Chemical synthesis solution reaction procedures

Supercritical COj is used in different procedures for the formation of small particles, and also as an antisolvent to precipitate substances out of a solution in conventional solvents. Such small particles improve the dissolving kinetics of pharmaceuticals and are a precondition for inhalative applications. Dense CO2 is applied as a solvent for reactions and chemical synthesis, e.g. for hydrogenation of vegetable oils, and it is increasingly important for preparative-scale chromatographic separations which require large amounts of solvent that can be simply recycled in the supercritical process. 

Accessible precursor architectures (building imits, dimensionality of the polymer molecule) are dictated by the methods of the chemical synthesis of the monomer units and the associated polymerization reactions. The type of shape-forming procedure used (fiber-extrusion firom solution or melt, spincoating, etc.) engenders constraints on what is considered useful polymer rheology. Especially in the case of fiber-drawing or -extrusion the precursor should exhibit thixotropic or non-Newtonian viscoelastic behavior. The viscosity should be sufficiently high at zero shear such that once formed, the material will retain its new shape. 

A research team at Rhone-Poulenc reported a four-component procedure for the synthesis of variously substituted heteroaromatic tetrazolo[l,5-zz]pyrazines <1998TL2735>. Thus, aldehydes, primary amines, trimethylsilyl azide, and methyl /3-(iV,iV-dimethylamino)-a-isocyanoacrylates 117 were reacted in a methanolic solution at room temperature to yield the product 119 in high yields. The reaction was rationalized to proceed via the formation of intermediate 118. The procedure proved to be efficient for combinatorial chemical applications. 

Solution-phase synthesis [5] often needs purification or clean-up procedures after each reaction step to remove excess reagent. These methods include scavenging, extractions and associated plate transfers. All these procedures cause the loss of the desired compound. Although the purity can be improved after treatment, the chemical yield is seriously compromised. In contrast, SPOS has a unique advantage in purifying bound compound without losing compound mass. However, if the reaction is not complete at each step, the side products will form on resin and they cannot be removed while bound to the resin. The final yield and purity wiU both suffer as a result. A 90% yield for a four-step synthesis wiU produce the final product in a disappointing 65% yield. 

When the derivatives are required to convert to the parent 5-FU in vivo, appropriate substituents were introduced across the carbonyl groups in the chemical modification [20-25]. Though the first synthesis of acryloyl derivatives of 5-FU, which is the simplest polymerizable derivative, was done by Gebelein, the monomer has not been purified and collected [23]. In the present case, as shown in Scheme 2, silylated 5-FU was used instead of just 5-FU so as to give selectivity to the 1 TV-acylation similar to that of the acryloyl derivatives of thymine [9]. For the preparation of acryloyl-5-FU (AFU), methacryloyl-5-FU (MAFU) and / -vinylbenzoyl-5FU (VBFU), trimethylsilylated 5-FU (1) was allowed to react with acryloyl chloride, methacryloyl chloride and vinyl-benzoyl-chloride, respectively. The reaction was carried out in water-free acetonitrile solution after the addition of acid chloride at room temperature the solution was stirred for 30 min. This procedure afforded AFU in 16%, MAFU in 56%, and VBFU in 63% yield. 

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