- Green synthesis improvement of tenofovir disoproxil
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Polyethylene glycol, known as 'Green Chemical', is a catalyst for the synthesis of tenofovir disoproxil. Some technological parameters were discussed by adoptting via single-factor experiments. Through the catalytic reaction, not only tenofovir disoproxil yield was improved but also by-products was reduced obviously. The results showed that the optimal conditions were as follows: 0.6 equiv PEG-600, 4.0 equiv triethylamine, 6.0 equiv N-methyl-2-pyrrolidone and temperature at 50°C for 16 h with a yield of 65.12 %.
- Wang, Gang,Xie, Yong Mei,Wang, Xing Hua
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Read Online
- 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 0018-0019
(2022/01/12)
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- Synthesis process of antiviral drug
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The invention discloses a synthesis process of an antiviral drug. The process comprises the following steps: reacting adenine (II) with (R)- propylene carbonate (III) to prepare a compound IV, carrying out alkylation reaction on the compound IV and a compound V to prepare a compound VI, and carrying out esterolysis reaction to prepare a compound VII; and carrying out esterification reaction on theprepared compound VII and chloromethyl isopropyl carbonate, and salifying with fumaric acid to prepare the final product tenofovir disoproxil fumarate (I). The synthetic route is simple, the reactionconditions are mild, the generation of impurities is reduced, the total yield and purity of the product are improved, and the method is suitable for industrial production.
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Paragraph 0050-0063
(2020/11/26)
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- METHODS FOR IMPROVING PURITY OF TENOFOVIR DISOPROXIL FUMARATE, AND COMPOSITIONS THEREOF
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Methods for producing tenofovir disoproxil fumarate with improved purity are provided. In particular, methods for producing tenofovir disoproxil fumarate with reduced levels of chloromethyl isopropyl carbonate are described. Also described are compositions containing tenofovir disoproxil fumarate with improved purity, and an analysis method that can be used to determine the purity of such compositions with improved accuracy and sensitivity.
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Paragraph 0188; 0196; 0198; 0200; 0202; 0204; 0206
(2020/07/16)
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- A [...] and its preparation method for
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The invention relates to the technical field of medicinal chemical engineering and particularly relates to a tenofovir disoproxil crystal form and a preparation method thereof. The tenofovir disoproxil has characteristic peaks when a diffraction angle 2[theta] is 7.3 +/- 0.2 degrees, 12.9 +/- 0.2 degrees, 14.4 +/- 0.2 degrees, 17.9 +/- 0.2 degrees, 19.1 +/- 0.2 degrees, 20.8 +/- 0.2 degrees and 22.9 +/- 0.2 degrees.
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Paragraph 0050; 0056; 0061; 0062; 0067; 0073
(2019/01/16)
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- Synthetic method for tenofovir disoproxil
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The invention discloses a synthetic method for tenofovir disoproxil. The method comprises the following steps: adding raw material tenofovir (PMPA), a phase transfer catalyst tetrabutylammonium bromide, an acid-binding agent and an auxiliary agent into an organic solvent under the protection of a nitrogen gas at room temperature, performing stirring for a period of time, performing heating to a certain temperature, adding chloromethyl isopropyl carbonate (POC) dropwise, performing a reaction for a period of time, after the reaction is completed, performing precipitation by brine ice to obtaincrude tenofovir disoproxil, performing filtration, adding a solvent, performing pulping, and performing drying to obtain the finished tenofovir disoproxil. According to the process provided by the invention, the appropriate reaction auxiliary agent is selected to reduce generation of impurities, multiple refining is avoided, the product purity is improved, the product yield is high, and the methodis suitable for large-scale industrial production.
