147127-20-6

Basic information

• Product Name: Tenofovir
• Synonyms: 1-(6-aminopurin-9-yl)propan-2-yloxymethylphosphonic acid;D,L-TENOFOVIR;TENOFOVIR;(R)-9-(2-PHOSPHONYLMETHOXYPROPYL)-ADENINE;(R)-9-(2-Phosphonomethoxypropyl)Adenine;Tenofovir(ForResearchOnly);(R)-PMPA;[[(1R)-2(6-Amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic Acid
• CAS NO: 147127-20-6
• Molecular Formula: C₉H₁₄N₅O₄P
• Molecular Weight: 287.21
• EINECS: 1308068-626-2
• Product Categories: Purine;ACTIVE PHARMACEUTICAL INGREDIENTS;Nucleotides and Nucleosides;Bases & Related Reagents;Intermediates & Fine Chemicals;Nucleotides;Pharmaceuticals;Phosphorylating and Phosphitylating Agents;Inhibitors
• Mol File: 147127-20-6.mol

Chemical Properties

• Melting Point: 276-280°C
• Boiling Point: 616.1 °C at 760 mmHg
• Flash Point: 326.4 °C
• Appearance: white crystalline solid
• Density: 1.79 g/cm³
• Storage Temp.: Store at -20°C
• Solubility: Aqueous Acid (Sparingly), DMSO (Slightly, Heated), Water (Slightly, Heated)
• PKA: 2.36±0.10(Predicted)
• Water Solubility: 13.4 mg/mL (25 ºC)
• Merck: 14,9146
• CAS DataBase Reference: Tenofovir(CAS DataBase Reference)
• NIST Chemistry Reference: Tenofovir(147127-20-6)
• EPA Substance Registry System: Tenofovir(147127-20-6)

Safety Data

• RTECS: SZ6563600
• Hazardous Substances Data: 147127-20-6(Hazardous Substances Data)

Usage

Uses

Used in Antiviral Applications:
Tenofovir is used as an anti-HIV agent for the treatment of chronic hepatitis B as well as prevention and treatment of HIV/AIDS. It is a nucleotide analog, acting as a reverse-transcriptase inhibitor (NtRTI). It inhibits the activity of HIV reverse transcriptase through competing with the natural substrate deoxyadenosine 5'-triphosphate, causing the termination of the DNA chain.
Used in Pharmaceutical Industry:
Tenofovir is used as an active pharmaceutical ingredient in combination therapy for the treatment of HIV infection. The bis(isopropyloxycarbonyloxyethyl) ester (disoproxil ester) prodrug is used as the fumaric acid salt, enhancing its efficacy and bioavailability in patients.

Indications and Usage

Tenofovir disoproxil (Viread) is the first nucleotide analogue approved by the American FDA to treat HIV-1 infections. Tenofovir disoproxil is a drug used in the AIDS cocktail treatment method, and research shows that it has the ability to increase monkeys’ immunity to immunodeficiency viruses (similar to the human AIDS virus). Tenofovir disoproxil is used in combination with other reverse transcriptase inhibitors to treat HIV-1 infections and hepatitis B.

Mechanisms of Action

Tenofovir disoproxil is an acyclic nucleoside antivirus drug and has an inhibiting effect on HBV multi-enzyme complexes and HIV reverse transcriptase. Its active content tenofovir phosphonate directly competitively binds to natural deoxyribose substrate to inhibit the virus multi-enzyme complex and inserts itself into the DNA to end the nucleotide chain. Tenofovir disoproxil is barely absorbed by the gastrointestinal duct, so it undergoes esterification and ionization to become tenofovir ester fumarate. Tenofovir is soluble in water and can be quickly absorbed and decomposed into the active substance tenofovir, which then transforms into the active metabolite tenofovir phosphonate. As this drug is not metabolized by the CYP450 enzyme system, it has a very low chance of drug interactions caused by this enzyme.

Pharmacokinetics

Tenofovir disoproxil reaches peak blood concentration 1-2 hours after intake. Tenofovir disoproxil’s bioavailability increases by about 40% when taken with food. The intracellular half-life of tenofovir phosphonate is about 10 hours, so doses can be taken once daily. This drug is mainly filtered through renal glomeruli and excreted through the renal tubule transport system, with 70-80% excreted in its original form through urine.

Pharmacokinetics

Oral absorption: c. 25% Cmax 300 mg once daily: 0.3 mg/L Plasma half-life: 17 h Volume of distribution: 1.3 ± 0.6 L/kg at 3.0 mg/kg intravenous dose Plasma protein binding: <0.7% (in vitro) Absorption and distribution Oral bioavailability is poor, but is enhanced by administration as the disoproxil prodrug. It may be taken with or without food. CSF penetration is likely to be minimal due to the anionic charge of the molecule at physiological pH. It accumulates in semen at higher concentrations than in plasma. It is not known if it is distributed into breast milk. Metabolism and excretion Tenofovir is not metabolized and is principally eliminated by the kidneys by a combination of glomerular filtration and active tubular secretion. In patients with renal dysfunction the dose should be adjusted accordingly. Compounds such as cidofovir, aciclovir (acyclovir), valaciclovir, ganciclovir, valganciclovir and probenecid may compete for renal excretion. Tenofovir levels are increased when prescribed with some HIV protease inhibitors. The co-administration of tenofovir with didanosine leads to didanosine accumulation which is thought to occur through inhibition of purine nucleoside phosphorylase. This has been associated with impaired immune recovery and several cases of lactic acidosis and pancreatitis. If tenofovir is combined with didanosine the dose of didanosine should be reduced to 200 mg (<60 kg) or 250 mg (≥60 kg) per day and the patient monitored for symptoms of didanosine toxicity.

