2-[(Methoxy)(4-phenoxyphenyl)methylene]malononitrile

To a stirred solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (500 g, 1.0 eq) in 2000 mL solvent of dioxane at r.t. was added NaHCO3 (480 g, 3.0 eq) and dimethyl sulfate (360 g, 271 mL, 1.5 eq). After addition was completed, the reaction mixture was heated to 80 °C, and stirred at that temperature for 3 h. The organic solvent was removed, and water was added. The mixture was extracted with EtOAc. The organic extract was washed with water and brine, dried with anhydrous Na2SO4, and evaporated the organic solvent to give the crude product which was recrystallized in hexane/ EtOAc (1:1) to give the pure product as a gray yellow solid(420 g, 88percent). ‘H NMR (400 MHz, CDC13) ö 7.48-7.5 1 (m, 2H), 7.41-7.45 (m, 2H), 7.25-7.27 (m, 1H), 7.07-7.11 (m, 4H), 3.99 (s, 3H).Step E: Step 3: preparation of 2-[(4-phenoxy-phenyl )-methoxy-methylene]-malonon itrile. To a solution of 2-[hydroxy-(4-phenoxy-phenyl)-methylene]-malononitrile (600 g, 2.29mol) in a mixture of dioxane / water (4/1, 5 L) at 0°C was added sodium bicarbonate (1.34 kg, 16 mol) portion wise. Dimethyl sulfate (1 .2 L, 13.74 mol) was added drop wise over 2h, after which the reaction was warmed to 80°C and allowed to stir for an additional 12h. The reaction was cooled to ambient temperature, diluted with water and5 extracted into ethyl acetate. The combined organic layers were washed with water, then brine, dried over sodium sulfate, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography to afford the title compound as an off white solid (300 g, 48percent). MS (M+H) m/z 277. 1H NMR (CDCI3) 6 7.47 (d, J = 8.8 Hz, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.23 (t, J = 7.6 Hz, 1 H), 7.07 (t, J = 8.8 Hz, 4H), 3.97 (s, 3H).Dimethyl sulfate (211.6 gms) and sodium carbonate (141 gms) were added to a mixture of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (220 gm) and 1 , 4-dioxane(1100 ml) at 0-5°C. Heated the reaction mixture to 70-75°C and stirred for 5 hrs. Cooled thereaction mixture to 25-30°C. Water followed by ethyl acetate were added to the reaction mixture. Both the organic and aqueous layers were separated. Aqueous layer was extracted with ethyl acetate. Organic layers were combined and washed with water. Distilled off the solvent from the organic layer completely under reduced pressure and co-distilled withisopropyl alcohol. Isopropyl alcohol (220 ml) was added to the obtained compound at 25-30°C. The reaction mixture was cooled to 0-5°C and stirred for 2 hrs at the same temperature.Filtered the precipitated solid, washed with isopropyl alcohol and dried to get the titlecompound. Yield: 86 gms; Melting range: 70-75°C.l, l-Dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene (56.5 g) in acetonitrile (780 mL) and methanol (85 mL) is stirred under nitrogen at 0°C while adding diisopropylethylamine (52.5 mL) followed by 2M trimethylsilyldiazomethane (150 mL) in THF. The reaction is stirred for 2 days at 20°C, and then 2 g of silica is added (for chromatography). The brown-red solution is evaporated in vacuo, the residue dissolved in EA and washed well with water then brine, dried and evaporated. The residue is extracted with diethyl ether (3x250 mL), decanting from insoluble oil. Evaporation of the ether extracts gives 22.5 g of l, l-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene as a pale orange solid. The insoluble oil is purified by flash chromatography to give 15.0 g of a red- orange oil.1, 1-Dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene (56.5 g) in acetonitrile (780 mL) and methanol (85 mL) is stirred under nitrogen at 0° C. while adding diisopropylethylamine (52.5 mL) followed by 2M trimethylsilyldiazomethane (150 mL) in THF. (0671) 1, 1-Dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene (56.5 g) in acetonitrile (780 mL) and methanol (85 mL) is stirred under nitrogen at 0° C. while adding diisopropylethylamine (52.5 mL) followed by 2M trimethylsilyldiazomethane (150 mL) in THF. The reaction is stirred for 2 days at 20° C., and then 2 g of silica is added (for chromatography). The brown-red solution is evaporated in vacuo, the residue dissolved in ethyl acetate and washed well with water then brine, dried and evaporated. The residue is extracted with diethyl ether (3×250 mL), decanting from insoluble oil. Evaporation of the ether extracts gives 22.5 g of 1, 1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene as a pale orange solid. The insoluble oil is purified by flash chromatography to give 15.0 g of a red-orange oil10019] 6.6 g of malononitrile (6.6 g, 0.i mol), 4.8 g of sodium hydride (4.8 g, 0.2 mol, 80percent dispersed in paraffin) and i 00 mL of freshly-treated anhydrous tetrahydrofuran were added to a three-neck reaction flask, added dropwise with 50 mL of 4-benzyloxybenzoyl chloride (II) (23.2 g, 0.i mol) in tetrahydroffiran solution while stirring; afier reaction 2 hours under room temperature, 250 mL of iM dilute hydrochloric acid was added to react 30 mm while stirring, thenextracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous magnesium sulfate, concentrated to get the solid, dissolved in 150 mE of dioxane and 50 mE of saturated sodium bicarbonate solution, then dimethyl sulfate (37.8 g, 0.3 mol) was added to heat to 80-90° C. and react 3 hours while stirring, to complete the reaction detected by TEC. 400 mE of deionized water was added, and extracted with methyl tert-butyl ether three times; then the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was recovered under a reduced pressure and the resulting crude product was recrystallized by methanol to get 17.6 g of white solid 4-benzyloxyphenyl (methoxy)vinylidenedicyanomethane (III), with a yield of63.8percent.