Citicoline sodium synthesis
- Product Name:Citicoline sodium
- CAS Number:33818-15-4
- Molecular formula:C14H26N4O11P2.Na
- Molecular Weight:511.31
987-78-0
33818-15-4
2-(((((((2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)oxophosphoryl)oxy)-N,N,N-trimethylethanaminium was used as a raw material to synthesize 2-((((((2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)oxophosphoryl)oxy)-N,N,N-trimethylammonium ethyl. -amino-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)oxidizedphosphoryl)oxy)-N,N,N-trimethylethane-1-ammonium sodium salt (1:1) in the following general procedure: CMP (100 mg, 0.31 mmol) was prepared in DMF (2 mL) and tributylamine (150 μL , 0.62 mmol) in a free acid-stirred suspension was heated at 50 °C for 10 min and subsequently cooled to room temperature. Upon addition of CDI (250 mg, 1.55 mmol), the suspension changed to a clarified solution within minutes. The reaction mixture was stirred anhydrically at room temperature for 30 min, followed by treatment with anhydrous methanol (100 μL, 2.48 mmol) to hydrolyze the excess of CDI.After 30 min, anhydrous zinc chloride (59 mg, 0.43 mmol) was added, followed by choline phosphate solution (0.77 M anhydrous DMF solution, 2 mL, 1.55 mmol). The reaction mixture was stirred at room temperature for 24 hours. After evaporation of the solvent in vacuo, CDP-Cho 5 was purified by anion-exchange chromatography.The residue was dissolved in water and purified by ion-exchange column chromatography on a Sephadex DEAE A-25 resin using a linear gradient elution of 0-0.5 M ammonium bicarbonate, followed by chromatographic separation on an RP-18. Triethylammonium counterbalance ions were exchanged for sodium ions by passing the nucleotide solution through a Dowex 50WX8 column. Freeze-drying gave 1-(β-D-ribofuranosyl)cytosine-5'-diphosphorylcholine (sodium salt) as a white solid (115 mg, 74% yield). hplc: tR = 8.8 min (λmax 276 nm); 1H NMR (400 MHz, D2O) δ 7.86 (d, 1H, H6, J6-5 = 7.6 Hz), 6.04 ( d, 1H, H5, J5-6 = 7.6 Hz), 5.92 (d, 1H, H10, J10-20 = 4.0 Hz), 4.31 (sl, 2H, CH2-O), 4.28-4.08 (m, 5H, H2O H30H40H50 and H50b), 3.60 (t, 2H, CH2-N, J = 4.2 Hz), 3.14 ( s, 9H, CH3); 13C NMR (101 MHz, D2O) δ 166.2 (s, C4), 157.7 (s, C2), 141.4 (s, C6), 96.6 (s, C5), 89.3 (s, C10), 82.6 (d, C40, JC-P = 8.9 Hz), 74.1 (s, C20), 69.3 (s C30), 65.9 (s, CH2N), 64.7 (d, C50, JC-P = 5.1 Hz), 59.9 (s, CH2O), 53.9 (s, CH3); 31P NMR (162 MHz, D2O) δ 11.35 (d, 2Jab = 21.4 Hz), 12.14 (d, 2Jab = 21.4 Hz); HRMS (ESI) m/z: [M + H]+ C14H26N4O11NaP2 calculated value 511.0971, measured value 511.0973.
987-78-0
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33818-15-4
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Yield:33818-15-4 115 mg
Reaction Conditions:
with sodium 2,2,2-trifluoroacetate;triethylamine carbonateInert atmosphere;
Steps:
1-(b-D-Ribofuranosyl)cytosine-50-diphosphate choline (5)
A stirred suspensionof the free acid of CMP (100 mg, 0.31 mmol) in DMF (2 mL) and tributylamine(150 lL, 0.62 mmol) was heated for 10 min at 50 °C and allowed to cool at room temperature. Then, CDI (250 mg, 1.55 mmol) was added and the suspension turned to a clear solution after a few minutes. The anhydrous reaction mixture was stirred for 30 min at room temperature and treated with anhydrous methanol (100 lL, 2.48 mmol) to hydrolyze the CDI excess. After 30 min, anhydrous zinc chloride (59 mg, 0.43 mmol) was added followed by a solution of choline phosphate (0.77 M solution in anhydrous DMF, 2 mL,1.55 mmol). The reaction mixture was stirred for 24 h at room temperature. After evaporation of the solvents in vacuo, CDP-Cho 5 was puried by anion-exchange chromatography. The residue dissolved in waterwas puried bySephadex DEAE A-25 resin ion exchange column chromatography with a linear gradient 0-0.5 M of ammonium bicarbonate, followed by chromatography on RP-18. The triethylammonium counter ions were exchanged to sodium by passing the nucleotide solution through a Dowex 50WX8 column. 1-(b-D-ribofuranosyl)cytosine-5'-diphosphate choline (sodium salt) was obtained as a white solid after freeze-drying (115 mg, 74% yield). HPLC: tR = 8.8 min (kmax276 nm); 1H NMR (400 MHz, D2O) d 7.86 (d, 1H, H6, J6-5 = 7.6 Hz), 6.04 (d, 1H,H5, J5-6 = 7.6 Hz), 5.92 (d, 1H, H10 , J10 -20 = 4.0 Hz), 4.31 (sl, 2H, CH2-O), 4.28-4.08(m, 5H, H20 H30 H40 H50 a H50 b), 3.60 (t, 2H, CH2-N, J = 4.2 Hz), 3.14 (s, 9H, CH3); 13CNMR (101 MHz, D2O) d 166.2 (s, C4), 157.7 (s, C2), 141.4 (s, C6), 96.6 (s, C5),89.3 (s, C10), 82.6 (d, C40, JC-P = 8.9 Hz), 74.1 (s, C20), 69.3 (s, C30), 65.9 (s, CH2N),64.7 (d, C50, JC-P = 5.1 Hz), 59.9 (s, CH2O), 53.9 (s, CH3); 31P NMR (162 MHz, D2O) d 11.35 (d, 2Jab = 21.4 Hz), 12.14 (d, 2Jab = 21.4 Hz); HRMS (ESI) m/z:[M+H]+ Calcd for C14H26N4O11NaP2 511.0971. Found 511.0973.
References:
Ghezal, Salma;Thomasson, Maggie S.;Lefebvre-Tournier, Isabelle;Périgaud, Christian;Macnaughtan, Megan A.;Roy, Béatrice [Tetrahedron Letters,2014,vol. 55,# 38,p. 5306 - 5310] Location in patent:supporting information
63-37-6
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4826-71-5
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33818-15-4
509 suppliers
$21.00/1g
1310-73-2
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33818-15-4
509 suppliers
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