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Paragraph 0023-0028
(2020/01/03)
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- A method for preparing for [...] (by machine translation)
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The invention relates to a method for preparing for [...]. Specifically, the invention relates to an industrial production level of preparation for fuwei two pyrrole fufu ester of the method, the method can improve the reaction yield, reducing the impurity, is simple and easy to control, is conducive to industrial expansion of production. (by machine translation)
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Paragraph 0041; 0052-0057
(2019/03/28)
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- Method for preparing tenofovir disoproxil
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The invention discloses a method for preparing tenofovir disoproxil and relates to the field of preparation of tenofovir disoproxil. The method for preparing the tenofovir disoproxil specifically comprises the following steps: A) preparing (R)-9-(2-hydroxypropyl) adenine; B) preparing (R)-9-(2-phosphonic acid methoxy-propyl) adenine di(ethyl) ester; C) preparing tenofovir; D) preparing tenofovir disoproxil; and E) carrying out finished product detection and inspection. Compared with the prior art, the method has the beneficial effects that while the medicine effect of the tenofovir disoproxilis ensured, the reaction steps are simplified, the yield is increased, the conversion rates of intermediates (R)-9-(2-hydroxypropyl) adenine, (R)-9-(2-phosphonic acid methoxy-propyl) adenine di(ethyl)ester and tenofovir reach 75%, 63.2% and 74.3% respectively, and the total yield of the tenofovir disoproxil is as high as 62.4% finally.
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Paragraph 0016; 0018-0020; 0023-0025; 0028-0030
(2019/09/17)
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- Preparation method and application of tenofovir monoester
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The invention belongs to the field of medicines, and in particular relates to a preparation method and application of tenofovir monoester. The method comprises the following steps: preparing tenofovirand chloromethyl isopropyl carbonate; dissolving the tenofovir into an organic solvent, adding an organic alkali and a catalyst, adding the chloromethyl isopropyl carbonate, and performing a reactionto obtain a solid tenofovir disoproxil; and performing hydrolysis on the solid tenofovir disoproxil in an alkali aqueous solution to obtain the tenofovir monoester. The preparation method of the tenofovir monoester provided by the invention has easily-available raw materials, is simple and convenient to operate, and has low requirements on equipment, and important significance for effectively controlling quality of tenofovir disoproxil fumarate.
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Paragraph 0040-0042; 0048-0050; 0053-0055; 0058-0060
(2019/10/01)
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- Preparation method of tenofovir disoproxil hemifumarate
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The invention provides a preparation method of tenofovir disoproxil hemifumarate, particularly a preparation method of tenofovir disoproxil hemifumarate in a one-pot manner. Through adding a water-binding agent, generation of impurities in a synthesis process of tenofovir disoproxil is controlled, and therefore, the intermediate tenofovir disoproxil does not need to be completely separated from the reaction system, reaction treatment steps are saved, the loss of the process is reduced, the purity of the prepared tenofovir disoproxil hemifumarate is greater than 99.0%, and the impurity tenofovir monosoproxil is less than 0.1%; and the total molar yield is stabilized at 77%-85%.
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Paragraph 0050-0053; 0056-0059; 0062-0065; 0068-0083; 1-6
(2020/01/11)
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- Amorphous semi-tenoforvirdisoproxilfumarate tablet and preparation method thereof
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The invention relates to the technical field of medicine and discloses an amorphous semi-tenoforvirdisoproxilfumarate tablet and a preparation method thereof. The amorphous semi-tenoforvirdisoproxilfumarate tablet is prepared from, by weight, 35-60 parts of amorphous semi-tenoforvirdisoproxilfumarate, 30-60 parts of a filler, 2-10 parts of a disintegrating agent, 3-8 parts of a binding agent and 0.1-2 parts of a lubricating agent. The amorphous semi-tenoforvirdisoproxilfumarate is taken as the raw material drug, and the tablet obtained on the basis of not adopting special auxiliary materials and equipment has good stability and is not easy to degrade; wet particles are dried through a fluidized bed, and high efficiency, simple operation and good particle fluidity are achieved; the entire process is good in stability, and related substances, crystal forms and the like do not change and are good in stability in the long-term storage process; simple process and good economic benefit are achieved.
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Paragraph 0054; 0057-0058
(2019/11/12)
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- Amorphous tenofovir disoproxil hemifumarate and preparation method thereof
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The invention relates to the technical field of medicine, and discloses amorphous tenofovir disoproxil hemifumarate and a preparation method thereof. The preparation method comprises the steps that (R)-9-(2-hydroxypropyl)adenine is taken as a starting raw material and subjected to condensation, hydrolysis and esterification reactions to prepare free tenofovir disoproxil, and then the amorphous state of tenofovir disoproxil hemifumarate is prepared from the tenofovir disoproxil and fumarate in absolute ethyl alcohol. The amorphous state of the amorphous state of tenofovir disoproxil hemifumarate accounts for 98% or above, the purity is up to 99.32%, solvent residue is 0.05%, an amorphous tenofovir disoproxil hemifumarate raw material and preparation are more stable than an existing crystaltenofovir disoproxil hemifumarate, and an existing tenofovir disoproxil fumarate raw material and preparation, and is not easy to degrade.
