2,6-DIMETHYLPYRIDINE-4-CARBOXYLIC ACID METHYL ESTER

Compound 99: 2, 6-Dimethyl-isonicotinic acid methyl ester. Under inert atmosphere, a mixture of methyl 2, 6-dichloropyridine-4-carboxylate (2, 00 g), dimethylzinc (2N in toluene, 14.6 mL, 3.0 equiv.) and PdClUnder inert atmosphere, a mixture of methyl 2, 6-dichloropyridine-4-carboxylate (2, 00 g), dimethylzinc (2N in toluene, 14.6 ml, 3.0 equiv.) and PdCI2(dppf)2 (400 mg, 0.05 equiv.) in dioxane (50 ml), was heated at 80°C for 4Hrs. The reaction mixture was cooled by an ice bath, hydrolysed with water (100 ml) and filtered through a pad of celite. The pad was rinsed with water and EtAOc. The filtrate was extracted with EtOAc (250 ml). The organic layer was washed with brine (1 00 ml), dried over MgSO4 and concentrated. Purification by flash chromatography (MeOH in CH2Cl2, 0 to 2percent) afforded compound 99 as an orange oil in 96percent yield. 1H-NMR (400 MHz, DMSO): 2.51 (s, 6H, 2CH3); 3.88 (s, 3H, O-CH3); 7.51 (s, 2H, Ar). M/Z(M+H)+ = 166.1.A mixture of 2 g of 2, 6-dimethylisonicotinic acid (2) (unpurified), 100 ml of methanol and 1 ml of 98% sulfuric acid is refluxed for 24 hours. After cooling, the reaction medium is neutralized with saturated NaHCO3 solution and then extracted five times with 60 ml of CHCl3. The combined chloroform phases are then dried over Na2SO4 and then concentrated. The resulting solid is then extracted four times with 50 ml of ether, after which the ether phase is concentrated. Chromatography on alumina [gradient: cyclohexane/CH2Cl2 (50/50) to pure CH2Cl2] of the white residue obtained gives 1 g of 4-methyl-2, 6-dimethyl isonicotinate (3). [0141] m.p.: 45-47 C. [0142] TLC: Rf: 0.3 [SiO2/CH2Cl2-MeOH (97/3)][0143] HPLC: Tr: 2.4 [0144] UV: CHCl3: 290.6 nm (3650) [0145] NMR: 1H CDCl3; internal reference TMS [0146] 2.59 (s, 6H, CH3); 3.93 (s, 3H, CO2CH3); 7.51 (s, 2H, Py) [0147] 13C CDCl3; internal reference 77.0 ppm [0148] 24.5 (CH3); 52.5 (OCH3); 119.5 (Ct); 137.9, 158.9 (Cq); [0149] 166.1 (CO). [0150] MS (EI): 165 (M+, 24); 134 (M+-OCH3, 13); 106 (M+-CO2Me)4-???2, 6-????????????(3)2g'2, 6-??????????(2)(??)?100ml?????????1ml'98%??24????????????????NaHCO3???????????60ml'CHCl3'5??????????????????????Na2SO4?????????????????????????50ml??????4????????????????????????????????????????????[?:???????/CH2Cl2(50/50)?CH2Cl2]????1g'4-???2, 6-????????????(3)????Compound 99: 2, 6-Dimethyl-isonicotinic acid methyl ester. Under inert atmosphere, a mixture of methyl 2, 6-dichloropyridine-4-carboxylate (2, 00 g), dimethylzinc (2N in toluene, 14.6 mL, 3.0 equiv.) and PdCl2(dppf)2 (400 mg, 0.05 equiv.) in dioxane (50 mL), was heated at 80C for 4Hrs. The reaction mixture was cooled by an ice bath, hydrolysed with water (100 mL) and filtered through a pad of celite. The pad was rinsed with water and EtAOc. The filtrate was extracted with EtOAc (250 mL). The organic layer was washed with brine (100 mL), dried over MgSO4 and concentrated. Purification by flash-chromatography (MeOH in CH2Cl2, 0 to 2%) afforded compound 99 as an orange oil in 96% yield. 1H-NMR (400 MHz, DMSO): 2.51 (s, 6H, 2CH3); 3.88 (s, 3H, O-CH3); 7.51 (s, 2H, Ar). M/Z (M+H)+ = 166.1.Under inert atmosphere, a mixture of methyl 2, 6-dichloropyridine-4-carboxylate (2, 00 g), dimethylzinc (2N in toluene, 14.6 ml, 3.0 equiv.) and PdCI2(dppf)2 (400 mg, 0.05 equiv.) in dioxane (50 ml), was heated at 80C for 4Hrs. The reaction mixture was cooled by an ice bath, hydrolysed with water (100 ml) and filtered through a pad of celite. The pad was rinsed with water and EtAOc. The filtrate was extracted with EtOAc (250 ml). The organic layer was washed with brine (1 00 ml), dried over MgSO4 and concentrated. Purification by flash chromatography (MeOH in CH2Cl2, 0 to 2%) afforded compound 99 as an orange oil in 96% yield. 