Adverse Effects

Weakness and exhaustion. Mild to moderate gastrointestinal reactions, including diarrhea, stomach pain, nausea, vomiting, bloating, lactic acid poisoning, hepatomegaly and fatty liver, and pancreatitis. These adverse reactions also commonly appear individually or combined when taking nucleoside analogues. Metabolic system hypophosphatemia (1% occurrence rate). Fat accumulation and redistribution, including centripetal obesity, buffalo hump, thin limbs, breast growth, and Cushing syndrome. May cause lactic acid poisoning, hepatomegaly related to steatosis, etc. Effects on nervous system: dizziness and headache. Effects on respiratory system: difficulty breathing. Effects on skin: drug rash.

Indications

Tenofovir disoproxil fumarate (Viread) is a prodrug of tenofovir, a phosphorylated adenosine nucleoside analogue, and is the only available agent of its class. It is converted by cellular enzymes to tenofovir diphosphate, which competes with deoxyadenosine triphosphate (dATP) for access to reverse transcriptase and causes chain termination following its incorporation. Tenofovir was approved as part of a combination therapy for HIV in adults who failed treatment with other regimens; it appears to be effective against HIV strains that are resistant to NRTIs.

Acquired resistance

HIV variants with the K65R mutation and the K70E mutation in the reverse transcriptase demonstrate reduced susceptibility to tenofovir.

Pharmaceutical Applications

A nucleotide analog structurally similar to adefovir. EC50 values for HBV, assessed in the HepG2 2.2.15 cell line, ranged from 0.14 to 1.5 μm; the cytotoxic concentration exceeded 100 μm. A decline in HBV DNA levels below 105 copies/mL at 48 weeks of therapy in 100% of patients receiving tenofovir compared with 44% on adefovir therapy has been reported. There are also case reports of patients with primary resistance to adefovir responding to tenofovir. It is generally well tolerated in patients with chronic HBV; the most common side effects include nausea and gastrointestinal upset, headache, dizziness, fatigue and rash.

Pharmaceutical Applications

An acyclic nucleoside phosphonate, formulated as the disoproxil fumarate salt for oral administration.

Biological Activity

Selectively inhibits HIV reverse transcriptase (RNA-dependent DNA polymerase). Prevents cytotoxicity in SIV-infected C-8166 cells in vitro (IC 50 = 1.5 μ M). Antiviral agent.

Biochem/physiol Actions

Tenofovir has a low oral bioavailability. Hence, it is available as a prodrug called tenofovir disoproxil fumarate. Once ingested, tenofovir disoproxil fumarate is hydrolyzed to tenofovir and phosphorylated. This is then incorporated into the viral DNA which leads to chain termination. Tenofovir is also effective against hepatitis B virus.

Clinical Use

Chronic hepatitis B infection

Side effects

In clinical trials of antiretroviral treatment-naive participants, the most commonly reported adverse events were mild to moderate gastrointestinal upset (nausea 8%, diarrhea 11%), headache (14%) and depression (11%). Tenofovir has the potential to result in nephrotoxicity, particularly through proximal tubular damage, but the risk of clinically significant renal dysfunction appears relatively low and seems to occur mainly in subjects with other identifiable risks for renal impairment. Minor elevations in serum creatinine and reductions in creatinine clearance occur, but rarely require drug discontinuation. A few (<0.1%) cases of osteomalacia and decreased bone density have been reported.

Side effects

Tenofovir is taken once daily and is generally well tolerated, perhaps because it produces less mitochondrial toxicity than the NRTIs. Nausea, vomiting, flatulence, and diarrhea occur in 10% or fewer patients. Resistance to tenofovir has been documented, and cross-resistance to NRTIs may occur.

InChI:InChI=1/C9H14N5O4P/c1-6(18-5-19(15,16)17)2-14-4-13-7-8(10)11-3-12-9(7)14/h3-4,6H,2,5H2,1H3,(H2,10,11,12)(H2,15,16,17)/t6-/m0/s1

Synthetic route

(R)-diethyl (((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (180587-75-1) → tenofovir (147127-20-6)

Conditions	Yield
With hydrogenchloride In N,N-dimethyl-formamide at 130℃; under 7500.75 Torr; for 0.0416667h; Solvent; Pressure; Temperature; Inert atmosphere;	95%
With trimethylsilyl bromide In acetonitrile at 65℃; for 1h;	90%
With sulfuric acid at 90 - 110℃;	83.8%

(R)-[1-iodo(2-propoxy)]methylphosphonic acid + 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) → tenofovir (147127-20-6)

