Author Topic: Looking for help with methadone synthesis  (Read 4967 times)

0 Members and 1 Guest are viewing this topic.

Toltechie

  • Guest
Looking for help with methadone synthesis
« on: February 10, 2003, 12:12:00 PM »
After lurking around here & Rhodium's site for a few years, slowly & patiently gathering knowledge (so much farther to go), equipment & chems swim is ready to try the methadone synthesis Rhodium worked so hard on. A few questions first; In the "Introduction" of the write up it states that 2,2-diphenyl-4-dimethylaminovaleronitrile, the high-melting "methadone nitrile" is the desired product while the low melting "isomethadone nitrile" 2,2-diphenyl-3-methyl-4-dimethylaminobutyronitrile is not desired. But the low melting 2,2-diphenyl-3-methyl-4-dimethylaminobutyronitrile headlines the first section on the preparation & isolation of the desired isomer and it is listed in each of the 3 methods outlined for preparing methadone. Swim wants to clear this up so to find out the formula of the desired nitrile to figure out the molecular weight. Swim is hoping to be able to either scale up the nitrile preparation reaction or scale down the methadone preparation. Swim is hoping to avoid doing 10 nitrile preparations in order to have enough of the desired isomer to move onto the methadone preparation. Swim has not been able to find the formula or molecular weights of either of the nitriles named. Swim has tried chemfinder, sigma-aldritch, infomine, an old Merck, TFSE and various internet search engines ie. google etc... If anyone can share with us the formula and the molecular weight for the desired nitrile and what the desired nitrile is or better yet where to find the formula & mol weight it would be greatly appreciated. I do not have ready access to a college library to look up the references. After swim gets that info swim is planning to post the math for review before experimenting on changing the scale of reactants. After that swim will of course "share" the results, rather the information, on what happens or what doesn't happen. Thank you.

Rhodium

  • Guest
Methadone nitriles
« Reply #1 on: February 10, 2003, 03:13:00 PM »
The structural formulas for the nitriles are drawn in the document, and their molecular weights are identical, as they are isomers. The exact molecular weight can be had by counting the atoms and multiply with their respective atomic weights. If that is too complicated, you can make use of the calculator at

https://www.the-hive.ws/forum/pt.pl?Cat=&Showtools=1&HidePt=1



You can either scale the precursor preparation up or the methadone synthesis down depending on how much product you aim for.

If I have made a mistake in the introduction part, I'll fix that.

Toltechie

  • Guest
Thank you
« Reply #2 on: February 11, 2003, 04:04:00 AM »
Chieftain, Thank you for your quick reply. Swim is still learning how to decipher chemical sturctures, though as swim asked you pointed swim in the right direction. Swim can not thank you enough for all your hard work with the methadone write up. For a little more than 1 month's fee at a maintenance clinic swim purchased enough of the two precursors to make a few years worth of product and now can tame the brown sugar habit. Thanks again.

hypo

  • Guest
in all honesty
« Reply #3 on: February 11, 2003, 04:17:00 AM »
if you are talking about the methadone synthesis:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/methadone.html



including the synthesis of all precursors, and this is
your first attempt at organic chemistry, then consider
to start with a much simpler syntheses.

most of the reagents in this synthesis could be invested into
simpler / more worthwhile compounds.

for example mandelonitrile can be turned into speed in three steps.
if you want to handle metal organyls, look into phencyclidines.
if you want an opiate, how about exctracting / acetylating morphine?
etc, etc...

Toltechie

  • Guest
I want a safety net
« Reply #4 on: February 11, 2003, 06:34:00 AM »
Before acetylating morphine swim wants to have something to help control the monkey. Swim already has the 2 main precursors in reagent grade for methadone. It is amazing what you can find if you look. As for the mol weight of the nitrile swim believes it is 278.40.

hypo

  • Guest
[OT] wow
« Reply #5 on: February 11, 2003, 07:08:00 AM »
so you plan to make heroin, indeed so much of it as to get physically
and mentally addicted to it, so before you even start making h, you make
methadone, which will help you through the turkey. sounds strange to me,
but why not!  :P

(what about making h and trading for methadone?)

Rhodium

  • Guest
Toltech: You got the molecular weight right.
« Reply #6 on: February 11, 2003, 05:05:00 PM »
Toltech: You got the molecular weight right.

apy

  • Guest
A Word On Addiction
« Reply #7 on: February 12, 2003, 04:09:00 PM »
I obviously cannot be certian how serious you are about making H/Methadone but I would suggest if you plan on getting addicted to H then maybe you should not start.  According to Boroughs (sp) it takes about a month of straight H to get really addicted, and I wouldn't rely on the methadone to save you.

