161599-46-8

Basic information

• Product Name: 2',3'-Di-O-acetyl-5'-deoxy-5-fuluro-D-cytidine
• Synonyms: InterMediate of Capecitabine;(2R,3R,4R,5R)-2-(4-aMino-5-fluoro-2-oxopyriMidin-1(2H)-yl)-5-Methyltetrahydrofuran-3,4-diyl diacetate;2',3'-Di-O-carbonyl-5'-deoxy-5-fluorocytidine;2 ', 3'-di-O-acetyl -5' - deoxy -5-- fluoro-D-cell pyridine;5'-deoxy - diacetyl -5-- fluoro cytidine;2',3'-DI-O-ACETYL-5'-DEOXY-5-FLUOROCYTIDIN;Capecitabine Diacetyl Amino Impurity;2',3'-Di-O-acetyl-5'-deoxy-5-fulurocytdine
• CAS NO: 161599-46-8
• Molecular Formula: C₁₃H₁₆FN₃O₆
• Molecular Weight: 329.282
• EINECS: 2017-001-1
• Product Categories: Bases & Related Reagents;Nucleotides;Intermediates
• Mol File: 161599-46-8.mol
• Article Data: 22

Chemical Properties

• Melting Point: 196-198?C
• Boiling Point: 427.4 °C at 760 mmHg
• Flash Point: 212.3 °C
• Appearance: WHITE
• Density: 1.57 g/cm³
• Storage Temp.: -20°C Freezer
• Solubility: soluble in Methanol
• PKA: 2.49±0.10(Predicted)
• CAS DataBase Reference: 2',3'-Di-O-acetyl-5'-deoxy-5-fuluro-D-cytidine(CAS DataBase Reference)
• NIST Chemistry Reference: 2',3'-Di-O-acetyl-5'-deoxy-5-fuluro-D-cytidine(161599-46-8)
• EPA Substance Registry System: 2',3'-Di-O-acetyl-5'-deoxy-5-fuluro-D-cytidine(161599-46-8)

Safety Data

• Safety Statements: 24/25
• Hazardous Substances Data: 161599-46-8(Hazardous Substances Data)

Usage

Chemical Properties

White to Off-White Solid

Uses

Different sources of media describe the Uses of 161599-46-8 differently. You can refer to the following data:
1. Capecitabine intermediate
2. A metabolite of Capecitabine.
3. A metabolite of Capecitabine. Capecitabine Diacetyl Amino Impurity (USP).

Definition

ChEBI: A member of the class of cytidines that is a metabolite of the drug capecitabine.

Synthetic route

Flucytosine (2022-85-7) + 1,2,3-tri-O-acetyl-5-deoxy-β-D-ribofuranose (27821-07-4, 27930-18-3, 37076-71-4, 62211-93-2, 63903-44-6, 76497-54-6) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
With titanium tetrachloride In dichloromethane at 10 - 20℃; for 4h; Solvent;	88.6%
Stage #1: Flucytosine With ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane In toluene for 3h; Reflux; Stage #2: 1,2,3-tri-O-acetyl-5-deoxy-β-D-ribofuranose With tin(IV) chloride In dichloromethane at -5℃; Inert atmosphere; Heating;	83.6%
Stage #1: Flucytosine With trifluorormethanesulfonic acid; 1,1,1,3,3,3-hexamethyl-disilazane In acetonitrile for 2h; Reflux; Stage #2: 1,2,3-tri-O-acetyl-5-deoxy-β-D-ribofuranose With trifluorormethanesulfonic acid at 20 - 55℃;	80%

di-O-acetyl-5-deoxy-ξ-D-ribofuranosyl chloride (110022-91-8) + 2-trimethylsilyloxy-4-trimethylsilylamino-5-fluoropyrimidine (111878-21-8) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
Stage #1: di-O-acetyl-5-deoxy-ξ-D-ribofuranosyl chloride; 2-trimethylsilyloxy-4-trimethylsilylamino-5-fluoropyrimidine In 1,2-dichloro-ethane for 4h; Inert atmosphere; Schlenk technique; Reflux; Stage #2: With water Inert atmosphere; Schlenk technique;	86%

