Description
Tegafur is an orally bioavailable prodrug form of 5-fluorouracil (5-FU; Item No.
14416).
1 It is converted to 5-FU
in vivo enzymatically or by cytochrome P450 oxidation. Tegafur inhibits proliferation of HT-29, BxPC-3, and Panc02 cells (IC
50s = 201, 172, and 179 μM, respectively).
2 It also reduces tumor growth in an HT-27 colon carcinoma mouse xenograft model when administered at a dose of 50 mg/kg and in a 4-1ST gastric carcinoma mouse xenograft model when used in combination with uracil.
2,3 Formulations containing tegafur, in combination with uracil, have been used in the treatment of cancer.
Originator
Futraful,Taiho,Japan,1974
Manufacturing Process
One process from US Patent 4,107,162: 27.4 g of 2,4-bis(trimethylsilyl)-5-
fluorouracil and 7.7 g of 2,3-dihydrofuran are dissolved in 70 ml of
acetonitrile, and 30 ml of an acetonitrile solution containing 1.3 g of
anhydrous stannic chloride are added thereinto with cooling and stirring. 50
ml of acetonitrile containing 1.3 ml of water dissolved therein are then
dropwise added over 15 minutes. After return to room temperature, the
reaction is further effected with stirring at 40°C for 5 hours. The reaction
mixture is neutralized by adding 1 N aqueous ammonia with cooling and stirring (conversion 83%). After the nondissolved substances are removed by
filtration, the filtrate is concentrated and dried under reduced pressure. 100
ml of water and 300 ml of dichloromethane are added to the residue to
completely dissolve the residue by stirring. The obtained dichloromethane
layer is separated. The water layer is subjected to extraction twice with
dichloromethane. The thus obtained extracts are combined with the separated
dichloromethane layer and the combined extracts, after drying with anhydrous
magnesium sulfate, are concentrated and dried. The obtained residue is
dissolved in ethanol, and the nondissolved substances are removed by
filtration. The filtrate is subjected to recrystallization to give white crystals,
followed by further recrystallization of the mother liquor. There are totally
obtained 15.6 g of N1-(2'-furanidyl)-5-fluorouracil.Yield: 78% of theory, with
respect to 2,4-bis(trimethylsilyl)-5-fluorouracil.
An alternative process from US Patent 3,635,946: A vigorously stirred reaction
mixture consisting of 32.87 g (0.1 mol) of 5-fluorouracilmercury, 100 ml of
dimethylformamide and 50 ml of toluene is dried by azeotropic distillation of
toluene. It is then cooled to -40°C in a stream of dry nitrogen, and a solution
of 21.3 g (0.2 mol) of 2-chlorofuranidin in 20 ml of dried dimethylformamide
is gradually added to the stirred mixture, the temperature being maintained
between -40°C and -30°C. After completion of the reaction (which is marked
by complete dissolution of the starting 5-fluorouracilmercury) i.e. after about
3 to 4 hours, 60 to 80 ml of the solvent are distilled off in vacuo at a bath
temperature not exceeding 35°C. 50 to 70 ml of dry acetone are then added
and also vacuum distilled. The residue is easily crystallized. It is collected,
washed three times with small quantities of ethanol - 10 ml each - and airdried.
12.2 g of N1-(2'-furanidyl)-5-fluorouracil are obtained in the form of
white crystalline solids; melting point 160°C to 162°C. Additional treatment of
the mother liquor yields 3.0 g more of the product. Yield: 75% of theory,
based on the starting 5-fluorouracilmercury.
After recrystallization from ethanol, 14.3 g of N1-(2'-furanidyl)-5-
fluorouracilare obtained, MP 164°C to 165°C.
