* 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.
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 6, p. 507 - 514
3
[ 24424-99-5 ]
[ 94885-52-6 ]
[ 113400-36-5 ]
Yield
Reaction Conditions
Operation in experiment
73.8%
With dmap In dichloromethane at 0 - 20℃;
D-1 (8 g, 36.5 mmol, 1 eq) was dissolved in DCM (150 mL). The mixture was stirred and was cooled to 0° C. Dimethylaminopyridine (DMAP, 4.9 g, 40.1 mmol, 1.1 eq) was added followed by Boc-anhydride ((BOC)2O, 8.75 g, 40.1 mmol, 1.1 eq). The mixture was allowed to warm to room temperature and was stirred for 2 hours. The mixture was then diluted with DCM (250 mL) and was washed successively with aqueous HCl (1N, 50 mL), aqueous saturated bicarbonate solution (350 mL) and brine. The organic phase was dried over sodium sulfate, was concentrated under reduced pressure, and was purified by silica gel chromatography to provide D-2 (8.6 g, 73.8percent). LCMS (ES+, m/e=656, [2M+NH4+]).
51.2 g
With dmap; triethylamine In dichloromethane at 20℃; for 16 h; Cooling with ice
Benzyl chloride (25.3ml, 0.22mol) was added to a solution of 5-oxo-l-proline (2) (25.8g, 0.20mol) with triethylamine (28.0ml, 0.20mol) in THF (260ml). The reaction mixture was refluxed at 70°C for 5days. After cooling the mixture to room temperature, the solvent was removed in vacuo. The residue was diluted with water, and extracted with chloroform. The organic layer was washed with brine, and dried over magnesium sulfate. The mixture was filtered, and the solvent was removed in vacuo to afford the crude product as pale brown oil. To a stirred solution of the product in dichloromethane (400ml) was added di-tert-butyl dicarbonate (44g, 0.20mol), triethylamine (28ml, 0.2mol) and DMAP (12.2g, 0.10mol) under an ice cooling bath. The solution was warmed to room temperature and stirred for 16h. The reaction mixture was diluted with water, and extracted with chloroform. The organic layer was washed with brine, and dried over magnesium sulfate. The mixture was filtered, and the solvent was removed in vacuo to afford crude product. The residue was purified by flash silica gel chromatography withn-hexane/EtOAc (2:1, v/v) to give the colorless solid (51.2g, 80percent yield);1H NMR (400MHz, CDCl3)δ: 1.42 (9H, s), 1.98–2.05 (1H, m), 2.26–2.37 (1H, m), 2.44–2.51 (1H, m), 2.57–2.66 (1H, m), 4.64 (1H, dd,J=9.5, 2.9Hz), 5.19 (1H, d,J=12.0Hz), 5.23 (1H, d,J=12.2Hz), 7.34–7.37 (5H, m); ESI/MS:m/z=342 (M+Na).
Reference：
[1] Tetrahedron Letters, 2002, vol. 43, # 19, p. 3499 - 3501
[2] Chemistry (Weinheim an der Bergstrasse, Germany), 2002, vol. 8, # 11, p. 2516 - 2525
[3] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 6, p. 507 - 514
[4] Tetrahedron, 2004, vol. 60, # 45, p. 10277 - 10284
[5] Patent: US2014/248242, 2014, A1, . Location in patent: Paragraph 0402; 0404
[6] Tetrahedron Letters, 1992, vol. 33, # 32, p. 4617 - 4620
[7] Synthetic Communications, 1995, vol. 25, # 24, p. 4045 - 4052
[8] Tetrahedron, 1998, vol. 54, # 9, p. 1753 - 1762
[9] Organic Letters, 2004, vol. 6, # 9, p. 1469 - 1471
[10] Journal of Organic Chemistry, 2000, vol. 65, # 7, p. 2163 - 2171
[11] Journal of the American Chemical Society, 2001, vol. 123, # 39, p. 9706 - 9707
[12] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 10, p. 3474 - 3488
[13] Patent: US6277851, 2001, B1,
[14] Journal of Medicinal Chemistry, 2010, vol. 53, # 18, p. 6572 - 6583
[15] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 14, p. 4319 - 4331
[16] Journal of the American Chemical Society, 2015, vol. 137, # 7, p. 2776 - 2784
4
[ 24424-99-5 ]
[ 4561-10-8 ]
[ 113400-36-5 ]
Yield
Reaction Conditions
Operation in experiment
94.6%
With N-ethyl-N,N-diisopropylamine In toluene at 30 - 95℃; for 9 h;
To a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser was added 18.2 g (0.05 mol) of L-glutamic acid dibenzyl ester hydrochloride prepared in Example 1,150 g of toluene, 7.8 g (0.06 mol) of diisopropylethylamine,12.0 g (0.055 mol) di-tert-butyl dicarbonate, heated,30-35°C for 4 hours, 90-95°C for 5 hours,Cool to 2025°C, filter and distill the filtrate to recover the solvent.To the residue was added 50 g of methyl tert-butyl ether, recrystallized, filtered and dried.15.1 g of white powder solidN-tert-butyloxycarbonyl-L-pyroglutamic acid benzyl esterThe liquid phase purity was 99.9percent and the yield was 94.6percent.
