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Author: Subject: Synthesis of dopamine from catechol
Melgar
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[*] posted on 22-10-2017 at 04:41
Synthesis of dopamine from catechol


Since dopamine is often referred to as a "catecholamine", I thought it would be interesting to make an educational video where catechol is converted to dopamine. Researching this subject has led me to conclude that the simplest way to do this would be to convert it to a benzaldehyde, then a nitroaldol reaction with nitromethane, then perhaps a reduction with zinc. Even though I have reagents like cyanide salts and sodium borohydride, I'd rather avoid using them, because sodium cyanide is quite toxic and hard for most people to get, and sodium borohydride feels like cheating.

One thing that I've noticed is that aromatic formylation reactions that are ortho-directing with phenol, seem to be para-directing with catechol. I don't know if this is typically the case, or only true of some reactions. If it's true of the Duff reaction, that might be the way to go:

https://en.wikipedia.org/wiki/Duff_reaction

Now, I've been recommended that it might be better to form benzodioxole first to protect the fairly reactive phenol groups. That seemed a little sketchy at first, but I guess benzaldehyde is a lot easier to get than piperonal, and if someone is able to source nitroethane already, they're better off reacting it with piperonal than benzaldehyde. Harm reduction! :P

Also, I smelled piperonal a long time ago, and it was amazing. Like maraschino cherries, and very strong. So that would be a good indication of success at that step.

Another option might be to just cleave a methyl or ethyl group off of vanillin/ethylvanillin, which I'd do instead if it was a lot less work and better yields. I probably would do that anyway if it was practical, just to compare different routes and make sure I was on the right track.

Any thoughts?

As an aside, the secret motive behind a portion of the video series that we're planning is to lure in the Walter White wannabes, then make them learn a whole bunch of background chemistry and biology. We had another idea to show faked reactions that look really neat and clean, but are actually some of the most horrible glassware-ruining reactions that exist; think pyrolysis of polystyrene to get styrene, for example. Ultimately, teaching them science seemed like a more noble motive, and besides, how many of us now have a legitimate interest in chemistry that started because we wanted to make explosives or idolized Shulgin?




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[*] posted on 22-10-2017 at 07:16


I think your secrete motive might actually work for one or two smart guys out there
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[*] posted on 22-10-2017 at 09:14


you can make protocatechualdehyde from catechol using the reimer tiemann reaction - Reimer and Tiemann, Ber. 9, 1268 (1876); Tiemann and Koppe, ibid. 14, 2015 (1881).
from there,dopamine is 2 steps away

EDIT- In that case,you could go balls to the wall and do a fenton on tyrosine to get DOPA and then decarboxylate that to get dopamine -https://www.ncbi.nlm.nih.gov/pubmed/1321588
or even better,directly hydroxylate tyramine -http://onlinelibrary.wiley.com/doi/10.1002/chem.200500361/fu...(they use a protein but you could try using just H2O2/NO2- ;))

[Edited on 23-10-2017 by CuReUS]
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[*] posted on 22-10-2017 at 09:21


Quote: Originally posted by CuReUS  
you can make protocatechualdehyde from catechol using the reimer tiemann reaction - Reimer and Tiemann, Ber. 9, 1268 (1876); Tiemann and Koppe, ibid. 14, 2015 (1881).
from there,dopamine is 2 steps away

Have you ever done this, or attempted it? I have, it's an enormous mess. It's a free-radical reaction, and the yields will necessarily be very low, after the nightmarish workup.

Okay, I exaggerated a little. But suffice to say the yield certainly wasn't worth the effort of the workup.




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[*] posted on 22-10-2017 at 09:31


Excellent choice of research.......... A most fascinating compound indeed

And an interesting choice of routes and precursors to boot


/CJ


[Edited on 22-10-2017 by Corrosive Joeseph]
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[*] posted on 22-10-2017 at 11:02


Have you considered going the natural route?

Extract L-dopa from broad beans and use your considerable experience with decarboxylations to make dopamine.

You could even do this as well as your other synthesis and then you'd be able to confirm their equivalence with a mixed melting point test.

As for the vanillin demethylation Idea there's a high yielding reaction that uses a 10% excess of aluminum chloride suspended in a methylene chloride solution of vanillin which then has pyridine added (4.4 equivalents) under stirring and is refluxed for 48 hrs to give a claimed 87% yield.

Robert G Lange, J. Org, 27, 2037 (1962)

I haven't looked up the journal entry as I'm pretty sure I'd have to pay through the nose for it, but it is summarized in Feiser and Feiser's Topics in Organic Chemistry.

Actually, I suppose L-dopa might be a little more heat sensitive than tryptophan so maybe that 1st Idea is a non-starter unless you protect those OH groups.

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[*] posted on 22-10-2017 at 12:01


Quote: Originally posted by Melgar  
Quote: Originally posted by CuReUS  
you can make protocatechualdehyde from catechol using the reimer tiemann reaction - Reimer and Tiemann, Ber. 9, 1268 (1876); Tiemann and Koppe, ibid. 14, 2015 (1881).
from there,dopamine is 2 steps away

Have you ever done this, or attempted it? I have, it's an enormous mess. It's a free-radical reaction, and the yields will necessarily be very low, after the nightmarish workup.

Okay, I exaggerated a little. But suffice to say the yield certainly wasn't worth the effort of the workup.


Small correction: the Riemer-Tiemann is not a free-radical reaction. It is a simple electrophillic aromatic substitution reaction by an in-situ generated dichlorocarbene species. First, chloroform is deprotonated to the trichloromethylide anion, and this then loses a chloride to become reactive dichlorocarbene. This carbene is very electron-poor, so it will attack the nearest source of electron density it can find, which happens to be the electron-rich ortho and para positions of a phenol. It replaces the proton which lies on the ring, the proton attaches itself to the carbene, and the chlorines are replaced with water to form the final formyl group.
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[*] posted on 22-10-2017 at 14:30


If you really REALLY wanted to go balls to the wall and were still contempt on the catechol route then you could extend the series to also cover the synthesis of catechol from the somewhat OTC naturally occurring salicylic acid.
By converting it to salicylamide and then hoffman degradation to 2-aminophenol and then diazotize the amine and finally hydrolize the diazonium anion in hot copper sulfate solution.
http://www.sciencemadness.org/talk/viewthread.php?tid=63327
I have done this and most of it is close to quantitative except the Hoffman which produced 80% yield if i recall correctly.

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[*] posted on 22-10-2017 at 15:12


Quote: Originally posted by Cryolite.  
Small correction: the Riemer-Tiemann is not a free-radical reaction. It is a simple electrophillic aromatic substitution reaction by an in-situ generated dichlorocarbene species. First, chloroform is deprotonated to the trichloromethylide anion, and this then loses a chloride to become reactive dichlorocarbene. This carbene is very electron-poor, so it will attack the nearest source of electron density it can find, which happens to be the electron-rich ortho and para positions of a phenol. It replaces the proton which lies on the ring, the proton attaches itself to the carbene, and the chlorines are replaced with water to form the final formyl group.

And isn't dichlorocarbene a free radical, with two vacancies? I guess another way to say it is that it is very electron poor, but the whole reason for that is that it's a free radical, no?

I wanted to do something that isn't going to require things that most people can only get on rare occasions, when eBay is looking the other way. I like vanillin because of how easy it is to get, although I kind of wanted to start with catechol. I might just explain that catechol is a component of coal tar and creosote, and that because of how bad that is for you, it's hard to get anymore. It's so common in creosote though, that it seems a bit masochistic to go through too much effort to make it.

The vanillin demethylation method that was mentioned earlier seems to be legitimate, although the pyridine part could be a sticking point. I read somewhere else that the bond disassociation energy is lowest for that particular methyl group, meaning that free radical temperatures with reducing conditions could do it too, if conditions were carefully controlled.

What about the Duff reaction though? Anyone have any experience with that?




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[*] posted on 23-10-2017 at 00:05


You think you could just alkylate catechol with nitroethylene directly and save a few steps? There are a few systems I know that carry out this rxn, eg:

http://onlinelibrary.wiley.com/doi/10.1002/ejoc.201300579/ab...

http://onlinelibrary.wiley.com/doi/10.1002/ejoc.201000271/fu...

http://www.sciencedirect.com/science/article/pii/S0021967300...

http://www.sciencedirect.com/science/article/pii/S0040403901...

Although an OTC procedure hasn't popped up I suspect that Bronsted acid catalyst shouldn't be too hard to manage if you pick the right one.

