- An Efficient Synthesis of Tenofovir (PMPA): A Key Intermediate Leading to Tenofovir-Based HIV Medicines
-
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)
-
- Synthesis process of antiviral drug
-
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 0026-0040
(2020/11/26)
-
- Method of preparing tenofovir by using microreactor
-
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.
- -
-
Paragraph 0053-0055; 0058-0060; 0063-0065
(2019/11/28)
-
- Tenofovir disoproxil fumarate analog preparation method
-
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.
- -
-
Sheet 0010; 0024
(2019/03/10)
-
- Method for preparing tenofovir disoproxil
-
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; 0021; 0026
(2019/09/17)
-
- Preparation method of high-purity tenofovir
-
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.
- -
-
Paragraph 0073; 0087; 0091; 0134; 0138; 0142; 0146; 0150
(2018/09/08)
-
- Preparation method for tenofovir
-
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.
- -
-
Paragraph 0080-0085
(2018/07/30)
-
- A method of synthesis for fuwei intermediates (by machine translation)
-
The invention discloses a method for synthesizing for fuwei intermediate of the method, the method comprises: formula 2 compound of formula 9 - propenyl adenine as raw materials, in the (S)- (-) - 2, 2 '- double (b benzene phosphine base) - 1, 1' - binaphthyl induction, and tetramethyl piperidine nitrogen oxide oxidation reaction to obtain the type 1 indicated by the tenofovir intermediate (R)- 9 - (2 - hydroxy-propyl) adenine; Through the method of the invention for the preparation of tenofovir intermediate (R)- 9 - (2 - hydroxy-propyl) adenine, mild reaction conditions, the industrial application and popularization; yield of the object product, good selectivity; without using a large amount of chiral compounds, the use of a small amount of chiral auxiliary can be induced oxidation, the cost is low. (by machine translation)
- -
-
-
- Method of preparing tenofovir
-
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.
- -
-
Paragraph 0055; 0058; 0059
(2017/08/25)
-
- Synthesis Method For Improved Tenofovir Disoproxil Fumarate Using Ion-Exchange Resin And Method For Preparing Oral Dissolving Film Form Using The Same
-
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.
- -
-
Paragraph 0101; 0102
(2018/01/14)
-
- for Fuwei ester bulk drug and tablet (by machine translation)
-
The invention relates to a raw material for the fuwei ester and tablet, the states for Fuwei the ester bulk drug preparation method comprises the following steps: compound 1 with R - propylene carbonate reaction, be R - 9 - (2 - hydroxy-propyl) adenine; R - 9 - (2 - hydroxy-propyl) adenine with toluene-sulfonyloxy diethyl phosphoric condensation reaction, generating compound 2 compound 2 hydrolysis to obtain the tenofovir, for fuwei with chloromethyl carbonic acid isopropyl ester condensation to get said states for Fuwei the ester. The states for Fuwei the ester tablet, comprises the following weight percentages of each component: for Fuwei ester bulk drug, microcrystalline cellulose, anhydrous lactose, or microcrystalline cellulose aqueous solution, sodium carboxy methyl cellulose, magnesium stearate. The preparation method of the raw material for the fuwei ester reaction yield is high, and the production process simple and convenient operation, all of the raw materials are cheap and easy to get with low operation difficulty, production risk is low, is conducive to the realization of large-scale industrial production. (by machine translation)
- -
-
Paragraph 0026; 0027; 0028; 0031; 0032
(2017/07/01)
-
- (R)- (+) - 9 - (2 - hydroxypropyl) adenine preparation method
-
The invention discloses a preparation method of (R)-(+)-9-(2-hydroxypropyl) adenine, which is a key intermediate for tenofovir disoproxil fumarate. The method comprises the following steps: (1) reacting 6-chloropurine and bromopropanone to obtain 6-chloro-9-(acetonyl)-purine; (2) performing an asymmetric hydrogenation reduction reaction of the resultant 6-chloro-9-(acetonyl)-purine to obtain (R)-(+)-6-chloro-9-(2-hydroxypropyl) adenine; and (3) performing an aminolysis reaction of the resultant (R)-(+)-6-chloro-9-(2-hydroxypropyl) adenine to obtain (R)-(+)-9-(2-hydroxypropyl) adenine. An achiral compound, cheap and easy to obtain, is taken as a raw material in the method; the reaction steps are small; the reaction is easy to deal with; the enantioselectivity of the product is high; and the yield is high, and thus the preparation method has industrialization value.
- -
-
Paragraph 0037
(2017/07/01)
-
- Preparation method of tenofovir intermediate
-
The invention discloses a preparation method of a tenofovir intermediate. The preparation method comprises the following steps: 1, contacting and reacting adenine with (Z)-1-halopropylene in an organic solvent in the presence of hexamethylphosphoramide to obtain (Z)-9-propenyladenine; and 2, reacting the (Z)-9-propenyladenine with metachloroperbenzoic acid under the catalysis of a chiral catalyst to obtain the tenofovir intermediate (R)-9-(2-hydroxypropyl)adenine, wherein the chiral catalyst is D-(-)-tartaric acid. The raw materials of the preparation method of the tenofovir intermediate are easy to obtain, so cost control is facilitated; the target product is obtained through introducing relative configuration Z shape alkene and carrying out selective oxidation without using a large amount of a chiral compound, so the product selectivity is good, and the yield is high; and the method has the advantages of no special strict conditions, mild reaction conditions, and convenience in amplified production operation and industrial application promotion.
- -
-
Paragraph 0039-0049
(2017/08/28)
-
- Synthesis of (R) - 9 - (2-hydroxy-propyl) adenine method
-
The invention discloses a method for synthesizing (R)-9-(2-hydroxy propyl) adenine. The method sequentially comprises the following steps: (1) primary amino acetylation: dissolving adenine in an organic solvent, adding alkali and a catalyst, stirring, and dripping acetic anhydride at 0-10 DEG C; holding at 80-85 DEG C, stirring and reacting for 6-10 h to obtain reaction liquid; (2) N-hydroxy propylation: regulating the pH of the reaction liquid to 9-10, adding propylene carbonate, stirring and reacting at 120-140 DEG C, cooling to 70-80 DEG C, adding toluene, stirring for 2-3 h, and separating and drying to obtain a solid product; (3) deacetylation reaction: adding the solid product into a sodium hydroxide aqueous solution, stirring to react at 90-95 DEG C for 2-4 h, cooling to the room temperature, neutralizing the pH to 6-8 through concentrated hydrochloric acid, separating and drying to obtain the product. The method provided by the invention is used for greatly increasing the reaction selectivity, avoiding the generation of byproduct (R)-6-(2-hydroxy propyl) adenine, increasing the yield of the (R)-9-(2-hydroxy propyl) adenine by more than 90% and greatly lowering the production cost of tenofovir disoproxil fumarate.
- -
-
Paragraph 0019; 0041; 0043
(2016/10/17)
-
- Synthesis and Structure Elucidation of (R)-3-(2′-hydroxyprop-1-yl) adenine
-
(R)-3-(2′-hydroxyprop-1-yl) adenine 4 was obtained by alkylation of adenine 1 with R-propylene carbonate 2 in the presence of pulverized sodium hydroxide in the synthetic process of tenofovir. The elucidation of the structure of 4 was confirmed by single crystal X-ray diffraction and NMR experiments such as 1D 1H, 13C, and DEPT, as well as 2D COSY, HSQC, and HMBC spectra.
- Gao, Yang,Zhong, Jia-Liang,Wu, Tai-Zhi,Jin, Lin-Yong,Zhang, Fu-Li
-
p. 579 - 582
(2016/04/19)
-
- Method of preparing tenofovir
-
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.
- -
-
Paragraph 0053; 0054
(2017/02/02)
-
- A fast dissolving film-formulation for oral dosage of tenofovir disoproxil fumarate and the manufacturing method thereof
-
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.
- -
-
Paragraph 0070; 0071; 0072; 0073
(2017/05/12)
-
- An Improved Process for the Preparation of Tenofovir Disoproxil Fumarate
-
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.
-
p. 742 - 750
(2016/05/19)
-
- A method for the synthesis of adenine derivative
-
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.
- -
-
Paragraph 0016; 0024-0025
(2017/04/03)
-
- Industrialization production technology for tenofovir disoproxil fumarate
-
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.
- -
-
Paragraph 0013-0014
(2017/04/11)
-
- A method for preparing high-purity tynofovir
-
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.
- -
-
Paragraph 0029; 0030
(2017/04/19)
-
- A process for the preparation of antiviral drugs
-
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.
- -
-
Paragraph 0037-0039
(2017/02/09)
-
- SYNTHESIS OF INTERMEDIATES USED IN THE MANUFACTURE OF ANTI-HIV AGENTS
-
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.
- -
-
Page/Page column 19
(2016/11/21)
-
- A new R-9 - (2-hydroxy-propyl) adenine purification treatment process
-
The invention relates to a novel purification processing process for R-9-(2-hydroxypropyl)adenine. R-9-(2-hydroxypropyl)adenine is prepared from adenine and R-propylene carbonate under alkaline conditions. According to the process, a solvent DMF after reacting is subjected to reduced-pressure distillation for mechanically applying, toluene is added into the residue so as to precipitate a crude product, and the yield of the crude product is higher than 90%; and then, the crude product is subjected to chromatographic separation by using resin PRP-6A, ethanol water serves as an eluant, an isomer II is eluted firstly, R-9-(2-hydroxypropyl)adenine I is then eluted, eluates of the two kinds of products are respectively collected, depressurized concentration evaporation is carried out so as to obtain white crystalline powder R-9-(2-hydroxypropyl)adenine I which has the purity higher than 99% and the separation yield higher than 90%, the purity of the isomer II is higher than 99%, and the separation yield of the isomer II is higher than 90%. According to the process disclosed by the invention, the processing is simple, a resin chromatographic column can be reused repeatedly without affecting the separating effect, and the eluant can be repeatedly applied mechanically, so that the separation cost is greatly reduced; two kinds of products are obtained, the product purity is high, the overall yield is higher than 80%, and the volume of the generated wastewater is small, so that the process is applicable to industrial production.
- -
-
Paragraph 0023; 0024; 0025; 0026; 0027; 0028; 0029-0034
(2016/12/16)
-
- NUCLEOTIDE ANALOGS
-
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
- -
-
Paragraph 0166; 0167; 0175
(2018/11/22)
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF TENOFOVIR DISOPROXIL AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
-
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.
- -
-
Page/Page column 6; 20; 21
(2015/04/28)
-
- An improved process for the preparation of Tenofovir disoproxil and pharmaceutically acceptable salts thereof
-
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.
- -
-
Paragraph 0018; 0027
(2015/04/22)
-
- The synthesis of tenofovir and its analogues via asymmetric transfer hydrogenation
-
A series of tenofovir analogues with potential antiviral and immunobiologically active compounds were synthesized through an asymmetric transfer hydrogenation reaction from achiral purine derivatives. Up to 97% ee and good to excellent yields were achieved under mild conditions through short reaction steps. The present report suggests an efficient process to acquire tenofovir and its analogues.
