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Sauron
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Well, it's not a 5% slurry of Pd/C, it's a slurry of 5% Pd/C. The 5% refers to the Pd content of the carbon, it comes in various strengths, you want
to purchase 5%, or you want to purchase PdCl2 and prepare your own 5% Pd/C according to Vogel.
IIRC the reductive formylation is initially exothermic. I think you then heat it to an intermediate temperature, 4045 C for a specified period and
then slowly ramp up to 75 C, over 90 min, and hold it there for another specified period. and then boil it, but follow the patent not me. There are
precipitations and color changes to look for, be punctillious about following procedure precidely.
The patent is quite sketchy about the Me2SO4, they just copped out with "in the usual manner" as patent lawyers love to do. Not very helpful unless
you know exactly what the usual manner is.
If you were using MeI rather than DMS, you would treat your theophylline with strong base to prepare the Na salt at the position to be methylated
(only one possible.) Then add the MeI and stir. I think this should be at RT and under a good reflux condenser to prevent the volatile MeI from
escaping. A Dewar condenser with dry ice-ethanol will do.
The exact procedure is described in Traube, and likely Fischer.
The condensation of maleic acid and urea is described in the attached communication from Synthesis 1971 p 154. Substituting the equiv. amount of 1,3
dimethylurea ought to work. I am surprised you like this better as it is more steps and requires fuming nitric acid, hard nto come by and costly. Also
lousy yield, whereas the other is very high yield.
The Synthesis article is in German, but it references a JACS article,
[Edited on 16-8-2007 by Sauron]
Attachment: s-1971-21689.pdf (39kB)
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Sauron
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Skip the Synthesis article, here's the JACS article.
Malic acid (not maleic!) and urea along with 15% oleum (fuming sulfuric acid, 15% free SO3) produces uracil in c.45-50% yields.
You can get around the oleum requirement by using polyphosphoric acid (115% H3PO4) instead, see reference 2 in the Synthesis article. I am requesting
this article from References.
Do this in a hood as some CO is evolved.
The authors also describe the methylation of uracil to 1,3-dimethyluracil with NaOH and methyl sulfate (dimethyl sulfate.)
So you can proceed from much more readily available urea rather than buying dimethylurea.
With dimethyluracil in hand you nitrate, reduce, nitrosate, and reductively formylate. That gets you to theophylline.
Then you methylate with your choice of MeI or Me2SO4.
Be extremely careful with both of the methylating reagents. Dimethyl sulfate in particular is a skin contact hazard and an inhalation hazard and is a
brain carcinogen. USE A HOOD. USE GLOVES. USE A RESPIRATOR, MASK or SCBA.
[Edited on 16-8-2007 by Sauron]
Attachment: ja01420a020.pdf (307kB)
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ssdd
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That last pdf was very helpful and seems like a better process for the uracil. So this is now the first challenge is to find all necessary ingredients
to make the uracil, once that is made move on from there... all this time I worked out of my high school lab rather than building a home lab, now that
my hs lab is gone I'm left to scavenge, so it may be some time before I finally get around to this bit. Unless someone knows of a cheap source for
this stuff, please inform me if you do. 
I have to ask Sauron, where do you manage to find all this information? I mean I search around but don't turn up nearly as much material, seems like
you found tons within a few hours...
-ssdd
All that glitters may not be gold, but at least it contains free electrons.
-- John Desmond Baernal
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Sauron
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Every bit of it was either from my pile of CDs, all obtained from the forum, forum library, or FTP site; or online.
Merck Index 12th on CD was entry point
Berichte online (Gallica free to 1901) also Wiley but not free
Then Org Syn online
JACS online
Patents online
Synthesis on CD
And I am not through yet.
Searching is an art.
You can buy polyphosphric acid a lot easier than you can fuming sulfuric acid. Or you can make it from phosphoric acid and P2O5, just add enough to
get rid of all water and then add enough excess to reach 115%.
You might well as yourself how we are getting from a four carbon acid (di-acid) and urea, to a 6-membered ring. Well, malic acid is decarboxylating on
one end under the acid conditions and the alpha-hydroxyl being oxidized by SO3 to carbonyl, so three carbons, aldehyde at one end and acid at the
other - a derivative of malonic acid. Malonic acid partially reduced. Were it malonic acid per se you would get barbituric acid.
This is explained in the JACS reference. The Science reference which uses PPA, is not very useful. I would say that it is reasonable to expect PPA to
work but perhaps less well than oleum. And the exact mechanism of the maleic acid reaction in the Synthesis ref. is not very clea. Decarboxylation
sure, but how to form carbonyl? And would oleum give better yield with maleic acid than PPA gives?
Malic acid and Oleum 15% 50% yld
Maleic acid and PPA 115% 20% yield
An open question.
