162204-20-8

Basic information

• Product Name: 5`-deoxy-5-fluore-N-[(pentoyloxy)carbonyl]cytidine 2`,3`-diacetate
• Synonyms: 5`-deoxy-5-fluore-N-[(pentoyloxy)carbonyl]cytidine 2`,3`-diacetate;5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]cytidine 2',3'-diacetate;Capecitabine Intermediate 1;[1-(2,3-Di-O-acetyl-5-deoxy-β-D-ribofuranosyl)-5-fluoro-1,2-dihydro-2-oxo-4-pyriMidinyl]carbaMic Acid Pentyl Ester;2',3'-Di-O-acetylcapecitabine;Capecitabine interMediate;Cytidine,5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-, 2',3'-diacetate;2',3'-Di-O-acetyl-5'-deoxy-5-fluoro-N4-(pentoxycarboxyl)cytidine
• CAS NO: 162204-20-8
• Molecular Formula: C₁₉H₂₆FN₃O₈
• Molecular Weight: 443.425
• EINECS: 2017-001-1
• Product Categories: Bases & Related Reagents;Nucleotides
• Mol File: 162204-20-8.mol

Chemical Properties

• Melting Point: 100-102?C
• Appearance: Powder
• Density: 1.4 g/cm³
• Storage Temp.: Refrigerator
• Solubility: soluble in Methanol
• PKA: 5.36±0.40(Predicted)
• CAS DataBase Reference: 5`-deoxy-5-fluore-N-[(pentoyloxy)carbonyl]cytidine 2`,3`-diacetate(CAS DataBase Reference)
• NIST Chemistry Reference: 5`-deoxy-5-fluore-N-[(pentoyloxy)carbonyl]cytidine 2`,3`-diacetate(162204-20-8)
• EPA Substance Registry System: 5`-deoxy-5-fluore-N-[(pentoyloxy)carbonyl]cytidine 2`,3`-diacetate(162204-20-8)

Safety Data

• Safety Statements: 24/25
• Hazardous Substances Data: 162204-20-8(Hazardous Substances Data)

Usage

Uses

Used in Organic Synthesis:
5'-deoxy-5-fluore-N-[(pentoyloxy)carbonyl]cytidine 2',3'-diacetate is used as an intermediate in the synthesis of various organic compounds. Its unique structure allows it to be a versatile building block for creating a wide range of molecules with different functionalities and applications.
Used in Pharmaceutical Industry:
In the pharmaceutical industry, 5'-deoxy-5-fluore-N-[(pentoyloxy)carbonyl]cytidine 2',3'-diacetate is used as a key component in the development of new drugs. Its chemical properties enable it to be modified and incorporated into drug molecules, potentially leading to the creation of novel therapeutic agents with improved efficacy and safety profiles.
Used in Research and Development:
5'-deoxy-5-fluore-N-[(pentoyloxy)carbonyl]cytidine 2',3'-diacetate is also employed in research and development settings. Scientists and researchers use this compound to study its chemical properties, reactivity, and potential applications in various fields, including material science, biotechnology, and nanotechnology.

Synthetic route

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%

(5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)carbamic acid amyl ester (862508-03-0) + C24H24O7 → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions	Yield
Stage #1: (5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)carbamic acid amyl ester With N,O-Bis(trimethylsilyl)trifluoroacetamide In acetonitrile at 50℃; for 0.5h; Inert atmosphere; Stage #2: C24H24O7 In acetonitrile at 20℃; for 0.75h; Inert atmosphere; Molecular sieve; Stage #3: With N-iodo-succinimide; trimethylsilyl trifluoromethanesulfonate In acetonitrile at 0 - 20℃; for 2h;	93%

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%

5'-iodo-2',3'-di-O-acetyl-5-fluoro-N4-(pentyloxycarbonyl)cytidine → 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 at 20℃; for 4h; Inert atmosphere;	74%

5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranose (37076-71-4) + N4-(n-pentyloxycarbonyl)-5-fluorocytosine (862508-03-0) → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions	Yield
Stage #1: 5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranose; N4-(n-pentyloxycarbonyl)-5-fluorocytosine In acetonitrile Inert atmosphere; Stage #2: With chloro-trimethyl-silane; 1,1,1,3,3,3-hexamethyl-disilazane In acetonitrile at 20℃; for 0.5h; Stage #3: With trimethylsilyl trifluoromethanesulfonate In acetonitrile at -78 - 20℃;	28%

