by Michael Valentine Smith

Since Hofmann's first trip in 1943, great deal of interest has been generated in the occurrence and properties of various lysergic acid derivatives. Fungi of the genus Claviceps, which grow on rye wheat, rice and other grasses, were the first natural source of these alkaloids to be discovered. In recent years related compounds have been found in the genera Penicillium (the blue-green mold that also produces penicillin), Aspergillus, and Rhizobus (the black bread mold). These compounds are now produced commercially by culturing certain strains of Clavicebs which produce as much as 4 g of ergotamine per Liter of culture medium. Growing pure cultures of fungi is not for amateurs, but those interested will find these references useful: JPS 58,143(1969); App. Microbiol. 18,464 (1969); HCA 47,1052(1964); Lloydia 32,327,401(1969); Can. J. Microbiol. 16,923(1970); CA 61,15314c-f, 67,84858e, 69, 36323w; Biotech. Bioeng. 13,331(1971); CA 76,57736(1972); U.S. Patent 3,483,086; Planta Med. 23,330(1973); J. Pharm. Educ. 36,598(1972); CA 78,41492(1973); French Patent 1,531, 205; German Patents 1,806,984 and 1,909,216; British Patent 1,158,380. For a description of a wild American Claviceps species see Mycologia 66,978(1974).

The occurrence of hallucinogens in the seeds (and to a lesser degree in the leaves and stems) of various members of the family Convolvulaceae (morning glories, etc.) was known to the Aztecs. Seeds of the genera Rivea, Impomoea, and Argyria (Hawaiian baby woodrose) contain lysergic acid derivatives; the woodrose being champion with about one hundred times as much as the other genera (about 7 mg alkaloids/g seeds). In view of the low yield (maximum 10 mg alkaloids/ 100 g seeds) even the famed pearly gates variety of morning glory is not worthwhile extracting, and the trip is commonly a bummer, resembling that produced by scopolamine or ibogaline and unlike that of LSD. However, the lysergic acid amide, etc., can be extracted, hydrolyzed to lysergic acid (as described below for ergot alkaloid hydrolysis), and converted to LSD by any of the methods described. For species variation of alkaloid content see Lloydia 29,35(1966). Crude ergot or woodrose seeds should yield ca. 1 g LSD/kg after conversion of the isolated alkaloids.

Alkaloid Extraction (short method)

Finely grind seeds (preferably woodrose) and add NaHCO3. Extract with ethyl acetate by soaking about one day. Filter and extract the ethyl acetate with tartaric acid solution. Basify the extract with NaHCO3 and extract it with ethyl acetate. Dry and evaporate in vacuum the ethyl acetate to get the alkaloids. Repeat this procedure on the seeds until no more residue is obtained. Alternatively, add 100 ml petroleum ether to 100 g finely ground seeds and let soak about two days. Filter, discard petroleum ether and let seeds dry. Add 100 ml methanol to the seeds and let soak about two days. Filter, repeat extraction with another 100 ml methanol and evaporate in vacuum the combined methanol extracts. The residual yellow oil contains the alkaloids.

For chromatographic purification of ergot alkaloids from seed extracts see Phytochem. 11,1479( 1972). For ergot extraction and separation see also Fr. Patent 2,089,081 (11 Feb 1972) and CA 79,105,457(1973). For a recent review of the ergot alkaloids see R. Manske (Ed.) The Alkaloids, vol. 15: 1-40(1975).

Extraction of Lysergic Acid Amides from Woodrose Seeds or Powdered Ergot

Reduce the seed material to a fine powder in a blender, and spread it out to dry. Grind it again if it is not fine enough after the first time due to dampness. Saturate the powdered seed material with lighter fluid, naphtha or ligroine. When completely saturated, it should have the consistency of soup. Pour it in a chromatography column and let it sit overnight. Remove the fatty oils from the material by dripping the lighter fluid or other solvent through the column slowly and keep testing the liquid that comes through for fats by evaporating a drop on clean glass until it leaves no greasy film. It will take several ounces of solvent for each ounce of seeds. Mix 9 volumes of chloroform with 1 volume of concentrated ammonium hydroxide and shake it in a separatory funnel. When it settles the chloroform layer will be on the bottom. Drain off the chloroform layer. Discard the top layer. Drip the chloroform wash through the column and save the extract. Test continuously by evaporating a drop on clean glass until it ceases to fluoresce under a black light. Evaporate the chloroform extracts and dissolve the residue in the minimum amount of a 3% tartaric acid solution. If all the residue doesn't dissolve, place it into suspension by shaking vigorously. Transfer the solution to a separatory funnel and wash the other vessel with acid in order to get all the alkaloid out. Pour the washings in the funnel also. Basify by adding sodium bicarbonate solution, and add an equal volume of chloroform. Shake this thoroughly, let it settle, remove the bottom layer and set it aside. Once again, add an equal portion of chloroform, shake, let it settle and remove the bottom layer. Combine the chloroform extracts (bottom layers) and evaporate to get the amides.

The Culture and Extraction of Ergot Alkaloids

Make up a culture medium by combining the following ingredients in about 500 milliliters of distilled water in a 2 liter, small-neck flask:

Sucrose..........................100 grams
Chick pea meal...................50 grams
Calcium nitrate..................1 gram
Moriopotassium phosphate.........0.25 grams
Magnesium sulphate...............0.25 grams
Potassium chloride...............0.125 grams
Ferrous sulphate heptahydrate....8.34 milligrams
Zinc sulphate heptahydrate.......3.44 milligrams

Add water to make up one liter, adjust to pH 4 with ammonia solution and citric acid. Sterilize by autoclaving. Inoculate the sterilized medium with Claviceps purpurea under sterile conditions, stopper with sterilized cotton and incubate for two weeks periodically testing and maintaining pH 4. After two weeks a surface culture will be seen on the medium. Large-scale production of the fungus can now begin. Obtain several ordinary 1 gallon jugs. Place a two-hole stopper in the necks of the jugs. Fit a short (6 inch) glass tube in one hole, leaving 2 inches above the stopper. Fit a short rubber tube to this. Fill a small (500 milliliter) Erlenmeyer flask with a dilute solution of sodium hypochlorite, and extend a glass tube from the rubber tube so the end is immersed in the hypochlorite. Fit a long, glass tube in the other stopper hole. It must reach near the bottom of the jug and have about two inches showing above the stopper. Attach a rubber tube to the glass tube as short or as long as desired, and fit a short glass tube to the end of the rubber tube. Fill a large, glass tube (1 inch x 6 inches) with sterile cotton and fit 1-hole stoppers in the ends. Fit the small, glass tube in end of the rubber tube into 1 stopper of the large tube. Fit another small glass tube in the other stopper. A rubber tube is connected to this and attached to a small air pump obtained from a tropical fish supply store. You now have a set-up for pumping air from the pump, through the cotton filter, down the long glass tube in the jug, through the solution to the air space in the top of the jug, through the short glass tube, down to the bottom of the Erlenmeyer flask and up through the sodium hypochlorite solution into the atmosphere. With this aeration equipment you can assure a supply of clean air to the Clauiceps purpurea fungus while maintaining a sterile atmosphere inside the solution. Dismantle the aerators. Place all the glass tubes, rubber tubes, stoppers and cotton in a paper bag, seal tight with wire staples and sterilize in an autoclave. Fill the 1-gallon jugs 2/3 to 3/4 full with the culture medium and autoclave. While these things are being sterilized, homogenize in a blender the culture already obtained and use it to inoculate the media in the gallon jugs. The blender must be sterile. Everything must be sterile. Assemble the aerators. Start the pumps. A slow bubbling in each jug will provide enough oxygen to the cultures. A single pump can, of course, be connected to several filters. Let everything sit at room temperature (25øC.) in a fairly dark place (never expose ergot alkaloids to bright light -- they decompose) for a period of ten days. After ten days adjust the cultures to 1% ethanol using 95% ethanol under sterile conditions. Maintain growth for another two weeks. After a total of 24 days growth period the culture should be considered mature. Make the culture acidic with tartaric acid and homogenize in a blender for one hour. Adjust to pH 9 with ammonium hydroxide and extract with benzene or chloroform/iso-butanol mixture. Extract again with alcoholic tartaric acid and evaporate in a vacuum to dryness. The dry material is the salt (i.e., the tartaric acid salt, the tartrate) of the ergot alkaloids, and is stored in this form because the free basic material is too unstable and decomposes readily in the presence of light, heat, moisture and air. To recover the free base for extraction of the amide or synthesis to LSD, make the tartrate basic with ammonia to pH 9, extract with chloroform and evaporate in vacuo. If no source of pure Claviceps purpurea fungus can be found, it may be necessary to make a field trip to obtain the ergot growths from rye or other cereal grasses. Rye grass is by far the best choice. The ergot will appear as a blackish growth on the tops of the rye where the seeds are. They are approximately the same shape as the seeds and are referred to as "heads of ergot." From these heads of ergot sprout the Claviceps purpurea fungi. They have long stems with bulbous heads when seen under a strong glass or microscope. It is these that must be removed from the ergot, free from contamination, and used to inoculate the culture media. The need for absolute sterility cannot be overstressed. Consult any elementary text on bacteriology for the correct equipment and procedures. Avoid prolonged contact with ergot compounds, as they are poisonous and can be fatal.

