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Author Topic: Blast from the past - Synthesis of Tropinone & 2-CMT  (Read 576 times)

no1uno

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Re: Blast from the past - Synthesis of Tropinone & 2-CMT
« Reply #20 on: December 14, 2009, 04:45:07 AM »
Ok - yes I am double-posting, but the previous post has been sitting there for a bit and I have to do some more...

For those who haven't noticed I have been researching the production of D-Arabinose from OTC materials, in order to work out a workable/feasible route to Furfural/furfuroic acid, and from there to the diethoxytetrahydrofuran & thus succindialdehyde...

I just had a wild thought (I looked into the other pentoses - D/L-Ribose are both available although they aren't cheap, but Xylose is not only available (also not cheap), but so is it's reduced form, Xylitol, the pentose alcohol, I am currently looking at it, seems likely that it can in fact be dehydrated to form furfuryl alcohol, which would be great as that is only a short step from furan (permanganate & decarboxylation)).

All of this might seem a bit much to most I suppose, it has always pissed me off that people never did put the work into the research on the tropinones - that ring-forming Mannich reaction is a classic and in the last month more references have been found than were found in the entire life of the Hive (thanks mainly to Heisenberg & Java)...

For mine, if this can be worked out, and "IF" that reference claiming the stereoselective reduction with Li/NH3 is actually right, then there is only going to be (-)-Pseudococaine and (-)-Cocaine in the pot at the end of the reduction, even if the 2-CMT is not resolved. That will boost yields massively (ie. instead of losing 75% straight away through resolution, it is down to 50% if that).

If anyone can find references on the dehydration/cyclization of Xylitol (the cheap as shit sugar substitute) to furfuryl alcohol, then this may in fact be a workable procedure for the home chemist.
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ausser_betrieb

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Re: Blast from the past - Synthesis of Tropinone & 2-CMT
« Reply #21 on: December 20, 2009, 12:34:24 PM »
Analogue to this reaction? http://en.wikipedia.org/wiki/Furfural#Production
"Under the (...) conditions of heat and acid, xylose and other five carbon sugars undergo dehydration, losing three water molecules to become furfural"
So it would be heating xylitol in sulfuric acid?

no1uno

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Re: Blast from the past - Synthesis of Tropinone & 2-CMT
« Reply #22 on: January 08, 2010, 03:01:55 AM »
I'm not sure, the five sugars in question are aldopentoses/ketopentoses, while xylitol is a sugar alcohol... Oxidising it would be necessary to form the cyclized product wouldn't it?

Anyway, another huge step for mankind, the stereospecificity of the Transfer hydrogenation of Tropinone with sodium isopropylate in boiling isopropyl alcohol is predominantly the wanted tropinol (as opposed to the pseudotropinol), which by analogy (by no means certainly though) means that the 2-CMT should give predominantly Ecgonine Methyl Ester (EME), not PseudoEcgonine Methyl Ester (PEME), without needing a Birch reduction/hydrogenation at all. ;D

Ok, now what would be good is some refs on the oxidation/ethoxylation of furan with chlorine & ethanol..., that will then take care of a short-ass route to succindialdehyde... Methylamine we know how to get at, the b-ketoglutaric acid is on orgsyn, while the refs for making the mono-methyl ester are given (above).

Nicodem just suggested that sodium isopropoxide is even easier to make than the ethoxide, must ask him about that... ;)
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jon

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Re: Blast from the past - Synthesis of Tropinone & 2-CMT
« Reply #23 on: January 08, 2010, 03:46:59 PM »
why not just take cocaine and make ridiculously potent phenyltropane derivatives from them?
why all the bother???

no1uno

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Re: Blast from the past - Synthesis of Tropinone & 2-CMT
« Reply #24 on: January 09, 2010, 01:36:48 PM »
Why all the concern?

Simply putting in the hours with the books (no lab access for obvious reasons), no money to replace fucked equipment/chemicals (not until I start working again) and a GENUINE interest in organic synthesis of natural products... Especially when that involves the added difficulty of designing ways for interested parties to acquire/synthesize the relevant precursors and working out ways to carry out such reactions in non-standard equipment.

