Toxicity 88-90 phosphorofluoridates

Turning again to primary phosphorofluoridates (R = H), if R is substituted, e.g. in di-(2-chloroethyl) phosphorofluoridates, the toxicity and myotic effect are greatly inferior to those shown by the unsubstituted diethyl phosphorofluoridates. Toxicity is also very low in the aromatic series for example, diphenyl phos-phorofluoridate is non-toxic and devoid of myotic properties. Similar remarks apply to certain sulphur analogues, e.g. diethyl phosphorofluoridodithiolate, POF(SEt)2 (preparation, p. 54). 

The esters of monofluorophosphoric acid are of great interest because of their cholinesterase inhibiting activity which causes them to be highly toxic nerve gases and also gives them medical activity (see Enzyme inhibitors). The most studied is the bis(l-methylethyl)ester of phosphorofluoridic acid also known as diisopropyl phosphorofluoridate [155-91 DFP (5), and as the ophthalmic ointment or solution Isoflurophate USP. It is used as a... 

Brief notes are added on phosphorofluoridates even though their destruction by microbial activity— though clearly possible—is limited by their toxicity to the requisite microorganisms. One of the motivations for their inclusion is the fact that the hydrolytic enzyme(s) responsible for defluorination—organophosphorus acid anhydrase (OPA)—is widespread, and is found in a number of bacteria (Landis and DeFrank 1990). The microbial hydrolysis of organophosphorus pesticides and cholinesterase inhibitors is accomplished by several distinct enzymes, which are collectively termed organophosphorus acid anhydrases (OPAs). These have been reviewed (DeFrank 1991), so that only a few additional comments are necessary. 

We carried out a great deal of work on the relationship between the above physiological effects and chemical constitution, and it was shown conclusively that the more potent compounds were those derived from secondary alcohols.3 Thus, for example, di-isopropyl phosphorofluoridate is very much more potent than diethyl phosphorofluoridate or di-ra-propyl phosphorofluoridate and the toxicity of the dicycZohexyl ester is of a high order (L.C. 50 for mice, rats and rabbits was 0-11 mg./l.). Din-butyl phosphorofluoridate had low toxicity and produced only feeble... 

Furthermore, in the particular type of phosphate molecule under discussion (VI) we showed that when X is fluorine, compounds of high toxicity result whereas myotic effect is absent and toxicity of a low order if X = H, Et, OH, OEt, OCH2CH2C3, OCH2CH2F, Cl, NH2, NHMe, NHPh, CH2CH2F, CN, SON, etc.1 In Chapters rv and vi, however, we consider in more detail cases where X is not fluorine, but nevertheless toxicity results. Toxicity is also of a low order in the aromatic series for example, diphenyl phosphorofluoridate is relatively non-toxic and devoid of myotic properties. We also showed that ethyl phosphoro-difluoridate, (C2H50)P0F2, had neither myotic nor toxic action.1... 

Many of these compounds were toxic for example, tetra-methyl phosphorodiamidic fluoride (dimethylaminofluorophos-phine oxide (VII)) had a l.c. 50 of 0-1 mg./l. Unlike the phosphorofluoridate esters, however, they were devoid of myotic action. 

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... 

Di 2 fluoroethyl phosphorofluoridate (XVIII) was prepared with the idea of combining the toxic principles of the fluoro-aoetates and of the phosphorofluoridates. It was readily obtained by the action of phosphorus oxydichlorofluoride on... 

The compound was therefore much less toxic than the corresponding unsubstituted dicycZohexyl phosphorofluoridate. 

The above proof of the extremely high affinity for cholinesterase of the phosphorofluoridates, especially those with branched-chain alkyl groups, suggested that the toxic and myotic power was due to inhibition of cholinesterase in vivo. Bloch1 showed... 

Structural Requirements for High Toxicity and Myotic Action of Esters of Phosphorofluoridic Acid... 

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. 

In view of the high toxicity and very pronounced myotic effect of di-isopropyl phosphorofluoridate, di ( 1 Z dichlorowo propyl) phosphorofluoridate (XVI) was of special interest. It was prepared from l 3-dichlorohydrin and phosphorus trichloride. It did not have any appreciable myotic effect and the toxicity was of alow order. Di ( 1 -ethylpropyl) phosphorofluoridate (XVII),... 

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.)... 

The myotic, toxic and other physiological properties of the dialkyl phosphorofluoridates, POF(O.R)2, have been fully described on pp. 42, 68 et seq. In 19444 we described an analogous compound of the phosphorofluoridite series, namely, diethyl phosphorofluoridite, PF(OEt)2. This could not be prepared by the action of sodium fluoride on the corresponding diethyl phosphorochloridite (the preparation of which is considered below). We obtained it, however, by the action of ethyl alcohol on phosphorus dichlorofluoride,... 

Diethyl phosphorofluoridite is readily hydrolysed by water. It is only feebly toxic in comparison with the corresponding phosphorofluoridate. Exposure to a concentration of 1 mg./l. 

Nevertheless, there is some similarity of structure between compounds (II) and (IV). It is known that with grem.-diethyl groups in the phosphorofluoridate molecule, e.g. di-(l-ethyl- -propyl) phosphorofluoridate (V), the toxicity is less than with <7em.-dimethyl groups (di-isopropyl phosphorofluoridate (IV)). We found that similarly tetraethylphosphorodiamidic fluoride... 

In view of the rapid toxic action and myotic effect of the dialkyl phosphorofluoridates and of the high toxicity of some of the phosphorodiamidic fluorides, we prepared2 and examined a hybrid molecule containing the essential features of each type of compound. The first to be examined was ethyl phenyl-phosphoramidofluoridate (VII). One mol. of phosphorus oxy-dichlorofluoride was added to 1 mol. of ethyl alcohol, and the resulting ethyl phosphorofluoridochloridate (which it was not necessary to isolate) was treated with aniline. 

It was obviously of interest to determine whether other esters of fluoroacetic acid would prove to be more or less toxic than the methyl ester. In the phosphorofluoridate series, for example, we found that esters of secondary alcohols were far more potent than those of primary alcohols for instance, di-isopropyl fluorophosphonate (I) was a compound of considerable activity. Accordingly ethyl, ra-propyl and isopropyl fluoroacetates were prepared by heating the corresponding esters of chloroacetic acid in the rotating autoclave with potassium fluoride. The toxicity figures of these esters were very similar to those of methyl fluoroacetate. 

In the phosphorofluoridate series, we found that the diphenyl ester (p. 53) was relatively non-toxic. Phenyl fluoroacetate, however, was toxic with an l.d. 50 of 6-10 mg./kg. for subcutaneous injection into mice. The symptoms were similar to those displayed by methyl fluoroacetate. 

The syntheses of dithymidylyl-3, 5 -phosphorofluoridate and phosphorothiof-luoridate (87) and (88) have been described. These involved the fluorinolysis of the P-Se bond in the bis-dimethoxytrityl selenomethyl esters (89) and (90). Compounds (87) and (88) were reported to be hydrolytically unstable, with no inhibitory activity on the snake venom and spleen phosphodiesterases and alkaline phosphatases. Finally, neither was considered as a highly toxic dinuc-leotide. ... 

AI3-16931 Albaphos Dental Na 211 Disodium fluorophosphate Disodium monofluorophosphate Disodium phosphorofluoridate EINECS 233-433-0 NSC 248 Phosphorofluoridic acid, disodium salt Sodium fluorophosphate (NazPOaF) Sodium monofluorophosphate Sodium phosphorofluoridate. A fluorine-containing component for toothpastes, the toxic effects of which are only 1/3 of those of sodium fluoride. Hoechst UK Ltd. 

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