* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 704,707
2
[ 3998-90-1 ]
[ 16830-24-3 ]
Yield
Reaction Conditions
Operation in experiment
61%
With palladium 10% on activated carbon; hydrogen; triethylamine In N,N-dimethyl-formamide at 20℃; for 15 h;
Methyl 2-chloro-6-methylpyridin-4-carboxylate (15.0 g, 80.8 mmol), 10percent palladium carbon powder (50percent water containing product) (5.00 g), and triethylamine (22.5 mL, 162 mmol) were stirred in N,N-dimethylformamide (200 mL) under hydrogen atmosphere, at room temperature, for 15 h. The mixture was filtered, and the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate: methanol= 100:0-50:1) to give the title compound (14.8 g, 61percent) as an oil. 1H NMR (CDCl3) d: 2.64 (3H, s), 3.95 (3H, s), 7.64 (1H, dd, J =5.2, 0.8 Hz), 7.72 (1H, s), 8.65 (1H, d, J = 4.7 Hz).
53%
With sodium hydroxide In methanol
A mixture of methyl 2-chloro-6-methyl-pyridine-4-carboxylate (1.8 g, 10 mmol) and 10percent palladium-on-charcoal catalyst (200 mg) in methanol (100 ml) was stirred under hydrogen at 5 atmospheres pressure. The catalyst was removed by filtration and the volatiles removed from the filtrate by evaporation. The residue was treated with 10percent aqueous sodium hydroxide solution and extracted with ether (3*30 ml). The combined extracts were dried (MgSO4) and the solvent removed by evaporation to give methyl 2-methyl-pyridine-4-carboxylate (800 mg, 53percent) as an oil.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 3, p. 647 - 660
[2] Patent: US5962458, 1999, A,
[3] Patent: US6362336, 2002, B1, . Location in patent: Example 63
[4] Helvetica Chimica Acta, 1955, vol. 38, p. 1046,1058
[5] Bulletin de la Societe Chimique de France, 1958, p. 687,691
[6] Journal of the American Chemical Society, 1959, vol. 81, p. 704,707
General procedure: To a stirred solution of POCl3 (10 mL, 107 mmol) was added acid 2 (2.37 g, 15.5 mmol), and the resulting solution was heated to reflux for 18 h. The excess POCl3 was removed under reduced pressure, the residue was cooled to -5°C, methanol (20 mL) was added drop wise, and the resulting mixture was stirred for 24 h at rt. Distilled off MeOH completely, neutralized with solid NaHCO3, and partitioned between H2O (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc, dried (Na2SO4), and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography over silica gel (CH2Cl2), to give ester 3a (2 g, 10.8 mmol, 69percent yield) as a white solid. Rf (Silica gel, CH2Cl2): 0.66; 1H NMR (300 MHz, CDCl3) δ 2.59 (s, 3H), 3.94 (s, 3H), 7.61(s, 1H), 7.67 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 24.2, 52.9, 120.8, 121.2, 140.3, 151.4, 160.5, 164.6; MS (EI, 70ev): m/z (percent) [M+H]+.186 (100).
Reference：
[1] Tetrahedron Letters, 2007, vol. 48, # 6, p. 999 - 1002
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4629 - 4635
[3] Chemistry - A European Journal, 2015, vol. 21, # 33, p. 11745 - 11756
General procedure: To a stirred solution of POCl3 (10 mL, 107 mmol) was added acid 2 (2.37 g, 15.5 mmol), and the resulting solution was heated to reflux for 18 h. The excess POCl3 was removed under reduced pressure, the residue was cooled to -5°C, methanol (20 mL) was added drop wise, and the resulting mixture was stirred for 24 h at rt. Distilled off MeOH completely, neutralized with solid NaHCO3, and partitioned between H2O (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc, dried (Na2SO4), and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography over silica gel (CH2Cl2), to give ester 3a (2 g, 10.8 mmol, 69percent yield) as a white solid. Rf (Silica gel, CH2Cl2): 0.66; 1H NMR (300 MHz, CDCl3) delta 2.59 (s, 3H), 3.94 (s, 3H), 7.61(s, 1H), 7.67 (s, 1H); 13C NMR (75 MHz, CDCl3) delta 24.2, 52.9, 120.8, 121.2, 140.3, 151.4, 160.5, 164.6; MS (EI, 70ev): m/z (percent) [M+H]+. 186 (100).
