Introduction
The Merck Index lists Dimenoxadol as 'analgesic' with the remark 'abuse leads to habituation or addiction', which is a strong indication that it's an opiate type substance. Additionally, it's a schedule I controlled substance. Unlike in many other opiates, minor structural changes completely abolish the opiate activity. The preparation from Benzilic acid (3) is quite easy but involves rather unpleasant chemicals like sodium metal. There are very easy synthesis steps which don't take special glassware or rare reagents. Benzilic acid (3) can be prepared from commercially available Vitamin B1 by few steps.
2-(Dimethylamino)ethyl 1-ethoxy-1,1-diphenylacetate hydrochloride:
Boiling Point: 444.5 °C at 760 mm Hg;
Melting Point: 170 - 172 °C;
Molecular Weight: 363.92 g/mole;
Density: N/D;
CAS Number: 2424-75-1.
Equipment and glassware:
- 2 L, 500 mL and 150 mL Round bottom flask;
- 5 mL Conical vial;
- Reflux condenser;
- Magnetic stirrer with heater;
- Water bath and ice;
- Retort stand and clamp for securing apparatus;
- Vacuum source;
- Buchner flask and funnel [Schott filter may be used for small quantities];
- Laboratory grade thermometer (0 °C to 100 °C);
- 500 mL x2; 100 mL x3; 50 mL x2 Beakers;
- Glass rod and spatula;
- Сonical flask 150 mL;
- Vacuum desiccator;
- A cork carrying a tube bent twice at right angles;
- Calcium chloride tube;
- Rotovap machine;
- Laboratory scale (0.005-100g is suitable).
- 1 L Separatory funnel;
Reagents:
- 0.135 g Thiamine hydrochloride (Vitamin B1);
- ~ 200 mL Distilled water;
- ~515 mL Ethanol (EtOH absolute);
- 0.27 mL 3 M Sodium hydroxide aq solution (NaOH);
- 0.75 mL Benzaldehyde;
- 25 mL Concentrated nitric acid;
- 5 g Potassium hydroxide (KOH);
- 3 mL Thionyl chloride (SOCl2);
- 23 g Sodium metal (Na);
- ~ 200 mL Diethyl ether;
- 100 mL Acetone;
- 20 g Potassium carbonate (K2CO3);
- 13 g 2-(dimethylamino)-ethyl chloride;
- ~50 mL 2N Hydrochloric acid aq solution (HCl).
Precursor synthesis
Benzoin (1)
Dissolve 0.135 g of Thiamine hydrochloride (Vitamin B1) [EASY TO BUY] in 0.27 mL deionized (or distilled) water in a 5-mL conical vial. Add 1.2 mL ethanol and cool the resulting solution in an ice bath. Slowly add 0.27 mL of cold 3 M sodium hydroxide dropwise over 2-3 min. Gently swirl the vial during the addition. Measure 0.75 mL of benzaldehyde and add it to the reaction mixture. Fit the vial with a condenser and reflux at ~60 °C for 75-80 min, or cap the reaction vial and allow it to stand for 48 h or more. Cool the reaction mixture to room temperature. Precipitate the benzoin by cooling the vial in an ice bath. Collect the solid by vacuum filtration and wash with cold water. Recrystallize the benzoin from ethanol.
Benzil (2)
Place 10 g of powdered benzoin (1) and 25 mL of concentrated nitric acid in a 150 mL flask fitted with a reflux water condenser, and heat the flask on a boiling water bath. A flask having a ground-glass neck fitting directly to the condenser is best for this purpose. If not available, fit the flask to the condenser by means of a cork (not a rubber stopper) and clamp both flask to the condenser securely in position during heating on the water bath: the nitrous fumes rot cork during the heating, and if only one clamp is used, the flask may possibly slip away from the condenser, or alternatively the latter may fall sideways under its own weight. Continue the heating for 1.5 h, when the crystalline benzoin will have been completely replaced by the oily benzyl. Then pour the mixture into a beaker of cold water, when on vigorous stirring the oil will crystallise into a yellow solid. Filter off the latter at the pump and wash thoroughly with water to ensure complete elimination of acid. Recrystallise from methylated or rectified spirit. Benzyl separates as clear yellow crystals, m.p. 95 °C yield 9 g.