Reference：
[1] Patent: CN107602436, 2018, A, . Location in patent: Paragraph 0055; 0056; 0058; 0059; 0066; 0067
5
[ 98-79-3 ]
[ 113400-36-5 ]
Reference：
[1] Patent: EP1970377, 2008, A1, . Location in patent: Page/Page column 55
[2] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 10, p. 3474 - 3488
[3] Tetrahedron, 2004, vol. 60, # 45, p. 10277 - 10284
[4] Organic Letters, 2004, vol. 6, # 9, p. 1469 - 1471
[5] Journal of the American Chemical Society, 2001, vol. 123, # 39, p. 9706 - 9707
[6] Journal of Organic Chemistry, 2000, vol. 65, # 7, p. 2163 - 2171
[7] Tetrahedron, 1998, vol. 54, # 9, p. 1753 - 1762
[8] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 6, p. 507 - 514
[9] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 14, p. 4319 - 4331
[10] Patent: US2014/248242, 2014, A1,
[11] Journal of the American Chemical Society, 2015, vol. 137, # 7, p. 2776 - 2784
Reference：
[1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 10, p. 3474 - 3488
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 14, p. 4319 - 4331
[3] Journal of the American Chemical Society, 2015, vol. 137, # 7, p. 2776 - 2784
10
[ 75-16-1 ]
[ 113400-36-5 ]
[ 113400-46-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 1998, vol. 41, # 15, p. 2819 - 2834
11
[ 100-51-6 ]
[ 113400-36-5 ]
Reference：
[1] Patent: US2014/248242, 2014, A1,
12
[ 113400-36-5 ]
[ 53100-44-0 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 6, p. 507 - 514
[2] Chemistry (Weinheim an der Bergstrasse, Germany), 2002, vol. 8, # 11, p. 2516 - 2525
[3] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 10, p. 3474 - 3488
13
[ 113400-36-5 ]
[ 334769-80-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 14, p. 4319 - 4331
D-1 (8 g, 36.5 mmol, 1 eq) was dissolved in DCM (150 mL). The mixture was stirred and was cooled to 0 C. Dimethylaminopyridine (DMAP, 4.9 g, 40.1 mmol, 1.1 eq) was added followed by Boc-anhydride ((BOC)2O, 8.75 g, 40.1 mmol, 1.1 eq). The mixture was allowed to warm to room temperature and was stirred for 2 hours. The mixture was then diluted with DCM (250 mL) and was washed successively with aqueous HCl (1N, 50 mL), aqueous saturated bicarbonate solution (350 mL) and brine. The organic phase was dried over sodium sulfate, was concentrated under reduced pressure, and was purified by silica gel chromatography to provide D-2 (8.6 g, 73.8%). LCMS (ES+, m/e=656, [2M+NH4+]).
With 2-(Dimethylamino)pyridine; In dichloromethane;
Step A: Benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate 11 mmol of dimethylaminopyridine and 11 mmol of di-tert-butyl dicarbonate are added at 0 C. to 10 mmol of benzyl (2S)-5-oxoprolinate (the preparation process of which is described by E. Campaigne et al. (J. Heterocycl. Chem. 1975, 12, 391)) dissolved in dichloromethane. After 24 hours' stirring at room temperature, the reaction mixture is washed and then dried and evaporated to yield the expected product in the form of a viscous oil.
