Author Topic: Lets synthesize some epinephrine!! (Read 222 times)

Douchermann · « **on:** April 26, 2009, 05:48:16 PM »

Hey guys, a couple of you may know, epinephrine (adrenaline) is a compound that interests me greatly. After doing some reading, I've found a couple of doable syntheses. For the record, doable is a broad term.

Synthesis A
protocatechualdehyde (3,4-hydroxylbenzaldehyde) is reacted with hydrogen cyanide to produce the cyanhydrin. This is then reduced to the amine. Unfortunately, the only ways to reduce nitriles involve either hydrogenation with palladium or lithium aluminum hydride. The resulting compound is the methylated. This is where I'm just not sure. I don't know if the methylating agent will prefer to attack the nitrogen or not; otherwise it will just methylate the hydroxyl groups on the other side. All in all, this route is pretty useless to us home chemists, as every step involves a hard to obtain material (or very dangerous material)

Synthesis B
Catechol is reacted with monochloroacetic acid in the presence of POCl3. As far as I can tell, the phosphorus oxychloride is only used as a catalyst, but the text did not specify very well. Perhaps thionyl chloride could be substituted as it's nearly impossible to get any phosphorus compounds other than phosphates. The resulting compound is reacted with aqueous methylamine, at which point the corresponding compound will precipitate. This is then simply reduced via an aluminum amalgam reduction.

Synthesis B seems quite feasible to me. Chloroacetic acid can be prepared with acetic acid and chlorine, and I'm sure sulfur can be used instead of phosphorus in the reaction. If thionyl chloride can be used, that can be made in the lab (however with some difficulty). Everything else is very easy for the moderately equipped home laboratory. Perhaps we can find a substitute for the phosphorus oxychloride and/or thionyl chloride all together?

Vesp · « **Reply #1 on:** April 26, 2009, 08:28:01 PM »

Wouldn't the ketone in the second reaction be reduced completely off when using the aluminum amalgam? I think it would be.

amides can be turned into an amine with one less carbon in the Hoffman rearrangement.. so instead of messing with cyanide and reductions, perhaps you could find the correct carboxylic acid, form the amide and then react that with some NaOCl like you would do in a classical Hoffman rearrangement.

Douchermann · « **Reply #2 on:** April 27, 2009, 06:23:34 AM »

Perhaps it's my tiredness, but how are you proposing this makes it easier? The hydroxyl would still be a problem, and the carboxyl would have to be at the end of a long chain. Not to mention, most substituted catechols are fairly unstable (4-allylcatechol a prime example).

zzhuchila_clocker · « **Reply #3 on:** April 27, 2009, 08:15:31 AM »

I think Al amalgam would not reduce benzylic OH (why do you think drug addicts are struggling to acquire banned I2 and P in order to reduce benzylic OH, if it is possible to do with OTC foil and mercury? ). I know only zinc amalgam in muriatic acid can reduce of C=O directly to CH2
If LiAlH4 is not a problem, i can suppose catechol +CHO-COOH -> 3,4-dihidroxymandelic acid -> 3,4-dihidroxymandelmethylamide + LiAlH4 -> epinephrine
Glyoxylic acid is not quite OTC, but can be made by oxydation of glycolic acid, electrolytic reduction of oxalic and hydrolysis of trichloacetaldehyde.
The examples of condensing glyoxylic acid with phenols:
http://www3.interscience.wiley.com/journal/114213525/abstract?CRETRY=1&SRETRY=0
http://www.freepatentsonline.com/6359172.html
http://www.freepatentsonline.com/4329497.html
btw, condensation also occurs with alkoxybenzenes (in acidic media)

zzhuchila_clocker · « **Reply #4 on:** April 27, 2009, 08:50:23 AM »

What about Akabori reaction? If N-alkylaminoacids can be used in it as well, then it would be a one step synth from N-methylglycine and 3,4-dihidroxyBA (otherwise, selective monomethylation of norepinephrine made from glycine would be a big problem).

timecube · « **Reply #5 on:** April 27, 2009, 01:53:32 PM »

I wonder if the methylenedioxy derivative would be similarly active.

