* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
To a 1-neck 1 L round bottom flask was charged 40 g (216 mmol) (S)-5-oxo- pyrrolidine-2-carboxylic acid fer/-butyl ester followed by 350 mL MeCN. The reaction was cooled to 5 0C followed by addition of DMAP (0.5 g., 4.32 mmol) and Boc2ψ (47.1 g.? 216 mmol). The reaction was allowed to warm to room temperature over 30 minutes. After 1.5 hours TLC indicated the reaction was complete. Water (300 mL) and IPAc (400 mL) were added and the solution was transferred to a 2 L separatory funnel. The aqueous layer was cut and the organics dried over MgSψ4 then filtered and concentrated to an oil. The oil was taken up in minimal amount of EtOAc and chromatographed using 600 g of silica on a linear gradient from 100percent hexanes to 1 :1 hexanes: EtOAc. The collected fractions were concentrated to an oil to give 60 g (210 mmol, 97percent yield) of (S)-5-oxo-pyrrolidine~l,2-dicarboxylic acid di-tert~butyl ester. lH NMR (500 MHz, CDCI3): δ 4.5 (dd, J-2.5, 6.85 Hz9 IH), 2.4-2.7 (m, 2H), 2.3 (m,IH), 2.0 (m, IH), 1.57 (S, 9H), 1.50 (S, 9H).
94%
With 1-methyl-1H-imidazole In <i>tert</i>-butyl alcohol at 20 - 30℃; for 3 h;
N-Methylimidazole (0.031 g, 0.378 mmol) and Boc anhydride (0.907 g, 4.16 mmol) were added to a mixture of tert-butyl pyroglutamate 4 (0.700 g, 3.78 mmol) in tert-BuOH (15 mL) at 30 °C. The solution was stirred 10 min at this temperature, and then at room temperature for 3 h. Solvents were removed under vacuum, the residue was dissolved in ethyl acetate (30 mL), the solution was washed with water (2*10 mL) and the aqueous phases were extracted with ethyl acetate (2*20 mL). The combined organic phases were dried (MgSO4), and the solvent was removed under vacuum. The residue was dissolved in absolute EtOH, and the solution was cooled at 0 °C to give of pure compound 3 (1.013 g, 94percent) with the same properties as described in literature. 6b 1H NMR (400 MHz, CDCl3) δ 1.49 (s, 9H, (CH3)3C), 1.51 (s, 9H, (CH3)3C), 1.95-2.05 (m, 1H, CH2CH2CH), 2.24-2.35 (m, 1H, CH2CH2CH), 2.43-2.53 (m, 1H, CH2CH2CH), 2.55-2.66 (m, 1H, CH2CH2CH), 4.48 (dd, J=9.4, 2.7 Hz, 1H, CH2CH2CH).
86%
With triethylamine In acetonitrile at 0 - 20℃;
The synthesis of the vinylproline derivative 6a was conducted proceeding from L-pyroglutamic acid (1a) in six steps (scheme 3). As an alternative, the synthesis of 6a was developed in five stages proceeding from L-proline (16a) with the aid of an electrochemical oxidation of 17a as the key step (step p). As a further suitable intermediate, compound 6b was synthesized by Cu-catalyzed substitution of the methoxy group in 4a (scheme 3).
84.8%
With dmap In acetonitrile at 0 - 20℃; for 48.58 h;
The (S)-tert-butyl 5-oxopyrrolidine-2-carboxylate (21.65 g, 116.9 mmol) was dissolved in acetonitrile (300 mL) with 4-dimethylaminopyridine (1.29 g, 10.6 mmol) and the mixture was cooled to 0 0C in a cooling bath. A solution of di-tert-butyl dicarbonate (33.20 g, 152.0 mmol) in acetonitrile (30 mL) was added slowly to the mixture over 5 minutes. The cooling bath was removed after 30 minutes and the mixture was stirred at ambient temperature for 48 hours. The mixture was concentrated in vacuo and the residue was dissolved in a 1 :1 hexanes/diethyl ether mixture (400 mL). The solution was washed with saturated sodium bicarbonate (2x20 mL) and then brine (40 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was passed through a short column of silica gel (eluted with a 4:1 hexanes/ethyl acetate mixture) to give a light yellow oil, which solidified upon standing. The solid was treated with hexanes and the solids were collected by filtration and dried to give a white solid (24.22 g). The mother liquor was concentrated to give a white solid (4.05 g). The solids were combined to give (S)-di-tert-butyl 5-oxopyrrolidine-l,2-dicarboxylate (28.27 g, 99.2 mmol, 84.8percent).
84%
at 0 - 20℃;
A solution of 20.0 g of lactam 206 (108 mmol) in 200 ml of anhydrous acetonitrile was added with 25.6 ml of Boc2O (120 mmol, 1.1 eq.) and 100 mg of DMAP (0.81 mmol, 0.75 mole percent) at 0° C. and subsequently stirred at RT overnight, during which time the solution assumed an intense orange color. For work-up, the solution was concentrated to dryness, and the remaining residue was taken up in 250 ml of a 1:1 mixture of ethyl acetate/cyclohexane and filtered over a short silica gel column. Removal of solvent under vacuum afforded a yellowish oily residue that was made to crystallize from diethyl ether/pentane to obtain 25.9 g of N-Boc-lactam 44 (90.7 mmol, 84percent) in the form of small white crystals.M (C14H23NO5)=285.3362.Rf=0.20 (SiO2, EE/CH 1:2).m.p.: 52-53° C. Lit.: 55-56° C.1H-NMR (300 MHz, CDCl3): δ (ppm)=4.45 (dd, 1H, J=9.3 Hz, J=2.6 Hz, H-2), 2.17-2.66 (m, 3H, H-3α, H-4), 1.9-2.0 (m, 1H, H-3β), 1.48 (s, 9H, OtBu), 1.46 (s, 9H, OtBu).13C-NMR (75 MHz, CDCl3): δ (ppm)=173.27 (lactam CO), 170.07 (ester CO), 148.94 (Boc CO), 82.84 (Cq, tBu), 81.86 (Cq, tBu), 59.25 (CH, C-2), 30.78 (CH2, C-4), 27.59 (CH3, OtBu), 21.30 (CH2, C-3).IR (ATR): {tilde over (ν)} (cm-1)=2977 (s), 2931 (m), 1790 (vs), 1738 (vs), 1715 (vs), 1476 (m), 1457 (m), 1392 (m), 1367 (vs), 1307 (vs), 1285 (vs), 1254 (vs), 1223 (s), 1148 (vs), 1045 (m), 1021 (m), 962 (w), 912 (w), 842 (s), 774 (m), 643 (w).MS (GCMS-EI, 70 eV): m/z (percent)=270 ([M+-CH3], 6), 239 (4), 227 (9), 207 (4), 185 (3), 171 (6), 153 (2), 143 (15), 129 (5), 101 (4), 97 (7), 87 (72), 74 (100), 57 (12), 55 (14).[α]D20=-35.3° (c=1.167, CHCl3). Lit.: -35.7° (c=0.9, CHCl3).
