Sciencemadness Discussion Board - Caffeine Synthesis

Caffeine Synthesis

ssdd - 12-8-2007 at 12:59

So I was looking for an interesting organic synthesis of sorts and thought that producing caffeine would be fun.

I know that dimethyl urea malonic acid are needed but I can't seem to find how to actually run the synthesis.

Anyone have anything that may help me out, or perhaps a better synthesis to run. (looking for anything involving neurochemistry)

-ssdd

The_Davster - 12-8-2007 at 13:45

A lot easier than synthesizing it: https://sciencemadness.org/talk/viewthread.php?tid=2234

ergoamide - 12-8-2007 at 17:22

True that would be easier but not nearly as challenging and rewarding as synthing it. I'm very interested in this synthesis to so if anyone does have some more info on it's synthesis i'd be keen.

ssdd - 12-8-2007 at 17:40

Yea I was thinking the same thing, the few times I have ran extractions I have found it to be not nearly as fun nor gratifying than making something from the ground up.

I'll keep looking but a patent search seems not to have turned up much...

Thanks
-ssdd

Sauron - 13-8-2007 at 03:56

Try Merck Index.

Synthesis: Fischer, Ach, Ber. 28, 2473, 3135 (1895); Gepner, Kreps, J. Gen. Chem. USSR 16, 179 (1946); Bredereck et al., Ber. 83, 201 (1950); Crippa, Crippa, Farmaco Ed. Sci. 10, 616 (1955); Swidinsky, Baizer, U.S. pats. 2,785,162 and 2,785,163 (1957 to Quinine Chem. Works); Bredereck, Gotsmann, Ber. 95, 1902 (1962).

Only the patents are readily accessible in English.

The Fischer and Ach prep is readily available, but in German.

In northern Thailand, adjacent to the Golden Triangle where most of the amphetamines are now produced in this region, caffeine is restricted as it is in great demand as an adulterant for amphetamines. But in the rest of Thailand it is an unrestricted commodity.

This is not a difficult preparation.

Attached are both of the 1895 Fischer and Ach papers and both of the 1957 US patents, in a zip file.

[Edited on 13-8-2007 by Sauron]

Attachment: caffeine.zip (1.1MB)
This file has been downloaded 1230 times

ssdd - 13-8-2007 at 06:04

Thanks Sauron.

Searching around for general chemical uses or experiments with caffeine I found the following I felt was useful:

Quote:

When moistened with strong nitric acid, or dissolved in chlorine water and evaporated on a water-bath, it leaves a reddish-yellow residue which, in contact with ammonia in solution or vapour, becomes purple from formation of murexide, the ammonia salt of purpuric acid. With potassium hydroxide the colour is discharged. The aqueous solution is not precipitated by Mayer's solution (distinction from other alkaloids except theobromine). With solution of silver nitrate it gives a granular crystalline precipitate; and with mercuric chloride, long needles soluble in hydrochloric acid.

-ssdd

Sauron - 13-8-2007 at 07:58

The US patents are improvements on a procedure by Traube published in Ber. in 1900, rather than that of Fischer and Ach.

I will ost the Traube paper here shortly, as the patents do not explain the preparation of the starting compound, a nitrosouracil, while the Traube article will doubtless do so, or anyway reference it.

Sometimes there is no escaping the German lit.

The starting point for this prep is 1,3-dimethyl-5,6-diaminouracil obtained from the corresponding 6-nitroso compound. Traube reduced the nitroso with ammonium sulfide and then forylated the diamon product and cyclized it, thus obtaining theophylline, which merely needed to be methylated to obtain caffeine.

The 1957 patents improved on Traube's prep by using 5% Pd/C and 80-85% formic acid on the nitroso compound to reductively formylate it to the immediate precursor to theophylline in one step.

So much is very clear (if it works). So the question is how to build the substituted uracil in the first place. For that we must launch ourselves into the German literature.

I do not believe this involves malonic acid. Dimethyl ureau, yes. So far it appears that the other component is syanoacetic acid. I will report back.

It sure helps to know that harnstoff is urea.

In the US patents one of the arrows in the rxn scheme is backwards. It should proceed from III to IV not from IV to III.

The Fischer articles elucidate the prep of the uracils.

Fischer employed PCl3 and this is going to be a potential problem for anyone following his route.

1,3-dimethylurea + malonic acid (or ester) gives you domethylbarbituric acid. I bet dollars to donuts this is a DEA Scheduled controlled substance. End of the line!!

"But, Your Honor, I was only making caffeine!"

Unless I find a route that does not proceed through a barbiturate, I am going to lose all interest in this prep.

[Edited on 14-8-2007 by Sauron]

[Edited on 14-8-2007 by Sauron]

Attachment: Traube.pdf (1.2MB)
This file has been downloaded 875 times

ssdd - 13-8-2007 at 12:24

Thanks for everything Sauron, I guess this one is off the list of things I can pull off. (seems barbiturates would be a bad thing to make as you pointed out.) Though I find it interesting in the link between Caffeine and Barbiturates. (I guess since they both interfere with the brains functions and the neurotransmitters?)

Anyway I'll move along to the Biochemistry section of the forum where there is some discussion of Caffeine extraction. (I found Caffeine Citrate while reading there and it sounds very very easy to make.) If anyone has any suggestions of any other cool and legal

synthesis please inform me.

-ssdd

bio2 - 13-8-2007 at 12:32

......."1,2-dimethylurea + malonic acid (or ester) gives you domethylbarbituric acid. I bet dollars to donuts this is a DEA Scheduled controlled substance.".......

No, but the non-active barbituric acid is a controlled substance so they would most likely view this as an analog
therefore controlled as well under the Analog/Designer Drug
Act.

GOOD NEWS

Sauron - 13-8-2007 at 19:09

Only Fischer & Ach went via barbituric acids.

Traube used dimethylurea and ethylcyanoacetate to prepare cyanoacetyl-N,N'-dimethylurea which cyclizes to 5-amino-1,3-dimethyluraciluracil

He then prepared the 6-nitroso derivative in the usual manner (sodium nitrite, HNO2 in situ) and reduced that to the 5,6-diamino derivative, formylated the 6 position, dehydrated that to get to theophylline, and methylated that to get caffeine.

NO BARBITURATES ANYWHERE AROUND.

The US patent drops the ammonium sulfide reduction and eliminated an intermediate step, instead using reductive formylation with 5% Pd/C and 80-85% formic acid which gives the 6-formyl product to then dehydrate to theophylline, hence to caffeine with MeI.

So you need

Dimethylurea (1,3-dimethylurea)
cyanoacetic acid (not the ester)
pyidine
phosphorus oxychloride
sodium ethoxide
sodium nitrite
acetic acid glscial
5% Pd/C
85% formic acid
dimethyl sulfate

I may have missed some details, am still studying Traube

Will come back and fill in, and add a reaction scheme drawn properly.

[Edited on 14-8-2007 by Sauron]

Sauron - 14-8-2007 at 01:58

The following is OCR'd out of the patent pdf. The procedure described goes straight from the dimethyl-4-amino-5-nitrosouracil to theophylline in one pot, the catalyst is then filtered out for re-use, and the same pot used for the methylation step. The inventors used dimethyl sulfate rather than methyl iodide as per Traube and did not specify the caustic. Traube used sodium ethoxide.

Example I.-Preparation of caffeine

A JTljxture of 100 g. of I monohydrate (.5 mole) and
950 cc. of water were stirred vigorously atroomtemperature.
A slurry of 4.00 g. of 5% palladium charcoal
in 50-cc. of water was added next and finally 90

cc. of 85% formic acid.·" The reaction is exothermic
and carbon dioxide is evolved. The temperature rises
to 33-40° (in about 1 hour). The mixture is then
heated slowly to 40-45 ° and kept at that ,ange until III
starts" to precipitate and most of I has disappeared (in
abotH 1 hour). The evolution of carbon dioxide abates.
The temperature is raised slowly to 75° (in about 1 and
~
hour) and kept there until the pink color of I has
completely disappeared and complete solution (except for
the catalyst) is obtained (in about 30 minutes); Then
the mixture is brought toboHing, diluted somewhat and
filtered to recover the catalyst for re-use. Strong caustic
is added to the filtrate to bring the pH to about
12-13. The solutionis boiled for one hour, cooled and
methylated with dimethylsulfate in the usual manner.
The pH is adjusted and the first crop of caffeinerecovered
from a volume of 1000 ml. The second crop is
recovered from about 250 m!. The combined weight of
these two crops, after drying .to constant weight at 110°
is 84.9 g. (87.3% based on n. The color is offcwhite
and the melting point is above 230° (can:.). The melting
point of caffeine given in the United States Pharmacopeia
XIV (1950) is 235 to 237.5°. Chloroform extraction
of the mother liquor yielded an additional quantity
of crude caffeine. Use of methylating agents other
than dimethylsulfate such as methyl chloride, methyl
iodide and the like, is also feasible. If desired, the process
may be interrupted to isolate the theophylline.

Sauron - 14-8-2007 at 02:08

And here is the overall reaction scheme. The nitrosouracil is compound I in the patent. All the steps to that are from Traube, q.v. All after that are from the patent.

Traube's use of POCl3 as a condensing agent in the cyclization of cyanoacetydimethylurea may be a trouble spot for most of us. I will hunt up some other uracil preps that are parallel and see if I can find a non CWC substitute.

NOTE: in the scheme below I mistakenly drew ethyl cyanoacetate rather than cyanoacetic acid. THIS IS WRONG. Traube used the free acid.

[Edited on 14-8-2007 by Sauron]

caffeine.jpg - 23kB

ergoamide - 14-8-2007 at 03:05

Thanks sauron i think i found my next project anyway. I'm surprised that caffiene is a common adulterant really. It and it's salts arent terribly water soluble I thought. It's citrate salt which is the most soluble i thought and is only 40g/100mL i think.

Sauron - 14-8-2007 at 05:05

I am not an expert on abuse drugs but I think amphetamines are usually smoked in Thailand. The local term is yaa baa (crazy drug) whereas in the Phillipines it is called shabu shabu.

Another common adulterant locally is strychnine, which complicates withdrawal significantly.

ssdd - 14-8-2007 at 05:22

Its not as bad a synthesis as I thought it would be. The issue now being how to obtain those chemicals. (perhaps wait till the fall till I get to college and use their labs...)

But in the mean time while researching caffeine alot in the past few days, as ergoamide pointed out, some of the caffeine salts look like thy could be fun and easy to make.

I will synthesize this at some point, just need those chemicals. (Or a way to make those...) Time for a search engine once more...

-ssdd

Sauron - 14-8-2007 at 05:48

I just corrected a mistake, cyanoacetic acid and not ethyl cyanoacetate is employed in the condensation with dimethylurea.

If it is any help you make cyanoacetic acid from chloroacetic acid and KCN or NaCN, and you can make your own chloroacetic acid by chlorinating glacial acetic acid in sunlight in presence of one of the usual halogen carrier catalysts (like red P.) Chloroacetic acid is however pretty easy to obtain.

The Pd/C can be reused. And you don't need much. 4 g of the 5% Pd?c on a half molar scale (100 g of starting material.)

So if you get 10 g of it and your mechanical losses are not too high you can get many runs out of it.

ssdd - 14-8-2007 at 05:57

Ok, well that eliminates one thing I would need to find, I know for a fact that I have access to all of the things needed to make chloroacetic acid, and I'm sure theres some kind of cyanide around I can get... A trip to my old high schools lab and I am set. (The teacher will still let me in if I wanted to make something. I knw they have all these things because I did the inventory on the room.

