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2
[ 1148-11-4 ]
[ 34381-71-0 ]
Reference：
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3
[ 1148-11-4 ]
[ 34079-31-7 ]
Yield
Reaction Conditions
Operation in experiment
49%
With pyridine; di-<i>tert</i>-butyl dicarbonate; ammonium bicarbonate In 1,4-dioxane at 20℃;
To a solution of starting 1-[(phenylmethyl)oxy]carbonyl}-L-proline (8.0 g, 32.09 mmol), pyridine (1.5 mL), (BoC)2O (9.1 g, 41.72 mmol) in 1 ,4-dioxane (40 ml_) at rt was added ammonium hydrogen carbonate (3.2 g, 40.43 mmol). After stirring at room temperature overnight, the reaction mixture was treated with EtOAc (100 mL), and then the mixture was washed with water (50 mL), followed by 5percent H2SO4- The organic layer was collected, dried(Na2SO4), filtered. The volatiles were removed by evaporation in vacuo. The resulting clear oil was triturated with ether. The precipitates were filtered and further dried under vacuum to yield the title compound as a white solid (3.9 g, 49percent). MH+ 249.
13.5 g
Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at -5℃; for 0.333333 h; Stage #2: With ammonium hydroxide In tetrahydrofuran at -5 - 20℃; for 18 h;
Step A - Syntheses of Intermediate Compound Int-13b (0313) (0314) Ethyl chloroformate (12 mL, 125 mmol) in 180 mL of THF was added drop-wise to a cooled solution (-5°C) of compound Z-Pro-OH (13.8 g, 55.5 mmol), TEA (7.71 mL, 55.5 mmol). The resulting slurry was allowed to stir for 20 minutes at -5°C before saturated NH4OH (15 mL) was added. The solution was allowed to stir at room temperature for 18 hours, volatiles were removed, and the resulting residue was taken up in EtOAc (180 mL). The undissolved white precipitate was filtered off and rinsed with EtOAc (100 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo to provide the desired product (13.5 g) as off-white amorphous solid (Int-13b). MS (ESI) m/e (M+H+): 249
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[ 1148-11-4 ]
[ 14631-43-7 ]
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5
[ 172876-96-9 ]
[ 1148-11-4 ]
[ 14631-43-7 ]
[ 119020-06-3 ]
Reference：
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6
[ 7517-19-3 ]
[ 1148-11-4 ]
[ 2873-37-2 ]
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[3] Organic Letters, 2004, vol. 6, # 13, p. 2285 - 2287
7
[ 2666-93-5 ]
[ 1148-11-4 ]
[ 2873-37-2 ]
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[2] Chemistry Letters, 1982, p. 825 - 828
[3] Chemical Communications, 2015, vol. 51, # 89, p. 16084 - 16087
8
[ 627-36-1 ]
[ 7517-19-3 ]
[ 1148-11-4 ]
[ 2873-37-2 ]
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9
[ 1148-11-4 ]
[ 2873-37-2 ]
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10
[ 1148-11-4 ]
[ 6404-31-5 ]
[ 147-85-3 ]
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11
[ 501-53-1 ]
[ 609-36-9 ]
[ 6404-31-5 ]
[ 1148-11-4 ]
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12
[ 1148-11-4 ]
[ 51207-66-0 ]
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[ 1148-11-4 ]
[ 92053-25-3 ]
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14
[ 1148-11-4 ]
[ 118971-00-9 ]
Reference：
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To a solution of (S)-1-((benzyloxy)carbonyl)pyrrolidine-2-carboxylic acid (10 g, 40.1 mmol) in MeOH (80 mL) was added concentrated H2SO4 (20 ml, 375 mmol) over 10 min at RT. An exothermic reaction resulted. The resulting solution was stirred at RT for 16 h. The reaction mixture was poured onto 300 g of crushed ice. The mixture was extracted with Et2O (2*200 ml). The combined organic layers were dried over K2CO3 and concentrated on a rotary evaporator to give 767A (clear syrup, 6.0 g, 22.79 mmol, 56.8% yield). 1H NMR (400 MHz, CDCl3) delta 7.26-7.36 (m, 5H), 5.03-5.20 (m, 2H), 4.33-4.41 (m, 1H), 3.75 (s, 3H), 3.49-3.64 (m, 2H), 2.20-2.24 (m, 1H), 1.88-2.04 (m, 3H).
