Introduction
(-)-Cocaine is a naturally derived alkaloid obtained from coca leaves. In contrast, racemic cocaine and its (+)-enantiomer can only be synthesized chemically. This article outlines a streamlined total synthesis method for both the single enantiomers of cocaine and racemic cocaine. The process utilizes standard laboratory glassware, commonly available reagents, and techniques that can be executed in most illicit laboratories. Additionally, a detailed procedure for isolating and purifying the dextrorotatory enantiomer of cocaine is provided.
Difficulty rating: 10/10
Difficulty rating: 10/10
Equipment and glassware:
- Round bottom flasks 100 ml, 250 ml, 500 ml, 10 L;
- Reflux condenser;
- Vacuum pump;
- Buchner flask and funnel;
- Separating funnel 500 ml;
- Paper filter;
- Funnel;
- Top stirrer;
- Cold water bath;
- Metal of plastic syringe 100 ml;
- Drip funnel 500 ml;
- Laboratory grade thermometer (0 °C to 100 °C) with flask adapter;
- Retort stand and clamp for securing apparatus;
- pH indicator paper;
- Rotary evaporator;
- Beakers 2 L x2; 500 ml x4; 100 ml x4; 50 ml x3;
- Erlenmeyer flask 500 ml;
- Spatula;
- Inert gas balloon;
- Laboratory scale (0.1 g-200 g is suitable);
- Crystallization dish;
- Measuring cylinders 1 L and 200 ml;
Reagents:
- Glacial acetic acid 130 ml;
- Acetic anhydride 22 ml;
- 1,3-acetonedicarboxylic acid 20g (0.684 mol);
- Benzene ~200 ml;
- Methanol dry 360 ml;
- Sulfuric acid (H2SO4) 451 ml 0.2N (~10%, 0.1M);
- Sulfuric acid 30%;
- 2,5-Dimethoxytetrahydrofuran 44.2 g (0.334 mol);
- Citric acid 35.3 g;
- Sodium citrate dihydrate 38.8 g;
- Distilled water;
- Methylamine hydrochloride 32.0 g (0.48 mol);
- Sodium hydroxide 12.8 g (0.32 mol);
- Absolute ethanol 445 ml;
- D-(-)-tartaric acid (CAS 147-71-7) 18.57 g (0.124 mol);
- Dry acetone 300 ml;
- Sodium carbonate;
- Methylene chloride (DCM; CH2Cl2) 400 ml;
- L-(+)-tartaric acid 12.0 g (0.08 mol);
- Bromophenol blue (approx. 2 mg) indicator;
- Sodium amalgam Na(Hg) 1028 g 1.5%;
- Sodium hydroxide;
- Chloroform 200 ml;
- Sodium sulfate anhydrous;
- Petroleum ether 200 ml;
- Diethyl ether 500 ml;
- Ethereal HCl;
- Chloroform 120 ml;
- Pyridine 12 ml;
- Benzoyl chloride 0.8 ml (6.85 mmol);
- Ammonium hydroxide 5%;
Cocaine synthesis scheme from citric acid, methylamine hydrochloride and succindialdehyde
Acetonedicarboxylic acid anhydride Synthesis
1.To a solution of 30 ml glacial acetic acid and 22 ml of acetic anhydride at 10°C was slowly added 20 g (0.684 mol) of 1,3-acetonedicarboxylic acid in 250 ml round bottom flask with reflux condenser.
2. The temperature was not allowed to rise above +12°C until the reaction was complete. For runs where precipitation of product had not occurred within 3 h, it was induced by the addition of benzene.
3. The product was filtered by suction filtration, washed with 100 ml of glacial acetic acid, and next washed with 100 ml of benzene. It was allowed to dry yielding 14.8 g of acetonedicarboxylic acid anhydride white powder (84%).
2. The temperature was not allowed to rise above +12°C until the reaction was complete. For runs where precipitation of product had not occurred within 3 h, it was induced by the addition of benzene.
3. The product was filtered by suction filtration, washed with 100 ml of glacial acetic acid, and next washed with 100 ml of benzene. It was allowed to dry yielding 14.8 g of acetonedicarboxylic acid anhydride white powder (84%).
