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yogi
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Registered: 21-12-2004
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debrominating 2-Br-Lysergic Acid / Lysergamides
Hello fellow bees.
Im quite new here after the hive went down.
This was a going thread in the hive before it died out.
So anyway im rekindleing this, along with some new info Ive found -
First of all theres this article by some russians -
"Debromination Reaction of 2-Bromocarboxylic Acids "
Abstract
2-Bromo-substituted carboxylic acids (RCHBrCOOH) undergo reductive debromination and form unsubstituted acids RCH2COOH.
DOI : 10.1070/MC1994v004n01ABEH000332
As much as it seems quite positive that their procedure will work for 2-bromo-lysergic acid, I have yet to find an online copy of it.
Second idea is Drone's - reacting bromo-ergo-alkaloids with magnesium and qwenching with H2O
Now theres this one more thing Ive found -
an article by some japanese scientists about how to introduce tritium (hydrogen isotope) into LSD via debromination of 2-bromo-lsd with NaBH4 and a
catalyst, with the NaBH4 being radoiactive.
Now the 1 problem I c about drones way, is yield. Seems like a grignard will affects the yields and not alow for a high yeilding product.
If anyone has any other info he is willing to share, please do.
YOGI~
OH BTW, Im trying to get access to axehandle's FTP but he is not answering my U2U. I have a lot of interesting articles to u/l
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dexter
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I came across a discussion about this a while ago.
Copied from
http://www.chataboutdrugsnetwork.com/=ISO-8859-1QBromocripti...
I've been researching the potential synthesis of certain amides of
ergot compounds, and had come across a few brief mentions of
Bromocriptine. From my studying, which thus far has consisted of
about 10 hours spent alone (around a good, though weak, 100+ hours
total on ergo-compounds and various related things) on potential
bromo->lysergide reduction synthesis, I have come to a few points that
I have questions regarding. The first being the mention that Grignon
reagents do not work in reactions involving acified hydrogen atoms.
This is seemingly countered by an example which leads me to believe
that proceeding with the reaction to place an atom of Mg between the C
and Br on the indole ring, and further to react a
3-methylcyclo-hexanol as the second part of the reaction, whereby the
MgBr would effectively cleave the H from the OH group on the
3-methylcyclo-hexanol, allowing it to bind to the former site of the
Br (and then MgBr) in place (filling the valence shell of the C
again), and leaving a -1 charged molecule with a single bond to the O,
or 3-methylcyclo-hexanone (where the O would be double bonded to the
ring). Would this line of thought be correct?
Further, in prior discussion there is mention of replacing the
non-lysergide formation in the compound (what I believe would be the
ergotaman group... perhaps I'm wrong about the name), and the likewise
bound H (of the same N site) with each an amine group prior to Grignon
reagent reaction. In this area I have come to learn that, regardless
of promises of some to the contrary, indeed Grignon reagents would
attack the starter compound to form any number of various unwanted
molecules. From what I have read, this is due to the instability of
the Amine (amide after bonded) group in the way it binds to the
primary molecular structure. In this regard, I am wondering, if there
is anyone out there with advanced organic chemistry, and organic
synthesis, knowledge, is this something that I should have to worry
about (assuming that I can figure out how to effectively attach the
Amine groups in the correct locations, something which I plan to look
further into today)? Does anyone have other advice for my theoretical
synthesis research?
How would people with the knowledge recommend going about implementing
the 3-methylcyclo-hexanol introduction so that the H(-) atom could be
free-ed for relocation onto the proper binding site after removal of
the Bromine atom?
I am fairly familiar with the process to use for instigating a Grignon
reaction, using either diethylether (I believe?), or THF
(Tetrahydrofuran), and mixing half of the solvent with the Mg
turnings, and the other half with the starter compound (in this case
the bromocriptine NOTE for those attempting to learn about this: a
Grignon reaction is theorized to work under the principle that Mg
should readily bind its-self inbetween the C-Br link as studied by the
late Nobel Prize winning chemist Dr. Grignon); after preparing the two
halves of solvent slowly mixing the starter/solvent solution into the
Mg/Solvent solution, stirring with a magnetic stirrer, making sure not
to allow the reaction to boil, placing reaction container into an
ice-water bath to aide in controlling the speed of reaction.
Actually, I am told that if using diethylether, the reaction should be
allowed to boil slightly.
Thank you to anyone who can shed any light for me, and to all those
who've taken the time to read what I've written.
I'm sorry for any rambling or confusion that I might have
inadvertently cause, it is now 3:10am on my clock, I am tired.
personal e-mail responses would be great, I will notice them sooner,
but also posting to the thread might aide others with questions too.
If you would rather just stick with responding in the thread, I will
hopefully check it before it goes the way of many a lost thread in the
past.
Re: Bromocriptine and the reduction synthesis of s￤ure - Drugs Chemistry - Masonic
2003-09-05 00:18:22.0
> I've been researching the potential synthesis of certain amides of
> ergot compounds, and had come across a few brief mentions of
> Bromocriptine. From my studying, which thus far has consisted of
> about 10 hours spent alone (around a good, though weak, 100+ hours
> total on ergo-compounds and various related things) on potential
> bromo->lysergide reduction synthesis, I have come to a few points that
> I have questions regarding. The first being the mention that Grignon
> reagents do not work in reactions involving acified hydrogen atoms.
> This is seemingly countered by an example which leads me to believe
> that proceeding with the reaction to place an atom of Mg between the C
> and Br on the indole ring, and further to react a
> 3-methylcyclo-hexanol as the second part of the reaction, whereby the
> MgBr would effectively cleave the H from the OH group on the
> 3-methylcyclo-hexanol, allowing it to bind to the former site of the
> Br (and then MgBr) in place (filling the valence shell of the C
> again), and leaving a -1 charged molecule with a single bond to the O,
> or 3-methylcyclo-hexanone (where the O would be double bonded to the
> ring). Would this line of thought be correct?
