55268-74-1 Usage
Pharmacology and mechanism of action
Praziquantel is a pyrazinoquinoline compound originally developed for the treatment of schistosomiasis but has been found to have a wide spectrum of anthelminthic activity. Praziquantel is a racemate but the R (+) enantiomer is solely responsible for its antiparasitic activity. It is active against trematodes (all Schistosoma species pathogenic to man, Paragonimus westermani, and Clonorchis sinensis) and cestodes (Taenia saginata, Taenia solium, Hymenolepis nana and Diphyllobothrium latum) 【1】. The mechanism of action of praziquantel is not clearly known. Schistosomes take up the drug rapidly. Drug uptake is immediately followed by increased muscular activity that proceeds to tetanic contraction and vacuolization of the parasite tegument 【2】. The muscular effects of the drug are presumed to be responsible for the shift of the parasites from the mesenteric veins to the liver in vivo. However, hepatic shift has been demonstrated with most known schistosomicides and may not provide any specific information of the drug’s mechanism of action. Recent experimental findings have suggested that the antischistosomal effects of the drug are related to its effect on the tegument rather than on the musculature 【3】. Another pharmacological effect of the drug includes an increase of membrane permeability to cations, particularly calcium 【4】. However, the role of this effect to the anthelminthic property of the drug is unknown.
Indications
Different sources of media describe the Indications of 55268-74-1 differently. You can refer to the following data:
1. Infections caused by Schistosoma species pathogenic to man (Schistosoma haematobium, S. mansoni, S. japonicum and S. mekongi). The drug is most cost-effective in mixed infections. It is also effective for infections with flukes (Paragonimus westermani and Clonorchis sinensis) and in cestodes (Hymenolepis nana, Diphyllobotrium latum, Taenia saginata, T. solium) including the larval stage of Taenia solium (cysticercosis).
Praziquantel has some effect against fascioliasis, but triclabendazole, a new anthelminthic drug still under clinical evaluation is more effective.
2. The neuromuscular effects of praziquantel (Biltricide)
appear to increase parasite motility leading to spastic
paralysis. The drug increases calcium permeability
through parasite-specific ion channels, so that the
tegmental and muscle cells of the parasite accumulate
calcium.This action is followed by vacuolization and the
exposure of hitherto masked tegmental antigens, lipidanchored
protein, and actin. Insertion of the drug into
the fluke’s lipid bilayer causes conformational changes,
rendering the fluke susceptible to antibody- and
complement-mediated assault.
Side effects
Different sources of media describe the Side effects of 55268-74-1 differently. You can refer to the following data:
1. In large-scale and community-based studies in patients and healthy volunteers, the drug showed only mild to moderate and transient side effects 【5—11】. The frequency and intensity of side effects seemed to be dose related. In one study【10】, the frequency of the side effects were: dizziness (29%), headache (15%), lassitude (19%), pain in the limbs (22%), and abdominal distress (9%). Nausea, insomnia, fever, and non-itching macular eruptions occurred in single patients. 40% of the patients remained free from any side effects. Abdominal colic and bloody diarrhoea due to praziquantel have been reported by others 【12, 13】. Praziquantel has not shown to be mutagenic or carcinogenic 【14, 15, 16】.
2. Very few side effects have been reported. In the treatment
of cerebral cysticercosis the death of cysts in the brain may
cause local inflammation and edema, but this usually subsides
quickly. Ocular cysticercosis should not be treated
with this drug, because parasite destruction in the eye can
lead to irreparable lesions. Adverse events seen in the treatment
of schistosomiasis, including abdominal pain, nausea,
anorexia, diarrhea and mild neurological effects, are almost
certainly due to the death and disintegration of the large
adult worms.
3. Adverse reactions tend to occur within a few hours of
administration. They include gastrointestinal intolerance
with nausea, vomiting, and abdominal discomfort. This
may be due to the liberation of helminth proteins from
dead worms rather than any direct effect of the drug.
Interactions
Phenytoin, carbamazepine, and dexamethasone have been reported to decrease the plasma concentrations of praziquantel by 10% to 50% 【17, 18】. The clinical relevance of these interactions for the treatment of parasitic infections needs further investigation.
