863329-66-2

Basic information

• Product Name: 2'-deoxy-2'-fluoro-2'-C-methyluridine
• Synonyms: 2'-deoxy-2'-fluoro-2'-C-methyluridine;(2'R)-2'-Deoxy-2'-fluoro-2'-methyluridine;PSI-6206;RO 2433;Uridine, 2'-deoxy-2'-fluoro-2'-Methyl-, (2'R)-;Uridine, 2'-deoxy-2'-fluoro-2'-Methyl-, (2'R)- PSI6206;2'-Deoxy-2-floro-2'Methyl-uridine;1-((2S,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxyMethyl)-3-Methyltetrahydrofuran-2-yl)pyriMidine-2,4(1H,3H)-dione
• CAS NO: 863329-66-2
• Molecular Formula: C₁₀H₁₃FN₂O₅
• Molecular Weight: 260.2190232
• EINECS: 1308068-626-2
• Product Categories: apis;Inhibitor;Sofosbuvir intermediate;Inhibitors
• Mol File: 863329-66-2.mol

Chemical Properties

• Melting Point: 237-238℃
• Appearance: /
• Density: 1.55
• Storage Temp.: Sealed in dry,Store in freezer, under -20°C
• Solubility: DMSO (Slightly), Methanol (Slightly, Heated)
• PKA: 9.39±0.10(Predicted)
• CAS DataBase Reference: 2'-deoxy-2'-fluoro-2'-C-methyluridine(CAS DataBase Reference)
• NIST Chemistry Reference: 2'-deoxy-2'-fluoro-2'-C-methyluridine(863329-66-2)
• EPA Substance Registry System: 2'-deoxy-2'-fluoro-2'-C-methyluridine(863329-66-2)

Safety Data

• Hazardous Substances Data: 863329-66-2(Hazardous Substances Data)

Usage

Uses

Used in Antiviral Applications:
2'-deoxy-2'-fluoro-2'-C-methyluridine is used as an antiviral agent for the treatment of hepatitis C virus (HCV) infections. It works by inhibiting the HCV RNA polymerase, thereby suppressing the replication of the virus and reducing viral load in infected individuals.
Used in Pharmaceutical Industry:
In the pharmaceutical industry, 2'-deoxy-2'-fluoro-2'-C-methyluridine is used as a key intermediate in the synthesis of antiviral drugs targeting hepatitis C virus. Its unique structure allows for the development of more effective and targeted therapies against the virus, potentially leading to improved treatment outcomes for patients suffering from HCV infections.

Biological Activity

psi-6206 (as known as ro-2433 or gs-331007), β-d-2’-deoxy-2’-fluoro-2’-c-methyluridine, is the deaminated derivative of psi-6130, β-d-2’-deoxy-2’-fluoro-2’-c-methylcytidine, which is a potent inhibitor of hepatitis c virus (hcv) replication in the subgenomic hcv reolicon system. psi-6206, itself, does not shown any inhibitory activity towards hcv replication in the hcv subgenomic replicon system. however, the its triphosphate form, ro2433-tp, is a potent inhibitor of rna synthesis by hcv polymerase, which inhibits both the rna sysnthesis activity of hcv replicase (ic50 = 1.19 um) and the rna synthesis activity of the recombinant hcv con1 ns58 on a heteropolymeric rna template derived from the 3’-end of the negative strand of the hcv genome (ic50 = 0.52 um and ki = 0.141 um).han ma, wen-rong jiang, nicole robledo, vincent leveque, samir ali, teresa lara-jamie, mohammad masjedizadeh, david b. smith, nick cammack, klaus klumpp, and julian symons. characterization of the metabolic ctivation of hepatitis c virus nucleoside inhibitor β-d-2’-deoxy-2’-fluoro-2’-c-methylcytidine (psi-6130) and identification of a novel active 5’-triphosphate species. the journal of biological chemistry 2007; 282(41): 29812-29820

Synthetic route

(2‘R)-2‘-deoxy-2’-fluoro-2-methyluridine-3’,5’-dibenzoate → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
With ammonia In methanol at 20℃;	100%
With ammonia In methanol at 20℃; for 17h;	93%
Stage #1: (2‘R)-2‘-deoxy-2’-fluoro-2-methyluridine-3’,5’-dibenzoate With N-butylamine at 45 - 50℃; Stage #2: With methanol In tert-butyl methyl ether at 60 - 70℃;	90.7%

C22H41FN2O7Si2 → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
With tetramethylammonium fluoride; acetic acid In N,N-dimethyl-formamide at 20℃; for 2h; Time; Inert atmosphere;	95%

(2'R)-2'-deoxy-2'-fluoro-2'-methyluridine-3',5'-dibenzoate → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
With ammonia In methanol at 0 - 15℃; for 27h;	94%

((2R,3R,5R)-3-acetoxy-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyltetrahydrofuran-2-yl)methyl acetate → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
With ammonia In methanol at 5 - 25℃; for 26h;	92.5%

C24H20N2O7 (944476-43-1) → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
With potassium fluoride; 2,3,5,6,8,9,11,12,14,15-decahydro-1,4,7,10,13,16-benzohexaoxacyclooctadecin In N,N-dimethyl-formamide; toluene for 5h; Reflux;	92.3%

C10H15FN2O5 → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
With manganese(IV) oxide In toluene at 20℃; for 2h;	91%

N-(1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide (874638-98-9) → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
With sodium hypochlorite; tetra(n-butyl)ammonium hydrogensulfate In tetrahydrofuran at 0 - 30℃; for 24h;	85%

1-((6aR,8R,9aS)-2,2,4,4-tetraisopropyl-9-methylenetetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)-pyrimidine-2,4(1H,3H)-dione (102789-14-0) → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
With potassium hydrogensulfate; hydrogen fluoride In 1,2-dichloro-ethane at 0℃; for 2h;	82%

C19H39FO5Si2 + uracil (66-22-8) → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
Stage #1: uracil With ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane In chlorobenzene Reflux; Stage #2: C19H39FO5Si2 With tin(IV) chloride In chlorobenzene at 50℃; Stage #3: With tetrabutyl ammonium fluoride In tetrahydrofuran at 55 - 60℃; Reagent/catalyst; Solvent;	72%

(2R,3R,4R,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-2-((benzoyloxy)methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate (817204-32-3) → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 87 percent / aq. HOAc / 12 h / Heating 2: 100 percent / NH3 / methanol / 20 °C View Scheme
Multi-step reaction with 2 steps 1: acetic acid / water / 5 h / 110 °C 2: ammonia; methanol / 30 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: acetic acid / water / 90 - 105 °C 2: sodium methylate / methanol / Reflux View Scheme

3',5'-O-dibenozyl-2'deoxy-2'-fluoro-2'-C-methyl-N4-benzoylcytidine → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: water; acetic acid / 20 h / 110 °C 2: ammonia / methanol / 27 h / 0 - 15 °C View Scheme

((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-hydroxy-4-methyltetrahydrofuran-2-yl)methyl benzoate → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: dmap / 1.5 h / -20 °C / Inert atmosphere 2.1: N,O-bis-(trimethylsilyl)-acetamide / chlorobenzene / 2 h / 80 °C 2.2: 16 h / 65 °C 3.1: acetic acid / water / 5 h / 110 °C 4.1: ammonia; methanol / 30 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / toluene / 1 h / -5 - 0 °C 2: tin(IV) chloride; N,O-bis-(trimethylsilyl)-acetamide / acetonitrile / Reflux 3: acetic acid / water / 90 - 105 °C 4: sodium methylate / methanol / Reflux View Scheme
Multi-step reaction with 4 steps 1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 1 h / 0 - 15 °C / Inert atmosphere 2: tin(IV) chloride / chlorobenzene / 75 °C 3: formic acid / water / 7.5 h / 25 - 100 °C 4: ammonia / 20 h / 0 - 15 °C View Scheme

((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (874638-80-9) → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: lithium tri-t-butoxyaluminum hydride / tetrahydrofuran / -20 °C / Inert atmosphere 2.1: dmap / 1.5 h / -20 °C / Inert atmosphere 3.1: N,O-bis-(trimethylsilyl)-acetamide / chlorobenzene / 2 h / 80 °C 3.2: 16 h / 65 °C 4.1: acetic acid / water / 5 h / 110 °C 5.1: ammonia; methanol / 30 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1: sodium bis(2-methoxyethoxy)aluminium dihydride / dichloromethane / -20 - -15 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / toluene / 1 h / -5 - 0 °C 3: tin(IV) chloride; N,O-bis-(trimethylsilyl)-acetamide / acetonitrile / Reflux 4: acetic acid / water / 90 - 105 °C 5: sodium methylate / methanol / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: Red-Al(OCH2CF3) / dichloromethane / 0.5 h / -10 °C 1.2: 16 h / -10 - 20 °C 2.1: ammonium sulfate / chlorobenzene / 1.5 h / 20 °C 2.2: 10 h / 70 °C 3.1: acetic acid / water / 20 h / Reflux 4.1: ammonia; methanol / 27 h / 0 - 15 °C View Scheme
Multi-step reaction with 5 steps 1: diisobutylaluminium hydride / dichloromethane / 2.5 h / Inert atmosphere 2: N-chloro-succinimide; triphenylphosphine / dichloromethane / 1 h / 0 - 15 °C / Inert atmosphere 3: tin(IV) chloride / chlorobenzene / 75 °C 4: formic acid / water / 7.5 h / 25 - 100 °C 5: ammonia / 20 h / 0 - 15 °C View Scheme
Multi-step reaction with 5 steps 1.1: aluminium / dichloromethane; 2,2,2-trifluoroethanol; toluene / 0 - 10 °C 2.1: triphenylphosphine; diethylazodicarboxylate / toluene / 0 - 30 °C 3.1: ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane / chlorobenzene / 90 - 100 °C 3.2: 65 - 70 °C 4.1: acetic acid / water / Reflux 5.1: N-butylamine / 45 - 50 °C 5.2: 60 - 70 °C View Scheme

(2R,3R,4R,5R)-5-acetoxy-2-((benzoyloxy)methyl)-4-fluoro-4-methyl-tetrahydrofuran-3-yl benzoate (874638-93-4) → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: N,O-bis-(trimethylsilyl)-acetamide / chlorobenzene / 2 h / 80 °C 1.2: 16 h / 65 °C 2.1: acetic acid / water / 5 h / 110 °C 3.1: ammonia; methanol / 30 h / 20 °C View Scheme

C14H11Cl6FN2O7 → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
With methanol; ammonia at 20℃; for 0.75h;	139 mg

1-(2'-C-methyl-β-D-arabinofuranosyl)uracil (114262-49-6) → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: pyridine; dmap / dichloromethane / 17 h / 20 °C / Inert atmosphere 2: ethanaminium,N-(difluoro-λ4-sulfanylidene)-N-ethyl-,tetrafluoroborate; triethylammonium dihydrofluoride / dichloromethane / 1 h / 20 °C / Inert atmosphere 3: ammonia; methanol / 0.75 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: pyridine 2: diethylamino-sulfur trifluoride / dichloromethane 3: ammonia / methanol View Scheme

1-(2'-C-methyl-β-D-arabinofuranosyl)uracil (114262-49-6) → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + 1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)-3-methylenetetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (119410-95-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: dichloromethane / 2.5 h / 20 °C / Inert atmosphere 2: triethylamine; triethylamine tris(hydrogen fluoride); ethanaminium,N-(difluoro-λ4-sulfanylidene)-N-ethyl-,tetrafluoroborate / dichloromethane / 4 h / 20 °C / Inert atmosphere View Scheme

(2R,3R,4S,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-hydroxy-4-methyl-2-((2,2,2-trifluoroacetoxy)methyl)tetrahydrofuran-3-yl 2,2,2-trifluoroacetate → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions

Yield

Multi-step reaction with 4 steps 1: triethylamine; triethylamine tris(hydrogen fluoride); ethanaminium,N-(difluoro-λ4-sulfanylidene)-N-ethyl-,tetrafluoroborate / dichloromethane / 4 h / 20 °C / Inert atmosphere 2: pyridine; dmap / dichloromethane / 17 h / 20 °C / Inert atmosphere 3: ethanaminium,N-(difluoro-λ4-sulfanylidene)-N-ethyl-,tetrafluoroborate; triethylammonium dihydrofluoride / dichloromethane / 1 h / 20 °C / Inert atmosphere 4: ammonia; methanol / 0.75 h / 20 °C View Scheme

(2R,3R,4S,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-hydroxy-4-methyl-2-((2,2,2-trifluoroacetoxy)methyl)tetrahydrofuran-3-yl 2,2,2-trifluoroacetate → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + 1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)-3-methylenetetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (119410-95-6) + 1-(2'-C-methyl-β-D-arabinofuranosyl)uracil (114262-49-6)

Conditions	Yield
Stage #1: (2R,3R,4S,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-hydroxy-4-methyl-2-((2,2,2-trifluoroacetoxy)methyl)tetrahydrofuran-3-yl 2,2,2-trifluoroacetate With triethylamine tris(hydrogen fluoride); triethylamine; ethanaminium,N-(difluoro-λ4-sulfanylidene)-N-ethyl-,tetrafluoroborate In dichloromethane at 20℃; for 4h; Inert atmosphere; Stage #2: With water	A 42 %Spectr. B 37 %Spectr. C 8 %Spectr.

C27H25FO8S → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: tin(IV) chloride; N,O-bis-(trimethylsilyl)-acetamide / acetonitrile / Reflux 2: acetic acid / water / 90 - 105 °C 3: sodium methylate / methanol / Reflux View Scheme

(2R)-2-deoxy-2-fluoro-2-methyl-α/β-D-erythro-pentofuranosyl chloride-3,5-dibenzoate → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: ammonium sulfate / chlorobenzene / 1.5 h / 20 °C 1.2: 10 h / 70 °C 2.1: acetic acid / water / 20 h / Reflux 3.1: ammonia; methanol / 27 h / 0 - 15 °C View Scheme
Multi-step reaction with 3 steps 1: tin(IV) chloride / chlorobenzene / 75 °C 2: formic acid / water / 7.5 h / 25 - 100 °C 3: ammonia / 20 h / 0 - 15 °C View Scheme

C24H22N2O7 → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium fluoride; 2,3,5,6,8,9,11,12,14,15-decahydro-1,4,7,10,13,16-benzohexaoxacyclooctadecin / N,N-dimethyl-formamide / 5 h / Reflux 2: manganese(IV) oxide / toluene / 2 h / 20 °C View Scheme

C21H20N2O6 → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene / ethanol / 4 h / Reflux 2: potassium fluoride; 2,3,5,6,8,9,11,12,14,15-decahydro-1,4,7,10,13,16-benzohexaoxacyclooctadecin / N,N-dimethyl-formamide; toluene / 5 h / Reflux View Scheme
Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide / 2 h / 75 °C 2: potassium fluoride; 2,3,5,6,8,9,11,12,14,15-decahydro-1,4,7,10,13,16-benzohexaoxacyclooctadecin / N,N-dimethyl-formamide / 5 h / Reflux 3: manganese(IV) oxide / toluene / 2 h / 20 °C View Scheme

3’,5’-O-benzoyl-2,2’-anhydrouridine (31616-01-0) → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions

Yield

Multi-step reaction with 6 steps 1: tetrabutylammomium bromide; sodium hydrogencarbonate / dichloromethane / 50 °C 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hypochlorite / dichloromethane / 0 - 20 °C 3: 2-methyltetrahydrofuran / -78 - -40 °C 4: sodium hydrogencarbonate; phosphoramide; bis(phenyl) carbonate / 150 °C 5: tetrabutyl ammonium fluoride / chlorobenzene / Reflux 6: monomethanolamine / 24 h / 25 - 30 °C View Scheme

3’,5’-dibenzoyluridine (54618-11-0) → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hypochlorite / dichloromethane / 0 - 20 °C 2: 2-methyltetrahydrofuran / -78 - -40 °C 3: sodium hydrogencarbonate; phosphoramide; bis(phenyl) carbonate / 150 °C 4: tetrabutyl ammonium fluoride / chlorobenzene / Reflux 5: monomethanolamine / 24 h / 25 - 30 °C View Scheme

C23H18N2O8 → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 2-methyltetrahydrofuran / -78 - -40 °C 2: sodium hydrogencarbonate; phosphoramide; bis(phenyl) carbonate / 150 °C 3: tetrabutyl ammonium fluoride / chlorobenzene / Reflux 4: monomethanolamine / 24 h / 25 - 30 °C View Scheme

