118-42-3 Usage
description
Hydroxychloroquine is a synthetic antimalarial agent which can also inhibit Toll-like receptor 7/9 (TLR7/9) signaling. Hydroxychloroquine is efficiently inhibits SARS-CoV-2 infection in vitro.Hydroxychloroquine, an analogue of chloroquine, was developed in 1946. Hydroxychloroquine and chloroquine are FDA-approved to treat or prevent malaria. Hydroxychloroquine is also FDA-approved to treat autoimmune conditions such as chronic discoid lupus erythematosus, systemic lupus erythematosus in adults, and rheumatoid arthritis.Hydroxychloroquine is often taken in combination with other drugs such as methotrexate.
Application in Particular Diseases
In Rheumatic Arthritis:
Hydroxychloroquine lacks the myelosuppressive, hepatic, and renal toxicities seen with some other DMARDs, which simplifies monitoring. Its onset may be delayed for up to 6 weeks, but the drug should not be considered a therapeutic failure until after 6 months of therapy with no response.
Short-term toxicities include GI (nausea, vomiting, diarrhea), ocular (accommodation defects, benign corneal deposits, blurred vision, scotomas, night blindness, preretinopathy), dermatologic (rash, alopecia, skin pigmentation), and neurologic (headache, vertigo, insomnia) effects. Periodic ophthalmologic examinations are necessary for early detection of reversible retinal toxicity.
Originator
Plaquenil,Winthrop,US,1956
Uses
Hydroxychloroquine is used to treat autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, in addition to malaria.Hydroxychloroquine is a disease-modifying anti-rheumatic drug (DMARD). It regulates the activity of the immune system, which may be overactive in some conditions. Hydroxychloroquine can modify the underlying disease process, rather than simply treating the symptoms.Hydroxychloroquine is used to treat:rheumatoid arthritisdiscoid and systemic lupus erythematosus (SLE)juvenile idiopathic arthritis (JIA).Over the long term hydroxychloroquine can reduce pain, swelling and joint stiffness. If you have lupus, it may also improve the rash. It may be as long as 12 weeks before you notice the benefits.
Definition
ChEBI: An aminoquinoline that is chloroquine in which one of the N-ethyl groups is hydroxylated at position 2. An antimalarial with properties similar to chloroquine that acts against erythrocytic forms of malarial parasites, it is mainly used
s the sulfate salt for the treatment of lupus erythematosus, rheumatoid arthritis, and light-sensitive skin eruptions.
Indications
Hydroxychloroquine (Plaquenil), like chloroquine, is a
4-aminoquinoline derivative used for the suppressive
and acute treatment of malaria. It also has been used for
rheumatoid arthritis and discoid and systemic lupus erythematosus.
Hydroxychloroquine has not been proved
to be more effective than chloroquine. Adverse reactions
associated with its use are similar to those described
for chloroquine.The drug should not be used in
patients with psoriasis or porphyria, since it may exacerbate
these conditions.
Manufacturing Process
A mixture of 323 grams of 1-chloro-4-pentanone, 480 grams of N-ethyl-N-2-
hydroxyethylamine and 400 grams of sodium chloride (to aid in subsequent
filtration) in 1.3 liters of xylene was heated with stirring on a steam bath for
two hours and then refluxed for three hours. After standing overnight, the
mixture was filtered and the filter cake washed with xylene. The filtrate was
fractionally distilled, yielding 207.3 grams of a fraction distilling at 89° to
90°C at 0.35 mm; nD25 = 1.4600. This fraction, 1-(N-ethyl-N-2-
hydroxyethylamino)-4-pentanone, was used in the next step of the synthesis.
A sample of the fraction was further purified by distillation through a column
and gave an analytically pure sample of 1-(N-ethyl-N-2-hydroxyethylamino)-
4-pentanone, boiling at 85° to 87°C at 0.4 mm.The 1-(N-ethyl-N-2-hydroxyethylamino)-4-pentanone from above (284.2
grams) was dissolved in 300 grams of 28% ammoniacal methanol and
reduced catalytically with Raney nickel (at an initial pressure of 1,000 pounds)
at room temperature. After 24 hours the catalyst was filtered off and the
product distilled in vacuo through a column, yielding 254 grams of a fraction
distilling at 88.5° to 96°C at 0.3 mm and comprising mainly 5-(N-ethyl-N-2-
hydroxyethylamino)-2-pentylamine. An analytical sample of this fraction
distilled at 93°C at 0.6 mm.
