kilomentor

One of the non-obvious outcomes of structural identification using spectroscopy (particularly NMR and MS) is the decrease in experience with distillation, among organic synthetic chemists. Because even an inexperienced student researcher can now routinely identify a substance using milligrams of pure compound, flash chromatography high performance liquid chromatography or preparative gas chromatography can replace old-fashioned distillation for making samples for identification in most steps in a laboratory. Corroborating evidence of this trend is the virtual disappearance of boiling point as part of physical characterization in the chemical literature.

Finally, as the catalogues of suppliers of chemical intermediates become thicker, more of the early steps in syntheses can simply be purchased. It is these lower molecular weight entities that used to be prepared and distilled in the lab.

Standard distillation has an inherent problem that became further reason to abandon this technology in the laboratory. Unless a distillation column receives an input of heat that at small scale is usually supplied by vigorously boiling the liquid mixture in the still pot It cannot achieved liquid-vapour equilibrium. Thus on the lab scale, there is hold-up of distillate that is inevitably lost and this can be up to about 30%. Compounding this inherent difficulty is the annoyance that all glass laboratory distillation equipment is expensive and does not easily accommodate the particular amount of crude that you may have. That is, the amount of crude distillate must be selected to fit the size of the physical assembly that you have and not the other way round. Fractional distillation assemblies are not available in your lab drawer in 100 ml, 200ml, 500ml, 1 L 5L and 15L sizes, like round bottom flasks are!

The days when distillation units were patched together with hardened cork or rubber stoppers between pieces of blown glass are long past. Now all glass assemblies are a single piece or pieces joined with ground glass joints. Because of this, now more than ever, distillation assemblies for vacuum distillation often use the same equipment as for simple distillation and don’t appreciate the special requirements imposed by the low-pressure condition.

The boiling point of the fluid mixture in the still pot of a distilling assembly depends upon the pressure at the surface of the liquid, not the pressure recorded on a pressure gauge, which may be and usually is, closer to the vacuum pump.

For pressures from 760 mm down to 15 mm of mercury, a regular distillation flask is satisfactory. For pressures below this level, and particularly pressures 2 mm or less, the diameter and location of the vapour port linking the distillation portion of the apparatus to the condensing portion becomes very important. This is not usually understood.

The increment in vapour pressure at the surface of the boiling liquid, over and above the vacuum pressure reading taken at the receiver is proportional to the length and inversely proportional to the fourth power of the diameter in centimetres of that side arm plus any other narrow portion of the path between still pot and condenser.

As Hickman, inventor of a famous low pressure still, pointed out many years ago, an experimenter may go to great lengths to produce a vacuum less than 1 micron, yet fail to benefit properly from his/her efforts because the pressure necessary to drive vapours from the distilling through neck and side arm is from 1 to 4 mm. The factor limiting te available vacuum is often the distilling assembly shape not the quality of the vacuum pump or vacuum pump oil. Take for example a vacuum distillation using a Liebig condenser attached by a ground glass joint to a simple distillation flask. A Liebig condenser has a narrow bore tube running inside a wide bore tube that serves to supply condenser water to the outside of the narrow bore tube. The vacuum is applied through the length of the condenser down the height of the distilling flask and column to the boiling liquid surface. Because the Liebig condenser tube is both long and narrow, it must add a large pressure to the reading of the vacuum guage at the receiver. Low pressure distillation is impossible.

Bumping from super-heating of the still pot liquid is a great time waster and many solutions have been offered. When distilling at atmospheric pressure boiling chips can be used or a bleed from a glass capillary but the former fails under vacuum and the latter adds to the pressure and is really co-distillation with the gas being bubbled. A very old but effective solution is to place glass wool into the flask so that it is partly above the liquid surface. Using this method magnetic stirring is not possible and an oil bath is the preferred source of heat to avoid over-heating at the flask wall. When using ground glass jointed flask the glass wool must be inserted carefully to make sure that no wool strands get trapped on the ground glass joint where it will destroy the vacuum seal.

When magnetic stirring is used anti bumping is usually not needed unless the stirring fails.

When performing a fractional distillation in a packed column some people do not realize the importance of a near perfect vertical positioning of the column above the flask. Fractionation is achieved by the equilibration of rising vapours and the descending liquid film and that equilibration is a function of the surface area and thickness of that film. If the column is tilted the returning liquid is not spread over all the walls and packing and where it does run it is in a thicker less effective layer. In a tilted fractionating column the height equivalent of a theoretical plate is longer so there is less rectification.

I have seen a large increase in traffic to this blog after I reviewed the titles of some articles from April 2007 to September 2007. Therefore, I continue with this updating.

