NO115328B - - Google Patents

Description

Process for the production of lysergic acid and/or homologues thereof.

This invention relates to the synthesis of lysergic acid and more particularly methods and products applicable to the production of lysergic acid and its homologues.

Lysergic acid and its homologues which can be prepared by the process according to this invention can be visualized by the formula I in the accompanying drawings where R represents an alkyl radical having from

one to eight carbon atoms.

This invention also includes the production of intermediate products used in the process for the production of lysergic acid and its N-alkyl homologues, as such intermediate products fall within the scope of the invention.

As is well known, lysergic acid (shown in formula I when R 1 is methyl) can be converted into ergot alkaloids and derivatives thereof. Thus, one can e.g. by reaction between d-lysergic acid ester with hydrazine, lysergic acid hydrazide is produced, and by subsequent conversion to azide and condensation with d-2-aminopropanol-1, ergono-wine is obtained.

Some of the intermediates and final products of the invention are tetracyclic structures that have not yet been assigned ordinary names. They may be named in accordance with the system set forth in the Ring Index, Reinhold Publishing Company, 1940, as Structure No. 2439, but such a system of nomenclature is long and complicated. The compounds can be named much more easily on the basis of the tetracyclic ring structure shown in structural formula II in the accompanying drawings.

We have mentioned the ring system in formula II

the ergol. The numbering in the ring system is in accordance with that in the Ring Index, in order to avoid misunderstandings, and to enable a straightforward conversion to the Ring Index and ordinary designations.

The method for producing lysergic acid and/or homologues thereof according to the present invention consists in introducing a double bond in the 5-5a position of a compound of the formula:

where R i is an alkyl radical with from 1 to 8 carbon atoms, R 2 is H or RCO, in which R is an alkyl radical with from 1 to 8 carbon atoms, a monocarbocyclic aromatic radical or a monocarbocyclic aromatic-substituted alkyl radical with from 1 to 8 carbon atoms in the alkyl chain, and R 3 is COOH when R 2 is H, and R 3 is CN when Ro is RCO, by reacting said compound with a dehydrogenating catalyst when R 2 is H, and successively exposing said compound to the action of a strong base and a dehydrogenating catalyst when R2 is RCO. The general method according to the invention can be illustrated by the following series of equations in connection with the accompanying drawings, in which RCO means an acyl radical, Rt means an alkyl radical, R2 means lower alkyl radicals, and x means chlorine or bromine .

With reference to the series of equations in which the tetracyclic compounds are named based on the ergolan structure, the course of the procedure is as follows:

An N-acyl-5-keto-i, 2, 2a, 3, 4, 5-hexa-hydrobenz(cd)indole is halogenated to form the corresponding N-acyl-4-halo-5-keto-1, 2, 2a, 3, 4, 5-hexahydrobenz(cd)indole. The halo ketone is treated with an alkylaminoacetone ketal, illustrated here with an alkylaminoacetoneethylene ketal, to produce an N-acyl-5-keto-4-alkylacetonyl-amino-1,2,2a,3,4, 5-hexahydrobenz(cd)-indo-ethylene-ketal, which after treatment with strong acid is converted into the corresponding di-keto compound, 5-keto-4-alkyl-acetonylamino-1, 2, 2a, 3, 4, 5- hexahydrobenz(cd)indole. After treatment with a strong base, the diketone undergoes cyclization to form a tetracyclic ketone which can be designated as 7-alkyl-9-keto-A10-ergolene (9-keto-7-alkyl-4, 5, 5a, 6, 6a, 7 . . -A1 "-ergolene (4-acyl-9-hydroxy-7-alkyl-4, 5, 5a, 6, 6a, 7, 8, 9-octahydro-indole (4.3.-fg) quinoline. Alternatively, 7-alkyl The -9-keto-A10-ergolene is acylated and then treated with sodium borohydride to form the corresponding 4-acyl-7-alkyl-9-hydroxy-A10-ergolene, whose halogen water acid addition salt after treatment with a thionyl halide forms the 4-acyl- 7-alkyl-9-halo-A1"-ergolene hydrohalide (4-acyl-9-halo-7-alkyl-4,5, 5a, 6, 6a, 7, 8, 9-actahydroindole (4.3-f g)-quinoline hydro-halide). After treatment of the halo-ergolene with sodium cyanide in liquid hydrogen cyanide, the corresponding 4-acyl-7-alkyl-9-cyano-Al0-ergolene (4-acyl-9-cyano-7-alkyl-4, 5, 5a, 6, 6a, 7, 8, 9-actahydroindole (4.3.-fg) quinoline. Alternatively, this compound can be prepared directly from the 4-acyl-9-hydroxy-7-alkyl-A10 -ergolene by the action of boron trifluoride in liquid hydrogen cyanide. Furthermore, the import of the cyano group is carried out using 7-alkyl-9-hydroxy-A1(l-ergolene by one of the methods extensively explained, followed by acylation to produce the corresponding 4-acyl-7 alkyl-9-cyano- A10-ergolene Alternatively, 4-acyl-7-alkyl-9-hydroxy-A10-ergolene can be epimerized by treatment with strong mineral acid to produce a 4-acyl-7-alkyl-9-epi hydroxy-A10-ergolene, . which can be halogenated to 4-acyl-7-alkyl-9-halo-A'°-ergolene, from which 4-acyl-7-alkyl-9 cyano-A1 "-ergolene is prepared as already described. By reaction between 9-cyano- ergolene with an alcohol in acid medium, followed by treatment with a weak base, the cyano group is alcoholized, and the N-acyl group is removed to give the 7-alkyl-9-carbalkoxy-A1"-ergolene (9-carbalkoxy-7-alkyl-4,5,5a,6 , 6a, 7, 8, 9-octahydroindole-(4.3-fg) quinoline). Hydrolysis of the carboxy-derivative with a strong base leads to the corresponding 7-alkyl-9-carboxy-A1"-ergolene (9-carboxy-7-alkyl-4,5,5a,6,6a,7,8, 9-octahydroindo (4.3-fg) quinoline, which on treatment with deactivated Raney nickel yields a 7-alkyl-9-carboxy-A51"-ergoladiene, which is lysergic acid when the 7-alkyl group is a methyl group, or a homologue of lysergic acid when the 7-alkyl group is other than methyl.

It will be understood that while each of the compounds described here as intermediates in the lysergic acid synthesis can be isolated and purified, this is not necessary for the successful performance of the method if the by-products of any reaction do not interfere with later steps, or are eliminated during the preparation of the intermediate did. Thus, two or more method steps can often be combined as is technically obvious. The invention is further illustrated by the following examples, which illustrate new processes and compounds included in this invention together with equivalents thereof.

Various attempts have been made to produce lysergic acid synthetically, but these attempts have so far not led to satisfactory results. The synthesis which is the object of the present invention is based on the use of substituted dihydroindoles as starting material and intermediate products. The compounds produced by the method according to the invention are intermediate products in the production of lysergic acid. These intermediates are distinguished by their stability and their applicability in the subsequent steps of the process. Their chemical properties are more specifically described in the following examples.

Examples:

Preparation of N-benzoyl-5-keto-1, 2, 2a, 3, 4, 5-hexahydrobenz(cd)indole.

A mixture of 118 g (0.4 mol) of N-benzoylindolin-3-propionic acid (prepared according to Robinson's method, J. Chem. Soc. 1931, 3158) and 200 ml of thionyl chloride was allowed to stand at room temperature. rature for iy2 hours and was then gently heated on a steam bath for about 20 minutes. The excess of thionyl chloride was distilled off in vacuo, and the residue, consisting of N-benzoylindoline-3-propionyl chloride, was dissolved in 200 ml of dry carbon disulfide. The solution was added in a thin stream to a vigorously stirred suspension of 240 g of aluminum chloride in 1750 ml of carbon disulfide. The mixture was heated under reflux and stirred for one hour, and treated with a mixture of 500 g of ice, 250 ml of concentrated hydrochloric acid, and 500 ml of water. The mixture was stirred during the addition of the ice mixture and. was cooled by stepwise distillation of a portion of carbon disulfide in vacuum. After adding the entire ice mixture, the remaining carbon disulfide was distilled off in vacuo, and the aqueous residue was extracted with two liters of benzene. The benzene extract was washed with dilute sodium hydroxide solution, dried over magnesium sulfate, and evaporated in vacuo to a small volume. Petroleum ether was added slowly to the concentrate in several portions, whereupon a yellow crystalline precipitate of N-benzoyl-5-keto-1, 2, 2a, 3, 4, 5-hexahydrobenz(cd)indole separated. The precipitate was filtered off, washed with petroleum ether, and recrystallized from a benzene-petroleum ether mixture. After recrystallization from benzene-petroleum ether mixture, it melted at about 145-147°C.

The acylated 5-keto-polyhydrobenz-(cd)indole prepared in accordance

with the method in this example can contain as acyl substituent any member of the group represented by the formula R-CO-, in which R represents a member of the group consisting of alkyl radicals with from one to eight carbon atoms, monocarbocyclic aromatic radicals, lower alkyl-substituted monocarbocyclic aromatic radicals, and monocarbocyclic-aromatic-substituted lower alkyl radicals. Thus, for example, when N-acetyl-indoline-3-propionic acid is used as starting material, N-acetyl-5-keto-1,2,2a,3,4,5-hexahydrobenz(cd)indole is produced, which melts at approximately 177.5-178° C. In the same way, the use of N-phenyl-acetyl-indoline-3-propionic acid and N-p-ethylbenzoyl-indoline-3-propionic acid as starting material for the synthesis of N-phenylacetyl-5- keto-1, 2, 2a, 3, 4, 5-hexahydrobenz(cd)indole, respectively to

N-p-ethyl-benzoyl-5-keto-1, 2, 2a, 3, 4, 5-hexahydrobenz(cd)-indole. By treating N-benzoyl-5-keto-1, 2, 2a, 3, 4, 5-hexahydrobenz(cd)indole with concentrated hydrochloric acid in glacial acetic acid solution, the benzoyl group is removed, and 5-keto-1, 2, 2a, 3, 4, 5-hexahydrobenz(cd)indole, which melts at" 126-127° C, after recrystallization from methanol. By the action of butyric anhydride on 5-keto-1, 2, 2a, 3, 4, 5- hexahydrobenz(cd)indole in pyridine solution gives N-butyoyl-5-keto-1,2,2a,3,4,5-hexahydrobenz(cd)indole, which melts at approximately 137.5-138.5°C after recrystallization from ethanol. By similar methods using the appropriate acyl halide or anhydride, N-toluyl, vareryl, heptanoyl and similar acyl derivatives of 5-keto-1, 2, 2a, 3, 4, 5-hexahydrobenz( cd)indole All N-acylated 5-keto-polyhydrobenz (cd)indole compounds can be used as intermediates for the further steps of the method.

Example 2:

Preparation of N-benzoyl-4-bromo-5-keto-1,2,2a,3,4,5-hexahydrobenz(cd)indole.

Solution 30.7 g (1.1 mol) of N-benzoyl-5-keto-1, 2, 2a, 3, 4, 5-hexahydrobenz(cd) indole in 2200 ml of glacial acetic acid was heated to approx. 40° C. The reaction mixture was illuminated with a 250 watt light bulb, and 352 g (1.1 mol) of pyridine hydrobromide perbromide was added portionwise over a period of approx. 5 minutes, while shaking. The reaction mixture was heated to about 60°C and held at about 55-60°C for about thirty minutes. The mixture was then treated with activated carbon, filtered and evaporated to a small volume in vacuo. The residue was dissolved in 2200 ml of chloroform, the solution was washed several times with water, and dried over magnesium sulphate. The solvent was then removed by distillation in vacuo. The residue was recrystallized from 2200 ml of a 1:1 mixture of acetic acid and ether. The N-benzoyl-4-bromo-5-keto-1,2,2a,3,4,5-hexahydrobenz(cd)indole thus prepared melted at approx. 180.5— 181.5° C.

Instead of pyridine hydrobromide perbromide which was used in the process. the way in this example, other halogenating agents can be used in the preparation of the corresponding N-benzoyl-4-halo-5-keto-1, 2, 2a, 3, 4, 5-hexahydrobenz(cd)indoles. Thus, e.g. bromine or N-chloro-succinimide is used for the process.