- Zhang, Qian,Ma, Bai-Wei,Wang, Qian-Qian,Wang, Xing-Xing,Hu, Xia,Xie, Ming-Sheng,Qu, Gui-Rong,Guo, Hai-Ming
-
supporting information
p. 2014 - 2017
(2014/05/06)
-
- A PROCESS FOR THE PREPARATION OF (R)-9-[2-(PHOSPHONOMETH-OXY)PROPYL]ADENINE (PMPA)
-
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 23
(2014/03/25)
-
- Ester prodrugs of acyclic nucleoside thiophosphonates compared to phosphonates: Synthesis, antiviral activity and decomposition study
-
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
-
p. 869 - 881
(2013/07/27)
-
- Process improvements for the manufacture of tenofovir disoproxil fumarate at commercial scale
-
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
-
experimental part
p. 1194 - 1201
(2011/04/26)
-
- Nucleotide Analogue Prodrug and the Preparation Thereof
-
(R)-9-[2-bis[pivaloyloxymeihoxy]phosphinoylmethoxypropyl]adenine (being abbreviated bis-POMPMPA, TD), the derivative and the use thereof. Also including the synthetic process of TD and the procedure for manufacturing solid TD, as well as the composition containing TD and the procedure for manufacturing the composition.
- -
-
Page/Page column 14
(2010/09/05)
-
- 8-Bromo-9-alkyl adenine derivatives as tools for developing new adenosine A2A and A2B receptors ligands
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Importance of making available selective adenosine receptor antagonists is boosted by recent findings of adenosine involvement in many CNS dysfunctions. In the present work a series of 8-bromo-9-alkyl adenines are prepared and fully characterized in radio
- Lambertucci, Catia,Antonini, Ippolito,Buccioni, Michela,Dal Ben, Diego,Kachare, Dhuldeo D.,Volpini, Rosaria,Klotz, Karl-Norbert,Cristalli, Gloria
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experimental part
p. 2812 - 2822
(2009/09/08)
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- NOVEL NUCLEOTIDE ANALOGUES AS PERCURSOR MOLECULES FOR ANTIVIRALS
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This invention relates to a purine or pyrimidine phosphonate compound of formula (I) or pharmaceutically acceptable salt thereof; wherein B, X, and R1-R3 are as defined in classes and subclasses herein. These compounds may be used as antiviral precursors. The invention also relates to therapeutic compositions of these compounds and their use for the preparation of a medication for treating and/or preventing a viral infection in a patient. The invention also provides methods for making these compounds. In particular, the invention provides an H- phosphinate precursor intermediate of formula (II) wherein B is a purine or pyrimidine base as defined herein and R1 is selected from the group comprising a hydrogen atom, and a methyl, ethyl, hydroxymethyl, hydroxyethyl and C1-6haloalkyl group.
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Page/Page column 69-70; 75; 81
(2008/12/05)
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- Synthesis, in vitro antiviral evaluation, and stability studies of novel α-borano-nucleotide analogues of 9-[2-(phosphonomethoxy)ethyl]adenine and (R)-9-[2-(phosphonomethoxy)propyl]adenine
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We describe here the synthesis of 9-[2-(Boranophosphonomethoxy)ethyl] adenine (6a) and (R)-9-[2-(Boranophosphonomethoxy)propyl]adenine (6b), the first α-boranophosphonate nucleosides in which a borane (BH3) group substitutes one nonbridging oxygen atom of the α-phosphonate moiety. H-phosphinates 5a and 5b and α-boranophosphonates 6a and 6b were evaluated for their in vitro activity against human immunodeficiency virus (HIV) infected cells and against a panel of DNA or RNA viruses. Compounds 5a, 5b, 6a, and 6b exhibited no significant antiviral activity in vitro and cytotoxicity. To measure the chemical and enzymatic stabilities of the target compounds 6a and 6b, kinetic data of decomposition for derivatives 5a, 5b, 6a, 6b, and standard compounds were studied at 37 °C in several media. The α- Boranophosphonates 6a and 6b were metabolized in culture medium into H-phosphinates 5a and 5b, with half-live values of 5.3 h for 6a and 1.3 h for 6b.
- Barral, Karine,Priet, Stéphane,Sire, Joséphine,Neyts, Johan,Balzarini, Jan,Canard, Bruno,Alvarez, Karine
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p. 7799 - 7806
(2008/02/02)
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- Nucleotide analog composition and synthesis method
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The invention relates to a composition comprising a solution of 9-[2-(phosphono-methoxy)propyl]adenine (PMPA) at a pH of about 2.7 ― 3.5 wherein the solution has less than about 0.1 g/ml (R, S)-PMPA and wherein about 90 ― 94 % of the PMPA is in the (R) configuration.
