3'-Demethoxy-3'-hydroxystaurosporine, 1 (CGP58 546), a novel staurosporine analogue, was isolated from a mutant of Streptomyces longisporoflavus R19 blocked in the last step of the biosynthetic pathway. CGP58 546 was less potent than staurosporine, but it showed a more selective inhibition pattern against various subtypes of protein kinase C. Staurosporine, 2, an indolo (2,3-a) carbazole alkaloid, was first isolated in 1977 by S. Omura and co-workers from Streptomyces sp. AM-22821}, later reclassified as Saccharothrix sp. Its structure and relative stereochemistry were determined by X-ray crystallographic analysis2'3) and by XH and 13C NMRstudies4). The
LCZ696 is a novel treatment for patients
suffering from heart failure
that combines the two active pharmaceutical ingredients sacubitril
and valsartan in a single chemical compound. While valsartan is an
established drug substance, a new manufacturing process suitable for
large-scale commercial production had to be developed for sacubitril.
The use of chemocatalysis, biocatalysis, and flow chemistry as state-of-the-art
technologies allowed to efficiently build up the structure of sacubitril
and achieve the defined performance targets.
An improved manufacturing process for fluvastatin 1 has been
developed by performing the condensation reaction of E-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-2-propenal, 4,
with the dianion of tert-butyl acetoacetate and the subsequent
low-temperature reduction to 7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid-1,1-dimethylethylester, 2, without isolation of the intermediate 7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-5-hydroxy-3-oxo-6-heptenoic acid-1,1-dimethylethylester, 3. To be successful,
a crucial selectivity problem in the conversion of aldehyde 4 to
aldol 3 had to be understood and solved. The improved process
allows the omission of two solvents, and the manufacture of
fluvastatin at considerably lower cost and in higher throughput.
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