874638-80-9

Basic information

• Product Name: ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)methyl benzoate
• Synonyms: 3,5-di-O-benzoyl-2-deoxy-2-fluoro-D-ribono-γ-latone;SFBM;(2R)-2-Deoxy-2-fluoro-2-methyl-D-erythropentonic acid γ-lactone 3,5-dibenzoate;Sofosbuvir intermediate;Sofosbuvir Impurity 30;3,5-Di-O-benzoyl-2-deoxy-2-fluoro-2C-methyl-D-ribono-1,4-lactone;(2R,3R,4R)-2-[(benzoyloxy)methyl]-4-fluoro-4-methyl-5-oxooxolan-3-yl benzoate;Sofosbuvir Intermediate 1
• CAS NO: 874638-80-9
• Molecular Formula: C₂₀H₁₇FO₆
• Molecular Weight: 372.3437832
• EINECS: 1312995-182-4
• Product Categories: Sofosbuvir intermediate;apis
• Mol File: 874638-80-9.mol

Chemical Properties

• Melting Point: 133℃
• Boiling Point: 458.6±34.0 °C(Predicted)
• Appearance: /
• Density: 1.33
• Storage Temp.: 2-8°C
• CAS DataBase Reference: ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)methyl benzoate(CAS DataBase Reference)
• NIST Chemistry Reference: ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)methyl benzoate(874638-80-9)
• EPA Substance Registry System: ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)methyl benzoate(874638-80-9)

Safety Data

• Hazardous Substances Data: 874638-80-9(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)methyl benzoate is used as a neuromuscular blocking agent for its ability to selectively bind to and inhibit the function of specific receptors in the neuromuscular junction, leading to muscle relaxation.
Used in Chemical Synthesis:
((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)methyl benzoate is used as a reactant in the synthesis of 1''-C-cyano-2''-fluoro-2''-C-methyl pyrimidine nucleosides, which are HCV polymerase inhibitors. These nucleosides have potential applications in the development of antiviral drugs for the treatment of Hepatitis C virus infections.

Synthetic route

[(2R,3R,4S)-4-fluoro-2,5-dihydroxy-4-methylpentane-1,3-diyl] dibenzoate → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
With pyridinium chlorochromate In dichloromethane at 20℃; for 12h; Reagent/catalyst; Solvent; Temperature; Molecular sieve;	95%
With hydrogenchloride; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid In dichloromethane; water at 10 - 20℃; for 2.5h;

C11H19FO5 (1033394-83-0) + benzoyl chloride (98-88-4) → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
Stage #1: C11H19FO5 With hydrogenchloride In ethanol; water at 20℃; for 22h; Stage #2: benzoyl chloride With pyridine In water; acetonitrile at 0 - 30℃; for 1.16667h; Temperature;	95%

(3R,4R,5R)-3-methyl-3-fluoro-4-benzoyloxy-5-hydroxymethylbutyrolactone + benzoyl chloride (98-88-4) → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
With pyridine In dichloromethane at 20℃;	91%
With triethylamine In dichloromethane at 0 - 20℃; for 3h;	87%
With triethylamine In dichloromethane at 0 - 20℃; for 3h;	87%

3,5-dibenzoyl-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
With triethylamine tris(hydrogen fluoride); triethylamine In acetonitrile Cooling with ice;	90%
With fluorosulfonyl fluoride; triethylamine tris(hydrogen fluoride); triethylamine In acetonitrile Cooling with ice;	87%
Stage #1: 3,5-dibenzoyl-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone With triethylamine tris(hydrogen fluoride); triethylamine In ethyl acetate at -17℃; for 1h; Stage #2: With fluorosulfonyl fluoride In ethyl acetate under 750.075 - 3750.38 Torr; Reagent/catalyst; Solvent; Temperature; Cooling;	87.6%
Stage #1: 3,5-dibenzoyl-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone With triethylamine tris(hydrogen fluoride); triethylamine In acetonitrile Stage #2: With potassium chloride In acetonitrile at 0℃; for 2h;	83%

(3R,4R,5R)-3‑fluoro‑4‑hydroxy‑5‑(hydroxymethyl)‑3‑methyltetrahydrofuran‑2‑one (879551-04-9) + benzoyl chloride (98-88-4) → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
With pyridine at 20℃; for 0.333333h;	87%
With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h;	86%
With dmap; triethylamine In acetonitrile at 5 - 20℃; for 2h; Temperature;	84.2%

