| 78% |
With 1-methyl-1H-imidazole; In dichloromethane; for 3h; |
Example 1 (0117) FIG. 1 shows four pentagol-containing (Eg5) protected monomeric building blocks (tetragol=(ethylene glycol)4) with different reactive side chain precursor groups (R2). The monomeric building blocks (BBs) have the general structure TsOEg4OCH(CH2R2)CH2OPG [R2=-N3 (10a), -CC-Tbdps (10b), -SPmb (10c) and -OCH2C(O3C6H9) (10d)], which are obtained according to the synthetic route described in FIG. 1. Different protecting groups [PG=-Dmtr, -Mip, -Cyc, -Mthp, -Thp and -SO3-] are used for simple protection and effective deprotection, with a range of stability/controllable rate of acid-labile deprotection during each chain-extension cycle. (0118) Three hetero-functionalized tetragol derivatives with different reactive side-groups, namely TsO-EG4(R)-OThp (R=-OBn, -N3 and -SPmb), were synthesised as building blocks according to the procedure shown in FIG. 2. Notably, the coupling reaction between compound 2 and compound 5 generates some side products. Thus, it is preferable to completely dry the starting materials using acetonitrile before adding NaH catalyst to initiate the reaction. The hydrogenolysis of compound 8 to produce compound 11 was found to work best in acetonitrile and ethyl acetate. Here, the acid-labile Thp group was selected as a protecting group due to its acid-sensitivity and its small size, which means that it can be both effectively deprotected after each chain-extension cycle and, also easily removed by OSN diafiltration. The Tosyl group has high reactivity with OH group using NaH as a catalyst, making it suitable for chain extension of PEGs. The three different side-groups including BnO-, N3- and PmbS- on these building blocks can be readily converted into highly reactive groups after deprotection procedure, such as -OH, -NH2 and -SH, respectively. (0119) The chemical structure and molecular weight of the resulting building blocks including BnO-BB, N3-BB and PmbS-BB, have been confirmed by NMR spectroscopy and mass spectroscopy in FIGS. 3 and 4. The clearly observed m/z peaks at 614.2, 549.3 and 660.3 are assigned to BnO-BB, N3-BB and PmbS-BB, respectively. |
| 73% |
With pyridine; dmap; at 20℃; |
General procedure: To a solution of ethylene glycol (19, 20, 21 or 22) (8-10 equiv) and DMAP (cat.) in dry pyridine (5 mL) was added TBDMS-Cl (1 equiv). The reaction mixture was stirred at room temperature overnight and then diluted with CH2Cl2 before the organic phase was washed twice with 1 M HCl, once with H2O and then satd NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The TBDMS-protected ethylene glycols (23, 24, 25 or 26) were used without further purification. |
| 48% |
With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 25℃; for 1.75h; |
NaH (60% oil dispersion, 10 mmol) was slowly added to solution of tetraethylene glycol (10 mmol) in dry THF (20 mL) at 25 C. and stirred the suspension for 45 minutes at same temperature. The reaction mixture was cooled to 0 C. with ice-bath and tert-Butyldimethylsilyl chloride (10 mmol) was added dropwise and ice-bath was removed and reaction was continued at 25 C. After 60 minutes, H2O (5 mL) was added to quenched the reaction and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine and dried over anhydrous sodium sulphate, filtered and evaporated to get oil. The crude oily product was purified by silica gel column chromatography using 2% Methanol/Dichloromethane to provide mono-TBDMS protected tetraethylene glycol, 3 (4.8 mmol, yield 48%) as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ 3.79 (t, J=4.0 Hz, 2H), 3.75 (t, J=4.0 Hz, 2H), 3.71-3.67 (m, 8H), 3.63 (t, J=4.0 Hz, 2H), 3.57 (t, J=4.0 Hz, 2H), 2.51 (s, 1H), 0.91 (s, 9H), 0.09 (s, 6H), ESI-LC/MS: Expected [M+H]+ for C14H32O5Si is 309.20, found m/z: 309.25 [M+H]+. |
