Synthesis of Methadone
- Thread starter William D.
- Start date
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.
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.
- By adrenochrome
1. 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
- By sossss123
Hi, I have a few questions.
You say that the beginning is ok, where he produces diphenylacetonitrile. And later you say that we need to purify the nitrille, are you talking about the same nitrille or about the other precursor 4-cyano-2-dimethylamino-4,4-diphenylbutane.
Later you say that you can not get Methadone with THF only ether, are you talking about the Grinier reagent, or the next step where he wrote that uses anhidrous xylen. In fact the last step looks a bit unclear for me, is it possible to give me pointers for that reactions... if possible.
Thank you in advance.
You say that the beginning is ok, where he produces diphenylacetonitrile. And later you say that we need to purify the nitrille, are you talking about the same nitrille or about the other precursor 4-cyano-2-dimethylamino-4,4-diphenylbutane.
Later you say that you can not get Methadone with THF only ether, are you talking about the Grinier reagent, or the next step where he wrote that uses anhidrous xylen. In fact the last step looks a bit unclear for me, is it possible to give me pointers for that reactions... if possible.
Thank you in advance.
We produced methadone in different ways.
Methadone bases are not suitable for consumption!
The base has a beautiful crystal shape, but if you inject it into yourself... you can die, it crystallizes right into you.
You need to use only hydrochloride salt and well purified!
Trust me, I have been producing methadone since 2006!
Methadone bases are not suitable for consumption!
The base has a beautiful crystal shape, but if you inject it into yourself... you can die, it crystallizes right into you.
You need to use only hydrochloride salt and well purified!
Trust me, I have been producing methadone since 2006!
↑View previous replies…
- By biogenpharma
so upon seperation of the nitriles, understandable that the vale nitrile is the wanted methadone and the butyonitrile isomethadone is unwanted.
say for instances this 60g (1.5 moles) of flake sodium hydroxide, 77.2g (0.4 moles) diphenylacetonitrile and 79g (0.5 moles) of 1-dimethylamino-2-choropropane hydrochloride were mixed in an erlenmeyer flask and heated with occasional stirring for 6-7 hours on a steam bath [or an oil bath with the temp at 100°C]. The reaction mixture was then extracted with ether and the ether in turn extracted ith dilute hydrochloric acid [~5% HCl(aq)]. The acid solution was made strongly alkaline with 25% sodium hydroxide solution, and the liberated base extracted with ether. The ether solution was dried over anhydrous potassium carbonate, filtered and the ether distilled off. The residue was vacuum distilled to give 89g of product, boiling at 173-174°C at 1 mmHg. It was then recrystallized from petroleum ether to give 49g (45.7%) of 2,2-Diphenyl-3-methyl-4-dimethylaminobutyronitrile, mp 89-90°C.
way was used, which leads to the isomethadone nitrile, then we follow up with the EMB-DE reflux , distill etc.. is the nitrile being seperated with this process with the following step , also have seen a few methods that employ the EMB in THF, that have said be successful. such as, but if it is not possible, can you briefly state as to why it would not.
A solution of 0.5 g of 2,2-diphenyl-4-dimethylaminovaleronitrile isomer has reacted in a certain amount of DESs and in another system 0.5 g of magnesium and in 8 ml of THF dry, react one hour, then 1.5 ml ethyl bromide was added by syringe glass which, during the addition the reaction starts to rise in temperature and boils, which indicates the formation of ethylene-magnesium bromide which ethyl magnesium bromide solution in dry THF
say for instances this 60g (1.5 moles) of flake sodium hydroxide, 77.2g (0.4 moles) diphenylacetonitrile and 79g (0.5 moles) of 1-dimethylamino-2-choropropane hydrochloride were mixed in an erlenmeyer flask and heated with occasional stirring for 6-7 hours on a steam bath [or an oil bath with the temp at 100°C]. The reaction mixture was then extracted with ether and the ether in turn extracted ith dilute hydrochloric acid [~5% HCl(aq)]. The acid solution was made strongly alkaline with 25% sodium hydroxide solution, and the liberated base extracted with ether. The ether solution was dried over anhydrous potassium carbonate, filtered and the ether distilled off. The residue was vacuum distilled to give 89g of product, boiling at 173-174°C at 1 mmHg. It was then recrystallized from petroleum ether to give 49g (45.7%) of 2,2-Diphenyl-3-methyl-4-dimethylaminobutyronitrile, mp 89-90°C.
way was used, which leads to the isomethadone nitrile, then we follow up with the EMB-DE reflux , distill etc.. is the nitrile being seperated with this process with the following step , also have seen a few methods that employ the EMB in THF, that have said be successful. such as, but if it is not possible, can you briefly state as to why it would not.
