- 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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Read Online
- Green and environment-friendly preparation method of tenofovir
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The invention relates to a green and environment-friendly preparation method of tenofovir, and belongs to the technical field of tenofovir preparation. The method comprises the following steps: (1) adding a solvent and R-hydroxypropyl adenine; adding a coupling catalyst in batches, heating, dropwise adding p-toluenesulfonyl methoxy dialkyl phosphonate, carrying out heat preservation and stirring; (2) cooling and adjusting the pH value; and heating and concentrating under reduced pressure; (3) cooling and adding acetone; and cooling, stirring, filtering and concentrating under reduced pressure; (4) adding SO4/ZrO2-Nd2O3 type solid acid, stirring, heating, and adding deionized water; (5) carrying out stirring reaction; and filtering; (6) stirring, decolorizing and filtering; (7) adjusting pH, cooling and stirring; and (8) centrifuging to be dry, and taking out a filter cake to obtain a tenofovir wet product; and drying under reduced pressure to obtain a finished product. The method is scientific and reasonable in design, mild in reaction condition, easy to operate and suitable for green and environment-friendly industrial production, and the product yield and purity are obviously improved.
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Paragraph 0063-0074; 0081-0086
(2021/08/07)
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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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supporting information
p. 789 - 798
(2021/03/01)
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- An Efficient Synthesis of Tenofovir (PMPA): A Key Intermediate Leading to Tenofovir-Based HIV Medicines
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Herein, we report further improvements to the synthesis of tenofovir 1, the precursor to tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF). Starting from acyclic precursor diaminomalononitrile 12, a four-step protocol to tenofovir 1 will allow for vertical integration for more manufacturers. The key transformation is a convergent one-step procedure from 6 as compared to the current commercial process, with an improved yield from 59% (two steps) to 70%. Further improvements include eliminating the need for problematic magnesium tert-butoxide (MTB) and significant solvent reduction by avoiding an intermediate workup. With the costs of HIV/AIDS treatments remaining a barrier for those most in need, lowering the raw material/processing costs and increasing the security of supply can increase patient access.
- Arduengo, Anthony J.,Cardoso, Flavio S. P.,Derstine, Brenden P.,Dietz, Jule-Phillip,Gupton, B. Frank,Herrera, Brenden T.,McQuade, D. Tyler,Opatz, Till,Paymode, Dinesh J.,Peck, Cheryl L.,Snead, David R.,Stringham, Rodger W.,Tomlin, John W.,Yue, Andrew C.
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p. 1420 - 1427
(2020/10/12)
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- Green and environment-friendly preparation method of tenofovir
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The invention discloses a green and environment-friendly tenofovir preparation method which comprises the following steps: dissolving a compound I, S-propylene carbonate and an inorganic weak base inan organic solvent, reacting for 3-6 hours at 85-120 DEG C, cooling to room temperature, and concentrating an obtained system under reduced pressure to obtain an intermediate II; dissolving the intermediate II, hydroxymethylphosphonic acid dialkyl ester and trialkyl (aryl) phosphine in an organic solvent, stirring at room temperature, slowly adding azodicarboxylic acid diester, and reacting for 20minutes to 3 hours to obtain an intermediate III; slowly adding an inorganic strong alkali into the intermediate III, carrying out ice bath, filtering, adjusting the pH value of an obtained filtrate,standing, carrying out suction filtration, washing an obtained filter cake, and carrying out vacuum drying under reduced pressure. According to the method, S-propylene carbonate, adenine and derivatives thereof are taken as initial raw materials; PMPA is generated through configuration inversion of Mitsunobu reaction, the used organic solvents can be recycled, the generated wastewater is mainly aharmless inorganic salt solution, the cost for further treatment and up-to-standard discharge is low, the method is environmentally friendly, the reaction is easy to control, the safety is high, andthe comprehensive economic benefit is high.
