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.

Preparing a Resolution Standard for Use to Validate the Analytical Method for an Active Pharmaceutical Ingredient (API)

 

No analytical method can be proven able to identify all potential impurities in a sample. What can be demonstrated is that a refined method can separate more impurities more completely from the pure substance than others. To develop such a method one needs an impure sample of the desired product containing as many of the process’s potential impurities as possible. This material is called the resolution standard. Besides being used to choose an appropriate analytic protocol, this material is used to show that the analytical equipment is functioning as required by the protocol before samples are run.

How to Make a Resolution Standard

Batches of synthetic API that are quite evidently impure, made by the envisioned process, using whatever unvalidated methods have been used in process development, are selected. As large a sample of each batch is taken as can be sacrificed, and these samples are combined, mixed, and as large a portion as will fit is packed into a mechanical blender. An anti-solvent is added to cover and completely moisten the solid, and the mixture is blended thoroughly but without substantially raising the temperature of the mass. The blending is stopped, and the mass is left for several hours. The wet mass is filtered to remove all the triturated solid. The clear filtrate was concentrated to dryness under vacuum, keeping any warming to a minimum. This solid from the evaporation will be a material with intensified impurities. If a further increase in the proportion of impurities is desired, the same procedure should be repeated, triturating this sample identically.

The method is called swishing.    

A Proposed Cheap Replacement for Quinoline -3-carboxylic acid as a Reversible Tag

 

In 1999, Hélène Perrier and Marc Labelle [J. Org. Chem. 1999, 64 2110-2113 ] proposed using a 3-quinolinecarboxylate protecting group on a growing intermediate substrate to assist in isolating them at each step in a process by precipitating these substances as insoluble quinolinium salts.

The proposal seemed promising but at scale the cost of that protecting group inhibited adoption.

The KiloMentor blog has always aimed to promote and enhance methods that streamline isolation, purification, and workup procedures in synthetic organic chemistry.

In this particular instance, KiloMentor wishes to propose an inexpensive synthesis of a related 6-methyl-3-pyridinecarboxylic acid that might serve in the same way but that could be much cheaper to prepare.

The chemical literature already teaches the high-yield, simple, scalable synthesis of 2-methyl-5-aldehydo-4-pyridone in 75% isolated yield. [ F. Arya, J. Bouquant J. Chuche, Synthesis Communications 1983, 946-948 ] by continuous hot tube pyrolysis from the inexpensive inputs isopropyl amine, ethylformate and dimethylmalonate. 

The conversion of this 2-methyl-5-aldehydo-4-pyridone to  6-methyl-pyridine-3-carboxylic acid has not, as far as I know, been reported; however, it would seem that it might be made simply by the addition of the compound gradually to strong aqueous alkali to oxidize the aldehyde, reduce the ketone (Cannizzaro like) and then dehydrate the ring to aromatize the moiety. The resultant amino acid should be easily separated because of its acid-base properties.

KiloMentor Process Development Strategy Reviewed

 

KiloMentor | revised 6th  January 2009 republished February 17/2017 and March 22nd 2025

This is a revision of one of the earliest articles from the KiloMentor archives. The original was written in 2007.  It restates for new readers the core idea of the KiloMentor process development philosophy and teaches an approach that KiloMentor thinks leads consistently to valuable ideas. for improving process throughput.

In synthesis, we talk about assembling, building, or constructing a molecular structure. This is a misleading metaphor because we are comparing an activity in the nano-world to an activity in the macro-world. Operating in the macroscopic world, for example in building a house, we handle the pieces, we position the pieces, and we join the pieces.

In chemical synthesis, we do none of these. The substructures we are endeavoring to unite are atomic in scale: too small to touch, to align, or even to see. 

In chemical synthesis, the chemist adjusts macroscopic conditions: solvent ratios, stoichiometry, stirring, temperature, duration of exposure, etc. Then the chemist presents the proposed reaction partners, to each other under the orchestrated conditions and they interact, as their nature dictates; but, hopefully, this is also as we have planned.  How is this perspective different from the conventional one?  Chemical process development is simply making these parameter choices that cause nature’s choice to comply with what we want the outcome to be, efficient. Nature to be commanded must be obeyed.

According to the academic synthetic chemistry tradition, synthetic accomplishments are scored based on the number of synthetic steps, the yield per step, and the overall yield for the combination of steps. High yields are good. A short sequence is good. The combination is elegant. According to this traditional perspective, the focus is on the reactants, the plan for reactant transformation, and the overall yield output from that plan. Separation of unreacted starting materials, by-products, co-products, catalysts, solvents, salts, and other excipients and processing chemicals are in the background (the attitude is that work-up/purification can be done and will be done BUT these are not important criteria to evaluate the quality of the synthesis).  The give-away phrase of those who harbor this philosophy is “the product was isolated in the usual way.”