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Paragraph 0046-0048; 0052-0054; 0058-0060; 0064-0066
(2019/11/13)
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- PREPARATION METHOD FOR HIGHLY PURE TENOFOVIR DISOPROXIL
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The present invention discloses a method for manufacturing high purity tenofovir disoproxil. The method comprises the steps of: (i) reacting crude tenofovir disoproxil with muconic acid to manufacture tenofovir disoproxil muconate; (TDM); and (ii) neutralizing the manufactured tenofovir disoproxil muconate to obtain tenofovir disoproxil. By using the method, 99.7% or more, or 99.9% or more of high purity tenofovir disoproxil can be obtained.COPYRIGHT KIPO 2018
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Paragraph 0071-0072
(2018/07/28)
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- Preparation method of tenofovir disoproxil fumarate
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The invention provides a preparation method of tenofovir disoproxil fumarate. The preparation method comprises the following steps: performing an etherification reaction, performing a hydrolysis reaction, performing a condensation reaction, and performing refining and performing a salt forming reaction to obtain the tenofovir disoproxil fumarate. According to the method provided by the invention,the tenofovir disoproxil fumarate prepared by the method has a high yield, and is easy to purify and suitable for industrialized mass production.
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Paragraph 7-21
(2018/10/11)
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- Preparation method of tenofovir dipifuratate
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The invention provides a preparation method for tenofovir dipifuratate. The tenofovir dipifuratate which is high in yield and easy to purify and is suitable for industrialized mass production is obtained through the reactions of etherifying, hydrolyzing, condensing and refining.
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Paragraph 0089; 0092; 0106; 0120; 0134; 0141; 0148; 0160
(2018/09/11)
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- Preparation method of high-purity tenofovir disoproxil fumarate
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The invention discloses a preparation method of high-purity tenofovir disoproxil fumarate. The preparation method comprises: (1) performing esterification reaction on tenofovir and chloromethyl isopropyl carbonate in a certain molar ratio in a N-methylpyrrolidone solvent under the catalyzing action of triethylamine and tetrabutylammonium bromide to obtain an esterification reaction solution; (2) adding esterification reaction solution into mixed crystallization liquid in a certain ratio, stirring at low temperature to achieve crystallization, filtering, and drying filter cakes to obtain high-purity tenofovirester, wherein the mixed crystallization liquid is a mixture of a water-insoluble solvent and icewater; and (3) dissolving the high-purity tenofovirester, and salifying to obtain tenofovir disoproxil fumarate. In the preparation method, the esterification reaction conversion rate is high, the quantity of by-products is small, the post-processing operation is easy, multiple extraction is avoided, the direct crystallization is adopted to obtain the high-purity tenofovir disoproxil fumarate, and finally the tenofovir disoproxil fumarate with the purity of more than or equal to 99.5% is obtained by salifying. The preparation method is low in cost, high in yield, economical, feasible, and suitable for industrial production.
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Paragraph 0020
(2018/12/02)
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- Tenofovir disoproxil preparation method
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The invention discloses a tenofovir disoproxil preparation method. The tenofovir disoproxil preparation method includes enabling tenofovir to react with halogenated chloromethyl isopropyl carbonate in ionic liquid in the presence of acid-capturers so as to obtain tenofovir disoproxil. The tenofovir disoproxil preparation method has the advantages that a great quantity of irritant N-methyl pyrrolidone and phase transfer catalysts are avoided, cost and post-treatment workload are both reduced, reaction time is shortened effectively and high yield is achieved.
