- Atovaquone preparation method
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The invention provides an atovaquone preparation method, which comprises: carrying out condensation, hydrolysis and decarboxylation under the action of an alkali by using o-phthalic acid diester and 2-trans-[4-(4-chlorphenyl)]cyclohexyl succinic acid diester as raw materials to obtain 2-trans-[4-(4-chlorphenyl)]cyclohexyl-2,3-dihydro-1,4-naphthalenedione, carrying out a halogen substitution reaction on the 2-trans-[4-(4-chlorphenyl)]cyclohexyl-2,3-dihydro-1,4-naphthalenedione and a halogenating reagent to obtain a dihalogenated compound mixture, eliminating hydrogen halide to obtain 2-trans-[4-(4-chlorphenyl)]cyclohexyl-3-halo-1,4-naphthalenedione, and finally hydrolyzing to obtain atovaquone (I). According to the invention, the method has advantages of cheap and easily available raw materials, safe and simple process operation, low cost, little wastewater generation, safety, environmental protection, easily achieved reaction conditions, high reaction activity, high selectivity and fewside reactions, and the prepared atovaquone is few in impurity, high in purity and high in yield.
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- Late-Stage C-H Alkylation of Heterocycles and 1,4-Quinones via Oxidative Homolysis of 1,4-Dihydropyridines
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Under oxidative conditions, 1,4-dihydropyridines (DHPs) undergo a homolytic cleavage, forming exclusively a Csp3-centered radical that can engage in the C-H alkylation of heterocyclic bases and 1,4-quinones. DHPs are readily prepared from aldehydes, and considering that aldehydes normally require harsh reaction conditions to take part in such transformations, with mixtures of alkylated and acylated products often being obtained, this net decarbonylative alkylation approach becomes particularly useful. The present method takes place under mild reaction conditions and requires only persulfate as a stoichiometric oxidant, making the procedure suitable for the late-stage C-H alkylation of complex molecules. Notably, structurally complex pharmaceutical agents could be functionalized or prepared with this protocol, such as the antimalarial Atovaquone and antitheilerial Parvaquone, thus evidencing its applicability. Mechanistic studies revealed a likely radical chain process via the formation of a dearomatized intermediate, providing a deeper understanding of the factors governing the reactivity of these radical forebears.
- Gutiérrez-Bonet, álvaro,Remeur, Camille,Matsui, Jennifer K.,Molander, Gary A.
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supporting information
p. 12251 - 12258
(2017/09/12)
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- A single-pot synthesis of atovaquone: An antiparasitic drug of choice
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The present article relates to a practical, economically viable, and validated at industrial scale, single-pot synthetic route for preparation of atovaquone, one of the most versatile antiparasitic drugs of choice used for the prophylaxis and treatment of diseases such as pneumocystis, toxoplasmosis, babesiosis, coccidiosis, and malaria. However, owing to the extremely poor yields of synthesis and very high doses of treatment (due to poor bioavailability) the cost of treatment with this drug is not affordable by the patients in need, particularly in the third world countries where these diseases are most prevalent. Unlike most of the reported processes which use 2-chloronaphthoquinone and pure trans-4-chlorophenyl cyclohexane carboxylic acid, our process is based on the decarboxylative alkylation of isomeric mixture of 4-chlorophenyl cyclohexane carboxylic acid with 1,4-naphthoquinone to give 42% overall yield of atovaquone, 10 times higher than from the reported process (4%) from the innovators of this drug.
