Methanesulfonyl chloride → N2'-((1R,3R)-3-aminocyclopentyl)-5'-chloro-N6-(3-fluorobenzyl)-2,4'-bipyridine-2',6-diamine

To (1S,3R)-3-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclopentanol (28 mg, 0.068 mmol) was added DCM (1 ml), diisopropyl ethylamine (0.030 ml, 0.170 mmol) then mesyl chloride (5.81 μl, 0.075 mmol), stirred at ambient temperature for 1 hr, and followed by LCMS. Another 3 uL of mesyl chloride was added and the reaction mixture was stirred an additional 30 minutes at ambient temperature. DCM was removed by rotary evaporation, and crude (1S,3R)-3-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclopentyl LCMS (m/z): 491.2 (MH+), retention time=0.76 min. was redissolved in 2 mL DMF. Sodium azide (8.82 mg, 0.136 mmol) and diisopropyl ethylamine (0.030 ml, 0.170 mmol) were added, and the reaction mixture was heated at 50° C. for 18 hours, at which point only N2′-((1R,3R)-3-azidocyclopentyl)-5′-chloro-N6-(3-fluorobenzyl)-2,4′-bipyridine-2′,6-diamine was observed by LCMS (m/z): 438.2 (MH+), retention time=0.83 min. The resulting reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was removed, and the organic layer was washed with water (1×) then saturated salt solution (1×), dried over sodium sulfate, and reduced to constant mass. Crude N2′-((1R,3R)-3-azidocyclopentyl)-5′-chloro-N6-(3-fluorobenzyl)-2,4′-bipyridine-2′,6-diamine (20 mg, 0.046 mmol, LCMS (m/z): 438.2 (MH+), retention time=0.83 min.) was dissolved in 1 mL of methanol, and 10% palladium on charcoal (4.86 mg, 0.046 mmol) was added under argon. H2 was bubbled through the solution while stirring for 1 hr at ambient temperature, and the reaction was followed by LCMS. The crude reaction mixture was filtered over celite washed with methanol, reduced, redissolved in DMSO, filtered and purified through prep LC. The resulting product fractions were combined, then 50 mL of 1 M NaOH and 50 mL of EtOAC were added. The aqueous layer was removed, the organic layer was washed with saturated salt solution, dried over sodium sulfate, and reduced to constant mass. 8 mg of the desired compound was obtained. LCMS (m/z): 412.1 (MH+), retention time=0.58 min.; 1H NMR (300 MHz, CHLOROFORM-d, 25° C.) δ ppm 1.31-1.54 (m, 2H) 1.71-1.86 (m, 4H) 1.98-2.13 (m, 1H) 2.20-2.35 (m, 1H) 3.54 (qd, J=6.35, 6.15 Hz, 1H) 4.14 (sxt, J=6.56 Hz, 1H) 4.55-4.67 (m, 3H) 5.11 (t, J=5.86 Hz, 1H) 6.40 (d, J=8.50 Hz, 1H) 6.56 (s, 1H) 6.88-7.02 (m, 1H) 7.12-7.16 (m, 1H) 7.29-7.34 (m, 1H) 7.47-7.52 (m, 1H) 8.09 (s, 1H).

1. customDCM was removed by rotary evaporation, and crude (1S,3R)-3-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclopentyl LCMS (m/z)
2. dissolution491.2 (MH+), retention time=0.76 min. was redissolved in 2 mL DMF
3. customThe resulting reaction mixture
4. customwas partitioned between ethyl acetate and water
5. customThe aqueous layer was removed
6. washthe organic layer was washed with water (1×)
7. dry with materialsaturated salt solution (1×), dried over sodium sulfate
8. customH2 was bubbled through the solution
9. stirringwhile stirring for 1 hr at ambient temperature
10. customThe crude reaction mixture
11. filtrationwas filtered
12. washover celite washed with methanol
13. dissolutionredissolved in DMSO
14. filtrationfiltered
15. custompurified through prep LC
16. addition50 mL of 1 M NaOH and 50 mL of EtOAC were added
17. customThe aqueous layer was removed
18. washthe organic layer was washed with saturated salt solution
19. dry with materialdried over sodium sulfate

ORD record

ord-9108fd78893e402c937a55727e2bc45a

Source dataset

uspto-grants-2014_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08778951B2