Abstract:Die Synthese verschiedener substituierter Indazole 6 aus substituierten o-Toluoldiazoniumsalzen 3 oder N-Nitroso-o-acetotoluidid 2 in Anwesenheit von DzO oder CH3C02D erfolgt ohne D-Einbau in die Diazoniumsalze 3. -Die Synthese von 3-Methyl-3H-indazol-3-carbonsauremethylester (23) aus optisch aktivem 2-[ 1 -(Methoxycarbonyl)ethyl]benzoldiazoniumsalz 21 erfolgt sowohl in Wasser als auch in der Jacobsonschen Indazolsynthese in Benzol unter vollstandigerRacemisierung. Es wird geschlossen, daB die 5-Diazo-6-methyl… Show more
“…However, two major issues still remained. The Jacobsen indazole synthesis involved intermediate formation of a hazardous diazonium salt, and the synthesis is long and inefficient. 1 Modified medicinal chemistry route to AG035029 …”
A practical process for the synthesis of PPARγ agonist
AG035029 was developed which involved six steps along the
longest linear path. The process development utilized automated
technology and computational chemistry extensively to accelerate the speed of the project in the areas of catalyst screening,
reaction optimization, mechanistic studies, and polymorph
control.
“…However, two major issues still remained. The Jacobsen indazole synthesis involved intermediate formation of a hazardous diazonium salt, and the synthesis is long and inefficient. 1 Modified medicinal chemistry route to AG035029 …”
A practical process for the synthesis of PPARγ agonist
AG035029 was developed which involved six steps along the
longest linear path. The process development utilized automated
technology and computational chemistry extensively to accelerate the speed of the project in the areas of catalyst screening,
reaction optimization, mechanistic studies, and polymorph
control.
A nitro group may be effectively delivered to the
ortho position of alkylbenzenes, provided that
a
suitable chaperon function is located in α-position and a
dilute solution of HNO3 in
CH2Cl2 is used.
The carbonyl function of an aldehyde or ketone is the best choice,
but a carboxyl, alkoxycarbonyl,
and amide groups all work well. The ether function showed a less
pronounced ortho orientation
effect, whereas the hydroxyl group was too prone to oxidation.
Side reactions were minimal under
the conditions employed. A para chaperon effect was
seemingly at work in the CH2Cl2 nitration
of
benzenepropanenitrile. All the results were compared with the
corresponding classical nitration
in H2SO4.
“…Two other tautomers, 2H-indazole and 3H-indazole, are also well-documented (Chart 2). 23,24 There has been some evidence that the indazole tautomer identity has an impact on biological properties. 25−27 Recent investigations on the antiproliferative activity of [Os IV Cl 5 (Hind)] − , where Hind is 1H-or 2Hindazole, showed different results in vitro and in vivo.…”
A one-electron reduction of osmium(IV) complexes trans-[Os(IV)Cl4(Hazole)2], where Hazole = 1H-pyrazole ([1](0)), 2H-indazole ([2](0)), 1H-imidazole ([3](0)), and 1H-benzimidazole ([4](0)), afforded a series of eight new complexes as osmium analogues of KP1019, a lead anticancer drug in clinical trials, with the general formula (cation)[trans-Os(III)Cl4(Hazole)2], where cation = H2pz(+) (H2pz[1]), H2ind(+) (H2ind[2]), H2im(+) (H2im[3]), Ph4P(+) (Ph4P[3]), nBu4N(+) (nBu4N[3]), H2bzim(+) (H2bzim[4]), Ph4P(+) (Ph4P[4]), and nBu4N(+) (nBu4N[4]). All complexes were characterized by elemental analysis, (1)H NMR spectroscopy, electrospray ionization mass spectrometry, UV-vis spectroscopy, cyclic voltammetry, while H2pz[1], H2ind[2], and nBu4[3], in addition, by X-ray diffraction. The reduced species [1](-) and [4](-) are stable in aqueous media in the absence of air oxygen and do not react with small biomolecules such as amino acids and the nucleotide 5'-dGMP. Cell culture experiments in five different human cancer cell lines (HeLa, A549, FemX, MDA-MB-453, and LS-174) and one noncancerous cell line (MRC-5) were performed, and the results were discussed and compared to those for KP1019 and cisplatin. Benzannulation in complexes with similar structure enhances antitumor activity by several orders of magnitude, implicating different mechanisms of action of the tested compounds. In particular, complexes H2ind[2] and H2bzim[4] exhibited significant antiproliferative activity in vitro when compared to H2pz[1] and H2im[3].
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