LSD Identification

Since LSD is an indole derivative, it gives a positive reaction (violet color) to the tests given in the indole section. LSD also fluoresces under an ultraviolet light (black light), but so do many other compounds. For infrared spectra of LSD and related compounds, see JACS 78,3087(1956) and J. Forensic Sci.12,538 (1967). For other information on identification see JPS 56,1526 (1967) and JAOAC 50,1362(1967), 51,1318(1968). For a microcrystalloscopic test see J. Pharm. Pharmacol. 22,839(1970). In order to make LSD, lysergic acid is needed. This can sometimes be obtained, but generally one of the lysergic acid containing ergot alkaloids such as ergotamine is more readily available. Ergot is the dried sclerotium of various species of fungi which infect rye (and other grasses), leading to the formation of large purple growths in place of the rye grains. These growths are collected, dried, powdered and the alkaloids extracted. For the extraction procedure see HCA 28,1283(1945), J. Pharm. Pharmacol. 7,1 (1955), JPS 50,201(1961), CA 75,137422(1971). Proc. Indian Acad. Sci. 71B,28,33(1970) gives production from artificially infected rye. Ergot is produced mainly in Europe (especially Switzerland) but some has been grown in the USA (e.g., in Minnesota). This production occurs primarily because of the use of ergotamine and related compounds in medicine (contracting the post-partum uterus, terminating migraineheadaches, etc.). Many of the ergot alkaloids are derivatives (amides) of lysergic acid. Unfortunately, these compounds have little hallucinogenic activity and it is necessary to hydrolyze (split with water) off the amide, producing lysergic acid, and to synthesize a different amide with greater psychedelic activity. This hydrolysis can be done with any of the following compounds or a mixture of them: ergometrine, ergine, ergotamine, ergosine, ergocristine, ergokryptine, ergonovine (ergo- metrine) and methysergide (Sansert). When -ine is added to the name (e.g., ergotaminine) this indicates the isomers which will lead to the production of the inactive iso-LSD. The papers cited here give simple techniques for converting these to the active forms (or see the technique for converting iso-LSD to LSD in method 1 following): HCA 37,820,2039(1954); CA 69,36322(1968); CCCC 34,694 (1969). For a review of the ergot alkaloids see THE ALKALOIDS, Manske and Holmes (Eds.), 8,725(1965), and F. Bove, THE STORY OF ERGOT (1970).

Ergot Alkaloid Hydrolysis

JBC 104,549(1934); HCA 47,1929(1964). Perhaps the best method is Hofmann's modern hydrazine hydrolysis given later, since this disposes of the necessity for isolating the lysergic acid (I); otherwise the following alkaline hydrolysis can be used: Dissolve 20 g of the alkaloid (e.g., ergotamine) in 200 ml 1M KOH in methanol (i.e., dissolve 56 g KOH pellets in 1L 100% methanol) in a 1 L heavy walled vacuum flask and evaporate in vacuum the methanol at room temperature. To prevent the solution from cooling, and thus greatly prolonging the evaporation time, put the flask in a pan of water kept at room temperature by gentle heating or by running warm water through it. Add 400 ml 8% KOH in water to the residue and boil for one hour (under N2 if possible, this can be done by filling the flask with a N2 stream and loosely stoppering or by allowing a gentle stream of N2 to flow through during heating). Cool, acidify with dilute sulfuric acid and shake in separatory funnel with 1 L ether. Discard the upper ether layer and filter with vacuum the aqueous suspension of lysergic acid (I). Wash precipitate with 20 ml dilute sulfuric acid. To recover the small amount of (I) remaining in solution, basify with Na carbonate and bubble C02 through it. Filter and add precipitate to first batch. Some isolysergic acid will remain in solution and can be precipitated by adding 10% HNO3. It can be converted to (I) by adding 3 ml 10% KOH for each 0.1 g acid, boiling on steam bath for one hour under N2 (if possible) and precipitating by acidifying with glacial acetic acid. Maximum yield is about 9 g (I) for 20 g ergotamine. A shorter method of hydrolysis which may work as well follows: dissolve 20 g alkaloid in 300 ml methanol and 300 ml 40% KOH and reflux two hours under N2 (if possible). Cool, saturate with CO2 and evaporate in vacuum. Extract the residue with hot ethanol three times and dry, evaporate in vacuum the combined ethanol extracts to get (I). Under ordinary conditions, about 20% of (I) will be converted by the action of hot water, etc., to the inactive isolysergic acid. Most of this remains in solution and can be isomerized to (I) as described above, or it can be converted to iso-LSD by any of the methods described later and isomerized to LSD (see method 1). It is unnecessary to purify (I), but this can be done as follows: dissolve 9 g (I) in 20 ml NH4OH, filter and concentrate in vacuum at room temperature to precipitate (I). After filtering, the grey crystals can be further purified by dissolving in boiling water and cooling in ice bath to precipitate (I). Melting point should be about 240o (decomposes). Alternatively, the dark-colored (I) resulting from hydrolysis can be shaken with 2x400 ml 2 M NH4OH in ethanol, and the combined extracts evaporated in vacuum to give (I). Dissolve the remaining residue in 500 ml hot methanol, cool to 0ø and filter out the (I) (recrystallize-water). Can remove colored impurities by shaking solution with decolorizing carbon and filtering. Recently a method for increasing the yield of (I) about 10% using 2.5% hydrazine hydrate was described (CA 69,36323(1968)). Dissolve 7 g alkaloid in 200 ml 6 N KOH in methanol and 200 ml ethanol, add 10 ml hydrazine hydrate and boil four hours under N2 (if possible) and proceed as above. Finally, the (I) must be thoroughly dried by heating at about 110ø/1 mm for two hours or 150ø if ordinary lab vacuum of 15 mm is used. A forced water vacuum (about 25 mm) can be used here as elsewhere. An oil bath (e.g., mineral oil) will allow temperature regulation.

LSD Synthesis


There are certain aspects of LSD production which are common to all synthetic methods. The first is a certain degree of danger; each uses dangerous reagents and solvents. Hydrazine and hydrazine hydrate are both violent poisons, and each can cause severe skin burns and eye damage. The vapor of each is irritating, and can cause severe eye irritation as well as liver and blood damage, but the symptoms don't always manifest right away, sometimes appearing three or four days after exposure, so it is easy for exposure to be much more dangerous than is immediately realized. In addition, anhydrous hydrazine is a sensitive and violent explosive, the explosion of which can be set off by certain types of stainless steel and such common things as wood and rust. Both trifluoroacetic acid and sulfur trioxide will cause very severe skin burns, and their vapors are extremely irritating. Sulfur trioxide is such a strong dehydrating agent that it chars organic material, and its heat of dehydration is so high that it will start a fire if spilled on wood, which could prove fatal were flammable solvents in use at the time or stored nearby. Phosgene is very poisonous; so insidious that it was used as a war gas in World War I. One deep breath can cause immediate collapse and death, and as it is not irritating there is no gag reflex to prevent one from taking that deep breath. Doses which are not high enough to be immediately lethal may not be noticed at all at the time of exposure, yet lead to death within 24 hours. Sub-lethal doses cause pulmonary edema and serious respiratory disability; again, the symptoms can appear well after an exposure which was hardly noticed. Diethylamine, used in every LSD synthesis, has a very low flash point, and its vapor is irritating. The vapor of DMF is also irritating, and prolonged exposure can cause liver damage. In fact, most of the solvents used in LSD production are either flammable or toxic or both. In addition to all the above, the starting material, the ergot alkaloids, is as a class quite toxic, and clean working conditions are necessary when working with it. Ergot alkaloid poisoning, known in the Middle Ages as Saint Antony's fire, can actually cause one's limbs to blacken, shrivel, and fall off! Any woman working with these compounds should also be aware that many of them are oxytoxics, that is, they cause uterine contractions, and are so used to induce labor, etc.

Working Conditions

There are certain procedures common to all syntheses of LSD which are based upon the sensitive nature of ergot compounds in general. Natural ergot alkaloids, lysergic acid, LSD, and the intermediate products associated with the various syntheses are all to a varying degree unstable. Even the most stable of these compounds will readily decompose under any but moderate conditions. Thus precautions must be taken against light, moisture, oxygen, and heat. Light of the ultraviolet region promotes addition of water at the delta-9-10 double bond to form the lumi-compounds. Thus reactions are best carried out in the light of red or yellow photographic darkroom bulbs, and storage should be in opaque or amber bottles. Most of the reactions involved in LSD synthesis require anhydrous conditions for good yield, and so protection must be made against moisture during the actual production. Furthermore, the final product must be thoroughly dried to prevent possible formation during storage of the lumi-compounds as mentioned above. Oxidizing agents, including atmospheric oxygen, will decompose ergot compounds. For this reason, all reactions are carried out in an atmosphere of an inert gas such as nitrogen. The danger of oxidation increases with temperature, so this precaution is of course most important with those reactions proceeding at elevated temperature. Various methods have been devised to prevent oxidation during storage. The most obvious is to store the LSD in nitrogen filled containers, but the excellent protection thus afforded is of course lost when the bottle or ampule is opened. Another method is to use an antioxidant; Brown and Smith recommend ascorbic acid. A more sophisticated method, recommended on the highest authority, is to make LSD maleate rather than the tartrate. Both maleic and tartaric acids are dicarboxylic, but the pK2 of maleic acid is too low to form a salt with LSD. Thus there is a free carboxyl group in LSD maleate, which group will serve to prevent oxidative decomposition. Excessive heat will cause decomposition of LSD and its precursors, and will also increase the possibility of racemization. Thus reactions at elevated temperature are not unnecessarily prolonged, nor are temperatures unnecessarily raised. All drying is done in vacuo in an inert atmosphere, and long term storage should be under refrigeration.