3,5-di-O-benzoyl-2-C-methyl-D-ribono-γ-lactone (729596-46-7) → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
Stage #1: 3,5-di-O-benzoyl-2-C-methyl-D-ribono-γ-lactone With pyridine; trifluoromethylsulfonic anhydride In dichloromethane at -40 - 20℃; for 1h; Stage #2: With fluorosulfonyl fluoride; triethylamine tris(hydrogen fluoride); triethylamine In acetonitrile Cooling with ice;	78%
Multi-step reaction with 3 steps 1.1: pyridine / dichloromethane / 0.08 h / -10 °C 1.2: 20 °C 2.1: dichloromethane; water; dimethyl sulfoxide / Cooling with ice 3.1: triethylamine; triethylamine tris(hydrogen fluoride); fluorosulfonyl fluoride / acetonitrile / Cooling with ice View Scheme
Multi-step reaction with 4 steps 1.1: pyridine / dichloromethane / 0.08 h / -10 °C 1.2: 20 °C 2.1: water / 0.42 h 3.1: triethylamine / water; acetone / 45 °C 4.1: triethylamine; triethylamine tris(hydrogen fluoride); fluorosulfonyl fluoride / acetonitrile / Cooling with ice View Scheme

2-C-methyl-D-ribono-1,4-lactone (492-30-8, 7306-56-1, 19774-08-4, 36791-96-5, 36791-97-6, 53008-90-5, 53008-96-1, 53008-97-2, 86204-17-3, 86204-18-4, 93636-22-7) + benzoyl chloride (98-88-4) → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
Stage #1: 2-C-methyl-D-ribono-1,4-lactone; benzoyl chloride With triethylamine In dichloromethane Cooling with ice; Stage #2: With pyridine; trifluoromethylsulfonic anhydride In dichloromethane at -40 - 20℃; for 1h; Stage #3: With triethylamine tris(hydrogen fluoride); triethylamine In acetonitrile Cooling with ice;	58%

(2R,3R,4R,5S)-5-(4-benzoylamino-2-oxopyrimidin-1(2H)-yl)-2-((benzoyloxy)methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
With ammonium cerium (IV) nitrate In 1,4-dioxane for 6h; Solvent; Irradiation;	52%

C6H9FO4 + benzoyl chloride (98-88-4) → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) + ((2R,3R,4S)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)methylbenzoate (1157884-58-6)

Conditions	Yield
With pyridine optical yield given as %de;

C6H9FO4 + benzoyl chloride (98-88-4) → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) + C20H17FO6

Conditions	Yield
With dmap; triethylamine In acetonitrile at 20 - 40℃;	A 12.7 g B n/a

(2S,3R)-3-[(4R)-2,2-dimethyl-[1,3]dioxolane-4-yl]-2,3-dihydroxy-2-methylpropionic acid ethyl ester (93635-76-8) → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: fluorosulfonyl fluoride; 1,8-diazabicyclo[5.4.0]undec-7-ene; triethylamine tris(hydrogen fluoride) / acetonitrile / 5 h / -15 - 90 °C 2: 2,2-dimethoxy-propane; hydrogenchloride; water / tetrahydrofuran / 3 h / 20 °C 3: hydrogenchloride; water / ethanol / 21 h / 20 °C 4: pyridine / 0.5 h / 20 °C / Cooling with ice View Scheme
Multi-step reaction with 4 steps 1.1: triethylamine; sulfuryl dichloride / dichloromethane / 2 h / 0 - 20 °C 2.1: tetraethylammonium fluoride / 1,4-dioxane / 16 h / 120 °C 2.2: 3 h / 20 °C 3.1: water; hydrogenchloride / ethanol / 48 h / 20 °C 4.1: pyridine / 0.75 h / 0 - 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: Isopropyl acetate; triethylamine; thionyl chloride / acetonitrile / 1 h / 6 - 9 °C 1.2: 0.5 h 2.1: triethylamine tris(hydrogen fluoride) / 2 h / 82 - 85 °C 3.1: hydrogenchloride / 0.5 h / 90 - 92 °C 3.2: 4 h 4.1: triethylamine; dmap / acetonitrile / 2 h / 5 - 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: acetic acid / ethanol / 15 h / 80 °C 2.1: pyridine / 2-methyltetrahydrofuran / Inert atmosphere 2.2: 0.5 h / 5 - 15 °C 3.1: triethylamine; triethylamine tris(hydrogen fluoride) / acetonitrile 3.2: 2 h / 0 °C View Scheme

C10H18O6 (1351925-17-1) → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: fluorosulfonyl fluoride; triethylamine; 1,8-diazabicyclo[5.4.0]undec-7-ene hydrofluoride / acetonitrile / 5 h / 0 - 55 °C 2: 2,2-dimethoxy-propane; water; sulfuric acid / 1,4-dioxane / 16 h / 20 °C / pH 2 - 3 / Cooling with ice 3: hydrogenchloride; water / ethanol / 18 h / 20 °C 4: pyridine / 0.5 h / 20 °C / Cooling with ice View Scheme

C11H18FO8S(1-) → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 2,2-dimethoxy-propane; hydrogenchloride; water / tetrahydrofuran / 3 h / 20 °C 2: hydrogenchloride; water / ethanol / 21 h / 20 °C 3: pyridine / 0.5 h / 20 °C / Cooling with ice View Scheme

