Preparation of Lysergic Acid

Ergot alkaloid (eg. 2 grams) can be transformed into lysergic acid when dissolved in (50 mL) normal methyl alcoholic potassium hydroxide solution and refluxed under inert gas. A small amount of water (approx. 50 mL) is added and the alcohol is evaporated under reduced pressure. The base is extracted with ether and the aqueous layer is acidified with sulfuric acid to precipitate the crude lysergic acid, which is then purified. 

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A— Preparation of Lysergic Acid with Sodium Hydroxide Alone... 

Amici, A.M., Minghetti, A, Tonolo, A., Spalla, C. Preparation of Lysergic acid Chemical Abstracts (19 ) 15314 e-g... 

Hofmann, A. Troxler, R Esters of Indoles US Patent 3,075,992 (1963) Hofmann, A. Troxler, R Preparation of Lysergic Acid Derivatives, and Intermediates US Patent 3,085,092 (1963)... 

Patelli, B. Bernard , L. Process for the Preparation of Lysergic Acid Amides US Patent 3,141,887... 

Pioch, R.P. Preparation of Lysergic Acid Amides US Patent 2,736,728 (1956) Chemical Abstracts (1956) 50 10803... 

Sandoz The Preparation of Lysergic Acid Hydrazide 1937 GB 463,936 Sandoz The Preparation of Synthetic Derivatives of Lysergic Acid 1938 GB 480,822... 

The vinyl triflate of Komfeld s ketone has been subjected to Heck reactions with methyl acrylate, methyl methacrylate, and methyl 3-(Af-rerf-butoxycarbonyl-lV-methyl)amino-2-methylenepropionate leading to a formal synthesis of lysergic acid [259]. A similar Heck reaction between l-(phenylsulfonyl)indol-5-yl triflate and dehydroalanine methyl ester was described by this research group [260]. Chloropyrazines undergo Heck couplings with both indole and 1-tosylindole, and these reactions are discussed in the pyrazine Chapter [261], Rajeswaran and Srinivasan described an interesting arylation of bromomethyl indole 229 with arenes [262]. Subsequent desulfurization and hydrolysis furnishes 2-arylmethylindoles 230. Bis-indole 231 was also prepared in this study. 

In the meantime amides of the A8,9 isomer (13) of lysergic acid and their derivatives have been prepared (42). Homologization of lysergic acid (43) to the so-called homolysergic acid (44) has been achieved (43) as indicated below. The same reaction was also carried out later on with the 9,10-dihydro derivatives (44). 

Several key reactions of this type are also performed by mammalian liver preparations. Thus, lysergic acid derivatives of type 30 are susceptible to N-(6)-demethylation and to side-chain hydroxylation by isolated rat liver preparations (46) and in a direct parallel to its normal biogenesis (66, 67), elymoclavine (32) is produced, although in low yield, from chanoclavine (31) in the presence of a commercial preparation from pigeon liver (77, 68). 

The reaction of the 9-hydroxy-ergoline derivative (74), prepared by reduction with diborane and anti-Markovnikov hydration of lysergic acid, with phosphorus oxychloride-pyridine results49 in expansion of ring C by displacement of the equa-49 L. Bernardi, C. Elli, and A. Temperilli, J.C.S. Chem. Comm., 1976, 570. 

A new efficient method for the direct amidation of /-lysergic acid was used to prepare a variety of lysergamides. A pharmacological evaluation of these compounds, their di- and tetrahydro derivatives, and derivatives bearing substituents in the indole portion of the molecule showed that, in general, only 9,10-dihydrolysergamides of primary amines possess activity comparable to the potent emetic activity of the components of dihydroergotoxine. 

Substitutions at the nitrogen and in position 2 of the indole portion of lysergic acid have a striking influence on pharmacodynamic properties. Many such substitution products have been prepared and pharmacologically investigated. The activity spectra of four such substances (Fig. 8) demonstrate how very diverse the effects of ergot substances can be made by substitutions in the indole nucleus. 

In the laboratory of A. Padwa, a novel synthetic approach to the fully functionalized core of lysergic acid was developed utilizing an intramolecular isomunchone cycloaddition pathway. The key cycloaddition precursor diazo imide was prepared using the standard Regitz diazo tranter conditions. The diazo imide then was heated with catalytic amouts of rhodium(ll)-perfluorobutyrate in dichloromethane to afford the desired cycloadduct as a single diastereomer and in excellent yield. The only reason the authors were not able to complete the total synthesis of lysergic acid was that they could not affect the isomerization of the double bond between the two six-membered rings. 

To a solution of 1 g. of freshly prepared rac. lysergic acid azide in... 

The Garbrecht Synthesis Preparation of Amides of Lysergic Acid... 

The mixed anhydride of lysergic and sulfuric acids is prepared by reacting a dispersion, i.e., a solution or suspension, of lysergic acid or one of its basic salts with sulfur trioxide. The formation of the mixed anhydride is rapid so that within a matter of minutes, the mixed anhydride is ready for utilization in the second step of the process. 

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