* 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.
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 6 h;
A) 2,6-Dichloro-4-methyl-nicotinic acid methyl ester To a solution of 8.05 g (39.1 mmol) of 2,6-dichloro-4-methyl-nicotinic acid [Lamm, G. Ger. Offen. (1977), DE 2538950] in 100 ml of DMF was added 8.10 g (58.6 mmol) of potassium carbonate. While stirring, 12.16 ml=27.7 g (195.4 mmol) of iodomethane was added drop by drop and the reaction mixture was stirred for 6 hours at RT. It was then poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated to give 8.47 g (99percent) of the title compound as light yellow solid. MS: 219.0 (M+, 2Cl).
99%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere
A) 2,6-Dichloro-4-methyl-nicotinic acid methyl ester; To a solution of 8.05 g (39.1 mmol) of 2,6-dichloro-4-methyl-nicotinic acid [Lamm, G. Ger. Offen. (1977), DE 2538950] in 100 ml of DMF was added 8.10 g (58.6 mmol) of potassium carbonate. While stirring, 12.16 ml=27.7 g (195.4 mmol) of iodomethane was added drop by drop and the reaction mixture was stirred for 6 hours at RT. It was then poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated to give 8.47 g (99percent) of the title compound as light yellow solid. MS: 219.0 (M+, 2Cl).
98%
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 3 h;
a) Synthesis of 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester To a solution of 5.0 g (24.3 mmol) 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid in DMF (73 ml) were added 5.0 g (36.4 mmol) K2CO3 and 7.6 ml (121.3 mmol) iodomethane at 0° C. The reaction mixture was stirred at RT for 3 h and was subsequently poured into water. This mixture was extracted with EtOAc and the organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 19:1) provided 5.2 g (23.7 mmol, 98percent) 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester.
98%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3 h;
a) Synthesis of 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester To a solution of 5.0 g (24.3 mmol) 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid in DMF (73 ml) were added 5.0 g (36.4 mmol) K2C03 and 7.6 ml (121.3 mmol) iodomethane at 0 °C. The reaction mixture was stirred at RT for 3 h and was subsequently poured into water. This mixture was extracted with EtOAc and the organic layer was washed with water and brine, dried over Na2S04 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 19:1 ) provided 5.2 g (23.7 mmol, 98percent) 2,6-dichloro-4-methyl-pyridine-3- carboxylic acid methylester.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6.0h;
A) 2,6-Dichloro-4-methyl-nicotinic acid methyl ester To a solution of 8.05 g (39.1 mmol) of 2,6-dichloro-4-methyl-nicotinic acid [Lamm, G. Ger. Offen. (1977), DE 2538950] in 100 ml of DMF was added 8.10 g (58.6 mmol) of potassium carbonate. While stirring, 12.16 ml=27.7 g (195.4 mmol) of iodomethane was added drop by drop and the reaction mixture was stirred for 6 hours at RT. It was then poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated to give 8.47 g (99%) of the title compound as light yellow solid. MS: 219.0 (M+, 2Cl).
99%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;
A) 2,6-Dichloro-4-methyl-nicotinic acid methyl ester; To a solution of 8.05 g (39.1 mmol) of 2,6-dichloro-4-methyl-nicotinic acid [Lamm, G. Ger. Offen. (1977), DE 2538950] in 100 ml of DMF was added 8.10 g (58.6 mmol) of potassium carbonate. While stirring, 12.16 ml=27.7 g (195.4 mmol) of iodomethane was added drop by drop and the reaction mixture was stirred for 6 hours at RT. It was then poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated to give 8.47 g (99%) of the title compound as light yellow solid. MS: 219.0 (M+, 2Cl).
98%
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 3.0h;
a) Synthesis of 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester To a solution of 5.0 g (24.3 mmol) 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid in DMF (73 ml) were added 5.0 g (36.4 mmol) K2CO3 and 7.6 ml (121.3 mmol) iodomethane at 0 C. The reaction mixture was stirred at RT for 3 h and was subsequently poured into water. This mixture was extracted with EtOAc and the organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 19:1) provided 5.2 g (23.7 mmol, 98%) 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester.
98%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3.0h;
a) Synthesis of 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester To a solution of 5.0 g (24.3 mmol) 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid in DMF (73 ml) were added 5.0 g (36.4 mmol) K2C03 and 7.6 ml (121.3 mmol) iodomethane at 0 C. The reaction mixture was stirred at RT for 3 h and was subsequently poured into water. This mixture was extracted with EtOAc and the organic layer was washed with water and brine, dried over Na2S04 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 19:1 ) provided 5.2 g (23.7 mmol, 98%) 2,6-dichloro-4-methyl-pyridine-3- carboxylic acid methylester.