Conditions	Yield
With sodium hydroxide In water for 5h; Reflux;	91.8%

bis(2-propyl) (R)-9-(2-phosphonomethoxypropyl)adenine (160616-04-6) → tenofovir (147127-20-6)

Conditions	Yield
With hydrogenchloride In water at 130 - 140℃; Microwave irradiation; Sealed tube;	91%
With hydrogenchloride In water at 140℃; for 0.5h; Temperature; Time; Reagent/catalyst; Microwave irradiation;	90%
With hydrogenchloride In water at 140℃; for 0.5h; Temperature; Reagent/catalyst; Microwave irradiation;	90%

(R)-[1-bromo(2-propoxy)]methylphosphonic acid + 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) → tenofovir (147127-20-6)

Conditions	Yield
With potassium hydroxide In water for 5h; Reflux;	88.7%

tenofovir disoproxil → tenofovir (147127-20-6)

Conditions	Yield
In ethyl acetate at 0 - 10℃; for 2h; Cooling with ice;	85.4%

(R)-diethyl (((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (180587-75-1) → magnesium para-toluenesulfonate + tenofovir (147127-20-6)

Conditions	Yield
With hydrogen bromide at 100℃; for 15h;	A n/a B 84.6%

(R)-[1-chloro(2-propoxy)]methylphosphonic acid + 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) → tenofovir (147127-20-6)

Conditions	Yield
With sodium hydroxide In water for 5h; Reflux;	82.5%

{[(4-methylbenzenesulfonyl)oxy]methyl}phosphonic acid (161760-09-4) + (R)-9-(2-hydroxypropyl)adenine (14047-28-0) → C9H14N5O4P + tenofovir (147127-20-6)

Conditions	Yield
In 1-methyl-pyrrolidin-2-one at 0 - 20℃; Solvent; Reagent/catalyst; Temperature; Inert atmosphere; Molecular sieve;	A 12% B 82%

C12H18N5O5P → tenofovir (147127-20-6)

Conditions	Yield
Stage #1: C12H18N5O5P With sodium hydroxide In water for 2h; Cooling with ice; Stage #2: With hydrogenchloride; sodium hydroxide In water at 5℃; for 10h; pH=2.5;	81.3%

C13H20N5O5P → tenofovir (147127-20-6)

Conditions	Yield
With hydrogenchloride In water at 90 - 110℃;	78.1%

1-ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate → tenofovir (147127-20-6)

Conditions	Yield
With hydrogenchloride In water at 90 - 110℃;	76.8%

C13H20N5O5P → tenofovir (147127-20-6)

Conditions	Yield
With hydrogenchloride In water at 90 - 110℃;	76.5%

(R)-[1-fluoro(2-propoxy)]methylphosphonic acid + 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) → tenofovir (147127-20-6)

Conditions	Yield
With sodium hydroxide In water for 5h; Reflux;	76.2%

C11H18N5O4P → tenofovir (147127-20-6)

Conditions	Yield
With hydrogenchloride In water at 90 - 110℃;	75.7%

C15H24N5O5P → tenofovir (147127-20-6)

Conditions	Yield
With hydrogenchloride In water at 90 - 110℃;	74%
Stage #1: C15H24N5O5P With lithium hydroxide for 2h; Cooling with ice; Stage #2: With hydrogenchloride; sodium hydroxide In water at 5℃; for 10h; pH=2.5;	74.5%

(di-tert-butoxyphosphoryl)methyl methanesulfonate + (R)-9-(2-hydroxypropyl)adenine (14047-28-0) → tenofovir (147127-20-6)

Conditions	Yield
Stage #1: (R)-9-(2-hydroxypropyl)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 23h; Schlenk technique; Inert atmosphere; Stage #3: With sulfuric acid at 60℃; Reagent/catalyst; Schlenk technique; Inert atmosphere;	72%

{[(4-methylbenzenesulfonyl)oxy]methyl}phosphonic acid (161760-09-4) + (R)-9-(2-hydroxypropyl)adenine (14047-28-0) → C10H17N5O7P2 + tenofovir (147127-20-6)

Conditions	Yield
With magnesium chloride In 1-methyl-pyrrolidin-2-one at -20 - 20℃; Inert atmosphere;	A 6% B 69%

(di-tert-butoxyphosphoryl)methyl 4-methylbenzenesulfonate + (R)-9-(2-hydroxypropyl)adenine (14047-28-0) → tenofovir (147127-20-6)

Conditions	Yield
Stage #1: (R)-9-(2-hydroxypropyl)adenine With magnesium 2-methylpropan-2-olate In N,N-dimethyl-formamide at 80℃; Schlenk technique; Inert atmosphere; Stage #2: (di-tert-butoxyphosphoryl)methyl 4-methylbenzenesulfonate In N,N-dimethyl-formamide at 80℃; for 23h; Schlenk technique; Inert atmosphere; Stage #3: With sulfuric acid at 60℃; Schlenk technique; Inert atmosphere;	68%

{[(4-methylbenzenesulfonyl)oxy]methyl}phosphonic acid (161760-09-4) + (R)-9-(2-hydroxypropyl)adenine (14047-28-0) → C10H17N5O7P2 + C9H14N5O4P + tenofovir (147127-20-6)