To a stirred solution of 13 (10.825 g, 43.43 mmol, 1 eq) in THF was added 1,1?-carbonyldiimidazole (9.365 g, 57.76 mmol, 1.33) and the reaction mixture is stirred for 15 min at room temperature. NaBH4 (2.743 g, 72.52 mmol, 1.67 eq) in 60 mL H2O is added slowly and let it stir for 30 min. Reaction mixtureis quenched with 1N HCl till the pH drops to 2 and the solution is extracted with EtOAc. The combined extracts were washed with aq. NaHCO3, brine, dried over MgSO4 and passed through a short pad of silica to afford yellow oil. Yield 10.116 g, 99%. [alpha]D25 -40.1 (c 1 g/100 mL, CH2Cl2). 1H NMR (400 MHz,CDCl3): delta = 7.39-7.27 (m, 5H), 5.16-5.06 (m, 2H), 4.34-4.03 (bs, 1H), 4.01-3.86 (m, 1H), 3.71-3.57 (d, J= 5.2, 2H), 3.55-3.44 (m, 1H), 3.42-3.32 (m, 1H), 2.04-1.71 (bm, 3H), 1.68-1.55 (m, 1H). 13C NMR (400MHz, CDCl3): delta = 156.88, 136.37, 128.37, 127.92, 127.75, 67.06, 66.51, 60.48, 47.15, 28.37, 23.86. MS(ESI): m/z calcd for [C13H17NO3 + H]+: 236, found: 236. Spectroscopic data agree with literature.25
81%
With dimethylsulfide borane complex; In tetrahydrofuran; dimethylsulfide; at 0 - 20℃; for 8h;
[33.1] To a stirred solution of 1 (benzyloxycarbonyl)-L-proline (15 g) in tetrahydrofuran (150 ml) at 0C., borane-methylsulfide complex (9 ml, 95% in dimethyl sulfide) was added and the reaction mixture was stirred at room temperature for 8 h. At the end of this time the reaction was quenched with 10% AcOH in methanol and the solvent was removed under reduced pressure. The crude product thus obtained was diluted with CHCl3 and washed with water, dried (CaCl2) and the solvent was removed under reduced pressure to get 11.5 g (81 %) of the title compound as a thick liquid. 1H NMR (CDCl3, 200 MHz): d 1.5 -2.2 (m, 4H), 3.3 - 3.8 (m, 4H), 4.0 (m, 1H), 5.15 (s, 2H). 7.36 (bs, 5H).
75%
General procedure: To a heterogeneous mixture of NaBH4 powder (3.71 mmol) in anhyd THF (15 mL) was added N-protected (S)-proline (S)-7a or (S)-7b (2.32 mmol) at 0 C during 1 h (evolution of H2). BF3·OEt2 (4.64 mmol) was then added and stirring was continued for 4 h, before the addition of 1 N aq NaOH (20 mL). Stirring was continued for 30 min and then the solvent was removed under reduced pressure. EtOAc (30 mL) was added to the residue and the organic layer was washed with 1 N HCl (20 mL) and H2O (20 mL). The organic layer was separated, dried over anhyd Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane-EtOAc, 3:1) to afford the corresponding N-protected (S)-prolinol.