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 3.0h;
To a solution of 2,6-dichloro-4-methylnicotinic acid (10 g, 48.5 mmol) in DMF (162 mL) was added potassium carbonate (10.06 g, 72.8 mmol) and MeI (12 mL, 192 mmol) at 0 C. The reaction mixture was stirred at RT for 3 h and was subsequently poured into water. This mixture was extracted with EtOAc and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was used without further purification.
In methanol; dichloromethane; at 0 - 20℃; for 32.0h;
B) 6-Chloro-2-methoxy-4-methyl-nicotinic acid methyl ester To a solution of 6.50 g (29.5 mmol) of <strong>[1013648-04-8]2,6-dichloro-4-methyl-nicotinic acid methyl ester</strong> in 75 ml of CH2Cl2 was added at 0 C. 6.56 ml (35.4 mmol) of a sodium methoxide solution (5.4 molar in MeOH). After 16 hours, the reaction mixture was warmed up to RT and stirred again 16 hours at this temperature and subsequently poured into crashed ice; then, the pH was adjusted to 4-5 with 2N acetic acid and the reaction mixture was extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (heptane/EtOAc 1.0 to 98:2) to give 5.79 g (91%) of the title compound as colorless solid. MS: 216.1 (MH+, 1Cl).
91%
In methanol; dichloromethane; at 0 - 20℃;Inert atmosphere;
B) 6-Chloro-2-methoxy-4-methyl-nicotinic acid methyl ester; To a solution of 6.50 g (29.5 mmol) of <strong>[1013648-04-8]2,6-dichloro-4-methyl-nicotinic acid methyl ester</strong> in 75 ml of CH2Cl2 was added at 0 C. 6.56 ml (35.4 mmol) of a sodium methoxide solution (5.4 molar in MeOH). After 16 hours, the reaction mixture was warmed up to RT and stirred again 16 hours at this temperature and subsequently poured into crashed ice; then, the pH was adjusted to 4-5 with 2N acetic acid and the reaction mixture was extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (heptane/EtOAc 1.0 to 98:2) to give 5.79 g (91%) of the title compound as colorless solid. MS: 216.1 (MH+, 1Cl).
With pyridine; In methanol; dichloromethane; cyclohexane; water; ethyl acetate;
Example 61A Methyl 2,6-dichloro-4-methylnicotinate A solution of 10.3 g (45.9 mmol) of 2,6-dichloro-4-methylnicotinyl chloride [for preparation see DE 23 63 470-A1] in 20 ml of dichloromethane is added rapidly with stirring and cooling in a water/ice bath to 4.5 ml of pyridine in 100 ml of methanol. The mixture is stirred for a further 20 minutes and then concentrated under reduced pressure. The residue is taken up in ethyl acetate and washed successively with saturated aqueous sodium hydrogencarbonate solution, water and saturated aqueous sodium chloride solution. After drying over magnesium sulfate and filtration, the mixture is concentrated under reduced pressure. For purification, the mixture is filtered through 150 ml of silica gel in cyclohexane/ethyl acetate (1:1) and the eluent, after concentration, is crystallized from ethyl acetate/cyclohexane. After filtration and drying under reduced pressure, 5.8 g (58% of theory) of the target compound are obtained. A further 2.4 g (24% of theory) of the product are obtained from the mother liquor by another crystallization. 1H NMR (400 MHz, DMSO-d6): delta=2.33 (s, 3H), 3.93 (s, 3H) 7.66 (s, 1H).
Example 62A Methyl 2-chloro-6-(2-fluoro-3-methoxyphenyl)-4-methylnicotinate The title compound is prepared analogously to Example 57A. For purification, the crude product is separated first by preparative HPLC (method 9) and then by chromatography on silica gel with cyclohexane/ethyl acetate (10:1) as the eluent. Starting from 200 mg (0.91 mmol) of <strong>[1013648-04-8]methyl 2,6-dichloro-4-methylnicotinate</strong> from Example 61A, 160 mg (57% of theory) of the target compound are thus obtained. 1H NMR (400 MHz, DMSO-d6): delta=2.39 (s, 3H), 3.90 (s, 3H), 3.95 (s, 3H), 7.25-7.35 (m, 2H), 7.38 (ddd, 1H), 7.79 (s, 1H).
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 16.0h;
b) Synthesis of 2-chloro-4-methyl-6-morpholino-pyridine-3-carboxylic acid methylesterA solution of 5.2 g (23.7 mmol) <strong>[1013648-04-8]2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester</strong>, 3.94 g (28.5 mmol) K2CO3 and 2.06 ml (23.7 mmol) morpholine in DMF (48 ml) was heated to 60 C. for 16 h. Then the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 4:1) provided 1.95 g (7.2 mmol, 30%) 2-chloro-4-methyl-6-morpholino-pyridine-3-carboxylic acid methylester.