Douchermann · « **Reply #6 on:** April 27, 2009, 05:26:22 PM »

Quote from: zz-zhuchila on April 27, 2009, 08:15:31 AM

I think Al amalgam would not reduce benzylic OH (why do you think drug addicts are struggling to acquire banned I2 and P in order to reduce benzylic OH, if it is possible to do with OTC foil and mercury? ). I know only zinc amalgam in muriatic acid can reduce of C=O directly to CH2
If LiAlH4 is not a problem, i can suppose catechol +CHO-COOH -> 3,4-dihidroxymandelic acid -> 3,4-dihidroxymandelmethylamide + LiAlH4 -> epinephrine
Glyoxylic acid is not quite OTC, but can be made by oxydation of glycolic acid, electrolytic reduction of oxalic and hydrolysis of trichloacetaldehyde.
The examples of condensing glyoxylic acid with phenols:
http://www3.interscience.wiley.com/journal/114213525/abstract?CRETRY=1&SRETRY=0
http://www.freepatentsonline.com/6359172.html
http://www.freepatentsonline.com/4329497.html
btw, condensation also occurs with alkoxybenzenes (in acidic media)

I wouldn't be reducing benzylic OH, I would be reducing to to benzylic OH. LAH is a problem, that's one of the reasons I ditched the first route.

Vesp · « **Reply #7 on:** April 27, 2009, 10:19:43 PM »

i was saying the ketone to hydroxyl won't work with the Al/Hg.
http://en.wikipedia.org/wiki/Clemmensen_reduction

I was also suggesting that this might possibly be another way to go about making it since you could turn an amide, into an amine while subtracting a carbon. You'd have to use a longer carboxylic acid or something like that. not to sure really.
http://en.wikipedia.org/wiki/Hofmann_rearrangement

Douchermann · « **Reply #8 on:** April 28, 2009, 05:32:12 AM »

This isn't a clemmenson reaction, that is far too powerful and will reduce the ketone to nothingness. Aluminum amalgam is a completely different reducing agent. It's what's used to reduce imines to amines in some phenethylamine syntheses (as you notice, there's no HCl used in those reductions).

zzhuchila_clocker · « **Reply #9 on:** April 28, 2009, 06:23:54 AM »

Quote

I wouldn't be reducing benzylic OH, I would be reducing to to benzylic OH. LAH is a problem, that's one of the reasons I ditched the first route.

I know, that was addressed to Vesp. Zn/Hg is different then Al/Hg

Vesp · « **Reply #10 on:** April 28, 2009, 11:05:36 PM »

Oh I see, my bad. Thanks for pointing that out.

Reaminator · « **Reply #11 on:** April 29, 2009, 08:29:52 PM »

How about doing the most obvious thing, that is checking the literature first, rather than all this idle talk?

Seems like nobody likes to read literature! Regardless, here is the Merck index entry for adrenaline:

Quote

Title: Epinephrine.

CAS Registry number: [51-43-4]

CAS name(s): (R)-4-[1-Hydroxy-2-(methylamino)ethyl]-1,2-benzenediol; (-)-3,4-dihydroxy-alpha-[(methylamino)methyl]benzyl alcohol
Additional name(s): l- 1-(3,4-dihydroxyphenyl)-2-(methyl amino)ethanol; l- 3,4-dihydroxy-1-[1-hydroxy-2-(methylami no)ethyl]benzene; l- methylaminoethanolcatechol; adrenaline ; levorenin
Trade name(s): Bronkaid Mist (Sterling Winthrop) ; Epiglaufrin (Allergan) ; Eppy (Chauvin) ; Glauposine (Alcon); Primatene Mist (Whitehall); Simplene (Chauvin); Sus-phrine (Forest); Suprarenaline (Armour)

Literature references: Endogenous catcholamine with combined alpha- and beta-agonist activity. Principal sympathomimetic hormone produced by the adrenal medulla. Isoln from animal adrenal glands: Takamine, J. Soc. Chem. Ind. 20, 746 (1901); Aldrich, Am. J. Physiol. 5, 457 (1901). Synthesis of dl- form: Stolz, Ber. 37, 4149 (1904); Payne, Ind. Chem. 37, 523 (1961). Historic review of syntheses: Loewe, Arzneimittel-Forsch. 4, 583 (1954). Resolution of dl- form: Flaumlch er, Z. Physiol. Chem. 58, 189 (1908). Configuration: Pratesi et al., J. Chem. Soc. 1958, 2069. Acute toxicity: A. M. Lands et al., J. Pharmacol. Exp. Ther. 90, 110 (1947). HPLC determn in plasma and urine: C. R. Benedict, J. Chromatog. 385, 369 (1987). Comprehensive description: D. H. Szulczewski, W.-H. Hong, Anal. Profiles Drug Subs. 7, 193-229 (1978). Physiologic review: Malmejac, Physiol. Rev. 44, 186 (1964). Review of biosynthesis: L. A. Pohorecky, R. J. Wurtman, Pharmacol. Rev. 23, 1-35 (1971); of pharmacology and clinical use in cardiopulmonary resuscitation: N. A. Paradis, E. M. Koscove, Ann. Emerg. Med. 19, 1288-1301 (1990); P. Hebert et al., J. Emerg. Med. 9, 487-495 (1991).