51.2 g
With dmap; triethylamine; In dichloromethane; at 20℃; for 16h;Cooling with ice;
Benzyl chloride (25.3ml, 0.22mol) was added to a solution of 5-oxo-l-proline (2) (25.8g, 0.20mol) with triethylamine (28.0ml, 0.20mol) in THF (260ml). The reaction mixture was refluxed at 70C for 5days. After cooling the mixture to room temperature, the solvent was removed in vacuo. The residue was diluted with water, and extracted with chloroform. The organic layer was washed with brine, and dried over magnesium sulfate. The mixture was filtered, and the solvent was removed in vacuo to afford the crude product as pale brown oil. To a stirred solution of the product in dichloromethane (400ml) was added di-tert-butyl dicarbonate (44g, 0.20mol), triethylamine (28ml, 0.2mol) and DMAP (12.2g, 0.10mol) under an ice cooling bath. The solution was warmed to room temperature and stirred for 16h. The reaction mixture was diluted with water, and extracted with chloroform. The organic layer was washed with brine, and dried over magnesium sulfate. The mixture was filtered, and the solvent was removed in vacuo to afford crude product. The residue was purified by flash silica gel chromatography withn-hexane/EtOAc (2:1, v/v) to give the colorless solid (51.2g, 80% yield);1H NMR (400MHz, CDCl3)delta: 1.42 (9H, s), 1.98-2.05 (1H, m), 2.26-2.37 (1H, m), 2.44-2.51 (1H, m), 2.57-2.66 (1H, m), 4.64 (1H, dd,J=9.5, 2.9Hz), 5.19 (1H, d,J=12.0Hz), 5.23 (1H, d,J=12.2Hz), 7.34-7.37 (5H, m); ESI/MS:m/z=342 (M+Na).
198 g
With 4-pyrrolidin-1-ylpyridine; at 50℃;
(3) The filtrate was transferred to a 1000 mL flask, and 262 g of Boc anhydride (1.2 mol) was added.1 g of catalyst 4-PPY (0.01 mol), heated to 50 C for reaction overnight;(4) After the reaction is completed, a citric acid solution is added to adjust the pH of the aqueous phase to about 5, and the organic phase is washed with water.Times.The organic phase is rotary evaporated to dryness, ethyl acetate + cyclohexane (ethyl acetate / cyclohexane = 10: 1) 1000g,Stir the crystals overnight, suction filtration, drying at 50 C,A yellow solid 198 g was obtained, the purity was more than 99.5%, and the yield was 77%.
With sodium tetrahydroborate; potassium dihydrogenphosphate; In methanol; water; at 0℃; for 2h;
A solution of potassium dihydrogen phosphate (K2H2PO4, 2.6 g, 19 mmol, 7.3 eq) in a mixture of methanol and water (5:1, 30 mL) was prepared. D-2 (823 mg, 2.6 mmol, 1 eq) was added and the mixture was cooled to 0 C. Sodium borohydride (700 mg, 19 mmol, 7.3 eq) was added and the mixture was stirred at 0 C. for 2 hours. Acetic acid (2 mL) was added and the mixture was stirred for another 20 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was extracted with ether. The ether solution was dried over sodium sulfate, was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel) to afford D-3 (100 mg, 12%). LCMS (ES+, m/e=346, [M+Na]+).
(i) Benzyl (S)-1-N-tert-butoxycarbonyl-5-oxopyrrolidine-2-carboxylate The title compound (200 g, two steps, yield 94%) was produced from (S)-5-oxopyrrolidine-2-carboxylic acid in the same manner as in the method described in Tetrahedron Lett., 43, (2002), 3499.
