- 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 0020-0021
(2022/01/12)
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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; 0054; 0055; 0057; 0060; 0061
(2019/08/30)
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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
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The invention provides a preparation method of adefovir dipivoxil. The preparation method is characterized by including the following steps: (1), hydrolyzing diethyl [(2-chloroethoxy)methyl]phosphonate to obtain [(2-chloroethoxy)methyl]phosphonate; (2), reacting the [(2-chloroethoxy)methyl]phosphonate with chloromethyl pivalate to obtain [[2-chloroethoxy]-methyl]phosphonate bis(pivaloyloxymethyl)ester; (3), reacting the [[2-chloroethoxy]methyl]phosphonate bis(pivaloyloxymethyl)ester with 6-amino-9H-purine to obtain the adefovir dipivoxil. Preferably, the invention also provides a final-product refining method. By the preparation method, high yield, a simple post-treatment method and high final-product purity can be acquired.
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Paragraph 0048; 0049
(2019/04/02)
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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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Paragraph 0026-0027
(2017/07/21)
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- Preparation method of adefovir dipivoxil
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The invention relates to a preparation method of adefovir dipivoxil. The preparation method includes: adopting N-methyl pyrrolidone as a solvent, tetra-n-butylammonium bromide as a phase transfer catalyst, triethylamide as an acid adsorbent and adefovir and chloromethyl pivalate as raw materials to prepare 9-{2-{{{di(trimethylacetoxy)methyl}phosphoroso}methoxy}-ethyl)adenine. The preparation method is safe, environment-friendly and controllable in reaction, high in economic benefit and more suitable for industrial production.
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Paragraph 0034; 0035; 0036; 0037; 0038; 0039; 0040-0044
(2017/02/02)
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- Synthesizing technology of adefovir dipivoxil
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The invention discloses a synthesizing technology of adefovir dipivoxil, and belongs to the technical field of preparation of drug compositions. The synthesizing technology comprises the following processes of dissolving adefovir (PMEA) and chloromethyl pivalate in a mixed solvent formed from N,N-dimethylformamide (DMF), N-methylpyrrolidone and absolute ethyl alcohol, performing stirring, and raising the temperature to 60-70 DEG C, and then dropwise adding triethylamine for a reaction. The mixed solvent and a new feeding manner are adopted, a reaction process and a reaction condition are strictly controlled, and a column chromatography method or a recrystallization method does not need to be used for refining and purifying, so that the adefovir dipivoxil with high purity and high stability can be obtained, and the purity can achieve 99.5% or above, the mole yield achieves 52-55%, the yield is increased, the production technology is simplified, the production cycle is shortened, the cost is reduced, and the synthesizing technology has high industrial values and potential social and economic benefits.
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Paragraph 0019; 0020; 0021; 0022
(2017/06/02)
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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 0035-0037
(2017/02/09)
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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 0036
(2020/05/05)
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- 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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p. 869 - 881
(2013/07/27)
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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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- PURIFICATION METHOD FOR ADEFOVIR DIPIVOXIL
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The present invention relates to a novel method of purifying adefovir dipivoxil of Formula 1. The purification method according to the present invention comprises the steps of dissolving impure adefovir dipivoxil containing byproducts generated during a synthetic reaction, salts thereof or complexes thereof in water or a water-containing mixed solvent; purifying the adefovir dipivoxil solution through a reverse-phase column; and adding a base to the purified adefovir dipivoxil solution and extracting the same with an organic solvent. Further, the present invention provides a method of preparing amorphous adefovir dipivoxil by removing the solvent from the high purity solution of adefovir dipivoxil represented by formula I purified by the above method.
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Page/Page column 10
(2011/06/23)
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- IMPROVED PRODUCTION METHOD FOR ADEFOVIR DIPIVOXIL
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The present invention relates to an improved method of preparing adefovir dipivoxil of Formula 1. The method of the present invention is characterized by using dimethylsulfoxide as a reaction solvent, and comprises a process of preparing adefovir dipivoxil of Formula 1 by allowing adefovir of Formula 2 to react with chloromethylpivalate at a reaction temperature of 30 to 50°C in the presence of dimethylsulfoxide and triethylamine as solvents.
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Page/Page column 6
(2011/06/24)
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- IMPROVED PRODUCTION METHOD FOR ADEFOVIR DIPIVOXIL
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The present invention relates to an improved method of preparing adefovir dipivoxil of Formula 1. The method of the present invention is characterized by using dimethylsulfoxide as a reaction solvent, and comprises a process of preparing adefovir dipivoxil of Formula 1 by allowing adefovir of Formula 2 to react with chloromethylpivalate at a reaction temperature of 30 to 50° C. under the presence of dimethylsulfoxide and triethylamine solvents.
