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

Uses

Used in Pharmaceutical Industry:
2',3'-Di-O-acetyl-5'-deoxy-5-fuluro-D-cytidine is used as an intermediate for the synthesis of capecitabine, an anticancer drug. It serves as a crucial component in the production process, contributing to the development of effective cancer treatments.
Used in Quality Control and Regulatory Compliance:
As a metabolite of capecitabine, 2',3'-Di-O-acetyl-5'-deoxy-5-fuluro-D-cytidine is used for quality control purposes and regulatory compliance in the pharmaceutical industry. It is essential for ensuring the safety, efficacy, and purity of capecitabine-based medications.
Used in Research and Development:
2',3'-Di-O-acetyl-5'-deoxy-5-fuluro-D-cytidine is also utilized in research and development for the study of capecitabine's mechanism of action, its metabolites, and potential improvements or modifications to enhance its therapeutic effects. Researchers use it to better understand the drug's interactions with the human body and to develop new cancer treatments.
Used in Capecitabine Diacetyl Amino Impurity (USP):
2',3'-Di-O-acetyl-5'-deoxy-5-fuluro-D-cytidine is recognized as a specific impurity (Capecitabine Diacetyl Amino Impurity) in the United States Pharmacopeia (USP). It is essential for the identification, quantification, and control of impurities in capecitabine formulations, ensuring the quality and safety of the drug for patients.

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

• 66335-38-4 5'-deoxy-5-fluorocytidine 
• 108-24-7 acetic anhydride 
• 50610-99-6 1-O-methyl-2,3-O-isopropylidene-5-O-(methanesulfonyl)-β-D-ribofuranoside 
• 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 
• 41108-04-7 5-fluoro-2-trimethylsilanyloxy-pyrimidin-4-ylamine 
• 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

• 162204-20-8 N¹-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N⁴-(pentyloxycarbonyl)cytosine 
• 154361-50-9 capecitabine 
• 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 
• 66335-38-4 5'-deoxy-5-fluorocytidine 
• 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

Preparation method of capecitabine key intermediate

The invention discloses a preparation method of a capecitabine key intermediate. According to the method, 2', 3', 5'-tri-0-acetyl-5-fluorocytidine servers as an initial raw material, selectively deacetylating through di-tert-butyl chlorotin hydroxide, and reducing through triethyl silane and trifluoroacetic acid to obtain a target product. The method has the advantages of cheap and easily available raw materials, short synthesis steps, simple operation, high product purity and high yield, and is especially suitable for industrial production.

AMPHIPHILE PRODRUGS

Amphiphilic prodrugs of general formula A-X are disclosed, wherein A is a biologically active agent or may be metabolised to a biologically active agent; and X is selected from the group consisting of R, or up to three R moieties attached to a linker, Y1, Y2 or Y3, wherein R is selected from a group consisting of alkyl, alkenyl, alkynyl, branched alkyl, branched alkenyl, branched alkynyl, substituted alkyl, substituted alkenyl and substituted alkynyl groups and their analogues; Y1 is a linker group which covalently attached to an R group at one site and is attached to A at a further independent site; Y2 is a linker group which is covalently attached to two R groups at two independent sites and is attached to A at a further independent site; and Y3 is a linker group which is covalently attached to three R groups at three independent sites and is attached to A at a further independent site. Self-assembly of the amphiphilic prodrugs into reverse lyotropic phases, particularly hexagonal, cubic and sponge, is disclosed. In preferred embodiments A is dopamine or a 5-fluorouracil prodrug.

Method for preparing capecitabine intermediate shown I

The invention discloses a method for preparing a Capecitabine intermediate represented by formula I. The method comprises the following reaction route shown in the description, wherein in the reaction a, 5-fluorocytosine reacts with hexamethyldisilazane to produce a compound represented by a formula III; in the reaction b, the compound represented by the formula III reacts with a compound represented by a formula II to produce the Capecitabine intermediate represented by the formula I; and in the general formula, R is H or a hydroxyl protecting group. According to the method, the high-yield preparation of the high-purity Capecitabine intermediate represented by the formula I is realized through strictly controlling the dropwise adding temperature and dropwise adding rate of Lewis acid, so that the subsequent preparation of high-purity Capecitabine is facilitated, and the requirements on industrialization of Capecitabine are met; and the method has a significant practical value.

Preparation method and product of capecitabine intermediate

The invention relates to a preparation method of a capecitabine intermediate. The capecitabine intermediate is 2',3'-di-O-acetyl-5'-deoxy-5-fuluro-D-cytidine, and the method comprises the following steps: 5-fluorocytosine is placed in a solvent, 1,2,3-tri-O-acetyl-5-deoxyribose is added, and Lewis acid is added with stirring for a catalytic reaction; sodium bicarbonate and water are added to a reaction liquid obtained after reaction completion for quenching, then separation and crystallization are performed, and the capecitabine intermediate is prepared. In the preparation method, 5-fluorocytosine does not need silylation protection and is subjected to glycosylation with 1,2,3-tri-O-acetyl-5-deoxyribose directly, so that reaction steps are reduced, and reaction time is shortened; energy consumption is reduced, production efficiency is increased, produced waste is reduced, and resources are saved; the obtained capecitabine intermediate is high in purity, alpha isomers are few or even cannot be detected, and optical purity of the product can reach 99.8% or higher.

