Introduction
Equipment and glassware:
The main starting material to make (3S)-methyl 4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate (3) is Arecoline (3,4-unsaturated N-methyl-piperidine-3-carboxylic acid methyl ester) (1), the active principle of the popular red betel nut. Treatment of this alpha, beta-unsaturated ester with the Grignard reagent 4-Chlorophenylmagnesium Bromide (2) gave rise to four products, easily grouped into two racemic forms of each cis- and trans- isomer. The racemic cis-isomer is twice as potent as cocaine, while the racemic trans-isomer is only half as strong.
We start with arecoline (1) (the active compound in betel nut: N-methyl-piperidine- 3-carboxylic acid methyl ester with a double bond between the 3 and 4 positions). Reaction of this with a 4-chlorophenylmagnesium bromide grignard reagent (2) gives a mixture of an total of four discrete entities: A cis- and trans-mixture in a 3:1 ratio, each constisting of a of two isomers, each isomer also being racemic, all which the authors resolve through fractional crystallization as their dibenzoyl tartaric acids, but this is not strictly necessary since each of the isomers are active. Arecoline Hydrobromide is a fairly cheap commercial starting material, about ~$30/kg from China market.
Difficulty Rating: 4/10
(3S)-methyl 4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate
We start with arecoline (1) (the active compound in betel nut: N-methyl-piperidine- 3-carboxylic acid methyl ester with a double bond between the 3 and 4 positions). Reaction of this with a 4-chlorophenylmagnesium bromide grignard reagent (2) gives a mixture of an total of four discrete entities: A cis- and trans-mixture in a 3:1 ratio, each constisting of a of two isomers, each isomer also being racemic, all which the authors resolve through fractional crystallization as their dibenzoyl tartaric acids, but this is not strictly necessary since each of the isomers are active. Arecoline Hydrobromide is a fairly cheap commercial starting material, about ~$30/kg from China market.
Difficulty Rating: 4/10
(3S)-methyl 4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate
Equipment and glassware:
- 3 L and 500 mL Round bottom flasks (RBF);
- 1 L Separatory funnel;
- Retort stand and clamp for securing apparatus;
- Salted ice bath (-10 °C);
- 3 L, 500 mL x3; 250 mL x3 Beakers;
- pH indicator paper;
- Vacuum source;
- Rotovap machine;
- Laboratory scale (0.01-100 g is suitable);
- Measuring cylinders 1000 mL and 100 mL;
- Laboratory grade thermometer (-50 °C to 100 °C) with flask adapter;
- Flash chromatography kit;
- Glass rod and spatula;
- Magnetic stirrer;
- Erlenmeyer flask 500 mL x2;
- Buchner flask and funnel [Schott filter may be used for small quantities].
Reagents:
- Arecoline Hydrobromide 19.63 g ;
- Sodium bicarbonate (NaHCO3) ~200 g;
- Methylene chloride (CH2Cl2) 300 mL;
- Magnesium sulfate (MgSO4) or sodium sulfate (NaSO4) anhydrous ~200 g;
- 4-Chlorophenylmagnesium bromide (2) 166 mL 1M;
- Diethyl ether (Et2O) 1.2 L;
- Distilled water ~1 L;
- Sodium chloride (NaCl) ~400 g;
- Ethyl acetate (EtOAc) ~250 mL;
- Hexane ~250 mL;
- Hydrochloric acid aq. (HCl) 200 mL, 10 %.
Procedure
The Arecoline freebase was prepared by treating the Arecoline Hydrobromide 19.63 g of commerce with concentrated aqueous sodium bicarbonate (NaHCO3) in 500 mL RBF, followed by extraction with methylene chloride (CH2Cl2) (100 mL x 3) in 1 L separatory funnel, thorough drying of the extracts over anhydrous magnesium sulfate (MgSO4) or sodium sulfate (NaSO4) in 500 mL Erlenmeyer flask, followed by suction filtration and evaporation of the solvent in vacuo. The freebase was then used as is in the next step.
(3S)-methyl 4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate
To a solution of 166 mL of 1M 4-chlorophenylmagnesium bromide (2) in 700 mL ether was added 12.9 g of arecoline freebase (1) in 300 mL ether at -10 °C in 3 L RBF or bigger on salted ice bath. The mix was stirred at -10 °C for 30 min, poured onto ice and treated with 200 mL of 10 % aq. HCl in 3 L beaker. The aqueous layer was separated by decantation, washed with 200 mL ether in a separatory funnel or in a beaker, cooled in an ice bath, and 100 mL of saturated sodium bicarb. solution (NaHCO3) added to obtain neutral 7 pH. The solution was extracted with 2 x 100 mL of ether in a separatory funnel, washed with brine, dried by anhydrous magnesium sulfate (MgSO4) or sodium sulfate (NaSO4), and concentrated in vacuo. The crude mixture was crystallized from EtOAc/Hexane to give racemic cis-isomer (3) as a white solid (5 g, 22 %). Additional cis-isomer (Total: 12.4 g, 56 %, mp 98-99 °C), as well as 2.0g (18 %) of the trans-isomer were obtained by flash chromatography of the mother liquor.
(3S)-methyl 4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate
To a solution of 166 mL of 1M 4-chlorophenylmagnesium bromide (2) in 700 mL ether was added 12.9 g of arecoline freebase (1) in 300 mL ether at -10 °C in 3 L RBF or bigger on salted ice bath. The mix was stirred at -10 °C for 30 min, poured onto ice and treated with 200 mL of 10 % aq. HCl in 3 L beaker. The aqueous layer was separated by decantation, washed with 200 mL ether in a separatory funnel or in a beaker, cooled in an ice bath, and 100 mL of saturated sodium bicarb. solution (NaHCO3) added to obtain neutral 7 pH. The solution was extracted with 2 x 100 mL of ether in a separatory funnel, washed with brine, dried by anhydrous magnesium sulfate (MgSO4) or sodium sulfate (NaSO4), and concentrated in vacuo. The crude mixture was crystallized from EtOAc/Hexane to give racemic cis-isomer (3) as a white solid (5 g, 22 %). Additional cis-isomer (Total: 12.4 g, 56 %, mp 98-99 °C), as well as 2.0g (18 %) of the trans-isomer were obtained by flash chromatography of the mother liquor.
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