I am going to post here synthetic procedures that pleased me. The experiments were joy to set up+run, the purifications were a piece of cake, the crystals were shiny and the yields were terrific – or maybe weren’t but I liked the preparation anyway. Many procedures came from the literature, some were modified and few are my own. I hoped (and tried) to make these write-ups reproducible and reasonably safe – but I could be wrong and lucky:
‘It is necessary that the operator takes all precautions to preserve himself from misfortune.’
Sorry if you are looking for psychoactive or energetic compounds, you won’t find help here – my work is related to cancer and neurology research. In medicinal chemistry, one often cannot present a full account. You will see some building blocks, precursors, reagents but most likely not the final stuff.
Update: End of daily posting. Please feel free to submit any good synthetic procedure you like to share here in Org Prep Daily. Cheers to Chris Douglas.
Update (8/24/08): 1,730 real comments and “Akismet has caught 33,700 spam comments” with about 30 legit ones filtered out unfairly. Please limit the number of inserted additional links in your comment-text to one link per post. Avoid foul language – the automatic spam filter is a prude. Thnx and sorry.
Nice site! You should consider a quick blerb about what the reagent is used for so younger chemists can learn why they might want to make these reagents.
Just a thought.
Comment by d-orbital — September 8, 2006 @ 5:37 pm
Delighted that you are putting up procedures for the rest. Also second the comments of d-orbital. However, i believe i look forward more to your comments on others blogs and the way you address problems in synthesis (guess it comes with doing a lot of chemistry).
Comment by sks — September 17, 2006 @ 4:02 pm
That sounds great milkshake! Great thought and all the best. I would love to see comments and appreciations for the procedures.
Comment by Joseph — September 26, 2006 @ 4:26 am
Dear Milkshake,
I couldnt resist the temptation (while evaporating toluene) of reading one of your comments in a magazine (In these days) three years ago, and I have to say that I quite symphatize with the comments you posted there (you’ve got guts and know very well what you are talking about).
I quite like this blog as well, (I think actually that you are really generous to the chem bloggers), and sure I will take into consideration if I will have to follow any similar procedure, but when are you going to gift us with comments in general about chemistry, chemistry news or more general topics? (and I am not speaking about gossips or any other rubbish, like it happen at one point in tenderbutton).
Comment by HOMO-LUMO — October 4, 2006 @ 4:59 pm
Thank you H-L but I put up this site for procedures that I did with my own hands (and liked for one reason or another). The motive behind doing this was that lots of work in medchem is spent on bits and pieces that are not publishable on their own and once the project is over they are forgotten and lost. But if I put these procedures on the web – with Google being so powerful and inteligent – they might be useful to someone in a medchem lab.
So I would like to have this page much like a private version of OrgSyn. I want to keep the noise here to minimum. Also, I am not particularly eager to write and post some well-thought opinions about chemical community or pharma industry in general and I am not going to write about my colleagues, workplace or private life either. Dylan’s Tenderbutton was a wonderfull hang-in place whereas Org Prep Daily is intended to be dull.
Comment by milkshake — October 4, 2006 @ 5:47 pm
Thanks for popping by my site and linking, but more importantly, thanks for your efforts on a particular patent. We won’t let you down!
T
Comment by Xcovery — January 12, 2007 @ 5:09 pm
Timmy, I have been following the Xcovery kinase blog regularly for couple of months – thanks to Kinasepro – not knowing who you were. (So you can imagine my suprize when I realized that you are in charge of a company that is going to develop our compounds). It’s a small world. Best luck to you with everything.
Comment by milkshake — January 12, 2007 @ 5:47 pm
Could you please give your e-mail or drop me a note on the address here, I have a few questions…
Comment by liquidcarbon — May 24, 2007 @ 11:03 am
I want to prepare mixed anhydride using isobutyl chloroformate of N-boc-l-2-amino butyric acid. but reaction did not complted unreated isobutyl chloroformate creat problems how can i remove unreacted isobutyl chloroformate.
Comment by grignard — January 17, 2008 @ 12:51 pm
Milkshake: no need to publish this. Since Paul has stopped posting > 2 months, I’ve decided to take your advice and use WordPress and start my own blog. Would you be willing to answer an occasional question? If so, send me your E-mail address. Any suggestions as to naming things: Woodward’s worst grad student and Chemist in Recovery come to mind
Comment by Retread — January 17, 2008 @ 9:34 pm
The last time I used it, iBuOCOCl from Aldrich has had some stuff in it so I would recommend to re-distil it carefully. I always use EtOCOCl instead, it is very similar in terms of the racemisation problem but it tends to be cleaner. But why mess with mixed anhydride? For aminoacid coupling I would normally use HATU or EDC+HOBt.
Retread: Please name your blog in any silly and memorable way you like – I wouldn’t overplay the Woodward thing though
Comment by milkshake — January 17, 2008 @ 10:26 pm
My goodness, where is Marcel now? We were at UCLA together.
Comment by Paul — August 21, 2008 @ 3:38 pm
right next office and hood from me – I will send you his e-mail if you want, I just gave him yours.
Comment by milkshake — August 21, 2008 @ 3:42 pm
Having trouble with a permangate oxidation of the methyl groups on a difluorobenzene – any suggestions?
Thanks in advance.
Comment by Andy — January 6, 2009 @ 2:05 pm
Unfortunately I don’t know what kind of trouble you have – is it overoxidation, or poor conversion due to poor solubility of the starting material, or the volatility problem (your substrate is likely to azeotrop with hot water)?; without knowing your actual problem is it is difficult to propose how to fix it. For comparison there is a procedure for oxidation with aq. permanganate, posted here on Nov 14, 2006.
I remember seeing some J Med Chem paper where they performed permanganate oxidation in pyridine as a solvent; the workup is not going to be fun though. Also I have a procedure here for organic-soluble Bu4N permanganate (March 16 2008] that I used for oxidizing material in dichloromethane as a solvent but I am not sure if it would work in your case.
There is an alternative methyl-to-carboxyl method that uses aqueous dichromate or chromate at elevated temperatures in a pressure vial, it should be quite easy to try if you have a microwave reactor.
If everything else fails you can try CrO3 in acetic acid, this should do the trick – but please be careful before scaling up, this mix can be treacherous if overheated, so use oil bath (not a heating mantle).
Also, fluorinated benzenes are very easy to ortho-lithiate (and quench with CO2), if your carboxylic acid is in the ortho position to F this may a better alternative than oxidizing a methyl group.
Comment by milkshake — January 6, 2009 @ 5:02 pm
during the synthesis on a industrial scale we use sulfur for aromatization of a buta diene derivative. after this we carry out fewmore steps. But the assay of final product seems to be below expected level. Feel strongly the presence of sulfur in the final material. How do you remove unwanted sulfur completely from the reaction mixture. your expert comments is highly appreciated.
Comment by pashu — April 15, 2009 @ 11:24 pm
Its not butadiene but 1,3-cyclohexadiene as mentioned above
Comment by pashu — April 15, 2009 @ 11:25 pm
I never had this problem, with removing sulfur, but if your product is crystalline I would suggest a re-crystallization from some polar solvents, like ethanol-water mix. Sulfur is practically insoluble in polar solvents. Alternatively you may try a wash with a solution of Na2S hydrate, sulfur dissolves in sulfide to form polysulfides. (But sodium sulfide is smelly, rather alkaline and oxidizes easily so I would first try a non-chemical removal method.)
Comment by milkshake — April 16, 2009 @ 9:02 am