The starting material was prepared as follows: Oxalyl chloride (1.9 g, 15 mmol) was added to 2-chloro-6-methyl-pyridine4-carboxylic acid (1.7 g, 10 mmol) in methylene chloride (30 ml) and the mixture stirred for 2 hours. The volatiles were removed by evaporation and methanol (20 ml) added to the residue. The mixture was stirred for 1 hour and the volatiles removed by evaporation to give methyl 2-chloro-6-methyl-pyridine-4-carboxylate (1.85 g, 100percent) as an off-white solid. 1 H NMR Spectrum: (CDCl3) 2.55(s, 3H); 3.90(s, 3H); 7.55(s, 1H); 7.60(s, 1H); MS - ESI: 186 [MH]+
2-Chloro-6-methyl-4-pyridine carboxylic acid (0.25 g, 1.46 mmol) was dissolved in 10 mL methanol under nitrogen, followed by the dropwise addition of BF3.MeOH (0.45 mL, 3 eq) via syringe. The solution was refluxed for three hours, then stirred at room temperature overnight. The solution was poured into 20 mL water and extracted with Et2 O (2*25 mL). The organics were collected, washed with 1.0 N NaOH, H2 O, dried over MgSO4, then concentrated to give methyl (2-chloro-6-methyl)isonicotinate (0.14 g) as a peach colored solid.
LiAlH4 (10.0 g, 0.264 mol, 1.24 eq) was added portionwise to a solution of methyl-2-chloro-6-methylpyridine-4-carboxylate 1 (39.62 g, 0.213 mol) in dry THF (800 mL) at room temperature with stirring over a period of 1.4 h. The resulting mixture was stirred for 1 h and quenched with water. 15percent aqueous NaOH (100 mL) was added, followed by aqueous sodium-potassium tartrate (1 L). The resulting mixture was stirred for a further 1.25 h and extracted with dichloromethane (2.x.1 L) to give, after concentration, (2-chloro-6-methylpyridin-4-yl)-methanol 2 (31.06 g, 93percent) as a yellow solid.
93%
Lithium aluminum hydride (10.0 g, 0.264 mol, 1.24 eq) was added port ion wise to a solution of methyl^-chloro-delta-methylpyridine^-carboxylate (5a, 39.62 g, 0.213 mol) in dry THF (800 mL) at room temperature with stirring over a period of 1.4 hours. The resulting mixture was stirred for I hour and quenched with water. Then 15percent aqueous NaOH (100 m L) was added followed by aqueous Na-K tartrate (1 L). The resulting mixture was stirred for an additional 1.25 hours and extracted with DCM (2 x I L) to provide (2-chloro-6-methylpyridin- 4-yl)-methanol 5b (31.06 g, 93percent) as a yellow solid
93%
Example 21; Preparation of Compound 21A ; LiAlH4 (10.0 g, 0.264 mol, 1.24 eq) was portionwise added to a solution of methyl-2-chloro-6-methylpyridine-4-carboxylate 54 (39.62 g, 0.213 mol) in dry THF (800 mL) at room temperature, with stirring, over a period of 1.4 h. The resulting mixture was stirred for 1 h and quenched with water. Then 15percent aqueous NaOH (100 mL) was added, followed by aqueous sodium-potassium tartrate (1 l). The resulting mixture was stirred for a further 1.25 h and extracted with DCM (2.x.1 l) to give, after concentration, (2-chloro-6-methylpyridin-4-yl)-methanol 55 (31.06 g, 93percent) as a yellow solid.