5-fluoro-2-trimethylsilanyloxy-pyrimidin-4-ylamine (41108-04-7) + 1,2,3-tri-O-acetyl-5-deoxy-β-D-ribofuranose (27821-07-4, 27930-18-3, 37076-71-4, 62211-93-2, 63903-44-6, 76497-54-6) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
With tin(IV) chloride; sodium hydrogencarbonate In dichloromethane; water at 0 - 20℃; for 0.5h;	78.4%

5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranose (37076-71-4) + 5-fluorocytosine → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
Stage #1: 5-fluorocytosine With 1,1,1,3,3,3-hexamethyl-disilazane In toluene for 4h; Autoclave; Reflux; Industrial scale; Stage #2: 5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranose With tin(IV) chloride In dichloromethane at 2 - 20℃; for 12h; Industrial scale;	74%

5'-deoxy-5-fluorocytidine (66335-38-4) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
With acetic anhydride In pyridine; water

5'-deoxy-2',3'-di-O-acetyl-5-fluoro-N4-((5-nitrothien-2-yl)methoxycarbonyl)cytidine (880633-97-6) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
In water; isopropyl alcohol G-values; Irradiation;

acetic anhydride (108-24-7) + 5'-deoxy-5-fluorocytidine (66335-38-4) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
With pyridine at 0℃; for 3h;
With pyridine at 0℃; for 3h;

Flucytosine (2022-85-7) + 5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranose (37076-71-4) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
Stage #1: Flucytosine With chloro-trimethyl-silane; 1,1,1,3,3,3-hexamethyl-disilazane In toluene at 110℃; for 0.5h; Stage #2: 5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranose With tin(IV) chloride In dichloromethane at 0 - 30℃; Stage #3: With water; sodium hydrogencarbonate In dichloromethane for 2h;

5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranose (37076-71-4) + 5-fluoro-2-trimethylsilanyloxy-pyrimidin-4-ylamine (41108-04-7) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
tin(IV) chloride In dichloromethane at 0℃; for 2h;

2',3',5'-tri-O-acetyl-5-fluorocytidine (128963-10-0) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: pyridine / dichloromethane / 1.5 h / 0 °C 2: alcalase enzyme cross linked aggregate / ethanol / 100 h / 20 °C / Enzymatic reaction 3: carbon tetrabromide / dichloromethane / 3 h / 20 °C / Inert atmosphere 4: 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride / tetrahydrofuran / Reflux View Scheme

N1-(2',3',5'-tri-O-acetyl-β-D-ribofuranosyl)-5-fluoro-N4-(n-pentyloxycarbonyl)cytosine (396684-34-7) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: alcalase enzyme cross linked aggregate / ethanol / 100 h / 20 °C / Enzymatic reaction 2: carbon tetrabromide / dichloromethane / 3 h / 20 °C / Inert atmosphere 3: 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride / tetrahydrofuran / Reflux View Scheme

2',3'-di-O-acetyl-5-fluoro-N4-(pentyloxycarbonyl)cytidine → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: carbon tetrabromide / dichloromethane / 3 h / 20 °C / Inert atmosphere 2: 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride / tetrahydrofuran / Reflux View Scheme

5'-bromo-2',3'-di-O-acetyl-5-fluoro-N4-(pentyloxycarbonyl)cytidine → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) + N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions	Yield
With 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride In tetrahydrofuran Reflux; Overall yield = 45 %;

methyl 2,3-O-isopropylidene-5-O-p-tolylsulfonyl-β-D-ribofuranoside (4137-56-8) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium tetrahydroborate / dimethyl sulfoxide 2: sulfuric acid / water / 80 - 90 °C / Large scale 3: triethylamine; dmap / 4 h / -5 - 5 °C / Large scale 4: tin(IV) chloride / dichloromethane / 5 - 10 °C View Scheme
Multi-step reaction with 3 steps 1.1: sodium tetrahydroborate; acetic acid / dimethyl sulfoxide / 20 h / 80 - 85 °C 2.1: sulfuric acid / 17 h / 80 - 90 °C 2.2: 16 h / 20 °C 3.1: 1,1,1,3,3,3-hexamethyl-disilazane / toluene / 100 °C 3.2: 2.33 h / 20 °C / Cooling with ice View Scheme

methyl 5-deoxy-2,3-O-isopropylidene-β-D-ribofuranoside (23202-81-5) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: sulfuric acid / water / 80 - 90 °C / Large scale 2: triethylamine; dmap / 4 h / -5 - 5 °C / Large scale 3: tin(IV) chloride / dichloromethane / 5 - 10 °C View Scheme
Multi-step reaction with 2 steps 1.1: sulfuric acid / 17 h / 80 - 90 °C 1.2: 16 h / 20 °C 2.1: 1,1,1,3,3,3-hexamethyl-disilazane / toluene / 100 °C 2.2: 2.33 h / 20 °C / Cooling with ice View Scheme

