2,4-Piperadinedione Chemical Properties

Melting point:

98.0 to 102.0 °C

Boiling point:

362.1±35.0 °C(Predicted)

Density 

1.184±0.06 g/cm3(Predicted)

storage temp. 

under inert gas (nitrogen or Argon) at 2-8°C

form 

powder to crystal

pka

12.00±0.70(Predicted)

color 

White to Orange to Green

InChI

InChI=1S/C5H7NO2/c7-4-1-2-6-5(8)3-4/h1-3H2,(H,6,8)

InChIKey

RDNZDMDLRIQQAX-UHFFFAOYSA-N

SMILES

N1CCC(=O)CC1=O

Safety Information

Hazard Codes 

Xn

Risk Statements 

22-36/37/38-43

Safety Statements 

26-36/37

RIDADR 

UN 3335

WGK Germany 

3

HS Code 

2933790090

2,4-Piperadinedione Usage And Synthesis

Description

2,4-Piperidinedione is an important piperidine ring-containing intermediate, and its 2,4-piperidinedione, as a characteristic fragment, is widely used as an intermediate in the synthesis of ibrutinib and paliperidone drugs.

Chemical Properties

White to light yellow solid

Uses

2,4-Piperidinedione is a reactant in the synthesis of 1,4-dihydropyridines as TGFβ/Smad inhibitors.

Preparation

The synthesis of 2,4-Piperidinedione involved dissolving 400 mg (2.34 mmol, 1.00 eq.) of Methyl 2,4-dioxo-piperidine-3-carboxylate in a mixture of acetonitrile (20 mL) and water (0.2 mL). The solution was then heated to approximately 86° C. and maintained at this temperature for around 4 hours. After completion of the reaction, the solvent was removed under vacuum, leaving behind a residue of 2,4-Piperidinedione. This residue was further purified using silica gel column chromatography with a mobile phase consisting of dichloromethane and methanol in a ratio of 100:1. The target product, 2,4-Piperidinedione, was obtained as a white solid, with a yield of 27%, corresponding to 70 mg.

Synthesis

The general procedure for the synthesis of 2,4-piperidinediones from tert-butyl 2,4-dipiperidone-1-carboxylate was as follows: at 0 °C and under nitrogen protection, Boc-β-alanine (25 g, 132 mmol), Meldrum acid (20.9 g, 145 mmol), and 4-dimethylaminopyridine (DMAP, 24.2 g, 198 mmol) were dissolved in 700 mL of anhydrous dichloromethane (DCM). To this solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 30.4 g, 158 mmol). The reaction mixture was slowly warmed to room temperature and stirred overnight. After completion of the reaction, the reaction mixture was washed with 5% KHSO4 aqueous solution (0.5 L x 4). The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product [tert-butyl [3-(2,2-dimethyl-4,6-dioxo-[1,3]dioxol-5-yl)-3-oxo-propyl]-carbamate. The crude product was dissolved in 600 mL of ethyl acetate and refluxed for 4 hours. It was concentrated under reduced pressure to a volume of about 150 mL and subsequently crystallized at 4°C overnight. The solid was collected by filtration and washed with cold ethyl acetate to afford 18.4 g (65% yield) of 2,4-piperidinedione.1H NMR (400 MHz, DMSO-D6) δppm: 1.44 (s, 9H), 2.44 (m, 2H), 3.71 (m, 2H), 4.95 (s, 1H), 11.2 (bs, 1H). The resulting product was converted quantitatively to piperidine-2,4-dione by dissolving in dichloromethane and treating with trifluoroacetic acid for 3 h at room temperature.

References

[1] Patent: WO2008/104475, 2008, A1. Location in patent: Page/Page column 22
[2] Patent: WO2012/35078, 2012, A1. Location in patent: Page/Page column 144
[3] Patent: US2014/45872, 2014, A1. Location in patent: Paragraph 0911
[4] Journal of Medicinal Chemistry, 2008, vol. 51, # 3, p. 487 - 501
[5] Angewandte Chemie - International Edition, 2014, vol. 53, # 14, p. 3594 - 3598

2,4-Piperadinedione(50607-30-2)Related Product Information

• DROPERIDOL
• Haloperidol
• 2',4'-Dichloroacetophenone
• 2,2,6,6-Tetramethyl-4-piperidinol
• Triacetonediamine
• METHYPRYLON
• Diphenoxylate
• 3,3-DIMETHYLGLUTARIMIDE
• DL-Glutethimide
• 2,6-Dioxopiperidine-3-ammonium chloride
• Aminoglutethimide
• Ethyl 4-(4,4-dimethyl-2,6-dioxopiperidin-1-yl)benzoate
• 1-benzylpiperidine-3,5-dione
• 5-ETHYL-2,4-PIPERIDINEDIONE
• Antineoplaston A10
• N-Benzyl-2,6-piperidinedion
• 6-Phenylazaperhydroine-2,4-dione
• 3-ETHYL-3-METHYLGLUTARIMIDE