This really doesn't sound right at all! The hydrogen atom of the alcohol
would, effectively, just replace the "Br" with "H". Of course, if you have
reliable information that what you suggests does indeed happen, then please
post the source of your information.
> Further, in prior discussion there is mention of replacing the
> non-lysergide formation in the compound (what I believe would be the
> ergotaman group... perhaps I'm wrong about the name), and the likewise
> bound H (of the same N site) with each an amine group prior to Grignon
> reagent reaction. In this area I have come to learn that, regardless
> of promises of some to the contrary, indeed Grignon reagents would
> attack the starter compound to form any number of various unwanted
> molecules. From what I have read, this is due to the instability of
> the Amine (amide after bonded) group in the way it binds to the
> primary molecular structure. In this regard, I am wondering, if there
> is anyone out there with advanced organic chemistry, and organic
> synthesis, knowledge, is this something that I should have to worry
> about (assuming that I can figure out how to effectively attach the
> Amine groups in the correct locations, something which I plan to look
> further into today)? Does anyone have other advice for my theoretical
> synthesis research?
You will probably have difficulties using Grignard reagents with compound
containing amine groups (even aromatic ones). I can't figure out exactly
what you are trying to do, but in any case, I doubt that this is the way to
go.
> How would people with the knowledge recommend going about implementing
> the 3-methylcyclo-hexanol introduction so that the H(-) atom could be
> free-ed for relocation onto the proper binding site after removal of
> the Bromine atom?
>
> I am fairly familiar with the process to use for instigating a Grignon
> reaction, using either diethylether (I believe?), or THF
> (Tetrahydrofuran), and mixing half of the solvent with the Mg
> turnings, and the other half with the starter compound (in this case
> the bromocriptine NOTE for those attempting to learn about this: a
> Grignon reaction is theorized to work under the principle that Mg
> should readily bind its-self inbetween the C-Br link as studied by the
> late Nobel Prize winning chemist Dr. Grignon); after preparing the two
> halves of solvent slowly mixing the starter/solvent solution into the
> Mg/Solvent solution, stirring with a magnetic stirrer, making sure not
> to allow the reaction to boil, placing reaction container into an
> ice-water bath to aide in controlling the speed of reaction.
> Actually, I am told that if using diethylether, the reaction should be
> allowed to boil slightly.
You need to be very careful with these reactions, since there is often a
delay before things start to happen. It's usually a good idea to add only a
small portion of the alkyl halide and wait for some indication that this has
reacted before adding more.
> Thank you to anyone who can shed any light for me, and to all those
> who've taken the time to read what I've written.
> I'm sorry for any rambling or confusion that I might have
> inadvertently cause, it is now 3:10am on my clock, I am tired.
> personal e-mail responses would be great, I will notice them sooner,
> but also posting to the thread might aide others with questions too.
> If you would rather just stick with responding in the thread, I will
> hopefully check it before it goes the way of many a lost thread in the
> past.
Re: =?ISO-8859-1?Q?Bromocriptine_and_the_reduction_synthesis_of_s=E4ure?= - Drugs Chemistry - A. Walsh
2003-09-05 00:51:17.0
"Masonic" <None@None.None> wrote in message
news:<bj8h7q$cph$2@news7.svr.pol.co.uk>...
{initial post removed for length}
>
> This really doesn't sound right at all! The hydrogen atom of the alcohol
> would, effectively, just replace the "Br" with "H". Of course, if you have
> reliable information that what you suggests does indeed happen, then please
> post the source of your information.
Perfect! What I am talking about in regards to the mentioned reaction
is exactly to replace the Bromine with and atom of Hydrogen. Though
this may be viewed as a total waste of a good molecule, it seems that
the theoretical organic chemist might have more ready access to a
bromofied form of the compound, though the Bromine atom is likely to
be unwelcome for such purpose as what I am researching.
> You will probably have difficulties using Grignard reagents with compound
> containing amine groups (even aromatic ones). I can't figure out exactly
> what you are trying to do, but in any case, I doubt that this is the way to
> go.
Thanks for informing me, I was a little unsure with my research of
Grignard reactions, but this seems to fit my suspicions. The addition
of two amine groups done after Grignard will suite just fine, as the
process is another, fairly unrelated step. By teh way, exactly what I
am talking about is theoretically stripping the Br off of
Bromocriptine (CAS No.:22260-51-1 I forget the Merck Index Ref. at
the moment), and then substituting the proper amine group on the
pyridine ring off of the (C=O)-N group (at the 3- site I believe..
maybe I'm wrong though, I have a poor memory for the naming
structure). On a molecule of Bromocriptine there is a rather complex
structure bonded to the ergoline structure at this site, which I am
seeking learning to cleave and replace with an ethylamine group
(CH3CH2) to each the Single Hydrogen bonded to the Nitrogen at this
site, as well as to the other bonding site at the Nitrogen atom.
> You need to be very careful with these reactions, since there is often a
> delay before things start to happen. It's usually a good idea to add only a
> small portion of the alkyl halide and wait for some indication that this has
> reacted before adding more.
Again, thank you for the advice, I will certainly follow, as it seems
you have given it me in good faith (as opposed to trying to cause
errors in my theoretical proceedures).
As far as adding the amine groups through replacement... might the
Shulgin process mentioned in Tihkal work? I know that in Tihkal [#26.
LSD-25], Shulgin uses a different compound (ergotamine tartrate) to
start his synthesis, however, the replacement site seems to be the
same. I ask this as a matter of example process, expecting that with
my actual replacement the process would differ at-least slightly, if
not drastically. I'm looking for a starting point though.
