DK141531B - Analogous procedure for the preparation of 1-methyl-9,10-dihydro-d-lysergic acid allylamide or acid addition salts thereof. - Google Patents

Description

\ via, (11) PUBLICATION 141531 DENMARK lnt C | a c 07 D 457/06 • (2!) Note No. 515/75 (22) »ndtovwetden 51 · J? ° * 1975 (23) Life Day 51- Jan. 1975 (44) The note presented and. ιηΟΛ

submitting lectures «oflantHggjortden Apr 14 lytHJ

DIRECTORATE OF T _ PATENT AND TRADEMARK <* »Priority moved from the

Feb 4 1972, GO 1186, HU

Feb 4 1972, GO 1187, HU

(71) RICHTER GEDEON VEGYESZETI GBR RT., 19-21, Gyoemroel ut, Budapest X # HU.

(72) Inventor: Erzeebet Mago, 18, Karinthy Frigyes ut, Budapest XI, HU:

Tibor Balogh, 47a, Ealocsai u., Budapest XIV, HU: Emilia Uskert, 8,

Vali u., Budapest XI, HU: Jozsef Borsi, 90 # Bartok Bela u ¥, Budapest XI, HU: Lajos Wolf, 28b, NemetvoeTgyl u., Budapest XII, HU.

(74) Power of Attorney during the process of blessing:

Office of Industrial Energetic v. Svend Sohønning.

The present invention relates to a process for the preparation of the novel compound 1-methyl-9,10-di-hydro-d-lysergic acid allylamide with the formula I or acid addition salts thereof shown in claim 1.

As you know, lysergic acid amides are compounds of great medical importance. Thus, £. eg all the ergot alkaloids found in nature, lysergic acid amides. ' The semi-synthetic processes based on lysergic acid are in most cases aimed at the preparation of lysergic acid amides and lysergic acid alkanolamides since these compounds can greatly extend the therapeutic utility of the lysergic acid derivatives.

Several processes have been developed for the semi-synthetic production of lysergic acid amides. The first of the widely used methods was devised by A. Stoll and A. Hofman (Helv. Chim.

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Acta 26, 944, 1943). In this process, lysergic acid peptides were cleaved to form lysergic acid hydrazide, this latter compound being converted to lysergic acid azide which was used to acylate various amides. However, a major disadvantage of this so-called azide method is that it proceeds with poor yield and that a considerable amount of by-products are also formed.

Another known process is the so-called mixed anhydride coupling method. In this process, a mixed anhydride is formed of lysergic acid and trifluoroacetic acid (U.S. Patent No. 2,736,728) or of lysergic acid and sulfur trioxide (German Patent No. 1,040,560) and the resulting mixed anhydride is used for acylation of alkano laminates. However, this process does not allow the production of uniform lysergic acid alkanolamides.

In a further known method, the acylation with lysergic acid halides is carried out. Preparation of the respective Lysergic Acid Halo Genes disclosed in the Unamanian Patent Specification no.

150,425 and 151,847. However, these processes are disadvantageous in many respects; Thus, for example, acid chloride formation can only be carried out under extremely aggressive reaction conditions (e.g., using phosphorus trichloride as solvent and phosphorus oxychloride and phosphorus pentachloride as chlorinating agent), and the resulting acid chloride contains large amounts of impurities (especially lysergic acid, inorganic phosphorus compounds, and lysergic acid chloride, which is also chlorinated in position 2), and finally there is no known process for purifying the acid chloride. In addition, acylation using lysergic acid chloride can only be performed with a yield of not more than 10%, and the impurities in the lysergic acid chloride also appear in the lighter gaseous amines produced in this way.

Austrian Patent Specification No. 216,679 discloses a process for the preparation of monosubstituted lysergic acid amides in which the process of lysergic acid and a primary amine is condensed with each other in the presence of carbodiimides. However, using this reaction, great yield cannot be obtained since the optically active lysergic acid is almost completely converted to the racemic form during the course of the reaction.

Other methods are also known for preparing lysergic acid alkanolamides, namely the direct condensation of lysergic acid with amino alcohols (Collection 31, 3415, 1966), and amidation of lysergic acid methyl ester (Collection 22, 1014, 1957).

However, these processes require very high temperatures (190-200 ° C) and long reaction times (eight to ten hours), and they proceed with extremely low yields.

It has now been found that it is advantageous to prepare the subject compound in a completely pure state when an active lysergic acid ester is reacted with allylamine, ie. by a method known in principle from the peptide chemistry. Neither isomerization nor racemization occurs during the course of the reaction, and the synthesis proceeds with almost quantitative yield.