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Paragraph 0028; 0033
(2020/06/16)
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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 0041-0049
(2020/11/26)
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- Repurposing Antiviral Drugs for Orthogonal RNA-Catalyzed Labeling of RNA
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In vitro selected ribozymes are promising tools for site-specific labeling of RNA. Previously known nucleic acid catalysts attached fluorescently labeled adenosine or guanosine derivatives through 2′,5′-branched phosphodiester bonds to the RNA of interest. Herein, we report new ribozymes that use orthogonal substrates, derived from the antiviral drug tenofovir, and attach bioorthogonal functional groups, as well as affinity handles and fluorescent reporter units through a hydrolytically more stable phosphonate ester linkage. The tenofovir transferase ribozymes were identified by in vitro selection and are orthogonal to nucleotide transferase ribozymes. As genetically encodable functional RNAs, these ribozymes may be developed for potential cellular applications. The orthogonal ribozymes addressed desired target sites in large RNAs in vitro, as shown by fluorescent labeling of E. coli 16S and 23S rRNAs in total cellular RNA.
- Dey, Surjendu,Ghaem Maghami, Mohammad,H?bartner, Claudia,Lenz, Ann-Kathrin
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p. 9335 - 9339
(2020/04/17)
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- Method for recycling byproduct p-toluene magnesium sulfonate to synthesize tenofovir
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The invention relates to the technical field of medicine chemicals and in particular discloses a method for recycling a byproduct p-toluene magnesium sulfonate to synthesize tenofovir. According to the method, hydroxymethylphosphonic acid diethyl ester and paratoluensulfonyl chloride are adopted as raw materials, magnesium carbonate is adopted as an acid-binding agent, p-toluenesulfonyl oxymethyldiethyl phosphate is synthesized, tenofovir is synthesized from the p-toluenesulfonyl oxymethyl diethyl phosphate and R-9-(2-hydroxypropyl), and meanwhile, a byproduct p-toluene magnesium sulfonate isgenerated; and magnesium carbonate and sodium p-toluenesulfonate are generated through a reaction of the p-toluene magnesium sulfonate and sodium carbonate. According to the method, the byproduct p-toluene magnesium sulfonate is mainly recycled, process treatment difficulties are reduced, byproducts p-toluene magnesium sulfonate and magnesium chloride which are obtained after treatment are high in purity, export sales can be achieved, the magnesium carbonate can be applied to synthesis of the p-toluenesulfonyl oxymethyl diethyl phosphate, and the production cost can be reduced.
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Paragraph 0037; 0038
(2019/10/01)
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- Method of preparing tenofovir by using microreactor
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The invention provides a method of preparing tenofovir by using a microreactor. The method comprises the following steps: performing a condensation reaction by using adenine and (R)-propylene carbonate as raw materials to prepare (R)-9-(2-hydroxypropyl)adenine, and performing a condensation reaction on the (R)-9-(2-hydroxypropyl)adenine and diethyl(tosyloxy)phosphonate under the action of magnesium tert-butoxide to prepare (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine; and performing a deesterification reaction by adopting a microreactor and using a hydrogen chloride gas as a deesterification reagent to prepare the tenofovir. According to the method provided by the invention, the deesterification reaction uses the hydrogen chloride as the deesterification reagent, and the hydrogen chloride used in the method has a low price and low costs; the quantitative reaction is used, and the deesterification reaction is carried out by using the microreactor technology, so that the reaction pressure and temperature are improved, and the mixing effect is enhanced; the generation amount of waste liquid is less, and the method is green and environmentally friendly; and the method has a fast reaction speed, high reaction efficiency, less side reactions, and high purity and a high yield of the target product, and facilitates industrial production.
