Belumosudil Impurity

Details:

Belumosudil Impurity ;144809-26-7

• Product Information

• Product Code：B075042

• English Name：Belumosudil Impurity 42

• English Alias：tert-butyl 5-((2-(3-(2-(isopropylamino)-2-oxoethoxy)phenyl)quinazolin-4-yl)amino)-1H-indazole-1-carboxylate

• CAS No.：911417-95-3

• Molecular Formula：C??H??N?O?

• Molecular Weight：552.62

• Advantages

• High-Purity Guarantee：Confirmed by HPLC with a purity of ≥99.0%, and the structure is verified through multiple methods including NMR (1H, 13C), HRMS, and elemental analysis, providing an accurate and reliable reference standard for Belumosudil impurity analysis.

• Excellent Stability：Stable for 36 months under storage conditions of -20℃ in the dark and sealed. The degradation rate is less than 0.3% within 6 months in common solvent systems such as acetonitrile - methanol, ensuring stable and reliable experimental data.

• Applications

• Quality Control Testing：Used for UPLC-MS/MS detection of Impurity 42 in Belumosudil API and formulations. Strictly control the impurity content to meet ICH Q3A standards (single impurity limit ≤0.1%), ensuring drug quality and safety.

• Process Optimization Research：Monitor the formation pathway of this impurity during the synthesis of Belumosudil. By adjusting parameters such as the condensation reaction temperature (e.g., 70 - 80℃), reaction time, and catalyst dosage, the generation of impurities can be reduced by more than 40%.

• Method Validation：As a standard for developing impurity detection methods, it can verify the resolution (≥3.0) and limit of detection (0.01 ng/mL) of UPLC, ensuring the accuracy and reliability of the detection method.

• Background Description

• Belumosudil is a Rho kinase (ROCK) inhibitor used for treating idiopathic pulmonary fibrosis, chronic graft-versus-host disease, and other diseases, exerting its effects by regulating intracellular signaling pathways. Impurity 42, as a process-related impurity in the synthesis of Belumosudil, may originate from side products of reactions involving intermediates such as indazole and quinazoline. Its complex structure contains functional groups such as indazole, quinazoline, ester, and amino groups, which may affect drug stability, solubility, and binding ability to the target. With the increasing requirements of global regulatory agencies for the quality of drugs for rare diseases, the study of Impurity 42 has become a key part of ensuring the quality and safety of Belumosudil.

• Research Status

• Detection Technology：UPLC-MS/MS technology is used, combined with a C18 column (1.7μm) and gradient elution with 0.1% formic acid - acetonitrile. Impurities can be separated within 10 minutes, and the limit of detection is as low as 0.003 ng/mL, enabling high-precision detection of trace impurities.

• Formation Mechanism：Studies have shown that Impurity 42 is formed by the stepwise condensation reaction of tert-butyl 5-amino-1H-indazole-1-carboxylate, 2-(3-hydroxyphenyl)quinazolin-4-amine, and 2-chloro-N-isopropylacetamide in an acetonitrile solvent under the alkaline condition of potassium carbonate. Optimizing the reaction sequence and the strength of the base can effectively inhibit side reactions.

• Safety Evaluation：In vitro cytotoxicity experiments show that the IC?? of this impurity against NIH/3T3 cells is 205.6 μM (Belumosudil IC?? = 12.3 μM). Although the toxicity is lower than that of the main drug, its content in drugs still needs to be strictly controlled. Currently, long-term stability tests are being carried out to systematically study its degradation characteristics under different humidity, light, and temperature condition