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Reference Example 31; 6,7-dihydro-5H-cyclopenta[c]pyridin-7-ylacetonitrile [Show Image]; To a solution of diethyl cyanomethylphosphonate (346 mg, 1.95 mmol) in tetrahydrofuran (10 mL) was added 60percent sodium hydride (54.0 mg, 1.35 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. The mixture was added to a solution of <strong>[51907-18-7]5,6-dihydro-7H-cyclopenta[c]pyridin-7-one</strong> (130 mg, 0.976 mmol) in tetrahydrofuran (5 mL) under ice-cooling, and the mixture was stirred for 15 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50-->80/20). To a solution of the purified product in methanol (10 mL) was added palladium-carbon powder (30 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hr. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60-->70/30) to give the title compound (95.0 mg, yield 62percent). 1H-NMR (CDCl3) delta: 1.87 - 2.03 (1H, m), 2.42 - 3.14 (5H, m), 3.53 - 3.66 (1H, m), 7.22 (1H, dd, J = 4.9, 0.8 Hz), 8.46 (1H, d, J = 4.9 Hz), 8.55 (1H, s).
4-<2-(ethoxycarbonyl)ethyl>nicotinic acid methyl ester[ No CAS ]
[ 51907-18-7 ]
Yield
Reaction Conditions
Operation in experiment
58%
Reference Example 29; 5,6-dihydro-7H-cyclopenta[c]pyridin-7-one [Show Image]; A solution of methyl 4-(3-ethoxy-3-oxopropyl)nicotinate (4.80 g, 20.2 mmol) in tetrahydrofuran (100 mL) was added to a suspension of 60percent sodium hydride (3.73 g, 93.3 mmol) in tetrahydrofuran (50 mL) at room temperature. Methanol (100 muL) was added to the mixture at room temperature, and the mixture was heated under reflux for 4 hr. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was added to 12M hydrochloric acid (50 mL) at 0°C, and the mixture was stirred at 110°C for 30 min. The mixture was alkalified with sodium hydrogen carbonate, the insoluble material was filtered off, and the filtrate was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with hexane to give the title compound (1.57 g, yield 58percent). 1H-NMR (CDCl3) delta: 2.66 - 2.76 (2H, m), 3.14 - 3.23 (2H, m), 7.42 - 7.50 (1H, m), 8.71 (1H, d, J = 5.2 Hz), 9.00 (1H, d, J = 0.8 Hz).
To a solution of methyl 4-(3-ethoxy-3-oxopropyl)nicotinate (200 mg, 0.84 mmol) in THF (20 mL) was added sodium hydride (0.08 g, 3.36 mmol).The reaction mixture was heated to 60 °C under N2 and stirred at that temperature for 3 h. The organics were concentrated in vacuo.12 M HCl (4mL) was added to the above mixture at 0 oC. The reaction was stirred at that temperature for 10 min. And then the mixture was heated to 100 °C and stirred at that temperature for 30 min. Saturated aqueous NaHCO3 (75 mL) was added to the reaction vessel and adjusted pH = 8. The mixture was extracted with (3 x 50 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The product was used for next step without further purification.
N-tert-butyl-4-(7-hydroxy-6,7-dihydro-5H-[2]pyrindin-7-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
c) N-tert-Butyl-4-(7-hvdroxv.6,7-dihydro-5H-[21vyridin-7-yl)benzamide; 5.3 ml of n-butyllithium (1.6M in hexane) are added dropwise to a solution of 4.250 mmol of 4-bromo-N-tert-butylbenzamide in 70 ml of tetrahydrofuran at -78°C. After 30 minutes, a solution of 3.270 mmol of 5,6-dihydro-[2]pyridin-7-one [51907-18-7] in 10 ml of tetrahydrofuran is added dropwise. The reaction mixture is stirred at-78°C for 1 hour and at room temperature for 2 hours and then quenched with saturated aqueous ammonium chloride solution. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate (2x). The combined organic phases are dried with sodium sulphate and evaporated. The title compound is obtained as a white foam from the residue by flash chromatography (Si02 60F). Rf = 0.29 (toluene: methanol = 85: 15), Rt = 5.00.
2-(7-hydroxy-6,7-dihydro-5H-[2]pyrindin-7-yl)-N-(3-methoxyphenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A solution of 50 mmol of N-(3-methoxyphenyl)acetamide [588-16-9] in 200 ml of tetrahydro- furan is cooled to -40°C. 110 mmol of butyllithium (1.6M in hexane) are added dropwise at -40 - -300C and the reaction mixture is subsequently stirred at 00C for 1 hour. The reaction mixture is cooled again to -40°C and a solution of 50 mmol of 5,6-dihydro[2]pyridin-7-one [51907-18-7] in 50 ml of tetrahydrofuran is added dropwise at this temperature. The reaction mixture is stirred at 0°C for 2-4 h and then poured into saturated aqueous ammonium chloride solution. The mixture is extracted with tert-butyl methyl ether and the combined organic extracts are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is obtained by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
With hydroxylamine hydrochloride; sodium acetate; In ethanol; water; for 12h;Reflux;
Step 1 : 5,6-Dihydro-[2]pyrindin-7-one oxime 5,6-Dihydro-[2]pyrindin-7-one (synthesis described in EP2098513A1 , 5 g, 37.5 mmol), hydroxylamine hydrochloride (3.13 g, 45.1 mmol) and sodium acetate (3.70 g, 45.0 mmol) are dissolved in water (8 ml), the mixture is stirred and ethanol (8 ml) is added to the solution. The mixture is stirred under reflux for 2 hours. The mixture is concentrated and ethyl acetate is added, salts are filtered off and the solution is concentrated to give the title compound (Yield 5.5 g)
5.5 g
With hydroxylamine hydrochloride; sodium acetate; In ethanol; water; for 2h;Reflux;
5,6-Dihydro-[2]pyrindin-7-one (synthesis described in EP2098513A1, 5 g, 37.5 mmol), hydroxylamine hydrochloride (3.13 g, 45.1 mmol) and sodium acetate (3.70 g, 45.0 mmol) are dissolved in water (8 ml), the mixture is stirred and ethanol (8 ml) is added to the solution. The mixture is stirred under reflux for 2 hours. The mixture isconcentrated and ethyl acetate is added, salts are filtered off and the solution is concentrated to give the title compound (Yield 5.5 g)LC (Method 1): tR = 0.61 mm; Mass spectrum (ES+): mlz = 149 [M+H].
To a solution of <strong>[51907-18-7]5H-cyclopenta[c]pyridin-7(6H)-one</strong> (300 mg, 2.25 mmol) in THF (10 mL) was added 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (0.66 g, 3.38 mmol). The reaction was stirred at ambient temperature for 10 min. Then potassium 2-methylpropan-2-olate (0.5 g, 4.5 mmol) was added in five portions. The reaction was stirred at ambient temperature for 15 min. TLC showed the starting material was consumed. The organics were concentrated in vacuo and used for next step without further purification.
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