Tihkal #26 excerpted from erowid.org:
"A solution of 6.7 g KOH in 100 mL H2O, under an inert atmosphere and
magnetically stirred, was brought to 75 ﾰC, and 10 g ergotamine
tartrate (ET) added. The reaction mixture turned yellow as the
ergotamine went into solution over the course of 1 h. The stirring was
continued for an additional 3 h. The reaction mixture was cooled to
about 10 ﾰC with an external ice bath, and acidified to a pH of about
3.0 by the dropwise addition of 2.5 N H2SO4. White solids started to
appear early in the neutralization; approximately 60 mL of sulfuric
acid was required. The reaction mixture was cooled overnight, the
solids removed by filtration, and the filter cake washed with 10 mL
Et2O. The dry solids were transferred to a beaker, suspended in 50 mL
15 % ammonia in anhydrous ethanol, stirred for 1 h, and separated by
decantation. This extraction was repeated, and the original
decantation and the second extract combined and filtered to remove a
few hundred milligrams of unwanted solids. The clear filtrate was
stripped of solvent under vacuum, the residual solids dissolved in 50
mL of 1% aqueous ammonia, and this solution was acidified as before
with 2.5 N H2SO4. The precipitated solids were removed by filtration
and washed with Et2O until free of color. After drying under vacuum to
a constant weight, there was obtained 3.5 g of d-lysergic acid
hydrate, which should be stored in a dark, sealed container.
A suspension of 3.15 g d-lysergic acid hydrate and 7.1 g of
diethylamine in 150 mL CHCl3 was brought to reflux with stirring. With
the external heating removed, there was added 3.4 g POCl3 over the
course of 2 min, at a rate sufficient to maintain refluxing
conditions. The mixture was held at reflux for an additional 5 min, at
which point everything had gone into solution. After returning to room
temperature, the solution was added to 200 mL of 1 N NH4OH. The phases
were separated, the organic phase dried over anhydrous MgSO4,
filtered, and the solvent removed under vacuum. The residue was
chromatographed over alumina with elution employing a 3:1 C6H6/CHCl3
mixture, and the collected fraction stripped of solvent under hard
vacuum to a constant weight. This free-base solid can be
recrystallized from benzene to give white crystals with a melting
point of 87-92 ﾰC. IR (in cm-1): 750, 776, 850, 937 and 996, with the
carbonyl at 1631. The mass spectrum of the free base has a strong
parent peak at mass 323, with sizable fragments at masses of 181, 196,
207 and 221.
This base was dissolved in warm, dry MeOH, using 4 mL per g of
product. There was then added dry d-tartaric acid (0.232 g per g of
LSD base), and the clear warm solution treated with Et2O dropwise
until the cloudiness did not dispel on continued stirring. This
opaqueness set to a fine crystalline suspension (this is achieved more
quickly with seeding) and the solution allowed to crystallize
overnight in the refrigerator. Ambient light should be severely
restricted during these procedures. The product was removed by
filtration, washed sparingly with cold methanol, with a cold 1:1
MeOH/Et2O mixture, and then dried to constant weight. The white
crystalline product was lysergic acid diethylamide tartrate with two
molecules of methanol of crystallization, with a mp of about 200 ﾰC
with decomposition, and weighed 3.11 g (66%)."
Sorry for the long post.
Thanks again for all the help.
Re: =?ISO-8859-1?Q?Bromocriptine_and_the_reduction_synthesis_of_s=E4ure?= - Drugs Chemistry - A. Walsh
2003-09-05 01:02:58.0
By the way, the source of my Grignard reaction information is
Wonderful Second Volume of the MacMillan Encyclopedia of Chemistry.
Page 701 (Figure 10, which is referenced, is on page 702) has the
information that I made reference to. (though the text seems to
assume that robbing the Hydrogen atom from the alcohol would be an
undesirable thing... go figure.)
Re: =?ISO-8859-1?Q?Bromocriptine_and_the_reduction_synthesis_of_s=E4ure?= - Drugs Chemistry - A. Walsh
2003-09-05 15:07:55.0
> So, effectively you want to debrominate, hydrolyse and then make the simple
> amide. The problem of the amine groups in the Grignard reaction, may not be
> an issue here, since I expect that the Grignard reagent will still form, but
> instead of being reacted with the alcohol to cleave the MgBr group, it would
> instead be quenched by the most acidic amino proton. If you actually wanted
> to do something else with the Grignard, then it would be a problem, but you
> can probably get away with it in this case.
Now I am just slightly confused, though I am gathering that indeed
nothing varying from what we have discussed is being said. To
clarify, just in case... Preforming a Grignard reaction on the
bromocriptine molecule would effectively cleave the Br and replace it
with an atom of Hydrogen if done in the presence of an alcohol? (I
got lost when you mentioned quenching the reagent with the acidic
amino proton....) In that same reference I mentioned in another post,
it describes Grignard reactions in presence of water as leaving an OH
group bonded to the site of the reagent... which I'm hoping to avoid.
Thank you for your patience with this area.
Also, as far as the hydrolyse and simple amide... would I be correct
in assuming that the process would allow for the addition of a
diethylamide in the replacement, or would I only be able to manage to
theoretically replace with only a single ethylamide?
And one more question about Bromocriptine... actually, dealing with
Bromocriptine Metthanesulfonate (also listed in some ref. as
mesylate)... Which has the additional compound CH3SO3H. Since this
compound isn't connected to the ergoline compound that I wish to work
with do I really need to worry about explicitly removing it from the
process, or will it fall out naturally as a part of one of the other
process that might be followed... Sorry that I'm not so clear at the
moment as to what I am asking with this question, I am not able to
readily find information of the mesylate form of Bromocriptine.
