- Practical synthesis of the anti-HIV drug, PMPA
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The anti-HIV nucleotide analogue PMPA can be prepared on a kilogram-scale by a three step sequence: i) condensation of adenine with (R)-propylene carbonate, ii) alkylation of the resulting (R)-9- (2-hydroxypropyl)adenine with diethyl p- toluenesulfonyloxymethanephosphonate using lithium tert-butoxide and iii) cleavage of the phosphonate ester functionalities with bromotrimethylsilane.
- Schultze, Lisa M.,Chapman, Harlan H.,Dubree, Nathan J. P.,Jones, Robert J.,Kent, Kenneth M.,Lee, Thomas T.,Louie, Michael S.,Postich, Michael J.,Prisbe, Ernest J.,Rohloff, John C.,Yu, Richard H.
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- Dealkylation of phosphonate esters with chlorotrimethylsilane
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Chlorotrimethylsilane completely dealkylates phosphonate esters at elevated temperature in a sealed reaction vessel. These conditions are tolerated by a variety of functional groups and lead to high conversions of dimethyl, diethyl and diisopropyl phosphonates to their corresponding phosphonic acids.
- Gutierrez,Prisbe,Rohloff
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- Di- tert-butyl Phosphonate Route to the Antiviral Drug Tenofovir
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Di-tert-butyl oxymethyl phosphonates were investigated regarding their suitability for preparing the active pharmaceutical ingredient tenofovir (PMPA). First, an efficient and simple access to the crystalline di-tert-butyl(hydroxymethyl)phosphonate was developed. O-Mesylation gave high yields of the active phosphonomethylation reagent. For the synthesis of tenofovir, a two-step sequence was developed using Mg(OtBu)2 as the base for the alkylation of (R)-9-(2-hydroxypropyl)adenine. Subsequent deprotection could be achieved with aqueous acids. (Di-tert-butoxyphosphoryl)methyl methanesulfonate showed to be the most efficient electrophile tested, affording PMPA in 72% yield on a 5 g scale. The developed protocol could also be applied for the preparation of the hepatitis B drug adefovir (64% yield/1 g scale).
- Dietz, Jule-Philipp,Ferenc, Dorota,Jamison, Timothy F.,Gupton, B. Frank,Opatz, Till
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- Acyclic nucleoside thiophosphonates as potent inhibitors of HIV and HBV replication
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9-[2-(Thiophosphonomethoxy)ethyl]adenine 3 and (R)-9-[2- (Thiophosphonomethoxy)propyl]adenine 4 were synthesized as the first thiophosphonate nucleosides bearing a sulfur atom at the α-position of the acyclic nucleoside phosphonates PMEA and PMPA. Thiophosphonates S-PMEA 3 and S-PMPA 4 were evaluated for in vitro activity against HIV-1 (subtypes A to G), HIV-2 and HBV-infected cells, and found to exhibit potent antiretroviral activity. We showed that their diphosphate forms S-PMEApp 5 and S-PMPApp 6 are readily incorporated by wild-type (WT) HIV-1 RT into DNA and act as DNA chain terminators. Compounds 3 and 4 were evaluated for in vitro activity against a broad panel of DNA and RNA viruses and displayed beside HIV a moderate activity against herpes simplex virus and vaccinia viruses. In order to measure enzymatic stabilities of the target derivatives 3 and 4, kinetic data and decomposition pathways were studied at 37 °C in several media.
- Barral, Karine,Weck, Clément,Payrot, Nadine,Roux, Loic,Durafour, Céline,Zoulim, Fabien,Neyts, Johan,Balzarini, Jan,Canard, Bruno,Priet, Stéphane,Alvarez, Karine
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- Bisamidate Prodrugs of 2-Substituted 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA, adefovir) as Selective Inhibitors of Adenylate Cyclase Toxin from Bordetella pertussis
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Novel small-molecule agents to treat Bordetella pertussis infections are highly desirable, as pertussis (whooping cough) remains a serious health threat worldwide. In this study, a series of 2-substituted derivatives of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA, adefovir), in their isopropyl ester bis(L-phenylalanine) prodrug form, were designed and synthesized as potent inhibitors of adenylate cyclase toxin (ACT) isolated from B. pertussis. The series consists of PMEA analogues bearing either a linear or branched aliphatic chain or a heteroatom at the C2 position of the purine moiety. Compounds with a small C2 substituent showed high potency against ACT without cytotoxic effects as well as good selectivity over human adenylate cyclase isoforms AC1, AC2, and AC5. The most potent ACT inhibitor was found to be the bisamidate prodrug of the 2-fluoro PMEA derivative (IC50=0.145 μM). Although the bisamidate prodrugs reported herein exhibit overall lower activity than the bis(pivaloyloxymethyl) prodrug (adefovir dipivoxil), their toxicity and plasma stability profiles are superior. Furthermore, the bisamidate prodrug was shown to be more stable in plasma than in macrophage homogenate, indicating that the free phosphonate can be effectively distributed to target tissues, such as the lungs. Thus, ACT inhibitors based on acyclic nucleoside phosphonates may represent a new strategy to treat whooping cough. Whooping cough combatted: With the aim to establish a new strategy against pertussis, C2-modified adefovir analogues in their bisamidate prodrug form were found to efficiently inhibit adenylate cyclase toxin (ACT) from Bordetella pertussis. The compounds show favorable plasma stability, effective distribution to target tissues, and good selectivity for ACT over human adenylate cyclase isoforms.