7.92 g
With dmap In acetonitrile at 20℃; for 42 h;
Step A22a. A solution of tert-butyl (S)-5-oxopyrrolidine-2-carboxylate (5.0 g, 27.0 mmol) in acetonitrile (100 mL) was treated with (Boc)20 (8.83 g, 40.5 mmol) in the presence of DMAP (660 mg, 5.4 mmol) at rt for 42 hours. After concentration, the residue was purified by chromatography (silica, hexanes-EtOAc) to give the desired compound as a light yellow oil (7.92 g, 103percent), which was used directly in the next step.
Reference：
[1] Tetrahedron Letters, 2008, vol. 49, # 12, p. 1957 - 1960
[2] Patent: WO2010/126820, 2010, A2, . Location in patent: Page/Page column 28; 29
[3] European Journal of Organic Chemistry, 2018, vol. 2018, # 4, p. 455 - 460
[4] Biochemistry, 2011, vol. 50, # 33, p. 7184 - 7197
[5] Organic letters, 2002, vol. 4, # 7, p. 1139 - 1142
[6] Tetrahedron, 2013, vol. 69, # 33, p. 6821 - 6825
[7] Journal of Organic Chemistry, 2006, vol. 71, # 11, p. 4164 - 4169
[8] Patent: US2012/172402, 2012, A1, . Location in patent: Page/Page column 13-14
[9] Journal of the American Chemical Society, 2012, vol. 134, # 1, p. 471 - 479
[10] Journal of Medicinal Chemistry, 2012, vol. 55, # 3, p. 1368 - 1381
[11] Patent: WO2010/45580, 2010, A1, . Location in patent: Page/Page column 90-91
[12] Angewandte Chemie - International Edition, 2010, vol. 49, # 39, p. 7111 - 7115
[13] Patent: US2011/34438, 2011, A1, . Location in patent: Page/Page column 30
[14] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 6, p. 507 - 514
[15] Tetrahedron Letters, 1996, vol. 37, # 44, p. 7963 - 7966
[16] Tetrahedron Letters, 1990, vol. 31, # 2, p. 283 - 284
[17] Tetrahedron Letters, 1992, vol. 33, # 32, p. 4617 - 4620
[18] Synthetic Communications, 1995, vol. 25, # 24, p. 4045 - 4052
[19] Tetrahedron Letters, 2004, vol. 45, # 16, p. 3241 - 3243
[20] Patent: US2003/36501, 2003, A1,
[21] Organic Letters, 2009, vol. 11, # 20, p. 4740 - 4742
[22] Patent: WO2005/12308, 2005, A1, . Location in patent: Page/Page column 16; 33
[23] Chemistry - A European Journal, 2010, vol. 16, # 38, p. 11624 - 11631
[24] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2010, vol. 65, # 7, p. 811 - 820
[25] Patent: WO2015/17382, 2015, A1, . Location in patent: Page/Page column 70
2
[ 24424-99-5 ]
[ 98-79-3 ]
[ 1446414-49-8 ]
[ 91229-91-3 ]
[ 35418-16-7 ]
Yield
Reaction Conditions
Operation in experiment
70%
With dmap In <i>tert</i>-butyl alcohol for 12 h; Reflux; Inert atmosphere
A stirred mixture of pyroglutamic acid 5 (5.0g, 38.7mmol), Boc anhydride (16.9g, 77.4mmol), and DMAP (0.2g, 1.6mmol) in tert-BuOH (20mL) was refluxed for 12h under nitrogen atmosphere. Upon cooling at room temperature, solvent was removed under vacuum, and the residue was purified by flash chromatography (SiO2, gradient n-heptane/ethyl acetate, 100/0 to 0/100), to give firstly compound 6 as an oil crystallizing in absolute EtOH to provide pure compound 6 (5.3g, 70percent) as a white solid; mp: 128–131°C; IR ν cm−1: 1794, 1746, 1708, 1225, 1147. 1H NMR (400MHz, CDCl3) δ 1.46 (s, 9H, (CH3)3C), 1.48 (s, 9H, (CH3)3C), 2.05–2.15 (m, 2H, 2CH2CH2), 2.34–2.76 (m, 6H, 2CH2CH2), 4.71 (dd, J=9.8, 2.7Hz, 1H, CH2CH2CHCO2tBu), 5.74 (dd, J=9.4, 2.4Hz, 1H, CH2CH2CHCON); 13C NMR (100MHz, CDCl3) δ 20.9 (CH2), 21.7 (CH2), 27.9 (3CH3), 28.0 (3CH3), 31.0 (CH2), 31.6 (CH2), 58.3 (CH), 59.6 (CH), 82.9 (C), 83.3 (C), 149.9 (C), 169.8 (C), 171.5 (C), 173.4 (C), 174.8 (C). Anal. Calcd for C19H28N2O7: C, 57.56; H, 7.12; N, 7.07. Found: C, 57.48; H, 7.51; N, 6.95. tert-Butyl pyroglutamate 4 (0.6g, 9percent) 4d then Boc ester 3 (1.2g, 11percent) with the same properties as described in literature,6b were also isolated after purification by flash chromatography.
Stage #1: With perchloric acid In water at 20℃; for 18 h; Stage #2: With sodium hydrogencarbonate In water
Aqueous perchloric acid (70percent, 5 mL) was added to a solution of (S)-5-oxopyrrolidine-2-carboxylic acid (20 g, 154.9 mmol) in tert-butyi acetate (260 mL) at ambient temperature. The mixture was stirred at ambient temperature for 18 hrs in a 500 mL round bottom flask sealed with a rubber septum and then poured carefully into sat. sodium bicarbonate (200 mL). The mixture was extracted with ethyl acetate (2x200 mL) and the combined extract was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product solidified under high vacuum. The solid was treated with a 10:1 hexanes/diethyl ether mixture. The solids were collect by filtration and dried to give (S)-tert-buty{ 5-oxopyrrolidine-2-carboxylate (21.65 g, 116.9 mmol, 75.5percent), clean as a white solid.
74%
at 20℃; for 24 h;
To a suspension of L-Pyroglutamic acid (6.46 g, 50.0 mmol) and tBuOAc (100 mL) in a pressure flask was added HCIO4 (70 percent, 1.51 mL 0.35 equiv.) and the solution was stirred for 24 h at room temperature. It was poured into a sat. aq. NaHCO3 solution(200 mL), the organic phase was separated and the aqueous phase was extracted with CH2CI2 (2 x 100 mL). The combined organic phases were dried over MgSO4, filtered and the solvent was evaporated under reduced pressure to afford the title compound (6.87 g, 37.1 mmol, 74 percent) as a colorless solid.Rf: 0.41 (EtOAc, KMnO4)1H-NMR (300 MHz, CDCI3): 6 = 1.44 (s, 9 H, 3 x CH3), 2.12—2.15 (m, 4 H, 2 x4.08—4.16 (m, 1 H, CH), 6.11 (Sbr, 1 H, NH).13C-NMR (75.5 MHz, CDCI3): 6 = 25.08, 28.18, 29.58, 56.25, 82.62, 171.2, 177.9.
