| 67% |
With sodium hydride In N,N-dimethyl-formamide at 70℃; for 24h; Inert atmosphere; |
4.2.1. Synthesis of N-(propargyloxy)phthalimide (3)
N-(propargyloxy)phthalimide (3) was synthesised following the procedure previously described.30 Briefly, N-hydroxyphthalimide (1000 mg, 6.1 mmol) was dissolved in dry dimethylformamide (DMF) under a nitrogen atmosphere. The N-hydroxyphthalimide in DMF was then added to NaH (7.3 mmol) suspended in DMF under an N2 atmosphere, yielding a red opaque solution. Then, propargyl bromide (12.2 mmol) in DMF was added dropwise. The reaction mixture was heated to 70 C and stirred for 24 h. The DMF solvent was removed at reduced pressure, the residue dissolved in chloroform (CHCl3) and washed with of H2O, NaHSO3/ Na2CO3 (aq). The CHCl3 layer was dried over anhydrous Na2SO4, evaporated under reduced pressure and recrystallized from hot ethanol giving rise a light-brown solid (816 mg, 67%). NMR characterization matches previously reported. |
| 64% |
With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 60℃; for 2h; Inert atmosphere; |
1-2 Preparation of SAC-1010
After 500 mg of hydroxyphthalimide (Aldrich) was dissolved in 5 ml of dimethylformamide under argon flow, 501 mg of propargyl bromide (Aldrich) was added, and 0.5 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene (Aldrich) was slowly added. After the mixture was stirred at 60° C. for 2 hours, the temperature was again lowered to room temperature, and then the reaction was stopped by adding a 2 N hydrochloric acid solution. The reaction liquid was diluted by adding 20 ml of ethyl acetate, followed by drying over magnesium sulfate and then filtering. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography using a mixed eluent of ethyl acetate/hexane (1:5) and then dried to obtain 396 mg of a white solid (yield: 64%). The white solid was dissolved in 5 ml of dichloromethane, and 0.17 ml of methyl hydrazine (TCI) was slowly added at 0° C. After the reaction liquid was stirred at room temperature for 2 hours, the temperature was again lowered to 0° C. The generated solid was then filtered out, and 1 ml of a 4 M-hydrochloric acid dioxane solution (Aldrich) was added to the residual filtrate, followed by filtration and drying, to obtain 230 mg of a solid (yield: 100%). 13 mg of the obtained solid and 55 mg of SAC-0906 obtained as obtained above were dissolved in 1 ml of pyridine (Aldrich) under argon flow, followed by stirring at 80° C. for 2 hours. After the temperature was lowered to room temperature, the reaction liquid was acidified by adding a 2 N hydrochloric acid solution, followed by extraction with 20 ml of diethyl ether, drying over magnesium sulfate, and filtering. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography using a mixed eluent of ethyl acetate/hexane (1:5) to obtain the target compound SAC-1010 (53 mg, yield: 88%). 1H-NMR (300 MHz, CDCl3) δ5.92-5.76 (m, 2H), 5.34-5.33 (m, 1H), 5.28-5.25 (m, 1H), 5.15 (m, 1H), 4.61 (d, J=2.4 Hz, 2H), 4.25-4.05 (m, 3H), 3.68-3.41 (m, 1H), 2.42-0.62 (m, 36H) |
|
With potassium carbonate In <i>N</i>-methyl-acetamide; ethanol |
1.1 Step 1.
Step 1. Synthesis of N-2-propynoxyphthalimide as an intermediate A stirred solution of 163.1 grams (1.00 mole) of N-hydroxyphthalimide, 448.0 grams (3.74 moles) of 2-propynyl bromide, 72.0 grams (0.52 mole) of potassium carbonate and 60.0 grams (0.82 mole) of dimethylformamide was heated under reflux for 16 hours. The reaction mixture containing a hardened solid was cooled. The solid was broken up by the addition of ethanol and stirring. The solid was collected by filtration and washed with additional ethanol, then with water until the washings were free of bromide ion when tested with silver ion. The solid was dried in a vacuum desiccator then recrystallized from hot ethanol to give 127.3 grams of N-2-propynoxyphthalimide; mp 146°-148.5°. |
|
With sodium hydrogencarbonate In tetrahydrofuran at 80℃; for 18h; Inert atmosphere; |
17
[00234] Intermediate compound (LIII) was prepared by reacting propargyl bromide with N-hydroxyphthalamide in a solution of tetrahydrofuran containing sodium bicarbonate at 80 C for 18 hours under an inert gas atmosphere. Intermediate compound (LIII): NMR (300M Hz, CDC13) : 7.73-7.95 (m, 4H, aromatic), 4.89 (d, 2H, -OGC≡CH), δ = 2.60 (t, 1H, -OCH2C≡GH). |
|
With triethylamine In N,N-dimethyl-formamide at 40 - 60℃; |
1
250mL in a three-necked flask , added N, N- dimethylformamide (DMF((150mL), 3-bromo-1-propyne (11.9g, 0. 1mol) and N- hydroxy-phthalimide (16.3g, 0.1mol), after stirring to dissolving dropwise added triethylamine (12.2g,0.12mol).after the reaction was stirred at 40~60 ° C for 10~14hr it was cooled to room temperature,poured into ice water (500mL), filtered, washed with water to give N- propargyloxy phthalimide. at 45~65 ° C, With 37% concentrated hydrochloric acid (100mL)togive the the title compound as a pale yellow 3.70g, yield 34.4%. |
|
With triethylamine In N,N-dimethyl-formamide at 20℃; Darkness; |
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