74%
With sodium tetrahydroborate; iodine; In tetrahydrofuran; at 0℃; for 18h;Reflux;
To a solution of Cbz-(S)-proline 7 (10.5 g, 46.25 mmol) in dry THF (100 mL) in a two necked round bottom flask was added NaBH4 (3.98 g, 105.3 mmol) in three portions at 0 C. After stirring the reaction mixture at 0 C for ½ hour, I2 (10.70 g, 42.16 mmol) dissolved in dry THF (25 mL) was added drop wise over a period of 30 min. This solution was refluxed for a period of 18 h till the TLC showed complete disappearance of the starting material. The milky reaction mixture was stirred further for 30 min at room temperature followed by the addition of methanol (50 mL) till a clear solution appears. A white paste was obtained after evaporation under reduced pressure. It was further quenched with 1N HCl and extracted with CH2Cl2 (3 × 20 mL). Column chromatography afforded a colorless gummy liquid Cbz-(S)-prolinol 8 (7.55 g, 74% yield). [alpha]D -41.6 (c 1.73, CHCl3) (lit. -41.8 (c 1.4, CHCl3) [22]); IR (Neat): v 3430, 3033, 2953, 2880, 1680, 1418, 1357, 1192, 1105, 1049, 747, 698 cm-1; 1H NMR (200 MHz, CDCl3): delta 1.60-1.72 (m, 1H), 1.77-2.10 (m, 3H), 3.36-3.45 (m, 1H), 3.50-3.66 (m, 3H), 3.91-4.01 (m, 1H), 4.15-4.27 (br s, 1H), 5.11-5.15 (d, 2H, J = 3.77 Hz), 7.25-7.37 (m, 5H); MS (ESI): m/z (%) = 236 (M + H, 100).
With acetic acid; In tetrahydrofuran; methanol; dimethylsulfide;
Preparation 4 (2S)-1-(Benzyloxycarbonyl)-2-hydroxymethyl pyrolidine STR39 To a stirred solution of 1(benzyloxycarbonyl)-L-proline (15 g) in tetrahydrofuran (150 ml) at 0 C., borane-methylsulfide complex (9 ml, 95% in dimethyl sulfide) was added and the reaction mixture was stirred at room temperature for 8 h. At the end of this time the reaction was quenched with 10% AcOH in methanol and the solvent was removed under reduced pressure. The crude product thus obtained was diluted with CHCl3 and washed with water, dried (CaCl2) and the solvent was removed under reduced pressure to get 11.5 g (81%) of the title compound as a thick liquid. 1 H NMR (CDCl3, 200 MHz): d 1.5-2.2 (m, 4H), 3.3-3.8 (m, 4H), 4.0 (m, 1H), 5.15 (s, 2H), 7.36 (bs, 5H).
In tetrahydrofuran;
23a. CBZ-L-prolinol To Carbobenzyloxy-L-proline (Aldrich, 9.80 g, 39.3 mmol) in THF (100 mL) at 0 C. was added BH3 -THF complex (Aldrich, 1M in THF, 100 mL, 100 mmol). The mixture was stirred at 0 C. for 2 hours, then at ambient temperature for 16 hr. The reaction mixture was poured into pH 7 phosphate buffer solution (500 mL) and ether (600 mL) and mixed well. The layers were separated and the aqueous portion was extracted with ether (500 mL). The combined organic layers were washed with brine (500 mL), dried (Na2 SO4) and filtered. The solvents were evaporated in vacuo leaving the crude carbobenzyloxy-L-prolinol as an oil (10.5 g).
In tetrahydrofuran;
23a. CBZ-L-prolinol To Carbobenzyloxy-L-proline (Aldrich, 9.80 g, 39.3 mmol)in THF (100 mL) at 0 C. was added BH3 -THF complex (Aldrich, 1M in THF, 100 mL, 100 mmol). The mixture was stirred at 0 C. for 2 hours, then at ambient temperature for 16 hr. The reaction mixture was poured into pH 7 phosphate buffer solution (500 mL) and ether (600 mL) and mixed well. The layers were separated and the aqueous portion was extracted with ether (500 mL). The combined organic layers were washed with brine (500 mL),dried (Na2 SO4) and filtered. The solvents were evaporated in vacuo leaving the crude carbobenzyloxy-L-prolinol as an oil (10.5 g).
