- Method for preparing antiviral drug tenofovir alafenamide fumarate
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The invention discloses a method for preparing an antiviral drug tenofovir alafenamide fumarate, which comprises the following steps of: (1) reacting adenine with (R)-propylene carbonate to generate a compound I; (2) treating the compound I with magnesium tert-butoxide, and then adding phosphonate S to react to obtain a compound II; (3) the compound III is obtained by hydrolyzing the compound II in hydrobromic acid; (4) reacting the compound III with thionyl chloride to obtain phosphonyl chloride, and directly reacting the phosphonyl chloride with L-alanine isopropyl ester without purification to generate a compound IV; and (5) obtaining a final product, wherein the preparation of the propionyl phenol fumarate tenofovir is completed by salifying the compound IV and fumaric acid. The method has the advantages of few synthetic route steps, mild reaction conditions and principle saving, and can improve the yield of the final product.
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- Chemical resolution method of tenofovir alafenamide
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The invention provides a chemical resolution method of tenofovir alafenamide. The method comprises the following steps: by using tenofovir alafenamide racemate and D-malic acid as raw materials and acetonitrile and water as reaction solvents, reacting at 70-90 DEG C for 3-10 hours under the protection of nitrogen, separating out solids at normal temperature, and continuing cooling to grow crystalsto obtain D-malate; and carrying out weak base hydrolysis, extraction and low-temperature seed crystal induced crystallization on the D-malate to obtain the tenofovir alafenamide crystal. According to the resolution method, tenofovir alafenamide reacts with D-malic acid to form a salt, resolution is completed, and hydrolysis, extraction and seed crystal induced crystallization are performed on the D-malate to obtain a tenofovir alafenamide crystal; and the method is mild in condition in the reaction process, simple in process, convenient to operate, high in universality and suitable for large-scale production. The obtained target product is high in yield and purity and stable in performance, the medicine effect of the medicine prepared from the target product can be effectively guaranteed, and the treatment effect is improved.
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Paragraph 0029; 0032-0037; 0039-0043
(2021/03/11)
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- NRTI THERAPIES
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Polymer-of-prodrug (POP) materials enable new nucleoside reverse transcriptase inhibitor (NRTI) therapy strategies. The materials are prodrugs of NRTIs in the form of polymers. Suitable materials include products which are polymeric NRTI delivery systems comprising polymeric materials which are capable of degradation after administration to release NRTIs or NRTI prodrugs which themselves are capable of metabolism to the parent NRTIs. The NRTIs may optionally be selected from tenofovir (TFV), emtricitabine (FTC), lamivudine (3TC) and MK-8591 (EFdA). The invention facilitates long-acting (LA) regimens. Constructs of the materials may be in the form of injectable compositions or implants.
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Page/Page column 71-72
(2020/07/14)
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- Preparation method of tenofovir alafenamide
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The invention relates to a preparation method of tenofovir alafenamide represented by a formula IV. The preparation method comprises the following steps: 1) performing a halogenation reaction on a compound I and a halogenation reagent to obtain a halogenated compound II, wherein the halogenated compound II is a raceme; 2) performing solvent-mediated asymmetric transformation on the halogenated compound II obtained in the step 1) in an organic solvent B, and removing the solvent after the complete reaction to obtain a compound III, wherein the asymmetric conversion reaction is carried out at atemperature lower than the reflux temperature of the organic solvent B, a ratio S/R of the two diastereoisomers in the compound III is greater than or equal to 90%, and the organic solvent B is one ora combination comprising one or a plurality of materials selected from toluene, dimethylbenzene, ethylbenzene and chlorobenzene; and (3) carrying out an amidation reaction on the compound III obtained in the step (2) and L-alanine isopropyl ester or a salt thereof to prepare the tenofovir alafenamide represented by the formula IV. The preparation method disclosed by the invention can be used forenhancing the reaction controllability and shortening the reaction time, and is suitable for industrial production of TAF.
