DE1198830B - Process for the production of optically active lysergic acid and isolysergic acid hydrazide derivatives - Google Patents

Description

FEDERAL REPUBLIC OF GERMAN LADMB

GERMAN

PATENT OFFICE

MJSLEGESCHEIFT

1198

Int. CL:

C07d

DeutsöhejKl .: Λ2φ-0/1/01

Number: 1198-830

File number: ¹ S 76201IV d / 12 ρ

Filing date: October 10, 1961

Display day: .19. August 1965

The invention relates to a process for the production of optically active lysergic acid and isolysergic acid hydrazide derivatives the general formula

CO-NH-NH ₂

N-CH ₃

wherein R ₁ denotes a hydrogen atom, a lower alkyl, alkenyl or aralkyl group, which is characterized in that 1 mol of an optically active lysergic acid or isolysergic acid derivative of the general formula

Process for the production of optically active
Lysergic acid and isolysergic acid hydrazide derivatives

Applicant:

Sapdoz A.G., Basel (Switzerland)

-Representative:

Pr. W. Sqhalk, Dipl.-Ing. P. Wirth,

Dipl.-Ing. G. E. M. Dannenberg

and Dr. V. Schmied-iKawarzik, patent attorneys,

Frankfurt / M., Große Eschenheimer Str. 39

Named as inventor:

Dr. Albert Hofmann, Bpttmingen;

Dr. Jürg Rujschmann, Oherwil;

Dr. Paul Stadler, Neuallschwil;

Dr. Franz Troxier, Bottmujgen (Switzerland)

CO-, R ₂

N-CH ₃

Switzerland from 12th jOfctofoer 196.0 (11 427),
of October 25, 1960 (11 896)

where R ₁ 'is a lower alkyl, alkenyl or aralkyl group and R _{2 is} an alkoxy group, a primary amino or monoalkylamino group or the tripeptide residue of the natural ergot alkaloids or R ₁ ' is a hydrogen atom and R _{2 is} the tripeptide residue of the natural ergot alkaloids, in the presence heating of at least 1 equivalent of proton with an excess of hydrazine at about 80 to 135 ⁰ C and the resulting mixture of Lysergsäure- and isolysergic acid hydrazide derivative by crystallization and / or chromatography separated into the components.

This process takes place without racemization. According to the invention for this purpose is the presence of Protons required in the reaction mixture. This condition is easiest to implement, though Salts with acids of the lysergic acid derivatives of the general formula II or of hydrazine for the reaction be used. In this case, the acid component of the salts provides the necessary protons. So can e.g. B. Ergotamine hydrochloride reacted with hydrazine or ergotamine with hydrazine dihydrochloride will. The amount of protons must be at least per mole of the compound of the general formula II Be equivalent. However, it can be greater, but free hydrazine is also present have to be. In practice, the use of more than 10 equivalents of protons per mole of compound brings in of the general formula II no advantage.

It is generally not necessary to add solvents. However, to increase the solubility it is sometimes advantageous to use inert solvents, e.g. B. to use lower aliphatic monohydric alcohols, glycols or ethers. The reaction is preferably carried out at a temperature of 80 to 9O ⁰ C. The use of a higher temperature accelerates the hydrazide formation, but favors the undesired racemization. The reaction time is, for example, at 90 ° C for one to several hours and at 135 ⁰ C a few minutes.

The process is carried out, for example, as follows: 1 part by weight of a lysergic acid derivative is heated of the general formula II in the form

5OD 657/429

of a salt, ζ. B. Ergotamine hydrochloride, with 4 Ge B e i s η i e 1 1

weight parts of anhydrous hydrazine for 1 hour at 90 ⁰ C.

The reaction mixture is then diluted. 1.16 g of ergotamine hydrochloride are heated with

advantageously with water, the excess 4 ecm of anhydrous hydrazine is distilled at 90 ° for 1 hour, closed of hydrazine azeotropically with the water and 5 sets thereupon with 20 ecm of water, distilled water and shakes off the residue between aqueous tartaric acid hydrazine hydrate and shakes the residue and an indifferent, water-immiscible between tartaric acid and ether. The after Alka solvent, For example, chloroform or ether, lize the aqueous phase released bases schütaus. The aqueous phase is made alkaline and taken out with chloroform and chromatographed the end product in a water-immiscible io the solution of after evaporation of the chloroform Solvents, e.g. B. chloroform on. obtained crude product in chloroform, the 0.5%

If lysergic acid derivatives of the general formula II contain ethanol, aluminum oxide. D-isolysergic acid, in which R _{2 is} a primary amino hydrazide, is then washed into the filtrate with chloroform, which means 0.5% ethanol or monoalkylamino group. Heating with hydrazine from methanol / ether and diluting 15 gives prisms; Yield: 83%; M.p. 202 °; with water, if necessary after adding Ammo [α] !? = + 445 ° (c = 0.5 in pyridine).
niak, the reaction product with a very small amount of D-lysergic acid hydrazide with water

Immiscible solvents, e.g. chloroform, are then mixed with chloroform, the 2% ethanol extracted. obtained, washed into the filtrate. You get prisms from

After evaporation of the solvent 20 methanol / ether; Yield: 5%; M.p. 215 °; [x]% ° = the crude product obtained is usually a mixture of + 10 ° (c = 0.5 in pyridine).
Hydrazides of the lysergic and isolysergic acid series, the.