C24H22N2O8 → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydrogencarbonate; phosphoramide; bis(phenyl) carbonate / 150 °C 2: tetrabutyl ammonium fluoride / chlorobenzene / Reflux 3: monomethanolamine / 24 h / 25 - 30 °C 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) → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
Multi-step reaction with 7 steps 1: pyridine / 24 h / 20 °C 2: lithium tri-t-butoxyaluminum hydride / tetrahydrofuran / -40 - -20 °C 3: triethylamine / ethyl acetate / 0 - 20 °C 4: ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane; urethane; tin(IV) chloride / 60 - 70 °C / Inert atmosphere 5: potassium carbonate; phosphoramide / 150 °C 6: tetrabutyl ammonium fluoride / chlorobenzene / Reflux 7: monomethanolamine / 24 h / 25 - 30 °C View Scheme
Multi-step reaction with 7 steps 1: pyridine / 24 h / 20 °C 2: lithium tri-t-butoxyaluminum hydride / tetrahydrofuran / -40 - -20 °C 3: Vilsmeier reagent / dichloromethane; ethyl acetate / 35 - 40 °C 4: ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane; urethane; tin(IV) chloride / chlorobenzene / 60 - 70 °C 5: potassium carbonate; phosphoramide / 150 °C 6: tetrabutyl ammonium fluoride / chlorobenzene / Reflux 7: monomethanolamine / 24 h / 25 - 30 °C View Scheme
Multi-step reaction with 4 steps 1.1: dmap / acetonitrile / 15 - 20 °C 2.1: triethylamine hydrofluoride; triethylamine / tetrahydrofuran / Reflux 3.1: lithium tri-t-butoxyaluminum hydride / tetrahydrofuran / 0.5 h / -20 - 0 °C 3.2: 20 °C 4.1: 1,1,1,3,3,3-hexamethyl-disilazane; ammonium sulfate / chlorobenzene / Reflux 4.2: 50 °C 4.3: 55 - 60 °C View Scheme

(3R,4R,5R)-5-((benzoyloxy)methyl)-3-methyl-2-oxotetrahydrofuran-3,4-diyl dibenzoate (7392-74-7) → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
Multi-step reaction with 6 steps 1: lithium tri-t-butoxyaluminum hydride / tetrahydrofuran / -40 - -20 °C 2: triethylamine / ethyl acetate / 0 - 20 °C 3: ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane; urethane; tin(IV) chloride / 60 - 70 °C / Inert atmosphere 4: potassium carbonate; phosphoramide / 150 °C 5: tetrabutyl ammonium fluoride / chlorobenzene / Reflux 6: monomethanolamine / 24 h / 25 - 30 °C View Scheme
Multi-step reaction with 6 steps 1: lithium tri-t-butoxyaluminum hydride / tetrahydrofuran / -40 - -20 °C 2: Vilsmeier reagent / dichloromethane; ethyl acetate / 35 - 40 °C 3: ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane; urethane; tin(IV) chloride / chlorobenzene / 60 - 70 °C 4: potassium carbonate; phosphoramide / 150 °C 5: tetrabutyl ammonium fluoride / chlorobenzene / Reflux 6: monomethanolamine / 24 h / 25 - 30 °C View Scheme

(3R,4R,5R)-5-((benzoyloxy)methyl)-2-hydroxy-3-methyltetrahydrofuran-3,4-diyl dibenzoate → 2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: triethylamine / ethyl acetate / 0 - 20 °C 2: ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane; urethane; tin(IV) chloride / 60 - 70 °C / Inert atmosphere 3: potassium carbonate; phosphoramide / 150 °C 4: tetrabutyl ammonium fluoride / chlorobenzene / Reflux 5: monomethanolamine / 24 h / 25 - 30 °C View Scheme
Multi-step reaction with 5 steps 1: Vilsmeier reagent / dichloromethane; ethyl acetate / 35 - 40 °C 2: ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane; urethane; tin(IV) chloride / chlorobenzene / 60 - 70 °C 3: potassium carbonate; phosphoramide / 150 °C 4: tetrabutyl ammonium fluoride / chlorobenzene / Reflux 5: monomethanolamine / 24 h / 25 - 30 °C View Scheme

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + tert-butyldimethylsilyl chloride (18162-48-6) → 1-((2R,3R,4R,5R)-5-((tert-butyldimethylsilyloxy)methyl)-3-fluoro-4-hydroxy-3-methyl-tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (1160557-97-0)

Conditions	Yield
In pyridine at 20℃; for 24h;	100%
With pyridine; 1-methyl-1H-imidazole at 0 - 5℃; for 3h;	100%
With pyridine; 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 12h; Inert atmosphere;	93%

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + acetic anhydride (108-24-7) → ((2R,3R,5R)-3-acetoxy-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyltetrahydrofuran-2-yl)methyl acetate

