* 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 hydrogencarbonate In 1,4-dioxane at 20 - 80℃; for 3 h;
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).
72%
at 20 - 80℃; for 3 h;
Step E: 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile To a mixed solvent of 1:1 (v/v) dioxane/H2O (50 mL) at room temperature was added 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (3.6 g,1.0 eq) followed by slow addition of Me2SO4 (2.6 g, 1.5 eq). After completion of addition, the reaction mixture was heated to 80 °C and stirred for 3 hours. After completion of the reaction, the solvent was removed with rotate evaporation, water was added, and the mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous Na2SO4, and isolated through silica gel column chromatography to provide the product as a colorless oil (2.7 g, 72percent). 1H NMR (400 MHz, CDCl3) δ 7.48-7.51 (m, 2H), 7.41-7.45 (m, 2H), 7.25-7.27 (m, 1H), 7.07-7.11 (m, 4H), 3.99 (s, 3H).
48%
With sodium hydrogencarbonate In 1,4-dioxane; water at 0 - 80℃; for 14 h;
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).
86 g
With sodium carbonate In 1,4-dioxane at 0 - 75℃; for 5 h;
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.
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; methanol; acetonitrile at 0 - 20℃; for 48 h; Inert atmosphere
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.
15 g
With N-ethyl-N,N-diisopropylamine In methanol; acetonitrile at 0 - 20℃; for 48 h; Inert atmosphere
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 2g 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 oil.
22.5 g
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; methanol; acetonitrile at 0 - 20℃; for 48 h; Inert atmosphere
(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 oil
Stage #1: With sodium hydride In tetrahydrofuran; paraffin oil at 20℃; for 2 h; Stage #2: With hydrogenchloride In tetrahydrofuran; water; paraffin oil for 0.5 h; Stage #3: With sodium hydrogencarbonate In 1,4-dioxane at 80 - 90℃; for 3 h;
10019] 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.
47.5%
at 75℃; for 16 h;
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.
47.5%
at 75℃; for 16 h;
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
47.5%
at 75℃; for 16 h;
2-(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.
25 g
at 75℃; for 16 h;
[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.
25 g
at 75℃; for 16 h;
A solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8 mmol) in CH(OMe)3 (500 mL) was heated to 75° C. for 16 hr. Then the mixture was 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. 1H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J=8.4 Hz, 2H), 7.52-7.45 (m, 2H), 7.28 (t, J=7.6 Hz, 1H), 7.22-7.06 (m, 4H), 3.93 (s, 3H). MS (ESI) m/e [M+1]+ 276.9.
25 g
at 75℃; for 16 h;
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(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.
25 g
at 75℃; for 16 h;
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(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.
25 g
at 75℃; for 16 h;
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(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.
25 g
at 75℃; for 16 h;
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.
25 g
at 75℃; for 16 h;
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.
25 g
at 75℃; for 16 h;
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.
71.7 kg
at 85℃; Large scale
Under 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. 1H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J 8.4 Hz, 2H) , 7.52-7.45 (m, 2H) , 7.28 (t, J 7.6 Hz, 1H) , 7.22-7.06 (m, 4H) , 3.93 (s, 3H) .
71.7 kg
at 85℃; Inert atmosphere; Large scale
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.
25 g
at 75℃; for 16 h;
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.
Stage #1: With sodium hydride In tetrahydrofuran for 1 h; Stage #2: at -10℃; for 0.5 h; Stage #3: for 8 h; Reflux
0.25 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.
Reference：
[1] Patent: CN107233344, 2017, A, . Location in patent: Paragraph 0035; 0036; 0037
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 oil.
3-amino-5-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrazine; In ethanol; for 1h;Heating / reflux;
<strong>[330792-69-3]1,1-Dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene</strong> (22.5 g) and <strong>[330792-69-3]<strong>[330792-69-3]1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethen</strong>e</strong> oil (15 g) are treated with a solution of hydrazine hydrate (18 mL) in ethanol (25 mL) and heated on the steambath for 1 hour. Ethanol (15 mL) is added followed by water (10 mL). The precipitated solid is collected and washed with ethanol:water (4:1) and then dried in air to give 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole as a pale orange solid.
With hydrazine; In ethanol; for 1h;Heating / reflux;
<strong>[330792-69-3]1,1-Dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene</strong> (22.5 g) and <strong>[330792-69-3]<strong>[330792-69-3]1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethen</strong>e</strong> oil (15 g) are treated with a solution of hydrazine hydrate (18 mL) in ethanol (25 mL) and heated on the steambath for 1 hour. Ethanol (15 mL) is added followed by water (10 mL). The precipitated solid is collected and washed with ethanol:water (4:1) and then dried in air to give 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole as a pale orange solid.
With hydrazine hydrate; In ethanol; for 1h;Heating;
<strong>[330792-69-3]1,1-Dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene</strong> (22.5 g) and <strong>[330792-69-3]<strong>[330792-69-3]1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethen</strong>e</strong> oil (15 g) are treated with a solution of hydrazine hydrate (18 mL) in ethanol (25 mL) and heated on the steambath for 1 hour. Ethanol (15 mL) is added followed by water (10 mL). The precipitated solid is collected and washed with ethanol:water (4:1) and then dried in air to give 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole as a pale orange solid.
With hydrazine hydrate; In ethanol; for 1h;
l,l-Dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene (22.5 g) and 1 , 1 -dicyano-2-methoxy-2- (4-phenoxyphenyl)ethene oil (15 g) are treated with a solution of hydrazine hydrate (18 mL) in ethanol (25 mL) and heated on the steambath for 1 h. Ethanol (15 mL) is added followed by water (10 mL). The precipitated solid is collected and washed with ethanol: water (4:1) and then dried in air to give 3-amino-4- cyano-5-(4-phenoxyphenyl)pyrazole as a pale orange solid.
With hydrazine hydrate; In ethanol; water; for 1h;Heating;
<strong>[330792-69-3]1,1-Dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene</strong> (22.5 g) and <strong>[330792-69-3]<strong>[330792-69-3]1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethen</strong>e</strong> oil (15g) are treated with a solution of hydrazine hydrate (18 mL) in ethanol (25 mL) and heated on the steambath for 1 hour. Ethanol (15 mL) is added followed by water (10 mL). The precipitated solid is collected and washed with ethanol:water (4:1) and then dried in air to give 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole as a pale orange solid.