(2R,3R,4S,5R)-5-methyltetrahydrofuran-2,3,4-triol (279673-09-5) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine; dmap / 4 h / -5 - 5 °C / Large scale 2: tin(IV) chloride / dichloromethane / 5 - 10 °C View Scheme

2-trimethylsilyloxy-4-trimethylsilylamino-5-fluoropyrimidine (111878-21-8) + 1,2,3-tri-O-acetyl-5-deoxy-β-D-ribofuranose (27821-07-4, 27930-18-3, 37076-71-4, 62211-93-2, 63903-44-6, 76497-54-6) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
With tin(IV) chloride In dichloromethane at 5 - 10℃;
With tin(IV) chloride In dichloromethane at -1 - 10℃; Temperature; Inert atmosphere;	31 g

β-D-ribofuranose (36468-53-8) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
Multi-step reaction with 6 steps 1: sulfuric acid / 0 - 20 °C 2: triethylamine / dichloromethane / 0 - 20 °C 3: sodium tetrahydroborate; lithium chloride / diethylene glycol dimethyl ether / 20 h / 80 - 90 °C 4: sulfuric acid / water / 80 - 90 °C / Large scale 5: triethylamine; dmap / 4 h / -5 - 5 °C / Large scale 6: tin(IV) chloride / dichloromethane / 5 - 10 °C View Scheme
Multi-step reaction with 5 steps 1.1: sulfuric acid; tin(II) chloride dihdyrate / 40 - 45 °C 2.1: pyridine / dichloromethane / 20 h / 0 - 5 °C 3.1: sodium tetrahydroborate; acetic acid / dimethyl sulfoxide / 20 h / 80 - 85 °C 4.1: sulfuric acid / 17 h / 80 - 90 °C 4.2: 16 h / 20 °C 5.1: 1,1,1,3,3,3-hexamethyl-disilazane / toluene / 100 °C 5.2: 2.33 h / 20 °C / Cooling with ice View Scheme

((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (4099-85-8) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: triethylamine / dichloromethane / 0 - 20 °C 2: sodium tetrahydroborate; lithium chloride / diethylene glycol dimethyl ether / 20 h / 80 - 90 °C 3: sulfuric acid / water / 80 - 90 °C / Large scale 4: triethylamine; dmap / 4 h / -5 - 5 °C / Large scale 5: tin(IV) chloride / dichloromethane / 5 - 10 °C View Scheme
Multi-step reaction with 4 steps 1.1: pyridine / dichloromethane / 20 h / 0 - 5 °C 2.1: sodium tetrahydroborate; acetic acid / dimethyl sulfoxide / 20 h / 80 - 85 °C 3.1: sulfuric acid / 17 h / 80 - 90 °C 3.2: 16 h / 20 °C 4.1: 1,1,1,3,3,3-hexamethyl-disilazane / toluene / 100 °C 4.2: 2.33 h / 20 °C / Cooling with ice View Scheme

1-O-methyl-2,3-O-isopropylidene-5-O-(methanesulfonyl)-β-D-ribofuranoside (50610-99-6, 75100-24-2, 81026-76-8, 96896-28-5) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium tetrahydroborate; lithium chloride / diethylene glycol dimethyl ether / 20 h / 80 - 90 °C 2: sulfuric acid / water / 80 - 90 °C / Large scale 3: triethylamine; dmap / 4 h / -5 - 5 °C / Large scale 4: tin(IV) chloride / dichloromethane / 5 - 10 °C View Scheme

(3aS,4S,6aR)-4-(iodomethyl)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole (50600-40-3) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 1-ethylpiperidine hypophosphite; di-isopropyl azodicarboxylate; triethylamine / 1,4-dioxane / Reflux; Inert atmosphere 2.1: sulfuric acid / water / 2 h / Reflux 2.2: 20 h / 20 °C 3.1: tin(IV) chloride; sodium hydrogencarbonate / water; dichloromethane / 0.5 h / 0 - 20 °C View Scheme
Multi-step reaction with 4 steps 1: hydrogen; triethylamine / palladium on activated charcoal / methanol / 24 h / 20 °C / Inert atmosphere 2: hydrogenchloride; water / 2 h / Reflux 3: pyridine / 24 h / 20 °C 4: tin(IV) chloride / dichloromethane / 2 h / 0 °C View Scheme

1-O-methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranose (78341-97-6) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sulfuric acid / water / 2 h / Reflux 1.2: 20 h / 20 °C 2.1: tin(IV) chloride; sodium hydrogencarbonate / water; dichloromethane / 0.5 h / 0 - 20 °C View Scheme
Multi-step reaction with 3 steps 1: hydrogenchloride; water / 2 h / Reflux 2: pyridine / 24 h / 20 °C 3: tin(IV) chloride / dichloromethane / 2 h / 0 °C View Scheme

D-Ribose (532-20-7, 613-83-2, 7261-25-8, 7687-39-0, 13221-22-2, 14795-83-6, 15761-67-8, 20074-49-1, 25545-03-3, 25545-04-4, 32445-75-3, 34436-17-4, 36441-93-7, 36468-53-8, 37110-85-3, 37388-49-1, 38029-69-5, 40461-77-6, 40461-89-0, 41546-19-4, 41546-20-7, 41546-21-8, 41546-26-3, 41546-29-6, 41546-30-9, 41546-31-0, 126872-16-0, 131064-98-7) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: hydrogenchloride / water / 3 h / Reflux 2.1: triethylamine / dichloromethane / 4 h / 0 - 5 °C 3.1: sodium iodide / acetonitrile / 12 h / Reflux 4.1: 1-ethylpiperidine hypophosphite; di-isopropyl azodicarboxylate; triethylamine / 1,4-dioxane / Reflux; Inert atmosphere 5.1: sulfuric acid / water / 2 h / Reflux 5.2: 20 h / 20 °C 6.1: tin(IV) chloride; sodium hydrogencarbonate / water; dichloromethane / 0.5 h / 0 - 20 °C View Scheme
Multi-step reaction with 7 steps 1: hydrogenchloride / water / 2 h / Reflux 2: pyridine / 18 h / 20 °C 3: sodium iodide / butanone / 24 h / Reflux 4: hydrogen; triethylamine / palladium on activated charcoal / methanol / 24 h / 20 °C / Inert atmosphere 5: hydrogenchloride; water / 2 h / Reflux 6: pyridine / 24 h / 20 °C 7: tin(IV) chloride / dichloromethane / 2 h / 0 °C View Scheme

methyl 2,3-O-isopropylidene-D-ribofuranoside (4099-85-8, 5531-21-5, 20672-63-3, 20672-65-5, 58763-00-1, 63029-07-2, 72402-14-3, 84894-45-1, 129263-68-9) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 4 h / 0 - 5 °C 2.1: sodium iodide / acetonitrile / 12 h / Reflux 3.1: 1-ethylpiperidine hypophosphite; di-isopropyl azodicarboxylate; triethylamine / 1,4-dioxane / Reflux; Inert atmosphere 4.1: sulfuric acid / water / 2 h / Reflux 4.2: 20 h / 20 °C 5.1: tin(IV) chloride; sodium hydrogencarbonate / water; dichloromethane / 0.5 h / 0 - 20 °C View Scheme
Multi-step reaction with 6 steps 1: pyridine / 18 h / 20 °C 2: sodium iodide / butanone / 24 h / Reflux 3: hydrogen; triethylamine / palladium on activated charcoal / methanol / 24 h / 20 °C / Inert atmosphere 4: hydrogenchloride; water / 2 h / Reflux 5: pyridine / 24 h / 20 °C 6: tin(IV) chloride / dichloromethane / 2 h / 0 °C View Scheme

((3aR,4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 4-methylbenzenesulfonate (4137-56-8, 5531-22-6, 6953-71-5, 52631-00-2, 63087-95-6, 84894-43-9, 13007-50-6) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium iodide / acetonitrile / 12 h / Reflux 2.1: 1-ethylpiperidine hypophosphite; di-isopropyl azodicarboxylate; triethylamine / 1,4-dioxane / Reflux; Inert atmosphere 3.1: sulfuric acid / water / 2 h / Reflux 3.2: 20 h / 20 °C 4.1: tin(IV) chloride; sodium hydrogencarbonate / water; dichloromethane / 0.5 h / 0 - 20 °C View Scheme
Multi-step reaction with 5 steps 1: sodium iodide / butanone / 24 h / Reflux 2: hydrogen; triethylamine / palladium on activated charcoal / methanol / 24 h / 20 °C / Inert atmosphere 3: hydrogenchloride; water / 2 h / Reflux 4: pyridine / 24 h / 20 °C 5: tin(IV) chloride / dichloromethane / 2 h / 0 °C View Scheme

