Finding Kilomentor Blog Articles that Mention a Specific Subject

 

The KiloMentor blog has quite a lot of commentary about organic solvents. Perhaps you would like to quickly see what the blog has to say about a solvent you are considering using. There is a simple way to scan all of these.

First, go to the KiloMentor blog and search for the solvent using the search tool at the top of the blog page. You will get a selection of all the blog articles that mention that solvent by that name.

Second, activate the ‘Find’ feature for your computer and insert the same name and search using ‘Find’. This will highlight this name throughout the selected blog articles.

Now, scroll down and quickly see the mentions.

The same method can be used to search and highlight any other search terms. 

Please note that the search tool in the KiloMentor blog sometimes fails to function but repeating the search often works even when the first try fails.

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 that 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 the 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 which simplifies the purification procedures and which 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.

The Context of a Chemical Process Development Training Blog like KiloMentor

 

If the KiloMentor blog were being written twenty years ago it would be different.  If it had been written thirty years ago it would have been different again.  The progress of a technical art, such as process development, creates dramatic changes. The step which had been a bottle-neck in the creation of a process becomes less demanding and another aspect of the art becomes the chief challenge to the scientist.  Thus, if any of these documents were revised in another dozen years, the relative difficulties of different aspects of the challenge will have again changed and the reasons for the proposals made here may have evaporated and the advice provided may become completely wrong-headed.  With this in mind, an author should at the outset state what the status quo is in his field at the time of writing so that future readers can decide for themselves whether the same state of affairs still exists and if not what logical changes should be inferred in the recommendations being offered.

To illustrate this point, forty-three years ago, when I was just beginning my activities as a process chemist, devising the sequence of organic reactions that could lead from commercially available starting materials to the target product was the great challenge.  Dependable reactions were limited.  HPLC did not exist.  IR and UV measurements were just being replaced by NMR methods for following reactions and identifying products.  But the more important difference was that on-line database searching did not exist.  Most significant of all, electronic substructure searching did not exist.  A close analog of the relevant portion of a molecule you wanted to synthesize might be present in the literature, but there was no dependable way to find it.  

To-day, although many would disagree about the degree of change, creating a realistic synthesis scheme for substances of moderate complexity is no longer the most challenging step simply because we have replaced our memories and our punch cards with computer memories professionally indexed available on our desktops.

In this earlier period, when creating the process step flow sheet was the dominant challenge, we synthetic chemists got into the habit of measuring excellence in synthesis by measuring the number of sequential steps in the longest arm of the contemplated process or the total number of reaction steps.  We also calculated the overall yield although this could only be determined after the proposed sequence was converted to a real process.

Because this challenge strained our ability to approximate we made some rough assumptions in inaccuracies of which we hoped would balance out between competing processes and still allow us to make a valid judgment of which was the most promising. For example, we assumed that the amount of crude impure product which one got out from a reaction step was proportional to the quantity of product, which was present in crude form in the mixture after the reaction was complete.  Why do I say we made that assumption? Because we looked at the yield of model reactions for simple substrates with just one or two functional groups and assumed that the recovery of pure product from these would be about the same when we used complicated substrates with multiple functional groups.  In the terminology I will use herein, we assumed that the isolation yield- the yield of pure product as a percent of the assay yield (the amount of product in the reaction mixture) is consistent for a reaction type.  The corollary of this which we also adopted as a simplifying assumption was that isolation although it might be tedious was routine and could be taken for granted as generally of similar difficult when integrated over all the steps of a process.  That is isolations can be ignored so long as the total reaction steps are minimized.

Today, the focus of attention has shifted.  Scientists can gather large amounts of relevant data about the likely properties not just of substances that have been reported somewhere in the vast chemical literature, but even predicted properties of unknown molecules.  What the electronic databases have not been able to do is help us select the simplest and most rugged purification methods to use with reactions at scale.  What we as scientists have not tried to do is ask ourselves the question, “What kinds of functional groups do I want in my intermediates because they will simplify the isolation and purification of that step?”

An axiom of the approach to process development that will be found here is that there is an advantage in ranking the degree of difficulty of isolation/purification of each process step and using it as an additional criterion of selection of the most preferable paper chemistry route along with the traditional criteria: number of steps, number of steps in the longest branch of a convergent process, and the known approximate yields for the reaction type.  The result of this I predict will be that preferred processes may on average contain more process steps but the speed with which these steps can be carried out will be much higher, the overall purity will be much higher, and the cost will be much lower because the time spent in the isolation purification is typically much more than the actual reaction time.

Top Ten Kilomentor Chemical Process Development Blog Articles

The Kilomentor Blog has existed for seven years. It was originally hosted on Chemical Blogs but for the last three years, it has been a Google Blogspot tenant. Although, as the editor, I can see which of my blog articles has received the most readership, this is not available to readers.

Readers do have access to an in the blog search engine that can select articles pertinent to the keywords they select; however, I thought it might interest all readers to have links to the top 10 articles that have appeared these last three years. If this is of interest I can do the same for more top articles in another blog.

1. Pamoates and Embonate Salts

2. Preparation of Pharmaceutical Salts

3. Recycling Mother Liquors in Chemical Process Development to Raise Yields

4. Solvent Replacement in the Plant at Scale

5. Getting Better Recovery from Recrystallization

6. Claisen’s Alkali Reagent for separating very Weak Acids like Enols and Cryptophenols

7. The Problem of Oiling Out in chemical Process Development

8. What Might be the Best Cleaning Solvent for Cleaning the Reactor Walls of a Plant Reactor

9. The 1,2-Diol Functionality as a Phase Tag for Process Separation

10. 10. PEG 400 (polyethylene glycol liquid) as a Useful Organic Reaction     Solvent

Byproducts, Side-products, and Co-products.

