- Ester prodrugs of acyclic nucleoside thiophosphonates compared to phosphonates: Synthesis, antiviral activity and decomposition study
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9-[2-(Thiophosphonomethoxy)ethyl]adenine [S-PMEA, 8] and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine [S-PMPA, 9] are acyclic nucleoside thiophosphonates we described recently that display the same antiviral spectrum (DNA viruses) as approved and potent phosphonates PMEA and (R)-PMPA. Here, we describe the synthesis, antiviral activities in infected cell cultures and decomposition study of bis(pivaloyloxymethoxy)-S-PMEA [Bis-POM-S-PMEA, 13] and bis(isopropyloxymethylcarbonyl)-S-PMPA [Bis-POC-S-PMPA, 14] as orally bioavailable prodrugs of the S-PMEA 8 and S-PMPA 9, in comparison to the equivalent "non-thio" derivatives [Bis-POM-PMEA, 11] and [Bis-POC-PMPA, 12]. Compounds 11, 12, 13 and 14 were evaluated for their in vitro antiviral activity against HIV-1-, HIV-2-, HBV- and a broad panel of DNA viruses, and found to exhibit moderate to potent antiviral activity. In order to determine the decomposition pathway of the prodrugs 11, 12, 13 and 14 into parent compounds PMEA, PMPA, 8 and 9, kinetic data and decomposition pathways in several media are presented. As expected, bis-POM-S-PMEA 13 and bis-POC-S-PMPA 14 behaved as prodrugs of S-PMEA 8 and S-PMPA 9. However, thiophosphonates 8 and 9 were released very smoothly in cell extracts, in contrast to the release of PMEA and PMPA from "non-thio" prodrugs 11 and 12.
- Roux, Lo?c,Priet, Stéphane,Payrot, Nadine,Weck, Clément,Fournier, Ma?lenn,Zoulim, Fabien,Balzarini, Jan,Canard, Bruno,Alvarez, Karine
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- Synthesis, in vitro antiviral evaluation, and stability studies of novel α-borano-nucleotide analogues of 9-[2-(phosphonomethoxy)ethyl]adenine and (R)-9-[2-(phosphonomethoxy)propyl]adenine
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We describe here the synthesis of 9-[2-(Boranophosphonomethoxy)ethyl] adenine (6a) and (R)-9-[2-(Boranophosphonomethoxy)propyl]adenine (6b), the first α-boranophosphonate nucleosides in which a borane (BH3) group substitutes one nonbridging oxygen atom of the α-phosphonate moiety. H-phosphinates 5a and 5b and α-boranophosphonates 6a and 6b were evaluated for their in vitro activity against human immunodeficiency virus (HIV) infected cells and against a panel of DNA or RNA viruses. Compounds 5a, 5b, 6a, and 6b exhibited no significant antiviral activity in vitro and cytotoxicity. To measure the chemical and enzymatic stabilities of the target compounds 6a and 6b, kinetic data of decomposition for derivatives 5a, 5b, 6a, 6b, and standard compounds were studied at 37 °C in several media. The α- Boranophosphonates 6a and 6b were metabolized in culture medium into H-phosphinates 5a and 5b, with half-live values of 5.3 h for 6a and 1.3 h for 6b.
- Barral, Karine,Priet, Stéphane,Sire, Joséphine,Neyts, Johan,Balzarini, Jan,Canard, Bruno,Alvarez, Karine
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- Process optimization in the synthesis of 9-[2-(diethylphosphonomethoxy)ethyl]adenine: replacement of sodium hydride with sodium tert-butoxide as the base for oxygen alkylation
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9-[2-(Diethylphosphonomethoxy)ethyl]adenine (diethyl-PMEA), a key intermediate in the production of the antiviral drug adefovir dipivoxil, was originally produced via a process utilizing sodium hydride (NaH) to couple hydroxyethyl adenine with diethyl p-toluenesulfonyloxymethanephosphonate. The use of NaH presented safety and consistency problems. It was found that sodium tert-butoxide (NaOBu) was a suitable replacement for NaH as the base to effect the coupling reaction. Optimization of reagent stoichiometry and introduction of a simplified filtration workup procedure led to a robust process affording diethyl-PMEA in consistent yields and purities. The modifications and process improvements were scaled-up successfully to batch sizes of >100 kg.
- Richard,Schultze, Lisa M.,Rohloff, John C.,Dudzinski, Pawel W.,Kelly, Daphne E.
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- Preparation method of nucleoside phosphate prodrug
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The invention belongs to the field of pharmaceutical chemicals, and relates to a preparation method of a nucleoside phosphate prodrug. A diphenol phosphate intermediate A and an alcohol compound B are subjected to a transesterification reaction to obtain the nucleoside phosphate prodrug. According to the method, rapid synthesis of different nucleoside prodrugs is achieved through exchange of the base-catalyzed nucleoside diphenyl phosphate intermediate and alcohol, synthesis of a target compound is achieved through one-step reaction, meanwhile, use of strong acid and high-toxicity chlorides is avoided, the safety of generation can be improved, the cost is reduced, and emission of three wastes is reduced.
