Fluorination process of anilide derivatives and benzothiazole fluorinate derivatives as in vivo imaging agents

#This application is a filing under 35 U.S.C. 371 of international application number PCT/GB2006/003009, filed Aug. 11, 2006, which claims priority to application number 0516564.2 filed Aug. 12, 2005, in Great Britain the entire disclosure of which is hereby incorporated by reference.

#The present invention relates to novel processes for fluorination, particularly [18F]fluorination of certain aromatic compounds, and to the novel precursors used in the process. The invention has particular utility for a class of benzothiazole derivatives which are known as in vivo imaging agents.

#Fluorination of aromatic compounds may be performed via electrophilic reaction with molecular fluorine, however, electrophilic fluorination of aromatic compounds with fluorine is generally a poor and non-selective method. Different electrophilic fluorinating reagents prepared from molecular fluorine, such as CH3COOF “AcOF” have been developed but suffer several drawbacks. For [18F]radiofluorination, the harsh conditions, and poor availability of electrophilic [18F]fluorination methods, and the low specific activity of the products obtained mean that it is not a favoured approach for commercial production of [18F]-labelled products. Nucleophilic fluorination methods, using fluoride are more commonly used. [18F]Fluoride is a more widely available reagent than the electrophilic reagents and the products obtained are of higher specific activity which is advantageous in the field of in vivo imaging. Nucleophilic fluorination of aromatic rings, particularly those which are electron rich can be problematic. For example, nucleophilic fluorination of anilines, where the amino group adds to electron density of the aromatic ring is difficult to perform. The present invention provides a precursor suitable for nucleophilic fluorination to give a fluorinated aniline, which combines a number of beneficial effects including improved activation of the aromatic ring to fluorination, few steric effects on the fluorination reaction, and facile conversion to the fluorinated aniline product.

#4-Acetamido-3-nitrobenzoic acid 1 (Alfa Aesar, 5.6 g, 25 mmol), oxalyl chloride (4.76 g, 38 mmol), chloroform (50 ml), DMF (few drops) were stirred at 40° C. for 3 hours. The solvent was removed in vacuo to give a yellow solid that was used in the next step without further purification.

#2-Amino-6-methoxy-benzothiazole 10 g (55.6 mmol) was suspended in 25% aqueous potassium hydroxide and the mixture heated under reflux for 24 h. The pale yellow solution was cooled and acidified to pH 6 with firstly aqueous 6N HCl then acetic acid. The precipitated solid was filtered, washed with water (3×100 ml), dried (high vac.) to afford the desired material as a pale yellow powder 8.18 g, 95%.

#5-Methoxy-2-aminobenzenethiol 3 (3.88 g, 25 mmol), pyridine (100 ml), and DMAP (few crystals) were stirred at room temperature.