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Paragraph 0028-0030; 0031-0036
(2017/08/29)
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- Preparation method for tenofovir disoproxil fumarate (TDF)
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The invention provides a novel preparation method for tenofovir disoproxil fumarate (TDF). The TDF is obtained by conducting esterifying and salifying refining on TDF-SM which is used as a raw material. The preparation method for the TDF has the characteristics that the reaction condition is mild, production cost is low, quality is good, and industrialized production is convenient.
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Paragraph 0015; 0018; 0022; 0026
(2017/06/02)
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- Efficient preparation method of Tenofovir
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The present invention relates to an effective manufacturing method for tenofovir. According to the present invention, (R)-9-[2-(hydroxy)propyl] adenine (HPA) and diethyl p-toluene sulfonyl oxymethylphosphonate (DESMP) are reacted with each other by a magnesium catalyst, and the (R)-9-[2-(hydroxy)propyl] adenine (HPA) is synthesized. The synthesized (R)-9-[2-(hydroxy)propyl] adenine (HPA) is dealkylated. Therefore, the affective manufacturing method for tenofovir can manufacture the tenofovir (PMPA) of high yield and high purity.COPYRIGHT KIPO 2017
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Paragraph 0146-0151
(2017/07/14)
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- Preparation method of tenofovir disoproxil
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The invention belongs to the field of pharmaceutical chemistry, and specifically relates to a preparation method of tenofovir disoproxil. The preparation method comprises the following steps: (1) mixing tenofovir, an organic alkali, a catalyst, and a reaction solvent to obtain a mixed solution, wherein the catalyst is 4-dimethylaminopyridine; (2) adding chloroformic acid isopropyl carbonate into the mixed solution to carry out reactions; and (3) carrying out separation to obtain tenofovir disoproxil. The preparation method has the advantages that 4-dimethylaminopyridine (DMAP) is taken as the catalyst, the monoester impurity can be controlled to be less than 4% without using recrystallization; under same technological conditions, the monoester impurity content of a product prepared by using other catalysts is 9 to 14%, and the monoester impurity content is 15 to 20% if no catalyst is used.
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Paragraph 0051; 0053; 0054; 0055
(2017/08/31)
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- For fuwei two pyrrole fufu ester solid and its preparation and use
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The invention relates to a solid of tenofovir disoproxil. The solid is (1) a tenofovir disoproxil compound represented by a formula IV or (2) a tenofovir disoproxil cocrystal or salt represented by a formula V. The invention further relates to a preparation method for the solid of tenofovir disoproxil, a pharmaceutical composition containing the solid and application of the solid in preparation of drugs used for preventing and/or treating virus infection, especially hepatitis b virus (HBV) and/or human immunodeficiency virus (HIV) infection.
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Paragraph 0271-0273
(2017/12/30)
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- For [...] a method for preparing and its fumarate (by machine translation)
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For [...] a method for preparing and its fumarate, which belongs to the field of preparation of compound, the method comprising the following steps: tynofovir anhydrous or tynofovir hydrate with methyl isopropyl carbonate reaction occur condensation reaction, the condensation reaction from the reaction solution obtained is poured into the supersaturated salt solution, mixing, filtration, washing, drying, obtain crude [...] ; crude [...] will be to add a certain amount of low boiling point non-polar organic solvent, heating to reflux temperature for the beating reflux, the gradient temperature after mixing, filtering, with a low boiling point non-polar organic solvent washing, drying, obtain powder [...] ; in the presence of isopropanol, powdery [...][...] with fumaric acid reaction. The method comprises after treatment is simple, high yield, high purity of the obtained product, low impurity content, and the like. (by machine translation)
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Paragraph 0018-0041; 0050-0051; 0060-0061; 0065-0066
(2017/10/27)
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- Method for the preparation of high purity Tenofovir Disoproxil Fumarate
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The present invention relates to a preparation method of tenofovir disoproxil fumarate and, more particularly, to a preparation method of tenofovir disoproxil fumarate having less than 0.04% of tenofovir mono-isoproxil fumarate by making a reaction between tenofovir disoproxil and fumaric acid in presence of water or a mixed solvent of water and an organic solvent. Different from the conventional method of forming salt in an organic solvent, the preparation method of the present invention forms salt in an aqueous solution, and thus is remarkably environment-friendly. In addition, the preparation method in the present invention can manufacture tenofovir disoproxil fumarate which hardly has a residual solvent, and thus is very useful for industrial purposes.COPYRIGHT KIPO 2016
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Paragraph 0042; 0043
(2017/03/17)
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- Synthetic method of tenofovir disoproxil fumarate
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The invention provides a synthetic method of tenofovir disoproxil fumarate. The method has the advantages of mild reaction conditions, low production cost, high yield and good quality of the product, and convenience for industrial production.
