Preferred Solvent for Synthesizing a Compound that can be Reversibly Extracted into Water.

 

Suppose I were presented with the problem of synthesising an organic compound that can be reversibly extracted into water at some pH (ie, an acid or base). Further, suppose that there is no powerful reason to use a particular solvent for the transformation, but I do know the plant reactor in which the reaction will likely be run in. What would my dream solvent be?

I know the minimum storable volume of the proposed reactor and the maximum volume of the reactor. So I would use a two-component solvent made up of o-dichlorobenzene and hexane. The ratio of hexane to o-dichlorobenzene would be (1/2 maximum volume - minimum stirrable volume) ÷ Minimum stirrable volume. 

Why o-dichlorobenzene? I want to be able to use enough o-dischlorobenzene to fully occupy the minimum storable volume in case it is necessary at some point to distil away all the hexane. Also, o-dichlorobenzene has a density of 1.31, so it will constitute the lower phase if I need to do a liquid-liquid extraction after distilling away hexane. Also, o-dichlorobenzene has a boiling point of 180 C, so it can serve as a chaser if I need to distil away any other solvents with significantly lower boiling points.

Why hexane? Hexane will ensure that the reaction temperature cannot, without resistance, go above 68.7 °C, the boiling point of hexane. I do not know what the optimal reaction temperature will be. A hydrocarbon cosolvent gives me the greatest number of very similar alternatives with different boiling points, which can serve as alternate stable reaction temperatures. Why the particular hexane: o-dichlorobenzene ratio? When I scale up, I want the o-dichlorobenzene to fill the minimum storable volume, while the reactor itself will be only half-filled in case I need to add more volume or perhaps an aqueous layer.

Hexane would be no more than my first choice for the second component of the solvent mixture, however, because any, preferably but not mandatory, water-immiscible solvent that can be distilled away from o-dichlorobenzene might function. I use a mixture of cosolvents because that makes the solvent composition adjustable during optimisation, knowing that waste solvents in the pharmaceutical and fine chemicals businesses are rarely recovered. 

The essential elements of this methodology for making a water-extractable product are (i) to use one cosolvent with a density greater than water and a boiling point distinctly different from that of the second solvent, and in a volume sufficient to occupy the minimum stirrable volume of the planned full-scale reactor and (ii) a final solvent that is immiscible with water.

The plan would be to conduct the chemical conversion at the best time-temperature combination studied. Then, optionally distil away the hexane, and add a water phase at the preferred pH to extract the desired product. Then drain away the lower chlorobenzene layer that contains any organically neutral & soluble co-products, byproducts, reagents or starting materials through the reactor’s bottom valve. Subsequently, any lighter than water organic solvent immiscible with water can be added into the reactor, and after adjusting the pH appropriately, the product will switch back into this upper organic layer, and the water can be drained off to waste. The product will remain partially worked-up, potentially in a solvent from which it can be crystallised or precipitated!

Building Organic Chemistry Synthetic Processes Retrosynthetically

To develop a synthetic process the chemist needs a sequence of chemical reactions and their work-ups, isolations, and intermediate purifications that can be scaled up.  

This is obvious. 

What is less obvious or unrecognized is that the sequence should most advantageously be planned so that the final intermediate before the transformation that gives the target final product, should be one which can be flexibly purified by some rugged methodology, so  that

1. Off-spec material can be upgraded and

2. New impurities introduced by changing prior steps in the reaction sequence will not make it into the final product, where they could change the product’s characteristics, require new impurity identifications, change the analytical methods that have been developed, or require, most critically, that clinical trials be repeated.

Although the functionality in this last intermediate can be anything that can meet this readily purified criterion, having an ionizable acidic and/or basic functionality is the most predictable way to achieve this. However, many targets will not have such a functionality, though most pharmaceutical products will, since salt forms are most desired for making oral tablets.

In US 6204383B1 issued to Torcan Chemical Ltd. for a new synthesis of Sildenafil, the route was planned so that the basic nitrogen functionality was inserted at the end of the synthesis, and the final intermediate was a neutral species.

In fact, the patent reads in its introduction:

 

“As a relatively complicated synthetic organic chemical molecule, sildenafil requires a multi-step chemical synthesis. Any organic synthesis step, which is part of a complex multi-step synthesis, results in contamination of the intermediate with solvents, catalysts, starting materials, and by-products, and so introduces the requirement for purification. If a pharmaceutical grade of final product is to result, this cleaning must be done either as the contamination is caused, that is, in the work-up of the particular step, or at some subsequent point in the process. A rugged process is desirable, which is not demanding with regard to the purity of the intermediates and which allows for a very efficient cleaning during the isolation of the final drug product.

It is an object of the present invention to provide novel processes for preparing sildenafil that simplify the purification procedures and produces sildenafil in substantially pure form without involving complex purification procedures.

It is a further object of the present invention to provide intermediates useful for the preparation of sildenafil by such novel processes.”  

The reason this patent’s stated objective so matches my own thinking is that I was the company patent officer who wrote those words and conceived the strategy!

When there is no appropriate functionality to simplify purification in the product, it would be very advantageous if the last step removes one that has been built into the last intermediate! This makes reactions that remove an acid or basic group from a molecule very important.

The chemist, working out his scheme retro-synthetically, can replace the ultimate target with a penultimate target, which is the target molecule with such a removable acidic or basic function appended!

An example of this can be found in my US43574730A, a patent for making omeprazole. Omeprazole is neither acidic nor basic; that is, it can’t be extracted reversibly into an aqueous liquid layer by adjusting the pH of the water.  I set as my actual synthetic target, therefore, an intermediate that had a carboxylic acid bound to the omeprazole substructure in a fashion so that the final transformation would be an easy decarboxylation. This intermediate had the advantage that, before decarboxylating to give omeprazole, this precursor could be phase shifted into water, leaving any non-acidic materials, whether starting materials, byproducts, or unreacted starting materials, behind in the organic phase. Then, adjusting the pH, this intermediate would transfer back into fresh organic solvent and be decarboxylated to give clean omeprazole. The idea worked just as contemplated. In practice, it turned out that a preliminary secondary amide was the best way to work with the extra carboxyl functionality.