Properties: Minute crystals, gradually browning on exposure to light and air. mp 211-212°C . mp approximately 215°C (dec) when rapidly heated . [alpha] D 25 -50.0° to -53.5° (in 0.6 N HCl). Very slightly sol in water, alc. Readily sol in aq solns of mineral acids, NaOH, and KOH. Insol in aq solns of ammonia and of the alkali carbonates. Insol in chloroform, ether, acetone, oils. LD 50 i.p. in mice: 4 mg/kg (Lands). Melting Point: 211-212°C; mp approximately 215°C (dec) when rapidly heated

Rotation: -50.0°; -53.5°

It is also interesting that nowhere in this thread I see anybody noticing that the preparation of adrenaline (or epinephrine as the US americans call it) requires asymmetric synthesis in at least on step or alternatively a chiral resolution.

Douchermann · « **Reply #12 on:** April 29, 2009, 08:35:24 PM »

Yes, this will create racemic epinephrine, but according to the literature in which I did read, it can be separated by created the tatrate salt. Dextro-epinephrine tartarate is soluble in methanol where as levo-epinephrine tartarate is not. I don't understand what you call idle talk, it was mostly confusion about the method of reduction.

zzhuchila_clocker · « **Reply #13 on:** April 30, 2009, 06:17:59 AM »

Nicodem chimes in

Sedit · « **Reply #14 on:** April 30, 2009, 07:06:24 AM »

I wish (and hope) that was Nicodem poping in. That would make me push for something even more. The way I see it as long as someone can tell you your wrong either A: they either have a good grasp on things but are misunderstanding.... or B:Your wrong...

Of course theres always C: where you have a halfwit that runs his mouth to much in an attempt to cause problems, but I dont feel thats the case here...... (dont make me wish I never said that please Reaminator)

Reaminator · « **Reply #15 on:** April 30, 2009, 08:33:37 PM »

The basis of science is to build on the foundations of knowledge gained by the ancestors. This is why citing references is just as important to the scientific method as is the process of forming a theory by starting from hypotheses. You can not propose a hypothesis unless it is supported by references. It is as simple as that. All other attitude is doomed to failure and I'm afraid that unless you guys learn what science actually is, this forum will drop to a level of certain other populated by tweakers and such. I'm sure those that were once members of The Hive know what kept it at its level.
I like this place was built by young enthusiasts and not having much knowledge in chemistry is not a limitation for its growing as long as you keep in mind that the knowledge is at the grasp of hands – in the scientific libraries! By the way, it was easy to recognize who Vesp is at Science Madness and I'm glad there are no hidden motivations behind this forum (unlike a certain other one). Unfortunately, I don't have much free time to participate in your discussions and will probably not check much what is going, so good luck.

Vesp · « **Reply #16 on:** April 30, 2009, 11:13:40 PM »

Glad to get to know you a little bit more Reaminator.

I agree with you completely, and hope you come and post often. You seem like a high quality member.

Douchermann · « **Reply #17 on:** May 01, 2009, 04:09:31 PM »

I agree with vesp, you are a high quality member and you do know your stuff (why else would you have argued with me hahaha)

However, This procedure is in 'dictionary of applied chemistry' however I don't know where. I agree, I made the mistake of not citing it, but I would have preferred to search for it, rather than just type "this is from somewhere in dictionary of applied chemistry"

Author Topic: Lets synthesize some epinephrine!! (Read 222 times)

Douchermann

Lets synthesize some epinephrine!!

Vesp

Re: Lets synthesize some epinephrine!!

Douchermann

Re: Lets synthesize some epinephrine!!

zzhuchila_clocker

Re: Lets synthesize some epinephrine!!

zzhuchila_clocker

Re: Lets synthesize some epinephrine!!

timecube

Re: Lets synthesize some epinephrine!!

Douchermann

Re: Lets synthesize some epinephrine!!

Vesp

Re: Lets synthesize some epinephrine!!

Douchermann

Re: Lets synthesize some epinephrine!!

zzhuchila_clocker

Re: Lets synthesize some epinephrine!!

Vesp

Re: Lets synthesize some epinephrine!!

Reaminator

Re: Lets synthesize some epinephrine!!

Douchermann

Re: Lets synthesize some epinephrine!!

zzhuchila_clocker

Re: Lets synthesize some epinephrine!!

Sedit

Re: Lets synthesize some epinephrine!!

Reaminator

Re: Lets synthesize some epinephrine!!

Vesp

Re: Lets synthesize some epinephrine!!

Douchermann

Re: Lets synthesize some epinephrine!!