Synthesis of Barbiturates

By far, the biggest class of hypnotic drugs are derivatives of barbituric acid. The action of barbiturates is reliable and reproducible, they are easy to administer and offer a wide range of activity.

It would be extremely tedious for you to read the synthesis of all the barbituric acid derivatives that exist today, so I will limit you to the more widely used and important ones. I have grouped the listed barbiturates by their clinical action and the duration of that action.

Long Acting Barbiturates

These need to be given one hour before the effect is desired and their effect is so prolonged that you will remain drowsy the following day.

Barbitone. This is also called barbital or veronol. I will start this synthesis with the intermediates (precursors) of the given formulas. Some of these formulas are given on a commercial basis and can be reduced to the size of your budget.

Sodium Malonate. 100 kilos of Chloroacetic acid are dissolved in the minimum amount of cold water (this may vary, but it is usually about 20 liters). This mixture is stirred slowly during the addition of a solution consisting of 120 kilos of anhydrous sodium carbonate in 350 liters of water, keeping the temp at 0°C. An excess of alkali is avoided throughout this entire step. 60 kilos of sodium cyanide is dissolved in 100 liters of water and heated to 70°C, then the above solution is added, rather slowly, with good stirring. The heat involved must be controlled internally as well as externally on the larger scale of production to keep the temp below 90°C. This can be accomplished by floating sealed packages of ice in the mixture or by using internal cooling coils filled with ice cold, running liquids. Air in and around the reaction kettle needs to be evacuated and well ventilated. The reaction is complete after about 20 min and the mixture is raised to a boil and a solution of 80 kilos of sodium hydroxide in 160 liters of water is added. This solution is boiled until the evolution of ammonia stops (about 3 hours for this size formula), you will no longer be able to smell ammonia. The solution is then evaporated and the residue is powdered. Yield: 220 kilos of powder, 155 kilos of which is sodium malonate and the rest is sodium chloride. (If you do not have the resources to make a huge batch, as the one just described, take the amounts given and divide by 1,000. 100 kilos is turned into 100 g. The reaction times may change slightly, but all temps given will remain the same.)

Diethyl Malonate. 200 kilos of the above powder (sodium malonate can be purchased cheaply without alarming DEA officials. I gave the above formula for do-it-yourselfers) is stirred with 160 kilos of ethanol (industrial spirit) and 500 kilos of benzene in an esterification kettle. About 240 kilos of coned sulfuric acid are added, at such a rate that the temp of this well stirred mixture never exceeds 25°C (this will take several hours for a formula this big). The temp is then raised to 60°C and maintained for at least 8 hours and then cooled. The top benzene layer is removed and the lower acid layer is`extracted with benzene repeatedly. The combined benzene layers are washed free of acid, with dilute sodium hydroxide, and dried over anhydrous sodium carbonate and then distilled under vacuo (20 mm). The fraction boiling at 96-98°C is collected as commercially pure diethyl malonate. Yield: 85-90% of theoretical.

Diethyl Malonic Ester (diethyl diethyl malonate). (Great care must be taken to keep H2O from this reaction, even the moisture in the air can hurt the yield.) A sodium ethylate solution is made by dissolving 13.2 kilos of clean sodium metal in 200 liters of absolute ethanol and heated to 60°C, then maintained at this temp during the addition of the above diethyl malonate (84 kilos). Now, raise the temp to 80°C and add 65 kilos of ethyl bromide over 3 hours. After the addition, reflux for 2 hours then distill until the temp reaches 110°C. At this point, a further solution of sodium ethylate (again consisting of 13.2 kilos of sodium and 200 liters of dry ethanol) is heated to 60°C and added to the distillation residue. The mixture is stirred and heated until homogenous, then a further 65 kilos of ethyl bromide is added over 3 hours and the temp maintained at 60°C. Reflux is again applied for 2 more hours, then distilled until the liquid temp reaches 110°C. After cooling slightly the residue is treated with the addition of 150 liters of water, agitated brisklY and allowed to separate into two layers. The upper layer is crude diethyl malonic ester and it is separated and dried over anhydrous sulphate, then distilled in vacuo. Collect the pure ester coming over at 132-135°C at 28 mm of vacuo. Yield: 80-85% (88 to 94 kilos).

