Mechanism of the reaction of 4-amino-6-chloro-m-benzenedisulfonamide with nitrous acid

Urbányi, Tibor; Pagliery, Miriam.

doi:10.1021/ac50156a048

Cited by 5 publications

(7 citation statements)

References 10 publications

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“…We have demonstrated that compound 3 is easily converted to diazonium salt 13 with an excess of nitrite. Thus, we assume that Rehm et al actually obtained diazonium salt 13 , which coupled with phenol and not the diazonium 19 that should be formed via water-promoted hydrolysis of thiatriazine 18 . This could also explain the observed diazonium group band in the IR spectra of the presumed compound 18 as well as its unusual instability.…”

Section: Resultsmentioning

confidence: 85%

“…Their conclusions are in contrast with our findings and warrant further investigation and clarification. Rehm et al pointed out in their work that N -substituted thiatriazines were easily prepared previously by reaction of alkyl-substituted disulfonamide analogues of 12 with nitrous acid via diazonium intermediates (Scheme ), while unsubstituted analogues provided unstable products. They implied that an equilibrium between diazonium species and N -substituted thiatriazine compounds exists in an acidic medium (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

“…This could also explain the observed diazonium group band in the IR spectra of the presumed compound 18 as well as its unusual instability. To confirm our assumption, we repeated the procedure described by Rehm et al using unlabeled and 15 N-labeled sodium nitrite and analyzed the isolated solid by 1 H, 13 C, 15 N, and 2D 1 H- 15 N HMBC as well as Raman spectroscopy, which confirmed that the obtained compound was the diazonium salt 13 (Supporting Information Pages S28–S32).…”

Section: Resultsmentioning

confidence: 99%

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Stability and Degradation Pathways of N-Nitroso-Hydrochlorothiazide and the Corresponding Aryl Diazonium Ion

Grahek¹,

Drev²,

Zupančič³

et al. 2023

Org. Process Res. Dev.

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Despite the fact that it was put on the market more than 60 years ago, hydrochlorothiazide (HCT) is still one of the most important antihypertensive drugs. Due to its chemical structure, which contains the secondary aryl-alkyl-amino moiety, it is vulnerable to the formation of N-nitrosamine drug substance-related impurity (NDSRI) N-nitroso-hydrochlorothiazide (NO-HCT). In our study, we reveal that NO-HCT degrades rapidly at pH values 6 to 8. The main degradation products identified are formaldehyde, thiatriazine, and aminobenzenesulfonic acid derivative. Interestingly, degradation of NO-HCT at pH values from 5 to 1 is significantly slower and provides a different impurity profile when compared to the profile generated between pH 6 and 8. Specifically, between pH 1 and 5, HCT is observed as one of the key degradation products of NO-HCT in addition to formaldehyde and aminobenzenesulfonic acid. Moreover, at pH 1, the aminobenzenesulfonic acid derivative is transformed to the corresponding diazonium salt in approximately 3% yield with the nitrosyl cation, which is released during the decomposition of NO-HCT to HCT. This diazonium is highly unstable above pH 5. To verify that degradation of NO-HCT does not produce the corresponding diazonium salt that could be formed via metabolic activation of NO-HCT, this diazonium salt and its hydrolytic and reduction degradation products were synthesized and used as standards for the identification of species formed during the degradation of NO-HCT. This enabled us to confirm that the corresponding aryl diazonium salt, which would be obtained from metabolic activation of NO-HCT, is not observed in the NO-HCT degradation pathway. Our study also demonstrates that this diazonium salt is stable only in the presence of a large excess of strong mineral acid under anhydrous conditions. In the presence of water, it is instantaneously converted to an aminobenzenesulfonic acid derivative. These findings suggest that the NO-HCT should not be considered as a typical compound belonging to the cohort of the concern.

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Section: Resultsmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Stability and Degradation Pathways of N-Nitroso-Hydrochlorothiazide and the Corresponding Aryl Diazonium Ion

Grahek¹,

Drev²,

Zupančič³

et al. 2023

Org. Process Res. Dev.

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show abstract

“…The corresponding diazonium derivative is produced in the presence of water (756). The corresponding diazonium derivative is produced in the presence of water (756).…”

Section: (257)mentioning

confidence: 99%

“…A sulfamoylbenzenesulfon ic acid derivative is formed first and then a thiatriazine derivative forms. The corresponding diazonium derivative is produced in the presence of w'ater (756).…”

Section: III Xylenolmentioning

confidence: 99%