Ethyl 2-chloroacetoacetate → HCID 70245761, compound

HRID 2213139Notes

Reaction equation

HRID 2213139 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.Cl[CH:20]([C:26]([CH3:28])=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CO.C(OCC)(=O)C>[CH3:28][C:26]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[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]

Participants

5

Reactant 2

HCID 11858Ethyl 2-chloroacetoacetateHCID 21956530HCID 21956530, compound

Product 1

HCID 70245761HCID 70245761, compoundYield 8.6%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8857Ethyl AcetateSolvent

Procedure

A stirred mixture of 2-amino-3-[(1-phenylcyclopropyl)methoxy]pyridine (2.82 g, 11.7 mmol, see example 23), ethyl 2-chloroacetoacetate (6.5 mL, 47 mmol) and molecular sieves (15.1 g, type 4 Å, beads, 8–12 mesh) in anhydrous methanol (55 mL) was refluxed for 39 h under argon. The molecular sieves were filtered off and the filtrate was concentrated in vacuo to give an oil which was dissolved in ethyl acetate (200 mL) and then washed successively with a 1:1 (v/v) mixture of saturated aq sodium bicarbonate and water (2×25 mL), and water (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the crude product. Purification by dry column (600 mL funnel with 450 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 isopropylarnine) afforded 0.352 g (8.6% yield) of ethyl 2-methyl-8-[(1-phenylcyclopropyl)methoxy]imidazo[1,2-α]pyridine-3-carboxylate (Rf=0.30 in ethyl acetate-hexanes, 1:3 v/v, containing 0.5% v/v isopropylamine). A stirred solution of ethyl 2-methyl-8-[(1-phenylcyclopropyl)methoxy]imidazo[1,2-α]pyridine-3-carboxylate (0.190 g, 0.542 mmol) in a mixture of dichloromethane (3.5 mL) and anhydrous diethyl ether (3 mL) was treated with ethereal hydrogen chloride to form the hydrochloride salt. Concentration of the solution in vacuo gave a residue which was triturated in anhydrous diethyl ether to afford the title compound as an off-white solid (0.168 g, 80% yield). 1H-NMR (300 MHz, CDCl3) δ 16.91 (br s, 1H, +NH), 9.05 (d, 1H, Ar), 7.65 (d, 2H, Ar), 7.18 (m, 4H, Ar), 6.92 (d, 1H, Ar), 4.45 (q, 2H, CH3CH2), 4.32 (s, 2H, CH2O), 3.03 (s, 3H, CH3), 1.42 (t, 3H, CH3CH2), 1.15 (m, 4H, CH2CH2); 13C-NMR (75 MHz, CDCl3, APT) δ 159.49 (+), 145.10 (+), 143.90 (+), 142.24 (+), 133.68 (+), 130.21 (−), 128.26 (−), 126.78 (−), 120.27 (−), 118.13 (−), 113.77 (+), 112.02 (−), 78.61 (+), 62.09 (+), 25.48 (+), 14.14 (−), 12.56 (−), 11.51 (+); LRMS-FAB m/z: MH+ 351 (100%); Anal. calcd for C21H22N2O3.HCl: C, 65.20; H, 5.99; N, 7.24%. found: C, 64.87; H, 5.96; N, 7.20%.

Workup

  1. temperaturewas refluxed for 39 h under argon
  2. filtrationThe molecular sieves were filtered off
  3. concentrationthe filtrate was concentrated in vacuo
  4. customto give an oil which
  5. washwashed successively with a 1:1 (v/v) mixture of saturated aq sodium bicarbonate and water (2×25 mL), and water (20 mL)
  6. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  7. concentrationconcentrated in vacuo
  8. customto yield the crude product
  9. customPurification
  10. customby dry column (600 mL funnel with 450 mL of silica gel 10–40μ, Sigma cat. S-6628)
  11. washeluted with a mixture of ethyl acetate-hexanes (1:3 v/v
  12. additioncontaining 0.5% v/v isopropylarnine)

Sources & evidence

ORD record
ord-972cedae0b0340b3a1433a61db70e7f1
Source dataset
uspto-grants-2006_09
Patent number
US07105534B2

Reaction notes

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