For those of you not familiar with Tamiflu, here is the structure.

And then here is the reaction that forms four sterocenters and three carbon-carbon bonds. It is asymmetric and catalyzed by a proline derivative. [Control of four stereocentres in a triple cascade organocatalytic reaction, Dieter Enders, et. al., Nature 441, 861 - 863 (15 Jun 2006)].

What is amazing to me is that the author of the C&EN review didn’t comment on how related these two items are. I did not read the Nature article and maybe it does mention the possibility of using this reaction for this specific compound. I’ve not sat down to analyze what would be needed and am not familiar enough with this reaction to know what groups it might tolerate without affecting the overall reaction, but it certainly is a fascinating idea.

Technorati Tags: Chemical & Engineering News, Tamiflu

This article looks at a variety of reaction solvents; DMSO, DMF, NMP, DMAc, TMU, DMI, THF, 1,4-dioxane, diglyme, and acetonitrile and how they perform with extraction solvents such as toluene, EtOAc, iPrOAC, 1-chlorobtuane and heptane in aqueous solutions such as water and salt water.

The article is well wroth reading and noting for future use.

This is in the first issue of the journal for this year and is available to everyone. Typically for some ACS journals the first issue of the year is free and available to everyone.

Removal of Reaction Solvent by Extractive Workup: Survey of Water and Solvent Co-extraction in Various Systems (pdf) or alternative html

Here is the Supporting Info.

Technorati Tags: extraction solvents, solvents

This article looks at a variety of reaction solvents; DMSO, DMF, NMP, DMAc, TMU, DMI, THF, 1,4-dioxane, diglyme, and acetonitrile and how they perform with extraction solvents such as toluene, EtOAc, iPrOAC, 1-chlorobtuane and heptane in aqueous solutions such as water and salt water.

The article is well wroth reading and noting for future use.

This is in the first issue of the journal for this year and is available to everyone. Typically for some ACS journals the first issue of the year is free and available to everyone.

Removal of Reaction Solvent by Extractive Workup: Survey of Water and Solvent Co-extraction in Various Systems (pdf) or alternative html

Here is the Supporting Info.

Technorati Tags: extraction solvents, solvents

Solvent Applications of 2-Methyltetrahydrofuran in Organometallic and Biphasic Reactions (abstract)
Aycock, D.F. Org. Process Res. Dev., 11, 1, 156 - 159, 2007, 10.1021/op060155c

Luckily for most, this is in the first issue of the year and is avaiable to everyone. Typically, it is for subscribers only. Free full aticle link Solvent Applications of 2-Methyltetrahydrofuran in Organometallic and Biphasic Reactions (pdf) or an alternate html.

I should point out though that the article is by David F. Aycock who works for Penn Speciality Chemicals and is a primary supplier of MeTHF.

There are several factors that make it such an interesting solvent.

• Unlike THF, it is not completely water miscible and does not readily form emulsions or rag layers.
• Its water solubility is low, 4 g per 100 g water.
• Moderate boiling point of 65.7 °C.
• Available from readily renewable resources (2-furaldehyde from corncobs).
• Forms azetropes with several solvents including water (10.6% water).
• Three times more stable than THF to 5N HCl at 60 °C.
• About the sme tendency as THF to form peroxides.
• Works well for forming Grignard reagents. Can form much more concentrated solutions than is possible with THF.
• Is a suitable replacement for dichloromethane.
• Effective for extracting polar alcohols such as 2-propanol from water. Two extractions with equal volumes extracted 94% of 2-propanol from water. Only 68% was removed using toluene.

On the downside though, this solvent is significantly more expensive than THF. Penn makes the argument though that you don’t have to use an extraction solvent that you must use with THF or that you can make more concentrated solutions of Grignard and so therefore use less solvent.

It is a good article and well worth reading and noting for future use for all chemists.

You can also view other articles in this free issue of Org. Proc Res. & Dev.

Other Resources

Products”>Penn Specialty Chemical Inc. > Products MeTHF
Methyltetrahydrofuran: How to Recover and Dry MeTHF Batchwise (pdf)
Penn Specialty Chemicals Inc.
ChemExper - catalog of chemical suppliers, physical characteristics and search engine (methyltetrahydrofuran)

Technorati Tags: MeTHF, PennSpeciality Chemicals, 2-methyltetrahydrofuran

• Journal of Organic Chemistry (JOC)
• Journal of the American Chemical Society (JACS)
• Organic Letters (OL)
• Organic Process Research and Development (OPRD)

I choose these four since they are the major organic journals from the ACS and I happen to have subscriptions to all of them. A search of these journals for “optimized” or optimal” in the title or abstract from Jan 2000 to June 2006 resulted in 1065 hits. Searching within those results for those articles containing the word “statistical” results in 144 articles that actually used design of experiments (DOE) to determine the optimal conditions. This means that only about 13.5% of those claiming to be optimal or optimized actually are. I’m sure that if this was expanded to other journals the results would most likely be even lower. This is because the journal OPRD tends to publish quite a few very good articles describing the use of designed experiments resulting in a bias to the high side. My best guess is that including more journals would give a lower percentage of around 8-10%. It should be obvious that the vast majority of those claiming to be optimal really aren’t. They are probably pretty good, but certainly can’t be said with confidence to be the best conditions.