Conditions	Yield
In N,N-dimethyl-formamide at 20℃; Reagent/catalyst; Solvent; Temperature; Inert atmosphere;	A 8% B 11% C 64%

diethyl (p-toluenesulfonyloxymethane)phosphonate (31618-90-3) + (R)-9-(2-hydroxypropyl)adenine (14047-28-0) → tenofovir (147127-20-6)

Conditions	Yield
With bis(isopropoxy) magnesium In N,N-dimethyl-formamide at 45 - 65℃; for 11h; Autoclave; Inert atmosphere; Large scale;	59.2%
Stage #1: diethyl (p-toluenesulfonyloxymethane)phosphonate; (R)-9-(2-hydroxypropyl)adenine With magnesium 2-methylpropan-2-olate In 1-methyl-pyrrolidin-2-one; toluene at 25 - 75℃; for 6h; Stage #2: With water; acetic acid In 1-methyl-pyrrolidin-2-one; water; acetic acid; toluene for 1h; Stage #3: With hydrogen bromide In 1-methyl-pyrrolidin-2-one; water; toluene at 90 - 95℃;
Stage #1: (R)-9-(2-hydroxypropyl)adenine With magnesium 2-methylpropan-2-olate In N,N-dimethyl-formamide at 20 - 35℃; for 0.5h; Stage #2: diethyl (p-toluenesulfonyloxymethane)phosphonate In N,N-dimethyl-formamide at 75 - 80℃; for 2h; Stage #3: With hydrogenchloride In N,N-dimethyl-formamide at 0 - 95℃; for 9h; Temperature; Reagent/catalyst;	82 g
With trimethylsilyl bromide; water; sodium hydroxide In dichloromethane at 0 - 5℃; for 3h; pH=2.5 - 3;
Stage #1: diethyl (p-toluenesulfonyloxymethane)phosphonate; (R)-9-(2-hydroxypropyl)adenine With alumina-supported potassium hydroxide In N,N-dimethyl-formamide at 40 - 130℃; for 18h; Stage #2: With water at 100 - 105℃; for 18h; Reagent/catalyst; Temperature; Solvent;

(R)-(((1-chloropropan-2-yl)oxy)methyl)phosphonic acid bis(diethylamide) + 7H-purin-6-ylamine (73-24-5) → tenofovir (147127-20-6)

Conditions	Yield
Stage #1: (R)-(((1-chloropropan-2-yl)oxy)methyl)phosphonic acid bis(diethylamide); 7H-purin-6-ylamine With potassium phosphate In N,N-dimethyl acetamide at 120℃; for 24h; Inert atmosphere; Stage #2: With hydrogenchloride In water at 80℃; for 0.75h; Inert atmosphere;	41%

(R)-diethyl (((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (180587-75-1) → tenofovir (147127-20-6) + (R)-9-(2-phosphonomethoxypropyl)hypoxanthine

Conditions	Yield
With hydrogenchloride

C15H30N5O4PSi2 → tenofovir (147127-20-6)

Conditions	Yield
With water	30.3 g
With water In acetonitrile

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) → tenofovir (147127-20-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: NaOH / dimethylformamide / 20 h / 140 °C 2: LiOt-Bu / dimethylformamide; tetrahydrofuran / 1 h / 30 - 35 °C 3: 1.) bromotrimethylsilane, 2.) NaOH / 1.) acetonitrile, reflux, 2.) H2O, pH 3 View Scheme
Multi-step reaction with 3 steps 1: sodium hydroxide / N,N-dimethyl-formamide / 120 °C 2: magnesium 2-methylpropan-2-olate / 1-methyl-pyrrolidin-2-one / 70 - 74 °C 3: chloro-trimethyl-silane; sodium bromide / 1-methyl-pyrrolidin-2-one / 0 - 75 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium hydroxide / N,N-dimethyl-formamide / 0.17 h / 25 - 30 °C 1.2: 25 - 120 °C 1.3: 0.17 h / 55 - 70 °C 2.1: magnesium 2-methylpropan-2-olate / dimethyl sulfoxide / 70 °C 3.1: sodium bromide; chloro-trimethyl-silane / 1-methyl-pyrrolidin-2-one / 16 h / 0 - 75 °C View Scheme

(R)-9-(2-hydroxypropyl)adenine (14047-28-0) → tenofovir (147127-20-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: LiOt-Bu / dimethylformamide; tetrahydrofuran / 1 h / 30 - 35 °C 2: 1.) bromotrimethylsilane, 2.) NaOH / 1.) acetonitrile, reflux, 2.) H2O, pH 3 View Scheme
Multi-step reaction with 2 steps 1: 44 percent / NaH / dimethylformamide / 0 - 20 °C 2: 1.) TMSBr, 2.) H2O / 1.) MeCN, RT, 2.) acetone, 4 deg C View Scheme
Multi-step reaction with 4 steps 1: 1.) chlorotrimethylsilane / 1) pyridine, room temperature, 1 h; 2) pyridine, room temperature, 2 h 2: sodium hydride / dimethylformamide / 48 h / Ambient temperature 3: sodium methoxide / dimethylformamide / Ambient temperature 4: 47 percent / bromotrimethylsilane / acetonitrile / Ambient temperature View Scheme