C11H19FO5 (1033394-83-0) → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride; water / ethanol / 21 h / 20 °C 2: pyridine / 0.5 h / 20 °C / Cooling with ice View Scheme

C10H16FO8S(1-) → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 2,2-dimethoxy-propane; water; sulfuric acid / 1,4-dioxane / 16 h / 20 °C / pH 2 - 3 / Cooling with ice 2: hydrogenchloride; water / ethanol / 18 h / 20 °C 3: pyridine / 0.5 h / 20 °C / Cooling with ice View Scheme

C10H17FO5 → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride; water / ethanol / 18 h / 20 °C 2: pyridine / 0.5 h / 20 °C / Cooling with ice View Scheme

(S)-3-((2R,3R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-fluoro-3-hydroxy-2-methylpropanoyl)-4-benzyloxazolidin-2-one (1616508-45-2) → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: dihydrogen peroxide; lithium hydroxide monohydrate / tetrahydrofuran; water / 1 h / 0 - 5 °C 2: triethylamine; dmap / tetrahydrofuran / 2 h / 0 - 40 °C View Scheme

(S)-3-((2R,3R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-fluoro-3-hydroxy-2-methylpropanoyl)-4-isopropyloxazolidin-2-one (1616508-57-6) → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: dihydrogen peroxide; lithium hydroxide monohydrate / tetrahydrofuran; water / 1 h / 0 - 5 °C 2: triethylamine; dmap / tetrahydrofuran / 2 h / 0 - 40 °C View Scheme

(S)-3-((2R,3R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-fluoro-3-hydroxy-2-methylpropanoyl)-4-isopropyl-5,5-diphenyloxazolidin-2-one → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: dihydrogen peroxide; lithium hydroxide monohydrate / tetrahydrofuran; water / 1 h / 0 - 5 °C 2: triethylamine; dmap / tetrahydrofuran / 2 h / 0 - 40 °C View Scheme

C11H18O4 (130606-67-6) → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: potassium permanganate / acetone / 5 h / 0 - 5 °C 2.1: triethylamine; sulfuryl dichloride / dichloromethane / 2 h / 0 - 20 °C 3.1: tetraethylammonium fluoride / 1,4-dioxane / 16 h / 120 °C 3.2: 3 h / 20 °C 4.1: water; hydrogenchloride / ethanol / 48 h / 20 °C 5.1: pyridine / 0.75 h / 0 - 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: sodium hydrogencarbonate; sodium permanganate; ethylene glycol / acetone / 1.5 h / -15 - 10 °C 2.1: Isopropyl acetate; triethylamine; thionyl chloride / acetonitrile / 1 h / 6 - 9 °C 2.2: 0.5 h 3.1: triethylamine tris(hydrogen fluoride) / 2 h / 82 - 85 °C 4.1: hydrogenchloride / 0.5 h / 90 - 92 °C 4.2: 4 h 5.1: triethylamine; dmap / acetonitrile / 2 h / 5 - 20 °C View Scheme

(4S,5R)-ethyl-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-meth-yl-1,3,2-dioxathiolane-4-carboxylate 2,2-dioxide (879551-01-6) → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: tetraethylammonium fluoride / 1,4-dioxane / 16 h / 120 °C 1.2: 3 h / 20 °C 2.1: water; hydrogenchloride / ethanol / 48 h / 20 °C 3.1: pyridine / 0.75 h / 0 - 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine tris(hydrogen fluoride) / 2 h / 82 - 85 °C 2.1: hydrogenchloride / 0.5 h / 90 - 92 °C 2.2: 4 h 3.1: triethylamine; dmap / acetonitrile / 2 h / 5 - 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: dmap / toluene / 12 h / 60 °C 2.1: tetraethylammonium fluoride / 1,4-dioxane / 16 h / 105 °C 2.2: 3 h / 20 °C 3.1: ethanol / 1 h / Reflux 4.1: hydrogenchloride / water; ethanol / 22 h / 20 °C 4.2: 1.17 h / 0 - 30 °C View Scheme

C12H21FO4 → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: water; hydrogenchloride / ethanol / 48 h / 20 °C 2: pyridine / 0.75 h / 0 - 20 °C View Scheme

((2R,3R,4R)-3-(benzoyloxy)-4-methyl-5-oxo-4-(((trifluoromethyl)sulfonyl)oxy)tetrahydrofuran-2-yl)methylbenzoate → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: dichloromethane; water; dimethyl sulfoxide / Cooling with ice 2: triethylamine; triethylamine tris(hydrogen fluoride); fluorosulfonyl fluoride / acetonitrile / Cooling with ice View Scheme
Multi-step reaction with 3 steps 1: water / 0.42 h 2: triethylamine / water; acetone / 45 °C 3: triethylamine; triethylamine tris(hydrogen fluoride); fluorosulfonyl fluoride / acetonitrile / Cooling with ice View Scheme
Multi-step reaction with 2 steps 1: dimethyl sulfoxide / ethyl acetate 2: triethylamine tris(hydrogen fluoride); triethylamine / acetonitrile / Cooling with ice View Scheme
Multi-step reaction with 3 steps 1: 0.5 h / 20 °C 2: triethylamine / acetone / 50 °C 3: triethylamine tris(hydrogen fluoride); triethylamine / acetonitrile / Cooling with ice View Scheme