In tetrahydrofuran;
23a. CBZ-L-prolinol To Carbobenzyloxy-L-proline (Aldrich, 9.80 g, 39.3 mmol)in THF (100 mL) at 0 C. was added BH3 -THF complex (Aldrich, 1M in THF, 100 mL, 100 mmol). The mixture was stirred at 0 C. for 2 hours, then at ambient temperature for 16 hr. The reaction mixture was poured into pH 7 phosphate buffer solution (500 mL) and ether (600 mL) and mixed well. The layers were separated and the aqueous portion was extracted with ether (500 mL). The combined organic layers were washed with brine (500 mL),dried (Na2 SO4) and filtered. The solvents were evaporated in vacuo leaving the crude carbobenzyloxy-L-prolinol as an oil (10.5g).
Reference Example 55 ; L(-)-proline (17.0 g) was dissolved in tetrahydrofuran (350 ml) and a 1 N aqueous sodium hydroxide solution (296 ml), and then benzyl chlorocarbonate (23.2 ml) was added dropwise thereto at 0C under a nitrogen atmosphere. The resulting mixture was returned to room temperature and stirred overnight. 1 N Hydrochloric acid (296 ml) was added thereto at 0C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 1-[(benzyloxy)carbonyl]-L-proline, which was as such dissolved in tetrahydrofuran (250 ml), and then triethylamine (26.8 ml) was added thereto. To the resulting solution was added dropwise ethyl chlorocarbonate (16.9 ml) at 0C under a nitrogen atmosphere. The mixture was returned to room temperature and stirred for 1 hour, and the insolubles were removed by filtration. To the filtrate was added dropwise an aqueous sodium borohydride (11.2 g) solution (100 ml) at 0C, and the mixture was returned to room temperature and stirred for 3 hours under a nitrogen atmosphere. Next, water was added thereto, and the mixture was extracted with ethyl acetate twice. The organic layer was washed with saturated brine. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane : ethyl acetate 2 : 1 ? 1 : 4) to give benzyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (25.0 g) as a colorless oily material. To a solution of oxalyl chloride (6.23 ml) in dichloromethane (70 ml) was added dropwise a solution of dimethyl sulfoxide (10.9 ml) in dichloromethane (100 ml) at -78C under an argon atmosphere. The mixture was stirred as such for 15 minutes, and then a solution of benzyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (12.0 g) in dichloromethane (80 ml) was added dropwise thereto. The mixture was stirred as such for 15 minutes, and then triethylamine (42.7 ml) was added dropwise thereto, followed by stirring as such for 20 minutes. The resulting mixture was returned to room temperature and then water was added thereto, followed by separation. The organic layer was washed with 1 N hydrochloric acid twice, an aqueous 4% sodium carbonate solution and saturated brine, respectively, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane : ethyl acetate = 2 : 1 ? 1 : 1) to give benzyl (2S)-2-formylpyrrolidine-1-carboxylate. To [2-(1,3-dioxolan-2-yl)ethyl]triphenylphosphonium bromide (90.4 g) was added tetrahydrofuran (400 ml), further added t-butoxypotassium, and the mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. To the resulting mixture was added dropwise a solution of benzyl (2S)-2-formylpyrrolidine-1-carboxylate in tetrahydrofuran (200 ml), and the mixture was stirred at room temperature for 1 hour and at 50C for 3 hours under a nitrogen atmosphere. After returning to room temperature, water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane : ethyl acetate = 3 : 1 ? 