[Edited on 23-10-2017 by clearly_not_atara]

[Edited on 23-10-2017 by clearly_not_atara]

[Edited on 23-10-2017 by clearly_not_atara]




[Edited on 04-20-1969 by clearly_not_atara]
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[*] posted on 23-10-2017 at 01:02


I think making catechol from aspirin looks like fun, but somehow I doubt the yields would be as good as they look on paper. Then again, aspirin is pretty cheap. I really need to finish working up the toxic mess sitting in my fume hood so I can do some other experiments....



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[*] posted on 23-10-2017 at 02:19


Dopamine was on our wish-list of cool things to make (and do an educational video on), so here's a summary of our journey on various paths:

We tried about 10 times with different ways and different conditions to demethylate vanillin, and with limited success and very poor yields. This is not easy! We make AlCl3 home-made from ZnCl2 however so maybe the zinc impurity interferes with the reaction.

We did successfully make piperonal from peppercorns (extraction, hydrolysis, then oxidation). Not great yields, but enough to play with (gram quantities are feasible), so that would open up the nitromethane route.

Another possible route was to prepare the vanillin-related compound first and then try to demethylate. Vanillin nitro-methane adduct we did produce and it's easy to make and purify. We reduced the nitrostyrene to the nitroalkane but didn't go any further. Can't remember why we didn't take this another step - not sure if we had any reducing agent capable of going that final step, or if we just thought it would be too controversial a reaction to do a video on (even though the product is not pharmacologically active).

We also wanted to try to make vanillyl chloride and then nucleophilically react with cyanide (plus a reduction), but vanillyl chloride turned out to be a lot harder than it looks to make (HCl + zinc chloride + vanillin seem to form a purple complex - again, zinc gets in the way)...




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[*] posted on 23-10-2017 at 04:57


Quote: Originally posted by Melgar  

One thing that I've noticed is that aromatic formylation reactions that are ortho-directing with phenol, seem to be para-directing with catechol.

where have you noticed this ?
Quote: Originally posted by Assured Fish  
I have done this and most of it is close to quantitative except the Hoffman which produced 80% yield if i recall correctly.

truly going BTW would be doing a one pot schmidt/diazotisation on aspirin.It would first get converted to acetyl aminophenol,then NaNO2 could be added which would react with the excess H2SO4 and diazotise the amine.Boiling this solution would convert the diazonium to OH and de-acetylate at the same time to give catechol.:D
Quote: Originally posted by Melgar  

And isn't dichlorocarbene a free radical, with two vacancies? I guess another way to say it is that it is very electron poor, but the whole reason for that is that it's a free radical, no?

this is quite interesting actually.Triplet carbenes are considered free radicals but not singlet carbenes.Which of the two is :CCl2 ?
Quote:
What about the Duff reaction though? Anyone have any experience with that?

I think a duff reaction on catechol would give benzodioxole instead of the desired product.Even if it worked,the formylation would be ortho and there might be double formylation as well
Quote: Originally posted by clearly_not_atara  
You think you could just alkylate catechol with nitroethylene directly and save a few steps? Although an OTC procedure hasn't popped up I suspect that Bronsted acid catalyst shouldn't be too hard to manage if you pick the right one.

That's pure genius :o . Do you think PPA or ZnCl2 could be used ?

[Edited on 24-10-2017 by CuReUS]
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[*] posted on 23-10-2017 at 05:39


Say, I was doing some reading on borohydride earlier, and Vogel Practical Organic Chemistry 3rd edition says that it won't reduce nitro groups or alkenes... will it reduce a nitrostyrene?



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[*] posted on 23-10-2017 at 14:42


Quote: Originally posted by JJay  
Say, I was doing some reading on borohydride earlier, and Vogel Practical Organic Chemistry 3rd edition says that it won't reduce nitro groups or alkenes... will it reduce a nitrostyrene?


If you use borohydride with nickel salt, such as nickel chloride you will produce nickel boride that's capable of easy reduct the nitro group and the double bond.

See: http://www.sciencemadness.org/talk/viewthread.php?tid=66278&...
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[*] posted on 23-10-2017 at 15:01


Quote: Originally posted by JJay  
Say, I was doing some reading on borohydride earlier, and Vogel Practical Organic Chemistry 3rd edition says that it won't reduce nitro groups or alkenes... will it reduce a nitrostyrene?