A co-product is defined in the KiloMentor Blog as follows; A co-product is a product created according to the stoichiometry of a balanced chemical equation representing a chemical transformation when it is not the material of interest.
 It is created in a defined ratio with respect to the material of interest and is an unavoidable result of that chemical reaction.

William Watson writing online has tried calling a material satisfying this definition a ‘byproduct’. The KiloMentor does not think this is a wise choice of terminology because 'byproduct' already has a contradicting meaning in common parlance. Byproduct according to one dictionary definition is “a secondary or incidental product, as in a process of manufacture” When we look up ‘incidental’ we find it defined as “1. happening or likely to happen in fortuitous or subordinate conjunction with something else. 2. Likely to happen or naturally appertaining (usually followed by to). 3. Incurred casually and in addition to the regular or main amount.”

Thus, in the common usage of ‘byproducts’ there is the implication that these can be prevented from occurring in some instances and the product retained. In contradiction, in Watson’s chemical usage, chemicals created in reactions, which he would call byproducts, are inevitable, since they are dictated by the particular stoichiometry. In my alternative, the word co-product contains this idea of inevitable relationship or complementarity. ‘Co’ is a prefix meaning complement of. The complement completes something; in this case, product and co-products complete the right-hand side of the chemical equation.

‘By the bye’ means incidentally. Incidental products or side products,  KiloMentor can accept these to identify products that are not dictated by the equation that represents the pertinent reaction creating the product. For further clarity in their identification, side products are substances that, at least in principle, can be reduced or eliminated by optimizing the reaction conditions.


Thus, in the common usage of ‘byproducts’ there is the implication that these can be prevented from occurring in some instances and the product retained. In contradiction, in Watson’s chemical usage, chemicals created in reactions, which he would call byproducts, are inevitable, since they are dictated by the particular stoichiometry. In my alternative, the word co-product contains this idea of inevitable relationship or complementarity. ‘Co’ is a prefix meaning complement of. The complement completes something; in this case, product and co-products complete the right-hand side of the chemical equation.
‘By the bye’ means incidentally. Incidental products or side products,  KiloMentor can accept these to identify products that are not dictated by the equation that represents the pertinent reaction creating the product. For further clarity in their identification, side products are substances that, at least in principle, can be reduced or eliminated by optimizing the reaction conditions.

Separation as the Focus of Chemical Process Development

KiloMentor | revised 6th  January 2009 republished February 17/2017

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.

An Overview and Update of ‘KiloMentor’

A Short History of the KiloMentor Blog

In 2006, I started a blog called ’KiloMentor’. The goal was to provide training and updating in the methods for chemical process development emphasizing scale-up of organic synthesis, particularly scale-up of high-value pharmaceutical products. I recognized that there were textbooks, symposia, and courses for this purpose but they were expensive and not equally available in different places in the world.

 

Moreover, in academia, the treatment of chemical process development was neither widespread nor generally thorough. The KiloMentor blog was free and available wherever access to the worldwide web was possible. My blog was originally hosted at a site called Chemical Blogs. Later the articles were transferred to a different, dedicated site. A few years ago this site was shut down when I did not pay for the web address. This Google blog will be a republication and supplementation of those articles.

Below is a revision of one of the earliest articles from the original KiloMentor archives. The original was written in 2007.  This article restates for new readers the core idea of the Kilomentor process development philosophy and offers an approach that I think leads consistently to valuable considerations, if not complete solutions.

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 efficiently making these parameter choices that cause nature’s choice to comply with what we want the outcome to be. Nature- to be commanded, must be obeyed.

Separation as the Focus of Chemical Process Development 

According to the academic, synthetic chemistry tradition, synthetic accomplishments are judged on the basis of 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 are in the background (the attitude is that it can be done and will be done BUT these are not pertinent criteria to evaluate the quality of the synthesis).  The giveaway 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 that have become the art element of the project. The deconstruction of the chemical soup and the fishing out of the desired product in an adequate state of purity has become paramount.

Is there any particular value in this way of looking at the process rather than the traditional way which was focusing on the series of chemical reactions and taking the separation of intermediates as obvious, merely technical, work?

 My perspective rather emphasizes:

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

The value in this KiloMentor perspective is that in chemical synthesis, the money, manpower, and resources consumed during the reaction phase, 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 can be focussed by 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, crystallized or distilled to give a practical purity intermediate adequate to use directly in the next step".

People have personal preferences and this is as it should be in a pluralistic society. Still, 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 or the yield in individual steps 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 are 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

5.   Number of ‘Phase Switches’ in the Synthetic Process

6.   Intermediates that are Acids or Bases

7.   Ease or Difficulty in reaching Practical Purity

How could we execute these ratings? 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. The product can be separated by crystallization or precipitation as a filterable solid.

C. Product can be separated by atmospheric or vacuum distillation assessed from an approximated difference in boiling points (based on molecular weights)

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

E. The previously unknown product must be crystallized to free from unknown impurities

F. 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-F type separations.

 ‘KiloMentor’ articles will offer up particular tactical tools that fit into its distinctive strategy of pharmaceutical or chemical process development. It will also review considerations particularly important for plant-scale processing as contrasted with laboratory-scale syntheses.