| 96% |
With 1H-imidazole In dichloromethane at 20℃; Cooling with ice |
To a solution of ethanolamine (9.6 mL, 159 mmol) in 100 mL of CH2Cl2 was dissolved imidazole (10.8 g, 159 mmol) and this solution was cooled in an ice-water bath. To this solution was added tert-butyldimethylsilyl chloride (24 g, 159 mmol) and the reaction mixure was stirred overnight at rt. Sat. NaHCO3 was added and the resulting mixture was partitioned. The organic fractions were dried over Na2SO4 and concentrated in vacuo to afford 2-(tertbutyldimethylsilyloxy) ethanamine as a clear light yellow oil (26.8 g, 96percent). |
| 92% |
With triethylamine In dichloromethane at 0 - 20℃; for 17 h; |
Synthesis 22 3-(2-(tert-Butyldimethylsilyloxy)ethyl)-4-oxo-3,4-dihydroimidazo[5,1-d][1 ,2,3,5]tetrazine-8- carboxamide (NN-001); te/-Butyldimethylsilylchloride (24.87 g, 165 mmol) was added portion wise to a solution of ethanolamine (11.84 mL, 150 mmol) in triethylamine (46.0 mL, 330 mmol) and dichloromethane (100 mL) at 00C. The reaction was stirred at this temperature for 1 hour and then allowed to warm to room temperature. After 16 hours, the reaction mixture was washed with sodium hydrogen carbonate solution (2 x 50 mL) and brine (50 mL), dried over magnesium sulfate, and concentrated in vacuo to give 2-(tert- butyldimethylsilyloxy)ethylamine as a colourless oil. Yield: 24.1 g, 137 mmol, 92percent. 1H NMR (400 MHz, CDCI3) δ: 3.63 (2H, t), 2.78 (2H1 1), 0.91 (9H, t), 0.07 (6H, s). |
| 90% |
With dmap; triethylamine In dichloromethane at 20℃; for 24 h; |
Synthesis of TBS protected ethanolamine(TBS protected ethanolamine = 2-(t-butyldimethylsilyloxy)ethylamine); A 500-mL single-necked, round-bottomed flask equipped with a magnetic stirring bar and fitted with nitrogen gas inlet was charged with 3.06 g (50 mmol) of ethanolamine, 23.0 mL (16.7 g, 165 mmol) of triethylamine, 34.0 mg (0.27 mmol) of 4-dimethylaminopyridine (DMAP), 250 mL of anhydrous methylene chloride and 9.11 g (60 mmol) of tertbutyldimethylsilyl chloride. The mixture was stirred at room temperature for 24 h. Then 200 mL of water was added and the mixture was stirred vigorously for 1.5 h. The organic solution was separated, washed with 100 mL of water and 100 mL of brine and dried over sodium sulfate. After the solvent was removed by rotary evaporation, 7.88 g (90 percent) of product was obtained as a colorless liquid. 1H-NMR (300 MHz, CDCl3): δ 3.61 (t, 2H), 2.76 (t, 2H), 1.50 (br, 2H), 0.89 (s, 9H), 0.06 (s, 6H). |
| 89% |
With triethylamine In dichloromethane for 12 h; |
2-(terM)utyldimethylsilyloxy)ethanamine (ICEC0293)[00271] Ethanolamine (2.0 g, 32.7 mmol) was dissolved in CH2Cl2 (50 mL) and NEt3(5 mL). The mixture was treated with TBSCl (5.40 g, 36 mmol) and DMAP (50 mg). After 12 h water (20 mL) was added and the resulting mixture stirred for 30 min. The aqueous phase was washed with CH2Cl2 (3x 50 mL). The crude product was purified by column chromatography on silica (EtOAc) to give ICEC0293 as colourless oil (5.13 g, 89percent; Palomo et al., Org. Lett., 2007, 9, 101-104).[00272] 1H NMR (400 MHz, CDCl3): δH 0.07 (m, 6H), 0.90 (s, 9H), 2.78 (t, J= 7.4 Hz,2H), 3.63 (t, J= 7.4 Hz, 2H; 13C NMR (CDCl3, 75 MHz) δc -5.3, 18.3, 25.9, 44.3, 65.3; MS (CI): m/z 176 (M+H); HRMS (CI) CaIc: 176.1471, Found: 176.1476 (M+H). |
| 84% |
With triethylamine In dichloromethane at 0 - 20℃; for 4 h; |
2-(tert-butyldimethylsilyloxy)ethanamine. To a solution of 2-aminoethanol (5 g, 82 mmol) and tert-butylchlorodimethylsilane (18 g, 123 mmol) in dichloromethane (200 mL) was added triethyl amine (16 g, 158 mmol) dropwise at 0°C. Once addition was completed, the resultant mixture was stirred at room temperature for 4 hours. The mixture was concentrated in vacuo to give a residue, and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 5:1) to give 2-(tert-butyldimethylsilyloxy)ethanamine as a colorless oil (12 g, 84percent). |