Acetonedicarboxylic Acid Monomethyl ester Synthesis
4. To a flask containing 41.0 g (0.32 mol) of acetonedicarboxylic acid anhydride was added 160 ml of cold dry methanol. 5. The mono-methyl ester solution was allowed to stand for one hour and filtered.
Succindialdehyde Synthesis From 2,5-Dimethoxytetrahydrofuran
6. To 400 ml of 0.2N sulfuric acid was slowly added 44.2 g (0.334 mol) of 2,5-dimethoxytetrahydrofuran and stirred for 15 min.
7. The succindialdehyde was allowed to stand for 4 h without further treatment.
7. The succindialdehyde was allowed to stand for 4 h without further treatment.
(±)-2-Carbomethoxytropinone Synthesis (2-CMT)
8. Six liters of 4.4 pH citrate buffer was made by diluting 35.3 g of citric acid and 38.8 g of sodium citrate dihydrate to volume by distilled water.
9. To the buffer was added 32.0 g (0.48 mol) of methylamine hydrochloride and 12.8g (0.32 mol) of sodium hydroxide.
10. The succindialdehyde solution was added dropwise to the buffer over 10 min with stirring at room temperature.
11. The mono-methyl ester solution was next added dropwise over 10 min with stirring.
12. The reaction was stirred 48 h at room temperature.
13. The reaction was extracted in 250ml portions by making the pH 12 with concentrated ammonium hydroxide and extracted 4 times with 200 ml of chloroform.
14. The extracts were dried over sodium sulfate and evaporated in vacuo.
15. The resulting yellow oil was dissolved in 200 ml of dry diethyl ether and filtered. The filtrate was evaporated in vacuo. 16. The oil was next dissolved into 200 ml of petroleum ether and filtered.
17. The filtrate was evaporated in vacuo and the resulting oil was allowed to hydrate upon standing. The crude hydrate was 95% pure and purified further by sublimation to yield snow white flakes, mp 96-98.5°C. Yield: 58.9 g (86%).
9. To the buffer was added 32.0 g (0.48 mol) of methylamine hydrochloride and 12.8g (0.32 mol) of sodium hydroxide.
10. The succindialdehyde solution was added dropwise to the buffer over 10 min with stirring at room temperature.
11. The mono-methyl ester solution was next added dropwise over 10 min with stirring.
12. The reaction was stirred 48 h at room temperature.
13. The reaction was extracted in 250ml portions by making the pH 12 with concentrated ammonium hydroxide and extracted 4 times with 200 ml of chloroform.
14. The extracts were dried over sodium sulfate and evaporated in vacuo.
15. The resulting yellow oil was dissolved in 200 ml of dry diethyl ether and filtered. The filtrate was evaporated in vacuo. 16. The oil was next dissolved into 200 ml of petroleum ether and filtered.
17. The filtrate was evaporated in vacuo and the resulting oil was allowed to hydrate upon standing. The crude hydrate was 95% pure and purified further by sublimation to yield snow white flakes, mp 96-98.5°C. Yield: 58.9 g (86%).
Resolution of (±)-2-Carbomethoxytropinone
18. To a solution of 26.60 g (0.124 mol) of sublimed racemic 2-CMT in 106 ml of absolute ethanol was added dropwise a solution of 18.57 g (0.124 mol) of D-(-)-tartaric acid (CAS 147-71-7) in 133 ml of absolute ethanol.
19. After 48 h the mother liquor was decanted and set aside. The crystals were washed with 50 ml of absolute ethanol and then dissolved into a minimal amount (approx. 200 ml) of hot dry methanol.
20. The solution was filtered while hot into an Erlenmeyer flask and covered.
21. The solution was left undisturbed for 72 h.
22. The solution was decanted off and combined with the first mother liquor.
23. The crystals of anhydrous (-)-2-CMT bitartrate were washed with 100 ml of dry acetone and dried yielding 6.8 g (30%), [α]D24 -16.9° (c=2, H2O). [α]D20 -16.9° (c=2, H2O) is reported.
24. The mother liquors were evaporated to dryness and dissolved into 200 ml of water, made pH 8 with sodium carbonate, and extracted 5 times with 200 ml of methylene chloride.
25. The extracts were dried over sodium sulfate and evaporated in vacuo. The (+)-enriched 2-CMT was hydrated yielding 17.5 g of powder.
