1-(1,1-Dimethylethyl) 3-ethyl 4-oxo-1,3-pyrrolidinedicarboxylate

White to slightly yellow crystalline powd

1000ml four-necked flask by adding Boc-pyrrolidone 120g, DMF 600ml, Stirring down to 0-5 , Sodium hydride was added to 26 g, 70.5 g of ethyl chloroformate was slowly added dropwise with stirring, 40min drop finished. 0-5 reaction 2h, TLC detection reaction is completed, Slowly add 3L ice water, With dilute hydrochloric acid to adjust the pH = 7 after ethyl acetate extraction, dry, Concentrated to give intermediate 1. Yield 85percent.The Preparation of Compound 14D: Sodium (27.6 g, 0.765 mol) was added stepwise to absolute ethanol (1.5 L). When the solid completely disappeared, compound 14C (300 g, 1.04 mol) was added to the solution. The reaction mixture was refluxed overnight, monitored with TCL (PE/EA=4:1), until the starting material was completely consumed. The reaction mixture was evaporated to remove most of the solvent. The residue was dissolved in water (1 L) and acidified with citric acid to pH 6. The mixture was extracted with EA (1 L×3). The extract liquors were combined, washed with brine (1 L×3), dried with anhydrous Na2SO4 and evaporated, to obtain compound 14D (169 g, 63.4percent) as a brown oily substance. The crude product was used directly in the next step without a further purification.Sodium ethoxide (27.6 g, 0.765 mol) was added stepwise to absolute ethanol (1.5 L). When the solid completely disappeared, compound 14C (300 g, 1.04 mol) was added to the solution. The reaction mixture was refluxed overnight, monitored with TCL (PE/EA=4:1), until the starting material was completely consumed. The reaction mixture was evaporated to remove most of the solvent. The residue was dissolved in water (1 L) and acidified with citric acid to pH 6. The mixture was extracted with EA (1 L×3). The extract liquors were combined, washed with brine (1 L×3), dried with anhydrous Na2SO4 and evaporated, to obtain compound 14D (169 g, 63.4percent) as a brown oily substance. The crude product was used directly in the next step without a further purification.Ethyl 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.4.2.2 tert-Butyl 3-ethyl 4-hydroxypyrrolidine-1, 3-dicarboxylate 2a To a suspension of NaBH4 (2.74 g, 72.3 mmol) in anhydrous methanol (290 mL) was added 1a (37.19 g, 144.6 mmol) at below 10 °C. The reaction mixture was stirred at the same temperature for 50 min, and then 20percent aqueous acetic acid was added dropwise to adjust pH 7.0 at 0 °C, and then concentrated under reduced pressure. The residue was dissolved with ethyl acetate (400 mL), and washed with water (50 mL * 3), brine (40 mL * 2), dried over anhydrous sodium sulfate, and evaporated under vacuo to afford the title compound 2a (37.11 g, 98.9percent) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) delta (ppm): 4.53-4.42 (m, 1H), 4.16-4.08 (m, 2H), 3.36-3.60 (m, 2H), 3.43 (brs, 1H), 3.28-3.25 (brs, 2H), 3.01-2.97 (brs, 1H), 1.42 (s, 9H), 1.28-1.21 (m, 3H). MS-ESI (m/z): 282.75 (M + Na)+.b) 4-Hydroxy-pyrrolidine-1, 3-dicarboxylic acid 1-tert.-butylester 3-ethylester To a solution of 5.15 g (20 mmol) 4-oxo-pyrrolidine-1, 3-dicarboxylic acid 1-tert. butylester 3-ethylester in 30 ml methanol was added 1.88 g (30 mmol) sodium cyanoborohydride and a small amount of methylorange. With stirring the pH was adjusted to 3 by dropwise addition of 1N hydrochloric acid (color change from yellow to orange). After no more acid was consumed the mixture was stirred for one hour. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed twice with water, then with brine, dried over magnesium sulfate and evaporated. The residual yellow oil was used in the next step without any further purification. GC/MS (HP 5890 II/HP 5972; column: HP 5, 30 m*25 mm*0.25 mum film thickness, carrier gas: helium, temperature gradient: 50° C., 3 min; then with 20° C./min to 250° C.;) tR=12.44 min (no separation of diastereomers) m/z [percent]=259 (M+, 0.3), 241 (0.7), 202(5), 186 (7), 158 (10), 112 (14), 68 (31), 57 (100).b 4-Hydroxy-pyrrolidine-1, 3-dicarboxylic acid 1-tert.-butylester 3-ethylester To a solution of 5.15 g (20 mmol) 4-oxo-pyrrolidine-1, 3-dicarboxylic acid 1-tert. butylester 3-ethylester in 30 ml methanol was added 1.88 g (30 mmol) sodium cyanoborohydride and a small amount of methylorange. With stirring the pH was adjusted to 3 by dropwise addition of 1N hydrochloric acid (color change from yellow to orange). After no more acid was consumed the mixture was stirred for one hour. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed twice with water, then with brine, dried over magnesium sulfate and evaporated. The residual yellow oil was used in the next step without any further purification. GC/MS (HP 5890 II/HP 5972; column: HP 5, 30 m*25 mm*0.25 (m film thickness, carrier gas: helium; temperature gradient: 50 ° C., 3 min; then with 20 ° C./min to 250 ° C.;) tR =12.44 min (no separation of diastereomers) m/z [percent]=259 (M+, 0.3), 241 (0.7), 202 (5), 186 (7), 158 (10), 112 (14), 68 (31), 57 (100).Potassium carbonate (23 g, 0.17 mol) was added to a mixture of l-/er/-butyl 3-ethyl 4- oxopyrrolidine-l, 3-dicarboxylate (29 g, 0.11 mol) and 3-bromoprop-l-ene (15 mL, 0.17 mol) in acetone (0.30 L) at 15 C, and the mixture was stirred at 40 C for 14 h. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (EtOAc in hexanes) to afford l-/er/-butyl 3 -ethyl 3 -allyl-4-oxopyrrolidine- 1, 3 -dicarboxylate. LCMS (1807) (CHHI6N05+) (ES, m/z): 242 [M+H-C4H8]+.

Molecular Weight:257.28
XLogP3:1.2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:5
Exact Mass:257.12632271
Monoisotopic Mass:257.12632271
Topological Polar Surface Area:72.9
Heavy Atom Count:18
Complexity:358
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes