1-(1,1-Dimethylethyl) 2-methyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate

(1) (2S)-5-Oxo-pyrrolidine-l, 2-dicarboxylic acid l-tert-buty\ ester 2-methyl ester (Compound 3).;To a suspension of pyroglutamic acid (15.0 g) in methanol (60.0 mL) was added thionyl chloride (27.6 g) at < 3O1 liter of the autoclave, Adding 129 g of L-pyroglutamic acid, 600 ml of anhydrous methanol and 58 g of p-toluenesulfonic acid.Close the high pressure reactor into the nitrogen replacement air three times, Start stirring up to 125 degrees, And insulation for 12 hours, After the reaction is cooled, The reaction solution was transferred to an additional reactor to recover excess methanol, The residue was dissolved in 800 ml of toluene, After the washing treatment, Dried over anhydrous sodium sulfate, The filtrate was added with 3.1 g of 4-dimethylaminopyridine, A mixture of 218 g of di-tert-butyl carbonate was added dropwise at 15 to 20 degrees, After dripping, The temperature is raised to 25 to 30 ° C for 1 to 2 hours.After the reaction is complete, Cooled to below 20 ° C, Washed with water and saturated brine.Combined with the separation of the lower wash water, Extraction with toluene.All the upper layers were combined and concentrated under reduced pressure.Cooling to about 30 , Add petroleum ether to about 20 ° C for 1 hour, And then cooled to 0 ~ 5 stirring crystallization 4 hours, Filtered, washed with petroleum ether to obtain a white solid after drying 98G.The total yield was 38percent.Anhydrous methanol 800kg added to the drying reactor, Dropping 10 ° C drop of thionyl chloride 50KG, Add a bit after the addition of pyroglutamate 200KG added after the start of mind, Control reaction system temperature 5 ~ 10 , Stirring reaction 7h, After adding 100KG of sodium bicarbonate to neutralize the acid, The temperature was concentrated under reduced pressure to the oil, Cooling the addition of methylene chloride dissolved product, After washing with water to remove salt, add anhydrous sodium sulfate, stir and dry 4H, After filtration to be the next step.The first step of the obtained pyroglutamate methylene chloride solution was about 1000 L, Add DMAP300G, Bis-di-tert-butyl dicarbonate 425KG was added in portions, (Adding speed control about 50 ~ 70KG per hour) about 10 hours plus, After adding the reaction 2H, Concentrated under reduced pressure to dry, Ethyl acetate (800 L) was dissolved in an oil, Washed with 0.1Mol / L HCL 5 to 8 times, Each time about 100L (to TLC detection no impurities so far), Saturated brine washed twice, anhydrous sodium sulfate drying 4H, Filtered, concentrated under reduced pressure to dry, About 400L in volume, Cooling below 30 , Pumping into the petroleum ether 400L, Stirring crystallization 4H, Centrifuge to dryness and vacuum dry at 45 ° C for 8H, Tert-butoxycarbonyl-L-pyroglutamic acid methyl ester 378KG.The total yield was 94.9percent1-(1.1-dimethvlethvl) 2-methvl (2S)-5-oxo-1.2-DvrrolidinedicarboxvlateCDr EPO To a solution of commercially available methyl 5-oxo-L-prolinate (2Og, 140mmol) in DCM (200ml) were added triethylamine (19.6ml, 140mmol), DMAP(17.2g, 140mmol) and then dropwise a solution of BOCTo a solution of commercially available methyl 5-oxo-L-prolinate (Sigma Aldrich Ltd.) (2Og, 140mmol) in DCM (200ml) were added TEA (19.6 ml, 140mmol), 4-DMAP (17.2g, 140mmol) and finally dropwise a solution of di-tert-butyl dicarbonate (61g, 280mmol) in DCM (100ml). The resulting red mixture was stirred at room temperature for 2 hours. After the reaction was finished, as shown by TLC, the solvent was removed in vacuo and the