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Paragraph 0053; 0057-0058; 0062-0063; 0067-0073
(2019/11/28)
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- Tenofovir disoproxil fumarate analog preparation method
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The present invention discloses a tenofovir disoproxil fumarate analog preparation method, which comprises: carrying out a substitution reaction on adenine as a raw material and (R)-propylene carbonate in the presence of an alkali, carrying out a substitution reaction with (diethoxyphosphoryl)methyl-4-methylbenzenesulfonate, hydrolyzing with a concentrated hydrochloric acid solution, crystallizingto obtain anhydrous tenofovir, carrying out a reaction on the anhydrous tenofovir and chloromethyl isopropyl carbonate to obtain tenofovir monoester, and carrying out a reaction with 2-bromopropane to obtain the target compound. According to the present invention, the selected starting raw materials are inexpensive and easy to obtain, the process is simple, and the material utilization rate and total yield are improved; and the intermediate of the method is purified by re-crystallization, such that the yield is high, and the purity is high.
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Paragraph 0010; 0026; 0027
(2019/03/10)
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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; 0047-0051
(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; 0017; 0021; 0022; 0026; 0027
(2019/09/17)
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- Preparation method for tenofovir
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The invention relates to the field of chemical synthesis, and in particular relates to a preparation method for tenofovir. The compound provided by the invention has a structure shown by a formula XIIin the description. The method for preparing the tenofovir based on a compound provided by the invention has the advantages that raw materials are cheap and easy to obtain, the process route is short, the conditions are mild and reliable, and the method is easily used for industrialized production.
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Paragraph 0086-0087
(2018/07/30)
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- Preparation method of high-purity tenofovir
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The invention provides a preparation method of high-purity tenofovir. The method at least comprises the following steps: (1) preparing R-propylene carbonate; (2) purifying a catalyst; (3) carrying outcondensation reaction on adenine with R-propylene carbonate; (4) carrying out etherification reaction on 9-(2-hydroxypropyl) adenine with diethyl p-toluenesulfonyloxymethylphosphonate; (5) carrying out hydrolysis reaction on tenofovir diester; and (6) refining crude tenofovir.
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Paragraph 0073; 0087; 0093-0094; 0134; 0140-0141; 0142; 0148
(2018/09/08)
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- Tenofovir synthesizing method
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The invention discloses a tenofovir synthesizing method. According to the method, diethyl p-toluenesulfonyloxymethylphosphonate (TSDEP), (R)-9-(2-hydroxyl propyl)adenine (HPA) and a solid base catalyst like KOH/Al2O3, strong acid cation exchange resin and the like are utilized as raw materials; a product is prepared by aftertreatment operation of condensing, hydrolysis two-step reaction, filtration, reduced pressure distillation, cooling and the like. The method disclosed by the invention has the characteristics of sufficient raw material sources, low cost, high synthesizing technology safety,high product yield, small three-waste pollution and higher industrial value; furthermore, the solid alkali catalyst and the strong acid cation exchange resin are easy to recycle and suitable for setuse after regeneration.
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Paragraph 0027-0034
(2019/01/15)
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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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- 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 0059
(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; 0091; 0105; 0119; 0133; 0140; 0147; 0159
(2018/09/11)
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- A process for preparing tynofovir method
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The invention discloses a tenofovir preparation method. The method comprises reactions with equations shown in the specification; and in the equations, A is a C1-C4 alkylcarbonyl group or an aryl-substituted C1-C4 alkylcarbonyl group, B is H, a C1-C4 alkylcarbonyl group or an aryl-substituted C1-C4 alkylcarbonyl group, R is a C1-C3 alkyl group or a phenyl group, R' is H, a C1-C3 alkyl group or a phenyl group, a reaction a is characterized in that a compound of formula III reacts with (R)-propylene carbonate and dialkyl (tosyloxy)methylphosphonate to generate an intermediate II, and a reaction b is characterized in that the intermediate II is hydrolyzed under the action of an inorganic acid to remove a protection group in order to obtain tenofovir. The method can realize synthesis of highly pure tenofovir in low cost and high yield by using cheap and easily available raw materials through simple operation under mild reaction conditions, has the advantages of energy saving and environmental protection, is suitable for large scale production, and has significant values for realizing the industrial production of tenofovir.