Thanks again.
Re: Bromocriptine and the reduction synthesis of s￤ure - Drugs Chemistry - Masonic
2003-09-05 18:22:33.0
>> This really doesn't sound right at all! The hydrogen atom of the
>> alcohol
>> would, effectively, just replace the "Br" with "H". Of course, if
>> you have reliable information that what you suggests does indeed
>> happen, then please
>> post the source of your information.
>
> Perfect! What I am talking about in regards to the mentioned reaction
> is exactly to replace the Bromine with and atom of Hydrogen. Though
> this may be viewed as a total waste of a good molecule, it seems that
> the theoretical organic chemist might have more ready access to a
> bromofied form of the compound, though the Bromine atom is likely to
> be unwelcome for such purpose as what I am researching.
In that case, you've obviously got the right idea. I was just thrown by
your peculiar choice of alcohol for this reaction. Any alcohol could be
used, or even water, so I thought that the alcohol itself had some
significance in what you were trying to do.
>> You will probably have difficulties using Grignard reagents with
>> compound containing amine groups (even aromatic ones). I can't
>> figure out exactly
>> what you are trying to do, but in any case, I doubt that this is the
>> way to
>> go.
>
> Thanks for informing me, I was a little unsure with my research of
> Grignard reactions, but this seems to fit my suspicions. The addition
> of two amine groups done after Grignard will suite just fine, as the
> process is another, fairly unrelated step. By teh way, exactly what I
> am talking about is theoretically stripping the Br off of
> Bromocriptine (CAS No.:22260-51-1 I forget the Merck Index Ref. at
> the moment), and then substituting the proper amine group on the
> pyridine ring off of the (C=O)-N group (at the 3- site I believe..
> maybe I'm wrong though, I have a poor memory for the naming
> structure). On a molecule of Bromocriptine there is a rather complex
> structure bonded to the ergoline structure at this site, which I am
> seeking learning to cleave and replace with an ethylamine group
> (CH3CH2) to each the Single Hydrogen bonded to the Nitrogen at this
> site, as well as to the other bonding site at the Nitrogen atom.
So, effectively you want to debrominate, hydrolyse and then make the simple
amide. The problem of the amine groups in the Grignard reaction, may not be
an issue here, since I expect that the Grignard reagent will still form, but
instead of being reacted with the alcohol to cleave the MgBr group, it would
instead be quenched by the most acidic amino proton. If you actually wanted
to do something else with the Grignard, then it would be a problem, but you
can probably get away with it in this case.
>> You need to be very careful with these reactions, since there is
>> often a
>> delay before things start to happen. It's usually a good idea to
>> add only a
>> small portion of the alkyl halide and wait for some indication that
>> this has reacted before adding more.
>
> Again, thank you for the advice, I will certainly follow, as it seems
> you have given it me in good faith (as opposed to trying to cause
> errors in my theoretical proceedures).
Why would you think any different? WEIL
> As far as adding the amine groups through replacement... might the
> Shulgin process mentioned in Tihkal work? I know that in Tihkal [#26.
> LSD-25], Shulgin uses a different compound (ergotamine tartrate) to
> start his synthesis, however, the replacement site seems to be the
> same. I ask this as a matter of example process, expecting that with
> my actual replacement the process would differ at-least slightly, if
> not drastically. I'm looking for a starting point though.
> Tihkal #26 excerpted from erowid.org:
<procedure snipped>
Yes, there's no reason why that shouldn't work for your substrate.
Re: =?ISO-8859-1?Q?Bromocriptine_and_the_reduction_synthesis_of_s=E4ure?= - Drugs Chemistry - Saint Jude, Patron of Lost Causes
2003-09-05 19:42:05.0
The very mention of orbitals makes my head hurt. When you form the
Grignard reagent by reacting bromocriptine with magnesium in dry
ether, the carbon that the bromine was attached to becomes
electron-enriched (carboanion.) Because of it's extra electrical
charge, it will react with any acidic hydrogens in the area (just as a
hydride would.) Those acidic hydrogens would include water molecules
or amines, which is why the Grignard reagent normally 'fails' in the
presence of either; the carbon that the halide (bromine) was attached
to ends up with a hydrogen in the halide's place. This is certainly
a bad thing in most cases, but if one were trying to convert
bromocriptine to lysergic acid something-or-other, then the 'failed'
Grignard would quite nicely get rid of the unwanted bromine. Acidic
water is an easy way to make sure that the reaction has run to
completion (plenty of acidic hydrogens for the grignard to react
with.)
At any rate, if the point is just to rid yourself of the bromine,
I believe you're over-thinking the reaction. Bromowhatever into
ether with magnesium, after Grignard forms, quench with acidic water
to provide the H.
Re: =?ISO-8859-1?Q?Bromocriptine_and_the_reduction_synthesis_of_s=E4ure?= - Drugs Chemistry - A. Walsh
2003-09-06 00:39:07.0
Alright... after looking at the molecular structure of Bromocriptine
for a while, I suddenly realized what was being said; you could say
that it was staring me in the face the whole time.
To recap then:
The removal of the Bromine atom from the molecule can be theoretically
accomplished through a Grignard reaction, which will "fail" due to the
acidic properties of the amino group that is present in the structure.
To replace the undesirable portion of the molecule with the desired
amine, one should hydrolyse first (with NaOH) and then react with said
amine. It seems that the Grignard reaction should still be carried
out prior to the formation of the amide to protect against the chance
that the Grignard reagent would attack the amide group (as,
apparently, Grignard reagents are known to do.)
