2,2,2-Trifluoroethanol → HCID 66802980, compound

HRID 341438Notes

Reaction equation

HRID 341438 reaction equation
[F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[NH2:9][C:10]1[N:15]=[C:14]([N:16]([CH2:23][CH2:24][O:25][CH3:26])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=[C:12]([C:27]2[N:31]=[C:30]([C:32]3[CH:33]=[CH:34][C:35]([CH2:38]OS(C)(=O)=O)=[N:36][CH:37]=3)[O:29][N:28]=2)[N:11]=1>C1COCC1>[CH3:26][O:25][CH2:24][CH2:23][N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]1[N:15]=[C:10]([NH2:9])[N:11]=[C:12]([C:27]2[N:31]=[C:30]([C:32]3[CH:37]=[N:36][C:35]([CH2:38][O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:34][CH:33]=3)[O:29][N:28]=2)[N:13]=1

Participants

5

Reactant 3

HCID 64092,2,2-TrifluoroethanolHCID 24758Sodium hydrideHCID 86710512HCID 86710512, compound

Product 1

HCID 66802980HCID 66802980, compoundYield 10%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of [5-(3-{4-amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5]triazin-2-yl}-[1,2,4]oxadiazol-5-yl)-pyridin-2-yl]-methanol (Intermediate 130, 185 mg, 0.44 mmol) in DCM (40 mL) was added methanesulfonyl chloride (48 μL, 0.61 mmol) drop-wise, followed by triethylamine (92 μL, 0.66 mmol). The resulting solution was stirred for 3 h under an inert atmosphere. Incomplete reaction was observed so additional methanesulfonyl chloride (9 μL, 0.10 mmol) and triethylamine (16 μL, 0.11 mmol) were added and stirring was continued for 1 h. The reaction mixture was washed with water (2×50 mL) and the organic phase dried over magnesium sulfate and evaporated to dryness to afford the methanesulfonic acid 5-(3-{4-amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5]triazin-2-yl}-[1,2,4]oxadiazol-5-yl)-pyridin-2-ylmethyl ester intermediate. In a separate flask 2,2,2-trifluoro-ethanol (190 μL, 2.64 mmol) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 97 mg, 2.42 mmol) in anhydrous THF (30 mL) at 0 C under nitrogen. The resulting solution was stirred at 0 C for 30 min and then transferred via cannula to a solution of the methanesulfonic acid 5-(3-{4-amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5]triazin-2-yl}-[1,2,4]oxadiazol-5-yl)-pyridin-2-ylmethyl ester intermediate (220 mg, 0.44 mmol) in anhydrous THF (30 mL) at 0 C drop wise. The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with a saturated ammonium chloride aq. solution (5 mL) and extracted with EtOAc (3×50 mL). Combined organics were washed with brine (25 mL), dried over magnesium sulfate and evaporated to dryness. The crude product was purified by silica chromatography (2% MeOH in DCM) and then further by preparative HPLC-MS (Method C) to afford the title compound as an off-white solid (21 mg, 10%).

Workup

  1. stirringThe reaction mixture was stirred at room temperature for 18 h
  2. customThe reaction was quenched with a saturated ammonium chloride aq. solution (5 mL)
  3. extractionextracted with EtOAc (3×50 mL)
  4. washCombined organics were washed with brine (25 mL)
  5. dry with materialdried over magnesium sulfate
  6. customevaporated to dryness
  7. customThe crude product was purified by silica chromatography (2% MeOH in DCM)

Sources & evidence

ORD record
ord-ea12c66813ef4e5491d809e54560f90b
Source dataset
uspto-grants-2014_11
Patent number
US08895733B2

Reaction notes

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