A mixture of 90 grams of 4,7-dichloroquinoline, 90 grams of phenol, 1 gram
of potassium iodide and 132 grams of 5-(N-ethyl-N-2-hydroxyethylamino)-2-
pentylamine from above was heated with stirring for 13 hours at 125° to
130°C. Methanol (1.9 liters) was added and the the mixture was filtered with
charcoal. The filtrate was treated with 270 cc of a solution of 100 grams of
phosphoric acid in 300 cc of methanol. The walls of the flask containing the
filtrate were scratched with a glass rod and the mixture was allowed to stand
for two days. The solid was filtered off, washed with methanol and dried,
yielding 101 grams of crude 7-chloro-4-[5-(N-ethyl-N-2-hydroxyethylamino)-
2-pentyl]aminoquinoline diphosphate, MP 155° to 156°C.
Additional quinoline diphosphate was obtained as a gummy mass from the
filtrate by concentrating the latter to about half its volume and adding
acetone. The crude gummy diphosphate was dissolved in water, basified with
ammonium hydroxide and the resulting liberated basic quinoline extracted
with chloroform. After removal of the chloroform by distillation, the residue
was dissolved in ether and crystallization was induced by scratching the walls
of the flask with the glass rod. About 30 grams of the crude quinoline base,
melting at 77° to 82°C, separated. Recrystallization of this material from
ethylene dichloride or ethyl acetate yielded the purified 7-chloro-4-[5-(Nethyl-N-2-hydroxyethylamino)2-pentyl] aminoquinoline, MP 89° to 91°C.
The base may then be dissolved in ethanol and precipitated as the sulfate by
reaction with an equimolar quantity of sulfuric acid.
Therapeutic Function
Antimalarial
Mechanism of action
Hydroxychloroquine, like chloroquine, is also used for treating acute forms of malaria
caused by P. vivax, P. malariae, P. ovale, and also sensitive forms of P. falciparum. It is
also effective and safe like chloroquine, although it does not have obvious advantages. The
only advantage is that it is somewhat better tolerated. Its use is somewhat more limited
than chloroquine. Synonyms of this drug are plaquenil, quensyl, toremonil, and others.
Clinical Use
Hydroxychloroquine is approved for the treatment
of both systemic and cutaneous lupus erythematosus.
Both chloroquine and quinacrine (Atabrine) are also effective
in this skin disease. Low-dose chloroquine is
used for the therapy of porphyria cutanea tarda in patients
in whom phlebotomy has failed or is contraindicated.
Other skin diseases in which the drugs are useful
(after sunscreens and avoidance of sun exposure) include
polymorphous light eruption and solar urticaria.
Synthesis
Hydroxychloroquine, 7-chloro-4-[4-[ethyl(2-hydroxyethyl)amino]-
1-methylbutylamino]quinoline (37.1.1.19), is made by a scheme similar to that of making
chloroquine. Reacting 1-chloro-4-pentanone with 2-ethylaminoethanol gives the corresponding aminoketone (37.1.1.17), which undergoes reductive amination in conditions
analogous to those described above, making 4-[ethyl(2-hydroxyethyl)amino]-1-methylbutylamine (37.1.1.18). Reacting this with 4,7-dichlroquinoline (37.1.1.1) makes the
desired hydroxychloroquine.
Check Digit Verification of cas no
The CAS Registry Mumber 118-42-3 includes 6 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 3 digits, 1,1 and 8 respectively; the second part has 2 digits, 4 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 118-42:
(5*1)+(4*1)+(3*8)+(2*4)+(1*2)=43
43 % 10 = 3
So 118-42-3 is a valid CAS Registry Number.
