Improved Large-Scale Preparation of 4-Iodopicolinic Acid

Lohse, Olivier

doi:10.1080/00397919608003557

Cited by 10 publications

(5 citation statements)

References 7 publications

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“…Introduction of acid chloride 5 into methanol at room temperature gave ester 6 in 88% yield. A previous protocol generated ester 6 in two separate steps with an overall yield of 46% after recrystallization from hot acetone to remove a dichlorinated impurity ( 6a ). , This sequence was improved by combining the first two steps into a single stage with an overall yield of 78%.…”

Section: Resultsmentioning

confidence: 99%

A Scaleable Synthesis of BAY 43-9006: A Potent Raf Kinase Inhibitor for the Treatment of Cancer

Bankston

Dumas

Natero

et al. 2002

Org. Process Res. Dev.

107

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Urea 3 (BAY 43-9006), a potent Raf kinase inhibitor, was prepared in four steps with an overall yield of 63%. Significant process research enabled isolation of each intermediate and target without chromatographic purification, and overall yield increases >50% were observed compared to those from previous methods. This report focuses on improved synthetic strategies for production of scaled quantities of 3 for preclinical, toxicological studies. These improvements may be useful to assemble other urea targets as potential therapeutic agents to combat cancer.

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Section: Resultsmentioning

confidence: 99%

A Scaleable Synthesis of BAY 43-9006: A Potent Raf Kinase Inhibitor for the Treatment of Cancer

Bankston

Dumas

Natero

et al. 2002

Org. Process Res. Dev.

107

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“…The second approach is shown in Scheme . A Curtius rearrangement was conducted on 21 to afford 22 . Alkylation of 22 followed by the organostannane formation reaction yielded 24 .…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Identification of [1,3,5]Triazine-pyridine Biheteroaryl as a Novel Series of Potent Cyclin-Dependent Kinase Inhibitors

et al. 2005

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On the basis of previous studies, we identified pyrazine-pyridine A as a potent vascular endothelial growth factor inhibitor and pyrimidine-pyridine B as a moderately potent cyclin dependent kinase (CDK) inhibitor. A proposed combination of CGP-60474 and compound B led to the discovery of [1,3,5]triazine-pyridine as a new series of potent CDK inhibitors. Palladium-catalyzed C-C bond formation reactions, particularly the Negishi coupling reaction, were used to assemble various triazine-heteroaryl analogues effectively. Among them, compound 20 displayed high inhibitory potency at CDK1 (IC(50) = 0.021 microM), CDK2, and CDK5 and submicromolar potency at CDK4, CDK6, and CDK7. Compound 20 also displayed high potency at GSK-3beta. It demonstrated potent antiproliferative activity on various tumor cell lines, including HeLa, HCT-116, U937, and A375. When 20 was administered intraperitoneally at 150 and 125 mg/kg to nude mice bearing human A375 xenografts, the compound produced a significant survival increase. Molecular docking studies were conducted in an attempt to enhance the understanding of the observed structure-activity relationship.

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“…The synthesis of biheteroaryl 47 was shown in Scheme 6. A Curtius rearrangement was conducted on 43 32 to give 44. Alkylation, organostannane formation, and Stille coupling reaction, followed by deprotection, gave the target 47.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Discovery of Pyrazine−Pyridine Biheteroaryl as a Novel Series of Potent Vascular Endothelial Growth Factor Receptor-2 Inhibitors

et al. 2004

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Pathological angiogenesis is associated with disease states such as cancer, diabetic retinopathy, rheumatoid arthritis, endometriosis, and psoriasis. There is much evidence that direct inhibition of the kinase activity of vascular endothelial growth factor receptor-2 (VEGFR-2) will result in the reduction of angiogenesis and the suppression of tumor growth. Attempts to optimize a cyclin-dependent kinase-1 (CDK1) inhibitor by using palladium-catalyzed C-C bond, C-N bond formation reactions to assemble diverse biheteroaryl molecules led to the unexpected discovery of a pyrazine-pyridine biheteroaryl as a novel series of potent VEGFR-2 inhibitors. Compound 15, which had IC(50) = 0.084 microM at VEGFR-2, showed very modest selectivity against fibroblast growth factor receptor-2 (IC(50) = 0.21 microM), platelet-derived growth factor receptor (IC(50) = 0.36 microM), and glycogen synthase kinase-3 (IC(50) = 0.478 microM), while it exhibited more than 10-fold selectivity against epidermal growth factor receptor (IC(50) = 1.36 microM) and insulin-R kinase (IC(50) = 1.69 microM). On the other hand, compound 15 exhibited more than 100-fold selectivity against calmodulin kinase 2; casein kinase-1 and -2; CDK1 and -4; mitogen-activated protein kinase; and protein kinase A, Cbeta2, and Cgamma (IC(50) >10 microM). Compound 15 also displayed high inhibitory potency on VEGF-stimulated human umbilical vein endothelial cell (HUVEC) proliferation (IC(50) = 0.005 microM) and good selectivity against cell lines such as HUVEC, human aortic smooth muscle cells, and MRC5 lung fibroblasts. Molecular docking studies were conducted in an attempt to rationalize the unexpected high VEGFR-2 selectivity of 15.

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Improved Large-Scale Preparation of 4-Iodopicolinic Acid

Cited by 10 publications

References 7 publications

A Scaleable Synthesis of BAY 43-9006: A Potent Raf Kinase Inhibitor for the Treatment of Cancer

A Scaleable Synthesis of BAY 43-9006: A Potent Raf Kinase Inhibitor for the Treatment of Cancer

Synthesis and Identification of [1,3,5]Triazine-pyridine Biheteroaryl as a Novel Series of Potent Cyclin-Dependent Kinase Inhibitors

Synthesis and Discovery of Pyrazine−Pyridine Biheteroaryl as a Novel Series of Potent Vascular Endothelial Growth Factor Receptor-2 Inhibitors

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