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Paragraph 0018; 0019
(2016/10/10)
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- New method for synthesizing tenofovir disoproxil fumarate
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The invention provides a new method for synthesizing tenofovir disoproxil fumarate. The reaction conditions are mild, the production cost is low, the product yield is high, the quality is high, and the method is convenient for industrial production.
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Paragraph 0020
(2016/10/27)
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- Preparation method for tenofovir disoproxil fumarate
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The invention provides a preparation method for tenofovir disoproxil fumarate. The reaction conditions are mild, the production cost is low, the product yield is high, the quality is high, and the preparation method is convenient for industrial production.
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Paragraph 0018; 0019
(2016/10/27)
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- Method for synthesizing tenofovir disoproxil fumarate
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The invention provides a method for synthesizing tenofovir disoproxil fumarate and belongs to the technical field of synthesis of organic compounds. According to the method, tenofovir is taken as a starting material and subjected to esterification and salt formation refining, and tenofovir disoproxil fumarate is prepared. The method for synthesizing tenofovir disoproxil fumarate has the advantages of mild reaction conditions, low production cost, high product yield and good quality and facilitates industrial production.
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Paragraph 0018; 0019
(2016/11/07)
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- New method for preparing tenofovir disoproxil fumarate
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The invention provides a new method for preparing tenofovir disoproxil fumarate. Reaction conditions are mild, production cost is low, product yield is high, quality is good, and industrial production can be conveniently realized.
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Paragraph 0018; 0019
(2016/11/09)
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- Method for preparing tenofovir disoproxil fumarate
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The invention provides a method for preparing tenofovir disoproxil fumarate, and belongs to the technical field of organic compound synthesis. According to the method, tenofovir is taken as a starting material, and tenofovir disoproxil fumarate is obtained through esterification, salt formation and refining. The method provided by the invention is mild in reaction condition, low in production cost, and high in product yield and quality, and facilitates industrialized production.
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Paragraph 0018; 0019
(2016/11/14)
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- Method for preparing tenofovir disoproxil fumarate through two-step method
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The invention provides a method for preparing tenofovir disoproxil fumarate through a two-step method. The reaction conditions are mild, the production cost is low, the product yield is high, the quality is good, and the method is convenient for industrial production.
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Paragraph 0018; 0019
(2016/11/17)
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- Method for synthesizing tenofovir fumarate by two-step process
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The invention provides a method for synthesizing tenofovir fumarate by a two-step process, belonging to the technical field of organic compound synthesis. By using tenofovir as an initial raw material, esterification and salification refinement are performed to obtain the tenofovir fumarate. The method provided by the invention has the advantages of mild reaction conditions, low production cost, high product yield and good quality, and is convenient for industrial production.
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Paragraph 0016; 0019
(2016/12/01)
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- A [...] can be industrialized mass production method for the preparation of (by machine translation)
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The invention relates to a can be industrialized mass production method for preparing [...], comprising the following steps : (R) - 9 - [2 - (b b oxygen phosphine acid radical methoxy ) propyl] adenine preparation, tenofovir synthetic, refining and dewatering, and [...][...] for the synthesis. The technical scheme of the invention the operation is simple, the selected reagent are relatively cheaper, less side reaction, high yield, less wastes of generated during the reaction process, the protection of the environment, and is suitable for industrial mass production. (by machine translation)
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Paragraph 0014
(2016/12/07)
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- A process for the preparation of antiviral drugs
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The invention discloses a preparation method of anantiviral medicine tenofovirdisoproxil fumarate. The preparation method disclosed by the invention comprises the following steps of: performing addition reaction on adenine serving as raw material and (R)-epoxypropane in the presence of alkali; then, performing substitution reaction with (diethyoxyl phosphoracyl) methyl-4-methyl benzenesulfonate; then, hydrolyzing by using a hydrobromic acid solution; crystallizing to obtain tenofovir monohydrate; and reacting the product tenofovir monohydrate with chloromethyl isopropyl carbonate and fumaric acid to obtain tenofovirdisoproxil fumarate. The selected initial raw material is low in cost and easily available, and the synthetic line is simplified and the utilization ratio of the raw material and the total yield are improved. The intermediate obtained in the reaction is purified by the recrystallization method, so that the yield is high, less three-wastes are generated in the reaction process, and the cost is low; therefore, the preparation method is favorable for industrial production.