- Dike, Suneel Y.,Singh, Dharmendra,Thankachen, Byju N.,Sharma, Brajesh,Mathur, Pramil K.,Kore, Swapnil,Kumar, Ashok
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p. 618 - 625
(2014/06/09)
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- ''3-(5-METHYL-2-OXO-L, 3-DIOXOL-4-YL) METHYLOXY-2- TRANS-[(4-CHLORO PHENYL) CYCLOHEXYL] [1,4]NAPHTHAQUINONE -ATOVAQUONE PRODRUG
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The present invention relates to atovaquone prodrug compound of formula (I). Accordingly, present invention provides a process involving condensation of Atovaquone (II) with 5-methyl-4- chloromethyl dioxalone (III) in suitable solvent system and optionally followed by distillation and crystallization to provide Atovaquone prodrug compound of formula (I) in high yields, purity, and suitable for large-scale manufacture.
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Page/Page column 11; 12
(2013/07/05)
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- IMPROVED SYNTHESIS OF 2-(4-(4-CHLOROPHENYL) CYCLOHEX-1-ENYL) -3, 4-DIHYDRONAPHTHALEN-1 (2H)-ONE; AN INTERMEDIATE FOR ATOVAQUONE
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A process for preparation of 2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3,4-dihydronaphthalen- 1(2H)-one (V), key intermediate for synthesis of Atovaquone [I]. The process for preparation of compound(V) comprising of the steps of; i) Reaction of 2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-3,4-dihydronaphthalen- 1(2H)-one (IV) with trifluro acetic anhydride in presence of base in organic solvent to yield compound of formula (XIa) ii) Elimination of trifluoroacetyl functionality of compound (XIa) in organic solvent and in presence of organic base to give compound of formula (V). The invention also provides a Process for preparation of compound(XIa) comprising of the steps of; i) reaction of 2-(4-(4-chlorophenyl)-l-hydroxy cyclohexyl)-3,4-dihydronaphthalen- 1(2H)-one (IV) with trifluro acetic anhydride in presence of organic base in organic solvent. A further process is provided for preparation of compound(V) from compound (XIa) comprising elimination reaction of trifluoroacetyl functionality compound (XIa) in organic solvent and in presence of organic base.
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Page/Page column 27; 28
(2013/03/26)
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- NOVEL METHOD FOR PREPARATION OF ATOVAQUONE
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Provided is a process of preparation of 2-[trans,-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy- 1,4-naphthoquinone, i.e. Atovaquone [I] which is cost effective, green, and eco-friendly process, without separation of any diastereomers or geometric isomers of intermediates obtained during the reactions. Also provided is separation of 'cis' and 'trans ' isomer of intermediates VI, VII and VIII through selective crystallization in an appropriate solvent. A method for converting 2-[cis,-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone to 2-[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone in presence of Lewis/ Bronsted acid is also provided. A process for preparation of compound 2-(4-(4- chlorophenyl)- 1 -hydroxy cyclohexyl)-3,4-dihydronaphthalen- 1 (2H)-one [IV] comprising condensation of (1,2-dihydronaphthalen-4-yloxy)trimethylsilane [II] with 4-(4- chlorophenyl)cyclohexanone [III] in presence of Lewis acid in organic solvent. The invention also encompasses a highly efficient and atomeconomic process for synthesis of compound [III] i.e. 4-(4-chlorophenyl)cyclohexanone as well as a process for synthesis of 2-[cis-4-(4'- chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone. Further provided is a process for isomerization of cis- Atovaquone i.e. 2-[cis-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l,4- naphthoquinone to tnms-Atovaquone i.e. 2-[trans-4-(4'-chlorophenyl)cyclohexyl]-3- hydroxy- 1,4-naphthoquinone in presence of Lewis acid.
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Page/Page column 33
(2012/12/13)
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- Process for the preparation of trans-2,3-disubstituted naphthoquinones
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The invention concerns a new process for the preparation of naphthoquinones, in particular an improved process for the preparation of 2,3-disubstituted 1,4-naphthoquinones, in the trans configuration.
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Page/Page column 3
(2010/06/16)
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- PROCESS FOR THE EPIMERIZATION OF ATOVAQUONE ISOMER, ATOVAQUONE INTERMEDIATES AND MIXTURE THEREOF
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Provided is a process for the epimerization of the cis isomer of atovaquone, atovaquone intermediates and isomeric mixtures thereof into their corresponding trans-isomers resulting in higher yield of pure atovaquone.
