G.Patton

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Introduction

Methoxetamine (also known as MXE, 3-MeO-2-Oxo-PCE, 2-(ethylamino)-2-(3-methoxyphenyl)cyclohexan-1-one) is an arylcyclohexylamine and a derivative of eticyclidine (PCE). It can also be thought of as the β-Keto-derivative of 3-methoxyeticyclidine (3-MeO-PCE), or the N-ethyl homologue of methoxmetamine (MXM) and methoxpropamine (MXPr). It is closely related structurally to ketamine, and more distantly to PCP.

Methoxetamine synthesis elementary except last stage, which takes a Microwave reactor. Microwave reactor can be replaced with three-necked RBF with thermometer and reflux condenser, you have to provide reaction under inert atmosphere (it's much easier than you think). 3-Methoxybenzonitrile underwent Grignard reaction to form 3-methoxyphenyl cyclopentyl ketone (1). Further bromination led to alpha-bromo ketone (2) which was treated with ethylamine to form Schiff's base (3) and final heating provided Methoxetamine (4).

Equipment and glassware:

  • 10 ml Drip funnel;
  • 100 ml and 50 ml Round-bottom flasks (RBF) or pear-shaped flasks;
  • Microwave reactor or 10-50 ml three-necked RBF with laboratory grade thermometer (0 °C to 200 °C) with flask adapter;
  • Magnetic stirrer with heating surface;
  • Reflux condenser;
  • Beakers 200 ml x2; 100 ml x2; 50 ml x2; 10 ml x2;
  • Glass rod;
  • Conventional funnel;
  • Retort stand and clamp for securing apparatus;
  • Laboratory scale (0.01 — 100 g is suitable);
  • Water-jet aspirator (optional);
  • Flash chromatography kit (optional);
  • Buchner flask and funnel (Schott filter may be used instead of Buchner funnel) 100-500 ml;
  • Nitrogen or Argon balloon 10-20 L is enough;
  • Separatory funnel 200 ml and/or 500 ml;
  • Water bath and Ice;
  • Rotovap machine (optional);
  • Glass rod and spatula.

Reagents:

  • Cyclopentylbromide 0.6 g, 4 mmol;
  • Tetrahydrofuran (THF) 20 ml;
  • Magnesium Mg 98 mg, 4.1 mmol;
  • Iodine (I2) cat. quantity;
  • 3-Methoxybenzonitrile 0.5 g, 3.8 mmol;
  • Ammonium chloride (NH4Cl) aq, 10 ml;
  • Distilled water (H2O) 50 ml;
  • Diethyl ether (Et2O) ~410 ml;
  • Anhydrous magnesium sulphate (MgSO4) ~100 g;
  • Ethyl acetate (EtOAc) ~ 100 ml;
  • Hexane ~100 ml;
  • Tetrachloromethane (CCl4) 10 ml;
  • Bromine (Br2) 480 mg, 6 mmol;
  • Saturated sodium bicarbonate (NaHCO3) aq., 15 ml
  • Dichloromethan (DCM) 110 ml;
  • Ethylamine (EtNH2) 5 ml;
  • Decalin 2 ml;
  • Hydrochloric acid aq. 15% (HCl) 45 ml;
  • Sodium hydroxide (NaOH) ~20 g;
  • Isopropyl alcohol (IPA; iPrOH) ~100 ml;
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Boiling Point: 389 °C at 760 mm Hg;
Melting Point: 244.9 °C (hydrochloride salt);
Molecular Weight: 247.33 g/mol;
Density: 1.1±0.1 g/ml (20 °C);
CAS Number: 1239943-76-0;
MXE hydrochloride is soluble in ethanol up to 10 mg/ml at 25 °C.

