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Stage #1: for 2 h; Cooling with ice Stage #2: With hydrogenchloride; water In tetrahydrofuran for 0.5 h; Cooling with ice
In a mixture of 54 g of 3-chloropyridine-2-carbonitrile and 300 mL of THF, 500 g of 1 M methylmagnesium bromide THF solution was added dropwise under ice cooling. The reaction mixture was stirred for 2 hours under ice cooling. The reaction mixture obtained was added to 2N hydrochloric acid under ice cooling, and the mixture was stirred for 30 minutes. A 1N sodium hydroxide aqueous solution was added to the mixture, and the mixture was adjusted to pH 8, followed by extraction with ethyl acetate. After washing the organic layer with saturated brine, the organic layer was dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain 58 g of an intermediate (12-1)
58 g
Stage #1: for 2 h; Cooling with ice Stage #2: With hydrogenchloride; water In tetrahydrofuran for 0.5 h; Cooling with ice
Preparation Example 2(1) (0639) To 3-chloropyridine-2-carbonitrile 54 g, and THF 300 mL, 1M THF solution of methyl magnesium bromide 500 mg was added dropwise under ice-cooling. The obtained reaction mixtures were stirred under ice-cooling for 2 hours. The obtained reaction mixtures were added to 2N hydrochloric acid under ice-cooling, and stirred for 30 minutes. To the mixtures was added 1N sodium hydroxide solution to adjust to pH 8, and the mixtures were extracted with ethyl acetate. The obtained organic layer was washed with brine and dried over anhydrous sodium sulfate. The organic layer was concentrated to give the Intermediate compound (4-1) 58 g. 1H-NMR (CDCl3) δ: 8.55 (1H, dd), 7.80 (1H, dd), 7.38 (1H, dd), 2.70 (3H, s).
58 g
Stage #1: for 2 h; Cooling with ice Stage #2: With hydrogenchloride In tetrahydrofuran; water for 0.5 h; Cooling with ice
Preparation Example 12(1) To a mixture of 3-chloropyridine-2-carbonitrile 54 g and THF 300 mL was added dropwise 1M methylmagnesium bromide solution in THF 500 g under ice-cooling. The reaction mixtures were stirred under ice-cooling for 2 hours. To 2N hydrochloric acid was added the resulting reaction mixtures under ice-cooling, and the mixtures were stirred for 30 minutes. The mixtures were made pH 8 with a 1N aqueous sodium hydroxide solution, and then the mixtures were extracted with ethyl acetate. The organic layers were washed with saturated brine, and then the organic layers were dried over anhydrous sodium sulfate. The organic layers were concentrated under reduced pressure to give an intermediate compound (12-1) 58 g.1H-NMR (CDCl3) δ: 8.55 (1H, dd), 7.80 (1H, dd), 7.38 (1H, dd), 2.70 (3H, s).
58 g
Stage #1: for 2 h; Cooling with ice Stage #2: for 0.5 h;
To a mixture of 3-chloropyridine-2-carbonitrile (54 g) and THF (300 mL) was added dropwise a 1 M solution of methylmagnesium bromide in THF (500 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 2 hours. The resulting reaction mixture was added to 2N hydrochloric acid under ice-cooling, and the mixture was stirred for 30 minutes. To the mixture was added a 1N aqueous solution of sodium hydroxide so that the pH of the solution was set to be 8, and then the mixture was extracted with ethyl acetate. The resulting organic layers were washed with saturated brine, and then the organic layers were dried over anhydrous sodium sulfate. The organic layers were concentrated under reduced pressure to give the Intermediate compound 7 represented by the following formula (58 g). Intermediate compound 7: 1H-NMR (CDCl3) δ: 8.55 (1H, dd), 7.80 (1H, dd), 7.38 (1H, dd), 2.70 (3H, s).
Reference：
[1] Patent: JP2017/36339, 2017, A, . Location in patent: Paragraph 0178
[2] Patent: US2017/295787, 2017, A1, . Location in patent: Paragraph 0639
[3] Patent: US2017/305896, 2017, A1, . Location in patent: Paragraph 0621
[4] Patent: US2019/40038, 2019, A1, . Location in patent: Paragraph 1261-1262
Dissolve 3-CHLORO-2-CYANOPYRIDINE (10.0 g, 0.072 mol, Chem. Pharm. Bull. (1985) 33: 565-571) in anhydrous THF (200 mL) under N2 atmosphere and cool in an ice bath. Add drop wise 3.0 M MEMGI in diethyl ether (48 ml, 0.14 mol) to the reaction mixture and stir in an ice bath for 2 hours. Pour the reaction mixture over ice cold water, acidify the mixture with 2.0 N aq. HCI to pH 2 to 3. Extract the reaction mixture with EtOAc (3 x 100 mL) and dry over anhydrous MGS04. Filter, concentrate under vacuum and then filter through a pad of silica gel using 20% ethyl acetate/hexane as eluent. Removal of solvent under reduced pressure gives pure 2-acetyl-3-chloropyridine as oil
A. [7- (3-CHLORO-PYRIDIN-2-VL)-2-METHOXYMETHVL-PYRID[2, 3-D] PYRIMIDIN-4-YL]- (L-METHVL- 123*4-TETRAHYDRO-QUINOLIN-7-YL .-AMINE (COMPOUND 1; 1. 2-ACETYL-3-CHLOROPYRIDINE; Dissolve 3-chloro-2-cyanopyridine (10.0 g, 0.072 mol, Chem. Pharm. Bull. (1985) 33: 565-571) in anhydrous THF (200 mL) under N2 atmosphere and cool in an ice bath. Add drop wise 3.0 M MEMGI in diethyl ether (48 ml, 0.14 mol) to the reaction mixture and stir in an ice bath for 2 hours. Pour the reaction mixture over ice cold water, acidify the mixture with 2.0 N aq. HCl to pH 2 to 3. Extract the reaction mixture with EtOAc (3 x 100 mL) and dry over anhydrous MGS04. Filter, concentrate under vacuum and then filter through a pad of silica gel using 20% ethyl acetate/hexane as eluent. Removal of solvent under reduced pressure gives pure 2-acetyl-3-chloropyridine as oil.
