Tetrahydro-2-(2-propynyloxy)-2H-pyran → 2-Amino-5-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-4-trifluoromethyl-benzoic acid methyl ester

HRID 906531Notes

Reaction equation

HRID 906531 reaction equation
[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[CH2:17]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[C:18]#[CH:19]>O1CCOCC1.CCN(CC)CC.[Cu](I)I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:19]#[C:18][CH2:17][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]

Participants

7

Reactant 2

HCID 98609Tetrahydro-2-(2-propynyloxy)-2H-pyranHCID 53436880Methyl 2-amino-5-iodo-4-(trifluoromethyl)benzoate

Product 1

HCID 591644212-Amino-5-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-4-trifluoromethyl-benzoic acid methyl esterYield 72.4%

Reagents, catalysts & solvents 4

HCID 83717Copper iodideCatalystHCID 178419050HCID 178419050, compoundCatalystHCID 8471TriethylamineSolventHCID 312751,4-DioxaneSolvent

Procedure

A solution of 2-amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (2.0 g, 5.80 mmol), tetrahydro-2-(2-propynyloxy)-2H-pyran (2.44 mL, 17.4 mmol), copper iodide (55.0 mg, 0.29 mmol) and bis(triphenylphosphine)palladium (II) dichloride (407 mg, 0.58 mmol) in dioxane (15 mL) and Et3N (15 mL) was heated to reflux for 16 h under nitrogen. The mixture was then allowed to cool to r.t., filtered and the filtrate was diluted with AcOEt. This mixture was washed once with water. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel 60, hexanes/EtOAc 5:1) to give an orange oil, which was recrystallized in hexanes to provide 2-amino-5-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-4-trifluoromethyl-benzoic acid methyl ester (1.50 g, 4.20 mmol, 72%) as a pale brown powder, m.p. 88° C., ESI-MS: m/z 358 [M+H]+.

Workup

  1. temperatureto reflux for 16 h under nitrogen
  2. filtrationfiltered
  3. additionthe filtrate was diluted with AcOEt
  4. washThis mixture was washed once with water
  5. dry with materialThe organic phase was then dried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude product was purified by flash chromatography (silica gel 60, hexanes/EtOAc 5:1)
  9. customto give an orange oil, which
  10. customwas recrystallized in hexanes

Sources & evidence

ORD record
ord-366c08099fce43338919007b10d3404c
Source dataset
uspto-grants-2011_09
Patent number
US08012988B2

Reaction notes

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