Synthesis of Methadone

WillD

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1. Diphenylacetonirile.
Bj7D1wE6VY

1. 1000 g of benzyl cyanide is placed in the flask and heated to 110 *C.
2. 1500 g of bromine is added over of 2 hours with good stirring. The temperature is maintained at 110 *C.
3. After the reaction mixture cooled below 80 *C, added 1000 ml of benzene.
4. In another flask added 3000 ml of benzene and 1200 g of powdered AlCl3, start stirring and heated to refluxing.
5. The Solution of step 3 is added to the boiling mixture of step 4 over of 2 hours in small portions.
6. After, the reaction mixture is refluxed for an additional hour and cooled.
7. Added of 5 kg of crushed ice and 600 ml of concentrated hydrochloric acid.
8. The benzene layer is separated and washed with sodium bicarbonate aq.soln and clear water.
9. The benzene is removed by heating on a steam bath and cooled, сrystallizing a yellow solid.
10. The solid is recrystallized from IPA (1 ml per g) at room temperature without shaking or stirring.
11. The crystals are then collected and washed with chilled isopropyl alcohol.
12. The yield of pure white product 900 g.

2. Dimethylamino-2-propanol.
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1. Propylene oxide (1000 g) and dimethylamine 40% (2600 ml aq. soln.) were added in flask.
2. Stirring at room temperature for 24 hours.
3. Extracted with 1500 ml diethyl ether (or DCM), washing extract with water and dried over anhydrous Na2SO4.
4. The solvent was removed under reduced pressure to give the dimethyaminel-2-propanol in the almost pure form (1500 g).

3. Dimethylamino-2-chloropropane hcl.
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1. 1000 g of dimethylamino-2-propanol and 2000 ml of DCM was cooled with stirring to about ice-water bath.
2. A solution of 1500 g thionyl chloride in 1000 ml DCM was added.
3. Left at room temperature and stirring for an 1 hour, after heated to the reflux another 1 hour. The precipitated material redissolved on heating.
4. Dimethylamino-2-chloropropane hydrochloride began to precipitate from the boiling solution.
5. The reaction mixture was cooled and filtered, washed cold IPA on filter. Yield 1500 g.

4. 4-cyano-2-dimethylamino-4,4-diphenylbutane.
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1. 1200 g of sodium hydroxide, 1500 g diphenylacetonitrile and 1500 g of dimethylamino-2-choropropane hcl were mixed in a flask.
2. Heated with occasional stirring for 6-7 hours, with the temp at 100 *C.
3. The reaction mixture was then extracted with ether and the ether in turn extracted with dilute aq. HCl acid 5%.
4. The acid solution was made strongly alkaline with 25% sodium hydroxide solution, and the liberated base extracted with ether.
5. The ether solution was dried over anhydrous potassium carbonate, filtered and the ether distilled off.
6. The residue was vacuum distilled to give 1700 g of product.
7. It was then recrystallized from petroleum ether to give 900 g of 4-cyano-2-dimethylamino-4,4-diphenylbutane.

5. Ethylmagnesium bromide.
1. 160 g magnesium turnings were placed in a flask.
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2. Add 1200 ml ahydrous tetrahydrofuran and 1 g of iodine crystal.
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3. When heated, bromoethane solution is added dropwise.
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4. After completing the addition, the mixture is heated for some time.
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5. Grignar reagent formation completed. A small amount of magnesium remains in the flask.
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6. Methadone HCl.
1. A solution of 900 g of 4-cyano-2-dimethylamino-4,4-diphenylbutane in 700 ml of hot (65 *C) anhydrous xylene was prepared and was added to a stirred solution of ethyl magnesium bromide.
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2. The mixture thereafter heated under reflux for 3 h.
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3. The condenser was arranged for distillation, and 5000 ml of 10% HCl was added to the mixture, and the organic solvent distilled from the reaction mixture.
4. The residue was then transferred to a beaker and 2000 ml of benzene added, whereupon three layers formed
5. Upon standing, the Methadone hydrochloride, which crystallized from the oily middle layer, was collected and dried to give 960 g.
 
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WillD

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Crystal partially evaporates and dissolves
 

Jack

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For the synthesis of diphenylacetonitrile can the anhydrous Aluminum trichloride be substituted for anhydrous Iron trichloride instead when reacting alpha bromo phenylacetonitrile with benzene.
 

khadiff

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1. Diphenylacetonirile.
View attachment 1719
1. 1000 g of benzyl cyanide is placed in the flask and heated to 110 *C.
2. 1500 g of bromine is added over of 2 hours with good stirring. The temperature is maintained at 110 *C.
3. After the reaction mixture cooled below 80 *C, added 1000 ml of benzene.
4. In another flask added 3000 ml of benzene and 1200 g of powdered AlCl3, start stirring and heated to refluxing.
5. The Solution of step 3 is added to the boiling mixture of step 4 over of 2 hours in small portions.
6. After, the reaction mixture is refluxed for an additional hour and cooled.
7. Added of 5 kg of crushed ice and 600 ml of concentrated hydrochloric acid.
8. The benzene layer is separated and washed with sodium bicarbonate aq.soln and clear water.
9. The benzene is removed by heating on a steam bath and cooled, сrystallizing a yellow solid.
10. The solid is recrystallized from IPA (1 ml per g) at room temperature without shaking or stirring.
11. The crystals are then collected and washed with chilled isopropyl alcohol.
12. The yield of pure white product 900 g.

2. Dimethylamino-2-propanol.
View attachment 1720
1. Propylene oxide (1000 g) and dimethylamine 40% (2600 ml aq. soln.) were added in flask.
2. Stirring at room temperature for 24 hours.
3. Extracted with 1500 ml diethyl ether (or DCM), washing extract with water and dried over anhydrous Na2SO4.
4. The solvent was removed under reduced pressure to give the dimethyaminel-2-propanol in the almost pure form (1500 g).

3. Dimethylamino-2-chloropropane hcl.
View attachment 1721
1. 1000 g of dimethylamino-2-propanol and 2000 ml of DCM was cooled with stirring to about ice-water bath.
2. A solution of 1500 g thionyl chloride in 1000 ml DCM was added.
3. Left at room temperature and stirring for an 1 hour, after heated to the reflux another 1 hour. The precipitated material redissolved on heating.
4. Dimethylamino-2-chloropropane hydrochloride began to precipitate from the boiling solution.
5. The reaction mixture was cooled and filtered, washed cold IPA on filter. Yield 1500 g.

4. 4-cyano-2-dimethylamino-4,4-diphenylbutane.
View attachment 1722
1. 1200 g of sodium hydroxide, 1500 g diphenylacetonitrile and 1500 g of dimethylamino-2-choropropane hcl were mixed in a flask.
2. Heated with occasional stirring for 6-7 hours, with the temp at 100 *C.
3. The reaction mixture was then extracted with ether and the ether in turn extracted with dilute aq. HCl acid 5%.
4. The acid solution was made strongly alkaline with 25% sodium hydroxide solution, and the liberated base extracted with ether.
5. The ether solution was dried over anhydrous potassium carbonate, filtered and the ether distilled off.
6. The residue was vacuum distilled to give 1700 g of product.
7. It was then recrystallized from petroleum ether to give 900 g of 2,2-Diphenyl-3-methyl-4-dimethylambutyronitrile.

5. Ethylmagnesium bromide.
1. 160 g magnesium turnings were placed in a flask.
View attachment 1723
2. Add 1200 ml ahydrous tetrahydrofuran and 1 g of iodine crystal.
View attachment 1724
3. When heated, bromoethane solution is added dropwise.
View attachment 1725
4. After completing the addition, the mixture is heated for some time.
View attachment 1726
5. Grignar reagent formation completed. A small amount of magnesium remains in the flask.
View attachment 1727

6. Methadone hcl.
1. A solution of 900 g of 2,2-Diphenyl-3-methyl-4-dimethylaminobutyronitrile in 700 ml of hot (65 *C) anhydrous xylene was prepared and was added to a stirred solution of ethyl magnesium bromide.
View attachment 1728
2. The mixture thereafter heated under reflux for 3 h.
View attachment 1729
3. The condenser was arranged for distillation, and 5000 ml of 10% HCl was added to the mixture, and the organic solvent distilled from the reaction mixture.
4. The residue was then transferred to a beaker and 2000 ml of benzene added, whereupon three layers formed
5. Upon standing, the Methadone hydrochloride, which crystallized from the oily middle layer, was collected and dried to give 960 g.
William DampierCan you share us with step by steps video please
 

Nikolas

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Hello friends . Do you need a rotary evaporator for the synthesis of methadone? I don't have a rotary evaporator but I have a vacuum pump, can I evaporate the solvents in another way?
 

G.Patton

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Hello friends . Do you need a rotary evaporator for the synthesis of methadone? I don't have a rotary evaporator but I have a vacuum pump, can I evaporate the solvents in another way?
AdelrainmanAlso, you can do it with help of Buchner flask + vacuum and warm water bath.
 

Hank Schrader

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There are a lot of errors in the synthesis here.
You write that you need 2,2-Diphenyl-3-methyl-4-dimethylambutyronitrile,
this is not the correct nitrile isomer and you can obtained from it only isomethadone.

2,2-Diphenyl-3-methyl-4-dimethylamino butyronitrile does not have a crystalline form.
You write: "It was then recrystallized from petroleum ether to give 900 g of 2,2-Diphenyl-3-methyl-4-dimethylambutyronitrile."

Initially, you started correctly,
and said that you need 4-cyano-2-dimethylamino-4,4-diphenylbutane.
4-cyano-2-dimethylamino-4,4-diphenylbutane (Premethadone)
CAS: 125-79-1 is the correct nitrile. Only from it you can get methadone.

In the synthesis of a nitrile, you don't use a solvent...
Also, you don't use a Catalyst, which shifts the reaction in the right direction to increase the yield of the desired nitrile.
You are left with a lot of unreacted precursor, since the deprotonation must be done in the presence of a catalyst.

I'll disappoint you, but you can't get methadone in THF, you can get methadone only through ethyl ether.. The addition reaction does not work in THF.
In your synthesis there is no word about the purification of nitrile, therefore it is dirty and black under the conditions that you describe.
I don't know where you got this synthesis, but you won't get anything good - sorry.
 

adrenochrome

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There are a lot of errors in the synthesis here.
You write that you need 2,2-Diphenyl-3-methyl-4-dimethylambutyronitrile,
this is not the correct nitrile isomer and you can obtained from it only isomethadone.

2,2-Diphenyl-3-methyl-4-dimethylamino butyronitrile does not have a crystalline form.
You write: "It was then recrystallized from petroleum ether to give 900 g of 2,2-Diphenyl-3-methyl-4-dimethylambutyronitrile."

Initially, you started correctly,
and said that you need 4-cyano-2-dimethylamino-4,4-diphenylbutane.
4-cyano-2-dimethylamino-4,4-diphenylbutane (Premethadone)
CAS: 125-79-1 is the correct nitrile. Only from it you can get methadone.

In the synthesis of a nitrile, you don't use a solvent...
Also, you don't use a Catalyst, which shifts the reaction in the right direction to increase the yield of the desired nitrile.
You are left with a lot of unreacted precursor, since the deprotonation must be done in the presence of a catalyst.

I'll disappoint you, but you can't get methadone in THF, you can get methadone only through ethyl ether.. The addition reaction does not work in THF.
In your synthesis there is no word about the purification of nitrile, therefore it is dirty and black under the conditions that you describe.
I don't know where you got this synthesis, but you won't get anything good - sorry.
Hank Schrader1. firstly, he wrote that he received the correct nitrile by recrystallized from petroleum ether (here you can use hexane) 2. Without a solvent, nitrile also comes out, since alkali acts as a catalyst and why does the reaction in tetrahydrofuran not go?) you don’t know how the Grignard reaction adds a substance
 

G.Patton

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2,2-Diphenyl-3-methyl-4-dimethylamino butyronitrile does not have a crystalline form.
You write: "It was then recrystallized from petroleum ether to give 900 g of 2,2-Diphenyl-3-methyl-4-dimethylambutyronitrile."

Initially, you started correctly,
and said that you need 4-cyano-2-dimethylamino-4,4-diphenylbutane.
4-cyano-2-dimethylamino-4,4-diphenylbutane (Premethadone)
CAS: 125-79-1 is the correct nitrile. Only from it you can get methadone.
Hank SchraderHello, you are right, I fixed this mistake. Thank you for notice!

In the synthesis of a nitrile, you don't use a solvent...
Also, you don't use a Catalyst, which shifts the reaction in the right direction to increase the yield of the desired nitrile.
You are left with a lot of unreacted precursor, since the deprotonation must be done in the presence of a catalyst.

I'll disappoint you, but you can't get methadone in THF, you can get methadone only through ethyl ether.. The addition reaction does not work in THF.
In your synthesis there is no word about the purification of nitrile, therefore it is dirty and black under the conditions that you describe.
I don't know where you got this synthesis, but you won't get anything good - sorry.
You can share us correct way here, we would like to see and discuss it. In general, I am agree that 4-cyano-2-dimethylamino-4,4-diphenylbutane have to be recrystallized before Grignard reaction.
 

reza

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Hello, chemist friends. I have a question, thank you for your help. We know methadone with the formula c21h27no, which is the result of synthesis, but methadone 10 and 20 mg tablets are introduced as methadone hydrochloride, that is, this formula is c21h28clno. Why and how to make methadone hydrochloride c21h27no + hcl = c21h28clno in the laboratory
 

G.Patton

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Why and how to make methadone hydrochloride c21h27no + hcl = c21h28clno in the laboratory
rezaIt is done in order to make methadone water soluble. Hydrochloride salt can be consumed by human body.
3. The condenser was arranged for distillation, and 5000 ml of 10% HCl was added to the mixture, and the organic solvent distilled from the reaction mixture.
4. The residue was then transferred to a beaker and 2000 ml of benzene added, whereupon three layers formed
5. Upon standing, the Methadone hydrochloride, which crystallized from the oily middle layer, was collected and dried to give 960 g.
this is the way
 

reza

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Thank you for the explanation
 

reza

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After going through the steps of synthesis, when we reach methadone hydrochloride, what tests should be done to confirm the synthesis? Or in other words, it refers to the substances produced by methadone and can be consumed
 

reza

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After going through the steps of synthesis, when we reach methadone hydrochloride, what tests should be done to confirm the synthesis? Or in other words, it refers to the substances produced by methadone and can be consumed
rezaIs this methadone converted to tablet formulation? How to know the quality of synthesized methadone?

NeIuZdCg8R
 

JustFuckMyShitUpFam

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Jesus, this is almost like trying to read Chinese to me. You guys are extremely admirable with your knowledge and dedication.

I wonder if some members actually do these synthesise themselves and have a huge stack of methadone laying around 😅

If so, hit me up and I will gladly help you get rid of it! 😋
 

reza

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Hello, chemist friends, good time: I am studying different methods of methadone synthesis and methadone precursors. The methods and tips mentioned for the synthesis in the articles are ambiguous for me. I will share with you and thank you for your guidance. First, a method for the synthesis of 1-dimethylamino-2-chloropropane:

Synthesis of 1-dimethylamino-2-chloropropane

2.25 milliliters of 1-dimethylamino-2-propanol together with 5 milliliters of chloroform solvent inside the double-necked flask
Put it under argon gas and put the system in an ice bath until the temperature reaches zero degrees Celsius And
Then dilute 2 ml of thionyl chloride with 1 ml of chloroform and then Then enter the system drop by drop with a Pasteur pipette They add and placed at room temperature for 30 minutes During this time, the liquid inside the balloon It is precipitated and and heated again for 30 minutes at a temperature of 61 degrees Celsius when the sediment is liquid and in
During boiling, SO2 and HCl gas is released. And then they continue heating until the substance inside the balloon form sediment again The precipitate formed is 1-dimethylamino-2-chloropropane hydrochloride . Then
Washed several times with ether to remove impurities and then with crystallized ethanol that has a melting point It is 191 degrees Celsius And then they poured water on the crystal to dissolve it completely. and then 20% NaOH added to it, that the desired substance is insoluble in NaOH and becomes two-phase,
that phase
It is above the desired material
which was dissolved in ether and separated by a decanter funnel
and then to ethereal solution NaSO4 is added
And after extraction with solvent, the raw material is obtained as an oil.

At the beginning of the mentioned reaction, 1-dimethylamino-2-propanol was placed in an ice bath with chloroform under argon until its temperature reached zero, and according to the instructions, a two-mouthed flask was used: I think one mouth is closed with a septum. And a balloon filled with argon gas is installed on the septum with the help of a syringe and a refrigerant or condenser is installed in the other opening? I mean, what is installed in these two openings of the reaction flask so that the reaction can be implemented?
I am having trouble setting up this system. Can you guide me to make the right choice and set up this system so that I can understand how to do the reaction steps.. Thank you My next question is that it is explained in the reaction protocol that thionyl chloride and chloroform are added to the reaction mixture with the help of a Pasteur pipette. Should we have a dropping funnel installed on the flask to add Pasteur with a pipette?

I think that in order to use the Pasteur pipette, we need to open the lid of the flask to destroy the atmosphere created by the argon? Isn't the existence of orgone important? please guide me . Thankful
 
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