(R)-1-(5-Amino-6-chloro-pyrimidin-4-ylamino)-propan-2-ol (17435-30-2) → tenofovir (147127-20-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: 86 percent / conc. HCl / Ambient temperature 2: 91 percent / NH3 / 65 °C 3: 44 percent / NaH / dimethylformamide / 0 - 20 °C 4: 1.) TMSBr, 2.) H2O / 1.) MeCN, RT, 2.) acetone, 4 deg C View Scheme

(R)-1-(6-chloro-9H-purin-9-yl) propan-2-ol (180587-74-0) → tenofovir (147127-20-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 91 percent / NH3 / 65 °C 2: 44 percent / NaH / dimethylformamide / 0 - 20 °C 3: 1.) TMSBr, 2.) H2O / 1.) MeCN, RT, 2.) acetone, 4 deg C View Scheme
Multi-step reaction with 2 steps 1: ammonium hydroxide / 1,4-dioxane / 100 - 110 °C / Sealed tube; Large scale 2: bis(isopropoxy) magnesium / N,N-dimethyl-formamide / 11 h / 45 - 65 °C / Autoclave; Inert atmosphere; Large scale View Scheme

(R)-9-<2-(2-tetrahydropyranyloxy)propyl>adenine (160616-02-4) → tenofovir (147127-20-6)

Conditions

Yield

Multi-step reaction with 5 steps 1: 85 percent / sulfuric acid / Ambient temperature 2: 1.) chlorotrimethylsilane / 1) pyridine, room temperature, 1 h; 2) pyridine, room temperature, 2 h 3: sodium hydride / dimethylformamide / 48 h / Ambient temperature 4: sodium methoxide / dimethylformamide / Ambient temperature 5: 47 percent / bromotrimethylsilane / acetonitrile / Ambient temperature View Scheme

(R)-9-(2-hydroxypropyl)-N6-benzoyladenine (160616-03-5) → tenofovir (147127-20-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydride / dimethylformamide / 48 h / Ambient temperature 2: sodium methoxide / dimethylformamide / Ambient temperature 3: 47 percent / bromotrimethylsilane / acetonitrile / Ambient temperature View Scheme

[(R)-2-(6-Benzoylamino-purin-9-yl)-1-methyl-ethoxymethyl]-phosphonic acid diisopropyl ester (627510-49-0) → tenofovir (147127-20-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium methoxide / dimethylformamide / Ambient temperature 2: 47 percent / bromotrimethylsilane / acetonitrile / Ambient temperature View Scheme

N,N-dimethyl-formamide (68-12-2, 33513-42-7) + tenofovir (147127-20-6) → C12H17Cl2N6O2P

Conditions	Yield
With oxalyl dichloride In dichloromethane at 20℃; for 3h; Inert atmosphere;	100%
With oxalyl dichloride In dichloromethane at 20℃; for 3h; Inert atmosphere;	100%

tenofovir (147127-20-6) → C9H13N5O4P(1-)*K(1+)

Conditions	Yield
With potassium hydrogencarbonate In water at 40℃;	99.5%

triphenyl phosphite (101-02-0) + tenofovir (147127-20-6) → ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoric acid monophenyl ester (379270-35-6)

Conditions	Yield
With pyridine at 50 - 115℃; for 6h;	98%
With dmap; triethylamine at 100 - 110℃; Reagent/catalyst; Temperature;	91%
With dmap; triethylamine In N,N-dimethyl acetamide at 105 - 110℃; for 20h; Reagent/catalyst; Temperature;	89.03%

tenofovir (147127-20-6) → C9H13N5O4P(1-)*Cs(1+)

Conditions	Yield
With caesium carbonate In water; acetone at 30℃;	97.6%

tenofovir (147127-20-6) → C9H13N5O4P(1-)*Li(1+)

Conditions	Yield
With lithium hydroxide In acetone at 30℃;	96.5%

diphenyl hydrogen phosphite (4712-55-4) + tenofovir (147127-20-6) + phenol (108-95-2) → ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoric acid monophenyl ester (379270-35-6)

Conditions	Yield
With pyridine at 100 - 110℃; for 2h;	95%

tenofovir (147127-20-6) + phenol (108-95-2) → ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoric acid monophenyl ester (379270-35-6)

Conditions	Yield
With pyridine; dicyclohexyl-carbodiimide at 70℃; for 4h;	93.63%
Stage #1: tenofovir; phenol In acetic acid butyl ester at 20℃; for 1h; Stage #2: With dmap; triethylamine; dicyclohexyl-carbodiimide In acetic acid butyl ester at 90℃; for 24h;	85%
With triphenyl phosphite; dmap; triethylamine In toluene; acetonitrile at 100℃; for 28h; Solvent; Temperature;	83%

tenofovir (147127-20-6) → C18H26N10O7P2

Conditions	Yield
With pyridine; dmap; phosphoric acid triphenyl ester In toluene; acetonitrile for 24h; Solvent; Temperature; Reagent/catalyst; Reflux;	92.9%
With pyridine; triethylamine; dicyclohexyl-carbodiimide at 70℃; for 3h; Temperature; Reagent/catalyst;	88.7%
With triethylamine; diisopropyl-carbodiimide In N,N-dimethyl-formamide at 90 - 100℃; for 22h; Solvent; Reagent/catalyst; Temperature;	45.5%

phosphoric acid triphenyl ester (115-86-6) + tenofovir (147127-20-6) → ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoric acid monophenyl ester (379270-35-6)

