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CAS No. : | 98-79-3 | MDL No. : | MFCD00005272 |
Formula : | C5H7NO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ODHCTXKNWHHXJC-VKHMYHEASA-N |
M.W : | 129.11 | Pubchem ID : | 7405 |
Synonyms : |
NSC 143034;L-pyroglutamate;NSC 9966;Glutimic acid;EINECS 202-700-3;(–)-Pyroglutamic Acid;5-oxo-L-Proline;(S)-5-Oxoproline;pidolic acid;5-Oxoproline
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.6 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 32.72 |
TPSA : | 66.4 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.63 cm/s |
Log Po/w (iLOGP) : | 0.5 |
Log Po/w (XLOGP3) : | -0.77 |
Log Po/w (WLOGP) : | -1.03 |
Log Po/w (MLOGP) : | -0.93 |
Log Po/w (SILICOS-IT) : | -0.08 |
Consensus Log Po/w : | -0.46 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -0.09 |
Solubility : | 105.0 mg/ml ; 0.814 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.15 |
Solubility : | 92.1 mg/ml ; 0.714 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.04 |
Solubility : | 119.0 mg/ml ; 0.923 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.67 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | at 0℃; for 15 h; | A suspension of 30.0 g of L-pyroglutamic acid 133 (232 mmol) in 100 ml of anhydrous ethanol was slowly added with 20 ml of SOCl2 (274 mmol, 1.2 eq.) at 0° C. and subsequently stirred for 15 h, and the batch was thawed to room temperature to form a clear solution. For work-up, all volatile components were completely removed under vacuum, the remaining residue was subsequently taken up in 500 ml of ethyl acetate and successively stirred over K2CO3 and MgSO4, each time removing the drying agent by suction. Filtration over a small amount of silica gel and solvent removal under vacuum afforded 36.0 g (230 mmol, 99percent) of ester 203 in the form of a slightly yellowish, viscous oil.M (C7H11NO3)=157.1672.Rf=0.47 (SiO2, CH2Cl2/MeOH 9:1).1H-NMR (300 MHz, CDCl3): δ (ppm)=7.04 (br, 1H, NH), 4.10-4.22 (m, 3H, H-2, ester CH2), 2.22-2.48 (m, 3H, H-3α, H-4), 2.07-2.22 (m, 1H, H-3β), 1.22 (t, 3H, J=7.1 Hz, ester CH3).13C-NMR (75 MHz, CDCl3): δ (ppm)=178.37 (lactam CO), 172.10 (ester CO), 61.58 (ester CH2), 55.59 (CH), 29.33 (CH2, C-4), 24.77 (CH2, C-3), 14.11 (ester CH3). |
98% | at -5 - 20℃; for 10 h; | The synthesis of compound II specific process: To the reaction flask was added Compound I (10mmol), which was dissolved in absolute ethanol (15ml), cooled to -5 ~ 0 ° C,Thionyl chloride (11 mmol) in ethanol (10 ml) was slowly added dropwise to the system,Dropping is completed, slowly rose to room temperature reaction 10h. TLC point plate, the raw material completely reacted.The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in dichloromethane (50 ml) and water (50 ml), the layers were separated and the aqueous phase was extracted with dichloromethane (20 ml * 3). The organic phases were combined,The organic phase was dried over anhydrous sodium sulfate, filtered with suction and the filtrate was concentrated under reduced pressure to give compound II (9.8 mmo 1) in 98percent yield. |
91% | at 20℃; for 12 h; | General procedure: To a solution of L-pyroglutamic acid (10 mmol) in anhydrous alcohol(30 mL) was added catalytic amount of SOCl2 (1 mmol). The reaction mixture was stirred at room temperature for 12 h until no change was observed by TLC. After evaporating the solvent under reduced pressure, the residue was dissolved in EtOAc (100 mL), stirred over K2CO3, and dried with MgSO4 to afford the crude product. Then the residue passed through a flash column chromatography (MeOH/CH2Cl2=1/10) on silica gel and removal of all volatiles were in vacuo to give the pure products. |
82% | at -5 - 0℃; for 5 h; Large scale | A reaction vessel was charged with ethanol (49.0 liters) and cooled to -5°C. The reaction vessel was thencharged with thionyl chloride (4.97 kg) in a manner so that the temperature of the mixture did not exceed 0°C. Aftercomplete addition of the thionyl chloride, the mixture was cooled again to -5°C and L-pyroglutamic acid (Formula E) wasadded portionwise so that the temperature was maintained between 0 and -5°C during the addition. Following additionof the acid, the reaction mixture was heated to 20 to 25°C and stirred for 5 hours. The reaction mixture was thenevaporated under vacuum (T max 45°C) to approximately 15percent of its original volume. The remaining oil was then dissolvedin toluene (49 liters). The toluene solution was then cooled to approximately 10°C and triethyl amine (8.45 kg) was addedslowly so that the maximum temperature was between 20 and 25°C. The