(2S,4S)-4-Carboxymethyl-1-{(2S,4S)-4-carboxymethyl-1-[(2S,4S)-4-carboxymethyl-1-(2,2-dimethyl-propionyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonyl}-pyrrolidine-2-carboxylic acid[ No CAS ]
With lithium hexamethyldisilazane; In tetrahydrofuran; at -78℃;
Enolization [(LIHMDS,] 33 mmol, 33 mL, 1.1 equiv) and alkylation of 7a (9.47 g, 29.7 mmol, 1 equiv) with [CIS-1-BROMO-2-PENTENE] (4.21 mL, 35.6 mmol, 1.2 equiv), in anhydrous THF at-78C under nitrogen, afforded a mixture of diastereomers of the lactam 7b [(R9'=2-] pentenyl) (43.2%) after silica gel purification. The lactam 7b (3.96g, 10. [22MMOL)] was reduced to the pyrrolidine 7c [(R9'=2-PENTENYL)] by the two-step sequence involving superhydride reduction of the lactam to the hemiaminal, at-78C in anhydrous THF, and the subsequent reduction of the hemiaminal with [ET3SIH/BF30ET2] in anhydrous DCM at-78C affording 7c [(R9'=2-PENTENYL) (71%)] after silica gel purification. The pyrrolidine 7c (2.71 g, 7.26 [MMOL),] 10% palladium on carbon [(560MG),] in anhydrous methanol [(30] mL) was subjected to Parr hydrogenolysis at 50 psi for 5 h. The reaction mixture was filtered through a celite pad and washed several times with methanol. The combined washings and filtrate were evaporated to dryness, affording, without further purification, a colorless oil 7d [(R9=PENTYL)] (1.68g, 80%). [[0196]] TLC: [RI=] 0.3 [Solvent system: DCM: hexanes: MeOH (6: 5: [1)].] MS (ESNEG): 284.5 [M-H].
Example 2 Synthesis of Boc-4(R)-(3-phenylpropyl)proline (2d). STR42 a) Synthesis of compound 2b: To a solution of Boc-pyroglutamic acid benzyl ester (2a) (prepared as described by A. L Johnson et al., J. Med. Chem. (1985), 28, 1596-1602) (500 mg, 1.57 mmol) in THF (10 mL) at -78 C., was slowly added lithium hexamethydisilylazide (1.72 mL, 1M solution in THF). After stirring for 1 h at -78 C., cinnamyl bromide (278 muL, 1.88 mmol) was added and the stirring continued for an additional 2 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl ether (3*20 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by flash column chromatography (8:2 hexane:ethyl acetate) to give compound 2b as an off-white solid (367 mg, 54% yield). 1 H NMR (CDCl3): delta 7.35-7.19 (m, 10H), 6.43 (d, J=15 Hz, 1H), 6.11 (ddd, J=15, J'=J"=8 Hz, 1H), 5.26 (d, J=16 Hz, 1H), 5.17 (d, J=16 Hz, 1H), 4.59 (dd, J=9.5, J'=2 Hz, 1H), 2.83-2.70 (m, 2H), 2.41-2.34 (m, 1H), 2.22-2.16 (m, 1H), 2.10-2.02 (m, 1H) 1.42 (s, 9H).
To a solution of 78.9 g of (S)-5-oxo-pyrrolidine-2-carboxylic acid benzyl ester in 400 mL ofdichloromethane is added 2.20 g of dimethylaminopyridine and 78.54 g of di-tert-butylcarbonate at room temperature. The mixture is stirred for 4 hours at room temperature. Thereaction mixture is then washed twice with 400 mL of 0.5 Mu sulphuric acid. The organicphase is separated and the solvent removed to give (S)-5-oxo-pyrrolidine-1,2-dicarboxylicacid 2-benzyl ester 1-tert-butyl ester as a semi-crystalline solid.
With ammonium chloride; methyllithium; In tetrahydrofuran; hexane; ethyl acetate;
(Step 1) Synthesis of benzyl (2S)-N-tert-butoxycarbonylamino-5-oxohexanoate Benzyl N-tert-butoxycarbonyl-(2S)-pyroglutamate (20.5 g, 64.2 mmol) was dissolved in THF (500 ml). Methyl lithium (a 1.04M ether solution, 61.7 ml, 64.2 mmol) was added dropwise at -78ØC. The temperature of the reaction mixture was caused to rise back gradually to room temperature under stirring, and the resulting mixture was stirred for 18 hours. A saturated aqueous solution of ammonium chloride was added and the resulting mixture was concentrated under reduced pressure. The concentrate was extracted with ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane/ethyl acetate (3/1) eluate fractions, benzyl (2S)-N-tert-butoxycarbonylamino-5-oxohexanoate (8.37 g, 39%) was obtained as a yellow oil. 1H-NMR (CDCl3) 5: 1.43 (s, 9H), 1.61-2.15 (series of m, 3H), 2.09 (s, 3H), 2.41-2.55 (m, 2H), 4.30 (brs, 1H), 4.70 (d, J=5.6Hz, 1H), 5.12-5.21 (m, 2H), 7.29-7.37 (m, 5H); MS (ESI) m/z 336 (M++H).