Preparations
Biltricide? (Bayer). Tablets 600 mg.
Cysticide? (E.Merck). Tablets 500 mg.
Cesol? (E.Merck). Tablets 150 mg.
The treatment of schistosomiasis
Schistosomiasis is parasitic disease with both human and animal being prone to get infected. Schistosome has a relative complicated life history. Adult parasites live in the mesenteric vein and portal vein blood of people, cattle, pigs and some other mammals, and therefore humans and these animals are called as the adult host or definitive host.
Praziquantel is a kind of common drugs for treatment of schistosomiasis with an extremely small animal toxicity. After its oral administration, it is rapidly absorbed in the digestive tract. The time of the plasma concentration for reaching peaks: 5 minutes for mice, l5~30 minutes for rat, 30 to 120 minutes for dogs, and 2 h for sheep. After its absorption this drug is widely distributed in all tissues and organs; it is even able to penetrate through the blood-brain barrier of rats and can also enter into the bile of dogs. It can induce of influx of the Ca 2+ located outside of the schistosome parasite muscle cell membrane, and thus causing muscle contractures and loss of ability of sucking parasite location. At the same time, it also causes deficiency in sugar metabolism and energy metabolism, disrupting the "With immunization" state and then working together with the host immune system for finally eliminating the parasites. Therefore, it has good killing efficacy in treating China branch schistosomiasis, tapeworm, lung fluke, cysticercosis and also immature parasites (cercariae and miracidia).
The common side effects of praziquantel are as follows:
1. during the first 1 hour of medication of the first time: dizziness, headache, nausea, abdominal pain, diarrhea, fatigue, aching limbs can occur, usually at a lesser extent and short duration, and does not affect the treatment without specific treatment.
2. in a few cases, there may be symptoms such as heart palpitations, chest tightness, and T wave change and primary contraction in ECG; supraventricular tachycardia and atrial fibrillation can sometimes also happen.
3. in a few cases there may be a transient increase in transaminases and toxic hepatitis.
4. it sometimes can induce mental disorders and gastrointestinal bleeding.
5. hernia, allergic reactions (rash, asthma), etc. are also seen.
Chemical Properties
Different sources of media describe the Chemical Properties of 55268-74-1 differently. You can refer to the following data:
1. It is white or almost white crystalline powder; it is odorless with a slightly bitter taste. It also has hygroscopic effect. Solubility (g/100m1): 9.7 in ethanol, 56.7 in chloroform, and 0.04 in water. It is easily soluble in dimethyl sulfoxide (DMSO), but insoluble in ether. It has a melting point of 136~141 ℃. Acute toxicity LD50 in mice and rats (mg/kg): 2000~3000 oral administration,> 3,000 subcutaneously injection.
2. White Solid
Uses
Different sources of media describe the Uses of 55268-74-1 differently. You can refer to the following data:
1. It is a kind of broad-spectrum anti-parasitic disease drug. It can be used for the treatment and prevention of schistosomiasis, cysticercosis, paragonimiasis, hydatid disease, fasciolopsiasis, hydatid disease, and worm infection.
It can also be used as anthelmintic and is effective in treating animal gastrointestinal nematodes. It can be mixed in the feed for application.
The product is a kind of anthelmintic drug effective in treating Schistosoma japonicum, Schistosoma mansoni and Schistosoma haematobium, Clonorchis sinensis, Paragonimus westermani, fasciolopsis buski, tapeworms and cysticercosis. It has a especially strong killing effect on tapeworm and is currently of highest efficiency among anti-schistosomiasis drug.
It is a kind of anthelmintics drug mainly used for treating schistosomiasis. It can also used for treating Fahrenheit schistosomiasis, taeniasis, paragonimiasis, and cysticercosis
2. anthelmintic; EMBAY-8440
3. Anthelmintic, effective against flatworms.
4. Praziquantel is a potent anthelmintic used against schistosome and many cestode infestations. It is used to study voltage-gated Ca2+ channels and is a potential small molecule neurogenic.