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Paragraph 0050; 0053; 0054; 0064-0067
(2020/05/01)
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- Method for synthesis of tenofovir alafenamide by oxidation process
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The invention discloses a preparation method of tenofovir alafenamide (TAF). The method includes: taking (R)-2-(6-amino-9H-purine-9-yl)isopropoxymethyl N'-[(S)-1-isopropoxyformyl]ethyl phenoxy phosphoramidite (2) is used as the raw material, carrying out amidation reaction, oxidation reaction and hydrolysis reaction, and then performing splitting to obtain tenofovir alafenamide (TAF, 1). The method provided by the invention has the advantages of green and environmental protection, no pollution, environmental friendliness, easily available raw materials, wide sources, low cost, simplicity and suitability for industrial production. The preparation method solves the problems of high preparation cost and difficult industrial production in the prior art.
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Paragraph 0015; 0020
(2020/01/12)
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- Preparation method of tenofovir alafenamide (TAF) synthesized through three-step method
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The invention discloses a preparation method of tenofovir alafenamide (TAF). The preparation method comprises the steps that phenoxy N-(1-isopropoxyformyl)ethyl phosphoramidite (2) is taken as a raw material, and after the raw material is subjected to a nucleophilic addition reaction, a sulfonylation reaction and a nucleophilic substitution reaction, splitting is conducted to obtain the TAF. The preparation method has the advantages that environmental protection is realized, pollution is avoided, environmental friendliness is realized, the raw material is easy to obtain, wide in source and lowin cost, and the method is simple and suitable for industrial production, and the problems of high preparation cost and difficult industrial production in the prior art are solved through the preparation method.
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- Preparation method for synthesizing tenofovir alafenamide in two steps
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The invention discloses a preparation method of tenofovir alafenamide (TAF). The method comprises the following steps: with (R)-2-(6-amino-9H-purin-9-yl)isopropoxymethyl di(N,N-dialkyl)phosphamide (2)as a raw material, carrying out a nucleophilic substitution reaction twice to obtain the tenofovir alafenamide (TAF). The preparation method has the advantages of greenness, environmental protection,no pollution, environmental friendliness, easily-available raw materials, a wide source, low costs, a simple method and suitability for industrial production, and solves the problems that preparationcosts are high, and industrial production is difficult to realize in the prior art.
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Paragraph 0016-0018
(2020/01/03)
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- THE ANTIVIRAL AGENT COMPRISING A NOVEL CRYSTALLINE FORM AND THE MANUFACTURING METHOD THEREOF
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The present invention relates to an antiviral agent used as a pharmaceutical composition for treating or preventing HIV-1 infection and chronic hepatitis B as a free base in a novel crystalline form of tenofovir alafenamide having the same water solubility as acid additional salt, excellent adhesion and uniformity which are easy to be formulated, and low elastic forces while overcoming a decomposition problem cause by moisture absorption of tenofovir alafenamide hemifumarate on the market.COPYRIGHT KIPO 2020
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Paragraph 0055-0062
(2019/11/27)
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- Efficient synthesis technology of tenofovir alafenamide
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The invention discloses an efficient synthesis technology of tenofovir alafenamide. The efficient synthesis technology comprises the steps that A, tenofovir reacts with triphenyl phosphite under an alkali catalysis condition to prepare tenofovir monophenyl ester, wherein the initial reaction temperature is 50-70 DEG C, the reaction temperature rises according to the gradient of 5-10 DEG C/h, and the total reaction duration is 6-10 h; B, the tenofovir monpohenyl ester is subjected to acylating chlorination to prepare tenofovir phenyl ester phosphoryl chloride; C, the tenofovir phenyl ester phosphoryl chloride is isomerized, then the isomerized tenofovir phenyl ester phosphoryl chloride reacts with an L-alanine isopropyl ester compound to prepare a target compound, wherein methylbenzene andother non-polar solvents are adopted for an isomerization solvent. The prepared tenofovir alafenamide has high purity and high yield, the technology operation is simple, the cost is low, complicated technology operation and purification means like using chiral resolution agents are omitted, and the efficient synthesis technology is very suitable for industrial production.
