solo
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Racemizing Optically Active Amines
Process for racemizing of optically active amines
US Patent 5969186
Àbstract
The present invention provides a process for effectively
racemizing an amine compound in which an asymmetric
carbon is located at the 0-position of the amino group or
more distant therefrom, which comprises reacting the amine
compound with a complex of an alkali metal and a polycyclic
aromatic hydrocarbon.
[Edited on 14-1-2009 by solo]
Attachment: Process for racemizing of optically active amines-pat05969186.pdf (828kB)
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solo
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Within the patent they use naphtalene sodium complex.....Aldrich doesn't list it ....I guess it has to be made, have started looking, ...............
I found this patent after having put to rest the fabled boil in HCL conc. of the active optical amine for 14 hours.....end result ....no
racemizing........solo
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Anionic Polymerization Initiated by Sodium Naphthalene and Synthesis of Block Copolymers
P. CLAES and G. SMETS
Die Makromolekulare Chemie Volume 44, Issue 1 , Pages212 - 220. 1961
Excerpt
Preparation of the sodium naphthalene complex
The preparation of the complex was carried out in a high-vacuum apparatus
Hg) in order to avoid any inhibition by carbon dioxide, water or oxygen. The reaction
was carried out in a 20 ml. three-necked vessel (Fig. 1, A). One of the side-arms was connected via a sintered glass filter (Fig. 1, E) to 3 tubes
with breakable tips (volume: 1 to 3 ml.) (Fig. 1, C). The other side-arm (Fig. 1, D) contained afew lumps of sodium. The centraltube (Fig. 1, A)
contained 500 mg. of naphthalene. The entire apparatus was connected to the vacuum line (Fig.2). On the standard taper joint (Fig. 2, C) of the vacuum
line a
25 ml. round bottomed flask was attached, containing 15 ml. tetrahydrofuran, some sodiumand naphthalene, in order to dry the solvent over the green
sodium naphthalene complex.
An empty 25 ml. flask, connected to the joint (Fig. 2, B), avoided any spattering of sol-213was carried out in a 20 ml. three-necked vessel (Fig. 1,
A). One of the side-arms was connecte via a sintered glass filter (Fig. 1, E) to 3 tubes with breakable tips (volume: 1 to3 ml.) (Fig. 1, C). The
other side-arm (Fig. 1, D) contained afew lumps of sodium. The central tube (Fig. 1, A) contained 500 mg. of naphthalene. The entire apparatus was
connectedto the vacuum line (Fig.2). On the standard taper joint (Fig. 2, C) of the vacuum line a25 ml. round bottomed flask was attached, containing
15 ml. tetrahydrofuran, some sodium and naphthalene, in order to dry the solvent over the green sodium naphthalene complex.
An empty 25 ml. flask, connected to the joint (Fig. 2, B), avoided any spattering of sol-vent during the distillation. The entire apparatus was
evacuated and the tetrahydrofurandegassed four times. Before the distillation of the solvent into the central tube (Fig. 1, A)containing the
naphthalene, the sodium in the side-arm was heated, giving a sodium mirror
on the walls of the central tube (Fig. 1, A). After distilling the solvent by condensation with liquid air, the reaction vessel (Fig. 1, A) was sealed
off at F (Fig. 1). After 2 hrs. of standing at room temperature the complex was formed. The breakable tubes were filled with the complex solution and
carefully sealed off; the tubes were filled by inverting the vessel."
[Edited on 14-1-2009 by solo]
Attachment: Sodium Naphthalene.pdf (417kB)
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solo
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.........the synthesis to the sodium naphthalene complex seems a bit too much .....currently looking for sources or an easier synthesis....some
assistance is welcomed.......solo
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sparkgap
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| Quote: | | In a dry, 500-mL, three-necked flask equipped with a mechanical stirrer, an addition funnel, and a nitrogen inlet are placed 25.6 g (0.20 mol) of
naphthalene, 250 mL of dry tetrahydrofuran (THF), and 10.8 g (0.47 mol) of sodium pieces. The mixture is stirred at room temperature for 30 min.
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(source)
Sodium naphthalide is one of the reagents that always has to be freshly prepared, so no luck really in seeing someone who sells it.
sparky (~_~)
"What's UTFSE? I keep hearing about it, but I can't be arsed to search for the answer..."
