3-Oxopyrrolidine-1-carboxylic acid tert-butyl ester

Brown Oil

To a cold (-78° C.) solution of oxalyl chloride (2.8 mL, 32.4 mmol) in CH[0356] Part A: To a solution of oxalyl chloride (1.3 mL, 15 mmol) in 20 mL of dichloromethane at -60° C. was added methyl sulfoxide dropwise over period of 10 min. After stirring at -60° C., a solution of 1, 1-dimethylethyl 3-hydroxypyrrolidine-1-carboxylate (1.87 g, 10 mmol) in 20 mL of dichloromethane was added over 20 min. Then, diisopropylethylamine (8.8 mL, 50 mmol) was added over 5 min. The resulting mixture was stirred at -60° C. for 25 min, and at room temperature for 30 min. The reaction was diluted with dichloromethane (100 mL). The organic layer was washed sequentially with saturated sodium bisulfate solution (2.x.), saturated sodium bicarbonate solution, water, and brine; dried over sodium sulfate; and concentrated to afford 1.8 g (97percent) of 1, 1-dimethylethyl 3-oxo-pyrrolidine-1-carboxylate: 1H-NMR (CDCl3) δ 3.75 (4H, m), 2.58 (2H, t, J=7.8 Hz), 1.49 (9H, s).To a solution of 3-hydroxy-pyrrolidine-1-carboxylic acid tert-b\xty\ ester (10 g, 54 mmol) in dichloromethane (300 mL) is added Dess-Martin Reagent (45.9 g, 108 mmol) in three portions. The resulting mixture is stirred for 16 hours. The mixture is filtered through CeIi te and the solvent removed in vacuo. The crude material is purified via silica gel chromatography using a gradient elution of 0-8percent ethyl acetate/hexanes to afford the desired product as a glassy solid (9.8 g, 97percent).A 3 L, four-necked round-bottomed flask was equipped with a mechanical stirrer, 500 mL addition funnel, cooling bath, K-type thermocouple and a nitrogen inlet. Oxalyl chloride (6.0 mL, 70.5 mmol) was added to 300 mL of DCM and cooled to - 78°C. DMSO (9.9 mL, 139mmol) was added thereto, and the mixture was stirred for 15 minutes. tert-butyl 3-hydroxypyrrolidin-1-carboxylate (8.98g, 48 mmol) obtained in Step A was added thereto, and the mixture was stirred for 20 minutes. TEA (32 mL, 0.23 mol)was added thereto, and the mixture was stirred at -78°C for 1 hour and addtionally stirred at room temperature for 1hour. After addition of water, the reaction solution was extracted with DCM. The organic layer was dried with MgSO4and purified by column chromatography to obtain the title compound (7.92 g, 89 percent).1H-NMR (CDCl3) δ 3.77 (4H, m), 2.59 (2H, t), 1.48 (9H, s)N-Boc-3-pyrrolidinol (17.192 g, 0.092 mole) in 50 mL anhydrous methylene chloride was added to a solution of (60 g, 0.276 mole) of pyridinechlorochromate in 300 mL anhydrous methylene chloride which was surrounded by a water bath at room temperature. After stirring at room temperature for 4 hours an additional (60 g, 0.276 mole) of pyridinechlorochromate was added and the reaction was stirred over night. The reaction had gone to completion by the next morning and was diluted with 400 mL diethyl ether and filtered through a pad of celite 521 filter aid using excess diethyl ether to wash through. Evaporation gave a black oil which was flash chromatographed over silica gel eluting with 40percent ethyl acetate in hexane to provide the title compound (12.5 g, 71percent) as an oil. a) 3-Oxo-pyrrolidine-l-carboxylic acid tert-butyl ester In a 1 1 three-necked flask, 10 g of N-Boc-3- hydroxypyrrolidine are dissolved in 350 ml of dimethyl sulphoxide in the presence of 52.3 ml of triethylamine . 28 g of pyridine-sulphur trioxide complex dissolved in 350 ml of dimethyl sulphoxide are added dropwise to the above solution. The reaction mixture is stirred for 4 hours at ambient temperature. The reaction medium is acidified to pH 4.5-5 with a IM solution of hydrochloric acid and the reaction mixture is then extracted with ethyl acetate. The organic phases are combined and then dried over anhydrous sodium sulphate. The residue is filtered through silica gel (1/1 heptane/ethyl acetate) . 5.7 g of 3-oxo-pyrrolidine-l- carboxylic acid tert-butyl ester are obtained. Yield: 58percent.Pyridinium chlorochromate (481 mmol) was added to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (160 mmol) in dichloromethane (800 mL) and the reaction mixture was maintained at rt for 16 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was purified by Flash chromatography (20/1 to 10/1 petroleum ether/ethyl acetate) to provide tert-butyl 3-oxopyrrolidine-1-carboxylate in 51percent yield as light yellow oil.To a stirred solution of tert-butyl (R)-3-hydroxypyrrolidine-l-carboxylate (Intermediate 8-step 1, 4.5 g, 24.1 mmol) in DCM (60 ml) under NTo a stirred solution of tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (4.5 g, 24.1 mmol) in DCM (60 ml) under N1) N-tert-Butoxycarbonyl-3-pyrrolidinone Pyridine-sulfur trioxide (4.12 g) was added to a solution of (3R)-N-tert-butoxycarbonyl-3-hydroxypyrrolidine (2.47 g) and triethylamine (9.19 mL) in dimethylsulfoxide (30 mL) at room temperature, and the resultant mixture was stirred overnight. The reaction solution was poured onto water and extracted with diethyl ether. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After separation by filtration, a residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane), to obtain N-tert-butoxycarbonyl-3-pyrrolidinone (855 mg, 34percent) as an oily product. b) tert-Butyl 3-oxopyrroIidine-l-carboxylate; To a solution of step a) product (10 g, 0.053 mol) in dry CHEthyl N-Boc pyrrolidonecarboxylate (20.0 g) (compound of formula (II) wherein R is Et) was dissolved in toluene (30 ml) and dimethylsulfoxide Mixture and 20 mg of 3, 5-di-tert-butyl-4-hydroxytoluene (BHT) was added.The resulting mixture was heated to 115 ° C (internal temperature) and water (4.2 ml, 3.0 eq) was added dropwise over 5 h maintaining the internal temperature at 110-115 ° C.The desired conversion was achieved 1 hour after the water addition was completed.The reaction mixture was cooled to 20 ° C and diluted with water (10 ml).The layers were separated and the aqueous layer re-extracted with toluene (20 ml).The combined organic layers were washed with 20 ml of 5percent w / w aqueous NaCl and then with 10percent w / w NaCl (40 ml) and finally with 20 ml of water.The resulting toluene solution was treated with activated carbon.After filtration, the filtrate was concentrated to dryness to give an orange oil (14 g).Cyclohexane (12 ml) was added at -5 / -10 ° C and the resulting suspension was filtered and washed twice with 3.5 ml of cyclohexane.The solid was dried under vacuum in a 25 ° C oven to give 10.8 g of a white solidbody.The molar yield after separation was 75percent.

1-tert-butoxycarbonyl-3-pyrrolidone is a starting material and a useful intermediate in organic synthesis.

Molecular Weight:185.22
XLogP3:0.7
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:185.10519334
Monoisotopic Mass:185.10519334
Topological Polar Surface Area:46.6
Heavy Atom Count:13
Complexity:230
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes