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Harmless
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5 amino acids
Hello everyone
We can easily find enzymatic way to produce amino acids in the net .
I'm looking for the chemical synthesis of the following amino acids and that's more difficult : dl-Histidine, dl-Proline, dl-Tyrosine, dl-Cystéine,
dl-Arginine. I know perfectly how to obtain the 15 other amino acids . I prefer to find patent , i don't look for book references so i searched and
searched again day after day but without any result for these 5 amino acids , perhaps i'll have more luck with the members of this forum 
thanks a lot and before your answer please be patient , describe me the synthesis with details , i'm really exausted ( mentally and physically ) after
my search that's why i need your help .
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chemrox
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Are you kidding? Have you tried Google? Science Direct? Sirius? I just got a whole bunch of hits for dl-Histidine synthesis. Try finding these on
your own and then ask for help getting the articles you want to read if they're not available to you. I can't imagine what kind of search would
exhaust you that didn't turn up any results when I found so many with barely a tap of the keyboard.
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Harmless
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Thanks a lot for your help Sauron ! your description is excellent , i'll follow these procedure to obtain dl-amino acids . Yes chemrox , we find
dl-amino acids in google but they talk about purification etc .. not about chemical synthesis , you'll never find what i want in google .
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Harmless
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can you reupload the zip file he look broken thanks a lot
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Sauron
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Try this one. It's a combined pdf assembled with Acrobat Pro.
[Edited on 19-10-2007 by Sauron]
Attachment: AAs.pdf (212kB)
This file has been downloaded 1518 times
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Harmless
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Wonderfull ! i don't regret my post in this forum !
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Harmless
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Your answer is exactly what i'm looking for , you have a great experience in organic chemistry , thanks a lot Sauron ,  excuse me , perhaps i'm abusing a little ... can you give me some examples (like add
x gramme of this product then ... ) or some links , i want to prepare these amino acids and i need to follow a process for the preparation of these
amino acids . thanks
[Edited on 20-10-2007 by learnmoreandmore]
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Sauron
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There is a general method for synthesis of DL-amino acids that works for all of your five exemplars except proline.
The common reagent is the sodium derivative of ethyl acetamidomalonate. This is readily preparable from diethyl malonate.
The amino acids are prepared as their N-acetyl derivatives by reaction of the above reagent with the appropriate alkyl halide.
For histidine, as example, the alkyl halide is 4-(5)-chloromethylimidazole. This is easily prepared from d-fructose (fruit sugar) or in somewhat
lower yield from sucrose (common table sugar) by reaction with aq.formaldehyde and aq. conc NH4OH in presence of copper carbonate and copper
hydroxide. The resulting hydroxymethylimidazole is chlorinated to the chloromethyl derivative.
Preparation of 4-(5)-hydroxymethylimidazole from d-fructose or sucrose: Org.Syn. CV3, p 450 and references therein.
Chlorination to 4-imidazolemethyl chloride Pyman, .Chem.Soc. 668, (1911)
Preparation of ethyl acetamidomalonate JACS 66 p 350 and 600
Preparation of DL-His using same malonic esterJACS 67 p 308.
Same article also covers preparation of DL-Phe and DL-Leu
and references a prep of DL-Trp by same authors.
Therefore the application to Tyr, Cys and Arg will be straightforward. Tyr especially so since Tyr is simply 4-hydroxy-Phe.
Racemic a-Amino Acids from Ethyl Acetamidomalonate and Related
Reagents (Aminomalonate, Benzamidomalonate and Phthalimidomalonate)
Amino Acid (Reference) Alkyl Halide
DL-His (1) 4-Imidazolemethyl chloride
DL-Tyr 4-hydroxybenzyl chloride
DL-Arg protected 3-guanidinopropyl chloride
DL-Pro (4) 1,3-dibromopropane
DL-Phe (1) Benzyl chloride
DL-Val (3) 2-Propyl iodide
DL-Leu (1) b-Methylallyl chloride
DL-Trp (2) 3-Indolylmethyl chloride
DL-Ala (3) Methyl chloride
DL-Asp (6) Ethyl chloroacetate
DL-Glu (7) Ethyl a-bromopropionate
Gly (5) none required
References
1. Albertson and Archer, JACS 67, 308 (1945)
2. Snyder and Smith, JACS 66, 350 (1944)
3. Redemann and Dunn, J.Biol.Chem., 341 (1939)
4. Putochin, Ber. 56, 2213 (1923)
5. Baeyer, Ann. Chem. u. Pharm., 131, 297 (1864)
6. Keimatsu and Kato, Bull.Pharm.Soc.Japan 49, 731, (1929)
7. Dunn et al, J.Biol.Chem. 94, 599 (1931-32)
[Edited on 21-10-2007 by Sauron]
[Edited on 22-10-2007 by Sauron]
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Sauron
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The ethyl acetamidomalonate reagent is prepared from diethyl malonate by the following steps
1. Reaction with sodium in absolute ethanol to form the sodio derivative
2. Reaction of the sodio derivative with sodium nitrite to give ethyl isonitrosomalonate
3. Reduction of the ethyl isonitrosomalonate to ethyl aminomalonate by catalytic hydrogenation with 25% Pd/C at 1500 psi (autoclave) room temperature.
4. Acetylation with acetic anhydride in glacial acetic acid.
When ready to alkylate, this reagent is again treated with Na metal in EtOH abs. and the alkyl halide introduced.
The reaction product is saponified to the malonic acid, decarboxylated to the N-acetyl a-amino acid, and the N-acetyl group removed.
Closely related antecedent reactions employed benzylamidomalonic ester, phthalimidomalonic ester, and aminomalonic ester, but the acetaminomalonic
ester is preferable.
This reaction is regarded as superior to the hydantoin method or the hippuric acid method which involve reactions of those reagents with
carboxaldehydes (e.g., indole-3-carboxaldehyde, or imidazone-4-carboxaldehyde), We will look at these preparations next.
[Edited on 21-10-2007 by Sauron]
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Harmless
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Thanks a lot Sauron ! you gave me an excellent description . I have now a pdf file about the preparation of proline from ornithine , citrulline or
arginine by Paul B. Hamilton , i'll prepare the other amino acids following what you described and using the references , thanks a lot again !
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Sauron
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Here's the Putochin article from Ber., describing the prep of DL-Proline-OH using ethyl aminomalonate and 1,3-dibromopropane.
You will do better to use the ethyl acetamidomalonate instead, It's only one more step, and solves a lot of headaches.
I have not looked at the ornithine route, but it seems to me that making an AA from another AA is more work.
How's your German?
[Edited on 22-10-2007 by Sauron]
Attachment: Putochin_Ber56.pdf (178kB)
This file has been downloaded 801 times
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Sauron
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As nearly ideal as the general synthesis of amino acids from ethyl acetamidomalonate is, the procedure has a couple of drawbacks for the amauer
chemist.
The diethyl malonate is a watched and in some cases restricted reagent because of its abuse in the making of illegal barbiturates.
The extensive use of sodium metal may be unattractive.
And the reduction step requires a rather large autoclave. Many amatuers have no pressure apparatus at all. I have a Parr 1 liter setup which I can
expand, at some expense, to 2 liters, with a working capacity of a little lett than 1.4 liters. A number of runs would be required to reduce the
amount of ethyl isonitrosomalonate required.
THEREFORE, let's look at alternative preparations.
1. Histiidine.
There i a classical exploitation of 4(5)-hydroxymethylimidazole for this purpose. This compound is available by two routes.
a. from d-Fructose (fruit sugar, levulose). This is a modified Radziszewski reaction in which fructose in presence of copper carbonate and copper
hydroxide is reacted with aqueous formaldehyde and aqueous ammonia. See Org.Syn. Coll.Vol 3, p.460.) This is shorter, but requires the isolation of
the intermediate as its picrate. These days this probably means making one's own picric acid for the purpose.
b. from citric acid via our old friends acetonedicarboxylic acid and di-isonitrosoacetone (DINA). The latter is reduced with Sn and HCl to
diaminoacetone, which is then reacted with sodium thiocyanate to give 4(5)-aminomethylimidazole-2-thiol. This is oxidized with HNO3 to the
hydroxymethylimidazole. This procedure was invented by Pyman (J.Chem.Soc. 99, 668 (1911)) and elaborated by Koessler and Hanke (JACS 40 1716 (1918).)