Production method
There are a variety of synthetic routes (isoquinoline route, piperazine route, and phenethylamine route). Isoquinoline has advantages such as wide sources of initial raw material and low cost. Isoquinoline can be converted to 1-benzoyl-2-cyano-1,2-dihydro-isoquinoline through Reissetr reaction. It is further converted to 1-benzoyl-aminomethyl-1, 2, 3, 4-tetrahydroisoquinoline through pressurized hydrogenation. Then followed by cyclization with chloroacetyl chloride to give 2-benzoyl-1,3, 4,6,7,11b-hexahydro-2H-pyrazino[2,1-b]isoquinolin-4-ketone. Finally, apply phosphoric acid hydrolysis and perform condensation reaction with cyclohexanecarboxylic acid chloride to obtain the final product.
There are a variety of synthetic routes for industrial production including isoquinoline route, piperazine route, and phenethylamine route, among which the isoquinoline route is the best. In this route, first perform adduct reaction between isoquinoline and benzoyl chloride as well as potassium cyanide, further go through catalytic hydrogenation and rearrangement to generate 1-benzoyl-methyl-amino-1,2,3,4-tetrahydroisoquinoline, and then sequentially go through chlorine acetylation, cyclization, hydrolysis under increased pressure, and cyclohexanone acylation to generate the final product.
Take phenethylamine as the raw material, after acylation through chloroacetyl chloride, further introduce the amino group after adding terephthalamide potassium for amination reaction, then have cyclization reaction in the action of phosphorus oxychloride to give 3,4-dihydroisoquinoline derivative; further go through hydrogenation and hydrolysis to obtain 1-aminomethyl-tetrahydroquinoline; successively use cyclohexane carboxylic acid chloride and chloroacetyl chloride for acylation and finally go through dehydrochlorination and cyclization to obtain praziquantel.
You can alternatively use isoquinoline as raw material; it first go through Reissert reaction to introduce a cyano group in l position and have nitrogen benzoylated, followed by hydrogenation while benzoyl group is transferred to the amino group of the side chain, further introduce a chlorine acetyl group to the amino group on the ring, then successively go through cyclization, hydrolysis, cyclohexanone formylation to obtain praziquantel.
The above information is edited by the lookchem of Dai Xiongfeng.
Category
Toxic substances
Toxicity grading
Poisoning
Acute toxicity
Oral rat LD50; 2840 mg/kg; Oral-Mouse LD50: 2454 mg/kg.
Flammability and hazardous characteristics
Combustible; combustion produces toxic fumes of nitrogen oxides.
Storage Characteristics
ventilation, low-temperature, and drying.
Extinguishing agent
Dry powder, foam, sand, carbon dioxide, water spray.
References
1.Andrews P, Thomas H, Pohlke R, Seubert J. Praziquantel (1983). Med Res Rev, 3, 147–200.
2. Xiao SH, Friedman PA, Catto BA, Webster LT Jr (1984). Praziquantel induced vesicle formation in the tegument of male mansoni is calcium dependent. J Parasitol, 70, 177–179.
3. Xiao SH, Catto BA, Webster LT Jr, Melborn H, Becker B (1984). Effects of praziquantel on different developmental stages of Schistosoma mansoni in vitro and in vivo. J Infect Dis, 151, 1130–1137.
4. Pax R, Bennett JL, Fetterer R (1978). A benzodiazepine derivative and praziquantel: effects on musculature of Schistosoma mansoni and Schistosoma japonicum. Naunyn Schmiedebergs Arch Pharmacol, 304, 309–315.
5. Davis A, Biles JE, Ulrich AM, Dixon H (1981). Tolerance and efficacy of praziquantel in phase IIA and IIB therapeutic trials in Zambian patients. Arzneimittelforschung, 31, 568–574.
6. Davis A, Biles JE, Ulrich AM (1979). Initial experiences in patients with Schistosoma mansoni previously treated with oxamniquine and/or hycanthone: Resistance of Schistosoma mansoni to schistosomicidal agents. Trans R Soc Trop Med Hyg, 76, 652–659.
7. Pugh RNH, Teesdale CH (1983). Single dose oral treatment in urinary schistosomiasis: a double blind trial. BMJ, 286, 429–432.
8. Ishizaki T, Kamo E, Boehme K (1979). Double-blind studies of tolerance to Praziquantel in Japanese patients with Schistosoma japonicum infections. Bull WHO, 57, 787–791.
9. Santos AT, Bias BL, Nosenas JS, Portillo GP, Ortega OM, Hayashi M, Boehme K (1979). Preliminary clinical trials with praziquantel in Schistosoma japonicum infections in the Philippines. Bull WHO, 57, 793–799.
10. Zhejiang Clinical Cooperative Research Group for praziquantel (1980). Clinical evaluation of praziquantel in treatment of schistosomiasis japonica. A report of 181 cases. Chin Med J, 93, 375–384.
11. Katz N, Rocha RS, Chaves A (1979). Preliminary trial with praziquantel in human infections due to Schistosoma mansoni. Bull WHO, 57, 781–785.
12. Watt G, Baldovino P, Castro J, Fernando M, Ranoa C (1986). Bloody diarrhea after praziquantel therapy. Trans R Soc Trop Med Hyg, 80, 345–346.
13. Polderman AM, Gryseels B, Gerold JL, Mpamila K, Manshande JP (1984). Side effects of praziquantel in the treatment of Schistosoma mansoni in Maniema, Zaire. Trans R Soc Trop Med Hyg, 78, 752–754.
14. Frohberg H, Schulze Schenking M (1981). Toxicological profile of praziquantel a new drug against cestode and Schistosoma infections as compared to some other schistosomicides. Arzneimittelforschung, 31, 555–565.
15. Pütter J, Held H (1979). Quantitative studies on the occurrence of praziquantel in milk and plasma of lactating women. Eur J Drug Metab Pharmacokinet, 4, 193–198.
16. Billings PC, Heidelberger C (1982). Effects of praziquantel a new antischistosomicide drug on the mutation and transformation of mamalian cells. Cancer Res, 42, 2692–2696.
17. Bittencourt PRM, Gracia CM, Martins R, Fernandes AG, Diekmann HW, Jung W (1992). Phenytoin and carbamazepine decrease oral bioavailability of praziquantel. Neurology, 42, 492–496.
18. Vazquez M, Jung H, Sotelo J (1987). Plasma levels of praziquantel decrease when dexamethasone is given simultaneously. Neurology, 37, 1561–1562.
Originator
Cesol ,Merck ,W. Germany ,1980
Manufacturing Process
15 g of a nickel-aluminum alloy (1:1) is introduced in incremental portions and under agitation into 200 ml of 20% sodium hydroxide solution within 5 minutes; the mixture is maintained at 80°C for 45 minutes, then allowed to settle, decanted off, washed with water, and 1,000 ml of 1% (-)-tartaric acid solution is added thereto, adjusted to pH 5 with 1 N sodium hydroxide solution. The mixture is heated under agitation for 90 minutes to 80°C, decanted, and washed with water and methanol. The thus-obtained (-)tartaric acid-Raney nickel catalyst is added to a solution of 2cyclohexylcarbonyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino[2,1-a]isoquinoline. The reaction mixture is hydrogenated under normal pressure and at room temperature. After the catalyst has been filtered off and the solvent evaporated, 2-cyclohexylcarbonyl-4-oxo-1,2,3,6,7,11b-hexahydro-4Hpyrazino[2,1-a]isoquinoline, melting point 136°C to 138°C, is produced.
Brand name
Biltricide (Bayer).
Therapeutic Function
Anthelmintic
Acquired resistance
There is evidence that resistance to praziquantel is emerging
in schistosomes, although there is debate as to whether treatment
failures are due to resistance or innate tolerance.
Pharmaceutical Applications
A synthetic pyrazinoquinoline formulated for oral administration.
It is stable in the dry state, but hygroscopic.
Mechanism of action
Praziquantel is readily absorbed (80% in 24 hours)
after oral administration, with serum concentrations being
maximal in 1 to 3 hours; the drug has a half-life of
0.8 to 1.5 hours. Its bioavailability is reduced by phenytoin
or carbamazepine and increased by cimetidine.
Dexamethasone decreases plasma praziquantel levels
by 50%. Praziquantel is excreted by the kidneys.
Pharmacokinetics
Oral absorption: >80%
Cmax 50 mg/kg oral: 1 mg/L after 1–2 h
Plasma half-life: parent drug: 1–1.5 h
metabolites: 4–6h
Plasma protein binding: 80%
Praziquantel is rapidly absorbed when given orally, but it
undergoes extensive first-pass biotransformation and the concentration
of unchanged drug in plasma is low. The major
metabolite, a 4-hydroxy derivative, retains little to no antiparasitic
activity. About 80% of the oral dose, as parent drug
and its metabolites, is excreted in the urine by the fourth day
post-treatment, 90% of this in 24 h. A higher peak plasma
concentration is achieved in infected people, but other pharmacokinetic
values are unchanged.
Clinical Use
Different sources of media describe the Clinical Use of 55268-74-1 differently. You can refer to the following data:
1. 2-(Cyclohexylcarbonyl)-1,2,3,6,7, 11b-hexahydro-4Hpyrazino[2,1-a]isoquinolin-4-one (Biltricide) is a broadspectrumagent that is effective against various trematodes (flukes). It has become the agent of choice for the treatmentof infections caused by schistosomes (blood flukes).The drug also provides effective treatment for fasciolopsiasis(intestinal fluke), clonorchiasis (Chinese liver fluke),fascioliasis (sheep liver fluke), opisthorchosis (liver fluke),and paragonimiasis (lung fluke). Praziquantel increases cellmembrane permeability of susceptible worms, resulting inthe loss of extracellular calcium. Massive contractions andultimate paralysis of the fluke musculature occurs, followedby phagocytosis of the parasite.Following oral administration, about 80% of the doseis absorbed. Maximal plasma concentrations are achievedin 1 to 3 hours. The drug is rapidly metabolized in theliver in the first-pass. It is likely that some of the metabolitesare also active. Praziquantel occurs as a white crystallinesolid that is insoluble in water. It is available as600-mg film-coated tablets. The drug is generally welltolerated.
2. Praziquantel is an extremely active broad-spectrum
anthelmintic that is well tolerated. It is the most effective
of the drugs used in the treatment of schistosomiasis,
possessing activity against male and female adults
and immature stages. Unlike other agents, it is active
against all three major species (S. haematobium, S. mansoni,
and S. japonicum). In addition, it has activity
against other flukes, such as C. sinensis, Paragonimus
westermani, O. viverrini, and the tapeworms (D. latum,
H. nana, T. saginata, and T. solium). It is not as effective
against F. hepatica. It is used effectively in the treatment
of clonorchiasis and paragonimiasis and is an effective
alternative agent to niclosamide in the treatment of
tapeworm infestations.
3. Schistosomiasis
Other trematode infections (except F. hepatica)
Tapeworm infection, including cerebral cysticercosis
Treatment may need to be prolonged in cerebral cysticercosis.
Safety Profile
Poison by intraperitoneal route.Moderately toxic by ingestion and other routes. Humanmutation data reported. When heated to decomposition itemits toxic fumes of NOx.
Synthesis
Praziquantel, 2-(cyclcohexylcarbonyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino [2,1a]isoquinolin-4-one (38.1.15), is a derivative of pyrazinoquinoline that is made in two ways. According to one of them, 1-aminomethyl-1,2,3,4-tetrahydroisoquinoline is alkylated with chloroacetic acid, and then the resulting amine is acylated with cyclohexanecarbonyl chloride to make 1-(N-carboxymethyl-N-cyclohexylcarbonylaminomethyl)-1,2,3,4-tetra-hydroisoquinoline (38.1.14), which is heated at 150°C to give the desired praziquantel.
Another way of synthesizing this drug begins with isoquinoline, which is reacted with a mixture of cyclohexanecarbonyl chloride / potassium cyanide to make a dihydro derivative of isoquinoline (38.1.16). This is reduced by hydrogen over Raney nickel to give the reduction–reamidation product—the amide 1-(N-cyclohexylcarbonylaminomethyl)- 1,2,3,4-tetrahydroisoquinoline (38.1.17). Acylating this with chloracetic acid chloride gives a chlroacetyl derivative (38.1.18), which when heated in the presence of diethylamine results in an intramolecular alkylation, giving the desired product—prazi quantel.
Veterinary Drugs and Treatments
Praziquantel is indicated for (approved labeling) for the treatment
of Dipylidium caninum, Taenia pisiformis, and Echinococcus granulosis
in dogs, and Dipylidium caninum and Taenia taeniaeformis in
cats. Fasting is not required nor recommended before dosing. A
single dose is usually effective, but measures should be taken to prevent
reinfection, particularly against D. caninum. Praziquantel can
also be used for treating Alaria spp. in dogs and cats and Spirometra
mansonoides infections in cats.
Praziquantel has been used in birds and other animals, but it
is usually not economically feasible to use in large animals. In humans,
praziquantel is used for schistosomiasis, other trematodes
(lung, liver, intestinal flukes) and tapeworms. It is not routinely effective
in treating F. hepatica infections in humans.
Combination products can give a wide spectrum of internal
parasite control in a variety of species.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: concentration reduced by rifampicin
- avoid.
Antiepileptics: concentration reduced by
carbamazepine, fosphenytoin, phenobarbital,
phenytoin and primidone.
Antimalarials: concentration reduced by chloroquine.
Ulcer-healing drugs: concentration reduced by
cimetidine.
Metabolism
Praziquantel is rapidly absorbed and undergoes hepatic first-pass metabolism. The metabolites are
either less active or inactive and consist of hydroxylated compounds. In the serum, the major
metabolite appears to be the monohydroxylated 4-hydroxycyclohexylcarboxylate, whereas in the
urine, 50 to 60% of the initial PZQ exists as dihydroxylated products.These
hydroxylation reactions are catalyzed by CYP2B6 and CYP3A4. The metabolites would be
expected to exist in the conjugated form in the urine.
Check Digit Verification of cas no
The CAS Registry Mumber 55268-74-1 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 5,5,2,6 and 8 respectively; the second part has 2 digits, 7 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 55268-74:
(7*5)+(6*5)+(5*2)+(4*6)+(3*8)+(2*7)+(1*4)=141
141 % 10 = 1
So 55268-74-1 is a valid CAS Registry Number.
InChI:InChI=1/C19H24N2O2/c22-18-13-20(19(23)15-7-2-1-3-8-15)12-17-16-9-5-4-6-14(16)10-11-21(17)18/h4-6,9,15,17H,1-3,7-8,10-13H2
55268-74-1Relevant articles and documents
Preparation method of praziquantel
-
, (2022/03/27)
The invention relates to the technical field of medical intermediates, and provides a praziquantel preparation method which comprises the following steps: S1, adding isoquinoline, cyanide, tetrabutylammonium bromide and dichloroethane into a reactor, and dropwise adding benzoyl chloride for reaction to obtain a first-step product; s2, performing catalytic hydrogenation on the first-step product to obtain a second-step product; and S3, adding ethyl acetate into the second-step product, stirring and dissolving, adding sodium bicarbonate, dropwise adding chloroacetyl chloride, stirring and reacting to obtain a praziquantel crude product, and recrystallizing to obtain praziquantel. Through the technical scheme, the problems of long reaction process, high energy consumption and low yield in the prior art are solved.
A Nickel(II)-Mediated Thiocarbonylation Strategy for Carbon Isotope Labeling of Aliphatic Carboxamides
Pedersen, Simon S.,Donslund, Aske S.,Mikkelsen, Jesper H.,Bakholm, Oskar S.,Papp, Florian,Jensen, Kim B.,Gustafsson, Magnus B. F.,Skrydstrup, Troels
supporting information, p. 7114 - 7123 (2021/03/03)
A series of pharmaceutically relevant small molecules and biopharmaceuticals bearing aliphatic carboxamides have been successfully labeled with carbon-13. Key to the success of this novel carbon isotope labeling technique is the observation that 13C-labeled NiII-acyl complexes, formed from a 13CO insertion step with NiII-alkyl intermediates, rapidly react in less than one minute with 2,2’-dipyridyl disulfide to quantitatively form the corresponding 2-pyridyl thioesters. Either the use of 13C-SilaCOgen or 13C-COgen allows for the stoichiometric addition of isotopically labeled carbon monoxide. Subsequent one-pot acylation of a series of structurally diverse amines provides the desired 13C-labeled carboxamides in good yields. A single electron transfer pathway is proposed between the NiII-acyl complexes and the disulfide providing a reactive NiIII-acyl sulfide intermediate, which rapidly undergoes reductive elimination to the desired thioester. By further optimization of the reaction parameters, reaction times down to only 11 min were identified, opening up the possibility of exploring this chemistry for carbon-11 isotope labeling. Finally, this isotope labeling strategy could be adapted to the synthesis of 13C-labeled liraglutide and insulin degludec, representing two antidiabetic drugs.
Synthetic method of praziquantel
-
, (2020/05/08)
The invention provides a synthetic method of praziquantel. The method comprises the following steps: (1) subjecting beta-phenylethylamine and chloroacetyl chloride to an acylation reaction under an alkaline condition by adopting water as a solvent, then adding an amino compound shown as a formula I into the reaction mixture and reacting to obtain a compound shown as a formula II; (2) carrying outa cyclization reaction on the compound shown as the formula II under the action of a cyclizing agent, and reacting with cyclohexanecarbonyl chloride in an alkaline environment to obtain the praziquantel. The method has the advantages of low cost, mild reaction conditions, simple and controllable operation method, capability of avoiding the use of a large amount of organic solvents in the reactionprocess, greenness, environmental protection, good safety and stable product quality, and the obtained product meets the medicinal requirements.
Aza-Henry Reaction with Nitrones, an Under-Explored Transformation
Messire, Gatien,Massicot, Fabien,Vallée, Alexis,Vasse, Jean-Luc,Behr, Jean-Bernard
, p. 1659 - 1668 (2019/02/19)
Nitromethylation of nitrones occurred efficiently in CH3NO2 in the presence of tetramethylammonium fluoride or triazabicyclodecene as promoters. The obtained adducts might be conveniently transformed into vicinal diamines. The process was extended to nitroethane and nitropropane affording mixtures of syn and anti stereoisomers with low diastereoselectivity.
A preparation method of praziquantel (by machine translation)
-
, (2019/02/27)
The invention discloses a method for preparation of praziquantel, comprises the following steps: S1, β - phenethylamine with chloroacetyl chloride in a polar aprotic solvent, under alkaline compound to promote the acylation reaction is carried out, to produce intermediate I: 2 - chloro - N - (2 - phenyl-ethyl) - acetamide; S2, intermediate I in ethanolamine in the condensation reaction, an intermediate II: 2 - (2 - hydroxy - ethylamino) - N - phenethyl - acetamide; S3, using the intermediate II and TEMPO as raw materials, after oxidation is carried out after the cyclization reaction to prepare the intermediate III: 4 - carbon yl - 1, 2, 3, 6, 7, 11b - hexahydro - 4 H - pyrazinyl [2, 1 - a] isoquinoline; S4, the intermediate III with the cyclohexyl chloride in a polar aprotic solvent, a basic compound for promoting the next, react to generate the target product pqt. The preparation method has the raw materials are easy, the price is cheap; the process is simple, the production safety; high yield, low cost and the like. (by machine translation)
PREPARATION METHOD FOR PRAZIQUANTEL AND INTERMEDIATE COMPOUNDS THEREOF
-
, (2018/02/28)
Disclosed is a preparation method for praziquantel and intermediates thereof. The method includes: obtaining a target product praziquantel by using β-phenethylamine as an initial raw material through a condensation reaction with chloroacetyl chloride, a substitution reaction with ethanolamine, and an acylation reaction with cyclohexanecarbonyl chloride, followed by an oxidation reaction and cyclization reaction. Also disclosed are two key intermediates, namely, a compound of formula IV and a compound of formula V for preparing praziquantel. The preparation method is reasonable and simple in its technological design, uses moderate reaction conditions, and is economical and environmentally friendly. Additionally, the raw materials are inexpensive and easy to obtain, the key intermediates are easy to prepare, and the total reaction yield and purity of the obtained target compound praziquantel is high, so that industrialized mass production is easy to achieve.
A palladium-catalyzed intramolecular Heck/Hydrogenation approach towards the synthesis of praziquantel
Williams, Alfred L.,St. Hilaire, Valentine R.
, p. 6712 - 6717 (2017/10/25)
Starting from 3-methoxy N-acylpyrazinium salts, a new approach towards the synthesis of the antischistosomal drug praziquantel (PZQ) has been developed. Utilization of a palladium-catalyzed intramolecular Heck reaction to form dehydro-PZQ followed by a Hydrogenation step, in a stepwise or one-pot manner, allowed for the gram scale synthesis of PZQ in 4 or 5 steps and in good overall yields. This methodology proved to be well suited for generating the pyrazino[1,2-a] isoindole and pyrazino[1,2-a] benzazepine analogues of PZQ.
Br?nsted acid-mediated cyclization-dehydrosulfonylation/reduction sequences: An easy access to pyrazinoisoquinolines and pyridopyrazines
Rao, Ramana Sreenivasa,Ramanathan, Chinnasamy Ramaraj
, p. 428 - 440 (2017/03/14)
An efficient and alternative synthetic approach has been developed to prepare various N-(arylethyl)piperazine-2,6-diones from 4-benzenesulfonyliminodiacetic acid and primary amines using carbonyldiimidazole in the presence of a catalytic amount of DMAP at ambient temperature. Piperazine-2,6-diones are successfully transformed to pharmaceutically useful pyridopyrazines or pyrazinoisoquinolines and ene-diamides via an imide carbonyl group activation strategy using a Br?nsted acid. Subsequent dehydrosulfonylation reactions of the ene-diamides, in a one pot manner, smoothly transformed them to substituted pyrazinones. A concise synthesis of praziquantel (1) has also been achieved through this method.
A concise and highly efficient synthesis of praziquantel as an anthelmintic drug
Yang, Zhezhou,Zhang, Lin,Jiao, Huirong,Bao, Rusheng,Xu, Weiwei,Zhang, Fuli
, p. 1983 - 1993 (2016/11/26)
A concise and practical synthesis of praziquantel as anthelmintic drug is described. The key steps include a monoalkylation of ethanolamine for the preparation of 2-(2-hydroxyethylamino)-N-phenethylacetamide and a mild oxidation protocol with SO3-Py/DMSO as oxidant to transform alcohol into the corresponding aza-acetal. The telescoped synthesis is composed of five steps without purification of the intermediates, providing an overall yield of 80% with 99.8% purity after crystallization.
Praziquantel synthetic technology
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, (2016/11/28)
The invention discloses a praziquantel synthetic technology; beta-phenylethylamine, amino acetyl halide hydrochloride, halogenated acetaldehyde alcohol and cyclohexyl formyl chloride are used as raw materials and subjected to condensation, cyclization and acylation to synthesize praziquantel. The method has the advantages of cheap and easily available raw materials, low toxicity, safe production and simple process; amino acetyl halide hydrochloride and beta-phenylethylamine are condensed, the activity is moderate and the yield is relatively high; with reaction of halogenated aldehyde alcohol and an intermediate A, because halogen of halogenated aldehyde alcohol is easy to remove, the reaction is easy to implement, and the yield is favorable to improve; secondly, the synthetic technology has the advantages of mild synthetic reaction conditions, atmospheric pressure operation, safe operation and concise synthetic steps, and the total yield can be more than 50%; and the synthetic process has less waste emissions, pollution is low, the technology is a clean and highly efficient synthetic technology, and the production cost can be reduced by about 30%.