26. To a solution of 17.2 g (0.08 mol) of (+)-enriched 2-CMT in 70 ml of absolute ethanol was added a solution of 12.0 g (0.08 mol) of L-(+)-tartaric acid in 86 ml of absolute ethanol.
27. Subsequent recrystallizations yielded 6.95 g of anhydrous (+)-2-CMT bitartrate (30%), [α]D24 +16.9° (c=2, H2O).
28. Freebasing the mother liquors and retreatment with D-(-)-tartaric acid yielded 6.0 g more anhydrous (-)-2-CMT bitartrate, [α]D24 -17.0° (c=2, H2O). Thus the overall yield of anhydrous (-)-2-CMT bitartrate was 12.8 g (57%).
19. After 48 h the mother liquor was decanted and set aside. The crystals were washed with 50 ml of absolute ethanol and then dissolved into a minimal amount (approx. 200 ml) of hot dry methanol.
20. The solution was filtered while hot into an Erlenmeyer flask and covered.
21. The solution was left undisturbed for 72 h.
22. The solution was decanted off and combined with the first mother liquor.
23. The crystals of anhydrous (-)-2-CMT bitartrate were washed with 100 ml of dry acetone and dried yielding 6.8 g (30%), [α]D24 -16.9° (c=2, H2O). [α]D20 -16.9° (c=2, H2O) is reported.
24. The mother liquors were evaporated to dryness and dissolved into 200 ml of water, made pH 8 with sodium carbonate, and extracted 5 times with 200 ml of methylene chloride.
25. The extracts were dried over sodium sulfate and evaporated in vacuo. The (+)-enriched 2-CMT was hydrated yielding 17.5 g of powder.
26. To a solution of 17.2 g (0.08 mol) of (+)-enriched 2-CMT in 70 ml of absolute ethanol was added a solution of 12.0 g (0.08 mol) of L-(+)-tartaric acid in 86 ml of absolute ethanol.
27. Subsequent recrystallizations yielded 6.95 g of anhydrous (+)-2-CMT bitartrate (30%), [α]D24 +16.9° (c=2, H2O).
28. Freebasing the mother liquors and retreatment with D-(-)-tartaric acid yielded 6.0 g more anhydrous (-)-2-CMT bitartrate, [α]D24 -17.0° (c=2, H2O). Thus the overall yield of anhydrous (-)-2-CMT bitartrate was 12.8 g (57%).
(+)-Ecgonine Methyl Ester ((+)-EME) Synthesis From (-)-2-Carbomethoxytropinone
29. Into a three-neck 500 ml round bottom flask was placed 7.70 g (0.036 mol) of (-)-2-CMT hydrate with 51 ml of ice cold 10% sulfuric acid.
30. Bromophenol blue (approx. 2 mg) indicator was added.
31. With stirring the solution was treated with 1028 g of 1.5% sodium amalgam in small portions over 2.5 h. The temperature was kept under +5°C. The pH was monitored via the indicator and kept between pH 3 and 4 with cold 30% sulfuric acid.
32. Periodic addition of water was necessary to dissolve sodium sulfate salts. The reaction was stirred an additional 45 min after the addition of amalgam was complete.
33. The solution was separated from the mercury, adjusted to pH 12 with sodium hydroxide and extracted three times with 200 ml of chloroform.
34. The extracts were dried over sodium sulfate and evaporated in vacuo to a light green oil containing a 3:1 ratio of EME to PEME.
35. The oil was dissolved into 200 ml of petroleum ether and filtered. The filtrate was evaporated in vacuo.
36. The resulting oil was dissolved into 500 ml of dry diethyl ether and the hydrochloride salts were made with ethereal HCl.
37. The salts were filtered and immediately dissolved into a minimal amount of dry methanol.
38. The methanol was evaporated in vacuo and 120 ml of dry chloroform was added to the crystals.
39. The slurry of crystals was filtered and dried yielding 2.28 g of (+)-ecgonine methyl ester hydrochloride (27%).
40. The product was recrystallized from methanol and diethyl ether to yield 2.2 g of pure product [α]D24 +52.3° c=1, MeOH), mp 213-214°C. Melting point is 213.5-214.5°C, [α]D24 +52.3° (c=1, MeOH).
