- Preparation method of praziquantel
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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.
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- A Nickel(II)-Mediated Thiocarbonylation Strategy for Carbon Isotope Labeling of Aliphatic Carboxamides
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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.
- Pedersen, Simon S.,Donslund, Aske S.,Mikkelsen, Jesper H.,Bakholm, Oskar S.,Papp, Florian,Jensen, Kim B.,Gustafsson, Magnus B. F.,Skrydstrup, Troels
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supporting information
p. 7114 - 7123
(2021/03/03)
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- Synthetic method of praziquantel
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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.
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Paragraph 0084-0086; 0089-0090; 0098-0099
(2020/05/08)
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- Aza-Henry Reaction with Nitrones, an Under-Explored Transformation
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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.
- Messire, Gatien,Massicot, Fabien,Vallée, Alexis,Vasse, Jean-Luc,Behr, Jean-Bernard
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p. 1659 - 1668
(2019/02/19)
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- A preparation method of praziquantel (by machine translation)
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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)
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-
Paragraph 0028; 0036; 0037
(2019/02/27)
-
- PREPARATION METHOD FOR PRAZIQUANTEL AND INTERMEDIATE COMPOUNDS THEREOF
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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.
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Paragraph 0084-0085
(2018/02/28)
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- A palladium-catalyzed intramolecular Heck/Hydrogenation approach towards the synthesis of praziquantel
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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.
- Williams, Alfred L.,St. Hilaire, Valentine R.
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p. 6712 - 6717
(2017/10/25)
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- Br?nsted acid-mediated cyclization-dehydrosulfonylation/reduction sequences: An easy access to pyrazinoisoquinolines and pyridopyrazines
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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.
- Rao, Ramana Sreenivasa,Ramanathan, Chinnasamy Ramaraj
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p. 428 - 440
(2017/03/14)
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- Approach to Isoindolinones, Isoquinolinones, and THIQs via Lewis Acid-Catalyzed Domino Strecker-Lactamization/Alkylations
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A one-pot, three-component synthesis of widely substituted isoindolinones and isoquinolinones, featuring a Lewis acid-catalyzed efficient Strecker reaction and lactamization sequence, affording products in good to high yields is reported. The method has also been extended to the synthesis of tetrahydroisoquinolines (THIQs) in high yields. (Chemical Equation Presented).
- Dhanasekaran, Sivasankaran,Suneja, Arun,Bisai, Vishnumaya,Singh, Vinod K.
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p. 634 - 637
(2016/03/01)
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- Praziquantel synthetic technology
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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%.
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Paragraph 0011
(2016/11/28)
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- A concise and highly efficient synthesis of praziquantel as an anthelmintic drug
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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.
- Yang, Zhezhou,Zhang, Lin,Jiao, Huirong,Bao, Rusheng,Xu, Weiwei,Zhang, Fuli
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p. 1983 - 1993
(2016/11/26)
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- Preparation method for praziquantel
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The invention discloses a preparation method for praziquantel. The method has a reaction route as described in the specification, wherein R1 is selected from the group consisting of C1-C4 alkanes. According to the invention, the purpose of synthesis of high-purity praziquantel from cheap and easily-available raw materials and with simple operation, mild reaction conditions, low toxicity, low hazard and low cost is realized; industrial production requirements are met; and significant application values are obtained.
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Paragraph 0047-0049
(2017/01/05)
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- METHOD FOR THE PRODUCTION OF PRAZIQUANTEL
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The present invention relates to a method for the racemization of enantiomerically pure or enantiomerically enriched Praziquantel under basic conditions and a method for the production of (R)-Praziquantel in enantiopure or enantiomerically enriched form, which comprises the racemization method.
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-
Page/Page column 9-10
(2016/06/21)
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- METHOD FOR PREPARING (R)-PRAZIQUANTEL
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The invention relates to a new method for preparing (R)-praziquantel. In the invention, by taking advantage of the high stereo selectivity, site selectivity and region selectivity of an enzyme, an intermediate of a pure optical and chiral (R)-praziquantel are obtained by means of the dynamic kinetic resolution of an enantiomer from the synthesized racemate or derivatives thereof, and the (R)-praziquantel is obtained by using various conventional and mature organic chemical reactions with higher yield. The method of the invention has the potential advantages of easily available raw materials, low cost, environmentally safer process and convenience for large-scale production. Also, the purity of the end product can be more than 98%. By adopting the invention, the quality of the product is improved and a basis for developing high quality of active pharmaceutical ingredients and formulations is established, and thus the pending industrial problem of purifying praziquantel over 30 years becomes solvable.
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Page/Page column
(2015/01/06)
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- METHOD FOR PREPARING (R)-PRAZIQUANTEL
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The invention relates to a new method for preparing (R)-praziquantel. In the invention, by taking advantage of the high stereo selectivity, site selectivity and region selectivity of an enzyme, an intermediate of a pure optical and chiral (R)-praziquantel are obtained by means of the dynamic kinetic resolution of an enantiomer from the synthesized racemate or derivatives thereof, and the (R)-praziquantel is obtained by using various conventional and mature organic chemical reactions with higher yield. The method of the invention has the potential advantages of easily available raw materials, low cost, environmentally safer process and convenience for large-scale production. Also, the purity of the end product can be more than 98%. By adopting the invention, the quality of the product is improved and a basis for developing high quality of active pharmaceutical ingredients and formulations is established, and thus the pending industrial problem of purifying praziquantel over 30 years becomes solvable.
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Page/Page column
(2015/01/06)
-
- Synthesis and SAR studies of praziquantel derivatives with activity against Schistosoma japonicum
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The synthesis and structure-activity relationship (SAR) studies of praziquantel derivatives with activity against adult Schistosoma japonicum are described. Several of them showed better worm killing activity than praziquantel and could serve as leads for further optimization.
- Wang, Wen-Long,Song, Li-Jun,Chen, Xia,Yin, Xu-Ren,Fan, Wen-Hua,Wang, Gu-Ping,Yu, Chuan-Xin,Feng, Bainian
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p. 9163 - 9178
(2013/09/23)
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- PROCESS FOR THE PREPARATION OF PRAZIQUANTEL
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The present disclosure describes a novel, cost-effective process for preparation of a 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino-[2,1-a]isoquinoline derivatives. Specifically, it discloses a process for the preparation of the anthelmintic drug praziquantel through the use of a novel intermediate, 2-[(2,2-dimethoxyethyl)benzyl amino]-N-phenethylacetamide. This present disclosure also describes a novel crystalline form of 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.
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-
Paragraph 0059; 0060
(2013/11/06)
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- Enhancing the usefulness of cross dehydrogenative coupling reactions with a removable protecting group
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A removable protecting group has been identified that allows the products of widely-used cross dehydrogenative couplings to be synthetically elaborated. The method can be used with enantiopure amines with no loss of enantiomeric excess. The methodology is exemplified by a new synthesis of enantiopure praziquantel, the drug used in the treatment of millions of people suffering from the neglected tropical disease, schistosomiasis.
- Tsang, Althea S.-K.,Ingram, Katrin,Keiser, Jennifer,Hibbert, D. Brynn,Todd, Matthew H.
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supporting information
p. 4921 - 4924
(2013/08/23)
-
- Synthesis of new praziquantel analogues: Potential candidates for the treatment of schistosomiasis
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An efficient synthesis of antischistosomal drug praziquantel and analogues was achieved and the synthetic route designed was to afford structurally diverse analogues for better structure-activity relationship understanding. Total of nineteen PZQ analogues with structural variations at amide, piperazine and aromatic moieties have been synthesized and fully characterized. Among all the new analogues tested for antischistosomal activity, one dimethoxy tetrahydroisoquinoline analogue and two tetrahydro-β-carboline analogues exhibited moderate activity against adult Schistosoma mansoni. Tetrahydro-β-carboline analogues showed moderate activity whereas the presence of p-trifluoromethylbenzoyl and p-toluenesulphonyl moieties resulted in complete suppression of antischistosomal activity.
- Sadhu, Partha Sarathi,Kumar, Singam Naveen,Chandrasekharam, Malapaka,Pica-Mattoccia, Livia,Cioli, Donato,Rao, Vaidya Jayathirtha
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supporting information; experimental part
p. 1103 - 1106
(2012/03/11)
-
- Efficient multicomponent reaction synthesis of the schistosomiasis drug praziquantel
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Shorter than ever: A convergent, efficient, and scalable access based on a key Ugi four-component reaction (4CR) followed by a Pictet-Spengler reaction comprises the shortest known synthesis to the schistosomiasis drug praziquantel (see scheme).
- Cao, Haiping,Liu, Haixia,Doemling, Alexander
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experimental part
p. 12296 - 12298
(2011/02/25)
-
- Solid phase synthesis of praziquantel
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The first solid phase synthesis of the important anthelmintic praziquantel is described. The synthesis is rapid and efficient. The method may be extended to the synthesis of libraries of urgently needed replacements for this drug.
- El-Fayyoumy, Shaimaa,Mansour, Wafaa,Todd, Matthew H.
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p. 1287 - 1290
(2007/10/03)
-
- Amino acid derived heterocycles: Lewis acid catalyzed and radical cyclizations from peptide acetals
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Bicyclization of peptide acetals via nucleophilic attack of a phenyl group on an endocyclic acyliminium ion 4 was explored as a route to novel amino acid derived heterocycles and peptidomimetic scaffolds. In the presence of protic acid, bridged structures such as 6 are formed readily from phenylalanine derivatives, but the fused-ring analogues 5 could not be obtained in good yield. In contrast, radical cyclization of the bromophenyl dihydropyrazinone 7 provides an effective alternative for the synthesis of 5 (n = 0, 1, 2). Additional versatility in this process was demonstrated by efficient synthesis of a different fused ring system, represented by the antihelmintic praziquantel, 8.
- Todd, Matthew H.,Ndubaku, Chudi,Bartlett, Paul A.
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p. 3985 - 3988
(2007/10/03)
-
- Synthesis of praziquantel via N-acyliminium ion cyclization of amtoo acetals through several synthetic routes
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Syntheses of praziquantel have been accomplished via an N-acyliminium ion by several routes including the tandem nucleophilic addition-cyclization sequence from amido acetal (8) or (10) and a stepwise cyclization of enamide (9) generated from the nucleophilic addition reaction of amido acetal (8) or (10).
- Kim, Joong Hyup,Lee, Yong Sup,Kim, Choong Sup
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p. 2279 - 2285
(2007/10/03)
-
- Formation of pyrazinoisoquinoline ring system by the tandem amidoalkylation and N-acyliminium ion cyclization: An efficient synthesis of Praziquantel
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An efficient synthesis of pyrazinoisoquinoline derivatives including Praziquantel has been accomplished by the tandem amidoalkylaion and N- acyliminium ion cyclization of amido-acetals.
- Kim, Joong Hyup,Lee, Yong Sup,Park, Hokoon,Kim, Choong Sup
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p. 7395 - 7400
(2007/10/03)
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- A NEW SYNTHESIS 2-ACYL-1,2,3,6,7,11b-HEXAHYDROPYRAZINOISOQUINOLIN-4-ONES BASED ON N-CYANOMETHYL DERIVATIVES OF 2-PHENYL-ETHYLAMIDES OF ACYLGLYCINES
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A new route for the synthesis of 2-acyl-1,2,3,6,7,11b-hexahydropyrazinoisoquinolin-4-ones has been studied which includes a stage in which substituted piperazinones are obtained by reductive cyclization of N-cyanomethyl derivatives of 2-phenylethylamides of acylglycines under influence of Raney alloy in formic acid.