(S)-4-(1-hydroxy-1-methylethyl)-5-oxopyrrolidine-1,2-dicarboxylic acid 2-benzylester 1-tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A solution of lithium hexamethyldisilazide in tetrahydrofuran is cooled to -78C and treatedwith a solution of 15.95 g of (S)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester in 100 mL of tetrahydrofuran maintaining the temperature at -78C. The resultingmixture was stirred for 40 minutes and a mixture of 40 mL of acetone and 7 mL of borontrifluoride diethyl etherate added within 20 minutes. The reaction mixture is stirred for 2.5hours at -78C and 300mL of a 10% solution of citric acid added and the reaction mixturewarmed to room temperature. The layers are separated and the aqueous layer is re-extracted with 300 mL of dichloromethane. The combined organic layers are dried, filteredand the solvent removed to give (S)-4-(1-hydroxy-1-methyl-ethyl)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzylester 1-tert-butyl ester as an oil.
Example 41 (3 S,6S,8aS)-6- [3 -((S)-4-Hydroxy-6-aza-spiro [2.5] oct-6-yl)-propyl] -3 -methyl-4-oxo- hexah dro-pyrrolo [1 ,2-a] pyrazine-2-carbox lic acid (3 ,4-dichloro-phenyl)-amide A) (S)-2-tert-Butoxycarbonylamino-5-oxo-non-8-enoic acid benzyl ester To a solution of (S)-5-oxo-pyrrolidine-l,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (Org. Lett. 2004, 5, 1469; 450 mg, 1.41 mmol) in THF (10 mL) was added 3- butenylmagnesium bromide solution (0.5 M in THF, 3.38 mL, 1.69 mmoL) at -40C, then after 3 h sat. aq. ammonium chloride solution (5 mL) was added. The reaction mixture was partitioned between EtOAc and water, the organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (Si02; heptane/EtOAc 2:1) afforded the title compound (329 mg, 62%). Colourless oil, MS: 376.4 (M+H)+.
62%
To a solution of (S)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (Org. Lett. 2004, 5, 1469; 450 mg, 1.41 mmol) in THF (10 mL) was added 3-butenylmagnesium bromide solution (0.5 M in THF, 3.38 mL, 1.69 mmoL) at -40 C., then after 3 h sat. aq. ammonium chloride solution (5 mL) was added. The reaction mixture was partitioned between EtOAc and water, the organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane/EtOAc 2:1) afforded the title compound (329 mg, 62%). Colourless oil, MS: 376.4 (M+H)+.
benzyl (2S)-2-((tert-butoxycarbonyl)amino)-6-(dimethyl(oxo)-λ6-sulfanylidene)-5-oxohexanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
At room temperature, tertiary butyl alcohol potassium (11.8 g, 1.1 eq) added trimethyl [...] (26.0 g, 1 . 25 eq) tetrahydrofuran (100 ml) and DMSO (150 ml) solution, stirring at the room temperature 1 h after, lowering the temperature to -10 C. To the reaction is dropped in the N - Boc - L - pyroglutamic acid benzyl ester (compound SM, 30.2 g, 1.0 eq) tetrahydrofuran (60 ml) solution, after dropping in the -10 C to continue stirring. TLC detection after the reaction, the reaction temperature to room temperature slowly, by adding 20% aqueous ammonium chloride solution (82 ml) quenching the reaction, extracted with ethyl acetate three times, the combined organic phase is used in 10% NaCl aqueous solution washing, drying with anhydrous sodium sulfate, filtered, concentrated, gain the light yellow oil of 40 g, yield 100%.
