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

HRID 1402260Notes

Reaction equation

HRID 1402260 reaction equation
C(O[C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]1[C:14]1[N:18]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]2=[N:16][N:15]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:23][C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([C@H:9]3[CH2:10][O:11][CH2:12][CH2:13][N:8]3[CH3:6])=[N:15][N:16]=2)[CH:19]=1

Participants

6

Reactant 4

HCID 712FormaldehydeHCID 6422Trifluoroacetic acid2×HCID 5049666Sodium triacetoxyborohydrideHCID 89624180(S)-3-(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-morpholine-4-carboxylic acid tert-butyl ester

Product 1

HCID 896242526-Fluoro-3-((S)-4-methyl-morpholin-3-yl)-[1,2,4]triazolo[4,3-a]pyridineYield 34.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of Intermediate 83b (297 mg, 0.92 mmol) in DCM (8.0 mL) at 0° C. was added TFA (400 μL) and the reaction stirred at RT overnight. Further TFA (600 μL) was added and the reaction stirred for 1 h then partitioned between DCM and sat. aq. NaHCO3 solution. The aqueous layer was then extracted with DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was taken up in DCM (4.0 ml) and MeOH (3 drops) added. Formaldehyde solution (37 wt % in water, 162 μL, 2.00 mmol) was added followed by sodium triacetoxyborohydride (372 mg, 2.40 mmol). The reaction was stirred overnight then loaded onto an SCX-2 cartridge, which was washed with MeOH and eluted with 2M NH3 in MeOH; concentration in vacuo gave the title compound (75.0 mg, 34%). 1H NMR (400 MHz, d4-MeOD): 2.09 (3H, s), 2.49 (1H, td, J 11.4, 3.8), 2.98 (1H, dt, J 11.9, 2.0), 3.79-3.90 (3H, m), 3.94 (1H, m), 4.01 (1H, dd, J 10.1, 4.0), 7.50 (1H, ddd, J 10.0, 7.7, 2.2), 7.81 (1H, ddd, J 10.1, 4.9, 0.8), 8.98 (1H, ddd, J 4.0, 2.3, 0.8).

Workup

  1. stirringthe reaction stirred for 1 h
  2. customthen partitioned between DCM and sat. aq. NaHCO3 solution
  3. extractionThe aqueous layer was then extracted with DCM (3×)
  4. washThe combined organic layers were washed with brine
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. customevaporated in vacuo
  8. additionMeOH (3 drops) added
  9. stirringThe reaction was stirred overnight
  10. washwas washed with MeOH
  11. washeluted with 2M NH3 in MeOH
  12. concentrationconcentration in vacuo

Sources & evidence

ORD record
ord-644cda9760a346c38cf3292518e7d9c1
Source dataset
uspto-grants-2014_12
Patent number
US08907094B2

Reaction notes

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