Di-<i>tert</i>-butyl Phosphonate Route to the Antiviral Drug Tenofovir

Dietz, Jule‐Philipp; Ferenc, Dorota; Jamison, Timothy F.; Gupton, B. Frank; Opatz, Till

doi:10.1021/acs.oprd.0c00473

Cited by 11 publications

(4 citation statements)

References 26 publications

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“…4 Diethyl hydroxymethyl phosphonate(DEHP) was used to synthesize tenofovir dipivoxil and adefovir dipivoxil as anti-HIV and anti-HBV drugs. 10,11 HPs were mainly prepared by hydroxymethylation reaction using phosphite esters and formaldehyde (HCHO) as the starting materials. Under the traditional synthetic technology in the conventional reactor, the molar ratio of raw materials (phosphite ester and HCHO) ranged from 1:1.0 to 1:1.3, reaction temperature ranged from 100 C to 120 C, reaction pressure ranged from 3 kPa to 5 kPa, and reaction time ranged from 1h to 5 h. [12][13][14] Because the reaction was extremely exothermic, the targeted HPs exhibited significantly increased byproducts with high acid value (AN), in turn, led to low purity and low yield.…”

Section: Hydroxymethylmentioning

confidence: 99%

A continuous synthesis method of hydroxymethyl phosphonates using the microfluidic reactor

WANG,

LIU,

WANG

et al. 2024

Rev.Roum.Chim.

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Hydroxymethyl phosphonates (HPs) are important organic chemical raw materials and intermediates. HPs are generally synthesized by phosphite esters and formaldehyde using the conventional organic synthesis device. It shows the disadvantages of strong heat-release and more by-products for the reaction, and high acid number (AN), low yield and low purity for the product. We have designed a microfluidic reactor to synthesize HPs that can overcome above mentioned disadvantages. During the microfluidic reaction process, a series of reaction conditions can be controlled precisely. According to adopt the optimal reaction conditions, five HPs were obtained with low AN (＜0.15 mg KOH/g), high yield (＞94%) and high purity (＞99%). The designed microfluidic reactor can reduce labor cost, save equipment area, and cut down the amount of wastewater. The synthesis process can also realize continuous production and scale-up production with no amplification effect.

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Section: Hydroxymethylmentioning

confidence: 99%

A continuous synthesis method of hydroxymethyl phosphonates using the microfluidic reactor

WANG,

LIU,

WANG

et al. 2024

Rev.Roum.Chim.

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“…First, the desired chirality was imported from readily available (R)-propylene carbonate as the chiral pool. 9,10 Second, the desired chirality arrived in 97% ee (enantiomeric excess) via regioselective and enantioselective kinetic resolution of racemic propylene oxide with TMSN 3 in the presence of (salen)CrN 3 complex. 11 Third, the desired chirality was synthesized in 96% ee through asymmetric transfer hydrogenation of achiral purine derivative.…”

Section: Introductionmentioning

confidence: 99%

Chiral Analysis of the Key Intermediates of Tenofovir Alafenamide Fumarate

Zhou

Zhang

2023

Pharmaceutical Fronts

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Abstract(R)-Tenofovir phenyl ester ((R)-1) and (R)-tenofovir diphenyl ester ((R)-2) are key intermediates for the practical synthesis of tenofovir alafenamide fumarate, which is a mainstay antiretroviral for the treatment of chronic hepatitis B and HIV-1 infections. This article deals with the chiral analysis of (R)-1 and (R)-2 against their respective optical impurity (S)-tenofovir phenyl ester ((S)-1) and (S)-tenofovir diphenyl ester ((S)-2) using a polysaccharide-coated chiral stationary phase (CSP) by normal-phase high-performance liquid chromatography (HPLC). To this end, a chiral synthetic strategy for (S)-2 was efficiently executed capitalizing on a classical Mitsunobu reaction to stereospecifically invert the configuration of chiral carbon in readily accessible (R)-HPA ((R)-4) to deliver (S)-HPA ((S)-4), from which (S)--tenofovir ((S)-3) was in turn prepared and further transformed into (S)-2. With reference substance (S)-2 in hand, a chiral analytical method for (R)-2 using Chiralpak AD-H as CSP by normal-phase HPLC has been developed and validated. The validation results indicated that this chiral analytical method has been achieved with satisfactory separation effect, high sensitivity, and good precision and accuracy, and thus can be deployed for the determination of optical impurities in samples of (R)-1 (via derivation to (R)-2) and (R)-2.

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“…Nevertheless, this process was compromised by tedious workup including the continuous extraction with chloroform. A di- tert -butyl phosphonate-based route was reported affording PMPA from HPA in 72% yield on a 5 g scale in 2020 . Although this route has addressed the deprotection issue of diethyl phosphonate-based routes, MTB was still used as the O -alkylation catalyst, and the efficiently electrophilic intermediate (di- tert -butoxyphosphoryl)methyl methanesulfonate might bring about potential genotoxic concerns.…”

Section: Introductionmentioning

confidence: 99%

Practical Synthesis of Tenofovir Alafenamide Fumarate Inspired by New Retrosynthetic Disconnection Featuring a Novel Carbon–Phosphorus Bond Construction Methodology

Liu

Chen

et al. 2023

Org. Process Res. Dev.

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Tenofovir alafenamide fumarate (TAF) is rising as a mainstay antiretroviral agent for the treatment of HIV and chronic HBV infections. A de novo practical synthesis of TAF circumventing tenofovir (PMPA) has been accomplished on a 7 g scale. This reimagined synthesis of TAF, inspired by a hitherto uncharted retrosynthetic disconnection, centers on the P-alkylation of silylated diphenyl phosphonate 11 (as acceptor) with methylthiomethyl (MTM) ether derivative 12 (as donor) in the presence of NIS/TfOH combination as a promoter to construct the strategic carbon–phosphorus bond. This PMPA-free synthesis of TAF not only removes the intrinsic drawbacks encountered by the PMPA-dependent commercial process but also is beneficial to the diversification of the synthetic portfolio of TAF. Furthermore, this type of P-alkylation reaction with defined stereochemistry could be deployed for the late-stage modification of druglike molecules and natural products to access valuable phosphonate derivatives.

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Di-tert-butyl Phosphonate Route to the Antiviral Drug Tenofovir

Cited by 11 publications

References 26 publications

A continuous synthesis method of hydroxymethyl phosphonates using the microfluidic reactor

A continuous synthesis method of hydroxymethyl phosphonates using the microfluidic reactor

Chiral Analysis of the Key Intermediates of Tenofovir Alafenamide Fumarate

Practical Synthesis of Tenofovir Alafenamide Fumarate Inspired by New Retrosynthetic Disconnection Featuring a Novel Carbon–Phosphorus Bond Construction Methodology

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