Category Archives: Chemistry

Handy Chart for the 2008 Top 200 Drugs

1 Reply

I ran across this handy pdf file from the website of Prof. Njardason at Cornell. It is a graphic compilation of the top selling drugs (in the USA?). Just click on the image and a pdf will download.  The site has compilations for the last several years as well.

A few of the drugs on the list are protected under patents that will expire in the next few years- Lipitor, Crestor, Lexapro, Advair, Singulair, Plavix, etc. Hours after the license to print money expires, the generic barbarians and visigoths will storm the gates and unceremoniously slaughter these cash cows. The horror, the horror.

Bruker’s New 1 Gigahertz NMR Spectrometer

5 Replies

June 1, 2009, Bruker announced the release of the AVANCE 1000 NMR Spectrometer. This 1000 MHz (1 GHz) instrument features a standard 54 mm bore within a 23.5 Tesla superconducting magnet. The magnet technology offers subcooling (below the bp of He) in the magnet, which Bruker claims to be necessary for the stability of the magnetic field. Bruker also offers nitrogen-free magnets that are able to keep the helium boil-off rates to a minimum. While it would be nice to avoid having to manage two cryogenic liquids, I wonder what the pay-back time is for the chiller equipment?

Imagine the hassles, begging, and incredulous stares that the users will have to contend with to to get some 1 GHz NMR time? I wonder if anyone will do 1-D experiments with it?

The AVANCE  1 GHz instrument is priced at a cryogenic ~$16,000,000 per copy with an 18-24 month lead time. I’ll have to stick with Anasazi Instruments for a while at least.

Separately, a link at the Bruker website will take you to the University of York where a site dedicated to one groups NMR work with parahydrogen is detailed. A technique called SABRE, Signal Amplification by Reversable Exchange, is described. The exposure of an NMR sample to parahydrogen (singlet H2) results in the transfer of polarization to the sample and subsequent increase in sensitivity.

The workers describe the operation of a device used for the conversion of triplet orthohydrogen to singlet parahydrogen as a ready source of this peculiar “isomer” of dihydrogen. Parahydrogen is the dominant form at 20 K, but drops to 25 % abundance at room temperature. Exposure of a mixture of ortho and parahydrogen to a paramagnetic catalyst does the conversion to achieve enriched singlet H2.

According to one on-line source, the conversion of ortho- to parahydrogen evolves 527 kJ/kg. I’d watch out.

HR 2868- Good intentions gone sour

6 Replies

There is a fine line between good sense and paranoia and HR 2868 has definitely crossed over into deep paranoia. This resolution, sponsored by Rep. Thompson (Mississippi), Rep. Waxman of CA, Rep. Jackson-Lee of TX, Rep. Markey of CA, and reps Clarke and Pascrell, is an amendment to the Homeland Security Act of 2002.  Its purpose is

“to extend, modify, and recodify the authority of the Secretary of Homeland Security to enhance security and protect against acts of terrorism against chemical facilities, and for other purposes.”

Well, how could anyone be against such a noble sounding piece of code? The sponsors are struggling to protect the homeland against attack on chemical facilities. Facilities whose hazardous material inventories could be maliciously released to cause harm to the surrounding neighborhoods of innocent and helpless citizens.

Sec. 2102 (a) (1) allows the Secretary to designate any chemical substance as a “substance of concern” and establish a threshold quantity for each substance of concern.

There are many goodies and zingers in this bill. Sec. 2115 (a) (1) (A) requires that the Secretary issue regulations for substantial background checks to establish personnel surety in covered chemical facilities. The security check will be deep and will serve as a reservoir of information collected by company on citizen employees and subject to inspection on demand by the Secretary.

Sec. 2116 (a) (1) states that any person may commence a civil suit against any person “who is alleged to be in violation of any standard, regulation, condition, requirement, prohibition, or order which has become effective pursuant to this title; or … “.  This citizen lawsuit provision will open the floodgates to lawsuits on companies running chemical plants and in so doing, under the rules of discovery, break through the IP protection afforded by trade secrecy.

This proposed law also provides for close oversight by the Secretary of Homeland Security as well as civil penalties (Sec. 2107 (b) (1)) of up to $50,000 per day of violation.

OK. Nobody wants acts of terrorism to happen and especially not on the site of a chemical plant. But to legislate the transformation of chemical plants into a “Fort Apache” scenario in the absence of a history of attacks on US plants is to invite needless cost and complication to an industry that is already heavily regulated. This is plainly the result of irrational fearfulness on the part of congressional sponsors. And Congressmen are in a position to convert their fears into law.