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Sauron
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Normally in peptide work we spend a lot of effort at minimizing or avoiding racemization altogether. When we start with amino acids of high EE we want
to end with a peptide of high EE at each chiral center. Racemization = bad.
In general resolution of a racemate is usually a pain in the ass
So why is racemization desirable in some instances? You want to gethfrom a starting material of high EE to the racemate and then resolve that to the
yarget of the opposite enantiomer, in high EE?
Methods of enantiomeric resolution:
1. Classical formation of a salt with an optically active compound of high EE, then seperating the two enantiomers by fractional crystallization.
Tedious.
2. Enzymatic. Specialized art. Hire a biochemist.
3. Chiral preparative chromatography. The coming thing but expensive and again a specialized art. The media is expensive. The hardware is expensive.
The solvents are expensive. Hire a sepparation-scientist. You will have to compete with Big Pharma for his affections if he is any good.
Sic gorgeamus a los subjectatus nunc.
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Ebao-lu
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Really, why racemizing is discussed.. As academic info, of course it is interesting, but it is harmful to use in practice. From the other hand, the
mechanism of this reaction could be extrapolated to give many interesting ideas By the way, what is the mechanism? Hydride/alkyl anion transfer?(i can
not read PDFs, sorry)
[Edited on 15-1-2009 by Ebao-lu]
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Sauron
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No one takes out a patent for academic purposes.
And I do not think solo posted it out of academic interest either.
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solo
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| Quote: | Originally posted by Sauron
And I do not think solo posted it out of academic interest either. |
........so who asked for your opinion? ....and furthermore who cares what you think..............solo
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Ebao-lu
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Yes, usually patents are not taken out for academic purposes, but this one seems not to have any practical application as well. It probably could help
to make chiral amines from racemic, if there is some other chiral center in the molecule (like induced chirality).
I dont understand the meaning of "more distant therefrom". Does in mean, that it would work on alkanes as well? Or amino(primary, secondary, or
tertiary-?)-group is relevant there? Sodium-naphtalene complex is known to be anion-radical, it can abstract proton from NHR, as well as abstract H
radical from tert-R-H (or sec-R-amine). This is further narrowing the "induced chirality" application only for amines, containing a chiral
tetrasubstituted C, because tert- will be racemized as well.
Sorry, due to problems with PC, i am unable to read the petent. Most of my questions and supposes should find answers there only..
[Edited on 15-1-2009 by Ebao-lu]
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Bolt
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TLDR
I made a potassium naphthalene complex as a lab exercise once. Not too hard, but it requires inert an atmosphere. Haven't read the patent, but this
might be what you're looking for solo
http://en.wikipedia.org/wiki/Sodium_naphthalenide
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ziqquratu
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I don't see that it really matters why solo would be interested in racemising an amine - perhaps purely academic interest, perhaps he has an
application in mind. Either way, the simple fact is it is sometimes a necessary step.
It can be used to improve yields (by resolving enantiomers, racemising the undesired one then resolving again. Very useful for large scale
preparations or expensive starting materials, where the waste could be ridiculous). It may be that a starting material is only available as the wrong
enantiomer (or that the "right" enantiomer is too damned expensive), or that you want to prepare a sample of the racemate or the other enantiomer for
study without going through a long synthesis all over again.
You may not be dealing with a single stereocentre, either, in which case racemisation of one results in diastereomers, which are often simple to
separate. It all depends on your application. (Sauron's absolutely right, though, that resolution of enantiomers is a right pain in the backside,
although there are a number of enzymes available these days which are excellent for a reasonably broad range of applications, and are easy enough to
use - although I'm not sure how expensive they are!)
Back to the chemistry. If you have an a-amino acid, a-amino ketone or similar, racemisation is of course simple enough with more common bases, DBU
being one I've used for epimerisation (but should work in a less constrained system to racemise).
For primary amines, a slightly less elegant solution may be to oxidise the amine to a carbonyl, followed by reductive amination (from memory KMnO4
would achieve the oxidation in quite respectable yields). Perhaps useful due to the simpler procedure (no air sensitive reagents), or where the sodium
naphthalide may not be suitable (for whatever reason).
Also, I vaguely recall that the protons of an sp3 hybridised carbon attached to the nitrogen of an imine are quite a bit more acidic than those of the
parent amine (and I imagine this is particularly the case for secondary amines, where enamine formation is more favoured). Perhaps this could be a
viable method for avoiding the sodium naphthalide in favour of a more accessible base (I'm guessing, but perhaps an alkoxide, sodium amide or similar
may be sufficient).
