Solution-phase synthesis evaporations

As second example for the scale-up of solid-phase reactions directly on solid support, we chose an arylsulfonamido-substituted hydroxamic acid derivative stemming from the matrix metalloproteinase inhibitor library (MMP) of our research colleagues (Breitenstein et al. 2001). In this case, there was already a solution-phase synthesis available for comparison (see Scheme 4). The synthesis starts with the inline formation of a benzaldehyde 18 with the glycine methyl ester, which is then reduced to the benzylamine 20 using sodium borohydride in methanol/ THF (2 1). The sulfonamide formation is carried out in dioxane/H20 (2 1) with triethylamine as the base and after neutralisation and evaporation the product 21 can be crystallised from tert. butylmethyl ether. After deprotection with LiOH, the acid is activated by treatment with oxalyl chloride and finally converted into the hyroxamic acid 23 in 33.7% yield overall. 

The groups of Giacomelli and Taddei have developed a rapid solution-phase protocol for the synthesis of 1,4,5-trisubstituted pyrazole libraries (Scheme 6.194) [356]. The transformations involved the cyclization of a monosubstituted hydrazine with an enamino-/8-ketoester derived from a /8-ketoester and N,N-dimethylformamide dimethyl acetal (DMFDMA). The sites for molecular diversity in this approach are the substituents on the hydrazine (R3) and on the starting j3-keto ester (R1, R2). Subjecting a solution of the /8-keto ester in DMFDMA as solvent to 5 min of microwave irradiation (domestic oven) led to full and clean conversion to the corresponding enamine. After evaporation of the excess DMFDMA, ethanol was added to the crude reaction mixture followed by 1 equivalent of the hydrazine hydrochloride and 1.5 equivalents of triethylamine base. Further microwave irradiation for 8 min provided - after purification by filtration through a short silica gel column - the desired pyrazoles in >90% purity. 

Garr C, The use of evaporative light scattering in quality control of combinatorial libraries, Proceedings of the Materials of Solid and Solution Phase Combinatorial Synthesis Meeting, Princeton, NJ, 1997. 

The differentiation between a combination of one of these reaction blocks and a magnetic stirplate and a manual synthesizer is largely arbitrary. Versatile manual synthesizers (Table 3) that can be used for both solution- and solid-phase synthesis range from the aapptec Labmate to the Biichi Syncore, Chemspeed MSW 500, and Heidolph Synthesis 1 (Fig. 5). The Biichi Syncore can be equipped with a concentrator cover, which converts it into a parallel evaporator, or -with a filtration unit that permits top filtration from the reaction mixture and collection of the filtrate (Fig. 5). 

C. Garr, The Use of Evaporative Light Scattering in Quality Control of Combinatorial Libraries, Strategic Research Institute Proceedings of the Conference on Solid and Solution Phase Combinatorial Synthesis, New Orleans (1997). 

An apparatus for continuous-flow solution-phase reactions has been described (68) combining a flow reactor with a solvent extraction, continuous evaporation, and liquid chromatography system. A scheme for the use of this apparatus in dinucleotide synthesis has been proposed (46), but applications to the preparation of longer oligonucleotides have not been reported. 

The most intensive development of the nanoparticle area concerns the synthesis of metal particles for applications in physics or in micro/nano-electronics generally. Besides the use of physical techniques such as atom evaporation, synthetic techniques based on salt reduction or compound precipitation (oxides, sulfides, selenides, etc.) have been developed, and associated, in general, to a kinetic control of the reaction using high temperatures, slow addition of reactants, or use of micelles as nanoreactors [15-20]. Organometallic compounds have also previously been used as material precursors in high temperature decomposition processes, for example in chemical vapor deposition [21]. Metal carbonyls have been widely used as precursors of metals either in the gas phase (OMCVD for the deposition of films or nanoparticles) or in solution for the synthesis after thermal treatment [22], UV irradiation or sonolysis [23,24] of fine powders or metal nanoparticles. 

---