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Paragraph 0019-0020
(2022/01/12)
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- An improved synthesis of adefovir and related analogues
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An improved synthesis of the antiviral drug adefovir is presented. Problems associated with current routes to adefovir include capricious yields and a reliance on problematic reagents and solvents, such as magnesium tert-butoxide and DMF, to achieve high conversions to the target. A systematic study within our laboratory led to the identification of an iodide reagent which affords higher yields than previous approaches and allows for reactions to be conducted up to 10 g in scale under milder conditions. The use of a novel tetrabutylammonium salt of adenine facilitates alkylations in solvents other than DMF. Additionally, we have investigated how regioselectivity is affected by the substitution pattern of the nucleobase. Finally, this chemistry was successfully applied to the synthesis of several new adefovir analogues, highlighting the versatility of our approach.
- Jones, David J.,O’Leary, Eileen M.,O’Sullivan, Timothy P.
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supporting information
p. 801 - 810
(2019/04/17)
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- Synthetic method of adefovir dipivoxil
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The invention relates to the field of chemical pharmaceuticals, in particular to an industrial production and synthesis process of an adefovir dipivoxil bulk drug. 9-(2-hydroxyethyl)-adenine and diethyl p-toluenesulfonyloxymethyl phosphate serve as raw materials, and under the action of a catalyst, adefovir dipivoxil is produced through esterification, desalination and hydrolysis. The adefovir dipivoxil is subjected to acid and alkali refining, then condensed with chloromethyl valerate, then separated and purified to obtain adefovir divalentyl oxymethyl ester raw materials. The synthetic process is an industrialized production process, the operation is simple, adefovir dipivoxil is suitable for large-scale production, and the production cost can be greatly reduced.
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Page/Page column 5-8
(2019/09/05)
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- Preparation method of adefovir dipivoxil crystals
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The invention belongs to the technical field of drug preparation and in particular relates to a preparation method of adefovir dipivoxil crystals. The preparation method comprises the following steps: synthesizing diethyl phosphite; synthesizing diethyl (p-phenylsulfonyloxy)methylphosphonate; synthesizing 9-(2-hydroxyethyl) adenine; synthesizing 4,9-[2-(diethylphosphonomethoxy)ethyl]adenine; synthesizing adefovir; synthesizing adefovir dipivoxil. Compared with the prior art, the preparation method of the adefovir dipivoxil crystals, provided by the invention, takes acetonitrile as a water-soluble organic medium, and the difficulty that DMF (Dimethyl Formamide) is difficult to remove is overcome; ethyl acetate is used for replacing isopropyl acetate in a previous process, isopropyl ether is used for replacing ethyl ether and ethanol is used for replacing acetone; the preparation method is simple to operate; the obtained product has good purity and high yield; the industrialized production is easy to realize and the production cost is reduced.
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- A method for preparation of adefovir dipivoxil
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The present invention discloses an adefovir dipivoxil preparation method, which comprises the following steps represented in the instruction. According to the present invention, base on the research of the existing adefovir dipivoxil synthesis route, the new synthesis route of 9-(2-hydroxyethyl)adenine is designed so as to provide the new method and the new idea for the synthesis of the drug adefovir dipivoxil, and provide help for the future drug development and production.
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- Adefovir dipivoxil a hydrate and its preparation method (by machine translation)
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Adefovir dipivoxil this invention relates to a method for preparing a hydrate thereof, with an aqueous acetone as the solvent, can be obtained by the freeze-drying of a water composition of adefovir dipivoxil freeze-dried powder. The method is simple and convenient to operate, can selectively obtain a hydrate, high product yield, purity is good, is very suitable for large-scale production. (by machine translation)
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Paragraph 0029-0031
(2017/02/09)
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- PROCESS FOR THE PREPARATION OF ADEFOVIR DIPIVOXIL
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An improved process for the preparation of adefovir dipivoxil and its pharmaceutically acceptable salts or solvates comprises the condensation of adefovir with chloro methyl pivalate in a mixture of two or more solvents in the presence of a base and isolating the resulting adefovir dipivoxil.
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Page/Page column 3
(2012/09/25)
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- PMEA LIPID CONJUGATES
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The present invention relates to PMEA lipid conjugates and to methods of using the conjugates to treat diseases caused by viruses such as herpes, cytomegalovirus, varicella, paramyxovirus, polyoma virus, and human papillomavirus. Methods for making the PMEA lipid conjugates are also provided.