Compliance with this law will require considerable effort and expense to be carried by industry. The downside to being out of compliance is too expensive. Over time companies may opt out of processes that use chemicals of concern simply to reduce the risk of noncompliance as determined by government audit.

The chemical industry uses hazardous chemicals of many varieties. Hazardous chemicals are often reactive chemicals. And reactive chemicals are useful chemicals.

The entire chemical industry is built around the exploitation of reactive attributes in order to cause a desired change in chemical composition. The unintended consequence of this legislation is that useful but reactive chemicals may be inherently prone to identification as chemicals of concern. The effect would then be that key substances at the core of a given technology platform would be regulated on the basis of what a terrorist could do with it rather than its value to technology and to civilization.

What constitutes adequate security? Who is to say what security measures are satisfactory? The security industry seems to attract the paranoid who see threats behind every shrub. To have such people deciding what chemical is acceptable for use in manufacturing is unacceptable.

Robustness Challenge Tests

6 Replies

I and my assistant have spent the last month devising experiments that are meant to chart out the stability or robustness of a small set of compounds whose manufacture has been problematic. This has been a kind of a process development activity wherein we are trying to understand what the specific sensitivities of this molecule are and how they might impact process stability.

My job these days is reactive hazards analysis and process safety. We have been trying to dream up experiments that tease out particular weaknesses a compound may have in normal or plausible off-normal conditions. While the compounds in question do not have apparent issues with reactive hazards, the skill set needed to find reactive hazards is useful in finding economic hazards as well.

An economic hazard would be something that threatens the profitability of a process. A production instability is simply a low threshold for a transition to off-normal processing conditions. Sometimes a process instability is physically dangerous and sometimes it is only an economic threat.

I have to say that this has been very enlightening so far.

National Organic Symposium. Wender Wednesday.

1 Reply

My final attendance at the National Organic Symposium was Wednesday evening. An award was presented to editor-in-chief, Scott Denmark, on behalf of the monograph series Organic Reactions. The original editor was none other than Roger Adams. Denmark presented a retrospective slide show on the history of Organic Reations.

The speaker for the evening was Prof. Paul Wender from Stanford.  Wender presented a long but fascinating talk on his work with several complex molecules including bryostatin. I have to say that I was rather blown away by this work. I guess I’ve been living on a desert island.

Wender has the great fortune of having access to facilities and people who can do complex chemical synthesis and biological assays and all of the other wondrous things that are necessary to rapidly expose a valuable biopharmaceuticals. The payoff is that questions relating to the biological activity of particular derivatives can be answered rapidly and productive leads can be isolated and further cultivated.

This confederation of resources is perhaps as important to Wender’s productivity as anything. My point is that to be a Wender, you need more than just smarts and money. You need a network of like-minded coworkers whose particular strengths can mesh with yours to produce these kinds of results.  I think that his ability to pull together these kinds of resources is just as impressive as his native ability with chemistry.

National Organic Symposium. Tuesday Morning.

6 Replies

Bad day for Th’ Gaussling to be away. The hounds are snapping at my heels at work.

I managed only to see Eric Jacobsen‘s talk on catalytic urea chemistry. Jacobsen’s system is pretty much a chiral proton ligand that can carry along a nucleophilic counter anion. Configured differently, urea’s and thiourea’s with BARF groups on the nitrogen can coordinate with chloride. This can lead to the abstraction of chloride to give a carbenium ion that can then participate in a enantioselective Pictet-Spengler type reaction. 

Jacobsen’s system resembles a radically stripped down enzyme in terms of 3-point binding interactions by hydrogen bonding.  Where Jacobsen went askew is the use of calculations to justify his mechanistic model. The models did not include solvent interactions when affording only 0-2 kcal/mol (!!) differences in energy. Naturally this did not set well with certain distinguished members of the Audience.  The ΔΔG’s did not correlate with the ee’s at all either.

A certain J.D. Roberts took great exception to Jacobsen’s molecular modeling results, resulting in the spectacle of a Harvard Professor frantically qualifying his slides and words as he back pedalled for all he was worth. There was some actual contrition there on the stage. It was quite a thing to see. There but for the grace of God go I.

National Organic Symposium. Monday Morning.

4 Replies

The speakers for the morning of June 8th were Bob Grubbs and Magid Abou-Gharbia. As usual, Bobby Grubbs’ talk was concerned with the latest wonders of olefin metathesis. We saw ATM’s of molecular Cheerios. Pretty cool, actually. Grubbs got the trip to Stockholm for a reason and the work of his group continues to produce molecular wonders.  He was able to demonstrate the production of rings with degrees of polymerization in excess of 5000.  Using NMR and a carefully chosen ring monomer, they could sort out linear polymers from cyclic polymers. Linear polymers will thread a crown ether while the cyclic form will not. By attaching a crown ether (24-crown-8 ??) to polystyrene beads, they could collect and physically separate the linear from the cyclic forms. They were also producing brush polymers.