96%
With potassium carbonate; In dimethyl sulfoxide; at 50℃; for 23h;
In a 3L three-necked flask, 900 mL of dimethyl sulfoxide and 55.2 g (2.0 eq, 250.9 mmol) of trimethylsulfoxonium iodide were added. 70.0 g (4.0 eq, 506.9 mmol) of potassium carbonate and 40.0 g (1.0 eq, 125.4 mmol) of N-Boc-pyroglutamic acid benzyl ester were heated to 50 C for 23 h. After that, the heating was stopped, and 500 mL of a saturated aqueous ammonium chloride solution was added dropwise. After the dropwise addition, 500 mL of purified water was added thereto, and the mixture was extracted with ethyl acetate (500 mL × 2). The organic phase was combined, washed with saturated brine and dried over anhydrous sodium sulfate. Concentrated under reduced pressure to give a pale yellow solid product 49.5 g, yield 96%, purity 96.0%,
Example 1aBenzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) may be prepared as described below.Dimethylsulfoxide (DMSO; 500 ml) was added to a mixture of trimethylsulfoxonium iodide (ME3SOI; 79.2 g, 360 mmol, 1.15 eq) and potassium tert-butoxide (KOtBu; 38.6 g, 344.4 mmol, 1.1 eq) in tetrahydrofuran (THF; 400 ml) at room temperature. The mixture was stirred until the reaction was deemed to be complete and cooled to -12 C. A solution of (S)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (100 g, 313.1 mmol, 1 eq) in tetrahydrofuran (THF; 300 ml) was added slowly. The mixture was stirred at -12 C. until the reaction was deemed to be complete. The reaction was quenched by the addition of saturated aqueous ammonium chloride (500 ml) and water (300 ml). The product was extracted with ethyl acetate (1000 ml), and the resulting organic solution was washed with aqueous sodium chloride. The organic layer was concentrated in vacuo to a final volume of 600 ml.To this solution was added O-benzylhydroxylamine hydrochloride (BnONH2HCl; 52.5 g, 328.8 mmol, 1.05 eq) and ethyl acetate (400 ml). The mixture was stirred at reflux until the reaction was deemed to be complete. The mixture was cooled and washed with water and saturated sodium chloride. The organic layer was concentrated in vacuo to afford a solution of (S)-5-Benzyloxyimino-2-tert-butoxycarbonylamino-6-chloro-hexanoic acid benzyl ester in ethyl acetate.Methane sulfonic acid (MSA; 61 ml, 939.3 mmol, 3 eq) was added to this solution. The solution was stirred at 42 C. until the reaction was deemed to be complete. The solution was added to a solution of potassium bicarbonate (156.7 g, 1565.5 mmol, 5 eq) in water (500 ml) and the resulting mixture was stirred vigorously at 52 C. until the reaction was deemed to be complete. The organic layer was washed with aqueous sodium chloride and concentrated in vacuo to afford a solution of (S)-5-Benzyloxyimino-piperidine-2-carboxylic acid benzyl ester in ethyl acetate.Propanoic acid (140.6 ml, 1878.6 mmol, 6 eq) was added to a suspension of sodium borohydride (23.2 g, 626.2 mmol, 2 eq) in ethyl acetate (600 ml) and held until the reaction was deemed to be complete. The resulting solution was added to a solution of benzyl (2S)-5-[(benzyloxy)imino]piperidine-2-carboxylic acid benzyl ester in ethyl acetate (600 ml total volume) and sulphuric acid (83.4 ml, 1565 mmol, 5 eq) at -20 C. and held until reaction was deemed to be complete. The reaction was quenched by the addition of water (1000 ml), then neutralized with aqueous ammonia solution. The organic layer was washed with water and concentrated in vacuo to 400 ml. The solution was warmed to 45 C. and held at this temperature. Methanol (200 ml) at 40 C. was added, followed by a freshly prepared solution of oxalic acid dihydrate (39.5 g, 313.1 mmol) in methanol (100 ml). The mixture was cooled and the product was isolated by filtration. The solid was washed with an ethyl acetate/methanol mixture, then with ethyl acetate. The solid was dried to give benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) as a single isomer (79.4 g, 185 mmol, 59%).