((3aR,4R,6aR)-2-(formyloxy)-6a-methyl-6-oxo-2-phenyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylbenzoate → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / water; acetone / 45 °C 2: triethylamine; triethylamine tris(hydrogen fluoride); fluorosulfonyl fluoride / acetonitrile / Cooling with ice View Scheme
Multi-step reaction with 2 steps 1: triethylamine / acetone / 50 °C 2: triethylamine tris(hydrogen fluoride); triethylamine / acetonitrile / Cooling with ice View Scheme

benzoyl chloride (98-88-4) → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triethylamine / ethyl acetate / Cooling with ice 2.1: pyridine / dichloromethane / 0.08 h / -10 °C 2.2: 20 °C 3.1: dichloromethane; water; dimethyl sulfoxide / Cooling with ice 4.1: triethylamine; triethylamine tris(hydrogen fluoride); fluorosulfonyl fluoride / acetonitrile / Cooling with ice View Scheme
Multi-step reaction with 5 steps 1.1: triethylamine / ethyl acetate / Cooling with ice 2.1: pyridine / dichloromethane / 0.08 h / -10 °C 2.2: 20 °C 3.1: water / 0.42 h 4.1: triethylamine / water; acetone / 45 °C 5.1: triethylamine; triethylamine tris(hydrogen fluoride); fluorosulfonyl fluoride / acetonitrile / Cooling with ice View Scheme
Multi-step reaction with 2 steps 1.1: triethylamine / ethyl acetate / Cooling with ice 2.1: pyridine; trifluoromethylsulfonic anhydride / dichloromethane / 1 h / -40 - 20 °C 2.2: Cooling with ice View Scheme

2-C-methyl-D-ribono-1,4-lactone (492-30-8, 7306-56-1, 19774-08-4, 36791-96-5, 36791-97-6, 53008-90-5, 53008-96-1, 53008-97-2, 86204-17-3, 86204-18-4, 93636-22-7) → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triethylamine / ethyl acetate / Cooling with ice 2.1: pyridine / dichloromethane / 0.08 h / -10 °C 2.2: 20 °C 3.1: dichloromethane; water; dimethyl sulfoxide / Cooling with ice 4.1: triethylamine; triethylamine tris(hydrogen fluoride); fluorosulfonyl fluoride / acetonitrile / Cooling with ice View Scheme
Multi-step reaction with 5 steps 1.1: triethylamine / ethyl acetate / Cooling with ice 2.1: pyridine / dichloromethane / 0.08 h / -10 °C 2.2: 20 °C 3.1: water / 0.42 h 4.1: triethylamine / water; acetone / 45 °C 5.1: triethylamine; triethylamine tris(hydrogen fluoride); fluorosulfonyl fluoride / acetonitrile / Cooling with ice View Scheme
Multi-step reaction with 2 steps 1.1: triethylamine / ethyl acetate / Cooling with ice 2.1: pyridine; trifluoromethylsulfonic anhydride / dichloromethane / 1 h / -40 - 20 °C 2.2: Cooling with ice View Scheme

C18H22FNO6 → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride / water; ethanol / 4 h / Reflux 2: triethylamine; dmap / ethyl acetate / 2 h / -5 °C View Scheme

C10H17FO5 → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: dmap; triethylamine / water; acetonitrile; ethyl acetate / 1 h / 0 - 20 °C / Inert atmosphere; Cooling with ice 1.2: 0.5 h / 0 °C / Inert atmosphere 2.1: Selectfluor / N,N-dimethyl-formamide / 1 h / -40 - 20 °C View Scheme

C25H29FO6Si + methyl iodide (74-88-4) → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
With Selectfluor In N,N-dimethyl-formamide at -40 - 20℃; for 1h;	3.5 g

((2R,3R,4R)-3-(benzoyloxy)-4-methyl-4-((methylsulfonyl)oxy)-5-oxotetrahydrofuran-2-yl)methylbenzoate → ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetra-(n-butyl)ammonium iodide; potassium nitrite / dimethyl sulfoxide; water / 75 °C 2: triethylamine tris(hydrogen fluoride); triethylamine / acetonitrile / Cooling with ice View Scheme

((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) → ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-hydroxy-4-methyltetrahydrofuran-2-yl)methyl benzoate

Conditions	Yield
With lithium tri-t-butoxyaluminum hydride In tetrahydrofuran Inert atmosphere;	100%
Stage #1: ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate With lithium tri-t-butoxyaluminum hydride In tetrahydrofuran at -10 - 0℃; Inert atmosphere; Stage #2: With water; ammonium chloride In tetrahydrofuran Inert atmosphere;	99%
With lithium tri-t-butoxyaluminum hydride In tetrahydrofuran at 0℃; for 3h;	99%

