106941-25-7

Basic information

• Product Name: Adefovir
• Synonyms: 9-[2- (phosphonomethoxy) ethyl] adenine, alternate name adefovir[PMEA];[2-(6-Amino-9H-purine-9-yl)ethoxymethyl]phosphonic acid;Phosphonic acid, [[2-(6-amino-9H-purin-9-yl)ethoxy]methyl]- (9CI);9-[2-(6-Amino-9H-purin-9-yl)et;Adefovir & Adefovir Dipivoxil;adefovir ,97%;2-(6-amino-9h-purin-;Adefovir dipivox (PMEA)
• CAS NO: 106941-25-7
• Molecular Formula: C₈H₁₂N₅O₄P
• Molecular Weight: 273.19
• EINECS: 1806241-263-5
• Product Categories: Other Products;Aromatics;Heterocycles;Intermediate of Adefovir Dipivoxil;ADEFOVIR DIPIVOXIL;(intermediate of adefovir);Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 106941-25-7.mol

Chemical Properties

• Melting Point: >260°C
• Boiling Point: 632.5 °C at 760 mmHg
• Flash Point: 336.3 °C
• Appearance: white to beige/
• Density: 1.88
• Storage Temp.: -20°C Freezer
• Solubility: 0.1 M NaOH: ≥5mg/mL
• PKA: pKa1 2.0, pKa2 6.8(at 25℃)
• CAS DataBase Reference: Adefovir(CAS DataBase Reference)
• NIST Chemistry Reference: Adefovir(106941-25-7)
• EPA Substance Registry System: Adefovir(106941-25-7)

Safety Data

• Hazard Codes: T
• Statements: 25
• Safety Statements: 45
• RIDADR: 2811
• WGK Germany: 3
• RTECS: SZ6563500
• HazardClass: 6.1
• PackingGroup: Ⅲ
• Hazardous Substances Data: 106941-25-7(Hazardous Substances Data)

Usage

Uses

Used in Antiviral Applications:
Adefovir is used as an antiviral agent for the treatment of chronic hepatitis B virus infections. It is effective in blocking the reproduction of the virus and has a lower likelihood of resistance development compared to other anti-HBV drugs.
Used in Research:
Adefovir has been used in research to study its anti-retroviral effect on porcine endogenous retrovirus (PERV) activity. This application helps in understanding the potential of Adefovir in combating other viral infections and its broader implications in the field of virology.
Used in Pharmaceutical Industry:
Adefovir is used as a key component in the development of antiviral medications for hepatitis B virus treatment. Its formulation as a pale brown solid allows for easy incorporation into various pharmaceutical products, making it a valuable asset in the fight against chronic hepatitis B infections.

References

https://www.drugbank.ca/drugs/DB00718 http://en.wikipedia.org/wiki/Adefovir

Acquired resistance

It has a lower propensity to induce drug resistance than lamivudine. Clinical trials of patients receiving 48 weeks of therapy did not identify any cases of resistance. Longer courses yield resistant strains of HBV with mutations in the DNA polymerase gene; other rare variants of resistant strains have been identified. Lamivudine-resistant strains of HBV retain susceptibility to adefovir.

Pharmaceutical Applications

A nucleotide analog of adenosine monophosphate, administered orally as its prodrug, adefovir dipivoxil.

Biochem/physiol Actions

Adefovir is an antiviral drug that after intracellular conversion to adefovir diphosphate inhibits hepatitis B virus (HBV) DNA polymerase (reverse transcriptase).

Pharmacokinetics

Oral absorption： c. 60% Cmax 10 mg/kg oral： 18.4 ng/mL Plasma half-life： c. 7.5 h. Volume of distribution： 392 mL/kg Plasma protein binding： Not known The prodrug is metabolized to adefovir, which is excreted by the kidneys and therefore requires dose adjustment in patients with impaired renal function. It does not induce cytochrome P450 at standard doses and does not influence the metabolism or plasma concentrations of the other licensed medications used in the treatment of hepatitis B.

Clinical Use

Treatment of chronic hepatitis B virus infection in patients >12 years of age

Side effects

It is generally well tolerated, with headache, pharyngitis, abdominal pain and peripheral neuropathy being the most common side effects. Nephrotoxicity has been observed in some patients, with those receiving higher doses and longer courses of therapy at greater risk. Exacerbation of hepatitis has been reported in patients immediately following discontinuation of treatment. Most exacerbations occur within 12 weeks of stopping therapy, and elevations of alanine aminotransferase (ALT) up to 10 times the upper limit of normal can be observed in over 25% of patients. Lactic acidosis has been reported in a few patients and is an indication for immediate discontinuation.