74%
at 20℃; for 24 h;
Example 5-3 Preparation of (2S)-tert-Butyl-pyroglutamate F1 To a suspension of L-Pyroglutamic acid (6.46 g, 50.0 mmol) and tBuOAc (100 mL) in a pressure flask was added HClO4 (70 percent, 1.51 mL 0.35 equiv.) and the solution was stirred for 24 h at room temperature. It was poured into a sat. aq. NaHCO3 solution (200 mL), the organic phase was separated and the aqueous phase was extracted with CH2Cl2 (2 * 100 mL). The combined organic phases were dried over MgSO4, filtered and the solvent was evaporated under reduced pressure to afford the title compound (6.87 g, 37.1 mmol, 74 percent) as a colorless solid. Rf: 0.41 (EtOAc, KMnO4) 1H-NMR (300 MHz, CDCl3): δ = 1.44 (s, 9 H, 3 * CH3), 2.12-2.15 (m, 4 H, 2 * CH2), 4.08-4.16 (m, 1 H, CH), 6.11 (sbr, 1 H, NH). 13C-NMR (75.5 MHz, CDCl3): δ = 25.08, 28.18, 29.58, 56.25, 82.62, 171.2, 177.9.
74%
at 20℃; for 24 h;
To a suspension of L-Pyroglutamic acid (6.46 g, 50.0 mmol) and tBuOAc (100 mL) in a pressure flask was added HClO4 (70percent, 1.51 mL 0.35 equiv.) and the solution was stirred for 24 h at room temperature. It was poured into a sat. aq. NaHCO3 solution (200 mL), the organic phase was separated and the aqueous phase was extracted with CH2Cl2 (2×100 mL). The combined organic phases were dried over MgSO4, filtered and the solvent was evaporated under reduced pressure to afford the title compound (6.87 g, 37.1 mmol, 74percent) as a colorless solid. (0291) Rf: 0.41 (EtOAc, KMnO4) (0292) 1H-NMR (300 MHz, CDCl3): δ=1.44 (s, 9H, 3×CH3), 2.12-2.15 (m, 4H, 2×CH2), 4.08-4.16 (m, 1H, CH), 6.11 (sbr, 1H, NH). (0293) 13C-NMR (75.5 MHz, CDCl3): δ=25.08, 28.18, 29.58, 56.25, 82.62, 171.2, 177.9
70%
With perchloric acid In water for 18 h; Inert atmosphere
[0492] To a solution of L-pyroglutamic acid (5.0 g, 38.73 mmol) in tert-butyl acetate (65 mL, 0.48 mol) was added 70percent aqueous perchloric acid (1.25 mL). The reaction mixture was stirred in a 250 mL round-bottom flask under N2 protection for 18 h and then carefully poured into saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (200 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, and then concentrated. The residue was precipitated from a mixture of hexanes/ether (10:1). The solid was collected by filtration, and then dried to give (S)-tert-butyl 5-oxopyrrolidine-2-carboxylate S2 as a white solid (5 g, yield 70percent).
61%
at 20℃;
The synthesis of the vinylproline derivative 6a was conducted proceeding from L-pyroglutamic acid (1a) in six steps (scheme 3). As an alternative, the synthesis of 6a was developed in five stages proceeding from L-proline (16a) with the aid of an electrochemical oxidation of 17a as the key step (step p). As a further suitable intermediate, compound 6b was synthesized by Cu-catalyzed substitution of the methoxy group in 4a (scheme 3).
60%
With perchloric acid In water
To a suspension of S- (-)-pyroglutamic acid (12.9 g, 0.1 mol) in 200 ml of t-butyl acetate, 70percent perchloric acid (3 ml, 0.11 mol) was added and the reaction mixture was stirred overnight in a tightly closed flask. Then the reaction mixture was slowly poured into a saturated solution of NAHC03 and the product was extracted with ether. The organic phase was washed with brine, dried over magnesium sulfate and evaporated to dryness to provide 11.3 g (60percent yield) of t- butyl L-PYROGLUTAMATE. An analytical sample can be obtained by crystallization in ether-hexane, m. p. 91-92 XB0;C.
Reference：
[1] Synthetic Communications, 2005, vol. 35, # 8, p. 1129 - 1134
[2] European Journal of Organic Chemistry, 2018, vol. 2018, # 4, p. 455 - 460
[3] Organic letters, 2002, vol. 4, # 7, p. 1139 - 1142
[4] Patent: WO2010/45580, 2010, A1, . Location in patent: Page/Page column 90
[5] Journal of Medicinal Chemistry, 2012, vol. 55, # 3, p. 1368 - 1381
[6] Tetrahedron, 1996, vol. 52, # 9, p. 3283 - 3302
[7] Organic Letters, 2014, vol. 16, # 20, p. 5254 - 5257
[8] Patent: WO2015/110271, 2015, A1, . Location in patent: Page/Page column 92; 94
[9] Patent: EP2899192, 2015, A1, . Location in patent: Paragraph 0150; 0151
[10] Patent: US2017/2003, 2017, A1, . Location in patent: Paragraph 0290-0293
[11] Angewandte Chemie - International Edition, 2010, vol. 49, # 39, p. 7111 - 7115
[12] Patent: WO2017/35360, 2017, A1, . Location in patent: Paragraph 0492
[13] Journal of Organic Chemistry, 2006, vol. 71, # 11, p. 4164 - 4169
[14] Patent: US2012/172402, 2012, A1, . Location in patent: Page/Page column 13-14
[15] Journal of Organic Chemistry, 1990, vol. 55, # 6, p. 1711 - 1721
[16] Tetrahedron Letters, 1996, vol. 37, # 44, p. 7963 - 7966
[17] Organic Letters, 2006, vol. 8, # 21, p. 4967 - 4970
[18] Patent: WO2004/50084, 2004, A2, . Location in patent: Page/Page column 60
[19] Chemistry - An Asian Journal, 2011, vol. 6, # 2, p. 372 - 375
[20] Chemistry - A European Journal, 2000, vol. 6, # 6, p. 949 - 958
[21] Tetrahedron Letters, 2008, vol. 49, # 12, p. 1957 - 1960
[22] Biochemistry, 2011, vol. 50, # 33, p. 7184 - 7197
[23] Tetrahedron Letters, 2004, vol. 45, # 16, p. 3241 - 3243
[24] Patent: WO2005/12308, 2005, A1, . Location in patent: Page/Page column 16; 33
[25] Organic Letters, 2009, vol. 11, # 20, p. 4740 - 4742
[26] Chemistry - A European Journal, 2010, vol. 16, # 38, p. 11624 - 11631
[27] Patent: US2011/34438, 2011, A1, . Location in patent: Page/Page column 30
[28] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2010, vol. 65, # 7, p. 811 - 820
4
[ 115-11-7 ]
[ 98-79-3 ]
[ 35418-16-7 ]
Yield
Reaction Conditions
Operation in experiment
78%
With sulfuric acid In dichloromethane at 0 - 20℃; Inert atmosphere
To a 2L 3-neck round bottom flask equipped with overhead stirring, nitrogen inlet, and thermocouple was charged L-pyroglutamic acid (40 g., 310 mmol), DCM (400 mL), and H2SO4 (16.51 mL, 310 mmol) the resulting slurry was cooled to 0 0C. Meanwhile 145 mL(1549 mmol) of isobutylene was condensed and added to the DCM slurry over 3 minutes; a slight exotherm was observed. The slurry became thicker after addition of isobutylene. The reaction was allowed to warm to room temperature over 1 hour. A cold finger with dry-ice/acetone was put in place to re-condense any gaseous isobutylene. The reaction was left at room temperature overnight. After the overnight age the reaction became homogenous and colorless. The reaction was poured into 350 mL of 0.5N NaOH and 400 mL IPAc, Once the reaction was quenched the aqueous layer was checked to make sure the pH was at least 10. The aqueous layer was removed and the organics were dried over MgSψ4 then filtered and concentrated to give (S)-5-Oxo- pyrrolidine-2-carboxylic acid tert~bnty\\ ester as an off-white solid (44 g., 241 mmol, 78percent). lH NMR (500 MHz3 CDCI3): δ 6.05 (br s>; IH), 4.15 (m, IH), 2.3-2.5 (m, 3H)5 2.2 (m, IH) 1.5 (S5 9H).
