14047-28-0

Basic information

• Product Name: (R)-(+)-9-(2-Hydroxypropyl)adenine
• Synonyms: R-9-(2-hydroxypropyl) adenine, 9-HPA;(R)-(+)-9-(2-HYDROXYPROPYL)ADENINE,98%;(R)-(+)-9-(2-Hydroxypropyl)adenine;6-Amino-alpha-methyl-9H-purine-9-ethanol;D-(-)-9-(2-Hydroxypropyl)adenine;(R)-9-[2-(Hydroxypropyl] Adenine (Desphosphoryl Tenofovir);(R)-6-aMino-alpha-Methyl-9H-purine-9-ethanol;(R)-9-(2-Hydroxypropyl)ademine
• CAS NO: 14047-28-0
• Molecular Formula: C₈H₁₁N₅O
• Molecular Weight: 193.21
• EINECS: 1592732-453-0
• Product Categories: Chiral Reagents;Bases & Related Reagents;Nucleotides;Tenofovir
• Mol File: 14047-28-0.mol
• Article Data: 37

Chemical Properties

• Melting Point: 193 °C
• Boiling Point: 457.7 °C at 760 mmHg
• Flash Point: 230.6 °C
• Appearance: /
• Density: 1.57
• Vapor Pressure: 3.6E-09mmHg at 25°C
• Refractive Index: 1.752
• Storage Temp.: -20°C Freezer
• Solubility: DMSO (Slightly), Ethanol (Slightly), Methanol (Slightly, Heated)
• PKA: 14.42±0.20(Predicted)
• CAS DataBase Reference: (R)-(+)-9-(2-Hydroxypropyl)adenine(CAS DataBase Reference)
• NIST Chemistry Reference: (R)-(+)-9-(2-Hydroxypropyl)adenine(14047-28-0)
• EPA Substance Registry System: (R)-(+)-9-(2-Hydroxypropyl)adenine(14047-28-0)

Safety Data

• Hazardous Substances Data: 14047-28-0(Hazardous Substances Data)

Usage

Description

(R)-(+)-9-(2-Hydroxypropyl)adenine, also known as Desphosphoryl Tenofovir, is a white powder chemical compound with the CAS number 14047-28-0. It is a significant reagent in the pharmaceutical industry, particularly for the preparation of the antiviral drug tenofovir.

Uses

Used in Pharmaceutical Industry:
(R)-(+)-9-(2-Hydroxypropyl)adenine is used as a key reagent for the synthesis of the antiviral drug tenofovir. It plays a crucial role in the development of medications that target various viral infections, contributing to the treatment and prevention of diseases caused by viruses.
Used in Antiviral Drug Preparation:
(R)-(+)-9-(2-Hydroxypropyl)adenine is utilized as an essential component in the preparation of antiviral drugs, specifically tenofovir. Its chemical properties make it a valuable asset in the creation of medications that can effectively combat viral infections, providing a vital tool in the fight against viral diseases.

InChI:InChI=1/C8H11N5O/c1-5(14)2-13-4-12-6-7(9)10-3-11-8(6)13/h3-5,14H,2H2,1H3,(H2,9,10,11)/t5-/m1/s1

Synthetic route

(R)-6-acetyl-9-(2-hydroxypropyl)adenine → (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
With sodium hydroxide In water at 93℃; for 2h; Temperature;	97.7%

(R)-1-(6-chloro-9H-purin-9-yl) propan-2-ol (180587-74-0) → (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
With ammonium hydroxide In 1,4-dioxane at 100 - 110℃; Sealed tube; Large scale;	96.3%
With ammonia at 65℃;	91%
With monomethanolamine In water at 0 - 60℃; for 48h;	76%

(Z)-6-amino-9-(prop-1-en-1-yl)-9H-purine → (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
With D-tartaric acid; 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0℃; Concentration; Reagent/catalyst; Temperature;	95.4%

