Description
(–)-Levamisole (hydrochloride) (Item No. 14874) is an analytical reference material categorized as an imidazothiazole. It is used as a cutting agent with cocaine, and levamisole-adulterated cocaine has led to cutaneous vasculopathy in some individuals.
1,2,3 This product is intended for research and forensic applications.
Chemical Properties
White to almost white crystalline powder
Originator
Solaskil,Specia,France,1971
Uses
Biological response modifier with anthelmintic activity. Anthelmintic (nematodes); immunomodulator.
Definition
ChEBI: Levamisole hydrochloride is an organic molecular entity.
Preparation
Levamisole hydrochloride was prepared from racemic tetraimidazole by splitting, alkali analysis and acidification into salt.
Dibenzoyl-D-tartaric acid is boiled in water for 40min, hydrolyzed and neutralized with sodium hydroxide solution to pH 7.5, and then added to racemic tetraimidazole. The levamisole is precipitated by generating salt with bisbenzoyl-tartaric acid. After separation, add sodium hydroxide solution to PH=9 and decompose levamisole. Then dissolved in dilute hydrochloric acid solution, after decolorization by activated carbon, the filtrate was concentrated nearly dry, and crystallized by adding acetone and cooling to 0℃. Filtered and dried to obtain levamisole hydrochloride.
Manufacturing Process
To a stirred and refluxed suspension of 17 parts of 1,2-dibromoethane, 7.8
parts of sodium hydrogen carbonate and 50 parts of 2-propanol is added a
mixture of 3.4 parts of dl-2-thio-1-phenyl-imidazolidine, 9 parts of a 20%
potassium hydroxide solution in 40 parts of 2-propanol over a period of about
1 hour. After the addition is complete, the whole is stirred and refluxed for an
additional 3 hours. The reaction mixture is evaporated. To the residue are
added 18 parts of a 15% potassium hydroxide solution. The whole is extracted
with toluene. The extract is dried and evaporated. The oily residue is dissolved
in acetone and gaseous hydrogen chloride is introduced into the solution. The
precipitated solid salt is filtered off and recrystallized from 2-propanol, yielding
dl-2,3,5,6-tetrahydro-6-phenyl-imidazo[2,1-b]thiazole hydrochloride; melting
point 264°C to 266°C.
dl-6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole hydrochloride, 188 g
(0.785 mol), is suspended in a mixture of 500 ml of water and 500 ml of
methylene chloride. The suspension is stirred mechanically while 20% sodium
hydroxide solution is added until the solution is basic. Ice is added from time
to time to keep the temperature below the boiling point of the methylene
chloride. The methylene chloride layer is separated, washed with water, dried
over potassium carbonate and evaporated. The oily residue crystallizes with
the evolution of the heat when poured into a beaker containing 100 ml of
ether. The free base is washed with ether. The yield of dl-6-phenyl-2,3,5,6-
tetrahydroimidazo[2,-b]thiazole is 151.4 g (0.746 mol), 94%. The product has
a melting point of 90°C.
A solution of 204.3 g (1 mol) of dl-6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-
b]thiazole and 232.3 g (1 mol) of d-10-camphorsulfonic acid in 1,750 ml of
chloroform is allowed to crystallize overnight at -28°C. The solvate is
recovered by filtration and washed with ice cold chloroform (400 ml). The
solvate is dried (decomposed) under nitrogen 7 hours and then in air
overnight. The yield of d(+)6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole
d-10-camphorsulfonate is 202.5 g (0.464 mol) 92.8%, melting point 139°C to
140°C [α]D25+ 82.6 (C = 16, H2O).
A solution of 150 g (0.344 mol) of d(+)6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole, d-10-camphorsulfonate in water is treated with 15.5 g (0.378
mol) of 98% sodium hydroxide and the liberated base extracted with
chloroform. The chloroform solution is washed with water followed by sodium
chloride solution and dried over magnesium sulfate. Evaporation of the solvent
left 72.1 g of residue which crystallized shortly. The free base hereby obtained
has a melting point of 60°C to 61.5°C and an optical rotation [α]D25+ 85.1 (C
= 10, CHCl3).
