The Preparation of 7-Chloro-4-(4-(N-ethyl-N-β-hydroxyethylamino)-1- methylbutylamino)-quinoline and Related Compounds

Surrey, Alexander R.; Hammer, Henry F.

doi:10.1021/ja01160a116

Cited by 69 publications

(42 citation statements)

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“…Hydroxychloroquine ( 1 ) is an antimalarial drug developed for both treatment and prevention of the disease in response to the widespread malaria resistance to chloroquine ( 2 , Fig. 1 ) [ 5 – 6 ].…”

Section: Introductionmentioning

confidence: 99%

High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine

Yu¹,

Mangunuru²,

Telang³

et al. 2018

Beilstein J. Org. Chem.

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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.

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Section: Introductionmentioning

confidence: 99%

High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine

Yu¹,

Mangunuru²,

Telang³

et al. 2018

Beilstein J. Org. Chem.

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“…HCQ was synthesized in 1950 by Surrey and Hammer. 11 Dennis et al 12 showed HCQ to be an immunomodulating agent. It is now widely prescribed for its antimalarial and antirheumatic effects.…”

Section: Introductionmentioning

confidence: 99%

Hydroxychloroquine reduces heart rate by modulating the hyperpolarization-activated current If: Novel electrophysiological insights and therapeutic potential

et al. 2015

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BackgroundBradycardic agents are of interest for the treatment of ischemic heart disease and heart failure, as heart rate is an important determinant of myocardial oxygen consumption.ObjectivesThe purpose of this study was to investigate the propensity of hydroxychloroquine (HCQ) to cause bradycardia.MethodsWe assessed the effects of HCQ on (1) cardiac beating rate in vitro (mice); (2) the “funny” current (If) in isolated guinea pig sinoatrial node (SAN) myocytes (1, 3, 10 µM); (3) heart rate and blood pressure in vivo by acute bolus injection (rat, dose range 1–30 mg/kg), (4) blood pressure and ventricular function during feeding (mouse, 100 mg/kg/d for 2 wk, tail cuff plethysmography, anesthetized echocardiography).ResultsIn mouse atria, spontaneous beating rate was significantly (P < .05) reduced (by 9% ± 3% and 15% ± 2% at 3 and 10 µM HCQ, n = 7). In guinea pig isolated SAN cells, HCQ conferred a significant reduction in spontaneous action potential firing rate (17% ± 6%, 1 μM dose) and a dose-dependent reduction in If (13% ± 3% at 1 µM; 19% ± 2% at 3 µM). Effects were also observed on L-type calcium ion current (ICaL) (12% ± 4% reduction) and rapid delayed rectifier potassium current (IKr) (35% ± 4%) at 3 µM. Intravenous HCQ decreased heart rate in anesthetized rats (14.3% ± 1.1% at 15mg/kg; n = 6) without significantly reducing mean arterial blood pressure. In vivo feeding studies in mice showed no significant change in systolic blood pressure nor left ventricular function.ConclusionsWe have shown that HCQ acts as a bradycardic agent in SAN cells, in atrial preparations, and in vivo. HCQ slows the rate of spontaneous action potential firing in the SAN through multichannel inhibition, including that of If.

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“…Classified as an essential medication for a basic healthcare system, hydroxycloroquine (Figure 2) is still syn according to the same route developed in 1950 Hammer [29]. The patent on the compound and the method of preparation HCQ as hydroxychloroquine diphosphate dichloroquinoline with N'-ethyl-N' pentadiamine in the presence of potassium iodide and ph a temperature of 125-130 °C for >18 h to eventually obtain hydroxychloroquine further isolated as diphosphate overall yield of 35% [9] has long expired.…”

Section: Industrial Supply Of Hydroxycloroquinementioning

confidence: 99%

Hydroxychloroquine for the Treatment of COVID-19: Evidence, Possible Mode of Action and Industrial Supply of the Drug

Pagliaro¹,

Meneguzzo²

2020

Preprint

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Hydroxychloroquine, a known antiviral metabolite of chloroquine, is increasingly used along with antibiotic azithromycin for the treatment of COVID-19 infection. In about one month India, the world’s largest manufacturer, delivered hydroxychloroquine for treating COVID-19 to over 50 countries. The therapy is being used across the world both for patients staying at home at the early phase of symptoms, as well as for patients hospitalized. We summarize achievements as of late April 2020, review possible modes of action and suggest avenues for the quick scale-up of production of hydroxychloroquine.

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The Preparation of 7-Chloro-4-(4-(N-ethyl-N-β-hydroxyethylamino)-1- methylbutylamino)-quinoline and Related Compounds

Cited by 69 publications

References 0 publications

High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine

High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine

Hydroxychloroquine reduces heart rate by modulating the hyperpolarization-activated current If: Novel electrophysiological insights and therapeutic potential

Hydroxychloroquine for the Treatment of COVID-19: Evidence, Possible Mode of Action and Industrial Supply of the Drug

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