Y-fluorobutyrate

From a study of the fluoroacetates so far mentioned, it appears that any compound which can give rise to fluoroacetic acid (or the fluoroacetate ion), either by hydrolysis or by oxidation (or both), is toxic. The toxic grouping is thus F-CH2-CO, and any substitution in this radical destroys the toxicity as far as relatively simple compounds are concerned. We had reached this conclusion by May 1943.1 We subsequently showed that esters of / -fluoropropionic acid were non-toxic, whereas esters of y-fluorobutyric acid were shown by American workers to be toxic. In 19442 we reported the synthesis of ethyl 5-fluoro-pentanecarboxylate, F,[CH2]g C02Et (I). This is a stable, colourless liquid and we showed that it possessed very potent toxic properties of the fluoroacetate type. By subcutaneous injection of the propylene glycol solution into mice the l.d. 50 was 4 mg./kg. Methyl fluoroacetate (II) may be taken as a convenient standard (p. 115) and has a l.d. 50 of about 6 mg./kg. for saline solutions, and 15 mg./kg. for propylene glycol solution.3 Therefore ethyl 5-fluoropentanecarboxylate was about 7 times as toxic as methyl fluoroacetate (molecule for molecule).4... 

The very high toxicity of ethyl 5-fluoropentanecarboxylate and its derivatives and the fluoroacetate-like symptoms produced seemed to us to be of particular interest, since by a process of /9-oxidation in the animal body 5-fluoropentanecarboxylic acid would readily give rise to the toxic fluoroacetic acid. Similar remarks apply to y-fluorobutyric acid and its derivatives prepared independently by American workers. The non-toxicity of /9-fluoropropionic acid and its derivatives may, on the other hand, be due to the inability of this acid to give the toxic fluoroacetic acid by a process of /9-oxidation. 

Although our results support the / -oxidation theory, one point must not be overlooked, namely, that fluoroacetic acid is not the actual toxic agent and has to be converted into fluoro-citrate before exerting its activity (see p. 142). It should also be noted that American workers1 showed that both methyl y-fluorobutyrate and methyl -fluorocrotonate,... 

The synthesis of (XVIII), (XIX), (XX) and (XXI) from methyl fluorocrotonate was accomplished according to the annexed scheme. Methyl y-fluorocrotonate had previously been prepared, and was reported by Kharasch and his co-workers to be a highly toxic compound. It possesses the carbon structure of methyl y-fluorobutyrate, and the double bond in the opposition would undoubtedly facilitate oxidation. The American workers prepared methyl y-fluorocrotonate by an ingenious five-stage process from epifluorohydrin. For the above syntheses we... 

The y -oxidation of the highly toxic ethyl y-fluorobutyrate could presumably be stopped by effectively blocking the yff-position in the chain. A simple compound satisfying this condition was ethyl y flmro fifi dimethylbutyrate,... 

Structurally, the prevention of y -oxidation was achieved by two means (a) side-chain inhibition and (6) ring inhibition, (o) The / -oxidation of the highly toxic ethyl y-fluorobutyrate could presumably be stopped by effectively blocking the / -position in the chain. A simple compound satisfying this condition was ethyl y-fiuoro- -dirneihylbutyrate, CH -CMe,-CH,-CO,Et,... 

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