Masonic, you mentioned doubt that the reaction could work when using
the salt; as there is a "pretty acidic proton"... Would this proton as
well be a likely candidate to quench the Grignard reagent as the
acidic amino proton would? If so, then I don't see the problem in
proceeding with the Grignard reaction first anyways. I can understand
how one might normally desire to hydrolyse before debromofication, if
they did not wish for the Grignard to "fail".
Also, in theory, if dealing with Bromocriptine (and not the salt
form), would the procedure follow similar/the same process? ("Failed"
Grignard to remove Br which is likely to be replaced by the existing
acidic proton, followed by hydrolyse reaction with NaOH to form the
carboxylic acid, allowing the desired amide to be generated using the
appropriate amine in the reaction.)
As far as Saint Jude's remark that I may be over-thinking the reaction
indeed this seems very true; I came onto a.d.c. understanding some
basic principles of Grignard reagents, the procedures one might follow
in attempting such reactions, and postulating the usefulness of a
"failed" reaction. My over-thinking came about due to attempting to
further understand how to go about accomplishing a reaction where the
'standard' procedure is undesirable, and indeed, as Masonic and St.
Jude concur (as well as the MMEoC) the "failed" reaction would
accomplish the desired effect. With a reaction that seems not to have
been explicitly studied do to the un-usefulness of it ("failing" the
Grignard), I just had a few more questions than one might expect
regarding 'standard' procedures.
I am sorry Saint Jude for any headaches I might have caused. And,
again, thank you (both of you) for your help, and patience.
I am fairly sure that I will have at least a few more questions... but
for the moment I need to wade through some more US patents.
Re: Bromocriptine and the reduction synthesis of s￤ure - Drugs Chemistry - Masonic
2003-09-06 01:09:32.0
>> So, effectively you want to debrominate, hydrolyse and then make the
>> simple amide. The problem of the amine groups in the Grignard
>> reaction, may not be an issue here, since I expect that the Grignard
>> reagent will still form, but instead of being reacted with the
>> alcohol to cleave the MgBr group, it would instead be quenched by
>> the most acidic amino proton. If you actually wanted to do
>> something else with the Grignard, then it would be a problem, but
>> you can probably get away with it in this case.
>
>
> Now I am just slightly confused, though I am gathering that indeed
> nothing varying from what we have discussed is being said. To
> clarify, just in case... Preforming a Grignard reaction on the
> bromocriptine molecule would effectively cleave the Br and replace it
> with an atom of Hydrogen if done in the presence of an alcohol? (I
> got lost when you mentioned quenching the reagent with the acidic
> amino proton....)
It's nothing to worry about, but because you have a (RELATIVELY) acidic
amino proton in bromocriptine, before you add any alcohol, that proton will
react with the Grignard reagent that you have formed, so it is that proton
(not the proton of the alcohol) that would replace MgBr.
> In that same reference I mentioned in another post,
> it describes Grignard reactions in presence of water as leaving an OH
> group bonded to the site of the reagent... which I'm hoping to avoid.
> Thank you for your patience with this area.
If you react a Grignard reagent with water, you get the same reaction as if
you react a Grignard reagent with an alcohol. The H atom (not the OH group)
of water replaces the MgBr.
> Also, as far as the hydrolyse and simple amide... would I be correct
> in assuming that the process would allow for the addition of a
> diethylamide in the replacement, or would I only be able to manage to
> theoretically replace with only a single ethylamide?
When you hydrolyse the amide, you will form the corresponding carboxylic
acid. You can then generate any amide from this, depending on the amine
that you then react it with.
>
> And one more question about Bromocriptine... actually, dealing with
> Bromocriptine Metthanesulfonate (also listed in some ref. as
> mesylate)... Which has the additional compound CH3SO3H. Since this
> compound isn't connected to the ergoline compound that I wish to work
> with do I really need to worry about explicitly removing it from the
> process, or will it fall out naturally as a part of one of the other
> process that might be followed... Sorry that I'm not so clear at the
> moment as to what I am asking with this question, I am not able to
> readily find information of the mesylate form of Bromocriptine.
> Thanks again.
This is just the acid, from which a salt has been formed (like, for example,
ammonium chloride is formed from ammonia and HCl). I doubt that you could
get the reaction to work on the salt itself, since it has a pretty acidic
proton, but you could either remove it by treating the bromocriptine
mesylate with a base, or even better, you could hydrolyse it (using NaOH,
which will remove it without adding another reaction step) and form the
appropriate amide first. It's lucky that you mentioned this, since I had
missed the fact that you were dealing with a salt.
Re: Bromocriptine and the reduction synthesis of s￤ure - Drugs Chemistry - Masonic
2003-09-06 10:09:50.0
> It seems that the Grignard reaction should still be carried
> out prior to the formation of the amide to protect against the chance
> that the Grignard reagent would attack the amide group (as,
> apparently, Grignard reagents are known to do.)
Your starting material is also an amide, though, so if that side-reaction
was a problem, it would be a problem for bromocriptine itself and for the
diethyl amide. The reaction between Grignard reagents and amides is
relatively slow, so the Grignard reagent is much more likely to pick up a
proton before it has a chance to react with the amide group.
> Masonic, you mentioned doubt that the reaction could work when using
> the salt; as there is a "pretty acidic proton"... Would this proton as
> well be a likely candidate to quench the Grignard reagent as the
> acidic amino proton would? If so, then I don't see the problem in
> proceeding with the Grignard reaction first anyways. I can understand
> how one might normally desire to hydrolyse before debromofication, if
> they did not wish for the Grignard to "fail".
