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Author Topic: Methadone synthesis  (Read 10289 times)

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aldoxime_amine

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Methadone synthesis
« on: April 20, 2009, 10:44:56 AM »

X is C14H10N-Na+

Z is C21H27N2-MgBr+

Intermediate C is a chloride salt and is prepared as follows:
1-(dimethylamino)-propan-2-ol + SOCl2 ----> A
2-(dimethylamino)-propan-1-ol + SOCl2 ----> B

A (warm)-----> C
B (warm)-----> C

My attempt:
Please tell me what is Br2 doing here????
I am getting different products from A and B according to my mechanism. Is this rearrangement named?

I am not aware of methadone structure and would not like to see beforehand without solving reaction scheme.
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azmanam

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Re: Methadone synthesis
« Reply #1 on: April 20, 2009, 12:50:09 PM »

First, I have a beef with the conditions for getting to intermediate X.  I suppose they'll get the job done, but imho a non-nucleophilic base is needed to avoid the undesired side reaction that sidetracked me for a while...

As for Br2... look at the next reaction.  It should look familiar.  You're missing one of the reagents for this named reaction.  I'd have expected peroxides and light/heat to accompany the Br2 for the reaction conditions, but perhaps Br2 will do it by itself.

As for int C.  Forget about nitrogen - it always throws people off.  Nitrogen does just about all the same things oxygen does (plus a few extra).  Pretend you're warming a chloroalcohol (a halohydrin) instead of an amino chloride.
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aldoxime_amine

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Re: Methadone synthesis
« Reply #2 on: April 20, 2009, 07:25:24 PM »

Firstly i am sorry for copying wrong mechanism onto Chemsketch for the "C from B" part. The nitrogen abstracts the alpha proton.

So, first there is alpha bromination, (strange, no reaction conditions indicate that, but you believe they are not needed?)  followed by F.C. alkylation onto benzene.

But after that, NaOH, wouldn't it hydrolyse the cyanide to say amide or acid?

Also warming a halohydrin, wouldn't give a chloride salt as the question demands...(would give cyclic ether linkage)

Can you be more clear about the need of non-nuceophilic base?
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azmanam

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Re: Methadone synthesis
« Reply #3 on: April 21, 2009, 12:15:57 AM »

Quote
So, first there is alpha bromination, (strange, no reaction conditions indicate that, but you believe they are not needed?)  followed by F.C. alkylation onto benzene.

yes, benzyllic bromination, followed by F.C. reaction.  I wouldn't have predicted that just Br2 would be enough... but I've never done the reaction.  imho you need a radical initiator. 

Quote
But after that, NaOH, wouldn't it hydrolyse the cyanide to say amide or acid?

Can you be more clear about the need of non-nuceophilic base

That's what I'm saying.  I was very confused because hydrolysis gives a mol formula that includes oxygen.  Your mol formula for X includes no oxygen.  NaOH is a nucleophilic base.  It will add into the nitrile and hydrolyze it like you and I thought.  LDA (http://en.wikipedia.org/wiki/Lithium_diisopropylamide) is a non-nucleophilic base.  It will not act as a nucleophile and will not add into electrophilic carbon atoms like the carbon atom of a nitrile.

Quote
Also warming a halohydrin, wouldn't give a chloride salt as the question demands...(would give cyclic ether linkage)

Yes, halohydrins give epoxides.  amino halides do the same thing.  They're called aziridines.
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aldoxime_amine

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Re: Methadone synthesis
« Reply #4 on: April 21, 2009, 12:29:37 AM »

My mechanism not ok?

And can you let me in on your X?
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azmanam

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Re: Methadone synthesis
« Reply #5 on: April 21, 2009, 01:48:26 AM »

Your mechanism for C is not ok.  use the lone pair on nitrogen the same way you used the lone pair on oxygen in the halohydrin example.

For X, use NaOH as a base, not a nucleophile.