1. 2-Acetyl-3-chloropyridine Dissolve 3-chloro-2-cyanopyridine (10.0 g, 0.072 mol, Chem. Pharm. Bull. (1985) 33:565-571) in anhydrous THF (200 mL) under N2 atmosphere and cool in an ice bath. Add drop wise 3.0 M MeMgI in diethyl ether (48 ml, 0.14 mol) to the reaction mixture and stir in an ice bath for 2 hours. Pour the reaction mixture over ice cold water, acidify the mixture with 2.0 N aq. HCl to pH 2 to 3. Extract the reaction mixture with EtOAc (3*100 mL) and dry over anhydrous MgSO4. Filter, concentrate under vacuum and then filter through a pad of silica gel using 20% ethyl acetate/hexane as eluent. Removal of solvent under reduced pressure gives pure 2-acetyl-3-chloropyridine as oil.
Heat <strong>[131109-75-6]2-acetyl-3-chloropyridine</strong> (0.77 g, 5.0 mmol) with N, N-dimethylformamide dimetylacetal (3.0 g) at 105C for 20 hours. Concentrate under reduced pressure to give 1- (3- chloro-pyridin-2-yl)-3-dimethylaminopropenone as oil
at 105℃; for 20h;
2. 1-(3-Chloro-pyridin-2-yl)-3-dimethylaminopropenone; Heat <strong>[131109-75-6]2-acetyl-3-chloropyridine</strong> (0.77 g, 5.0 mmol) with N, N-DIMETHYLFORMAMIDE dimetylacetal (3.0 g) at 105C for 20 hours. Concentrate under reduced pressure to give 1- (3-chloro-pyridin-2-yl)-3-dimethylaminopropenone as oil.
at 105℃; for 20h;
2. 1-(3-Chloro-pyridin-2-yl)-3-dimethylaminopropenone Heat <strong>[131109-75-6]2-acetyl-3-chloropyridine</strong> (0.77 g, 5.0 mmol) with N,N-dimethylformamide dimetylacetal (3.0 g) at 105 C. for 20 hours. Concentrate under reduced pressure to give 1-(3-chloro-pyridin-2-yl)-3-dimethylaminopropenone as oil.
5-chloro-2-(3-chloropyridin-2-yl)-[1,8]naphthyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium tert-butylate; In tetrahydrofuran; at -20 - 10℃; for 2h;
Dissolve 2-AMINO-4-CHLORONICOTINALDEHYDE (312 mg, 2.0 mmol) and 2-acetyl-3- chloropyridine (310 mg, 2.0 mmol) in anhydrous THF (5.0 mL) and cool it to-20C under N2 atmosphere. Add in portion t-BuOK (448 mg, 4.0 mmol) to the reaction mixture and stir the mixture at 10C for 2 hours. Concentrate the reaction mixture under vacuum, dilute the residue with water (10 mL), filter the solid, wash the solid with water and dry under high vacuum to afford the title product as a yellow solid.
With hydrogen bromide; bromine; In acetic acid; at 20℃; for 16h;
To a solution of <strong>[131109-75-6]1-(3-chloro-2-pyridinyl)ethanone</strong> (3.3 g, 21.2 mmol), 25% hydrobromic acid in acetic acid (15 ml) and acetic acid (30 ml) was added bromine (1.2 ml, 23.3 mmol) dropwise at room temperature and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with diethylether (50ml), then the formed precipitate was filtrated and washed with diethylether to furnish the 2-bromo-<strong>[131109-75-6]1-(3-chloro-2-pyridinyl)ethanone</strong> hydrobromide (6.5 g, 98 %).H-NMR (DMSO-cfe); 5 4.97 (2H, s), 7.69-7.74 (1H, m), 8.12-8.17 (1H, m), 8.68-8.69 (1H, m). Pale yellow solid. MS (ESI) m/z 235 (M + H)+.
1.4 g
With hydrogen bromide; bromine; acetic acid; In water; at 85℃; for 1h;
1-(3-chloro-2-yl)ethanone 1.21 g,25% hydrogen bromide-acetic acid solution 3ml, acetic acid 5ml and water 2.5ml, bromine was dropped at 85 C to a mixture, the mixture was stirred for 1 hour at 85 C.The reaction mixture was allowed to cool to room temperature, and the precipitated solid was filtered.The obtained solid was washed with tert- butyl methyl ether and dried to give 2-bromo-1- (3-chloropyridin-2-yl) - ethanone hydrobromide 1.40 g.
1.40 g
With hydrogen bromide; bromine; acetic acid; In water; at 85℃; for 1h;
1.21 g of <strong>[131109-75-6]1-(3-chloropyridin-2-yl)ethanone</strong>, 3 ml of 25% hydrogen bromide-acetic acid solution, 0.48 ml of bromine was added dropwise at 85 C. to a mixture of 5 ml of acetic acid and 2.5 ml of water, followed by stirring at 85 C. for 1 hour.The reaction mixture was allowed to cool to room temperature and the precipitated solid was filtered. The obtained solid was washed with tert-butyl methyl ether and dried to obtain 1.40 g of 2-bromo-<strong>[131109-75-6]1-(3-chloropyridin-2-yl)ethanone</strong> hydrobromide.
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