From the KiloMentor perspective, in this age of online substructure searching, coming up with creative transformations with strong literature analogies is no longer the domain of the synthetic genius but has come within the scope of good synthetic chemists. We do not have to depend upon our neuronal computers alone anymore. Now it is creative ideas for separation and purification that are not easy to search for and have become the greater artist skill of the project. The deconstruction of the chemical soup and the fishing out of the desired product in an adequate state of purity is paramount. 

Is there any particular value in this way of looking at processes that surpasses the traditional way which focuses on the series of chemical reactions while taking the separation of intermediates as an obvious technical work? My perspective emphasizes: 

• The work involved in setting up and controlling the necessary reaction conditions. 
• The work involved quenching the reaction condition/then working up the reaction and finally isolating and purifying the desired product. 

The value in this perspective is that in chemical synthesis, the money, manpower, and resources consumed during the reaction step phase, ie. while A & B are reacting with each other, is minuscule compared to the money, manpower, and resources expended preparing for the reaction and recovering pure product from the reaction. 

The clash of these perspectives leads to the question, “Which would I rather do- a four-step synthesis in which every conversion has many parameters that must be rigorously controlled and from which each intermediate must be isolated by gradient column chromatography and evaporated to a foam OR an eight-step synthesis which is rugged and forgiving of process deviations and from which each intermediate can be cleanly extracted in a separatory funnel or crystallized or distilled to give an adequate practical purity intermediate."

People have personal preferences and this is as it should be in a pluralistic society BUT I pick the second sequence and as the need for larger quantities and higher quality intensifies, I increasingly prefer the second route. 

Please note- I am not saying the number of chemical steps doesn’t matter. I am not saying that the overall yield does not matter. I am saying that elegance also encompasses simplicity, ruggedness, time economy, and scalability. 

OK, so what. How does this insight change our behavior in the synthetic laboratory, office, or library? Based on an examination of what really goes on in a chemical process step a method of rating the difficulties of the separation is proposed as a quantitative tool to rank the challenges of a process scale-up.

We should evaluate or rate synthetic schemes using more criteria:

1. Number of Chemical Steps
2. Isolated overall Yield
3. Yields of the Individual Steps.
4. Difficulty Rating for Each Reaction Mixture Separation

The fourth point comprises the new insight. How could we execute this new difficulty rating? We could classify work-ups:

A. The product can be separated practically pure by simply liquid-liquid extraction (ie acid-base pH or other phase switching)

B. Product can be separated by crystallization of precipitation as a filterable solid.

C. Product can be separated by atmospheric or vacuum distillation based on a projected difference in boiling points (based on molecular weights)

D. Product can be separated based on chemical reactivity (formation of reversible simply separable derivative, or destruction of contaminant by reaction)

E. The product seems likely only to be separable in practical purity by chromatography.

Clearly, as process chemists, we want to face more A-C separations and fewer D-E type separations.

The KiloMentor blog will highlight methods to augment isolations and purifications so chemists can improve their ability to assign these ratings and take them into account when designing synthetic chemical processes that can be readily and ruggedly scaled up into the plant.

The Advantages of Ethanol-Cyclohexane Mixtures as Organic Reaction Solvent Media

In designing process steps for fine chemical synthesis a bias has existed against multi-component solvent systems. In the past, it was argued that using combinations of solvents meant that money would be lost because it would be necessary to separate these solvents in a recovery step. What was not then properly recognized was that recovery of solvents from mixtures for reuse was rarely undertaken in the fine chemical and pharmaceutical industries mainly because recovering and recycling solvents required extensive expensive analytical work to prove that the specifications were being consistently met.

Here I will look at combinations of cyclohexane and absolute ethanol.

There are contradictory teachings in the literature concerning the miscibility or immiscibility of ethanol and cyclohexane. This confusion may be because the UCST (upper critical solution temperature ) of the combination is reported to be -16℃. In the laboratory, it is difficult to maintain the contents of a separatory funnel at any temperature less than 0℃  but this should be much less a problem in the plant where extractions are conducted in a reactor completely surrounded by a heating/cooling jacket and the entire charge is maintained throughout under inert gas. Therefore, one could predict that two phases might not be seen in the laboratory but would be reasonably easily achieved with the more readily accessible plant peripherals.

Ethanol and cyclohexane do have an azeotrope ( bp 64.9℃ ) that boils significantly below the boiling point of either pure ethanol ( bp 78.5℃ ) or pure cyclohexane ( bp 81.4℃ ). Mixtures in any proportion of these two pure liquids will give a homogeneous reaction medium above -16℃ and fractional distillation of the reaction mixture will remove the azeotropic composition and leave any non-volatile substrates in either ethanol or cyclohexane depending upon what solvent predominated in the starting mix.

Alternatively, the reaction mixture can be cooled to below -16℃ to see whether or not two liquid phases separate and if so how the substrates of interest partition between them. It needs to be noted however that even if two liquid phases separate, that separation may be slow since these liquid layers are expected to have very close densities. A small addition of water may cause separation in cases where nothing is apparently happening.