Search engines have the shortcoming that they give higher rankings to recent material. This is appropriate for news, fashion and opinion but not nearly as appropriate for scientific educational materials. Thus with the passage of time it becomes harder to locate pertinent kilomentor blogs. To counteract this I am providing a review of the titles of some of the early Kilomentor articles. Regular readers can of course find all my articles in the Kilomentor archives in the kilomentor blog.

The Use of Mesityl Oxide as a Dehydrating Agent by the Chemical Reaction of Water catalyzed by Primary Amines

Extraction and Phase Switching Hydrolysis-Purifying Phenols.

Avoiding the Impurity from Hell:(chemical process development; purification of organic chemicals; process optimization; impurity identification in organic synthesis)

Reactions “On Water” (immiscible water makes a great heat sink)

Kilomentor moves the discussion from Steam Distillation to other Co-distillations

Polymorphism in Organic Syntheses, Process Development and Formulation

Inverted Filtration: A chemical synthesis laboratory technique particularly helpful at 5-10 litre scales.

Recovering More Product by Crystallization in Organic Synthesis:Trituration with a modified water phase as a potential Chemical Process Development Method

The Complete Blog for the Preparation of Pharmaceutical Salts

Kilomentor weighs in as “Pharmaceutical Manufacturing Goes Green”.

Another Way to Separate Phenolics by Crystallizing of Co-crystals?

Green /Recyclable Solvents: Low Vapour pressure compositions for storage and recycling of solvents that are highly volatile or gaseous at room temperature

Symmetrical Bis-N,N-(3-nitrophenyl)urea: A Super Co-crystal Former that might have applications in Product Purification.

The Importance of the Molecular Weight of a Salt Former in choosing a Pharmaceutical Salt (the choice of salt is not as broad as you think)

Pamoates or Embonates: crystalline Pharmaceutical Salts or Derivatives for Isolation and Purification

Biocatalytic Methods of Enantioselective Synthesis in Pharmaceutical Process Development

Separation by Substantial Differences in Chemical Reactivity of the Same Nominal Functional Group.

Reently Amelia sent Kilomentor a question. She wrote:

Hi, I would like to know what is a good method to remove DMF from my compound. My compound is very polar (with acid and 2 phenol groups)and might not be very soluble in ether. As the compound is a sticky solid, I suspect a tiny amount of DMF is trapped in the solid as I tried freeze-dry vacuum and passing through silica gel column. Do you have a good idea? Thanks.

It is always more difficult to recommend a purification strategy without knowing the full structure. At the same time there is usually good reason for confidentiality.

You say, Amelia, that you think your compound might be insoluble in diethyl ether. If so then triturating with such antisolvent could be an excellent method to remove traces of DMF if present. DMF is miscible with diethyl ether so if your product is essentially insoluble the separation could be excellent and it would certainly be simple and rugged. If too much of your product is dissolved a mixture of ether and hexanewould further reduce the solubility of the diphenolic acid.

Another off the wall idea is from the Kilomentor article “Another Way to Separate Phenolics by Crystallizing of Co-crystals?” 21 March, 2008. Carboxylic acids that are also phenols might be expected for structural reasons to form quite insoluble co-crystals from dry dioxane. The article points out an exception that ortho hydroxy benzoic acids would not be expected to work.

Yet again, if the DMF is tightly complexed to your compound and this is suggested by the failure of freeze drying and passing it through a silica column you might need to make a hydrophobic derivative in order to remove the hydrogen bonds of that hypothetical complex. Complete silylation of your compound would attach at least three trimethylsilyl groups. The derivative would become more and could become soluble in hydrocarbon solvents. Hexane and acetonitrile are immiscible phases and DMF would I think prefer to be in the nitrille phase while your persilylated product may now prefer the hydrocarbon. Kilomentor has written an article about catalysts for quick persilylations and hydrolysis back to product would be facile.

Finally, if your compound is soluble in benzene, you might try adding some sodium iodide to a solution in benzene or other similar solvent. in J. Am. Chem. Soc. 82, 2895 (1960) it is reported in footnote a of Table III that DMF and sodium iodide form an insoluble complex from benzene in a molecule ratio of 1:3! I do not know whether this is actually true and I have never tried this so I would test it out with some DMF in benzene but none of your compound first.

Maximizing chemical yield by recycling mother liquors from crystallizations is underutilized in chemical and pharmaceutical processing, particularly outside the developing world. One of the few articles on this subject is Alan A.Smiths, A Model for Mother Liquor Recycle in Batch Processing, Org. Process Research & Development 1997, 1, 165-167.

Kilomentors discussion here is indebted to this paper.

When crystallizing or recrystallizing product (i) from a reaction mixture, r (ii) a partially treated work up solution, or (iii) from a crude solid isolate, none of the impurities’ concentrations exceeds their solubility product in the solution. That is, more of each impurity could be dissolved in the filtrate without precipitating any solid. The solution has the potential to extract more of the impurities from the desired product. Besides having residual capacity to dissolve impurities, the filtrate is saturated with the desired product, which is going to be lost if the filtrate is sent as waste.

