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Omeprazole Prilosec / Losec

Taken for peptic ulcers, reflux and other conditions caused by too much stomach acid. It shuts down the pump that moves acid into the stomach, and is on the WHO list of essential medicines.

  • Proton pump inhibitor (H⁺/K⁺-ATPase)
  • FDA 1989
  • C17H19N3O3S · 345.42 g/mol
  • CAS 73590-58-6

One-pot industrial process

2 stages · 83% average yield

The racemic drug is made in one pot: the thioether bond forms first, then the sulfur is oxidised to the sulfoxide without isolating the intermediate. The physico-chemical study behind this paper changed one thing about the standard process, the methanol-to-water ratio of the first stage, by measuring how easily each precursor gives up its proton in each solvent mixture. Because the deprotonated form of the thiol is the reactive one, the wetter solvent makes the condensation so fast that it finishes in minutes at scale and gives off enough heat to drive the reaction to completion, which removes the reflux step altogether.

Scale: large-scale batches, 1164 L of methanol per batch instead of 1267 L

2-(Chloromethyl)-4-methoxy-3,5-dimethylpyridine hydrochloride (OM-Cl) no public CAS
+
5-Methoxy-1H-benzimidazole-2-thiol (OM-M) no public CAS
Step 1
NaOH, MeOH / H2O
V(MeOH) : V(H2O) = 5.73 : 1, no reflux
condensation of the two deprotonated forms, giving the thioether · minutes at scale, and the heat it gives off finishes the conversion
Thioether intermediate (OM-S), not isolated no public CAS
Thioether intermediate (OM-S), not isolated no public CAS
Step 2 83% over the whole process
H2O2, aqueous heptamolybdate catalyst
pH controlled, same pot
sulfide to sulfoxide · thiosulfate then destroys the leftover peroxide, which shifts the pH and precipitates the product
Omeprazole (Prilosec, Losec)
5 h time per batch vs 8 h none reflux vs 1 h 1164 L methanol per batch vs 1267 L 83% average yield vs 82%

The proposed process against the existing one, as reported for large-scale batches. The E-factor is unchanged at about 11.2, so the gain here is time, energy and solvent rather than waste.

Vojčić, N.; Bregović, N.; Cindro, N.; Požar, J.; Horvat, G.; Pičuljan, K.; Meštrović, E.; Tomišić, V.
Optimization of Omeprazole synthesis: physico-chemical steering towards greener processes
ChemistrySelect 2017, 2, 4899–4905 · Scheme 1

Open the paper · DOI 10.1002/slct.201700433 Read the PDF

Background on the chemistry

Why the oxidation step is run with a catalyst and watched so carefully. This kinetic study measures how fast a thioether is oxidised to the sulfoxide, and then on to the sulfone, by hydrogen peroxide and by hypochlorite. It was done on simple aryl thioethers in buffer, not on omeprazole, but it is the clearest published picture of the two competing oxidations that sit behind this step.

Abdelfattah, A. G.; Bansal, S.; Quaye, J. A.; Kondengadan, S. M.; Gadda, G.; Wang, B.
Thioether Oxidation Chemistry in Reactive Oxygen Species (ROS)-Sensitive Trigger Design: A Kinetic Analysis
Org. Lett. 2025, 27, 3071–3076 · Tables 1 and 2

Open the paper · DOI 10.1021/acs.orglett.5c00747 Read the PDF Open access, CC BY 4.0

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