InChI:InChI=1/C8H13N5O4P/c9-7-6-8(11-3-10-7)13(4-12-6)1-2-17-5-18(14,15)16/h3-4,12H,1-2,5H2,(H2,9,10,11)(H2,14,15,16)

Synthetic route

[[2-(6-amino-9H-purine-9-yl)ethoxy]methyl]phosphonic acid diethyl ester (116384-53-3) → Adefovir (106941-25-7)

Conditions	Yield
With trimethylsilyl bromide	95%
Stage #1: [[2-(6-amino-9H-purine-9-yl)ethoxy]methyl]phosphonic acid diethyl ester With trimethylsilyl bromide In acetonitrile at 20℃; for 3h; Large scale; Stage #2: With sodium hydroxide In water for 2h; Reflux; Large scale;	86.3%
With hydrogen bromide In water at 90℃; for 5h; Temperature; Time;	86%

[2-(6-Amino-purin-9-yl)-ethoxymethyl]-phosphonic acid diisopropyl ester (142340-94-1) → Adefovir (106941-25-7)

Conditions	Yield
With hydrogenchloride In water at 140℃; for 0.166667h; Microwave irradiation; Sealed tube;	95%
Multi-step reaction with 2 steps 1: acetonitrile 2: aq. NH3 View Scheme

Methyl Ester of 9-(2-Phosphonylmethoxyethyl)adenine (107021-27-2) → Adefovir (106941-25-7)

Conditions	Yield
With trimethylsilyl iodide; triethylamine carbonate 1) DMF, R.T., 16 h 2) 80 deg C; Yield given. Multistep reaction;

diethyl (p-toluenesulfonyloxymethane)phosphonate (31618-90-3) + 9-(2-hydroxyethyl)adenine (707-99-3) → Adefovir (106941-25-7)

Conditions	Yield
With trimethylsilyl bromide; sodium t-butanolate 1.) DMF; Yield given. Multistep reaction;

C14H28N5O4PSi2 → Adefovir (106941-25-7)

Conditions	Yield
With ammonium hydroxide Yield given;
With water	33.0 g

[2-(5-Amino-6-chloro-pyrimidin-4-ylamino)-ethoxymethyl]-phosphonic acid diethyl ester (212894-84-3) → Adefovir (106941-25-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: 92 percent / 3 h / 120 °C 2: 87 percent / NH3 liquid / tetrahydrofuran; dimethylsulfoxide / 24 h / 25 °C 3: 95 percent / TMSBr View Scheme

O,O-diethyl((2-(6-chloro-9H-purin-9-yl)ethoxy)methyl)phosphonate (185900-69-0) → Adefovir (106941-25-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 87 percent / NH3 liquid / tetrahydrofuran; dimethylsulfoxide / 24 h / 25 °C 2: 95 percent / TMSBr View Scheme

9-(2-Hydroxyethyl)-N6-benzoyladenine (55343-28-7) → Adefovir (106941-25-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1) NaH 2) 0.5 mol l-1 NaOH / 1)DMF, R.T., 48 h, 2) 50 deg C, 6 h 2: 1) iodotrimethylsilane 2) 2 mol l-1 triethylammonium hydrogen carbonate / 1) DMF, R.T., 16 h 2) 80 deg C View Scheme