Legal Acid

I want to emphasize that "legal acid" can be obtained if other amines are substituted for diethylamine in LSD synthesis. These other lysergamides should give identical trips, but most of them are less potent than LSD. Precise potency data do not exist, so it remains for an enterprising chemist to gain immortality by adding each of the following amines (and any others that come to mind) to separate aliquots of the final step of LSD synthesis (they could easily be done simultaneously), isolating the tartrates and assaying them for potency: piperidine, diisopropylamine, ethylisopropylamine, ethylpropylamine, methylethylamine, methylisopropylamine, tetrahydrooxythiazine, tetrahydroisoxazine, dioxazole, 2-methylmorpholine, 2,5-dimethyl (or dimethoxy) pyrrolidine, cyclo-butyl-amine, cyclopentylamine, etc. Published potency data expressed as a fraction of LSD activity follow: pyrrolidide (1/20), dimethylamide (1/20), morpholide (1/10 or 1/3), ethylpropyl (1/3), dipropyl (1/10), methylethyl (less than 1/10), methylpropyl (less than 1/10).


LSD via the Hydrazide HCA 38,429(1955), HCA 26,953(1943)
CA 57,12568(1962), U.S. Patent 3,239,530(1966).

Perhaps the simplest method is the following devised by Hofmann, which proceeds directly from the ergot alkaloid via hydrazine, and is not to be confused with his earlier use of hydrazine under more violent conditions which led to a racemized product and reduction of the yield by one-half.

Add 1.16 g ergotamine HCl to 4 ml anhydrous hydrazine and heat one hour at 90ø. Add 20 ml water and evaporate in vacuum. Can proceed to the next step or can purify by adding ether and aqueous tartaric acid, basify the aqueous phase and extract aqueous phase with CHCl3 to get mainly d-iso-lysergic hydrazide (I). Can chromatograph on alumina and elute with 0.5% ethanol in CHCl3 to purify. To 1 g (I), finely ground, in 40 ml 0.1 N ice cold HCl, add with good stirring at 0ø 4 ml 1N Na nitrite. Quickly over two-three minutes, add 40 ml 0.1 N HCl so pH is about 5. Let stand five minutes, basify with 1N NaHCO3 and extract with 100 ml ether, then 50 ml ether. Wash ether with water and dry and evaporate in vacuum at 10ø. Dissolve the resulting yellow azide in about 5 ml diethylamine (DEA) at 0ø and heat one hour at 60ø in a bomb (sealed metal pipe), or heat 3 to 4 hours at 45øC in a vented flask. Let stand several hours and evaporate in vacuum to get about 0.7 g d-LSD and 0.15 g d-iso-LSD (which can be converted to d-LSD as described in method 1 following). Alternatively, the DEA can be added to the cooled ether solution of the azide and let stand several hours or overnight at room temperature in the dark in a vented flask. An alternate method of proceeding from the hydrazide follows (U.S. Patent 3,085,092). To a solution of 1.4 g (I) in 5.5 ml 1 N HCl, 5 ml water, 5 ml EtOH, add 1 g acetylacetone (2,4 pentanedione), let stand 1 hour at room temperature and neutralize with 5.5 ml 1 N NaOH. Filter off the lysergyl pyrazole (II) and wash with water. Can purify by drying in vacuum at 60øC and recrystallizing from chloroform by the addition of ether. Heat 0.4 g (ll) and 2.5 ml DEA at 100ø C for 2 hours (or let stand 15 hours at room temperature, evaporate to dryness and heat a few minutes at 100øC in vacuum). Can recrystallize from CHCl3, petroleum ether or as described elsewhere here.

Technical Scale Details For This Method // Hydrazide Production

In dim yellow light, (preferably) three tared and fully dried 250 ml round-bottom flasks containing stirring bars are each charged with 30 g dry ergotamine tartrate and 120 ml anhydrous hydrazine. The flasks are fitted with gas inlet tubes adjusted to just above the liquid level and streams of nitrogen passed through, the exhaust gas being led through wash bottles equipped with traps and containing dilute acid to remove hydrazine vapors. The flasks are lowered into oil baths preheated to 90øC, and heated with slow stirring for one hour. The contents of the three reaction flasks are then emptied into a 2000 ml beaker containing 900 ml distilled water, and this solution transferred to a 3000 ml two-neck round bottom flask. An additional 900 ml water is used to rinse the residue in the flasks, beaker, etc. into the 3000 ml flask. This large flask is fitted with siphon tube, gas inlet tube, and gas outlet connected to wash bottle and trap. The aqueous hydrazide solution is evaporated from a tared 2000 ml flask on an efficient rotary evaporator, using a bath temperature of 40øC and an ice-cooled condenser; the 3000 ml siphon flask assembly is used as storage for the vacuum feed. The weight of the crude hydrazide so obtained is determined, it is dissolved in about 170 ml 1 N tartaric acid, the aqueous solution washed with three 30 ml portions ether, made alkaline with 190 ml 1 N ammonium hydroxide, and exhaustively extracted with successive portions of chloroform, the first two portions being 100 ml each, the following 50 ml. Completeness is ensured by testing with UV light, extraction ceasing only when the chloroform extract exhibits no blue fluorescence. The chloroform solution is washed with three 30 ml portions distilled water, dried over chloroform moistened magnesium sulfate, and the hydrazide recovered by vacuum evaporation in tared 500 ml flasks, one such flask being used for each two 90 g batches. These flasks are flushed with nitrogen, stoppered, and stored in a dark and dry refrigerator. As the hydrazide is stable, all the ergotamine tartrate will be converted to it prior to the next step. Theoretical yield from 1000 g ergotamine tartrate is 429.65 g; 80% yield is 343 g.

Pyrazole Production

In dim red light, the weighed hydrazide contained in one of the 500 ml flasks (ca. 67 g; 95% of theory) is washed into a 1000 ml beaker with 263 ml 1N hydrochloric acid. 239 ml distilled water, 239 ml ethanol (95%), and 37 ml 2,4-pentanedione are added, and the well-mixed solution left to stand in the dark at room temperature until the reaction is complete, i.e., about 30 minutes. The reaction mixture is neutralized with the addition of 263 ml 1 N sodium hydroxide, and the beaker covered with parafilm and refrigerated to ensure complete precipitation. The pyrazole is filtered at the pump, the mother liquor being returned to the beaker and used to wash out the last few crystals, washed with cold water, and sucked dry under a stream of dry nitrogen. The product is dried in vacuo over barium oxide or phosphorus pentoxide for at least twelve hours before proceeding to the next step, wherein anhydrous conditions will increase yield. Hofmann calls for drying the pyrazole in vacuo at 60øC, which indicated the product to be fairly stable. So all the hydrazide is converted prior to aminization.

Amide Production

In dim red light, 50 g of the well-dried pyrazole and 700 ml freshly dried diethylamine are placed in a tared and well-dried 1500 ml flask equipped with gas inlet tube and stirring bar. The flask is lowered into a bath preheated to 45øC, and the contents stirred under a stream of nitrogen for four hours. On a rotary evaporator, using a 6 atm temperature of 40øC and an ice-cooled condenser, the diethylamine is removed in vacuo and set aside for purification and re-use. Briefly and in high vacuum the flask is heated to 100øC, the split-off pyrazole being thereby driven off. The residue so obtained is immediately placed in solution with methanolic potassium hydroxide to effect interconversion of the stereoisomers. Amination and Transposition will proceed simultaneously, the first batch being transposed while the second is aminated.

Production Scale Isomerization of iso-LSD to LSD

In dim red light, the amide residue from the last step is dissolved in the least possible amount of dry methanol and washed into a 1500 ml round-bottom flask. A two-fold volume of 4 N methanolic potassium hydroxide is added, and the well-mixed solution left to stand at room temperature, in the dark and under a slow stream of nitrogen, for four hours. At the end of this period, the solution is neutralized with methanolic hydrogen chloride (ca. 5 N), washed into a 4000 ml Erlenmeyer flask, and dried over methanol-moistened anhydrous magnesium sulfate (0.10 g MgSO4 per ml KOH solution). The methanolic acid should be added slowly and with good stirring to prevent possible hydration of the 9-10 double bond to give lumi-LSD. Together with 100 ml dry isopropanol (to remove the last trace of water azeotropicly) the dried solution is transfered to a 3000 ml siphon flask assembly, and the solvent removed in vacuo in a tared 500 ml two-part freeze-dry flask. The weighed gummy residue is scraped into the thimble of a Soxhlet extractor, the adhering residue being washed into the thimble with portions of warm chloroform, the total volume of which is 12.5 ml per gram amide (total weight minus weight KCl). A 3000 ml flask is used with the extracter, and it is previously charged with 37.5 ml dry benzene per gram amide. Under a stream of dry nitrogen, the solvent is in vacuo at 40øC refluxed through the thimble, thus extracting the amide from the inorganic salt and at the same time preparing the solution for use in the chromatographic separation of the stereoisomers. The above solution is stored over a small amount of benzene-moistened calcium sulfate in a nitrogen flushed flask which is placed in a dark refrigerator. All the pyrazole is converted to this benzene-chloroform solution prior to separation of the isomers.

The following methods all proceed from lysergic acid (I). Methods 1, 2, 4, and 6 give less than 20% iso-LSD in the product but methods 2, 5, and 9 seem to have the highest total yield (about 80%) of LSD plus iso-LSD. Since unreacted lysergic acid can be recovered and run through the synthesis again, and iso-LSD isomerized to LSD as described here, it is probably best to use the simplest methods. These comparative yields come mostly from the reference to method 9.

