Selective substitution of secondary amines in the presence of primary amines is performed by using the reaction solvent, methyl isobutylketone (MIBK), as a temporary protecting group for the primary amine. After acylation or alkylation of the secondary amine, the resulting imine intermediate is smoothly hydrolysed, leading to the free primary amine in high yield and purity. This procedure represents a cheap and scalable alternative to multistep methods requiring several protections and deprotections.
The stepwise optimization towards a safe, reproducible, and high-yielding oxidation of azepine 2 into the prochiral nitrone 4 is described, with emphasis on the elimination of Davis reagent 3. m-Chloroperoxybenzoic acid (mCPBA) was found to be an elegant and scalable alternative oxidant regarding safety, yield, and easy workup procedures. Nitrone 4 was obtained in 95% yield and used without purification or isolation in the cycloaddition step to provide oxazolidone 6 in high yield. The process was scaled up successfully to an 800-L scale (60 mol of starting material).
A practical process to make N-(2,6-dimethylphenyl)-2-piperazin-1-yl-acetamide 1 is described, starting from piperazine 2 and N-chloroacetyl-2,6-xylidine 3. The unwanted N,N′-bis-alkylated product 4 can be removed by simple filtration of the reaction mixture, while the excess of piperazine remains in the aqueous phase after extracting the filtrate with toluene at 70°C. The product precipitates from the organic phase with 68% active yield.
Herein we describe the scalable diastereoselective and enantioselective syntheses of eight enantiomers of hydroxy metabolites of saperconazole. The in vitro antifungal activity of the eight stereoisomers (compounds 1-8) was compared against a broad panel of Candida spp. (n=93), Aspergillus spp. (n=10), Cryptococcus spp. (n=19), and dermatophytes (n=27). The four 2S isomers 1-4 of the new agent were generally slightly more active than the four 2R isomers 5-8. All eight isomers were tested in a model of experimental A. fumigatus infection in guinea pigs by intravenous inoculation of the fungal conidia. Treatment doses were 1.25 mg kg(-1) and 2.5 mg kg(-1) per day. Infection severity was measured in terms of mean survival time (MST) after infection and mean tissue burdens in brain, liver, spleen, and kidney at postmortem examination. Among the eight isomers, the 2S diastereomers 1-4 showed a generally higher level of activity than the 2R diastereomers 5-8, revealing compounds 1 and 4 as the most potent overall in eradicating tissue burden and MST. Compared with reference compounds itraconazole and saperconazole, the hydroxy isomers 1-8 are less potent inhibitors of the growth of A. fumigatus in vitro and of ergosterol biosynthesis in both A. fumigatus and C. albicans.
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