Trimethylsulfonyl iodide (16 g, 72.7 mmol) and potassium tert-butoxide (8 g, 71.3 mmol) were added to tetrahydrofuran (100 mL), DMSO (100 mL) was added, stirred and reacted at 25C for 2 h, cooled to about -10C. The solution of <strong>[113400-36-5](S)-2-benzyl 1-tert-butyl 5-oxopyrrolidine-1,2-dicarboxylate</strong> (20 g, 62.6 mmol) in tetrahydrofuran (60 mL) was added. After addition, the reaction was performed at a low temperature under stirring for 8 h. The reaction solution was quenched with an aqueous saturated solution (100 mL) of ammonium chloride, ethyl acetate (100 mL*3) was added for extraction, and the organic phases were combined, dried over anhydrous sodium sulfate, filtrated, concentrated to 120 mL. The crude product was directly used in the next reaction step.
In tetrahydrofuran; diethyl ether; at -78 - 20℃; for 2h;Inert atmosphere;
General procedure: To a stirred solution of compound3(11.0g, 0.034mol) in dry THF (100ml) was added methyllithium (1.04M in Et2O, 34.0ml, 0.034mol) at -78C under a nitrogen atmosphere, and the resulting solution was warmed to room temperature and stirred for 2h. The reaction mixture was diluted with saturated aqueous NH4Cl under an ice cooling bath, and extracted with EtOAc. The organic layer was washed with brine, and dried over magnesium sulfate. The mixture was filtered, and the solvent was removed in vacuo to afford the crude product. The residue was purified by flash silica gel chromatography withn-hexane/EtOAc (3:1, v/v) to give the colorless oil (9.2g, 91% yield);1H NMR (400MHz, CDCl3)delta: 1.43 (9H, s), 1.88-1.95 (1H, m), 2.09 (3H, s), 2.10-2.15 (1H, m), 2.43-2.57 (2H, m), 4.29-4.34 (1H, br m), 5.12-5.21 (3H, m), 7.34-7.39 (5H, m); ESI/MS:m/z=358 (M+Na).
In tetrahydrofuran; diethyl ether; at -78 - 20℃; for 2h;Inert atmosphere;
General procedure: To a stirred solution of compound3(11.0g, 0.034mol) in dry THF (100ml) was added methyllithium (1.04M in Et2O, 34.0ml, 0.034mol) at -78C under a nitrogen atmosphere, and the resulting solution was warmed to room temperature and stirred for 2h. The reaction mixture was diluted with saturated aqueous NH4Cl under an ice cooling bath, and extracted with EtOAc. The organic layer was washed with brine, and dried over magnesium sulfate. The mixture was filtered, and the solvent was removed in vacuo to afford the crude product. The residue was purified by flash silica gel chromatography withn-hexane/EtOAc (3:1, v/v) to give the colorless oil (9.2g, 91% yield);
(2S,4R)-4-methyl-5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64.9%
31.9 g (0.1 mol) Boc-L-pyroglutamic acid benzyl ester was dissolved in dry tetrahydrofuran, Cooled to -80 C, 110 ml of 1N LiHMDS solution was added dropwise, After stirring for 30 minutes, 28.4 g (0.2 mol) of methyl iodide was added dropwise, Drip, stir for about 1 hour, naturally warm to room temperature, stirring overnight. After cooling with ice bath, 200 ml of saturated ammonium chloride solution was added and the ethyl acetate was extracted. The organic layer was washed with water to neutral and dried to dryness under reduced pressure. 600 g of silica gel column chromatography eluting with ethyl acetate: n-hexane = 1: 4, To give 21.6 g of the intermediate. Yield 64.9%
With N-ethyl-N,N-diisopropylamine; In toluene; at 30 - 95℃; for 9h;
To a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser was added 18.2 g (0.05 mol) of <strong>[4561-10-8]L-<strong>[4561-10-8]glutamic acid dibenzyl ester hydrochloride</strong></strong> prepared in Example 1,150 g of toluene, 7.8 g (0.06 mol) of diisopropylethylamine,12.0 g (0.055 mol) di-tert-butyl dicarbonate, heated,30-35°C for 4 hours, 90-95°C for 5 hours,Cool to 2025°C, filter and distill the filtrate to recover the solvent.To the residue was added 50 g of methyl tert-butyl ether, recrystallized, filtered and dried.15.1 g of white powder solidN-tert-butyloxycarbonyl-L-pyroglutamic acid benzyl esterThe liquid phase purity was 99.9percent and the yield was 94.6percent.
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