The halogenation can be carried out over a range of temperatures, from approximately room temperature to approx. 75° C. It is obvious that the reaction takes place faster at elevated temperatures.

Other polar solvents, such as dimethylformamide, acetonitrile, other lower aliphatic acids, chloroacetic acid, bromoacetic acid and the like can be used.

When N-acetyl-5-keto-1, 2, 2a, 3, 4, 5-hexahydrobenz(cd) indole is used according to the procedure in this example, N-acetyl-4-bromo-5-keto-1, 2 , 2a, 3, 4, 5-hexahydrobenz(cd)indole, which melts at approx. 190°C.

In an analogous manner, as described in example 1, other N-acylated-5-keto-1,2,2a,3,4,5-hexahydrobenz(cd)indoles can be halogenated according to the method in this example. Such halogenated compounds are also suitable intermediates in the method according to the invention.

Example 3:

Preparation of methylaminoacetone ethylene ketal.

A mixture of 1200 ml of liquid methylamine and 300 g of chloroacetone ethylene ketal was heated in a high pressure autoclave at

160-165° C for about 25 hours. The reaction mixture was cooled and excess methylamine driven off. The residue, consisting of methylaminoacetone ethylene ketal, was dissolved in several portions of ether. The ether solution was mixed with a solution of 130 g of potassium hydroxide in 65 ml of water and was decanted from the precipitate. The ether extract, which contained the reaction formed

methyl aminoacetone ethyl ketal, was dried

over solid potassium hydroxide, the ether was removed by distillation, and the residue was distilled. The fraction boiling at 158-162° C. was collected, dissolved in two liters of dry ether, and dry hydrogen chloride gas was passed into the solution until the precipitation of the hydrochloric acid addition salt of the base was complete. The thus produced methylaminoacetoneethylene ketal hydrochloride melted at approx. 165-167° C. It can be represented by formula V where R1 is methyl (CH3).

The methylaminoacetone-ethylene ketal hydrochloride produced was suspended in one liter of dry ether, and a solution of 110 g of potassium hydroxide in 55 ml of water was added to the mixture while stirring. Sufficient excess of solid potassium hydroxide was added to render the ether anhydrous, the ether layer was decanted, and the ether was evaporated. The residue was distilled and yielded methylaminoacetone ethylene ketal which boiled at approx. 158—159°'C.

Instead of methylamine as used above, other amines having from two to eight carbon atoms can be used in the process. Thus, by using ethylamine, isopropylamine, butylamine and heptylamine by the method in this example, the corresponding ethylaminoacetoneethylene ketal, isopropylaminoacetoneethylene ketal, butylaminoacetoneethylene ketal and heptylaminoacetoneethylene ketal are produced. In a similar way, other ketals, such as chloroacetone propylene ketal, can be used to prepare the corresponding aminoacetone ketals, such as, for example, methylaminoacetone propylene ketal. The aminoacetone ketals described are suitable for use in the method according to the invention. In the same way, aminoacetone dialkyl ketals, where the amino group can be substituted with an alkyl radical with from 1 to 8 chemical atoms, such as methylaminoacetone diethyl ketal, amylaminoacetone diethyl ketal, n-heptylaminoacetone diethyl ketal and the like, can be used according to the method to prepare the corresponding N -benzoyl-5-keto-4-(N-acyl-N acetonyl)-amino-1,2,2a,3,4,5-hexahydrobenz(cd)-indolediethyl ketals, which can be treated with strong acid to form 5- keto-4-(N-alkyl-N-acetonyl)-amino-1, 2 2a, 3, 4, 5-hexahydrobenz(cd) indoles, in which the acetonylamino group is substituted with an alkyl radical of from 1 to 8 carbon atoms.

Example 4:

Preparation of N-benzoyl-5-keto-4 (N-methyl-N-acetonyl)-amino-1, 2, 2a, 3, 4, 5-hexahydrobenz (cd) indoleethylene ketal.

A mixture of 270 g (0.76 mol) N-benzoyl-4-bromo-5-keto-1, 2, 2a, 3, 4, 5-hexahydrobenz(cd)indole, 307 g (2.35 mol) methylaminoacetoneethylene ketal and 4500 ml of dry benzene were heated under reflux under a nitrogen atmosphere for approx. 21 hours. The reaction mixture was cooled and a precipitate of methyleneaminoacetone-ethylene ketal hydrobromide which separated from the solution was removed by filtration. The filtrate was washed several times with one liter portions of ice water, and was then extracted with three subsequent one liter portions of cold dilute hydrochloric acid each containing 150 ml of 37% HCl. The acidic extract was immediately added to an excess of ice-cold dilute sodium hydroxide solution. The alkaline mixture was extracted with one liter of chloroform, and the chloroform solution was dried over magnesium sulfate and decolorized with activated charcoal. The decolorized chloroform solution was distilled in vacuo to remove the chloroform. The residue consisting of N-benzoyl-5-keto-4-(N-methyl-N-acetonyl)-amino-1,2,2a,3,4,5-hexahydrobenz(cd)indoleethylene ketal was recrystallized from acetone. It melted at approx. 135-137°C.

Amino ketals substituted with alkyl-

groups containing from 1 to 8 carbon atoms, and likewise alkylene chains containing from 2 to 4 carbon atoms, and ordinary dialkyl ketals, as described in the previous example, can be used to prepare the N-alkyl-N-acetonylamino-polyhydrobenz(cd)indole ketones in this example. In a similar way, other inert organic solvents can be used, such as toluene, heptane, xylene and the like.

The temperature at which the reaction is carried out can be varied from approx. 50° to approx. 150° C. In general, the reaction is faster at the higher temperatures.

4-halo-5-keto-polyhydrobenz(cd) indoles which are acylated with other acylating groups described in previous examples can be treated analogously to the procedure in the example for the preparation of the corresponding N-acyl-4-(N-alkyl- acetonylamino-1, 2, 2a, 3, 4, 5-hexahydrobenz(cd) iridol ketals.

Example 5:

Preparation of 5-keto-4-(N-methyl-N-acetonyl)-amino-1, 2, 2a, 3, 4, 5-hexa hydrobenz(cd)indoles.

A solution of 20 g of N-benzyl-5-keto-4-(N-methyl-N-acetonyl)-amino-1,2,2a,3,4,5-hexahydrobenz(cd)indolethylene ketal in a mixture of 250 ml concentrated hydrochloric acid and 250 ml of water were kept under a nitrogen atmosphere at a temperature of 37° C. for about five days. The mixture was then cooled, treated with decolorizing charcoal and filtered. The filtrate was concentrated to a small volume in vacuo, and the residue containing the non-volatile portion of the reaction mixture included 5-keto-4-(N-methyl-N-acetonyl)-amino-1, 2, 2a, 3, 4, 5-hexahydrobenz(cd)indole in salt form was treated with an excess of solid sodium bicarbonate. The alkaline residue was then extracted with three 100 ml portions of chloroform. The combined chloroform extracts were evaporated to dryness in vacuo at room temperature. The dry residue was collected, pulverized and slurried with approx.

75 ml of a mixture of equal parts benzene

and ether. The benzene ether solvent was removed by filtration to leave the solid, crystalline 5-keto-4-(N-methyl-N-acetonyl)-amino-1,2,2a,3,4,5-hexahydrobenz( cd)indole, which melted at 105

—107° C. After recrystallization from a mixture of benzene and ether, the compound melted at approx. 109—110° C."

Other strong, non-oxidizing acids, e.g. hydrobromic and sulfuric acid, can be used for the hydrolysis.

When other acylated 5-keto-4-(N-alkyl-N-acetonyl)-amino-polyhydrobenz(cd)

indole ketals are used as starting materials, they are converted to the corresponding 5-keto-4-(N-alkyl-N-acetonyl)-amino-1, 2, 2a, 3, 4, 5-hexahydrobenz(cd)indoles. Thus, e.g. if N-acetyl-5-keto-4-(N-methyl-N-acetonyl)-amino-1, 2, 2a, 3, 4, 5-hexahydrobenz (cd)indolethylene ketal is used, then 5-keto-4- (N-methyl-N-acetonyl)-amino-1,2,2a,3,4,5-hexahydrobenz(cd)indole.

Similarly, if N-benzoyl-5-keto-4-(N-ethyl-N-acetonyl)-amino-1,2,2a,3,4,5-hexahydrobenz (cd)indolepropylene ketal is used for the reaction, then 5-keto-4-(N-ethyl-N-acetonyl)-amino-1,2,2a,3,4,5-hexahydrobenz(cd)indole is produced.

The reaction which this step of the method according to the invention comprises, can be carried out at temperatures which can be from room temperature to approx. 100° C. However, the formation of unwanted, dark-coloured by-products increases at the higher temperatures.

Example 6:

Preparation of 9-keto-7-methyl-α>°-ergolene. 1 g of 5-keto-4-(N-methyl-N-acetonyl)-amino-1,2,2a,3,4,5-hexahydrobenz(cd)indole was dissolved in 40 ml of absolute alcohol while stirring under nitrogen at approx. . 40° C. The solution was cooled to approx. ~ 20° C., and 0.63 g (3 equivalents) of sodium methoxide was added. The solution was stirred at approx. 10° C for approx. 10 minutes, during which a crystalline precipitate of the desired product formed. The crystalline substance was removed by filtration and washed with successive portions of cold water, methanol and ether. The 9-keto-7-methyl-A1"-ergole thus produced melted at approx. 145-147° C. The dihydrochloride salt of 9-keto-7-methyl-A10-ergole was prepared by adding the calculated amount of concentrated hydrochloric acid to a solution of 0.25 g of the base in 5 ml of acetone After recrystallization from aqueous acetone, 9-keto-7-methyl-A10-ergolene dihydrochloride melted decomposing at about 270°C.

Other strong bases can be used to effect the ring closure in this process. Thus, e.g. sodium ethoxide, potassium methoxide, potassium t-butoxide, sodium hydroxide, potassium hydroxide and other equally strong bases are used.

The reaction can be carried out at temperature

tours in the area from approx. 20° C to approx. 35° C. Really any inert organic solvent can be used for the reaction.

Starting materials for the method in this example may include other 5-keto-4-(N-alkyl-N-acetonyl)-amirib-1-, 2, 2a, 3, 4, 5-hexahydrobenz(cd)indoles, such as . 5-keto-4-(N-ethyl, 5-keto-4-(N-propyl- and

5-keto-4-(N-n-heptyl-N-acetonyl)-amino-hexa-hydrobenz(cd)indole. In such cases, the end products are 9-keto-7-ethyl-A1"-ergolene and 9-keto-7-propyl-A1"-ergolene and 9-keto-7-7i-heptyl-A'"-ergolene, respectively.

Example 7:

Preparation of 9-hydroxy-7-methyl-Ain- the ergol.

A mixture of 10 g of 9-keto-7-methyl-A1"-ergolene, 10 ml of water and 200 ml of methanol was treated with 1.5 g of sodium borohydride. The mixture was stirred for about 2 hours and was diluted with 150 ml of methanol and 25 ml of water. The aqueous mixture was heated to boiling and treated with decolorizing gold. The decolorized solution was concentrated to a small volume in vacuo. A precipitate was formed consisting of 9-hydroxy-7-methyl-A1"-ergolene. It was filtered off, washed with water and methanol "and dried. This 9-hydroxy-7 methyl-A1 "-ergole melted during decomposition at ca. 210—220° C.

To a solution of 1 g of 9-hydroxy-7-methyl-A1 "-ergolene in 25 ml of aqueous ethanol was added the calculated amount of concentrated hydrochloric acid. The hydrochloric acid salt of 9-hydroxy-7-methyl-A1 "-ergolene which formed itself, was recrystallized from aqueous acetone, and melted during decomposition at approx. 242—243° C.

To carry out the hydration of the 9-keto-Al0-ergolene, other mildly hydrating agents can be used instead of sodium borohydride. Such agents include lithium borohydride, zinc and acid and the like.

9-keto-7-ethyl-A]"-ergolene, 9-keto-7-propyl-A10-ergolene and 9-keto-7-n-heptyl-A1"-ergolene, which were described in Example 6, can be hydrogenated by the above method for preparing the corresponding 9-hydroxy-7-ethyl-A1 "-ergolene, 9-hydroxy-7-propyl-A1 "-ergolene and 9-hydroxy-7-n-heptyl-A1 "-ergolene.