crude material was purified by chromatography on silica gel eluting with cyclohexane / ethyl acetate (7:3 to 4:6) to afford (after a trituration in hexane / diethylether 1 :1) the title compound as a white solid (32.4g, 96percent); RIn a 1-L RBF, (5)-methyl 5-oxopyrrolidine-2-carboxylate (Aldrich Chemical Company, St. Louis, MO, 20.00 g, 140 mmol) was treated with EtOAc (200 mL) followed by DMAP (1.71 g, 13.97 mmol) and B0C2O (33.50 g, 154 mmol). The solution was stirred at RT for 2 h. The reaction mixture was cooled to 0 °C and treated with IN HC1 (16 mL) and stirred 10 min. The reaction mixture was transferred to a separatory funnel and the aqueous layer was removed. It was washed with water (25 mL) and concentrated on the rotovap. The residue was treated with MTBE (33 mL) and stirred slowly at 0 °C. The crystals that formed were filtered to give (5)-l-teri-butyl 2-methyl 5-oxopyrrolidine-l, 2-dicarboxylate (29.52 g, 121 mmol, 87 percent yield) as a pale yellow crystalline solid after washing two more times with MTBE (2 x 15 mL) drying under high vacuum. MS (ESI, pos. ion) m/z: 266.1 (M+NaTo a solution of compound 2-1 -B (6.45 g, 45.06 mmol) in MeCN (30 mL) was added DMAP (0.5503 g. 4.5 mmol) at 0 °C, followed by di- /7-butyl dicarbonate (10.816 g, 49.56 mmol) dropwise, and the mixture was stirred at 0 °C for 30 mins and then at rt for another 2 hrs. After the reaction was completed, the mixture was concentrated in vacuo, the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) - 1/1 ) to give the title compound 2-1 -C as colorless liquid (5.0 g, 45.6percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z: 144.2 [M-Boc] To a solution of compound 3-2 (6.45 g, 45.06 mmol) in MeCN (30 mL) was added DMAP (0.55 g, 4.5 mmol) at 0 °C. After the mixture was stirred for 10 mins, di-tert-butyl dicarbonate (10.82 g, 49.56 mmol) was added dropwise. At the end of the addition, the mixture was stirred at 0 °C for 30 mins and at rt for another 2.0 hrs. After the reaction was completed, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as colorless liquid (5.0 g, 45.6percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 144.2 [M-Boc]. . . mmol) at 0 °C, followed by di -/To a solution of compound 42-1 (6.45 g, 45.06 mmol) in MeCN (30 mL) was added DMAP (0.5503 g, 4.5 mmol) and di-tert-butyl dicarbonate (10.816 g, 49.56 mmol) slowly in turn in an ice bath. The mixture was stirred at 0 °C for 30 minutes and at rt for another 18 hours and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound 42-2 as colorless liquid (5.0 g, 45.6percent, HPLC: 95percent). The compound was characterized by the following spectroscopic data: MS-ESI: m/z 144.2 [M-99]To a solution of compound 4-2 (6.45 g, 45.06 mmol) in MeCN (30 mL) at 0 °C was added DMAP (0.55 g, 4.5 mmol). The mixture was stirred for 10 mins and then di-tert-butyl dicarbonate (10.82 g, 49.56 mmol) was added dropwise. At the end of the addition, the mixture was stirred at this temperature for 30 mins and then stirred at rt for 2 hour. After the reaction was completed, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as colorless liquid (5.0 g, 45.6percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 144.2 [M-BOC]+; and *H NMR (400 MHz, CDC13): δ 4.60-4.57 (m, 1H), 3.75 (s, 3H), 2.65-2.55 (m, 1H), 2.50-2.42 (m, 1H), 2.36-2.24 (m, 1H), 2.04-1.96 (m, 1H), 1.45 (s, 9H) ppm.10753] Step 2) the Preparation of Compound 2-1-C10754] To a solution of compound 2-1-B (6.45 g, 45.06 mmol) in MeCN (30 mE) was added DMAP (0.5503 g, 4.5 mmol) at 0° C., followed by di-tert-butyl dicarbonate (10.816 g, 49.56 mmol) dropwise, and