9-(2-hydroxyethyl)adenine (707-99-3) → Adefovir (106941-25-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: 81 percent / chlorotrimethylsilane / pyridine 2: 1) NaH 2) 0.5 mol l-1 NaOH / 1)DMF, R.T., 48 h, 2) 50 deg C, 6 h 3: 1) iodotrimethylsilane 2) 2 mol l-1 triethylammonium hydrogen carbonate / 1) DMF, R.T., 16 h 2) 80 deg C View Scheme
Multi-step reaction with 2 steps 1: 1) NaH, 2) 0.5 mol l-1 NaOH / 1) DMF, R.T., 48 h, 2) 50 deg C, 6 h 2: 1) iodotrimethylsilane 2) 2 mol l-1 triethylammonium hydrogen carbonate / 1) DMF, R.T., 16 h 2) 80 deg C View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 1 h / 5 °C / Large scale 1.2: 5 h / 5 °C / Large scale 2.1: trimethylsilyl bromide / acetonitrile / 3 h / 20 °C / Large scale 2.2: 2 h / Reflux; Large scale View Scheme
Multi-step reaction with 2 steps 1: magnesium 2-methylpropan-2-olate / N,N-dimethyl-formamide / 12 h / 80 °C 2: chloro-trimethyl-silane / chlorobenzene / 10 h / 120 °C View Scheme
Multi-step reaction with 2 steps 1.1: magnesium 2-methylpropan-2-olate / N,N-dimethyl-formamide / 1 h / 78 - 82 °C 1.2: 78 - 82 °C 2.1: trimethylsilyl bromide / 80 - 85 °C View Scheme

9-(2-Diethoxyphosphonomethoxyethyl)adenine + trimethylsilyl bromide (2857-97-8) → Adefovir (106941-25-7)

Conditions	Yield
In dichloromethane; water; acetone

disodium {[2-(6-amino-9H-purin-9-yl)ethoxy]methyl}phosphonothioate → Adefovir (106941-25-7)

Conditions	Yield
for 24h; Conversion of starting material; Complete medium (extra-cellular medium mimick);
With CEM-SS culture medium at 37℃; pH=7.4; aq. buffer;

{[2-(6-amino-9H-purin-9-yl)ethoxy]methyl}phosphinic acid (159531-21-2) → Adefovir (106941-25-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: pyridine; N,O-bis-(trimethylsilyl)-acetamide / 1 h / 20 °C / Inert atmosphere 1.2: 0.5 h / Inert atmosphere 1.3: Dowex 50WX2 (Na+ form) 2.1: CEM-SS culture medium / 37 °C / pH 7.4 / aq. buffer View Scheme

adenine (66224-66-6, 66224-67-7, 66224-68-8, 66224-69-9, 134434-48-3, 134434-49-4, 134454-76-5, 134461-75-9) → Adefovir (106941-25-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 25 - 85 °C 1.2: 20 h 2.1: water; hydrogen bromide / 4 h / 90 - 95 °C 2.2: 25 - 30 °C / pH 2.8 View Scheme
Multi-step reaction with 3 steps 1: triethylamine / acetonitrile / 14 h / 125 °C / Inert atmosphere 2: magnesium 2-methylpropan-2-olate / N,N-dimethyl-formamide / 12 h / 80 °C 3: chloro-trimethyl-silane / chlorobenzene / 10 h / 120 °C View Scheme

C32H41FN7O6P → Adefovir (106941-25-7) + PMEA-F

Conditions	Yield
With ethylenediaminetetraacetic acid; DL-dithiothreitol; water; magnesium chloride In aq. buffer at 37℃; for 18h; pH=7.5; Enzymatic reaction;

adefovir dipivoxyl (142340-99-6) → Adefovir (106941-25-7)

Conditions	Yield
With ethylenediaminetetraacetic acid; DL-dithiothreitol; water; magnesium chloride In aq. buffer at 37℃; for 1h; pH=7.5; Enzymatic reaction;

C32H42N7O6P → Adefovir (106941-25-7)

Conditions	Yield
With ethylenediaminetetraacetic acid; DL-dithiothreitol; water; magnesium chloride In aq. buffer at 37℃; for 18h; pH=7.5; Enzymatic reaction;

C18H30N7O6P (168537-58-4) → Adefovir (106941-25-7)

Conditions	Yield
With ethylenediaminetetraacetic acid; DL-dithiothreitol; water; magnesium chloride In aq. buffer at 37℃; for 18h; pH=7.5; Enzymatic reaction;

6-Chloro-9-(β-hydroxyethylamino)purine (1670-62-8) → Adefovir (106941-25-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / -20 - 0 °C / Inert atmosphere 1.2: 48 h / 50 °C 2.1: trimethylhalosilane / acetonitrile / 20 °C / Inert atmosphere; Cooling with ice View Scheme

6-chloro-9-(ethoxycarbonylmethyl)-9H-purine (56791-59-4) → Adefovir (106941-25-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: methanol; sodium tetrahydroborate / 0 °C 2.1: sodium hydride / tetrahydrofuran / -20 - 0 °C / Inert atmosphere 2.2: 48 h / 50 °C 3.1: trimethylhalosilane / acetonitrile / 20 °C / Inert atmosphere; Cooling with ice View Scheme