((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) → (3R,4R,5R)-3‑fluoro‑4‑hydroxy‑5‑(hydroxymethyl)‑3‑methyltetrahydrofuran‑2‑one (879551-04-9)

Conditions	Yield
With methanesulfonic acid In ethanol for 5h; Reagent/catalyst; Solvent; Reflux;	95.3%
With sodium methylate In methanol at 20℃; for 2h;

((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) → ((2R,3R,4R,5R)-3-(benzoyloxy)-4-fluoro-5-hydroxy-4-methyltetrahydrofuran-2-yl)methyl benzoate (1199809-22-7)

Conditions	Yield
In tetrahydrofuran; toluene at -10 - -5℃; for 3h; Inert atmosphere;	90%
Stage #1: ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate With lithium tri-t-butoxyaluminum hydride In tetrahydrofuran at -30 - -10℃; for 1.25h; Inert atmosphere; Stage #2: With ammonium chloride In tetrahydrofuran; ethyl acetate at 0℃;	77%
With lithium tri(tert-butoxy)aluminum hydride In tetrahydrofuran at -30 - -10℃; for 2.25h; Inert atmosphere;	77%
With aluminium In dichloromethane; 2,2,2-trifluoroethanol; toluene at 0 - 10℃;
With lithium tri-(tert-butoxy)aluminum hydride In tetrahydrofuran at -20℃; Inert atmosphere;

((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) → ((2R,3R,4R,5S)-3-(benzoyloxy)-4-fluoro-5-hydroxy-4-methyltetrahydrofuran-2-yl)methyl benzoate

Conditions	Yield
With sodium bis(2-methoxyethoxy)aluminium dihydride In tetrahydrofuran; toluene at -10 - -5℃; for 3h; Inert atmosphere;	90%

((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) → (2R)-2-deoxy-2-fluoro-2-methyl-α/β-D-erythro-pentofuranosyl chloride-3,5-dibenzoate

Conditions	Yield
Stage #1: ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate With 2,2,2-trifluoroethanol; sodium bis(2-methoxyethoxy)aluminium dihydride In acetic acid butyl ester; toluene at -20 - -15℃; Stage #2: With sulfuryl dichloride; tetrabutylammomium bromide In acetic acid butyl ester; toluene at -20 - 20℃;	86%
Multi-step reaction with 2 steps 1: sodium bis-(2-methoxyethoxy) (2,2,2,trifluoroethoxy) aluminum hydride / toluene; acetic acid butyl ester / -20 - -15 °C 2: tetrabutylammomium bromide; sulfuryl dichloride / toluene; acetic acid butyl ester / 1 h / -20 - 0 °C View Scheme
Stage #1: ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate In dichloromethane at -10℃; for 0.5h; Stage #2: With sulfuryl dichloride; tetrabutylammomium bromide In dichloromethane at -10 - 20℃; for 16h;

((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) + 7-bromo-2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine (1062135-87-8) → C27H25FN4O6S2

Conditions	Yield
Stage #1: 7-bromo-2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine With n-butyllithium In tetrahydrofuran; hexanes at -78℃; for 0.0833333h; Stage #2: ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate With boron trifluoride diethyl etherate In tetrahydrofuran at -78℃; for 2h;	67%
Stage #1: 7-bromo-2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine With n-butyllithium In tetrahydrofuran; hexane at -78℃; Stage #2: ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate With boron trifluoride diethyl etherate In tetrahydrofuran; hexane at -78℃; for 2h; Stage #3: With ammonium chloride In tetrahydrofuran; hexane	67%

((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) → (((2R,3R,4R,5R)-3-(benzoyloxy)-5-bromo-4-fluoro-4-methyltetrahydrofuran-2-yl)methyl benzoate) (1199809-24-9)

Conditions	Yield
Stage #1: ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate With lithium tri-t-butoxyaluminum hydride In tetrahydrofuran at -30 - -15℃; for 1.5h; Inert atmosphere; Stage #2: With carbon tetrabromide; triphenylphosphine In tetrahydrofuran; dichloromethane at -20 - 0℃; for 2.16h; Inert atmosphere;	62%
With lithium tri-(tert-butoxy)aluminum hydride In tetrahydrofuran; ethyl acetate at -30 - -15℃; for 1.5h; Inert atmosphere;	62%
Multi-step reaction with 2 steps 1: lithium tri-t-butoxyaluminum hydride / tetrahydrofuran / 0.67 h / -30 - -15 °C / Inert atmosphere 2: carbon tetrabromide; triphenylphosphine / dichloromethane / 1.75 h / -20 - -15 °C / Inert atmosphere View Scheme

((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) + 7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (937046-98-5) → C26H23FN4O6