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Page/Page column 11
(2010/04/03)
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- NOVEL CRYSTALLINE FORMS OF ATOVAQUONE
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The present invention relates to two novel and stable crystalline forms of atovaquone, to processes for their preparation and to pharmaceutical compositions comprising them. The present invention also provides crystalline particles of atovaquone having a specific surface area of from about 0.7 m2/g to about 4 m2/g, methods for the manufacture of said crystalline particles and pharmaceutical compositions comprising said crystalline particles. The present invention further provides an improved and commercially viable process for preparation of atovaquone substantially free of its undesired isomeric impurity, namely cis-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone.
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Page/Page column 5-6
(2010/06/22)
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- PREPARATION OF NAPHTHOQUINONE COMPOUNDS USING 2, 3-DIHALONAPTHOQUINONE
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The present invention relates the use of 2, 3-dihalonaphthoquinone compounds of Formula (I) wherein R1 and R2 are leaving groups like halogens selected from the group comprising Cl, Br, I and F and the R1 and R2 may be the same halogen or may contain different halogen groups, or sulphonyl groups, for making napthoquinone compounds of Formula (IA) wherein X is any aryl, heteroaryl, alkyl, cyclohexyl, substituted cylohexyl groups and the like.
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Page/Page column 25
(2009/10/30)
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- Medicaments for the treatment of toxoplasmosis
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The present invention relates to the use of 2-?4-(4-chlorophenyl)cyclohexyl!-3-hydroxy-1,4-naphthoquinone or a physiologically acceptable salt or other physiologically funtional derivative thereof for the manufacture of a medicament for the treatment and/or prophylaxis of toxoplasmosis in animals, to pharmaceutical compositions for the treatment and/or prophylaxis of toxoplasmosis, comprising said compound as active ingredient and to a method of treating or preventing toxoplasmosis in an animal which comprises administering to said animal an effective amount of said compound.
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- Synthesis of atovaquone
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A short synthesis of atovaquone I is achieved via the radical coupling of the trans-1,4-substituted cyclohexyl mono-oxalate 2 and 2- chloronapthoquinone under phase transfer conditions.
- Williams, David R.,Clark, Michael P.
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p. 7629 - 7632
(2007/10/03)
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- Method for treating animals infected with Babesia spp.
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The present invention relates to pharmaceutical compositions for the treatment and/or prophylaxis of protozoal infections caused by Kinetoplastida, Apicomplexa, Anaerobic protozoa and Mircosporidia comprising 2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone or a physiologically acceptable salt or other functional derivative thereof as active ingredient and to a method of treating or preventing siad protozoal infections in an animal which comprises administering to said animal an effective amount of siad compound.
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- Use of 2-(4-(4-chlorophenyl)cyclohexyl)-3-hydroxy-1,4-Naphthoquinone for the treatment of cancer
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The present invention relates to the use of 2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone or a physiologically acceptable salt or other physiologically functional derivative thereof for the manufacture of a medicament for the treatment of tumours in animals, to pharmaceutical compositions for the treatment of tumours in animals, to pharmaceutical compositions for the treatment of tumours, comprising said compound as active ingredient and to a method of treating tumours in an animal which comprises administering to said animal an effective amount of said compound.
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- Medicaments for the treatment of toxoplasmosis
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The present invention relates to the use of 2-[4-(4-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone or a physiologically acceptable salt or other physiologically funtional derivative thereof for the manufacture of a medicament for the treatment and/or prophylaxis of toxoplasmosis in animals, to pharmaceutical compositions for the treatment and/or prophylaxis of toxoplasmosis, comprising said compound as active ingredient and to a method of treating or preventing toxoplasmosis in an animal which comprises administering to said animal an effective amount of said compound.
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