- ?esnek, Michal,Jansa, Petr,?mídková, Markéta,Mertlíková-Kaiserová, Helena,Dra?ínsky, Martin,Brust, Tarsis F.,Pávek, Petr,Trejtnar, Franti?ek,Watts, Val J.,Janeba, Zlatko
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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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- 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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- Preparation method of high-stability adefovir dipivoxil
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The invention belongs to the field of pharmaceutical synthesis. A preparation method of high-stability adefovir dipivoxil is characterized by comprising the following steps: 1) a compound 1 undergoestrimethylbromosilane substitution, followed by hydrolysis with a NaOH aqueous solution to obtain a compound 2; 2) the compound 2 and a compound 3 are catalyzed by triethylamine in N-methylpyrrolidoneto obtain a compound 4; 3) the compound 4 is refined to obtain a compound 5, namely [[2-(6-amino-9H-purine-9-yl)ethoxy]methyl]phosphodi(pivaloyloxymethyl)ester. The preparation method of high-stability adefovir dipivoxil has advantages of good stability of bulk drugs and simple production process, and is suitable for large-scale commercial production.
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Paragraph 0020; 0051; 0052; 0057; 0058; 0063; 0064
(2019/08/30)
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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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- Preparation method of adefovir
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The invention discloses a preparation method of adefovir. The preparation method comprises the following steps: adding 9-[2-(diethoxylphosphorylmethoxyl)ethyl]adenine into a water solution of HBr, heating to carry out reactions, cooling, and adjusting the pH to 2-3.5 to precipitate white solids namely white adefovir. The preparation method has the advantages that during the hydrolysis of 9-[2-(diethoxylphosphorylmethoxyl)ethyl]adenine, the step of evaporating organic solvents is eliminated, the reaction time is reduced, thus the preparation time is shortened; trimethyl iodo-silane, trimethyl bromo-silane, or trimethyl chloro-silane is replaced by a water solution of HBr, and the cost is reduced by nearly 100 to 400 yuan. Secondary solvent acetonitrile is not used, influence of pollution and solvent residue on drug quality is reduced; trimethyl bromo-silane is easy to decompose and is harmful to human body, and after HBr substitution, the harm to workers is largely reduced.
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Paragraph 0035; 0036; 0039; 0040; 0046; 0047; 0048
(2017/08/28)
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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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- 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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Paragraph 0035
(2020/05/05)
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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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- Microwave-assisted hydrolysis of phosphonate diesters: An efficient protocol for the preparation of phosphonic acids
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A new highly efficient method for the hydrolysis of acyclic nucleoside phosphonate diesters (or generally of any organophosphonates) to the corresponding phosphonic acids has been developed. This novel methodology employs inexpensive hydrochloric acid in equimolar amounts to the number of ester groups present in the molecule and thus, avoids using trimethylsilyl halogenides, the standard reagents for these types of transformations. Moreover, simple and easy work-up of the reaction mixture affords very clean products in high yields (usually 77-93%). Another advantage of the described hydrolysis of phosphonate diesters is the fact that the course of the reaction can be instantly monitored through pressure changes in the reaction vessel. This 'green' method has also been successfully used for the preparation of otherwise synthetically difficult to access (phosphonomethoxy)ethyl (PME) derivatives of guanine (PMEG) and hypoxanthine (PMEHx), and furthermore, the method gains access to important novel acyclic nucleoside phosphonates derived from 2-chlorohypoxanthine and from xanthine (e.g. PMEX).
- Jansa, Petr,Baszczynski, Ondrej,Prochazkova, Eliska,Dracinsky, Martin,Janeba, Zlatko
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supporting information; experimental part
p. 2282 - 2288
(2012/09/08)
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- AZA-peptide protease inhibitors
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The invention is related to compounds of Formula I: or a pharmaceutically acceptable salt, solvate, ester, and/or phosphonate thereof, compositions containing such compounds, and therapeutic methods that include the administration of such compounds.
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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 115-116
(2008/12/05)
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- Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same
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A novel method is provided for screening prodrugs of methoxyphosphonate nucleotide analogues to identify prodrugs selectively targeting desired tissues with antiviral or antitumor activity. This method has led to the identification of novel mixed ester-amidates of PMPA for retroviral or hepadnaviral therapy, including compounds of structure (5a) having substituent groups as defined herein. Compositions of these novel compounds in pharmaceutically acceptable excipients and their use in therapy and prophylaxis are provided. Also provided is an improved method for the use of magnesium alkoxide for the preparation of starting materials and compounds for use herein.
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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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- Method for the preparing ?9-12-(Diethoxyphosphonomethoxy)ethyl!adenine and analogues thereof
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Unprotected adenine, 6-chloropurine, 2,6-diaminopurine, and 2-amino-6-chloropurine have been directly coupled with 2-(diethoxyphosphonomethoxy)ethanol under a disclosed method to provide acyclic phosphonate nucleotide analogues which are intermediates for antiviral agents such as 9-?2-(phosphonomethoxy)ethyl!adenine (PMEA) and its analogues having a structure of formula I: STR1 wherein Z represents N or CH; R1 represents hydrogen, alkyl, aryl, or arylalkyl; R2 and R3 are independently selected from H, OH, halo, NH2, C6 H5 CH2 O, or R4 R5 N wherein R4 and R5 are independently selected from alkyl, aryl, or arylalkyl.
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- Structure-antiviral activity relationship in the series of pyrimidine and purine N-[2-(2-phosphonomethoxy)ethyl] nucleotide analogues. 1. Derivatives substituted at the carbon atoms of the base
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A series of dialkyl esters of purine and pyrimidine N-[2- (phosphonomethoxy)ethyl] derivatives substituted at position 2, 6, or 8 of the purine base or position 2, 4, or 5 of the pyrimidine base were prepared by alkylation of the appropriate heterocyclic base with 2- chloroethoxymethylphosphonate diester in the presence of sodium hydride, cesium carbonate, or 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) in dimethylformamide. Additional derivatives were obtained by the transformations of the bases in the suitably modified intermediates bearing reactive functions at the base moiety. The diesters were converted to the corresponding monoesters by sodium azide treatment, while the free acids were obtained from the diester by successive treatment with bromotrimethylsilane and hydrolysis. None of the PME derivatives in the pyrimidine series, their 6-aza or 3-deaza analogues, exhibited any activity against DNA viruses or retroviruses tested, except for the 5-bromocytosine derivative. Substitution of the adenine ring in PMEA at position 2 by Cl, F, or OH group decreased the activity against all DNA viruses tested. PMEDAP was highly active against HSV-1, HSV-2, and VZV in the concentration range (EC50) of 0.07-2 μg/mL. Also the 2-amino-6-chloropurine derivative was strongly active (EC50 = 0.1- 0.4 μg/mL) against herpes simplex viruses and (EC50 = 0.006-0.3 μg/mL) against CMV and VZV. PMEG was the most active compound of the whole series against DNA viruses (EC50 ~0.01-0.02 μg/mL), though it exhibited significant toxicity against the host cells. The base-modified compounds did not show any appreciable activity against DNA viruses except for 7-deazaPMEA (IC50 ~7.5 μg/mL) against HIV-1 and MSV. The neutral (diisopropyl, diisooctyl) diesters of PMEA were active against CMV and VZV, while the corresponding monoesters were inactive. The diisopropyl ester of the 2- chloroadenine analogue of PMEA showed substantially (10-100x) higher activity against CMV and VZV than the parent phosphonate. Also, the diisopropyl and diisooctyl ester of PMEDAP inhibited CMV and VZV, but esterification of the phosphonate residue did not improve the activity against either MSV or HIV.
- Holy, Antonín,Günter, Jaroslav,Dvo?áková, Hana,Masojídková, Milena,Andrei, Graciela,Snoeck, Robert,Balzarini, Jan,De Clercq, Erik
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p. 2064 - 2086
(2007/10/03)
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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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