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Paragraph 0042-0043; 0045
(2018/02/04)
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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 0092; 0093; 0098-0102
(2017/07/14)
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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; 0017; 0021; 0025
(2017/06/02)
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- Method of preparing tenofovir
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The invention provides a method for preparing tenofovir. The method is characterized by comprising the following steps: 1) reacting 9-(2-hydroxy propyl) adenine with a compound as shown in the formula (1) in the specification in the presence of magnesium alkoxide to prepare tenofovir ethyl ester, wherein Y is selected from methyl, trifluoromethyl, phenyl or 4-trifluoromethylphenyl; 2) hydrolyzing the tenofovir ethyl ester in the presence of a dealkylation reagent to prepare tenofovir. The method for preparing tenofovir provided by the invention has the advantages of safe process, good product quality, high yield and suitability for industrialization.
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Paragraph 0055; 0062; 0063
(2017/08/25)
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- Synthesis Method For Improved Tenofovir Disoproxil Fumarate Using Ion-Exchange Resin And Method For Preparing Oral Dissolving Film Form Using The Same
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The present invention relates to a synthesis method of preventing the formation of impurities and byproducts in the synthesis of tenofovir disoproxil fumarate (Teno-DF) used as a medicine for hepatitis B and HIV treatment due to its function to promote bioactivities. In the synthesis method of the present invention, an ion-exchange resin (Dowex 50W hydrogen form, sulfonic acidic cation exchange resin) is used to enhance the yield and purity of the compound. The present invention also relates to a method of preparing an oral dissolving film dosage form in the manufacture of a medicine using the tenofovir compound with high purity obtained by the synthesis method of the present invention as an effective ingredient.
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Paragraph 0111; 0126; 0127
(2018/01/14)
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- Process for preparing tynofovir
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The invention discloses a process for preparing tenofovir. The method is characterized by comprising the steps: with adenine, (R)-propylene carbonate and p-toluenesulfonyloxy methyl phosphonic diester as raw materials, adopts a one-pot process to prepare an intermediate 2, and followed by hydrolyzing the intermediate 2 by an inorganic acid to obtain tenofovir, wherein the following reaction formula is shown in the description. With utilization of the process, the purpose that high-purity tenofovir is synthesized with utilization of cheap and easily available raw materials and with simple operation, mild reaction conditions, low cost and high yield is achieved; and the process has the advantages of energy saving and environmental protection, is suitable for large scale production, and has practical value in realization of industrial production of tenofovir.
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Paragraph 0037-0039
(2017/02/24)
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- A [1-halo-(2-propoxy)]-methylphosphonic acid compound and its preparation and use
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The invention relates to [1-halo-(2-propoxy)]-methylphosphoric acid compounds as well as preparation and an application thereof. The compounds are [1-halo-(2-propoxy)]-methylphosphoric acid, (R)-[1-halo-(2-propoxy)]-methylphosphoric acid or (S)-[1-halo-(2-propoxy)]-methylphosphoric acid, the structural formulae are respectively shown in the specification. The compounds provided by the invention are used for preparing tenofovir and can better solve the defects in the existing process. The self process has the advantages of high yield, good product quality and the like, the production cost of tenofovir can be greatly lowered, and the compounds are suitable for industrial production.
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Paragraph 0159; 0160; 0161; 0162
(2018/02/04)
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- Method of preparing tenofovir
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The invention provides a method for preparing tenofovir. The method is characterized by comprising the following steps: 1) reacting 9-(2-hydroxy propyl) adenine with p-fluorobenzenesulfonyl diethyl methylphosphonite in the presence of magnesium alkoxide to prepare tenofovir ethyl ester; 2) hydrolyzing the tenofovir ethyl ester in the presence of a dealkylation reagent to prepare tenofovir. The method for preparing tenofovir provided by the invention has the advantages of safe process, good product quality, high yield and suitability for industrialization.
