Org Prep Daily

June 10, 2015

The power of blunder – based optimization

Filed under: industry life, procedures — milkshake @ 8:46 pm

I have been trying to optimize a difficult reaction; I thought a presence of zinc chloride might help so I gave this a try and there was an improvement: The results were getting better, week after week.

Some time later – by now with improved product purity and filtrability – I begun to wonder if the zinc chloride effect was real, or maybe something else was going on, so I finally got around to run a control. And sure enough, the reaction worked even better without zinc chloride. So, after many tries with quantities of reagents and additives, I arrived at optimized procedure which looked almost exactly like the one that I started with, except few minor details – the little changes that were incidentally co-introduced because of the ZnCl2 addition – few small changes that make a difference… I would have never tried these changes without it. And I would have given up if I had run the control experiments earlier and found out it does nothing.

It is delightful to read methodology papers, the observations and explanations arranged neatly, flowing like a good detective story, with a chain of clear logical reasoning based on the experimental evidence. But I suspect it is mostly fictional (There is no good place in a process paper to explain that after very slow reagent addition because of a clogged valve that no-one cared to inspect before the pilot run, the impurity profile improved and the troublesome sideproduct from the second step no longer buggers up the recrystallization). I worry that reading published accounts of process research can give the management a very unrealistic impression what a normal project should look like.

March 19, 2015

How to leave a strong impression

Filed under: lab destruction — milkshake @ 9:14 pm

I got a summer internship in a natural product synthetic group, a quarter century ago when I was in high school. It was a very nice lab doing medicinal chemistry on cardioglycosides and I really liked it there. But I didn’t realize that the PI from the group wasn’t thrilled to have me (he was asked to take some random kid as a community outreach initiative, and he could not turn it down.) He promptly sent me out of the way, to the library.

In those days, the literature search used to be done with printed indexes of Chemical Abstracts. It was like slogging away through a supermarket shelf filled with phone books; I spent three weeks doing this.

Undeterred, I was nagging the PI to have me try experimental chemistry. Finally, he would let me prepare an acetylated analog of a frog cardanolide, as analytical standard. He instructed me to weight out 10mg of the material, dissolve it in 1mL of pyridine, add 1mL of acetanhydride, and let it sit overnight. Then evaporate, work up with diluted sulfuric acid and DCM.

I tried to hit exactly 10.0mg and it wasn’t easy: it took me forever to weight on precision balances, and meanwhile the guy was looming over me, unimpressed, rolling his eyes. During all this, I somehow put a tip of the little spatula to my lips – the working end of the spatula – and then asked the dour PI if bufanolides were supposed to have such a bitter taste.

For a moment, it wasn’t clear who was going to suffer the heart attack first but eventually the shouting subsided, I got my face wiped clean with alcohol swabs and was ready to set up the experiment.

So I dissolved the material in exactly 1.0 mL of pyridine, then carefully added 1.0 mL of pyridine to it (I must have grabbed the wrong brown bottle, they looked the same) and isolated 9 mg of a very pure starting material a day later; it was my last experiment in that lab…

Whenever I have to work with someone young and unbearable, it helps to recall the many asinine things I did unto others.

November 6, 2014

Pleasures of Process Development

Filed under: industry life — milkshake @ 8:32 pm


A reflux in 12 molar HCl
Carefully watched for a frothing,
Painstakingly drained from the reactor,
To strip down and scrub off that gross thing.

My bosses, I tried please believe me,
I’m doing my best as you insist,
I’m ashamed of the material I burned through,
I’m ashamed of the deadlines I missed.

But if you could just see the beauty,
These things I could never describe,
These pleasures of process perfection,
This is my one lucky prize.

refrain: Product isolation…

My apologies to Joy Division

July 4, 2014

Happy 4th of July!

Filed under: Uncategorized — milkshake @ 9:50 pm

In Dependency Day
Credit: Jiri Sliva

May 22, 2014

A kilo-scale hydrogenation reactor?