If anyone can work out a nice, facile route from xylitol to furfural (or we work further on the glucose/glucosamine conversion to arabinose) and thus furan, then the electrosynthesis of dialkoxy-dihydrofuran from that is well and truly documented (using either bromine or chlorine), which gives us the succindialdehyde in useful yields... That solves that major headfuck, given the only documented procedures all seem to want to go via mucic acid & pyrrole (MAJOR turnoff right fucking there).

Then, the orgsyn procedure for acetonedicarboxylic acid, citric acid is cheap & available, strong H2SO4 ain't so easy to get here, might have to go the battery route, then GC's oleum from bisulfate to get sufficient quantities of the fuming acid. That is unless anyone else can suggest an alternative?

Methylamine is cheap and piss easy to make (either acetamide or via HMTA)...

The problems of the condensation rxn are simplified in ALL the articles on the subject - strict control of pH is ESSENTIAL

Resolution of the 2-CMT gives the natural (-)-2-CMT, refluxing which in abs. i-Pr with NaO-i-Pr will give (touch wood & hope the analogy holds), the natural enantiomer as the major product...

No fancy, schmantzy hydrogenation apparatus, no fucking Na/Hg, no sub-zero temps, no fucking hard to get reagents... (some are difficult and must be made, that ain't like saying uranium bisfuckknowswhat is ESSENTIAL).
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jon

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Re: Blast from the past - Synthesis of Tropinone & 2-CMT
« Reply #25 on: January 09, 2010, 02:20:46 PM »
i'd rather stomp on the leaves there's a reason merck and co. does'nt even bother with this it's not practical in reality when i can get a kilo for 14 k
or go south on  35  and get a brick of 96% for 10 k why go through all this shit?

this is how you make cocaine

http://www.youtube.com/watch?v=U_bZZt1zs60&NR=1&feature=fvwp
« Last Edit: January 09, 2010, 03:54:26 PM by jon »

no1uno

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Re: Blast from the past - Synthesis of Tropinone & 2-CMT
« Reply #26 on: January 11, 2010, 12:39:01 PM »
Considering where Merck & Co got their bucks, probably not that big an issue for them, they have the money and the German Govt sanctions there import of such substances...

I don't have the money and my government doesn't like my importing a fucking heating mantle, so I strongly, yet somehow strangely, suspect they might quibble at cocaine...
"...     "A little learning is a dang'rous thing;
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    There shallow draughts intoxicate the brain,
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nk40ouvm

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Re: Blast from the past - Synthesis of Tropinone & 2-CMT
« Reply #27 on: January 13, 2010, 06:48:18 AM »
I may be missing something, but are corn cobs not OTC where you are? Other cheap pentosan-rich materials include oat hulls, almond husks, birch wood, and sunflower husks.

For more than you ever wanted to know about furfural production, check out The Chemistry of Furfural and its Many By-Products, downloadable here.

no1uno

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Re: Blast from the past - Synthesis of Tropinone & 2-CMT
« Reply #28 on: January 13, 2010, 08:53:16 AM »
Yeah, but going from that angle there is a one hell of a messy process (destructive distillation of organic waste is going to be BULKY)...

I was wondering, what if the Mannich reaction was carried out with the monomethyl ester (presuming it can be made), or even the dimethyl B-Phenylglutarate? That would give access DIRECTLY to the substituted products which have much better binding (ie. the benzene attached to the ring) ability, without the need to fuck around attaching the fucking thing after forming the Tropane ring (organometallic chemistry ain't precisely amateur friendly).
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    There shallow draughts intoxicate the brain,
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jon

