N -Nitroso derivative

Cupferron, the ammonium salt of the N-nitroso derivative of phenylhydr-oxylamine, is prepared by passing ammonia gas into an ethereal solution of phenylhydroxylamine and n butyl nitrite ... 

Treatment of piperidine with nitrous acid affords the N-nitroso derivative (190) reduction gives the corresponding hydrazine (191). Condensation of this intermediate with the carbamate (192) obtained from p-toluenesulfonamide leads to the oral hypoglycemic agent tolazemide (193). In a similar vein, reaction of the hydrazine obtained by the same sequence from azepine (194) with the carbamate, 188, gives azepinamide (195). ... 

Therefore, the N-nitroso derivative must be denitrosated to make the process economical as well as avoid high concentrations of the N-nitroso derivative in the product. The preferred method of nitration and denitrosation of... 

Secondary and tertiary amines are not generally prepared in the laboratory. On the technical scale methylaniUne is prepared by heating a mixture of aniline hydrochloride (55 parts) and methyl alcohol (16 parts) at 120° in an autoclave. For dimethylaniline, aniline and methyl alcohol are mixed in the proportion of 80 78, 8 parts of concentrated sulphuric acid are added and the mixture heated in an autoclave at 230-235° and a pressure of 25-30 atmospheres. Ethyl- and diethyl-aniline are prepared similarly. One method of isolating pure methyl- or ethyl-aniline from the commercial product consists in converting it into the N-nitroso derivative with nitrous acid, followed by icducticm of the nitroso compound with tin and hydrochloric acid ... 

A similar mechanism was invoked by Ohshima and Kawabata (2) to account for their results in the nitrosation of tertiary amines and amine oxides. In applying these concepts to the nitrosative dealkylation of tetraalkyltetrazenes, Michejda al. 5) introduced an interesting variant by suggesting that immonium ions could be formed in two successive one-electron oxidation steps (for example by ferric ion oxidation of tertiary amine to the radical cation followed by radical abstraction of a hydrogen atom from the alpha position), rather than exclusively through the one-step removal of a hydride ion as nitroxyl. The resulting immonium ion was again considered to react directly with nitrite to produce the N-nitroso derivative. These reactions are summarized in Fig. 2b. 

Figure 4. Proposed mechanism of formaldehyde action in promoting conversion of primary amines to N-nitroso derivatives...

Several other 8-hydroxynitrosamines have been or are likely to be found in environmental samples. Among these are N-nitroso-3-hydroxypyrrolidine X (l ) (found in bacon), N-nitrosobis(2-hy-droxypropyl)amine XI (a potent pancreatic carcinogen in hamsters, the amino progenitor of which is used in many of the same applications as diethanolamine) (16), and the N-nitroso derivatives of the common drugs ephedrine XII (17) and ethambutol XIII (18), both of which have been shown to be carcinogenic. 

Although additional data would be desirable for all three of these relationships, there seems little doubt that they are real and that structure-activity relationships can therefore probably be generated for additional subclasses of N-nitroso derivatives given sufficient quantitative data. 

Some amines react very rapidly with nitrite in aqueous solution, which limits the interpretation which can be placed on the results of testing the combination in drinking water such compounds are better tested in food. Other amines are too insoluble in water to ensure administration of an adequate dose to the animals, The doses that can be administered are somewhat restricted, since no more than 0.2% of nitrite in food or water can be given to rats without risking induction of often fatal methemoglobinemia. The dose of amine given simultaneously is such that there is a ratio of amine to nitrite between 1 to 2 and 1 to 4, which favors formation of N-nitroso derivatives and ensures effective utilization of nitrite. 

In Table 1 is a list of the environmental secondary and tertiary amines which have been tested by feeding to rats together with nitrite. Of these, several react very readily with nitrite in acid solution, but some, for example phenmetrazine (2 , 27), give rise to a noncarcinogenic N-nitroso derivative. On the other hand, aminopyrine reacts extremely readily with nitrous acid, although it is a tertiary amine, and forms the potent carcinogen nitrosodimethylamine in high yield (28, ). The other amines vary considerably in the extent to which they form N-nitroso derivatives by reaction with nitrous acid, especially at the relatively low concentrations which model human exposure more closely... 

Chemists have long been aware that amines can react with various nitrosating agents, under a variety of conditions, to form a wide array of N-nitroso derivatives (1 ). It was generally assumed that only secondary amines can effectively form stable N-nitrosamines. However, it has now become apparent that primary and tertiary amines, as well as tetraalkylammonium salts, can all form N-nitroso derivatives under the appropriate reaction conditions (2-10). It has also become apparent that there are several mechanisms possible for the formation of the most common N-nitroso derivatives. Thus, in addition to the more customary reaction of an amine with nitrous acid, N-nitroso derivatives can also form via the reaction of an amine with NO (NO2, N2O3, N2O4) ( ). Amines can also be transnitrosated with already formed N-N-nitroso or C-nitro compounds via a transnitrosation reaction, they can be converted into their N-nitroso derivatives ). 

By comparison with other areas of consumer products, relatively little is known about the possible presence of N-nitroso derivatives in pharmaceuticals. Eisenbrand et, have reported on the presence of dimethylnitrosamine in all 68 samples of aminopyrine analyzed in Germany (23). They suggested that DMN could have been formed in various drug formulations by two main routes. One was by the in situ reaction of aminopyrine with nitric oxides in the air, and the other involved the synthetic process used in the manufacturing process itself (23). The levels of DMN found ranged from less than 10 ppb to just under 400 ppb. It has been found for several years that animals fed aminopyrine and sodium nitrite in their diets show the formation of malignant tumors (24, 25). In view of the presence of substantial amounts of DMN in the... 

For the over-the-counter formulations, two of the thirty-nine items tested contained TEA responsive materials. For these tvo instances, exposure of the organic extracts to glacial acetic acid alone led to the complete disappearance of the TEA responsive materials (34). This observation suggests that the unknown materials are probably not simple N-nitroso derivations, and the results are more compatible with their being O-nitroso compounds (nitrites) (34h... 

In the presence of nitrogen dioxide, the reaction proceeds differently, and the N-nitroso derivative is formed. When 99% nitric acid is used together with N02, a mixture of di- and trinitro nitroso derivative is produced, while 40% nitric acid gives only a dinitro derivative... 

Dinttro-N-nitroso-diphenylamine [called Bis-(2-nitrophenyl)-nitrosamin in Gef], 03N.C6H4.N.N0.C(iH.4.N02 not obtd in pure state dec in ale to 2,2l-Dinitro-DPhA obtd with the 2,4l-Dinitro-N-nitroso deriv by nitrating 2-nitro-N-nitroso-diphenylamine in glac acet ac with nitric acid below 10° (Ref 1) 2,4>-Dinitro N-nitroso-diphenylamine,... 

Hunold, SS 33, 213, 244(1938) CA 32, 9501(1938) (Prepn St formation of DPhA Dinitto-N-nitroso derivs) 7) W.A. Schroeder et al, IEC 41, 2818(1949) CA 44, 1707(1950) (Nitro-nitroso derivs of DPhA formed in double base proplnts during accelerated aging)... 

Monosubstituted amides can be converted into N-nitroso derivatives by use of a sufficiently powerful nitrosating agent, such as ni-... 

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