Conditions	Yield
With pyridine at 0 - 20℃; for 2h;	100%
With dmap; triethylamine at 20℃; for 2h;	81%
With dmap at 20℃; for 2h;	81%

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) → sofosbuvir (1190307-88-0)

Conditions	Yield
With pyridine; aluminum (III) chloride In dichloromethane at 20℃; Reagent/catalyst; Temperature;	97.5%
With 2,6-dimethylpyridine; dimethylaluminum chloride In tetrahydrofuran; hexane at 0 - 45℃; for 20h;	86%
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With 3,3-diphenyl-2-propenal; tert-butylmagnesium chloride In tetrahydrofuran at -5 - 5℃; for 19h; Inert atmosphere; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran Reagent/catalyst;	86.2%

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + C17H20ClN2O5P → sofosbuvir (1064684-44-1)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; zinc(II) chloride In tetrahydrofuran at 55 - 60℃; Inert atmosphere;	96.4%

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + (S)-2-[((S)-(2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester (1334513-02-8) → (S)-2-{(R)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-ylmethoxy](phenoxy)phosphorylamino}propionic acid isopropyl ester (1190308-01-0)

Conditions	Yield
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With isopropyl magnesium chloride lithium chloride complex In tetrahydrofuran at -60℃; for 1h; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran at -50℃; for 1h; Temperature; Reagent/catalyst;	95%
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 0℃; for 1.16667h; Inert atmosphere; Stage #2: (S)-2-[(S)-((2,3,4,5,6-pentafluorophenoxy)(phenoxy)phosphoryl)amino]propionic acid isopropyl ester In tetrahydrofuran at 5 - 20℃; for 10h; Inert atmosphere;	76%

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) → 1-[(2R,3R,4R,5S)-3-fluoro-4-hydroxy-5-(iodomethyl)-3-methyloxolan-2-yl]-1,2,3,4-tetrahydropyrimidine-2,4-dione (1365257-00-6)

Conditions	Yield
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With 1H-imidazole; triphenylphosphine In tetrahydrofuran at 20℃; for 0.333333h; Inert atmosphere; Stage #2: With iodine In tetrahydrofuran at 20℃; for 18.5h; Inert atmosphere;	94%
With pyridine; iodine; triphenylphosphine In tetrahydrofuran at 20℃; for 12h;	85%
With pyridine; iodine; triphenylphosphine In tetrahydrofuran at 20℃; for 12h;	85%

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + 4,4'-dimethoxytrityl chloride (40615-36-9) → 5'-O-(4,4'-dimethoxytrityl)-2'-deoxy-2'-fluoro-2'-C-methyluridine (1244762-79-5)

Conditions	Yield
With pyridine at 0 - 20℃; for 8h;	93%
With dmap; triethylamine In ethyl acetate at 50℃; for 3h; Inert atmosphere;	88.9%
With pyridine In N,N-dimethyl-formamide
With pyridine In dichloromethane at 0℃; for 4h;

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + (R)-2-((R)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphorylamino)propionic acid isopropyl ester → C22H29FN3O9P

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 0℃;	92%

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + (S)-2-[(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphorylamino]propionic acid isopropyl ester (1256490-52-4) → sofosbuvir (1064684-44-1)

Conditions	Yield
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride; lithium chloride In tetrahydrofuran at 0 - 5℃; for 1h; Inert atmosphere; Stage #2: (S)-2-[(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphorylamino]propionic acid isopropyl ester In tetrahydrofuran at -10 - -5℃; for 24h;	90.5%
With tert-butylmagnesium chloride In tetrahydrofuran at -20 - 20℃; Inert atmosphere;	61.4%
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 20℃; for 0.5h; Stage #2: (S)-2-[(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphorylamino]propionic acid isopropyl ester In tetrahydrofuran at 20℃; for 72h;

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + (R)-2-((R)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphorylamino)propionic acid isopropyl ester → ((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-pyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alanine isopropyl ester

Conditions	Yield
With triethylamine; magnesium chloride In tetrahydrofuran at 40℃; for 2.5h;	89%

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + C18H17F5NO5P → sofosbuvir (1190307-88-0)