With hydrazine hydrate; In ethanol; for 1h;Heating;
<strong>[330792-69-3]1,1-Dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene</strong> (22.5 g) and <strong>[330792-69-3]<strong>[330792-69-3]1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethen</strong>e</strong> oil (15 g) are treated with a solution of hydrazine hydrate (18 mL) in ethanol (25 mL) and heated on the steambath for 1 hour. Ethanol (15 mL) is added followed by water (10 mL). The precipitated solid is collected and washed with ethanol:water (4:1) and then dried in air to give 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole as a pale orange solid.
45 g
With hydrazine hydrate; In methanol; at 25 - 30℃; for 2h;
80% Hydrazine hydrate (32.5 ml) was added to a mixture of 2-(methoxy(4- phenoxyphenyl)methylene)malononitrile (48 gms) and methanol (192 ml) at 25-30C and stirred for 2 brs at the same temperature. Water was added to the reaction mixture at 25-30C. Cooled the reaction mixture to 0-5C and stirred for 60 mins at the same temperature.Filtered the precipitated solid, washed with water and dried to get the title compound.Yield: 46 gms; Melting range: 172-176C; purity: 96.89%
6 g
With hydrazine hydrate; In ethanol; for 1h;Reflux;
l,l-Dicyano-2-methoxy-2-(4-phenoxyphenyl)ethen (6 g) was suspended in ethanol (25 mL) and hydrazine hydrate (6 g) was added. After 1 h of reflux the forming precipitate was filtered and washed with ethanol/water (1/4 mixture). 6g (92%) of 3- amino-4-cyano-5-(4-phenoxyphenyl)pyrazole were obtained.
With hydrazine hydrate; In ethanol; at 80℃; for 1h;
Preparation steps: IB-E was added to the reaction vessel, and 80% hydrazine hydrate was added to the ethanol solution. After the addition was completed, the reaction mixture was mixed.The mixture was refluxed at 80 C. for 1 h and concentrated under reduced pressure to recover ethanol. Crystals were added with water, centrifuged, and dried to give solid IB-F.
1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene oil[ No CAS ]
[ 330792-69-3 ]
3-amino-5-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrazine hydrate; In ethanol; water;
3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (Intermediate AB) <strong>[330792-69-3]1,1-Dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene</strong> (Intermediate AA) (22.5 g) and <strong>[330792-69-3]<strong>[330792-69-3]1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethen</strong>e</strong> oil (15 g) were treated with a solution of 18 mL hydrazine hydrate in 25 mL ethanol and heated on the steambath for 1 hour, 15 mL ethanol added followed 10 mL water. The precipitated solid was collected and washed with 4:1 ethanol:water then dried in air giving 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole as a pale orange solid 30.0 g (80%) m.p. 187-188.5 C. 1H NMR (DMSO-d6, 400 MHz) 12.11 (broad s, 1H), 7.80 (d, 2H), 7.42 (m, 2H), 7.18 (m, 1H), 7.09 (m, 4H), 6.47 (broad s, 2H). Calculated for C16H12N4O C, 69.6; H, 4.3; N, 20.3; Found C, 69.5; H, 4.4; N, 20.2
With hydrazine hydrate; In ethanol; water;
3-Amino-4-Cyano-5-(4-phenoxyphenyl)pyrazole (Intermediate AB) <strong>[330792-69-3]1,1-Dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene</strong> (Intermediate AA) (22.5 g) and <strong>[330792-69-3]<strong>[330792-69-3]1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethen</strong>e</strong> oil (15 g) were treated with a solution of 18 mL hydrazine hydrate in 25 mL ethanol and heated on the steambath for 1 hour, 15 mL ethanol added followed 10 mL water. The precipitated solid was collected and washed with 4:1 ethanol:water then dried in air giving 3-amino-4-Cyano-5-(4-phenoxyphenyl)pyrazole as a pale orange solid 30.0 g (80%) m.p. 187-188.5 C. 1H NMR (DMSO-d6, 400 MHz) 12.11 (broad s, 1H), 7.80 (d, 2H), 7.42 (m, 2H), 7.18 (m, 1H), 7.09 (m, 4H), 6.47 (broad s, 2H). Calculated for C16H12N4O C, 69.6; H, 4.3; N, 20.3; Found C, 69.5; H, 4.4; N, 20.2.
2-[hydroxy-(4-phenoxy-phenyl)-methylene]-malononitrile[ No CAS ]
[ 330792-69-3 ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; methanol; ethyl acetate; acetonitrile;
1,1-Dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene (Intermediate AA) 1,1-Dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene (Intermediate Z) (56.5 g) in 780 mL acetonitrile and 85 mL methanol was stirred under nitrogen at 0 C. while adding 52.5 mL diisopropylethylamine then 150 mL 2M-trimethylsilyldiazomethane in THF. After stirring for 2 days at 20 C., 2 g silica for chromatography was added: no further evolution of nitrogen was noted. The brown-red solution was evaporated in vacuo, the residue dissolved in ethyl acetate and washed well with water then brine, dried and evaporated. The residue was extracted with diethyl ether (3*250 mL), decanting from insoluble oil. Evaporation of the ether extracts gave 22.5 g of 1,1-Dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene as a pale orange solid almost pure by t.l.c. (3:2 ethyl acetate:cyclohexane). The insoluble oil was purified by flash chromatography giving 15.0 g red-orange oil. Combined yield (63%) 1H NMR (DMSO-d6, 400 MHz) 7.71 (d, 2H), 7.48 (m, 2H), 7.29 (m, 1H), 7.16 (m, 4H), 3.93 (s, 3H).
2-[hydroxy-(4-phenoxy-phenyl)-methylene]-malononitrile[ No CAS ]
[ 18107-18-1 ]
[ 330792-69-3 ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; methanol; acetonitrile; at 20℃; for 48h;
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 oil.
