Effects of mixed aqueous‐organic solvents on the rate of intramolecular carboxylic group‐catalyzed cleavage of <i>N</i>‐(4′‐methoxyphenyl)phthalamic acid

Leng, Sim Yoke; Ariffin, Azhar; Khan, M. Niyaz

doi:10.1002/kin.20003

Cited by 9 publications

(2 citation statements)

References 20 publications

(19 reference statements)

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“…An increase in the reaction rate with the decrease in amount of aprotic dipolar solvent (ACN) in the organic solvent-water mixture has been already observed for the hydrolysis reactions of esters and other compounds. , From a qualitative point of view, this result can be explained by the greater stabilization of the ion pair (Na + ,OH – ) by the lone electron pair of the organic solvent (ACN). The higher solvation decreases the reactivity of the OH – ion which is less present in free form in solution . Furthermore, another explanation could be the dependence on the dielectric constant of the medium.…”

Section: Resultsmentioning

confidence: 99%

“…The higher solvation decreases the reactivity of the OH – ion which is less present in free form in solution. 36 Furthermore, another explanation could be the dependence on the dielectric constant of the medium. According to MoKa 37 predictions, in a strong basic environment (1 M NaOH, pH = 14) olaparib behaves as a weak acid (predicted p K a : 11.54, Figure S2 ) and it is mainly present in dissociated form in the reaction mixture.…”

Section: Resultsmentioning

confidence: 99%

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MassChemSite for In-Depth Forced Degradation Analysis of PARP Inhibitors Olaparib, Rucaparib, and Niraparib

et al. 2023

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Drugs must satisfy several protocols and tests before being approved for the market. Among them, forced degradation studies aim to evaluate drug stability under stressful conditions in order to predict the formation of harmful degradation products (DPs). Recent advances in LC–MS instrumentation have facilitated the structure elucidation of degradants, although a comprehensive data analysis still represents a bottle-neck due to the massive amount of data that can be easily generated. MassChemSite has been recently described as a promising informatics solution for LC–MS/MS and UV data analysis of forced degradation experiments and for the automated structural identification of DPs. Here, we applied MassChemSite to investigate the forced degradation of three poly(ADP-ribose) polymerase inhibitors (olaparib, rucaparib, and niraparib) under basic, acidic, neutral, and oxidative stress conditions. Samples were analyzed by UHPLC with online DAD coupled to high-resolution mass spectrometry. The kinetic evolution of the reactions and the influence of solvent on the degradation process were also assessed. Our investigation confirmed the formation of three DPs of olaparib and the wide degradation of the drug under the basic condition. Intriguingly, base-catalyzed hydrolysis of olaparib was greater when the content of aprotic-dipolar solvent in the mixture decreased. For the other two compounds, whose stability has been much less studied previously, six new degradants of rucaparib were identified under oxidative degradation, while niraparib emerged as stable under all stress conditions tested.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

MassChemSite for In-Depth Forced Degradation Analysis of PARP Inhibitors Olaparib, Rucaparib, and Niraparib

et al. 2023

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Intramolecular carboxylic group‐assisted cleavage of N‐(2‐hydroxyphenyl)phthalamic acid (7) and N‐(2‐methoxyphenyl)phthalamic acid (8): Absence of intramolecular general acid catalysis due to 2‐OH in 7

Sim

Ariffin

Khan

2006

Int J of Chemical Kinetics

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The values of pseudo first-order rate constants (k obs ) for the cleavage of N-(2-hydroxyphenyl)phthalamic acid (7), obtained at 4.9 × 10 −2 M HCl, 35 • C, and within CH 3 CN content range 2-80% (v/v) in mixed aqueous solvent are smaller than k obs for the cleavage of N-(2-methoxyphenyl)phthalamic acid (8) INTRAMOLECULAR CARBOXYLIC GROUP-ASSISTED CLEAVAGE 747 by nearly 1.5-to 2-fold. These observations show the absence of expected intramolecular general acid catalysis due to 2-OH group in 7. The values of k obs for the cleavage of 7 and 8 decrease by more than 20-fold with the increase in the content of CH 3 CN from 2 to 80-82% (v/v) in mixed aqueous solvent. The kinetic data reveal that in acidic aqueous cleavage of 7, N-cyclization (leading to the formation of imide) and O-cyclization (leading to the formation of phthalic anhydride) vary from ∼10 to 15% and ∼90 to 85%, respectively, with the increase in CH 3 CN content from 2 to 80% (v/v). Similar increase in CH 3 CN content causes increase in N-cyclization from ∼0 to 5% and decrease in O-cyclization from ∼100 to 95% in the acidic aqueous cleavage of 8. Some speculative, yet conceivable, reasons for nearly 10 and 0% N-cyclization in the cleavage of respective 7 and 8 at low content of CH 3 CN have been described.

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Efficient Rate Enhancement Due to Intramolecular General Base (IGB) Assistance in the Hydrolysis of N-(o-Hydroxyphenyl)phthalimide

2007

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The rates of the hydrolyses of N-(o-hydroxyphenyl)phthalimide (1) and N-(o-methoxyphenyl)phthalimide (2), studied at different pH, show that the hydrolysis of 1 involves intramolecular general base (IGB) assistance where the o-O- group of ionized 1 acts as IGB and H2O as the reactant. The rate enhancement due to the IGB-assisted reaction of H2O with ionized 1 is>8x10(4)-fold. Pseudo-first-order rate constant for the reaction of water with 2 is approximately 2x10(3)-fold smaller than the first-order rate constant (0.10 s-1) for pH-independent hydrolysis of 1 within the pH range of 9.60-10.10. Second-order rate constants (kOH) for hydroxide ion-assisted hydrolysis of ionized 1 and 2 are 3.0 and 29.1 M-1 s-1, respectively. The solvent deuterium kinetic isotope effect (dKIE) on the rate of alkaline hydrolysis of 1 and 2 reveals that the respective values of kOH/kOD are 0.84 and 0.78, where kOD represents the second-order rate constant for DO--assisted cleavage of these imides (1 and 2). The value of kwH2O/kdD2O is 2.04, with kwH2O and kdD2O representing pseudo-first-order rate constants for the reactions of ionized 1 with H2O and D2O, respectively.

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Effects of mixed aqueous‐organic solvents on the rate of intramolecular carboxylic group‐catalyzed cleavage of N‐(4′‐methoxyphenyl)phthalamic acid

Cited by 9 publications

References 20 publications

MassChemSite for In-Depth Forced Degradation Analysis of PARP Inhibitors Olaparib, Rucaparib, and Niraparib

MassChemSite for In-Depth Forced Degradation Analysis of PARP Inhibitors Olaparib, Rucaparib, and Niraparib

Intramolecular carboxylic group‐assisted cleavage of N‐(2‐hydroxyphenyl)phthalamic acid (7) and N‐(2‐methoxyphenyl)phthalamic acid (8): Absence of intramolecular general acid catalysis due to 2‐OH in 7

Efficient Rate Enhancement Due to Intramolecular General Base (IGB) Assistance in the Hydrolysis of N-(o-Hydroxyphenyl)phthalimide

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