the mixture was stirred at 0° C. for 30 mins and then at it for another 2 irs. After the reaction was completed, the mixture was concentrated in vacuo, the residue was purified by a silica gel colunm chromatography (PE/EtOAc (v/v)=1/1) to give the title compound 2-1-C as colorless liquid (5.0 g, 45.6percent). The compound was characterized by the following spectroscopic data:10755] MS (ESI, pos.ion) mlz: 144.2 [M-Boc]10756] ‘H NMR (400 MHz, CDC13) ö (ppm): 4.57-4.60 (m, 1H), 3.75 (s, 3H), 2.55-2.65 (m, 1H), 2.42-2.50 (m, 1H), 2.24-2.36 (m, 1H), 1.96-2.04 (m, 1H), 1.45 (s, 9H).To a solution of compound 42-1 (6.45 g, 45.06 mmol) in MeCN (30 mL) was added DMAP (0.5503 g, 4.5 mmol)and di-tert-butyl dicarbonate (10.816 g, 49.56 mmol) slowly in turn in an ice bath. The mixture was stirred at 0 °C for 30minutes and at rt for another 18 hours and concentrated in vacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v) = 1/1) to give the title compound 42-2 as colorless liquid (5.0 g, 45.6percent, HPLC: 95percent). Thecompound was characterized by the following spectroscopic data:MS-ESI: m/z 144.2 [M-99]+; and1H NMR (400 MHz, CDCl3): δ 4.57-4.60 (m, 1H), 3.75 (s, 3H), 2.55-2.65 (m, 1H), 2.42-2.50 (m, 1H), 2.24-2.36 (m, 1H), 1.96-2.04 (m, 1H), 1.45 (s, 9H).DMAP (0.55 g, 4.5 mmol) was added to a solution of compound 12-2 (6.45 g, 45.06mmol) in MeCN (30 mL) at 0 ° C. After stirring for 10 minutes, a solution of di-tertbutyldicarbonate g, 49.56mmol) was added dropwise. After the completion of the dropwiseaddition, the reaction was carried out at a constant temperature for 30 minutes and atroom temperature for 2.0 hours. After the reaction was completed, the reaction solutionwas concentrated and purified by column chromatography (eluent: PE / EtOAc (v / v) =1/1) to give 5.0 g of a colorless liquid. Yield: 45.6percent.Thionyl chloride (5.6 mL, 77 mmol) was added dropwise over 10 min. to a solution of (2S)-5-oxopyrrolidine-2-carboxylic acid (Aldrich, 5.0 g, 39 mmol) in MeOH (30.0 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was concentrated under reduced pressure and the resulting residue was dissolved in EtOAc (25 mL). After slow addition of triethylamine (5.4 mL, 39 mmol), the mixture was filtered. DMAP (0.48 g, 3.9 mmol) was added to the filtrate, followed by di-tert-butyl dicarbonate (8.4 g, 39 mmol) and the mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with EtOAc (25 mL) and cooled to 0° C. 1 M HCl (50 mL) was added slowly. The organic layer was separated, washed with a saturated aq. NaHCOL-Pyroglutamic acid 5 (387.3 g, 3mol) was slurried in MeOH (1 L), thionyl chloride (652.1 g, 5.7 mol) was added in a manner so that the temperature was maintained between -5–0 °C. After complete addition of the thionyl chloride, the reaction mixture was heated to 25–30°C and stirred for 5 h. Then the reaction mixture was evaporated under vacuum (T < 45 °C) to approximately 15percent of its original volume. The remaining oil was then dissolved in toluene (1 L). Triethylamine (303.6 g, 3 mol) was added dropwise so that the temperature was maintained between -5–0 °C, then filtered. The filtrate was used in the next step directly. To another 5 L three necked bottle, Boc2O (870 g, 3.99 mol), 4-dimethlyaminopyridine (54.9 g, 0.45 mol) and toluene 1 L were combined and cooled to -5–0°C. The filtrate was added dropwise while keep the tempreture between 0–5 °C. After addition, the reaction mixture was heated to 25–30°C and stirred for 12 h (monitored by TLC, DCM/MeOH = 7/1). To the reaction vessel was added saturated aqueous NaCl(1 L) and 2 N HCl to adjust