| 82% |
With 1H-imidazole In dichloromethane at 18℃; for 1 h; |
2-(tert-Butyldimethylsilyloxy)ethanamine (7). A solution of TBDMSC1 (3.15 g, 21 mmol) inanhydrous DCM (10 mL) was added dropwise over 3 mm to a stirred solution of ethanolamine (1.2mL, 20 mmol) and imidazole (2.72 g, 40 mmol) in DCM (20 mL) at 18 °C and the mixture was stirredfor 1 h. The mixture was washed with H20 (50 mL). The aqueous phase was extracted with DCM (3 X50 mL), the combined organic phase was dried and the solvent was evaporated to give ethanamine 7(2.88 g, 82percent) as a pale yellow oil which was used in the next step without further purification: 1HNMR 6 3.64 (t,J 5.3 Hz, 2 H, CH2OSi), 2.79 (t,J 5.3 Hz, 2 H, CH2NH2), 0.91 [s, 9 H, SiC(CH3)3],0.07 [s, 6 H, Si(CH3)2]. |
| 77.9% |
With 1H-imidazole In dichloromethane at 20℃; for 1.33333 h; |
6.11 g (0344) (100 mmol) of ethanolamine and 13.62 g (2 equiv.) of imidazole were dissolved in DCM (100 mL) in a 500 mL round bottom flask. 15.83 g (105 mmol) of tert- butyldimethylchlorosilane dissolved in DCM (50 mL) was added dropwise over the course of 20 minutes, and the reaction mixture was stirred for one hour at room temperature. At that time, all of the starting material had been consumed as confirmed by TLC; 100 mL of water was added and the layers were separated. The aqueous layer was extracted twice with DCM (2 x 100 mL), and the combined organics washed with water (50 mL), dried over sodium sulfate and evaporated to give 13.68 g (77.9percent yield) of 9 as a clear oil. XH NMR (300 MHz, CDCb) δ 3.57 (t, J = 5.36 Hz, 2H), 2.71 (t, = 5.25 Hz, 2H), 2.08 (s, 2H, NH2), 0.84 (s, 9H), 0.00 (s, 6H). 13C NMR (75 MHz, CDCb) δ 65.13, 44.27, 25.96, 18.35, -5.27. HRMS (ESI) calculated mass (C9H22NOSi) [M+H] 1+: 188.1471, mass found m/z: 188.1495 [M+H] 1+. |
| 70% |
With 1H-imidazole In dichloromethane at 20℃; for 12 h; |
According to the previous work [12], a solution of tert-butyldimethylsilyl chloride (9.06 g, 60.0 mmol) in CH2Cl2 (15.0 mL) was added drop-wise under stirring to a solution of ethanolamine (3.63 g, 59.0 mmol) and imidazole (7.57 g, 111 mmol) in CH2Cl2 (20 mL). The mixture was allowed to stir at room temperature for 12 h, and then aqueous ammonia (10.0 mL) and CH2Cl2 (50.0 mL) were added. After that, the mixture was washed with brine three times. The organic fraction was dried over MgSO4 and concentrated under reduced pressure. Yield: 70percent. 1H NMR (400 MHz, CDCl3): δ 3.573 (t, 2H, -CH2-O-), 2.708 (t, 2H, NH2-CH2-), 1.591 (s, 2H, -NH2), 0.845 (s, 9H, -Si-C(CH3)3), 0.012 (s, 6H, -Si-CH3); 13C NMR (100 MHz, CDCl3): δ 64.85, 44.07, 25.93, 18.3, -5.31. |
| 63% |
With dmap In N,N-dimethyl-formamide at 20℃; for 16 h; |
To a stirred solution of ethanolamine (1 .980 mL, 32.7 mmol), DMAP (0.040 g, 0.327 mmol) andtriethylamine (6.85 mL, 49.1 mmol) in DCM (50 mL) was added TBDMSCI (5.68 g, 37.7 mmol). Thereaction was allowed to stir at rt for 16 h. The reaction was quenched with NH4CI(aq) and extracted with DCM, the organic phase was washed with water, dried using a hydrophobic frit and concentrated and dried to give the product (3.607 g, 20.57 mmol, 63percent) as a yellow oil.LCMS (2mm Eormic): Not observed. |
| 52% |
With 1H-imidazole In dichloromethane at 0 - 20℃; |
