Quinolones also come from anilines by cyclization to an ortho position
المؤلف:
Jonathan Clayden , Nick Greeves , Stuart Warren
المصدر:
ORGANIC CHEMISTRY
الجزء والصفحة:
ص782-784
2025-07-15
428
Quinolones also come from anilines by cyclization to an ortho position
The usual method for making quinolone antibiotics is possible because they all have a carboxylic acid in the 3-position. The disconnection we used for quinoline suggests a rather unstable malonic ester derivative as starting material.
In fact, the enol ether of this compound is easily made from diethyl malonate and ethyl orthoformate [HC(OEt)3]. The aromatic amine reacts with this compound by an addition elimination sequence, giving an enamine that cyclizes on heating. This time the geometry of the enamine is not a concern.
For examples of quinolone antibiotics we can choose ofloxacin, whose synthesis was dis cussed in detail , and rosoxacin, whose synthesis is discussed below. Both mole cules contain the same quinolone carboxylic acid framework, outlined in black, with another heterocyclic system at position 7 and various other substituents here and there.
To make rosoxacin two heterocyclic systems must be constructed. Workers at the pharmaceutical company Sterling decided to build the pyridine in an ingenious version of the Hantzsch synthesis using acetylenic esters on 3-nitrobenzaldehyde. The ammonia was added as ammonium acetate. Oxidation with nitric acid made the pyridine, hydrolysis of the esters and decarboxylation removed the acid groups, and reduction with Fe(II) and HCl converted the nitro group into the amino group required for the quinolone synthesis.
Now the quinolone synthesis can be executed with the same reagents we used before and all that remains is ester hydrolysis and alkylation at nitrogen. Notice that the quinolone cyclization could in theory have occurred in two ways as the two positions ortho to the amino group are different. In practice cyclization occurs away from the pyridine ring as the alternative quinolone would be impossibly crowded.
Since quinolones, like pyridones, can be converted into chloro-compounds with POCl3, they can be used in nucleophilic substitution reactions to build up more complex quinolines.
We will give just one important synthesis of isoquinolines here. It is a synthesis of a dihydro isoquinoline by what amounts to an intramolecular Vilsmeier reaction in which the electrophile is made from an amide and POCl3. Oxidation (in this case a dehydrogena tion with Pd(0)) gives the quinoline.
الاكثر قراءة في مواضيع عامة في الكيمياء العضوية
اخر الاخبار
اخبار العتبة العباسية المقدسة
