Solvent switching

Presently, the on-line coupling of NPLC and GC via heart-cutting is an established procedure which has been used successfully for several bioanalytical applications. Obviously, dfrect analysis of aqueous samples is not possible by NPLC, and therefore, a solvent switch by a sample pretreatment step (e.g. liquid-liquid extraction or SPE) is always requfred when biological samples are analysed by NPLC-GC. 

Fragmentation occurs because the repeller voltage increases the kinetic energy of the ions, not only making collision-induced dissociation (CID) more likely but also allowing endothermic ion-molecule and solvent-switching reactions to occur. 

As mentioned earlier, a major cause of high costs in fine chemicals manufacturing is the complexity of the processes. Hence, the key to more economical processes is reduction of the number of unit operations by judicious process integration. This pertains to the successful integration of, for example, chemical and biocatalytic steps, or of reaction steps with (catalyst) separations. A recurring problem in the batch-wise production of fine chemicals is the (perceived) necessity for solvent switches from one reaction step to another or from the reaction to the product separation. Process simplification, e.g. by integration of reaction and separation steps into a single unit operation, will provide obvious economic and environmental benefits. Examples include catalytic distillation, and the use of (catalytic) membranes to facilitate separation of products from catalysts. 

C in a TH F-toluene-hexane mixture. After the mixture was cooled below —50 °C, ketone 41 was added. After 60min, the reaction was quenched with aqueous citric acid. The organic layer was then solvent switched into toluene, and the product 50 was crystallized by the addition of heptane (91-93% isolated yield, >99.5% ee). The chiral modifier 46 is easily recycled from the aqueous layer by basification with NaOH and extraction into toluene to recover 46 (>99% purity, 98% recovery yield). The modifier has been recycled up to nine times in subsequent chiral addition reactions without any problem. 

IC1 was quenched with sodium thiosulfate. A solvent switch from MeOH to EtOAc followed by water wash allowed isolation of the crude iodoaniline 28 in solution in EtOAc. Subsequent crystallization from EtOAc-heptane afforded iodoaniline 28 in 95% yield in >99A% purity. The procedure was quite robust and produced high quality 28 that could readily be used in the coupling step. 

The ratio of 8Z to HE is slightly better in the presence of DABCO in THF (Table 6.2 entry 9) than in pure methanol (Table 6.2 entry 7). Since the DABCO must be removed prior to the thermal rearrangement and the minimal impact on overall yield, we decided to run the Michael addition in methanol to afford a mixture of Z- and -adducts 8 in quantitative yield. The resulting solution of adducts 8 was solvent-switched to xylenes and heated at 125 °C for 2h, and at 135 °C for 4h to give a 62% assay yield of desired product 3. The reaction mixture was concentrated and hydroxypyrimidinone 3 was directly crystallized in 54% isolated yield as a white crystalline solid. 

An alternative system proved to be both simpler and more user friendly (Unger et al., 2004 Machtejevas et al., 2006). Thus far we have used this configuration to analyze human plasma, sputum, urine, cerebrospinal fluid, and rat plasma. For each particular analysis we set up an analytical system based on a simple but specific strategy (Figure 9.5). The analysis concept is based on an online sample preparation and a two-dimensional LC system preseparating the majority of the matrix components from the analytes that are retained on a RAM-SCX column followed by a solvent switch and transfer of the trapped peptides. The SCX elution used five salt steps created by mixing 20 mM phosphate buffer (pH 2.5) (eluent Al) and 20 mM phosphate buffer with 1.5 M sodium chloride (eluent Bl) in the following proportions 85/15 70/30 65/45 45/55 0/100 with at the constant 0.1 mL/min flow rate. Desorption of the... 

Z.H. Ge, B. Buchanan, J. Timmermans, D. De Tora, D. Elhson and J. Wyvratt, On-hne monitoring of the distillates of a solvent switch process hy near-infrared spectroscopy. Process Contr. Qual., 11(4), 277-287 (1999). 

TTiese include an IBM PC/AT computer that functions in conjunction with a Zymate System V Controller located beneath the table top. Other devices located on this table include an autotitrator with solvent/titrant reservoirs, a pneumatic solvent switching valve, a metering pump, and a Zymark Power and Event Controller (PEC). A bar code printer provides labels for sample vials, and a printer is used for hard copy report generation. The devices mounted on the robot table (approximately 90x 1 SO cm) are listed in Table 6.S. 

Such monosolvated ions are of interest themselves, for thermochemical reasons. The solvent-switching reactions just described can be carried out in an equilibrium fashion, as shown in reactions (14) and (15). 

The approach to method development is similar to the one described for HPLC and can be characterized as a rapid stationary phase screen using column and solvent switching with gradient elution followed by development of an isocratic preparative method. SFC has been successfully applied to the analytical and preparative separation of achiral and chiral compounds. 

Mass intensity measures the amount of material needed to synthesize the desired product. It takes into account yield, reaction stoichiometry, solvents, and reagents in a reaction mixture, and this covers everything that is put into a reaction vessel. It also includes all mass used in acid, base, salt and organic solvent washes, and organic solvents used in extractions, crystallizahons, or solvent switching. 

The tartrate salt was then converted to the phosphate salt, the desired salt form of sitagliptin by free-basing first with KOH in aqueous THF, solvent-switching the organic phase to ethanol and adding phosphoric acid to crystallize the phosphate salt in 93% yield with high enantiomeric and chemical purities. 

Ge, Z. Buchanan, B. Timmermans, J. etal., On-line monitoring of the distillates of a solvent switch process by near-infrared spectroscopy Process Contr. Quad. 1999, 11, 277-287. 

Utilizing this interesting phenomenon, a practical continuous resolution procedure was devised with a solvent switch method.47,48 At first, (.V)-saJt was resolved with (S)-TPA from MeOH, and the mother liquor containing (R)-enriched ACL and equimolar resolving agent (S)-TPA was concentrated to dryness. To the residue was... 

Sakai, K., Sakurai, R., Yuzawa, A. and Hirayama, N. (2003) Practical continuous resolution of a-amino-E-caprolactam by diastereomeric salt formation using a single resolving agent with a solvent switch method, Tetrahedron Asymmetry 14, 3713-3718. 

Assembling a line of reactors Linear, divergent as well as convergent multistep syntheses are also feasible Issue solvent switching. If reaction times are not similar, switching and recycling valves are required... 

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