Both of these situations can very often be improved upon if a portion of the crystallization filtrate from a first batch can be used as part of the crystallization solvent in a subsequent batch.

There are other situations, easily identified, where filtrate recycling is not promising. For example, when an anti-solvent has been added to cause crystallization and this anti-solvent is not easily removed. The reason is easy to understand. Adding this modified filtrate back into a second batch will not reproduce the precipitation conditions of the first batch. It is unreasonable to expect an equivalent product.

A similar unpromising situation occurs with crystallization from mixed solvents when the product is dissolve in a first solvent and then the solution achieved diluted with a second solvent before awaiting crystallization.

In general it is crystallization achieved with the assistance of cooling that is amenable to partial filtrate recycling because the original condition can be recreated simply by reheating to the original dissolution temperature.

If x is the fraction of mother liquors you contemplate recycling in place of an equal volume of solvent and 0 < x < 1, the paper referenced above shows that the impurities in the mother liquors of each subsequent batch will tend towards a limit that at infinite batches becomes

I_infinite = I₁ X 1/(1- x)

Thus with x=0.5 and the level of impurity in the first batch I₁ = 2%

I_infinite = 2% X 1/(1-0.5) = 4%

Or with x=0.7 and the level of impurity in the first batch I₁ = 3%

I_infinite = 3% X 1/(1-0.7) = 10%

Or with x=0.6 and the level of impurity in the first batch I₁ = 0.8%

I_infinite = 0.8% X 1/(1-0.6) = 0.2%

Of course if you recycle all the mother liquors no matter what the level of I₁ is I_infinite = number X 1/(1-1.0) = infinite; that is to say the impurities come out on the product.

The motivation for recycling some of the mother liquors is not of course usually to save solvent but to increase the recovered yield of the desired product. To illustrate this, for simplicity let us suppose that what Kilomentor defines as the 'reaction yield’ (the assay of the desired product in the isolation solution as a % of the theoretical quantity of desired product) is 100%. The ‘recovery yield’ (the weight % recovered product as a percentage of the weight of desired product based on the assay yield) in this situation becomes equal to what we all call the reaction yield (the weight of product isolated over the theoretical weight of product possible as a percentage). If under these circumstances the reaction yield is 70%, there will bes 30% of the material left in the saturated mother liquors (so long as no degradation has occurred). If half of it is recycled, the overall yield will be increased by ½ X 30% = 15% and will become 85%.

Now even if the solubility product limit of all the different impurities in the mother liquor is never exceeded, the desired product which is isolated by crystallization using some mother liquor recycling will be less pure than when the technique is not used. One reason for this is that the mother liquors do contain a higher concentration of impurities and more of these by-products will either co-precipitate or be adsorbed on the pure solid crystalline product. Another possibility is that separation of the desired crystalline solid from mother liquor solution is incomplete. Mother liquor solution is trapped on the surface of the solid and evaporates there or is deposited there when the crystals are place in the drier. Certainly the wash solution used on the filtered crystal product becomes more critical both to preserve the yield improvement achieved (by not dissolving the product) and by removing this film of mother liquor without precipitating impurities.

The crystallization from a solution in which a portion of mother liquors is being recycled will likely be different from an isolation without recycling. Optimal crystallization temperature, and cooling time will change as the percentage of impurities changes. Typically crystallization proceeds more slowly in the presence of a higher concentration of impurities and greater care needs to be taken to prevent co-precipitation.

It would be unusual to recycle more than 50% of the mother liquors from one run of a campaign to the next. Remember to save all the mother liquors from run A until the product of run B certified to be trouble free. If run B has a problem and needs to be investigated, you will not want to use run B mother liquors in run C. You still want to have at least 50% of the mother liquors from run A to use while you check to see if there is some deviation in run B.

If you intend to use mother liquor recycling in a validated process, you will need to use mother liquor recycling in the validation batches and have in place the analytical testing protocols required to show that the mother liquors you are transferring from one batch to the next meet preset standards, have been stored for a validated time under validated conditions.

The Problem of Resolving Enantiomers of Chiral Basic Compounds does not have a general solution. There is no chiral acidic substance that that quite dependably will form diastereomeric salts that can be separated at useful synthetic scale .

There will probably never be a reagent that will work for resolving every enantiomeric pair but a solution might be closer than is commonly apparent. TABA which is (2,4,5,7-tetranitro-9-fluorenylideneaminooxy) propionic acid has been available by an Organic synthesis preparation since 1973. The compound was developed initially to resolve chiral polycyclic aromatic molecules with neither acidic nor basic functional groups. It works by forming diastereomeric charge transfer complexes between the pi donor rings of the chiral polycyclic aromatic racemate and the pi acceptor, electron deficient rings of the TABA reagent.