As you can see, this binary solvent mixture provides options in the work-up and isolation.

The Advantage of Methanol-Hydrocarbon Solvent Mixtures for Organic Synthesis

This blog article is speculative. It is not based on experimental data. However, the information about the compositions and boiling points of the hexane, cyclohexane, and heptane azeotropes with methanol are accurate, as are the upper critical solution temperatures (UCSTs).

In designing process steps for fine chemical synthesis a bias has existed against multi-component solvent systems. In the past, it was argued that using combinations of solvents meant that money would be lost because it would be necessary to separate these solvents in a recovery step. What was not then properly recognized was that recovery of solvents from mixtures for reuse was rare in the fine chemical and pharmaceutical industries mainly because recovering and recycling solvents was a poor use of reactor time and required extensive expensive analytical work to prove that the specifications were being consistently met.

KiloMentor thinks that using solvent mixtures has so many advantages that they should be considered more frequently than not. In particular mixtures of lower alcohols and various hydrocarbons that provide protic media of a wide range of polarities and dielectric constants should be among the first systems considered.

Utilizing multi-component solvent systems turns the solvent composition into a continuous rather than a discrete variable in the process optimization. This does not rule out eventually finding a process step optimum that is 100% of one of your original solvent combinations.

If a lower proportion of solvent can be used in a chemical process step the the amount of material that can be processed in a single batch is increased and a higher throughput is achieved for the step. This leads to cost savings for a campaign that includes that step. 

It is often the case that a homogeneous mixture of polar and non-polar solvent liquids that is homogeneous is better at dissolving a substrate that has distinct polar and apolar subdomains than either pure liquid alone. That would mean, mutatis mutandis, that such mixtures should increase the throughput in reactions of such substrates.

Specifically, this suggests that a homogeneous single-phase mixture of a hydrocarbon and methanol could realistically be better at dissolving some reaction substrates and producing more concentrated solutions that give higher throughputs.

Hexane, cyclohexane, and heptane all give constant boiling binary azeotropes with methanol and these azeotropic compositions fulfill the criteria of having both a polar and a non-polar component and being homogeneous at the azeotrope's boiling point. 

Reaction mixtures of the azeotropic compositions in each of these cases would be obtained by mixing a chosen hydrocarbon and methanol in their correct proportions but with a consistently biased slight excess of methanol, which has the lowest boiling point among these liquids. Thus, when any such mixture is brought to reflux the excess methanol will be distilled over first before the refluxing settles at the actual constant boiling point of each particular azeotrope.

The upper critical solution temperature (UCST) designates the temperature above which the two pure solvents form a single liquid phase. In every case, whether cyclohexane, hexane, or heptane is paired with methanol, the upper critical solution temperature of each azeotropic composition is below that azeotrope’s boiling point. That is to say, refluxing will in every case maintain a single homogenous phase that can serve as a homogeneous reaction medium.

Besides potentially providing a throughput advantage, these particular azeotropes offer something else. When these mixtures are cooled below their  UCSTs,  when the reaction is complete and the reactor contents are cooled for quenching, work-up, separation, and/or purification, two liquid layers are expected to separate. This might prove useful because it provides a ‘natural’ ‘free’ phase switching extraction which might simplify the work-up.

But let us not delude ourselves about how frequently this will be useful.

Neither of these two phases is predominantly methanol or hydrocarbon. 

The azeotrope between hexane and methanol has bp.50℃. The composition of the upper layer will be 85% hexane and 15% methanol with a specific gravity of 0.675 and the composition of the lower layer will be 42% hexane and 58% methanol with a specific gravity of 0.724. It is decidedly not upper almost pure hexane; lower mostly methanol.

The UCST of methanol with n-hexane is only 35℃. That means that the partitioning of a substrate between these solvents can be accelerated by heating above 35℃ where a single phase can be formed, then cooled down so that the phases separate as a lot of small bubbles with lots of surface area. There are 15 Cº between the azeotropic boiling point and the UCST.

With heptane and methanol, a UCST  is reported to occur at 51℃ but handbooks do not report separating phases on cooling. This is confusing and needs to be examined experimentally. The azeotrope is reported to have bp. 59.1℃.

With cyclohexane and methanol, the UCST is 45℃. The azeotrope bp. is 45.2℃. As you would expect the azeotrope separates into two phases in the receiver. There is essentially no point where we can exploit a single homogeneous liquid phase. 

Whether two liquid phases separate upon cooling a reaction mixture using one of these azeotropic systems and whether any two phases that might separate are useful for partitioning reaction mixture components, in every case adding a bit of water will cause the compositions of the two phases to shift- the methanol phase becoming more nearly essentially methanol and the hydrocarbon phase more nearly all hydrocarbon. This at least will dependably occur!