Four-solvent optimization

A four-solvent optimization procedure that uses the mixture design statistical technique was applied by Coenegracht et al. [30]. 

Using the results of an earlier study concerning enantioselective copper-catalyzed intramolecular C—H insertion of metal carbenoids,109 an interesting system for optimizing the proper combination of ligand, transition metal, and solvent for the reaction of the diazo compound (75) was devised (see Scheme 19).110 The reaction parameters were varied systematically on a standard 96-well microtiter/filtration plate. A total of five different ligands, seven metal precursors, and four solvents were tested in an iterative optimization mode. Standard HPLC was used to monitor stereoselectivity following DDQ-induced oxidation. This type of catalyst search led to the... 

Telescoping, selecting reagents, and reaction optimization can afford significant decreases in the COG. The process route initially used to prepare 200 kg of the API intermediate acid 44 involved seven steps, four solvents, bromination, diazotization, and reaction with CO at 120°C, and produced the drug candidate in 20% yield. The optimized route shown in Scheme 2.12 was operationally simpler (using the same vessel for every... 

Coenegracht et al. [3] have introduced a four solvent system to compose mobile phases for the separation of the parent alkaloids in different medicinal dry plant materials, like Cinchona bark and Opium. Through the use of mixture designs and response surface modeling an optimal mobile phase was found for each type of plant material. These new mobile phases resulted in equally good or better separations than obtained by the procedures of the Pharmacopeias. Although separations were as predicted, the accuracy of the quantitative predictions needed to be improved. 

The second approach is the one followed by Drouen et al. [502]. It is based on the experience that only in very few cases does the optimization of a quaternary mobile phase composition in RPLC yield an optimum that is truly quaternary, i.e. contains all four solvents. Hence, the procedure discussed before for ternary solvents usually leads to the global optimum. This argument, correct though it may be, only applies to the particular problem of mobile phase optimization in RPLC, and prohibits the application of the same method to other two-parameter optimization problems [582]. 

The present model predicts how solvent selectivity will vary with mobile-phase composition, and this allows the selection of extreme solvents for maximum differences in selectivity. This information plus the ability to calculate solvent strength versus composition of the mobile phase then allows development of a general strategy for optimizing retention of any sample, so as to maximize resolution. This four-solvent approach can be further refined by use of computer-assisted procedures, such as the overlapping-resolution-mapping technique. 

Moreover, low-pressure systems often use three or four solvents. This multiple-solvent blending might also be useful for the optimization of both isocratic and gradient elution methods. This is an advantage that the high-pressure system also has when not using a gradient system, the operator has two independent isocratic pumps. 

OPTIMIZATION OF AN ISOCRATIC CHROMATOGRAM USING FOUR SOLVENTS... 

This type of optimization is tiresome to carry out in practice unless the chromatograph is provided with four solvent reservoirs and a suitable computer control facility. The latter can also be used to calculate and control the seven eluent mixtures. 

The new combined process is further optimized by using the more benign solvent, ethanol. This change eliminated the need to use, distill, and recover four solvents (methylene chloride, tetrahydrofuran, toluene, hexane) from the original synthesis. 

A four-solvent, seven-mixture optimization approach, similar to that described in Section IV.A above but based on Snyder s RP solvent strength (S) values (133), was illustrated by Sherma and Charvat (134) for C-18 RPTLC using methanol, acetonitrile, and THF, with water as the weak, strength-adjusting carrier. Additional solvent modifiers recommended for RPTLC include isopropanol, dimethylformamide, and DMSO. 

The PRISMA model method was introduced by Nyiredy and co-workers [19] for optimization of the mobile phase in reversed-phase HPLC. It has been effectively used in planar chromatography [20-23]. The PRISMA model is a structured trial and error approach and is a three-dimensional model, correlating the solvent strength and the selectivity of mobile phases. The solvent selection is performed according to Snyder s solvent classification [24], With this optimization model, the most advantageous mobile phase composition may be systematically elaborated, and from one to four solvents can be combined to achieve a suitable separation. 

With these four solvent combinations, chances are good to identify good separations, without investing too much time in looking for other possibilities. The immobilized CSPs offer of course much more possibilities, but in view of time and budget constraints frequently encountered in an industrial environment it is essential to make a compromise between the desire to find the optimal conditions and the objective to deliver the HPLC separation when it is needed. 

It was also shown that poly(ethylene glycol) (PEG), but not ILs, was the suitable solvent for Sonogashira reaction using carbapalladacycle complex as catalyst, Scheme 2.12 [55]. Here, the influence of [BMIm][PF, ], [BMMIm][PFg], [BMImJCl, and PEG on the reaction of l-(4-bromophenyl)ethanone and phenylacetylene was compared with CsOAc as co-catalyst. Under optimized reaction conditions and with a solvent-to-substrate ratio of 50 (w/w), the yields to the coupling product were 0%, 52%, 2%, and 88% in these four solvents. In the case of using PEG as solvent, CsOAc can be well dissolved in PEG and an active Pd NPs/PEG catalyst system could be obtained during the first run. The whole catalyst system could be recovered and reused for the next run without deactivation. Meanwhile, although Pd NPs were also formed in [BMIm][PF5] and [BMIm]Cl, the poor solubility of CsOAc in ILs resulted in low catalytic activity. 

Related to the nitrile oxide cycloadditions presented in Scheme 6.206 are 1,3-dipolar cycloaddition reactions of nitrones with alkenes leading to isoxazolidines. The group of Comes-Franchini has described cycloadditions of (Z)-a-phenyl-N-methylnitrone with allylic fluorides leading to enantiopure fluorine-containing isoxazolidines, and ultimately to amino polyols (Scheme 6.207) [374]. The reactions were carried out under solvent-free conditions in the presence of 5 mol% of either scandium(III) or indium(III) triflate. In the racemic series, an optimized 74% yield of an exo/endo mixture of cycloadducts was obtained within 15 min at 100 °C. In the case of the enantiopure allyl fluoride, a similar product distribution was achieved after 25 min at 100 °C. Reduction of the isoxazolidine cycloadducts with lithium aluminum hydride provided fluorinated enantiopure polyols of pharmaceutical interest possessing four stereocenters. 

The complexity of the method in terms of number of steps and solvents needed depends on the sorbent chemistry. The development in a simplified scenario involves running an analyte in several concentrations in multiple replicates and assaying for recovery and performance. This procedure is described in detail for several silica and polymeric sorbents by Wells.42 However, if a number of sorbents are to be evaluated, the process becomes time-consuming if multiple 96-well plates (each with one sorbent packed in all the wells) must be screened separately. This process may take a week or more and consume an analyst s precious time as well. The most plausible solution is to pack different sorbents in the same well plate and use a universal procedure that applies to all of them. An example of such a multisorbent method development plate is the four-sorbent plate recently introduced by Phenomenex demonstrated124 to require only 1 to 2 hr to determine optimal sorbent and SPE conditions. 

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