氰基乙醛缩二乙醇

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 100-mL round-bottom flask was charged with 3,3-diethoxypropanenitrile (0.600 g, 4.19 mmol), cyclopropylhydrazine di-hydrochloride (0.610 g, 4.21 mmol) and ethanol (20 mL), and the resulting solution stirred for 18 h at 80° C. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 10:1, dichloromethane/methanol) to afford 1-cyclopropyl-1H-pyrazol-5-amine (0.206 g, 36%) as light yellow oil. MS (ESI, pos. ion) m/z 124 [M+H]+. The reaction mixture was cooled to room temperature concentrated under vacuum The residue was purified via column chromatography on silica gel (eluting with 10:1, dichloromethane/methanol)

反应条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a round bottom flask was added the methane sulfonic acid salt of methyl 1-amino-4-bromo-1H-pyrrole-2-carboxylate (140 g, 0.444 mol), isopropanol (700 mL) and 3,3-diethoxypropionitrile (128 g, 0.888 mol). The reaction mixture was slowly brought to 85° C. over 1 hour and then stirred at 85° C. for 2 hours. At this time, the ethanol that was generated and the isopropanol was removed under vacuum. The resulting residue was dissolved in CH2Cl2 and washed with water and brine solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The resulting residue was transferred into a 2 L round bottom flask and dichloroethane (900 mL) and DBU (210 gm, 1.36 mol) were successively added to the reaction mixture. The resulting mixture was then stirred at 85° C. for 5 hours then cooled to rt and diluted with CH2Cl2 followed by washing with water then brine solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash silica gel column chromatography to yield 58 g of title compound as the crude product containing residual DBU. This material was used as is in the next transformation. LCMS (condition A) m/z=236.0 −ve. H1 NMR (400 MHz, DMSO-d6) δ ppm: 9.76 (1H, br.s), 7.62 (1H, s), 7.39 (1H, d, 2.0 Hz), 6.43 (1H, d, 2.0 Hz). The product is contaminated with DBU and was used directly as such without further purification in the next step. the isopropanol was removed under vacuum The resulting residue was dissolved in CH2Cl2 washed with water and brine solution The organic layer was separated dried over Na2SO4 filtered concentrated The resulting residue was transferred into a 2 L round bottom flask The resulting mixture was then stirred at 85° C. for 5 hours then cooled to rt by washing with water The organic layer was separated dried over Na2SO4 filtered concentrated The resulting residue was purified by flash silica gel column chromatography

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 3,3-bis(ethyloxy)propanenitrile (2.3 g, 20 mmol) and 2,3-dimethylbenzaldehyde (2.1 g, 16 mmol) in methanol (10 mL) was added a 25-30% of sodium methoxide in methanol over 20 minutes. The reaction mixture was stirred at room temperature overnight. Most of solvent was evaporated in vacuo and the residue was dissolved with ethyl acetate (30 mL) and water (15 mL). The two layers were separated. Organic layer was separated, washed with brine (15 mL), dried and concentrated in vacuo. The residue was then purified to give product. It was used in next step. (1.55 g, 33%); 1H NMR (600 MHz, DMSO-d6) δ ppm 2.20 (s, 3H) 2.28 (s, 3H) 3.37 (s, 6H) 5.13 (s, 1H) 7.17-7.22 (m, 1H) 7.27 (d, J=7.55 Hz, 1H) 7.39-7.45 (m, 1H) 7.79 (s, 1H). Most of solvent was evaporated in vacuo the residue was dissolved with ethyl acetate (30 mL) and water (15 mL) The two layers were separated Organic layer was separated washed with brine (15 mL) dried concentrated in vacuo The residue was then purified to give product

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 3,3-bis(ethyloxy)propanenitrile (2.3 g, 20 mmol) and 2,3-dimethylbenzaldehyde (2.1 g, 16 mmol) in methanol (10 mL) was added a 25-30% of sodium methoxide in methanol over 20 minutes. The reaction mixture was stirred at room temperature overnight. Most of solvent was evaporated in vacuo and the residue was dissolved with ethyl acetate (30 mL) and water (15 mL). The two layers were separated. Organic layer was separated, washed with brine (15 mL), dried and concentrated in vacuo. The residue was then purified to give product. It was used in next step. (1.55 g, 33%); 1H NMR (600 MHz, DMSO-d6) δ ppm 2.20 (s, 3H) 2.28 (s, 3H) 3.37 (s, 6H) 5.13 (s, 1H) 7.17-7.22 (m, 1H) 7.27 (d, J=7.55 Hz, 1H) 7.39-7.45 (m, 1H) 7.79 (s, 1H). Most of solvent was evaporated in vacuo the residue was dissolved with ethyl acetate (30 mL) and water (15 mL) The two layers were separated Organic layer was separated washed with brine (15 mL) dried concentrated in vacuo The residue was then purified to give product

