G.Patton

Expert
Joined
Jul 5, 2021
Messages
2,501
Solutions
3
Reaction score
2,533
Points
113
Deals
1

Introduction
GQo7x41CKB

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:

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).
BauT8IGezO

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.
JwHpUZ9W86
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.
RXGynfEe8i
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.
3xrAtMz0y2
 
Last edited:

BakingBad

Don't buy from me
New Member
Joined
Mar 18, 2022
Messages
1
Reaction score
0
Points
1
Very interesting topic.
Do you know a way to synthesize
  • 1-Phenyl-2-(piperidin-1-yl)ethanone-1,2-dione; (ethane instead of ethanone?)
 
Last edited:

G.Patton

Expert
Joined
Jul 5, 2021
Messages
2,501
Solutions
3
Reaction score
2,533
Points
113
Deals
1
ethane instead of ethanone?
BakingBadYes, thank you for note!
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.
1IkfJqpvcY
 
Last edited by a moderator:

Chefy77

Don't buy from me
New Member
Joined
Jan 16, 2023
Messages
5
Reaction score
1
Points
3
Yes, thank you for note!

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.
G.Pattonhey you make 4f or anything stinger
 

ossi

Don't buy from me
Resident
Joined
Sep 15, 2022
Messages
69
Reaction score
29
Points
18

Introduction View 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:

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

Attachments

  • grw5vUMq7I.jpg
    grw5vUMq7I.jpg
    3 MB · Views: 380

G.Patton

Expert
Joined
Jul 5, 2021
Messages
2,501
Solutions
3
Reaction score
2,533
Points
113
Deals
1
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?
 

ossi

Don't buy from me
Resident
Joined
Sep 15, 2022
Messages
69
Reaction score
29
Points
18
When mixed with ethanol, it immediately clumps into a jelly-like mass. almost does not mix with ethanol
 

G.Patton

Expert
Joined
Jul 5, 2021
Messages
2,501
Solutions
3
Reaction score
2,533
Points
113
Deals
1
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.
 

ossi

Don't buy from me
Resident
Joined
Sep 15, 2022
Messages
69
Reaction score
29
Points
18
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
 

Attachments

  • Y7RbO0LoqJ.jpg
    Y7RbO0LoqJ.jpg
    2.4 MB · Views: 341
  • xQbVnv0PiW.MOV
    732.8 KB · Views: 0

G.Patton

Expert
Joined
Jul 5, 2021
Messages
2,501
Solutions
3
Reaction score
2,533
Points
113
Deals
1
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?
 

cokemuffin

Don't buy from me
Resident
Joined
Sep 11, 2022
Messages
66
Reaction score
26
Points
18
Would you get other esters of ritalinic acid if you'd do the last step in other solvents (IPA = isopropylphenidate, EtOH = ethylphenidate etc.)?
 

G.Patton

Expert
Joined
Jul 5, 2021
Messages
2,501
Solutions
3
Reaction score
2,533
Points
113
Deals
1
View previous replies…

cokemuffin

Don't buy from me
Resident
Joined
Sep 11, 2022
Messages
66
Reaction score
26
Points
18
Hi, yes, you will.
G.PattonCould you also do it with a ritalinic acid ester? I'd assume that as an example you could just hydrolyse methylphenidate HCl with NaOH in ipa to get the sodium salt of ritalinic acid, then just add hydrochloric acid to the solution to get isopropylphenidate HCl, saturate the solution with NaCl to push the IPH out of the water and let the solution form two layers, than decant the top layer and let the IPH crystallize from it (let the solvent evaporate). But that's just an assumption, so would that work?
 

Chefy77

Don't buy from me
New Member
Joined
Jan 16, 2023
Messages
5
Reaction score
1
Points
3
Could you also do it with a ritalinic acid ester? I'd assume that as an example you could just hydrolyse methylphenidate HCl with NaOH in ipa to get the sodium salt of ritalinic acid, then just add hydrochloric acid to the solution to get isopropylphenidate HCl, saturate the solution with NaCl to push the IPH out of the water and let the solution form two layers, than decant the top layer and let the IPH crystallize from it (let the solvent evaporate). But that's just an assumption, so would that work?
cokemuffinoh i'm sorry that comment was meant for you. ever make 4f?
 

G.Patton

Expert
Joined
Jul 5, 2021
Messages
2,501
Solutions
3
Reaction score
2,533
Points
113
Deals
1
Could you also do it with a ritalinic acid ester? I'd assume that as an example you could just hydrolyse methylphenidate HCl with NaOH in ipa to get the sodium salt of ritalinic acid, then just add hydrochloric acid to the solution to get isopropylphenidate HCl, saturate the solution with NaCl to push the IPH out of the water and let the solution form two layers, than decant the top layer and let the IPH crystallize from it (let the solvent evaporate). But that's just an assumption, so would that work?
cokemuffinHi. NaOH in IPA will completely spoil your ritalin*HCl. You can get ritalin freebase by aqueous NaOH and then carry out esterification.
 

Chefy77

Don't buy from me
New Member
Joined
Jan 16, 2023
Messages
5
Reaction score
1
Points
3

Introduction View 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:

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.
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.
G.Pattondamn i live on 4f never tried ritalin tho heard it was similar
 
  • Free product samples

    Testing products from new vendors and manufacturers.

    Get free samples for testing now!

  • Always stay in touch with BB forum. Element/Matrix.

    Connect notifications to always stay in touch with the forum!

    Connect

Top