Hexachloroethane → 6-Fluoro-3-((S)-3-methyl-morpholin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine

HRID 630940Notes

Reaction equation

HRID 630940 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])=O)N)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([N:40](CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:8]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]3[CH3:18])=[N:40][N:6]=2)[CH:7]=1

Participants

6

Reactant 4

HCID 6214HexachloroethaneHCID 8471TriethylamineHCID 11776TriphenylphosphineHCID 86687241(S)-3-Methyl-morpholine-4-carboxylic acid N-(5-fluoro-pyridin-2-yl)-hydrazide

Product 1

HCID 896241616-Fluoro-3-((S)-3-methyl-morpholin-4-yl)-[1,2,4]triazolo[4,3-a]pyridineYield 29%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
55 °C

Procedure

To an ice cold solution of Intermediate 139a (574 mg, 2.26 mmol) in THF (23.0 mL) was added sequentially triphenylphosphine (1.18 g, 4.52 mmol), triethylamine (1.26 mL, 9.04 mmol) and hexachloroethane (1.07 g, 4.52 mmol). The cooling bath was removed and the reaction was heated to 55° C. overnight. The reaction was cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was taken up in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH and eluted with 2M NH3 in MeOH. The residue was concentrated in vacuo and then re-submitted to the above reaction conditions overnight. The reaction was cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC using 0-10% [2M NH3 in MeOH] in DCM to give the title compound (154 mg, 29%). 1H NMR (300 MHz, CDCl3): 0.94 (3H, d, J=6.3 Hz), 3.13 (1H, dt, J=12.2, 3.1 Hz), 3.32 (1H, ddd, J=12.4, 9.5, 3.2 Hz), 3.49 (1H, dd, J=11.1, 8.6 Hz), 3.56-3.68 (1H, m), 3.84 (1H, ddd, J=12.1, 9.4, 2.7 Hz), 3.92-4.01 (2H, m), 7.16 (1H, ddd, J=9.9, 7.5, 2.3 Hz), 7.68 (1H, ddd, J=10.0, 4.8, 0.8 Hz), 7.85 (1H, m).

Workup

  1. customThe cooling bath was removed
  2. temperatureThe reaction was cooled
  3. custompartitioned between EtOAc and water
  4. extractionThe aqueous layer was then extracted with EtOAc (3×)
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. customevaporated in vacuo
  9. washwas washed with MeOH
  10. washeluted with 2M NH3 in MeOH
  11. concentrationThe residue was concentrated in vacuo
  12. customre-submitted to the above reaction conditions overnight
  13. temperatureThe reaction was cooled
  14. custompartitioned between EtOAc and water
  15. extractionThe aqueous layer was then extracted with EtOAc (3×)
  16. washThe combined organic layers were washed with brine
  17. dry with materialdried (MgSO4)
  18. filtrationfiltered
  19. customevaporated in vacuo
  20. customThe residue was purified by FCC

Sources & evidence

ORD record
ord-a7568d77c4024cf1bae57a10c61c6cb9
Source dataset
uspto-grants-2016_04
Patent number
US09315503B2

Reaction notes

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