The free base d(+)6-phenyl-2,3,5.6-tetrahydroimidazo[2.1-b]thiazole is
dissolved in 112 ml of acetone and 178 ml of isopropanolic hydrogen chloride
is added all at once. The hydrochloride crystallizes at once. After cooling to
below 0°C, the salt is recovered by filtration and washed with acetone. The
product weighs 75.2 g (0.312 mol), 91%, from the camphorsulfonate, melting
point 227°C to 227.5°C [α]D25+ 123.1 (C = 15, H2O).
Brand name
Ergamisol (Janssen);Vermisol.
Therapeutic Function
Antiinflammatory
General Description
Pharmaceutical secondary standards for application in quality control provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards
Biochem/physiol Actions
Shows both immunostimulant and immunosuppressant effects, depending on several controllable factors. Very effective in treatment of ascariasis (hookworm infestation). Useful in chemotherapy of colorectal cancers, possibly due to its stimulation of IL-1 production and direct activation of macrophages.
Pharmacokinetics
Levamisole Hydrochloride is the hydrochloride salt of the synthetic imidazothiazole derivative levamisole with anthelminthic and immunomodulating activities. In immunosuppressed states, levamisole may restore immune function by: 1) stimulating antibody formation, 2) stimulating T-cell activation and proliferation, 3) potentiating monocyte and macrophage phagocytosis and chemotaxis and 4) increasing neutrophil mobility, adherence, and chemotaxis.
Pharmacology
Levamisole Hydrochloride is the hydrochloride salt of the synthetic imidazothiazole derivative levamisole with anthelminthic and immunomodulating activities. In immunosuppressed states, levamisole may restore immune function by: 1) stimulating antibody formation, 2) stimulating T-cell activation and proliferation, 3) potentiating monocyte and macrophage phagocytosis and chemotaxis and 4) increasing neutrophil mobility, adherence, and chemotaxis.
Side effects
Levamisole hydrochloride oral side effects are dose-related, mild and transient. The most common side effects are fever and gastrointestinal symptoms. Other possible side effects include: rash, changes in taste and smell, granulocytopenia and/or leukopenia, arthralgia/myalgia, convulsions, failure, peripheral neuropathy, tachycardia, thrombocytopenia, vasculitis, and vertigo.
Synthesis
To a 1000 mL four-necked flask was added 50 g of (S)-6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole (L-tetramidazole) followed by 500 g of isopropanol. The mixture was heated until completely dissolved, then 0.5 g of activated carbon and 0.75 g of sodium bisulfite were added and the decolorization process was carried out with continuous stirring for 30 minutes. After completion of the reaction, the solid impurities were removed by filtration. Hydrogen chloride gas 9 g was passed into the filtrate to adjust the pH to 4-5. filtering again, the solid product was collected, i.e., (S)-6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole hydrochloride (levamisole hydrochloride), which was obtained after drying to give 54.3 g with a yield of 92.1 %. The resulting product was a colorless bulk solid with stable quality under long-term storage conditions.
Mode of action
Levamisole is a cholinergic receptor agonist and elicits spastic muscle paralysis due to prolonged activation of the excitatory nicotinic acetylcholine receptors (nAChR) on nematode body wall muscle.
Toxicity evaluation
Symptoms of levamisole toxicity mimic organophosphate toxicity (salivation, lacrimation, urination and defecation, hyperesthesia, seizures and irritability). There is no antidote for levamisole toxicity.
The World Health Organization reviewed hematological studies in animals and humans and derived acceptable daily intake for levamisole as 0.006 mg/kg body weight. This suggests a person can ingest 0.36 mg of levamisole/day over a lifetime without any appreciable risk.
levamisole
References
[1] Patent: CN104230959, 2016, B. Location in patent: Paragraph 0021; 0022