15 g
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; methanol; acetonitrile; at 0 - 20℃; for 48h;Inert atmosphere;
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 0C while adding diisopropylethylamine (52.5 mL) followed by 2M trimethylsilyldiazomethane (150 mL) in THF. The reaction is stirred for 2 days at 20C, 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.
15 g
With N-ethyl-N,N-diisopropylamine; In methanol; acetonitrile; at 0 - 20℃; for 48h;Inert atmosphere;
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 2g 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 oil.
22.5 g
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; methanol; acetonitrile; at 0 - 20℃; for 48h;Inert atmosphere;
(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 oil
2-[hydroxy-(4-phenoxy-phenyl)-methylene]-malononitrile[ No CAS ]
[ 77-78-1 ]
[ 330792-69-3 ]
Yield
Reaction Conditions
Operation in experiment
88%
With sodium hydrogencarbonate; In 1,4-dioxane; at 20 - 80℃; for 3h;
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, 88%). ?H NMR (400 MHz, CDC13) oe 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).
72%
In 1,4-dioxane; water; at 20 - 80℃; for 3h;
Step E: 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile To a mixed solvent of 1:1 (v/v) dioxane/H2O (50 mL) at room temperature was added 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (3.6 g,1.0 eq) followed by slow addition of Me2SO4 (2.6 g, 1.5 eq). After completion of addition, the reaction mixture was heated to 80 C and stirred for 3 hours. After completion of the reaction, the solvent was removed with rotate evaporation, water was added, and the mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous Na2SO4, and isolated through silica gel column chromatography to provide the product as a colorless oil (2.7 g, 72%). 1H NMR (400 MHz, CDCl3) delta 7.48-7.51 (m, 2H), 7.41-7.45 (m, 2H), 7.25-7.27 (m, 1H), 7.07-7.11 (m, 4H), 3.99 (s, 3H).
48%
With sodium hydrogencarbonate; In 1,4-dioxane; water; at 0 - 80℃; for 14h;
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 0C 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 80C 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, 48%). 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).
86 g
With sodium carbonate; In 1,4-dioxane; at 0 - 75℃; for 5h;
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 0-5C. Heated the reaction mixture to 70-75C and stirred for 5 hrs. Cooled thereaction mixture to 25-30C. 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 25-30C. The reaction mixture was cooled to 0-5C 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: 70-75C.
With sodium hydrogencarbonate; In 1,4-dioxane; water; for 2h;Reflux;
. l,l-Dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene (11 g) and NaHC03 (28 g) were suspended in a mixture of 1,4-Dioxane (70 mL) and H2O (11 mL). Dimethylsulfate (29 niL) was added dropwise under vigorous stirring. The mixture was refluxed for 2 h and treated with cold water. The mixture was extracted with EtOAc (3x30 mL) and the combined extracts were dried over Na2SC>4. Evaporation of the solvent under reduced pressure gives 11 ,5g crude product as dark brown oil. After the treatment of the crude product with cold ethanol at 5-10C 6.5 g (57%) of l,l-dicyano-2-methoxy-2- (4-phenoxyphenyl)ethen were obtained (compound D).
With sodium hydrogencarbonate; In toluene; at 25 - 90℃;
Dimethyl sulfate (200ml) and sodium bicarbonate (200g) were added to the resulting organic layer at a temperature of 25-30C. Thereafter, temperature of reaction mass was raised to 80-90C and reaction mass was stirred for 1-2 hours. After completion of reaction, the reaction mass was cooled to a temperature of 25-30C, demineralized water (2000ml) was added and stirred for 10-15 minutes. The layers were separated and the aqueous layer was extracted with toluene (1000ml). All the organic layers were combined and washed with sodium chloride solution (10%). Activated carbon (20g) was added and reaction mixture was stirred for 30 minutes. The solution was filtered through hyflo bed and to the resulting organic layer hydrazine hydrate (120ml) was added at a temperature of 25-30C. During the addition exothermicity was observed, and temperature of the reaction mass was rose up to 40-50C. Thereafter, the reaction mass was stirred at a temperature of 25-30C for 1-2 hours. The resulting precipitated solid was filtered, slurry washed with dichloromethane (400ml) and finally, dried to obtain title compound of formula V (140g) purity 93.28% measured by HPLC.
With potassium carbonate; In 1,4-dioxane; at 70℃; for 2h;
Preparation steps: Add IB-D, dioxane, potassium carbonate and dimethyl sulfate to the reaction vessel. After the addition,The reaction mixture is heated to 70 C., stirred for 2 hours, and concentrated under reduced pressure to recover dioxane and add water.After extraction with ethyl acetate, the organic extract was washed with water and concentrated under reduced pressure to recover ethyl acetate to give a crude product.Recrystallization with 1:1 heptane/ethyl acetate, centrifugation, and drying gave the product IB-E as a pale yellow solid.
With hydrazine hydrate; In ethanol; at 20 - 90℃; for 4h;Reflux;
Step F: 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile To 50 mL of EtOH at room temperature was added 2-(methoxy(4-phenoxyphenyl) methylene)malononitrile (1 g, 1.0 eq) followed by slow addition of hydrazine hydrate (0.5 g, 85%, 2.0 eq). After completion of addition, the reaction mixture was heated to 90 C and refluxed for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was removed with rotate evaporation. Water (50 mL) was added and the mixture was stirred at room temperature for 5 minutes. The white solid thus precipitated was collected and dried as the product (1.0 g, 99%). 1H NMR (400 MHz, DMSO) delta 7.78-7.81 (m, 2H), 7.40-7.44 (m, 2H), 7.16-7.20 (m, 1H), 7.06-7.11 (m, 4H), 6.26 (brs, 2H).
88%
With hydrazine hydrate; In ethanol; at 20 - 90℃; for 2h;
To a stirred solution of <strong>[330792-69-3]2-(methoxy(4-phenoxyphenyl)methylene)malononitrile</strong> (78.5 g, 1.0 eq) in 400 mL EtOH at r.t. was added hydrazine hydrate (50 mL, 85%, 3.0 eq). After addition was completed, the reaction was refluxed at 90 C for 2 h. The mixture was concentrated to crude product and recrystallized in hexane to give pure product as a white solid (72.4 g, 88%). ?H NMR (400 MHz, DMSO) oe 7.78-7.8 1 (m,2H), 7.40-7.44 (m, 2H), 7.16-7.20 (m, 1H), 7.06-7.11 (m, 4H), 6.26 (brs, 2H).