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Paragraph 0058-0059
(2017/02/09)
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- A method for preparing [...]
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The invention discloses a preparation method of tenofovir disoproxil fumarate, belonging to the technical field of synthesis of tenofovir disoproxil fumarate. The preparation method comprises the following steps: preparing tenofovir disoproxil, preparing a tenofovir disoproxil fumarate crude product and refining the tenofovir disoproxil fumarate, wherein in the step of refining the tenofovir disoproxil fumarate, by virtue of a 65% ethanol solution which is used as a tenofovir disoproxil fumarate recrystallizing solvent, the tenofovir disoproxil fumarate is kept in an environment at 5-10 DEG C for 3-6h until the tenofovir disoproxil fumarate is naturally separated out and crystallized. The preparation method disclosed by the invention can be used for solving the problems of high contents of organic residue and side reactant in the process of preparing the tenofovir disoproxil fumarate, and the total yield can reach more than 40%; in addition, the tenofovir disoproxil fumarate occupies a high content in a final product, and the preparation method is simple and convenient to operate in the recrystallizing process, low in cost, and free from toxic and harmful side reactions or products.
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Paragraph 0033-0039
(2017/04/03)
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- Method for synthesizing tenofovir disoproxil fumarate conveniently
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The invention provides a method for synthesizing tenofovir disoproxil fumarate conveniently and belongs to the technical field of synthesis of organic compounds. Tenofovir is taken as a starting material and subjected to esterification and salifying refining, and the tenofovir disoproxil fumarate is obtained. The method for synthesizing the tenofovir disoproxil fumarate conveniently has the advantages of mild reaction conditions, low production cost, high product yield, good quality and facilitation of industrial production.
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Paragraph 0028; 0018; 0019
(2016/10/31)
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- NUCLEOTIDE ANALOGS
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PROBLEM TO BE SOLVED: To provide, e.g., intermediates for phosphonomethoxy nucleotide analogs, in particular, intermediates suitable for use in efficient oral delivery of such analogs. SOLUTION: Novel compounds are provided that comprise esters of antiviral phosphonomethoxy nucleotide analogs with carbonates and/or carbamates having the structure -OC(R2)2OC(O)X(R)a, The compounds are useful as intermediates for the preparation of antiviral compounds or oligonucleotides, or are useful for administration directly to patients for antiviral therapy or prophylaxis (R2 is as described in the specifications ). COPYRIGHT: (C)2015,JPOandINPIT
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Paragraph 0196; 0197
(2018/11/22)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF TENOFOVIR DISOPROXIL AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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An improved process for the preparation of Tenofovir disoproxil and pharmaceutically acceptable salts thereof, comprising following steps: a) alkylation of adenine with (R)-4-methyl-1,3-dioxolan-2-one and isolation of (R)-1-(6-amino-9H-purin-9-yI)propan-2-ol; b) alkylation of (R)-1-(6-amino-9H-purin-9-yl) propan-2-ol with a dialkyl p-toluenesulphonyloxymethylphosphonate or dialkyl halomethylphosphonate to give dialkylester of (R)-9-[2-(phosphonomethoxy)propyl]adenine; c) preparation of (R)-9-[2-(phosphonomethoxy)propyl]adenine ((R)-PMPA; Tenofovir) by dealkylation of the phosphonate moiety with a mineral acid under microwave irradiation; d) preparation of Tenofovir disoproxil; e) preparation of the fumarate salt or other pharmaceutically acceptable salt of Tenofovir disoproxil.