9-propenyladenine (4121-40-8) → (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine) In dichloromethane at 15℃; for 5h; Temperature; Concentration;	94.7%

(R)-5-amino-1-(2-hydroxypropyl)-1H-imidazole-4-carbonitrile (852954-49-5) + formamidine acetic acid (3473-63-0) → (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
With barium hydroxide monohydrate In N,N-dimethyl-formamide for 16h; Solvent; Concentration; Heating;	93%

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) + (R)-1,2-propylene carbonate (16606-55-6) → (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
With sodium hydroxide In N,N-dimethyl-formamide at 145℃; Temperature; Large scale;	89.5%
With sodium hydroxide In N,N-dimethyl-formamide at 90 - 140℃; for 12h; Inert atmosphere;	87%
With sodium hydroxide In N,N-dimethyl-formamide at 130 - 140℃; for 12h; Inert atmosphere;	87%

(R)-9-<2-(2-tetrahydropyranyloxy)propyl>adenine (160616-02-4) → (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
With sulfuric acid Ambient temperature;	85%

7H-purin-6-ylamine (73-24-5) + (R)-1,2-propylene carbonate (16606-55-6) → (R)-3-(2′-hydroxyprop-1-yl)adenine + (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
With sodium hydroxide In N,N-dimethyl-formamide for 8h; Reflux;	A 8% B 80%

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) + (R)-propylene oxide (15448-47-2) → (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
With sodium carbonate In N,N-dimethyl-formamide at 95℃; for 6h; Reagent/catalyst; Temperature;	69%

1-(6-amino-9H-purin-9-yl)propan-2-one (105970-02-3) → (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
With dichloro(benzene)ruthenium(II) dimer; sodium formate; (R)-α,α-diphenylprolinol In acetonitrile at 20 - 30℃; for 48h; enantioselective reaction;	64%

(R)-1-(5-Amino-6-chloro-pyrimidin-4-ylamino)-propan-2-ol (17435-30-2) → (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 86 percent / conc. HCl / Ambient temperature 2: 91 percent / NH3 / 65 °C 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) → (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: pyridine; dmap / N,N-dimethyl-formamide / 10 h / 5 - 85 °C 2.1: 4 h / 130 °C 2.2: 2 h / 20 °C / pH 9 / Cooling 3.1: sodium hydroxide / water / 2 h / 93 °C 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) + (R)-1,2-propylene carbonate (16606-55-6) → C8H11N5O + (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
Stage #1: adenine With sodium hydroxide In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: (R)-1,2-propylene carbonate at 120 - 130℃; for 16h;	A 97.9 %Chromat. B 92.9 %Chromat.

7H-purin-6-ylamine (73-24-5) + (R)-propylene oxide (15448-47-2) → (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
Stage #1: 7H-purin-6-ylamine With sodium hydroxide In water at 100 - 110℃; for 5h; Stage #2: (R)-propylene oxide With ammonium chloride In water at 25℃; Reagent/catalyst; Solvent; Temperature;	5.5 g

6-chloropurine (87-42-3) → (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 0.17 h / Cooling with ice 1.2: 1 h / Cooling with ice 2.1: ruthenium; D-Prolin; sodium formate / acetonitrile / 24 h / 20 °C 3.1: monomethanolamine / water / 48 h / 0 - 60 °C View Scheme

9-propenyladenine (4121-40-8) → (S)-1-(6-amino-9H-purin-9-yl) propan-2-ol (14047-27-9) + (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl In dichloromethane at 25℃; for 5h; Temperature; Concentration; Overall yield = 43.8 %; Overall yield = 4.2 g;

N6-acetyladenine (6034-68-0) → (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: formic acid ethyl ester / 7 h / Reflux 2: sodium hydroxide / water / 2 h / 70 °C 3: lithium ethoxide / tetrahydrofuran; ethanol / 0.5 h / 20 °C 4: (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / dichloromethane / 5 h / 15 °C View Scheme

