1-Bromo-3-methylbutan-2-one → HCID 131725931, compound

HRID 2213142Notes

Reaction equation

HRID 2213142 reaction equation
[NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:20][C:21](=O)[CH:22]([CH3:24])[CH3:23]>C(O)C>[CH:22]([C:21]1[N:1]=[C:2]2[C:7]([O:8][CH2:9][C:10]3([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:12][CH2:11]3)=[CH:6][CH:5]=[CH:4][N:3]2[CH:20]=1)([CH3:24])[CH3:23]

Participants

4

Reactant 2

HCID 108990371-Bromo-3-methylbutan-2-oneHCID 21956530HCID 21956530, compound

Product 1

HCID 131725931HCID 131725931, compoundYield 76%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

A stirred mixture of 2-amino-3-[(1-phenylcyclopropyl)methoxy]pyridine (0.84 g, 3.50 mmol, see example 23), 1-bromo-3-methyl-2-butanone (0.69 g, 4.2 mmol) and molecular sieves (4.2 g, type 4 Å, beads, 8–12 mesh) in anhydrous ethanol (10 mL) was refluxed for 24 h under argon. The molecular sieves were filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in a 1:1 (v/v) mixture of saturated aq sodium bicarbonate and water (20 mL) and then extracted with ethyl acetate (3×40 mL). The organic extracts were combined, washed with water (2×5 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the crude product. Purification by dry column (600 mL funnel filled with 300 mL of silica gel 10–40μ, Sigma cat. S-6628) eluted with a mixture of ethyl acetate-hexanes (1:3 v/v, containing 0.5% v/v isopropylamine) yielded 0.814 g (76% yield) of 2-isopropyl-8-[(1-phenyl-cyclopropyl)methoxy]imidazo[1,2-α]pyridine as a free base (Rf=0.60 in ethyl acetate-hexanes, 1:1 v/v, containing 0.5% v/v isopropylamine). A stirred solution of the free amine (0.755 g, 2.46 mmol) in anhydrous diethyl ether (10 mL) was treated with ethereal hydrogen chloride (50 mL) to form the hydrochloride salt. After 1 h, the solvent was decanted and the title compound was isolated as a solid (0.844 g, quantitative). 1H-NMR (300 MHz, CDCl3) δ 15.59 (br s, 1H, +NH), 8.36 (m, 1H, Ar), 7.85 (d, 1H, Ar), 7.63 (d, 2H, Ar), 7.24 (m, 2H, Ar), 7.13 (m, 1H, Ar), 7.01 (t, 1H, Ar), 6.74 (d, 1H, Ar), 4.29 (s, 2H, CH20), 3.64 (m, 1H, CH), 1.40 (d, 6H, 2CH3), 1.12 (m, 4H, CH2CH2); 13C-NMR (75 MHz, CDCl3, APT) δ 145.64 (+), 144.89 (+), 142.33 (+), 133.36 (+), 130.04 (−), 128.27 (−), 126.78 (−), 120.09 (−), 116.68 (−), 110.31 (−), 109.82 (−), 77.99 (+), 25.51 (−), 25.45 (+), 21.99 (−), 11.45 (+); LRMS-ES m/z: MH+ 307.3.

Workup

  1. temperaturewas refluxed for 24 h under argon
  2. filtrationThe molecular sieves were filtered off
  3. concentrationthe filtrate was concentrated in vacuo
  4. dissolutionThe residue was dissolved in a 1:1 (v/v) mixture of saturated aq sodium bicarbonate and water (20 mL)
  5. extractionextracted with ethyl acetate (3×40 mL)
  6. washwashed with water (2×5 mL)
  7. dry with materialdried over anhydrous magnesium sulfate
  8. concentrationconcentrated in vacuo
  9. customto yield the crude product
  10. customPurification
  11. customby dry
  12. additioncolumn (600 mL funnel filled with 300 mL of silica gel 10–40μ, Sigma cat. S-6628)
  13. washeluted with a mixture of ethyl acetate-hexanes (1:3 v/v
  14. additioncontaining 0.5% v/v isopropylamine)

Sources & evidence

ORD record
ord-fb40729d630546a2a4ca4b103d0d7d9f
Source dataset
uspto-grants-2006_09
Patent number
US07105534B2

Reaction notes

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