68.8%
With hydrazine hydrate; In ethanol; at 20℃; for 16h;
[0175] To a solution of 2-(methoxy( 4-phenoxyphenyl)methylene )malononitrile (80 g, 290mmol) in ethanol (200 mL) was added hydrazine hydrate (20 mL). The mixture was stirred atRT for I6 hr then was concentrated to give the crude product and washed with MeOH (30 mL)to afford 55 g (68.8%) of 5-amino-3-(4-phenoxyphenyl)- IH-pyrazole-4-carbonitrile as a offwhitesolid. 1H NMR (DMSO-d6) 8 I2.11 (br s, IH), 7.80 (d, J = 8.8 Hz, 2H), 7.46-7.39 (m,2H), 7.I8 (t, J = 7.6 Hz, IH), 7.I2-7.04 (m, 4H), 6.43 (br s, 2H).
68.8%
With hydrazine hydrate; In ethanol; at 20℃; for 16h;
To a solution of <strong>[330792-69-3]2-(methoxy(4-phenoxyphenyl)methylene)malononitrile</strong> (80 g, 290 mmol) in ethanol (200 mL) was added hydrazine hydrate (20 mL). The mixture was stirred at RT for 16 hr then was concentrated to give the crude product and washed with MeOH (30 mL) to afford 55 g (68.8%) of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile as a off-white solid. 1H NMR (400 MHz, DMSO-d6) delta 12.11 (br s, 1H), 7.80 (d, J=8.8 Hz, 2H), 7.46-7.39 (m, 2H), 7.18 (t, J=7.6 Hz, 1H), 7.12-7.04 (m, 4H), 6.43 (br s, 2H).
68.8%
With hydrazine hydrate; In ethanol; at 20℃; for 16h;
To a solution of <strong>[330792-69-3]2-(methoxy(4-phenoxyphenyl)methylene)malononitrile</strong> (80 g, 290mmol) in ethanol (200 mL) is added hydrazine hydrate (20 mL). The mixture is stirred at RT for16 hours then is concentrated to give the crude product and washed with MeOH (30 mL) toafford 55 g (68.8%) of 5 -amino-3 -(4-phenoxyphenyl)- 1H-pyrazole-4-carbonitrile as a off-whitesolid.
68.8%
With hydrazine hydrate; In ethanol; at 20℃; for 16h;
To a solution of <strong>[330792-69-3]2-(methoxy(4-phenoxyphenyl)methylene)malononitrile</strong> (80 g, 290mmol) in ethanol (200 mL) is added hydrazine hydrate (20 mL). The mixture is stirred at RT for16 hours then is concentrated to give the crude product and washed with MeOH (30 mL) toafford 55 g (68.8%) of 5 -amino-3 -(4-phenoxyphenyl)- 1H-pyrazole-4-carbonitrile as a off-whitesolid.
68.8%
With hydrazine hydrate; In ethanol; at 20℃; for 16h;
Step 3. Preparation of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile: To a solution of <strong>[330792-69-3]2-(methoxy(4-phenoxyphenyl)methylene)malononitrile</strong> (80 g, 290 mmol) in ethanol (200 mL) is added hydrazine hydrate (20 mL). The mixture is stirred at RT for 16 hours then is concentrated to give the crude product and washed with MeOH (30 mL) to afford 55 g (68.8%) of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile as a off-white solid.
68.8%
With hydrazine hydrate; In ethanol; at 20℃; for 16h;
Step 3. Preparation of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile: To a solution of <strong>[330792-69-3]2-(methoxy(4-phenoxyphenyl)methylene)malononitrile</strong> (80 g, 290 mmol) in ethanol (200 mL) is added hydrazine hydrate (20 mL). The mixture is stirred at RT for 16 hours then is concentrated to give the crude product and washed with MeOH (30 mL) to afford 55 g (68.8%) of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile as a off-white solid.
68.8%
With hydrazine hydrate; In ethanol; at 20℃; for 16h;
Step 3. Preparation of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile: To a solution of <strong>[330792-69-3]2-(methoxy(4-phenoxyphenyl)methylene)malononitrile</strong> (80 g, 290 mmol) in ethanol (200 mL) is added hydrazine hydrate (20 mL). The mixture is stirred at RT for 16 hours then is concentrated to give the crude product and washed with MeOH (30 mL) to afford 55 g (68.8%) of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile as a off-white solid.
68.8%
With hydrazine hydrate; In ethanol; at 20℃; for 16h;
To a solution of <strong>[330792-69-3]2-(methoxy(4-phenoxyphenyl)methylene)malononitrile</strong> (80 g, 290 mmol) in ethanol (200 mL) is added hydrazine hydrate (20 mL). The mixture is stirred at RT for 16 hours then is concentrated to give the crude product and washed with MeOH (30 mL) to afford 55 g (68.8%) of 5-amino-3-(4-phenoxyphenyl)-lH-pyrazole-4-carbonitrile as a off-white solid.
68.8%
With hydrazine hydrate; In ethanol; at 20℃; for 16h;
To a solution of <strong>[330792-69-3]2-(methoxy(4-phenoxyphenyl)methylene)malononitrile</strong> (80 g, 290 mmol) in ethanol (200 mL) is added hydrazine hydrate (20 mL). The mixture is stirred at RT for 16 hours then is concentrated to give the crude product and washed with MeOH (30 mL) to afford 55 g (68.8%) of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile as a off-white solid.
68.8%
With hydrazine hydrate; In ethanol; at 20℃; for 16h;
To a solution of <strong>[330792-69-3]2-(methoxy(4-phenoxyphenyl)methylene)malononitrile</strong> (80 g, 290 mmol) in ethanol (200 mL) is added hydrazine hydrate (20 mL). The mixture is stirred at RT for 16 hours then is concentrated to give the crude product and washed with MeOH (30 mL) to afford 55 g (68.8%) of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile as a off-white
68.8%
With hydrazine hydrate; In ethanol; at 20℃; for 16h;
Step 3. Preparation of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile To a solution of <strong>[330792-69-3]2-(methoxy(4-phenoxyphenyl)methylene)malononitrile</strong> (80 g, 290 mmol) in ethanol (200 mL) is added hydrazine hydrate (20 mL). The mixture is stirred at RT for 16 hours then is concentrated to give the crude product and washed with MeOH (30 mL) to afford 55 g (68.8%) of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile as an off-white solid.