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Page/Page column 30-31
(2009/01/24)
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- NOVEL NUCLEOTIDE ANALOGUES AS PERCURSOR MOLECULES FOR ANTIVIRALS
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This invention relates to a purine or pyrimidine phosphonate compound of formula (I) or pharmaceutically acceptable salt thereof; wherein B, X, and R1-R3 are as defined in classes and subclasses herein. These compounds may be used as antiviral precursors. The invention also relates to therapeutic compositions of these compounds and their use for the preparation of a medication for treating and/or preventing a viral infection in a patient. The invention also provides methods for making these compounds. In particular, the invention provides an H- phosphinate precursor intermediate of formula (II) wherein B is a purine or pyrimidine base as defined herein and R1 is selected from the group comprising a hydrogen atom, and a methyl, ethyl, hydroxymethyl, hydroxyethyl and C1-6haloalkyl group.
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Page/Page column 69-70; 72-73; 81
(2008/12/05)
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- Process for preparation of cyclic prodrugs of PMEA and PMPA
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The method of preparing compounds of Formula I is described: wherein: M and V are cis to one another and MPO3H2 is a phosphonic acid selected from the group consisting of 9-(2-phosphonylmethoxyethyl)adenine, and (R)-9-(2-phosphonylmethoxypropyl)adenine; wherein V is phenyl, optionally substituted with 1-2 substituents selected from a group consisting of fluoro, chloro, and bromo; comprising: coupling a chiral 1-phenylpropane-1,3-diol, wherein the phenyl may be optionally substituted, with MPOCl2 or an N-6 substituted analogue thereof. Additionally, methods and salt forms are described that enable isolation and purification of the desired isomer.
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- A new regio-defined synthesis of PMEA
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A new regio-defined synthesis of PMEA was developed suitable for gramscale synthesis. Key to this synthesis was the early introduction of the phosphonomethoxy ethyl moiety and subsequent cyclization for the construction of the purine ring. This synthesis is regiospecific when compared to the commonly used adenine alkylation methods.
- Dang, Qun,Liu, Yan,Erion, Mark D.
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p. 1445 - 1451
(2007/10/03)
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- Synthesis, Oral Bioavailability Determination, and in Vitro Evaluation of Prodrugs of the Antiviral Agent 9-adenine (PMEA)
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A series of phosphonate prodrugs were evaluated in an attempt to increase the oral bioavailability of the anti-HIV agent 9-adenine (PMEA; 1).The majority of the bis(alkyl ester) and bis(alkyl amide) prodrugs were prepared by alcohol or amine displacement of dichlorophosphonate 2.Basic hydrolysis of the bis(esters) or bis(amides) provides the corresponding monoesters or momoamides.Synthesis of bis phosphonates 10a-c was accomplished by alkylation of PMEA with the appropriate chloromethyl ether in the presence of N,N'-dicyclohexylmorpholinecarboxamidine.The systemic levels of PMEA following oral administration of a PMEA prodrug to rats were determined by measuring the concentration of PMEA in the urine for 48 h after administration of the prodrug.The oral bioavailability of PMEA employing this method was determined to be 7.8percent.Oral dosing with bis(alkyl) phosphonates 3a,b resulted in apparent absorption of the prodrugs (equal or >40percent), although neither of the esters were completely cleaved to liberate the parent phosphonate PMEA.The mono(alkyl esters) 7a-e and 8a,b exhibited poor oral bioavailability (equal or phosphonates 10a-c demonstrated significantly improved oral bioavailabilities of 17.6percent, 14.6percent, and 15.4percent, respectively.When evaluated in vitro against HSV-2, (acyloxy)alkyl phosphonates 10a-c were greater than 200-fold more active than PMEA.
- Starrett, John E.,Tortolani, David R.,Russell, John,Hitchcock, Michael J. M.,Whiterock, Valerie,et al.
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p. 1857 - 1864
(2007/10/02)
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- SYNTHESIS OF 9-(2-PHOSPHONYLMETHOXYETHYL)ADENINE AND RELATED COMPOUNDS
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Diethyl 2-hydroxyethoxymethanephosphonate (VIII) was converted into diethyl 2-halogenoethoxymethanephosphonates IXa and IXb by reaction with triphenylphosphine and tetrachloromethane or tetrabromomethane; analogous reaction of VIII with p-toluenesulfonyl chloride afforded diethyl 2-(p-toluenesulfonyloxy)ethoxymethanephosphonate (IXc).Reaction of sodium salt of adenine with compounds IX led to 9-(2-diethoxyphosphonylmethoxyethyl)adenine (X).Compound X was converted into 9-(2-phosphonylmethoxyethyl)adenine (II) by treatment with bromotrimethylsilane whereas alkaline hydrolysis of X gave ethyl ester Vb.Reaction of 9-(2-hydroxyethyl)adenine (IIIa) or its N6-benzoyl derivative IIIb with dimethyl p-toluenesulfonyloxymethanephosphonate (IV) in the presence of sodium hydride, followed by alkaline hydrolysis yielded methyl ester Va.Morpholide XI reacted with an inorganic phosphate and diphosphate to give 9-(2-phosphorylphosphonylmethoxyethyl)adenine (XII) and 2-(diphosphorylphosphonylmethoxyethyl)adenine (XIII), respectively.
- Holy, Antonin,Rosenberg, Ivan
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p. 2801 - 2809
(2007/10/02)
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