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Paragraph 0040; 0049-0056
(2019/10/01)
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- Simple synthesizing process for tenofovir alafenamide fumarate
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The invention discloses a simple synthesizing process for tenofovir alafenamide fumarate. According to the simple synthesizing process for the tenofovir alafenamide fumarate, a target product, namely,tenofovir alafenamide fumarate, is synthesized by taking tenofovir as a raw material through four steps of esterifying by using triphenyl phosphite, amidating by using L-alanine isopropyl ester hydrochloride, regulating pH by using phenol and DBU for resolving, and salifying by using fumaric acid. The process is simple and low in reaction temperature, and is more suitable for industrialization.
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- Preparation method of tenofovir alafenamide hemifumarate
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The invention discloses a preparation method of tenofovir alafenamide hemifumarate. The preparation method comprises the following steps of: reacting tenofovir with triphenyl phosphite under the condition of alkali catalysis to prepare tenofovir phenol ester; preparing tenofovir alafenamide through acylating chlorination and a reaction with L-alanine isopropyl ester; preparing tenofovir alafenamide hemifumarate by a special salt-forming process with fumaric acid. The tenofovir alafenamide hemifumarate prepared by the process is accurate in control of a salt type ratio, and simple in process operation, and avoids complex process operation and purification means such as chiral resolution, the total purity can reach 99% or more, and indexes of related substances are qualified.
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Paragraph 0010; 0040-0046; 0047
(2018/03/25)
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- Efficient synthesis and resolution of tenofovir alafenamide
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Background: Tenofovir alafenamide (TAF) is an oral antiviral prodrug of tenofovir (TFV), we have developed a facial and efficient method for the synthesis and chiral resolution of TAF. Method: The practical synthetic route of a mixed two diastereomers at phosphorous could start from (R)-9-[2-(Phosphonomethoxy)propyl]adenine (PMPA), the esterification reaction between PMPA and phenol occurred under the catalysis of dicyclohexylcarbodiimide (DCC) in 1-methyl-2-pyrrolidinone (NMP) at the temperature of 100o C to afforded 1. Phosphonochloridate was synthesized from 1 by chloride acetylation with thionyl chloride, and then react with an excess of L-Alanine isopropyl ester hydrochloride to give the diastereomer mixture of 9-[(R)-2-[[(R,S)-[[(S)-1-(isopropoxycarbonyl)ethyl] amino]-phenoxyphosphinyl]methoxy]propyl]adenine (2). The antipodes of 2 were separated in a satis-factory yield and diastereomeric excess (99% de) by resolution via formation diastereoisomer salt or inclusion complex to afford the more potent diastereomer (3). Tenofovir Alafenamide hemifumarate could be afforded by 3 and fumaric acid in a 1:0.5 ratio. Results: The diastereomeric excess of 3 could reach to 99% de. Conclusion: In a word, we have developed an efficient and chromatography-free route for the prepara-tion of TAF. In consideration of the expensive equipment and higher operation cost of SMBC, we chose a traditional resolution route to obtain chiral phosphorus.
- Gan, Yongjun,Ran, Kerui,Xie, Hongmeng,Yang, Bin
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- Preparation method of fumaric acid tenofovir alafenamide
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The invention provides a preparation method of fumaric acid tenofovir alafenamide. By esterification reaction, halogenating reaction, condensation reaction, refining and salt forming reaction, the fumaric acid tenofovir alafenamide which is high in yield, easy to purify and suitable for industrial mass production is obtained.
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Paragraph 0069; 0073; 0074
(2018/09/11)
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- Tenofovir alafenamide hemifumarate novel crystal form
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The invention discloses a tenofovir alafenamide hemifumarate, ((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxyl)methyl(phenoxyl) phosphono)-L-alanine isopropyl hemifumarate, novel crystal form (crystal form B), drug preparations containing the tenofovir alafenamide hemifumarate novel crystal, and treatment applications and preparation methods of the tenofovir alafenamide hemifumarate novel crystal. The tenofovir alafenamide hemifumarate novel crystal is stable at high temperature high moisture conditions; large-scale preparation is convenient to realize; and application prospect is promising.
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Paragraph 0028; 0030
(2018/03/24)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF TENOFOVIR ALAFENAMIDE OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The present invention generally relates to an improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof and preparation thereof. The present invention also relates to crystalline forms of monophenyl PMPA, an important intermediate of tenofovir alafenamide, and their preparation.
