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With trichlorophosphate In toluene at 80℃; for 2.5h;
2-(5-methyl-l,3,4-oxadiazol-2-yl)acetonitrile
Intermediate 163 (90%, 2.8 g, 17.86 mmol) was stirred in toluene (75 mL). POCI3 (4.55 g, 29.68 mmol) was added and the suspension was heated at 80 °C for 2.5 hours. The reaction was allowed to cool and the suspension was added to water (100 mL) then taken to pH7 using saturated aq. Na CC> . The aqueous solution was extracted with ethyl acetate (3 x 100 mL), the organics were dried over sodium sulfate and concentrated in vacuo to afford the title compound (980 mg, 44%) as a red solid. dH (500 M Hz, Chloroform-d) d 4.02 (s, 2H), 2.58 (s, 3H). dH (500 MHz, DMSO-d6) d 4.57 (s, 2H), 2.51 (s, 3H).
With trichlorophosphate for 6h; Heating; or acetic anhydride; Yield given;
With trichlorophosphate In toluene at 80℃; for 4h;
31.3 2-(5-methyl-l,3,4-oxadiazol-2-yl)acetonitrile
POCI3 (6.5 g, 42.6 mmol) was added in several batches to a solution of N-acetyl-2- cyanoacetohydrazide (4.0 g, 28.4 mmol) in toluene (150 mL). Then the reaction was stirred for 4 h at 80°C in an oil bath. The resulting mixture was concentrated in vacuo and quenched by the addition of 100 mL of water. The pH value of the solution was adjusted to 7 with sodium carbonate (19%) and extracted with 3x100 mL of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. The solids were filtered off. The resulting solution was concentrated in vacuo to afford 2-(5-methyl-l,3,4-oxadiazol-2-yl) acetonitrile as orange oil (2.5 g, 70%).
Multi-step reaction with 3 steps
1: toluene / 3 h / 85 °C
2: hydrazine hydrate / ethanol / 1 h / 90 °C
3: toluene-4-sulfonic acid / butan-1-ol / 5 h / 130 °C
31.4 (E)-3-(dimethylamino)-2-(5-methyl-l,3,4-oxadiazol-2-yl)acrylonitrile
To a solution of 2-(5-methyl-l ,3,4-oxadiazol-2-yl)acetonitrile (2.5 g, 20.3 mmol) in toluene (10 mL) was added DMF-DMA (3.6 g, 30.5 mmol), and the reaction mixture was stirred for 3h at 85°C in an oil bath. The resulting mixture was concentrated in vacuo to afford (E)-3-(dimethylamino)-2-(5-methyl-l,3,4- oxadiazol-2-yl)acrylonitrile as a crude orange red oil.
(E)-2-hydroxyimino-2-(5-methyl-1,3,4-oxadiazol-2-yl)acetonitrile[ No CAS ]
(Z)-2-hydroxyimino-2-(5-methyl-1,3,4-oxadiazol-2-yl)acetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tert.-butylnitrite; potassium hydroxide In ethanol at 20℃; for 20h; Cooling with ice;
2-hydroxyimino-2-(5-methyl-l,3,4-oxadiazol-2-yl)acetonitrile
Intermediate 217 (880 mg, 7.15 mmol) was stirred in dry ethanol (10 mL) and powdered KOH (441 mg, 7.86 mmol) was added followed by lbutyl nitrite (935 mI, 7.86 mmol). An exotherm was observed and the reaction was cooled in an ice bath for 10 minutes then stirred at room temperature for 18 hours. Further lbutyl nitrite (250 mI, 2.1 mmol) was added and the reaction stirred for 2 hours at room temperature. The brown suspension was diluted with diethyl ether and the solid was collected by vacuum filtration to give an orange solid which was dissolved in water (50 mL) and acidified to pHl using 1M aq. HCI. The product was extracted into EtOAc (3 x 50 mL), dried over sodium sulfate and concentrated in vacuo to afford the title compound as a 1:1 mixture of E/Z isomers, (912 mg, 80% at 95% purity) as a red solid. dH (250 MHz, DMSO-d6) d 15.02 (s, 2H Isomer A+B), 2.61 (s, 3H Isomer A), 2.58 (s, 3H Isomer B).
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