English description of the reaction apparatus
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A 3 L three-necked round bottom flask equipped with mechanical stirrer (or magnetic stirrer), addition funnel and thermometer (or Dean-Stock; drying tube)
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All flasks used in the reaction were heated under vacuum for 30 minutes and purged with N2 for 10 minutes. (Anhydrous reaction apparatus)
English description of the feeding process
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To a mixture (suspension/solution/slurry) of compound 12 (487 mg, 1 mmol) and o-phenylenediamine (648 mg, 6 mmol) in CH2Cl2 (15 mL) cooled to 0 °C was added DCC (226 mg, 1.1 mmol).
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Anhydrous lithium iodide (1.38 g, 10.3 mmol) was added in five portions (dropwise/in one portion/in portions/portionwise) to a stirred solution of compound 12 (10.93 g, 51.5 mmol) in CH2Cl2 (120 mL).
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A 3 L three-necked round bottom flask equipped with mechanical stirrer, addition funnel and thermometer (or Dean-Stock; drying tube) were charged with A (10 mL, 1mol), B (2 g, 1 mol) and C (50 mL).
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Add in portions/portionwise
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Add in one portion
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Add dropwise
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A round-bottom flask was charged with compound 33 (1.75 g, 5.27 mmol), LiCl (1.17g, 26.3 mmol), DMSO (100 mL) and H2O (378 μL).
A solution of compound 1 (10 g , 1 mole) in EtOAc (20 mL) was added dropwise (via addition funnel or syringe) to the above mixture at 10 °C (while maintaining gentle reflux; while keeping internal temperature between 10 °C – 30 °C) under N2.
Et3N (20 mL, 142 mmol) and a catalytic amount of DMAP were added to a solution of compound 1 (4.549 g, 46.4 mmol) in CH2CH2 (120 mL) at 0 °C.
To a stirred –78 °C solution of trimethylsilylacetylene (4.44 g, 45.2 mmol) in THF (10 mL) under Argon was added dropwise n-butyllithium (1.6 M in hexane, 28.25 mL).
An ozone-enriched stream of oxygen was bubbled through a cold (-78 °C) solution of compound 9a (128 mg, 0.409 mmol) in CH2Cl2 (5 mL) until it turned light blue. The solution was purged with argon at -78 °C for 10 min to remove excess O2.
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This mixture was added to a solution of compound 2 (3.00 g, 12.8 mmol) in THF (48 mL) via cannula over a period of 30 min.
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A solution of compound 29 (100 mg, 0.19 mmol, 1.0 equiv) in dry DMSO (0.5 mL) was cannulated under Ar to a vigorously stirred mixture of powdered potassium superoxide (62 mg, 0.87 mmol, 4.5 equiv) and 18-crown-6-ether (23 mg, 0.087 mol, 0.45 equiv) in dry DMSO (0.5 mL).
To a stirred solution of compound 15a (8.61 g, 21.2 mmol) was added a solution of p-toluenesulfonic acid (6.0 mg) in CH2Cl2 (4.0 ml) via syringe over 5 min.
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The reaction mixture (solution or suspension) was stirred at 5 °C for 2 hrs and then kept at room temperature (or ambient temperature) for another 2 hrs (or overnight)
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The reaction mixture (solution or suspension) was refluxed (or heated to reflux) for 2 hrs (or overnight)
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The reaction mixture (solution or suspension) was heated at 60 °C for 2 hrs (or overnight)
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The reaction mixture (solution or suspension) was allowed to reflux (or heat to reflux) for 2 hrs (or overnight)
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After 1 h, TLC analysis (CH2Cl2/hexanes 3:1) showed the complete consumption of compound 15.
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The reaction was complete (incomplete or messy) detected by TLC (Petroleum ether/EtOAc 4:1), LC-MS, HPLC or NMR.
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The mixture was left standing overnight.
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The mixture was allowed to stand at room temperature for 1 day.
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The mixture was allowed to stand in a freezer at -15 °C.
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Compound 4A (1.97 g, 6.63 mmol) was coevaporated with toluene five times to remove H2O.
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The residue was subjected to toluene azeotrope to give the corresponding acid chloride as a brown oil.