Reference：
[1] Organic Letters, 2012, vol. 14, # 20, p. 5254 - 5257
[2] Patent: WO2010/126820, 2010, A2, . Location in patent: Page/Page column 28
[3] Journal of Medicinal Chemistry, 1985, vol. 28, # 11, p. 1596 - 1602
[4] Journal of the American Chemical Society, 2012, vol. 134, # 1, p. 471 - 479
[5] Liebigs Annalen der Chemie, 1986, # 2, p. 269 - 279
[6] Tetrahedron Letters, 1990, vol. 31, # 2, p. 283 - 284
[7] Patent: WO2010/77836, 2010, A2, . Location in patent: Page/Page column 144
5
[ 98-79-3 ]
[ 35418-16-7 ]
Yield
Reaction Conditions
Operation in experiment
55%
With perchloric acid In tert-butyl methyl ether at 20℃; for 0.0833333 h;
70percent Perchloric acid (0.85 cm3, 9.90 mmol) was added dropwise to a solution of L- pyroglutamic acid 1 (1.70 g, 13.20 mmol) in tert-butyl acetate (17.0 cm3, 126.20 mmol) at room temperature over a period of 5 min. The solution was stirred for 20 h and then solid sodium carbonate was slowly added portionwise until pH 7 was reached. The aqueous layer was extracted with diethyl ether (40 cm3) and ethyl acetate (40 cm3). The combined extracts were dried (MgSO4), filtered and evaporated under reduced pressure to yield a clear oil, which was purified by flash column chromatography (ethyl acetate) to produce ester 2 (1.33 g, 55percent) as a white solid. : mp 101- 103 0C, lit. l mp 102 0C; [α]D + 9.7 ( c 0.14 in MeOH), lit. * +11 (c 3 in MeOH) ; δH (200 MHz; CD3OD) 1.44 [9H, s C(CHs)3], 2.30-2.39 (4Η, m, Pyroβ-H2 and Pyroγ-H2), 4.10-4.13 (IH, m, Pyroα-H) and 6.71 (IH, br s, NH) ; δc (50 MHz; CD3OD) 24.8 (CH2, Pyroβ-C), 27.9 [CH3, C(CHs)3], 29.4 (CH2, Pyroγ-C), 56.1 (CH, Pyroα-C), 82.2 [quat, C(CH3)3], 171.2 (quat. Pyro-CO) and 178.3 (quat., Pyro-CONH).
72%
With perchloric acid; sodium hydrogencarbonate In acetic acid tert-butyl ester
tert-Butyl (S)-5-oxo-2-pyrrolidinecarboxylate (1a) To a suspension of L-pyroglutamic acid (13.2 g, 102 mmol) in t-butyl acetate (200 mL), was added perchloric acid (70percent, 9.7 mL, 113 mmol). The mixture was stirred at rt for 20 h, then poured into sat. NaHCO3. NaHCO3 (s) was added until neutral. The aqueous phase was extracted with EtOAc (6*). The combined organic extract was dried (Na2SO4) and concentrated to afford 13.68 g (72percent) of the title compound, 1a. 1H NMR (300 MHz, CDCl3) δ6.17 (br s, 1H), 4.13 (dd, J=7.4, 5.2, 1H), 2.44-2.31 (m, 3H), 2.22-2.15 (m, 1H), 1.47 (s, 9H).
To a stirred suspension of isopropyl (+)-L-pyroglutamate (5g, 38 mmol), in AcOtBu (50 mL, 11 equiv.) was addeddeopewise 70percent aq. HClO4 (2.5 mL, 30 mmol) and the solution was left to react overnight at room temperature.Na2CO3 (2.53.3 g, 0.0250.033 mol) was then added portionwise followed by Et2O (50 mL). The organic phase waswashed with 1M aq. Na2CO3 (20 mL×2) and brine (20 mL×2), the aqueous phase was extracted with AcOEt (100 mL).The organic phases were dried over anhydrous MgSO4 and evaporated to give an oil which crystallized in Et2O ascolorless crystals and was collected in first crystallization 2.850 g in 40percent yield.
Reference：
[1] Letters in Organic Chemistry, 2018, vol. 15, # 3, p. 196 - 205
7
[ 507-19-7 ]
[ 98-79-3 ]
[ 35418-16-7 ]
Yield
Reaction Conditions
Operation in experiment
82%
at 40℃; for 15 h;
Triethylamine (14.5 g, 0.143 mol) was added to a stirred suspension of l-pyroglutamic acid 5 (5.2 g, 0.040 mol) in propylene carbonate (40 mL). Upon solubilization, zinc bromide (22.5 g, 0.100 mol) was slowly (30 min) added to the stirred solution to give a cloudy suspension (exothermic solubilization; cooling bath), then tert-butyl bromide (16.4 g, 0.120 mol) was added all at once. The mixture was heated for 15 h by using an oil bath (40 °C). The solvent was evaporated in part, and then water (150 mL) was added leading precipitation of a crystallized precipitate, which was washed with water (20 mL). The solid was dissolved in ethyl acetate, and the combined aqueous phases were extracted with ethyl acetate (3*40 mL), and then the organic phases were combined, washed with water (3*30 mL), dried (MgSO4) then evaporated under reduced pressure (100 mmHg). Propylene carbonate was distilled under vacuum (0.3 mmHg) Bp=45 °C. Upon cooling, the residue crystallized to give pure product 4 (6.2 g, 82percent) with the same properties as described in literature. 4d 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 9H, (CH3)3C), 2.13-2.23 (m, 1H, CH2CH2CH), 2.29-2.49 (m, 3H, CH2CH2CH), 4.14 (q, J=8.2, 5.5 Hz, 1H, CH2CH2CH), 6.23 (broad s, 1H, NH).