6-chloropurine (87-42-3) → Adefovir (106941-25-7)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: scandium tris(trifluoromethanesulfonate) / acetonitrile / 0.17 h / 20 °C 2.1: methanol; sodium tetrahydroborate / 0 °C 3.1: sodium hydride / tetrahydrofuran / -20 - 0 °C / Inert atmosphere 3.2: 48 h / 50 °C 4.1: trimethylhalosilane / acetonitrile / 20 °C / Inert atmosphere; Cooling with ice View Scheme

(di-tert-butoxyphosphoryl)methyl methanesulfonate + 9-(2-hydroxyethyl)adenine (707-99-3) → Adefovir (106941-25-7)

Conditions	Yield
Stage #1: 9-(2-hydroxyethyl)adenine With magnesium 2-methylpropan-2-olate In N,N-dimethyl acetamide at 90℃; for 0.5h; Schlenk technique; Inert atmosphere; Stage #2: (di-tert-butoxyphosphoryl)methyl methanesulfonate In N,N-dimethyl acetamide at 90℃; for 22h; Schlenk technique; Inert atmosphere; Stage #3: With hydrogenchloride In water at 60℃; Schlenk technique; Inert atmosphere;

morpholine (110-91-8) + N,N'-di-cyclohexylformamidine (2303-89-1) + Adefovir (106941-25-7) → 9-(2-Morpholinophosphonylmethoxyethyl)adenine N,N'-dicyclohexylcarboxamidinium salt

Conditions	Yield
With dicyclohexyl-carbodiimide In water; tert-butyl alcohol for 11h; Heating;	96%

Adefovir (106941-25-7) → 9-(2-Phosphonylmethoxyethyl)hypoxanthine (113884-65-4)

Conditions	Yield
With isopentyl nitrite In acetic acid for 72h; Ambient temperature;	93%

3,5-Dihydroxybenzoic acid (99-10-5) + Adefovir (106941-25-7) → C8H12N5O4P*C7H6O4*H2O

Conditions	Yield
With water at 90℃; for 3h;	90%

N-formyldiethylamine (617-84-5) + Adefovir (106941-25-7) → C13H19Cl2N6O2P (1056998-35-6)

Conditions	Yield
With oxalyl dichloride In dichloromethane for 4.5h; Heating / reflux;	89%
With oxalyl dichloride In dichloromethane for 4.5h; Heating / reflux;

Adefovir (106941-25-7) + (Z)-4-(2-chloroethylidenyl)-2,3-dimethoxy-Δα,β-butenolide (347363-99-9) → [2-(6-amino-purin-9-yl)-ethoxymethyl]-phosphonic acid mono-[2-(3,4-dimethoxy-5-oxo-5H-furan-2-ylidene)-ethyl] ester

Conditions	Yield
With sodium hydrogencarbonate In N,N-dimethyl-formamide at 25℃; for 1h;	88%

1,1,1-trichloroethanol (115-20-8) + Adefovir (106941-25-7) → 9-<2-(phosphonomethoxy)ethyl>adenine, mono-2,2,2-trichloroethyl ester

Conditions	Yield
With thionyl chloride In N,N-dimethyl-formamide for 16h; Ambient temperature;	86%

methanol (67-56-1) + Adefovir (106941-25-7) → Methyl Ester of 9-(2-Phosphonylmethoxyethyl)adenine (107021-27-2)

Conditions	Yield
With thionyl chloride In N,N-dimethyl-formamide for 16h; Ambient temperature;	85%

Adefovir (106941-25-7) + ethylenediamine (107-15-3) → C10H18N7O3P

Conditions	Yield
With hydrogenchloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water at 20℃;	85%

Adefovir (106941-25-7) + vitamin E (895518-38-4) → C66H108N5O6P

Conditions	Yield
With triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 24h;	79.36%

2-chloroethanal (107-20-0) + Adefovir (106941-25-7) → 9-(2-phosphonylmethoxyethyl)-1,N6-ethenoadenine (120139-27-7)

Conditions	Yield
In water at 40℃; for 24h; pH 4.5;	78.1%

Chloromethyl pivalate (18997-19-8) + Adefovir (106941-25-7) → adefovir dipivoxyl (142340-99-6)