68.8%
With hydrazine hydrate; In ethanol; at 20℃; for 16h;
To a solution of <strong>[330792-69-3]2-(methoxy(4-phenoxyphenyl)methylene)malononitrile</strong> (80 g, 290 mmol) in ethanol (200 mL) was added hydrazine hydrate (20 mL).The mixture was stirred at room temperature for 16 hours.The mixture was concentrated to give a crude product, which was washed with MeOH (30 mL).An off-white solid 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (55 g, 68.8%) was obtained.
68.8%
With hydrazine hydrate; In ethanol; at 20℃; for 16h;
To a solution of <strong>[330792-69-3]2-(methoxy(4-phenoxyphenyl)methylene)malononitrile</strong> (80 g, 290 mmol) in ethanol (200 mL) is added hydrazine hydrate (20 mL). The mixture is stirred at RT for 16 hours then is concentrated to give the crude product and washed with MeOH (30 mL) to afford 55 g (68.8%) of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile as a off-white solid.
68.8%
With hydrazine hydrate; In ethanol; at 20℃; for 16h;
To a solution of <strong>[330792-69-3]2-(methoxy(4-phenoxyphenyl)methylene)malononitrile</strong> (80 g, 290 mmol) in ethanol (200 mL) is added hydrazine hydrate (20 mL). The mixture is stirred at RT for 16 hours then is concentrated to give the crude product and washed with MeOH (30 mL) to afford 55 g (68.8%) of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile as a off-white solid.
With hydrazine hydrate; In toluene; at 25 - 50℃;
Dimethyl sulfate (200ml) and sodium bicarbonate (200g) were added to the resulting organic layer at a temperature of 25-30C. Thereafter, temperature of reaction mass was raised to 80-90C and reaction mass was stirred for 1-2 hours. After completion of reaction, the reaction mass was cooled to a temperature of 25-30C, demineralized water (2000ml) was added and stirred for 10-15 minutes. The layers were separated and the aqueous layer was extracted with toluene (1000ml). All the organic layers were combined and washed with sodium chloride solution (10%). Activated carbon (20g) was added and reaction mixture was stirred for 30 minutes. The solution was filtered through hyflo bed and to the resulting organic layer hydrazine hydrate (120ml) was added at a temperature of 25-30C. During the addition exothermicity was observed, and temperature of the reaction mass was rose up to 40-50C. Thereafter, the reaction mass was stirred at a temperature of 25-30C for 1-2 hours. The resulting precipitated solid was filtered, slurry washed with dichloromethane (400ml) and finally, dried to obtain title compound of formula V (140g) purity 93.28% measured by HPLC.
66.9 kg
With hydrazine hydrate; In ethanol; at 15 - 20℃;Inert atmosphere; Large scale;
Under nitrogen atmosphere, to a solution of BG-3 (71.6 kg, 1.0 eq. ) in ethanol (2.5 v) hydrazinium hydroxide (1.0 eq) in ethanol (0.6 v) was charged dropwise to the reactor below 15. The solution was heated to RT and stirred until the reaction was completed. Water (4.0 v) was added to the reactor. The solution was then cooled to 5, centrifuged and the cake was washed with water (1.0 v) . The cake was dried under vacuum. This gave 66.9 Kg of product. 1H NMR (DMSO-d6) delta 12.11 (br s, 1H) , 7.80 (d, J 8.8 Hz, 2H) , 7.46-7.39 (m, 2H) , 7.18 (t, J 7.6 Hz, 1H) , 7.12-7.04 (m, 4H) , 6.43 (br s, 2H) .
66.9 kg
With hydrazine; In ethanol; at 15 - 20℃;Inert atmosphere; Large scale;
In a nitrogen atmosphere, below 15 C into the reactor,To BG-3 (71.6 kg, 1.0 eq.) in ethanol (2.5 v)The solution in the solution is added with hydrazine(1.0 eq.) a solution in ethanol (0.6 v). The solution was warmed to room temperature and stirred until the reaction was complete. Water (4.0 v) was added to the reactor. The solution was then cooled to 5 C, centrifuged and the filter cake was washed with water (1.0 v). The filter cake was dried under vacuum. This gave 66.9 Kg of product.
66.9 kg
With hydrazine hydrate; In ethanol; at 15 - 20℃;Inert atmosphere; Large scale;
[0108] Under nitrogen atmosphere, to a solution of BG-3 (71.6 kg, 1.0 eq.) in ethanol (2.5 v) hydrazinium hydroxide (1.0 eq) in ethanol (0.6 v) was charged dropwise to the reactor below 15C. The solution was heated to RT and stirred until the reaction was completed. Water (4.0 v) was added to the reactor. The solution was then cooled to 5C, centrifuged and the cake was washed with water (1.0 v). The cake was dried under vacuum. This gave 66.9 Kg of product. 1H NMR (DMSO-de) delta 12.11 (br s, 1H), 7.80 (d, J= 8.8 Hz, 2H), 7.46-7.39 (m, 2H), 7.18 (t, J = 7.6 Hz, 1H), 7.12-7.04 (m, 4H), 6.43 (br s, 2H).
2-[hydroxy-(4-phenoxy-phenyl)-methylene]-malononitrile[ No CAS ]
[ 330792-69-3 ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; diazomethyl-trimethyl-silane; In tetrahydrofuran; acetonitrile; at 0 - 20℃; for 48h;Inert atmosphere;
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 oil.