5-O-deoxy-D-ribofuranose (158112-55-1) → (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: pyridine / 24 h / 20 °C 2: tin(IV) chloride / dichloromethane / 2 h / 0 °C View Scheme

(2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → 5'-deoxy-5-fluorocytidine (66335-38-4)

Conditions	Yield
With ammonia In methanol; water at 45 - 55℃; Product distribution / selectivity;	95%
With methanol; diethylamine at 20 - 50℃; for 2h; Inert atmosphere;	80%
With methanol; diethylamine at 55℃; for 2h;

pentyl chloroformate (638-41-5) + (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions	Yield
With potassium phosphate In dichloromethane; isopropyl alcohol at 0 - 25℃; for 4h; Reagent/catalyst; Inert atmosphere;	94.2%
With pyridine In dichloromethane at 0℃; for 1h;	93%
With dmap; potassium carbonate In dichloromethane at 5℃; for 0.75h; Temperature; Solvent; Reagent/catalyst;	90.6%

pentan-1-ol (71-41-0) + 1,1'-carbonyldiimidazole (530-62-1) + (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions	Yield
In dichloromethane at 20℃; for 4h;	91.6%

1,3-thiazolone formyl chloride + (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → C17H19FN4O8S

Conditions	Yield
With pyridine In dichloromethane at -15 - 20℃; for 2h;	85%

3,7,11,15-tetramethyl-hexadecyl chloroformate + (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → 2’,3’-di-O-acetyl-5’-deoxy-5-fluoro-N4-(3,7,11,15-tetramethylhexadecyloxycarbonyl)cytidine

Conditions	Yield
With pyridine In dichloromethane at 20℃;	84.1%

CH2 Cl + neopentyl chloroformate (20412-38-8) + (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → 5'-deoxy-5-fluoro-N4-(neopentyloxycarbonyl)-cytidine (162204-44-6)

Conditions	Yield
With pyridine; sodium hydroxide; sodium carbonate In methanol; ethanol; dichloromethane	84%

pentyl chloroformate (638-41-5) + (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → capecitabine (154361-50-9)

Conditions	Yield
With sodium hydroxide In water; acetone at 30℃; for 5h; Green chemistry;	82%
Stage #1: pentyl chloroformate; (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate With pyridine In dichloromethane at 0℃; for 1h; Stage #2: With sodium hydroxide In ethanol; water at -5 - 0℃; for 0.233333h;	80.2%
Multi-step reaction with 2 steps 1: dichloromethane 2: sodium hydroxide / methanol View Scheme
Multi-step reaction with 2 steps 1: pyridine / dichloromethane / 1 h / 0 °C 2: sodium methylate / methanol / 1 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: potassium phosphate / isopropyl alcohol; dichloromethane / 4 h / 0 - 25 °C / Inert atmosphere 2: sodium hydroxide / methanol; water / 1 h / -10 - 5 °C / Autoclave View Scheme

pentyl chloroformate (638-41-5) + (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → C27H42FN3O10

Conditions	Yield
With sodium hydroxide In water; acetone at 30℃; for 1h; Flow reactor;	35%

n-hexyl chloroformate (6092-54-2) + (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → Acetic acid (2R,3R,4R,5R)-4-acetoxy-2-(5-fluoro-4-hexyloxycarbonylamino-2-oxo-2H-pyrimidin-1-yl)-5-methyl-tetrahydro-furan-3-yl ester (162204-21-9)

Conditions	Yield
With pyridine In dichloromethane at -20 - 20℃; Acylation;

n-heptyl chloroformate (33758-34-8) + (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → Acetic acid (2R,3R,4R,5R)-4-acetoxy-2-(5-fluoro-4-heptyloxycarbonylamino-2-oxo-2H-pyrimidin-1-yl)-5-methyl-tetrahydro-furan-3-yl ester

