Product Number: R018038
English Name: Riociguat Nitroso Impurity 38
English Alias: N-(4,6-diamino-2-(1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl)-N-methylnitrous amide
CAS Number: None
Molecular Formula: C₁₈H₁₆FN₉O
Molecular Weight: 393.38
As the nitroso impurity 38 of Riociguat, this compound has the following advantages:
Well-defined with distinct polyfunctional features: Contains pyrimidine ring (4,6-diamino-substituted), pyrazolo[3,4-b]pyridine ring, 2-fluorobenzyl side chain, and N-methylnitrous amide (-N(CH₃)-NO) structure. Unlike riociguat (soluble guanylate cyclase activator with N-methylamino group), its nitrosoamide polarity, fluorine electronegativity, and polyheterocyclic conjugation create significant differences, enabling precise differentiation via HPLC/SFC as a specific marker;
High stability and traceability: Rigid polyheterocyclic (pyrimidine, pyrazolopyridine) structures and stability of amide bonds ensure stability under dark, low-temperature conditions. As a byproduct from amino nitrosation during storage/degradation of riociguat, it directly reflects N-methylamino reactivity and nitrite exposure risk, improving process tracing accuracy;
High detection sensitivity: Polyheterocyclic conjugation shows strong UV absorption (260-300nm), combined with m/z 394 [M+H]⁺ enabling ppb-level analysis via LC-MS, compatible with soluble guanylate cyclase activator nitroso impurity systems.
Pharmaceutical quality control: Used as an impurity reference standard to quantify Riociguat Nitroso Impurity 38 in APIs, ensuring compliance with genotoxic impurity limits in pharmaceutical standards;
Stability studies: Monitoring impurity levels under varying conditions (pH, light) to assess nitrosation trends and support safety assurance over shelf life;
Synthesis assessment: Evaluating purity of N-methylamino-containing intermediates in riociguat synthesis to reduce nitrosation risk at the source.
Riociguat is a soluble guanylate cyclase activator with polyheterocyclic structure, used to treat pulmonary hypertension, containing an N-methylamino group (-NHCH₃) at the pyrimidine 5-position. Upon exposure to nitrous acid (e.g., from nitrate conversion) during production or storage, this amino group may undergo nitrosation to form N-methylnitrosoamide (-N(CH₃)-NO) derivatives like Riociguat Nitroso Impurity 38. Due to potential genotoxicity and carcinogenicity, nitrosoamides are strictly regulated, and their residues may affect riociguat safety, making detection and control critical for quality assurance.
Current research focuses on:
Analytical method validation: Developing UPLC-MS/MS methods with C18 columns for separation, achieving 0.01 ppb detection limits;
Nitrosation mechanism: Studying impurity formation kinetics under varying nitrite concentration and pH to clarify N-methylamino-to-nitrosoamide conversion pathways;
Control strategies: Exploring nitrosation inhibitors (e.g., ascorbic acid) to keep impurity levels below safety limits (<0.001%);
Toxicity evaluation: Conducting in vitro Ames tests and cell mutation assays to assess potential genotoxicity and support limit setting.
China