2 : 1) to give benzyl (2S)-2-[3-(1,3-dioxolan-2-yl)-1-propenyl]pyrrolidine-1-carboxylate (15.1 g). Benzyl (2S)-2-[3-(1,3-dioxolan-2-yl)-1-propenyl]pyrrolidine-1-carboxylate (15.0 g) was dissolved in ethanol (200 ml), and then 10% palladium carbon (4.0 g, water content: 50%) was added thereto, followed by overnight stirring at room temperature under a hydrogen atmosphere. The insolubles were removed by filtration, and then the solvent was distilled off under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (200 ml) and a 1 N aqueous sodium hydroxide solution (150 ml), and then benzyl chlorocarbonate (10.1 ml) was added dropwise thereto at 0C under a nitrogen atmosphere. The mixture was returned to room temperature, stirred for 3 hours and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane : ethyl acetate = 7 : 1) to give benzyl (2R)-2-[3-(1,3-dioxolan-2-yl)propyl]pyrrolidine-1-carboxylate (13.6 g). Benzyl (2R)-2-[3-(1,3-dioxolan-2-yl)propyl]pyrrolidine-1-carboxylate (13.0 g) was dissolved in tetrahydrofuran (130 ml), and then 2 N hydrochloric acid (305 ml) was added thereto at 0C. After stirring the resulting mixture at room temperature for 3.5 hours, a 1 N aqueous sodium hydroxide solution (610 ml) was added thereto at 0C. The mixture was extracted with ethyl acetate, the organic layer was then washed with satur...
With CaH2; trifluoroborane diethyl ether; In methanol; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; toluene;
B. N-Benzyloxycarbonyl-(S)-proline methyl ester A dry 1-L, one-necked, round-bottomed flask was equipped with a Liebig condenser fitted with a rubber septum and a magnetic stirrer. The condenser was temporarily removed, and the flask was charged with 33.7 g (0.135 mol) of N-benzyloxycarbonyl-(S)-proline and 400 mL of anhydrous methanol (Mallinckrodt). The flask was flushed with nitrogen through the septum. The mixture was stirred, and 24.6 mL (28.4 g, 0.2 mol) of boron trifluoride etherate was added via cannula. The resulting mixture was stirred and refluxed for 1 hr under nitrogen. After the solvent was removed under reduced pressure, the residue was vigorously stirred with 200 mL of ice-water. The mixture was extracted with ethyl acetate (3*100 mL). The extacts were combined and successively washed with brine (2*20 mL), a 1M aqueous sodium hydrogen carbonate solution (3*20 mL), and brine (2*20 mL), and dried over anhydrous sodium sulfate. After the removal of the solvent under reduced pressure, a colorless oil was obtained. The oil was dissolved in 100 mL of dry toluene (distilled over CaH2), and the solvent was removed under reduced pressure to remove water from the oil. This treatment was repeated to give 35.9 g of N-benzyloxycarbonyl-(S)-proline methyl ester is a colorless oil (containing a small amount of toluene), [alpha]D21 -53.9° (methanol, c 1.0).
With sodium hydroxide; sodium borohydrid; In tetrahydrofuran; methanol;
24c. Alternate preparation of N-Cbz-L-prolinol To a stirred suspension of sodium borohydride (7.59 g, 200 mmol) in 100 mL of THF cooled to 0° C. was added a solution of 20 g (80.28 mmol) of N-Cbz-L-proline, from step 24a above, in 50 mL of ether. To this solution was added dropwise a solution of 5 mL of H2 SO4 in 20 mL of ether, with stirring and while maintaining the temperature below 20° C. The reaction mixture was warmed to room temperature and stirred for 16 hr. The reaction was quenched by the addition of 100 mL of methanol dropwise. The solvents were removed, 30 mL of 4N NaOH was added, and the mixture was extracted with ethyl acetate. The organic extract was dried over Na2 SO4 and concentrated to afford the title product, 16.61 g (88 percent yield).