Maybe redraw with what you have so far?
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aldoxime_amine

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Re: Methadone synthesis
« Reply #6 on: April 21, 2009, 03:13:05 AM »

Thanks for all the inputs.  ;)
The note on LDA helped.  ;)

Here is methadone synthesis:

(PS: Do you think this question was well framed, especially about NaOH and Br2?)
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azmanam

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Re: Methadone synthesis
« Reply #7 on: April 21, 2009, 03:38:46 AM »

well done... except you cheated and didn't draw Z (didn't think i'd notice, did you :))  What do you think Z is.  it's actually an important structure (why?)

yes, i think the question was well framed - it's an interesting question and it's neat to see that 2 semesters of work is really paying off and you can make these interesting and useful compounds using the simple chemistry you've learned.  the format of the question is just fine... i just have problems with those 2 reagents I mentioned.  That sub-part of the question is poorly framed.  I'm not sure Br2 will get the job done.  NaOH probably will, but you'd probably have to keep it cold (maybe colder than water will allow?).  I'd have added peroxides to 1 and changed NaOH in 2.  otherwise a fine question.
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aldoxime_amine

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Re: Methadone synthesis
« Reply #8 on: April 21, 2009, 03:51:07 AM »

I didn't want to crowd the Chemsketch window, so didn't draw Z. Instead of the C=O, we have C=NMgBr and N of the amine is not protonated. What is important in this structure?


yes, i think the question was well framed - it's an interesting question and it's neat to see that 2 semesters of work is really paying off and you can make these interesting and useful compounds using the simple chemistry you've learned.

lol, I just completed high school.
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azmanam

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Re: Methadone synthesis
« Reply #9 on: April 21, 2009, 03:55:08 AM »

Quote
lol, I just completed high school.

cool.  for reference, the stuff you're learning is second year undergrad material.  impressive.

Quote
Instead of the C=O, we have C=NMgBr and N of the amine is not protonated. What is important in this structure?

nitriles are at the acid oxidation state - the same as esters and acid chlorides.  Again with the exception of the nucleophilicity of NaOH, we could have theoretically done this synthesis with an ester instead of a nitrile - they're both at the same oxidation state.  why the nitrile?

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aldoxime_amine

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Re: Methadone synthesis
« Reply #10 on: April 21, 2009, 04:01:38 AM »

Reaction would run away till alcohol in case of ester?
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azmanam

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Re: Methadone synthesis
« Reply #11 on: April 21, 2009, 04:03:03 AM »

yes.  what about nitrile keeps that from happening?
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aldoxime_amine

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Re: Methadone synthesis
« Reply #12 on: April 21, 2009, 04:09:48 AM »

Electron density would become too high on the nitrogen, since the N-Mg bond has high ionic character..?
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azmanam

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Re: Methadone synthesis
« Reply #13 on: April 21, 2009, 04:12:55 AM »

essentially.  there's already one full negative charge on nitrogen.  C=X double bonds are typically very electrophilic at carbon (ketone, aldehyde, ester, imine...)  but with one negative charge on nitrogen, a second equivalent of Grignard will not attack the C=N double bond.  This limits the nucleophilic addition to only one equivalent of Grignard. (and allows for the acid hydrolysis of the 'deprotonated imine' to the ketone)
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diodema

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Re: Methadone synthesis
« Reply #14 on: September 21, 2009, 10:48:30 AM »

Synthesis Methadone :

In 30 ml. Dry Dimethylformamide dissolve 10gr. 1,1-diphenylbutane-2-sulfonic acid also add in a mix 6гр. sodium hydroxyde (a powder or small granules "micropearls") in 20ml. Dry Dimethylformamide . A mix heat up to 75? 5ºС at intensive hashing in a current 20 min*. Further in a mix gradually pour in 13мл. dimethylamino-2-chloropropane (received from dimethylamino-2-chloropropane a hydrochloride and a water solution of alkali, then dried up over firm NaOH). Reaction as a result Dimethylformamide  boils **. A mix intensively mix 1 hour at 75-+ 5ºС. Further the received weight pour out in 100ml. Waters also add 100мл. Benzene for extract the bases Methadone. A mix intensively mix and pour in separating funnel a funnel. The bottom water layer reject, and top transfer to a glass with a solution, 27ml. Waters containing 8ml. The concentrated hydrochloric acid, hot to 60*C. The mix is mixed strongly by 1-2 minutes Also transfer in hot separating funnel after stratified mixture the bottom water layer transfer to a glass for hydrochloride crystallisation Methadone***. A water layer cool and the allocated crystals of a hydrochloride Methadone strongly wring out on a funnel. Further crystals dry at a room temperature ****.
Notes:
* - a flask with a reagent isolate from air oxygen.
** - If necessary put a return reflux and isolate from air oxygen. 
*** - procedure is necessary for spending quickly since crystallisation directly in separating funnel to a funnel is possible.
**** - drying at the raised temperature (even 50*C) leads to preparation decomposition.
« Last Edit: September 21, 2009, 11:01:12 AM by diodema »
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