Ethyl 2-(ethoxymethylene)acetoacetate Chemical Properties

Boiling point:

266°C(lit.)

Density 

1.049±0.06 g/cm3(Predicted)

refractive index 

1.4730 to 1.4770

storage temp. 

Keep in dark place,Sealed in dry,Room Temperature

form 

powder to lump to clear liquid

color 

Light yellow to Yellow to Orange

InChI

InChI=1S/C9H14O4/c1-4-12-6-8(7(3)10)9(11)13-5-2/h6H,4-5H2,1-3H3

InChIKey

FNASCUBBFNCFQO-UHFFFAOYSA-N

SMILES

C(OCC)(=O)C(=COCC)C(=O)C

CAS DataBase Reference

3788-94-1(CAS DataBase Reference)

Safety Information

HS Code 

2916399090

Ethyl 2-(ethoxymethylene)acetoacetate Usage And Synthesis

Uses

Ethyl 2-(ethoxymethylene)acetoacetate is an active metabolite of leflunomide, a pyrimidine synthesis inhibitor with anti-inflammatory and immunomodulatory properties that reduces the number of activated central nervous system lymphocytes.

Application

Ethyl 2-(ethoxymethylene)acetoacetate is a mono-, di-, and trifunctional three-carbon electrophile in carbonyl reactions and cyclization reactions; a β-ketoester equivalent.

Preparation

Ethyl 2-(ethoxymethylene)acetoacetate is obtained by heating Ethyl Acetoacetate with Triethyl Orthoformate in Acetic  Anhydride.

Synthesis

Step a) Synthesis of the intermediate 2-(ethoxymethylene)-3-oxobutanoic acid ethyl ester: A mixed solution of ethyl acetoacetate (20 g, 154 mmol), triethyl orthoformate (51.1 mL, 307 mmol) and acetic anhydride (43.5 mL, 461 mmol) was heated and reacted for 5 hrs at 130 °C. After completion of the reaction, the mixture was cooled to room temperature. Subsequently, excess triethyl orthoformate and acetic anhydride were removed by concentration under reduced pressure. The residual acetic anhydride and triethyl orthoformate were further removed by distillation under reduced pressure (30 mbar, 30-70°C). Finally, the target product ethyl 2-(ethoxymethylene)-3-oxobutanoate was purified by distillation (6 mbar, 80 °C to 128 °C) as a viscous yellow oil (22.8 g, 80% yield). The structure of the product was confirmed by 1H NMR (400 MHz, CDCl3): δ 7.59-7.69 (m, 1H), 4.17-4.34 (m, 4H), 2.29-2.44 (m, 3H), 1.25-1.44 (m, 6H).

storage

May be kept for a few weeks at 0 °C in the dark with addition of  hydroquinone. The enol ether hydrolyses slowly in contact with water. Use in a fume hood.

References

[1] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 4, p. 946 - 950
[2] Mendeleev Communications, 2016, vol. 26, # 1, p. 54 - 56
[3] Patent: WO2011/83316, 2011, A1. Location in patent: Page/Page column 52-53
[4] Letters in Drug Design and Discovery, 2016, vol. 13, # 9, p. 912 - 920
[5] Journal of Medicinal Chemistry, 2012, vol. 55, # 7, p. 3563 - 3567

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