DE1013288B - Process for the production of derivatives of the lysergic acid series acylated on the indole nitrogen - Google Patents

Description

GERMAN

It has been found that derivatives of the lysergic acid series of the general series acylated on the indole nitrogen Formula I,

Method of manufacture
of acylated on indole nitrogen
Derivatives of the lysergic acid series

Tr CO-R ₁

JH ¹

N-CH,

Applicant:
Sandoz Aktiengesellschaft, Basel (Switzerland)

Representative: Dr. W. Schalk and Dipl.-Ing. P. Wirth,

Patent attorneys,
Frankfurt / M., Große Eschenheimer Str. 39

Claimed priority:
Switzerland from December 29, 1954

in which R _{1 is} an alkoxyl, monoalkylamino or dialkylamino radical, R _{2 is} a —COCH ₃ or —COCH ₂ COCH ₃ radical and χ ^ y is a —CH ₂ —CH <(- radical (dihydrolysergic acid derivatives) or —-CH = C <(- means residue (lysergic acid derivatives) can be prepared by lysergic acid derivatives of the general formula II,

D ^ N-CH,

Dr. Arthur Stoll, Ariesheim, Basel!.,

Dr. Albert Hofmann, Bottmingen, Basell,

and Dr. Franz Troxler, Basel (Switzerland),

have been named as inventors

II

in which R ₁ , x ^ _, y have the same meaning as in formula I, treated with gaseous ketene in a suitable solvent, optionally with the addition of a tertiary base as a catalyst.

So far, no acylation products of lysergic acid or simple lysergic acid derivatives have been found in the literature has been described because it does not succeed with the usual acylation process, acyl residues to introduce into the lysergic acid molecule. The usual acylating agents, such as acetic anhydride or acetyl chloride, do not react under mild conditions. If the temperature is increased to force the reaction, then profound changes take place in the lysergic acid molecule, and most of the known to be very sensitive connections will be destroyed. If you heat z. B. lysergic acid or dihydrolysergic acid with acetic anhydride, an extensive conversion of the molecule takes place. Of the nitrogen-containing ring D is split open and a lactam is formed (A. Stoll, A. Hofmann and F. Troxler, Helvetica Chimica Acta, Vol. 32, 1949, p. 506), but acetylation does not take place in this case either. According to the newly discovered process at hand, derivatives of the lysergic acid series that have been acylated on the indole nitrogen are now become accessible. The process is carried out, for example, by using a lysergic acid derivative of the formula II dissolves in a suitable solvent and through the solution a stream of gaseous Keten directs. The acylation mixture is worked up in a manner known per se, after which finally the Acylation product can be purified by chromatography.

The lysergic acid derivatives of the formula II used as starting material are z. B. according to the procedure by A. Stoll and A. Hofmann (Helvetica Chimica Acta, vol. 26, 1943, p. 944) and A. Stoll, J. Rutschmann and W. Schlientz (Helvetica Chimica Acta, Vol. 32, 1950, p. 375).

Suitable solvents are benzene, toluene, acetone and other organic compounds that are themselves with Keten don't respond.

In non-polar solvents, such as benzene, only acetyl derivatives are formed, whereas in acetone they are formed as a result

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partial polymerization of the ketene in addition to acetyl derivatives and acetoacetyl compounds.

To achieve a smooth flow in non-polar solvents to achieve acetylation, it is advantageous to use a catalytic amount of a tertiary base, e.g. B. trimethylamine, to add. In polar solvents, e.g. B. in acetone, the basicity of the compound to be acylated is sufficient for the smooth course of the acylation. The acylation takes place at a lower rate without external heat input Self-heating.

During treatment with ketene, ketene polymerization products are always also formed, but sodium bicarbonate gives excess to the acidic filtrate and shakes out the acylation products with chloroform due to the basic character of the latter. The benzene solution of the evaporation residue of the chloroform extract is filtered through a column of 30 g of aluminum oxide to purify the acylation products. 0.21 g of 1-acetyllysergic acid methyl ester is obtained from the more rapidly migrating fractions, which crystallizes from its acetone solution when diluted with petroleum ether in coarse short prisms ίο; F. = 172 to 173 °, [a] | ° = + 15 ° (c = * 0 E in chloroform). C ₁₉ H ₂₀ O ₃ N ₂ , molecular weight = 324.4

calculated C 70.35%, H 6.22%, N 8.64%;

found C 69.92%, H 6.11%, N 8.35 ⁰ Jy

which contains 2% alcohol, the more adhesive *

Compounds easily removed by the usual methods. 15 When developing the chromatogram with benzene let separate.

The new 1-acyl derivatives of the lysergic acid series are mostly well-crystallized compounds that form crystallized salts. You can relieve yourself from the starting materials by means of the color reaction
chloride - glacial acetic acid - sulfuric acid) slightly
While the unacylated derivatives of lysergic acid and dihydrolysergic acid with glacial acetic acid and concentrated sulfuric acid containing ferric chloride suddenly appear when shaken, the new acyl derivatives initially give a colorless solution from which a characteristic color only develops in the course of a few minutes. The 1-acetyllysergic acid derivatives are marked by a violet-blue color, while the 1-acetyldihydrolysergic acid compounds give a greenish-blue color reaction. In the case of the 1-acetoacetyllysergic acid or dihydrolysergic acid derivatives, Keller's reagent turns green.

1-Acetoacetyllysergsäuremethylester dissolved, the solvent evaporated, the residue dissolved in acetone UM diluted the solution with petroleum ether, whereby 0.2 g latmk Keller (iron-20 skewers from the F. = 168 to 169 °. B4 differentiate the color reaction according to Keller 1-acetoacetyllysergic acid methyl ester gives a yellowish green coloration ij [a] * ° = - 7.5 ° (c = 0.5 in chloroform). Cs ₁ H ₂₈ O ₄ Ns, molecular weight = 366.4;

calculated C 68.83%, H 6.05%, N 7.65%;

found C 68.98%, H 6.18%, N 7.64%.

Example 2

1-acetyldihydrolysergic acid methyl ester j

and 1-acetoacetyldihydrolysergic acid methyl ester
A vigorous stream of ketene is passed through the solution of 2.0 g of methyl dihydrolyserate in 60 ecm of acetone over the course of 1 hour. Then the acylation *

The new acyl derivatives are resistant to a dilute acid mixture, diluted with 500 ecm of water, for 2 hours. When warming with soda solution or when shaking and then not leaving the excreted with alkali, on the other hand, the acyl radical of basic by-products is filtered off. From the acidic split off hydrolytically. Solution, the acylation products are made with sodium

The new derivatives of bicarbonate, which are acylated on the indole nitrogen, are released, they are extracted with chloroform and evaporated Lysergic acid series generally show similar phar- 4 ° this, dissolves the residue in benzene and chromatomacodynamic The benzene solution graphs properties like the corresponding ones on a column of 90 g unsubstituted lysergic acid derivatives. After all, aluminum oxide does it.

e.g. the acetylation but not just a complete change - When washing with benzene, the 1-acetyldi-

tion of all pharmacodynamic properties of methyl hydrolyser into the filtrate. As evaporation of the starting materials in the same direction, but there is 45 residue of the filtrate obtained 0.49 g of crystallized can the individual physiological properties
can be influenced quite differently. The serotonin inhibition by lysergic acid diethylamide, for example, is the case with the derivative acetylated on the indole nitrogen

amplified up to 2.5 times, while the toxic 5 ° pyridine); Yield 22% effect is around ten times lower. Lysergic acid diethyl molecular weight = 326.4; amid causes temperature increase after administration
in large quantities in the rat. This effect is absent
the 1-Acetyllysergsäurediethylamid, which like that
Mixture of equal parts of dihydro-ergocristin, 55
-ergocornine and -ergocryptine (known under the brand name "Hydergin") only have a temperature-lowering effect. the
New compounds are said to be used as remedies as well as
Intermediate products used in their manufacture

60 1-Acetyldihydrolysergsäuremethylester.When recrystallizing from benzene, it separates in coarse prisms that melt at 182 to 183 °; the color reaction according to Keller is greenish blue; [a) f = -98 ° (c = 0.5

the theory. C ₁₉ H ₈₂ Ot ₁

Calculated C 69.92%, H 6.79%, N 8.58, acetyl 13.19 ^η _r found C 69.61%, H 6.67%, N 8.78, 12.28%.

will.

example 1

1-Acetyllysergic acid methyl ester and 1-Acetoacetyllysergic acid methyl ester

A vigorous stream of ketene is passed through the solution of 0.65 g of D-lysergic acid methyl ester in 50 ecm of acetone within 50 minutes. After this time, the acylation is already complete. 300 ecm of water are added to the solution and the mixture is shaken with chloroform The more strongly adhering methyl l-acetoacetyldihydrolysergic acid was washed out of the aluminum oxide. The evaporation residue, 0.61 g, was recrystallized from benzene, giving crystal flakes with a melting point of 190 to 191 °; [a] f = - 114 ° (c = 0 , 5 in pyridine). The Kellsi color reaction is green; the yield is 30% of theory. C ₂₁ H ₂₄ O4 N ₃ , molecular weight = 368.4;

calculated C 68.46%, H 6.57%, N 7.60%,

found C 68.51%, H 6.66%, N 7.65%

Example 3

1-Acetyldihydrolysergic acid methyl ester
0.55 g of methyl dihydrolyser acid are added

Hours, filtered off the non-basic precipitate, 7 ° addition of 0.1 ecm 33% aqueous trimethylamine

solution dissolved in 30 ecm benzene; guides through this solution if a vigorous stream of ketene within 30 minutes, the solution of the acylation product is evaporated in Vacuum to dryness and filter the benzene solution of the residue through a column of 30 g of aluminum oxide. The residue from evaporation of the filtrate is 0.45 g of crystallized 1-acetyldihydrolysergic acid methyl ester, the 0.30 g pure compound after recrystallization from benzene with those in the previous example properties described result.

Example 4
1 -acetyllysergic acid diethylamide

After adding 0.1 ml of triethylamine, a stream of ketene is passed through the solution of 1.0 g of D-lysergic acid diethylamide in 30 ecm of benzene, the solution of the acylation products is evaporated to a syrup, this is diluted with 30 ecm of acetone and shaken the solution after adding 500 ecm of water and 1.5 ecm of glacial acetic acid for 1 hour. The non-basic by-products which separate out are then filtered off, the acidic aqueous filtrate is made alkaline with bicarbonate and, after alkalinization, the acetylation product is shaken out with chloroform. The residue from evaporation of the chloroform solution is dissolved in benzene and filtered through a column of 30 g of aluminum oxide. 0.47 g of 1-acetyllysergic acid diethylamide, which does not crystallize as a base, is obtained from the filtrate by evaporation; [af _p ° = -14 ° (c = 0.5 pyridine); The color reaction according to Keller is violet.

The compound gives a water-soluble, crystallized acidic tartrate, which is prepared by combining equimolecular amounts of 1-acetyllysergic acid diethylamide and D-tartaric acid in acetone, from which the bitartrate is immediately deposited in fine crystals; M.p. = 178 to 180 °; [a] | ° = -6 ° (c = 0.5 pyridine). C ₂₂ H ₂₇ O ₂ N ₃ -C ₄ H ₆ O ₆ , molecular weight = 515.6;

calculated C 60.57%, H 6.45%, N 8.15%;

found C 60.67%, H 6.71%, N 8.27%.

40

Example 5

l-acetyllysergic acid monoethylamide
0.5 g of lysergic acid monoethylamide is dissolved in 40 ecm of absolute benzene, 0.1 ecm of triethylamine is added and the solution is treated with a vigorous stream of ketene for 10 minutes. After the same work-up as in the preceding examples, 0.6 g of crude acylation product is obtained, which is stirred with a little absolute benzene. The part which is insoluble in benzene is pure 1-acetyllysergsäuremonoäthylamid and can be recrystallized directly from acetone or chloroform, it is microcrystalline from MP = 220 to 223 °. If the fraction soluble in benzene is chromatographed on a column of 25 g of aluminum oxide, a further amount of the acetylation product can be washed out ^{with a mixture of benzene and 1} J ₂ ⁰ U alcohol; the total yield is 0.4 g; the color reaction according to Keller becomes violet-blue in the course of a few minutes; Mo = -20 ° (c = 0.4 in pyridine). C ₂₀ H ₂₃ O ₂ N ₃ , molecular weight = 337.4;

calcd C 71.19%, H 6.87%, 0 9.48%;

found C 70.92%, H 7.05%, O 9.97%.

Claims (1)

Claim: Process for the preparation of derivatives of the lysergic acid series acylated on the indole nitrogen of the general formula H CO-R ₁ N-CH, y - in which R _{1 is} an alkoxyl, monoalkylamino or dialkylamino radical, R _{2 is} a - COCH ₃ - or - COCH ₂ COCH ₃ remainder and X- ^ y a - CH ₂ CH ^ residue (dihydrolysergic acid derivatives) or - CH = C <VRest (lysergic acid derivatives) means characterized in that one lysergic acid derivatives of the general formula H ₂ in which R ₁ , χ ^ _, y have the above meaning, treated with gaseous ketene in a suitable solvent, if a non-polar solvent is used, advantageously in the presence of catalytic amounts of a tertiary base, or in a suitable polar solvent without the addition of a catalyst. © 709 656/324 7.57