Purification problems

Solid phase peptide synthesis does not solve all purification problems however Even if every coupling step m the ribonuclease synthesis proceeded in 99% yield the product would be contaminated with many different peptides containing 123 ammo acids 122 ammo acids and so on Thus Memfield and Gutte s six weeks of synthesis was fol lowed by four months spent m purifying the final product The technique has since been refined to the point that yields at the 99% level and greater are achieved with current instrumentation and thousands of peptides and peptide analogs have been prepared by the solid phase method... 

Solvent Preparation. The most critical aspect of the solvent is that it must be dry (less than 0.02 wt % of H2O) and free of O2. If the H2O content is above 0.02 wt %, then the reaction of Mg and RX does not initiate, except for an extremely reactive RX species, such as benzyl bromide. Although adventitious O2 does not retard the initiation process, the O2 reacts with the Grignard reagent to form a RMg02X species. Furthermore, upon hydrolysis, the oxidized Grignard reagent forms a ROH species that may cause purification problems. 

Purification. Purification problems are primarily solved by two methods continuous vacuum fractionation and chemical combination to yield a high boiling ester, separation of the noncombining impurities by distillation, and hydrolysis of the ester. Although the product produced by continuous vacuum fractionation satisfies most needs, shows no impurities by glc, is odor-acceptable, and thus is used to produce most of the PEA for commercial use, for highest requirements chemical purification by the borate ester is required. 

Supercriticalfluid solvents are those formed by operating a system above the critical conditions of the solvent. SolubiHties of many solutes ia such fluids often is much greater than those found for the same solutes but with the fluid at sub atmospheric conditions. Recently, there has been considerable iaterest ia usiag supercritical fluids as solvents ia the production of certain crystalline materials because of the special properties of the product crystals. Rapid expansion of a supercritical system rapidly reduces the solubiHty of a solute throughout the entire mixture. The resulting high supersaturation produces fine crystals of relatively uniform size. Moreover, the solvent poses no purification problems because it simply becomes a gas as the system conditions are reduced below critical. 

References to recent examples may be found in the reviews of Owyang and Walker. Selenium dioxide has been superseded in most instances by DDQ, which generally gives higher yields and fewer purification problems. 

Although primary catalyst cost is not a major factor in the price of the product, the work of the catalyst chemist of course crucially affects a wide variety of process costs that are of far greater significance. What goes on in the reactor dictates feedstock requirements, capital charges, downtime for catalyst recharging, and strongly influences the purification problems... 

The general procedure described here was originally published by the submitters.3 Both ketones and aldehydes may be prepared, and this method is particularly effective when the mild conditions of the Moffat oxidation are required, but the dicyclohexylurea by-product formed with the usual reagents causes purification problems. 

Previous syntheses An example of this point can be recognized by examination of one known synthesis of thienobenzazepines (Scheme 6.1). This synthetic route involves a key palladinm-catalyzed cross-conpling of stannyl intermediate 3, prepared by method of Gronowitz et al., with 2-nitrobenzyl bromide. Acetal deprotection and reductive cyclization afforded the desired thienobenzazepine tricycle 4. In support of structure activity relationship studies, this intermediate was conveniently acylated with varions acyl chlorides to yield several biologically active componnds of structure type 5. While this synthetic approach does access intermediate 4 in relatively few synthetic transformations for stractnre activity relationship studies, this route is seemingly nnattractive for preparative scale requiring stoichiometric amounts of potentially toxic metals that are generally difficult to remove and present costly purification problems at the end of the synthesis. 

Owing to the expense, toxicity, and purification problems associated with use of stoichiometric amounts of tin hydrides, there has been interest in finding other hydrogen atom donors.205 The trialkylboron-oxygen system for radical generation (see Part A, Section 11.1.4) has been used with fra-(trimethylsilyl)silane or diphenylsilane as a hydrogen donor.206... 

The ubiquity of lignin in plant tissue presents an obstacle to the removal and purification of xylan. Lignin retards or prevents the complete solution of xylan either because of mechanical obstruction or perhaps by reason of attachment through as yet unidentified covalent bonds. Furthermore, lignin is partially soluble in the various aqueous alkaline solutions used for dissolving xylan and, consequently, poses a purification problem in various subsequent steps designed to isolate the pure polysaccharide. 