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Paragraph 0057; 0058
(2017/02/02)
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- SYNTHESIS OF INTERMEDIATES USED IN THE MANUFACTURE OF ANTI-HIV AGENTS
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The present invention relates to a process of preparing intermediates of Formula (I). The process comprises of reacting compound of Formula (III) with compound of Formula (V) in the presence of a solvent selected from an alcohol, ether or water to form compound of Formula (I) wherein, R1 is selected from –NH2, Cl, Br, NHCOR", wherein R" is alkyl, aryl, Schiff's base of formula N=CHR', wherein R' is alkyl or aryl; R2 is selected from H, alkyl; R3 and R4, each independently is H; R5 and R6, each independently is H, alkyl; R7 is H, alkyl; and R8 is H, alkyl.
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Page/Page column 24-25
(2016/11/21)
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- Preparation method of (R)-9-[2-(phosphoryl methoxyl)propyl]-adenine
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The invention discloses a preparation method of (R)-9-[2-(phosphoryl methoxyl)propyl]-adenine, and relates to a preparation method of an antiviral drug for an acquired immune deficiency syndrome. The method comprises the steps that when (R)-9-[2-(diethyl phosphoryl methoxyl)propyl]-adenine is prepared, (R)-hydroxypropyl adenine and diethyl p-toluenesulfonyloxymethylphosphonate (DESMP) are subjected to a condensation reaction under the action of magnesium tert-butoxide to generate the (R)-9-[2-(diethyl phosphoryl methoxyl)propyl]-adenine; PMPA diethyl ester is subjected to deethylation through trimethylbromosilane by taking water as solvent to obtain the (R)-9-[2-(phosphoryl methoxyl)propyl]-adenine (PMPA). According to the technology, the product yield is increased, the technology is cleaner, the production cost is lowered, the product yield is increased, the raw materials are easy to obtain, and industrialization is easy to achieve.
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Paragraph 0008; 0022; 0023; 0024
(2017/01/02)
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- Preparation method for tenofovir
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The invention relates to a preparation method for tenofovir. The preparation method comprises the following steps: 1) subjecting hydroxypropyl adenine and diethyl p-sulfonyloxymethylphosphonate to a condensation reaction in an organic solvent in the presence of alkali and salt so as to prepare tenofovir diester, wherein a mol ratio of hydroxypropyl adenine to diethyl p-sulfonyloxymethylphosphonate is 1: 1-3, a mol ratio of hydroxypropyl adenine to alkali is 1: 1-5, and a mol ratio of salt to alkali is 1: 1-5; and 2) subjecting tenofovir diester to a hydrolysis reaction in an acidic condition so as to prepare tenofovir, wherein a mol ratio of tenofovir diester to acid is 1: 3-15. The method has the advantages of high yield, low cost, safety, environment friendliness, convenience in operation, etc.
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Paragraph 0070; 0071; 0072; 0073; 0074; 0075; 0076-0078
(2016/12/22)
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- An Improved Process for the Preparation of Tenofovir Disoproxil Fumarate
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The current three-step manufacturing route for the preparation of tenofovir disoproxil fumarate (1) was assessed and optimized leading to a higher yielding, simpler, and greener process. Key improvements in the process route include the refinement of the second stage through the replacement of the problematic magnesium tert-butoxide (MTB) with a 1:1 ratio of a Grignard reagent and tert-butanol. The development of a virtually solvent-free approach and the establishment of a workup and purification protocol which allows the isolation of a pure diethyl phosphonate ester (8) was achieved.
- Riley, Darren L.,Walwyn, David R.,Edlin, Chris D.