88%
With sodium hydroxide; sodium borohydrid; In tetrahydrofuran; methanol;
24c. Alternate preparation of N-Cbz-L-prolinol To a stirred suspension of sodium borohydride (7.59 g, 200 mmol) in 100 mL of THF cooled to 0° C. was added a solution of 20 g (80.28 mmol) of N-Cbz-L-proline, from step 24a above, in 50 mL of ether. To this solution was added dropwise a solution of 5 mL of H2 SO4 in 20 mL of ether, with stirring and while maintaining the temperature below 20° C. The reaction mixture was warmed to room temperature and stirred for 16 hr. The reaction was quenched by the addition of 100 mL of methanol dropwise. The solvents were removed, 30 mL of 4N NaOH was added, and the mixture was extracted with ethyl acetate. The organic extract was dried over Na2 SO4 and concentrated to afford the title product, 16.61 g (88percent yield).
With sodium borohydrid; sodium hydrogencarbonate; acetic acid; lithium chloride; In tetrahydrofuran; ethanol; water; ethyl acetate; N,N-dimethyl-formamide;
(1) L-N-benzyloxycarbonylprolinol 5 g of L-N-benzyloxycarbonylproline was dissolved in 100 ml of DMF, 8.1 ml of ethyl iodide and 3.4 g of sodium hydrogencarbonate were added thereto. The mixture was stirred at room temperature for 24 hours. Then, water was added to the reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue thereby obtained was dissolved in a solvent mixture of 72 ml of ethanol and 48 ml of THF, and reacted at room temperature for two hours by an addition of 2.28 g of sodium borohydride and 2.25 g of lithium chloride. 3.45 ml of acetic acid was added to the reaction solution, and the mixture was concentrated under reduced pressure to dryness. Water and ethyl acetate were added to the residue, and the organic layer was separated, washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 3.57 g of the above identified compound as colorless oily substance. Rf: 0.23 (n-hexane/ethyl acetate=1/1).
To a solution of 2-bromo-l-(6-bromonaphthalen-2-yl)ethanone (57.7 g, 175.9 mmol, 80% pure) in acetonitrile (1 L), L-Cte-Proline (43.8 g, 175.9 mmol) was added, followed by diisopropylethylamine (33.4 mL, 193.5 mmol) and the reaction was stirred 40 minutes at room temperature. The solvent then was removed under reduced pressure and the obtained residue was redissolved in dichloromethane (500 mL), washed with 1%) HC1 (500 mL) and aqueous saturated NaHC03 (500 ml). The organic phase was dried with MgSC^, filtrated and the solvent was removed under reduced pressure resulting in a brown oily residue (80 g) which was used as such in next step.Part of the above residue (69.8 g, 140.6 mmol) and ammoniumacetate (162.6 g, 2.11 mol) were stirred in toluene and refluxed overnight. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The obtained residue was stirred in a mixture of dichloromethane and water (1/1, 1500 mL) to precipitate compound VIIIc. After filtering and rinsing with water, compound VIIIc (61.3 g, 92 %) was obtained as a white powder.1H NMR (400 MHz, DMSO-de) delta ppm 1.84 - 2.38 (m, 4 H), 3.42 - 3.56 (m, 1 H), 3.58 - 3.73 (m, 1 H), 4.84 - 5.20 (m, 3 H), 6.97 - 7.46 (m, 5 H), 7.54-7.60(m, 1 H), 7.63-7.71 (m, 1 H), 7.83 - 7.91 (m, 2 H), 7.95-8.05 (m, 1 H), 8.10-8.16 (m, 1 H), 8.22-8.37 (m, 1 H), 11.92 - 12.44 (m, 1 H)
