Introduction
Procaine is a local anesthetic belonging to the amino ester class. It is most commonly employed in dental treatments to numb the area around a tooth and is also utilized to alleviate discomfort during intramuscular penicillin injections. In some regions, due to the widespread use of the brand name Novocain or Novocaine, the term "novocaine" is often used as a generic reference for procaine. Its primary mechanism of action is as a sodium channel blocker. In modern medicine, procaine is still used therapeutically in certain countries for its sympatholytic, anti-inflammatory, circulation-boosting, and mood-enhancing properties.
Procaine was first developed in 1905, following the earlier synthesis of amylocaine. It was created by chemist Alfred Einhorn, who named the compound Novocaine, derived from the Latin novus (meaning "new") and the suffix -caine, commonly used for alkaloids with anesthetic properties. Surgeon Heinrich Braun later introduced it into clinical practice.
Procaine was first developed in 1905, following the earlier synthesis of amylocaine. It was created by chemist Alfred Einhorn, who named the compound Novocaine, derived from the Latin novus (meaning "new") and the suffix -caine, commonly used for alkaloids with anesthetic properties. Surgeon Heinrich Braun later introduced it into clinical practice.
Difficulty rating: 5/10 Equipment and glassware:
- 5 L and 1 L round bottom flasks;
- Reflux condenser;
- Funnel;
- Distillation apparatus;
- Rotary evaporator;
- Vacuum pump;
- Buchner flask and funnel;
- Beakers 2 L x2; 500 ml x3; 100 ml x3;
- Measuring cylinders 100 ml and 20 ml;
- Water bath;
- Heating plate;
- Magnetic or top stirrer;
- Laboratory grade thermometer (20 °C to 250 °C) with flask adapter;
- Retort stand and clamp for securing apparatus;
- Laboratory scale (0.1 g-200 g is suitable);
- Crystallization dish;
- 4-Nitrobenzoic acid 200 g;
- Phosphorus pentachloride PCl5 250 g;
- Carbon tetrachloride (CCl4)
- Diethylethanolamine 117 g;
- Diluted hydrochloric acid 800 ml (5% aq);
- Granulated tin (Sn) 240 g;
- Sodium carbonate (Na2CO3);
- EtOH;
- Distilled water;
- Hydrochloric acid (HCl 35% aq);
4-Nitrobenzoyl Chloride Synthesis From 4-Nitrobenzoic Acid
1. 4-Nitrobenzoic acid 200 g and phosphorus pentachloride PCl5 250 g are mixed in a 5 L flask fitted with a reflux air condenser in a fume cupboard.
2. The flask is heated on a water bath with occasional shaking until the evolution of hydrogen chloride nearly ceases and a clear homogeneous liquid is obtained.
3. The reaction product is transferred to a distilling flask and distilled up to 220° C to remove phosphorus oxychloride.
4. The residue of 4-nitrobenzoyl chloride may be purified by crystallization from carbon tetrachloride (CCl4) or, by distillation under reduced pressure b.p. 155°C/20mm. The reaction yield is 200 g, 90%, yellow needles; m.p. 73°C.
2. The flask is heated on a water bath with occasional shaking until the evolution of hydrogen chloride nearly ceases and a clear homogeneous liquid is obtained.
3. The reaction product is transferred to a distilling flask and distilled up to 220° C to remove phosphorus oxychloride.
4. The residue of 4-nitrobenzoyl chloride may be purified by crystallization from carbon tetrachloride (CCl4) or, by distillation under reduced pressure b.p. 155°C/20mm. The reaction yield is 200 g, 90%, yellow needles; m.p. 73°C.
p-Nitrobenzoyl Diethylethanolamine Hydrochloride Synthesis From 4-Nitrobenzoyl Chloride
5. Diethylethanolamine 117 g is mixed with 185.4 g of para-nitrobenzoyl chloride in 1 L round bottom flask with installed reflux condenser.
6. The reaction, which takes place spontaneously, is completed by heating the mixture for 2 hours at 120°C.
6. The reaction, which takes place spontaneously, is completed by heating the mixture for 2 hours at 120°C.
Procaine Hydrochloride Synthesis From p-Nitrobenzoyl Diethylethanolamine Hydrochloride
7. The solid reaction product consists of the of para-nitrobenzoyl diethylethanolamine hydrochloride, which is dissolved in 800 ml of diluted hydrochloric acid (5% aq) and treated gradually with 240 g of granulated tin (Sn), the temperature being kept at 35-40° C.
8. After reduction is completed the solution is saturated with from hydrogen sulfide in order to remove tin.
9. Then the solution is made alkaline with sodium carbonate (Na2CO3), when the base separates as an oil which presently crystallizes.
10. The mass is separated and recrystallized from dilute alcohol, from which crystals containing 2 molecules of water and melting at 51°C are obtained.
11. These are filtered off and neutralized with one molecule of hydrochloric acid (HCl 35% aq) to the neutral pH.
12. The procaine hydrochloride obtained on evaporation crystallizes from alcohol in needles melting at 156° C. Procaine is a white, odorless, crystalline powder, soluble in an equal weight of water.
8. After reduction is completed the solution is saturated with from hydrogen sulfide in order to remove tin.
9. Then the solution is made alkaline with sodium carbonate (Na2CO3), when the base separates as an oil which presently crystallizes.
10. The mass is separated and recrystallized from dilute alcohol, from which crystals containing 2 molecules of water and melting at 51°C are obtained.
11. These are filtered off and neutralized with one molecule of hydrochloric acid (HCl 35% aq) to the neutral pH.
12. The procaine hydrochloride obtained on evaporation crystallizes from alcohol in needles melting at 156° C. Procaine is a white, odorless, crystalline powder, soluble in an equal weight of water.
Sources
- Barrowcliff, Marmaduke, and Francis Howard Carr. Organic Medicinal Chemicals (synthetic and Natural). Baillière, Tindall and Cox, 1921.
- https://www.prepchem.com
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