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Page/Page column 6; 23
(2015/04/28)
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- An improved process for the preparation of Tenofovir disoproxil and pharmaceutically acceptable salts thereof
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An improved process for the preparation of Tenofovir disoproxil and pharmaceutically acceptable salts thereof, comprising following steps: a) alkylation of adenine with (R)-4-methyl-1,3-dioxolan-2-one and isolation of (R)-1-(6-amino-9H-purin-9-yl)propan-2-ol; b) alkylation of (R)-1-(6-amino-9H-purin-9-yl) propan-2-ol with a dialkyl p-toluenesulphonyloxymethylphosphonate or dialkyl halomethylphosphonate to give dialkylester of (R)-9-[2-(phosphonomethoxy)propyl]adenine; c) preparation of (R)-9-[2-(phosphonomethoxy)propyl]adenine ((R)-PMPA; Tenofovir) by dealkylation of the phosphonate moiety with a mineral acid under microwave irradiation; d) preparation of Tenofovir disoproxil; e) preparation of the fumarate salt or other pharmaceutically acceptable salt of Tenofovir disoproxil.
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- Antiviral Compounds in the Form of Solid and Method for Preparing thereof
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The present invention relates to a novel crystal form of a tenofovir disoproxil free base. According to the present invention, the tenofovir disoproxil free base ensures to enhance a stability of a medicine by reducing an impurity production during storage by being able to minimize a production of impure elements due to changes by a time flow compared to a tenofovir disoproxil fumarate or a previously known tenofovir disoproxil free base. In addition, the novel crystal form of the tenofovir disoproxil free base has an improved hygroscopicity, an excellent solubility in each pH, and physicochemically outstanding properties, thereby being able to be used as a useful active ingredient for a pharmaceutical composition.COPYRIGHT KIPO 2015
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Paragraph 0076; 0077
(2017/01/02)
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- THE NOVEL TENOFOVIR DISOPROXIL SALT AND THE PREPARATION METHOD THEREOF
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The present invention relates to a novel tenofovir disoproxil aspartate compound. The aforementioned salt compound allows minimal formation of related substances occurring with passage of time, increasing the stability of the formulation by drastically reducing the formation of impurities during storage. Also, the need for a separate study of toxicological effects is eliminated. Moreover, the salt compound of the present invention possesses superior physicochemical properties, with a significant improvement in stability, hygroscopicity, and solubility, thereby allowing it to be used as an active ingredient along with pharmaceutically acceptable carriers for a pharmaceutical composition for the treatment of HIV infection and chronic hepatitis B.
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Paragraph 71-76
(2014/03/25)
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- PROCESS FOR THE PREPARATION OF TENOFOVIR DISOPROXIL FUMARATE
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The present invention relates to an improved process for the preparation of Tenofovir Disoproxil and its pharmaceutically acceptable salts comprising the steps of: a) esterifying Tenofovir with chloromethyl isopropyl carbonate in presence of a base, phase transfer catalyst and optionally dehydrating agent, in a suitable solvent; b) optionally purifying Tenofovir Disoproxil; and c) converting of Tenofovir Disoproxil into its pharmaceutically acceptable salts. The present invention further relates to a process for the preparation of Tenofovir by reacting 1-(6-amino-purin-9-yl)-propan-2-ol with toluene-4-sulfonic acid diethoxy phosphoryl methyl ester in presence of a base in a non-polar solvent medium followed by hydrolysis.
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Page/Page column 4
(2013/02/28)
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- PROCESS FOR THE PREPARATION OF TENOFOVIR
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The present invention provides a process for preparation of tenofovir by dealkylation of its phosphonate ester using Ionic complexes. The present invention also provides a process for preparation of tenofovir disoproxil or a salt thereof using the tenofovir of the present invention.
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Page/Page column 15; 16
(2013/06/05)
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- PROCESS FOR THE PREPARATION OF TENOFOVIR
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The present invention provides a process for the preparation of tenofovir. The present invention also provides a process for the preparation of tenofovir disoproxil or a salt thereof and its pharmaceutical composition using the tenofovir of the present invention.
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Paragraph 0125
(2013/07/05)
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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 tenofovir
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The present invention provides a process for the preparation of tenofovir. The present invention also provides a process for the preparation of tenofovir disoproxil or a salt thereof and a pharmaceutical composition containing the tenofovir of the present invention.
