反应详情

A solution of 384 mg (0.853 mmol) of the product of Step B and 208 mg (1.28 mmol) of 1,1'-carbonyldiimidazole in 2 mL of dry tetrahydrofuran was refluxed 2 minutes by placing the reaction mixture into a preheated oil bath. After brief refluxing and gas evolution, TLC analysis (90:10:1 chloroform/methanol/acetic acid) indicated that the desired intermediate had formed. The reaction mixture was then cooled to room temperature and 255 mg (1.28 mmol) of dry 4-iso-propylbenzenesulfonamide, 10 mg (0.085 mmol) of CDI followed by 191 μL (1.28 mmol) of DBU was added. The reaction mixture was refluxed for 3 minutes, allowed to cool and stir at room temperature 1 hour after which TLC analysis (96:3:1 chloroform/methanol/acetic acid) indicated the desired product had been formed. The reaction mixture was poured into 10% citric acid and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was partially purified by silica-gel flash chromatography eluting first with ethyl acetate and then with (92:7:1 chloroform/methanol/acetic acid). The purified fractions were combined to afford 48 mg (9%) of the title compound. Upon standing, material precipitated from the ethyl acetate fractions to afford an addition 55 mg (10%) of the title compound. The remainder of semi-purified material was combined and purified using a Waters Delta Prep 4000 HPLC applying the residue in 6 mL total volume (4.5 mL methanol and 1.5 mL water) to an M1000 Prep-Pak module containing a 47×300 mm 15 μM DeltaPak C18 column and eluting isocratically at 50 mL/min using 60% A (95-5 acetonitile-water) and 40% B (95-5 water-acetonitrile) each with 0.1% TFA. The column effluent was monitored simultaneously at 210 and 277 nM with a Waters model 490 UV-visible detector and the purified fractions were combined in a round bottom flask, frozen in a -78° C. dry ice-acetone bath and lyophylized. The HPLC purified lyophylizate 155 mg (29%), the silica gel purified amorphous solid 48 mg (9%) and the precipitated amorphous solid 55 mg (10%) were combined to afford 258 mg (48%) of the title compound.

1. temperatureAfter brief refluxing
2. customhad formed
3. additionwas added
4. temperatureThe reaction mixture was refluxed for 3 minutes
5. temperatureto cool