N6-acetyladenine (6034-68-0) → (S)-1-(6-amino-9H-purin-9-yl) propan-2-ol (14047-27-9) + (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: formic acid ethyl ester / 7 h / Reflux 2: sodium hydroxide / water / 2 h / 70 °C 3: lithium ethoxide / tetrahydrofuran; ethanol / 0.5 h / 20 °C 4: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl / dichloromethane / 5 h / 25 °C View Scheme

C8H7N5O2 → (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide / water / 2 h / 70 °C 2: lithium ethoxide / tetrahydrofuran; ethanol / 0.5 h / 20 °C 3: (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / dichloromethane / 5 h / 15 °C View Scheme

C8H7N5O2 → (S)-1-(6-amino-9H-purin-9-yl) propan-2-ol (14047-27-9) + (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide / water / 2 h / 70 °C 2: lithium ethoxide / tetrahydrofuran; ethanol / 0.5 h / 20 °C 3: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl / dichloromethane / 5 h / 25 °C View Scheme

9-formyladenine → (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: lithium ethoxide / tetrahydrofuran; ethanol / 0.5 h / 20 °C 2: (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / dichloromethane / 5 h / 15 °C View Scheme

C8H11ClN4O2 → (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride; trimethyl orthoformate / N,N-dimethyl-formamide; water / 20 - 30 °C 2: ammonium hydroxide / 1,4-dioxane / 100 - 110 °C / Sealed tube; Large scale View Scheme

7H-purin-6-ylamine (73-24-5) + (R)-1,2-propylene carbonate (16606-55-6) → (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
With sodium hydroxide In N,N-dimethyl-formamide at 125 - 138℃;

5-amino-1-(2-hydroxypropyl)-1H-imidazole-4-carbonitrile → (R)-9-(2-hydroxypropyl)adenine (14047-28-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: barium hydroxide monohydrate / acetonitrile; water / 2 h / 25 °C 2: barium hydroxide monohydrate / N,N-dimethyl-formamide / 16 h / Heating View Scheme

bis(2-propyl)-p-toluenesulfonyloxymethylphosphonate (35717-98-7) + (R)-9-(2-hydroxypropyl)adenine (14047-28-0) → bis(2-propyl) (R)-9-(2-phosphonomethoxypropyl)adenine (160616-04-6)

Conditions	Yield
With magnesium 2-methylpropan-2-olate In water; N,N-dimethyl-formamide at -15 - 20℃; for 44h; Inert atmosphere;	91%
With magnesium 2-methylpropan-2-olate In water; N,N-dimethyl-formamide at -15 - 20℃; for 44h; Inert atmosphere;

diethyl (p-toluenesulfonyloxymethane)phosphonate (31618-90-3) + (R)-9-(2-hydroxypropyl)adenine (14047-28-0) → (S)-9-(2-phosphonylmethoxypropyl)adenine (147127-19-3)

Conditions	Yield
Stage #1: (R)-9-(2-hydroxypropyl)adenine With bis(isopropoxy) magnesium In N,N-dimethyl-formamide at 65℃; for 1h; Inert atmosphere; Stage #2: diethyl (p-toluenesulfonyloxymethane)phosphonate In N,N-dimethyl-formamide at 45 - 55℃; for 10h; Stage #3: With hydrogenchloride In water at 90℃; for 10h;	88%

diethyl (p-toluenesulfonyloxymethane)phosphonate (31618-90-3) + (R)-9-(2-hydroxypropyl)adenine (14047-28-0) → (R)-diethyl (((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (180587-75-1)

Conditions	Yield
With magnesium 2-methylpropan-2-olate In N,N-dimethyl-formamide at 80℃; for 5h; Solvent;	85%
With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃;	44%
Stage #1: (R)-9-(2-hydroxypropyl)adenine With sodium t-butanolate In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: diethyl (p-toluenesulfonyloxymethane)phosphonate In N,N-dimethyl-formamide for 64h;	29%