80%
Methyl 2-chloro-6-methylpyridine-4-carboxylate (6.50 g, 35.0 mmol) was dissolved in dry THF(110 mL). Lithium aluminium hydride (1.65 g, 43.4 mmol) was added portionwise within 60 mm.The reaction mixture was stirred at room temperature fort he next 1.5 hours. Afterwards 50 mLwater and 100 mL of an aqueous sodium hydroxide solution (15percent) were added. This mixturewas stirred for another hour and extracted three times with dichioromethane. The organic phase was washed with saturated sodium carbonate solution, dried (Whatman filter) and the solvent was removed in vacuum to give 4.4 g (80 percent yield) of the title compound which was used without further purification.LC-MS (Method 2): R = 0.67 mm; MS (ESIpos): m/z = 158 [M+H] 1H-NMR (400 MHz, DMSO-d6) [ppm]: 1.352 (0.50), 1.854 (0.64), 1.859 (0.61), 2.427 (16.00),2.437 (1.41), 2.523 (0.74), 3.158 (1.14), 3.172 (1.31), 3.386 (1.09), 4.499 (3.82), 4.513 (3.88),5.491 (1.29), 5.506 (2.86), 5.520 (1.25), 7.185 (3.22), 7.200 (3.13).
2-Chloro-6-methyl isonicotinic acid was treated in ethanol (0.04 M) with diazomethane in ether to obtain the methyl ester derivative. The solution was concentrated to afford the title compound
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 48h;
15. Methyl 2-chloro-6-methylpyridine-4-carboxvlate-N-oxide; <n="61"/>A solution of MCPBA (6.6 g, 29.6 mmol) in 50 ml OfCH2Cl2 is added dropwise to a solution of <strong>[3998-90-1]methyl 2-chloro-6-methylpyridine-4-carboxylate</strong> (5.0 g, 26.9 mmol) in 30 ml OfCH2Cl2 at RT. The reaction mixture is stirred for 2 days, and then it is evaporated to dryness. Sat. NaHCO3 (20 ml) and EtOAc (30 ml) are added. The layers are separated, and the aqueous layer is extracted twice more with EtOAc (30 ml each). The combined organic extracts are dried (Na2SO4), filtered, and evaporated in vacuo to give an off-white solid. Purification by silica gel column chromatography (gradient from Hex to EtOAc) affords the title compound as a white solid. 1H NMR (400 MHz, CDCl3) delta 8.0 (IH, s), 7.80 (IH, s), 3.94 (3H, s), 2.57 (3H, s).
With 3-chloro-benzenecarboperoxoic acid; In benzene; at 20℃; for 48h;Inert atmosphere;
General procedure: A mixture of (0.5g, 2.7mmol) of 3-chloro-1-methylisoquinoline (2a), (0.8 g, 4.6mmol) of m-chloro per benzoic acid, and benzene (8 mL) was stirred until a solution formed and was allowed to stand at room temperature for 2 days. Treatment of the reaction mixture with sodium carbonate solution followed by extraction with dichloromethane afforded 0.35 g (60percent yield) of crude product. Rf: 0.4 (30percent EtOAc in Petroleum Ether), mp 120 °C; IR (cm-1): 3066, 2928, 1716 (CO ester), 1527, 1439, 1235(N-O), 1176, 935(N-O); 1H NMR (300 MHz, CDCl3) delta 2.50 (s, 3H), 3.87 (s, 3H), 7.73 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H) ; 13C NMR (75 MHz, CDCl3) delta 18.7, 52.9, 124.0, 124.6, 125.1, 142.4, 151.0, 163.6; MS (EI, 70ev): m/z (percent) [M]+. 201(98.75), 184 (100).
With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tetrahydrofuran; 1,4-dioxane; at 90℃; for 15h;Inert atmosphere;
2-Ethylamino-6-methyl-isonicotinic acid methyl ester Under argon, Cs2CO3 (6.85 g, 21.0 mmol), Xantphos (1.39 g, 2.40 mmol) and Pd(OAc)2 (314 mg, 1.40 mmol) and 2 Methylamine in THF (30 mL) are added to a solution of 2-chloro-6-picoline-4-carboxylic acid methyl ester (1.30 g, 7.00 mmol) in dioxane (20 mL). The reaction mixture is stirred at 90° C. for 15 h. The reaction mixture is then filtered, and concentrated under vacuum. The residue is diluted with water and extracted with EA (twice). The org. extracts are dried over MgSO4, filtered, concentrated and purified by CC (eluding with heptane: EA 7/3) to give the title compound as a yellow oil (0.6 g); LC-MS: tR=0.56 min, [M+H]+=195.00. 1H NMR (CDCl3) delta1.28 (t, J=7.0 Hz, 3H), 2.44 (s, 3H), 3.33 (m, 2H), 3.93 (s, 3H), 4.62 (m, 1H), 6.76 (m, 1H), 6.99 (s, 1H).