[Edited on 16-8-2007 by Sauron]
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Sauron
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@ssdd, the uracil preps are interesting and you seem to be attracted to them. However it seems the nitration of uracil or 1,3-dimethyluracil nitrates
the position closest to the carbonyl rather than the next carbon over. What you need is 6-nitrouracil (or 6-nitrodimethyluracil) rather than 5-nitro.
That is so that after reduction to 6-aminodimethyluracil, you need to nitrosate it to 6-amino-5-nitrosodimethyluracil, which is what the patent calls
Ia.
Therefore it seems like the cyanoacetodimethyl urea method is the only way to go.
In my opinion the high yield and simplicity of this route more than compensate for the annoyance of preparing ethyl cyanoacetate. Furthermore this way
you need neither fuming nitric acid nor fuming sulfuric acid.
I am continuing to review the material I have collected and to add to it.
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ssdd
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Yea the prep for ethyl cyanoacetate kinda annoyed me because it seemed to be adding alot of steps, but it does seem better in the end.
I'll keep reading everything you have posted and ask any questions I can think of along the way.
I am also gona hunt around and see if I can build a reference database here, the site library has been great but I was unaware that there is a ftp
site... guess I'll look into that.
I have to go at the moment, but perhaps later I'll print all that we have here and it should be simpler to compile it in my head while reading it from
paper...
-ssdd
All that glitters may not be gold, but at least it contains free electrons.
-- John Desmond Baernal
http://deepnorth.info/ |
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Sauron
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Ethyl cyanoacetate is about $50 a Kg (or liter). If you can buy it you can save yourself a lot of work, and having to deal with corrosive chloroacetic
acid, toxic cyanide, and the highly irritating vapors of the ethyl cyanoacetate while you purify it.
You might think that it does not matter whether the nitro group is introduced into uracil at 5 or 6, but the two carbons of that pi bond are not
equivalent. One is alpha to a carbonyl. That is why it is nitrosated so readily. Also why when you treat uracil with HNO3, it nitrates there
preferentially.
If the 5 position would nitrosate, all would be well. But I have found no examples.
In this context the inconsistency between the numbering of the pyrimidine ring and the uracil ring become very confusing and therefore, very important
to understand thoroughly.
A helpful hint:
You will notice in the older lit. the pyrimidines and uracils are often drawn rectangularly - in a fasion that makes it really easy to see the urea
and the other partner in the condensation.
Malonic acid or ester if product is a barbituric acid
Cyanoacetic acid or ester if product is an aminopyrimidine
That is visually useful. We don't need to draw those unattractive and unrealistic rectangles to achieve same result. Just rotate the 6 membered ring
to a horizontal orientation.
It is also very helpful to bear in mind that cyanoacetic acid is the half nitrile of malonic acid, in fact that is how we make malonic acid in the
lab, by acid hydrolysis of cyanoacetic acid, built from sodium chloroacetate.
The dinitrile of malonic acid is of course malononitrile and I bet it will also condense with urea under basic conditions, and the product would be
4,6-diaminopyrimidine-2-one.
[Edited on 17-8-2007 by Sauron]
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ssdd
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So the other day my research partner asked to see the synthesis as we worked it out for this. So I am going to show her tomorrow. If the college has
the materials we are going to attempt the reaction to see how it comes out.
It's nice to be back in the labs again, and better ones than before.  The
research I am working on is amazing as well...
I just have one question I found while rereading all of this:
At the end where it is time to actually extract the caffeine from the liquids. Chloroform extraction is mentioned, but only as the last time, how is
the caffeine extracted all the other times? If chloroform extraction could be done the other two times would this work? then I could just extract it
and use the schools Rotary Evaporator to bring the caffeine to solid.
Thanks
-ssdd
[Edited on 24-9-2007 by ssdd]
All that glitters may not be gold, but at least it contains free electrons.
-- John Desmond Baernal
http://deepnorth.info/ |
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Sauron
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Sorry, do you mean in the examples from the patent?
I's been a while since I read the patent so I will have to refresh my memory. The final step is always the alkylation with your choice of methyl
iodide or dimethyl sulfate (be careful in either case.) Then extraction and workup. Rotavaping sounds good.
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MagicJigPipe
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 Damn "drug cooks". (sarcasm)
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Sauron
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Yeah, DEA is about to raid Starbucks. Stimulants!
After all, Starbucks extracts this alkaloid from plant beans that are imported from Columbia (among other places) and I hear that there's a drug lord
named Juan Valdez behind the entire caffeine conspiracy.
It's intensely addictive and produces caffeinds.
Just Say No. Stick to Sanka like Nacy Reagan.
[Edited on 25-9-2007 by Sauron]
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ssdd
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So will the caffeine precipitate? (My thinking tells me no...)
Or, if it will not precipitate how do you recommend that I extract it from the liquor? I'm sure I could probably just crystallize it but I could see
this as being very impure and well I'd prefer something pure.
-ssdd
All that glitters may not be gold, but at least it contains free electrons.
-- John Desmond Baernal
http://deepnorth.info/ |
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