# Methylphenidate (Ritalin) synthesis



## G.Patton

*Introduction


*​Methylphenidate (Ritalin; Concerta) synthesis method can be learned in this topic. It is the simplest way to produce this substance which isn't taking any elaborated glassware, equipment and special conditions such as high pressure, inert atmosphere or extremely low or high temperatures. The hardest problem of this synthesis is rare precursors such as 1-Phenyl-2-(piperidin-1-yl)ethanone-1,2-dione. Nevertheless, you can buy them in special stores.

Four isomers of methylphenidate are possible, since the molecule has two chiral centers. One pair of threo isomers and one pair of erythro are distinguished, from which primarily d-threo-methylphenidate exhibits the pharmacologically desired effects. The erythro diastereomers are pressor amines, a property not shared with the threo diastereomers. When the drug was first introduced, it was sold as a 4:1 mixture of erythro:threo diastereomers, but it was later reformulated to contain only the threo diastereomers. "TMP" refers to a threo product that does not contain any erythro diastereomers, i.e. (±)-threo-methylphenidate. Since the threo isomers are energetically favored, it is easy to epimerize out any of the undesired erythro isomers. The drug that contains only dextrorotatory methylphenidate is sometimes called d-TMP, although this name is only rarely used, and it is much more commonly referred to as dexmethylphenidate, d-MPH, or d-threo-methylphenidate.​*Equipment and glassware:*​
Three necked round bottom flask;
Magnetic stirrer;
Retort stand and clamp for securing apparatus;
Laboratory scale;
Buchner flask and funnel (or small Schott filter);
Rotary evaporator;
Vacuum source;
Beakers;
Glass rod;
Ice water bath;
HCl dry gas apparatus;
Reflux condenser;
TLC kit (optional);
Separatory funnel;
Conventional funnel;
Filter paper;
Flash chromatography kit;
Laboratory grade thermometer (-10 °C to 50 °C) with flask adapter;
Drip funnel;
Erlenmeyer flasks.
*Reagents:*​
1-Phenyl-2-(piperidin-1-yl)ethane-1,2-dione;
p-Toluenesulfonhydrazide;
Hydrochlorica acid gas (HCl) anhydrous;
Diethyl ether (Et2O);
Ethanol (EtOH);
Toluene;
Potassium tert-butoxide;
Tert butanol;
Distilled water (H2O);
Sodium chloride (NaCl);
Ethyl acetate (EtOAc);
Magnesium sulphate (MgSO4);
Methanol (MeOH).



_Methylphenidate hydrochloride [Methyl phenyl(piperidin-2-yl)acetate hydrochloride]_
Boiling Point: 327.6 °C at 760 mm Hg;
Melting Point: 224-226 °C;
Molecular Weight: 269.767 g/mol;
Density: 1.1±0.1 g/mL (20 °C);
CAS Number: 298-59-9.
*Procedures*​*Step 1:* To a solution of 1-phenyl-2-(piperidin-1-yl)ethane-1,2-dione *(1)* in dimethoxyethane was added p-toluenesulfonhydrazide *(2)* (1.1 equivalent) at room temperature. This solution was cooled to 0 °C and anhydrous HCl gas bubbled through the solution for 30 seconds. The reaction mixture was gently refluxed for 3-12 hours with reflux condenser (as determined by monitoring by TLC). The solution was cooled first to room temperature at which point a precipitate formed and then further cooled to 0 °C. Diethyl ether was added to induce more crystallization. The precipitate was collected by filtration, washed with cold ether, and subsequently allowed to air dry to give pure tosylhydrazone *(3)*. The tosylhydrazone was recrystallized in ether:ethanol (3:1) to give needle like crystals of *(3)* (80%): Melting point: 191 °C.​

​*Step 2: *To a solution of tosylhydrazone *(3)* in toluene was added a 1 M solution of potassium tert-butoxide in tertbutanol (1.1 equiv.) dropwise at room temperature. The mixture was heated to reflux and monitored by both thin layer chromatography (TLC) and by the color of the reaction mixture. The originally yellow solution turns bright orange as the diazo compound is formed. After 30 minutes of reflux, the solution returns to a yellow color and TLC showed no starting material. The reaction mixture is washed with water (2 times) and then washed with brine. The aqueous portions are combined and extracted with ethyl acetate. The organic extracts were combined, dried over MgSO4 filtered, and evaporated. The resulting oil or semi-solid was purified by flash column chromatography. Further purification by recrystallization from ether yielded a single diastereomer as white crystals of *(4)* (60%; threo:erythro 6:1): Melting point: 87 °C.​

