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
• Article Data: 27

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

Different sources of media describe the Uses of 874638-80-9 differently. You can refer to the following data:
1. neuromuscular blocking agent
2. (2R)-2-Deoxy-2-fluoro-2-methyl-D-erythropentonic Acid γ-Lactone 3,5-Dibenzoate is a reactant used in the synthesis of 1''-C-cyano-2''-fluoro-2''-C-methyl pyrimidine nucleosides as HCV polymerase inhibitors.

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

• 879551-04-9 (3R,4R,5R)-3?fluoro?4?hydroxy?5?(hydroxymethyl)?3?methyltetrahydrofuran?2?one 
• 98-88-4 benzoyl chloride 
• 1616508-45-2 (S)-3-((2R,3R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-fluoro-3-hydroxy-2-methylpropanoyl)-4-benzyloxazolidin-2-one 
• 1616508-57-6 (S)-3-((2R,3R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-fluoro-3-hydroxy-2-methylpropanoyl)-4-isopropyloxazolidin-2-one 
• 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 
• 1946820-88-7 C₁₁H₂₀O₆ 
• 127642-52-8 ethyl (E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methyl-2-propenoate 

Downstream Products

• 1199809-22-7 ((2R,3R,4R,5R)-3-(benzoyloxy)-4-fluoro-5-hydroxy-4-methyltetrahydrofuran-2-yl)methyl benzoate 
• 1064684-44-1 sofosbuvir 

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 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.

PROCESS FOR PREPARATION OF LACTONE DERIVATIVES AND INTERMEDIATES THEREOF

A novel process for the preparation of lactone derivatives, and intermediates thereof is described. The lactone derivatives are important precursors for the synthesis of anti-hepatitis C virus agents, including sofosbuvir.