Conditions	Yield
With pyridine In dichloromethane at -20 - 20℃; Acylation;

octyl chloroformate (7452-59-7) + (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → Acetic acid (2R,3R,4R,5R)-4-acetoxy-2-(5-fluoro-4-octyloxycarbonylamino-2-oxo-2H-pyrimidin-1-yl)-5-methyl-tetrahydro-furan-3-yl ester (161599-33-3)

Conditions	Yield
With pyridine In dichloromethane at -20 - 20℃; Acylation;

chloroformic acid n-nonyl ester (57045-82-6) + (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → Acetic acid (2R,3R,4R,5R)-4-acetoxy-2-(5-fluoro-4-nonyloxycarbonylamino-2-oxo-2H-pyrimidin-1-yl)-5-methyl-tetrahydro-furan-3-yl ester

Conditions	Yield
With pyridine In dichloromethane at -20 - 20℃; Acylation;

3,5-dichlorobenzoyl chloride (2905-62-6) + (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → Acetic acid (2R,3R,4R,5R)-4-acetoxy-2-[4-(3,5-dichloro-benzoylamino)-5-fluoro-2-oxo-2H-pyrimidin-1-yl]-5-methyl-tetrahydro-furan-3-yl ester

Conditions	Yield
With pyridine In dichloromethane at -20 - 20℃; Acylation;

chloroformic acid ethyl ester (541-41-3) + (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → Acetic acid (2R,3R,4R,5R)-4-acetoxy-2-(4-ethoxycarbonylamino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)-5-methyl-tetrahydro-furan-3-yl ester

Conditions	Yield
With pyridine In dichloromethane at -20 - 20℃; Acylation;

3,4,5-Trimethoxybenzoyl chloride (4521-61-3) + (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → Acetic acid (2R,3R,4R,5R)-4-acetoxy-2-[5-fluoro-2-oxo-4-(3,4,5-trimethoxy-benzoylamino)-2H-pyrimidin-1-yl]-5-methyl-tetrahydro-furan-3-yl ester (161599-31-1)

Conditions	Yield
With pyridine In dichloromethane at -20 - 20℃; Acylation;

3,5-dimethoxybenzoyl chloride (17213-57-9) + (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → Acetic acid (2R,3R,4R,5R)-4-acetoxy-2-[4-(3,5-dimethoxy-benzoylamino)-5-fluoro-2-oxo-2H-pyrimidin-1-yl]-5-methyl-tetrahydro-furan-3-yl ester

Conditions	Yield
With pyridine In dichloromethane at -20 - 20℃; Acylation;

methyl chloroformate (79-22-1) + (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → Acetic acid (2R,3R,4R,5R)-4-acetoxy-2-(5-fluoro-4-methoxycarbonylamino-2-oxo-2H-pyrimidin-1-yl)-5-methyl-tetrahydro-furan-3-yl ester

Conditions	Yield
With pyridine In dichloromethane at -20 - 20℃; Acylation;

carbonochloridic acid, butyl ester (592-34-7) + (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → Acetic acid (2R,3R,4R,5R)-4-acetoxy-2-(4-butoxycarbonylamino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)-5-methyl-tetrahydro-furan-3-yl ester (162204-19-5)

Conditions	Yield
With pyridine In dichloromethane at -20 - 20℃; Acylation;

3,5-dimethylbenzoyl chloride (6613-44-1) + (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → Acetic acid (2R,3R,4R,5R)-4-acetoxy-2-[4-(3,5-dimethyl-benzoylamino)-5-fluoro-2-oxo-2H-pyrimidin-1-yl]-5-methyl-tetrahydro-furan-3-yl ester

Conditions	Yield
With pyridine In dichloromethane at -20 - 20℃; Acylation;

(2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) + propoxycarbonyl chloride (109-61-5) → Acetic acid (2R,3R,4R,5R)-4-acetoxy-2-(5-fluoro-2-oxo-4-propoxycarbonylamino-2H-pyrimidin-1-yl)-5-methyl-tetrahydro-furan-3-yl ester (162204-18-4)

Conditions	Yield
With pyridine In dichloromethane at -20 - 20℃; Acylation;

(2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → 5'-deoxy-5-fluoro-N4-(3,4,5-trimethoxybenzoyl)cytidine (124012-42-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: pyridine / CH2Cl2 / -20 - 20 °C 2: NaOH / methanol; H2O / -20 - -5 °C View Scheme

