High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine

Abstract

Numerous synthetic methods for the continuous preparation of fine chemicals and active pharmaceutical ingredients (API’s) have been reported in recent years resulting in a dramatic improvement in process efficiencies. Herein we report a highly efficient continuous synthesis of the antimalarial drug hydroxychloroquine (HCQ). Key improvements in the new process include the elimination of protecting groups with an overall yield improvement of 52% over the current commercial process. The continuous process employs a combination of packed bed reactors with continuous stirred tank reactors for the direct conversion of the starting materials to the product. This high-yielding, multigram-scale continuous synthesis provides an opportunity to achieve increase global access to hydroxychloroquine for treatment of malaria.

Reviews on Biological Activity, Clinical Trial and Synthesis Progress of Small Molecules for the Treatment of COVID-19

“…Yu et al [ 101 ] and Frank et al [ 102 ] used continuous-flow method for high-yield preparation of CLQ-OH (Scheme 7 ), which is not suitable for large-scale production. Iodization of I with hydroiodic acid and reaction with III in the presence of K 2 CO 3 yielded IV , then oxime was obtained with hydroxylamine, and hydrogenation using Raney Nickel in high pressure obtained VI ; finally, VI and VII reacted at high temperature in base conditions yielded CLQ-OH.…”

Methods of Synthesis of Remdesivir, Favipiravir, Hydroxychloroquine, and Chloroquine: Four Small Molecules Repurposed for Clinical Trials during the Covid-19 Pandemic

“…Recently, Gupton and co-workers 31 developed an efficient process for the synthesis of hydroxychloroquine. The key intermediate 4 was obtained quantitatively in a reproducible and continuous-flow process.…”

“…The key intermediate 4 was obtained quantitatively in a reproducible and continuous-flow process. 31 Starting from -acetyl butyrolactone 21, the precursor 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine (4) was obtained in a high-yielding, four-step sequence. Firstly, acidic hydrolysis of lactone with aqueous HI and subsequent decarboxylation produced iodopentan-2-one 31, which, in turn, underwent a nucleophilic substitution with aminoethanol to produce 30.…”

“…In 2018, Gupton and co-workers reported a fully integrated continuous-flow process for the synthesis of hydroxychloroquine. 31 The process was conducted at 200 mg scale, wherein 4,7-dichloroquinoline (1) and 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine (4) were dissolved in ethanol, followed by treatment with a mixture of potassium carbonate and triethylamine. Heating the mixture for 6 hours at 125 °C afforded hydroxychloroquine 5 in 78% yield after purification by silica chromatography (Scheme 10).…”

Hydroxychloroquine for the Treatment of Coronavirus Disease 2019: Evidence, Possible Mode of Action and Industrial Supply

“…[31] An alternative and more efficient route (52% yield increase on conventional process) mostly based on flow chemistry was reported by Gupton and co-workers in 2018. [32] Showing the industry's awareness of the obsolescence of the route developed in 1950, another new process for preparing hydroxychloroquine by reacting 4,7-dichloroquinoline with N'-ethyl-N'-β-hydroxyethyl-1,4-pentadiamine under solvent-free and catalyst-free conditions by simply carrying out the process under 10-20 pressure in a moisture-free N2 atmosphere was reported by industrial researchers in South Korea in 2010. [33] The method inhibits the formation of byproducts, avoids the use of toxic phenol used as reaction solvent, and decreases production costs by decreasing the reaction temperature and reaction time…”