Just something to keep in mind.

Toltechie

  • Guest
I appreciate the concern
« Reply #8 on: February 13, 2003, 04:34:00 AM »
I appreciate the concern. Swim is not going to synth something up in order to become an addict. Swim already enjoys the "junk". Swim wants to take a break from swim's "brown sugar baby" habit but does not want to get dope-sick ever again or pay the ridiculous cost of methadone maintenance. Anyway this thread was started asking for help on this procedure.

Toltechie

  • Guest
How to figure how to scale-up/down the reactants?
« Reply #9 on: February 13, 2003, 12:24:00 PM »
If I should enter this in another thread please let me know. I am now trying to learn about  stoichiometry,writing and balancing equations, determining limiting reagents, and the math to do this on my own. Progress is slow but I am learning. Anyway while preparing to write out and balance the equation for method 1 of the nitrile synth in

https://www.thevespiary.org/rhodium/Rhodium/chemistry/methadone.html

it is stated that 4.1 grams of 1-dimethylamino-2-chloropropane is 0.034 mol, but my calculations suggest that 4.1 grams is .026 mol. I "found" the molecular weight of the mentioned compound to be 158.07 using C5H13Cl2N as the formula. I am interested in scaling up the nitrile synthesis or scaling down the methadone synthesis but I am not sure how to proceed.  For example if the write-up now lists: "A suspension of 1.36g (0.034 mol) of finely ground sodium hydroxide was prepared in 10 ml of dried DMF. A solution containing 6.0g (0.031 mol) of diphenylacetonitrile in 8 ml of DMF was added thereto at room temperature. After stirring the mixture for 15 minutes, 5.37g (0.034 mol) of 1-dimethylamino-2-chloropropane were added. The reaction mixture was heated with stirring to about 50°C for about 1.5 hours and was then cooled.........etc..."
Can I move the decimal point in the mol calculations one place in the same direction for each compound? So the above mentioned example would then read; "A suspension of 13.59g (0.34 mol) of finely ground sodium hydroxide was prepared in 10 ml of dried DMF. A solution containing 59.9g (0.31 mol) of diphenylacetonitrile in 8 ml of DMF was added thereto at room temperature. After stirring the mixture for 15 minutes, 53.74g (0.34 mol) of 1-dimethylamino-2-chloropropane were added. The reaction mixture was heated with stirring to about 50°C for about 1.5 hours and was then cooled.........etc..." Would this keep the ratios similar. Also how do I determine by how much to change the quantity of solvents used? All replies welcome. Please view the write-up at

https://www.thevespiary.org/rhodium/Rhodium/chemistry/methadone.html

If someone were motivated enough to give the quantities of everything for a scale-up or scale-down please include the equations, formulas, theories, etc... so swim can follow along. I honestly want to learn how to do this for myself I just need a tutor right now. Thank you.

Rhodium

  • Guest
1-dimethylamino-2-chloropropane
« Reply #10 on: February 13, 2003, 02:44:00 PM »
1-dimethylamino-2-chloropropane is C5H12ClN with a mw of 121.61 - you have a chlorine atom too much. If you look at the structures on my page, you see that the "2" signifies the placement of the chlorine atom, not that it would be two of them.

Can I move the decimal point in the mol calculations one place in the same direction for each compound?

Yes, to scale up or down, just multiply every weight and volume (both reactants and solvents) with 10 or 0.1 depending on if you want to scale up or down. Temperatures and reaction times stays the same. If scaling up 10x, perhaps you could cut back on the solvents with 25% or so, and if you scale down, use 25% more than calculated.

Toltechie

  • Guest
Thank you Chieftain
« Reply #11 on: February 14, 2003, 01:12:00 PM »
Chieftain, Thank you so very much for your help! From your website to the writeup;

https://www.thevespiary.org/rhodium/Rhodium/chemistry/methadone.html

to just so generously sharing your knowledge.

Toltechie

  • Guest
Help please, another question about this procedure
« Reply #12 on: April 08, 2003, 04:07:00 AM »
I believe I have made a mistake and overlooked a very important item. Swim was only able to aquire 1-dimethylamino-2-chloropropane hydrochloride which I now realize has a mol weight of 158. If I am now correct what needs to happen is that this hydrochloride needs to bee turned into the freebase form for this procedure to work;

https://www.thevespiary.org/rhodium/Rhodium/chemistry/methadone.html

. I realized my oversight after trying to separate the nitriles from hexane and recovering almost everything upon cooling the solvent instead of the noted 50% desired high-melting nitrile. Am I now correct? Is this the proper and/or easiest method for turning this hydrochloride into it's freebase form "30g of 1-dimethylamino-2-chloropropane hydrochloride was dissolved in 40-50ml water and made strongly basic with 20% sodium hydroxide solution. The chloroamine layer was separated, dried over solid potassium hydroxide and vacuum distilled under a weak vacuum, bp 62-63°C/100-110mmHg. Yield 19g (82%)."? Please help when you have time. Thank you. T-

Rhodium

  • Guest
methadone precursors
« Reply #13 on: April 08, 2003, 02:06:00 PM »
Correct, you need to use the freebase in the procedure, or use the solventless version where twice the amount of NaOH is used.