6(I)-[(2S)-1-benzyloxycarbonylpyrrolidin-2-yl]-carbonylamino-6(I)-deoxy-β-cyclodextrin[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
To a solution of N-carboxybenzyl-l-proline (8) (200 mg, 0.489 mmol) in anhydrous DMF (18 mL), DIC (0.246 mL, 1.587 mmol) and HOBt (246 mg, 1.587 mmol) were added successively. The reaction mixture was stirred under Ar atmosphere for 1 h at room temperature, and then 7 (370 mg, 0.326 mmol) dissolved in 18 mL of anhydrous DMF was added. The mixture was stirred for 48 h at room temperature. After this time, solvent was evaporated under reduced pressure, and acetone was added over the residue obtained, giving a white precipitate that was filtered and washed with acetone. The precipitate was purified by flash chromatography (MeCN/H2O 7:1). Compound 9 was obtained (0.342 g, 77percent) as a white foam. 1H NMR (300 MHz, DMSO-d6): delta 7.4-7.2 (m, 5H), 5.8-5.6 (m, 14H), 5.2-5.0 (m, 2H), 4.9-4.8 (m, 7H), 4.6-4.4 (m, 6H), 4.3-4.2 (m, 1H), 3.7-3.4 (m, 28H), 3.4-3.2 (m, overlaps with HOD), 2.1-2.0 (m, 2H), 1.9-1.7 (m, 2H); MS (ESI) m/z 1364.9 [M+H]+. Anal. Calcd (percent) for C55H84N2O37: C, 48.39; H, 6.20; N, 2.05. Found: C, 48.68; H, 6.63; N, 1.92.
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 24.5h;Inert atmosphere;
2-Amino-5-methoxy-1H-benzimidazole was obtained from 4-methoxybenzene-1,2-diamine following the reported operation. 17 To a solution of N-carbobenzyloxy-l-proline (2.49 g, 10.0 mmol, 1.0 equiv) and 2-amino-5-methoxy-1H-benzo[d]imidazole (1.79 g, 11.0 mmol, 1.1 equiv) in CH2Cl2 (30.0 mL) N,N'-dicyclo-hexylcarbodiimide (2.26 g, 11.0 mmol, 1.1 equiv) and 4-dimethylamino pyridine (1.34 g, 11.0 mmol, 1.1 equiv) were added at 0 °C under N2 atmosphere. The reaction mixture was stirred for 30 min at 0 °C, then at room temperature for 24 h. The reaction mixture was filtrated through silica gel pad (SiO2 15 g) to remove dicyclohexylurea. Further purification was through flash column chromatography (Methanol/DCM=1:10). 1H NMR (400 MHz, CHCl3-d): delta 7.50-7.30 (4H, m), 7.20-6.80 (4H, m), 5.15-5.05 (2H, m), 4.60-4.40 (1H, m), 3.84 (3H, d, J=7.80 Hz), 3.72-3.48 (2H, m), 2.38-2.20 (1H, m), 2.10-1.75 (3H, m). 13C NMR (400 MHz, CHCl3-d): delta 179.3, 156.6, 154.5, 146.6, 136.7, 128.3, 128.0, 127.7, 127.4, 111.9, 66.5, 59.4, 55.7, 46.8, 30.8, 23.3. HRMS (ESI): m/z [M+H+] calcd for C21H23N4O4 395.1719, found 395.1714.
With lithium hydroxide monohydrate; water; In tetrahydrofuran; methanol; at 20℃; for 16h;
Preparation of(S)-] -((benzyloxy)carbonyl)pyrrolidine-2-carboxylic acid (27)Crude (S)-1-Benzyl 2-methyl pyrrolidine-1,2-dicarboxylate (26) (4.08 g, 15.5 mmol) and LiOHH2O (848 mg, 20.2 mmol) were stirred in THF/H20/MeOH (50 mL, 3/3/1) at room temperature for 16 h. The organic solvent was removed in vacuo, and the aqueous phase wasacidified with 1 M HC1 and extracted with EtOAc (3 x 50 mL). The organics were dried (Na2SO4) and concentrated in vacuo to give (S)-1-((benzyloxy)carbonyl)pyrrolidine-2- carboxylic acid (27) (2.86 g, 74 percent) which was used as a crude for the next step. The product was confirmed by LCMS and MS (negative ion mode).
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