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With sulfuryl dichloride; acetic acid; at 10 - 54℃; for 4.5h;
3-cyano-4-methoxy-2-H-pyridone (6.0 g, 0.04 mol)45ml glacial acetic acid into 250 ml three-necked flask,Cooling to below 15 ,Then 6.18 g (0.045 mol) g of sulfonyl chloride was added dropwise,Solution temperature control between 10 ~ 15 ,The rate of dropping can be controlled according to the temperature change.After dripping,Stirring for half an hour,Heating up to 52 ± 2 ,Insulation 50-54 reaction 4h,TLC (TLC developing agent: ethyl acetate: methanol = 9: 1) monitoring the reaction of raw materials is completed,The reaction solution was cooled to 20 ± 2 ° C,Stir for 2 hours,filter,The filter cake was washed with 58 ml of water,The wet product was dried at 80 ° C under normal pressure for 12 hours to dry,To give 7.01 g of 3-cyano-4-methoxy-5-chloro 2- (1H) pyridone as a white powder,Yield 95.0percentTheoretical yield 7.38g.
92.7%
With thionyl chloride; at 0 - 5℃; for 6.0h;Reflux;
At a temperature of 0 ° C to 5 ° C,Sulfuryl chloride was slowly added dropwise to 3-cyano-4-methoxy-2 (1 H) pyridone, the temperature was not more than 5 ° C, the rate of thionyl chloride dropping was 1.5 ml / min, Raise the temperature to produce reflux,The reaction was carried out for 6 hours, and the thionyl chloride was evaporated to dryness under reduced pressure,Add 1 ml of n-hexane solid beating 1 hour, filter, dry, that is, too. Yield 92.7percent
With potassium carbonate; In acetonitrile; at 100℃; for 12.0h;
The reaction was carried out under N2 atmosphere. To a solution of commercially available 4-methoxy-2-oxo-l,2-dihydro-pyridine-3-carbonitrile (1.00 g, 6.60 mmol, 1 eq) in acetonitrile (45 ml) was added K2CO3 (2.73 g, 19.8 mmol, 3 eq) and isopentyl- 0 bromide (441 mg, 8.65 mmol, 1.3 eq). The resulting solution was heated at 100 0C for 12 hours. The reaction was then cooled to room temperature and filtered through a pad of celite. The filtrate was then concentrated in vacuo. Subsequently, the crude residue thus obtained was purified by flash chromatography (SiO2, eluting with a gradient elu- tion of between 0 - 2 percent MeOH in DCM) to yield intermediate compound 1 as a creamy 5 solid (82 percent, 5.40 mmol).
With potassium carbonate; In acetonitrile; at 140℃; for 16.0h;
Commercially available 4-methoxy-2-oxo-l,2-dihydro-pyridine-3-carbonitrile (4.70 g, 31.29 mmol, 1 eq), 4-(trifluoromethoxy)benzylbromide (5.44 ml, 32.86 mmol, 1.05 eq) and K2CO3 (12.9 g, 93.8 mmol, 3 eq) were mixed in acetonitrile (200 ml). The mixture was heated at 140 0C for 16 hours into a sealed tube. The reaction was then cooled to room temperature and the solvents were evaporated in vacuum. The resulting residue was dissolved in DCM and filtered through a pad of celite. The filtrate was then concentrated in vacuo. Subsequently, the white solid thus obtained was triturated with di- ethylether to yield intermediate compound 10 as a white solid (9.20 g, 91 percent).
With potassium carbonate; In acetonitrile; for 16.0h;Heating / reflux;
A solution of commercially available 4-methoxy-2-oxo-l,2-dihydro-pyridine-3- carbonitrile (4.0 g, 0.0266 mol), beta-bromophenetole (5.62 g, 0.0279 mol) and K2CO3 (11.0 g, 0.0799 mol) in CH3CN (150 ml) was heated at reflux for 16 hours. The reaction mixture was then filtered off and the filtrate concentrated in vacuo. The residue was recrystallised from ethylether to yield intermediate compound 17 (7 g, 97 percent).