Preparation method of 2'-3'-bis-O-acetyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine

The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of 2'-3'-bis-O-acetyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine; the method comprises: reacting a compound of formula IV as a raw material with n-amyl chloroformate under the action of K3PO4 to obtain the compound of formula V, 2',3'-bis-O-acetyl-5'-deoxy-5-fluorine-N4-[(pentyloxy)carbonyl]cytidine. The invention also provides application of the method in the preparation of capecitabine. The preparation method has the advantages that reaction yield can be significantly increased, product purity is high, reaction conditions are mild, the use of pyridine is avoided, pyridine residue in the product is avoided, and the method is suitable for industrial production of medicine.

Effective synthesis of nucleosides utilizing O-acetyl-glycosyl chlorides as glycosyl donors in the absence of catalyst: Mechanism revision and application to silyl-hilbert-johnson reaction

An effective synthesis of nucleosides using glycosyl chlorides as glycosyl donors in the absence of Lewis acid has been developed. Glycosyl chlorides have been shown to be pivotal intermediates in the classical silyl-Hilbert-Johnson reaction. A possible mechanism that differs from the currently accepted mechanism advanced by Vorbrueggen has been proposed and verified by experiments. In practice, this catalyst-free method provides easy access to Capecitabine in high yield.

2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine synthesis method

The present invention discloses a 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine synthesis method, which comprises: (1) suspending 5-fluorocytosine in anhydrous toluene, adding hexamethyldisilazane, and carrying out a heating reflux reaction; (2) carrying out pressure reducing concentration on the solution obtained in the step (1) at a temperature of less than or equal to 60 DEG C to achieve a dry state, adding 5-triacetyl deoxyribose and anhydrous 1,2-dichloroethane to the remaining substance, adding anhydrous tin tetrachloride and an anhydrous 1,2-dichloroethane solution in a dropwise manner at a temperature of -5 DEG C, and carrying out a reaction at a temperature of 0 DEG C after completing the adding; (3) adding a sodium bicarbonate solution to the solution obtained in the step (2), stirring for a certain time at a room temperature, filtering, washing with a 5% sodium bicarbonate solution, drying with anhydrous sodium sulfate, and concentrating to achieve a dry state; and (4) purifying the remaining substance obtained in the step (3) with a silica gel chromatography column so as to obtain the crystal 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine, wherein the solution obtained in the step (2) is slowly added to the -5 DEG C sodium bicarbonate aqueous solution in a dropwise manner in the step (3). The method of the present invention has characteristics of less operation and low loss.

Capecitabine and wherein the intermediate preparation method

The invention discloses a preparation method of capecitabine. The method comprises the following steps: based on D-ribose serving as a starting raw material, carrying out hydroxyl protection, 5-site tosylation, iodine substitution, hypophosphorous acid deiodination and acetylation so as to obtain the key intermediate 12,3-tri-O-acetyl-5-deoxy-beta-D-ribofuranose; carrying out glycosylation on the key intermediate and 5-fluorocytosine; and finally, carrying out N-4 site acylation and deprotection so as to obtain the capecitabine. In the method, a metal catalyst dose not need to be used for participating in reaction, the reaction condition is mild, and the yield is high, thus the method is economical and effective as well as suitable for industrial production on a large scale.

The capecitabine industrial preparation method

The invention optimizes the synthesis process of capecitabine bulk drug, especially improves the purification method of capecitabine. The method involved in the invention is suitable for industrial production, remarkably reduces the quantity and limit of related impurities in the capecitabine bulk drug, and improves the quality of the capecitabine bulk drug.

Safe and Alternate Process for the Reductions of Methanesulfonates: Application in the Synthesis of 1,2,3-Triacetyl-5-deoxy-d-ribofuranoside

Diethylene glycol dimethyl ether, diglyme, and 1,2-bis(2-methoxyethoxy)ethane, triglyme, are found to be suitable and safe alternate solvents to DMSO for the reduction of methanesulfonate in sodium borohydride. Addition of anhydrous lithium chloride led to the complete reduction of methanesulfonate esters to the corresponding alkanes in the presence of sodium borohydride in these solvents (diglyme and triglyme). This protocol is useful in the preparation of 1,2,3-triacetyl-5-deoxy-d-ribofuranoside, 7, a key intermediate of Capecitabine, 1, on the commercial scale.