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Page/Page column 34
(2018/04/12)
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- Preparation method and application for high-purity tenofovir alafenamide fumarate intermediate
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The invention discloses a preparation method and an application for a high-purity tenofovir alafenamide fumarate intermediate. The preparation method for the tenofovir alafenamide fumarate intermediate namely tenofovir alafenamide II provided by the invention comprises the following steps: subjecting crude tenofovir alafenamide fumarate intermediate namely tenofovir alafenamide II to recrystallization in a mixed solvent of a nitrile solvent and water or a mixed solvent of the nitrile solvent and an aromatic hydrocarbon solvent so as to obtain the high-purity tenofovir alafenamide fumarate intermediate namely tenofovir alafenamide II. The high-purity tenofovir alafenamide II has an optical purity larger than 99.50% and a chemical purity larger than 99.60%; and the crude tenofovir alafenamide fumarate intermediate namely tenofovir alafenamide II has the optical purity in a range of 60.00% to 99.00% and the chemical purity in a range of 60.00% to 99.00%. The preparation method provided by the invention has the advantages of simple and safe operation, high yield, high product purity, low production cost, and applicability to industrial production.
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- Industrialized continuous production method of hemifumarate tenofovir alafenamide
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The invention discloses an industrialized continuous production method of tenofovir alafenamide and hemifumarate. The method comprises the following steps: firstly, in the presence of an acid-binding agent, reacting tenofovir with triphenyl phosphate to obtain a TAF-I M shown as a formula II; secondly, continuously preparing a TAF-II M by using the TAF-I M; thirdly, carrying out a salt forming reaction on the TAF-II M to obtain the hemifumarate tenofovir alafenamide. According to the industrialized continuous production method disclosed by the invention, a key compound tenofovir alafenamide is obtained by continuous production; the hemifumarate tenofovir alafenamide is obtained by accurately feeding fumaric acid and the tenofovir alafenamide; and in addition, a diastereoisomer of the tenofovir alafenamide is inhibited by using high catalytic enantioselectivity of a proline catalyst, and industrial production of optically-pure tenofovir alafenamide of which the purity is greater than 99.9 percent is realized by primary crystallization. The industrial production method disclosed by the invention has the advantages of simplicity, safety and low production cost; and besides, a high-purity product is obtained.
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Paragraph 0057; 0059; 0069; 0072; 0073; 0074;0083-0087
(2018/01/19)
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- Method of preparing nucleoside analogs and intermediates thereof which has advantages of high reaction yield, high product purity, convenient post-treatment, and suitable for industrial mass production
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The present invention relates to a method of preparing nucleoside analogs and intermediates thereof, which is the method of preparing the compound as shown by formula (I) and intermediates thereof. The disclosed method has advantages of high reaction yield, high product purity, convenient post-treatment, and suitable for industrial mass production, wherein the compound (III) is the key intermediate to produce the high purity compound (I), and the definitions of the substitution groups in the compound (III) are the same as those in the specification.
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- COMBINATION THERAPY COMPRISING TENOFOVIR ALAFENAMIDE HEMIFUMARATE AND COBICISTAT FOR USE IN THE TREATMENT OF VIRAL INFECTIONS
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The use of the hemifumarate form of {9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine} (tenofovir alafenamide hemifumarate) in combination with cobicistat is disclosed. In addition, the combination of tenofovir alafenamide hemifumarate, cobicistat, emtricitabine, and elvitegravir, and the combination of tenofovir alafenamide hemifumarate, cobicistat, emtricitabine, and darunavir, are disclosed.
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- A PREPARATION METHOD OF DIASTEREOMERICALLY PURE TENOFOVIR ALAFENAMIDE OR ITS SALTS
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The invention relates to an efficient preparation method of diastereomerically pure Tenofovir Alafenamide (TA) of structure la with the absolute configuration (S) at the phosphorus atom - Sp-diastereoisomer. Tenofovir Alafenamide Fumarate of formula 2 (TAF) is a reverse transcriptase inhibitor, which is currently in the clinical study stage as a prodrug of Tenofovir 3 for the treatment of HIV infection and hepatitis B. Compared to the hitherto used prodrug, Tenofovir disoproxil fumarate of formula 4, TAF exhibits greater antiviral activity and better distribution in the lymphatic system.
