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With piperazine; In ethanol; at 20 - 65℃; for 15.5h;
Reference Example 15 3-Cyano-6-cyclopropyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid ethyl ester While stirring at room temperature, 19.2 g of 2-cyanoacetamide was added to 300 ml of ethanol solution containing 41.9 g of <strong>[21080-80-8]2,4-dioxocyclopropanebutyric acid ethyl ester</strong>.. After completely dissolving the reagent by warming up to 65° C., 7.4 ml of piperazine was added dropwise to the solution.. One hour thereafter, this was cooled to room temperature and stirred for additional 15 hours and 30 minutes.. The thus precipitated crystals were collected by filtration and then washed with diethyl ether to obtain 24.1 g of the title compound.. This compound was used in the subsequent reaction without further purification.
3-Cyano-6-cyclopropyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid ethyl ester While stirring at room temperature, 19.2 g of 2-cyanoacetamide was added to 300 ml of ethanol solution containing 41.9 g of <strong>[21080-80-8]2,4-dioxocyclopropanebutyric acid ethyl ester</strong>. After completely dissolving the reagent by warming up to 65°C, 7.4 ml of piperazine was added dropwise to the solution. One hour thereafter, this was cooled to room temperature and stirred for additional 15 hours and 30 minutes. The thus precipitated crystals were collected by filtration and then washed with diethyl ether to obtain 24.1 g of the title compound. This compound was used in the subsequent reaction without further purification.
Step K: 3-hydroxy-l-isopropyl-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile (13; R=R=H). To a solution of 2-isobutyrylcyclohexanone (12; 4.33 g, 25.76 mmol) and 2-cyanoacetamide (2.17 g, 25.76 mmol) in 26 mL of EtOH was added diethylamine (2.7 mL, 25.76 mmol). The reaction mixture was stirred at room temperature for 72 hours until LC-MS indicated the complete formation of the product. The reaction mixture was then heated to reflux and enough EtOH was added to make a clear solution. After cooling back to room temperature, the desired product and its regioisomer were precipitated out from EtOH solution. After vacuum filtration and air-dry, 4.1 g of the title compound together with its regioisomer were obtained as a mixture of white solid and used without further purification in the next step. MS (ES) M+H expected 217.1 , found 217.1.
To a solution of 2-isobutyrylcyclohexanone (13g, 0.0772 mol) in ethanol (250 mL) were added 2-cyano acetamide (6.5 g, 0.0772 mol) and catalytic amount of piperidine (3 mL) at RT. After completion of the reaction (by LCMS), the precipitated solids were collected by filtration and dried under vacuum. It was slurred with ethyl acetate to afford (10 g, 59percent) of the titled compound as white solid. 1H NMR (400MHz, DMSO-d6) delta 11.87 (s, 1 H), 3.17-3.10 (m, 1 H), 2.74 (s, 2H), 2.50-2.47 (m, 2H), 1.66 (s, 4H), 1.19-1.17 (d, J = 7.0 Hz, 6H).
2-(5-tert-butyl-1H-benzimidazol-2-yl)acetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In neat (no solvent); at 200℃; for 0.5h;
General procedure: The mixture of o-phenylenediamine (1) and cyanoacetamide (2) were stirred in 200 °C for 30 min without any solvent. After cooling, the mixture was dissolved in ethanol. The crude product was purified by silica gel column chromatography using dichloromethane-methanol (60:1) as eluant to give the pure compound 3.
methyl 6-(2-amino-1-cyano-2-oxoethyl)-5-nitronicotinate[ No CAS ]
(Z)-methyl 6-(2-amino-1-cyano-2-oxoethylidene)-5-nitro-1,6-dihydropyridine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.80g
NaH (0.776 g, 19.39 mmol, 60percent weight) was added to a 5°C solution of 2-cyanoacetamide (0.815 g, 9.70 mmol) in DMF (12 ml). The mixture was brought to it for 15 mm then back to 5°C. Methyl 6-chloro-5- nitronicotinate (2.00 g, 9.23 mmol) in THE (6 ml) was added slowly to the previous solution and then brought to rt. After 3h of stirring, the solution was cooled to 5°C and quenched with 24 ml of water followed 10 mm later by HCICOC (0.81 ml, 9.7 mmol). The solid obtained was filtered and dried overnight under vacuum to give 0.80g of methyl 6-(2-amino-1-cyano-2-oxoethyl)-5-nitronicotinate. LCMS m/z 263.2 (M-H); 1H NMR (400 MHz, DMSO-d6) oe ppm 3.95 (5, 3 H) 5.99 (5, 1 H) 7.81 (5, 1 H), 8.15 (5, 1 H) 8.86 (d, Jz2.0 Hz, 1 H) 9.38 (d, J= 2.0 Hz, 1 H) with some of the regioisomer (Z)-methyl 6-(2-amino-1-cyano-2- oxoethylidene)-5-nitro-1 , 6-di hydropyridi ne-3-carboxyl ate.
With morpholine; sulfur; In ethanol; for 4h;Reflux;
General procedure: Cyclohexanone (for 18a), 1-benzoylpiperidin-3-one (for 18b) or 1-benzoylpiperidin-4-one (for 18c) (0.42mmol), cyanoacetamide (34mg, 0.40mmol) and sulfur (16mg, 0.50mmol) were suspended in EtOH (1mL). To this was added morpholine (70mg, 0.80mmol). The resulting mixture was refluxed gently with stirring for 4h, and was allowed to cool to room temperature. Solvent was removed and the residue was purified by flash chromatography on silica gel using hexanes:EtOAc (1:2) to give compounds 18a-c as off white powder.
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