It'll reduce it to a nitroalkane. Because the double bond is highly polarized, NaBH4 can actually reduce it, which is a fairly common thing to do, since nitroalkanes reduce easier, and with the double bond reduced, they won't react with each other during the nitro reduction stage.




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[*] posted on 23-10-2017 at 19:12


Hmm... I meant to buy some nickel chloride a while back and never got around to it. That will definitely have to go on the list.

I just read about a borane-THF adduct capable of reducing carboxylic acids to alcohols. There are papers that describe making it with sodium borohydride and iodine in THF.




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[*] posted on 24-10-2017 at 01:26


Quote: Originally posted by Melgar  
Quote: Originally posted by JJay  
Say, I was doing some reading on borohydride earlier, and Vogel Practical Organic Chemistry 3rd edition says that it won't reduce nitro groups or alkenes... will it reduce a nitrostyrene?

It'll reduce it to a nitroalkane. Because the double bond is highly polarized, NaBH4 can actually reduce it, which is a fairly common thing to do, since nitroalkanes reduce easier, and with the double bond reduced, they won't react with each other during the nitro reduction stage.


By the way @Melgar, could you explain to me why sodium borohydride alone can reduce phenyl nitropropene with methylamine directly to metamphetamine in a kind of reductive amination?

I read about an experiment like this on this book:

A Laboratory History of Narcotics
Vol. 1: Amphetamines and derivatives
A Laboratory Manual - 2007 - page nº 111
Jared B. Ledgard


But I can't explain why this can go on, since I ever thought borohydrides alone only reduce the double bond of the alkene to an alkane, but not the nitro group.

Could you or someone here explain to me the mechanisms envolved in this reaction below showed on that book? Is it possible?



Nitroalkenes and redutive amination with methylamine and borohydride.JPG - 25kB
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[*] posted on 24-10-2017 at 02:38


@ChemiPharma Sodium borohydride can only reduce double bonds that are sufficiently polarized by the groups on either side of it. For most alkenes, this isn't the case, but if, say, there's a strongly electron-withdrawing group on one side and not the other, that will be enough for borohydride to be able to align itself right to reduce it. Sodium borohydride can reduce imines for the same reason it can reduce aldehydes and ketones: because nitrogen (like oxygen) is more electronegative than carbon, and sodium borohydride is good at reducing double bonds to carbon when the carbon is double-bonded to something more electronegative than itself.

Sort of a simplified explanation, but it helps to realize that when sodium borohydride reduces double bonds in imines and nitroalkenes, it's really the same mechanism as when it reduces aldehydes and ketones.

Oh, also, you'll have to quote someone more authoritative than that notorious idiot if you want anyone here to believe that the reaction you describe is real.

[Edited on 10/24/17 by Melgar]




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[*] posted on 24-10-2017 at 02:58


This is an interesting alternative to dopamine, via a pummerer rearrangement and subsequent reduction.

https://www.jstage.jst.go.jp/article/cpb1958/37/12/37_12_339...

The only problem might be preparing the needed methylsulfinylacetamide.




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[*] posted on 24-10-2017 at 03:02


The THF-borane adduct will reduce nitro groups, but I think it hydroborates styrenes. So I suppose it could be used for anti-Markovnikov hydration of some styrenes, but I am not exactly sure what would happen here.



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[*] posted on 24-10-2017 at 03:08


Quote: Originally posted by Melgar  
Oh, also, you'll have to quote someone more authoritative than that notorious idiot if you want anyone here to believe that the reaction you describe is real.


Sorry @Melgar, but I didn't understand the last part.

This reaction was extracted from a published book.

Do You believe that's impossible to occurs? The author is a fraud? yes or not? why?