(2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → 5'-deoxy-5-fluoro-N4-(methoxycarbonyl)cytidine

Conditions	Yield
Multi-step reaction with 2 steps 1: pyridine / CH2Cl2 / -20 - 20 °C 2: NaOH / methanol; H2O / -20 - -5 °C View Scheme

(2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → 5'-deoxy-5-fluoro-N4-(ethoxycarbonyl)cytidine

Conditions	Yield
Multi-step reaction with 2 steps 1: pyridine / CH2Cl2 / -20 - 20 °C 2: NaOH / methanol; H2O / -20 - -5 °C View Scheme

(2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → 5'-deoxy-5-fluoro-N4-(propoxycarbonyl)cytidine

Conditions	Yield
Multi-step reaction with 2 steps 1: pyridine / CH2Cl2 / -20 - 20 °C 2: NaOH / methanol; H2O / -20 - -5 °C View Scheme

(2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → 5'-deoxy-5-fluoro-N4-(butoxycarbonyl)cytidine

Conditions	Yield
Multi-step reaction with 2 steps 1: pyridine / CH2Cl2 / -20 - 20 °C 2: NaOH / methanol; H2O / -20 - -5 °C View Scheme

(2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate (161599-46-8) → capecitabine (154361-50-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1311 g / pyridine / CH2Cl2 / -20 - 20 °C 2: 170 g / NaOH / methanol; H2O / -20 - -5 °C View Scheme
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 20 - 30 °C / Inert atmosphere 2: sodium hydroxide / acetone / 2 h / -15 - 10 °C View Scheme

Upstream product

• 108-24-7 acetic anhydride 
• 66335-38-4 5'-deoxy-5-fluorocytidine 
• 37076-71-4 5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranose 
• 41108-04-7 5-fluoro-2-trimethylsilanyloxy-pyrimidin-4-ylamine 
• 1054449-33-0 2',3'-di-O-ethanoyl-5-fluorocytidine 
• 158112-55-1 5-O-deoxy-D-ribofuranose 
• 110022-91-8 di-O-acetyl-5-deoxy-ξ-D-ribofuranosyl chloride 
• 111878-21-8 2-trimethylsilyloxy-4-trimethylsilylamino-5-fluoropyrimidine 
• 4137-56-8 ((3aR,4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 4-methylbenzenesulfonate 
• 4099-85-8 methyl 2,3-O-isopropylidene-D-ribofuranoside 
• 532-20-7 D-Ribose 
• 27821-07-4 1,2,3-tri-O-acetyl-5-deoxy-β-D-ribofuranose 
• 78341-97-6 1-O-methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranose 
• 50600-40-3 (3aS,4S,6aR)-4-(iodomethyl)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole 

Downstream Products

• 66335-38-4 5'-deoxy-5-fluorocytidine 
• 154361-50-9 capecitabine 
• 162204-20-8 N¹-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N⁴-(pentyloxycarbonyl)cytosine 
• 162204-22-0 C₁₉H₂₆FN₃O₈ 
• 1394845-09-0 5'-deoxy-5-fluoro-N₄-(4-chlorophenyloxycarbonyl)cytidine-2',3'-carbonate 
• 1394845-08-9 5'-deoxy-5-fluoro-N₄-(4-nitrophenyloxycarbonyl)cytidine-2',3'-carbonate 
• 1394845-05-6 5'-deoxy-5-fluoro-N₄-(4-chlorophenyloxycarbonyl)cytidine 
• 1394845-04-5 5'-deoxy-5-fluoro-N₄-(4-nitrophenyloxycarbonyl)cytidine 
• 910129-15-6 5'-deoxy-5-fluoro-N4-(2-methyl-1-butyloxycarbonyl)cytidine 
• 124012-42-6 5'-deoxy-5-fluoro-N⁴-(3,4,5-trimethoxybenzoyl)cytidine 
• 162204-19-5 Acetic acid (2R,3R,4R,5R)-4-acetoxy-2-(4-butoxycarbonylamino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)-5-methyl-tetrahydro-furan-3-yl ester 
• 161599-31-1 Acetic acid (2R,3R,4R,5R)-4-acetoxy-2-[5-fluoro-2-oxo-4-(3,4,5-trimethoxy-benzoylamino)-2H-pyrimidin-1-yl]-5-methyl-tetrahydro-furan-3-yl ester 

Relevant articles and documents

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