From Lysergic Acid - Method 1 CA 50,10803d( 1956) (Pioch)

Dissolve 5.3 g dry (I) in 125 ml acetonitrile (or dimethylformamide or proprionitrile) and cool to -20ø (freezer or dry ice-acetone or ethanol mixture). Add 8.82 g trifluoroacetic anhydride in 75 ml acetonitrile cooled to -20ø carefully. Let stand at -20ø 1 1/2 hours or until all the (I) dissolves. Then add 7.6 g DEA in 150 ml acetonitrile and let stand at room temperature in dark two hours. Evaporate in vacuum to get LSD. If purification is desired, dissolve the residue in 150 ml CHCl3 and add 20 ml ice water. Pour into 1/2 L separatory funnel and drain out the lower CHCl3 layer into a beaker (after shaking). Add 50 ml CHCl3 to funnel, shake and drain bottom layer into same beaker. Repeat with 3x50 ml CHCl3 and discard the water. Extract the combined CHCl3 extracts with 4x50 ml ice cold water and dry, evaporate in vacuum the CHCl3 to get 3.5 g d-LSD. This is composed partly of the inactive d-iso-LSD, which, while it will not effect the trip, can be recovered and converted to d-LSD as follows: dissolve the residue in 120 ml benzene and 40 ml CHCl3 (or 200 ml methanol), add tartaric or maleic acid and shake to precipitate mainly d-LSD (add a little ether and cool in refrigerator several days if necessary to ensure complete precipitation; evaporate in vacuum the solvent to get d-iso-LSD. Add 50 ml ethanol and 5 ml 4N KOH per g iso-LSD and let stand at room temperature two hours; evaporate in vacuum (or extract with CHCl3 as above) to get LSD. 4 hours in 2.66 N methanolic KOH is said to be optimal for isomerization.

From Lysergic Acid - Method 2 JOC 24,368(1959) (Galbrecht)

This method is supposed to give little iso-LSD but it gives some of the monomethylamide. Add 1 L dimethylformamide (freshly distilled, if possible) to dry flask fitted with stirrer, ice bath, dropping funnel and condenser, both protected from water by Ca chloride drying tubes. Add dropwise with stirring over four-five hours at 0ø 0.21 lbs (90.7 g) SO3 (sulfuric anhydride, available as Sulfan from Allied Chem. Co.). If precipitate forms, stir until it dissolves. Sulfan may be made in larger amounts and is good for several months if kept dry and cool. Molarity of fresh 503-DMF reagent should be about 1M, but for precise determination, add a little water to an aliquot and titrate with standard NaOH to phenolphthalein end point. Add 6.45 g dry (I) (or 7.15 g (I) monohydrate) and 1.06 g LiOH hydrate (or NaOH or KOH but these absorb water so they must be dissolved in absolute methanol, titrated and added in equimolar amounts) to 200 ml methanol in a 1 L vacuum flask and evaporate in vacuum. Dissolve residue in 400 ml anhydrous dimethylformamide and distill off 200 ml DMF at about 15 mm Hg through a twelve inch column packed with glass helices or other material. Cool to 0øC and rapidly add 50 ml SO3-DMF solution (1 M). Stir at 0øC for ten minutes and add 91.5 g (12.9 ml) DEA and stir ten minutes. Add 400 ml of water stir and add 200 ml saturated NaCl. Extract the LSD by shaking with several 500 ml portions ethylene dichloride (can use indole test given in indole section to show completeness of extraction). Combine extracts (lower layer in separatory funnel) and dry, evaporate in vacuum to get LSD (can purify as above).

From Lysergic Acid - Method 3 JOC 24,368(1959) (Garbrecht)

This route is said to give a lower yield than method 2. Dissolve 13.4 g dry (I) in 250 ml dry dimethylformamide and cool to 0ø. Add cooled solution of 3.4 ml 0.35 M methane-sulfonic acid anhydride in dry dimethylformamide. After thirty minutes at 0øC add 14.6 g (20.4 ml) DEA and keep at 0øC one hour. Evaporate in vacuum to get LSD and proceed as above.

From Lysergic Acid - Method 4 CA 57,5979(1962) (Hofmann)

Dissolve 0.536 g (I) in 10 ml freshly distilled POCl3; stir and add 416 mg powdered, freshly sublimed PCl5. Hold two minutes at room temperature, two minutes at 90øC, and evaporate in vacuum. Extract the residue with hexane to give the lysergic acid chloride-HCl (can also extract the reaction mixture with hexane instead of evaporating in vacuum). Alternatively, use 6 ml POCl3 and 240 mg SOCl2 and heat three minutes at 90øC to get the acid chloride. To 5 g of the acid chloride add 1.4 ml DEA in 50 ml methylene chloride and cool to 0ø. Stir and add 27.5 ml pyridine and stir one-half hour at 0øC. Warm to room temperature and stir 1 1/2 hours; evaporate in vacuum to get LSD.

From Lysergic Acid - Method 5
CCCC 27,1590(1962) (Cerny and Semonsky) cf. CA 75,77110(1971)

To a suspension of 13.4 g dry (I) in 800 ml dry dimethylformamide (DMF) in a 2 L vacuum flask at 20ø, add a solution of 8.9 g N,N'-carbonyldiimidazole in 250 ml DMF and stir at 20ø in dark for one-half hour. Add a solution of 4 g DEA in 50 ml DMF and let stand two hours at 20ø; then twenty hours at 5ø. Evaporate in vacuum to get LSD. Can purify as above or dissolve residue in 2 1/2 L 2% tartaric acid; extract with ether and discard ether. Filter, basify with NH4OH and extract with a 9:1 solution of ether:ethanol. Dry and evaporate in vacuum to get LSD in 81% yield.

From Lysergic Acid - Method 6 JMC 16,532(1973) (Johnson et al)

This method gives very little iso-LSD.

To a refluxing slurry of 3.15 g dry (I) or monohydrate) in 150 ml CHCl3 add 0.1 mole of the amine in 25 ml CHCl3 and 2 ml POCl3 simultaneously from separate dropping funnels over 2 to 3 minutes. Reflux 3 to 5 minutes more till a clear amber solution results. Cool to room temperature and wash with 200 ml 1M NH4OH. Dry and evaporate in vacuum (below 40ø). Can dissolve in the minimum amount of methanol and acidify with a fresh solution of 20% maleic acid in methanol. Filter and wash crystals with cold methanol to get the LSD or other amide. This method works with a wide variety of amines. For LSD itself, the POCl3 can be added first. The yield is about 50%.

From Lysergic Acid - Method 7 German Patent 1.965,896 (1970) (Julia et al.)

See end of total synthesis of LSD given below.

From Lysergic Acid - Method 8 U.S. Patent 3,141,887 (Patelli and Bernardi)

Note: Phosgene is very hazardous and only professional chemists working with a fume hood should even think about using this method. It can be dissolved in a weighed container of DMF (dimethylformamide) and a second weighing will give the phosgene concentration. 0.5 g anhydrous lysergic acid suspended in 10 ml DMF or acetonitrile at -10øC are reacted with 2 ml of DMF containing 0.34 g of the phosgene-DMF complex for 20 minutes. Add 0.7 g diethylamine in 10 ml DMF (or acetonitrile), keep at -10øC for ten minutes and then at room temperature for 10 minutes. Dilute with chloroform, wash with NaOH (1 normal), then water and distill off the solvent in a vacuum. Dissolve the oily residue in methanol, acidify with tartaric or maleic acid; add ether to start crystallization. Keep overnight at 0øC, filter and wash with ether. Dissolve the product in methanol, decolorize with charcoal and precipitate with ether to obtain the tartrate or maleate (tartrate melts 192-198 C). D20 = + 25ø (C = 1 in water).

From Lysergic Acid - Method 9 CT 13,373(1978) (Losse and Mahlberg)

This method gives about 2/3 iso-LSD, and about 80% total yield.

Add 134 mg (0.5 mM) dry (I), 103 mg (0.SmM) N,N-dicyclohexylcarbo- diimide, 90 mg (0.67mM) 1-hydroxybenzotriazol (N-hydroxybenzotriazol) and 0.5 mM diethylamine to 2.5 ml CH2Cl2 and 2.5 ml tetrahydrofuran and stir in the dark at 20ø C for 24 hours. filter, wash precipitate with CH2Cl2 and evaporate the filtrate at 15 mm Hg, 30ø C to get LSD.


This and the following method are expanded versions of Garbrecht's method. My own prejudice is that it makes much more sense to use one of the other, simpler methods since the unreacted lysergic acid can be recycled, and the initial yield is consequently of little import. However, the details as presented here derive from the practical experience of underground chemists and contain many points of interest for any technique.

Notes on Processes:

1. Chemicals to process one kilogram of ergotamine tartrate:

Alumina, Activity II, 100-200 mesh...................8 Lbs.
Benzene, Reagent..................................20 Liters
Charcoal, activated powder, Norit A...............100 Grams
Congo red papers.....................................1 Vial
Dichloromethane (methylene chloride), Purified....60 Liters
Diethylamine, Reagent..................500 Grams or 725 ml.
Dimethylformamide, Reagent........................12 Liters
Ergotamine tartrate..............................1 Kilogram
Ether, Absolute......................................5 Lbs.
Ethyl alcohol, Anhydrous, Denatured................10Liters
Lithium hydroxide hydrate, Reagent................200 Grams
Methanol, Reagent..................................24 Pints
Molecular sieve, Linde 4 A............................1 Lb.
Petroleum ether, B.P. 40ø=70øC...................2.5 Liters
Phenolpthalein, White................................1 Gram
Phosphorus pentoxide, Reagent.....................100 Grams
Potassium hydroxide, Reagent.........................2 Lbs.
Sodium Chloride, Reagent.............................5 Lbs.
Sulfuric acid, Fuming 33%............................3 Lbs.
Sulfuric acid, Reagent...............................4 Lbs.
Tartaric acid, natural, powder, Reagent...........200 Grams

2. Cylinder gasses:
Ammonia, anhydrous...................................1 Lb.
Nitrogen, Dry.....................1 small welding cylinder

