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LSD-25 Synthesisfrom "Psychedelic Guide to the Preparation of the Eucharist"
Preparatory arrangements
Starting material may be any lysergic acidderivative, from ergot on rye grain or from culture, or morning glory seeds orfrom synthetic sources. Preparation #1 uses any amide, or lysergic acid asstarting material. Preparations #2 and #3 must start with lysergic acid only,prepared from the amides as follows:
10 g of any lysergic acid amide from variousnatural sources dissolved in 200 ml of methanolic KOH solution and the methanolremoved immediately in vacuo. The residue is treated with 200 ml of an 8%aqueous solution of KOH and the mixture heated on a steam bath for one hour. Astream of nitrogen gas is passed through the flask during heating and theevolved NH3 gas may be titrated is HCl to follow the reaction. The alkalinesolution is made neutral to congo red with tartaric acid, filtered, cleaned byextraction with ether, the aqueous solution filtered and evaporated. Digestwith MeOH to remove some of the coloured material from the crystals of lysergicacid.
Arrange the lighting in the lab similarly to thatof a dark room. Use photographic red and yellow safety lights, as lysergic acidderivatives are decomposed when light is present. Rubber gloves must be worndue to the highly poisonous nature of ergot alkaloids. A hair drier, or,better, a flash evaporator, is necessary to speed up steps where evaporation isnecessary.
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Preparation #1
Step I. Use Yellow light
Place one volume of powdered ergot alkaloidmaterial in a tiny roundbottom flask and add two volumes of anhydroushydrazine. An alternate procedure uses a sealed tube in which the reagents areheated at 112 C. The mixture is refluxed (or heated) for 30 minutes. Add 1.5volumes of H2O and boil 15 minutes. On cooling in the refrigerator, isolysergicacid hydrazide is crystallised.
Step II. Use Red light
Chill all reagents and have ice handy. Dissolve2.82 g hydrazine rapidly in 100 ml 0.1 N ice-cold HCl using an ice bath to keepthe reaction vessel at 0 C. 100 ml ice-cold 0.1 N NaNO2 is added and after 2 to3 minutes vigorous stirring, 130 ml more HCl is added dropwise with vigorousstirring again in an ice bath. After 5 minutes, neutralise the solution withNaHCO3 saturated sol. and extract with ether. Remove the aqueous solution andtry to dissolve the gummy substance in ether. Adjust the ether solution byadding 3 g diethylamine per 300 ml ether extract. Allow to stand in the dark,gradually warming up to 20 C over a period of 24 hours. Evaporate in vacuum andtreat as indicated in the purification section for conversion of iso-lysergicamides to lysergic acid amides.
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Preparation #2
Step I. Use Yellow light
5.36 g of d-lysergic acid are suspended in 125ml of acetonitrile and the suspension cooled to about -20 C in a bath ofacetone cooled with dry ice. To the suspension is added a cold (-20 C) solutionof 8.82 g of trifluoroacetic anhydride in 75 ml of acetonitrile. The mixture isallowed to stand at -20 C for about 1.5 hours during which the suspendedmaterial dissolves, and the d-lysergic acid is converted to the mixed anhydrideof lysergic and trifluoroacetic acids. The mixed anhydride can be separated inthe form of an oil by evaporating the solvent in vacuo at a temperature below 0C, but this is not necessary. Everything must be kept anhydrous. Step II. UseYellow light
The solution of mixed anhydrides in acetonitrilefrom Step I is added to 150 ml of a second solution of acetonitrile containing7.6 g of diethylamine. The mixture is held in the dark at room temperature forabout 2 hours. The acetonitrile is evaporated in vacuo, leaving a residue ofLSD-25 plus other impurities. The residue is dissolved in 150 ml of chloroformand 20 ml of ice water. The chloroform layer is removed and the aqueous layeris extracted with several portions of chloroform. The chloroform portions arecombined and in turn washed with four 50 ml portions of ice-cold water. Thechloroform solution is then dried over anhydrous Na2SO4 and evaporated invacuo.