I would worry that in this case, the presence of such an acidic proton might
stop the reaction from happening at all. The mechanism of the Grignard
reaction involves free radicals and my understanding of radical chemistry
leaves a lot to be desired, but when water is present in a Grignard
reaction, it does not simply cause the product to be quenched; it inhibits
any reaction from taking place at all. Presumably, it is the conjugate base
(e.g. OH- in this case) that is involved in this effect. Whether the
same is true of other similarly acidic substances, I don't know. Other much
less acidic protons (e.g. amine protons) would be much less of a problem in
this respect, since the H-X bonds in these substances are much stronger.
> Also, in theory, if dealing with Bromocriptine (and not the salt
> form), would the procedure follow similar/the same process? ("Failed"
> Grignard to remove Br which is likely to be replaced by the existing
> acidic proton, followed by hydrolyse reaction with NaOH to form the
> carboxylic acid, allowing the desired amide to be generated using the
> appropriate amine in the reaction.)
Yes, it just adds the step of removing that salt. The benefit of converting
the amide first is that this is conveniently done under the reaction
conditions of the hydrolysis step.
Re: =?ISO-8859-1?Q?Bromocriptine_and_the_reduction_synthesis_of_s=E4ure?= - Drugs Chemistry - A. Walsh
2003-09-06 23:18:38.0
Thanks for all the help with getting me over the learning curve.
So the process goes something along these lines?:
Bromocriptine hydrolysed with NaOH > Bromolysergic Acid
react with desired amine group (in this case diethylamine) >
Bromolysergide
Form Grignard reagent (Bromo-magnesium-lysergide?)
'fail' reaction with introduction of an alcohol group > Lysergide
(d-lysergic acid diethylamide)
Is there a way to make the Lysergide more stable? (through
introduction of tartaric acid.. for salt formation? and if that would
work, what is the principle theory behind it? I'm not just looking
for the "just add the tartaric acid, and you should be good" style
answer, I can already gather that a slow introduction might do
something to give the o'le stabilization... Does anyone have a fairly
good reference on the general subject matter of free-base
stabilization through salt formation?)
Either way, then proceed to chromatograph the Lysergide, or repeatedly
recrystallize... what are the benefits of either one over the other
for purification? My thoughts seem to be that chromatography would be
a slightly less involved process that might take less time; though I
have the feeling that actually going through the process of
chromatography is a bit more difficult than it seems. If I were to
put all of this theory to practice I would likely be inclined to
'build' my own chromatography unit as per standard setup reference
that I have found (Chemical Technicians Ready Reference Handbook
p743-755 or so)
And once more, sorry for all the headaches that I might have caused.
(side note: seems like if in theory I were to go about all of this
that it might be far more easy to come about Bromocriptine than the
salt form, I wouldn't want to have to go through attempting to divert
any medicines when a simple order can be placed to a wide number of
nation-wide chemical supply companies; just thought I'd include the
information.)
Much thanks Masonic. Perhaps I will still have a few more questions
in the near future.
Re: Bromocriptine and the reduction synthesis of s￤ure - Drugs Chemistry - Masonic
2003-09-07 16:29:33.0
> Thanks for all the help with getting me over the learning curve.
> So the process goes something along these lines?:
> Bromocriptine hydrolysed with NaOH > Bromolysergic Acid
> react with desired amine group (in this case diethylamine) >
> Bromolysergide
> Form Grignard reagent (Bromo-magnesium-lysergide?)
> 'fail' reaction with introduction of an alcohol group > Lysergide
> (d-lysergic acid diethylamide)
That would be the approach that I'd use.
> Is there a way to make the Lysergide more stable? (through
> introduction of tartaric acid.. for salt formation? and if that would
> work, what is the principle theory behind it? I'm not just looking
> for the "just add the tartaric acid, and you should be good" style
> answer, I can already gather that a slow introduction might do
> something to give the o'le stabilization... Does anyone have a fairly
> good reference on the general subject matter of free-base
> stabilization through salt formation?)
Whether or not salt formation aids in stability in this case, I don't know.
The principle reason for generating salts is usually one of convenience,
since salts are nearly always clean crystalline solids, easy to handle,
water soluble etc. The nitrogen of the indole ring system is nonbasic, so
protonation would occur exclusively at the N of the tetrahydropyridine
ring - I don't see why that would afford the molecule any added stability.
> Either way, then proceed to chromatograph the Lysergide,
If you were purifying by chromatography, you would be best off working with
the freebase at that stage.
> or repeatedly
> recrystallize... what are the benefits of either one over the other
> for purification? My thoughts seem to be that chromatography would be
> a slightly less involved process that might take less time; though I
> have the feeling that actually going through the process of
> chromatography is a bit more difficult than it seems. If I were to
> put all of this theory to practice I would likely be inclined to
> 'build' my own chromatography unit as per standard setup reference
> that I have found (Chemical Technicians Ready Reference Handbook
> p743-755 or so)
Recrystallisation is easier when it works well! Often recrystallisation
fails or leads to a loss of too much of the material (it can always be
recovered). In your case, a suitable recrystallisation has been developed,
so these problems should not apply. Chromatography may give higher yields,
but the cost of the additional material saved would probably not outweigh
the costs of carrying out the procedure.
Re: Bromocriptine and the reduction synthesis of s￤ure - Drugs Chemistry - Carike
2003-09-13 00:00:50.0
"A. Walsh" <thebigbadme@hotmail.com> wrote in message
news:964e45a5.0309062218.589944ce@posting.google.com...
> Thanks for all the help with getting me over the learning curve.
> So the process goes something along these lines?:
> Bromocriptine hydrolysed with NaOH > Bromolysergic Acid
> react with desired amine group (in this case diethylamine) >
> Bromolysergide
> Form Grignard reagent (Bromo-magnesium-lysergide?)
