carbamate (J. Med. Chem. 1992, 35, 11, 2033-2039) (11 mmol), 19.5 g aesium carbonate (60 mmol) and 200 ml DMSO were combined in a round bottom flask and stirred at room temperature for 4 days. The reaction mixture was diluted with ethyl acetate and the organic layer washed with IM aq. KHSO4 solution, and then saturated aq. NaHCtheta3 solution, then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The product was purified by column chromatography on silica, using a gradient from 5% to 35% ethyl acetate in hexanes as eluent. 2.3 g of the title compound were isolated as an oil (59% yield)
To a suspension of <strong>[3218-45-9]2,3-dichlorophenylacetonitrile</strong> (45 kg, 241.9 mole) in methanol (90 litres) was charged 30% w/w sodium methoxide in methanol solution (1 13.5 kg, 630.6 mole) then ethylfluoroacetate (29.7 kg, 280.1 mole). The reaction mixture was stirred overnight and the product was precipitated from aqueous hydrochloric acid (63.7 kg, 648 mole) in water (350 litres). The slurry was filtered and the solid was dissolved in ethyl acetate and washed with brine solution. Ethyl acetate (100 litres) was removed by vacuum distillation. DMF (70 litres) was added and the distillation continued to remove the remaining ethyl acetate. To the resulting enol in DMF was added potassium carbonate (20 kg, 145 mole) over a period of 10 minutes. Alkylation of the potassium enolate was achieved using ethyl iodide (37.7kg, 241.9 mole) at 7O C for VA hours. The reaction mixture was partitioned between toluene (140 litres) and water (75 litres) and the toluene phase was washed with water (50 litres). Toluene (75 litres) was removed by distillation to afford the crude product as a toluene solution.
With trimethylaluminum; ammonium chloride; In toluene; at 5 - 80℃; for 14h;
To a stirred suspension of NH4Cl (4.29 g, 80.21 mmol) in dry toluene (120 mL) was added trimethyl aluminium (2M in toluene, 41 mL, 80.21 mmol) at 5 C. The mixture was then warmed to room temperature and stirred for 2 h. A solution of (2,3-dichlorophenyl)-acetonitrile (128) (5 g, 26.73 mmol) in toluene (25 mL) was added to the mixture and stirred for 14 h at 80 C. After completion of the reaction, it was quenched with a suspension of silica gel in chloroform and the reaction mixture was stirred for half an hour at room temperature and filtered through a sintered funnel. The silica gel was washed with methanol and the combined filtrate was concentrated under reduced pressure to get 2-(2,3-dichlorophenyl)-acetamidine hydrochloride salt (129) (5 g, 78%) as an off-white solid. [0591] LC-MS: 203 (M+H).
1-(2,3-dichlorophenyl)cyclobutane-1-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54.5%
<strong>[3218-45-9]2-<strong>[3218-45-9](2,3-dichlorophenyl)acetonitrile</strong></strong> (5.581 g, 29.999 mmol) in N,N-dimethylformamide (50 mL) and sodium hydride (60.00%, 3.000 g, 74.997 mmol) was added at 0 C and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture 1,3-dibromopropane (3.059 mL, 29.999 mmol) was added and further stirred at room temperature for 21 hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, and water was removed with anhydrous magnesium sulfate, followed by filtration and concentration under reduced pressure. The concentrate was purified by column chromatography (SiO2, 40 g cartridge; ethyl acetate / hexane = 0% to 50%) and concentrated to give the desired title compound (3.696 g, 54.5%) as a white solid.
With triethylamine; In N,N-dimethyl-formamide; at 120℃; for 0.333333h;Microwave irradiation;
General procedure: A solution of aryl acetonitrile 2 (50 mg), and triethylamine (1.1 equiv.) in dimethylformamide dimethyl acetal (0.5 mL, 3.76 mmol) was heated in a microwave reactor at 120 C for 20 minutes. The mixture was cooled to RT, and solvents were then evaporated. To the resulting crude product 3 was added hydrazine mono-hydrobromide (3.0 equiv.), 200 proof EtOH (1.0 mL), and H2O (0.3 mL). The mixture was heated in a microwave reactor at 120 C for 20 minutes. The mixture was cooled to RT and concentrated in vacuo. The resulting residue was subjected to liquid-liquid extraction using saturated NaHCO3 (aq) and CH2Cl2. The organic layer was collected, dried over anhydrous MgSO4, filtered and removed under vacuum to afford 4.The resulting crude product 4 and 2-arylsubstitutedmalondialdehydes or 1,1,3,3tetramethoxypropane (1.0 equiv.) were dissolved in glacial AcOH (1.0 mL) and 200 proof EtOH (1.5 mL). The mixture was heated in a microwave reactor at 120 C for 20 minutes. After cooling on ice, the precipitate was collected on a fine scintered-glass frit and washed with icecold EtOH (2 x 1.0 mL). The resulting crystals 5-32 were dried and collected.
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