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Preparation #3
This procedure gives good yield and is very fastwith little iso-lysergic acid being formed (its effect are mildly unpleasant).However, the stoichometry must be exact or yields will drop.
Step I. Use White light
Sulfur trioxide is produced in anhydrous stateby carefully decomposing anhydrous ferric sulfate at approximately 480 C. Storeunder anhydrous conditions.
Step II. Use White light
A carefully dried 22 litre RB flask fitted withan ice bath, condenser, dropping funnel and mechanical stirrer is charged with10 to 11 litres of dimethylformamide (freshly distilled under reducedpressure). The condenser and dropping funnel are both protected againstatmospheric moisture. 2 lb of sulfur trioxide (Sulfan B) are introduceddropwise, very cautiously stirring, during 4 to 5 hours. The temperature is keptat 0-5 C throughout the addition. After the addition is complete, the mixtureis stirred for 1-2 hours until some separated, crystalline sulfurtrioxide-dimethylformamide complex has dissolved. The reagent is transferred toan air- tight automatic pipette for convenient dispensing, and kept in thecold. Although the reagent, which is colourless, may change from yellow to red,its efficiency remains unimpaired for three to four months in cold storage. Analiquot is dissolved in water and titrated with standard NaOH to aphenolphthalein end point.
Step III. Use Red light
A solution of 7.15 g of d-lysergic acid monohydrate (25 mmol) and 1.06 g of lithium hydroxide hydrate (25 mmol) in 200 mlof MeOH is prepared. The solvent is distilled on the steam bath under reducedpressure. the residue of glass-like lithium lysergate is dissolved in 400 ml ofanhydrous dimethyl formamide. From this solution about 200 ml of the dimethylformamide is distilled off at 15 ml pressure through a 12 inch helices packedcolumn. the resulting anhydrous solution of lithium lysergate left behind iscooled to 0 C and, with stirring, treated rapidly with 500 ml of SO3-DMFsolution (1.00 molar). The mixture is stirred in the cold for 10 minutes andthen 9.14 g (125.0 mmol) of diethylamine is added. The stirring and cooling arecontinued for 10 minutes longer, when 400 ml of water is added to decompose thereaction complex. After mixing thoroughly, 200 ml of saturated aqueous salinesolution is added. The amide product is isolated by repeated extraction with500 ml portions of ethylene dichloride. the combined extract is dried and thenconcentrated to a syrup under reduced pressure. Do not heat up the syrup duringconcentration. the LSD may crystallise out, but the crystals and the motherliquor may be chromatographed according to the instructions on purification. --------------------------------------------------------------------------------
Purification of LSD-25
The material obtained by any of these threepreparations may contain both lysergic acid and iso-lysergic acid amides.Preparation #1 contains mostly iso-lysergic diethylamide and must be convertedprior to separation. For this material, go to Step II first.
Step I
Use darkroom and follow with a long wave UV Thematerial is dissolved in a 3:1 mixture of benzene and chloroform. Pack thechromatography column with a slurry of basic alumina in benzene so that a 1inch column is six inches long. Drain the solvent to the top of the aluminacolumn and carefully add an aliquot of the LSD-solvent solution containing 50ml of solvent and 1 g LSD. Run this through the column, following the fastestmoving fluorescent band. After it has been collected, strip the remainingmaterial from the column by washing with MeOH. Use the UV light sparingly toprevent excessive damage to the compounds. Evaporate the second fraction invacuo and set aside for Step II. The fraction containing the pure LSD isconcentrated in vacuo and the syrup will crystallise slowly. This material maybe converted to the tartrate by tartaric acid and the LSD tartrate convenientlycrystallised. MP 190-196 C.
Step II. Use Red light
Dissolve the residue derived from the methanolstripping of the column in a minimum amount of alcohol. Add twice that volumeof 4 N alcoholic KOH solution and allow the mixture to stand at roomtemperature for several hours. Neutralise with dilute HCl, make slightly basicwith NH4OH and extract with chloroform or ethylene dichloride as inpreparations #1 or #2. Evaporate in vacuo and chromatograph as in the previousstep.