3. Notes on preparing reagents:

Ammoniacal ethanol is prepared by chilling ten liters of anhydrous denatured ethyl alcohol as commercially purchased in a freezer to well below 0ø C. Next, 600 to 750 ml of liquid ammonia is drawn from a pressure cylinder into a 1000 ml graduate in a well ventilated area. The contents of the graduate are carefully poured into the chilled alcohol. The solution is then stirred to mix and warmed to room temperature. The solution should be at least two molar as determined by titration against standard acid solution to a methyl red endpoint. If titration is to be attempted, a little methyl red should be added to the chemical list. Dilute sulfuric acid is prepared by pouring 750 ml of sulfuric acid into about 11.25 liters of ice cold water in a large acid resistant container such as a polyethylene jug or 5 gallon gasoline container, etc. Anhydrous dimethylformamide for making up sulfur trioxide-DMF reagent is prepared by shaking three liters of reagent dimethylformamide with 100 to 200 grams of Linde molecular sieve, and allowing the mixture to stand overnight with occasional shaking. Next, the dimethylformamide is decanted off and poured into a five liter boiling flask. The flask is fitted with a helices packed fractionating column and distilled at 25 millimeters pressure. 800 ml is distilled off as a forerun and discarded or re-dried over molecular sieve. The next fraction of about two liters is collected and kept so as to protect from atmospheric moisture (drying tube, etc.). A little dimethylformamide is left in the boiling flask. Dimethylformamide when prepared in this manner is excellent for preparing the sulfur trioxide reagent. Commercially available spectro-quality or pesticide quality dimethylformamide may also be used if the water content is specified to be less than .O5%, but the reagent obtained from these products has always appeared darker in color than that made by the above method. Commercial reagent quality dimethylformamide is suitable for the main reaction.

4. Preparation of the sulfur trioxide-dimethylformamide reagent (503-DMF).

Sulfur trioxide is distilled from fuming sulfuric acid. About 200 grams are necessary and can be obtained from varying amounts of fuming sulfuric acid depending upon the concentration of sulfur trioxide in the commercially available product. Occasionally it is possible to purchase fuminþ sulfuric acid which contains as much as 70% sulfur trioxide (S03). Fuming sulfuric acid containing 30-33% is usually easily available and 200 grams of 503 can be obtained by distilling about one kilogram of it. The distillation is done at atmospheric pressure in a simple distillation apparatus which utilizes a large bore condenser of the West or similar typ;. The receiving flask should be connected to the condenser in a closed fashion as in a vacuum distillation and vented to the atmosphere through a drying tube or similar device. Corks, rubber stoppers and any kind of joint grease cannot be used in contact with sulfur trioxide or fuming sulfuric acid as they will char. Tapered glass fittings should be used throughout without grease. All fittings should be cleaned in benzene to remove grease before distilling. Sulfur trioxide fumes are very irritating and good ventilation is a must. Glass stoppers and small empty flasks with tapered fittings should be used to close openings in the distilling apparatus when changing receiving or boiling flasks. This will help considerably to keep fumes out of the atmosphere.

Experimental procedure:

200 grams of sulfur trioxide are distilled from the appropriate amount of fuming sulfuric acid. The boiling range should be 5ø or less. The 200 grams are collected in a small round bottom flask previously weighed with a glass stopper in place. Next, a small unweighed portion of phosphorus pentoxide is added to the sulfur trioxide in the flask (1 teaspoonful). The flask is swirled and then placed on the distilling apparatus as the boiling flask. A forerun of 5 ml is distilled into a small receiving flask. This is returned to the boiling flask and the apparatus is fitted with a receiving flask (3 liter boiling flask) already containing 1500 ml anhydrous dimethyl-formamide and a magnetic stirring bar teflon coated. The flask is surrounded by an ice water bath in a nonmagnetic container and a magnetic stirring motor is placed underneath to rotate the stirring bar in the flask. The remaining sulfur trioxide is distilled into the receiving flask containing the dimethylformamide. The receiving flask should be absolutely dry before filling it with the dimethyl-formamide. The sulfur trioxide should distill off over a 2ø boiling range the second time. A hot water bath or an oil bath is convenient when heating the boiling flask and prevents overheating. When the distillation is complete, the receiving flask is removed carefully and stoppered. The flask is warmed and swirled to dissolve any crystalline material and then cooled to around 5øC. and left several hours. If any material precipitates, a little anhydrous dimethyl-formamide is added to dissolve the residue. The flask is swirled and the contents decanted into a storage bottle. The temperature in the storage bottle is recorded and a ten milliliter aliquot withdrawn with a pipette. The aliquot is run into a 250 ml Erlenmeyer flask and diluted with 10 ml water to decompose the complex. The mixture is then titrated to a phenolpthalein endpoint with a standard base solution. A convenient standard base solution can be made by dissolving 1 mole of lithium hydroxide hydrate (41.96 gr) in distilled water to make one liter in a volumetric flask. Three consecutive titrations should be done and an average taken. One mole of sulfur trioxide reacts with two moles of lithium hydroxide. The reagent bottle should be labeled as to sulfur trioxide concentration (about 1.5 molar) and the temperature at which the concentration was determined since the reagent has a rather high coefficient of expansion.

If at any time during the distillation of the sulfur trioxide, crystals of solid sulfur trioxide form in the condenser or receiving flask, they may be melted by careful local heating with a propane torch flame or by running hot water through the condenser jacket. The water in the condenser should be above 23øC during distillation of sulfur trioxide to prevent crystallization of sulfur trioxide polymers.

5. Notes on changing the scale of reactions:

The ergotamine to lysergic acid reaction may be scaled up or down by multiplying the quantities involved by a proportionality constant: all quantities should be multiplied by the same constant. It has been found that the quantities of water and potassium hydroxide used in the hydrolysis of ergotamine are not particularly critical and their relative concentrations may be varied somewhat to meet other considerations. As a rule, ergotamine should be hydrolysed with about a 1.5 to 2.5 molar potassium hydroxide solution. The lysergic acid to lysergic acid amide reaction has been designed to utilize minimal quantities of solvents in order to squeeze as much material as possible into ordinary laboratory glassware. Some workers have suggested that the quantity of dichloromethane (or chloroform) can be further reduced and still effectively extract the amide, but this may prove difficult, especially if emulsions are encountered. When scaling down the reaction, if desired, the quantities of methanol, dimethylformamide, saline solution, and dichloromethane may be in greater quantity than calculated by direct proportion to the other reagents. The proportional relationship between lysergic acid, lithium hydroxide and sulfur trioxide must be strictly adhered to. The molar proportions are: lysergic acid, 1 mole; lithium hydroxide, 1 mole; sulfur trioxide, 2 moles. Diethylamine should be added in at least five molar equivalents. 6.5 equivalents are used in the example given. In general, two thirds of the dimethylformamide should be distilled off from the lithiumlysergate solution. It is convenient to do the reaction in a small quantity of dimethylformamide if doing large quantities of lysergic acid since the product is contained in smaller volume and extraction may be done with less solvent.

6. Notes on purification of amide

The chromatography detailed in the example has been used and works fairly well, however, the removal of all colored impurities is not achieved and there is room for improvement. It is suggested that further experimentation be done to improve the process. An ultraviolet light is indispensable when doing experimentation with these compounds. The lysergic acid amide displays a blue fluorescence. Benzene has been used successfully as an eluant on activity 4 alumina, but the results were no better than the example given. Chloroform and chloroform-benzene mixtures also have been used on varying grades of alumina but no useful data is available.

7. Notes on crystallization of tartrate

Methanol and methanol-ether mixtures have both been used to crystallize the amide tartrate. Crystallization proceeds more readily if ether is present. Usually, the quantity of solvent from which the tartrate is crystallized should be around 4.0 to 6.0 times the weight of the free base amide (in grams) expressed in milliliters. For example, if the free base lysergamide weighs 20 grams, then the crystallization should be done in 80 to 120 milliliters of solvent. The purer the free base amide, the less solvent that may be effectively used and the higher the yield. The solvent is reagent grade methanol containing 10% to 25% ethyl ether. It is usually preferable to dissolve the amide in the methanol and then to add the ether. Ether should not be added after the tartaric acid is added since it precipitates the impurities at the site of addition. Crystallization occurs more slowly with impure preparations. Considerable time should be allowed in the cold before filtering. Overnight is excellent.

Lysergic Acid Monohydrate

350 grams of potassium hydroxide are dissolved in 3500 ml of water in a five liter three-neck boiling flask equipped with a reflux condenser and a small tube introducing a slow stream of nitrogen gas. The mixture is then heated to about 80øC, when 500 grams of ergotamine tartrate is added to the flask. The temperature is maintained at 80ø for about 2 1/2 hours while continuously bubbling nitrogen gently through the mixture. The reaction mixture is next poured into a ten liter polyethylene bucket and diluted by addition of ice to an approximate volume of six liters. The bucket is then placed in an ice water bath and the mixture cooled below 10øC, after which the mixture is slowly neutralized by the careful addition of cold dilute sulfuric acid (15 parts water:1 part acid) to a congo red endpoint (pH 4.0 - 4.4). Lysergic acid and considerable potassium sulfate precipitates at this time. The bucket is allowed to stand in the ice water bath several hours when the precipitate is filtered off on a large buchner funnel (15 cm or larger) and sucked as dry as possible on the funnel. The slightly moist filter cake is broken up and placed in a four liter beaker containing 2 1/2 liters of two molar ammoniacal ethanol (about 300 ml liquid ammonia poured into 5.0 liters of chilled anhydrous denatured ethanol). The contents of the beaker are stirred for one hour and then filtered. The filtrate is kept and the filter cake is broken up and extracted in the previous manner with a second portion of two liters ammoniacal ethanol. This extract is filtered using 500 ml of ammoniacal ethanol to wash down the filter cake and the combined filtered extracts are taken to total dryness in a rotary vacuum evaporator over a boiling water bath. The tan colored residue is easily scraped from the sides of the evaporator flask by means of two bent wire rods, one bent less than 90ø and one bent greater than 90ø. The residue is scraped into a large mortar as well as possible with the bent rods and then 225 ml of methanol mixed with 75 ml of water is used in divided portions to wash the remaining residue in the flask into the mortar. The last portion of the methanol-water mixture (about 100 ml) is left in the evaporator flask to be used to wash the mortar clean later. The slurry in the mortar is ground with a pestle to an even consistency free of lumps when it is then poured and scraped into a large Buchner funnel (15 cm or larger) and filtered. The remaining portion of the methanol-water mixture is used to wash down the mortar and the filter cake. Next the filter cake is washed with at least 250 ml of water and sucked dry for an hour. The filter cake is broken up and dried to a constant weight under high vacuum at 90øC in a dessicator.

