| 74% |
With triethylamine; In dichloromethane; at 0 - 20℃; for 18h;Inert atmosphere; |
Protocole 2 A solution of pentaethylene glycol (0.04 mmol ; 25.00 g) in dry CH2Cl2 (15 mL), under argon, was cooled to 0C with an ice bath and triethylamine (0.015 mmol ; 2.10 mL). Subsequently p-toluenesulfonyl chloride (0.0104 mmol ; 1.98 g) was added in the portions to the cooled reaction mixture. After complete addition, the solution was allowed to warm to room temperature and was stirred for 18 h. The mixture was washed with water (3 x 100 mL), the aqueous layers were re-extracted with CH2Cl2 and the combined organic layers washed with 5% citric acid (3 x 25 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography on silica gel (99% CH2Cl2/MeOH) to give the desired compound 3e as a colorless oil in 74% yield (3.01 g). |
| 69% |
|
To a solution of 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethanol (15 g, 62.95 mmol, 13.27 mL, 2 eq) in tetrahydrofuran (150 mL) was added sodium hydride (1.26 g, 31.48 mmol, 60% purity, 1 eq) at 0 C. The mixture was stirred at 0 C for 0.5 hour. Then p- toluenesulfonyl chloride (6.00 g, 31.48 mmol, 1 eq) was added, the mixture was stirred at 25 C for 2 hours. The mixture was poured into saturated ammonium chloride aqueous solution (100 mL), the water layer was extracted with ethyl acetate (80 mL x 2). Then the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was condensed to get the residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1 to dichloromathane/methanol = 10/1) to get 2-[2-[2-[2-(2- hydroxyethoxy)ethoxy] ethoxy] ethoxy] ethyl 4-methylbenzenesulfonate (8.62 g, 21.96 mmol, 69% yield) as a light yellow oil. |
| 66% |
With triethylamine; In dichloromethane; at 20℃; for 15h; |
The compound tetrapentaethylene glycol (6.0 g, 25.2 mmol) was dissolved in 20 mL of dichloromethane, and triethylamine (4.9 g, 48, 4 mmol) was added dropwise while TsCl was placed in dichloromethane. The funnel was slowly added dropwise to the solution and stirred at room temperature for 15 h.The reaction was monitored by thin layer chromatography (EA) and the TsCl portion of the compound remained.The solution was adjusted to pH = 7 with 4M HCl, 10 mL of water was added, and extracted three times with 30 mL of dichloromethane.Column chromatography (EA) gave a product of 6.52 g, yield 66%. |
| 61.22% |
With silver(I) oxide; In dichloromethane; at 0 - 20℃; for 2h; |
Into a 500-mL round-bottom flask, was placed 3,6,9,12-tetraoxatetradecane-1,14-diol (9.53 g, 39.995 mmol, 1 equiv) in dichloromethane (200 mL), to which was added Ag2O (13.90 g, 59.982 mmol, 1.50 equiv) and TsCl (7.78 g, 40.808 mmol, 1.02 equiv) at 0 in a water/ice bath. Then KI (1.33 g, 8.012 mmol, 0.20 equiv) was added. The resulting mixture was stirred for 2 hr at room temperature. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was applied onto a silica gel column eluting with dichloromethane/methanol (12/1). This resulted in 9.61 g (61.22%) of 14-[(4- methylbenzenesulfonyl)oxy]-3,6,9,12-tetraoxatetradecan-1-ol as a light yellow oil. MS (ES+): m/z 392.95[MH+] |
| 51% |
With potassium iodide; In dichloromethane; at 20℃; |
Into a 250-mL round-bottom flask, was placed a solution of 3,6,9,12-tetraoxatetradecan-1,14-diol (5.0 g, 20.98 mmol, 1.00 equiv) in dichloromethane (100 mL), Ag2O (7.3 g, 31.50 mmol, 1.50 equiv), 4-methylbenzene-1-sulfonyl chloride (4.0 g, 20.99 mmol, 1.00 equiv ), KI (695.0 mg, 4.19 mmol, 0.30 equiv). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of water (80 mL). The solids were filtered out. The resulting solution was extracted with dichloromethane (60 ml x 3) and the organic layers combined. The resulting mixture was washed with brine (60 ml x 1), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1/1). This resulted in 4.2 g (51 %) of 14-[[4-methylbenzenesulfonyl]oxy]-3,6,9,12-tetraoxatetradecan-1-ol as yellow oil. |
| 46% |
With triethylamine; In dichloromethane; at 0 - 20℃; for 16h; |
The title compound (6.1 g, 46%) was furnished as a colorless oil. It was prepared from 3,6,9,12-tetraoxatetradecane-1,14-diol (8.0 g, 33.57 mmol) following the procedure outlined for Example 2, Step 1. 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.16 (t, J = 4.8 Hz,, 2H), 3.72 - 3.58 (m, 18H), 2.45 (s, 3H). |
| 43% |
With N-Trimethylamine hydrochloride; triethylamine; In dichloromethane; for 18h; |
A solution of pentaethylene glycol (35g, 147mmol), TEA (41mL, 294mmol) and trimethylamine-HCl (1.4g, 14.7mmol) in CH2C12 (600mL) was treated with tosyl chloride (29.4g, 154mmol). After stirring (18h) the reaction mixture was washed with H20-brine (1 :1), dried (MgS04), filtered, concentrated and subjected to chromatography to yield 82 (24.6g, 43%) as a pale yellow oil. Rf 0.8 (10% CH30H-CH2C12). |
| 43% |
With N-Trimethylamine hydrochloride; triethylamine; In dichloromethane; for 18h; |