Barbitone. (Barbital, veronal, 5,5-diethyl malonyl urea) The exclusion of water is also paramount in this step (use drying tubes, etc.). 30 kilos of dry urea and 76.5 kilos of the above malonate (dry diethyl diethyl malonate) are placed in the reaction vessel and stirred very well. To this mixture is added a solution of hot (75°C) sodium ethylate (18 kilos of clean sodium metal in 270 liters of dry ethanol) and the mixture is brought to a boil with good stirring. The alcohol is removed with the boiling action (the reaction vessel is equipped with a slanted vapor condenser) and the mixture becomes more viscous. The alcohol (ethanol) is distilled out completely and the heat is then removed. The residue left behind should be a creamy white powder.

The free acid 5,5 diethyl malonyl urea or diethyl barbituric acid is prepared as follows. 85 kilos of coned hydrochloric acid is diluted with 100 liters of water and cooled by adding 300 kilos of crushed ice. The above dry powder is added to this mixture, gradually, with good stirring, so that the mixture is always acidic to congo red. Cool to keep the temp down below 0°C. Stir for several hours, centrifuge or filter with vacuo, wash with 20 to 30 liters of water, centrifuge, wash again, and centrifuge. The crude acid resulting is dissolved in 800 liters of water at boiling temp, is treated with 1/2-1 kilo of decolorizing charcoal, and boiled for another minute. The boiling mixture is filtered, as hot as possible, through a heated funnel with a suitable dravity filter. The crystals precipitate from the filtrate, which is cooled externally and stirred slowly (cold running water is good for the cooling). The precipitate is centrifuged or filtered and washed with 20 liters of cold water and dried in vacuo at 50°C. Yield of pure diethyl barbituric acid (barbitone) is about 50 kilos, 90%.

Another Method for 5,5-Diethyl Barbituric Acid. (This is a scaled down version.) 16 g of clean sodium is dissolved in 300 g of absolute ethanol. To this cooled solution is added 20 g of dry urea and 50 g of diethyl malonic ester (diethyl diethyl malonate). The mixture is heated in an autoclave (pressure cooker, very strong) for 4 to 5 hours at 100-110°C. After removing from the autoclave, the mixture is cooled. Upon cooling, the sodium salt of diethyl barbituric acid separates, is filtered off, dissolved in water, and the free acid precipitated by the addition of hydrochloric acid. The acid is filtered and recrystallized from water, using decolorizing carbon, if necessary.

Yield: Depends on your ability to exclude H2O from the beginning of reaction.

Phenobarbitone (Sometimes called luminal)

Diethyl phenyl ethyl malonate. 1 mole of benzyl cyanide is added dropwise to a solution of 1 mole of ethyl carbonate in 2 liters of anhydrous ethanol containing 5 g of clean sodium metal. This mixture is refluxed (preferably on a steam bath) for 5 hours. It is then cooled and to it is added a cooled mixture of 40 g of sulfuric acid in 100 ml of anhydrous ethanol. This alcoholic solution is refluxed for 5 hours, cooled, neutralized with sodium ethylate (use external indicator). The mixture is evaporated to half bulk, filtered from the sodium sulphate and to it is added 1 mole of clean metallic sodium. Reflux while adding 1 mole of ethyl bromide dropwise. Heat for another 2 hours after the addition is completed. Remove the alcohol by distillation and dissolve the remaining residue in water. Extract the substance from the water with benzene and after drying, the benzene is recovered and the ester should be purified by distilling in vacuo.

Phenobarbitone. One mole of the above malonate (or any other suitable malonate analog) and 1.2 moles of dry urea are stirred together in a vessel equipped with drying tubes at all possible air inlets, a distillation condenser, and an efficient stirring device. To the above mixture add a solution of 1.2 moles of clean metallic sodium in 400 ml of dry ethanol. Heat to boiling and distill the ethanol off slowly, over six hours with stirring. When the alcohol is completely distilled out of the mixture, the remaining white powder is added to a stirred mush of about 126 ml of coned hydrochloric acid and 148 ml of water (or an equimolar amount of ice) and 445 g of finely crushed ice. The mixture is kept at 0°C until the acid has crystallized, then it is filtered (or centrifuged) and recrystallized from boiling water, using decolorizing charcoal if necessary. Yield: 65% of theoretical, mp: 178°C. It is a white, odorless, crystalline substance with bitter taste. Dosage is normally % to 2 grains (30 to 120 mg).

