Process-Related Impurities of Pazopanib

Terentjeva, S.; Muceniece, D.; Lusis, V. K.

doi:10.1021/acs.oprd.9b00117

Cited by 7 publications

(5 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Modifications and improvements of this synthesis have since been reported. 125,126 drug discovery program, 128 showing potent MET inhibition in the low-nanomolar range. Later, 13 also showed potent activity against ALK and ROS1, compared with other kinases.…”

Section: Fda-approved Kinase Inhibitors From 1999 To 2010mentioning

confidence: 99%

See 1 more Smart Citation

Small Molecule Kinase Inhibitor Drugs (1995–2021): Medical Indication, Pharmacology, and Synthesis

et al. 2021

View full text Add to dashboard Cite

The central role of dysregulated kinase activity in the etiology of progressive disorders, including cancer, has fostered incremental efforts on drug discovery programs over the past 40 years. As a result, kinase inhibitors are today one of the most important classes of drugs. The FDA approved 73 small molecule kinase inhibitor drugs until September 2021, and additional inhibitors were approved by other regulatory agencies during that time. To complement the published literature on clinical kinase inhibitors, we have prepared a review that recaps this large data set into an accessible format for the medicinal chemistry community. Along with the therapeutic and pharmacological properties of each kinase inhibitor approved across the world until 2020, we provide the synthesis routes originally used during the discovery phase, many of which were only available in patent applications. In the last section, we also provide an update on kinase inhibitor drugs approved in 2021.

show abstract

Section: Fda-approved Kinase Inhibitors From 1999 To 2010mentioning

confidence: 99%

“…Methylation of the secondary linker amine with methyl iodide is followed by a final condensation reaction with 5-amino-2-methylbenzenesulfonamide to afford the product, 12 . Modifications and improvements of this synthesis have since been reported. , …”

Section: Fda-approved Kinase Inhibitors From 1999 To 2010mentioning

confidence: 99%

Small Molecule Kinase Inhibitor Drugs (1995–2021): Medical Indication, Pharmacology, and Synthesis

et al. 2021

View full text Add to dashboard Cite

show abstract

“…These latter findings have been utilized to great effect by Conrow et al to give regioselective access to N-1 alkylindazoles on kilogram scale, albeit over two steps from the corresponding N-1 acylindazole via reductive acetylation-deacetoxylation [20]. Although electronic and steric factors can influence the regiochemical outcome of indazole N-alkylation, varying reaction conditions, such as the choice of base [17,21], acid [22], solvent, and/or N-alkylating reagent may also facilitate regioselective indazole N-alkylation [23][24][25]. Bookser et al have investigated the N-alkylation of related bicyclic azolofused-ring heterocycles, including 1H-indazole, employing NaHMDS in tetrahydrofuran (THF) or dimethyl sulfoxide (DMSO), and observed solvent-dependent regioselectivity [24].…”

Section: Introductionmentioning

confidence: 99%

Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution

Alam¹,

Keating²

2021

Beilstein J. Org. Chem.

View full text Add to dashboard Cite

The indazole scaffold represents a promising pharmacophore, commonly incorporated in a variety of therapeutic drugs. Although indazole-containing drugs are frequently marketed as the corresponding N-alkyl 1H- or 2H-indazole derivative, the efficient synthesis and isolation of the desired N-1 or N-2 alkylindazole regioisomer can often be challenging and adversely affect product yield. Thus, as part of a broader study focusing on the synthesis of bioactive indazole derivatives, we aimed to develop a regioselective protocol for the synthesis of N-1 alkylindazoles. Initial screening of various conditions revealed that the combination of sodium hydride (NaH) in tetrahydrofuran (THF) (in the presence of an alkyl bromide), represented a promising system for N-1 selective indazole alkylation. For example, among fourteen C-3 substituted indazoles examined, we observed > 99% N-1 regioselectivity for 3-carboxymethyl, 3-tert-butyl, 3-COMe, and 3-carboxamide indazoles. Further extension of this optimized (NaH in THF) protocol to various C-3, -4, -5, -6, and -7 substituted indazoles has highlighted the impact of steric and electronic effects on N-1/N-2 regioisomeric distribution. For example, employing C-7 NO2 or CO2Me substituted indazoles conferred excellent N-2 regioselectivity (≥ 96%). Importantly, we show that this optimized N-alkylation procedure tolerates a wide structural variety of alkylating reagents, including primary alkyl halide and secondary alkyl tosylate electrophiles, while maintaining a high degree of N-1 regioselectivity.

show abstract

“…The impurities in new drugs are not easily accessible, mainly because they are present at a very low level, as well as their chemical properties are often very similar to those of the parent drug and therefore their separation is very difficult. It has to be pointed out that the side products closely related to the process are convoluted in the next stages along with the main products, thus generating subsequent impurities. , …”

Section: Introductionmentioning

confidence: 99%

“…It has to be pointed out that the side products closely related to the process are convoluted in the next stages along with the main products, thus generating subsequent impurities. 6,7 The unambiguous identification of process impurities can increase the process understanding, which in turn allows for better impurity control in the final API. Impurity profile studies are thus necessary to certify the purity, quality, safety, and efficacy of the drug product during API development.…”

Section: ■ Introductionmentioning

confidence: 99%

Efficient Synthesis of Potential Impurities in Levonadifloxacin (WCK 771)

et al. 2021

View full text Add to dashboard Cite

Levonadifloxacin (WCK 771) is a novel broad-spectrum anti-methicillin-resistant Staphylococcus aureus (MRSA) agent recently launched in India. Five process impurities and one degradation impurity were synthesized as reference standards for their quantification by high-performance liquid chromatography (HPLC) methodology in drug substance and drug product. These compounds are not easily commercially available. The synthesis and characterization of these impurities are discussed in detail.

show abstract

Process-Related Impurities of Pazopanib

Cited by 7 publications

References 15 publications

Small Molecule Kinase Inhibitor Drugs (1995–2021): Medical Indication, Pharmacology, and Synthesis

Small Molecule Kinase Inhibitor Drugs (1995–2021): Medical Indication, Pharmacology, and Synthesis

Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution

Efficient Synthesis of Potential Impurities in Levonadifloxacin (WCK 771)

Contact Info

Product

Resources

About