An efficient route
to (S)-N-(2-bromo-6-methoxypyridin-4-yl)-2-hydroxy-2,4-dimethylpentanamide 1, a new topical antiandrogen, is described. The target compound
has been manufactured on kilogram scale with an overall yield of 25%
(HPLC purity 98.8% and >99% ee) from citrazinic
acid.
The key amide coupling between aminopyridine 4 and α-hydroxy-acid 6 was performed using a temporary protecting group to facilitate
the acyl chloride formation. Aminopyridine 4 was manufactured
from commercially available citrazinic acid via dibromide formation
using phosphorus(V) oxybromide followed by mono SNAr reaction
with sodium methoxide and a final Hofmann rearrangement. Enantiopure
α-hydroxy-acid 6 was obtained using an enantioselective
cyanosilylation followed by salt resolution with (S)-α-methyl benzylamine. The absolute configuration of compound 1 was determined with anomalous scattering and the final crystallization
of API was performed after seeding a liquid–liquid mixture
below the monotectic temperature and afforded a crystalline powder
presenting a “desert rose” shape clusters.
A concise and economically attractive process for the synthesis of a novel tyrosinase inhibitor has been developed and implemented on a multikilogram scale under GMP. A major achievement to the success of the process is the development of a direct coupling between free resorcinol and ketone. First developed under basic conditions, this coupling has been turned to a novel titanium(IV) mediated process allowing good selectivity, easy isolation, and high atom efficiency. Other key steps feature an alkene reduction by palladium catalyzed transfer hydrogenation and a urea formation using N,N′-disuccinimidyl carbonate as the carbonyl source. This route allowed us to produce kilogram batches of the candidate to support preclinical and clinical studies.
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