General procedure: Step 4: preparation of 2-((4-(4-chloro-3-methylphenoxy)phenyl)(methoxy)methylene)-malononitrile. A solution of malononitrile(252 mg, 3.81 mmol) in anhydrous tetrahydrofuran (3 mL) was added to a suspension ofsodium hydride (183 mg, 3.807 mmol) in tetrahydrofuran (15 mL) at 0C. A solution of 4- (4-chloro-3-methylphenoxy)benzoyl chloride (1.0 g, 3.81 mmol) in tetrahydrofuran (5 mL) was then added drop wise over 10 mm. The mixture was then treated with dimethyl sulfate and heated to reflux for 3h, after which it was quenched with saturated aqueousammonium chloride and extracted into ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo to afford the title compound as an oil.
30
[ 330792-69-3 ]
5-amino-1-(2-cyano-2-azabicyclo[2.2.1]hept-5-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide[ No CAS ]
Step 9: preparation of benzyl 3-[5-amino-4-cyano-3-(4-phenoxy-phenyl)-pyrazol- 1 -yl]-pi peridine- 1 -carboxylate. To a solution of 2-[(4-phenoxy-phenyl )-methoxymethylene]-malononitrile (step 3; 146 g, 0.53 mol) in ethanol (500 mL) was added benzyl 3-hydrazino-piperidine-1-carboxylate (step 8; 150.6g, 0.53 mol) and triethylamine5 (1 07g, 1 .05 mol), causing the temperature of the solution to reach 55C. The reaction was then allowed to cool to ambient temperature over 16 h, after which a precipitate had formed. The precipitate was filtered off and added to 2-methyl tetrahydrofuran (3.5 L), which dissolved the desired product, leaving behind triethyl aminehydrochloric acid, which was then removed by vacuum filtration. The filtrate was then washed with brine10 L) and concentrated in vacuo to afford the title compound as a white solid. MS (M+H) m/z 494.
benzyl 5-hydrazinyl-2-azabicyclo[2.2.1]heptane-2-carboxylate[ No CAS ]
benzyl 5-(5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80.1%
With triethylamine; In ethanol; at -10 - 20℃; for 2h;
Step 6: preparation of benzyl 5-(5-ami no-4-cyano-3-(4-phenoxyphenyl )-1 Hpyrazol- 1 -yl)-2-azabicyclo[2.2. 1 ]heptane-2-carboxylate. To a solution of benzyl 5-hydrazinyl-2-azabicyclo[2.2.i]heptane-2-carboxylate (6.5 g, 0.017 mol) and 2-[(4- phenoxy-phenyl)-methoxy-methylene]-malononitrile (Example I, Step 3) (4.78 g, 0.017 mol) in ethanol (200 mL) was added triethylamine (5 mL, 0.035 mol) at -10 C. The mixture was stirred at room temperature for 2 h and then filtered to afford the titlecompound (7.0 g, 80.1 %) as a white solid.
Step 2: preparation of 2-[hyd roxy-(4-phenoxy-phenyl)-methylene]-malonon itrile.solution of malononitrile (154 mL, 2.55 mol) in anhydrous tetrahydrofuran (500 mL)was added drop wise under nitrogen to a suspension of sodium hydride (205 g, 5.12 mol) in tetrahydrofuran (2 L) over 1 .5 h at 0C. The reaction mixture was allowed to stir for an additional 30 mm, after which addition of a solution of 4-phenoxy benzoyl chloride (540 g, 2.32 mol) in tetrahydrofuran (750 mL) was added. The reaction was then allowed to stir for 16 h at ambient temperature, cooled to 0C and quenched with 1 Nhydrochloric acid (1 L). Product was extracted into ethyl acetate and the combined organic layers were washed with water, then brine, dried over sodium sulfate, and concentrated in vacuo to afford the title compound as an off-white solid, which was carried on to the next step without purification. MS (M-H) m/z 261. 1H NMR (CDCI3) 6 7.74 (d, J = 8.8 Hz, 2 H), 7.39 (t, J = 7.6 Hz, 2 H), 7.21 (t, J = 7.2 Hz, 1 H), 7.06 (d, J = 8Hz, 2 H), 7.00 (d, J = 8.8 Hz, 2 H).
To a stirred solution of <strong>[330792-69-3]2-(methoxy(4-phenoxyphenyl)methylene)malononitrile</strong> (225 mg, 1.0 eq) in 20 mL EtOH were added Et3N (164.8 mg, 2.0 eq) and cyclohexyihydrazine hydrochloride (123 mg, 1.0 eq). After addition was completed, the reaction was stirred at 90 C overnight. The mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried and concentrated. The residue was purified with silica gel chromatography (petrol ether:EtOAc = 5/1 to 3/1) to give the product (148 mg, 50%). 1HNMR (400 MHz, CDC13) oe7.89-7.91(m, 2H), 7.34-7.38(m, 2H), 7.12-7.15(m, 1H), 7.04-7.07(m, 4H), 4.22(s, 2H), 3.79-3.83(m, 1H), 1.95-2.00(m, 5H), 1.74-1.78(m, 1H), 1.28-1.44(m, 4H). mlz = 359[M+1].