Place 10 g of powdered benzoin (1) and 25 mL of concentrated nitric acid in a 150 mL flask fitted with a reflux water condenser, and heat the flask on a boiling water bath. A flask having a ground-glass neck fitting directly to the condenser is best for this purpose. If not available, fit the flask to the condenser by means of a cork (not a rubber stopper) and clamp both flask to the condenser securely in position during heating on the water bath: the nitrous fumes rot cork during the heating, and if only one clamp is used, the flask may possibly slip away from the condenser, or alternatively the latter may fall sideways under its own weight. Continue the heating for 1.5 h, when the crystalline benzoin will have been completely replaced by the oily benzyl. Then pour the mixture into a beaker of cold water, when on vigorous stirring the oil will crystallise into a yellow solid. Filter off the latter at the pump and wash thoroughly with water to ensure complete elimination of acid. Recrystallise from methylated or rectified spirit. Benzyl separates as clear yellow crystals, m.p. 95 °C yield 9 g.
Dimenoxadol hydrochloride synthesis way
Benzilic Acid (3)
Dissolve 5 g of benzyl (2) in 15 mL of boiling ethanol in a conical flask fitted with a reflux water-condensor. Then add a solution of 5 g of KOH in 10 mL water, and heat the mixture (which rapidly develops a purple colour) on a boiling water-bath for about 15 min. Cool and stir the solution, from which the potassium benzilate separates in fine crystals. Filter the product at the pump, using an alkali-resisting filter-paper, or a sintered glass filter funnel. Wash the crystals on the filter with a small quantity of ethanol to remove the purple colour, and then drain thoroughly.
To obtain the free acid, dissolve the potassium salt in 50 mL of cold water, filter the solution if a small undissolved residue remains; and boil the clear solution gently whilst dilute H2SO4 is added until the separation of the acid is complete. Cool the solution and filter off the pale orange-coloured crystals of the benzilic acid (3); wash the crystals on the filter with some hot water, drain well, and then dry in a desiccator. Yield of crude acid, 4 g. Recrystallise from much hot water. The benzilic acid is obtained as colourless crystals, m.p. 150 °C.
Dry powdered benzilic acid (3) (10 g) is taken in a conical flask fitted with a cork carrying a tube bent twice at right angles and terminating in a calcium chloride tube. Thionyl chloride (3 mL) is added and the mixture shaken and kept overnight. Large crystals are formed and on washing with a little benzene-petrol mixture give m.p. 119-120 °C (decomp.). Yield is 10
Benzilic acid ethyl ether (5)
23 g of sodium metal were dissolved in 450 mL absolute ethanol and heated with 123 g (0.5 mol) of diphenylchloroacetic acid (4) in 2 L RBF on a water bath for 30 min, and the alcohol was distilled off in vacuo. The residue, dissolved in water, was shaken with ether, then acidified and again shaken with ether. The ether was evaporated and the residue, about 100 g, was recrystallized from ethanol to give benzilic acid ethyl ether, m.p. 110-111 °C (lit. 114 °C).
23 g of sodium metal were dissolved in 450 mL absolute ethanol and heated with 123 g (0.5 mol) of diphenylchloroacetic acid (4) in 2 L RBF on a water bath for 30 min, and the alcohol was distilled off in vacuo. The residue, dissolved in water, was shaken with ether, then acidified and again shaken with ether. The ether was evaporated and the residue, about 100 g, was recrystallized from ethanol to give benzilic acid ethyl ether, m.p. 110-111 °C (lit. 114 °C).
Dimenoxadol hydrochloride (6)
25 g of benzilic acid ethyl ether (5) was boiled in 100 mL acetone with 20 g of potassium carbonate and 13 g of 2-(dimethylamino)-ethyl chloride in 500 RBF for 24 h on a water bath. The acetone was distilled off and the residue partitioned between ether and water, the alkaline aqueous solution again shaken with ether, and the combined with ether extracted with 2N HCl until the extracts were clearly acid. The water was evaporated in vacuum, and the residue recrystallized from ethanol to give 65% of Dimenoxadol hydrochloride (6), m.p. 165-166 °C.
25 g of benzilic acid ethyl ether (5) was boiled in 100 mL acetone with 20 g of potassium carbonate and 13 g of 2-(dimethylamino)-ethyl chloride in 500 RBF for 24 h on a water bath. The acetone was distilled off and the residue partitioned between ether and water, the alkaline aqueous solution again shaken with ether, and the combined with ether extracted with 2N HCl until the extracts were clearly acid. The water was evaporated in vacuum, and the residue recrystallized from ethanol to give 65% of Dimenoxadol hydrochloride (6), m.p. 165-166 °C.
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