Yield: 125 to 150 grams of lysergic acid monohydrate, MW.286.35. A slightly off-white powder.

N,N-Diethyllysergamide (LSD)

143.20 grams of lysergic acid monohydrate (0.5 mole) and 21.0 grams of lithium hydroxide hydrate (0.5 mole) are dissolved in 2500 ml of methanol with stirring and warming in a four liter beaker. When the lysergic acid is completely dissolved, the contents of the beaker are admitted to a rotary vacuum evaporator and taken to total dryness over a boiling water bath. A little methanol is used to rinse any lysergate residue that may remain in the beaker into the evaporator. The crumbly, tan colored dry residue is dissolved and rinsed into a five liter boiling flask with three liters of anhydrous dimethylformamide. Considerable care should be exercised when transferring solutions from one vessel to another to avoid loss of lysergate since small deviations from the calculated quantities of reagents result in considerable reduction in overall yield. The five liter flask is next fitted with a 600 mm helices packed fractionating column and about 2050 ml of dimethylformamide is carefully distilled off at 10.0 millimeters pressure to remove water from the lysergate solution. The boiling flask containing lithium lysergate in the remaining dimethylformamide is tightly stoppered and chilled in an ice water bath to below 5øC. 1.0 mole of sulfur trioxide is now added to the flask by addition of the appropriate amount of sulfur trioxide-dimethylformamide reagent (previously prepared by double distilling sulfur trioxide from fuming sulfuric acid and slowly adding it to anhydrous dimethylformamide to make a solution of approximately 1.5 molar strength as determined by titration against standard base solution). Cooling and swirling are continued for 15 minutes when 335 ml of diethylamine is added. Cooling and swirling are continued 15 minutes longer when the reaction mixture is poured into 3800 ml of a 20% saline (sodium chloride) solution to break the reaction complex. The reaction mixture is now extracted with 10.0 to 12.0 liters of methylene chloride (dichloromethane) or chloroform in divided portions in a separatory funnel. A scheme for division of the extraction solvent is as follows:

Extract Quantity Total Solvent Used
First 2000ml 2000ml
Second 1800 3800
third 1500 5300
Fourth 1200 6500
Fifth 1000 7500
Sixth 1000 8500
Seventh 800 9300
Eighth 700 10,000
etc. etc. etc.

Continue until clear lower layer appears.

The extracts from the reaction are combined and shaken up with a little anhydrous magnesium sulfate (120 grams) and filtered. The filtrate is evaporated to dryness in the rotary vacuum evaporator, care being taken not to heat the extracts or the residual syrup above 55øC. A good mechanical vacuum pump and effective cold traps in the line are necessary to remove the residual dimethylformamide from the residue. A brown to black bubbly residue should remain when evaporation is complete. This residue contains the amide product and considerable impurities. A general method of purifying the amide follows.

Method A

The material to be purified (the above residue or other material containing N,N-diethyl lysergamide) is taken up in 1200 ml of methylene chloride containing 20% benzene and applied to a chromatographic column containing two pounds of basic alumina 100-200 mesh Brockmann activity two or three. The column is eluted with nine liters of methylene chloride containing 20% benzene. At this point, the column when viewed with visible light should display three distinct color bands. The uppermost band will be a dark brown or greyish color, the next band will be a reddish brown color, and the lowest band will be a light brown or tan color. The eluant should be amber colored. The column may now be eluted with about one liter methylene chloride containing 0.5% methanol. This will bring the reddish band nearly to the bottom of the column. At no time should any portion of the reddish band be eluted from the column. If any of the reddish band reaches the bottom of the column, elution should be stopped. Next, the total eluant is shaken up with 30 grams of activated charcoal (Norit A) mixed with 30 grams of alumina and filtered. The filter is washed with 600 ml of methylene chloride and the total filtrate taken to dryness on the rotary vacuum evaporator. Care is taken not to heat the residue or solution above 55ø C. The residue is taken up in one liter of benzene and immediately taken to near dryness when another liter of benzene is added to dissolve the residue and the solution is again taken to near dryness. This procedure is repeated until four to five liters of benzene have been added and evaporated. The residue is finally taken to complete dryness at about 45ø C. If sufficient benzene has been added and evaporated, a light tan bubbly, crystalline material will fill the interior of the evaporator flask. It is important that this residue be completely dry before proceeding. The evaporation of benzene from the residue aids removal of solvents and other volatile materials (as azeotropes) which promotes formation of the bubbly crystalline structure in the residue. 700 ml of petroleum ether is next added to the evaporator flask which is then removed from the evaporator and tightly stoppered. The flask is shaken vigorously to loosen the residue from the sides of the flask. Usually all the material comes loose from the flask and forms a slurry in the petroleum ether. If necessary, a bent wire rod may be used to scrape material from the flask. The slurry is now decanted into a buchner funnel and filtered. The filtrate is used to further wash material from the flask into the filter funnel. The filter cake is sucked as dry as possible and then dried to a constant weight under high vacuum at 45øC in a dessicator.

Yield: approximately 130 grams N,N-diethyllysergamide MW 323.42.

The material remaining on the column may be removed with methanol, evaporated in a vacuum and recycled through the isomerization and subsequent procedures by itself or combined with fresh material. Also, all leftover solutions and residues may be neutralized with sodium bicarbonate, evaporated in vacuo, extracted with ammoniacal chloroform, the extract evaporated to dryness, and the residue re-used.

N,N-Diethyllysergamide Tartrate

130 grams of N,N-diethyllysergamide is dissolved in 400 ml methanol and filtered. The filter is washed with 30 ml methanol and the filtrate and washing is poured into a one liter beaker. 30 ml more methanol is used to further wash the filter and filter flask and the wash is also poured into the beaker. 130 ml of diethyl ether is now added to the contents of the beaker. The beaker is gently warmed on a hot plate and 32.0 grams of tartaric acid are then added with constant stirring and warming until they are completely dissolved. The beaker is then allowed to cool. Crystallization of the tartrate usually begins as soon as the tartaric acid dissolves completely. The beaker and contents are refrigerated for at least four hours. Occasional stirring of the crystallizing solution will produce smaller crystals, whereas if the solution is left unstirred during the crystallization, larger crystals will grow. Either is satisfactory. After the beaker has been allowed to stand in the cold four hours or more, the contents are filtered off on a 110 mm buchner funnel with suction. The crystals are washed on the funnel with first 200 ml of a two part methanol:one part ether mixture, and then with 250 ml of a two part ether:one part methanol mixture. Next the crystals are washed with 600 ml of ether and sucked dry. The filter cake is broken up and allowed to air dry in a warm, dark place.

First crop yield: Approximately 80 grams pale yellow to white needles.

The mother liquors and the two washes containing methanol are collected and combined. A one normal solution of potassium hydroxide in methanol is added in approximately equal volume to the combined washes and mother liquors. The solution is then filtered and the filter washed with a few ml of methanol. The filtrates are allowed to stand at room temperature for two to three hours to re-equilibrate the iso-lysergic acid amides from the mother liquors. About 500 ml of water is then added and the mixture extracted with 2.5 liters of methylene chloride in divided portions in a separatory funnel. The combined extracts are shaken with 25 grams of anhydrous magnesium sulfate and filtered. The filtrate is taken to dryness on the rotary vacuum evaporator, care taken not to heat above 55øC. The material is purified in the same manner as that from the original reaction mixture using approximately one fourth the quantities of solvents and alumina as for the original.

Second crop yield: Approximately 20 grams white needles.

The mother liquors may again be worked up as before, or alternatively, they may be saved and included in subsequent batches.

Third crop yield: Approximately 5 grams white needles.

Total yield: Approximately 105 grams N,N-diethyllysergamide tartrate MW = 430.51 (includes one mole methanol per mole of amide).