Procedure

Synthesis of Cyclopentyl-(3-(methoxyphenyl)ketone (1)
A solution of cyclopentylbromide (0.6 g, 4 mmol) in dry THF (5 ml) was added dropwise via 10 ml drip funnel to the mixture of Mg (98 mg, 4.1 mmol) and I2 (cat. quantity) in dry THF (10 ml) under argon or nitrogen atmosphere at room temperature in 100 ml RBF. The reaction mixture was heated under reflux for 1 hour and then cooled to 0 °C (ice water bath). 3-Methoxybenzonitrile (0.5 g, 3.8 mmol) in dry THF (5 ml) was added dropwise at 0 °C and the reaction mixture was stirred for 72 hours at room temperature. The reaction mixture was treated with saturated NH4Cl (aq, 10 ml), diluted with water (50 ml) and extracted with Et2O (3 x 60 ml). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Further purification was done by flash chromatography (EtOAc/Hexane, 1:10). Compound cyclopentyl-(3-methoxyphenyl)-methanone (1) was isolated as a colorless liquid (253 mg, yield 33%).
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Synthesis of 1-Bromocyclopentyl-(3-methoxyphenyl)ketone (2)
Compound (1) (1 g, 4.9 mmol) was dissolved in CCl4 (5 ml) and Br2 (480 mg, 6 mmol) in CCl4 (5 ml) was added dropwise via 10 ml drip funnel at 0 °C in 50 ml RBF. The reaction mixture was stirred at RT for 30 minutes. The reaction mixture was treated with saturated NaHCO3 (aq., 15 ml) and extracted with DCM (3 x 30 ml). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to yield 1-bromocyclopentyl-(3-methoxyphenyl)methanone (2) as a colorless liquid (973 mg, yield 80%).
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Synthesis of 1-((ethylimino)(3-methoxyphenyl)methyl)cyclopentan-1-ol (3)
The mixture of compound (2) (0.9 g, 3.2 mmol) and EtNH2 (5 ml) was stirred at 0 °C for 2 hours. You can carry out reaction in 50 ml flask or take 10 ml flask. The ethylamine was evaporated, Et2O was added to the residue and solids were filtered off through Buchner flask and funnel (or Schott filter). The filtrate was evaporated and compound 1-((ethylimino)(3-methoxyphenyl)methyl)cyclopentan-1-ol (3) was obtained as a yellowish liquid (694 mg, yield 88%).
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Synthesis of Methoxetamine (4)
The compound (3) (600 mg, 2.4 mmol) was dissolved in decalin (2 ml) and stirred 15 hours at 190 °C in a microwave reactor or simple heating with asbestos or aluminum mantle, also you have to use round bottom flask for 10-50 ml with thermometer, reflux condenser and inert atmosphere. The reaction mixture was cooled to room temperature, diluted with DCM (20 ml) and extracted with 15% HCl (3 x 15 ml). The aqueous layer was separated, then it was made alkaline with saturated aqueous NaOH (30 ml) and extracted with Et2O (3 x 40 ml). The organic layer was dried over MgSO4, filtered, treated with a solution of HCl in Et2O (2 ml) and the solvent was evaporated. Further purification was done by recrystallization from isopropyl alcohol. Methoxetamine hydrochloride was isolated as ayellowish solid and confirmed by NMR analysis (130 mg, 19% yield). Melting point: 248 – 249 °C (isopropanol).
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beetlebb

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Final conversion of 19% is crazy low. Another solvent that can be used in the final converstion step is ethylbenzoate, works quite well but again yiels are around 50%. SWIM heard that ethylene glycol works even better, but who really knows.
 

beetlebb

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lol just found it
The title compd. (ketamine) (I) is prepd. by thermal rearrangement of 1-hydroxycyclopentyl 2-(chlorophenyl) ketone methylimine-HCl (II) in anhyd. ethylene glycol (III) at 185-190. III 2000 mL was added to II 2000 g, and the resulting soln. was stirred 50 min at 190 and cooled to give crude cryst. I 1500 g (75%).
 

beetlebb

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For the alpha bromo ketone, any other solvents you would suggests other than carbon tetrachloride?
 

WillD

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For the alpha bromo ketone, any other solvents you would suggests other than carbon tetrachloride?
beetlebbWhat do you like. Acetic acid, DCM, benzene or variants with aqueous phase
 

WillD

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lol just found it
The title compd. (ketamine) (I) is prepd. by thermal rearrangement of 1-hydroxycyclopentyl 2-(chlorophenyl) ketone methylimine-HCl (II) in anhyd. ethylene glycol (III) at 185-190. III 2000 mL was added to II 2000 g, and the resulting soln. was stirred 50 min at 190 and cooled to give crude cryst. I 1500 g (75%).
beetlebbYes, yes, you are absolutely right. Rearrangement temperature is light.
 
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beetlebb

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thanks.
 
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