Org Prep Daily

November 6, 2014

Pleasures of Process Development

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


A reflux in 12 molar HCl
Carefully watched for the frothing,
Painstakingly drained from the reactor,
To filter and dry that brown 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 we 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


  1. That is my favourite scale ever! It’s so sad that I haven’t had a chance since a summer placement years ago to do kilo-scale reactions. 😦 Unfortunately during my PhD it’s even less likely to do reactions like this, but I’d love to scale one of my fluorinations to a reactor this size!

    Comment by Fluorine Chemist — November 7, 2014 @ 1:01 pm

  2. But ist looks like you wear no safety goggles…

    Comment by Christian Gege — November 7, 2014 @ 2:18 pm

    • of that I’m ashamed too. (I had a full face shield on, when pouring two gallons of HCl into the reactor)

      Comment by milkshake — November 7, 2014 @ 2:21 pm

  3. Reflux in 12M HCl: what is the (area of) chemistry?

    Comment by Neil — November 12, 2014 @ 9:00 am

    • it is an inorganic compound – a heavy metal complex. It is just a precursor for other stuff.

      Comment by milkshake — November 12, 2014 @ 10:06 am

  4. Dear Milkshake,

    Long time reader first time asker.

    I have a protecting group/deprotecting group question. I have a compound with a a phenol and secondary alcohol. I need to selectively modify the secondary alcohol without modifying the phenol in the final product. Do you know of any protecting groups that I can selectively add to the phenol instead of the secondary alcohol?

    Thank you,

    Comment by Sam — November 13, 2014 @ 1:32 pm

    • I think this should be pretty easy because phenols are both more nucleophilic and more acidic. One sure way (if your molecule can tolerate high pH) would be biphasic Schotten-Baumann conditions with dilute aqueous NaOH and a chloroformate ClCO2R (1.2 equiv) with cooling to 0C on ice with some water-immiscible solvent like ether, MTBE or DCM to dissolve your starting material. The carbonate ester deprotection is done with NaOH or MeOH+NaOMe, with hydroxylamine or methylamine (in case of benzyl or allyl chloroformate, you can do hydrogenation resp. Pd(PPh3)4 + Et2NH).
      But I would first try something simpler/cleaner, like Boc2O or Ac2O in DMF at room temp without any catalyst, followed by vacuum evaporation

      Comment by milkshake — November 13, 2014 @ 2:16 pm

      • Thank you so much. I will let you know how that plays out

        Comment by Sam — November 13, 2014 @ 2:21 pm

  5. just a layman’s question (was a hobby chemist in the late 1970ies, as a kid)
    on the photo i see a large reaction vessel, heated by a jacket of watervapour or silicone oil, or whatever.
    But where’s the reflux condenser?

    Comment by haarp — November 23, 2014 @ 7:09 pm

    • this is exactly right question – there was a connection adapter and a reflux connector and gas outlet tube on top of the reactor vented into the nearby fume hood when this reactor was heated (by hot oil circulating in the jacked) but the picture was taken next morning, after the whole thing was left to cool down, and I have already taken off the adaptors and the condenser and cleaned them, now I am just emptying the reaction vessel with a finished cooled reaction mix inside (draining hot concentrated HCl would be a very nasty undertaking because of all the corrosive HCl fumes released into the lab. Even cold it was unpleasant, that is why I am wearing gas mask. We should do this kind of work in a walk-in fume hood but we don’t have it at our company. This is a one-time trial run, to see how it behaves on a larger scale in a reactor before we go with this chemistry to a contract manufacturing company where they have all the right equipment)

      Comment by milkshake — November 24, 2014 @ 9:52 am

  6. Hi,

    Do you know of anyway to use an aryl bromide to alkylate Maleimide?



    Comment by Sam — December 3, 2014 @ 1:56 pm

    • I have never attempted anything like this myself, but you will likely need Buchwald arylation conditions (Pd catalyst) or Ulman conditions (Cu catalyst) and there will be problems with the choice of base because C=C in maleimide is highly reactive to Michael addition and Heck reaction. You will need to run a Scifinder search first

      Comment by milkshake — December 4, 2014 @ 2:25 pm

  7. My favorite is to do the hot filtration of acid mixtures like HCl in Acetic Acid or Nitric and Sulfuric. It’s also easier on the flooring to have a plastic tray underneath; but it appears to be to late for this lab.

    Comment by Ray Reeves — December 3, 2014 @ 5:15 pm

    • our cement floor is soaked with light silicone oil used in the circulating bath…

      Comment by milkshake — December 4, 2014 @ 2:29 pm

  8. Hi,

    I am reacting a amine-lipid (saturated C16) with and NHS-ester (hydrophobic) do you have any recomended methods for purification? Can I precipitate or is a column needed?

    Comment by Sam — February 23, 2015 @ 9:28 pm

    • If you are making it the first time, and the material is not too precious, I would maybe run it on a 1-2 gram scale and purify it on a silica column, and then thoroughly dry the material in vacuo, to obtain a pure material that you can characterize by NMR, TLC and melting point. Only then, with the pure material in hand, one can see how crystalline and soluble it is (for example, it is painful to crystallize compounds from solvents in which they are very soluble, and oiling out often happens once you get within 10-20C of the melting point, and so on.)

      Tell you boss that you can try to develop a non-chromatographic purification based on crystallization/precipitation eventually but not on the first run. Ask him to let you work on it for 2-3 weeks, to find out. BTW, my thesis work was on hydrogenated alkyl phospholipids, both synthetic and natural.

      Comment by milkshake — February 23, 2015 @ 10:21 pm

  9. Reblogged this on New Drug Approvals.

    Comment by DR ANTHONY MELVIN CRASTO Ph.D — March 21, 2015 @ 9:40 pm

  10. Chemglass 10 liters reactor? There was plenty of old julabo FP51 used heaters/chillers on online auctions… they can do the job at a pretty cheap price. An hosing adapter on the drain valve, a teflon tube and a closed can maybe are better than an open bucket, in order to drain the reactor….

    Comment by processchemist — March 30, 2015 @ 8:21 am

    • the reactor is actually 15L; it looks a little smaller next to an elephant…

      Comment by milkshake — June 7, 2015 @ 12:06 am

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