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p. 742 - 750
(2016/05/19)
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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 0051-0053
(2017/02/09)
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- PREPARATION METHOD FOR (R)-9-[2-(PHOSPHONOMETHOXY)PROPYL]ADENINE WITH HIGH PURITY
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The present invention relates to a method for preparing (R)-9-[2-(phosphonomethoxy)propyl]adenine (PMPA) with high purity. The method includes easy processing steps and uses, as an intermediate, (diethoxyphosphoryl)methyl naphthalen-2-sulfonate or (diethoxyphosphoryl)methyl naphthalen-2-sulfonate generating little impurities to provide high purity. Thus, it is possible to obtain PMPA with high purity. Particularly, (diethoxyphosphoryl) methyl naphthalen-1-sulfonate is a solid material, is handled with ease during the use for preparation of PMPA, is suitable for mass production, allows production with uniform and constant quality, and thus can be introduced in a precise equivalent amount during the reaction. In addition, the method uses no reagent sensitive to contact with moisture and air, and thus is safe, shows high reproducibility, and is suitable for mass production. Further, PMPA obtained by the method according to the present invention has significantly high purity. Thus, when such PMPA is used, it is possible to obtain tenofovir disoproxil and acid addition salts thereof with high purity, thereby facilitating production of high-quality material medicine.COPYRIGHT KIPO 2016
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Paragraph 0106; 0107; 0109; 0113; 0114; 0116; 0117
(2016/10/17)
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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 0013
(2016/12/07)
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- A method for the synthesis of adenine derivative
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The invention discloses the technical field of medicines and particularly discloses a new prodrug, namely (R)-9-(2-(phosphonyl methoxyl)propenyl) adenine, a cyclodextrin inclusion compound of the prodrug and a non-toxic and pharmaceutically acceptable salt of the prodrug. The prodrug disclosed by the invention can be metabolized into PMPA in vivo, and has the bioavailability of about 39%, and the bioavailability of the prodrug is better than that of tenofovir disoproxil fumarate (Bis-(POC)-PMPA); and the prodrug has more excellent antiviral activity and better safety compared with the tenofovir disoproxil fumarate.
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Paragraph 0016; 0026-0027
(2017/04/03)
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- Industrialization production technology for tenofovir disoproxil fumarate
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The invention relates to an industrialization production technology for tenofovir disoproxil fumarate. The production technology comprises the following steps that firstly, R-1,2-polylene glycol, diethyl carbonate and sodium ethoxide are added into a reaction kettle; absolute ethyl alcohol and diethyl phosphite are added into the reaction kettle and stirred, paraformaldehyde and triethylamine are added after stirring is completed, after the complete reaction is achieved, anhydrous sodium sulfate is added, drying, filtering and steaming are carried out, and a steamed product is a diethyl p-toluenesulfonyloxymethylphosphonate fine product; adenine, R-propylene carbonate, DMF and NaOH are added into the reaction kettle, after the complete reaction is achieved, magnesium tert-butoxide is added, p-toluenesulfonyloxy phosphonate is dropwise added, after the complete reaction is achieved, acetic acid is added, vacuum concentration is carried out, hydrochloric acid is added, filtering is carried out, solids are filtered out and dried at the normal pressure, and a PMPA fine product is obtained. The industrialization production technology has the advantages of being high in yield and product purity, low in impurity content and capable of being completely applied to industrialization production.
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Paragraph 0013-0014
(2017/04/11)
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- A method for preparing high-purity tynofovir
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The invention discloses a preparation method of high-purity tenofovir. The method comprises the following steps: preparing a crude tenofovir product by using adenine and (R)-propylene carbonate serving as raw materials through a one-pot method, and purifying through an acid-alkali method to obtain the high-purity tenofovir. According to the method disclosed by the invention, tenofovir is prepared through the one-pot method, three steps of reaction are not separated and can be completed at one time; the preparation method is simple, raw materials are easily available, the reaction yield is high and the product quality is good. The method is favorable for environmental protection, applicable to industrial production and high in application value. And the method disclosed by the invention is described as a reaction formula shown in specification.