With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;palladium diacetate; In tetrahydrofuran; 1,4-dioxane; at 90℃; for 15h;Inert atmosphere;
Under argon, Cs2CO3 (6.85 g, 21.0 mmol), Xantphos (1.39 g, 2.40 mmol) and Pd(OAc)2 (314 mg, 1.40 mmol) and 2 M ethylamine in THF (30 mL) are added to a solution of 2- chloro-6-picoline-4-carboxylic acid methyl ester (1.30 g, 7.00 mmol) in dioxane (20 mL).The reaction mixture is stirred at 90°C for 15 h. The reaction mixture is then filtered, and concentrated under vaccum. The residue is diluted with water and extracted with EA(twice). The org. extracts are dried over MgSO4, filtered, concentrated and purified by CC (eluting with heptane: EA 7/3) to give the title compound as a yellow oil (0.6 g); LC-MS: tR =0.56 min, [M+H]+ = 195.00. 1H NMR (CDCI3) .51.28 (t, J = 7.0 Hz, 3 H), 2.44 (s, 3 H), 3.33(m, 2 H), 3.93 (s, 3 H), 4.62 (m, 1 H), 6.76 (m, 1 H), 6.99 (s, 1 H).
With tetrabutyl ammonium fluoride;palladium bis[bis(diphenylphosphino)ferrocene] dichloride; In tetrahydrofuran; at 75℃; for 3h;
According to Scheme 49, a solution of compound 31 (1.1 g, 5.9 mmol, Aldrich), 4-(4'-fluorophenoxy)phenyl pinacol boronate (1.85 g, 5.9 mmol), Pd(dppf)2Cl2 (385 mg, 0.47 mmol, Aldrich) in 1.0 M TBAF THF solution (10 mL) was heated at 75°C for 3 h. After cooling to room temperature, the reaction mixture was purified by column chromatography (silica gel, 0-30percent EtOAc/Hexane) to give compound 32 (1.0 g, 3.2 mmol).
With potassium phosphate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 150℃; for 1h;microwave irradiation;
A mixture of <strong>[3998-90-1]<strong>[3998-90-1]methyl 2-chloro-6-methylisonicotinat</strong>e</strong> (2.00 g, 10.8 mmol), acetamide (1.27 g, 21.6 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.20 g, 0.22 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.37 g, 0.65 mmol), tripotassium phosphate (2.74 g, 12.9 mmol) and 1,4-dioxane (26 mL) is heated by microwave irradiation at 150 oC for 1 hr. After cooling to room temperature, the mixture is filtered through a pad of celite. The filtrate is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel eluting with n-hexane / ethyl acetate (4:1~1:3) to give 1.99 g (89percent yield) of the title compound as a yellow solid.1H-NMR (270 MHz, CDCl3) delta 8.50 (1H, br s), 8.17 (1H, br s), 7.47 (1H, br s), 3.94 (3H, s), 2.50 (3H, s), 2.22 (3H, s), MS (ESI) m/z: 209 (M+H)+.
89%
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 150℃; for 1h;Microwave irradiation;
A mixture of <strong>[3998-90-1]<strong>[3998-90-1]methyl 2-chloro-6-methylisonicotinat</strong>e</strong> (2.00 g, 10.8 mmol), acetamide (1.27 g, 21.6 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.20 g, 0.22 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.37 g, 0.65 mmol), tripotassium phosphate (2.74 g, 12.9 mmol) and 1,4-dioxane (26 mL) is heated by microwave irradiation at 150 oC for 1 hr.After cooling to rt, the mixture is filtered through a pad of celite.The filtrate is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel eluting with n-hexane / EtOAc (4:1 to1:3) to give 1.99 g (89percent yield) of the title compound as a yellow solid. 1H-NMR (270 MHz, CDCl 3) delta 8.50 (1H, br.s), 8.17 (1H, br.s), 7.47 (1H, br.s), 3.94 (3H, s), 2.50 (3H, s), 2.22 (3H, s), MS (ESI) m/z: 209 (M+H) +.
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