Lysergic acid compounds are unstable to heat,light and oxygen. In any form it helps to add ascorbic acid as an anti-oxidant, keeping the container tightly closed, light-tight with aluminum foil,and in a refrigerator.
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Synthesis of d-LSD maleate or tartrate fromlysergic acid with POCl3
Ref:
Johnson, Ary, Teiger, Kassel. "EmeticActivity of Reduced Lysergamides." Journal of Medicinal Chemistry.16(5):532-537. 1973.
Related:
Huang, Marona-Lewicka, Pfaff, Nichols."Drug Discrimination and Receptor Binding Studies of N-IsopropylLysergamide Derivates." Pharmacology, Biochmistry and Behavior.47(3):667-673, 1994.
Oberlender, Pfaff, Johnson, Huang, Nichols."Stereoselective LSD-like Activity in d-Lysergic Acid Amides of (R)- and(S)-2-Aminobutane." Journal of Medicinal Chemistry. 35(2):203-211, 1992.
Hoffman-AJ, Nichols. "Synthesis andLSD-like Descriminative Stimulus Properties in a Series of N(6)-alkylNorlysergic Acid N,N-Diethylamide Derivates." Journal of MedicinalChemistry. 28:1252-1255, 1985.
NOTE: JMC 35(2):203-211 has some amazingstereoviews of LSD which might interest non-chemists who like to cross theireyes. Under reducedlight (or red light) a stirred solution of 3.15g (11 mmol) of d-lysergic acidmonohydrate and 4.45g (99 mmol) of diethylamine was brought to reflux byheating. Heat was removed, and reflux was maintained by the addition of 2ml(3.4g, 22mmol) of phosphorous oxychloride (POCl3) over a 2 minute period. Themixture was then refluxed for an additional 4-5 mins until an amber-coloredsolution resulted. The solution was brought to room temperature and was washedwith 200ml of 1M NH4OH. The CHCl3 solution was dried (MgSO4), filtered, andconcentrated under vacuum (not allowing the solution to exceed 40 degrees C).The last traces of the solvent were removed at 2-5 mm. The viscious residue wasdissolved in a minimum amount of MeOH and acidified with a freshly prepared 20%solution of maleic acid in MeOH. Crystallization occured spontaneously. Theneedles were filtered, washed with cold MeOH and air-dried. Yield was 66% afterfurther purification by column chromatography over alumina (Brockman) andelution with 3:1 benzene-chloroform. The chromatography takes appx 8-9 hours.Alternatively, it can be crystallized as the (+)-tartrate from MeOH. Aftercrystallizing from cold MeOH, it is diluted with ethyl acetate, filtered andthe the crystals are washed with ethyl acetate.
This procedure also works for primary amines andsmall dialkyl amines. LSD, however, probably remains the most worthwhileproduct. Other interesting amines might be the N-ethyl-N-propyl derivative(LEP) and the morpholide (LSM-775). 75ug of the morpholide have been reportedto have been as effective as 50ug of d-LSD but with 45 min onset (vs 1 hour)and a 1 hour peak (vs 4 hours). The procedure would probably work well for LEP,but yields would be reduced for the morpholide. Other N(20)-alkyl-lysergic acidderivatives tend to be more than 10 times less potent than LSD if noteffectively inactive. N(6)-ethyl- (and -allyl- and -propyl-) derivates of LSDmay be more active than LSD itself, but synthetic routes to these chemicalspresently start with LSD and yields would probably inhibit their appearance onthe illicit market. (N(6) is the other nitrogen on the ring structure inaddition to the N(1) pyrrole/indole nitrogen). Derivatives of LSD (besidesLSA/LA-111 and lysergic acid) are not scheduled, but would be prosecutableunder the designer drugs act after testimony from a DEA agent that _in theiropinion_ the defendant was planning to distribute them.
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