Conditions	Yield
With triethylamine In 1-methyl-pyrrolidin-2-one at 50 - 55℃; Solvent; Reagent/catalyst; Temperature; Inert atmosphere; Large scale;	78.1%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 25℃; for 24h;	75%
With tetrabutylammomium bromide; triethylamine In 1-methyl-pyrrolidin-2-one at 65 - 75℃; for 2h; Temperature; Reagent/catalyst; Solvent;	57.5%

Pyridine-2,6-dicarboxylic acid (499-83-2) + Adefovir (106941-25-7) → C8H12N5O4P*C7H5NO4

Conditions	Yield
In ethanol; water at 90℃; for 3h;	75%

2,2,2-trifluoroethanol (75-89-8) + Adefovir (106941-25-7) → 9-(2-phosphonomethoxyethyl)adenine 2,2,2-trifluoroethyl ester

Conditions	Yield
With thionyl chloride In N,N-dimethyl-formamide for 16h; Ambient temperature;	74%

propan-1-ol (71-23-8) + Adefovir (106941-25-7) → 9-(2-phosphonomethoxyethyl)adenine propyl ester

Conditions	Yield
With thionyl chloride In N,N-dimethyl-formamide for 16h; Product distribution; Ambient temperature; various hydroxylic components under different reaction conditions;	73%
With thionyl chloride In N,N-dimethyl-formamide for 16h; Ambient temperature;	73%

Adefovir (106941-25-7) + 4-amino-benzoic acid (150-13-0) → 2C8H12N5O4P*C7H7NO2*3H2O

Conditions	Yield
With water at 90℃; for 2h;	70%

2-(morpholin-4-yl)ethanol (622-40-2) + Adefovir (106941-25-7) → 9-(2-phosphonomethoxyethyl)adenine 2-morpholinoethyl ester

Conditions	Yield
With thionyl chloride In N,N-dimethyl-formamide for 16h; Ambient temperature;	68%

2,2,2-tribromoethanol (75-80-9) + Adefovir (106941-25-7) → 9-(2-phosphonomethoxyethyl)adenine 2,2,2-tribromoethyl ester

Conditions	Yield
With thionyl chloride In N,N-dimethyl-formamide for 48h; Ambient temperature;	64%

N,N-dimethylformamide dibenzyl acetal (2016-04-8) + Adefovir (106941-25-7) → 9-(2-phosphonomethoxyethyl)adenine benzyl ester

Conditions	Yield
at 60℃; for 48h;	60%

Adefovir (106941-25-7) + ethylene glycol (107-21-1) → 9-(2-phosphonomethoxyethyl)adenine 2-hydroxyethyl ester

Conditions	Yield
With thionyl chloride In N,N-dimethyl-formamide for 16h; Ambient temperature;	57%

Adefovir (106941-25-7) + hexan-1-ol (111-27-3) → 9-(2-phosphonomethoxyethyl)adenine hexyl ester

Conditions	Yield
With thionyl chloride In N,N-dimethyl-formamide for 16h; Ambient temperature;	56%

Adefovir (106941-25-7) + 3-Hydroxypropionitrile (109-78-4) → 9-(2-phosphonomethoxyethyl)adenine 2-cyanoethyl ester

Conditions	Yield
With thionyl chloride In N,N-dimethyl-formamide for 4h; Ambient temperature;	51%

Adefovir (106941-25-7) + glycine ethyl ester hydrochloride (5680-79-5) → 9-(bis(N,N'-(methoxycarbonylmethyl)phosphonamido)methoxyethyl)adenine (1041402-65-6)

Conditions	Yield
With 2,2'-dipyridyldisulphide; triethylamine; triphenylphosphine In pyridine at 90℃; for 24h; Mukaiyama reaction; Inert atmosphere;	51%

3,6,9,12,15,1 8-hexaoxaicosyl p-toluensulfonate + Adefovir (106941-25-7) → 9-[2-(phosphonomethoxy)ethyl]adenine bis(3,6,9,12,15,18-hexaoxaeicosyl) ester (1313815-78-9)

Conditions	Yield
Stage #1: Adefovir With tetra(n-butyl)ammonium hydroxide In methanol Stage #2: 3,6,9,12,15,1 8-hexaoxaicosyl p-toluensulfonate In N,N-dimethyl-formamide at 100℃;	50%

