1-BOC-D-PYROGLUTAMIC ACID ETHYL ESTER

163A. Step 1. (0138) (0139) Step 1 title compound was synthesized by following the literature procedure [] or with the following modifications. L-pyroglutamic acid ethyl ester was N-protected as the t-butylcarbamate (BocO, DMAP or NaH) and then dehydrated to the 4, 5-dehydroproline ethyl ester in one pot by carbonyl reduction (triethylborohydride, toluene, -78°C) followed by dehydration (TFAA, lutidine). The title compound was obtained by cyclopropanation of the 4, 5-dehydroproline ethyl ester (EtZn, ClCHI, 1, 2-dichloroethane, -15°C). A more detailed protocol is as follows: Synthesis of 4, 5-dehydro-L-proline ethyl ester: L-pyroglutamic acid ethyl ester (200 g, 1.27 mol) was dissolved in 1.2 liters of methylene chloride and treated sequentially with di-tert-butyldicarbonate (297 g, 1.36 mol) and a catalytic DMAP (1.55 g, 0.013 mol) at ambient temperature. After 6 h, the mixture was quenched with saturated brine and the organic phase was dried (NaA solution of 7.00 g of pyroglutamic acid ethyl ester 203 (44.5 mmol) in 60 ml of anhydrous acetonitrile was cooled to 0° C. and added with 6.3 ml of NEtTo a solution of (S)-ethyl 5- oxopyrrolidine-2-carboxylate 76 (15 g, 95.54 mol) and dimethylaminopyridine ( 1.166 g, 9.554 mol) in dichloromethane (40 mL) was added B0C2O (20.85 g, 95.54 mol). The resulting mixture was stirred at room temperature overnight. The crude mixture was washed with saturated NH4CI solution. The organic phase was separated, dried over anhydrous Na2SC>4, filtered and concentrated. The residue was purified by silica gel column (PE : EA = 5 : 1) to give title compound 77, (S)-l-tert-butyl 2-ethyl 5-oxopyrrolidine- 1, 2-dicarboxylate (22 g, 89.6percent yield) . LC-MS (LC method 1): m/z 258 (M+l)To a solution of compound 18-2 (25.2 g, 0.176 mol) and DMAP (2.20 g, 0.018 mol) in CHTo a solution of compound 18-2 (25.2 g, 0.176 mol) and DMAP (2.20 g, 0.018 mol) in CH3CN (150 mL) wasadded Boc2O (40.0 g, 0.178 mol) in two portions. The mixture was stirred at rt for 18 hours. The reaction was monitoredby TLC and the mixture was concentrated in vacuo after the process stopped. To the residue were added NaHSO4aqueous solution (1 M, 75 mL) and EtOAc (200 mL). After the layers were partitioned, the aqueous phase was extractedwith EtOAc (250 mL x 3). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/ EtOAc (v/v) = 1/1) togive the title compound 18-3 (23.2 g, 88percent). The compound was characterized by the following spectroscopic data:1H NMR (400 MHz, CDCl3): δ 4.58 (dd, J = 9.4, 2.8 Hz, 1H), 4.20 (m, 2H), 2.59 (m, 1H), 2.48 (m, 1H), 2.30 (m, 1H), 2.01 (m, 1H), 1.47 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H).To a solution of the commercially available L-pyroglutamic acid ethylester (15.7 g) in methylene chloride (90 ml) was sequentially added at rt di-tert-butyldicarbonate(24 g) and a catalytic amount of DMAP (120 mg). After stirring for 6 h at rt the reaction mixture was quenched with saturated brine and extracted with methylene chloride.(3 x 30 ml). The organic phase was dried over MgSOL-pyroglutamic acid ethyl ester (200 g, 1.27 mol) was dissolved in 1.2 liters of methylene chloride and treated sequentially with di-tert-butyldicarbonate (297 g, 1.36 mol) and a catalytic DMAP (1.55 g, 0.013 mol) at ambient temperature. G. To a 500 ml four-necked flask equipped with a stirrer, thermometer and reflux condenser was added 12.0 g (0.05 mol) of the one prepared in Example 3L-glutamic acid diethyl ester hydrochloride, 120 g 2-methyltetrahydrofuran, 8.5 g (0.06 mol) potassium carbonate, 8.2 grams (0.06 moles)Tert-butyl chloroformate, react at 2530°C for 5 hours, 75-80°C for 7 hours, cool to 20-25°C, filter, The filtrate was distilled and the solvent was recovered. To the residue was added 40 g of methyl tert-butyl ether, which was recrystallized, filtered, and dried to give 11.5 g of a white powdery solid.N-tert-butyloxycarbonyl-L-pyroglutamic acid ethyl esterThe liquid purity was 99.5percent and the yield was 89.3percent.A round bottom flask was charged with a stir-bar, L-pyroglutamic acid (3.0 g, 0.022 mol), and 30 mE of ethanol. The mixture was cooled to 0° C. and thionyl chloride (3.4 mE, 0.044 mmol) was added dropwise. The reaction was allowed to stir for 16 irs as it warmed to room temperature. Complete conversion was determined by EC/MS and the reaction was concentrated under reduced pressure and reconcentrated twice from ethanol. The crude was determined to be (S)-ethyl 5-oxopyrrolidine-2-carboxylate hydrochloride. MS (EC/MS) mlz expected 158.08. observed 158.04. [M+H]. Compound was confirmed using EC/MS and moved to next step as it was. To the round bottom flask containing a stir-bar and the crude pyrrolidine hydrochloride, at 0° C., were added 45 mE acetonitrile, DIPEA (8.6 mE, 0.05 1 mol), and DMAP (270 mg, 0.002 mol). While at 0° C., a solution of 13oc20 (6.3 g, 0.029 mol) in 10 mE of acetonitrile was added dropwise. The reaction was allowed to stir in air as it warmed to RT. Afier 54 irs of reaction conversion of the starting lactam was observed and the reaction was concentrated under reduced pressure. The residue was redissolved in EtOAc (60 mE) and washed an equal volume of a saturated solution of NaHCO3(aq), citric acid(aq, saturate’ and again with NaHCO3(aq). The organic phase was dried over anhydrous sodium sulphate and concentrated. The residue was purified on normal phase flash chromatography (EtOAc/Hexanes). (S)-i -tert-l3utyl 5-ox- opyrrolidine-1, 2-dicarboxylate ethyl ester was obtained as a yellow oil (4.0 g, 0.016 mol, 71percent). ‘H NMR (400 MHz, DMSO-d6) ö 4.04 (2H, t, J=8 Hz), 3.95 (1H, m), 2.36 (1H, m), 1.95 (1H, m), 1.78 (1H, m), 1.37 (9H, s), 1.17 (3H, t, J8 Hz), MS (EC/MS) mlz expected 280.12. observed 279.79. [M+Na].Triethyl orthoformate (16.6 mL, 100 mmol) andp- toluenesulfonic acid monohydrate (0.95 g, 5 mmol) were added to a solution of (S)S- oxopyrrolidine-2-carboxylic acid (12.9 g, 100 mmol) in dry ethanol (100 mL). The solution was heated to reflux for 1.5 hours, distilling off ethyl formate (~18 mL). The reflux was continued for 2.5 hours and then the mixture was concentrated by evaporation under reduced pressure. The residue was placed under vacuum at 50

1-Boc-D-Pyroglutamic acid ethyl ester is a crucial compound that could be used as a pharmaceutical intermediate in pharmaceutical synthesis and scientific research. It could synthesise (2S,5S)-N-Boc-5-methylpyrrolidine-2-carboxylic acid.

Molecular Weight:257.28
XLogP3:1.3
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
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes