DE1092923B - Process for converting L-propanolamide- (2) or (+) - butanolamide- (2) of l-lysergic acid or l-isolysergic acid into the same amides of d-lysergic acid or d-isolysergic acid - Google Patents

Description

GERMAN

It is known that the derivatives of d-lysergic acid, e.g. B. Ergobasin, Methylergobasin and Ergotamine are pharmacodynamically effective and therefore therapeutically valuable; also have further significance Derivatives of d-isolysergic acid, e.g. B. Ergobasinin, Methylergobasinin or Ergotaminin, which are easy and in can be converted into the epimeric derivatives of d-lysergic acid in good yield.

Some therapeutically valuable d-lysergic acid derivatives, especially the more simply substituted amides, such as ergobasin and methylergobasin, i.e. L-propanolamide- (2) of d-lysergic acid and (+) - butanolamide- (2) of d-lysergic acid can be produced partially synthetically (cf. A. Stoll and A. Hofmann, Helvetica Chimica Acta, Vol. 26, 1943, p. 944, British Patent 573 514 and M. Semonsky, A. Cerny and V. Zikan, Chem. Listy, Vol. 50, 1956, p. 116. In a partial synthesis of the both compounds mentioned are used to separate the mixtures of L-propanolamides- (2) or (+) - butanolamides- (2) of d- and 1-isolysergic acid the easily accessible one Dibenzoyl-d-tartaric acid used. L-propanolamide- (2) and also (+) - butanolamide- (2) of 1-isolysergic acid have no therapeutic significance and their transformation into a therapeutically usable one Connection, e.g. B. in the hydrazide of d, l-isolysergic acid via 1-lysergic acid and its methyl ester is uneconomical. Especially with the alkaline cleavage of the substituted 1-lysergic acid amides into 1-lysergic acid high losses occur, the maximum yield of pure 1-lysergic acid is about 35%.

L-Propanolamide- (2) or f - (-) - Butanolamide- (2) der d- and 1-isolysergic acids and d- and 1-lysergic acids are diastereomers. A conversion of the substituted amides of 1-lysergic and 1-isolysergic acid into the corresponding, therapeutically valuable amides of d-isolysergic and d-lysergic acid, without the asymmetric position To change the carbon atom in the optically active residue of the amino alcohol, is in the literature up to now not been described. One described by Stoll and Hofmann in Helvetica Chimica Acta, Vol. 26, 1943, p. 922 Formation of the d, l-isolysergic acid hydrazide by hydrazinolysis of the natural ergot alkaloids a polypeptide residue is associated with a chemical conversion of the alkaloid used as a starting material. The same applies to the preparation of the racemic isolysergic acid hydrazide by reacting optically active esters of lysergic acid with hydrazine. By The action of hydrazine on the Ergobasin also causes the alkaloid molecule to split and form of the racemic isolysergic acid hydrazide (cf. German patents 656 741 and 659 085.)

It has now been found that L-propanolamide- (2) or (+) - butanolamide- (2) of 1-isolysergic acid or the ! -Lysergic acid into the same amides of the d-isolysergic acid process for converting of L-propanolamide- (2) or (+) -butanol-

amide- (2) of 1-lysergic acid or 1-isolysergic acid into the same amides d-lysergic acid or d-isolysergic acid

Applicant:

Dr. Miroslav Semonsky, Prague,

and Dr. Antonin Cerny, Celäkovice (Czechoslovakia)

Representative: Dipl.-Ing. A. Spreer, patent attorney, Göttingen, Groner Str. 35

Claimed priority: Czechoslovakia from May 22, 1956

Dr. Miroslav Semonsky, Prague,

and Dr. Antonin Cerny,

Celäkovice (Czechoslovakia),

have been named as inventors

or the d-lysergic acid can convert through partial racemization and separation of the diastereomers, by the 1-lysergic acid or the 1-isolysergic acid amide dissolves the solution in a primary aliphatic ^ raliphatic amine or amino alcohol 1 to 10 hours at 110 to 160 ° C until equilibrium between the four diastereomers is reached heated and the amides of d-lysergic acid or d-isolysergic acid in itself from the mixture obtained separated off in a known manner and the residue is further racemized in each case under the same conditions.