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) → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: HMDS / toluene / 3 h / 100 °C 1.2: 76 percent / SnCl4 / CH2Cl2 / 2 h / 20 °C 2.1: 1311 g / pyridine / CH2Cl2 / -20 - 20 °C View Scheme
Multi-step reaction with 2 steps 1: tin(IV) chloride / dichloromethane / 5 - 10 °C 2: pyridine / dichloromethane / -5 - 5 °C View Scheme

pentyl (5-fluoro-2-((trimethylsilyl)oxy)pyrimidin-4-yl)carbamate (1071455-34-9) + 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) → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions	Yield
With 2,6-di-tert-butyl-4-methylpyridinium trifluoromethanesulfonate In acetonitrile at 140℃;

pentyl chloroformate (638-41-5) → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: pyridine 2: acetonitrile / 0.5 h / 75 °C 3: 2,6-di-tert-butyl-4-methylpyridinium trifluoromethanesulfonate / acetonitrile / 140 °C View Scheme
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
Multi-step reaction with 5 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: lithium iodide / acetone / 6 h / Reflux 5: 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride / tetrahydrofuran / 4 h / 20 °C / Inert atmosphere View Scheme

pentyl chloroformate (638-41-5) + 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) → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions	Yield
With 2,6-di-tert-butyl-4-methylpyridinium trifluoromethanesulfonate In acetonitrile at 130℃;

2',3',5'-tri-O-acetyl-5-fluorocytidine (128963-10-0) → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

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
Multi-step reaction with 5 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 5: dichloromethane View Scheme
Multi-step reaction with 5 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: lithium iodide / acetone / 6 h / Reflux 5: 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride / tetrahydrofuran / 4 h / 20 °C / Inert atmosphere View Scheme

N1-(2',3',5'-tri-O-acetyl-β-D-ribofuranosyl)-5-fluoro-N4-(n-pentyloxycarbonyl)cytosine (396684-34-7) → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

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
Multi-step reaction with 4 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 4: dichloromethane View Scheme
Multi-step reaction with 4 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: lithium iodide / acetone / 6 h / Reflux 4: 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride / tetrahydrofuran / 4 h / 20 °C / Inert atmosphere View Scheme

2',3'-di-O-acetyl-5-fluoro-N4-(pentyloxycarbonyl)cytidine → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

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
Multi-step reaction with 3 steps 1: carbon tetrabromide / dichloromethane / 3 h / 20 °C / Inert atmosphere 2: 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride / tetrahydrofuran / Reflux 3: dichloromethane View Scheme
Multi-step reaction with 3 steps 1: carbon tetrabromide / dichloromethane / 3 h / 20 °C / Inert atmosphere 2: lithium iodide / acetone / 6 h / Reflux 3: 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride / tetrahydrofuran / 4 h / 20 °C / Inert atmosphere 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 %;

5'-bromo-2',3'-di-O-acetyl-5-fluoro-N4-(pentyloxycarbonyl)cytidine → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: lithium iodide / acetone / 6 h / Reflux 2: 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride / tetrahydrofuran / 4 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride / tetrahydrofuran / Reflux 2: dichloromethane View Scheme

methyl 2,3-O-isopropylidene-5-O-p-tolylsulfonyl-β-D-ribofuranoside (4137-56-8) → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions	Yield
Multi-step reaction with 5 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 5: pyridine / dichloromethane / -5 - 5 °C View Scheme

methyl 5-deoxy-2,3-O-isopropylidene-β-D-ribofuranoside (23202-81-5) → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions	Yield
Multi-step reaction with 4 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 4: pyridine / dichloromethane / -5 - 5 °C View Scheme

(2R,3R,4S,5R)-5-methyltetrahydrofuran-2,3,4-triol (279673-09-5) → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine; dmap / 4 h / -5 - 5 °C / Large scale 2: tin(IV) chloride / dichloromethane / 5 - 10 °C 3: pyridine / dichloromethane / -5 - 5 °C View Scheme

β-D-ribofuranose (36468-53-8) → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions

Yield

Multi-step reaction with 7 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 7: pyridine / dichloromethane / -5 - 5 °C View Scheme