Coupling the substituents to the polyacid core is a key step. The reaction must have a high yield to limit purification problems and show high selectivity between the amines and alcohols present to limit side reactions. The amidifica-tion reaction chosen is a coupling reaction used in peptide chemistry. The reaction is carried out at room temperature in the presence of a coupling reagent such as NjAT -dicyclohexylcarbodiimide, l-(3-dimethylaminopropyl)-3-ethylcar-bodiimide or l-ethoxycarbonyl-2-ethoxyl-l,2-dihydroquinoline, possibly in the presence of an activator such as hydroxybenzotriazole or N-hydroxysuccimide (Fig. 8). 

A virtue of the silane donors is that they avoid the by-products of stannane reactions, which frequently cause purification problems. 

Column chromatographic techniques have been utilized for the most part. The development of analogous HPLC methods will certainly assist in solving the purification problems. 

An early synthesis of A5-palmitoy]-.S -[2,3-bis(palmitoyloxy)propyl]cysteine employed cysteine methyl ester, however, this leads to difficulties in the saponification step of the tri-palmitoylated residue. 96 The optimized procedure, in which the cystine di-fert-butyl ester is used, 90 is outlined in Scheme 6 after N-acylation with palmitoyl chloride, the ester is reduced to the cysteine derivative for S-alkylation with l-bromopropane-2,3-diol to yield chirally defined isomers if optically pure bromo derivatives are used. Esterification of the hydroxy groups is best carried out with a 1.25-fold excess of palmitic acid, DCC, and DMAP. The use of a larger excess of palmitoyl chloride is not recommended due to purification problems. The diastereomeric mixture can be separated by silica gel chromatography using CH2Cl2/EtOAc (20 1) as eluent and the configuration was assigned by comparison with an optically pure sample obtained with 2R)- -bromopropane-2,3-diol. 

The radiation-induced oxidation of cyanide and sulfide have been suggested by Selke (Sll) as an attractive method of waste disposal. By using radiation for destruction rather than for synthesis, side-product and purification problems are eliminated. 

Therefore, the determination of ultra-high molecular weight polymers is, in general, not easy to perform (purification problem), and in addition the determination of increasing molecular weight becomes increasingly limited. 

Purification. Purification problems are primarily solved by two methods continuous vacuum fractionation and chemical combination to yield a high boiling ester, separation of the noncombining impurities by distillation, and hydrolysis of the ester. 

Dilution with a solvent causes however a lower productivity and, at times, downstream purification problems solventless "neat" processes are occasionally claimed [21]. 

In general, biosynthetic procedures are likely to be laborious and limited to small-scale operations. One often encounters purification problems when attempting to isolate specific biological compounds in a typical system. 

The procedure described represents the conversion, through a change in the coordination number of boron and nitrogen, of a six-membered boron nitrogen ring to a four-membered boron nitrogen ring.1 The absence of other reaction products in the direct union simplifies the purification problem. 

The Schering synthesis of a A9,11-intermediate, essentially by dehydration of an 1 la-hydroxy intermediate, always resulted in the formation of approximately 10% (frequently more) of an unwanted A11,12-olefine. Formation of this impurity not only diverted valuable starting steroid into useless product, but also caused purification problems in later process steps. Although dehydration of 9 a-hydroxysteroids can lead to formation of a A8,9-olefine impurity (see (footnote 92(a)), this unwanted reaction has been shown to be avoidable [see Beaton, J. M., Huber, J. E., Padilla, A. G., and Breuer, M. E. U.S. Patent 4,127,596, 1978 (to Upjohn) and VanRheenen, V., and Shephard, K. P. J. Org. Chem., 1979, 44, 1582.]... 

The electrochemical reduction process applied to cephalosporins gave <70% yield of desired exomethylene product, thereby introducing substantial purification problems to add to the yield losses. 

Yields are scattering very likely due to purification problems in some cases (Table 11). Similar to the thiophene series, oxidation of the hemiaminal 229 leads to the unsaturated lactam 230. 

We have already seen that the SN1 and SN2 reactions may be in competition under certain circumstances. In addition, other reactions also compete with these two. If we are trying to prepare a specific compound, these competing reactions often result in a lower yield of the desired compound and may also cause purification problems. 

The direct chlorination of ethylene usually is run in the liquid phase and is catalyzed with ferric chloride. High-purity ethylene normally is used to avoid product purification problems. The cracking (pyrolysis) of EDC to VCM typically is carried out at temperatures of 430-530°C without a catalyst. The hot gases are quenched and distilled to remove HC1 and then VCM. The unconverted EDC is returned to the EDC purification train. The... 

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