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Re: Blast from the past - Synthesis of Tropinone & 2-CMT
« Reply #29 on: January 20, 2010, 01:49:24 AM »
there is a mannich scheme where acteone dicarboxylic acid monomethyl ester is used to give the carbomethoxy compound witout having to methylate the tropine with dmc and a strong base.
come to think of it i may have been the diester.
can't remember but that would make life a lot easier for sure.
now that i remeber is was the mono ester
« Last Edit: January 20, 2010, 02:33:06 AM by jon »

zzhuchila_clocker

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Re: Blast from the past - Synthesis of Tropinone & 2-CMT
« Reply #30 on: January 23, 2010, 01:57:32 PM »
Quote
I was wondering, what if the Mannich reaction was carried out with the monomethyl ester (presuming it can be made), or even the dimethyl B-Phenylglutarate?
no, as they don't possess active(enough) methylene hydrogens. but with 2 additional carbethoxy groups, that should become possible.
Condensation of benzaldehyde with 2 equivalents of mallonic acid diester would give the substrate(knoevenagel condensation, followed by michael addition). After the tropinone is formed you can decarboxylate 2 of the COOH groups. One more you may remove if there was a double bond inbetween
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no1uno

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Re: Blast from the past - Synthesis of Tropinone & 2-CMT
« Reply #31 on: June 15, 2010, 12:01:26 PM »
Been a busy lil bee, but I found these again (I knew I'd read them - pet hate that).

Anyway, these papers deal with the stereochemistry of the reduction of Tropinone (to either pseudotropine or tropine) and the ratios thereof, using a variety of reducing agents and conditions. Strangely enough, at least to me, the best of the lot appears to be Al(i-OPr)3 with yields of the natural isomer (ie. the one we want) up to around the 80% mark.

All we need now is a decent route to the Al(i-OPr)3 which doesn't use Hg, I've seen many fleeting references, but has anyone ever actually tried dropping an I2 crystal in dry 2-Propanol with Al foil? I'm interested to know if it does in fact work, because if it does, then that gets rid of another major problem with this synthesis.

Let's recap - so far we have the use of sucrose & hypochlorite to give arabinose, which gives furan in about 90% yield. Then we can react the furan with chlorine/bromine + electrical current (in alcohol) to give the dialkoxydihydrofuran, which can then be reduced to give the dialkoxytetrahydrofuran which is the cyclic acetyl of succindialdehyde.

Ok, that gets rid of a whole bunch of nasty shit, we have also found the paper where the monomethyl ester of ketoglutaric acid was used directly to form the 2-CMT (along with the succindialdehyde and methylamine, noting that the pH is critical).

The papers all seem to agree that the easiest way to separate the d,l-2-CMT is via the varying solubility, so that is the preferred route. Virtually stereospecific reduction with the easiest reducing agent to source in the whole wide world, gives the (-)(-)-Cocaine (one isomer is removed by solvent selection, the other is avoided by carefully choosing the reducing agent).

Seems like it is getting closer to fruition, to me anyway...
"...     "A little learning is a dang'rous thing;
    Drink deep, or taste not the Pierian spring:
    There shallow draughts intoxicate the brain,
    And drinking largely sobers us again.
..."

no1uno

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Re: Blast from the past - Synthesis of Tropinone & 2-CMT
« Reply #32 on: June 16, 2010, 01:37:24 PM »
I seem to have lost the set of articles in which the authors methodically set about labelling atropine in each carbon succesively... I'm sure people here remember the articles I mean, there was a whole list of them (tropine labeled atropine was made from arabinose in fucking good yield). If anyone remembers where they are, could you please throw them back up on here?

Thanks
 
"...     "A little learning is a dang'rous thing;
    Drink deep, or taste not the Pierian spring:
    There shallow draughts intoxicate the brain,
    And drinking largely sobers us again.
..."

no1uno

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Re: Blast from the past - Synthesis of Tropinone & 2-CMT
« Reply #33 on: June 04, 2011, 10:17:37 AM »
By the way, found another article by Findlay on the tropine-alkaloids, it should have been obvious - the nitrogen atom on Tropine/Tropane/etc. is pseudo-asymmetric (regardless of which way up the molecule is, the nitrogen is bonded to the opposite sides of the two opposing carbons.
"...     "A little learning is a dang'rous thing;
    Drink deep, or taste not the Pierian spring:
    There shallow draughts intoxicate the brain,
    And drinking largely sobers us again.
..."
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