((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (4099-85-8) → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions	Yield
Multi-step reaction with 6 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 6: pyridine / dichloromethane / -5 - 5 °C 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) → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions	Yield
Multi-step reaction with 5 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 5: pyridine / dichloromethane / -5 - 5 °C View Scheme

5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranose (37076-71-4) → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 1,1,1,3,3,3-hexamethyl-disilazane / toluene / 4 h / Autoclave; Reflux; Industrial scale 1.2: 12 h / 2 - 20 °C / Industrial scale 2.1: pyridine / dichloromethane / -15 - -5 °C / Industrial scale View Scheme

(3aS,4S,6aR)-4-(iodomethyl)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole (50600-40-3) → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions	Yield
Multi-step reaction with 4 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 4.1: pyridine / dichloromethane / 1 h / 0 °C View Scheme

1-O-methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranose (78341-97-6) → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions	Yield
Multi-step reaction with 3 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 3.1: pyridine / dichloromethane / 1 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) → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions

Yield

Multi-step reaction with 7 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 7.1: pyridine / dichloromethane / 1 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) → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions

Yield

Multi-step reaction with 6 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 6.1: pyridine / dichloromethane / 1 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) → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions

Yield

Multi-step reaction with 5 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 5.1: pyridine / dichloromethane / 1 h / 0 °C View Scheme

5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranose (37076-71-4) + (5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)carbamic acid amyl ester (862508-03-0) → N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8)

Conditions	Yield
With boron trifluoride diethyl etherate at 5 - 40℃; for 3h;	330.8 g

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

Conditions	Yield
Stage #1: N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine With water; sodium hydroxide In methanol at -15℃; Stage #2: With hydrogenchloride In methanol; water at -15℃; pH=5;	98%
With potassium hydroxide In methanol at 0 - 15℃; for 1h; Reagent/catalyst;	96.1%
With sodium hydroxide In methanol; water at -10 - 5℃; for 1h; Autoclave;	87.5%

N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8) → 5'-deoxy-5-fluoro-N4-(n-pentyloxycarbonyl)cytidine-2',3'-carbonate (921769-65-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide / acetone / 2 h / -15 - 10 °C 2: dichloromethane / 20 °C / Inert atmosphere View Scheme

dimethyl sulfate (77-78-1) + N1-(2',3'-di-O-acetyl-5'-deoxy-β-D-ribofuranosyl)-5-fluoro-N4-(pentyloxycarbonyl)cytosine (162204-20-8) → C20H28FN3O8 + C20H28FN3O8

Conditions	Yield
With triethylamine In 1,2-dichloro-ethane at 50℃;	A 0.2 g B 0.59 g

Upstream product

• 638-41-5 pentyl chloroformate 
• 161599-46-8 (2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyl-tetrahydrofuran-3,4-diyl diacetate 
• 37076-71-4 5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranose 
• 862508-03-0 N₄-(n-pentyloxycarbonyl)-5-fluorocytosine 
• 1071455-34-9 pentyl (5-fluoro-2-((trimethylsilyl)oxy)pyrimidin-4-yl)carbamate 
• 27821-07-4 1,2,3-tri-O-acetyl-5-deoxy-β-D-ribofuranose 
• 41108-04-7 5-fluoro-2-trimethylsilanyloxy-pyrimidin-4-ylamine 
• 128963-10-0 2',3',5'-tri-O-acetyl-5-fluorocytidine 
• 396684-34-7 N¹-(2',3',5'-tri-O-acetyl-β-D-ribofuranosyl)-5-fluoro-N⁴-(n-pentyloxycarbonyl)cytosine 
• 4137-56-8 methyl 2,3-O-isopropylidene-5-O-p-tolylsulfonyl-β-D-ribofuranoside 
• 23202-81-5 methyl 5-deoxy-2,3-O-isopropylidene-β-D-ribofuranoside 
• 279673-09-5 (2R,3R,4S,5R)-5-methyltetrahydrofuran-2,3,4-triol 
• 36468-53-8 β-D-ribofuranose 
• 4099-85-8 ((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol 

Downstream Products

• 154361-50-9 capecitabine 

Relevant articles and documents

Multinuclear NMR measurements and DFT calculations for capecitabine tautomeric form assignment in a solution

The molecular structure of capecitabine (a widely applied prodrug of 5-fluorouracil) was studied by multinuclear NMR measurements and DFT quantum mechanical calculations. One or two tautomeric forms in a solution were detected depending on the solvent used. In the organic solvents, a mixture of two forms of capecitabine was observed: carbamate and imine tautomers. In the aqueous solution, only the carbamate form was found. The methylation of capecitabine yields mainly two products in different proportions: N3-methylcapecitabine and N7-methylcapecitabine. The protonation of capecitabine in organic solvents with perchloric acid occurs at the N3 nitrogen atom. DFT calculations strongly support the results coming from the analysis of the NMR spectra.