Phenobarbitone is used to treat epilepsy, migraine headache, dental infections, pregnancy vomiting, tetanus, enuresis, chorea, pre and post operative sedation, hypertension, anxiety states, neurosis, and in the treatment of drug and alcohol addiction. This drug is also called phenobarbital.

Methylphenobarbitone. 1 mole of phenobarbitone (232.23 g) is dissolved in 2.5 liters of 95% (not dry) ethanol. To this is added a solution of 45 g NaOH (sodium hydroxide) in 500 ml of 95% ethanol. This mixture is heated, with stirring, until reflux is achieved. 70 g of dimethyl sulphate is added dropwise and refluxing is continued for 3 hours after this addition. Change the reflux condenser into a distillation condenser and distill the ethanol from the mixture. Add water and pour into an ice-hydrochloric acid mixture at 0°C. Recrystallize the resulting precipitation, after collection by filtration, from boiling water using decolorizing charcoal. Yield: 70% of theoretical, mp: 178-181°C.

Methylphenobarbitone has the advantage of being 30% less toxic than phenobarbitone and does not have such a strong hypnotic effect. It is well tolerated over long periods, tasteless, and seldom causes skin rash and other unpleasant side effects. The average dose is from 30 to 400 mg.

Moderate Acting Barbiturates

Allobarbitone. (Also called Dial.) This is prepared by using the method given for Barbitone. The only difference in the formula is the intermediates involved. Given below is the intermediate for Allobarbitone, use it in place of the intermediate used in the Barbitone formula, and carry out the formula as stated.

Preparation of the intermediate for Allobarbitone (diethyl diallyl malonate). Diethyl malonate is dissolved in anhydrous alcohol and treated with one mole of clean sodium metal per every one mole of the ester. To this solution add one mole of allyl chloride and reflux for about 4'h hours. Another equimolar ratio (1 mole of sodium per mole of ester) of sodium is added, followed by the same ratio of allyl chloride (1 mole per 1 mole), and this mixture is boiled for 2 hours. The alcohol is removed by distillation and the ester is extracted with benzene and distilled or evaporated in vacuo, recrystallized with a suitable "dry" solvent, and filtered. Evaporate again to remove traces of solvent. Keep this product, and any other substances that require dry reagents or solvents, stored away from contact with the atmosphere. When evaporating, filter the air coming into the evaporating vessel with a suitable drying agent. Use a little common sense. After the above intermediate is used in the formula for Barbitone, production of Allobarbitone is achieved. Yield: about the same as for Barbitone, mp: 174°C. Dosage: % to 3 grains.

Pentobarbitone. (Called Nembutal or Pentobarbital.) 26.7 g of clean metallic sodium are dissolved in 400 g of anhydrous (dry) ethanol. To this, a solution of 100 g of 1-methyl butyl-ethyl malonic ester and 37.2 g of dry urea is added. The mixture is heated for 4 to 6 hours in an autoclave, or refluxed for 20 to 40 hours. The alcohol is then removed by distillation. The residue is dissolved in water and this aqueous solution is acidified with hydrochloric acid. The precipitated product is filtered, washed with cold water, and recrystallized from boiling water. Yield: depends on your ability to exclude H2O from the beginning of the reaction, mp: 127-130°C.

Cyclobarbitone. (Sometimes called Phanodorm.)

Cyanacetic ester. Ethyl chloroacetate is dissolved in ethanol and boiled under reflux, with an alcoholic solution of potassium cyanide. The mixture is then filtered hot from resulting potassium chloride and the alcohol is distilled from the filtrate. The resulting residual ester is purified by crystallization or distillation. Bp: 207°C

Ethyl-cyanacetic ester. 772 parts of the above ester is added and dissolved in a solution of 92 parts sodium in 1,500 parts of dry ethanol. 750 parts of ethyl iodide are gradually added to the mixture, while it boils gently under reflux. Filter the sodium iodide that forms from the solution and distill off the alcohol. After adding water to the residue the ester separates and is purified by vacuum distillation. Collect the fraction around 125°C at 4 mm.

Cyclobarbitone. Use the intermediate directly above in the formula for Barbitone. This drug is less toxic than most barbiturates and side effects are seldom encountered. It is quite powerful as far as barbiturates go. Dosage is 100 to 200 mg (172 to 3 grains), 400 mg maximum, mp: 173- 176°C.

Hexobarbitone. (Cyclonal,Evipan.)

