A convenient approach to arenediazonium tosylates

Mihelač, Mateja; Siljanovska, Ana; Košmrlj, Janez

doi:10.1016/j.dyepig.2020.108726

Cited by 13 publications

(10 citation statements)

References 36 publications

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“…Mass spectrometric analysis indicated that the mass of unidentified compound 7 was 296.9514 Da (orange peaks in Figure and orange lines in Figures and ). This is the same exact mass that is expected for the HCT-diazonium 5 , although the chemical shifts in the 1 H NMR spectra (orange peaks in Figure ) do not correspond to aryl diazonium salt species, which usually show the signal of the ortho proton adjacent to a diazonium functionality at a lower field close to or above 9 ppm. , To further investigate if the unidentified compound 7 was the HCT-diazonium 5 , we performed a Sandmeyer reaction in situ by the addition of CuBr to the NO-HCT 2 degradation mixture in order to form the corresponding aryl bromide; however, this could not be detected in the reaction mixture (Figure S19). Thus, this experiment, in addition to 1 H NMR data, suggested that the detected unidentified compound 7 does not correspond to HCT-diazonium 5 .…”

Section: Resultsmentioning

confidence: 87%

“…For this purpose, tetrafluoroborate and tosylate diazonium salts seemed reasonable choices, as they are known typically to be isolable as crystalline solids. Tetrafluoroborate salt 5a (X = BF 4 ) preparation was attempted according to the procedure of Doyle et al, and the tosylate salt 5b (X = OTs) preparation was attempted using the recently published method of Košmrlj and co-workers (Scheme ).…”

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: 87%

Section: Resultsmentioning

confidence: 99%

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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“…Another group investigated the reaction of p -substituted benzenediazonium ions of structure p -X-ArN 2 + with calf-thymus DNA and showed the formation of 8-arylguanine adducts. Aryl diazonium salts are more stable than their alkyl counterparts benefiting from charge delocalization and particularly if they are paired with a non-nucleophilic counterion such as tetrafluoroborate, hexafluorophosphate or tosylate . Such differential stability probably explains why aryl diazonium ions can form both azo-aryl and aryl DNA adducts.…”

Section: Resultsmentioning

confidence: 99%

“…Aryl diazonium salts are more stable than their alkyl counterparts benefiting from charge delocalization and particularly if they are paired with a non-nucleophilic counterion such as tetrafluoroborate, hexafluorophosphate or tosylate. 69 Such differential stability probably explains why aryl diazonium ions can form both azo-aryl and aryl DNA adducts.…”

Section: Relative Contributions Of Denitrosation and α-Carbon Hydroxy...mentioning

confidence: 99%

Mechanisms of Nitrosamine Mutagenicity and Their Relationship to Rodent Carcinogenic Potency

Snodin,

Trejo-Martin,

Ponting

et al. 2024

Chem. Res. Toxicol.

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A thorough literature review was undertaken to understand how the pathways of N-nitrosamine transformation relate to mutagenic potential and carcinogenic potency in rodents. Empirical and computational evidence indicates that a common radical intermediate is created by CYP-mediated hydrogen abstraction at the α-carbon; it is responsible for both activation, leading to the formation of DNA-reactive diazonium species, and deactivation by denitrosation. There are competing sites of CYP metabolism (e.g., β-carbon), and other reactive species can form following initial bioactivation, although these alternative pathways tend to decrease rather than enhance carcinogenic potency. The activation pathway, oxidative dealkylation, is a common reaction in drug metabolism and evidence indicates that the carbonyl byproduct, e.g., formaldehyde, does not contribute to the toxic properties of N-nitrosamines. Nitric oxide (NO), a side product of denitrosation, can similarly be discounted as an enhancer of N-nitrosamine toxicity based on carcinogenicity data for substances that act as NO-donors. However, not all N-nitrosamines are potent rodent carcinogens. In a significant number of cases, there is a potency overlap with non-N-nitrosamine carcinogens that are not in the Cohort of Concern (CoC; high-potency rodent carcinogens comprising aflatoxin-like-, N-nitroso-, and alkyl-azoxy compounds), while other N-nitrosamines are devoid of carcinogenic potential. In this context, mutagenicity is a useful surrogate for carcinogenicity, as proposed in the ICH M7 (R2) (2023) guidance. Thus, in the safety assessment and control of N-nitrosamines in medicines, it is important to understand those complementary attributes of mechanisms of mutagenicity and structure−activity relationships that translate to elevated potency versus those which are associated with a reduction in, or absence of, carcinogenic potency.

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“…To eliminate the potential danger of the diazotization step, we pursued to develop a safe and 'easy to handle' procedure to form the intermediate D. Inspired by the work of Jacq and Pasau [16] this involved 1) Substituting sodium nitrite (NaNO2) with tert-butyl nitrite (TBN) as a safer diazonium reagent, which would also enable the reaction to be run safely at higher temperatures. 2) Transferring the first step of the synthesis from batch to flow synthesis, hereby avoiding accumulation of the unstable intermediate C. TBN has been reported as a mild, nonexplosive and stable diazonium reagent [17][18][19][20] with a high safety profile in both batch and flow processes [16,21] from small to bulk multikilogram scale [22,23]. Diazotization reactions using TBN have been run at temperatures ranging from room temperature to 80°C [24,25].…”

Section: Step 1 -Diazotisationmentioning

confidence: 99%

Upscaling and Risk Evaluation of the Synthesis of the 3-5-Diamino-1H-Pyrazole, Disperazol

Jansen,

Grier,

Andersen

et al. 2024

Preprint

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This paper presents the work done to transition the lab scale synthesis (1 g) to a large scale (400 g) synthesis of the 3-5-diamino-1H-Pyrazole Disperazol; a new pharmaceutical for treatment of antibiotic resistant Pseudomonas aeruginosa biofilm infections. The potentially hazardous diazotisation step in the lab scale synthesis was transformed to a safe and easy to handle flow chemistry step. Additionally, the paper presents an OSHA recommended safety assessment of the active compound E, performed by Fauske and Associates, LLC.

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A convenient approach to arenediazonium tosylates

Cited by 13 publications

References 36 publications

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

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

Mechanisms of Nitrosamine Mutagenicity and Their Relationship to Rodent Carcinogenic Potency

Upscaling and Risk Evaluation of the Synthesis of the 3-5-Diamino-1H-Pyrazole, Disperazol

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