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Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 0.5 h; Stage #2: for 2 h;
Ethyl 2-chloro-5-methylnicotinate. To a solution of 2-chloro-5-methylnicotinic acid (3.90 g, 22.7 mmol) in DCM (100 ml_) was added oxalyl chloride (9.95 ml_, 1 14 mmol) followed by 1 drop of DMF. The resulting mixture was stirred at RT for 30 min and evaporated in vacuo. The residue thus obtained was taken up into EtOH (66 ml_), stirred for a further 2 hr and then evaporated in vacuo. The crude product obtained was purified by flash column chromatography (S1O2, 120 g, 0-50percent DCM in isohexane, gradient elution) to afford the title compound as a colourless oil (3.71 g, 82percent yield); 1 H NMR δ: 1.32 (3H, t), 2.34 (3H, s), 4.34 (2H, q), 8.06-8.07 (1 H, m), 8.41-8.43 (1 H, m). [See also: Yamamoto S. et al., Bioorg. Med. Chem. 2012, 20, 422-434.]
82%
Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 0.5 h; Stage #2: for 2 h;
To a solution of 2-chloro-5-methylnicotinic acid (3.90 g, 22.7 mmol) in DCM (100 mL) was added oxalyl chloride (9.95 mL, 114 mmol) followed by 1 drop of DMF. The resulting mixture was stirred at RT for 30 min and evaporated in vacuo. The residue thus obtained was taken up into EtOH (66 mL), stirred for a further 2 hr and then evaporated in vacuo. The crude product obtained was purified by flash column chromatography (S1O2, 120 g, 0-50percent DCM in isohexane, gradient elution) to afford the title compound as a colourless oil (3.71 g, 82percent yield); 1 H NMR δ: 1.32 (3H, t), 2.34 (3H, s), 4.34 (2H, q), 8.06-8.07 (1 H, m), 8.41 -8.43 (1 H, m). [See also: Yamamoto S. et al., Bioorg. Med. Chem. 2012, 20, 422-434.]
Stage #1: at 0 - 80℃; for 2 h; Stage #2: Cooling with ice
To a mixture of ethyl (2E)-2-cyanopent-2-enoate 34 (30.0 g, 196 mmol) and DMF (76 mL, 982 mmol) was added phosphoryl chloride (36 mL, 386 mmol) dropwise at 0 °C. After stirring at 80 °C for 2 h, the mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give 35 (21.1 g, 54percent) as an oil. 1H NMR (200 MHz, CDCl3) δ: 1.42 (3H, t, J = 7.2 Hz), 2.37 (3H, s), 4.42 (2H, q, J = 7.2 Hz), 7.96 (1H, d, J = 2.6 Hz), 8.32 (1H, d, J = 2.6 Hz).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 1, p. 422 - 434
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 90℃; for 5h;
A mixture of 35 (14.7 g, 73.6 mmol), AIBN (1.31 g, 7.98 mmol), N-bromosuccinimide (17.1 g, 96.1 mmol), and CCl4 (200 mL) was stirred at 90 C for 5 h. The mixture was partitioned between EtOAc and brine. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give 36 (10.5 g, 51%) as an oil. 1H NMR (200 MHz, CDCl3) delta: 1.39-1.45 (3H, m), 4.30-4.55 (4H, m), 7.97 (1H, d, J = 2.6 Hz), 8.19 (1H, d, J = 2.6 Hz).
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 90℃; for 5h;
A mixture of <strong>[894074-85-2]ethyl 2-chloro-5-methylnicotinate</strong> (14.7 g) , 2, 2' -azobis (isobutyronitrile) (1.31 g) , N- bromosuccinimide (17.1 g) and carbon tetrachloride (200 ml) was heated at 900C for 5 hours. After an aqueous saturated sodium chloride solution (100 ml) was added to the reaction mixture, this was extracted with ethyl acetate, and the ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the desired product (10.5 g) as an oil. 1H-NMR (CDCl3) delta 1.4 - 1.5 (3H, m) , 4.3-4.5 (4H, m) , 7.97 (IH, d) , 8.19 (IH, d) .
To a mixture of ethyl (2E)-2-cyanopent-2-enoate 34 (30.0 g, 196 mmol) and DMF (76 mL, 982 mmol) was added phosphoryl chloride (36 mL, 386 mmol) dropwise at 0 C. After stirring at 80 C for 2 h, the mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give 35 (21.1 g, 54%) as an oil. 1H NMR (200 MHz, CDCl3) delta: 1.42 (3H, t, J = 7.2 Hz), 2.37 (3H, s), 4.42 (2H, q, J = 7.2 Hz), 7.96 (1H, d, J = 2.6 Hz), 8.32 (1H, d, J = 2.6 Hz).