Conditions	Yield
Stage #1: 7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine With n-butyllithium In tetrahydrofuran; hexanes at -78℃; for 0.5h; Stage #2: With 1,2-bis-(chlorodimethylsilyl)ethane In tetrahydrofuran for 0.75h; Stage #3: ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate Product distribution / selectivity;	40%
Stage #1: 7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Stage #2: ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate With 1,2-bis-(chlorodimethylsilyl)ethane In tetrahydrofuran; hexane; water at -78℃; for 3.75h; Inert atmosphere; Stage #3: With ammonium chloride; acetic acid In tetrahydrofuran; hexane Product distribution / selectivity;	40%

((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) + Tebbe's reagent → C21H19FO5

Conditions	Yield
With pyridine In tetrahydrofuran at -40℃; for 1h; Tebbe Olefination;	20%

((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) + 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-ylamine (1238579-07-1) → C27H23FN2O6S2

Conditions	Yield
Stage #1: 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-ylamine With n-butyllithium In tetrahydrofuran; hexane at -78℃; Stage #2: ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate In tetrahydrofuran; hexane at -78℃;

((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) → C27H25FN4O5S2 (1273029-03-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexanes / 0.08 h / -78 °C 1.2: 2 h / -78 °C 2.1: boron trifluoride diethyl etherate; triethylsilane / dichloromethane / 184 h / 20 °C View Scheme

((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) → C12H16FN5O3S (1273029-04-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexanes / 0.08 h / -78 °C 1.2: 2 h / -78 °C 2.1: boron trifluoride diethyl etherate; triethylsilane / dichloromethane / 184 h / 20 °C 3.1: ammonia / 16 h / 50 °C / Sealed tube 3.2: 0.67 h / 60 °C View Scheme

((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) → C12H16FN5O5S (1273029-05-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran; hexanes / 0.08 h / -78 °C 1.2: 2 h / -78 °C 2.1: boron trifluoride diethyl etherate; triethylsilane / dichloromethane / 184 h / 20 °C 3.1: ammonia / 16 h / 50 °C / Sealed tube 3.2: 0.67 h / 60 °C 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 16 h / 20 °C View Scheme

((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) → C11H15FN6O3 (1273029-06-3)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: n-butyllithium / tetrahydrofuran; hexanes / 0.08 h / -78 °C 1.2: 2 h / -78 °C 2.1: boron trifluoride diethyl etherate; triethylsilane / dichloromethane / 184 h / 20 °C 3.1: ammonia / 16 h / 50 °C / Sealed tube 3.2: 0.67 h / 60 °C 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 16 h / 20 °C 5.1: ammonia / 72 h / 115 °C / Sealed tube View Scheme

((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) → C11H14FN5O4 (1273029-07-4)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: n-butyllithium / tetrahydrofuran; hexanes / 0.08 h / -78 °C 1.2: 2 h / -78 °C 2.1: boron trifluoride diethyl etherate; triethylsilane / dichloromethane / 184 h / 20 °C 3.1: ammonia / 16 h / 50 °C / Sealed tube 3.2: 0.67 h / 60 °C 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 16 h / 20 °C 5.1: ammonia / 72 h / 115 °C / Sealed tube 6.1: water / bovine spleen type IX sdenosine deaminase A5168 / 4 h / 37 °C / Enzymatic reaction View Scheme

((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) → C27H22FN5O5 (1272971-36-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexanes / 0.5 h / -78 °C 1.2: 0.75 h 2.1: trimethylsilyl trifluoromethanesulfonate / acetonitrile / 73 h / 20 - 65 °C View Scheme

((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) → (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-carbonitrile (1273029-08-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexanes / 0.5 h / -78 °C 1.2: 0.75 h 2.1: trimethylsilyl trifluoromethanesulfonate / acetonitrile / 73 h / 20 - 65 °C 3.1: water; ammonia / methanol / 16 h / 20 °C View Scheme

((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) → C12H15FN4O4

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexanes / 0.5 h / -78 °C 1.2: 0.75 h 2.1: water; ammonia / methanol / 16 h / 20 °C View Scheme

((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) → C11H17FN5O13P3 (1273029-12-1)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: n-butyllithium / tetrahydrofuran; hexanes / 0.08 h / -78 °C 1.2: 2 h / -78 °C 2.1: boron trifluoride diethyl etherate; triethylsilane / dichloromethane / 184 h / 20 °C 3.1: ammonia / 16 h / 50 °C / Sealed tube 3.2: 0.67 h / 60 °C 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 16 h / 20 °C 5.1: ammonia / 72 h / 115 °C / Sealed tube 6.1: water / bovine spleen type IX sdenosine deaminase A5168 / 4 h / 37 °C / Enzymatic reaction 7.1: trichlorophosphate; trimethyl phosphite / 0 °C View Scheme

