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
• Article Data: 26

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

Description

(2'R)-2'-Deoxy-2'-fluoro-2'-methyluridine / PSI-6206 is the deaminated metabolite of β-D-2'-Deoxy-2'-fluoro-2'-C-methylcytidine, an effective inhibitor of hepatitis C virus (HCV) RNA polymerase.

Uses

RO 2433 is the deaminated metabolite of β-D-2''-Deoxy-2''-fluoro-2''-C-methylcytidine, an effective inhibitor of hepatitis C virus (HCV) replication in vitro.

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

• 102789-14-0 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 
• 817204-33-4 (2'R)-2'-deoxy-2'-fluoro-2'-methylcytidine 
• 84828-97-7 1-((6aR,8R,9aR)-2,2,4,4-tetraisopropyl-9-oxotetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)pyrimidine-2,4(1H,3H)-dione 
• 69304-38-7 3',5'-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)uridine 
• 944476-44-2 ((2R,3R,4S,5R)-3-(benzoyloxy)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-hydroxy-4-methyltetrahydrofuran-2-yl)methyl benzoate 
• 114262-45-2 1-<2-C-methyl-3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-β-D-arabino-pentofuranosyl>-uracil 
• 76700-76-0 (6aR,8R,9R,9aS)-2,2,4,4-tetraisopropyl-8-methoxytetrahydro-6H-furo[3,2- f][1,3,5,2,4]trioxadisilocin-9-ol 
• 7473-45-2 1-O-methyl-D-ribofuranose 
• 36468-53-8 β-D-ribofuranose 
• 897035-15-3 1-O-methyl-3-O,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-2-oxo-β-D-ribose 
• 874638-98-9 N-(1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide 
• 1199809-22-7 ((2R,3R,4R,5R)-3-(benzoyloxy)-4-fluoro-5-hydroxy-4-methyltetrahydrofuran-2-yl)methyl benzoate 
• 66-22-8 uracil 
• 879551-04-9 (3R,4R,5R)-3?fluoro?4?hydroxy?5?(hydroxymethyl)?3?methyltetrahydrofuran?2?one 

Downstream Products

• 1064684-44-1 sofosbuvir 
• 1064684-71-4 (R)-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 isopropyl ester 
• 1337482-15-1 C₂₂H₂₉FN₃O₉P 
• 1337482-15-1 C₂₂H₂₉FN₃O₉P 
• 1337482-15-1 C₂₂H₂₉FN₃O₉P 
• 1015073-43-4 GS-606965 
• 1496552-16-9 ((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 
• 1868135-06-1 [D₇]propan‐2‐yl ((S)‐(((2R,3R,4R,5R)‐5‐(2,4‐dioxo‐3,4‐dihydropyrimidin‐1(2H)‐yl)‐4‐fluoro‐3‐hydroxy‐4‐methyltetrahydrofuran‐2‐yl)methoxy)(phenoxy)phosphoryl)‐L‐alaninate 
• 1190308-01-0 (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 
• 1190307-88-0 sofosbuvir 
• 1015073-42-3 GS-461203 

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