Ethanol → HCID 86676335, compound

To a solution of (R)-2-(Cyclohept-2-enyl)isoindoline-1,3-dione (4.00 g, 16.58 mmol) in chloroform (40.0 ml) and ethanol (1.400 mL) was added N-bromosuccinimide (3.78 g, 21.22 mmol) as a solid over 5 minutes at room temperature. After addition was complete, the reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. An additional portion of N-bromosuccinimide (1.9 g) and 1.4 mL of ethanol were then added and the mixture was allowed to continue to mix at room temperature overnight under a nitrogen atmosphere. A third portion of N-bromosuccinimide (1.0 g) and 1.4 mL additional ethanol were added to the mixture and it was again mixed at room temperature for a third night under a nitrogen atmosphere. The reaction mixture was then concentrated to dryness. The resulting residue was triturated with 25 mL fresh chloroform. The solids were filtered, rinsed with chloroform, and the filtrate concentrated under reduced pressure to dryness. THF (40 mL) and 1N hydrochloric acid (aq.) (10 mL) were added to the concentrated filtrate and the resulting mixture was stirred at room temperature for 90 minutes. The solution was concentrated under reduced pressure to remove THF. The concentrate was diluted with 125 mL ethyl acetate and 75 mL of a 1:1 mixture of water:saturated aqueous sodium bicarbonate. The layers were separated and the aqueous was back extracted with 75 mL ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford an oil that was purified by silica gel chromatography (0-30% ethyl acetate in hexanes). Fractions containing the desired product were concentrated under reduced pressure to the title compound (3.9 g, 11.53 mmol, 69.6% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.88 (d, J=7.42 Hz, 4H), 5.48 (d, J=5.47 Hz, 1H), 4.73 (dd, J=10.54, 6.25 Hz, 1H), 4.24-4.38 (m, 1H), 3.91-3.99 (m, 1H), 2.32 (br. s., 1H), 1.67-1.96 (m, 5H), 1.40-1.60 (m, 2H). MS (ESI) m/z 320.1 [M−18]+. A COSY NMR experiment and the 1H NMR data reported above were used to verify the bromohydrin regiochemistry. An NOE (via NOESY experiment) was observed between the protons on the amino group carbon and the hydroxyl group carbon. This verifies a cis relationship between these two functional groups (a trans relationship, lacking this spacial proximity, would not show such an effect).

1. additionAfter addition
2. additionto mix at room temperature overnight under a nitrogen atmosphere
3. additionwas again mixed at room temperature for a third night under a nitrogen atmosphere
4. concentrationThe reaction mixture was then concentrated to dryness
5. customThe resulting residue was triturated with 25 mL fresh chloroform
6. filtrationThe solids were filtered
7. washrinsed with chloroform
8. concentrationthe filtrate concentrated under reduced pressure to dryness
9. additionTHF (40 mL) and 1N hydrochloric acid (aq.) (10 mL) were added to the concentrated filtrate
10. stirringthe resulting mixture was stirred at room temperature for 90 minutes
11. concentrationThe solution was concentrated under reduced pressure
12. customto remove THF
13. additionThe concentrate was diluted with 125 mL ethyl acetate and 75 mL of a 1:1 mixture of water
14. customThe layers were separated
15. extractionthe aqueous was back extracted with 75 mL ethyl acetate
16. washThe combined ethyl acetate layers were washed with brine
17. dry with materialdried over anhydrous magnesium sulfate
18. filtrationfiltered
19. concentrationconcentrated under reduced pressure
20. customto afford an oil that
21. customwas purified by silica gel chromatography (0-30% ethyl acetate in hexanes)
22. additionFractions containing the desired product

ORD record

ord-2377c97861b04272a98a405b0ccff491

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09139534B2