Subsequently, the enantiomeric TAPA reagents were used to resolve chiral antimalarial agents that had large hydrophobic amine groups that formed salts poorly. [F. Ivy Carroll, Bertold Berrang and C.P. Linn. Resolution of Antimalarial Agents via Complex formation with alpha-(2,4,5,7-tetranitro-9-fluorenylideneaminooxy) propionic acid. J. Med. Chem.. 1978, 21(4) 326-330.]

When the structure of the enantiomers to be resolved has both a primary, secondary or tertiary amine and a potential electron donating ring there are two points of attachment between the enantiomers and the chiral resolving agent increasing the potential for success. In the paper referenced above 5 different compounds were successfully resolved using this pair of (+)-TAPA and (-)-TAPA. No compounds are reported to have failed resolution.

Even when there is no polycyclic aromatic pi donor in the racemic basic material that you are trying to resolve a solution may be possible if the amine is primary or secondary. Introduction of a benzylic protecting group that incorporates such a pi donor might provide a new compound that can be easily resolved. Removal of the benzylic group by hydrogenolysis for example would return the resolved material that is sought.

Phenols may be separable from neutral substances by liquid/liquid extraction with aq. base, if the molecular weight is not too high. This is not a guaranteed success because phenols are only weak acids and the alkali phenolate, particularly as the molecular weight increases, may simply be water insoluble. Because the free phenol in this situation is lipophilic, the phenolate in the presence of both water and an organic phase may substantially hydrolyse back to sodium hydroxide and the free phenol. the neutral phenol “happily” jumps into the organic layer. For example, if a 10 ml. solution of 0.01 mol of 2,4-dimethylphenol is reacted with one equivalent of alkali in water and is then shaken with 20 ml of ethyl ether for about 10 minutes, the amount of the phenol found in the ether is 43% and the water is strongly basic. The amount extracted depends upon the ratio of alkali to phenol, the ratio of the phases, and the particular organic solvent used. In the case of 2-isopropyl-5-methyl-phenol (thymol) the amounts extracted by different solvents under the above conditions are: ether, 88; benzene, 38; carbon tetrachloride, 25; and pet. ether 22 percent.

In the extreme case of di-ortho substituted phenols there is steric hindrance to the solvation shell that is needed around the oxygen anion, which makes the anion formation energetically disfavoured. With di-ortho phenols, even when the molecular weight is rather low- the phenol will not dissolve in aqueous sodium hydroxide. For that reason such species were called cryptophenols in the days before spectroscopic testing, because these phenols did not give the characteristic qualitative test for a phenol. Cryptophenols can be dissolved in methanolic-KOH called Claisen’s alkali. Kilomentor has an article about Claisen’s Alkali.

Phase Switching Hydrolysis

In some situations another trick can be employed to separate a weak phenol or cryptophenol from a non-phenol. Suppose for example you are trying to separate two carboxylic acid esters that differ only because one also contains a free phenol while the other contains a phenol alkyl ether. If one places the compound mixture in a two phase solution of say toluene and water, adds sodium hydroxide to the water and stirs the phases gently after some time the phenolic ester will be found transferred to the aqueous base phase and converted to the carboxylate while the ether-ester is untouched in the toluene phase.

I have used this trick several times. It works if the phenol functionality increases the solubility of its ester substrate to a slightly greater extent in the water than the substrate containing the ethr. Once in the aqueous alkaline layer, the phenolic ester substance is quickly hydrolysed. In the form of the sodium carboxylate, it is stuck quantitatively in the water. The ether -ester on the other hand is comparatively insoluble in the water. It cannot “see” the alkali because the stirring is gentle and there is little interface so it remains unreacted in the toluene. Conditions for the separation can be optimized by adjusting the organic solvent, the stirring and the temperature of the two phase mixture.

Although I have not tried the method with any combinations other than phenol-esters and ether-esters, other functional groups might be useful to replace the phenol by creating this initial small water solubility. Perhaps thiol, primary and secondary sulfonamide, imide, terminal acetylene, alpha unsubstituted alkyl nitro or dithiane might work. Any compound that can act as a weak acid in aqueous alkali has a good chance to succeed.

I have seen a large increase in traffic to this blog after I reviewed the titles of some articles from December 2006 to March 2007. Therefore, I continue with this update.

Search engines have the shortcoming that they give higher rankings to recent material. This is appropriate for news, fashion and opinion but not nearly as appropriate for scientific educational materials. Thus with the passage of time it becomes harder to locate pertinent kilomentor blogs. To counteract this I am providing a review of the titles of some of the early Kilomentor articles. Regular readers can of course find all my articles in the Kilomentor archives in the kilomentor blog.

I have placed at the top the blog articles that I remember had the most visits.