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Page/Page column 4
(2011/09/16)
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- DH-TYPE CRYSTALLINE FORM OF ADEFOVIR DIPIVOXIL, PREPARING METHOD THEREOF, AND PHARMACEUTICAL COMPOSITION FOR ANTIVIRAL AGENT COMPRISING THE SAME
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The present invention relates to a DH-type crystalline form of adefovir dipivoxil, a method of preparing the same, and a pharmaceutical composition for an antiviral agent comprising the same.
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Page/Page column 7
(2010/11/03)
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- METHOD FOR PREPARING CRYSTALLINE ADEFOVIR DIPIVOXIL AND ADEFOVIR DIPIVOXIL BUTANOLATE USED THEREIN
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Pure Form V crystals of adefovir dipivoxil can be prepared by a high-yield process comprising the steps of dissolving adefovir dipivoxil in butanol, cooling the resulting solution to give crystalline adefovir dipivoxil butanolate, dissolving the adefovir dipivoxil butanolate in ethyl acetate, and adding the resulting solution to diethyl ether.
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Page/Page column 10
(2010/11/04)
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- NOVEL PROCESS FOR ACYCLIC PHOSPHONATE NUCLEOTIDE ANALOGS
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The present invention provides a novel process for the preparation of acyclic phosphonate nucleotide analogs using novel intermediates. Thus, for example, (R)-9-(2-phosphonomethoxypropyl)adenine is reacted with dimethylformamide dimethylacetal to give N4-dimethylaminomethyledino-9-(2-phosphonomethoxy ethyl) adenine, which is then reacted with chloromethyl-2-propyl carbonate in presence of triethylamine to give (R)—N4-Dimethylaminomethyledino-9-(2-phosphono methoxypropyl) adenine disoproxil, followed by deprotection with acetic acid to get tenofovir disoproxil. Tenofovir disoproxil is then treated with fumaric acid to give tenofovir disoproxil fumarate.
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Page/Page column 4
(2009/01/24)
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- NOVEL PROCESS FOR ACYCLIC PHOSPHONATE NUCLEOTIDE ANALOGS
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The present invention provides a novel process for the preparation of acyclic phosphonate nucleotide analogs using novel intermediates. Thus, for example, (R)-9-(2-phosphonomethoxypropyl)adenine is reacted with dimethylformamide dimethylacetal to give N4-dimethylaminomethyledino-9-(2-phosphonomethoxy ethyl) adenine, which is then reacted with chloromethyl-2-propyl carbonate in presence of triethylamine to give (R)-N4-Dimethylaminomethyledino-9-(2-phosphono methoxypropyl) adenine disoproxil, followed by deprotection with acetic acid to get tenofovir disoproxil. Tenofovir disoproxil is then treated with fumaric acid to give tenofovir disoproxil fumarate.
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Page/Page column 10-11
(2008/06/13)
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- Synthesis, in vitro antiviral evaluation, and stability studies of bis(s-acyl-2-thioethyl) ester derivatives of 9-[2- (phosphonomethoxy)ethyl]adenine (PMEA) as potential PMEA prodrugs with improved oral bioavailability
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A new series of hitherto unknown 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) phosphonodiester derivatives incorporating carboxyesterase-labile S- acyl-2-thioethyl (SATE) moieties as transient phosphonate-protecting groups was prepared in an attempt to increase the oral bioavailability of the antiviral agent PMEA. We report here a direct comparison of the in vitro anti-HIV and anti-HSV activities as well as the in vitro stability between the bis(SATE) derivatives and the already known PMEA prodrugs, namely, bis[(pivaloyloxy)methyl (POM)]and bis[dithiodiethy] (DTE)]PMEA. All of the compounds tested showed an enhanced in vitro antiviral activity compared to the parent PMEA. The bis(POM)- and bis(tBu-SATE)PMEA derivatives were the most effective. However, striking differences between these two compounds were found during the stability studies. In particular the bis(tBu-SATE)PMEA was found to be more stable than bis(POM)PMEA in human gastric juice and human serum, suggesting it could be considered as a promising candidate for further in vivo development.
- Benzaria, Samira,Pélicano, Hélène,Johnson, Richard,Maury, Georges,Imbach, Jean-Louis,Aubertin, Anne-Marie,Obert, Georges,Gosselin, Gilles
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p. 4958 - 4965
(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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