Acetic Acid → HCID 70873767, compound

To a stirred solution of methyl 3-[(4-{[(tert-butoxy)carbonyl]amino}cyclohexyl)amino]-5-chloro-2-ethylbenzoate (200 mg, 0.49 mmol) in dry 1,2-dichloroethane (5.0 ml), was added acetaldehyde (54 μl, 1.0 mmol), followed by acetic acid (167 μl, 2.9 mmol). The reaction mixture was stirred for 50 minutes, sodium triacetoxyborohydride (309 mg, 1.5 mmol) was added over 2 hours and the reaction was stirred for 20 hours. The reaction mixture was treated with acetaldehyde (54 μl, 1.0 mmol) stirred for 1 hour and sodium triacetoxyborohydride (309 mg, 1.5 mmol) was added portionwise over 2 hours. The reaction mixture was stirred for a further 22 hours and then treated with acetaldehyde (136 μl, 2.4 mmol) and stirred for 1 hour, followed by sodium triacetoxyborohydride (516 mg, 2.4 mmol) over 1.5 hours and stirred for 22 hours. The reaction mixture was treated with acetaldehyde (109 μl, 2.0 mmol) and stirred for 1.5 hours before sodium triacetoxyborohydride (413 mg, 2.0 mmol) was added over 2 hours, along with dichloroethane (5.0 ml) to aid stirring. The reaction mixture was stirred for 19 hours before the addition of acetaldehyde (82 μl, 1.5 mmol), stirred for 1.5 hours, followed by sodium triacetoxyborohydride (309 mg, 1.5 mmol) over 45 minutes. The reaction mixture was stirred for a further 70 hours before being diluted with water (20 ml) and the pH was adjusted to 8 by the gradual addition of solid NaHCO3 (2.53 g). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×20 ml). The combined organic phases were washed with brine (60 ml), dried (MgSO4), filtered and concentrated in-vacuo. The crude residue was purified by flash column chromatography (10 g SNAP cartridge, Isolera, 0-30% EtOAc/Heptanes) to give the title compound (163 mg, 73%) as a yellow oil and a mixture of cis/trans-isomers. LC-MS 100%, 5.83 min (7 minute LC-MS method), m/z=439.2, 441.2; 1H NMR (500 MHz, Chloroform-d) δ ppm 7.45-7.55 (m, 1H) 7.22 (dd, J=4.33, 2.13 Hz, 1H) 4.25-4.67 (m, 1H) 3.90 (d, J=2.21 Hz, 3H) 3.29-3.76 (m, 1H) 2.95-3.11 (m, 4H) 2.58-2.96 (m, 1H) 1.62-2.03 (m, 4H) 1.38-1.53 (m, 11H) 1.01-1.14 (m, 4H) 0.81-0.94 (m, 4H).

1. stirringthe reaction was stirred for 20 hours
2. stirringstirred for 1 hour
3. stirringThe reaction mixture was stirred for a further 22 hours
4. stirringstirred for 1 hour
5. stirringstirred for 22 hours
6. stirringto aid stirring
7. stirringstirred for 1.5 hours
8. stirringThe reaction mixture was stirred for a further 70 hours
9. customThe layers were separated
10. extractionthe aqueous layer was extracted with CH2Cl2 (3×20 ml)
11. washThe combined organic phases were washed with brine (60 ml)
12. dry with materialdried (MgSO4)
13. filtrationfiltered
14. concentrationconcentrated in-vacuo
15. customThe crude residue was purified by flash column chromatography (10 g SNAP cartridge, Isolera, 0-30% EtOAc/Heptanes)

ORD record

ord-3efedda49a144e19a2e662789a194b83

Source dataset

uspto-grants-2016_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09376422B2