30. Bromophenol blue (approx. 2 mg) indicator was added.
31. With stirring the solution was treated with 1028 g of 1.5% sodium amalgam in small portions over 2.5 h. The temperature was kept under +5°C. The pH was monitored via the indicator and kept between pH 3 and 4 with cold 30% sulfuric acid.
32. Periodic addition of water was necessary to dissolve sodium sulfate salts. The reaction was stirred an additional 45 min after the addition of amalgam was complete.
33. The solution was separated from the mercury, adjusted to pH 12 with sodium hydroxide and extracted three times with 200 ml of chloroform.
34. The extracts were dried over sodium sulfate and evaporated in vacuo to a light green oil containing a 3:1 ratio of EME to PEME.
35. The oil was dissolved into 200 ml of petroleum ether and filtered. The filtrate was evaporated in vacuo.
36. The resulting oil was dissolved into 500 ml of dry diethyl ether and the hydrochloride salts were made with ethereal HCl.
37. The salts were filtered and immediately dissolved into a minimal amount of dry methanol.
38. The methanol was evaporated in vacuo and 120 ml of dry chloroform was added to the crystals.
39. The slurry of crystals was filtered and dried yielding 2.28 g of (+)-ecgonine methyl ester hydrochloride (27%).
40. The product was recrystallized from methanol and diethyl ether to yield 2.2 g of pure product [α]D24 +52.3° c=1, MeOH), mp 213-214°C. Melting point is 213.5-214.5°C, [α]D24 +52.3° (c=1, MeOH).
Note: racemic and (-)-EME can be synthesized by the same reduction procedure and clean-up using (±)-2-CMT and (+)-2-CMT respectively.
(+)-Cocaine Synthesis From (+)-Ecgonine Methyl Ester
41. In an oven-dried 100-ml round bottom flask was added 1.00g (4.25 mmol) of (+)-ecgonine methyl ester HCl with 7 ml of dry pyridine and stirred in an ice bath. The reaction was protected from moisture with argon. [Note: argon can be substituted by nitrogen gas]
42. Dropwise over 5 min was added a solution of 0.8 ml (6.85 mmol) of benzoyl chloride in 5 ml of pyridine.
43. After addition was complete, the ice bath was removed and the reaction was stirred 24 h under argon.
44. Dry acetone (200 ml) was added and the slurry was filtered by suction filtration.
45. The crude (+)-cocaine hydrochloride was washed with an additional 100 ml of dry acetone. The product was dried yielding 1.28 g (89%).
46. The hydrochloride was dissolved into 20 ml of water, made pH 8 with 5% ammonium hydroxide, and extracted 4 times with 50 ml of methylene chloride.
47. The solvent was dried over sodium sulfate and evaporated in vacuo.
48. The free base was recrystallized from diethyl ether and petroleum ether yielding 1.01 g (78%) of pure (+)-cocaine base, [α]D24 +35.8° (c=1, 50% aqueous EtOH), mp 96.0-97.5°C. The literature lists the (-)-enantiomer at [α]D24 -35° (c=1, 50% aqueous EtOH), mp 98°C.
42. Dropwise over 5 min was added a solution of 0.8 ml (6.85 mmol) of benzoyl chloride in 5 ml of pyridine.
43. After addition was complete, the ice bath was removed and the reaction was stirred 24 h under argon.
44. Dry acetone (200 ml) was added and the slurry was filtered by suction filtration.
45. The crude (+)-cocaine hydrochloride was washed with an additional 100 ml of dry acetone. The product was dried yielding 1.28 g (89%).
46. The hydrochloride was dissolved into 20 ml of water, made pH 8 with 5% ammonium hydroxide, and extracted 4 times with 50 ml of methylene chloride.
47. The solvent was dried over sodium sulfate and evaporated in vacuo.
48. The free base was recrystallized from diethyl ether and petroleum ether yielding 1.01 g (78%) of pure (+)-cocaine base, [α]D24 +35.8° (c=1, 50% aqueous EtOH), mp 96.0-97.5°C. The literature lists the (-)-enantiomer at [α]D24 -35° (c=1, 50% aqueous EtOH), mp 98°C.
Note: racemic and (-)-cocaine can be synthesized using the same benzoylation procedure and clean-up using (+)-EME and (-)-EME respectively.
Total yield of (+)-cocaine hydrochloride from 2-CMT is 11.8%.
