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
• Article Data: 21

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

Chemical Properties

White to Off-White Solid

Uses

2’,3’-Di-O-acetyl-5’-deoxy-5-fluoro-N4-(pentoxycarbonxyl)cytidine (cas# 162204-20-8) is a compound useful in organic synthesis.

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 
• 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 
• 37076-71-4 5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranose 
• 71-41-0 pentan-1-ol 
• 530-62-1 1,1'-carbonyldiimidazole 
• 862508-03-0 (5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)carbamic acid amyl ester 
• 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 
• 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

• 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.

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 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.