Preparation of capecitabine intermediate

The invention belongs to the field of medicine synthesis, and provides a preparation method of capecitabine intermediate, in particular to a compound of the formula I II in the presence of a ketone solvent and an organic base.

Cytidine derivative and method for preparing capecitabine medicines through derivative

The invention discloses a 5-deoxy-D-ribofuranose 1-[2-(1-styyl) benzoate] derivative as shown in a general formula (I) and a preparation method of the derivative, and a method for preparing a N4-deoxycarbonyl cytidine derivative and antitumor medicines namely capecitabine by using the general formula (I) as a raw material, wherein the structure of the general formula (I) is as shown in the description. The 5-deoxy-D-ribofuranose 1-[2-(1-styyl) benzoate] derivative as the raw material of a reaction is used as a glycosyl donor and can be activated under the condition of Lewis acid trimethylsilyl trifluoromethanesulfonate and N-lodosuccinimide in catalysis quantity, so that Lewis acid in traditional use equivalent or excessive quantity is avoided, and a reaction system is mild, free from occurrence of other side reactions and efficient.

A capecitabine synthetic method

The invention belongs to the technical field of medicine preparation and relates to a synthetic method of capecitabine. The method comprises the following steps: 1) condensation reaction: reacting 2', 3'-bi-O-acetyl-5'-deoxy-5-fluoro-cytidine with halo n-amyl formate in the presence of an acid applying agent and a dimethylamino-pyridine catalyst to prepare N-pentyloxy carbonyl-2' 3'-bi-O-actyl-5'-deoxy-5-fluoro-cytidine; and 2) hydrolysis reaction: carrying out hydrolysis reaction on N-pentyloxy carbonyl-2' 3'-bi-O-actyl-5'-deoxy-5-fluoro-cytidine in the presence of an inorganic base to prepare the final product capecitabine. Compared with the prior art, the method provided by the invention has the advantages that by taking the inorganic base as the acid applying agent, use of a lot of organic bases is avoided and therefore the yield is improved, the production cost lowered, the environmental pollution is reduced, the physical health of the worker is ensured, and industrial production is facilitated.

A capecitabine key intermediate synthesis method

The invention discloses a synthetic method for capecitabine key intermediate 2`,3`-O-diacetylpyridine-5`-deoxygenation-5-fluorine-N4-[(pentyloxy) carbonyl] cytidine. The synthetic method for the capecitabine key intermediate comprises the following steps that 1, 5- fluorocytosine, an acid-binding agent, chloroform, water and phase transfer catalyst are mixed, pentyl chloroformate is added dropwise under stirring, and the chloroform solution of (5-fluorine-2-oxo-1,2-dihydropyrimidine-4-base) amylcarbamate is obtained; 2, 1,2,3-three-O-acetyl-5-deoxygenation-6- ribofuranose is added into the chloroform solution obtained in the step 1, lewis acid is added dropwise, the reaction is performed for 2-10 hours after adding, and the capecitabine key intermediate is obtained after post-processing. The synthetic method is simple and convenient in operation, a silicane protective agent and intermediate product purification are not needed, the high yield of finished products is achieved, the proportion of alpha isomer in the products is effectively controlled, and compared with literature data, the purity of the obtained products is greatly improved.

Synthesis method of capecitabine intermediate

The invention provides a synthesis method of a capecitabine intermediate. The synthesis method comprises the following steps of performing a reaction on 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine, carbonyldiimidazole and n-pentanol at a low temperature to produce 2', 3'-di-O-acetyl-5'-deoxy-5-fluoro-N4-(n-pentyloxycarbonyl) cytidine. By the synthesis method, the reaction yield is increased, and the yield is higher than or equal to 91%. By the synthesis method, the step is simple, the operation is convenient, few byproducts are produced, and industrial production is facilitated.

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.

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.

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.

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.