1H-NMR (400 MHz, DMSO): 2.51 (s, 6H, 2CH3); 3.88 (s, 3H, O-CH3); 7.51 (s, 2H, Ar). M/Z(M+H)+ = 166.1.General procedure: Compound 100: 3-(2, 6-Dimethyl-pyridin-4-yl)-3-oxo-propionitrile. Compound 100 was obtained according to general procedure VII(ii) starting from compound 99. Compound 100 was used in the next step without further purification. M/Z (M+H)+ = 175.2. Method (ii): Under anhydrous condition, to a solution of acetonitrile (2.0 equiv.) in THF (c=0.4 mol.L-1) cooled at -78C, BuLi (1.6N in hexane - 2 equiv.) was added dropwise. The reaction mixture turned light beige. The mixture was stirred for 1 hour at -78C, then the acid derivative (acid chloride or ester - 1.0 equiv.) was added dropwise. The reaction mixture was stirred at -78C for 1 hour, after which time it was allowed to warm to 0C and hydrolysed with AcOH. The reaction mixture was concentrated, dried under reduced pressure at 50C with P2O5 for 18 hours.A mixture of 1.372 g (8.3 mmol) of (3), 60 mg of AlBN and 2.866 g (16.1 mmol) of NBS in 120 ml of CCl4 is refluxed under a nitrogen atmosphere and under irradiation with a 100 W lamp, for 8 hours. The reaction medium is then returned to room temperature, after which it is washed with 200 ml of saturated NaHCO3 solution. After removing the lower phase (CCl4), the aqueous phase is extracted 4 times with 50 ml of CHCl3; the combined organic extracts are then washed with 100 ml of H2O, dried (Na2SO4) and then concentrated to dryness. Purification of the residue obtained by chromatography on silica [gradient: cyclohexane-CH2Cl2 (80/20) to pure CH2Cl2) makes it possible to separate out a first fraction of the bromo derivative (4), from the polybromo species, from a mixture of isomers of symmetrical and asymmetrical dibromo derivatives and from the monobromo species also formed. [0153] In order to have available a larger amount of methyl 2, 6-dibromomethyl isonicotinate, the monobromo compound isolated above [0.543 g (2.2 mmol)] is mixed with 0.4 g (2.2 mmol) of NBS, 23 mg of AIBN and 50 ml of CCl4 and is then treated under the above bromination conditions to give a second fraction of (4). [0154] Finally, a purification by chromatography on silica [gradient: pure cyclohexane to cyclohexane/EtOAc (85/15)] of the mixtures of dibromoisomers, isolated in the above two reactions, gives a final fraction of (4), i.e. 596 mg in total (22%). [0155] m.p.: 90-92 C. [0156] TLC: Rf: 0.6 (SiO2/CH2Cl2) [0157] HPLC: Tr: 20 min 5 sec [0158] UV: CHCl3: 290.8 nm (4270); 240.3 nm (3010) [0159] NMR: 1H CDCl3; internal reference TMS [0160] 3.98 (s, 3H, CH3); 4.58 (s, 4H, CH2); 7.92 (s, 2H, Py) [0161] 13C CDCl3; internal reference 77.0 ppm [0162] 32.8 (CH2); 52.9 (OCH3); 122.2 (Ct); 139.8, 157.9 (Cq); [0163] 164.7 (CO). [0164] MS (EI): 322.9 (M+, 15); 243.9 (M+-Br, 100); 163 (M+-2Br, 15.7). [0165] MA: C9H9NO2Br2 (322.98) [0166] Calculated: C 33.47H 2.80 N 4.33 O 9.90 [0167] Found: C 33.69H 2.81 N 4.29 O 10.17120ml'CCl4'1.372g(8.3mmol)?(3)?60mg'AIBN???2.866g(16.1mmol)?NBS??????????????100W??????????8???????????????????????????200ml??NaHCO3??????????(CCl4)???????????50ml'H2O'4?????????????????100ml'H2O???????(Na2SO4)???????????????????????????????????????[?:???????-CH2Cl2(80/20)?CH2Cl2]?????????????????????????????????????????????????????????????(4)??1???????????????

Molecular Weight:165.19
XLogP3:1.5
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:165.078978594
Monoisotopic Mass:165.078978594
Topological Polar Surface Area:39.2
Heavy Atom Count:12
Complexity:160
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes