A new method for the synthesis of 5-fluorouracil prodrugs

Synlett

Volumn , Issue 11, 1999, Pages 1829-1831

  Jolimaître, Pascale ^a   André Barres, Christiane ^a   Malet Martino, Myriam ^a   Martino, Robert ^a   Rico Lattes, Isabelle ^a  

^a Université Paul Sabatier   (France)

Author keywords

Artificial nucleosides; BROP; N1 retinoyl 5 fluorouracil; Prodrug

Indexed keywords

FLUOROURACIL DERIVATIVE; PRODRUG;

ARTICLE; CHEMICAL REACTION; DRUG PURIFICATION; DRUG SOLUBILITY; DRUG STABILITY; DRUG STRUCTURE; DRUG SYNTHESIS; REACTION ANALYSIS;

EID: 18244421652     PISSN: 09365214     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-1999-2938     Document Type: Article

References (16)

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10. Typical experimental procedure for both methods: Method 1: in a first step, reaction of a suitable acid (1.5 mmol) with oxalyl chloride (7.5 mmol) in dry toluene (20 ml) for 1 hour led to the desired acid chloride. At the same time, stirring FU (1.02 mmol) with potassium hydroxyde (1 mmol) in methanol (5 ml) for 30 minutes gave the potassium salt of FU. In a second step, the acid chloride was added dropwise to a solution, refrigerated at 0°C, containing the white residue of FU potassium salt in acetonitrile (10 ml). The mixture was then stirred at room temperature for 4 hours. Method 2: the carboxylic acid (1 mmol) and FU (1.5 mmol) were dissolved in anhydrous DMF (35 ml), and stirred at 0°C. Triethylamine (3 mmol) and BROP (1.5 mmol) were added. The mixture was then stirred at 0°C for 2 hours.
11. 3F: C, 61.51; H, 8.07; N, 8.97. Found: C, 61.46; H, 7.95; N, 8.98. White solid: mp 92°C.
12. +, 265 (loss of one FU molecule). Viscous oil.
13. 3F: C, 56.68; H, 5.95; N, 11.02, Found: C, 56.83; H, 6.04; N, 10.98. White solid: mp 77°C.
14. +, 283 (loss of one FU molecule). Orange solid: mp 151°C.
15. Coste, J.; Dufour, M.J.; Pantaloni, A.; Castro, B. Tetrahedron Lett. 1990, 31, 669.
16. Using another coupling reagent, bromo-tris-pyrrolidino-phosphonium-hexafluorophosphate, can prevent the formation of HMPA, which is very toxic. The by-product formed is tris-pyrrolidinophosphoramide and the yields are close to those obtained with BROP.