They employed the method of von Pechmann to prepare the ADCA and convert to DINA. There are a number of threads on this reaction already. The crux is
that using ordinary conc H2SO4 is cheap and convenient but relatively low yielding whereas the use of oleum is high yielding but costly. The method of
Koessler and Hanke is quick and gives comparable yields to that in Org.Syn., q.v. (85-90%, the latter method being quite slow.
Conversion of ADCA to DINA in every reported instance is low yield. So this is a bottleneck. Fortunately, the starting material (ciytic acid) is
cheap.
The JACS article is more useful. Pyman's paper only describes the reaction from diaminoacetone forward; the preparation of diaminoacetone in three
steps from citric acid is referenced to Kalischer's method (Ber., 28, 1519 (1895).) This is available free from Gallica, of course, but the JACS
article is not only in English but contains the full process from citric acid through hydroxymethylimidazole, not spread over two articles and two
languages. Furthermore it contains improvements over Pyman's prep.
Neither of these routes require any autoclave.
Once the hydroxymethylimidazole is in hand, the options diverge. The choice is to chlorinate to chloromethylimidazole, or oxidize to
imidazolecarboxaldehyde.
I, From the chlorination product of imidazole-4(5)-methanol:
Imidazole-4(5)-methyl chloride is reacted with ethyl sodiochloromalonate to produce, after saponification and decarboxylation,
imidazole-4(5)-a-chloropropionic acid in 60% tield.
This compound treated with conc aq ammonia at 100 C gives racemic Histidine in 38% yield. Thus the overall tield from the starting methyl chloride is
24% in two steps.
Pyman, J.Chem.Soc. 99, 1386 (1911)
ethyl sodiochloromalonate:
Conrad, Ann. 209 241 (1881)
Imidazole-4(5)-methyl chloride:
Pyman, J.Chem.Soc., 99 668 (1911)
Pyman employed PCl5 to chlorinate the imidazolemethanol, I would suggect instead TCT/DMF by method of Lydia DeLuca.. Yield should be quantitative.
II. From the condensation of Imidazole-4(5)-carboxaldehyde with Hippuric acid
Pyman, J.Chem.Soc. 186 (1916)
The imidazolemethanol is oxidized with HNO3, 56% yield.
Imidazole-4(5)-carboxaldehyde is condensed with hippuric acid in presence of acetic anhydride and fused sodium acetate to provide
2-phenyl-4-(1-acetylimidazole-4(5)-methylene)oxazolone. 68-76% yield
The oxazolone is converted to a-Benzoylamino-b-imidazole-4(5)-acrylic acid by boiling with aq sodium carbonate, decolorizing then acidifying with
glacial acetic acid. Yield 88%.
This acrylic acid derivative was reduced with 2% sodium amalgam in aq suspension and worked up tp benzoyl-DL-histidine. 42% yield.
The DL-His was liberated with NaOH, 70% yield.
Overall yield from the starting material 9% in four steps.
Conclusion: I would advise using the Org.Syn. preparation of imidazolemethanol from fructose, then assuming the chlorination reagent performs well,
apply method (I) as the route is shorter and the overall yield superior.
[Edited on 23-10-2007 by Sauron]
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Harmless
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Thanks a lot !
It's true that pressure apparatus is not given to everyone
I'll try to read the file about proline , german language look a little difficult ..
The best is to see the full process , you can see the exact quantity of product , time necessary etc ...
If you find other preparation of the 5 amino acids ( chemical syntesis with high yield ) please post full process there ( maybe pdf format if possible
)
[Edited on 22-10-2007 by learnmoreandmore]
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Sauron
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That is what I am doing now. I am in midst of DL-His which is the most interesting of the five, so I am doing it first. Read the posts above, I will
be adding attachments in pdf.
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Harmless
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Thanks sauron , that's very nice !
[Edited on 25-10-2007 by learnmoreandmore]
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Harmless
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excuse me , please if you can post the files faster , i want to begin all preparation and my lab is ready , thanks a lot
it's a lot of request i know excuse me a lot for this work
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Harmless
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Hello Sauron , in fact yes i didn't read my u2u but there is nothing there , thanks a lot for your pdf file , your link is great ! we find everything
there , peptide synthesis etc.. my mail is necronomiconexmortis@hotmail.fr . i need only DL-arginine synthesis now ( full description ) , i have all
amino acids except this one !
[Edited on 29-10-2007 by learnmoreandmore]
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