Filed under: procedures — milkshake @ 8:22 pm

I have been running some hydrogenations of our polymers on kilo scale, at atmospheric pressure under balloons, and it is a bit of a chore. It would be nice to have something akin to a beer keg-sized Parr shaker and run the hydrogenation under few bars of H2, to reduce the catalyst loading and shorten the reaction time.

I wanted to ask the readers from process groups if they worked with a low-pressure batch stirred hydrogenation reactor that they liked and could recommend – for us to buy. Specifically,  we would need a hydrogenator that can accommodate 8-10 liters of a reaction mixture that has tendency to initially foam under reduced pressure (this means that the total available volume should be about 15-20 liters). Maximum operating pressure 3 bar would be enough, no heating or cooling is required and the typical solvent is water. I am not really interested in flow hydrogenation systems because they would be unsuitable to our particular case. A glass vessel or at least a glass window on the top would be nice to have, because of the foaming problem during evacuation.  Thank you for your suggestions!


September 24, 2013

O-selective acetylation of tyrosine

Filed under: procedures — milkshake @ 7:30 pm

1. HTyr(Ac)OH.MsOH:

Methanesulfonic acid 80mL (1.2 mol) solution in acetic acid 0.5L was added to L-tyrosine 181.2g (1.0 mol, Aldrich 97%+) in a 5L 29/42 joint flask and the mixture was stirred vigorously without cooling until complete tyrosine dissolution (about 2 hours). The flask was placed in +10C water bath and the mixture was stirred till the internal temperature was about 15C. Neat acetanhydride 105mL (1.1 mol) was added dropwise over a 30 min period with a vigorous stirring and cooling on cold water bath, then continued at 15-20C for additional 90 min, at which time a voluminous precipitate solidified the reaction mixture. Peroxide-free THF 1L was added to the crystalline mass, the mixture was mashed up with a large spatula to break the lumps and then stirred vigorously for 20 min. The precipitate was collected by filtration, washed thoroughly with THF, the product was dried by suction under N2 blanket and then in vacuo until only a faint smell of AcOH remained with the product (10 Torr, 1 day). Y=259.8g of white solid (84% th)
1H(d6-DMSO, 400MHz): 8.28(br s, 3H), 7.29(app d, 8.6Hz, 2H), 7.10(app d, 8.6Hz, 2H), 4.20(br t, 6.4Hz, 1H), 3.10(br d, 6.4Hz, 2H), 2.33(s, 3H), 2.26(s, 3H)

2. HTyr(Ac)OH:

The O-acetyl tyrosine mesylate salt from the first step was dissolved in D.I. water 0.5L in a 4L large beaker, a solution of triethylamine 118mL (0.84 mol; 1 eq.) in ethanol 0.5L was added rapidly with stirring, the crystallized mixture was combined with additional ethanol 1L and agitated with a large spatula, then stirred for 30 min and finally placed into a refrigerator (+ 4C) overnight. The precipitated product was collected by filtration, rinsed thoroughly with chilled 200-proof ethanol (0.5L, +4C) and then with few small portions of ambient ethanol (4x20mL), dried by suction under N2 blanket and then thoroughly dried in vacuo. Y=168.4g (79.5% overall) of a white fluffy solid.
1H(D2O 0.7mL/10mg, 400MHz): 7.36(app d, 8.4Hz, 2H), 7.14(app d, 8.4Hz, 2H), 4.79(s, 3H; HOD), 3.98(dd, 8.0Hz, 5.5Hz, 1H), 3.29(dd-ABX, 14.7Hz, 5.3Hz, 1H), 3.14(dd-ABX, 14.7Hz, 7.8Hz, 1H), 2.34(s, 3H)

Note:  Effective stirring and cooling during the Ac2O addition is important for achieving good results. Using a cheap grade of tyrosine (a yellowish muddy powder, with some impurities detectable on NMR in aromatic region) is tolerable – and MsOH from an old bottle that was already a bit dark worked fine in this procedure – but the used THF should be aldehyde+peroxide free.

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