A novel reductive amination procedure for electron-poor heterocyclic amines with aromatic and aliphatic aldehydes has been developed. The key to success was the use of triethylsilane (Et3SiH) as reducing agent, in combination with trifluoroacetic acid (TFA) in refluxing CH2Cl2. The reductive aminations are fast, clean and allow for the isolation of the alkylated amines in high yields and purity after crystallization or chromatographic purification. The robustness and scalability of the process has been demonstrated for one substrate combination on 750 g scale, leading to the isolation of the corresponding product in 93% yield.
A scalable route to 3-fluoro-6-methoxyquinoline
needed to be developed
as multi-kg amounts of this heterocycle were required. Initial route
development focused on the formation of the key C–F bond via
a Balz–Schiemann reaction or electrophilic fluorination using
Selectfluor. Both routes were developed on laboratory scale and provided
gram amounts of 3-fluoro-6-methoxyquinoline. However, due to process
safety concerns and high step counts, both routes were not suitable
for further scale up. Therefore, a third approach was developed, in
which the desired heterocycle was formed via condensation of p-anisidine with 2-fluoromalonic acid, two inexpensive and
commercially available starting materials. After intensive optimization
and safety studies, this POCl3-mediated process was successfully
scaled up to a 32 kg scale. After final hydrodechlorination, 12 kg
of 3-fluoro-6-methoxyquinoline with excellent purity was produced.
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