We were very frugal. Individual laboratories were considered a rare extravagance.

During the first six years of my employment with Sandoz, I shared a laboratory with two colleagues. We three chemists, plus an assistant each, worked in the same room on three different fields: Dr. Kreiss on cardiac glycosides; Dr. Wiedemann, who joined Sandoz around the same time as I, on the leaf pigment chlorophyll; and I ultimately on ergot alkaloids. The laboratory was equipped with two fume hoods (compartments supplied with outlets), providing less than effective ventilation by gas flames. When we requested that these hoods be equipped with ventilators, our chief refused on the ground that ventilation by gas flame had sufficed in Willstatter's laboratory.

During the last years of World War I, Professor Stoll had been an assistant in Berlin and Munich to the world-famous chemist and Nobel laureate Professor Richard Willstatter, and with him had conducted the fundamental investigations on chlorophyll and the assimilation of carbon dioxide. There was scarcely a scientific discussion with Professor Stoll in which he did not mention his revered teacher Professor Willstatter and his work in Willstatter's laboratory.

The working techniques available to chemists in the field of organic chemistry at that time (the beginning of the thirties) were essentially the same as those employed by Justus von Liebig a hundred years earlier. The most important development achieved since then was the introduction of microanalysis by B. Pregl, which made it possible to ascertain the elemental composition of a compound with only a few milligrams of specimen, whereas earlier a few centigrams were needed. Of the other physical-chemical techniques at the disposal of the chemist today—techniques which have changed his way of working, making it faster and more effective, and created entirely new possibilities, above all for the elucidation of structure - none yet existed in those days.

For the investigations of Scilla glycosides and the first studies in the ergot field, I still used the old separation and purification techniques from Liebig's day: fractional extraction, fractional precipitation, fractional crystallization, and the like. The introduction of column chromatography, the first important step in modern laboratory technique, was of great value to me only in later investigations. For structure determination, which today can be conducted rapidly and elegantly with the help of spectroscopic methods (UV, IR, NMR) and X-ray crystallography, we had to rely, in the first fundamental ergot studies, entirely on the old laborious methods of chemical degradation and derivatization.

Lysergic Acid and Its Derivatives

Lysergic acid proved to be a rather unstable substance, and its rebonding with basic radicals posed difficulties. In the technique known as Curtius' Synthesis, I ultimately found a process that proved useful for combining lysergic acid with amines. With this method I produced a great number of lysergic acid compounds. By combining lysergic acid with the amino alcohol propanolamine, I obtained a compound that was identical to the natural ergot alkaloid ergobasine. With that, the first synthesis—that is, artificial production—of an ergot alkaloid was accomplished. This was not only of scientific interest, as confirmation of the chemical structure of ergobasine, but also of practical significance, because ergobasine, the specifically uterotonic, hemostatic principle, is present in ergot only in very trifling quantities. With this synthesis, the other alkaloids existing abundantly in ergot could now be converted to ergobasine, which was valuable in obstetrics.

After this first success in the ergot field, my investigations went forward on two fronts.

First, I attempted to improve the pharmacological properties of ergobasine by variations of its amino alcohol radical. My colleague Dr. J. Peyer and I developed a process for the economical production of propanolamine and other amino alcohols. Indeed, by substitution of the propanolamine contained in ergobasine with the amino alcohol butanolamine, an active principle was obtained that even surpassed the natural alkaloid in its therapeutic properties. This improved ergobasine has found worldwide application as a dependable uterotonic, hemostatic remedy under the trade name Methergine, and is today the leading medicament for this indication in obstetrics.

I further employed my synthetic procedure to produce new lysergic acid compounds for which uterotonic activity was not prominent, but from which, on the basis of their chemical structure, other types of interesting pharmacological properties could be expected. In 1938, I produced the twenty-fifth substance in this series of lysergic acid derivatives: lysergic acid diethylamide, abbreviated LSD-25 (Lyserg-säure-diäthylamid) for laboratory usage.

I had planned the synthesis of this compound with the intention of obtaining a circulatory and respiratory stimulant (an analeptic). Such stimulating properties could be expected for lysergic acid diethylamide, because it shows similarity in chemical structure to the analeptic already known at that time, namely nicotinic acid diethylamide (Coramine). During the testing of LSD-25 in the pharmacological department of Sandoz, whose director at the time was Professor Ernst Rothlin, a strong effect on the uterus was established. It amounted to some 70 percent of the activity of ergobasine. The research report also noted, in passing, that the experimental animals became restless during the narcosis. The new substance, however, aroused no special interest in our pharmacologists and physicians; testing was therefore discontinued.

For the next five years, nothing more was heard of the substance LSD-25. Meanwhile, my work in the ergot field advanced further in other areas. Through the purification of ergotoxine, the starting material for lysergic acid, I obtained, as already mentioned, the impression that this alkaloidal preparation was not homogeneous, but was rather a mixture of different substances. This doubt as to the homogeneity of ergotoxine was reinforced when in its hydrogenation two distinctly different hydrogenation products were obtained, whereas the homogeneous alkaloid ergotamine under the same condition yielded only a single hydrogenation product (hydrogenation = introduction of hydrogen).

Extended, systematic analytical investigations of the supposed ergotoxine mixture led ultimately to the separation of this alkaloidal preparation into three homogeneous components. One of the three chemically homogeneous ergotoxine alkaloids proved to be identical with an alkaloid isolated shortly before in the production department, which A.

Stoll and E. Burckhardt had named ergocristine. The other two alkaloids were both new.

The first I named ergocornine; and for the second, the last to be isolated, which had long remained hidden in the mother liquor, I chose the name ergokryptine (kryptos = hidden).

Later it was found that ergokryptine occurs in two isomeric forms, which were differentiated as alfa- and beta-ergokryptine.

The solution of the ergotoxine problem was not merely scientifically interesting, but also had great practical significance. A valuable remedy arose from it. The three hydrogenated ergotoxine alkaloids that I produced in the course of these investigations, dihydroergocristine, dihydroergokryptine, and dihydroergocornine, displayed medicinally useful properties during testing by Professor Rothlin in the pharmacological department.

From these three substances, the pharmaceutical preparation Hydergine was developed, a medicament for improvement of peripheral circulation and cerebral function in the control of geriatric disorders. Hydergine has proven to be an effective remedy in geriatrics for these indications. Today it is Sandoz's most important pharmaceutical product.