(aqua(diethylenetriamine)platinum(II))nitrate + Adefovir (106941-25-7) → (diehylenetriamine)Pt(dianion of 9-[2-(phosphonomethoxy)ethyl]adenine)*HNO3*NaNO3*H2O

Conditions	Yield
With aq. HNO3 In water aq. soln. of org. compd. slowly added to soln. of complex (pH= 1.3 adjusted with 1 M HNO3) during 3 h, stirred for 24 h at 35°C; volatiles evapd. at room temp. in N2 stream, treated twice with MeOH (12 h, ambient temp.), foltered, elem. anal.;	49%

Adefovir (106941-25-7) + dimethylformamide 1,3-butylene acetal → 9-(2-phosphonomethoxyethyl)adenine 3-hydroxybutyl ester + [2-(6-Amino-purin-9-yl)-ethoxymethyl]-phosphonic acid mono-(3-hydroxy-1-methyl-propyl) ester

Conditions	Yield
at 70℃; for 16h;	A 48% B n/a

(S)-(-)-1-(3'-Chlorophenyl)-1,3-Propanediol (51699-45-7) + Adefovir (106941-25-7) → (rac)-cis-9-{2-[4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-methyleneoxy]eth-1-yl}adenine + (rac)-trans-9-{2-[4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-methyleneoxy]eth-1-yl}adenine

Conditions	Yield
With pyridine; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 100℃;	A 48% B n/a
With pyridine; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 100℃;

Adefovir (106941-25-7) + 1,2,3-tri-O-acetylthreitol → 9-(2-phosphonomethoxyethyl)adenine 2,3,4-trihydroxy-1-butyl ester

Conditions	Yield
With thionyl chloride In N,N-dimethyl-formamide for 16h; Ambient temperature;	47%

octanol (111-87-5) + Adefovir (106941-25-7) → 9-(2-phosphonomethoxyethyl)adenine octyl ester

Conditions	Yield
With thionyl chloride In N,N-dimethyl-formamide for 16h; Ambient temperature;	46%

Upstream product

• 116384-53-3 [[2-(6-amino-9H-purine-9-yl)ethoxy]methyl]phosphonic acid diethyl ester 
• 107021-27-2 Methyl Ester of 9-(2-Phosphonylmethoxyethyl)adenine 
• 31618-90-3 diethyl (p-toluenesulfonyloxymethane)phosphonate 
• 707-99-3 9-(2-hydroxyethyl)adenine 
• 142340-94-1 [2-(6-Amino-purin-9-yl)-ethoxymethyl]-phosphonic acid diisopropyl ester 
• 55343-28-7 9-(2-Hydroxyethyl)-N⁶-benzoyladenine 
• 2857-97-8 trimethylsilyl bromide 
• 159531-21-2 {[2-(6-amino-9H-purin-9-yl)ethoxy]methyl}phosphinic acid 
• 142340-99-6 adefovir dipivoxyl 
• 168537-58-4 C₁₈H₃₀N₇O₆P 
• 1670-62-8 6-Chloro-9-(β-hydroxyethylamino)purine 
• 56791-59-4 6-chloro-9-(ethoxycarbonylmethyl)-9H-purine 
• 87-42-3 6-chloropurine 
• 66224-66-6 adenine 

Downstream Products

• 113884-65-4 9-(2-Phosphonylmethoxyethyl)hypoxanthine 
• 142340-99-6 adefovir dipivoxyl 
• 928651-99-4 2-tert-butoxycarbonylamino-3-phenyl-propionic acid [2-(6-amino-purin-9-yl)-ethoxymethyl]-(2-tert-butoxycarbonylamino-3-phenyl-propionyloxymethoxy)-phosphinoyloxymethyl ester 
• 928651-91-6 2-tert-butoxycarbonylamino-3-phenyl-thiopropionic acid S-(2-{[2-(6-amino-purin-9-yl)-ethoxymethyl]-[2-(2-tert-butoxycarbonylamino-3-phenyl-propionylsulfanyl)-ethoxy]-phosphinoyloxy}-ethyl) ester 
• 928651-82-5 2-tert-butoxycarbonylamino-3-phenyl-propionic acid 2-{[2-(6-amino-purin-9-yl)-ethoxymethyl]-[2-(2-tert-butoxycarbonylamino-3-phenyl-propionyloxy)-ethoxy]-phosphinoyloxy}-ethyl ester 
• 625095-60-5 (+)-cis-9-{2-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-methyleneoxy]eth-1-yl}adenine 
• 116384-53-3 [[2-(6-amino-9H-purine-9-yl)ethoxy]methyl]phosphonic acid diethyl ester 
• 142341-05-7 9-<2-(phosphonomethoxy)ethyl>adenine, mono(pivaloyloxy)methyl ester 
• 142341-04-6 9-<2-(phosphonomethoxy)ethyl>adenine, monoethyl mono(pivaloyloxy)methyl ester 
• 142341-24-0 9-<2-(phosphonomethoxy)ethyl>adenine, bis(phenyl ester) 