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Paragraph 0029; 0030
(2017/04/19)
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- A fast dissolving film-formulation for oral dosage of tenofovir disoproxil fumarate and the manufacturing method thereof
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The present invention relates to an oral dissolving film dosage form using tenofovir disoproxil fumarate (Teno-DF), which is used as a therapeutic agent for hepatitis B or AIDS due to physiological activity promoting function thereof, and to a preparing method therefor. The method for preparing tenofovir disoproxil fumarate of the present invention can increase the yield and purity in the synthesis of the compound by using an ion exchange resin (Dowex 50W hydrogen form, sulfonic acidic cation exchange resin), and furthermore, unlike a dosage form obtained by coating a film on a tablet as the conventional art, the oral dissolving film dosage form provided in the present invention is convenient for a patient to take.
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Paragraph 0080
(2017/05/12)
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- Selective lewis acid catalyzed assembly of phosphonomethyl ethers: Three-step synthesis of tenofovir
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Described herein is a novel Lewis acid catalyzed rearrangement-coupling of oxygen heterocycles and bis(diethylamino)chlorophosphine that provides direct formation of the phosphonomethyl ether functionality found in several important antiretroviral agents. A wide range of dioxolanes and 1,3-dioxanes may be employed, furnishing the desired products in good yield. The utility of this method is demonstrated in a novel synthesis of tenofovir, an antiretroviral drug used in the treatment of HIV/AIDS and hepatitis B.
- Ocampo, Charles E.,Lee, Doris,Jamison, Timothy F.
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supporting information
p. 820 - 823
(2015/03/18)
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- Improved Method for Preparing (R)-9-[2-(phosphonomethoxy)propyl]adenine
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The present invention relates to a method for preparing high purity (R)-9-[2-(phosphonomethoxy)propyl]adenine (PMPA), According to the present invention, the method uses dialkyl methylsulfonyl-oxymethyl phosphonate, which generates only a small amount of impurities in a reaction and has high purity, as an intermediate to prepare the high purity PMPA with a small amount of impurities. The present invention does not use a reagent sensitive to air and moisture contact to enhance safety and allow reproducible production and is easily handled to enable mass production. The high purity PMPA prepared by using the method can be used to prepare tenofovir disoproxil and acidic salt thereof in order to give a very favorable advantage for the production of high quality drug ingredient.COPYRIGHT KIPO 2016
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Paragraph 0072; 0078-0082
(2021/06/15)
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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 0166; 0167; 0176
(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 22; 23; 6
(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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Paragraph 0018; 0031
(2015/04/22)
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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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Paragraph 0080; 0081; 0082
(2014/10/16)
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- A PROCESS FOR THE PREPARATION OF (R)-9-[2-(PHOSPHONOMETH-OXY)PROPYL]ADENINE (PMPA)
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This invention relates to a process for the preparation of (R)-9-[2- (phosphonometh-oxy)propyl]adenine (PMPA). This invention also relates to the preparation of Tenofovir disoproxil fumarate (TDF), a compound which can be produced from PMPA. The claimed process comprises reacting compound (6) with compound (7) in presence of 2,2,6,6- tetramethylpiperidinylmagnesium to compound (2), which is hydrolysed to (3).
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Page/Page column 50
(2014/03/25)
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- PHARMACEUTICAL ANTIRETROVIRAL COMPOSITION
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The present invention relates to a pharmaceutical antiretroviral composition comprising (i) a nucleoside reverse-transcriptase inhibitor selected from lamivudine and emtricitabine, (ii) extended release nevirapine, and (iii) tenofovir; a process for preparing such composition and the use of such composition in medicine, particularly for the prophylaxis and/or treatment of diseases caused by retroviruses.
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Page/Page column
(2014/07/22)
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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 12; 13
(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 0115; 0116; 0117; 0118
(2013/07/05)
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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 a pharmaceutical composition containing the tenofovir of the present invention.
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Page/Page column 12
(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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Page/Page column 17-18
(2012/06/30)
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