{[(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%

(R)-9-(2-hydroxypropyl)adenine (14047-28-0) + tenofovir (147127-20-6) → C17H23N10O4P

Conditions	Yield
With dmap; triethylamine; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 90℃; Inert atmosphere;	77.8%
With dmap; triethylamine; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 90℃; Inert atmosphere;	55%

(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;

2-(2-(2-methoxyethoxy)ethoxy)ethyl p-toluenesulfonate (62921-74-8) + (R)-9-(2-hydroxypropyl)adenine (14047-28-0) → C15H25N5O4

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 7h;	49.4%

benzoyl chloride (98-88-4) + (R)-9-(2-hydroxypropyl)adenine (14047-28-0) → (R)-9-(2-hydroxypropyl)-N6-benzoyladenine (160616-03-5)

Conditions	Yield
With chloro-trimethyl-silane 1) pyridine, room temperature, 1 h; 2) pyridine, room temperature, 2 h; Yield given. Multistep reaction;

(R)-9-(2-hydroxypropyl)adenine (14047-28-0) → (R)-9-[2-(phosphanylmethoxy)propyl]adenine (919512-64-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium tert-butoxide / dimethylformamide / 1 h / 20 °C 1.2: 740 mg / dimethylformamide / 64 h / 20 °C 2.1: 65 percent / TMSCl; LiAlH4 / tetrahydrofuran / 2 h / 20 °C View Scheme

(R)-9-(2-hydroxypropyl)adenine (14047-28-0) → ({[(2R)-1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy}methyl)phosphinic acid (919512-65-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium tert-butoxide / dimethylformamide / 1 h / 20 °C 1.2: 740 mg / dimethylformamide / 64 h / 20 °C 2.1: 65 percent / TMSCl; LiAlH4 / tetrahydrofuran / 2 h / 20 °C 3.1: 100 percent / aq. H2O2 / tetrahydrofuran / 1 h / 20 °C View Scheme

(R)-9-(2-hydroxypropyl)adenine (14047-28-0) → C15H30N5O3PSi2

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium tert-butoxide / dimethylformamide / 1 h / 20 °C 1.2: 740 mg / dimethylformamide / 64 h / 20 °C 2.1: 65 percent / TMSCl; LiAlH4 / tetrahydrofuran / 2 h / 20 °C 3.1: 100 percent / aq. H2O2 / tetrahydrofuran / 1 h / 20 °C 4.1: tetrahydrofuran / 1 h / 20 °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)-9-(2-hydroxypropyl)adenine (14047-28-0) → bis(2-propyl) (R)-9-(2-phosphonomethoxypropyl)adenine (160616-04-6)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme

(R)-9-(2-hydroxypropyl)adenine (14047-28-0) → [(R)-2-(6-Benzoylamino-purin-9-yl)-1-methyl-ethoxymethyl]-phosphonic acid diisopropyl ester (627510-49-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) chlorotrimethylsilane / 1) pyridine, room temperature, 1 h; 2) pyridine, room temperature, 2 h 2: sodium hydride / dimethylformamide / 48 h / Ambient temperature View Scheme

(R)-9-(2-hydroxypropyl)adenine (14047-28-0) → C15H24N5O8P (1244022-55-6) + C20H32N5O11P (1244022-53-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: magnesium 2-methylpropan-2-olate / 1-methyl-pyrrolidin-2-one / 70 - 74 °C 2.1: chloro-trimethyl-silane; sodium bromide / 1-methyl-pyrrolidin-2-one / 0 - 75 °C 3.1: triethylamine / 1-methyl-pyrrolidin-2-one / 45 °C 3.2: 5.5 h / 45 - 50 °C View Scheme