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Page/Page column 10; 11
(2017/10/13)
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- PHOSPHORIC ACID/PHOSPHONIC ACID DERIVATIVES AND MEDICINAL USES THEREOF
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The present invention relates to phosphoric acid/phosphonic acid derivatives shown by formula (I), wherein, R1 or R2 represents the following structures: (Q1), or (Q2), or (Q3). Q1 represents ester derivatives of L-amino acid, wherein R3 is alkyl with 1-6 carbon atoms or cycloalkyl, R4 is H or alkyl with 1-6 carbon atoms; Q2 represents hydroxyl substituted benzodioxane derivatives; Q3 represents hydroxyl substituted benzodioxolane derivatives; R1 or R2 is the same or different, but at least one of them is Q2 or Q3; D represents residues of pharmacologically active molecules containing a phosphate/phosphonate group, i.e. formula (II) represents pharmacologically active molecules containing a phosphate/phosphonate group; and when R1 and R2 are different, the configuration of the P atom connected to R1 and R2 is of R or S type.
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Paragraph 0042
(2016/05/19)
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- A RECYCLING PROCESS FOR PREPARING TENOFOVIR ALAFENAMIDE DIASTEREOMERS
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The present invention relates to an efficient and economical process to recycle the undesired diastereomer of Tenofovir alafenamide to desired diastereomer by racemization of the undesired diastereomer followed by separation of the desired diastereomer from the racemic mixture.
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- AN IMPROVED PROCESS FOR THE PREPARATION OF TENOFOVIR ALAFENAMIDE OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The present invention provides an improved process for the preparation of Tenofovir alafenamide or pharmaceutically acceptable salts thereof in high yield and purity. Also provided is a process for the separation of diastereomers of Tenofovir alafenamide by simulated moving bed chromatography or preparative high performance liquid chromatography.
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- AN EFFICIENT PROCESS FOR SEPARATION OF DIASTEREOMERS OF 9-[(R)-2-[[(R,S)-[[(S)-1-(ISOPROPOXYCARBONYL)ETHYL]AMINO]-PHENOXYPHOSPHINYL] METHOXY]PROPYL]ADENINE
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The present invention relates to an efficient process for the separation of diastereomers of 9-[(R)-2-[[(R,S)-[[(S)-1-(Isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl]methoxy]propyl]adenine and to a process for preparing 9-[(R)-2-[[(R)-[[(S)-1-(Isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine and 9-[(R)-2-[[(S)-[[(S)-1-(Isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl] adenine.
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Page/Page column 13
(2015/01/06)
-
- Methods for preparing anti-viral nucleotide analogs
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Methods for isolating 9-{(R)-2-[((S)-{[(S)-1-(isopropoxycarbonyl)ethyl]amino}phenoxyphosphinyl)methoxy]propyl}adenine (compound 16): a method for preparing, in high diastereomeric purity, intermediate compounds 13 and 15: and a method for preparing intermediate compound 12: 9-{(R)-2-[((S)-{[(S)-1-(isopropoxycarbonyl)ethyl]amino}phenoxyphosphinyl)methoxy]propyl}adenine has anti-viral properties.
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- Practical synthesis, separation, and stereochemical assignment of the PMPA pro-drug GS-7340
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The practical synthesis of a mixed phenoxy-amidate derivative of PMPA with high oral bioavailability and favorable pharmacokinetics is described. The non-stereoselective synthetic route produces a 1:1 mixture of two diastereomers at phosphorous. Simulated moving bed chromatography using Chiralpak AS enabled kilo-scale isolation of the more potent diastereomer (GS-7340). The GS-7340 phosphorous chiral center was found to be (S) by X-ray crystallography.
- Chapman,Kernan,Prisbe,Rohloff,Sparacino,Terhorst,Yu
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p. 621 - 628
(2007/10/03)
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