Mechanochemical techniques for formation

Pyridyl ureas obtained by this protocol were used in the next synthetic step, formation of pyridinium salts, a tripodal anion receptors 149 by Af-alkylation (Scheme 3.41). In aU cases the solid reactants consisting of a pyridine derivative 148 and bromomethylaled triethylbenzene derivative 147 were milled for 1 h. LAG technique was used in aU cases (acetonitrile), except for compound R=H (Br ) where a liquid was used as a reagent. The solid-state synthesis appears to be significantly cleaner than the solntion-state method with significantly less impurity. Addition of methanol, filtration, and precipitation of product with NH4PF6 were employed for purification. In most cases, the mechanochemical technique is able to... 

Besides synthesis of pharmaceutical co-crystals, mechanosynthesis has been successfully applied to the synthesis of pharmaceutical salts. Trask et al. have demonstrated mechanochemical screening for pharmaceutical salts by grinding the model API molecules trimethoprim and pyrimethamine with seven pharmaceutically acceptable carboxylic acids formic, acetic, maleic, fumaric, succinic, glutaric and salicylic. The results of screening experiments (Table 8.2) demonstrate that LAG is more versatile than neat grinding in screening for pharmaceutical salts. More importantly, the application of mechanochemical techniques not only led to the formation of already reported salt forms but also enabled the discovery of 14 new salt forms. 

The real-time in situ synchrotron PXRD technique found its next application in the mechanistic study of mechanochemically promoted co-crystallization of carbamazepine and nicotinamide as representatives of active pharmaceutical ingredients (API) [62], In the case of carbamazepine saccharin co-crystal, in situ analysis confirmed previous studies by cryomiUing that neat grinding led to amorphization while LAG synthesis rapidly produced the co-crystal. The other investigated system involved two-step neat grinding synthesis of nicotinamide suberic acid 2 1 co-crystal. The ex situ PXRD analysis had revealed a stepwise mechanism with the 1 1 cocrystal as the intermediate. Whereas LAG synthesis was too fast for ex situ approach, in situ monitoring enabled the discovery of an unknown phase that preceded the rapid formation of the 1 1 intermediate (Fig. 1.28). However, the authors were not successful at full characterization of the new phase due to its pronounced instability. 

Hapiot et al. used ball-milling technique to transform a-, p-, and y-cyclodextrins (CDs) 36-38 into their epoxides 42-44 (Scheme 4.10). This reaction was achieved with zirconia jar and ball in two reaction steps 0-tosylation of vicinal diols and subsequent epoxide formation by internal displacement of tosylate [6]. Authors have found that CDs could be tosylated with Af-tosylimidazole (Tsim), in the presence of an inorganic base (in stoichiometric proportions). Results were dependent on the inorganic base applied, but for all bases applied in short time (optimal conversion within 6min), for which KOH gave the highest yields in only 80s. Mechanochemical... 

Evaporating solid polymeric particles (accompanied by considerable pyrolysis) and codepositing the volatile products (mostly radicals) with the metal vapor are used less often. This technique is employed for the formation of 10-mn-diameter copper islets in a polyethylene matrix. The explosive evaporation of a metal wire coated with a polymer and pulsed mechanochemical interactions (of the Bridgeman anvil type), etc. are the modifications of this method. Recently, interest has been shown in the ionic spraying of metals onto polymeric surfaces. Studies of the vacuum deposition of Au and Zn on PE and PTFE should be noted. " ... 

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