Upstream product

• 180587-74-0 (R)-1-(6-chloro-9H-purin-9-yl) propan-2-ol 
• 66224-66-6 adenine 
• 16606-55-6 (R)-1,2-propylene carbonate 
• 105970-02-3 1-(6-amino-9H-purin-9-yl)propan-2-one 
• 1464851-21-5 (Z)-6-amino-9-(prop-1-en-1-yl)-9H-purine 
• 73-24-5 7H-purin-6-ylamine 
• 852954-49-5 (R)-5-amino-1-(2-hydroxypropyl)-1H-imidazole-4-carbonitrile 
• 3473-63-0 formamidine acetic acid 
• 6034-68-0 N⁶-acetyladenine 
• 4121-40-8 9-propenyladenine 
• 87-42-3 6-chloropurine 
• 15448-47-2 (R)-propylene oxide 
• 17435-30-2 (R)-1-(5-Amino-6-chloro-pyrimidin-4-ylamino)-propan-2-ol 
• 160616-02-4 (R)-9-<2-(2-tetrahydropyranyloxy)propyl>adenine 

Downstream Products

• 180587-75-1 (R)-diethyl (((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate 
• 147127-20-6 tenofovir 
• 1354647-85-0 (R)-9-[2-(pivaloyloxymethyl)-(isopropoxycarbonyloxymethyl)phosphonoylmethoxypropyl]adenine p-toluenesulfonate 
• 201341-05-1 tenofovir disoproxil 
• 1432630-26-6 tenofovir disoproxil fumarate 
• 147127-19-3 (S)-9-(2-phosphonylmethoxypropyl)adenine 
• 211364-69-1 Tenofovir mono-POC 
• 1246812-40-7 propan-2-yl {[(propan-2-yloxy)carbonyl]oxy}methyl {[(2R)-1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy}methanephosphonate 
• 1432630-26-6 tenofovir disoproxil fumarate 
• 201341-05-1 tenofovir disoproxil 
• 202138-50-9 tenofovir disoproxyl fumarate 
• 1244022-55-6 C₁₅H₂₄N₅O₈P 
• 1244022-53-4 C₂₀H₃₂N₅O₁₁P 
• 160616-03-5 (R)-9-(2-hydroxypropyl)-N⁶-benzoyladenine 

Relevant articles and documents

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.

An Improved Process for the Preparation of Tenofovir Disoproxil Fumarate

The current three-step manufacturing route for the preparation of tenofovir disoproxil fumarate (1) was assessed and optimized leading to a higher yielding, simpler, and greener process. Key improvements in the process route include the refinement of the second stage through the replacement of the problematic magnesium tert-butoxide (MTB) with a 1:1 ratio of a Grignard reagent and tert-butanol. The development of a virtually solvent-free approach and the establishment of a workup and purification protocol which allows the isolation of a pure diethyl phosphonate ester (8) was achieved.

The synthesis of tenofovir and its analogues via asymmetric transfer hydrogenation

A series of tenofovir analogues with potential antiviral and immunobiologically active compounds were synthesized through an asymmetric transfer hydrogenation reaction from achiral purine derivatives. Up to 97% ee and good to excellent yields were achieved under mild conditions through short reaction steps. The present report suggests an efficient process to acquire tenofovir and its analogues.

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.

Method for preparing tenofovir disoproxil

The invention discloses a method for preparing tenofovir disoproxil and relates to the field of preparation of tenofovir disoproxil. The method for preparing the tenofovir disoproxil specifically comprises the following steps: A) preparing (R)-9-(2-hydroxypropyl) adenine; B) preparing (R)-9-(2-phosphonic acid methoxy-propyl) adenine di(ethyl) ester; C) preparing tenofovir; D) preparing tenofovir disoproxil; and E) carrying out finished product detection and inspection. Compared with the prior art, the method has the beneficial effects that while the medicine effect of the tenofovir disoproxilis ensured, the reaction steps are simplified, the yield is increased, the conversion rates of intermediates (R)-9-(2-hydroxypropyl) adenine, (R)-9-(2-phosphonic acid methoxy-propyl) adenine di(ethyl)ester and tenofovir reach 75%, 63.2% and 74.3% respectively, and the total yield of the tenofovir disoproxil is as high as 62.4% finally.