Ethanol → (11aS)-2-(4-Aminophenyl)-8-[[5-[[(11aS)-5,11a-dihydro-7-methoxy-2-(4-methoxyphenyl)-5-oxo-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl]oxy]pentyl]oxy]-1,11a-dihydro-7-methoxy-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one

Fresh LiBH4 (66 mg, 3.04 mmol) was added to a stirred solution of the SEM-dilactam 12 (428 mg, 0.42 mmol) in THF (3 mL) and EtOH (3 mL) at 0° C. (ice bath). The ice bath was removed and the reaction mixture was allowed to reach room temperature (vigorous effervescence). After 2 hours LC/MS analysis indicated the complete consumption of starting material. The reaction mixture was poured onto ice (50 mL) and allowed to warm to room temperature with stirring. The aqueous mixture was extracted with DCM (3×50 mL) and the combined organic layers washed with H2O (50 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The resulting residue was treated with DCM (2 mL), EtOH (5 mL), H2O (2.5 mL) and silica gel (3.7 g). The viscous mixture was allowed to stir at room temperature for 3 days. The mixture was filtered through a sinter funnel and the silica residue washed with 90% CHCl3: 10% MeOH (˜250 mL) until UV activity faded completely from the eluent. The organic phase was dried (MgSO4) filtered and evaporated in vacuo to provide the crude material. The crude product was purified by flash chromatography (99.5% CHCl3: 0.5% MeOH to 97.5% CHCl3: 2.5% MeOH in 0.5% increments)) to provide the pure C2/C2′ aryl PBD dimer 13 (59 mg, 52%).

1. customat 0° C.
2. customThe ice bath was removed
3. customto reach room temperature
4. customthe complete consumption of starting material
5. additionThe reaction mixture was poured onto ice (50 mL)
6. extractionThe aqueous mixture was extracted with DCM (3×50 mL)
7. washthe combined organic layers washed with H2O (50 mL), brine (50 mL)
8. dry with materialdried (MgSO4)
9. concentrationconcentrated in vacuo
10. additionThe resulting residue was treated with DCM (2 mL), EtOH (5 mL), H2O (2.5 mL) and silica gel (3.7 g)
11. stirringto stir at room temperature for 3 days
12. filtrationThe mixture was filtered through a sinter funnel
13. washthe silica residue washed with 90% CHCl3
14. dry with materialThe organic phase was dried (MgSO4)
15. filtrationfiltered
16. customevaporated in vacuo
17. customto provide the crude material
18. customThe crude product was purified by flash chromatography (99.5% CHCl3: 0.5% MeOH to 97.5% CHCl3: 2.5% MeOH in 0.5% increments))

ORD record

ord-4a11230b806d401bb55da96b7c007031

Source dataset

uspto-grants-2016_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09242013B2