With triethylamine; In tetrahydrofuran; ethanol; water; at 5 - 25℃; for 1h;Inert atmosphere;
Charge 0.41 g (1.0 eq.) of VI (in THF solution). Dissolve 0.32g (1.0 eq.) of X-Boc in EtOH(2V) /H2O(0.5mL, 1.5V)/ Et3N (3.0eq). Add drop-wise X-Boc to Rl at 5-10C. Warm to 25 C under N2 and stir Rl for lh at 25 C. Add water (10V) drop-wise at 5-10 C. Concentrate the mixture under vacuum and extract it with ethyl acetate (20ml*3). Wash the organic phase with H20. Evaporate solvent under vacuum to get crude XI-Boc as yellow oil. The de-Boc compound, Imp-A, was generated as the main product. XI-Boc was obtained in 29% yield with 96% purity by column chromatography
With sodium methylate; In methanol; at 0 - 25℃; for 2h;pH Ca. 9;
Procedure S-l The reaction procedure was followed in accordance with the following steps 1. Dissolve Y20 (0.058g, 1.5eq) in 0.5mL MeOH in a first reaction vessel 2. Add dropwise a MeOH solution of NaOMe into Y20 to adjust pH value to ~9 3. Add Y3 (1.Oeq) and 0.45 niL MeOH into a second reaction vessel 4. Cool the reaction mixture in the second reaction vessel to 0-10C 5. Add dropwise the MeOH solution of Y20 in the first reaction vessel to the reaction mixture in the second reaction vessel at 0-10C 6. Stir the subsequent reaction mixture at 20-25C for 2hrs 7. Cool the reaction mixture to 0-10C 8. Add dropwise 2mL H20 into the reaction mixture (off-white solid separated out) 9. Filter the mixture and dry the product under vacuum
With triethylamine; In ethanol; water; at 5 - 25℃; for 1h;Inert atmosphere;
Charge 4.29 g (1.0 eq.) of VI under N2 with 60mL (13 V.) ethanol and 43ml (10V) of water. Cool the mixture to 5 C. Add X-Cbz in three portions at 5-10 C under N2. Add dropwise 3.15g (2.0.eq.) NEt3 at 5-10 C. Warm to 25C under N2 and stir for 1 h at 25C (solid separate out). Add dropwise 17V H20 into the reaction mixture at 25 C. Cool the reaction mixture 0 -5C and stir for lh. Filter the mixture. The cake was dried under vacuum at 40-45 C to result in 7.79g (100%Yield) with a purity of 99.81% (ESI):m/z =494.1 (M+l)
With triethylamine; In ethanol; water; at 5 - 30℃; for 1h;Inert atmosphere;
Charge 0.496 g (1.0 eq.) of VI under N2 with 4mL (8V.) ethanol. Cool the mixture to 5C. Add X-Bn (dissolve in 5V EtOH and 10V H20) in three portions at 5-10 C under N2. Add dropwise 0.5 lg (2.0.eq.) NEt3 at 5-10 C. Warm to 25-30C under N2 and stir for 1 h at 25-30C (solid separate out). Add dropwise 17V H20 into the reaction mixture at 25 C. Cool the reaction mixture 0 -5C and stir for lh. Filter the mixture. The cake was dried under vacuum at 40-45 C to yield 0.65g of XI-Bn (80% Yield) with 94.03% purity. (ESI):m/z =450 (M+l)
2-[hydroxy-(4-phenoxy-phenyl)-methylene]-malononitrile[ No CAS ]
[ 149-73-5 ]
[ 330792-69-3 ]
Yield
Reaction Conditions
Operation in experiment
47.5%
at 75℃; for 16h;
[001 63j A solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8 mmol) in CH(OMe3) (500 mL) is heated to 75C for 16 hours. Then the mixture is concentrated to a residue and washed with MeOH (50 mL) to give 25 g (47.5%) of 2-(methoxy(4- phenoxyphenyl)methylene)malononitrile as a yellow solid.
47.5%
at 75℃; for 16h;
A solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8 mmol) in CH(OMe3) (500 mL) is heated to 75C for 16 hours. Then the mixture is concentrated to a residue and washed with MeOH (50 mL) to give 25 g (47.5%) of 2-(methoxy(4- phenoxyphenyl)methylene)malononitrile as a yellow solid.
47.5%
at 75℃; for 16h;
A solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8 mmol) in CH(OMe3) (500 mL) is heated to 75C for 16 hours. Then the mixture is concentrated to a residue and washed with MeOH (50 mL) to give 25 g (47.5%) of 2-(methoxy(4- phenoxyphenyl)methylene)malononitrile as a yellow solid
47.5%
at 75℃; for 16h;
2-(Hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8 mmol) was added to trimethyl orthoformate (500 mL). Heat to 75C 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, 47.5%) was obtained.
25 g
at 75℃; for 16h;
[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 (47.5%) 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.
25 g
at 75℃; for 16h;
A solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8 mmol) in CH(OMe)3 (500 mL) was heated to 75 C. for 16 hr. Then the mixture was concentrated to a residue and washed with MeOH (50 mL) to give 25 g (47.5%) of 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile as a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 7.70 (d, J=8.4 Hz, 2H), 7.52-7.45 (m, 2H), 7.28 (t, J=7.6 Hz, 1H), 7.22-7.06 (m, 4H), 3.93 (s, 3H). MS (ESI) m/e [M+1]+ 276.9.
25 g
at 75℃; for 16h;
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(OMe3) (500 mL) is heated to 75C for 16 hours. Then the mixture is concentrated to a residue and washed with MeOH (50 mL) to give 25 g (47.5%) of 2-(methoxy(4- phenoxyphenyl)methylene)malononitrile as a yellow solid.
25 g
at 75℃; for 16h;
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(OMe3) (500 mL) is heated to 75C for 16 hours. Then the mixture is concentrated to a residue and washed with MeOH (50 mL) to give 25 g (47.5%) of 2-(methoxy(4- phenoxyphenyl)methylene)malononitrile as a yellow solid.
25 g
at 75℃; for 16h;
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(OMe3) (500 mL) is heated to 75C for 16 hours. Then the mixture is concentrated to a residue and washed with MeOH (50 mL) to give 25 g (47.5%) of 2-(methoxy(4- phenoxyphenyl)methylene)malononitrile as a yellow solid.
25 g
at 75℃; for 16h;
A solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8 mmol) in CH(OMe3) (500 mL) is heated to 75C for 16 hours. Then the mixture is concentrated to a residue and washed with MeOH (50 mL) to give 25 g (47.5%) of 2-(methoxy(4- phenoxyphenyl)methylene)malononitrile as a yellow solid.
25 g
at 75℃; for 16h;
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 (47.5%) of 2-(methoxy(4- phenoxyphenyl)methylene)malononitrile as a yellow solid.
25 g
at 75℃; for 16h;
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 (47.5%) of 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile as a yellow solid.
71.7 kg
In acetonitrile; at 85℃;Large scale;
Under 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. 1H NMR (400 MHz, DMSO-d6) delta 7.70 (d, J 8.4 Hz, 2H) , 7.52-7.45 (m, 2H) , 7.28 (t, J 7.6 Hz, 1H) , 7.22-7.06 (m, 4H) , 3.93 (s, 3H) .
71.7 kg
In acetonitrile; at 85℃;Inert atmosphere; Large scale;
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.
25 g
at 75℃; for 16h;
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 (47.5%) of 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile as a yellow solid.