> 'fail' reaction with introduction of an alcohol group > Lysergide
> (d-lysergic acid diethylamide)
>
FWIW - T. Nagasaki et al. disclose in Journal of Labelled Compounds and
Radiopharmaceuticals, 44 (2001) 993, the smooth debromination of 2-bromo-LSD
with sodium borohydride in dimethylformamide (30 minutes at 70ﾰC).
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Re: Bromocriptine and the reduction synthesis of s￤ure - Drugs Chemistry - Masonic
2003-09-13 09:51:10.0
> FWIW - T. Nagasaki et al. disclose in Journal of Labelled Compounds
> and Radiopharmaceuticals, 44 (2001) 993, the smooth debromination of
> 2-bromo-LSD with sodium borohydride in dimethylformamide (30 minutes
> at 70ﾰC).
It should be worth a lot! This is a much easier procedure to carry out and
it removes all of the functional group compatibility issues associated with
the Grignard reaction.
Re: =?ISO-8859-1?Q?Bromocriptine_and_the_reduction_synthesis_of_s=E4ure?= - Drugs Chemistry - A. Walsh
2003-09-14 19:13:29.0
"Carike" <carike@hotmail.com> wrote in message
news:<3f6242a0_6@news.Usenet.com>...
>
> FWIW - T. Nagasaki et al. disclose in Journal of Labelled Compounds and
> Radiopharmaceuticals, 44 (2001) 993, the smooth debromination of 2-bromo-LSD
> with sodium borohydride in dimethylformamide (30 minutes at 70ﾰC).
After considerable searching through a number of libraries... and
eventually comming across the stated Journal.... I found this:
"A new practical tritium labelling procedure using sodium borotritide
and tetrakis(triphenylphosphine)palladium(0)
Journal of Labelled Compounds and Radiopharmaceuticals
Volume 44, Issue 14, Date: December 2001, Pages: 993-1004
Tohru Nagasaki, Katsunori Sakai, Masaharu Segawa, Yoshihiko Katsuyama,
Nobuhiro Haga, Masahiro Koike, Kenji Kawada, Shozo Takechi"
Indeed T. Nagasaki is listed as an author, as well as many others; and
the year, Volume, and page citations all match up... Sadly though, the
ref. somehow got goofed up. Does such a document exist as the prior
poster has noted?
Further... Something has just crossed my mind. I am under the
impression that even theoretical lysergic acid diethylamide would be
rather sensitive to heat, under such circumstance as noted by Carike
there doesn't seem to be a way to preform such a process at the
prescribed temperature, followed by decreasing the temp. to a level
which would be less likely to induce the breakdown of the compound.
Maybe I'm just off my rocker...
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yogi
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Yea Ive read this discussion as well. And they do not add much to the lot of information ive said in my previous post.
And trhis paper by Nagasaki et al. is what I have, which looks like a promising way to dehalogenate (even that it is at 70degC, which should not
really harm the molecule).
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dexter
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Any help?
Indium and samarium may be expensive, but I can't see them being suspicious.
www.sioc.ac.cn/chub/zghx/2004863.pdf
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yogi
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very interesting indeed...
though im unfamiliar with the properties of Indium and Samarium, it is advisable to look further into this to make sure it will not harm the rest of
the molecule.
great new info 
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Sandmeyer
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This is a debromination of an aromatic system, there are many more Zn-based methods: http://www.orgsyn.org/orgsyn/prep.asp?rxntypeid=103&prep...
Method involves using acetic acid (but other suitable solvents can be used) and potential problem in applying this to 2-bromo-lysergic acid analogues
is the irreversible isomersation of the 9,10-double bond into fully aromatic ring C-indoline, the latter system is much more stable, if you're lucky a
bit harsher conditions than acetic acid are required for that, I suppose that a quick TLC check would reveal if this occured or not as naphtalene-like
systems in general tend to give fluorescent spots. The Drone's story of making grignard and quenching is at least entertaining .
[Edited on 25-7-2006 by Sandmeyer]
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jon
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would this approach be less likely to cause aromatic irreversable isomerization??
pp 616-618
http://ejournal.stpi.org.tw/NSC_INDEX/KSP/journalView/volumn...
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jon
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ok i'll illustrate the reaction.
in summary, zinc, ammonium chloride, and tetrahydrofuran with just sufficient water to dissolve the ammonium chloride in a beaker set the stir rate
and add the substrate the rxn time is 3-5 hours at room temp.
my question what impact would the lewis acid (mixed zinc halides) have on the quaternary double bond?
would contact with the lewis acid at room temperature effect aromatization ?
can someone more knowledgable or ergoline compounds chime in?
[Edited on 7-7-2010 by jon]
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peach
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I don't get why they're suggesting recrystalization over columns there. Surely you'll obtain a far more pure isomer using columns. I've heard from
numerous people buying lysergides that have a distinct color to them, and it probably hasn't been run through a column for ease of synthesis; it's
often lavender colored, or similar.
I have heard people going on about the specific salt stabilities. I think the citric salt is more stable than the tartrate in terms of oxidative
potential. Not sure about the malate.
I don't understand this kind of chemistry well enough to discuss this with you; I don't know why you specifically want the bromo. I do know that a
huge amount of work has been done with ergocryptine as opposed to lysergic acid. I'm not entirely sure why the cryptine specifically.
I do know that lysergide based compounds have worked wonders for clearing my headaches. I know there is paracetamol and ibuprofen or the power trio
(paracetamol, ibu + codeine), but lysergides do seem to work better, at least for me. I know they're still used in some cluster headache tablets. I'd
love to get some of those, as when I've tried them they're entirely outstripped the other two commonly available alternatives. I end up feeling so
clear and fresh, without headaches. Having headaches everyday is a like a living knightmare; and yes, I've tried drinking more water, changing my diet
(to extremes, e.g. only drinking water and eating brown carbohydrates) and SAD lamps. Lysergides work better.