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2-methyl-3-(trifluoromethyl)benzaldehyde (3.0 g, 16 mmol) and 3,3-bis(ethyloxy)propanenitrile (2.3 g, 20 mmol) in methanol (10 mL) was added a 25% sodium methoxide in methanol over 20 minutes. The mixture was stirred at room temperature overnight. Most of solvent was evaporated in vacuo and the residue was dissolved with ethyl acetate (30 mL) and water (15 mL). Two layers were separated. Organic layer was separated, washed with brine (15 mL), dried and solvent was evaporated in vacuo. The residue was then purified to give product. (3.66 g, 64%); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.40 (s, 3H) 2.94 (m, J=11.37 Hz, 1H) 3.08 (m, J=4.80 Hz, 1H) 3.20 (s, 1H) 3.43 (d, J=10.36 Hz, 1H) 3.42 (d, J=11.12 Hz, 6H) 3.45-3.52 (m, 1H) 4.60 (d, J=4.80 Hz, 1H) 7.39 (t, J=7.71 Hz, 1H) 7.59 (dd, J=17.18, 7.83 Hz, 2H). Most of solvent was evaporated in vacuo the residue was dissolved with ethyl acetate (30 mL) and water (15 mL) Two layers were separated Organic layer was separated washed with brine (15 mL) dried solvent was evaporated in vacuo The residue was then purified to give product

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2-methyl-3-(trifluoromethyl)benzaldehyde (3.0 g, 16 mmol) and 3,3-bis(ethyloxy)propanenitrile (2.3 g, 20 mmol) in methanol (10 mL) was added a 25% sodium methoxide in methanol over 20 minutes. The mixture was stirred at room temperature overnight. Most of solvent was evaporated in vacuo and the residue was dissolved with ethyl acetate (30 mL) and water (15 mL). Two layers were separated. Organic layer was separated, washed with brine (15 mL), dried and solvent was evaporated in vacuo. The residue was then purified to give product. (3.66 g, 64%); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.40 (s, 3H) 2.94 (m, J=11.37 Hz, 1H) 3.08 (m, J=4.80 Hz, 1H) 3.20 (s, 1H) 3.43 (d, J=10.36 Hz, 1H) 3.42 (d, J=11.12 Hz, 6H) 3.45-3.52 (m, 1H) 4.60 (d, J=4.80 Hz, 1H) 7.39 (t, J=7.71 Hz, 1H) 7.59 (dd, J=17.18, 7.83 Hz, 2H). Most of solvent was evaporated in vacuo the residue was dissolved with ethyl acetate (30 mL) and water (15 mL) Two layers were separated Organic layer was separated washed with brine (15 mL) dried solvent was evaporated in vacuo The residue was then purified to give product

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 40.9 g. of cyanacetaldehyde diethylacetal, 26.2 g. of formic acid ethyl ester and 100 ml. of absolute ether are added dropwise with stirring to a suspension of 7.4 g. of powdered sodium in 500 ml. of absolute ether. The mixture is stirred at room temperature until disappearance of the sodium (16 hours). Then, the brown precipitate formed (crude sodium salt of hydroxymethylene-cyanacetaldehyde diethylacetal) is left to settle and the supernatant solution is removed by decantation. The residue is washed by decanting twice with 200 ml. of absolute ether each time. The product is stored at 0° C. under absolute ether, since it changes on drying. A mixture of 40.9 g

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 40.9 . of cyanacetaldehyde diethylacetal, 26.2 g. of formic acid ethyl ester and 100 ml. of absolute ether are added dropwise with stirring to a suspension of 7.4 g. of powdered sodium in 500 ml. of absolute ether. The mixture is stirred at room temperature until disappearance of the sodium (16 hours). Then, the brown precipitate formed (crude sodium salt of hydroxymethylene-cyanacetaldehyde diethylacetal) is left to settle and the supernatant solution is removed by decantation. The residue is washed by decanting twice with 200 ml. of absolute ether each time. The product is stored at 0° C. under absolute ether, since it changes on drying.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3,3-diethoxypropanenitrile (1.80 mL, 12.00 mmol), 2-amino-4-bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Stark apparatus for 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of DMF, diluted with chloroform, and washed with aq. sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by flash chromatography (0-3% methanol in dichloromethane) followed by trituration in diethyl ether provided the title compound (1.75 g, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.95 (dd, J=8.72, 1.89 Hz, 1 H) 8.08 (d, J=8.84 Hz, 1 H) 8.38 (d, J=2.02 Hz, 1 H) 9.13 (d, J=1.52 Hz, 1 H) 9.21 (d, 1 H). was heated under reflux for 3 h The reaction was cooled evaporated under reduced pressure the residue was dissolved in a small amount of DMF diluted with chloroform washed with aq. sodium bicarbonate solution The aqueous layer was extracted with chloroform the combined extracts were washed with brine dried (Na2SO4) concentrated in vacuo Purification by flash chromatography (0-3% methanol in dichloromethane)