A mixture of compound 1 (190 g, 0.88 mol) and Raney Ni (20 g) in ethanol (1500 mL) and ethyl acetate (500 mL) was stirred under 1 atm of H2 at room temperature for 1 hour.
A mixture of TsOH.H2O (56.91 g, 0.30 mol) and toluene (400 mL) was heated to reflux to remove water by Dean-Stark trap.
The reaction was exothermic.
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The sealed vial was irradiated in the microwave on a Biotage Smith Synthesizer at 150 °C for 10 min.
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After the mixture was heated under microwave irradiation at 130 °C for 15 min, Boc2O (33 mg, 157 μmol) and triethylamine (16 μl, 117 μmol) were added.
The mixture was degassed for 10 min and refilled with N2.
The device for absorbing the evolved hydrogen bromide was attached to the reaction flask. [care!! The reaction evolves HBr and is best connected to a HBr gas trap (bubbler containing 1 M NaOH solution)].
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To the solution which is protected from light was added dropwise Br2 (3.45 g, 22 mmol) in CH2Cl2 (10 mL) over 5 min and the mixture was stirred for 1 h.
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A mixture of compound 8 (213 mg, 0.186 mmol) and compound 9 (220 mg, 0.279 mmol) was refluxed for 20 h under dark in a nitrogen atmosphere.
Common expressions in the post-processing process
The mixture was filtered through a Celite pad, and the filtrate was concentrated to
give crude product.
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The reaction mixture was quenched by the addition of saturated aqueous NH4Cl.
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An aqueous solution of A (0.5 M, 10 mL) was added dropwise into the reaction mixture once the reaction mixture (solution or suspension) was warmed (or cooled) to -5 °C or room temperature (ambient temperature).
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The hot (or cold) reaction mixture (solution or suspension) was poured into water (ice water) or poured onto ice.
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The reaction mixture (solution or suspension) was concentrated (distilled) under reduced pressure (in vacuum) or evaporated to remove MeOH (THF; DMF etc.) or excess SOCl2 (reagent). The residue (or the residual) was diluted with solvent and poured into water (ice water) or poured onto ice.
After quenching the reaction, the reaction mixture was poured into separatory funnel
and separated.
The residue was triturated with ether and filtered to afford a white solid.
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The residue was partitioned between EtOAc (100 mL) and 1 N aq. HCl (50 mL). The organic layer was washed with H2O, dried (MgSO4) and evaporated to dryness.
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EtOAc (100 mL) and 1 N aq. HCl (50 mL) were added to the residue, and the layers were separated.
The crude product was purified by prep. HPLC to give compound 4 as a colorless
thick oil which was solidified on standing.
The white solid (105249x43A) was re-crystallized from water, dried by hyophilization
to give WP-100418 (105249x43B, 45.0 g, 39.2%) as a white solid.
Column chromatography:
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The crude product was chromatographed on silica gel (acetone/dichloromethane 10:90→10:80→10:70) to give compound 8 (0.282 g, 51%) as a white solid.
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The crude product was purified by column chromatography on silica gel eluted with acetone/dichloromethane (10:90~10:80~10:70) to give compound 8 (0.282 g, 51%) as a white solid.
Preparative HPLC purification
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be purified by preparative HPLC to afford/give/yield
Preparative TLC purification
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be purified by preparative TLC to afford/give/yield
Recrystallization
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recrystallized from
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The pH was adjusted to around 9 by progressively adding solid NaHCO3.
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The mixture was adjusted to pH 9 with solid NaHCO3.
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Acidification: be acidified to
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Basification: be basified to
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Neutralization: be neutralized
The combined aqueous layers were extracted with EtOAc (100 mL×4) (or 4 times) to remove neutral impurities. The aqueous phase was acidified (or basified) with aqueous HCl (or NaHCO3) and extracted with CH2Cl2 (100 mL×5). The combined organic layers were dried over MgSO4 and concentrated.
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The mixture was evaporated to afford the crude product.
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The mixture was concentrated to afford the crude product.
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The solvent was removed to afford the crude product.
The precipitate was filtered and dried in vacuo (in/under vacuum; under reduced
pressure).