In this partial racemization, only the steric arrangement of substituents on the carbon atom is used 5 and 8 of the lysergic acid and isolysergic acid residue changed, while the steric arrangement in the amide residue remains unchanged. In the partial racemization of (-f) -butanolamide- (2) of 1-isolysergic acid and 1-lysergic acid there is an equilibrium of (+) - butanolamide- (2) d- and 1-isolysergic acid and d- and 1-lysergic acid, which behaves like 3.5: 3.5: 1.5: 1.5. The partially Racemization of L-propanolamide- (2) of 1-isolysergic acid or 1-lysergic acid leads to the same Ratio of all four stereoisomers.

009 648/396

From the through partially; Racemization obtained methanol), the: values found agree with the

Mixtures of the diastereomers can match those calculated in a larger one.

Amount of d-compound present easily separated The filtrate F ₁ , which is predominantly the (-J -) - butanoI-

will. So you can z. B. that in a larger amount of amide (2) of the d- and 1-lysergic acid and the 1-isolysergic

Easily separate any amide of d-isolysergic acid containing 5 acid is evaporated to dryness and the

and then the residue as a new partially racemized residue, 2.6 g, from a mixture of 2.6 ecm of methanol

and the newly formed d-isolysergic acid amide recrystallized again and 52 ecm acetone. That crystallized out

split off. Through such a partial racemization, crude acidic dibenzoyl-d-tartrate of (+) - butanolamide- (2)

which can be repeated five to six times, one obtains the 1-isolysergic acid, 1.1g, is suctioned off with acetone

z. B. from the (- + -) - butanolamide- (2) of 1-isolysergic acid (the combined filtrates are washed with F ₂

pure (+) - butanolamide- (2) of the d-isolysergic acid referred to in one) and repeated from a mixture of

Yield from 60 to 65%. This amide can be recrystallized to give methanol and acetone. The received

therapeutically valuable methylergobasin epimerizes pure acidic salt of (+) - butanolamide- (2) the 1-isolyserg-

will. acid forms almost colorless needle-shaped crystals; his

According to the method of the invention, these properties can be in conflict with those of one another

significant L (+) - propanolamide- (2) or the (+) - buta- way produced acidic salt of (+) - butanol-

nolamide- (2) of 1-isolysergic acid and 1-lysergic acid amide- (2) of 1-isolysergic acid match. The connection

in the therapeutically valuable ergobasin or methyl melts at 164 to 166 ° C with decomposition (corrected):

ergobasin to be converted. Because of the sensitive- [α]!? - - 221 ° (c = 0.525, in methanol). The found

The ability of ergot alkoloids to increase 20 values corresponds to the formula:

Temperatures it is surprising that Ergobasin and rwnwrTinrwn

Methylergobasin by partially repeating O ₂₀ H ₂₅ U ₂ W ₃ several times. O ₁₈ H ₁₄ U ₈ · C ₃ M ₆ U.

Racemization of the amides of 1-lysergic acid mentioned on drying at 100 ° C and 0.2 mm of mercury and 1-Isolysergic acid at 135 to 140 ° C in a yield pressure, the compound loses 7.55% of its weight of 60% can be gained. 25 (calculated for 1 mole of acetone = 7.68%). The crystal

The state of equilibrium and the solvent-free connection that can be achieved with it shows the optical rotation

Yields of the individual compounds are of the type of [a] ² S - —240 ° (c = 0.84 in methanol),

of the solvent, on the temperature and the the filtrate F _8, which mainly the acidic dibenzoyl

Duration of heating depends. The simultaneous d-tartrate of the (+) - butanolamide- (2) of the d- and 1-lyserg-

trending undesired cleavages depend on 30 acid contains, is in a vacuum at 15 mm of mercury

these conditions. The state of equilibrium is pressure and 40 ° C evaporated to dryness, from the

in most cases, after about 4 hours of warming, the residue is removed by excess sodium bicarbonate

reached at a bath temperature of 135 to 14O ⁰ C, released carbonate in aqueous ethanol, the bases

when the solvent is a primary aliphatic, and incorporated into ether. After evaporation of the

Araliphatic amine or amino alcohol used 35 combined alcoholic-ethereal extracts will that

will. By further heating the equilibrium crude amorphous mixture of d- and 1-lysergic acid amides,

state no longer changed. 0.62 g, first from 31 ecm chloroform and then from

600 ecm of benzene recrystallized. This creates a

Example 1 molecular compound of (+) - butanolamide- (2) der

40 d- and 1-lysergic acid in the form of short prisms

1.79 g of (+) - butanolamide- (2) of 1-isolysergic acid obtained. The molecular compound melts at 212

Contains 16.5% crystal solvent and 1.5 g of the up to 213 ° C with decomposition (corrected). When drying

pure compound corresponds to, F. = 90 to 94 ° C, at 100 ° C and 0.2 mm mercury pressure suffers the

[α] a> = - 352 ° (c = 0.435 in chloroform), there will be no weight loss with compound, [α] f = - 202 °

4.5 ecm benzylamine in a nitrogen environment for 4 hours 45 (c = 0.451 in pyridine).

In an oil bath heated to 135 to 140 ° C under reflux, heated in the qualitative and semi-quantitative evaluation, the direct light being excluded from the paper chromatogram of the compound. The reflux condenser was closed with a tube filled with the presence of (+) - butanolamides- (2) or d- and potassium hydroxide. Determined from the 1-lysergic acids in a ratio of 1: 1. The dark-colored mixture is in a vacuum at 15 mm 50 analytical values correspond to the overall formula mercury pressure and 75 to 100 ° C the benzylamine C ₂₀ H ₂₅ O ₂ N ₃ .
distilled off, and the residue is after 1 hour -o · · 1 ο
Drying at 100 ° C and 0.2 mm mercury pressure in ceispiei c
Dissolved 18 ecm of anhydrous methanol. A solution of 1.83 g of dibenzoyl-d-wein-55 with 14.4% crystal solvent, that is 4.42 g, is added to this warm 4.0 g of crude (+) - butanolamide- (2) der 1-isolysergic acid solution Dissolving acid given in 4.5 ecm anhydrous methanol. After medium-free connection, 4 hours with 12 ecm of filtering the solution and after inoculating the benzylamine under the same conditions as in the solution with a crystal of the acidic dibenzoyl-d- Example 1 is heated. The mixture obtained contains a tartrate of the (+) - butanolamide- (2) of the d-isolysergic acid. Crude mixture of the four diastereomeric (+) - butanol, the solution will stand overnight in the refrigerator- 60 amide- (2). Allowed to separate the methyl formed. Then the precipitated salt, 0.94 g, ergobasinins, the mixture, 3.% g, is suctioned off in 40 ecm of water des Methylergobasinins, dissolved with a small amount of free methanol and this solution is washed with a solution of methanol (the combined filtrates of 4.14 g of dibenzoyl-d-tartaric acid in 10 ecm of anhydrous are designated as F ₁ ) and methanol is added from 90% methanol. The filtered solution is recrystallized with a. The obtained acidic dibenzoyl-d-tartrate 65 crystal of the acidic dibenzoyl-d-tartrate of (-J -) - Budes methylergobasinins forms almost colorless acicular tanolamides- (2) of d-isolysergic acid inoculated and via crystals and has the same properties as a Left to stand overnight in a refrigerator at -5 ° C., acidic dibenzoyl-d-tartrate prepared in another way. The precipitated crystals, possibly also those of methylergobasinine; F, = 215 to 217 ° C with decomposition. A small amount of the acidic dibenzoyl-d-tartrate of the settlement corrected, [a] ² S '= ■ · - 95 ° (c = 0.466 in 90% 70 benzylamine , are sucked off and

washed with methanol. 1.6 g of crude, acidic methylergobasinine salt are obtained.

The mother liquor is evaporated to dryness with the washing liquids in vacuo at 15 mm mercury pressure and 40 ⁰ C, and the amides freed from the salts in a known manner are further partially racemized in the manner described, the specified weight ratio between the amide and the benzylamine must be adhered to.

After repeating these treatments five times, the proportions of the acidic methylergobasinin-dibenzoyl-d-tartrate are combined and the base is freed from them as in Example 1. There are / ₀ of 2.10 g = 61 ° (H -) - Butanolamides- condition (2) of the d-isolysergic acid (Methylergobasinin) having a smaller content of methylergobasine. F. = 185 to 188 ° C with decomposition (corrected), [a] ¹ S = + 350 ° (c = 0.4 in chloroform). Upon drying at 100 ⁰ C and 0.2 mm of mercury pressure, the compound is about loses 3 ° / ₀ of its weight.

This Methylergobasinin can be therapeutically valuable in an aqueous alcoholic potassium hydroxide solution Methylergobasin can be epimerized, the yield being the same as for the analytically pure Methylergobasinin.

Example 3 ² p

2.0 g (-j -) - butanolamide of 1-lysergic acid with 9.0% crystal benzene, which corresponds to 1.82 g of the pure compound, with a melting point of 192 to 194 ° C with decomposition, [a] f? = - 2.1 ° ± 0.5 ° (c = 1 in pyridine), are dissolved in 6 ecm of racemic 2-aminobutanol- (l), and the solution is heated under the same conditions as in Example 1. The aminobutanol is distilled off from the brown-colored reaction mixture at 70 to 100 ° C in vacuo at 15 mm mercury pressure, and the residue, consisting of (4 -) - butanolamides of d-lysergic acid, d-isolysergic acid, 1-lysergic acid and 1-isolysergic acid in a ratio of about 3.5: 3.5: 1.5: 1.5, is dissolved in 20 ecm of anhydrous methanol and by adding 2.12 g of dibenzoyl-d-tartaric acid in 5 ecm of methanol in the acidic dibenzoyl d-tartrate transferred. The acidic dibenzoyld-tartrate of the methylergobasinine, which separates out after inoculating the solution, is filtered off with suction. It has a melting point of 213-214 ° C, under cerium ratio, [α] f + 89 ° (c = 0.472 in 90 ° / ₀ aqueous methanol). The salts of the bases contained in the filtrate are further processed according to Example 2 by repeated partial racemization to form further proportions of the acidic dibenzoyl-d-tartrate of methylergobasinine.

In a known manner, from the combined proportions of acid dibenzoyl-d-tartrate of Methylergobasinins 1.09 g recovered, equal to 60 ° / ₀ of theory, Methylergobasinin. After recrystallization from acetone, the compound has a melting point of 192 to 194 ° C. with decomposition and [a] ² S = + 386 ° (c = 0.4 in chloroform).

Example 4

2.74 g of crude L-propanolamide- (2) of 1-isolysergic acid, which contains 4.5% moisture, [α] % ° = - 247 ° (c = 0.476 in chloroform), is used in the first treatment with 8, 2 ecm benzylamine partially racemized, the same working conditions as in Examples 1 and 2 being observed. There are obtained 1.64 g = 61 ° / ₀ ergobasinine which may be epimerized to ergobasine; F. = 185 to 187 ° C with decomposition (corrected), [α] % ° = + 352 ° (c = 0.57 in chloroform). When the compound is dried at 100 ° C. and 0.2 mm mercury pressure, there is a weight loss of 2.5%.

Claims (4)

Claim: Process for converting L-propanolamide- (2) or (H -) - butanolamide- (2) of 1-lysergic acid or 1-isolysergic acid into the same amides of d-lysergic acid or d-isolysergic acid by partial racemization and Separation of the diastereomers, characterized in that the 1-lysergic acid or. the 1-isolysergic acid amide dissolves in a primary aliphatic, araliphatic amine or amino alcohol, the solution is heated to 110 to 160 ° C for 1 to 10 hours until equilibrium between the four diastereomers is reached, and the amides of d-lysergic acid or from the mixture obtained The d-isolysergic acid is separated off in a manner known per se and the residue is further racemized in each case under the same conditions. Considered publications:
German Patent Nos. 656 741, 659 085;
U.S. Patent Nos. 2,214,034, 2,586,154;
Austrian Patent No. 182 479;
British Patent No. 573,514;
Helvetica Chimica Acta, Vol. 26, 1943, pp. 922 and 944; Chem. Listy, Vol. 50, 1956, p. 116;
Houben-Weyl, "Methods of Organic Chemistry", Vol. 4, part 2, 4th edition, 1955, p. 512 and following. A priority document was displayed when the registration was announced. © 009 648/396 11.60