the pH to 2-3. The aqueous phase was extracted with EtOAc (200 mL×3), the combined organic layer was washed with brine and dried over magnesium sulfate. Concentrated under reduced pressure and the residue was stirred for 3 h, then filtered to give 6 (580.9 g, HPLC: 97.3percent, yield:80percent for 2 steps) as an orange-red solid, the product can be used in the next step without furtherpurification. [α]D20 - 29.7 (c 1.0, CHCl3). {lit.11 [α]D20 - 30.4 (c 1.0, CHCl3)}.1H NMR (500 MHz, CDCl3) δ 4.63 (dd, J = 9.4, 3.0 Hz, 1H), 3.79 (s, 3H), 2.64-2.50 (m, 1H), 2.39-2.26(m, 2H), 2.04 (ddt, J = 13.2, 9.6, 3.3 Hz, 1H), 1.50 (s, 9H). ESI-MS m/z: 244.2 (M+1)+.To a solution of methyl (2S)-5-oxopyrrolidine-2-carboxylate (27.90 g, 194.91 mmol, 1.00 eq) and DMAP (2.86 g, 23.39 mmol, 0.12 eq) in EtOAc (150.00 mL) was added dropwise tert-butoxycarbonyl tert-butyl carbonate (55.30 g, 253.39 mmol, 58.21 mL, 1.30 eq). The mixture was stirred at 20 C for 16 h. The reaction mixture was washed with HCl (1M, 50 mL), Sat. NaHCO3 (150 mL), brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by re-crystallization from MTBE (250 mL) to afford the title compound (21.75 g, 88.52 mmol, 45.41percent yield, 99percent purity) as a yellow solid.(2S)-1-(1, 1-Dimethylethyl)-5-oxo-1, 2-pyrrolidinedicarboxylic acid-2-methyl ester, (2). A 50-L reactor is charged with compound (1) (5.50 Kg, 42.60 mol), methanol (27 L) and cooled to 10-15° C. Thionyl chloride (10.11 Kg, 2.0 equiv.) is added via addition funnel over a period of 65 min, with external cooling to maintain temperature at <30°. The resulting solution is stirred at 25° C.+/-5° C. for 1.0 hour, after which the methanol is distilled off under reduced pressure. The resulting thick oil is azeotroped with ethyl acetate (3.x.2.5 L) to remove residual methanol. The residue is dissolved in ethyl acetate (27.4 L), charged into a 50 L reactor, and neutralized by the addition of triethylamine (3.6 Kg) from an addition funnel over 30 minutes. The temperature of the neutralization is maintained below 30° C. via external cooling. The resulting suspension of triethylamine hydrochloride is removed by filtration, and the clarified mother liquor solution is charged to a 50 L reactor, along with DMAP (0.53 Kg). Di-tert-butyl dicarbonate (8.43 Kg) is added via hot water heated addition funnel, over a period of 30 min with external cooling to maintain temperature at about 20-30° C. The reaction is complete after 1 hour as determined by TLC analysis. The organic phase is washed with ice cold 1N HCl (2.x.7.5 L), saturated sodium bicarbonate solution (1.x.7.5 L), and dried over magnesium sulfate. The mixture is filtered through a nutsche filter and ethyl acetate is removed under reduced pressure to yield a crystalline slurry that is triturated with MTBE (10.0 L) and filtered to afford intermediate (2) as a white solid (5.45 Kg, 52.4percent). Anal. Calcd for CThionyl chloride (5.6 mL, 77 mmol) was added dropwise over 10 min. to a solution of (2S)-5-oxopyrrolidine-2-carboxylic acid (Aldrich, 5.0 g, 39 mmol) in MeOH (30.0 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was concentrated under reduced pressure and the resulting residue was dissolved in EtOAc (25 mL). After slow addition of triethylamine (5.4 mL, 39 mmol), the mixture was filtered. DMAP (0.48 g, 3.9 mmol) was added to the filtrate, followed by di-tert-butyl dicarbonate (8.4 g, 39 mmol) and the mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with EtOAc (25 mL) and cooled to 0° C. 1N HCl (50 mL) was added slowly. The organic layer was separated, washed with a saturated aq. NaHCO