according to known methods by crystallization and / Example 2

or chromatographic adsorption into the compo- Man heats a solution of 1.6 g of 1-methyl-ergot-

nents can be decomposed. 25 amine hydrochloride in 6.4 ecm anhydrous hydrazine

The hydrazides produced according to the invention take 1 hour at 90 °, diluted with 50 ecm of water, distillate, therapeutically usable, phäfmakodynami- lated water and hydrazine hydrate and repeatedly see properties that make them valuable medicines- this operation. Then the residue will make th. They have a sedative effect on motor functions and, between a dilute tartaric acid solution and chloroform, psychological functions and influence the toiius when shaken out. The after the alkaline ■ the wine vessels. For example, they are characterized by bases released in an acidic solution, which are shaken out with a strong monoamine oxidase inhibition. In addition to chloroform and the solution is chromatographed, the process products can also be used as an intermediate ** of the products remaining after the chloroform has evaporated for the manufacture of drugs. Crude product in chloroform, the 0.5% ethanol. 35 holds on a column of 25 g of aluminum oxide. It was known that hydrazides of lysergic acid are washed into the filtrate with 1-methyl-D-isolysergic acid hydrazide with chlorine series, which are made from lysergic acid amides or lysergic acid form containing 0.5% ethanol, polypeptides by treatment with anhydrous hy- From ethanol the compound crystallizes in beautiful drazin can be made in the warmth, only in flakes; Yield: 45%; M.p. 201-204 °; [λ]? = racemic form can be obtained. From the ¹ 4 "+ 400 ° (c = 0.5 in pyridine); Keller's color reaction: the racemic mixture obtained was yellow-blue.

desired optically active compounds then the 1-methyl-D-lysergic acid-hy-

with an optically active acid, - e.g. B. Bi- (p-toluyl) -i.- drazid with chloroform, which contains 1 to 2% ethanol, tartaric acid. washed into the filtrate. Prisms are obtained from ethanol;

It has now been found, surprisingly, that 45 Yield: 45%; M.p. 194 to 195 °; [a] ² ₀ ⁰ = + 14 ° the optically active hydrazides of the lysergic acid series (c = 0.5 in pyridine); Keller's color reaction: blue. Lysergic acid derivatives of the general formula H. . . ,

Treating with anhydrous hydrazine: jk · Presence P

can be obtained directly from protons ^. since 14 g of 1-allyl-D-lysergic acid are suspended in one

this process completely adds racemization to a mixture of 200 ml each of methanol and acetone remain. The present method thus enables excess diazomethane ethereal solution to be added optically active hydrazides of the lysergic acid series. without and stir until the nitrogen evolution ceases, Subsequent lossy and time-consuming & final race - at the same time the acid goes completely into solution, Efficient production of mat cleavage - one now evaporates to dryness.

Another advantage of this new process is that the residue obtained is dissolved, consisting of in that the reaction temperature is lower and the 1-AUyl-D-lysergic acid methyl ester, in 75 ml of n-propanol, The reaction time is shorter than with the previously known method adds 4.6 g of hydrazine dihydrochloride and 20 ml of water. add free hydrazine and stir at 50 ° for 1 hour. Man

The new process therefore means an important addition of 90 ml of n-NaOH and 500 ml of water technical progress and also allows the 60 and shakes out with chloroform. That through manufacture the process products in technical steam the chloro-scale dried over potash. The crude product obtained from the form solution is

In the following examples, which form the execution, which contains 0.5% ethanol, dissolved and attached to 400 g explain the process, all temperature aluminum oxide is chromatographed, with chlorine information in degrees Celsius and are uncorrected. 65 form, which contains 0.25% alcohol, initially 1-AHyI-D-

For the method given in Example 3 for Herisolysergic acid hydrazide is eluted, the ether is recrystallized from alcohol / position of the ester required as starting material, forms prisms; M.p. 129 to 130 °; no protection claimed here. [ä] ² _d ° = + 399 ° (0.5 in pyridine). This is followed by

Chloroform, which contains 3% alcohol, washed 1-allyl-D-lysergic acid hydrazide into the filtrate, which does not crystallize; Yield: 40%; [x] f = + 18 ° (c = 0.5 in pyridine).

Bimaleate: m.p. 172; [«] !? = + 70 ° (c = 0.5 in Water).

Claims (1)

Claim: Process for the production of optically active lysergic acid and isolysergic acid hydrazide derivatives the general formula CO-NH-NH ₂
/ N-CH ₃ wherein R ₁ denotes a hydrogen atom, a lower alkyl, alkenyl or aralkyl group, characterized in that 1 mol of an optically active lysergic acid or isolysergic acid derivative of the general formula CO-R ₂ N-CH, where R ₁ 'is a lower alkyl, alkenyl or aralkyl group and R _{2 is} an alkoxy group, a primary amino or monoalkylamino group or the tripeptide residue of the natural ergot alkaloids or R ₁ ' is a hydrogen atom and R _{2 is} the tripeptide residue of the natural ergot alkaloids, in the presence heating of at least 1 equivalent of proton with an excess of hydrazine at about 80 to 135 ⁰ C and the resulting mixture of Lysergsäure- and isolysergic acid hydrazide derivative by crystallization and / or chromatography separated into the components. Considered publications:
German Auslegeschrift No. 1 074 590;
HeIv. chim. acta, 26 (1943), pp. 922 to 928
(1955), pp. 421 to 433.