4-(Trifluoromethoxy)aniline (CAS 461-82-5) is a versatile trifluoromethoxy-substituted aromatic amine used in pharmaceuticals, agrochemicals, and specialty materials. 4-(Trifluoromethoxy)aniline is used in the synthesis of anticancer agents and antitumor medicaments. Also, its an intermediate in the production of labelled Riluzole, a neuroprotective agent.

Synthesis of 4-(Trifluoromethoxy)aniline

(1) Add 1 mol of trifluoromethoxybenzene and anhydrous DMSO to the reaction vessel under argon and vigorous stirring. Then add sodium ferrate and sodium bromide as auxiliary reaction mixture, heat to 95 ° C for 4 h, then add sodium amide, The temperature was raised to 155 ° C, the reaction pressure was raised to 4 atm, and the reaction was continued for 10 h; The ratio of trifluoromethoxybenzene to sodium amide is 1:4.5, The ratio of the amount of the trifluoromethoxybenzene to the auxiliary reaction mixture was 1:1.4. The ratio of sodium ferrate to sodium bromide is 1:1. (2) After cooling the system, pour it into 8 volumes of water. The extract was extracted with 4 times the original reaction volume of chloroform, and the extract was washed with water and dried over anhydrous sodium sulfate. Then concentrated to give the product 4-(Trifluoromethoxy)aniline in a molar yield of 98.2%, HPLC purity 97.7%.[1]

Expanding the Diversity of Allosteric Bcr-Abl Inhibitors

Inhibition of Bcr-Abl kinase activity by imatinib for the treatment of chronic myeloid leukemia (CML) currently serves as the paradigm for targeting dominant oncogenes with small molecules. In sharp contrast to the range of functionality that was tolerated at the pyrimidine C4-position, very few replacements to the 4-trifluoromethoxyaniline were tolerated at the pyrimidine C6-position. For example, replacement of the aniline NH with an N-methyl substitution or oxygen or direct phenyl ring connection resulted in a complete loss of cellular activity, suggesting that this group maybe responsible for a critical contact with the enzyme. N-Methyl substitution was chosen as the modification to prepare the negative control for both the affinity chromatography and NMR-binding studies. Similarly, regioisomeric m-4-(Trifluoromethoxy)aniline or p-4-(Trifluoromethoxy)aniline substituted compounds were completely inactive. Scientists created a series of compounds that would be structurally similar but exhibit different preferences for cis or trans conformations due to potential steric interactions between ortho position of the p-trifluoromethoxyaniline ring and the pyrimidine C5 in the cis-conformation.  Scientists demonstrate that the 4-(Trifluoromethoxy)aniline is an obligate structural feature for achieving submicromolar potency as a cellular Bcr-Abl inhibitor but that the pyrimidine ring can be elaborated to include a variety of other heterocyclic ring systems.[2]

The metabolism of 4-(Trifluoromethoxy)aniline in the rat

Given the importance of substituted anilines in the production of a wide range of pharmaceuticals, pesticides and other industrial chemicals, there is widespread potential for human and animal exposure to these chemicals. We were therefore interested to see whether 4-(Trifluoromethoxy)aniline and its acetanilide would also undergo biotransformation to an N-oxanilic acid and also to investigate the metabolic stability of the trifluoromethoxy-group. 1H NMR of the urine samples obtained following the administration of 4-TFMeA and TFMeAc over the time course of the study, revealed signals consistent with the presence of metabolites in the 0–8 and 8–24 hpd samples. Typical 19F NMR spectra from the urine of rats dosed with 4-TFMeA for the period 0–8, 8–24 and 24–48 hpd are shown. Essentially, the same metabolite profiles were seen for 4-(Trifluoromethoxy)aniline, although some differences in the proportions of the various metabolites were apparent. These spectra show that excretion was rapid, with the majority of the metabolites being present in samples collected in the first 24 hpd and only trace amounts of fluorine-containing compounds detectable in the 24–48 hpd urine. Based on standard addition, it was possible to identify the peak at δ19F ?58.43 as 4-TFMeA and the minor peak at δ19F ?58.08 as 4-TFMeAc. In samples from animals dosed with 4-(Trifluoromethoxy)aniline, ≈8.2% of material was excreted apparently unchanged, whilst ≈2.7% of material appeared to correspond to the N-acetylated metabolite. For animals receiving 4-TFMeAc, much less of the dose was recovered as the free aniline (≈0.8%) but comparable amounts of the acetanilide were excreted (≈3.5%).[3]

The significant amount of 4-TFMeA detected in the urine (8.2±2.5% for TFMeA) may reflect the decomposition of unstable metabolites rather than excretion unchanged; the presence of an as yet unidentified, unstable metabolite that spontaneously decomposed to 4-TFMeA is consistent with this notion. As discussed, para-substitution of anilines can, under some circumstances, result in the production of unusual N-glycolanilides and oxanilic acids via the oxidation of N-acetylated metabolites. Indeed, in the case of 4-(Trifluoromethoxy)aniline, the N-oxanilic acid is the major metabolite. However, the formation of such metabolites does not appear to be a feature of the metabolism of 4-TFMeA, which is consistent with the rapid deacetylation of the acetanilide. The data in this study have focussed only on urine. Assuming that absorption of the compounds was complete following i.p. dosing, the incomplete total urinary recoveries (≈50% for 4-TFMeAc and 69% for 4-(Trifluoromethoxy)aniline related material) suggest that a proportion of the dose for both compounds may be secreted in bile. It has to be accepted that the profile of the metabolites secreted in bile may not be the same as that in urine.

The overall urinary metabolic profiles of both the parent aniline and its acetanilide were the same, with the major metabolite for both 4-(Trifluoromethoxy)aniline and 4-TFMeAc identified as a phenolic sulphate. N-acetylation did not seem to be a major pathway for the metabolism of 4-(Trifluoromethoxy)aniline compared to the production of the phenolic sulphate and this is probably explained by the fact that N-deacetylation was the major route of metabolism of the acetanilide. The trifluoromethoxy-group seems to be comparatively stable, as no paracetamol-related metabolites were observed. Unlike 4-trifluoromethylaniline and other 4-substituted anilines, the formation of N-oxanilic acids did not appear to be a major route of metabolism.

References

[1]JINAN KEHAI - CN109134277，2019, A

[2]Deng X, Okram B, Ding Q, Zhang J, Choi Y, Adrián FJ, Wojciechowski A, Zhang G, Che J, Bursulaya B, Cowan-Jacob SW, Rummel G, Sim T, Gray NS. Expanding the diversity of allosteric bcr-abl inhibitors. J Med Chem. 2010 Oct 14;53(19):6934-46.

[3]Tugnait M, Lenz EM, Phillips P, Hofmann M, Spraul M, Lindon JC, Nicholson JK, Wilson ID. The metabolism of 4-trifluoromethoxyaniline and [13C]-4-trifluoromethoxyacetanilide in the rat: detection and identification of metabolites excreted in the urine by NMR and HPLC-NMR. J Pharm Biomed Anal. 2002 Jun 1;28(5):875-85.