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The deficiency of nucleos(t)ide analogues (NAs) as anti-hepatitis B virus (HBV) drugs in clinical use is attributable to their insufficient enrichment in liver and non-target organ toxicity. We aimed to develop potent anti-HBV adefovir derivatives with hepatotrophic properties and reduced nephro...detailed

Identification of novel Adefovir (cas 106941-25-7) dipivoxil-saccharin cocrystal polymorphs and their thermodynamic polymorphic transformations08/06/2019

In this paper, two novel polymorphs of adefovir dipivoxil-saccharin (AD-SAC) cocrystals, forms II and III, were prepared and characterized by PXRD, DSC, FT-IR and SEM. Polymorphic transformations of these two forms and the known form (form I) were also investigated. In comparison to form I, form...detailed

Relevant articles and documents

Practical synthesis of the anti-HIV drug, PMPA

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.

Dealkylation of phosphonate esters with chlorotrimethylsilane

Chlorotrimethylsilane completely dealkylates phosphonate esters at elevated temperature in a sealed reaction vessel. These conditions are tolerated by a variety of functional groups and lead to high conversions of dimethyl, diethyl and diisopropyl phosphonates to their corresponding phosphonic acids.

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

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).

Acyclic nucleoside thiophosphonates as potent inhibitors of HIV and HBV replication

9-[2-(Thiophosphonomethoxy)ethyl]adenine 3 and (R)-9-[2- (Thiophosphonomethoxy)propyl]adenine 4 were synthesized as the first thiophosphonate nucleosides bearing a sulfur atom at the α-position of the acyclic nucleoside phosphonates PMEA and PMPA. Thiophosphonates S-PMEA 3 and S-PMPA 4 were evaluated for in vitro activity against HIV-1 (subtypes A to G), HIV-2 and HBV-infected cells, and found to exhibit potent antiretroviral activity. We showed that their diphosphate forms S-PMEApp 5 and S-PMPApp 6 are readily incorporated by wild-type (WT) HIV-1 RT into DNA and act as DNA chain terminators. Compounds 3 and 4 were evaluated for in vitro activity against a broad panel of DNA and RNA viruses and displayed beside HIV a moderate activity against herpes simplex virus and vaccinia viruses. In order to measure enzymatic stabilities of the target derivatives 3 and 4, kinetic data and decomposition pathways were studied at 37 °C in several media.

Bisamidate Prodrugs of 2-Substituted 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA, adefovir) as Selective Inhibitors of Adenylate Cyclase Toxin from Bordetella pertussis

Novel small-molecule agents to treat Bordetella pertussis infections are highly desirable, as pertussis (whooping cough) remains a serious health threat worldwide. In this study, a series of 2-substituted derivatives of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA, adefovir), in their isopropyl ester bis(L-phenylalanine) prodrug form, were designed and synthesized as potent inhibitors of adenylate cyclase toxin (ACT) isolated from B. pertussis. The series consists of PMEA analogues bearing either a linear or branched aliphatic chain or a heteroatom at the C2 position of the purine moiety. Compounds with a small C2 substituent showed high potency against ACT without cytotoxic effects as well as good selectivity over human adenylate cyclase isoforms AC1, AC2, and AC5. The most potent ACT inhibitor was found to be the bisamidate prodrug of the 2-fluoro PMEA derivative (IC50=0.145 μM). Although the bisamidate prodrugs reported herein exhibit overall lower activity than the bis(pivaloyloxymethyl) prodrug (adefovir dipivoxil), their toxicity and plasma stability profiles are superior. Furthermore, the bisamidate prodrug was shown to be more stable in plasma than in macrophage homogenate, indicating that the free phosphonate can be effectively distributed to target tissues, such as the lungs. Thus, ACT inhibitors based on acyclic nucleoside phosphonates may represent a new strategy to treat whooping cough. Whooping cough combatted: With the aim to establish a new strategy against pertussis, C2-modified adefovir analogues in their bisamidate prodrug form were found to efficiently inhibit adenylate cyclase toxin (ACT) from Bordetella pertussis. The compounds show favorable plasma stability, effective distribution to target tissues, and good selectivity for ACT over human adenylate cyclase isoforms.