In the normal practice, a variety of solvents are chosen and then the best one selected and this is used to further optimize the conditions such as base. This “one factor at a time” process is quite common but ignores the interaction between the solvent and other conditions such as concentration, temperature, catalyst, reagent (i.e. base), etc. Also, at the end of an “optimization” performed using one factor at a time, you still don’t know for sure if you have found the best conditions. You only know that this set of conditions of those studied gave better results than the other conditions (but not necessarily the best). If a designed experiment is used, then you can arrive at a model for the system and predict where in the experimental space the best reaction conditions are, even if that set of conditions were not part of the design (however, you should always check and make sure this predict is correct). The use of designed experiments allows for the development of mathematical models (typically a quadratic equation) to predict results within the space studied. You can also study as many results as are of interest.

One reason DOE has not been used extensively is that you typically have to change your system to fit a design from a book or article. More recently, computer generated designs have overcome some of this although my experience is that most compute generated deigns are not of the best quality. They typically are what are called D-optimal designs and these designs concentrate on giving the narrowest confidence limits on the b coefficients. This means they are good at finding out how important a certain factor is, but are not the best for predicting the results which is typically what is of interest in industry. Here is an equation for a hypothetical example of a system looking at temperature (T), concentration (C) and catalyst (K).

Result = b0 + (b1 x T) + (b2 x C) + (b3 x K) + (b4 x T x C) + (b5 x T x K) + (b6 x C x K) + (b7 x T^2) + (b8 x C^2) + (b9 x K^2)

A D-optimal design will give you the best value for each of the b’s. This is good in cases where you may be studying eight or ten factors and you want to know the critical process parameters; say the three most important. They do not necessarily give the best results for the prediction of the result.

I-optimal designs however, are generated such that the best possible prediction of the result is what is of interest. It may not be entirely obvious but these are indeed different. Sometimes they may be the same but that is not necessarily the case.

QD information Services offers you the chance to use I-optimal designs that are specific for your set of circumstances. If you want to study four solvents and concentration as well as only three temperatures then we can provide you with an I-optimal design for that. If you are interested in a customized experimental design, feel free to send me an email and we can discuss your specific needs. We also offer help in analyzing the results and finding the true optimal conditions.

Technorati Tags: design of experiments, process development

Modeling the Scale-Up of Contact Drying Processes: Org. Process Res. Dev., 10 (3), 409 -416, 2006.

It should be noted that the model is not universal; only 5 of the 8 systems investigated worked. It also should be pointed out that there is still quite a bit of unpredictability. If, during the evaporation, the material forms one large lump (not an uncommon occurrence) then the model doesn’t work. The two other cases that failed were also due to aggregation during the drying process. While this aggregation can be reduced by reducing the rotation speed, this also slows down the drying process and resulted in longer drying times.

While this paper outlines a useful approach, processes such as drying still depend very much on the product itself.

Technorati Tags: process development

This is from a paper by E. S. Shanley and G. A. Melhem of Arthur D. Little, Inc., entitled “The Oxygen Balance Criterion For Thermal Hazards Assessment“. Originally published in Process Safety Progress Volume 14, Issue 1 , Pages 29 - 31 Published Online: 17 Jun 2004

Here is the equation:
Oxygen balance = [1600 * (2x + (y/2) - z)] / M

Where:

M = molecular weight
x = number of carbon atoms
y = number of hydrogen atoms
z = number of oxygen atoms
(other heteroatoms are ignored)

If M (oxygen balance) is between -80 to +120 then the hazard potential is high
If M is +240 to +120 or -160 to -80 then the hazard potential is medium
If M is > +240 or is < -160 then the hazard potential is low.

An example: anisole C7H8O1 MW: 108.14

oxygen balance = [1600 * (2 * 7 + ( 8 / 2 ) - 1 ] / 108.14
oxygen balance = [1600 * ( 14 + 4 - 1 ) ] / 108.14
oxygen balance = [1600 * 17 ] / 108.14
oxygen balance = 27200 / 108.14
oxygen balance = + 252 therefore it isn’t a thermal hazard since it is > +240

The spreadsheet allows you to enter the molecule’s molecular weight and number of carbons, hydrogens and oxygens in it and the spreadsheet will then calculate the oxygen balance and color code the result. Below is a screenshot.

