| 75% |
|
5-(Difluoromethyl)-2-methoxypyridin-3 -amine a) Methyl 6-chloro-5-nitronicotinateLambda/,Lambda/'-Dimethylformamide (0.4 mL) was added to a suspension of 6-hydroxy-5- nitronicotinic acid (10.0 g, 50 mmol) in thionyl chloride (50 mL) and the mixture was stirred and heated to 60 °C. After gas evolution had ceased, the mixture was heated to 80 °C and stirred overnight. The mixture was concentrated in vacuo and then co- evaporated with toluene three times. The residue was taken up in dichloromethane (20 mL), cooled to 0 °C and methanol (12 mL) was added dropwise with stirring. The mixture was stirred for 1 hour then evaporated. The residue was partitioned between ethyl acetate and water and the organic layer was separated, dried (MgS04) and evaporated to give the title compound (8.83 g, 75percent) as a pale yellow solid.LRMS (m/z): 217 (M+1 )+.1H NMR delta (300 MHz, CDCI3): 4.03 (s, 3H), 8.77 (d, 1 H), 9.18 (d, 1 H). |
| 54% |
|
To a solution of phosphoryl pentachloride (12.98 g, 62.3 mmol) in phosphoryl chloride (18 mL), was added 3 (4.00 g, 21.7 mmol), and the mixture was stirred for 3 h at 100 oC equipped with condenser. Then, the excess amount of phosphoryl chloride was removed in vacuo at 50 oC, and the residue was dissolved in MeOH (30 mL) at 0 oC and further stirred for 30 min. Excess amount of MeOH was removed in vacuo and the residue was dissolved in AcOEt. This organic layer was washed with water, brine and dried over anhydrous Na2SO4. After the solvent was removed in vacuo, the resultant residue was purified by column chromatography on silica gel using hexane/AcOEt (6:1) as an eluant to give 4 as pale yellow needles (2.54 g, 54percent); 1H NMR (300 MHz, CD3OD) 4.00 (s, 3H), 8.52 (d, J = 2.1Hz, 1H), 9.14 (d, J = 2.1 Hz, 1H); HRMS (ES+): m/z 217.0006 (M+H+) (calcd for C7H6N2O4Cl: 217.0016). |
| 52% |
|
A. 6-Chloro-5-nitro-nicotinic acid methyl ester; To a suspension of 49.0 g (0.27 mol) 6-hydroxy-5-nitro-nicotinic acid in thionyl chloride (240 ml) is added DMF (2 ml). This mixture is stirred at 60°C and after gassing stops it is stirred at 80°C for further 18 h. The thionyl chloride is removed under vacuo and the residue is coevaporated with toluene three times. Subsequently this reaction mixture is dissolved in dichloromethane (100 mi) and cooled to 0°C before methanol (55.5 ml) is dropwise added. The precipitated solid is filtered off and dried under vacuo at 50°C to give 27.6 g (13.7 mmol/52 percent) of the titled compound as a light yellow solid with a melting point of 78°C (dichloromethane/methanol). |
| 18.2 g |
|
Compound 2 (20.0 g) and N,N-dimethylformamide (8.44 mL, 0.109 mmol) were added to a 500 mL recovery flask in an argon gas stream, and thionyl chloride (158.3 mL, 2.18 mmol) was added while cooling by ice bath. After the entire amount of thionyl chloride had been added, the flask was returned to room temperature. It was then gradually heated using an oil bath, and stirring was conducted for 16 hours at 80° C. After stopping heating and allowing to cool to room temperature, the reaction solution was concentrated under reduced pressure. Dichloromethane (50 mL) was added to the residue obtained, which was again concentrated, and the remaining thionyl chloride was distilled off azeotropically. After concentration, the residue obtained was cooled by an ice bath, and methanol (50 mL) was added. Compound 3 (18.2 g, 0.084 mmol) was obtained by concentration and drying under reduced pressure. 1H NMR (300 MHz, CD3OD) 4.00 (s, 3H), 8.52 (d, J=2.1 Hz, 1H), 9.14 (d, J=2.1 Hz, 1H); HRMS (ES+): m/z 217.0006 (M+H)+ (calcd for C7H8N2O4Cl: 217.0016). |
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
120K+ Compounds
Competitive Price
1-2 Day Shipping