Here's the complete text at the book I have cited, on pages 111/113:

Nitroalkenes and redutive amination with methylamine and borohydride.JPG - 25kB

Procedure C: Preparation of racemic-methamphetamine hydrochloride (ICE)
Materials•

I. 27 grams of benzaldehyde 8. 30 grams of anhydrous sodium sulfate
2. 20 grams ofnitroethane 9. 3.75 grams of sodium borohydride
3. 5 milliliters of cyclohexylamine 10. 200 mi IIi I iters of methylene chloride
4. 300 milliliters of dry hexane 11. 60 grams of dry hydrogen chloride gas
5. 500 milliliters of dry methanol 12. 50 grams of sodium hydroxide
6. 25 grams of methylamine gas 13. 450 milliliters of diethyl ether
7. 55 grams of anhydrous magnesium sulfate

Summary: racemic-Methamphetmaine (ice), is prepared by reacting phenyl -2-nitropropene with methylamine and sodium borohydride in the presence of methanol. The phenyl-2-nitropropene is formed by the condensation of benzaldehyde with nitroethane in the presence of cyclohexylamine. After the reaction of phenyl-2-nitropropene with sodium borohydride and methanol , the reaction mixture is treated with methylene chloride, and this resulting methylene chloride mixture is then treated with hydrogen chloride, and the resulting acidified mixture is then evaporated to remove the bulk of the methylene chloride. After the bulk of the methylene chloride has been removed, the left over remaining concentrate is then filtered to recover the precipitated product. The precipitated product is then treated with sodium hydroxide to liberate the freebase, which is then extracted into ether. The ether extract is then treated with hydrogen chloride to precipitate the ICE, which is then filtered-off and then vacuum dried or air-dried.

Step I: Preparation of phenyl-2-nitropropene

Into a suitable reflux apparatus, place all at once, 27 grams of benzaldehyde, followed by 20 grams of nitroethane, followed by 5 milliliters of cyclohexylamine. Thereafter, reflux the entire mixture at about 100 Celsius for 3 hours. After refluxing for 3 hours, remove the heat source, and allow the two-phase reaction mixture to cool to room temperature. Then pour the entire reaction mixture into a seperatory funnel , and remove the lower (organic) layer. The upper layer can be recycled or discarded if desired as it will contain the cyclohexylamine catalyst. Then place the recovered lower organic layer into a suitable sized beaker, and then add in 25 milliliters of cold water. Immediately thereafter, rapidly stir the mixture using magnetic stirrer, or other means, for about 30 minutes at room temperature. Then remove the upper water layer by decanting it off, and then place the lower organic layer (containing the desired product), into an ice bath and chi ll to about 0 Celsius. Then, add in about 10 milliliters of cold water, and then allow the total mixture to stand at room temperature for several hours to allow the desired product of phenyl-2-nitropropene to crystal! ize. After 2 hours, most of the desired nitro compound should have precipitated and afterwards, filter-off the precipitated crystals, and then vacuum dry or air-dry them. Finally, recrystallize these dried collected crystals from 150 milliliters of dry hexane, and after the recrystallization process, vacuum dry or air-dry the crystals.