71.7 kg
In acetonitrile; at 85℃;Inert atmosphere; Large scale;
[0107] Under 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 85C. 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. 1H NMR (400 MHz, DMSO-de) delta 7.70 (d, J= 8.4 Hz, 2H), 7.52-7.45 (m, 2H), 7.28 (t, J= 7.6 Hz, lH), 7.22- 7.06 (m, 4H), 3.93 (s, 3H).
25 g
at 75℃; for 16h;
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 (47.5%) of 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile as a yellow solid.
ethyl 1‐benzyl‐4‐hydrazinylpiperidine‐4‐carboxylate hydrochloride[ No CAS ]
4-(5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)-1-benzylpiperidine-4-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34.2%
With triethylamine; In chloroform; for 16h;Inert atmosphere; Reflux;
Under nitrogen protection,1-Benzyl-4-mercapto-4'-carboxylic acid ethyl ester piperidine hydrochloride (580 mg, 1.57 mmol),2-Methoxy(4-phenoxyphenyl)methylene)malononitrile (433 mg, 1.57 mmol)A mixture of TEA (475 mg, 4.71 mmol) in CHCl3 (20 mL) was heated at reflux for 16 hours.The mixture was concentrated and purified on a tannin extract column and eluted with 50% EA in PE to give the desired product as a yellow solid (280 mg 34.2%).
280 mg
With triethylamine; In chloroform; for 16h;Reflux; Inert atmosphere;
[0365] A mixture of ethyl 1-benzyl-4-hydrazinylpiperidine-4-carboxylate hydrochloride (580mg, 1.57 mmol), <strong>[330792-69-3]2-(methoxy(4-phenoxyphenyl)methylene)malononitrile</strong> (433 mg, 1.57 mmol)and TEA (475 mg, 4.71 mmol) in CHCb (20 mL) was heated to reflux for 16 hr under N2? Themixture was concentrated and purified by chromatography column on silica gel using 50% ofEA in PEas eluant to give the product (280 mg 34.2%) as a yellow solid. MS (ESI, m/e) [M+1t521.9.
ethyl 1‐benzyl‐4‐hydrazinylpiperidine‐4‐carboxylate hydrochloride[ No CAS ]
1‐benzyl‐2'‐oxo‐6'‐(4‐phenoxyphenyl)‐1',2'‐dihydrospiro[piperidine‐4,3'‐pyrazolo[1,5‐a]imidazole]‐7'‐carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In methanol; for 16h;Reflux;
[0543] A mixture of ethyl 1-benzyl-4-hydrazinylpiperidine-4-carboxylate hydrochloride (350mg, 1.0 mmol), <strong>[330792-69-3]2-(methoxy(4-phenoxyphenyl)methylene)malononitrile</strong> (276 mg, 1.0 mmol) andK2C03 (414 mg, 3.0 mmol) in MeOH (20 mL) was heated to reflux for 16 hr. The mixture wasfiltered and the filtrate was concentrated to give the crude product (280 mg, 58.9%) as a yellowsolid. MS (ESI, m/e) [M+1t 475.9.
5‐amino‐1‐(3‐bromopyridin‐4‐yl)‐3‐(4‐phenoxyphenyl)‐1H‐pyrazole‐4‐carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
In ethanol;Reflux; Inert atmosphere;
2-(Methoxy(4-phenoxyphenyl)methylene)malononitrile (7.3 g, 0.026 mol)And a mixture of 3-bromo-4-hydrazinopyridine (4.2 g, 0.022 mol) in ethanol (300 mL),The solution was refluxed under nitrogen overnight.The reaction solution was slowly cooled to room temperature and stirred at room temperature for about 4 hours until a solid precipitated.The solids are filtered and collectedThis was washed with n-hexane to give 5-amino-1-(3-bromopyridin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (3.38 g, 35) as a pale yellow solid. %).
3.38 g
In ethanol;Inert atmosphere; Reflux;
[0451] A mixture of <strong>[330792-69-3]2-(methoxy(4-phenoxyphenyl)methylene)malononitrile</strong> (7.3 g, 0.026 mol)and 3-bromo-4-hydrazinylpyridine (4.2 g, 0.022 mol) in ethanol (300 mL) was stirred at refluxunder N2 overnight. The reaction was cooled toRT slowly and stirred at RT for about 4 hr tillsolid precipitated. The solid was filtered, collected and washed with hexane to get 3.38 g (35%)of 5-amino-I-(3-bromopyridin-4-yl)-3- ( 4-phenoxyphenyl)-IH-pyrazole-4-carbonitrile as a lightyellow solid. MS (ESI) m/e [M+ It 431.8, 433.8.
5-amino-1-(2-bromo-5-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
21%
In ethanol; at 70℃;Inert atmosphere;
[0470] To a solution of <strong>[330792-69-3]2-(methoxy(4-phenoxyphenyl)methylene)malononitrile</strong> (392 mg, 1.42mmol) in ethanol (30 mL) was added (2-bromo-5-nitrophenyl)hydrazine (300 mg, 1.29 mmol) inone portion, then the mixture was stirred at 70 C under N2 overnight. The mixture wasconcentrated to dryness and chromatographed on 5 g of silica gel using PE/EA (1 011 to 211) aseluant to afford 128 mg (21 %) of 5-amino-1-(2-bromo- 5-nitrophenyl)-3-(4-phenoxyphenyl)IH-pyrazole-4-carbonitrile as a yellow solid. MS (ESI) m/e [M+ It 476, 478.
21%
In ethanol; at 70℃;Inert atmosphere;
To <strong>[330792-69-3]2-(methoxy(4-phenoxyphenyl)methylene)malononitrile</strong> (392 mg, 1.42 mmol) in ethanol (30 mL),(2-Bromo-5-nitrophenyl)hydrazine (300 mg, 1.29 mmol) was added in one portion.After that, the mixture was stirred overnight under nitrogen protection at 70C.The mixture was concentrated to dryness and purified on a tannin extract column (5 g tannin extract, PE/EA=10/1 to 2/1 elution).This gave a yellow solid 5-amino-1-(2-bromo-5-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (128 mg, 21%).
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