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- Practical synthesis of the anti-HIV drug, PMPA
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The anti-HIV nucleotide analogue PMPA can be prepared on a kilogram-scale by a three step sequence: i) condensation of adenine with (R)-propylene carbonate, ii) alkylation of the resulting (R)-9- (2-hydroxypropyl)adenine with diethyl p- toluenesulfonyloxymethanephosphonate using lithium tert-butoxide and iii) cleavage of the phosphonate ester functionalities with bromotrimethylsilane.
- Schultze, Lisa M.,Chapman, Harlan H.,Dubree, Nathan J. P.,Jones, Robert J.,Kent, Kenneth M.,Lee, Thomas T.,Louie, Michael S.,Postich, Michael J.,Prisbe, Ernest J.,Rohloff, John C.,Yu, Richard H.
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p. 1853 - 1856
(2007/10/03)
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- SYNTHESIS OF ENANTIOMERIC N-(2-PHOSPHONOMETHOXYPROPYL) DERIVATIVES OF PURINE AND PYRIMIDINE BASES. I. THE STEPWISE APPROACH
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The (R)- and (S)-N-(2-phosphonomethoxypropyl) derivatives of purine and pyrimidine bases (PMP derivatives) exhibit very high activity against retroviruses.This paper describes the synthesis of enantiomeric 9-(2-phosphonomethoxypropyl)adenines (I and XXVII), 9-(2-phosphonomethoxypropyl)-2,6-diaminopurines (II and XXXI), 9-(2-phosphonomethoxypropyl)guanines (III and XXIX) and 1-(R)-(2-phosphonomethoxypropyl)cytosine (XIX) by alkylation of N-protected N-(2-hydroxypropyl) derivatives of the corresponding bases with bis(2-propyl) p-toluenesulfonyloxymethylphosphonate (X), followed by stepwise N- and O-deprotection of the intermediates.The key intermediates, N-(2-hydropxypropyl) derivatives IX and XXV, were obtained by alkylation of the appropriate heterocyclic base with (R)- or (S)-2-(2-tetrahydropyranyloxy)propyl p-toluenesulfonate (VII or XXIII) ans acid hydrolysis of the resulting N- derivatives VIII and XXII.The chiral synthons were prepared by tosylation of (R)- or (S)-2-(2-tetrahydropyranyloxy)propanol (VI or XXI) available by reduction of enantiomeric alkyl 2-O-tetrahydropyranyllactates V and XXI with sodium bis(2-methoxyethyoxy)aluminum hydride.This approach was used for the synthsis of cytosine, adenine and 2,6-diaminopurine derivatives, while compounds derived from guanine were prepared by hydrolysis of 2-amino-6-chloropurine intermediates.Cytosine derivative IXe was also synthesized by alkylation of 4-methoxy-2-pyrimidone followed by ammonolysis of the intermediate IXf.
- Holy, Antonin,Masojidkova, Milena
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p. 1196 - 1212
(2007/10/02)
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- 9-(AMINOALKYL)-8-HYDROXYADENINES: PREPARATION, MECHANISM OF FORMATION AND USE IN AFFINITY CHROMATOGRAPHY OF S-ADENOSYL-L-HOMOCYSTEINE HYDROLASE
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Bromine reacts with 9-(2-hydroxyethyl)- (Va), 9-(3-hydroxypropyl)- (Vb), 9-(2-hydroxypropyl)- (Vc), 9-(2,3-dihydroxypropyl)- (Vd), 9-(1,3-dihydroxy-2-propyl)- (Ve), 9-threo-(2,3-dihydroxybutyl)- (Vf) and 9-threo-(2,3,4-trihydroxybutyl)adenine (Vg) to give
- Holy, Antonin,Kohoutova, Jitka,Merta, Ales,Votruba, Ivan
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p. 459 - 477
(2007/10/02)
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