Conditions	Yield
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine; C18H17F5NO5P With N-ethyl-N,N-diisopropylamine; magnesium chloride In tetrahydrofuran at 30 - 40℃; Stage #2: With hydrogenchloride In tetrahydrofuran; water for 0.5h; Reagent/catalyst; Temperature; Solvent;	88%
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at -5 - 30℃; for 1h; Inert atmosphere; Stage #2: C18H17F5NO5P In tetrahydrofuran at 10 - 15℃;	67.5%

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + C17H20ClN2O5P → sofosbuvir (1064684-44-1)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; zinc(II) chloride In tetrahydrofuran at 55 - 60℃; Inert atmosphere;	84.6%

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + 1,3-Dichloro-1,1,3,3-tetraisopropyldisiloxane (69304-37-6) → C22H41FN2O7Si2 (1256490-55-7)

Conditions	Yield
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine; 1,3-Dichloro-1,1,3,3-tetraisopropyldisiloxane In pyridine at 20℃; for 16h; Stage #2: With water; trifluoroacetic acid In tetrahydrofuran at 0℃; for 6h;	84%

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + (S)-2-[[(S)-(1,1'-biphenyl-4-oxy)(pentafluorophenoxy)phosphoryl]amino]propionic acid isopropyl ester → (S)‐2‐[[[(1,1’‐biphenyl-4-yloxy)][((2R,3R,4R,5R)‐5‐(2,4‐dioxo‐3,4‐dihydropyrimidin-1(2H)-yl)‐4‐fluoro‐3‐hydroxy‐4-methyltetrahydrofuran-2-yl)methoxy]-(S)-phosphoryl]amino]propionic acid isopropyl ester

Conditions	Yield
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at -10 - 5℃; for 1h; Inert atmosphere; Large scale; Stage #2: (S)-2-[[(S)-(1,1'-biphenyl-4-oxy)(pentafluorophenoxy)phosphoryl]amino]propionic acid isopropyl ester at 5 - 10℃; Large scale;	81.72%
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine In tetrahydrofuran at -10 - 5℃; for 1h; Inert atmosphere; Stage #2: (S)-2-[[(S)-(1,1'-biphenyl-4-oxy)(pentafluorophenoxy)phosphoryl]amino]propionic acid isopropyl ester In tetrahydrofuran at 5 - 10℃; Inert atmosphere;
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at -10 - 5℃; for 1h; Inert atmosphere; Large scale; Stage #2: (S)-2-[[(S)-(1,1'-biphenyl-4-oxy)(pentafluorophenoxy)phosphoryl]amino]propionic acid isopropyl ester In tetrahydrofuran at 5 - 10℃; Inert atmosphere; Large scale;
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at -10 - 5℃; for 1h; Inert atmosphere; Stage #2: (S)-2-[[(S)-(1,1'-biphenyl-4-oxy)(pentafluorophenoxy)phosphoryl]amino]propionic acid isopropyl ester In tetrahydrofuran at 5 - 10℃;

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + C17H20ClN2O5P → sofosbuvir (1190307-88-0)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; zinc(II) chloride In tetrahydrofuran; water at 55℃; for 20h; Reagent/catalyst; Concentration;	80%

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + (S)-2-[(S)-(2,3,4,5,6-pentafluoro-phenoxy)-phenoxy-phosphorylamino]propionic acid isopropyl ester (1337529-56-2) → sofosbuvir (1190307-88-0)

Conditions	Yield
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With magnesium chloride In tetrahydrofuran at 25 - 30℃; for 2h; Inert atmosphere; Stage #2: (S)-2-[(S)-(2,3,4,5,6-pentafluoro-phenoxy)-phenoxy-phosphorylamino]propionic acid isopropyl ester In tetrahydrofuran at 25 - 30℃; Reagent/catalyst;	80%

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + C17H20ClN2O5P → sofosbuvir (1064684-44-1)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; zinc(II) chloride In tetrahydrofuran at 55 - 60℃; Inert atmosphere;	76.9%

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + (S)-pentafluorophenylphenyl-(1-(2-methylbenzyloxy)propan-2-yl)phosphoramidate → C27H33FN3O8P

Conditions	Yield
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 0 - 30℃; for 1h; Inert atmosphere; Stage #2: (S)-pentafluorophenylphenyl-(1-(2-methylbenzyloxy)propan-2-yl)phosphoramidate In tetrahydrofuran at 0 - 25℃; for 10h; Inert atmosphere;	76%