Accordingly, the method of the invention is peculiar to the characterizing part of claim 1. The yield is particularly high if one according to the invention proceeds as set forth in claim 2, and particularly simple becomes the synthesis if one fails to isolate the active ester and thus according to the invention proceeds as set forth in claim 3.

The subject compound has specific anti-serotonin activity, an effect also found in those of Danish patent no.

107 229 and Danish Disposal Gazette No. 117 501 known light energy officials. when tested for isolated organs under in vitro conditions, these compounds inhibit serotonin activity in smooth muscle contraction. whereas the compound, under in vivo conditions at low doses, antagonizes the edema-inducing and circulating effects of serotonin. In addition, the compound exerts surprising antidepressant effect on the central nervous system similar to the tricyclic anti-depressants; thus, at doses of 2.5-10 mg / kg, it antagonizes intraperitoneally and orally in rats and mice the neuroleptic properties of reserpine and tetrabenazine. It potentiates the psychostimulatory effect of amphetamine. However, these compounds differ from the tricyclic antidepressants by not increasing the vasopressor activity of norepinephrine.

The compounds of general formula II used as starting compounds in the process of the invention can be prepared by reacting 1-methyl-9,10-dihydrolyseric acid of formula III

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OC - OH

With a phenol of the general formula wherein Z and n have the meanings set forth above, in the presence of a dehydrating agent.

Among the active lysergic acid esters mentioned above, the pentachlorophenyl ester can be used with particular advantage. The reaction is preferably carried out in the presence of an inert solvent such as tetrahydrofuran, acetonitrile, methylene chloride or dimethylformamide.

The method according to the invention will now be illustrated by an exemplary embodiment.

Example 1-Methyl-9,10-dihydro-d-lysergic acid allylamide 5.53 g of 1-methyl-9,10-dihydro-d-lysergic acid pentachlorophenol ester are dissolved in 100 ml of dry chloroform with stirring, after which the solution is cooled with ice water and 1.0 g of 1-allylamine dissolved in 10 ml of chloroform are added dropwise. The solution is stirred at room temperature for one hour and then extracted with 6 x 25 ml of 1 / 6s aqueous tartaric acid solution. The aqueous extracts are combined and the pH of the combined extracts is adjusted to 8 by the addition of a few ml of 10% aqueous ammonium hydroxide solution. The aqueous solution is shaken with chloroform (5 x 50 ml). The chloroform solutions are combined and dried over sodium sulfate, filtered and evaporated in vacuo. The residue is dissolved in 10 ml of benzene and the benzene solution is poured into 300 ml of dry petroleum ether. The precipitated precipitate is filtered off, washed with a small amount of petroleum ether and dried in vacuo. The product is chromatographed on an alumina column using an 8: 2 mixture of chloroform and benzene as the eluent. In this way 3.1 g (96¾) of 1-methyl-9,10-dihydro-d-lysergic acid allylamide is obtained. Melting point 189 ° C.

The starting compound, 1-methyl-9,10-dihydro-d-lysergic acid pentachlorophenol ester is prepared as follows: 1.43 g of 1-methyl-9,10-dihydri-d-lysergic acid, which is water-free, is suspended in a mixture of 60 ml of absolute tetrahydrofuran and 60 ml of absolute dichloromethane, after which 1.35 g of pentachlorophenol is added. The resulting solution is cooled with stirring to a temperature between 0 and 5 ° C and over two hours, 1.25 g of di-cyclohexylc arbo di imide are added in small portions. The solution is gradually heated to 20 ° C and stirred for a further two hours.

The dicyclohexylurea separated in crystalline form is filtered and washed with 10 ml of tetrahydrofuran. The filtrate and washing liquid are combined and evaporated to dryness under reduced pressure. The dry residue is dissolved in hot state in 5 ml of benzene and the resulting solution is poured with stirring into 50 ml of petroleum ether. The resulting suspension is treated with ice for 24 hours after which the product is filtered, washed with 20 ml of cold petroleum ether and dried under vacuum. Yield 2, o g (75%), 0¾ = -20 ° (c - = 0.5 in ethanol).

Claims (2)

6 msn An analogous process for the preparation of 1-methyl-9,10-dihydro-d-lysergic acid allylamide of the formula oc-nh-ch 2 -ch = ch 2 / n-ch 3 Ov 3 or acid addition salts thereof, characterized in that a Formula (P-CK 3 / O CH 3 where Z represents hydrogen and / or halogen atoms and / or nitro groups and n represents an integer 1-5, is amidated with 1-allylamine or an acid addition salt thereof and then the compound of formula I formed, if desired is converted into an acid addition salt thereof.