With dmap In <i>tert</i>-butyl alcohol for 12 h; Reflux; Inert atmosphere
A stirred mixture of pyroglutamic acid 5 (5.0g, 38.7mmol), Boc anhydride (16.9g, 77.4mmol), and DMAP (0.2g, 1.6mmol) in tert-BuOH (20mL) was refluxed for 12h under nitrogen atmosphere. Upon cooling at room temperature, solvent was removed under vacuum, and the residue was purified by flash chromatography (SiO2, gradient n-heptane/ethyl acetate, 100/0 to 0/100), to give firstly compound 6 as an oil crystallizing in absolute EtOH to provide pure compound 6 (5.3g, 70percent) as a white solid; mp: 128–131°C; IR ν cm−1: 1794, 1746, 1708, 1225, 1147. 1H NMR (400MHz, CDCl3) δ 1.46 (s, 9H, (CH3)3C), 1.48 (s, 9H, (CH3)3C), 2.05–2.15 (m, 2H, 2CH2CH2), 2.34–2.76 (m, 6H, 2CH2CH2), 4.71 (dd, J=9.8, 2.7Hz, 1H, CH2CH2CHCO2tBu), 5.74 (dd, J=9.4, 2.4Hz, 1H, CH2CH2CHCON); 13C NMR (100MHz, CDCl3) δ 20.9 (CH2), 21.7 (CH2), 27.9 (3CH3), 28.0 (3CH3), 31.0 (CH2), 31.6 (CH2), 58.3 (CH), 59.6 (CH), 82.9 (C), 83.3 (C), 149.9 (C), 169.8 (C), 171.5 (C), 173.4 (C), 174.8 (C). Anal. Calcd for C19H28N2O7: C, 57.56; H, 7.12; N, 7.07. Found: C, 57.48; H, 7.51; N, 6.95. tert-Butyl pyroglutamate 4 (0.6g, 9percent) 4d then Boc ester 3 (1.2g, 11percent) with the same properties as described in literature,6b were also isolated after purification by flash chromatography.
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5 h; Stage #2: for 20 h;
To a solution of Fl (2.29 g, 12.4 mmol) in THE (62 mL) was added NaH (60 percent oil dispersion, 546 mg, 13.6 mmol, 1.1 equiv.) and it was stirred for 30 mm at room temperature. Subsequently Benzyl chloroformate (1.94 mL, 13.6 mmol, 1.1 equiv.) was added and stirring was continued for further 20 h. The solvent was evaporatedunder reduced pressure, sat. aq. NH4CI solution (100 mL) was added and extrated with EtOAc (2 x 100 mL). The organic phase was dried over Mg504, filtered and the the solvent was evaporated under reduced pressure. Column chromatography on Si02 (cyclohexane/EtOAc 3:1) afforded the title compound (3.56 g, 11.1 mmol, 90percent) as colorless oil.Rf: 0.18 (Cyclohexane/EtOAc 3:1, KMnO4)1H-NMR (300 MHz, CDCI3): 6 = 1.39 (s, 9 H, 3 x CH3), 1.97—2.70 (m, 4 H, 2 x4.54 (dd, J = 9.3, 2.7 Hz, 1 H, CH), 5.27 (dd, J = 16.2, 12.3 Hz, 2 H, CH2), 7.27—7.43(m, 5 H, 5 x Ar-H).13C-NMR (75.5 MHz, CDCI3): 6 = 25.11, 27.12, 31.23, 59.60, 68.43, 82.76, 128.4,128.6, 128.7, 135.3, 151.1, 170.3, 173.3.
90%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5 h; Stage #2: at 20℃; for 20 h;
Example 5-4 Preparation of (2S)-N-Cbz-tert-Butyl-pyroglutamate F2 To a solution of F1 (2.29 g, 12.4 mmol) in THF (62 mL) was added NaH (60 percent oil dispersion, 546 mg, 13.6 mmol, 1.1 equiv.) and it was stirred for 30 min at room temperature. Subsequently Benzyl chloroformate (1.94 mL, 13.6 mmol, 1.1 equiv.) was added and stirring was continued for further 20 h. The solvent was evaporated under reduced pressure, sat. aq. NH4Cl solution (100 mL) was added and extrated with EtOAc (2 * 100 mL). The organic phase was dried over MgSO4, filtered and the the solvent was evaporated under reduced pressure. Column chromatography on SiO2 (cyclohexane/EtOAc 3:1) afforded the title compound (3.56 g, 11.1 mmol, 90 percent) as colorless oil. Rf: 0.18 (Cyclohexane/EtOAc 3:1, KMnO4) 1H-NMR (300 MHz, CDCl3): δ = 1.39 (s, 9 H, 3 * CH3), 1.97-2.70 (m, 4 H, 2 * CH2), 4.54 (dd, J = 9.3, 2.7 Hz, 1 H, CH), 5.27 (dd, J = 16.2, 12.3 Hz, 2 H, CH2), 7.27-7.43 (m, 5 H, 5 * Ar-H). 13C-NMR (75.5 MHz, CDCl3): δ = 25.11, 27.12, 31.23, 59.60, 68.43, 82.76, 128.4, 128.6, 128.7, 135.3, 151.1, 170.3, 173.3.
