Print version Print setup

One step synthesis of thalidomide.; Thalidomide

SyntheticPage 964
Submitted Oct 30, 2023, published Nov 07, 2023
Emanuel Bruno Savini (, Edoardo Bandieri (

			Reaction Scheme: One step synthesis of thalidomide.

Chemicals Used

Glutamine - C5H10N2O3 - [56-85-9] - ≥99,9% (Food grade supplement)
- TEA - C6H15N - [121-44-8] - ≥99,5%, for synthesis (Carl Roth)
Phtalic anhydride - C8H4O3 - [85-44-9] - 99% (Fisher)
Acetic anhydride - C4H6O3 - [108-24-7] - 99,5% (Sigma-Aldrich)
Toluene - C7H8 - [108-88-3] - ≥99,5%, ACS reagent (Sigma-Aldrich)
Tetrahydrofuran - THF - C4H8O - [109-99-9] - ≥99,5%, ACS reagent (Sigma-Aldrich)
1,4-Dioxane - C4H8O2 - [123-91-1] - ≥99%, (Sigma-Aldrich)
Diethyl ether - C4H9O - [60-29-7] - ≥99% (Honeywell)
Cyclohexane - C6H12 - [110-82-7] - ≥99% (Sigma-Aldrich)


Phthalic anhydride (5.00g, 33.8mmol, 1.00 eq.) and L-glutamine (5.00g, 34.2mmol, 1.01 eq.) were ground together for 2 minutes in a blender. Next, the powder was weighed again (9.80g typically) and transferred into a single neck round bottom flask. The powder was then suspended in 55 mL of toluene. Triethylamine (NEt3, 4.7mL, 33.8mmol, 1.00eq.) and acetic anhydride (Ac2O, 9.5mL, 0.10mol, 3.00eq.) were added.
The reaction mixture was then heated to reflux and maintained refluxing at approximately 110oC for 9 hours. After reflux, the reaction was quenched by allowing it to cool to room temperature and immersing the flask in an ice-salt bath for 30min at -5oC. The product was recovered through simple vacuum filtration on a Gouch G3 funnel, resulting in a yellow-brown solid. It was subsequently washed with 10 mL of a saturated sodium bicarbonate solution in water and with 3 x 10 mL of diethyl ether.
The average yield was 2.40g. A small sample was dissolved in dioxane, spotted, and appeared to be pure on TLC with BuOAc 10: AcOH 5: n-BuOH 1 as the eluent (Rf: 0.87). It exhibited UV absorption at 254 nm and reacted with KMnO4 stain only while heated vigorously causing thalidomide to appear as black spots on a white background. Further purification of the sample could be achieved through flash column chromatography using the solvent mixture THF 4: Cyclohexane 6 (Rf: 0.60) or by dry column vacuum chromatography (DCVC) using a Cyclohexane:THF gradient.
Both the product before and after column chromatography displayed complete purity (≥95%) in 1H-QNMR analysis . Any attempts at recrystallization using common solvent systems were found to be either low-yielding or ineffective in removing trace-colored impurities.

Author's Comments

- The reaction mixture tends to go dark during the first our of reflux, it's a normal sign of the reaction's progress.
- Vigorous stirring is mandatory due the low solubility of the reagent in the solvent.
- The same reaction was conducted in microwave condition, without TEA and acetic anhydride using instead DMSO (2.5% w/w) as a catalist, the yield of thalidomide was lower compared to the reported method but reaction times are significantly reduced.
- Thalidomide is almost insoluble in most organic solvents (EtOAc, Et2O, Hexane, DCM...). We observed it to be soluble in DMSO, DMF, pyridine, dioxane, THF and sparingly soluble in acetone, methanol and boiling ethanol.
- Thalidomide may be hydrolised in concentrated, strong, acqueos acids and bases.
- Polarimetric measurements revealed the product to be racemic. Anyways, for medical purposes, enantiopure Thalidomide isn't used. [2]
- FTIR spectra were collected on a "Cary 630 FTIR Spectrometer" equipped with an ATR module.
- NMR spectra were collected on "Varian Oxford 300MHz NMR" and "Varian Oxford 400MHz NMR".
- Procedure is based of an example reaction from the patent [1].
- We sincerely thank Professor M. Fochi, PhD.; S. Cerini, PhD. and Dr. Magdalena Medrzycka for the spectroscopic analysis.
- All the autors contributed equally to this work.


1H NMR (300 MHz, dmso) δ 11.11 (s, 1H), 8.01 – 7.77 (m, 4H), 5.23 – 5.06 (m, 1H), 3.01 – 2.77 (m, 1H), 2.64 – 2.50 (m, 2H), 2.15 – 1.93 (m, 1H).

13C NMR (75 MHz, dmso) δ 173.21, 170.30, 167.62, 135.35, 131.71, 123.88, 49.45, 31.39, 22.44.


Lead Reference

[1] Rao, D. R. WO2009083724A1 - Processes for the preparation of thalidomide          - Google Patents.

Other References

[2] Thalidomide: Uses, interactions, mechanism of action | DrugBank Online. DrugBank.
[3] Pharmakon. Spotify.

Supplementary Information

NMR 1H 13C QNMR (NMR_thalidomide.pdf)

This page has been viewed approximately 4122 times since records began.

Get structure file (.cdx, .sk2, .mol)

Keywords: amides, heterocyclic compounds, imide, nucleophilic, substitution

Loading ...