Phosphorofluoridates myosis

Combination of fluoroacetate activity and certain other recognizable physiological effects have been successfully combined in fluoroaspirin (drugged sleep), triethyl-lead fluoroacetate (sternutation), difluoroethyl phosphorofluoridate (myosis, but not powerful). In general, quaternary ammonium... 

As a matter of interest, we obtained a compound, diethyl phosphorofluoridite (IX), of a lower state of oxidation than the corresponding phosphorofluoridate by the action of phosphorus dichlorofluoride on ethyl alcohol. The new compound, unlike the phosphorofluoridate, was readily hydrolysed by water, was relatively non-toxic and did not produce myosis.1... 

We found that the toxicity and myotic activity of di-isopropyl phosphorofluoridate (XI) were far greater than that of di- propyl phosphorofluoridate. In Report no. 6 on fluoro-phosphonates to the Ministry of Supply3 we described the preparation of di aec.-butyl phosphorofluoridate (XII) by the hydrogen phosphite method (p. 6). The compound was found to be very toxic and to produce severe myosis in man and animals. The symptoms displayed during and after exposure were identical with those produced by di-isopropyl phosphorofluoridate. The L.c. 50 for di-sec.-butyl phosphorofluoridate for mice for deaths within 2 hr. was 0-6 mg./l., and that for deaths within 48 hr. was 0-54 mg./l. 

Negligible sensory irritation was caused by di-isopropyl phosphorofluoridate at a concentration of 1 part in 10. This, coupled with the fact that the odour was practically undetectable, means that sufficient warning is not usually given at this concentration to suggest the use of respirators. Exposures at this concentration cause severe myosis which persists for several days and causes considerable incapacitation (Report no. 12 by McCombie and Saunders to Ministry of Supply, 4 August 1943). 

Di (l carbethoxyethyl) phosphorofluoridate (XV) was readily produced by the action of sodium fluoride on the corresponding phosphorochloridate obtained from di-(l -carbethoxyethyl) hydrogen phosphite, which in turn was obtained by the action of phosphorus trichloride on ethyl lactate. Although (XV) contained secondary groupings, it was found to be relatively nontoxic and to produce only slight myosis in the pupils of the eyes of rabbits and guinea-pigs. 

It was important to determine whether the fluorine atom must be attached directly to the phosphorus atom in order to produce phosphorofluoridate-like activity. For this purpose we treated the toxic di-sec.-butyl phosphorofluoridate1 with diazomethane and obtained a compound which was undoubtedly di- ec.-butyl fluoromethylphosphonate (XIX). Unlike the parent phosphorofluoridate, the fluoromethylphosphonate was only slightly toxic and produced negligible myosis. (It may be mentioned here that thionyl chloride and carbonyl chloride were converted by means of diazomethane into bis-(chloromethyl)-sulphoxide and S-dichloroacetone respectively.)... 

In view of the greater toxicity often observed with derivatives of o-cresol compared with derivatives of phenol itself, it seemed worth while to prepare di-(o-methylcycfohexyl) phosphorofluoridate. At a concentration of 0-65 mg./l. only three out of a batch of twenty-three animals (rabbits, guinea-pigs, rats and mice) were killed. The animals which died (the rabbits) exhibited muscular twitchings, but myosis was not very marked. 

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