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Page/Page column 13-14
(2012/06/18)
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- PROCESS FOR THE PREPARATION OF TENOFOVIR
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The present invention provides a process for the preparation of tenofovir. The present invention also provides a process for the preparation of tenofovir disoproxil or a salt thereof and its pharmaceutical composition using the tenofovir of the present invention.
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- AN IMPROVED PROCESS FOR THE PREPARATION OF TENOFOVIR DISOPROXIL FUMARATE
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The present invention relates to an improved process for the preparation of Tenofovir Disoproxil and its pharmaceutically acceptable salts comprising the steps of: a) esterifying Tenofovir with chloromethyl isopropyl carbonate in presence of a base, phase transfer catalyst and optionally dehydrating agent, in a suitable solvent; b) optionally purifying Tenofovir Disoproxil; and c) converting of Tenofovir Disoproxil into its pharmaceutically acceptable salts. The present invention further relates to a process for the preparation of Tenofovir by reacting l-(6-amino-purin-9-yl)-propan- 2-ol with toluene-4-sulfonic acid diethoxy phosphoryl methyl ester in presence of a base in a non-polar solvent medium followed by hydrolysis.
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Page/Page column 9; 10
(2011/10/05)
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- Process improvements for the manufacture of tenofovir disoproxil fumarate at commercial scale
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The three-step manufacturing process used in the synthesis of tenofovir disoproxil fumarate (1) was studied and optimized, leading to a more productive and robust process. The yield was improved from about 13% overall to 24%. Key process improvements identified included implementation of a telescoped process for the second stage that obviated the need for an extraction and solvent exchange, and significant optimization of the final reaction, including the beneficial effect of adding a quaternary ammonium salt to the alkylation reaction and development of a nonaqueous process for removal of NMP and triethylamine from the product mixture to decrease the level of decomposition of product during the isolation.
- Ripin, David H. Brown,Teager, David S.,Fortunak, Joseph,Basha, Shaik Mahaboob,Bivins, Nylea,Boddy, Christopher N.,Byrn, Stephen,Catlin, Kelly K.,Houghton, Stephen R.,Jagadeesh, S. Tirumala,Kumar, K. Anesh,Melton, Jack,Muneer, Shaik,Rao, L. Nagaprasada,Rao, R. Venkateswara,Ray, Puma Chandra,Reddy, Nardla Gopal,Reddy, Ravi Mallikarjuna,Shekar, K. Chandra,Silverton, Tricia,Smith, Daniel T.,Stringham, Rodger W.,Subbaraju, Gottumukkala V.,Talley, Frajovon,Williams, Adrian
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p. 1194 - 1201
(2011/04/26)
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- Rapid, mild method for phosphonate diester hydrolysis: Development of a one-pot synthesis of tenofovir disoproxil fumarate from tenofovir diethyl ester
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A rapid, low temperature hydrolysis of tenofovir diethyl ester mediated by TMSCl and NaBr was identified and demonstrated to be superior to the current production method, TMSBr-mediated hydrolysis. This mild phosphonate ester hydrolysis was then coupled to alkylation of the phosphonic acid, providing a one-pot procedure for formation of tenofovir disoproxil from tenofovir diethyl ester. The hydrolytic conditions developed here dramatically improve the synthesis of tenofovir disoproxyl and will lead to lower cost HIV/AIDS treatment in the developing world.
- Houghton, Stephen R.,Melton, Jack,Fortunak, Joseph,Brown Ripin, David H.,Boddy, Christopher N.
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experimental part
p. 8137 - 8144
(2010/10/21)
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- CRYSTALLINE FORM OF TENOFOVIR DISOPROXIL AND A PROCESS FOR ITS PREPARATION
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Crystalline Form C of tenofovir disoproxil, salts thereof and a process for its preparation. The process involves adding a solution comprising tenofovir disoproxil and an organic solvent to salt-saturated water, whereby the crystalline Form C of tenofovir disoproxil precipitates. The crystalline Form C of tenofovir disoproxil may be converted to a salt thereof. There is also provided a process for purifying a crude product comprising tenofovir monoisoproxil and tenofovir disoproxil.
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Page/Page column 11-12
(2009/12/05)
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