​*Step 3: *To a solution of B-lactam *(4)* in MeOH at 0 °C, anhydrous HCl gas was gently bubbled through the solution for approximately five minutes. The reaction mixture was allowed to stir at room temperature for 1-5 hours (until all starting material was gone by TLC). The solvent was evaporated, and the resultant solid was triturated with ether. The offwhite solid was collected by filtration and washed with ether to give an amine salt. This was recrystallized in MeOH ether to give white crystals of *(5)* (86%); melting point: 206 °C.​

​


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## BakingBad

Very interesting topic.
Do you know a way to synthesize

1-Phenyl-2-(piperidin-1-yl)ethanone-1,2-dione; (ethane instead of ethanone?)


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## G.Patton

BakingBad said:


> ethane instead of ethanone?



BakingBadYes, thank you for note!


BakingBad said:


> Do you know a way to synthesize


*1-(phenylglyoxylyl)piperidine*
Methyl phenylglyoxylate (12.5 kg, 76.1 mol, 1 eq) was added dropwise to a stirred mixture of piperidine (19.45 kg, 228 mol, 3 eq) and methanol (5.0 L) for 3.5 h to maintain the temperature at 45-55 °C). The mixture was stirred at the same temperature for 30 min and kept overnight at +4 °C. The precipitated solid was filtered off, washed on the filter with cold methanol (5 L) and dried under reduced pressure to a constant weight to give 15.90 kg (yield 96%) of 1-(phenylglyoxylyl)piperidine with 99.9% purity by GC.​

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## ossi

G.Patton said:


> *IntroductionView attachment 3792*​Methylphenidate (Ritalin; Concerta) synthesis method can be learned in this topic. It is the simplest way to produce this substance which isn't taking any elaborated glassware, equipment and special conditions such as high pressure, inert atmosphere or extremely low or high temperatures. The hardest problem of this synthesis is rare precursors such as 1-Phenyl-2-(piperidin-1-yl)ethanone-1,2-dione. Nevertheless, you can buy them in special stores.
> 
> Four isomers of methylphenidate are possible, since the molecule has two chiral centers. One pair of threo isomers and one pair of erythro are distinguished, from which primarily d-threo-methylphenidate exhibits the pharmacologically desired effects. The erythro diastereomers are pressor amines, a property not shared with the threo diastereomers. When the drug was first introduced, it was sold as a 4:1 mixture of erythro:threo diastereomers, but it was later reformulated to contain only the threo diastereomers. "TMP" refers to a threo product that does not contain any erythro diastereomers, i.e. (±)-threo-methylphenidate. Since the threo isomers are energetically favored, it is easy to epimerize out any of the undesired erythro isomers. The drug that contains only dextrorotatory methylphenidate is sometimes called d-TMP, although this name is only rarely used, and it is much more commonly referred to as dexmethylphenidate, d-MPH, or d-threo-methylphenidate.​*Equipment and glassware:*​
> Three necked round bottom flask;
> Magnetic stirrer;
> Retort stand and clamp for securing apparatus;
> Laboratory scale;
> Buchner flask and funnel (or small Schott filter);
> Rotary evaporator;
> Vacuum source;
> Beakers;
> Glass rod;
> Ice water bath;
> HCl dry gas apparatus;
> Reflux condenser;
> TLC kit (optional);
> Separatory funnel;
> Conventional funnel;
> Filter paper;
> Flash chromatography kit;
> Laboratory grade thermometer (-10 °C to 50 °C) with flask adapter;
> Drip funnel;
> Erlenmeyer flasks.
> *Reagents:*​
> 1-Phenyl-2-(piperidin-1-yl)ethane-1,2-dione;
> p-Toluenesulfonhydrazide;
> Hydrochlorica acid gas (HCl) anhydrous;
> Diethyl ether (Et2O);
> Ethanol (EtOH);
> Toluene;
> Potassium tert-butoxide;
> Tert butanol;
> Distilled water (H2O);
> Sodium chloride (NaCl);
> Ethyl acetate (EtOAc);
> Magnesium sulphate (MgSO4);
> Methanol (MeOH).
> View attachment 3788
> _Methylphenidate hydrochloride [Methyl phenyl(piperidin-2-yl)acetate hydrochloride]_
> Boiling Point: 327.6 °C at 760 mm Hg;
> Melting Point: 224-226 °C;
> Molecular Weight: 269.767 g/mol;
> Density: 1.1±0.1 g/mL (20 °C);
> CAS Number: 298-59-9.
> *Procedures*​*Step 1:* To a solution of 1-phenyl-2-(piperidin-1-yl)ethane-1,2-dione *(1)* in dimethoxyethane was added p-toluenesulfonhydrazide *(2)* (1.1 equivalent) at room temperature. This solution was cooled to 0 °C and anhydrous HCl gas bubbled through the solution for 30 seconds. The reaction mixture was gently refluxed for 3-12 hours with reflux condenser (as determined by monitoring by TLC). The solution was cooled first to room temperature at which point a precipitate formed and then further cooled to 0 °C. Diethyl ether was added to induce more crystallization. The precipitate was collected by filtration, washed with cold ether, and subsequently allowed to air dry to give pure tosylhydrazone *(3)*. The tosylhydrazone was recrystallized in ether:ethanol (3:1) to give needle like crystals of *(3)* (80%): Melting point: 191 °C.​View attachment 3789​*Step 2: *To a solution of tosylhydrazone *(3)* in toluene was added a 1 M solution of potassium tert-butoxide in tertbutanol (1.1 equiv.) dropwise at room temperature. The mixture was heated to reflux and monitored by both thin layer chromatography (TLC) and by the color of the reaction mixture. The originally yellow solution turns bright orange as the diazo compound is formed. After 30 minutes of reflux, the solution returns to a yellow color and TLC showed no starting material. The reaction mixture is washed with water (2 times) and then washed with brine. The aqueous portions are combined and extracted with ethyl acetate. The organic extracts were combined, dried over MgSO4 filtered, and evaporated. The resulting oil or semi-solid was purified by flash column chromatography. Further purification by recrystallization from ether yielded a single diastereomer as white crystals of *(4)* (60%; threo:erythro 6:1): Melting point: 87 °C.​View attachment 3790​*Step 3: *To a solution of B-lactam *(4)* in MeOH at 0 °C, anhydrous HCl gas was gently bubbled through the solution for approximately five minutes. The reaction mixture was allowed to stir at room temperature for 1-5 hours (until all starting material was gone by TLC). The solvent was evaporated, and the resultant solid was triturated with ether. The offwhite solid was collected by filtration and washed with ether to give an amine salt. This was recrystallized in MeOH ether to give white crystals of *(5)* (86%); melting point: 206 °C.​View attachment 3791​