Building block B23: 1 -((2-((tert-butyldimethylsilyl)oxy) ethyl) amino) cvclopentanecarbonitrile B23 a) 2-((tert-butyldimethylsilyl)oxy)ethanamine To a stirred solution of 2-aminoethanol (10 g, 0.16 moles) in DCM (90 mL) at 0 °C was added TBDMS-CI (37 g, 0.25 moles), followed by the addition of imidazole (16.7 g, 0.25 moles). The reaction mixture was stirred at rt for 3 h. Once the starting material was consumed (monitored by TLC), the reaction mixture was extracted with DCM. The organic phase was washed with water, brine then dried over Na2S04 and concentrated. Purification by column chromatography (silica gel, 2percent methanol in DCM) provided the title compound (14.8 g, 52percent) as a colorless gummy solid. 1 H NMR (400 MHz, DMSO): δ 3.50 (t, J = 5.9 Hz; 2H), 2.58-2.50 (m, 2H), 0.86 (s, 9H), 0.03 (s, 6H); MS (ES-MS): m/z 176.3 (M + 1 ). |
| 51% |
With 1H-imidazole In dichloromethane at 0 - 20℃; for 12 h; |
STEP-1:Synthesis of compound 2
Procedure:To a solution of 2-Aminoethanol 1 (101.0 g, 165.35 mmol; 1.0 eq) in DCM (2.0 L; LR grade), imidazole (280 g, 411.28 mmol; 2.5 eq) was added, followed by tert- butyldimethylsilyl chloride (250 g, 165.35 mmol; 1.0 eq) in DCM (1 L; LR grade) at 0 °C. The reaction mixture was allowed to stir for 12 h at room temperature. On completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM (2 L), washed with water (2 L) followed by brine solution (1 L), dried over anhydrous Na2S04and evaporated under reduced pressure. The crude residue 2 was purified by vacuum distillation at 75 °C , 200 mm pressure to yield 150 g (51 percent) of compound 2 a colorless as oil.TLC system: ethyl acetate Rf value: 0.2 |
| 30% |
With 1H-imidazole In dichloromethane at 20℃; |
Scheme 28. Preparation of rifabutin bisphosphonate conjugates 164.; [00357] f-Butyldimethyl(2-aminoethoxy)silane (157): 1.97 ml. (32.74 mmol) of 156 and 2.455 g (36.06 mmol) of imidazole were dissolved in 15 ml. of CH2CI2 and 5.18 g (34.37 mmol) of TBSCI was carefully added. After 1 h at room temperature, the mixture was concentrated and loaded on a silica gel flash chromatographic column. Elution with a mixture of 20:1 (v/v) CH2CI2/methanol containing 0.5 percent (by volume) triethylamine failed to afford pure product. The eluted mixture was dissolved in water, extracted with diethyl ether (3x) and dried over sodium sulfate. Removal of the solvent yielded 1.73 g (30percent) of 157 as a brown oil. 1H NMR (400 MHz, CDCI3) δ 0.06 (s, 6H), 0.90 (s, 9H), 1.74 (br s, 2H), 2.77 (t, J = 5.1 , 2H), 3.63 (t, J = 5.2, 2H). |
| 22% |
With dmap; triethylamine In dichloromethane at 20℃; |
Preparation of 2-((tert-butyldimethylsilyl)oxy)ethanamine (Compound 1) To a stirred solution of 2-aminoethanol (50 g, 0.82 mol), Et3N (124 g, 1.23 mol), and DMAP (2 g) in anhydrous DCM (1 L) was added TBSCl (135 g, 0.9016 mol). The reaction was stirred at room temperature overnight, quenched with aqueous NH4Cl, and extracted with DCM (× 3). The combined organic layers were washed with H2O, dried over MgSO4, filtered, concentrated, and purified by flash column chromatography to give the title compound (30.5 g, 22percent yield). 1H NMR (400 MHz, CDCl3) 3.6 (t, J=5.5 Hz, 2H), 2.74 (t, J=5.5 Hz, 2H), 1.36 (brs, 1 H), 0.87 (s, 9H), 0.04 (s, 6H). |
| 22% |
With dmap; triethylamine In dichloromethane at 20℃; |
2-(tert-Butyldimethylsilyloxy)ethanamine (149)[00522] To a stuffed solution of 2-aminoethanol (50 g, 0.82 mol), triethylamine (124 g, 1.23 mol), and DMAP (2 g) in dry DCM (1 L) was added TBSC1 (135 g, 0.9016 mol). The reaction mixture was stilTed overnight at room temperature, and quenched with aqueous NH4C1. The mixture was extracted with DCM (3x). The combined organic layers were washed with water, and dried over MgSO4. The solvents were removed under reduced pressure to give a residue, which was purified by flash column chromatography to give 30.5 g (22percent) of compound149.[00523] ‘H NMR (400 MHz, CDC13) 5 3.6 (t, 1=5.5 Hz, 2H), 2.74 (t, 1=5.5 Hz, 2H), 1.36 (brs, 1 H), 0.87 (s, 9H), 0.04 (s, 6H). |
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