If the number is medium the result cell turns yellow; if it is high, the cell will turn red. This gives a visual feedback in addition to the number itself.

This is by no means a substitute for actual testing, but can give you a rough idea of the potential explosive hazard. The authors state that it is conceptually flawed and often dangerously misleading as a guide to energy release in general since it is based on stoichimetery. To fully answer such questions, you need to use thermochemical and kinetic considerations.

Technorati Tags: thermal hazard

A Simple Modification to Prevent Side Reactions in Swern-Type Oxidations Using Py·SO3 Lijian Chen,* Steven Lee, Matt Renner, Qingping Tian, and Naresh Nayyar Chemical Research and Development, La Jolla Laboratories, Pfizer Inc.

The article describes using excess pyridine to convert the pyridine•sulfuric acid 1:1 salt which is present in commercial pyridine•sulfur trioxide to a 2:1 salt. This prevents unwanted side reactions from occurring, at least in this report. In this case they are oxidizing a primary alcohol to an aldehyde and then performing a Wittig reaction without isolating the aldehyde (a common approach in chemical development and production).

I just find it interesting that as widely used as the Swern oxidation is, this hasn’t been reported before. It is interesting to know that there are still “well-known reactions”, that actually aren’t. My usually reaction to being presented with a route containing a Swern oxidation is to ask what other oxidizing conditions have been tried. Unfortunately, at least early in the development process, nothing else was tried because the Swern oxidation worked so well.

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Technorati Tags: nickle catalyst, Suzuki reaction

A Short Enantioselective Pathway for the Synthesis of the Anti-Influenza Neuramidase Inhibitor Oseltamivir from 1,3-Butadiene and Acrylic Acid
J. Am. Chem. Soc., ASAP Article 10.1021/ja0616433 S0002-7863(06)01643-X
Web Release Date: April 25, 2006

De Novo Synthesis of Tamiflu via a Catalytic Asymmetric Ring-Opening of meso-Aziridines with TMSN₃
J. Am. Chem. Soc., ASAP Article 10.1021/ja061696k S0002-7863(06)01696-9
Web Release Date: April 25, 2006

Both of these reports use cheaper more readily available starting materials than shikimic acid that Roche currently uses.

The first article is from E.J. Corey’s lab and describes a synthesis starting from butadiene and an acrylic flouro-ester. It involves 11 steps and from a development and scale-up perspective the synthesis has several reagents that would need to be removed. This includes TMSOTf and SnBr₄ (although it is catalytic) as well as CCl₄ solvent. These are all problems that development chemists deal with on a daily basis and should be fairly easily overcome. The overall yield is 28% according to my calculations (they claim 30%) with only one low yielding step (61% but not optimized) but these were all on a very small scale (total of 80 mg of the final intermediate was made). As those who spend time scaling up chemical processes these yields rarely translate directly on scale and usually require optimization. However, in general, the reactions used are fairly common and should scale readily. It is also interesting to note that the paper specifically states that this route is in the public domain and presumably they do not intend to patent this process.

The second paper is from the Masakatsu Shibasaki group in Japan and has more serious concerns from a scale-up perspective since the key step involves TMSN₃. Not only is this a hazardous and expensive reagent but it is also used in large excess (3 molar eqv). It also involves a large catalytic amount of a Y(OiPr)₄ (10mol%) and a chiral additive (20mol%). Also the sequence is rather lengthy at 15 steps and overall yield of 0.01% according to the reported yields. Several steps are low to moderate yields and the last two steps have yields of 53% and 50%, the worst possible place to have low yielding steps. It also involves a Dess-Martin oxidation; these are never scaled up due to the hazards and so another method would have to be demonstrated. Ni(COD), SeO₂, TMSCN are other reagents that would have to be eliminated. I don’t hold much optimism for this route as a great amount of development work would be needed before even kilo-lab quantities could be produced.

In the development process there is always the need to weigh how quickly the material is needed with how much material needs to be produced. That is, it doesn’t make sense to spend a large amount of time perfecting a synthesis only to find the drug fails in phase 1 or early phase 2 trials. However, in this case, the drug is already approved and so perfecting the route should be a high priority. However, post-apporval chances are time consuming and costly since that route would need to be validated and shown to produce equal or better material than is currently produced. Also the different route will result in different impurities that must be dealt with both in terms of analytical chemistry as well as toxicology.

So, although it is interesting to see these developments, it won’t have any immediate impact on the Tamiflu supply issues.

Technorati Tags: Tamiflu