30%
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 16.0h;
) Synthesis of 2-chloro-4-methyl-6-morpholino-pyridine-3-carboxylic acid methylesterA solution of 5.2 g (23.7 mmol) <strong>[1013648-04-8]2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester</strong>, 3.94 g (28.5 mmol) K2C03 and 2.06 ml (23.7 mmol) morpholine in DMF (48 ml) was heated to 60 C for 16 h. Then the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2S04 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 4:1 ) provided 1.95 g (7.2 mmol, 30%) 2-chloro-4-methyl-6-morpholino-pyridine-3-carboxylic acid methylester.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); acetic acid; In tetrachloromethane; at 60℃; for 24.0h;
a) Synthesis of 4-(bromomethyl)-2,6-dichloro-pyridine-3-carboxylic acid methylester To a solution of 5.3 g (24.1 mmol) <strong>[1013648-04-8]2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester</strong> in CCl4 (92 ml) were added 3.1 g (26.5 mmol) N-Bromosuccinimide, 395 mg (2.4 mmol) AlBN and 1.45 ml (25.3 mmol) acetic acid. The mixture was irradiated with a 200 W Wolfram lamp at 60 C. for 24 h. Subsequently the mixture was filtered through celite and the filtrate was concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 97:3) provided 5.2 g of a mixture of <strong>[1013648-04-8]2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester</strong> and 4-(bromomethyl)-2,6-dichloro-pyridine-3-carboxylic acid methylester which was used in subsequent reactions without further purification.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); acetic acid; In tetrachloromethane; at 60℃; for 24.0h;irradiated with a 200W Wolfram lamp;
a) Synthesis of 4-(bromomethyl)-2,6-dichloro-pyridine-3-carboxylic acid methylesterTo a solution of 5.3 g (24.1 mmol) <strong>[1013648-04-8]2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester</strong> in CCI4 (92 ml) were added 3.1 g (26.5 mmol) N-Bromosuccinimide, 395 mg (2.4 mmol) AIBN and 1.45 ml (25.3 mmol) acetic acid. The mixture was irradiated with a 200W Wolfram lamp at 60 C for 24 h. Subsequently the mixture was filtered through celite and the filtrate was concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 97:3) provided 5.2 g of a mixture of <strong>[1013648-04-8]2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester</strong> and 4-(bromomethyl)-2,6-dichloro-pyridine-3-carboxylic acid methylester which was used in subsequent reactions without further purification.
6.4 g
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 85℃;
to a 250 ml flask were added <strong>[1013648-04-8]methyl 2,6-dichloro-4-methylnicotinate</strong> (4.24 g, 19.268 mmol), N-bromosuccinimide (4.1 g, 23.036 mmol), azobisisobutyronitrile (160 mg, 0.974 mmol) and 50 ml of carbon tetrachloride. The reaction mixture was stirred at 85 C. overnight. The reaction mixture was concentrated to remove carbon tetrachloride, and 50 ml of ethyl acetate was added, which was then washed with 50 ml of brine and 50 ml of water successively. The organic phase was dried over anhydrous sodium sulfate, concentrated to give 6.4 g of methyl 4-(bromomethyl)-2,6-dichloronicotinate as an oil, MS m/z (ESI): 300.1[M+H]+.
With tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In N,N-dimethyl-formamide; at 110℃; for 6.0h;
Example 4040-A. Methyl 2-chloro-4-methyl-6-(3-methyl-l-tosyl-lH-indol-4-yl)nicotinate.A mixture of <strong>[1013648-04-8]methyl 2,6-dichloro-4-methylnicotinate</strong> (0.250 g, 1.14 mmol), 3-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-lH-indole (Example 6) (0.514 g, 1.25 mmol), Pd(Ph3P)4 (0.131 g, 0.114 mmol), and CsF (0.345 g, 2.27 mmol), in DMF (5 mL) was heated at 110 C for 6 h. At that time the vessel was removed from the oil bath and allowed to cool to rt. The mixture was diluted with brine (50 mL) and EtO Ac (50 mL). The layers were mixed and then separated. The aqueous layer was further extracted with EtO Ac (50 mL) and the combined organic layers were dried (Na2S04), filtered, and concentrated. The residue was then purified via FCC (0-10% EtO Ac/heptane) to give the title compound. MS ESI m/z 469.0 & 470.9 (M+H)+.
methyl 6-chloro-2-cyano-4-methylnicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In 1-methyl-pyrrolidin-2-one; at 180℃; for 2.0h;Inert atmosphere; Microwave irradiation;
A solution of <strong>[1013648-04-8]methyl 2,6-dichloro-4-methylnicotinate</strong> (3 g, 13.6 mmol) and copper(I) cyanide (1.83 g, 20.5 mmol) in NMP (13.6 mL) was degassed and placed under nitrogen. The system was heated to 180 C. for 2 h under microwave irradiation. The mixture was diluted with 10% aqueous ammonium hydroxide (22 mL) and was filtered over Celite (EtOAc wash). The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by column chromatography on silica gel (0-20% EtOAc in hexanes) to yield the title compound. MS: 211 (M+1).