((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) → C25H40FN6O8PS2 (1273029-18-7)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: n-butyllithium / tetrahydrofuran; hexanes / 0.08 h / -78 °C 1.2: 2 h / -78 °C 2.1: boron trifluoride diethyl etherate; triethylsilane / dichloromethane / 184 h / 20 °C 3.1: ammonia / 16 h / 50 °C / Sealed tube 3.2: 0.67 h / 60 °C 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 16 h / 20 °C 5.1: ammonia / 72 h / 115 °C / Sealed tube 6.1: 1H-tetrazole; phosphorous acid trimethyl ester / 2 h / 0 °C 7.1: dihydrogen peroxide / water / 0.5 h / 0 - 20 °C View Scheme

Upstream product

• 98-88-4 benzoyl chloride 
• 93635-76-8 (2S,3R)-3-[(4R)-2,2-dimethyl-[1,3]dioxolane-4-yl]-2,3-dihydroxy-2-methylpropionic acid ethyl ester 
• 1351925-17-1 C₁₀H₁₈O₆ 
• 729596-46-7 3,5-di-O-benzoyl-2-C-methyl-D-ribono-γ-lactone 
• 492-30-8 2-C-methyl-D-ribono-1,4-lactone 
• 74-88-4 methyl iodide 
• 81997-76-4 (S,E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropionic acid ethyl ester 
• 1033394-83-0 C₁₁H₁₉FO₅ 

Downstream Products

• 1199809-22-7 ((2R,3R,4R,5R)-3-(benzoyloxy)-4-fluoro-5-hydroxy-4-methyltetrahydrofuran-2-yl)methyl benzoate 
• 1273029-03-0 C₂₇H₂₅FN₄O₅S₂ 
• 1272971-36-4 C₂₇H₂₂FN₅O₅ 
• 1273029-19-8 C₂₄H₂₈FN₆O₇P 
• 1273029-20-1 C₂₅H₂₉ClFN₆O₇P 
• 1273029-28-9 C₂₆H₃₂FN₆O₇P 
• 1273029-50-7 C₃₄H₃₂FN₅O₅ 
• 1273029-51-8 C₆₀H₅₉FN₅O₉PS 
• 1273029-52-9 C₆₇H₆₆FN₆O₉PS 
• 1273029-53-0 C₂₇H₃₄FN₆O₇PS 
• 1273029-54-1 C₂₅H₃₄FN₆O₈P 
• 1272971-51-3 C₂₉H₂₇FN₄O₇S₂ 
• 1233335-83-5 (2R,3R,4R,5S)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-(benzoyloxymethyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate 
• 1199809-26-1 (2R,3R,4R,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-((benzoyloxy)methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate 

Relevant articles and documents

BI- AND MONOCYCLIC NUCLEOSIDE ANALOGS FOR TREATMENT OF HEPATITIS E

The present disclosure is directed toward bi- and monocyclic nucleoside analogs, and compositions comprising these compounds for use in the treatment of hepatitis E infections.

Preparation method of anti-hepatitis C medicine sofosbuvir

The invention discloses a preparation method of an anti-hepatitis C medicine sofosbuvir. The method comprises the following steps: taking r-ethyl glycerate acetonide as an initial raw material, enabling the r-ethyl glycerate acetonide to react with ethyl alpha-fluoropropionate under the action of potassium tert-butoxide, performing carbonyl reduction, hydroxyl acylation, hydrolytic cyclization under an acidic condition, hydroxyl acylation, red aluminum reduction and chiral column separation so as to obtain a sofosbuvir key intermediate ((2R,3R,4R,5R)-3-(benzoyloxy)-5-hydroxy-4-fluoro-4-methyltetrahydrofuran-2-yl) methyl benzoate, performing 2-hydroxyl acetylation, enabling acetylized material to react with 2-trimethylsiloxy-4-benzamidopyrimidine, removing benzamido under an acidic condition, performing dehydroxylation protection, and finally enabling obtained material to react with N-[(S)-(2,3,4,5,6-Pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-methylethyl ester to obtain the sofosbuvir. The method has the advantages of short synthesis route, high yield, avoidance of a fluorination reaction step in the synthesis process, and mild synthesis reaction conditions.

Preparation method of sofosbuvir key intermediate

The invention discloses a preparation method of a sofosbuvir key intermediate ((2R,3R,4R,5R)-3-(benzoyloxy)-5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl)benzoic acid methyl ester. The preparation method comprises the following steps: by using (R)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid as a starting material, performing acylating chlorination, performing a reaction with alpha-fluoropropionic acid, performing carbonyl reduction, performing hydroxyl protection, performing hydrolytic cyclization, performing hydroxymethyl protection, performing reduction, and performing chlorination to prepare the sofosbuvir key intermediate ((2R,3R,4R,5R)-3-(benzoyloxy)-5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl)benzoic acid methyl ester. The preparation scheme has a short synthetic route and a high yield, and avoids a fluorination reaction step in the synthetic process.