| 42% |
With triethylamine; In dichloromethane; at 20℃; for 2h; |
Tetraethylene glycol, 4c (1.12 g, 5.77 mmol) and TBDMSCl (0.87 g,5.77 mmol) were dissolved in dichloromethane (25 ml) followed by triethyl amine (1.46 g, 14.4 mmol). The solution was stirred at room temperature for 2 hours. After standard workup with dichloromethane, the residue was purified by silica gel column chromatography (50 % ethyl acetate in hexane) to afford 5c (744 mg, 42 %): 1H NMR δ 3.66 (m, 16 H), 2.51 (t, IH, J = 5.86 Hz), 0.89 (s, 9H), 0.07 (s, 6H). |
| 41% |
|
A solution of sodium hydride (60% in mineral oil, 2.94g, 73.5mmol) in anhydrous THF (135mL) was stirred at room temperature for 5min under argon. Dried tetraethylene glycol (8.80mL, 51.0mmol) was added dropwise at 0C and the reaction mixture was stirred for 5 more min before addition of tert-butyldimethylsilyl chloride (TBDMSCl, 12.00g, 79.6mmol). The resulting mixture was stirred at room temperature for 1h and the reaction was stopped by addition of water (150mL). The mixture was extracted with ethyl acetate (3×100mL). The organic layers were combined, washed successively with a saturated aqueous ammonium chloride solution (150mL) and brine (150mL), dried on magnesium sulphate, filtered and evaporated under vacuum. The crude product was purified by chromatography (SiO2 pad, EtOAc/pentane, 75/25, v/v then 50/50, v/v and finally CH2Cl2/EtOH, 98/2, v/v) to yield compound 21 (6.42g, 20.8mmol) as a yellow oil. Yield 41%; Rf (SiO2, EtOAc/pentane, 75/25, v/v) 0.16; IR (ATR diamond accessory) ν 778, 837, 1109, 1255, 1472, 2859, 2930, 3300-3600cm-1; 1H NMR (200MHz, CDCl3) δ 0.05 (s, 6H, (CH3)2Si), 0.88 (s, 9H, (CH3)3C), 2.63 (br s, 1H, OH), 3.65 (m, 16H, 8CH2O); 13C NMR (50MHz, CDCl3) δ-5.2 (2C), 18.4, 26.0 (3C), 61.8, 62.8, 70.4-70.7 (4C), 72.6, 72.7; MS m/z 251 (M-57, 9), 163 (26), 119 (46), 103 (55), 89 (100), 75 (93). |
| 41% |
|
A solution of sodium hydride (60% in mineral oil, 2.94 g, 73.5 mmol) in anhydrous tetrahydroiuran (135 mL) was stirred at room temperature for 5 min under argon. Dried tetraethylene glycol (8.80 mL, 51.0 mmol) was added dropwise at 0C and the reaction mixture was stirred for 5 min before addition of teri-butyldimethylsilyl chloride (12.00 g, 79.6 mmol). After return back to room temperature, the resulting mixture was stirred for 1 h and the reaction was quenched by addition of water (150 mL). The mixture was extracted with ethyl acetate (3x100 mL). The organic layers were combined, washed successively with a saturated aqueous ammonium chloride solution (150 mL) and brine (150 mL), dried on magnesium sulfate, filtered and evaporated under vacuum. The crude product was purified by chromatography (Si02 pad, EtOAc/pentane, 75/25, v/v then 50/50, v/v and finally CH2Cl2/EtOH, 98/2, v/v) to yield the expected compound (6.42 g, 20.8 mmol) as a yellow oil. Yield 41%. Rf (Si02, EtOAc/pentane, 75/25, v/v) 0.16. IR (ATR diamond accessory) v 778, 837, 1109, 1255, 1472, 2859, 2930, 3300-3600 cm"1. 1H NMR (200 MHz, CDC13) δ (ppm) 0.05 (s, 6H), 0.88 (s, 9H), 2.63 (brs, 1H), 3.65 (m, 16H). 13C NMR (50 MHz, CDC13) δ (ppm) -5.2 (2C), 26.0 (3C), 61.8, 62.8, 70.4-70.7 (4C), 72.6, 72.7. MS m/z 309 (1, [M+H]+), 163 (26), 147 (22), 133 (23), 119 (46), 103 (55), 89 (100), 87 (9), 75 (93), 73 (61), 59 (29). |
