Fluorouracil derivatives

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

Pyridine appears to have the role of protecting acid-labile dihydrofuran and dihydropyran in fluorination reactions however, the resulting fluorinated salts could not be obtained in a pure form due to their oily quality, and were thus converted into 5-fluorouracil derivatives 26.52... 

As in the case of electrochemical reduction, the photochemical transformation of 5-fluorouracil derivatives differs from that of the other 5-halogeno uracils. The primary photoproduct of 5-fluorouracil, its glycosides and poly(5-FU) is the photohydrate. However, at shorter wavelengths of irradiation, e.g. 254 nm where the photohydrate exhibits absorption, there is elimination of HF from the 5,6 bond and formation of barbituric acid 129 13I>. There is also some evidence for acetone photosensitized formation of cyclobutane dimers of 5-fluorouracil132), as well as dimer formation in irradiated poly(5-FU)133>. 

Fluoro-6-hydroxy-5,6-dihydrouracil derivatives 4451.456.457,459.463 an(j 5458.468 can Syn thesized by fluorination of the corresponding uracil derivatives with fluorine in the presence of water448,451,4 54-459-463 468-469 or with l-(chloromethyl)-4-fluoro-l,4-diazabicyclo[2.2.2]oc-tane bis(tetrafluoroboratc) in the presence of water.712 These compounds are of interest because they are intermediates in the synthesis of the corresponding 5-fluorouracil derivatives which can be prepared by a dehydration reaction. 

Uracil undergoes addition of trifluoromethyl hypofluorite at — 78 CC and this adduct reacts with triethylamine to give 5-fluorouracil (13, X = O R = H).396 Other 5-fluorouracil derivatives 13, important fluoronucleic bases and fluoronucleosides, can be prepared in an analogous... 

Electrolysis of A-carbamoylaspartic acid or A-ethoxycarbamoylaspargine in MeOH-MeONa-(C) affords the corresponding methoxylated products [140], A 5-fluorouracil derivative (LXIII), a potent antitumor agent, can be prepared via electrolytic methoxylation of A-acylazacycloalkane-2-carboxylic acids (LXI) in MeOH-MeONa-(C) and subsequent condensation of (LXII) with 2,4-bis-(trimethylsilyl)-5-fluorouracil (TMS-5-FU) [Eq. (31)] [133,141]. Recently, the decarboxylative methoxylation of o -amino acids has been extended to prepare useful chiral building blocks [127-130]. 

Zhang, G., Moore, D.J., Sloan, K.B., Flach, C.R. and Mendelsohn, R. (2007) Imaging the prodrug-to-drug transformation of a 5-fluorouracil derivative in skin by confocal Raman microscopy. J. Invest. Dermatol, 127, 1205-9. 

Several 5-fluorouracil derivatives having oxacycloalkane moieties also exhibit significant antitumor activity. Thus, fluorouracil derivative (85) has been prepared by the reaction of trimethyl-silyloxy acetal (84) with SnCU and 5-fluoro-substituted pyrimidine base (81), but this reaction gave only 28% of (85) together with 45% of acyclic product ( ) <80JAP55130975,81TL1029>. 

A pol mer-drug conjugate is obtained by the reaction of a chlorinated poly(phosphoester) with the 5-fluorouracil derivative in the... 

Studies on the mechanism of inhibition of thymidine phosphorylase by 6-substituted-5-fluorouracil derivatives... 

Pyrrolo[2,l-a]isoquinoline derivatives (27) were synthesized using Cgo-Bodipy dyads (28) as excellent photosensitizers (Scheme 13)/ Direct irradiation of glycine methyl ester to Ceo afforded [3 - - 2] cycloadduct/ Akasaka and his coworkers found the photocycloaddition of 2-ada-mantane-2,3-[3ff]diazirine and disilyliranes to Cso-metallofullerenes/ Intra- and inter-molecular photocycloaddition of alkenes to coumarin, quinolone, and isoquinolone derivatives have been reported by several groups. Griesbeck et al. found that the intramolecular photocycloaddition of cyclohexene moiety to coumarin (29) was catalysed by molecular ojygen. [2 + 2] Photocross dimer (33) of coumarin derivative (31) and 5-fluorouracil derivative (32) was obtained by laser irradiation/ Bach reported enantioselective intramolecular photocycloaddition of coumarins (34) to alkenes catalysed by a chiral Lewis acid (36) (Scheme 14)/ ... 

Alvarez P, Marched JA, Boulaiz H, Carrillo E, Velez C, Rodtfguez-Serrano E, Melguizo C, Prados J, Madeddu R, Aranega A (2012) 5-fluorouracil derivatives a patent review. Expert OpinTher Pat 22 107-123... 

Ozaki S (1996) Synthesis and antitumor activity of 5-fluorouracil derivatives. Med Res Rev 16 51-86... 

Sugimachi K, MaeharaY (2000) A phase 11 trial of a new 5-fluorouracil derivative, BOF-A2 (Emitefur), for patients with advanced gastric cancer. Surg Today 30 1067-1072... 

Iwasaki T, Nishitani T, Hoiikawa H, Inoue I (1981) A novel synthesis of 5-fluorouracil derivatives having oxacycloalkane moieties. Tetrahedron Lett 22 1029-1032... 

Ozaki S, Ike Y, Mizuno H, Ishikawa K, Mori H (1977) 5-fluorouracil derivatives. I. The synthesis of l-carbamoyl-5-fluorouracils. Bull Chem Soc Jpn 50 2406-2412... 

Hirohashi M, Kido M, Yamamoto Y, Kojima Y, Jitsukawa K, Fuji S (1993) Synthesis of 5-fluorouracil derivatives containing an inhibitor of 5-fluorouracil degradation. Chem Pharm Bull 41 1498... 

On the other hand, the most potent among these in the cytosine series are DMDC (3a) and FDMDC (3b), the cytotoxicities of which are comparable to that of SMDC (li). It is important to note that FDMDC would act as a 5-fluorocytosine derivative but not as a 5-fluorouracil derivative via the deamination by cytidine deaminase since DMDC was reported not to be a substrate of cytidine deaminase from mouse kidney.33 The 5-methylcytosine derivative 3f was about 170 times less active than DMDC and FDMDC. The other 5-halogeno- and 5-ethyl derivatives, 3c-e and h, were found to be devoid of the activity. Therefore, it is conceivable that the order of cytotoxicity might be related to the substrate specificity of the first activation enzymes, such as thymidine kinase or deoxycytidine kinase. 

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