Delta-cyclohexenyl-methyl-cyanacetic ester. 1 mole of clean sodium metal is dissolved in 1,500 ml dry ethanol. 1 mole of delta-cyclohexene bromide is added gradually to the solution, which is then refluxed for 3 hours. Filter to remove the unwanted byproduct, sodium bromide. Distill the alcohol off and add water to the residue to separate the ester. Distill under reduced pressure, or dry with drying agent to remove water. 1 mole of this dried ester is added to 1 mole of sodium in 1,500 ml of dry ethanol, as before, and 1 mole of methyl iodide is added gradually. After the addition, reflux for 3 hours and fflter the resulting sodium from the solution. Distill the alcohol from the solution and add water to make the ester separable. After separation distill in vacuo to purify. (See how to tell which fraction coming over is the product by reading the distillation section of the equipment chapter.)

Hexobarbitone. (If you have not purified the above ester properly, this final step will most likely fail. This goes for most any formula in this book. If any of the steps listed in any formula could be bypassed they would not be written down.)

12.5 parts (parts by weight not volume, in this and most other formulas) clean sodium metal is dissolved in 300 parts dry ethanol. 40 parts of mono methyl urea and 50 parts of delta- cyclohexenyl-methyl cyanacetic ester are added to the alcohol solution. Reflux for 6 to 8 hours, remove the alcohol by distillation in vacuo, and boil the residue (reflux) with ten times its weight of 20% sulfuric acid. Hexobarbitone crystallizes on cooling and is recrystallized from ethyl acetate.

Hexobarbitone produces deep sleep, its action is rapid, but transitory. Dosage is 15 to 30 mg (1/4 to 1/2 grain) for sleep, more than this may lead to respiratory collapse and death.

Thiopentone. (Pentothal, Intraval.) 34 g of clean metallic sodium are dissolved in 1 liter of dry ethanol. To this solution add 130 g of ethyl-1-methyl butyl malonic ester. This mixture is stirred, 60 g of powdered thiourea is added and the whole is refluxed for lO hours. Remove the alcohol by distilling under reduced pressure, dissolve the residue with water and acidify with hydrochloric acid. The precipitate is filtered, washed with cold water and dissolved in a minimum amount of 5% aqueous ammonia solution. A rapid current of carbon dioxide is passed through the solution and the resulting Thiopentone is filtered from the solution, washed with cold water, recrystallized from 95% ethanol using decolorizing charcoal, if necessary. Mp: 158-159°C Dosage: 100 to 150 mg.

Synthesis of Malonic Acid

100 g of powdered chloroacetic acid is treated with 150 g of broken ice and dissolved in 125 g of caustic soda (33 1/4%) solution. The solution should be made exactly neutral, if it is not already (this refers to the mixture). After neutralizing, add 69 g of 98% potassium cyanide in 130 g of water, which has been warmed to 40°C. An hour after the addition, the mixture is slowly warmed to 100°C and held at this temp for an hour. Cool slowly to 25°C and add another 125 g of 33 1/4% caustic soda solution. Slowly heat the mixture to 100°C and hold at that temp until no more ammonia is evolved (2 to 3 hours). To test: add sodium hydroxide solution to a sample and boil. If no ammonia evolves, then the reaction is complete. When the reaction is complete, the solution is cooled, acidified with dilute HCl acid, and carefully evaporated to complete dryness on a water bath. The residue is powdered, extracted repeatedly with ether, and the ether is removed by gently heating on a water bath. You may purify further by dissolving in the minimum amount of caustic soda solution, boiling with decolorizing carbon, acidifying and extracting with ether, as before. Yield: 95 g, mp: 132°C.

Synthesis of Urea

50 g of potassium cyanide is heated in an iron crucible under a large flame until it begins to fuse. 140 g of red lead is added in small portions, while the mixture is stirred with a rod. When the addition is complete and the frothing has stopped, the fused mass is poured onto an iron tray. When cold, the mass is separated from metallic lead, ground up, and digested with 200 cc of cold water for 1 hour. The filtrate from this mixture is treated with 25 g of ammonium sulphate and evaporated to dryness on a water bath. The residue is powdered well, transferred to a flask and is boiled with 3 installments of ethanol under reflux, to dissolve the urea from the potassium sulphate. Each of the 3 ethanol extracts is filtered, then combined, and evaporated to a small bulk, until crystals of urea separate on cooling and standing. Mp: 132°C.