ethyl 3-(cyclopentylamino)propanoate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 1.85 g (0.01 mole) of 3-cyclopentylamino-propanoic acid ethyl ester in 30 mL of water was added dropwise to a solution of 1.94 g (0.01 mole) of 2,4-dichloro-5-nitro-pyrimidine in 30 mL of ethyl ether. At 0 degrees, 2.0 g (0.020 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-80:20) gave 3.05 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-propanoic acid ethyl ester (IV-10) The layers were then separated the aqueous layer extracted twice with 30 mL of ether The combined organic layers were dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure Purification by silica gel chromatography eluting with hexanes-ethyl acetate (100:0-80:20)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 2.0 g (0.0108 mole) of 3-cyclopentylamino-propanoic acid ethyl ester and 10 mL of anhydrous tetrahydrofuran, at −78 degrees, was added 24.0 mL (0.0236 mole) of lithium bis(trimethylsilyl)amide. The mixture was stirred for 1 hour and then a solution of 2.0 g (0.0119 mole) of iodopropane in 2.0 mL of tetrahydrofuran was added slowly. The mixture was stirred at room temperature for 24 hours and then quenched by the addition of water. The mixture was concentrated under reduced pressure and then extracted three times with 50 mL of ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 1.2 g of (rac)-2-cyclopentylaminomethyl-pentanoic acid ethyl ester, which was used without further purification in subsequent steps. The mixture was stirred at room temperature for 24 hours quenched by the addition of water The mixture was concentrated under reduced pressure extracted three times with 50 mL of ethyl acetate The combined extracts were dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 1.0 g (0.0054 mole) of 3-cyclopentylamino-propanoic acid ethyl ester, 0.842 g (0.00542 mole) of iodoethane and 15 mL of dry tetrahydrofuran, at −78 degrees, was added 11.4 mL (0.0114 mole) of a 1M solution of lithium bis(trimethylsilyl)amide in hexanes over 5 minutes. The mixture was stirred for one hour at −78 degrees, then the cooling bath was removed and the mixture stirred overnight at room temperature, and then poured into ice water containing 5 mL of 1M sodium hydroxide solution. The mixture was extracted with ether, and the ether extract washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.5125 g of (rac)-2-cyclopentylaminomethyl-butanoic acid ethyl ester, which was used without further purification in subsequent steps. the cooling bath was removed the mixture stirred overnight at room temperature poured into ice water containing 5 mL of 1M sodium hydroxide solution The mixture was extracted with ether the ether extract washed with brine dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 11.5 g (0.075 mole) of beta-alanine ethyl ester hydrochloride and 6.3 g (0.073 mole) of cyclopentanone in 200 mL of dichloromethane was added 6.5 g (0.082 mole) of sodium acetate and 22.5 g (0.107 mole) of sodium triacetoxyborohydride. The mixture was stirred 24 hours and then quenched by the addition of 200 mL of saturated sodium bicarbonate solution. After 20 minutes, the organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined dichloromethane layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide 12.0 g of 3-cyclopentylamino-propanoic acid ethyl ester, which was used without further purification. quenched by the addition of 200 mL of saturated sodium bicarbonate solution After 20 minutes the organic layer was separated the aqueous layer was extracted twice with dichloromethane The combined dichloromethane layers were dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Cyclopentylamino-propionic acid ethyl ester (1.0 g, 5.4 mmol) and 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.25 g, 5.4 mmol) were combined in DCM (10 mL) and diisopropylethylamine (0.83 g, 6.5 mmol) was added. After 16 h, the solution was partitioned between water and DCM and the organic layer was dried (MgSO4) and concentrated. Chromatography (0-20% EtOAc/hexanes gradient) provided the title compound that was directly carried on to the next step. Sodium (25 wt % dispersion in paraffin wax, 0.25 g, 6.0 mmol) was added to t-butanol (5.0 mL) at rt. After 10 minutes, a solution of 4-[cyclopentyl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (2.0 g, 5.4 mmol) in 10 mL of toluene was added to the sodium t-butoxide solution and the resulting mixture was heated at 90° C. for 30 minutes. The reaction mixture was then cooled and the solution was adjusted to pH 7 using a 1N HCl solution. The solution was then extracted with EtOAc (2×20 mL) and the organic layer was dried (MgSO4) and concentrated to provide 0.26 g (14%). 1H-NMR (400 MHz, CDCl3:) 5 ppm 12.0 (br s, 1H), 8.20 (s, 1H), 5.10-5.18 (m, 1H), 4.26-4.31 (m, 3H), 3.72 (q, 2H, J=7.0 Hz), 2.50 (s, 3H), 1.63-1.86 (m, 5H), 1.20-1.35 (m, 5H). the solution was partitioned between water and DCM the organic layer was dried (MgSO4) concentrated

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Cyclopentylamine (1.72 g, 17.5 mmol) and 3-chloro-propionic acid ethyl ester (2.4 g, 18 mmol) were combined neat and K2CO3 (2.4 g, 18 mmol) and a catalytic amount of tetrabutylammonium iodide (ca. 5 mg) was added. The mixture was heated at 80° C. overnight. The resulting mixture was then partitioned between water and DCM. The organic layer was dried (MgSO4) and concentrated to provide 2.68 g (83%) of the title compound. 1H-NMR (400 MHz, CDCl3:) δ ppm 4.13 (p, 2H, J=7.0 Hz), 3.07 (p, 1H, J=6.7 Hz), 2.81-2.94 (m, 4H), 2.51 (t, 1H, J=6.5 Hz), 2.44 (t, 1H, J=7.4 Hz), 1.29-1.88 (m, 6H), 1.25 (t, 3H, J=7.1 Hz) The resulting mixture was then partitioned between water and DCM The organic layer was dried (MgSO4) concentrated