| 41% |
|
A solution of sodium hydride (60% in mineral oil, 2.94 g, 73.5 mmol) in anhydrous tetrahydroiuran (135 mL) was stirred at room temperature for 5 min under argon. Dried tetraethylene glycol (8.80 mL, 51.0 mmol) was added dropwise at 0C and the reaction mixture was stirred for 5 min before addition of teri-butyldimethylsilyl chloride (12.00 g, 79.6 mmol). After return back to room temperature, the resulting mixture was stirred for 1 h and the reaction was quenched by addition of water (150 mL). The mixture was extracted with ethyl acetate (3x100 mL). The organic layers were combined, washed successively with a saturated aqueous ammonium chloride solution (150 mL) and brine (150 mL), dried on magnesium sulfate, filtered and evaporated under vacuum. The crude product was purified by chromatography (Si02 pad, EtOAc/pentane, 75/25, v/v then 50/50, v/v and finally CH2Cl2/EtOH, 98/2, v/v) to yield the expected compound (6.42 g, 20.8 mmol) as a yellow oil. Yield 41%. Rf (Si02, EtOAc/pentane, 75/25, v/v) 0.16. IR (ATR diamond accessory) v 778, 837, 1109, 1255, 1472, 2859, 2930, 3300-3600 cm"1. 1H NMR (200 MHz, CDC13) δ (ppm) 0.05 (s, 6H), 0.88 (s, 9H), 2.63 (brs, 1H), 3.65 (m, 16H). 13C NMR (50 MHz, CDC13) δ (ppm) -5.2 (2C), 26.0 (3C), 61.8, 62.8, 70.4-70.7 (4C), 72.6, 72.7. MS m/z 309 (1, [M+H]+), 163 (26), 147 (22), 133 (23), 119 (46), 103 (55), 89 (100), 87 (9), 75 (93), 73 (61), 59 (29). |
| 22% |
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 6h; |
To a stirred solution of 2,2'-(2,2'-oxybis(ethane-2,l-diyl)bis(oxy))diethanol 4-1 (5 g, 25.7 mmol) in DCM (100 mL) was added imidazole (2.1 g, 30.9 mmol) and teri-butyldimethylsilyl chloride (TBDMSC1; 3.48 g, 23.1 mmol) at 0 C and stirred to RT for 6 hr. The reaction mixture was diluted with DCM (100 mL) and washed with water (2 X 100 mL) and brine (50 mL). The organic layer was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (100-200 silica) using 30% EtOAc/pet. ether gave 4-2 (1.8 g, 5.8 mmol, 22% yield) as an off-white solid. |
| 5.7 g |
|
Compound 20-2: To a solution of tetra (ethylene glycol) 20-1 (8.0 g, 41.2 mmol)in 100 mL of tetrahedrofuran was added 1.65 g of sodium hydride at 0C. The reaction mixture was stirred at room temperature for 30min. 6.21 g of TBS-Cl was added to thissolution. The reaction mixture was stirred at room temperatme overnight. The reactionmixture was concentrated in vacuo and quenched with 2 mL of 1 N HCl. The residue wassuspended in brine and extracted with ethyl acetate (1 00 mLXl, 50 mL X2). The organic5 layer was combined and washed with brine, dried over sodium sulfate and concentrated invacuo. The residue was purified by flash column chromatography to give 5.7g of compound20-2. |
| 5.7 g |
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; |
To a solution of tetra (ethylene glycol) 20-1 (8.0 g, 41.2 mmol) in 100mL of tetrahedrofuran was added 1.65 g of sodium hydride at 0C. The reaction mixture was stirred15 at room temperature for 30min. 6.21 g of TBS-Cl was added to this solution. The reaction mixture-was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo andquenched with 2 mL of 1 N HCl. The residue was suspended in brine and extracted with ethylacetate (100 mLXl, 50 mL X2). The organic layer was combined and washed with brine, dried oversodium sulfate and concentrated in vacuo. The residue was purified by flash column5 chromatography to give 5.7g of compound 20-2. |
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