)

Have you tried this yet sauron, or intend to, I'd be interested in hearing how it turns out. (photos would be amazing.)

-ssdd

Sauron - 14-8-2007 at 06:46

Org.Syn., as one might expect, has been very helpful. I found a prep of 4,5-diaminouracil from urea and ethyl chloroacetate that employs in-situ sodium ethoxide (from Na metal and absolute ethanol) as condensing agent, to get to the 4-aminouracil, then sodium nitrite in AcOH to get the 5-nitroso compound, then Na2S2O4 to make the 4,5-diaminouracil.

Just omit the last step to get your starting material for the patent procedure and of course start with dimethylurea instead or urea.

No POCl3 around.

Do not let the structure throw you. That is just the enol form of uracil, a tautomer, which cannot form when the urea nitrogens are substituted. This uracil is the same as the substituted pyrimidine shown in Traube, and the uracil shown in patent. Compare.

[Edited on 14-8-2007 by Sauron]

Attachment: CV4P0247.pdf (140kB)
This file has been downloaded 1431 times

Sauron - 14-8-2007 at 06:51

And here is prep of ethyl cyanoacetate (and cyanoacetic acid) starting with chloroacetic acid, which is made into sodium chloroacetate, metathesized to sodium cyanoacetate, the acid liberated and optionally esterified.

You can save a step by obtaining sodium chloroacetate rather than chloroacetic acid

[Edited on 14-8-2007 by Sauron]

Attachment: CV1P0254.pdf (124kB)
This file has been downloaded 1814 times

ssdd - 14-8-2007 at 08:01

I think dealing with chloroacetic acid seems simpler in the end, it is a simpler prep and seems like less steps when you look at the prep for the sodium chloroacetate.

But then again being I am learning a good deal in just reading this stuff I may have misread something.

Sauron thanks again, learning quite a bit from you.

-ssdd

Sauron - 14-8-2007 at 21:15

IIRC it is necessary to convert chloroacetic acid to the salt, prior to treating with alkili cyanide. You can't treat the acid directly with the cyanide. My suggestion was to buy sodium chloroacetate rather than prepare it. Or just buy cyanoacetic acid or ethyl cyanoacetate and skip the whole drill. Otherwise use a good hood, chloroacetic acid is hazardous, as a cyanides. Wear gloves and goggles.

I pulled up two JACS articles referenced from the Org.Syn. paper on diamouracil. Between those three there is a lot of detailed description of the reaction of dimethylurea and ethyl cyanoacetate using Na and EtOH to make NaOEt in situ to condense them. Be careful with the sodium.

The nitroso compound forms rapidly (almost instantly) and the precipitate is voluminous and stirrer may need to be stopped. Use an overhead stirrer as a magnetic one won't hack this. A heavy duty overhead stirrer with a SS or teflonn shart (unbreakable) will be preferable to a pyrex shaft, if these are available. If the motor won't turn even at low speed (higher torque) turn it off. The JACS articles describe what to do.

You will not be using the hydrosulfite reduction, but proceeding directly to the Pd/C reductive formylation and the conversion to theophylline. According to the patent those are about 5 hrs worth of procedures.

If for some reason the patent does not work (this happens!) you have several alternative reductions to try:

Ammonium sulfide (Fischer/Ach, and Traube)
Sodium hydrosulfite (Org.Syn. and references)
others referenced from patent

And then formylation and dehydration stepwise.

I suppose it is worth emphasizing that the initial formation of the uracil (pyrimidine) is a variant of the classical active methylene reactions (acetoacetic ester, malonic ester.) Cyanoacetic ester is in same class. You might care to review the mechanism, so that you are proceeding with understanding of the steps, if you are not already well familiar with this kind of reaction.

You mentioned earlier being surprised at the connection between caffeine and the barbirurates structurally. But this is often the case. Nicotine is another example, being closely akin to the vitamin Niacin (nicotinamide). Powerful medicines and powerful poisons alike are often structurally close to some vital and necessary benevolent compound.