Wolf & Lamb Reactions or Site Isolation Reactions

10 July, 2007

Solvent Replacement: The need to change solvent either from a reaction solvent to a crystallizing solvent or during reaction telescoping in a process

09 April, 2007

pKas of Common Organic Substances

07 June, 2007

A Practical Scheme for Working Up a Reaction Mixture based upon real Liquid-Liquid Extraction Possibilities and Logical Solubility Testing (An updated entry)

09 June, 2007

Solvent Exchanges for Special High Boiling Solvents

29 April, 2007

Polymeric Reagents and Immobilized Catalysts: When in a Process They Can Pay the Best Dividends

08 August, 2007

Urea Complexes for the Separation of Straight Chain Solvents

29 April, 20

Purification of Chemical Products by Treatment with Mixtures of Solid Adsorbants like Charcoal: Identifying Useful Absorbants by a Combinatorial Method

14 April, 20

Alcohols: Organic Chemistry Isolations with Reversible Derivatives particularly Phthalate Esters

01 April, 2007

Improved Extractive Separations with Organic/Organic Biphasic Solvent Systems: Catalyzed Total Silylation to Improve Partition Coefficients

14 May, 2007

Imminium Perchlorates & Fluoborates: Solid Crystalline Reversible Derivatives of Carbonyls

06 May, 2007

Hydrotropes as Solvents for Extraction and Separation

22 July, 2007

Search engines have the shortcoming that they give higher rankings to recent material. This is appropriate for news, fashion and opinion but not nearly as appropriate for scientific educational materials. Thus with the passage of time it becomes harder to locate pertinent kilomentor blogs. To counteract this I am providing a review of the titles of some of the early Kilomentor articles. Regular readers can of course find all my articles in the Kilomentor archives in the kilomentor blog.

I have placed at the top the blog articles that I remember had the most visits.

Kilomentors Selected Oxidation Bibliography

08 February, 2007

Comparison of Preparative Chromatography Methods

30 December, 2006

Balancing Chemical Equations and Calculating Heats of Reaction: Two Often Overlooked

Helps for Chemical Process Developers.

28 February, 200

List for Developing a Scaled up Step in a Chemical Process

30 December, 2006

What to Do When Your Chemical Reaction Fails?

02 February, 2007

Context of Process Chemical Development Training

04 January, 2007

Separation as the Focus of Process Development

19 January, 2007

CheckDerivatives that make phase switching easy-The Preparation and Use of Alcohol Sulfuric Acid Esters

24 January, 2007

The Carboxylic Acid Group- A functional group that make phase switching easy

24 January, 2007

Simple, Rapid Optimization of a Chemical Process Step

24 February, 2007

Inorganic Non-Stoichiometric Metal Salt Complexes with Organic Molecules as a particularly Useful Method for Purifying Neutral Substances.

16 February, 2007

Dissociation Extraction and Dissociation Leaching and so called Dissociation Extraction Crystallization

11 February, 2007

Stoichiometry & the Rate of Addition of Reactants: An Important Consideration for Mentoring / Training in Chemical Process Development

09 March, 2007

As a Valentine gift to Kilomentor chemical process development readers here is a way to easily improve your network security using your specialized knowledge of chemistry to improve your passwords.

Steps for making a Password for use on the web

• 1. choose the word
• 2. starting with the first two letters identify whether it is a chemical element and if it is these two letters will be part of the password written as capital then small ie Ti
• 3. if the first two letters are not a chemical element then is the first letter one
• 4. if so it becomes part of the password ie W (tungsten) from Winchester
• 5. Now move to the next letters if the first two letters have been accepted, or to the second letter if only the first letter was accepted.
• 6. repeat the operation examining first two letters together and then the first of the two letters.
• 7. Continue until you reach the end of the word selected
• 8. Always prefer two letter elements over one letter ones

9. Omit letters that do not make up elements

Examples:

Mississippi ISSiSSiPPI

kiIomentor KIONO

chemistry CHeISY

engineer NINeEr

inauguration InAuURaTiON

Winchester WInCHeSTe

You will find that you can quickly and easily choose the capitals, small letters and omitted letters as you type the password. Now your password is not a word at all and is enhanced with both capital and small letters apparently randomly selected. Even if this method were known to a person trying to break your password constructed in this fashion, it would be at least as strong as the word you are presently using.

Does microwave heating have a place in process development? In June of 2008 I attended a conference that raised this question quite a lot. The question I kept asking anyone who cared to talk about it was simply, what can microwave heating do that other methods cannot?

Microwave heating heats liquids or solids that have polar bonds. The heating comes from the flipping back and forth that the bonds dipole does trying to stay aligned with the radiation.

This heat is generated right inside the solution so that it does not have to be transmitted from the heated walls of a reactor. Thus the walls of a vessel heated by microwaves are cooler than the bulk material.