90%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5 h; Stage #2: for 20 h;
To a solution of F1 (2.29 g, 12.4 mmol) in THF (62 mL) was added NaH (60percent oil dispersion, 546 mg, 13.6 mmol, 1.1 equiv.) and it was stirred for 30 min at room temperature. Subsequently Benzyl chloroformate (1.94 mL, 13.6 mmol, 1.1 equiv.) was added and stirring was continued for further 20 h. The solvent was evaporated under reduced pressure, sat. aq. NH4Cl solution (100 mL) was added and extrated with EtOAc (2×100 mL). The organic phase was dried over MgSO4, filtered and the the solvent was evaporated under reduced pressure. Column chromatography on SiO2 (cyclohexane/EtOAc 3:1) afforded the title compound (3.56 g, 11.1 mmol, 90percent) as colorless oil. (0296) Rf: 0.18 (Cyclohexane/EtOAc 3:1, KMnO4) (0297) 1H-NMR (300 MHz, CDCl3): δ=1.39 (s, 9H, 3×CH3), 1.97-2.70 (m, 4H, 2×CH2), 4.54 (dd, J=9.3, 2.7 Hz, 1H, CH), 5.27 (dd, J=16.2, 12.3 Hz, 2H, CH2), 7.27-7.43 (m, 5H, 5×Ar—H). (0298) 13C-NMR (75.5 MHz, CDCl3): δ=25.11, 27.12, 31.23, 59.60, 68.43, 82.76, 128.4, 128.6, 128.7, 135.3, 151.1, 170.3, 173.3
78%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.5 h; Stage #2: at 20℃; for 48 h;
A dry two necked flask, flushed with dry nitrogen and protected with calcium chloride guard tube, was charged with anhydrous tetrahydrofuran (50 ml) and t-butyl pyroglutamate (1.86 g, 10 mmol) and cooled in an ice bath. Sodium hydride (0.73 g, 60percent suspension in paraffin oil, 11 mmol) was added to the reaction flask in portions and the reaction mixture was left to stir at room temperature for 30 min. Benzyl CHLOROFORMATE (1.87 g, 11 mmol) dissolved in anhydrous THF was added dropwise and after the addition was complete the reaction mixture was stirred at room temperature for 48 hours. The solvent was removed under reduced pressure and the residue was extracted with ethyl acetate and washed with 5percent citric acid solution, water and brine. The organic phase was dried with magnesium sulfate and evaporated to dryness. The crude product was chromatographed on silica gel (hexane-ethyl acetate 3: 1) to afford the title product as a white solid (yield 78percent, m. p 43-45 C).
Stage #1: acetic acid tert-butyl ester; L-Pyroglutamic acid With perchloric acid at 20℃; for 48h; Inert atmosphere;
Stage #2: With perchloric acid for 48h; Inert atmosphere;
90%
With perchloric acid at 20℃; for 96h; Inert atmosphere;
2.1. (S)-tert-Butyl-5-oxopyrrolidine-2-carboxylate (16)
To a suspension of L-pyroglutamic acid 10 (50.0 g, 0.39 mol, 1.0 eq.) in tBuOAc (650 ml) was added dropwise HClO4 (12.5 ml, 70 %) and the mixture was stirred at room temperature for 48 h. After a further addition of HClO4 (12.5 ml, 70 %) stirring was continued for 48 hours.The reaction mixture was then quenched with saturated sodium bicarbonate solution (600ml) and extracted with ethyl acetate (3 x 300 ml). The combined organic layers were driedover Na2SO4, filtered and evaporated to dryness. The white residue was finally washed withEt2O/nHexan (1:10) and concentrated to dryness to give pure 16 (64.7 g, 0.35 mol, 90 %) as awhite crystalline solid.
76%
With 70percent HClO4
75.5%
Stage #1: acetic acid tert-butyl ester; L-Pyroglutamic acid With perchloric acid In water at 20℃; for 18h;
Stage #2: With sodium hydrogencarbonate In water
4.a
Aqueous perchloric acid (70%, 5 mL) was added to a solution of (S)-5-oxopyrrolidine-2-carboxylic acid (20 g, 154.9 mmol) in tert-butyi acetate (260 mL) at ambient temperature. The mixture was stirred at ambient temperature for 18 hrs in a 500 mL round bottom flask sealed with a rubber septum and then poured carefully into sat. sodium bicarbonate (200 mL). The mixture was extracted with ethyl acetate (2x200 mL) and the combined extract was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product solidified under high vacuum. The solid was treated with a 10:1 hexanes/diethyl ether mixture. The solids were collect by filtration and dried to give (S)-tert-buty{ 5-oxopyrrolidine-2-carboxylate (21.65 g, 116.9 mmol, 75.5%), clean as a white solid.
75%
With perchloric acid In water at 20℃; for 18h;
74%
With perchloric acid Ambient temperature;
74%
With perchloric acid at 20℃; for 24h; Inert atmosphere;
74%
With perchloric acid at 20℃; for 24h;
5-3 Example 5-3: Preparation of (2S)-tert-Butyl-pyroglutamate Fl
To a suspension of L-Pyroglutamic acid (6.46 g, 50.0 mmol) and tBuOAc (100 mL) in a pressure flask was added HCIO4 (70 %, 1.51 mL 0.35 equiv.) and the solution was stirred for 24 h at room temperature. It was poured into a sat. aq. NaHCO3 solution(200 mL), the organic phase was separated and the aqueous phase was extracted with CH2CI2 (2 x 100 mL). The combined organic phases were dried over MgSO4, filtered and the solvent was evaporated under reduced pressure to afford the title compound (6.87 g, 37.1 mmol, 74 %) as a colorless solid.Rf: 0.41 (EtOAc, KMnO4)1H-NMR (300 MHz, CDCI3): 6 = 1.44 (s, 9 H, 3 x CH3), 2.12-2.15 (m, 4 H, 2 x4.08-4.16 (m, 1 H, CH), 6.11 (Sbr, 1 H, NH).13C-NMR (75.5 MHz, CDCI3): 6 = 25.08, 28.18, 29.58, 56.25, 82.62, 171.2, 177.9.
74%
With perchloric acid at 20℃; for 24h;
5-3 Example 5-3 Preparation of (2S)-tert-Butyl-pyroglutamate F1
Example 5-3 Preparation of (2S)-tert-Butyl-pyroglutamate F1 To a suspension of L-Pyroglutamic acid (6.46 g, 50.0 mmol) and tBuOAc (100 mL) in a pressure flask was added HClO4 (70 %, 1.51 mL 0.35 equiv.) and the solution was stirred for 24 h at room temperature. It was poured into a sat. aq. NaHCO3 solution (200 mL), the organic phase was separated and the aqueous phase was extracted with CH2Cl2 (2 * 100 mL). The combined organic phases were dried over MgSO4, filtered and the solvent was evaporated under reduced pressure to afford the title compound (6.87 g, 37.1 mmol, 74 %) as a colorless solid. Rf: 0.41 (EtOAc, KMnO4) 1H-NMR (300 MHz, CDCl3): δ = 1.44 (s, 9 H, 3 * CH3), 2.12-2.15 (m, 4 H, 2 * CH2), 4.08-4.16 (m, 1 H, CH), 6.11 (sbr, 1 H, NH). 13C-NMR (75.5 MHz, CDCl3): δ = 25.08, 28.18, 29.58, 56.25, 82.62, 171.2, 177.9.