Just as an example, the cancer chmotherapeutics are mostly mofifications of nitrogen mustards - deadly chemical warfare agents. It's an ill wind that blows no good. The CW agents came first.

The uracil ring is a biologically important one, main portion of uridine, the nucleoside and is also the parent of 5FU, a potent anticancer drug, 5-fluorouracil.

Sauron - 15-8-2007 at 01:35

Just a short note on nomenclature

Some of the lit. on this prep refers to the intermediates as substitutes pyrimidines and some as substituted uracils. While these are the same structure they are numbered differently and to those not familiar with both heterocyclic ring numbering and the conventions of biochemistry and molecular biology this can be a little confusing.

Pyrimidines are numbered from a nitrogen and the numbering proceeds so that the second ring nitrogen has the lowest possible number (3 not 5). Thus the cyclized condensation product of dimethyl urea and ethyl cyanoacetate is according to IUPAC

6-amino-1,3-dimethyl-1H-pyrimidine-2,4-dione.

Uracil, a purine base, is numbered not as a heterocycle but from the first carbonyl carbon which is usually drawn at the 12 o'clock position, and numbering proceeds so that the second carbonyl is 3 not 5

So our compound is named

5-amino-2,4-dimethyluracil

They are the same compound.

ssdd - 15-8-2007 at 10:17

OK so I am gona see if I can manage to work out exactly what steps there are in this synth... I'll post back later with results...

-ssdd

Sauron - 15-8-2007 at 10:32

I found a different route which is interesting but the yields are poor.

While uracil is usually obtained by hydrolysis of nucleic acids, it can be synthesized from urea and maleic acid catalyzed by sulfuric acid or polyphosphoric acid. The yield is 20%

Substitute 1,3-dimethylurea and you have dimethyluracil.

Nitrate that with fuming nitric acid (d 1.5) and you have 6-nitro-1,3-dimethyluacil which reduced to the 6-aminodimethyluracil we are already familiar with.

Hit that with sodium nitrate and fou have the 5-nitroso-6-aminodimethyluracil, rose red color.

From there proceed as per patent cited upthread.

The cyanoacetyldimethylurea route is better. But it is nice to have alternatives.

I will add references to this tomorrow, time for some sleep now.

ssdd - 15-8-2007 at 15:00

Alright, so I've reread everything that has been posted so far and heres my guess as to what needs to be done, let me know how on track I am.

Step 1. Take 100g of nitrosouracil (produced by any method... I like the one that you just posted even with the low yields.) And mix this with ~950ml of water.

2. Add to this a 5% mix of Pd/C slurry.

3. Next add the 90ml of Formic Acid.

4. When CO2 is done evolving raise the temperature to 75* C?

5. Filter the solution to recover the pd/c and raise the ph with NaOH to about 13.

6. Add dimethylsulfate and recover the caffeine. (raise the ph again and repeat this step.)

I think this is the base of which we are working off of, now as I read on and on you have provided some great shortcuts depending as to what I can get my hands on.

Sauron, thank you thank you thank you... Its been a great learning experience over the ast few days working on this thread with you.

-ssdd

Sauron - 15-8-2007 at 18:37

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)
This file has been downloaded 1160 times

Sauron - 15-8-2007 at 19:49

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)
This file has been downloaded 991 times

ssdd - 15-8-2007 at 20:53

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

Sauron - 15-8-2007 at 21:25

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]

Sauron - 16-8-2007 at 06:58

@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.

ssdd - 16-8-2007 at 08:05

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

Sauron - 16-8-2007 at 18:20

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]

ssdd - 24-9-2007 at 13:52

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]

Sauron - 24-9-2007 at 18:33

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.

MagicJigPipe - 24-9-2007 at 19:54

Damn "drug cooks". (sarcasm)

Sauron - 24-9-2007 at 19:57

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]

ssdd - 25-9-2007 at 12:27

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