Method for preparing sofosbuvir intermediate

The invention provides a method for preparing a sofosbuvir intermediate. The method includes following steps: allowing 2-C-methyl-4, S-O-(1-methylethylene)-D-arabonic acid ethyl cyclosulfate and 4-phenyl-2-oxazolidone to be in condensation reaction to obtain a first compound; allowing the first compound and a fluorinating agent for fluorinating reaction, and adding acid for deprotection reaction to obtain a second compound; allowing the second compound to react with sodium ethoxide to obtain a third compound; allowing the third compound to be in rearrangement reaction, and allowing a rearrangement product to react with benzoyl chloride to obtain the sofosbuvir intermediate. The method provides a new idea for synthesizing the sofosbuvir intermediate.

PROCESS FOR PREPARATION OF LACTONE DERIVATIVES AND INTERMEDIATES THEREOF

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Preparation method of sofosbuvir intermediate

The invention discloses a preparation method of a sofosbuvir intermediate of (2R)-2-deoxy-2-fluoro-2-methyl-D-erythro-pentonic acid-g-lactone 3,5-dibenzoate. The intermediate structure corresponds toa formula I shown as the description. The method comprises the step that the sofosbuvir intermediate shown as the formula I is finally obtained by using (D2) (S)-(+)-4-phenyl-2-oxazolidinone of a compound shown as a formula II as a raw material through six-step reaction of condensation, fluorination, Adol addition, oxidation cyclization, isomerization and benzoylation. The preparation method hasthe advantages that the raw materials are cheap and can be easily obtained; the reaction conditions are mild; the route is short; the yield is high; three wastes are few; the pollution is little; thepreparation method is suitable for industrial production.

A method for the synthesis of pharmaceutical intermediates (by machine translation)

The invention relates to medical and chemical field, in particular to a method for synthesis of pharmaceutical intermediates. The method in order to compound I as the raw material, under the action of the oxidizing agent in the oxidizing reaction to produce compound II. The invention is directed to the present synthetic route in industrial production, the production cost of products is relatively high, the problem of low yield, innovative use of oxidizing agent of the high yield for preparing compound II, synthesize the low cost, simple process, and is suitable for industrial mass production. (by machine translation)

Method for preparing sofosbuvir intermediate and recovering byproduct

The invention relates to a method for preparing a sofosbuvir intermediate [(2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-hydroxy-4-methyltetrahydrofuran-2-yl] methylbenzoate represented by formula (II) and recovering a byproduct (2R,3R,4S)-4-fluoro-2,5-dihydroxy-4-methylpentane-1,3-diyl]dibenzoate represented by formula (III). The method comprises the following steps: (1) reacting a compound (I) 3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribosinic acid-gamma-lactone in a first solvent under the action of a reducing agent at a temperature of from 0 DEG C to the reflux temperature of the first solvent for 1-20 hours to produce the sofosbuvir intermediate (II) and the byproduct (III); and (2) filtering the above product to obtain a filter cake which is the byproduct (III), dissolving the filter cake in a second solvent, and reacting the obtained solution in an acidic environment with the pH value of 1-6 under the action of an oxidant and a catalyst at a temperature from 0 DEG C to the reflux temperature of the second solvent for 0.5-5 hours in order to generate the compound (I).

Synthetic method of sofosbuvir intermediate

The invention provides a synthetic method of a sofosbuvir intermediate, wherein the method, with a compound (II) as an initial raw material, includes the steps of: 1) performing a de-protective reaction and a cyclization reaction to the compound (II) to obtain an inter-product (VIII); 2) performing esterification to the inter-product (VIII) with benzoyl chloride to obtain an inter-product (IX); and 3) dissolving the inter-product (IX) in a solvent, and slowly adding dropwise a sulfonyl chloride solution in the presence of organic alkali and triethylamine trihydrofluoride, wherein in the reaction process, the compound (X) serves as an intermediate and is unnecessary to separate, so that a fluoronation reaction thereof can be completed directly in the reaction system, thereby producing the sofosbuvir intermediate.

Preparation method for 3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribono-gamma-lactone

The invention discloses a preparation method for 3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribono-gamma-lactone. The preparation method comprises the following steps: subjecting a starting raw material D-mannitol to acetone protection and sodium periodate oxidation; then subjecting the treated D-mannitol and a self-made ylide reagent to the Witting reaction; then carrying out selective oxidation by using an aqueous sodium permanganate solution; then successively carrying out sulfonylation, fluorination with potassium fluoride, and ring closing with a concentrated protective group protective group; protecting the hydroxyl group by using benzoyl chloride; and then carrying out purification so as to obtain the final product 3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribono-gamma-lactone. The preparation method provided by the invention uses easily available and cheap raw materials, so production cost is greatly reduced; and the operation of the preparation method is coherent and simple, and the quantity of waste gas, waste water and industrial residues is lower than the quantity of waste gas, waste water and industrial residues reported in the prior art.