Step 2: Preparation of racemic-methamphetamine

Into a suitable beaker, place 250 milliliters of dry methanol, and then bubble into this methanol , 25 grams of methylamine gas. After the addition of the methylamine gas, add to the resulting methylamine/methanol solution, 25 grams of anhydrous magnesium sulfate (to absorb water), and then place this entire mixture into a suitable flask , and then stopper the flask .
Immediately thereafter, stir the entire mixture for about 10 minutes. After I 0 minutes, carefully filter-off the magnesium sulfate, and do it as fast as possible to avoid moisture absorption by the methylamine/methanol mixture. After the filtration,
place the methylamine/methanol mixture into a suitable 3-neck flask (equipped with motorized stirrer, thermometer, and addition funnel), and then place a phenyl-2-nitropropene solution into the addition funnel-this solution being prepared by adding and dissolving 34 grams of phenyl-2-nitropropene (obtained in step I) into 150 milliliters of dry hexane. Note: the 3-neck reaction flask should be equipped with a calcium chloride drying tube to keep moisture from entering the apparatus. Then
place the 3-neck reaction flask into a cold-water bath at about I 0 to 15 Celsius. Then add to the methylamine/methanol mixture, 30 grams of anhydrous sodium sulfate. Note: this sodium sulfate is to absorb any water formed during the reaction. Note: dried silica gel pieces can be used instead of sodium sulfate if desired. Now, slowly add drop-wise, the phenyl-2- nitropropene/hexane solution form the addition funnel , to the methylamine/methanol mixture over a period sufficient to keep the reaction mixture below 25 Celsius at all times. During the addition, moderately stir the reaction mixture with the motorized stirrer. After the addition of the nitropropene/hexane solution, continue to stir the reaction mixture for I hour at a temperature below 25 Celsius. After this additional I hour of mixing, stop stirring, and then quickly filter the reaction mixture to remove the insoluble sodium sulfate. Then place this filtered reaction into a clean flask, and then place this flask into an ice bath, and chill to - I 0 Celsius. Note: while waiting for the reaction mixture to chill, stopper the flask to keep moisture out. When the temperature of the reaction mixture reaches - I 0 Celsius, remove the stopper, and replace it with a standard powder funnel , and then slowly add in, in small portions at a time, 3.75 grams of sodium borohydride, and after each portion, add in 25 milliliters of methanol (ten 375-milligram portions of sodium borohydride and ten 25-milliliter portions of methanol). During the entire addition, rapidly stir the reaction mixture, and maintain its temperature below 20 Celsius at all times. After the addition of the sodium borohydride and methanol portions, continue to stir the entire reaction mixture at a temperature below 20 Celsius for about 3 hours. After 3 hours, pour the entire reaction mixture into a large flask, and then add in 1200 milliliters of water. Shortly thereafter, add in 200 milliliters of methylene chloride, and then rapidly stir the reaction mixture for about 30 minutes at room temperature. Then decant-off (pour-off) the upper aqueous layer, and then place the remaining lower methylene chloride layer into a seperatory funnel , and drain-off the lower methylene chloride layer- as there will be some upper aqueous layer still remaining. Thereafter, place the methylene chloride layer into a beaker, and then add in 15 grams of anhydrous magnesium sulfate (to absorb water) . Then stir the entire mixture for about 10 minutes, and then filter-off the magnesium sulfate. Then, place the entire mixture into a suitable sized beaker, and then bubble into the mixture, 30 grams (excess) of dry hydrogen chloride gas. After the addition of the hydrogen chloride gas, place the entire acidified mixture into a distillation apparatus or rotary evaporator, and distill-off the methylene chloride at 40 Celsius until only 80% of the total volume remains. Once this point is reached, stop the distillation process, and then remove the left over remaining contents (after it has cooled to room temperature), and then filter these contents to recover the precipitated impure product. Then vacuum dry or air-dry the filtered-off crystals. Thereafter, place these crystals into a clean beaker, and then add in a sodium hydroxide solution prepared by adding and dissolving 50 grams of sodium hydroxide into 250 milliliters of water, and after the addition, stir the entire three 150-millilter portions of diethyl ether, and after the extraction, combine all ether portions (if not already done so), and then dry this combined ether portion by adding to it , 15 grams of anhydrous magnesium sulfate. Then stir the entire mixture for mixture for about 30 minutes at room temperature. Note: sodium hydroxide generates much heart when dissolved in water, so allow the solution to cool before using. After stirring the alkaline mixture for about 30 minutes, extract the entire mixture with with three 150-millilter portions of diethyl ether, and after the extraction, combine all ether portions (if not already done so), and then dry this combined ether portion by adding to it , 15 grams of anhydrous magnesium sulfate. Then stir the entire mixture for about 10 minutes, and then filter-off the magnesium sulfate. Finally, place the filtered ether mixture into an ice bath, and chill to 0 Celsius. Thereafter, bubble into the ether mixture, 30 grams of dry hydrogen chloride gas (excess), and after the addition, stir the entire ether mixture for about 30 minutes. Thereafter, filter-off the precipitated crystals, and then vacuum dry or air-dry the crystals.


[Edited on 24-10-2017 by Chemi Pharma]
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JJay
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[*] posted on 24-10-2017 at 03:40


No yields. Gas measurements don't look very practical. I mean, sure, you could weigh your methylamine and hydrogen chloride cylinders while in use, but you would need a high-capacity scale. And you could also weigh the methanol solution, but that won't work for the hydrogen chloride. I don't think these procedures were tested. Also, the link to dopamine synthesis here is rather sketchy.



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[*] posted on 24-10-2017 at 04:03


you could do a fries rearrangement on catechol with chloro acetylchloride to get 3,4-dioxychloracetophenone.then replace the Cl with NH2 and reduce the ketone to get dopamine
I wonder if glycine could be used directly instead of chloro acetylchloride.

dopamine.bmp - 311kB
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[*] posted on 24-10-2017 at 04:27


This is the first time I have heard of the Fries rearrangement... interesting. Why doesn't the chloro acetylchloride react with pyridine?





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