Method B

The residue from the previous step is taken up in two liters of chloroform and filtered with suction through a column 50 millimeters in diameter packed with 400 grams of basic alumina, Brockman activity 1. The filtrate is then refiltered through the same column in the same manner four or five times until the filtrate appears light amber and further repetition of this process fails to remove significant color from the filtrate. The column is now eluted by adding several liters of fresh chloroform to the top and sucking it through into the previous filtrate. Sufficient chloroform should be added to remove all blue fluorescent material from the column but not greenish or yellow (use a blacklight in a darkened room). A band of greenish yellow material should remain in the upper 2/3 of the column when viewed in ultraviolet light (blacklight). The total filtrate is taken to dryness in vacuo in a three liter round bottom flask on a rotary evaporator over a 60ø hot water bath. The residue is taken up in 500 ml of benzene and again taken to dryness in the same manner. 500 ml of benzene is again added and taken to dryness. The flask is left on the evaporator under full vacuum for a considerable length of time after the residue appears dry to remove any traces of dimethylformamide that may still remain. A bubbly, crystalline residue should fill the interior of the flask at the end of this step. If any tarry, gummy appearing material appears to remain on the sides of the flask, repeat the addition of 500 ml of benzene and evaporate to dryness again to get a glassy, crystalline appearance. When the material in the flask is totally dry, remove the flask from the evaporator and add sufficient petroleum ether (a commercial mixture of hexanes is excellent for this purpose) to the flask to be able to swirl the crysþalline material around and loosen it from the sides of the flask. Filter this slurry on the buchner funnel with a fritted glass disk and use the filtrate to further wash the remaining material from the evaporator flask into the buchner funnel. Suck the material dry on the funnel and then place in a vacuum dessicator and dry to a constant weight. Record the dry weight of this material N. Calculate the weight of one equivalent of tartaric acid as follows:

Weight of tartaric acid =.232N

Add methanol to a small beaker in a quantity equal to four times N in milliliters. Dissolve the dried material of weight N in this. Dissolve one equivalent of tartaric acid in the same solution, warming the solution gently and stirring. Slowly with stirring, add ether to the solution in the quantity of no greater than.5 N ml. Addition of ether causes a precipitate which dissolves quickly. Ether should be added dropwise with stirring between drops to dissolve any precipitate before addition of the next drop. Crystallization of LSD tartrate should begin shortly after or during addition of the ether. This precipitate does not dissolve and should not be confused with the precipitate caused by the addition of ether. The mixture should be stirred until the solution becomes thickened by formation of crystals. Once crystallization of LSD tartrate is begun it is unnecessary to continue addition of ether. The beaker should be refrigerated several hours and the contents then filtered on a buchner funnel with a fritted glass disk. The crystals are sucked dry and washed with 2.0 N milliters of methanol previously chilled below -5øC and then with 4 N milliliters of a 1:1 mixture of cold ether and methanol. The crystals are sucked completely dry, washed with 8 N ml of ether, sucked dry, and placed in a vacuum dessicator to remove last traces of solvent.

The total filtrates from the crystals (mother liquors plus washings) are made basic by addition of 2 molar ammoniacal ethanol in approximately equal volume and allowed to stand several days at room temperature when the mixture is filtered and taken to dryness and treated in the same manner as the residue from step 2 for a second crop of crystals.

LSD Via SO3 Method 2
Lysergic Acid

Ergotamine tartrate (10g) is added to a stirred de-aerated (nitrogen stream) solution of 38 g potassium hydroxide in 100 ml of methanol and 200 ml of water. The solution turns pink to red. The solution is heated to reflux and the methanol is slowly removed using a partial takeoff. Methanol is allowed to distill until the pot temperature reaches 90-95ø C. The mixture is then maintained at total reflux until the evolution of ammonia ceases (hold pH paper in outlet of reflux condenser to test for ammonia). Nitrogen should be bubbled through the mixture to entrain the ammonia. The hot dark solution is then allowed to cool somewhat and then cautiously acidified with a mixture of 60 ml acetic acid and 60 ml water. The resulting hot solution is quickly treated with Norite "A" decolorizing carbon and filtered hot. The clear purple-hued filtrate is allowed to cool to room temperature (crystallization begins) and then in an ice bath or refrigerator. The crystalline precipitate of lysergic acid (grey to purplish white) is collected, washed with a small amount of cold water (5 ml), followed by cold methanol (5 ml) and ether. Yield 3.2 to 3.8 g. Digestion of the crude acid with about 50 ml of methanol (to remove some of the colored impurities) gave after cooling to 0-10øC and filtering an almost quantitative recovery of lighter colored acid. This material is suitable for conversion into LSD.

Lysergic Acid Diethylamide

1. Sulfur Trioxide-Dimethylformamide Comþlex

Into a carefully dried two liter three necked round bottomed flask fitted with a mechanical stirrer, thermometer and a pressure equalizing dropping funnel protected from the atmosphere with a CaCl2 drying tube, was placed approximately one (I) liter of freshly distilled dimethylformamide (DMF) (a one to three degree fraction BP ca. 62-63øC/20 mm). The DMF was cooled to 0-5ø C by means of an external ice-salt-water bath. Sulfur trioxide (Sulfan B) (ca. 100 g) was then placed in the dropping funnel and added dropwise over a period of 30 to 40 minutes to the stirred DMF. The temperature is carefully maintained between 0 and 5ø C throughout the course of the addition. Stirring is continued thereafter until all of the crystalline material is brought into solution. The resulting reagent solution is then transferred into a suitable reservoir fitted with an automatic burette (protected from the atmosphere with a Drierite tube) and refrigerated. If kept dry, the reagent will be good for a month or two even though it will turn yellow and then orange in color. The molarity of the reagent is then determined by titration against standard base. An aliquot (1 or 5 ml) is first diluted with water (20 or 100 ml) to convert the sulfur trioxide-DMF complex into sulfuric acid. The resulting solution is titrated to phenolphtalein end-point with standard 0.1 or 0.01 N aqueous alkali (NaOH or KOH) to determine the molarity (1/2 of the Normality). It should be in the range of 0.9 to 1.2 depending on the amounts of 503 and DMF used.

2. Lysergic Acid Diethylamide (LSD)

For best results all lysergic acid and LSD solutions should be protected from direct light (yellow light is non-damaging) and the working temperatures should never exceed 25ø C. Lysergic acid monohydrate (7.15 g, 25.0 mmol on a 100% basis) and lithium hydroxide monohydrate (1.06 g, 25.0 mmol) were added to 200 ml of anhydrous methanol and stirred until complete solution occurs. Use magnetic stirrer and keep solution under dry nitrogen in the dark. The solvent methanol is then removed by evaporation under reduced pressure to leave a frothy glass-like residue of lithium lysergate. A solution of the calculated amount of tartaric acid is prepared in methanol (ca. 8 ml/g). Approximately 1/2 of the methanol to be used and 20% of the tartaric acid solution is added to the flask containing the LSD base. The flask is swirled and/or shaken until the solid material has dissolved (5-10 minutes) and the solution is then transferred into an Erlenmeyer flask. The balance of the methanol, in two portions, is used to complete the transfer. At this point the rest of the tartaric acid solution is added. lt may be helpful to titrate the solution to an end-point pH of 5.3, since adding excess tartaric acid solution inhibits crystallization somewhat. However this is optional. If seed crystals are available, they should be added at this point. Crystallization should begin within a 1/2 hour: The flask should then be refrigerated for 12-24 hours at 5-10ø C and then for another 12 hours at -10 to -20øC. For 5 g of LSD base 1 g of tartaric acid in 7-8 ml methanol and an additional 17-18 ml of methanol are used. The crystalline mass of needles is broken up and the cold solution filtered (suction). The filter cake is sucked dry and then washed with anhydrous ether. lf necessary the product may be recrystallized from methanol using 5 ml for each gram. The snow white product melts at 198-200øC.

3. Recrystallization Procedure

The crude tartrate (10 g) is placed in a 125 ml Erlenmeyer flask and boiling methanol (50 ml) is added and the mixture stirred and heated for a minute or two (no longer) until solution is complete. The hot solution is quickly filtered through a previously warmed buchner funnel and the filtrate cooled immediately by swirling in a cold water bath until the temperature drops to 25ø C. Crystallization should be well on the way by this time. The mixture is further cooled to 5 to 10øC and then to -10 to -20øC as previously described, to complete the crystallization. Recovery is between 50 and 70%.

4. Additional Crops of Crystals

The mother liquors from initial crystallizations and from re-crystallizations of LSD can be concentrated by evaporation under reduced pressure to produce additional crops of crystals. The second and third crops of crystals are usually dirty enough to require re-crystallization. After three crops, the mother liquors usually become very syrup-like. They then contain mostly iso-LSD (as the tartrate salt). The iso-LSD salt can be converted back into the base by the addition of methanolic KOH or potassium methoxide to the mother liquor. The resulting mixture should be added to a separatory funnel containing salt solution and ethylene dichloride. The LSD base is extracted into the ethylene dichloride layer (the lower layer). The lower layer is removed and fresh ethylene dichloride used to extract the last traces of LSD base from the salt water-base mixture. The ethylene dichloride extracts are combined, dried with MgSO4, decolorized and filtered through diatomaceous earth as earlier. The resulting ethylene dichloride solution may be combined with the chloroform solutions of iso-LSD which eluted from the chromatographic column. The combined solution may be evaporated to dryness under reduced pressure.

5. Isomerization

The dry iso-LSD base can then be dissolved in methanol and potassium methoxide added. The resulting mixture is stirred for about 30 minutes. During this time isomerization takes place; about 70% of the iso-LSD is converted into the desired "normal" form of LSD. The methanolic solution is poured into a separatory funnel containing salt water solution and ethylene dichloride. The salt water layer is repeatedly extracted with ethylene dichloride to separate the LSD base from the water-base mixture. The ethylene dichloride extracts are combined, dried with MgSO4, decolorized and filtered. The ethylene dichloride solution is then evaporated to dryness under reduced pressure. The resulting dry LSD base is chromatographed on basic alumina (activity grade 1) as previously described. The blue band is collected as before, evaporated and converted into the tartrate salt. The iso-LSD band may be collected and saved for further re-cycling. NOTE: If you only have mother liquors to isomerize, the second mixing with potassium methoxide is unnecessary. Simply prolong the initial mixing to about 1/2 hour.