With trichlorophosphate; for 19.0h;Heating / reflux; Neat (no solvent);
2,4-dichloronicotinonitrile A solution of 5.0 g of commercial 4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile in 50 ml of phosphorus oxychloride is refluxed for 19 hours. After cooling, the reaction medium is poured into a mixture of water and ice. The precipitate formed is filtered off and the filtrate is extracted twice with a 90/10 ethyl acetate/methanol solution. The combined organic phases and the precipitate are dried over magnesium sulfate and then concentrated under reduced pressure to give 6.76 g of a yellowish powder. The crude product is purified on a prepacked Biotage KP-Sil column of 60 A SiO2 32-63 muM (5/95 to 10/90 gradient ethyl acetate in cyclohexane) to give 2.08 g of a white powder of 2,4-dichloronicotinonitrile. MS-IE: 172=[M+] (base peak), 137=[M+]-Cl IR spectrum (KBr): 3072; 2236; 1559; 1539; 1445; 1368; 1220; 1197; 1069; 859; 818; 791 and 416 cm-1 1H NMR spectrum (400 MHz, (CD3)2SO, delta in ppm): 7.92 (d, J=5.5 Hz, 1H); 8.67 (d, J=5.5 Hz, 1H)
(107a) 2-chloro-4-methoxynicotinonitrile; A phosphorus oxychloride (10 mL) solution of <strong>[21642-98-8]4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile</strong> (1.50 g, 10 mmol) which was synthesized by a method of Ogawa et al. (Heterocycles, 36,145-148,1993) was heated under reflux for two hours. The reaction liquid was concentrated and a sodium hydrogen carbonate aqueous solution (10 mL) added to the obtained residual substance and the mixture was extracted with ethyl acetate (3x10 mL), and the solvent was evaporated under reduced pressure after the extract was dried over sodium sulfate. The obtained residue was powderized with ether and the title compound was obtained (1.31 g, yield 78percent). Pale yellow powder 1H NMR(DMSO-d6, 400 MHz) delta 4.05 (3H, s), 7.40 (1H, d, J = 4.3 Hz), 8.55 (1H, d, J = 4.3 Hz).
2-(dimethylaminoethoxymethylene)malononitrile[ No CAS ]
[ 21642-98-8 ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid; at 20℃; for 6.5h;
A solution of 2- (DIMETHYLAMINOETHOXYMETHYLENE) malononitrile (1.97 g) in concentrated sulfuric acid (7.0 mL) was stirred at room temperature for 6.5 h. The reaction mixture was poured into water, and the precipitate was collected by filtration. lH NMR (300 MHz, DMSO-D6) 8 12.14 (br s, 1H), 7.79 (d, J= 9 Hz, 1H), 6.35 (d, J= 9 Hz, 1H), 3. 98 (s, 3H).
To a solution of commercially available 4-methoxy-2-oxo-l,2-dihydro-3- pyridinecarbonitrile (95.47 g, 333 mmol) [C.A.S. 21642-98-8] in acetonitrile (670 ml), <n="52"/>phosphoras(V) oxybromide (250 g, 166 mmol) was added portionwise. The resulting suspension was heated at 6O0C for 16 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with water. The organic layer was separated and washed with NaHCO3 (aqueous sat. solution), dried (MgSO4) and evaporated in vacuo. The crude product thus obtained was triturated with diisopropyl ether to yield compound DIl (34.5 g, 79percent) as a white solid.GCMS (EI): MW (theor): 262; [M-2H+]: 260; RT (min): 9.67.
79%
Description 7; 2,4-Dibromo-nicotinonitrile (D7); To a solution of commercially available 4-methoxy-2-oxo-l,2-dihydro-3- pyridinecarbonitrile (95.47 g, 333 mmol) [C.A.S. 21642-98-8] in acetonitrile (670 ml), phosphorus (V) oxybromide (250 g, 166 mmol) was added portionwise. The resulting suspension was heated at 60 0C for 16 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with water. The organic layer was separated and washed with NaHCO3 (aqueous sat. solution), dried (MgSO4) and evaporated in vacuo. The crude product was triturated with DIPE to yield compound D7 (34.5 g, 79percent) as white solid. GCMS (EI): MW (theor): 262; [M-2H+]: 260; RT (min): 9.67.
79%
With phosphorus(V) oxybromide; In acetonitrile; at 60℃; for 16.0h;
To a solution of commercially available 4-methoxy-2-oxo-l,2-dihydro-3- pyridinecarbonitrile (95.47 g, 333 mmol) [C.A.S. 21642-98-8] in CH3CN (670 ml), was added phosphorus(V) oxybromide (250 g, 166 mmol) portionwise. The resulting suspension was heated at 60 0C for 16 h. After cooling to r.t., the reaction mixture was diluted with EtOAc and washed with water. The organic layer was separated and washed with NaHCO3 (aqueous sat. solution), dried (MgSO4) and concentrated in vacuo. The crude product thus obtained was triturated with diisopropyl ether to yield intermediate compound Dl (34.5 g, 79percent) as a white solid.GCMS (EI): MW (theor): 262; [M-2H+]: 260; RT (min): 9.67.
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