Prof. Magid Abou-Gharbia, Temple University, gave a talk with lots of fascinating insights into some current thinking on industrial drug discovery. At least from the point of view of a former Wyeth guy. I have been away from the pharma-related work for a number of years now and haven’t really missed it. But his talk has revived enthusiasms in me that have been in a long slumber. 

Anyway, he described the development of the anti-depressant Effexor and their efforts to keep the molecule simple and free of excessive stereocenters. Studies of the metabolism of Effexor lead to the discovery of the des-methyl analog, now called Pristiq.

Concerning High Throughput Synthesis (HTS)-

“… you’re going to get a lot of decorated molecules, but they are not going to be biopharmaceutically useful.”

Abou-Gharbia lamented the languishing of natural products chemistry. He gave some examples of Rapamycin work, which according to his presentation, was originally isolated from a soil sample from Easter Island.  Much productive work apparently has been derived from the modification of this macrocycle. It’s all in the literature.

One of the main take-away lessons from Abou-Gharbia is that workers shouldn’t get too focused on SAR. His advice was that structure-property relationships need an early examination as well. Dual optimization. If the bioavailability is low, then the in vivo activity will not match the in vitro activity- an expensive and time consuming realization.

Organic Symposium

4 Replies

Despite my previous gritching about it and despite trying to stay below the radar at work, the boss has requested and required that I attend the Organic Symposium at CU Boulder. I’ll bop over there later today to register and walk the poster session. Maybe there will be some useful grist for the blogmill.

No better reminder of the scientific pecking order than to skuttle around in the shadows of the great grant writers of our time. A certain speaker with a Nobel Prize casts a shadow so large that it is reported to weigh nearly 5 kilograms. Fancy that!

Thermochemical Snipe Hunt

1 Reply

Spent the better part of the day hunting snipe in the chemical literature. I’ve been looking for some English language literature relating to the Yoshida explosive potential correlation between DSC heat of formation and DSC onset temperature. I have some sketchy relationships from Yoshida in Chemical Abstracts CAN 108:58900 –

Shock Sensitivity = log (QDSC) – 0.72*log(TDSC-25) – 0.98

Explosive Potential = log (QDSC) – 0.38*log(TDSC-25) – 1.67

QDSC is the magnitude of the exotherm as measured by DSC (presumably in J/g, not J/mol), and TDSC is the onset temp also determined by DSC. A separate reference suggests that compositions with EP>0 are potentially explosive.

I want some better grounding in the assumptions going into the correlation before I pony up my own results. This is potentially a very useful relationship in reactive hazards work and something I can do in the lab myself.

It’s a pity I do not speak Japanese since much of the cited work is in Kogyo Kayaku and in Japanese.

Scheiss!!

Ever pondered the merits of mixing up a batch of N5 salt? Polynitrogen chemistry. Yikes. Check out this link (rather large).

May Linkfest

1 Reply

A friend sent me the link to Wolfram|Alpha  just a while ago. So far it seems to be a bit lean in textbook-style content in the chemistry area. For instance, when you enter “aromatic solvents” into the dialog box, it returns with

Wolfram|Alpha isn’t sure what to do with your input.

But if you type in “toluene”, suddenly it is the CRC and is flush with data. The stated goals of the Wolfram|Alpha developers are-

Wolfram|Alpha’s long-term goal is to make all systematic knowledge immediately computable and accessible to everyone. We aim to collect and curate all objective data; implement every known model, method, and algorithm; and make it possible to compute whatever can be computed about anything. Our goal is to build on the achievements of science and other systematizations of knowledge to provide a single source that can be relied on by everyone for definitive answers to factual queries.

I do not yet know enough about this resource, but it seems to be a data engine rather than a prose engine.

Landscheidt Cycles Research is a site devoted to the Planetary Influence Theory. This theory pertains to the possible gravitational influence of the planets on solar cycles. it is worth a look.

Watts Up With That? is a blog concerned with global climate issues. The blogger and many of the commentors seem to have their facts straight about global climate change. The site is very data intensive.

If you are a scientist or manage scientists, it is worth considering the file drawer effect.

An online NMR predictor can be found at nmrdb. In my experience the splitting and chemical shifts seem to be in the “not too awful” range.