- Shekhter, O. V.,Kuklenkova, O. B.,Sergovskaya, N. L.,Tsizin, Yu. S.
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p. 170 - 173
(2007/10/02)
-
- USE OF INTERPHASE CATALYSIS IN THE SYNTHESIS OF 2-ACYL-4-OXOPYRAZINOISOQUINOLINES AND 4-ACYL-2-PIPERAZINONES
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2-acetyl-4-oxopyrazinoisoquinolines and 4-acyl-2-piperazinones have been synthesized, with interphase catalysis, by the intramolecular N-alkylation of the corresponding diamides.
- Sergovskaya, N. L.,Chernyak, S. A.,Shekhter, O. V.,Tsizin, Yu. S.
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p. 888 - 891
(2007/10/02)
-
- Process for the production of (±)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline derivatives
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This invention discloses a process for the preparation of (±)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline derivatives which comprises conducting an intramolecular cyclization reaction of the compounds of formulas II III in an acid medium. STR1
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- 4-Acyl-2,6-dioxo-1-phenethyl piperozines
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2-Acyl-1,3,4,6,7,11b-hexahydro-2H-pyrazino-[2,1-a]-4-isoquinoleinones having anthelmintic activity of the formula STR1 are prepared from 4-acyl-2,6-dioxopierazines by reaction with a phenethyl halide, selective reduction of one of the oxo groups and cyclization, by the novel intermediates of formula STR2 in which Y represents O or H, OH.
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- NEW SYNTHESES OF PRAZIQUANTEL : 2-(CYCLOHEXYLCARBONYL)-1,2,3,6,7,11b-HEXAHYDRO-4H-PYRAZINOISOQUINOLIN-4-ONE
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This paper describes two different synthetic pathways for praziquantel, a new broad spectrum schistosomicide and cestocide.Easy to apply on an industrial scale, they involve a selective reduction of 4-acyl-1-phenethylpiperazine-2,6-dione in 4-acyl-6-hydroxy-1-phenethylpiperazin-2-one, the cyclisation of wchich in acetic medium gives tricyclic compounds 2-acyl-1,2,3,6,7,11b-hexahydro-4H-pyrazinisoquinolin-4-one.
- Frehel, Daniel,Maffrand, Jean-Pierre
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p. 1731 - 1735
(2007/10/02)
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- Process for preparing (1-acylaminomethyl)-1,2,3,4-tetrahydroisoquinolines
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Novel tetrahydroquinolines of the formula STR1 wherein R is cycloalkyl or cycloalkenyl each containing 4-7 ring carbon atoms and the cycloalkyl optionally being substituted by one of methyl, hydroxyl or oxo; phenyl substituted by 1-2 of amino, acylamino of up to 4 carbon atoms, Hal, hydroxyl, methoxy or nitro, wherein Hal is fluorine, chlorine, bromine or iodine; thienyl; pyridyl; tetrahydropyranyl; tetrahydrothiopyranyl; and when at least one of R2, R3, R4, R5 or R6 is other than H, also phenyl; R2, R3 and R4 each are H or methyl; R5 and R6 each are H, methyl or methoxy; R7 is H or --CO--CH2 --X wherein X is chlorine, bromine or iodine; the acid addition salts thereof; which compounds are useful as antihelmintics and as intermediates for the production of 2-acyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino-[2,1-a]isoquinoline derivatives; and the corresponding compounds wherein R is alkyl of 1-6 carbon atoms, phenyl substituted by three of the substituents named above, and phenyl when all of R2, R3, R4, R5 and R6 are H; are produced by acylating the corresponding 1-aminomethyl-1,2,3,4-tetrahydroisoquinoline wherein R7 is H, and optionally thereafter reducing the R group and/or reacting the ring nitrogen atom with an acylating group.
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