Isomeric impurities

Heating with cuprous chloride in aqueous hydrochloric acid isomerizes 2-butene-l,4-diol to 3-butene-l,2-diol (98)] Various hydrogen-transfer catalysts isomerize it to 4-hydroxybutyraldehyde [25714-71-0] (99), acetals of which are found as impurities in commercial butanediol and... 

Naturally Derived Materials. The following are descriptions of some of the most important naturally derived materials in use. Importance in this context is defined in terms of the total value of the materials, which range from expensive, low volume materials that have great aesthetic value to relatively inexpensive and widely used products. Eor some of the naturals, it is indicated whether they can be distilled to provide individual chemicals for use as such or as intermediates. Materials produced in this way from a given natural source are usually not interchangeable with those from other naturals or synthetics. In some cases this may be due to optical isomerism, which can have a significant effect on odor, but usually it is due to trace impurities. 

A study was conducted to measure the concentration of D-fenfluramine HCl (desired product) and L-fenfluramine HCl (enantiomeric impurity) in the final pharmaceutical product, in the possible presence of its isomeric variants (57). Sensitivity, stabiUty, and specificity were enhanced by derivatizing the analyte with 3,5-dinitrophenylisocyanate using a Pirkle chiral recognition approach. Analysis of the caUbration curve data and quaUty assurance samples showed an overall assay precision of 1.78 and 2.52%, for D-fenfluramine HCl and L-fenfluramine, with an overall intra-assay precision of 4.75 and 3.67%, respectively. The minimum quantitation limit was 50 ng/mL, having a minimum signal-to-noise ratio of 10, with relative standard deviations of 2.39 and 3.62% for D-fenfluramine and L-fenfluramine. 

Refining and Isomerization. Whatever chlorination process is used, the cmde product is separated by distillation. In successive steps, residual butadiene is stripped for recycle, impurities boiling between butadiene (—5° C) and 3,4-dichloto-l-butene [760-23-6] (123°C) are separated and discarded, the 3,4 isomer is produced, and 1,4 isomers (140—150°C) are separated from higher boiling by-products. Distillation is typically carried out continuously at reduced pressure in corrosion-resistant columns. Ferrous materials are avoided because of catalytic effects of dissolved metal as well as unacceptable corrosion rates. Nickel is satisfactory as long as the process streams are kept extremely dry. 

Isomerization of ethylene oxide to acetaldehyde occurs at elevated temperatures ia the presence of catalysts such as activated alumina, phosphoric acid, and metallic phosphates (75). Iron oxides also catalyze this reaction. Acetaldehyde may be found as a trace impurity ia ethylene oxide. 

The impurities present in aromatic nitro compounds depend on the aromatic portion of the molecule. Thus, benzene, phenols or anilines are probable impurities in nitrobenzene, nitrophenols and nitroanilines, respectively. Purification should be carried out accordingly. Isomeric compounds are likely to remain as impurities after the preliminary purifications to remove basic and acidic contaminants. For example, o-nitrophenol may be found in samples ofp-nitrophenol. Usually, the ri-nitro compounds are more steam volatile than the p-nitro isomers, and can be separated in this way. Polynitro impurities in mononitro compounds can be readily removed because of their relatively lower solubilities in solvents. With acidic or basic nitro compounds which cannot be separated in the above manner, advantage may be taken of their differences in pK values (see Chapter 1). The compounds can thus be purified by preliminary extractions with several sets of aqueous buffers... 

Tri-p-tolyl phosphate [20756-92-7, 1330-78-5 (isomeric tritolyl phosphate mixture)] M 368.4, b 232-234 , d 1.16484, n 1.56703. Dried with CaCl2, then distd under vacuum and percolated through a column of alumina. Passage through a packed column at 150°, with a counter-current stream of nitrogen, under reduced pressure, removed residual traces of volatile impurities. 

The only practical method of preparing 1,4-aminonaphthol is from a-naphthol through an azo dye, the nitroso compound not being readily available. The majority of investigators have reduced technical Orange I with stannous chloride Mi.is.is.ir.is by the procedures discussed above, and benzeneazo-a-naphthol has been reduced by the same reagent. In order to make possible the use of crude, technical a-naphthol a method has been developed for the preparation of the benzeneazo compound, its separation from the isomeric dye coming from the d-naphthol present as well as from any disazo compound by extraction with alkali, and the reduction of the azo compound in alkaline solution with sodium hydrosulfite. The process, however, is tedious and yields an impure product. 