A solution of pentaethylene glycol (35g, 147mmol), TEA (41mL, 294mm ol) and trimethylamine-HCl (1.4g, 14.7mmol) in CH2CI2 (600mL) was treated with tosyl chloride (29.4g, 154mmol). After stirring (18h) the reaction mixture was washed with EbO-brine (1 : 1), dried (MgS04), filtered, concentrated and subjected to chromatography to yield 82 (24.6g, 43%) as a pale yellow oil. Rf 0.8 (10% CH3OH-CH2CI2). |
| 43% |
With N-Trimethylamine hydrochloride; triethylamine; In dichloromethane; for 18h; |
A solution of pentaethylene glycol (35g, 147mmol), TEA (41mL, 294mmol) and trimethylamine-HCl (1.4g, 14.7mmol) in CH2CI2 (600mL) was treated with tosyl chloride(29.4g, 154mmol). After stirring (18h) the reaction mixture was washed with EhO-brine (1 : 1), dried (MgS04), filtered, concentrated and subjected to chromatography to yield 82 (24.6g, 43%) as a pale yellow oil. Rf 0.8 (10% CH3OH-CH2CI2). |
| 43% |
With N-Trimethylamine hydrochloride; triethylamine; In dichloromethane; for 18h; |
A solution of pentaethylene glycol (35g, 147mmol), TEA (41mL, 294mmol) and trimethylamine-HCl (1.4g, 14.7mmol) in CH2Cl2 (600mL) was treated with tosyl chloride (29.4g, 154mmol). After stirring (18h) the reaction mixture was washed with H2O-brine (1:1), dried (MgSO4), filtered, concentrated and subjected to chromatography to yield 82 (24.6g, 43%) as a pale yellow oil. Rf 0.8 (10% CH3OH-CH2Cl2). |
| 42% |
With triethylamine; |
To a stirred solution of 3,6,9,12-tetraoxatetradecane-1,14-diol (70 g, 293.8 mmol) in DCM (500 mL) was added TEA (29.7 g, 293.8 mmol) followed by the addition of a solution of 4- methylbenzene-1-sulfonyl chloride (56.0 g, 293.8 mmol) in DCM (500 mL) over 30 min at room temperature under nitrogen atmosphere. The resulting solution was stirred for an additional 16 h at room temperature. Upon completion, the resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with EtOAc to afford 14-[(4-methylbenzenesulfonyl)oxy]-3,6,9,12-tetraoxatetradecan-1-ol (48 g, 42%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) d 7.81 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.17 (t, J = 4.9 Hz, 2H), 3.80-3.56 (m, 18H), 2.50 (d, J = 4.4 Hz, 1H), 2.46 (s, 3H) LC/MS (ESI, m/z): [(M + 1)]+ = 393.00 |
| 38% |
With potassium iodide; silver(I) oxide; In dichloromethane; at 0 - 20℃; for 16h; |
To a solution of 3,6,9,12-tetraoxatetradecan-1,14-diol (0.50 g, 2.1 mmol), potassium iodide (69 mg, 0.42 mmol), and silver oxide (48 mg, 0.21 mmol) in methylene chloride (50 ml) was added p-toluenesulfonyl chloride (0.36 g, 1.9 mmol) at 0 C., and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was purified by preparative TLC (methylene chloride:methanol=10:1) to give Compound (p-2) (0.31 g, 38% yield). (1171) 1H-NMR (CDCl3, 400 MHz) δ: 7.80 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 4.17-4.15 (m, 2H), 3.71-3.60 (m, 19H), 2.45 (s, 3H). |
|
With triethylamine; In tetrahydrofuran; |
FIGURE 36 shows the synthetic scheme used to obtain IBA-GN3. Pentaethylene glycol was treated with tosyl chloride in the presence of base to give the mono-tosylated alcohol, which was then treated with sodium azide at elevated temperature to give the azidoalcohol. This compound was then oxidized using Jones reagent, then reduced with Palladium on carbon under hydrogen atmosphere to give a carboxylic acid-amine. Separately, indole butyric acid was treated with N-hydroxysuccinimide, EDC, and DIPEA to give the NHS-ester indole, which was then reacted with the above carboxylic acid-amine. The product was again reacted with N-hydroxysuccinimide, EDC, and DIPEA to give a NHS ester. This NHS ester was reacted with NH2-GN3, which was prepared as described previously. The subsequent amide was deprotected with NaOMe in MeOH to give compound IBA-GN3. |
|
With sodium hydroxide; In tetrahydrofuran; water monomer; at 0 - 20℃; for 2h; |
General procedure: Tetraethylene glycol (10.0g, 51.5mmol) was dissolved in tetrahydrofuran (30mL) at 0C. An aqueous solution of sodium hydroxide (0.3g, 7.7mmol) and TsCl (1.0g, 5.2mmol) were added to the reaction solution, stirred at 0C for 5min, and then stirred at room temperature for 2h. After the completion of the reaction, the reaction solution was filtered, and the filter cake was rinsed with dichloromethane. The filtrate was concentrated and washed twice with 10% NaHCO3 solution. The organic phase was concentrated and dried to obtain 1.7g of a colorless oil V-1 with a yield of 93%. |
|
With sodium hydroxide; In tetrahydrofuran; water monomer; at 0 - 20℃; for 2h; |
General procedure: Tetraethylene glycol (10.0g, 51.5mmol) was dissolved in tetrahydrofuran (30mL) at 0C. An aqueous solution of sodium hydroxide (0.3g, 7.7mmol) and TsCl (1.0g, 5.2mmol) were added to the reaction solution, stirred at 0C for 5min, and then stirred at room temperature for 2h. After the completion of the reaction, the reaction solution was filtered, and the filter cake was rinsed with dichloromethane. The filtrate was concentrated and washed twice with 10% NaHCO3 solution. The organic phase was concentrated and dried to obtain 1.7g of a colorless oil V-1 with a yield of 93%. |
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