74%
With perchloric acid at 20℃; for 24h;
5-3 Preparation of (2S)-tert-Butyl-pyroglutamate F1
To a suspension of L-Pyroglutamic acid (6.46 g, 50.0 mmol) and tBuOAc (100 mL) in a pressure flask was added HClO4 (70%, 1.51 mL 0.35 equiv.) and the solution was stirred for 24 h at room temperature. It was poured into a sat. aq. NaHCO3 solution (200 mL), the organic phase was separated and the aqueous phase was extracted with CH2Cl2 (2×100 mL). The combined organic phases were dried over MgSO4, filtered and the solvent was evaporated under reduced pressure to afford the title compound (6.87 g, 37.1 mmol, 74%) as a colorless solid. (0291) Rf: 0.41 (EtOAc, KMnO4) (0292) 1H-NMR (300 MHz, CDCl3): δ=1.44 (s, 9H, 3×CH3), 2.12-2.15 (m, 4H, 2×CH2), 4.08-4.16 (m, 1H, CH), 6.11 (sbr, 1H, NH). (0293) 13C-NMR (75.5 MHz, CDCl3): δ=25.08, 28.18, 29.58, 56.25, 82.62, 171.2, 177.9
72%
With perchloric acid at 0 - 20℃;
70%
With perchloric acid In water for 18h; Inert atmosphere;
6.1 Step 1: (5)-tert-Butyl 5-oxopyrrolidine-2-carboxylate (S2)
[0492] To a solution of L-pyroglutamic acid (5.0 g, 38.73 mmol) in tert-butyl acetate (65 mL, 0.48 mol) was added 70% aqueous perchloric acid (1.25 mL). The reaction mixture was stirred in a 250 mL round-bottom flask under N2 protection for 18 h and then carefully poured into saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (200 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, and then concentrated. The residue was precipitated from a mixture of hexanes/ether (10:1). The solid was collected by filtration, and then dried to give (S)-tert-butyl 5-oxopyrrolidine-2-carboxylate S2 as a white solid (5 g, yield 70%).
67%
With perchloric acid at 23℃; for 18h;
67%
With perchloric acid at 20℃;
2 tert- Butyl (S)-5-oxopyrrolidine-2-carboxylate (16):
To the suspension of L-pyroglutamic acid (10 g, 77.5 mmol) (12) and tert-butyl acetate (100 mL) were added 70% HCIO4 (2.3 mL). The suspension was stirred overnight at rt. Diethyl ether was added to the clear reaction mixture followed by slow addition of saturated solution of sodium bicarbonate to neutralize the acid. The reaction mixture was extracted twice with diethyl ether, dried over sodium sulfate and evaporated in vacuo to afford compound 16 (9.54 g, 67 % yield) as a viscous liquid. (0112) [0084] 6.79 (s, 1H), 4.05 (td, / = 8.9, 8.4, 4.6 Hz, 1H), (0113) 2.29 (qt, J = 17.4, 6.6 Hz, 3H), 2.17 - 1.94 (m, 1H), 1.53 - 1.23 (m, 9H); 13C NMR (101 MHz, CDCI3) d 178.1, 171.1, 82.2, 56.1, 29.4, 27.9, 27.9, 24.8.
61%
With perchloric acid
61%
With perchloric acid at 20℃;
3.a
The synthesis of the vinylproline derivative 6a was conducted proceeding from L-pyroglutamic acid (1a) in six steps (scheme 3). As an alternative, the synthesis of 6a was developed in five stages proceeding from L-proline (16a) with the aid of an electrochemical oxidation of 17a as the key step (step p). As a further suitable intermediate, compound 6b was synthesized by Cu-catalyzed substitution of the methoxy group in 4a (scheme 3).
60%
With perchloric acid Ambient temperature;
60%
With perchloric acid Ambient temperature;
60%
With perchloric acid
60%
With perchloric acid In water
3
To a suspension of S- (-)-pyroglutamic acid (12.9 g, 0.1 mol) in 200 ml of t-butyl acetate, 70% perchloric acid (3 ml, 0.11 mol) was added and the reaction mixture was stirred overnight in a tightly closed flask. Then the reaction mixture was slowly poured into a saturated solution of NAHC03 and the product was extracted with ether. The organic phase was washed with brine, dried over magnesium sulfate and evaporated to dryness to provide 11.3 g (60% yield) of t- butyl L-PYROGLUTAMATE. An analytical sample can be obtained by crystallization in ether-hexane, m. p. 91-92 XB0;C.
60%
With perchloric acid at 20℃; for 12h;
57%
With perchloric acid at 20℃;
50.2%
With perchloric acid at 20℃; for 12h;
44%
With perchloric acid for 72h;
31%
With perchloric acid In water for 24h; Inert atmosphere;
With perchloric acid
Stage #1: acetic acid tert-butyl ester; L-Pyroglutamic acid With perchloric acid In water at 20℃; for 12h;
Stage #2: With sodium hydroxide In water at 0℃;
With perchloric acid In water at 20℃; for 8h;
Stage #1: acetic acid tert-butyl ester; L-Pyroglutamic acid With perchloric acid at 20℃; for 15h;
Stage #2: With sodium hydrogencarbonate
30.0 g of L-pyroglutamic acid 133 (232 mmol) was suspended in 500 ml of tert-butyl acetate and added with 12 ml of 60% perchloric acid. After stirring for 15 h at RT, the resulting clear solution was cooled to 0° C. and adjusted to a pH value of 4-5 by adding 30.0 g of solid NaHCO3. After removing the solid by filtration, the filtrate was concentrated to dryness, thereby obtaining 25.4 g (136 mmol, 58%) of the tert-butyl ester 206 as a white solid that was reacted without further purification. An analytical sample was obtained by column chromatographysilica gel (eluant: EE).M (C9H15NO3)=185.2203.Rf=0.25 (SiO2, EE).m.p.: 97-98° C. Lit.: 98-99° C.1H-NMR (300 MHz, CDCl3): δ (ppm)=6.13 (br, 1H, NH), 4.06-4.14 (m, 1H, H-2), 2.22-2.43 (m, 3H, H-3α, H-4) 2.04-2.20 (m, 1H, H-3β), 1.44 (s, 9H, OtBu).13C-NMR (75 MHz, CDCl3): δ (ppm)=177.97 (lactam CO), 171.07 (ester CO), 82.18 (Boc Cq), 56.07 (CH, C-2), 29.34 (CH2, C-4), 27.87 (CH3 OtBu), 24.75 (CH2, C-3).IR (ATR): {tilde(ν)} (cm-1)=3239 (br), 2976 (s), 2934 (m), 1731 (vs), 1695 (vs), 1457 (s), 1419 (s), 1392 (s), 1366 (vs), 1227 (vs), 1147 (vs), 1037 (m), 1009 (m), 971 (m), 953 (m), 885 (w), 845 (s), 810 (s).MS (GCMS-EI, 70 eV): m/z (%)=186 ([MH+], <1), 142 (<1), 84 (100), 57 (38).
