kilomentor

Using the Bisulfite Adduct for Purification at Scale: Practical Purity and Purging of Impurities by the Process Steps

kilomentor | 25 March, 2013 19:01

I received the following comment regarding a recent blog post.

Dear Kilomentor,

I am trying to isolate CF3COAr (80% w/w assay) derivative compound from the ArBr (10% w/w and Piperidine COCF3 derivative (10% w/w) mixture . CF3COAr derivative is low melting solid (mp ~ 52 °C) and I don’t have the distillation data of the same. I just would like to know whether bisulfite adduct isolation can be attempted on 25 kg scale or which method you would suggest. Small scale preparation involves isolation by precipitation in cylcohexane (~ 50 % recovery) at lower temp (- 20 °C). Please suggest me if you have any experience.

Dear Marto,

Certainly the carbonyl of your desired product is electrophilic enough to react with bisulfite! My slight concern is that the trifluoromethyl anion might be displaced in a competing fragmentation reaction. A small scale test would quickly find this out. The conditions will need to be mild. This is an excellent example where isolating an easily reversed derivative should easily remove some substantial impurities. Note that it is not necessary that the bisulfite adduct actually precipitate for the method to work. It is sufficient that the ionic sodium bisulfite salt form and be extracted into an aqueous phase. If an appropriate inert, water-immiscible organic layer is also provided the bromobenzene and the piperidine trifluoroacetamide will remain substantially in the organic layer while the bisulfite adduct is in the water. Separating the liquid phases and acidification breaking the adduct should allow the trifluoroacetophenone to be taken back into a fresh organic layer from which it can be crystallized, precipitated or used directly in a subsequent reaction.

A separate concept can be used to remove the piperidine trifluoroacetamide, if it were somehow to still contaminate your product. It would seem it can be removed from your product mixture by treatment with some aqueous hydrochloric acid with a small amount of acetic acid cosolvent to promote solubility. This tertiary amide is probably rather sensitive to acid catalyzed hydrolysis because of the strong electron withdrawing strength of the trifluoromethyl. Furthermore, both hydrolysis cleavage products, piperidine hydrochloride, trifluoracetic acid as well as the acetic acid cosolvent all go to water. Although trifluoroacetophenone might have some sensitivity to basic fragmentation, it will be untouched by aqueous acid.

Bear in mind always, however, that what is done by way of purification is always dependent upon how you plan to use the product. If the subsequent transformations of your trifluoroacetophenone do not touch the impurities you have, then later separation may be easier or more convenient, or better still, the subsequent reactions may purge them for you. Even an intermediate with a rather low purity, like your 80%, might be practically pure enough, if the impurities don’t use up expensive reagents and don’t produce even more troublesome impurities by reacting further. Bear in mind though when using a low assay intermediate such as yours to do subsequent chemistry that your assay must be accurate because the upcoming stoichiometry will be dependent upon it! 

,

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The Potential Use of Acetic Acid and Acetic Anhydride for performing Solvent Switches during Work-Ups

kilomentor | 05 March, 2013 03:47


Each reaction in a chemical process has solvents in which the conversion works better and the preferred solvents for consecutive reactions in a scheme are usually different. As a consequence performing solvent switches is key to telescoping process steps thereby avoiding unnecessary intermediate isolations.

The boiling points of acetic acid and acetic anhydride respectively are 117 and 140 C. Acetic acid is infinitely miscible with water and is an excellent solvent for broad classes of substances. Mixing solutes dissolved in the acid with water leads to decreasing solubility of most organic compounds.

 Acetic anhydride is a solvent that reacts with solute molecules that have nucleophilic functionalities and particularly those with what is termed active hydrogen. Because of its high boiling point acetic anhydride can chase lower boiling solvents during distillation. It can then be itself removed by hydrolysis to acetic acid, optionally neutralized with dilute aqueous alkali, and washed away from lipophilic materials with water. Heating a solvent mixture in which acetic anhydride is a constituent dries it. Only enough acetic anhydride needs to be added to a crude product to provide liquidity then distillation can be continued until all the reaction solvent has been removed. Even if an acetate ester or amide is formed during the isolation, that can be reversed by alkaline hydrolysis after the solvent of the first reaction is removed.

Consider for example acetic anhydride’s potential for changing from the high boiling solvent chlorobenzene to ethyl acetate before crystallization. In such a scenario, a mixture of chlorobenzene and acetic anhydride could be distilled to remove chlorobenzene and some acetic anhydride. The still pot comprises in acetic anhydride and non-volatile reaction products. This residue does not solidify because of the presence of acetic anhydride. The minimum stirrable volume is maintained. Water is added along with the new second solvent which must be water immiscible, in this case ethyl acetate. Dilute mineral acid or base may be added to accelerate hydrolysis of the acetic anhydride. The acetic acid or acetate anion dissolves in the aqueous phase and is removed. The reaction mixture is left dissolved in the ethyl acetate.

In a different scenario, if the first solvent is low enough in boiling point, acetic acid itself can serve as the chase liquid for distilling out the first solvent. The product may not be particularly soluble in anhydrous acetic acid or the acetic acid can be subsequently diluted with water used as an antisolvent to cause precipitation or the acetic acid can be optionally neutralized and washed away in water after adding the new water-immiscible second solvent.

Potentially chloroacetic acid and chloroacetic acid anhydride can be considered for similar usage as acetic acid/acetic anhydride above. A key difference is that the chloroacetic acid esters are more easily hydrolyzed and can even be removed without exposure to either acid or base by treatment with thiourea. 

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A Question about Genotoxic Impurities

kilomentor | 02 March, 2013 21:15


Do medicinal and pharmaceutical development chemists suffer a greater incidence of cancers than the general population? This is a question for epidemiologists. I don’t know whether the answer is known or not. I suspect from anecdotal data, the answer is that our health is equal to or better than our peers. If this turns out to be so, then this casts serious doubt on the level of concern regarding genotoxic impurities. Let’s admit it. We medicinal and development chemists have come into contact with many compounds that on the basis of structure would be deemed likely genotoxic materials. If a substantial number of them are as dangerous as is claimed, why are we still doing all right healthwise? This isn’t to say we shouldn't take proper precautions, but remember, lots of us were doing chemistry for years before anyone thought about genotoxicity. Just to exemplify the situation in the past, I can vividly remember when I cleaned mercury metal  by wrapping it in a tea towel and squeezing it through into a large funnel using my bare hands!

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