resulting suspension was stirred for 30 minutesand then filtered. The filter cake was washed with toluene (about 5 liters). The filtrate was reduced at 50°C under vacuumto a total volume of about 10 liters. Crystallization was initiated by slow addition of cyclohexane (8 liters) at 50°C andsubsequent cooling to approximately 30°C. After seed formation the mixture was cooled to 20 to 25°C and charged witha second 8 liter portion of cyclohexane. The mixture was then cooled to 6 to 8°C, stirred for one hour, and the resultingcrystals were filtered off. The crystals were washed twice with cyclohexane (4 liters each wash). The yield was 4.89 kg(82percent) L-pyroglutamic acid ethyl ester (Formula F) as colorless needles. |
82% | at 0℃; for 3 h; | To a solution of L-pyroglutamic acid 1 (13 g, 100 mmol) in anhydrous ethanol (50 mL) was slowly added SOCl2 (16.7 g, 130 mmol at 0°C, and the reaction mixture was stirred at this temperature for additional 3 h. The crude mixture was concentrated to dryness, the residue was dissolved in DCM (300 mL). The organic layer was washed brine and dried over anhydrous Na2SC>4, filtered and concentrated to dryness to give title compound 76, (S)-ethyl 5-oxopyrrolidine-2-carboxylate (13 g, 82percent yield). (LC method 1): m/z 158 (M+l)+. |
80% | at 0 - 20℃; | Thionyl chloride (1 1.2 mL, 154 mmol) was added to a solution of acid (20.0 g, 155.0 mmol) in ethanol (200 mL) at 0 °C slowly. The reaction mixture was allowed to stir at room temperature overnight. The mixture was concentrated in vacuo to remove ethanol. The crude residue was diluted with DCM, washed with saturated aqueous NaHC03 solution, water and brine. The organic layer was dried over Na2S04 and concentrated to give L1 (19 g, 80 percent) as yellow liquid. Rf: 0.3 in 100percent EtOAc (KMn0 active). |
70% | at 0 - 20℃; for 3.5 h; | To a solution of compound 18-1 (10.0 g, 77.5 mmol) in ethanol (150 mL) was added SOCl2 (9.22 g, 77.5 mmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 0.5 hour and at rt for another 3 hours. The reaction was monitored by TLC and the mixture was concentrated in vacuo after the process stopped. The residue was purified by silica gel column chromatography (EtOAc/MeOH (v/v) = 15/1) to give the title compound 18-2 as oil (8.5 g, 70percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3): δ 7.04 (br, 1H), 4.10-4.22 (m, 3H), 2.22-2.48 (m, 3H), 2.07-2.22 (m, 1H), 1.22 (t, J = 7.1 Hz, 3H). |
70% | at 0 - 20℃; for 3.5 h; | To a solution of compound 18-1 (10.0 g, 77.5 mmol) in ethanol (150 mL) was added SOCl2 (9.22 g, 77.5 mmol)dropwise at 0 °C. The mixture was stirred at 0 °C for 0.5 hour and at rt for another 3 hours. The reaction was monitoredby TLC and the mixture was concentrated in vacuo after the process stopped. The residue was purified by silica gelcolumn chromatography (EtOAc/MeOH (v/v) = 15/1) to give the title compound 18-2 as oil (8.5 g, 70percent). The compoundwas characterized by the following spectroscopic data:1H NMR (400 MHz, CDCl3): δ 7.04 (br, 1H), 4.10-4.22 (m, 3H), 2.22-2.48 (m, 3H), 2.07-2.22 (m, 1H), 1.22 (t, J = 7.1 Hz, 3H). |
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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.5% | 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. |
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). |
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). |
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). |
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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.3% | Stage #1: at 30℃; for 1 h; Stage #2: With dmap; triethylamine In ethyl acetate at 30℃; |
(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 < 3O0C with stirring. After an hour, HPLC showed completion of the reaction. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (200 mL). After slow addition of triethylamine (13.5 g) at < 3O0C, the mixture was filtered. DMAP (1.5 g) was added to the filtrate in one portion followed by addition of BoC2O (27.8 g) at < 3O0C. After HPLC showed completion of the reaction, the mixture was cooled to O0C and IN HCl (13.0 niL) was added at < 3O0C and stirred for 10 min. The organic layer was removed, washed with H2O (20.0 mL), and evaporated under reduced pressure. Then, tert-butyl methyl ether (27.0 mL) was added to the obtained residue and cooled to O0C with stirring. The crystals that deposited slowly were filtered to give Compound 3 (21.9 g, 77.3 percent). |
38% | Stage #1: at 125℃; for 12 h; Autoclave; Inert atmosphere Stage #2: at 15 - 30℃; |
1 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. |