With sulfuric acid In dichloromethane at 0 - 20℃; Inert atmosphere;
1.1
To a 2L 3-neck round bottom flask equipped with overhead stirring, nitrogen inlet, and thermocouple was charged L-pyroglutamic acid (40 g., 310 mmol), DCM (400 mL), and H2SO4 (16.51 mL, 310 mmol) the resulting slurry was cooled to 0 0C. Meanwhile 145 mL(1549 mmol) of isobutylene was condensed and added to the DCM slurry over 3 minutes; a slight exotherm was observed. The slurry became thicker after addition of isobutylene. The reaction was allowed to warm to room temperature over 1 hour. A cold finger with dry-ice/acetone was put in place to re-condense any gaseous isobutylene. The reaction was left at room temperature overnight. After the overnight age the reaction became homogenous and colorless. The reaction was poured into 350 mL of 0.5N NaOH and 400 mL IPAc, Once the reaction was quenched the aqueous layer was checked to make sure the pH was at least 10. The aqueous layer was removed and the organics were dried over MgSθ4 then filtered and concentrated to give (S)-5-Oxo- pyrrolidine-2-carboxylic acid tert~bnty ester as an off-white solid (44 g., 241 mmol, 78%). lH NMR (500 MHz3 CDCI3): δ 6.05 (br s>; IH), 4.15 (m, IH), 2.3-2.5 (m, 3H)5 2.2 (m, IH) 1.5 (S5 9H).
65%
With sulfuric acid In dichloromethane at 25℃; for 48h;
51%
With sulfuric acid In 1,4-dioxane at -78 - 20℃; for 144h;
14%
With sulfuric acid In 1,4-dioxane for 12h;
With sulfuric acid In 1,4-dioxane
With sulfuric acid In dichloromethane at 20℃; Cooling with acetone-dry ice;
17.1
Step 1: Synthesis of (S)-5-oxo-pyrrolidine-2-carboxylic acid tert-butyl ester; A pressure flask is charged with (S)-(-)-2-pyrrolidone-5-carboxylic acid (25 g, 193.6 mmol) and dichloromethane (100 mL) and the stirred suspension is cooled in a dry ice acetone bath. Liquid 2-methylpropene (150 mL) is added followed by concentrated sulfuric acid (0.5 mL). The pressure flask is sealed and the reaction mixture is stirred at room temperature for 48 h. The pressure flask is cooled in a dry acetone bath and the reaction mixture is diluted with dichloromethane (500 mL) and treated with a saturated solution of sodium bicarbonate until the effervescence is ceased. The organic layer is separated, washed with saturated solution of sodium bicarbonate (300 mL), brine (300 mL), dried over anhydrous Na2SO4 and solvent removed in vacuo to give the title compound as a white crystalline solid. The crude material is used without purification.
With toluene-4-sulfonic acid In dichloromethane for 96h; Sealed tube;
3 Comparative Example 3
Add 1000ml DCM into a 3000ml three-necked flask, then add 100g (0.77mol) L-pyr-oh, mechanically stir, cool down, add 300g p-toluenesulfonic acid at -5°C, and pass 200g isobutylene, seal the reaction for 4 days, then Cool down and release excess isobutylene, then adjust the pH to 7-8 with sodium carbonate, then separate, and then wash the DCM phase with a 10% mass percent sodium carbonate aqueous solution twice, saturated brine once, dry and concentrate to obtain oil 100g is the crude product of h-pyr-otbu. Dissolve the oil in DMF, then add z-osu, then DMAP, then react overnight, add ethyl acetate to dissolve, and wash twice with water and once with saturated brine, then Dry, concentrate and crystallize with n-hexane. Dry 43g to obtain z-pyr-otbu. After that, the obtained z-pyr-otbu is subjected to acid hydrolysis to remove the tert-butyl ester, and finally 27g of z-pyr-oh is obtained. The target molecule was obtained, but the yield was low, and the use of isobutylene in the process requires pressure reaction, which is a high-risk process.
With perchloric acid In tert-butyl methyl ether at 20℃; for 0.0833333h;
3.3.1
70% Perchloric acid (0.85 cm3, 9.90 mmol) was added dropwise to a solution of L- pyroglutamic acid 1 (1.70 g, 13.20 mmol) in tert-butyl acetate (17.0 cm3, 126.20 mmol) at room temperature over a period of 5 min. The solution was stirred for 20 h and then solid sodium carbonate was slowly added portionwise until pH 7 was reached. The aqueous layer was extracted with diethyl ether (40 cm3) and ethyl acetate (40 cm3). The combined extracts were dried (MgSO4), filtered and evaporated under reduced pressure to yield a clear oil, which was purified by flash column chromatography (ethyl acetate) to produce ester 2 (1.33 g, 55%) as a white solid. : mp 101- 103 0C, lit. l mp 102 0C; [α]D + 9.7 ( c 0.14 in MeOH), lit. * +11 (c 3 in MeOH) ; δH (200 MHz; CD3OD) 1.44 [9H, s C(CHs)3], 2.30-2.39 (4Η, m, Pyroβ-H2 and Pyroγ-H2), 4.10-4.13 (IH, m, Pyroα-H) and 6.71 (IH, br s, NH) ; δc (50 MHz; CD3OD) 24.8 (CH2, Pyroβ-C), 27.9 [CH3, C(CHs)3], 29.4 (CH2, Pyroγ-C), 56.1 (CH, Pyroα-C), 82.2 [quat, C(CH3)3], 171.2 (quat. Pyro-CO) and 178.3 (quat., Pyro-CONH).
13.68 g (72%)
With perchloric acid; sodium hydrogencarbonate In acetic acid tert-butyl ester
1 tert-Butyl (S)-5-oxo-2-pyrrolidinecarboxylate (1a)
tert-Butyl (S)-5-oxo-2-pyrrolidinecarboxylate (1a) To a suspension of L-pyroglutamic acid (13.2 g, 102 mmol) in t-butyl acetate (200 mL), was added perchloric acid (70%, 9.7 mL, 113 mmol). The mixture was stirred at rt for 20 h, then poured into sat. NaHCO3. NaHCO3 (s) was added until neutral. The aqueous phase was extracted with EtOAc (6*). The combined organic extract was dried (Na2SO4) and concentrated to afford 13.68 g (72%) of the title compound, 1a. 1H NMR (300 MHz, CDCl3) δ6.17 (br s, 1H), 4.13 (dd, J=7.4, 5.2, 1H), 2.44-2.31 (m, 3H), 2.22-2.15 (m, 1H), 1.47 (s, 9H).
Step 1: Synthesis of (S)-l-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-5-oxo-pyrrolidine-2- carboxylic acid tert-butyl ester; To a stirred solution of (S)-5-oxo-pyrrolidine-2-carboxylic acid tert-butyl ester (740 mg, 4 mmol) in N, N-dimethylformamide (5 mL) sodium hydride (180 mg of 60% dispersion in mineral oil, 4.5 mmol) is added at room temperature. After 10 minutes, 3-chloro-2-fluoro-5- trifluoromethylpyridine (1 mL, 8 mmol) is added and the suspension stirred at room temperature. After 3 h the reaction mixture is treated with saturated ammonium chloride solution (150 mL), extracted with dichloromethane (2 X 100 mL). Combined extracts washed with brine (2 X 50 mL), water, dried over anhydrous Na2SO4 and solvent removed in vacuo. The crude is purified by chromatography over silica gel eluting with hexanes/ethyl acetate to give the title compound, ESI m/z 365 [M+H]+.
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