N-(2-fluoro-6-methylphenyl)-6-(4-(5-methyl-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)nicotinamido)benzoyl)-5,6-dihydro-4H-benzo[b]thieno[2,3-d]azepine-2-carboxamide[ No CAS ]
ethyl 5-methyl-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 150℃; for 2h;
Ethyl 5-methyl-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)nicotinate. A mixture of <strong>[894074-85-2]ethyl 2-chloro-5-methylnicotinate</strong> (3.70 g, 18.5 mmol), 7-oxa-2-azaspiro[3.5] nonane hemi oxalate (9.57 g, 55.6 mmol) and DIPEA (19.4 ml_, 11 1 mmol) in NMP (50 ml_) was heated at 150C for 2 hr. After cooling to RT the crude mixture was poured into water (200 ml_) and extracted with EtOAc (3 x 200 ml_). The combined organic extracts were washed with brine (2 x 100 ml_), and then dried and evaporated in vacuo to afford the title compound (4.81 g, g, 88% yield); R' 1.32 min; m/z 291 (M+H)+ (ES+); 1 H NMR delta: 1.29 (3H, t), 1.67 (4H, br t), 2.18 (3H, s), 3.52 (4H, br t), 3.67 (4H, s), 4.25 (2H, q), 7.74 (1 H, apparent dd), 8.12 (1 H, apparent dd).
Ethyl 2-chloro-5-methylnicotinate. To a solution of <strong>[66909-30-6]2-chloro-5-methylnicotinic acid</strong> (3.90 g, 22.7 mmol) in DCM (100 ml_) was added oxalyl chloride (9.95 ml_, 1 14 mmol) followed by 1 drop of DMF. The resulting mixture was stirred at RT for 30 min and evaporated in vacuo. The residue thus obtained was taken up into EtOH (66 ml_), stirred for a further 2 hr and then evaporated in vacuo. The crude product obtained was purified by flash column chromatography (S1O2, 120 g, 0-50% DCM in isohexane, gradient elution) to afford the title compound as a colourless oil (3.71 g, 82% yield); 1 H NMR delta: 1.32 (3H, t), 2.34 (3H, s), 4.34 (2H, q), 8.06-8.07 (1 H, m), 8.41-8.43 (1 H, m). [See also: Yamamoto S. et al., Bioorg. Med. Chem. 2012, 20, 422-434.]
82%
To a solution of <strong>[66909-30-6]2-chloro-5-methylnicotinic acid</strong> (3.90 g, 22.7 mmol) in DCM (100 mL) was added oxalyl chloride (9.95 mL, 114 mmol) followed by 1 drop of DMF. The resulting mixture was stirred at RT for 30 min and evaporated in vacuo. The residue thus obtained was taken up into EtOH (66 mL), stirred for a further 2 hr and then evaporated in vacuo. The crude product obtained was purified by flash column chromatography (S1O2, 120 g, 0-50% DCM in isohexane, gradient elution) to afford the title compound as a colourless oil (3.71 g, 82% yield); 1 H NMR delta: 1.32 (3H, t), 2.34 (3H, s), 4.34 (2H, q), 8.06-8.07 (1 H, m), 8.41 -8.43 (1 H, m). [See also: Yamamoto S. et al., Bioorg. Med. Chem. 2012, 20, 422-434.]
N-(2,6-difluorophenyl)-4-(4-(5-methyl-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)nicotinamido)benzoyl)-5,6-dihydro-4H-dithieno[3,2-b:2',3'-d]azepine-8-carboxamide[ No CAS ]
N-(2,6-difluorophenyl)-4-(4-(5-methyl-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)nicotinamido)benzoyl-2,3,5,6-d4)-5,6-dihydro-4H-dithieno[3,2-b:2',3'-d]azepine-8-carboxamide[ No CAS ]
7-oxa-2-azaspiro[3.5]nonane hemioxalic acid[ No CAS ]
ethyl 5-methyl-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 150℃; for 2h;
A mixture of <strong>[894074-85-2]ethyl 2-chloro-5-methylnicotinate</strong> (3.70 g, 18.5 mmol), 7-oxa-2-azaspiro[3.5] nonane hemioxalate (9.57 g, 55.6 mmol) and DIPEA (19.4 mL, 111 mmol) in NMP (50 mL) was heated at 150C for 2 hr. After cooling to RT the crude mixture was poured into water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with brine (2 x 100 mL), and then dried and evaporated in vacuo to afford the title compound (4.81 g, 88% yield); R .32 min (Method 1 a); m/z 291 (M+H)+ (ES+); 1 H NMR delta: 1.29 (3H, t), 1.67 (4H, br t), 2.18 (3H, s), 3.52 (4H, br t), 3.67 (4H, s), 4.25 (2H, q), 7.74 (1 H, apparent dd), 8.12 (1 H, apparent dd).
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