More heteroatoms in fused rings mean more choice in synthesis
المؤلف:
Jonathan Clayden , Nick Greeves , Stuart Warren
المصدر:
ORGANIC CHEMISTRY
الجزء والصفحة:
ص784-785
2025-07-15
348
More heteroatoms in fused rings mean more choice in synthesis
The imidazo-pyridazine ring system forms the basis for a number of drugs in human and animal medicine. The synthesis of this system uses the chemistry discussed to build the pyridazine ring. There we established that it was easy to make dichloropyridazines and to displace the chlorine atoms one by one with different nucleophiles. Now we will move on from these intermediates to the bicyclic system.
A 2-bromo-acid derivative is the vital reagent. It reacts at the amino nitrogen atom with the carbonyl group and at the pyridazine ring nitrogen atom with the alkyl halide. This is the only way the molecule can organize itself into a ten-electron aromatic system.
we also gave the structure of timolol, a thiadiazole-based β-blocker drug for reduction of high blood pressure. This compound has an aromatic 1,2,5-thiadiazole ring system and a saturated morpholine as well as an aliphatic side chain. Its synthesis relies on ring forma tion by rather a curious method followed by selective nucleophilic substitution, rather in the style of the last synthesis. The aromatic ring is made by the action of S2Cl2 on ‘cyanamide’.
This reaction must start by attack of the amide nitrogen on the electrophilic sulfur atom. Cyclization cannot occur while the linear nitrile is in place so chloride ion (from disproportionation of ClS−) must fi rst attack CN. Thereafter cyclization is easy.
Reaction with epichlorohydrin followed by amine displacement puts in one of the side chains and nucleophilic substitution with morpholine on the ring completes the synthesis.
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