[001 63j A solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8 mmol) in CH(OMe3) (500 mL) is heated to 75°C for 16 hours. Then the mixture is concentrated to a residue and washed with MeOH (50 mL) to give 25 g (47.5percent) of 2-(methoxy(4- phenoxyphenyl)methylene)malononitrile as a yellow solid.A solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8 mmol) in CH(OMe3) (500 mL) is heated to 75°C for 16 hours. Then the mixture is concentrated to a residue and washed with MeOH (50 mL) to give 25 g (47.5percent) of 2-(methoxy(4- phenoxyphenyl)methylene)malononitrile as a yellow solid.A solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8 mmol) in CH(OMe2-(Hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8 mmol) was added to trimethyl orthoformate (500 mL). Heat to 75°C and stir for 16 hours. The mixture was concentrated and the residue was washed with MeOH (50 mL). A yellow solid product, 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile (25 g, 47.5percent) was obtained.[0173] A solution of 2-(hydroxy( 4-phenoxyphenyl)methylene )malononitrile (50 g, I90.8 mmol)in CH(OMe)3 (500 mL) was heated to 75 °C for I6 hr. Then the mixture was concentrated to aresidue and washed with MeOH (50 mL) to give 25 g (47.5percent) of 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile as a yellow solid. 1H NMR (DMSO-d6) 8 7.70 (d, J =8.4 Hz, 2H), 7.52-7.45 (m, 2H), 7.28 (t, J = 7.6 Hz, IH), 7.22-7.06 (m, 4H), 3.93 (s, 3H). MS(ESI) m/e [M+ It 276.9.A solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8 mmol) in CH(OMe)Step 2. Preparation of 2-(Methoxy(4-phenoxyphenyl)methylene)malononitrile: A solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8 mmol) in CH(OMeStep 2. Preparation of 2-(Methoxy(4-phenoxyphenyl)methylene)malononitrile: A solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8 mmol) in CH(OMeStep 2. Preparation of 2-(Methoxy(4-phenoxyphenyl)methylene)malononitrile: A solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8 mmol) in CH(OMeA solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8 mmol) in CH(OMeA solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8 mmol) in CH(OMe3) (500 mL) is heated to 75 °C for 16 hours. Then the mixture is concentrated to a residue and washed with MeOH (50 mL) to give 25 g (47.5percent) of 2-(methoxy(4- phenoxyphenyl)methylene)malononitrile as a yellow solid.A solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8 mmol) in CH(OMeUnder nitrogen atmosphere, a solution of BG-2 (79.9 kg, 1.0 eq. ) in MeCN (5.0 v) was added into trimethoxymethane (12.0 v) at 85. The resultant mixture was stirred until the reaction was completed. Sampled for HPLC analysis. Concentrated under vacuum. The residue was precipitated from i-PrOH and hexane. The mixture was centrifuged, and the cake was washed with hexane and dried under vacuum. This gave 71.7 Kg of product. A solution of BG-2 (79.9 kg, 1.0 eq.) in MeCN (5.0 v) was added to trimethoxymethane (12.0 v) at 85 ° C under a nitrogen atmosphere. The resulting mixture was stirred until the reaction was completed. Sampling was used for HPLC analysis. Concentrate in vacuo. The residue was precipitated from i-PrOH and hexane. The mixture was centrifuged and the filter cake was washed with hexanes and dried in vacuo. This gave 71.7 Kg of product.A solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8 mmol) in CH(OMe0.25 mol of malononitrile and 0.4 mol of sodium hydride were added to 200 mL of dry THF, Reaction 1h, 0.1 mol of Compound VI was dissolved in 200 mL of dry THF and the solution was slowly added dropwise to the above malononitrile solution at -10 ° C, After dripping for 30min, TLC detection reaction is completed by adding 100mL ice saturated NaCl solution quenching, Ethyl acetate was extracted three times, Combined organic phase, Dried over anhydrous sodium sulfate, The concentrated solid was added to 200 mL of trimethyl orthoformate, Heating reflux reaction 8h, After the TLC detection reaction was completed, 100 mL of saturated NaCl solution was added, Followed by extraction with ethyl acetate three times, Combined organic phase, Dried over anhydrous sodium sulfate, The solvent was distilled off under reduced pressure, The residue was recrystallized from methanol to give 18.2 g of white solid VII, The yield of the two-step reaction was 67percent.

Molecular Weight:276.29
XLogP3:3.3
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:4
Exact Mass:276.089877630
Monoisotopic Mass:276.089877630
Topological Polar Surface Area:66
Heavy Atom Count:21
Complexity:448
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes