Armin Roessler

Direct, metal-free amination of heterocyclic amides/ureas with NH-heterocycles and N-substituted anilines in POCl3.

A POCl(3)-mediated, direct amination reaction of heterocyclic amides/ureas with NH-heterocycles or N-substituted anilines is described. Compared to the existing methods, this operationally simple protocol provides unique reactivity and functional group compatibility because of the metal-free, acidic reaction conditions. The yields are generally excellent.

An Improved Non-chromatographic Scale-up Synthesis of a New 1,6,7,8-Substituted-4-oxo-1,4-dihydroquinoline-3-carboxylic Acid as a Potent Bacterial Topoisomerase Inhibitor

7-[4-(2-Amino-1-chloroethylidene)piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4oxo-1,4-dihydroquinoline-3-carboxylic acid (10) is a potent bacterial topoisomerase inhibitor. In vitro, compound 10 is two-fold more potent than gemifloxacin when tested against ciprofloxacin-resistant Streptococcus pneumoniae clinical isolates (MIC90 = 1 μg/mL); it is also more potent than ciprofloxacin and gemifloxacin when tested against a collection of methicillin-resistant Staphylococcus aureus (MIC90 = 2 μg/mL) and coagulase-negative staphylococci isolates (MIC90 = 1 μg/mL).1,2 In order to prepare 100 g of compound 10 to facilitate in vivo investigation, it was decided to attempt to improve some of the steps of the original discovery medicinal chemistry (Discovery) route, an eight-step convergent synthesis with merely 6% overall yield of 10,1,2 and address the scale up issues that were identified in the following steps: first, the high exothermicity of the use of sodium hydride (NaH) to generate triethyl 2-chloro-2phosphonoacetate anion in the Horner-Wadsworth-Emmons reaction and its quenching (Step 1, Schemes 1), second, the reduction of ester 2 using DIBALH resulted in a 44% yield of alcohol 3 after chromatography (Step 2, Schemes 1), third, the product 4 of Mitsunobu reaction also required chromatographic purification (Step 3, Schemes 1), fourth the preparation of difluoroborate ester 7 required a large excess (11.9 equiv) of borontrifluoride etherate and extended reaction times (48–72 h), but gave only moderate to fair yields (50–78%) of 7 by precipitation of the crude product with diethyl ether