379270-37-8

Basic information

• Product Name: Tenofovir Alafenamide
• Synonyms: (S)-Isopropyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl);GS-7340/GS7340;Tenofovir Alafenamide fumarate, N-[[S(P)]-[2-(Adenin-9-yl)-1(R)-methylethoxymethyl](phenoxy)phosphoryl]-L-alanine isopropyl ester;Tenofovir Alafenamide fumarate;(S)-Isopropyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)amino)propanoate;Tenofovir Alafenamide (GS-7340);Tenofovir alafenamide hemifumarate;GS-7340 Tenofovir alafenamide
• CAS NO: 379270-37-8
• Molecular Formula: C₂₁H₂₉N₆O₅P
• Molecular Weight: 476.465921
• EINECS: 1592732-453-0
• Product Categories: Inhibitors
• Mol File: 379270-37-8.mol

Chemical Properties

• Boiling Point: 640.4±65.0 °C(Predicted)
• Appearance: /
• Density: 1.39±0.1 g/cm3(Predicted)
• Storage Temp.: 2-8°C(protect from light)
• Solubility: Chloroform (Slightly), DMSO (Slightly), Methanol (Slightly)
• PKA: 4.21±0.10(Predicted)
• Stability: Hygroscopic
• CAS DataBase Reference: Tenofovir Alafenamide(CAS DataBase Reference)
• NIST Chemistry Reference: Tenofovir Alafenamide(379270-37-8)
• EPA Substance Registry System: Tenofovir Alafenamide(379270-37-8)

Safety Data

• Hazardous Substances Data: 379270-37-8(Hazardous Substances Data)

Usage

Uses

Used in Antiviral Applications:
Tenofovir Alafenamide is used as an antiviral agent for the treatment of HIV and Hepatitis B. It acts as a reverse transcriptase inhibitor, preventing the replication of the virus and reducing the viral load in the body.
Used in HIV Treatment:
Tenofovir Alafenamide is used as an antiretroviral medication in combination therapy for the treatment of HIV-1 infection. It helps in suppressing the viral replication and maintaining the health of patients living with HIV.
Used in Hepatitis B Treatment:
Tenofovir Alafenamide is used as an antiviral medication for the treatment of chronic hepatitis B virus infection with compensated liver disease. It helps in reducing the viral load and preventing the progression of liver disease.
Used in Drug Development:
Tenofovir Alafenamide serves as a potentially safer form of the previously approved tenofovir disoproxil fumarate (Viread), contributing to the development of more effective and safer antiviral medications for the treatment of HIV and Hepatitis B.

Synthesis

A multikilogram synthesis of tenofovir alafenamide fumarate was described in a Gilead patent. Additional process improvements on specific steps of the Gilead process have been reported on 100 g scale, and these will be noted throughout the description of the synthesis. The synthesis was initiated with the alkylation of adenine (72) with (R)-propylene carbonate (73) to give hydroxypropyl adenine 74 in 75% yield. It should be noted that sodium hydroxide can be replaced by potassium bases with increased yields on 100 g scale.27 Alkylation of 74 with diethyl p-toluenesulfonyloxymethylphosphonate (75) gave intermediate 76, which was not isolated. Hydrolysis of the phosphonate esters with trimethylsilyl bromide followed by recrystallization from water gave phosphonic acid 77 in 50% yield. Interestingly, replacing Mg(Ot-Bu)2 with PhMgCl/t-BuOH led to improved yields for the alkylation step (74 → 76) on a 100 g scale. Additionally, the authors note that conditions for hydrolyzing the phosphonate ester can be modified using HCl or HBr for improved yields on smaller scale. Dicyclohexylcarbodiimide (DCC) coupling of 77 with phenol produced phosphonate 78 in 51% yield. This step was also reported to proceed in higher yield on smaller scale by changing the solvent to cyclopentylmethyl ether. Monophosphonate ester 78 was treated with thionyl chloride followed by L-alanine isopropyl ester (79) and triethylamine to give tenofovir alafenamide rac-80 as a mixture of phosphonate diastereomers in 47% yield. The diastereomers were separated using simulated moving bed chromatography to give the desired diastereomer ent-80 in 47% yield and 99% diastereomeric purity. The diastereomers could also be separated using a crystallization-induced dynamic resolution of rac-80. Tenofovir alafenamide fumarate (VI) was prepared from ent-80 and fumaric acid in 83% yield.

Upstream product

• 39825-33-7 isopropyl L-alanine 
• 379270-35-6 ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoric acid monophenyl ester 
• 147127-20-6 tenofovir 
• 108-95-2 phenol 
• 39613-92-8 alanine isopropyl ester hydrochloride 
• 2053424-88-5 (2S)-isopropyl2-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)amino)propanoate 
• 101-02-0 triphenyl phosphite 
• 383365-04-6 N-[(R)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphonyl]-L-alanine-1-methylethyl ester 
• 1392275-56-7 (S)-isopropyl-2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)amino)propanoate hemifumarate 
• 14047-28-0 (R)-9-(2-hydroxypropyl)adenine 

Downstream Products

• 1392275-56-7 (S)-isopropyl-2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)amino)propanoate hemifumarate 
• 1392275-56-7 tenofovir alafenamide fumarate 
• 1392275-56-7 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine monomaleate 
• 1392275-56-7 tenofovir alafenamide sesquifumarate 

Relevant articles and documents

Method for preparing antiviral drug tenofovir alafenamide fumarate

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.

Chemical resolution method of tenofovir alafenamide

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.

Preparation method of tenofovir alafenamide

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.

NRTI THERAPIES

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.

Preparation method for synthesizing tenofovir alafenamide in two steps

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.

Preparation method of tenofovir alafenamide (TAF) synthesized through three-step method

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.

THE ANTIVIRAL AGENT COMPRISING A NOVEL CRYSTALLINE FORM AND THE MANUFACTURING METHOD THEREOF

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

Efficient synthesis technology of tenofovir alafenamide

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.

Method for synthesis of tenofovir alafenamide by oxidation process

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.

Preparation method of tenofovir alafenamide hemifumarate

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.