InChI:InChI=1/C18H26ClN3O.H2O4S/c1-3-22(11-12-23)10-4-5-14(2)21-17-8-9-20-18-13-15(19)6-7-16(17)18;1-5(2,3)4/h6-9,13-14,23H,3-5,10-12H2,1-2H3,(H,20,21);(H2,1,2,3,4)
118-42-3Relevant articles and documents
Novel drug delivery of dual acting prodrugs of hydroxychloroquine with aryl acetic acid NSAIDs: Design, kinetics and pharmacological study
Poorvashree, Joshi,Suneela, Dhaneshwar
, p. 709 - 730 (2017)
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by restricted movements of joints of hand, feet, elbow, knees and neck but principally the synovial joints. Though etiopathology is not exactly known, treatment paradigms are evolving to provide a tighter control over symptoms and disease progression. Current trend is introduction of disease modifying anti-rheumatoid drugs (DMARDs) at early stages. Hydroxychloroquine (HCQ) and nonsteroidal anti-inflammatory drugs (NSAIDs) are two mechanistically different categories widely used in the management of RA where the first arrests the disease progression while the latter offers symptomatic relief. Present work aims at minimizing problems of slow onset and accumulation of HCQ in non-targeted sites and local gastric intolerance to NSAIDs by designing their mutual ester prodrugs. Synthesis of prodrugs was achieved by CDI coupling and structures were confirmed by IR, 1H–NMR, 13C–NMR, mass spectroscopy and elemental analysis. Prodrugs resisted hydrolysis in acidic environment of the stomach but exhibited significant release in small intestine. Upon oral administration of prodrugs to rats, 40.5–49% HCQ and 53.4–66.8% of NSAIDs were recovered in 8.5–10?h in blood. Urine and feces samples pooled over a period of 24?h exhibited 2.3–3.5% and 0.75–0.9% of HCQ, respectively, without any presence of intact prodrugs or NSAIDs. Prodrugs were pharmacologically evaluated for analgesic and anti-inflammatory activities using standard animal models. Among all, prodrugs of HCQ with licofelone (HL) and aceclofenac (HA) produced superior analgesia, improved weight gain, normalization of joint diameter/paw volume than HCQ and physical mixtures of HCQ and NSAIDs. Hematological and biochemical studies indicated significant step up in RBC, Hb, platelet count, total protein nutrient (TPN) levels and step down in WBC, serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) by the treatment with HL and HA. Through these novel codrugs, problems of slow onset and accumulation of HCQ in non-targeted sites and local gastric intolerance to NSAIDs were well addressed. These dual acting mutual prodrugs of two mechanistically different anti-arthritic agents could be explored further as promising strategy for effective management of RA.
High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine
Yu, Eric,Mangunuru, Hari P.R.,Telang, Nakul S.,Kong, Caleb J.,Verghese, Jenson,Gilliland, Stanley E.,Ahmad, Saeed,Dominey, Raymond N.,Gupton, B. Frank
, p. 583 - 592 (2018)
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.
Preparation method of hydroxychloroquine
-
Paragraph 0022; 0034-0039, (2021/05/05)
The invention relates to a preparation method of hydroxychloroquine, which comprises the following steps: protecting hydroxyl of 5-(N-ethyl-N-ethoxyl)-2-aminopentane through a silanization reagent, removing amino protons from tetrahydrofuran or toluene by using a bis(trimethylsilyl lithium amide) solution to form amino anions, and carrying out a substitution reaction with 4.7 dichloroquinoline to generate hydroxychloroquine. The hydroxychloroquine and sulfuric acid are salified in an alcoholic solution to generate hydroxychloroquine sulfate, and the hydroxychloroquine sulfate preparation method provided by the invention has the characteristics of low toxicity, low pollution, high purity, low reaction temperature, short reaction time, high yield and the like, and is suitable for industrialization.
Hydroxychloroquine sulfate and preparation method thereof
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Paragraph 0039-0041; 0044-0046; 0049-0051; 0054-0056; ..., (2021/07/31)
The invention discloses hydroxychloroquine sulfate and a preparation method thereof, and relates to the technical field of medicinal chemistry. The preparation method comprises the steps of mixing 4, 7-dichloroquinoline with a hydroxychloroquine side chain, carrying out heating condensation in the presence of an organic base catalyst, adding water and liquid, and carrying out cooling crystallization to obtain hydroxychloroquine; and dissolving hydroxychloroquine in an ethyl acetate and ethanol aqueous solution, heating, dissolving and clarifying, dropwise adding concentrated sulfuric acid, cooling, crystallizing, filtering and drying to obtain hydroxychloroquine sulfate. The method has the beneficial effects that a solvent-free reaction is used, and a catalyst is added, so that high pollution is avoided, the reaction process is accelerated, and the operation is simple; and meanwhile, the HPLC purity of the obtained hydroxychloroquine refined product is not less than 96.50%, the maximum single impurity content is less than 0.10%, the yield can reach 85%, the HPLC purity of hydroxychloroquine sulfate is not less than 98.00%, the maximum single impurity content is less than 0.10%, and the yield can reach 90%.