Conditions	Yield
With dmap; triethylamine In 5,5-dimethyl-1,3-cyclohexadiene at 100 - 110℃; for 12h; Temperature; Solvent;	91.97%

diphenyl hydrogen phosphite (4712-55-4) + tenofovir (147127-20-6) → ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoric acid monophenyl ester (379270-35-6)

Conditions	Yield
With pyridine at 110 - 120℃; for 4h;	91.7%

chloromethyl isopropyl carbonate (35180-01-9) + tenofovir (147127-20-6) → tenofovir disoproxil

Conditions	Yield
With tetrabutylammomium bromide; triethylamine In 1-methyl-pyrrolidin-2-one at 50℃; Temperature;	91.5%
With triethylamine; N-butylpyridinium tetrafluoroborate at 40℃; for 1.5h; Reagent/catalyst; Temperature;	90.6%
Stage #1: tenofovir With tetrabutylammomium bromide; triethylamine In 1-methyl-pyrrolidin-2-one at 50℃; for 0.5h; Stage #2: chloromethyl isopropyl carbonate In 1-methyl-pyrrolidin-2-one at 60℃; for 4h; Reagent/catalyst; Solvent;	87.6%

tenofovir (147127-20-6) → C9H13N5O4P(1-)*Na(1+)

Conditions	Yield
With sodium hydroxide In water; acetone at 30℃; Reagent/catalyst; Solvent; Temperature;	90.6%

chloromethyl isopropyl carbonate (35180-01-9) + (2E)-but-2-enedioic acid (110-17-8) + tenofovir (147127-20-6) → tenofovir disoproxyl fumarate (202138-50-9)

Conditions	Yield
Stage #1: tenofovir With triethylamine In 1-methyl-pyrrolidin-2-one at 63℃; for 0.5h; Stage #2: chloromethyl isopropyl carbonate In 1-methyl-pyrrolidin-2-one at 63℃; for 4h; Stage #3: (2E)-but-2-enedioic acid In isopropyl alcohol at 50℃; for 0.5h; Concentration;	90%
Stage #1: chloromethyl isopropyl carbonate; tenofovir With tetrabutylammomium bromide; triethylamine at 50℃; for 3h; Inert atmosphere; Stage #2: (2E)-but-2-enedioic acid In isopropyl alcohol Reagent/catalyst; Temperature; Reflux;	78.8%
Stage #1: chloromethyl isopropyl carbonate; tenofovir With tetrabutylammomium bromide; triethylamine In 1-methyl-pyrrolidin-2-one; toluene at 45 - 55℃; for 5h; Stage #2: (2E)-but-2-enedioic acid In isopropyl alcohol at 50 - 55℃; for 2h;	63.6%

formaldehyd (50-00-0) + tenofovir (147127-20-6) → C19H28N10O8P2

Conditions	Yield
Stage #1: formaldehyd With hydrogenchloride In N,N-dimethyl-formamide at 35 - 40℃; for 1h; Stage #2: tenofovir at 10 - 15℃; for 48h;	89.5%

Diphenyliodonium triflate (66003-76-7) + tenofovir (147127-20-6) → ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoric acid monophenyl ester (379270-35-6)

Conditions	Yield
With triethylamine In toluene Inert atmosphere; Heating;	88.3%

diphenyliodonium tetrafluoroborate + tenofovir (147127-20-6) → ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoric acid monophenyl ester (379270-35-6)

Conditions	Yield
With dmap In acetic acid butyl ester Inert atmosphere; Heating;	87%

diphenyliodonium bromide (1483-73-4) + tenofovir (147127-20-6) → ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoric acid monophenyl ester (379270-35-6)

Conditions	Yield
With toluene In acetic acid butyl ester at 80℃; Inert atmosphere;	86.3%

tenofovir (147127-20-6) + phenol (108-95-2) → 9-[(R)-2-[[(S)-[bis(phenoxy)phosphinyl]]methoxy]propyl]adenine

Conditions	Yield
Stage #1: tenofovir With thionyl chloride In acetonitrile at 70℃; for 2h; Inert atmosphere; Large scale; Stage #2: phenol In acetonitrile at 80℃; for 13h; Large scale;	85%

diphenyliodonium hexafluorophosphate (58109-40-3) + tenofovir (147127-20-6) → ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoric acid monophenyl ester (379270-35-6)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile Inert atmosphere; Heating;	84.2%

diphenyliodonium nitrate + tenofovir (147127-20-6) → ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoric acid monophenyl ester (379270-35-6)

