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
• Article Data: 21

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

Description

Adefovir (Trade name: Preveon, Hepsera) is a prescription drug used for the treatment of chronic infections of hepatitis B virus. It can be formulated as the pivoxil prodrug adefovir dipivoxil. However, it shows no effect against HIV-1. As a orally administrated acyclic nucleotide analog reverse transcriptase inhibitor, it blocking the reproduction of HBV through inhibiting the reverse transcriptase in the body. One of its advantages over another anti-HBV drug, lamivudine is that it is much harder for the virus to develop resistance to it.

References

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

Chemical Properties

Pale Brown Solid

Uses

Different sources of media describe the Uses of 106941-25-7 differently. You can refer to the following data:
1. Used as an antiviral
2. Adefovir has been used to study its anti-retro viral effect on porcine endogenous retrovirus (PERV) activity.

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 
• 31618-90-3 diethyl (p-toluenesulfonyloxymethane)phosphonate 
• 707-99-3 9-(2-hydroxyethyl)adenine 
• 142340-99-6 adefovir dipivoxyl 
• 168537-58-4 C₁₈H₃₀N₇O₆P 
• 87-42-3 6-chloropurine 
• 56791-59-4 6-chloro-9-(ethoxycarbonylmethyl)-9H-purine 
• 1670-62-8 6-Chloro-9-(β-hydroxyethylamino)purine 
• 66224-66-6 adenine 
• 159531-21-2 {[2-(6-amino-9H-purin-9-yl)ethoxy]methyl}phosphinic acid 
• 2857-97-8 trimethylsilyl bromide 
• 55343-28-7 9-(2-Hydroxyethyl)-N⁶-benzoyladenine 
• 185900-69-0 O,O-diethyl((2-(6-chloro-9H-purin-9-yl)ethoxy)methyl)phosphonate 
• 212894-84-3 [2-(5-Amino-6-chloro-pyrimidin-4-ylamino)-ethoxymethyl]-phosphonic acid diethyl ester 

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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.

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).

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.

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

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.