反应条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a round bottom flask was added the methane sulfonic acid salt of methyl 1-amino-4-bromo-1H-pyrrole-2-carboxylate (140 g, 0.444 mol), isopropanol (700 mL) and 3,3-diethoxypropionitrile (128 g, 0.888 mol). The reaction mixture was slowly brought to 85° C. over 1 hour and then stirred at 85° C. for 2 hours. At this time, the ethanol that was generated and the isopropanol was removed under vacuum. The resulting residue was dissolved in CH2Cl2 and washed with water and brine solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The resulting residue was transferred into a 2 L round bottom flask and dichloroethane (900 mL) and DBU (210 gm, 1.36 mol) were successively added to the reaction mixture. The resulting mixture was then stirred at 85° C. for 5 hours then cooled to rt and diluted with CH2Cl2 followed by washing with water then brine solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash silica gel column chromatography to yield 58 g of title compound as the crude product containing residual DBU. This material was used as is in the next transformation. LCMS (condition A) m/z=236.0 −ve. 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.76 (1H, br.s), 7.62 (1H, s), 7.39 (1H, d, 2.0Hz), 6.43 (1H, d, 2.0 Hz). The product is contaminated with DBU and was used directly as such without further purification in the next step. the isopropanol was removed under vacuum The resulting residue was dissolved in CH2Cl2 washed with water and brine solution The organic layer was separated dried over Na2SO4 filtered concentrated The resulting residue was transferred into a 2 L round bottom flask The resulting mixture was then stirred at 85° C. for 5 hours then cooled to rt by washing with water The organic layer was separated dried over Na2SO4 filtered concentrated The resulting residue was purified by flash silica gel column chromatography

反应条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a round bottom flask was added the methane sulfonic acid salt of methyl 1-amino-4-bromo-1H-pyrrole-2-carboxylate (140 g, 0.444 mol), isopropanol (700 mL) and 3,3-diethoxypropionitrile (128 g, 0.888 mol). The reaction mixture was slowly brought to 85° C. over 1 hour and then stirred at 85° C. for 2 hours. At this time, the ethanol that was generated and the isopropanol was removed under vacuum. The resulting residue was dissolved in CH2Cl2 and washed with water and brine solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The resulting residue was transferred into a 2 L round bottom flask and dichloroethane (900 mL) and DBU (210 gm, 1.36 mol) were successively added to the reaction mixture. The resulting mixture was then stirred at 85° C. for 5 hours then cooled to rt and diluted with CH2Cl2 followed by washing with water then brine solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash silica gel column chromatography to yield 58 g of title compound as the crude product containing residual DBU. This material was used as is in the next transformation. LCMS (condition A) m/z=236.0−ve. 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.76 (1H, br.s), 7.62 (1H, s), 7.39 (1H, d, 2.0 Hz), 6.43 (1H, d, 2.0 Hz). The product is contaminated with DBU and was used directly as such without further purification in the next step. the isopropanol was removed under vacuum The resulting residue was dissolved in CH2Cl2 washed with water and brine solution The organic layer was separated dried over Na2SO4 filtered concentrated The resulting residue was transferred into a 2 L round bottom flask The resulting mixture was then stirred at 85° C. for 5 hours then cooled to rt by washing with water The organic layer was separated dried over Na2SO4 filtered concentrated The resulting residue was purified by flash silica gel column chromatography

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 8 g of bromo-acetaldehyde diethyl-acetal, 3 g of sodium-cyanide and 20 ml of dimethyl-sulfoxide is admixed at a temperature of 80° C. for 5 hours. The reaction mixture is poured on 80 ml of water, then twice extracted with 50 ml of chloroform. The chloroform extract is washed twice with 30 ml of water, dried on magnesium sulfate, then distilled in vacuo. twice extracted with 50 ml of chloroform The chloroform extract is washed twice with 30 ml of water dried on magnesium sulfate distilled in vacuo