Innovative approach - Lower yields

Details


Summary:

This paper reports the synthesis of a new class of acrylamide thioglycoside derivatives utilizing a one-pot synthesis. Further heating of the resultant glycosides with hydrazine is reported to give pyrazole derivatives. Among those synthesized, some compounds were tested for cytotoxicities toward the hepatoma cell line (HEPG2). A few of those are reported in this paper to have high cytotoxic activity against (HEPG2) cell line. The importance of the OH moieties in the free glycosides has been highlighted as being vital for their potency.

The Reactions of Interest:

All the reactions in this paper are summarized in Chart 1. A simplified form is presented here. Each class of compounds is further subdivided in their naming using a, b, c, d, e & so on as synthesized/ used. Refluxing anilide derivatives 1a-d with thioacetamide 2 in EtONa/EtOH is reported to give the corresponding stable sodium 2-cyano-ethylene-1-thiolate salts 3a-d. These salts 3a-d were chosen as the key intermediates to react with gluco- (4a) galacto- (4b), xylo- (4c) and arabino- (4d) pyranosyl derivatives in ethanol at room temperature to give the corresponding S-glucosides 5a-d, S-galactosides 5e-h, S-xylosides 5i-l, and S-arabinosides 5m-p, respectively. Condensation of 5 with hydrazine in ethanol gave the corresponding 5-aminopyrazole derivatives 8. Alternatively, pyrazoles 8 could be prepared by reaction of 7 with hydrazine hydrate. Ketene compounds 7 were prepared by the reaction of the sodium 2-cyano-ethylene-1-thiolate salts 3 with methyl iodide in ethanol at room temperature.

Practical observations:

  • The described protocol was used to prepare the mentioned compounds as follows:

Gluco- or galacto- pyranosylthioacrylamides derivatives 5a-h (mostly orange crystalline compounds), Yield: 20-55%. S-xylosides 5i-l, and S-arabinosides 5m-p, respectively were either yellow-orange crystalline or oily compounds with yields around 15 to 45%.

5-Amino-N-aryl-3-(methyl)-1H-pyrazole-4-carboxamides 8a-d (yellow powder), Yield: 20- 55%.

  • The described sequence for preparation of the target compounds could be easily followed to obtain the mentioned compounds.
     

Comments:

  • I did not try the cytotoxicity test towards the hepatoma cell line (HEPG2) but, the procedure mentions IC50 values ranging from 11.7 to 23.9 (µg/mL) to have been compared with standard drug 5-fluorouracil. This approach is good.
  • I would suggest 13C NMR for compounds of class 8. The characterization of compounds 8e,f is not mentioned in the paper.
  • The lower yields are something that needs to be improved.


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