Conditions	Yield
With potassium tert-butylate In dichloromethane Inert atmosphere; Heating;	80.1%

alanine isopropyl ester hydrochloride (39613-92-8, 62062-56-0, 62062-65-1) + tenofovir (147127-20-6) → P-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}-N-[(1S)-1-methyl-2-(1-methylethoxy)-2-oxoethyl]phosphonamidic acid

Conditions	Yield
Stage #1: tenofovir With thionyl chloride In toluene at 80 - 90℃; for 20h; Stage #2: alanine isopropyl ester hydrochloride With sodium sulfate In dichloromethane; toluene at -15℃; for 4h; Inert atmosphere;	80%
With 1,2-dichloro-ethane; triethylamine In water at 20 - 40℃; for 16h; pH=7.2 - 7.6;
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In water at 80 - 90℃; for 48h;

Upstream product

• 123155-85-1 methyl hydrogen ({[1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy}methyl)phosphonate 
• 14047-26-8 6-amino-α-methyl-9H-purine-9-ethanol 
• 87-42-3 6-chloro-7H-purine 
• 100682-42-6 1-(6-chloro-9H-purin-9-yl)-2-propanone 
• 75166-59-5 1-(6-chloro-9H-purin-9-yl)propan-2-ol 
• 160616-04-6 bis(2-propyl) (R)-9-(2-phosphonomethoxypropyl)adenine 
• 180587-75-1 (R)-diethyl (((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate 
• 206646-04-0 (R)-9-[2-(phosphonomethoxy)propyl]adenine phosphate 
• 31618-90-3 diethyl (p-toluenesulfonyloxymethane)phosphonate 
• 14047-28-0 (R)-9-(2-hydroxypropyl)adenine 
• 919512-65-5 ({[(2R)-1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy}methyl)phosphinic acid 
• 73-24-5 7H-purin-6-ylamine 
• 15448-47-2 (R)-propylene oxide 
• 3167-63-3 diethyl chloromethylphosphonate 

Downstream Products

• 206646-04-0 (R)-9-[2-(phosphonomethoxy)propyl]adenine phosphate 
• 379270-35-6 ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphoric acid monophenyl ester 
• 201341-05-1 tenofovir disoproxil 
• 308367-90-0 C₁₃H₂₁N₆O₄P 
• 873425-08-2 C₂₅H₃₈N₅O₁₀P 
• 873425-06-0 C₂₇H₃₀N₅O₁₀P 
• 202138-50-9 tenofovir disoproxyl fumarate 
• 1432630-26-6 tenofovir disoproxil fumarate 
• 201341-05-1 tenofovir disoproxil 
• 1392275-56-7 (x)C₄H₄O₄*C₂₁H₂₉N₆O₅P 

Relevant articles and documents

Rapid, mild method for phosphonate diester hydrolysis: Development of a one-pot synthesis of tenofovir disoproxil fumarate from tenofovir diethyl ester

A rapid, low temperature hydrolysis of tenofovir diethyl ester mediated by TMSCl and NaBr was identified and demonstrated to be superior to the current production method, TMSBr-mediated hydrolysis. This mild phosphonate ester hydrolysis was then coupled to alkylation of the phosphonic acid, providing a one-pot procedure for formation of tenofovir disoproxil from tenofovir diethyl ester. The hydrolytic conditions developed here dramatically improve the synthesis of tenofovir disoproxyl and will lead to lower cost HIV/AIDS treatment in the developing world.

Green and environment-friendly preparation method of tenofovir

The invention relates to a green and environment-friendly preparation method of tenofovir, and belongs to the technical field of tenofovir preparation. The method comprises the following steps: (1) adding a solvent and R-hydroxypropyl adenine; adding a coupling catalyst in batches, heating, dropwise adding p-toluenesulfonyl methoxy dialkyl phosphonate, carrying out heat preservation and stirring; (2) cooling and adjusting the pH value; and heating and concentrating under reduced pressure; (3) cooling and adding acetone; and cooling, stirring, filtering and concentrating under reduced pressure; (4) adding SO4/ZrO2-Nd2O3 type solid acid, stirring, heating, and adding deionized water; (5) carrying out stirring reaction; and filtering; (6) stirring, decolorizing and filtering; (7) adjusting pH, cooling and stirring; and (8) centrifuging to be dry, and taking out a filter cake to obtain a tenofovir wet product; and drying under reduced pressure to obtain a finished product. The method is scientific and reasonable in design, mild in reaction condition, easy to operate and suitable for green and environment-friendly industrial production, and the product yield and purity are obviously improved.

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).

Synthesis process of antiviral drug

The invention discloses a synthesis process of an antiviral drug. The process comprises the following steps: reacting adenine (II) with (R)- propylene carbonate (III) to prepare a compound IV, carrying out alkylation reaction on the compound IV and a compound V to prepare a compound VI, and carrying out esterolysis reaction to prepare a compound VII; and carrying out esterification reaction on theprepared compound VII and chloromethyl isopropyl carbonate, and salifying with fumaric acid to prepare the final product tenofovir disoproxil fumarate (I). The synthetic route is simple, the reactionconditions are mild, the generation of impurities is reduced, the total yield and purity of the product are improved, and the method is suitable for industrial production.