If you have a reaction that requires a high temperature and which shows degradation/impurity formation from charring on the hot walls, microwave heating can help you. Small scale reactions display the largest wall effects because they have a greater proportion of wall area to total volume, so scaling up is likely to help you anyway, even without microwave heating. The problem is that as one scales up it takes longer to reach your desirable high operating temperature. Microwave heating can help because, since the entire solution is heated from inside itself, energy can be delivered more rapidly and the temperature can be rapidly ramped up. Of course an alternative exists if you don’t want to use the technology. The solvent could be heated to a high temperature before mixing with the substrate, which could be added as a slurry.

Aficianados of the technology may tell you that because the energy is being directed into specific molecules (the ones with the dipolar bonds) special reactive effects may be at work but other experienced people quietly say not to believe it. It reminds me of the efforts years ago trying to get special activation by irradiating particular IR frequencies.

What we know is that the technique is being used a lot in discovery chemistry because it works well on a small scale and it is fast. Where microwave synthesis could save process chemists time by using the larger scale continuous flow microwave devices to make kilogram quantities of lead compounds without changing the discovery chemistry. This coud save experimentation time that can be redirected to improving the real process without dividing our attention. Microwave synthesis can keep those urgent requests for a few kilograms at bay, while we work out the synthesis as it ought to be done.

A pharmaceutical process that has been scaled-up is monitored using the results of in-process controls. These are tests that either conform or do not conform to a preset standard. If the test conforms, the operators proceed to the next instruction of the batch process, but if the result is nonconforming, the result is reported to the manager who decides what action to take next. For an in-process test, the actions to be taken are characteristically thought out in advance. If there is no possible corrective action for an out of specification result, the test is not a proper in-process test but rather just a datum that may be part of the analysis of the result when the final outcome is known.

When a process has been optimized it is taken for granted that it will operate within its control limits and no more testing than the in process ones will be required to guide the operators to a successful result.

Pilot Plant Experiments and Forensic Testing.

Although the chemical plant or kilo lab process can be modelled using a laboratory scale procedure, it cannot be optimized without results from representative samples from the scaled up process taken at critical decision points in the process.

The pilot plant runs are still experiments even if the equipment is handled by personnel who are not research chemists. Although the chemist may think that (s)he understands completely the experimental reaction and subsequent purifications steps being scaled up, at least for all practical purposes, this isat least immodest and usually foolish. The experimenter is wisest who anticipates the most potential problems and collects useful samples at every convenient sampling point every time the process is executed on scale. Taking many more samples than simply those, which are mandatory for in-process control. These extra samples we will call forensic samples because they are very often only analyzed when a result is unsatisfactory. When the result is unexpectedly disappointing in any respect. these samples can provide the evidence useful to determine what went wrong and how to correct it.

Forensic samples are carefully stored so they will not deteriorate. They are in addition to the process control samples Forensic samples are not analyzed during the time the process is running, but are for retrospective testing by the process chemists.

There is only one downside to the collection of forensic. If the process runs perfectly and gives a product of the exact same quality as the laboratory samples but with a lower yield, the question may arises whether taking samples might be predominantly responsible for the reduced yield. Most often the size of the samples or the mechanical losses that can occur when taking forensic samples cannot explain a noticeable reduced yield on scale. The samples are typically just not large enough compared to the size of the process.

Recrystallization can efficiently purify organic solids. The weakness of the methodology from the perspective of devising optimal synthetic processes is that a good recrystallization cannot be predict based on molecular structures of starting materials, co-products, by-products and product to the same extent one can predict, for example, the results of acid-base extractions or methyl alcohol/heptane solvent partitioning.

It is for this reason that Kilomentor in synthesis planning for chemical process development gives preference to intermediates that are acids, bases or salts.

Nevertheless, many process intermediates will be compounds that offer no practical alternative to purification by recrystallization and so it is useful to consider simple ways to increase the recovery from recrystallization steps.

Recrystallization separates impurities in two ways during the operations. Typically, the solid is first dissolved in the minimum amount of a hot solvent. The temperature for dissolution is typically the boiling point of that solvent although for high boiling solvents a lower temperature, such as steam bath temperature, may be used. These temperatures are convenient because there is no problem holding a solution at these points. The hot solution then is filtered to remove insoluble substances. This filtration is the first phase separation; solution from insoluble solid. Very often this purification opportunity is not properly recognized because a good solvent usually dissolves essentially everything when warmed or, in instances where it does not, some kind of filter aid is added, obscuring the presence of insolubles. Then, in the second stage, the clear solution (i) may be cooled to a lower temperature (ii) an anti-solvent may be added to reduce the solubility or (iii) both may be combined in use. The crystalline solid phase appears, is separated by filtration and the impurities are retained in the mother liquors.

In the most frequently used techniques, recrystallization is conducted from a single solvent or a mixture of two solvents by dissolving the solid hot, filtering hot, and then cooling to recover a crop of crystals.

