Ethyl Acetoacetate → HCID 66746528, compound

HRID 1467033Notes

Reaction equation

HRID 1467033 reaction equation
O=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:12]=1[C:13]#[N:14].Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[NH2:14][C:13]1[C:12]2[C:11](=[CH:18][CH:17]=[CH:16][C:15]=2[O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[N:10]=[C:2]([CH3:9])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]

Participants

5

Reactant 3

HCID 8868Ethyl AcetoacetateHCID 24287Tin tetrachlorideHCID 66745877HCID 66745877, compound

Product 1

HCID 66746528HCID 66746528, compoundYield 85.1%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
110 °C

Procedure

A solution of ethyl 3-oxobutanoate (29.9 g, 0.230 mol) in anhydrous toluene (200 mL) was added to a solution of 2-amino-6-(cyclohexyloxy)benzonitrile (Example 36b, 49.8 g, 0.230 mol) in anhydrous toluene (1000 mL) under nitrogen in a 3 L round bottom flask sitting in an oil bath at room temperature. SnCl4 (53.9 mL, 0.461 mol) was added slowly over a period of approximately 1 h. The oil bath temperature was then raised to 110° C. and the reaction mixture was stirred at that temperature for 2.5 h. It was then cooled down to 5° C., still under nitrogen, and the toluene was decanted away from the immiscible viscous oil at the bottom of the flask. The viscous oil was further concentrated under vacuum at 60° C., re-dissolved in boiling ethyl acetate (1 L), and transferred to a 4 liter Erlenmeyer flask. The solution was diluted with more EtOAc (1.5 L), cooled down to −15° C., and neutralized with NaOH (3 N, 500 mL). The organic layer was separated, and the aqueous emulsion was extracted once more with ethyl acetate. The insoluble tin salts were filtered out from the aqueous layer, then both the salts and aqueous filtrate were washed once more with ethyl acetate. The combined organic layers were dried over MgSO4, concentrated, and passed through a silica column using 0% to 60% ethyl acetate in hexanes. The product was purified by recrystallization from EtOAc to give the title compound as an off-white solid (64.3 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ 1.28-1.34 (m, 1H), 1.32 (t, 3H), 1.37-1.45 (m, 2H), 1.51-1.63 (m, 3H), 1.67-1.71 (m, 2H), 1.99-2.03 (m, 2H), 2.54 (s, 3H), 4.28-4.33 (q, J=6.8 Hz, 2H), 4.64 (m, 1H), 6.95-6.97 (d, J=7.6 Hz, 1H), 7.19-7.21 (d, J=8.4 Hz, 1H), 7.65 (t, J=8.4 Hz, 1H), 8.15 (brs, 2H). MS 329 (MH+).

Workup

  1. customsitting in an oil bath at room temperature
  2. temperatureIt was then cooled down to 5° C., still under nitrogen
  3. customthe toluene was decanted away from the immiscible viscous oil at the bottom of the flask
  4. concentrationThe viscous oil was further concentrated under vacuum at 60° C.
  5. dissolutionre-dissolved
  6. additionThe solution was diluted with more EtOAc (1.5 L)
  7. temperaturecooled down to −15° C.
  8. customThe organic layer was separated
  9. extractionthe aqueous emulsion was extracted once more with ethyl acetate
  10. filtrationThe insoluble tin salts were filtered out from the aqueous layer
  11. washboth the salts and aqueous filtrate were washed once more with ethyl acetate
  12. dry with materialThe combined organic layers were dried over MgSO4
  13. concentrationconcentrated
  14. customThe product was purified by recrystallization from EtOAc

Sources & evidence

ORD record
ord-34eed81989b046c8858d4e9d60ab405d
Source dataset
uspto-grants-2015_04
Patent number
US09000054B2

Reaction notes

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