The listed method is definitely the easiest way to produce clean freebase, it might also work without the final distillation, if the freebase is not colored after drying it over some NaOH pellets until it's not cloudy anymore.

Toltechie

  • Guest
Thank you!
« Reply #14 on: April 09, 2003, 03:57:00 AM »
Thank you for your help! Swim will write again.

Toltechie

  • Guest
Failure so far
« Reply #15 on: April 14, 2003, 05:30:00 AM »
Swim was able to make the freebase of 1-dimethylamino-2-chloropropane. It stayed an oil with a seeming emulsion below it after separating it from the NaOH mix. Swim tried extracting with anhydrous ethyl ether but did not realize the low boiling point of the freebase until the dish was all but empty. So swim "created" the freebase again & used the oil. Heating & cooling in hexane left about half of what was put in so I assumed it worked though I do not have melting point equipment. Swim also failed to research Grignard reactions & tried the 2nd method for methadone listed in 

https://www.thevespiary.org/rhodium/Rhodium/chemistry/methadone.html

in a very humid environment & forgot the drying tubes. Live & learn! What should one expect to witness when a Grignard reaction takes place, I mean in this case when the magnesium is mixed with the ethyl bromide in anhydrous ether? Any suggestions for kick starting the reaction? I have read in other Grignards that a very small piece of I2 can help start things going. Would that bee effective in this case? Swim is going to try the solventless method for forming the nitriles when time permits so the hydrochloride of 1-dimethylamino-2-chloropropane can bee used. Thank God I was able to aquire pharm methadone & have ended the brown sugar nightmare for now so I do not have the pressing need to rush things along. But my interest in chemistry continues & I want to say I successfully completed this project. Thank you in advance for your help.

Rhodium

  • Guest
Almost all grignards look the same when ...
« Reply #16 on: April 15, 2003, 05:41:00 AM »
Almost all grignards look the same when initiated - they heat up and the magnesium begins to be consumed. UTFSE on "grignard initiation".

murmur

  • Guest
Synthesis of methadone
« Reply #17 on: April 17, 2003, 04:23:00 AM »
1. For preparing of nitrile try to make PTC reaction like in

Patent US4242274

. In this method you can use hydrochloride of 1-dimethylamino-2-chloro-propane. It's very simple method. For separation of isomeric nitriles see

Patent US2540636

with 91% IPA. You'll get very pure methadone nitrile. For Grignard the best method (high-yielding) is Method 1 from Rhodium's site.
2. How to make Grignard reagent?
1 step. Dry your Mg thoroughly.
2 step. Place Mg in flask, add 2-3 crystals of I2 and heat up the flask until vapours of iodine appear.
3. Cool the flask to room temp.
4. Pour ether in the flask, add approx. 1/10 of EtBr needed and wait the beginning of reaction. If rxn doesn't begin, slightly heat up the flask
5. After rxn has begun, add EtBr dropwise. Ether must slightly boils
That's all.
Good luck

Toltechie

  • Guest
Thank you
« Reply #18 on: April 17, 2003, 11:56:00 AM »
I'll report back when time permits.

Toltechie

  • Guest
Trouble crystallizing crude product
« Reply #19 on: May 01, 2003, 12:55:00 PM »
Swim ran the grignard sucessfully with I2, thanks Murmur, & using method 1 for methadone in 

https://www.thevespiary.org/rhodium/Rhodium/chemistry/methadone.html

ran the reflux at specified temp & for specified time. After adding the 18% HCL the remaining solvent came over & the suspension was drawn off, it was not very hot at this time though, I did save it just in case . After cooling the acid solutions the crude methadone hydrochloride did not crystalize. I have no seed crystals to use, I tried scratching with a glass rod & I put it in the fridge for a little while to really cool it down. I scaled down all reactants throughout the entire procedure 1 decimal place to the left, though I did not change the quantity or percentage of the HCL. Could the solution be too acidic for the crude product to crystallize? If so what ph should I strive for & which base would suffice? I only reduced the solvent levels by around 25%. All chems are lab grade. Any help welcome.