5-2-Methoxy-5-(4-pyridinyl)phenyl-2,1,3-benzoxadiazole (PDE472) is a selective inhibitor of the phosphodiesterase PDE4D isoenzyme, which is a recognised drug target for the treatment of asthma. ...Different synthetic routes to PDE472 were investigated, and the research synthesis was optimised to prepare a phase I batch on pilot-plant scale with the focus on the elimination or minimization of inherent process risks. An important refinement of the key Negishi aryl−aryl coupling involved preforming the arylpalladium complex, which was then added to the arylzinc intermediate. Residual palladium was removed from PDE472 via crystallization of the hemi-maleate salt, which afforded drug-substance containing <2 ppm Pd.
The Synthesis of a Novel Inhibitor of B-Raf Kinase Denni-Dischert, Donatienne; Marterer, Wolfgang; Bänziger, Markus ...
Organic process research & development,
01/2006, Letnik:
10, Številka:
1
Journal Article
Recenzirano
A scaleable synthetic route to 4,7‘bis-isoquinolinyl-1-yl-(2-tert-butyl-pyrimidine-5-yl)amine (1), an inhibitor of B-Raf kinase is described. The key step in the synthesis is the Pd-catalyzed Negishi ...coupling of 4-bromo-1-chloroisoquinoline with trifluoromethanesulfonic acid isoquinoline-7-yl ester to yield 1-chloro4,7‘bis-isoquinolinyl. This intermediate is transformed to the desired drug substance in one additional step, by reaction with 2-tert-butyl-5-aminopyrimidine in the presence of NaH. A special focus was put on the finally successful removal of traces of Zn and Pd in the drug substance, which came from the Negishi coupling.
8-Methylquinoxalines are nitrated surprisingly efficiently at C-5 following a simple nitration protocol with mixed acid at 40−50 °C. The implications of halogen functionalisation at C-6 and ...modification of the mixed acid conditions on the relative rates of conversion and process safety are discussed. Competing side reactions for 6-halo-8-methylquinoxalines involve hydrolysis at C-6 and halogenation at C-7 or C-5.
Different synthetic routes to the enantiomerically pure octahydrobenzogquinoline derivative JNZ092 were evaluated for their suitability to rapidly prepare a first clinical batch on a kilogram scale. ...On the basis of the experience of previous octahydrobenzogquinoline projects a new linear synthesis of JNZ092 was established and scaled up successfully. The overall yield was increased by a factor 10 and the preparation time shortened significantly as compared to those of the medicinal chemistry route. As the key strategy all atoms of the octahydrobenzogquinoline skeleton were introduced early by the reaction of the 6-lithiated 1,7-dimethoxynaphthalene with ethyl-2-cyano-3-ethoxyacrylate. As a valuable technological refinement the practicability of a chromatographic technique with repetitive feed injection for the problematic separation of the enantiomers was demonstrated.
Three actual examples from the current product palette within Novartis Process Research will demonstrate the some of the variety and challenges encountered in modern chemical development.
Visual neglect has been frequently described in a horizontal direction. Altitudinal neglect, however, has rarely been described and has been associated with bilateral lesions in the parieto-occipital ...or temporo-occipital region. The following case report presents a patient with marked altitudinal neglect of the inferior space which was elicited using a line bisection test. The previously healthy patient had well-defined lesions solely in the occipital cortex following an embolic infarction. The present case report underlines the possibility that bioccipital lesions themselves can be responsible for altitudinal neglect.
Calculation abilities tested by 12 additive and 12 multiplicative tasks were investigated in 19 patients suffering from vascular dementia and in 23 patients suffering from dementia of Alzheimer's ...type as well as in 17 age-matched controls. Arithmetic impairment expressed by the number of correct results showed a significant correlation with the degree of dementia, measured by the Mini-Mental State Examination. An error type analysis was performed, but was of no help in the differential diagnosis of dementia. Calculation abilities are similarly impaired in both vascular dementia and dementia of Alzheimer's type.
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