When more of the recrystallizing solvent mixture is needed to completely dissolve the crude solid prior to filtering than is needed to effectively hold impurities in solution after cooling good product is likely being lost using this simple process.

It is easy to discover whether good product is being unnecessarily lost in any particular recrystallization situation by the following simple test.

Instead of recrystallizing the solid in a single charge, divide it into two equal homogeneous portions. Recrystallize the first portion as usual with the only difference that if the crystals are washed on the filter, keep the wash liquid separate from the regular filtrate. Dry, and weigh this first portion. Now recrystallized the second portion of crude only using as solvent the mother liquors from the first portion. Again dry and weigh the product and analyze both for purity.

If both the recovery from the second portion is greater than from the first and the purities of the two portions are not significantly different, changing your processing methodology will save you product.

At scale, recrystallization in two portions rather than one will save product but double processing costs. The same result, however, can usually be obtained by dissolving and filtering the entire crude amount in a single charge and then reducing the volume by half before cooling and recovering the solid. When the two conditions are met, the two stage laboratory experiment provides the evidence that you only need half the solvent to efficiently dissolve away the impurities. The second half of the solvent was more than anything else just dissolving away your product.

Note that in order to practice this method without problems the hot solution of crude solid must be stable to any extended boiling during the concentration stage. Of course, if there is a stability problem, the concentrating can be done under reduced pressure to lower the heat requirement.

Innovator pharmaceutical companies today are experiencing difficulties like never before.

A medical need is only unmet when there is no treatment for the condition. An improved therapy competes with the previous treatment and to-day that treatment is increasingly becoming generic. The choice is no longer between the one treatment at any cost or nothing. It is now between the relative costs of different treatments. With second and higher generation drugs, there is no treatment monopoly. The old breakthrough medicine, now genericized, remains as a viable option. When there is only one realistic treatment, we are all blackmailed to prove our love for the patient is authentic. When there are treatment options, we re-enter the rational world.

Never have so many scientists been looking for new medicines. Never have they been raised so high upon the shoulders of prior generations of scientists. Never have we worked with tools of such power. Never have we had so much data so instantly at hand. But still we cannot increase the output of drug products.

Perhaps our human biology has limits to how it can be tweaked by any pure drug substance? Perhaps the biological differences among us as individual human specimens are so great that what is a useful treatment for many will always be lethal for a few.

Whether we are innovators or genericizers we are all ultimately in the same boat. If innovators fail, then not so far down the road there can be no new generic products.

As process development specialists in the pharmaceutical industry we can only fill our brains with the best information we can find, be unselfish in teaching our colleagues, and thank God we have such spiritually stimulating work in an awesome universe.

It is the opinion of Kilomentor that the most significant presentation at the Scientific Update Process Development Conference held in Montreal from June 24-26^th of this year was that of Alex Tao, Vice President and Chief Scientific Officer of Bioverdant. Dr. Tao was a recipient of the 2006 IChemE-AstraZeneca award for Excellence in Green Chemistry and Engineering for his process for Pregabalin. What I hear Dr. Tao saying is that the state of scientific knowledge now calls for a paradigm shift in our perspective on organic chemical process development most particularly for pharmaceuticals.

According to the presentation, because of the availability now of so much genomic data, the number of enzymes available for conducting the equivalent of common API process steps has increased to the point that now such a broad substrate spectrum can be handled that a screen for potential enzymes to catalyze a reaction step is more likely than not to provide a usable hit. This means that for the first time in history, chemists can be optimistic that they will be able to identify an enzyme, available in commercial quantities, that will catalyze any one of a dozen very common chemical conversions.

Furthermore, even if the best wild-type enzyme discovered has only a poor enantiomeric selectivity for the substrate of interest, the science of site-directed mutagenesis has developed so quickly that a wild-type enzyme that only provides say 61.4% of the correct enantiomer can be used to create a new mutant enzyme with 99.5% ee in something like 3-6 months more work and this can be scaled up to provide production quantities.

This Dr. Tao confirmed to me would make it very likely that, if the innovating company has not already done so, a generic pharmaceutical company can expect to improve the route available to make drugs coming off patent using these biocatalytic methods. Moreover, this opportunity is more likely because the technology was not available in its present robust state when the innovator was developing its chemistry.

Using one biotransformation in a process usually removes the need for any resolution because only one enantiomer reacts. This also opens up the possibility of racemizing the wrong enantiomer and so recycling the 50% of the racemic intermediate that is usually not useful. Also prochiral intermediates give chiral products with enzymes; in one step resolving the intermediate and selecting one of two superficially identical groups.