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Nicodem
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Indeed, like Ziqquratu explained, racemisations of any type of compound are of great interest to the pharmaceutical industry where drugs are still
commonly prepared using symmetric synthesis and enantiomers resolved. Nothing can be cheaper than to recycle the waste enantiomer, particularly when
compared to the alternative option of just discarding it and synthesizing a new batch for resolution (and the syntheses of many drugs are expensive
multistep procedures!).
| Quote: | Originally posted by ziqquratu
For primary amines, a slightly less elegant solution may be to oxidise the amine to a carbonyl, followed by reductive amination (from memory KMnO4
would achieve the oxidation in quite respectable yields). Perhaps useful due to the simpler procedure (no air sensitive reagents), or where the sodium
naphthalide may not be suitable (for whatever reason). |
This can be achieved in a single step trough dehydrogenation/hydrogenation by treating non-epimerizable amines with nickel catalysts. Essentially,
nickel dehydrogenates the primary or secondary amine to the imine or enamine and then the so formed Ni/H2 regenerates the amine by hydrogenation (a
step which is symmetric and thus causes racemisation). Unfortunately, I don't have a reference at hand...
However, the patent at first glance (I have not actually read it...) appears not to be about the racemisation of the carbon atom at which the amino
group is attached, but rather the epimerization of the carbon at which the phenyl group is attached (the example compound is
3-methyl-2-phenylbutylamine). The use of sodium naphthalenide thus makes much more sense.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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Sauron
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@Solo
I do not know what your problem is but your remarks are uncalled for and unwelcome.
YOU asked for my opinion by opening a thread on a forum of which I am a longtime member.
All members are free to express their opinions in any thread. If you do not agree with this then do not start a thread. There are no private threads
on this forum.
I could care less what you are up to if anything. I was merely replying to the absurd proposition by another poster that this matter is entirely
"academic". It isn't. Perhaps I touched a nerve?
Still, why so hostile? I have given you no cause.
@Nicodem
Indeed the example compound has only one chiral carbon, and that is C2 the benzylic carbon. A closer look at the patent ought to elucidate whether or
not the scope of this procedure is limited to such chiral centers.
--------------------
As I surmized the patent specifically excludes racemization of the alpha (amino bearing) carbon. The scope is limited to compounds with chiral beta
carbons or chiral carbons more removed from the C1.
Wouldn't it be interesting to enumerate some well known phenylalkylamines that meet those requirements? I doubt that one would have to look very far.
http://pubs.acs.org/doi/abs/10.1021/op010081z
PBA is the example compound and is a resolving agent for chiral carboxylic acids in particular.
[Edited on 16-1-2009 by Sauron]
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solo
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Improved method for converting l-1-phenylpropan-2-amine into d,l-1-phenylpropan-2-amine
Elmer E. Hartgerink
US Patent 2797243 1957
[Edited on 17-1-2009 by solo]
Attachment: Recemization`- `improved method for converting l. 1-phenylpropan-2-amine to d,l. 1-phenylpropan-2-amine-pat02797243.pdf (173kB)
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solo
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Process for Recimization of an Optically Active Alpha-Amino Acidamides and process for producing Optically Active Alpha -Amino Acids
Masaharu Doya, Toya Kondo, Hideo Igarashi, Takako Uchiyama
US Patent 49181961990
[Edited on 17-1-2009 by solo]
Attachment: racemization of an aminoacid amide-pat04918196.pdf (893kB)
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Sauron
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"Recimization" ?
Anyway I will read these with interest because I have to resolve some racemic Nle which I was planning to do enzymatically (activated papverine
selectively hydrolyzing the L-anilide derivative only).
But I am not too optimistic since the Nle (norleucine) is aliphatic. However I will not despair till I read these patents.
I doubt anyone on the forum does not recognize 1-phenylpropane-2-amine by its trivial name so I won't bother to mention.
----------------
The older Mitsubishi Gas patent is concerned with a microbial resolution) enzymatic resolution of a racemate of amino acid amide with the enzyme
generated in situ by microorganisms.) I do not see any advantage over the use of enzymes proper, there are many such enzymes commercially available
and cheap.
[Edited on 18-1-2009 by Sauron]
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