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + C17H20ClN2O5P → sofosbuvir (1064684-44-1)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; zinc(II) chloride In tetrahydrofuran at 55 - 60℃; Inert atmosphere;	73.1%

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + C17H20BrN2O5P → sofosbuvir (1064684-44-1)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; zinc(II) chloride In tetrahydrofuran at 55 - 60℃; Inert atmosphere;	69.2%

2'-deoxy-2'-fluoro-2'-methyluridine (863329-66-2) + (S)-2-[(S)-(4-nitro-phenoxy)-phenoxy-phosphorylamino]propionic acid isopropyl ester (1256490-31-9) → sofosbuvir (1190307-88-0)

Conditions	Yield
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 20℃; for 1h; Stage #2: (S)-2-[(S)-(4-nitro-phenoxy)-phenoxy-phosphorylamino]propionic acid isopropyl ester In tetrahydrofuran at 20℃; for 48h;	67.6%
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 20 - 50℃; for 21h; Stage #2: (S)-2-[(S)-(4-nitro-phenoxy)-phenoxy-phosphorylamino]propionic acid isopropyl ester In tetrahydrofuran at 20℃; for 60.25h;	40%
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With 1-methyl-pyrrolidin-2-one In tetrahydrofuran for 0.166667h; Stage #2: With tert-butylmagnesium chloride In tetrahydrofuran at 20℃; for 0.166667h; Stage #3: (S)-2-[(S)-(4-nitro-phenoxy)-phenoxy-phosphorylamino]propionic acid isopropyl ester at 55℃; for 2.5h;

Upstream product

• 863329-65-1 (2‘R)-2‘-deoxy-2’-fluoro-2-methyluridine-3’,5’-dibenzoate 
• 1500076-79-8 (2R)-2-deoxy-2-fluoro-2-methyl-α/β-D-erythro-pentofuranosyl chloride-3,5-dibenzoate 
• 944476-43-1 C₂₄H₂₀N₂O₇ 
• 31616-01-0 3’,5’-O-benzoyl-2,2’-anhydrouridine 
• 54618-11-0 3’,5’-dibenzoyluridine 
• 944476-44-2 C₂₄H₂₂N₂O₈ 
• 492-30-8 2-C-methyl-D-ribono-1,4-lactone 
• 7392-74-7 (3R,4R,5R)-5-((benzoyloxy)methyl)-3-methyl-2-oxotetrahydrofuran-3,4-diyl dibenzoate 
• 23643-36-9 2′,3′,5′-tri-O-benzoyl-2′-C-methyluridine 
• 31448-54-1 2'-C-methyluridine 
• 944476-40-8 (2R,3R,3aS,9aR)-3-hydroxy-2-(hydroxymethyl)-3a-methyl-2,3,3a,9a-tetrahydro-6H-furo[2',3':4,5]oxazolo[3,2-a]pyrimidin-6-one 
• 58-96-8 uridine 
• 3736-77-4 2,2'-Anhydrouridine 
• 879551-04-9 (3R,4R,5R)-3?fluoro?4?hydroxy?5?(hydroxymethyl)?3?methyltetrahydrofuran?2?one 

Downstream Products

• 1015255-46-5 (S)-2-{[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-ylmethoxy](phenoxy)phosphorylamino}propionic acid methyl ester 
• 1064684-23-6 (S)-2-{[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-ylmethoxy](phenoxy)phosphorylamino}-3-methylbutyric acid methyl ester 
• 1064684-24-7 (S)-2-{(4-bromophenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-ylmethoxy]phosphorylamino}-3-methylbutyric acid methyl ester 
• 1064684-25-8 (S)-2-{(4-bromophenoxy)[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-ylmethoxy]phosphorylamino}propionic acid methyl ester 
• 1064684-64-5 (S)-2-{[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-ylmethoxy](phenoxy)phosphorylamino}butyric acid methyl ester 
• 1064684-46-3 (S)-2-{[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-ylmethoxy](4-fluorophenoxy)phosphorylamino}propionic acid ethyl ester 
• 1250830-04-6 (S)-2-{(4-chlorophenoxy)[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-ylmethoxy]phosphorylamino}propionic acid isopropyl ester 
• 1064684-74-7 (S)-2-{(4-bromophenoxy)[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-ylmethoxy]phosphorylamino}propionic acid isopropyl ester 
• 1250829-96-9 {[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-ylmethoxy](phenoxy)phosphorylamino}acetic acid methyl ester 

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