Cryptand Kryptofix

In the early days of fluorine-18-chemistry the low reactivity of p F]fluoride ion in aqueous solution constituted a major obstacle to the advance of nucleophilic radiofluorination with high specific radioactivity, a problem that would later be solved with the introduction of the cryptand Kryptofix-222 , giving the highly reactive K[ F]F-K222 complex (see Section 4.1) [3], For this reason active research for anhydrous reactive fluorine-18 labelling species continued. Scheme 1 reviews a number of these early reagents. 

To monitor tumor response to capecitabine therapy noninvasively, Zheng and co-workers, from the Indiana University School of Medicine, developed the synthesis of the fluorine- 18-labeled capecitabine as a potential radiotracer for positron emission tomography (PET) imaging of tumors.28 Cytosine (20) was nitrated at the C-5 position with nitric acid in concentrated sulfuric acid at 85°C, followed by neutralization to provide 5-nitrocytosine (27) in moderate yield. This nitro pyrimidine was then carried through the glycosylation and carbamate formation steps, as shown in the Scheme below, to provide the 6/s-protected 5-nitro cytidine 28 in 47% for the three-step process. Precursor 28 was then labeled by nucleophilic substitution with a complex of 18F-labeled potassium fluoride with cryptand Kryptofix 222 in DMSO at 150 °C to provide the fluorine-18-labe led adduct. This intermediate was not isolated, but semi-purified and deprotected with aqueous NaOH in methanol to provide [l8F]-capecitabine in 20-30% radiochemical yield for the 3-mg-scale process. The synthesis time for fluorine-18 labeled capecitabine (including HPLC purification) from end of bombardment to produce KI8F to the final formulation of [18F]-1 for in vivo studies was 60-70 min. 

F is often introduced by nucleophilic displacement using potassium fluoride with the cryptand Kryptofix... 

In any case, it may be asserted that free ions play a decisive role at high temperatures and in media of high permittivity, while at low temperatures and in low polar media, the involvement of ion pairs is more influential. A significant inaease in dissociation (i.e., conductivity) and in the rate of polymerization of some lactams has been observed by addition of the cryptand Kryptofix[2.2.2], namely 4,7,13,16,21,24-hexaoxa-l,10-diazabi-cyclo[8.8.8]-hexacosane (26) to 2-pyrrolidone and 2-piperidone ... 

In the case of Kryptofix 221D, a cryptand able to complex the alkali metal cations [141-143], it has been observed that it is solubilized mainly in the palisade layer of the AOT-reversed micelles. And from an analysis of the enthalpy of transfer of this solubilizate from the organic to the micellar phase it has been established that the driving force of the solubilization is the complexation of the sodium counterion. In addition, the enthalpy... 

Since non-bound or non-coordinated nucleophiles are even more reactive, crown-ethers [138] and cryptands (polyaminoethers) [139,140] have been used to chelate the alkali metal cations, notably the potassium ion of K[ F]F. This allows the [ F]fluoride anion to be less tightly paired with the cation and therefore to be more reactive, which has been coined the naked ion effect. In practice, the crown-ether (e.g. 18-crown-6) or better the polyaminoether Kryptofix-222 (4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane) is added to the aqueous K[ F]F/K2C03 solution which is then concentrated to dryness [139,140]. The complex (KP FIF-K ) can be further dried, if needed, by one or more cycles of addition of dry acetonitrile and azeotropic evaporation. 

---