Synthesis of Enarodustat
Chemical synthesis of enarodustat, a medication that was approved by the Japan Pharmaceuticals and Medical Devices Agency for the treatment of anemia associated with chronic kidney disease.
Biology Notes
Kidneys produce a hormone called erythropoietin, which signals the body to make red blood cells. In a person with chronic kidney disease, the kidneys cannot produce enough erythropoietin, leading to reduced numbers of red blood cells.
Anemia is a condition in which you lack enough healthy red blood cells to carry adequate oxygen to your body’s tissues. The primary cause of renal anemia is the depression of erythropoietin production in the kidney associated with the kidney disorder. A promising strategy for the treatment of renal anemia involves the inhibition of prolyl hydroxylase, because inhibition of this enzyme may increase internal erythropoietin levels as a result of hypoxia inducible factor stabilization (HIF-PH), which is a key transcription factor that plays a central role in regulating erythropoietin production.
Enarodustat functions as a inhibitor of (HIF-PH).
Retrosynthetic Analysis
Enarodustat is a non-chiral compound that contains a phenyl ring attached to a triazolopyridine through a two-carbon alkyl chain. The molecule contains a carboxylic acid, an amide bond, and a hydroxyl group.
A large-scale synthesis of the drug was reported by Japan Tobacco. The key steps for the synthesis of this molecule involve an amide coupling with glycine and a C–C bond formation. Formation of the triazole ring and regioselective halogenation was accomplished through an intermediate that could be easily prepared from commercial 2,4-dichloropyridine.
Synthesis of Enarodustat
The synthesis begins with the directed orthometalation of the pyridine ring by LDA. In this case, the effects of two directing groups and the use of LDA delivered an intermediate that was immediately quenched by the presence of CO2 to give dichloronicotinic acid. A Lewis-acid catalyzed esterification employing the depicted imidate gave the tert-butyl ester in 96% yield over two steps.
Sequential nucleophilic aromatic substitution reactions with benzyl alcohol first and hydrazine next delivered an intermediate (bottom left) that was treated with trimethyl orthoformate under acidic conditions to give the triazolopyridine derivative in 63% yield over three steps. In general terms, pyridines undergo nucleophilic aromatic substitution, usually faster at C-4 than C-2/6, but it is highly dependent on the nucleophile and the conditions employed.
In order to secure the regiochemistry of the triazolopyridine derivative, the substrate was subjected to a Dimroth rearrangement in the presence of morpholine in refluxing ethyl acetate.
Regioselective iodination gave the coupling precursor that was subjected to a Sonogashira coupling.
A plausible mechanism for the Dimroth rearrangement would involve the attack of the heterocyclic ring by the nucleophile, elimination of the triazole subunit followed by a 180 degrees rotation about a single bond, and subsequent ring closure and elimination of morpholine to deliver the desired triazolopyridine in an outstanding 97% yield.
Sonogashira coupling with phenylacetylene and removal of the tert-butyl group provided the carboxylic acid in 80% yield over two steps.
In a Sonogashira reaction, the palladium precatalyst is first activated. Then, the cycle begins with the oxidative addition of the aryl halide to the palladium 0 catalyst. The Palladium catalyst inserts itself into the carbon-halogen bond and gets oxidized from Pd(0) to Pd(II). The resulting complex reacts with copper acetylide in a transmetalation step, regenerating the copper catalyst and yielding a complex that undergoes reductive elimination to yield the coupled organic product and regenerate the palladium catalyst. Previous to this last step, a trans-cis isomerization may occur to locate the substrate motifs in close vicinity.
Amide bond formation with the ethyl ester of glycine was accomplished under these conditions with EDC and HOBt. Reduction of the alkyne and removal of the benzyl protecting group liberated the phenol. Subsequent hydrolysis gave enarodustat as the free carboxylic acid in 67% yield over three steps.
Accordingly, EDC activates the carboxylic acid that is attacked by HOBt to generate an active ester that is displaced by the amine. (Extracted from the synthesis of lascufloxacin.)
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