The reactions that can be confidently replaced now are:

• Regio and enantioselective reduction of ketones to alcohol
• Regio and enatioselective hydrolysis of nitriles to acids
• Regio and enantioselective reduction of ketone to primary amines
• Regio and enantioselective conversion of aldehyde to the corresponding homologated α-hydroxyacid, 2-hydroxy-1-amine; α-hydroxyamide
• Regio and enantioselective reduction of αβ-unsaturated aldehydes/ketones/acids/nitrile/nitro.
• Regio and enantioselective conversion of nitrile to primary amide

In his presentation Dr. Tao provided examples of completed improvements for synthesizing levetiracetam, montelukast, pregabalin, (S)-dimethenamid (an agricultural product), synthetic pyrethroids (insecticides), moxifloxacin, paroxetine and atorvastatin.

In an effort to improve the predictability of retrosynthetic analysis, the simplifying assumption is implied that all functional groups of the same class react for all practical purposes with the same ease. Thus it is assumed that the classes: aldehydes, ketone, nitrile, nitro etc. display similarity in reaction. Sometimes a distinction is drawn between the functionality when attached to aryl as opposed to alkyl, but refinement rarely goes further than this. The combined particular electronic and steric effects in the vicinity of the functional groups is essentially ignored. Usually this simplification is a good one.

The more reactive group must usually be more than 100 times more reactive to obtain a quantitatively selective reaction. This can be seen to be true because to be essentially quantitative, when a reaction is 99% complete, the final 1% of starting material must be more reactive than the 99% of product, which could react further at the second functional group. If it is not that much more reactive, the reaction cannot expect to be quantitative (kinetic control assumed here).

This explains the widespread use of protecting groups to address the situation wherein a substrate contains two functionalities of the same type and the reaction of only a particular one is required.

There are situations however where it is documented that the same functional group in different environments react at usefully different rates. This can be the basis for separation of compound mixtures by reaction where the competition in reactivity is between the same nominal group in different substrates. Alternately, such a marked difference in reactivity can be the basis for a synthetic step which converts only one of two functional groups of the same class in an intramolecular competition.

For example suppose one is presented with a mixture of regioisomers, 4-methylethylbenzonitrile and 2-methylethyl-benzonitrile. Although each isomer contains a nominal nitrile, the nitrile groups are not equal in reactivity. It is reported that ortho substituted aryl nitriles do not readily for imidates by reaction with ethanol and anhydrous hydrogen chloride.

Thus if we were to treat a mixture of these nitriles with anhydrous hydrogen chloride in ethanol, we can expect only the para substituted compound to react and this can be used in a simple separation.

Another application can be found using the Zinn reduction of aryl nitro compounds to perform a selective reduction.

Thomas R. Nickson wrote a research article J. Org. Chem. 1986, 51, 3903-3904. The article taught that in the specific case of 3-trifluoromethyl toluene, when it is nitrated the compound formed in largest amount, the 2-nitro could be isolated in pure form because it was the only isomer than did not undergo the Zenin reduction with sodium sulphide and sulphur. Dr. Nickson however also taught that 3-methyl benzaldehyde and 3-methyl benzoic acid both nitrated preferentially in the 2 position. From my own experience I know that the compound 3,4-dichlorobenzaldehyde nitrates preferentially in the 2-position. It is possible that all 1,3-substituted compounds with one electron withdrawing group and one electron donating group nitrate preferentially in the 2 position AND may be separable by their failure to react in the Zenin reduction! Nickson tells us that one electron withdrawing group is advantageous to achieve a fast reduction but he was able to obtain 2-nitro m-xylene and separate it cleanly although in poor yield by reducing the other isomers but this reduction went slowly.

Also when the two substituents are both ortho-para directing the yield of the 2 isomer is much lower (10%) in the case of m-xylene. It is not clear whether the reaction scheme would work with two deactivating groups meta to each other.

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• Understanding Distillation is still important for Chemical Process Development and Organic Synthesis At Scale.
• Chemical and Pharmaceutical Process Development Update Materials from the Earlier Kilomentor Articles (September 2007-September 2008)
• Kilomentor suggests some crazy purification ideas
• Recycling Mother Liquors in Chemical Process Development to Raise Yields and Reduce Solvent Usage
• A Potential Widely Applicable Solution for Resolving Chiral Bases
• Extractive and Phase Switching Hydrolysis in Chemical Process Development.
• Chemical and Pharmaceutical Process Development Update Materials from the Earlier Kilomentor Articles (April-September 2007)
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• Use your Chemical Knowledge to Improve Your Network Security While Improving your Remembering of the Periodic Table
• Microwave Heating as a Tool for Process Chemists?
• In Process Controls and Forensic Samples in Chemical Process Development
• Making a Good Recrystallization Process Step Better.
• Common Ground for Generic and Innovator Pharmaceutical Companies
• Biocatalytic Methods of Enantioselective Synthesis in Pharmaceutical Process Development
• Separation by Substantial Differences in Chemical Reactivity of the Same Nominal Functional Group.

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