G.Pattonsomeone brought me a yellow liquid and said it‘s methylphenidat base.
someone know how to crystallize?


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## ossi

how do this?



G.Patton said:


> and the resultant solid was triturated with ether



G.Patton


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## G.Patton

ossi said:


> someone brought me a yellow liquid and said it‘s methylphenidat base.
> someone know how to crystallize?



ossiIs it pure free base or solution in a solvent?


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## ossi

G.Patton said:


> Is it pure free base or solution in a solvent?



G.Pattoni think pur free base.
little thick oil


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## ossi

When mixed with ethanol, it immediately clumps into a jelly-like mass. almost does not mix with ethanol


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## G.Patton

ossi said:


> how do this?



ossiIt means that you have to add small amount of ether to solid crystals with trace of oil in order to get more crystalline product. I think you have something different because Methylphenidate is solid at room temperature. You have to clarify what do you have.


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## ossi

G.Patton said:


> *Step 3: *To a solution of B-lactam *(4)* in MeOH at 0 °C, anhydrous HCl gas was gently bubbled through the solution for approximately five minutes. The reaction mixture was allowed to stir at room temperature for 1-5 hours (until all starting material was gone by TLC). The solvent was evaporated, and the resultant solid was triturated with ether. The offwhite solid was collected by filtration and washed with ether to give an amine salt.



G.Pattonstill i try this, It's no longer mush, but granular, I see when I stir it up.
stirred long time with ethanol and dropped H2SO4


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## G.Patton

ossi said:


> still i try this, It's no longer mush, but granular, I see when I stir it up.
> stirred long time with ethanol and dropped H2SO4



ossiHave you reached pH 5.5-6, right? How have you measured H2SO4 amount?


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## ossi

G.Patton said:


> Have you reached pH 5.5-6, right?



G.Pattonyes


G.Patton said:


> How have you measured H2SO4 amount?



I did it by feel, just like with amph base


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## G.Patton

ossi said:


> I did it by feel, just like with amph base



ossiDo you have superpower to measure pH by feelings? pH man


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## ossi

G.Patton said:


> Do you have superpower to measure pH by feelings? pH man



G.Patton I didn't know how much acid to drip so I just went by feel


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