A new regio-defined synthesis of PMEA

A new regio-defined synthesis of PMEA was developed suitable for gramscale synthesis. Key to this synthesis was the early introduction of the phosphonomethoxy ethyl moiety and subsequent cyclization for the construction of the purine ring. This synthesis is regiospecific when compared to the commonly used adenine alkylation methods.

Synthetic method of adefovir dipivoxil

The invention relates to the field of chemical pharmaceuticals, in particular to an industrial production and synthesis process of an adefovir dipivoxil bulk drug. 9-(2-hydroxyethyl)-adenine and diethyl p-toluenesulfonyloxymethyl phosphate serve as raw materials, and under the action of a catalyst, adefovir dipivoxil is produced through esterification, desalination and hydrolysis. The adefovir dipivoxil is subjected to acid and alkali refining, then condensed with chloromethyl valerate, then separated and purified to obtain adefovir divalentyl oxymethyl ester raw materials. The synthetic process is an industrialized production process, the operation is simple, adefovir dipivoxil is suitable for large-scale production, and the production cost can be greatly reduced.

Preparation method of high-stability adefovir dipivoxil

The invention belongs to the field of pharmaceutical synthesis. A preparation method of high-stability adefovir dipivoxil is characterized by comprising the following steps: 1) a compound 1 undergoestrimethylbromosilane substitution, followed by hydrolysis with a NaOH aqueous solution to obtain a compound 2; 2) the compound 2 and a compound 3 are catalyzed by triethylamine in N-methylpyrrolidoneto obtain a compound 4; 3) the compound 4 is refined to obtain a compound 5, namely [[2-(6-amino-9H-purine-9-yl)ethoxy]methyl]phosphodi(pivaloyloxymethyl)ester. The preparation method of high-stability adefovir dipivoxil has advantages of good stability of bulk drugs and simple production process, and is suitable for large-scale commercial production.

Preparation method of adefovir dipivoxil crystals

The invention belongs to the technical field of drug preparation and in particular relates to a preparation method of adefovir dipivoxil crystals. The preparation method comprises the following steps: synthesizing diethyl phosphite; synthesizing diethyl (p-phenylsulfonyloxy)methylphosphonate; synthesizing 9-(2-hydroxyethyl) adenine; synthesizing 4,9-[2-(diethylphosphonomethoxy)ethyl]adenine; synthesizing adefovir; synthesizing adefovir dipivoxil. Compared with the prior art, the preparation method of the adefovir dipivoxil crystals, provided by the invention, takes acetonitrile as a water-soluble organic medium, and the difficulty that DMF (Dimethyl Formamide) is difficult to remove is overcome; ethyl acetate is used for replacing isopropyl acetate in a previous process, isopropyl ether is used for replacing ethyl ether and ethanol is used for replacing acetone; the preparation method is simple to operate; the obtained product has good purity and high yield; the industrialized production is easy to realize and the production cost is reduced.

Preparation method of adefovir

The invention discloses a preparation method of adefovir. The preparation method comprises the following steps: adding 9-[2-(diethoxylphosphorylmethoxyl)ethyl]adenine into a water solution of HBr, heating to carry out reactions, cooling, and adjusting the pH to 2-3.5 to precipitate white solids namely white adefovir. The preparation method has the advantages that during the hydrolysis of 9-[2-(diethoxylphosphorylmethoxyl)ethyl]adenine, the step of evaporating organic solvents is eliminated, the reaction time is reduced, thus the preparation time is shortened; trimethyl iodo-silane, trimethyl bromo-silane, or trimethyl chloro-silane is replaced by a water solution of HBr, and the cost is reduced by nearly 100 to 400 yuan. Secondary solvent acetonitrile is not used, influence of pollution and solvent residue on drug quality is reduced; trimethyl bromo-silane is easy to decompose and is harmful to human body, and after HBr substitution, the harm to workers is largely reduced.