[Edited on 8-7-2010 by peach]
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jon
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maleic acid is better to prevent oxidation due to it's double bond.
the idea is that bromocriptine is commony available and not watched hence the impetus for it's debromination to use as a pharmacuetically active d2
agonist ahhheemm.
some may have more sinister motive but mine are entirely pure.
so back to the topic at hand the system i referenced is a viable chemoselective aryl dehalogenation method circa 2009.
it's done under gentle conditions at room temperature.
the only question is: would a lewis acid such as zinc chloride activate that quaternary double bond and initiate aromatization?
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jon
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ok the zinc/ammonium chloride/thf system at room temperature turns out to be highly chemoselective as evidenced by this abstract.
the propylargyl group is reduced to it's corresponding alkene.
1&_user=10&_coverDate=06%2F18%2F2007&_rdoc=1&_fmt=high&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=141114
6393&_rerunOrigin=google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3927d2f57e8c757e1574da4b55d65790
[Edited on 25-7-2010 by jon]
sorry guys the other link refed on pp 616 does'nt work this is the file i'm talking about.
Attachment: Zn NH4Cl.pdf (60kB)
This file has been downloaded 1065 times
[Edited on 25-7-2010 by jon]
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jon
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after scratching my nuts on this i found out yes indeed lysergamides will stand up to zinc and acetic acid.
not only that, it is possible to make lysergic acid amides from elymoclavine too.
you know for my migraines.
have a gander.
reduction of compd. 3
http://www.erowid.org/archive/rhodium/chemistry/elymoclavine...
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jorgejch
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Freebase of bromocriptine mesylate
Reviving this post. lol. What do you think would be a optimal procedure for freebasing bromocriptine mesylate? Being that it's solubility in water is
only 0.8 mg/ml. Way less than that of Ergotamine Tartrate.
Cheers!
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jon
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base in methanol then crash with water.
Give me librium or give me meth!
Patrick Henry....
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jorgejch
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Do you fancy any particular concentration of alcoholic ammonia?
Thanks for the reply by the way.
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jon
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ah yes walden inversion at c-8 with strong bases this only happens if there is locallized high ph.
but i imagine since it's slightly soluble in water you want you ammonia as concentrated as possible.
you can easily attain 15% by bubbling it in
[Edited on 12-12-2012 by jon]
Give me librium or give me meth!
Patrick Henry....
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OhYeah25
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Can someone give more detail on freebasing the mesylate? Are you saying take up in basic methanol...say methanolic KOH? Then crash with water?
Assuming H3O? Seems hydrolysis would be pretty tough for someone to do if they cant get it into water. Bromocriptine would seem a feasible route if
not for the only slight solubility. Wouldnt something like basing in 1 m methanolic KOH, evaporating to residue, and then following hydrolysis
suffice? Having a hard time envisioning this one.
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bfesser
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Illicit Drug Discussion
<img src="../scipics/_warn.png" /> <em>If you continue using 'cook' terminology ("freebasing,"* "H3O," "basing," etc.), your posts may be
removed.</em> <img src="../scipics/_warn.png" />
Discussion of the theoretical aspects of illicit compounds is fine, but please try to keep it as scientific as possible. You'll find that many
members will object to 'spoon feeding' of information on synthesis of such compounds. Also, please note that it's
H<sub>3</sub>O<sup>+</sup> (<a href="https://en.wikipedia.org/wiki/Hydronium" target="_blank">hydronium cation</a>
<img src="../scipics/_wiki.png" /> , not "H3O." Thank you.
* I am aware that "free base" is an accepted <a href="http://en.wikipedia.org/wiki/Free_base" target="_blank">chemistry term</a> <img
src="../scipics/_wiki.png" />; but "freebasing" generally is not, and it must be taken in context.
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OhYeah25
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Ok, my apologies, and yes I know hydronium is H3O+ cation, will be more specific from now on. This is a very interesting thread, follow up until the
last part, hoping for just a little more clarification on forming the free base the lasts posts were somewhat unclear to me, and would just like to
figure it out for peace of mind at this point, after stumbling on to this thread. Just elaborating on jorgejch post.
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sonogashira
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It would be easier to extract it directly into the reaction solvent for your next step. What solvent do you plan to use?
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OhYeah25
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Im not sure I follow your logic. Are you referring to the debromination, hydrolysis, or free basing of mesylate salt?
If youre referring to the the 1 M methanolic KOH theory, then the solvent used is water. AFAIK all hydrolysis use water as solvent. I guess that would
be the theoretical "plan". I like to brush up on psychedelic chemistry every few years for fun. Been a long time since school.
[Edited on 7-8-2013 by OhYeah25]
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sonogashira
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You were asking about converting a salt to a base, were you not? I was talking about extracting the base into a solvent. I assumed that you would be
attempting debromination first, because if you were trying to hydrolyse it directly it would make no sense in asking how to convert the salt to a
base, you would simply do acid or base hydrolysis using the salt. Why do you want to extract the free base form?
[Edited on 7-8-2013 by sonogashira]
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OhYeah25
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As mentioned earlier, bromocriptine is only slightly soluble in water(.8mg/ml). Doesnt seem like ideal condiitions.
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sonogashira
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How much bromocryptine shall you be using?
[Edited on 7-8-2013 by sonogashira]
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OhYeah25
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Quote: Originally posted by jorgejch  | Reviving this post. lol. What do you think would be a optimal procedure for freebasing bromocriptine mesylate? Being that it's solubility in water is
only 0.8 mg/ml. Way less than that of Ergotamine Tartrate.
Cheers!
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This is where it seems using bromocriptine mesylate isnt ideal. If one had wanted to carry out some of the routes mentioned here, it seems the
solubility could pose a real problem.
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