A solution of 0.5 g of 2,2-diphenyl-4-dimethylaminovaleronitrile isomer has reacted in a certain amount of DESs and in another system 0.5 g of magnesium and in 8 ml of THF dry, react one hour, then 1.5 ml ethyl bromide was added by syringe glass which, during the addition the reaction starts to rise in temperature and boils, which indicates the formation of ethylene-magnesium bromide which ethyl magnesium bromide solution in dry THF
@Hank Schrader is absolutely right on most points.
However, it is actually possible to produce the methadone precursor without a solvent through a reaction of diphenylacetonitrile,
dimethylamino-2-chloropropane HCl and sodium hydroxide. The reaction partners involved should be ground very finely and
mixed well. After the reaction has taken place, extraction can be carried out with diethyl ethe
What seems very strange to me, however, is the ethylmagenesium bromide. I have already prepared EMB countless times (for methadone
synthesis, but also for other syntheses). EMB does not have a yellowish color and is not a clear reagent. EMB that I have made so far always
had a brown-grey color and had always a slight cloudiness.
to THF: All I can say is that I have never used THF to make EMB. Therefore I can't say whether methadone synthesis is possible with it (it is
definitely usable for Grignard). I don't use it as a Grignard solvent because it has unlimited miscibility with H2O.
You were also right about the name of the methadone precursor. The correct IUPAC name is (4S)-4-(dimethylamino)-2,2-diphenylpentanenitrile.
(3S)-4-(dimethylamino)-3-methyl-2,2-diphenylbutanenitrile is the IUPAC name for the Isomethadone precursor.
and here is Levomathadone & Dexromethadone
However, it is actually possible to produce the methadone precursor without a solvent through a reaction of diphenylacetonitrile,
dimethylamino-2-chloropropane HCl and sodium hydroxide. The reaction partners involved should be ground very finely and
mixed well. After the reaction has taken place, extraction can be carried out with diethyl ethe
What seems very strange to me, however, is the ethylmagenesium bromide. I have already prepared EMB countless times (for methadone
synthesis, but also for other syntheses). EMB does not have a yellowish color and is not a clear reagent. EMB that I have made so far always
had a brown-grey color and had always a slight cloudiness.
to THF: All I can say is that I have never used THF to make EMB. Therefore I can't say whether methadone synthesis is possible with it (it is
definitely usable for Grignard). I don't use it as a Grignard solvent because it has unlimited miscibility with H2O.
You were also right about the name of the methadone precursor. The correct IUPAC name is (4S)-4-(dimethylamino)-2,2-diphenylpentanenitrile.
(3S)-4-(dimethylamino)-3-methyl-2,2-diphenylbutanenitrile is the IUPAC name for the Isomethadone precursor.
and here is Levomathadone & Dexromethadone
Last edited:
what about path with 1,1-diphenylbutane-2-sulfonic acid as precursor?
It is not profitable for China to sell and synthesize such a substance, and you will not be able to cope - this requires significant investments.
ok, I will publish my synthesis here for revision and advice.
step 4 changed: diphenylacetonitrile (50 g), 1-dimethylamino-2-chloropropane hydrochloride (50 g)(think can use any 1-dimethylamino-2-halopropane), 50% sodium hydroxide solution (80 g), water (40 ml), toluene (125 ml) and tetrabutylammonium bromide (5g) boiled under reflux for 2 hours. Then I separated the aminonitriles. The yield was 30 grams, the melting point was 90.
step 4 changed: diphenylacetonitrile (50 g), 1-dimethylamino-2-chloropropane hydrochloride (50 g)(think can use any 1-dimethylamino-2-halopropane), 50% sodium hydroxide solution (80 g), water (40 ml), toluene (125 ml) and tetrabutylammonium bromide (5g) boiled under reflux for 2 hours. Then I separated the aminonitriles. The yield was 30 grams, the melting point was 90.
Again update stage4: no more solvent needed (btw DMSO, DMF work. Acetone and ethyl acetate does not work) as in the original step, I add a catalyst and the reaction is completed in two hours at a temperature of 75 C. After that I wash with water and do the separation of nitriles-no ABC, just wash with petrol. Of course I optimize for myself, I don’t have an evaporator or equipment. Besides, I don’t want to work with toluene and benzene.