Total Synthesis of Lysergic Acid

Of the many attempts at the total synthesis of lysergic acid from simple starting materials, only two have been successful (JACS 78,3087(1956), which is very complicated, and CA 74,3762 (1970), which follows). However, it is very likely that some of the intermediates in each attempt are psychedelic. ln fact, this is one of the most promising and least investigated areas of psychedelic chemistry. Following are some references to the synthesis of intermediates: CCCC 33,1576(1968); HCA 33,67,375,1796, 2254,2257(1950), 34,382(1951), 35,1249,2095(1952), 36,839 1125,1137(1953), 37,1826(1954), 38,463,468(1955), 44,1531 (1961); JCS 3399,3403(1954); BSC 861(1965); JOC 10,76 (1945), 26,4441(1961), 29,843(1964); Chem. and Ind. 1151 (1953); CJC 41,2585(1963); CPB 12,1405,1493(1964),13,420 (1965), 14,1227(1966); JACS 61,2891(1939), 67,76(1945), 71,761(1949), 73,2402(1951), 78,3087(1956), 79,102(1957), 82,1200(1960), 88,3941 (1966); BER 86,25,404(1953), 87,882 (1954), 88,370,550(1955), 89,270,2783(1956), 90,1980,1984 (1957), 93,2024,2029 (1960), 96,1618(1963),100,2427(1967), 101,2605(1968); JMC 8,200(1965); C.R. Acad. Sci. Paris 264 (C), I 18(1967), 265 (C), 110( 1967); BSC 1071 (1968); CJC 41,2585(1963); CPB 12,1405,1493(1964), 13,420(1965), 14, 1227(1966); JCS (P.T.1.) 1121(1972), 760(1973), 438(1973); CA 78,71830,72200(1973).

Various analogs containing part of the LSD structure have been synthesized, but few have any activity. See JPS 60,809(1971) for a review of these compounds. For other LSD analogs see JMC 16,804,1015(1973); BSC 2046(1973); CA 48,4489(1954); JPS 62,1881(1973). Some other useful references on LSD chemistry: U.S. Patents 3,856,821 and 3,856,822; Swiss Patent 517,680(1970); Belgian Patent 738,926; French Patent 1,368,420 and addition 91,948 (1968). Total Synthesis of LSD German Patent 1,965,896 (1 Oct 1970). German Patent 1,947,063 is the same as 1,965,896. For synthesis of 5-Br-isatin from isatin see CA 33,2516(1939) or BER 40,2492(1907). For the use of cycloaliphatic or aromatic esters in place of methyl- 6-methylnicotinate or of isatin or 4 or 5 chloroisatin or 4-bromoisatin in place of 5-bromoisatin see French Patent Addition #2,052,237 (14 May 1971).

Total yield of LSD from starting materials is probably about 1%

Mix 32.8 g (0.217M) methyl-6-methylnicotinate (other alkyl groups can replace either methyl group) with 45.2 g (0.2M) 5-bromoisatin (apparently 4-Br or 4 or 5 Cl isatin will also work) in a 250 ml flask at 100ø in an oil bath and raise the temperature of the bath to 180ø over 15 minutes. Lower temperature to 170ø and let react for 70 minutes. Cool and then grind the solid as fine as possible in a mortar. Recrystallize from 150 ml dimethylformamide and wash with ether to get 40 g (57%) methyl-a(5-bromo-3-isatylidene)-6-methylnicotinate (I). Suspend 10 g (I) in 250 ml glacial acetic acid and heat to boiling. Add in small portions over 30 minutes excess powdered zinc. Reflux 1 hour, filter and evaporate in vacuum and recrystallize the residue from dioxane to get 9.7 g (95%) methyl-a-(5-bromo-2-oxindol-3-yl)-6-methylnicotinate (II). To a suspension of 18 g dry NaBH4 in 300 ml dry tetrahydrofuran add with stirring at 0ø over 30 minutes about 75 g BF3 etherate. Stir 3 hours at 0ø, add 18 g (II) and heat exactly 20 minutes at precisely 22-24ø. Add carefully 150 ml concentrated HCl while cooling in an ice bath. Add 200 ml water and stir 12 hours. Basify, extract the product with ethyl acetate and dry, evaporate in vacuum to get 11 g of residue which recrystallizes from methanol to give methyl-a-(2,3-dihydro-5-bromo-3-indolyl)-6-methylnictotinate (111).

The following step may be unnecessary but it gives stability to (III). The acetyl group can be split off at the end of synthesis, but this is unnecessary since the 1-acetyl-LSD is as active as LSD.

Treat 12 g (Ill) at room temperature for 24 hours with acetic anhydride then hydrolyze and extract to get 11.5 g residue which is ground in petroleum ether and recrystallized from cyclohexane (can chromatograph on alumina and elute with petroleum ether to wash out an oil, then with benzene containing 5% ethyl acetate to elute the produce) to give methyl-a-(1-acetyl-5-bromo-2,3-dihydro-3-indolyl)-6-methylnicotinate (IV). Heat 5 g (IV),12.5 ml acetone,12.5 ml methanol and 1.8 ml methyl iodide for 18 hours in a Carius tube at 70-80ø. Cool, filter, wash with acetone and recrystallize from methanol to get methyl-a(1-acetyl-2,3-dihydro-5-bromo-3- indolyl)-1,6-dimethylnicotinate iodide (V). To 9.4 g (V) in 250 ml water and 250 ml methanol at 35ø add over 5 minutes 2.9 g KBHþ and stir 10 minutes. Add 2.9 g more KBH4 and stir 30 minutes. Evaporate in vacuum and extract the residue with methylene chloride to get 6.2 g oily mixture containing about 2 g of the d isomer (can separate by chromatography if desired) of methyl-a(1-acetyl-2,3-dihydro-5-bromo-3-indolyl)-6-methyl- 1,2,5,6-tetrahydronicotinate (VI). To a suspension of finely powdered NaNH2 (6.1 g) in 2 liters dry ammonia, add with stirring 8 g (VI) in 50 ml dry tetrahydrofuran. Stir 1 hour, add NH4Cl and evaporate the ammonia as fast as possible in a nitrogen stream. Extract at pH 8 with methylene chloride to get 6 g (can chromatograph on 300 g silica gel and 250 g Celite and elute with 98% benzene-2% absolute ethanol and evaporate in vacuum) of methyl-1-acetyl-2,3-dihydro-lysergate (VII). (VII) can be converted to 2,3-dihydro-LSD (not to be confused with 9,10-dihydro-LSD, which is inactive), which is about ten times less active than LSD. (VII) can be converted to lysergic acid prior to conversion to LSD, which will triple the yield in terms of LSD activity (considering 30% yield). The process (which follows) is somewhat complicated and an easier dehydrogenation process may work. 2,3-dihydro-LSD can be converted directly to 12-hydroxy-LSD, which has about the same activity as LSD and this process is also given below.

Lysergic Acid from 2,3-Dihydrolysergic Acid JACS 78,3114 (1956)

Dissolve 4 g (VII) in 78 ml 1.5% KOH and reflux five minutes (under N2 if possible). Add 8.5 g Na arsenate hydrate and 16 g Raney-Ni (wet) (deactivated by boiling in xylene suspension - see JOC 13,455(1948)) and reflux twenty hours (under N2 if possible). Filter, precipitate lysergic acid by taking pH to 5.6 with HCl; filter and wash precipitate with water to get 1 g lysergic acid. Evaporate in vacuum the filtrate to get more product.

12-Hydroxylysergamides from 2,3-dihydrolysergamides HCA 47,756(1964)

Warm to dissolve 1.5 g 2,3-dihydro-LSD in 5 ml acetone, 40 ml water and 40 ml saturated NaHCO3. Cool to 20ø and add all at once with vigorous stirring 2.46 g potassium nitro-sodisulfonate dissolved in 90 ml water and 10 mI saturated NaHCO3. After 1 minute, extract 7 times with ethylacetate, wash the combined extracts with water, dry and carefully remove solvent to get a mixture of 12-OH-LSD, LSD and starting material which can be chromatographed to give about 0.2 g 12-OH-LSD. The following method of converting (IV) to the diethylamide (which can probably be used in place of (IV) to give the diethylamide of (V), (VI), and (VII)) will probably also work admirably for (VII) or lysergic acid. Reflux 0.5 g (IV) with 0.5 g KOH in 30 ml methanol for 4 hours. Evaporate in vacuum and add water to the residue. Adjust the pH to between 5 and 6 and filter or centrifuge to get 0.3 g of the free acid. Suspend 1.8 g of the acid in 125 ml chloroform, cool to -5ø and add 0.5 g triethylamine, then 0.6 g ethylchloroformate and stir 45 minutes. Add 2 ml diethylamine and stir 3 hours at room temperature to get, after the usual workup, 1 g of the diethylamide (recrystallize from benzene).

Summary of Procedures and Materials For 1 Kilogram Ergotamine

* Starred chemicals are carefully watched.

**** diethylamine 500 g (725 ml)
methylethylamine 50 g (75 ml)
ethylisopropylamine 50 g (75 ml)
diethyl ether 5 lbs
potassium hydroxide pellets 2 Ibs
methanol 5 L
activated charcoal powder 100 g
tartaric or maleic acid powder 200 g
small cylinder N2 or N2O or freon  
HCL or sulphuric acid concentrated 500 ml
chloroform 5 L (optional but desirable)
ethanol 9 L (optional but desirable)
NH4OH concentrated 500 ml (optional but desirable)


First choice

N,N-dicyclohexylcarbodiimide 500 g
N-hydroxybemotriazol 500 g
tetrahydrofuran 10 L
methylene chloride 10 L

Second choice

N,N carbonyldiimidazole 200 g
dimethylformamide 15 L

Third choice

** anhydrous hydrazine 4 L
HCl conc. 1 L
sodium nitrite 1 kg

Fourth choice

** phosphorous oxychloride 200 ml
chloroform 10 L
methanol 5 L

Fifth choice

acetonitrile or DMF 15 L
** trifluoroacetic anhydride 500 g