Linalol, CjoHjgO, is isomeric with geraniol and nerol, but it is structurally isomeric, and not stereoisomeric, as it is known in both optical forms. It was first isolated by Morin from oil of linaloe. The same body has been isolated from various other essential oils, an[Pg.114]

Schimmel Co. attempted to acetylise the alcohol by means of acetic anhydride, but the reaction product only showed 5 per cent, of ester, which was not submitted to further examination. The bulk of the alcohol had been converted into a hydrocarbon, with loss of water. Ninety per cent, formic acid is most suitable for splitting off water. Gne hundred grams of the sesquiterpene alcohol were heated to boiling-point with three times the quantity of formic acid, well shaken, and, after cooling, mixed with water. The layer of oil removed from the liquid was freed fi-om resinous impurities by steam-distillation, and then fractionated at atmo.spheric pressure. It was then found to consist of a mixture of dextro-rotatory and laevo-rotatory hydrocarbons. By repeated fractional distillation, partly in vacuo, partly at ordinary pressure, it was possible to separate two isomeric sesquiterpenes, which, after treatment with aqueous alkali, and distillation over metallic sodium, showed the following physical constants —... 

Hydrogenation of acetylenic carbinols is sometimes accompanied by isomerization to the ketone. In the case of 13, the isomerization to 15 was most pronounced when hydrogenations proceeded very slowly as when impure 13 was used (39). 

It is essential to determine the concentration of each isomer and define limits for all isomeric components, impurities, and contaminants of the compound tested preclin-ically that is intended for use in clinical trials. The maximum level of impurities in a stereoisomeric product used in clinical studies should not exceed that in the material evaluated in nonclinical toxicity studies. This point is expanded in the ICH impurities guideline (Section 13.5.3). 

Gas chromatographic analysis, using an HMDS-treated Chromo-sorb W column with 7% Craig polyester as the stationary phase, indicated the product to have a purity of 97%. The 3% impurity is most probably the isomeric 1-methylcyclohexene. 

It has been found50 that such a multielectron step does not exist with 58, which exhibits a classical two-electron scission. In general, allylic sulphones (59) without an unsaturated system in a suitable position are not reducible. Thus, they do not exhibit a cathodic step in protic solutions. However, in aprotic media the isomerization may be base catalyzed, since small amounts of electrogenerated bases from electroactive impurities, even at low concentration, may contribute to start the isomerization. Figure 10 shows the behaviour of t-butyl allylic sulphone which is readily transformed in the absence of proton donor. On the other hand, 60 is not isomerized but exhibits a specific step (Figure 10, curve a) at very negative potentials. 

Replacement of organic solvents by water may be done for environmental, cost e.g. reduction in raw materials and VOC containment costs) or technical reasons. In the flavour and fragrance industry, where the presence of even trace amounts of volatile impurities can be detected by the expert nose , significant process costs are entailed in ensuring complete removal of solvent. If reactions can be carried out in water then these additional costs can be saved. As an example geraniol can be isomerized to the important fragrance intermediates a-terpinol and linalol in water at 220 °C (Scheme 5.9). 

Rearrangement of trivalent (5-hexenyl)Co(salen) proceeds via a radical chain process leading to the isomeric cyclopentylmethyl complex.1387 The efficiency with which this rearrangement occurs is dependent on the presence of trace impurities or 02. The selective reaction of alcohols (ROH) with arylglyoxals (ArCOCHO) to give a-aryl-a-hydroxyacetic esters ArCH(0H)C02R is catalyzed by compounds of this family.1388... 

Nitration of the ester with 90% nitric acid was effected according to a literature method. Examination of the reaction mixture by TLC showed that both expected mononitro derivatives had been formed, and it was allowed to stand at ambient temperature overnight. Ice and dichloromethane were then added, and the separated solvent layer was washed with aqueous sodium hydrogen carbonate, dried, and then freed of solvent by evaporation. The viscous oily residue decomposed and ignited in the flask. The preparation was repeated, but worked up immediately and under nitrogen while still cold, and furnished samples of both of the pine isomeric nitro derivatives. Thermal analysis of these showed both to be thermally stable. It was concluded that the decomposition was due to an impurity formed during the 16 h interval between nitration and work-up. 

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