An Efficient Synthesis of Tenofovir (PMPA): A Key Intermediate Leading to Tenofovir-Based HIV Medicines

Herein, we report further improvements to the synthesis of tenofovir 1, the precursor to tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF). Starting from acyclic precursor diaminomalononitrile 12, a four-step protocol to tenofovir 1 will allow for vertical integration for more manufacturers. The key transformation is a convergent one-step procedure from 6 as compared to the current commercial process, with an improved yield from 59% (two steps) to 70%. Further improvements include eliminating the need for problematic magnesium tert-butoxide (MTB) and significant solvent reduction by avoiding an intermediate workup. With the costs of HIV/AIDS treatments remaining a barrier for those most in need, lowering the raw material/processing costs and increasing the security of supply can increase patient access.

Green and environment-friendly preparation method of tenofovir

The invention discloses a green and environment-friendly tenofovir preparation method which comprises the following steps: dissolving a compound I, S-propylene carbonate and an inorganic weak base inan organic solvent, reacting for 3-6 hours at 85-120 DEG C, cooling to room temperature, and concentrating an obtained system under reduced pressure to obtain an intermediate II; dissolving the intermediate II, hydroxymethylphosphonic acid dialkyl ester and trialkyl (aryl) phosphine in an organic solvent, stirring at room temperature, slowly adding azodicarboxylic acid diester, and reacting for 20minutes to 3 hours to obtain an intermediate III; slowly adding an inorganic strong alkali into the intermediate III, carrying out ice bath, filtering, adjusting the pH value of an obtained filtrate,standing, carrying out suction filtration, washing an obtained filter cake, and carrying out vacuum drying under reduced pressure. According to the method, S-propylene carbonate, adenine and derivatives thereof are taken as initial raw materials; PMPA is generated through configuration inversion of Mitsunobu reaction, the used organic solvents can be recycled, the generated wastewater is mainly aharmless inorganic salt solution, the cost for further treatment and up-to-standard discharge is low, the method is environmentally friendly, the reaction is easy to control, the safety is high, andthe comprehensive economic benefit is high.

Repurposing Antiviral Drugs for Orthogonal RNA-Catalyzed Labeling of RNA

In vitro selected ribozymes are promising tools for site-specific labeling of RNA. Previously known nucleic acid catalysts attached fluorescently labeled adenosine or guanosine derivatives through 2′,5′-branched phosphodiester bonds to the RNA of interest. Herein, we report new ribozymes that use orthogonal substrates, derived from the antiviral drug tenofovir, and attach bioorthogonal functional groups, as well as affinity handles and fluorescent reporter units through a hydrolytically more stable phosphonate ester linkage. The tenofovir transferase ribozymes were identified by in vitro selection and are orthogonal to nucleotide transferase ribozymes. As genetically encodable functional RNAs, these ribozymes may be developed for potential cellular applications. The orthogonal ribozymes addressed desired target sites in large RNAs in vitro, as shown by fluorescent labeling of E. coli 16S and 23S rRNAs in total cellular RNA.

Method of preparing tenofovir by using microreactor

The invention provides a method of preparing tenofovir by using a microreactor. The method comprises the following steps: performing a condensation reaction by using adenine and (R)-propylene carbonate as raw materials to prepare (R)-9-(2-hydroxypropyl)adenine, and performing a condensation reaction on the (R)-9-(2-hydroxypropyl)adenine and diethyl(tosyloxy)phosphonate under the action of magnesium tert-butoxide to prepare (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine; and performing a deesterification reaction by adopting a microreactor and using a hydrogen chloride gas as a deesterification reagent to prepare the tenofovir. According to the method provided by the invention, the deesterification reaction uses the hydrogen chloride as the deesterification reagent, and the hydrogen chloride used in the method has a low price and low costs; the quantitative reaction is used, and the deesterification reaction is carried out by using the microreactor technology, so that the reaction pressure and temperature are improved, and the mixing effect is enhanced; the generation amount of waste liquid is less, and the method is green and environmentally friendly; and the method has a fast reaction speed, high reaction efficiency, less side reactions, and high purity and a high yield of the target product, and facilitates industrial production.

Tenofovir disoproxil fumarate analog preparation method

The present invention discloses a tenofovir disoproxil fumarate analog preparation method, which comprises: carrying out a substitution reaction on adenine as a raw material and (R)-propylene carbonate in the presence of an alkali, carrying out a substitution reaction with (diethoxyphosphoryl)methyl-4-methylbenzenesulfonate, hydrolyzing with a concentrated hydrochloric acid solution, crystallizingto obtain anhydrous tenofovir, carrying out a reaction on the anhydrous tenofovir and chloromethyl isopropyl carbonate to obtain tenofovir monoester, and carrying out a reaction with 2-bromopropane to obtain the target compound. According to the present invention, the selected starting raw materials are inexpensive and easy to obtain, the process is simple, and the material utilization rate and total yield are improved; and the intermediate of the method is purified by re-crystallization, such that the yield is high, and the purity is high.

A method for preparing for [...] (by machine translation)

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