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1.1.B (1) Synthesis of 4-(2,3,5,6-tetramethylpyrazin-1-yl)-4′-demethylepipodophyllotoxin
(B) Synthesis of 4-(2,3,5,6-tetramethylpyrazin-1-yl)-4'-demethylepipodophyllotoxin: 2 mmol of the activation product of 4-position in C ring of 4'-demethylepipodophyllotoxin, and 4 mmol tetramethylpyrazine hydrochloride were dissolved into 10 mL acetonitrile, reacting at 80° C. for 48 h to complete the reaction. The reactant was condensed under reduced pressure to dryness, using 50 mL ethyl acetate to recrystallize to separate out the white floccule precipitation, the precipitation was dried in vacuo, preserved in refrigerator at 4° C. avoiding light, used as sample for separation and purification.
Stage #1: ligustrazine hydrochloride With sodium hydroxide In water at 0℃;
Stage #2: With dihydrogen peroxide In water; acetic acid at 90℃;
3.1.1. General Procedure for the Preparation of 1
NaOH (8.0 g, 200 mmol) and ligustrazine hydrochloride (41.8 g, 200 mmol) weredissolved in 300 mL and 100 mL of water at 0 C to prepare solutions, respectively. To thestirred solution of ligustrazine hydrochloride was added slowly the NaOH solution. Afterstirring for one hour, water was removed under reduced pressure, and the product wascollected by filtration and dried by a standard method to obtain ligustrazine trihydrate.Then, a solution of ligustrazine trihydrate (20.4 g, 107 mmol) in glacial acetic acid (30 mL)was added to the 30% H2O2 aqueous solution (12.1 mL, 107 mmol). The reaction mixturewas stirred at 90 C for 2 h before another portion of the 30% H2O2 aqueous solution(12.1 mL, 107 mmol) was added and stirred at 90 C for another 2 h. The resultant mixturewas cooled to room temperature, alkalized to pH = 10 with 50% sodium hydroxide andextracted with dichloromethane (150 mL, 50 mL 3). The organic layer was combined anddried with anhydrous sodium sulfate for 8 h and evaporated in vacuo to afford ligustrazinemono-N-oxide (1).
Multi-step reaction with 7 steps
1.1: sodium hydroxide / water / 1 h / 0 °C
1.2: 4 h / 90 °C
2.1: 2.5 h / 130 °C
3.1: sodium hydroxide / water / 12 h / 20 °C
4.1: manganese(IV) oxide / ethanol / 6 h / Reflux
5.1: sodium hydride / toluene / 0.5 h / Cooling with ice
5.2: 20 °C / Darkness
6.1: water / tetrahydrofuran / 16 h / Alkaline conditions
7.1: dicyclohexyl-carbodiimide; dmap / dichloromethane
7.2: 4 h / 20 °C
Multi-step reaction with 7 steps
1.1: sodium hydroxide / water / 1 h / 0 °C
1.2: 4 h / 90 °C
2.1: 2.5 h / 130 °C
3.1: sodium hydroxide / water / 12 h / 20 °C
4.1: manganese(IV) oxide / ethanol / 6 h / Reflux
5.1: sodium hydride / toluene / 0.5 h / Cooling with ice
5.2: 20 °C / Darkness
6.1: water / tetrahydrofuran / 16 h / Alkaline conditions
7.1: dicyclohexyl-carbodiimide; dmap / dichloromethane
7.2: 4 h / 20 °C
Multi-step reaction with 7 steps
1.1: sodium hydroxide / water / 1 h / 0 °C
1.2: 4 h / 90 °C
2.1: 2.5 h / 130 °C
3.1: sodium hydroxide / water / 12 h / 20 °C
4.1: manganese(IV) oxide / ethanol / 6 h / Reflux
5.1: sodium hydride / toluene / 0.5 h / Cooling with ice
5.2: 20 °C / Darkness
6.1: water / tetrahydrofuran / 16 h / Alkaline conditions
7.1: dicyclohexyl-carbodiimide; dmap / dichloromethane
7.2: 4 h / 20 °C
Multi-step reaction with 7 steps
1.1: sodium hydroxide / water / 1 h / 0 °C
1.2: 4 h / 90 °C
2.1: 2.5 h / 130 °C
3.1: sodium hydroxide / water / 12 h / 20 °C
4.1: manganese(IV) oxide / ethanol / 6 h / Reflux
5.1: sodium hydride / toluene / 0.5 h / Cooling with ice
5.2: 20 °C / Darkness
6.1: water / tetrahydrofuran / 16 h / Alkaline conditions
7.1: dicyclohexyl-carbodiimide; dmap / dichloromethane
7.2: 4 h / 20 °C
Multi-step reaction with 7 steps
1.1: sodium hydroxide / water / 1 h / 0 °C
1.2: 4 h / 90 °C
2.1: 2.5 h / 130 °C
3.1: sodium hydroxide / water / 12 h / 20 °C
4.1: manganese(IV) oxide / ethanol / 6 h / Reflux
5.1: sodium hydride / toluene / 0.5 h / Cooling with ice
5.2: 20 °C / Darkness
6.1: water / tetrahydrofuran / 16 h / Alkaline conditions
7.1: dicyclohexyl-carbodiimide; dmap / dichloromethane
7.2: 4 h / 20 °C
Multi-step reaction with 3 steps
1.1: sodium hydroxide / water / 1 h / 0 °C
1.2: 4 h / 90 °C
2.1: 2.5 h / 130 °C
3.1: sodium hydroxide / water / 12 h / 20 °C
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