Example 8:

Preparation of 4-acetyl-9-hydroxy-7- methyl-A1"-ergolene.

A solution of 5 g of 9-hydroxy-7-methyl-A1"-ergolene in 100 ml of ethanol was treated with 10 ml of acetic anhydride. The reaction mixture was allowed to stand at room temperature for about 2 hours. The volatile parts of the reaction mixture were then removed by distillation in vacuo, and the residue, which consisted of 4-acetyl-9-hydroxy-7-methyl-A1"-ergolene, was taken up in hot ethyl acetate. The 4-acetyl-9-hydroxy-7-methyl-A10-ergolene separated out in crystalline form and was filtered off. The substance melted during decomposition at approx. 182-184°C.

Other 9-hydroxy-7-alkyl-A10-ergolenes can be acylated using the method of this example to prepare the corresponding 4-acyl-9-hydroxy-7-alkyl-A10-ergolenes.

The hydrochloric acid salt of 4-acetyl-9-hydroxy-7-methyl-A10-ergol is prepared by adding the theoretical amount of hydrochloric acid to an ethanol solution of the base, after which crystalline 4-acetyl-9-hydroxy-7-methyl-Ai°- the ergol is secreted. After recrystallization from aqueous ethanol, the salt melts during decomposition at approx. 248—250° C.

If other acid anhydrides, such as propionic anhydride, benzoic anhydride, butyric anhydride, and phenylacetic anhydride are used, then the corresponding 4-propioyl-, 4-benzoyl-, 4-buturyl-, and 4-phenyl-acetyl-9-hydroxy-7 methyl-A10-ergolene respectively appear. The acid anhydrides having the formula (RCO)20, in which R means an aliphatic radical with from 1 to 8 carbon atoms, a monocarbocyclic aromatic radical, or a monocarbocyclic aromatic-substituted lower alkyl radical can thus be used for acylation.

Example 9:

Preparation of 4-acetyl-9-chloro-7-methyl-A1"-ergolene.

To a solution of 3.1 g of 4-acetyl-9-hydroxy-7-methyl-A10-ergblene hydrochloride in approx. 75 ml of liquid sulfur dioxide was added to 1.2 ml of thionyl chloride. The mixture was placed in a gas-lined autoclave and kept at approx. 25° C for approx. 5 hours. The autoclave was then opened, the reaction mixture removed, and the sulfur dioxide allowed to evaporate while the volume of the solution was kept constant by the slow addition of anhydrous ether. An amorphous precipitate of the hydrochloric acid salt of 4-acetyl-9-chloro-7-methyl-A1"-ergolene formed. It was filtered, washed with ether and dried in vacuo. The substance melted with decomposition at about 130-135 °C.

When using 4-benzoyl-9-hydroxy-7-methyl-A10-ergolene hydrochloride in re-

the action gets mon 4-benzoyl-9-chloro-7-methyl-A10-ergolene hydrochloride.

Analogously, if 4-acetyl-9-hydroxy-7-propyl-A1 "-ergolene hydrochloride is used, 4-acetyl-9-chloro-7-propyl-A1 "-ergolene hydrochloride is obtained, and if 4-acetyl-9 -hydroxy-7-ethyl-i"A-ergolene hydrochloride is used, then 4-acetyl-9-chloro-7-ethyl-■"A-ergolene hydrochloride is prepared.

If thionyl bromide and the corresponding hydrobromic acid addition salts of the aforementioned compounds are used in the method of this example, then corresponding substituted 9-bromo-A1"-ergolene hydrobromic acid addition salts are prepared. Thus, for example, if the procedure of this example is repeated using 4 -acetyl-9-hydroxy-7-methyl-A1"-ergolene hydrobromide and thionyl bromide, then 4-acetyl-9-bromo-7-methyl-A10-ergolene hydrobromide is obtained, which melts during decomposition at approx. 125-130°C.

The halogenation process in this example can be carried out at temperatures in the range of approx. 0° C to 50° C. While the reaction takes place satisfactorily at even higher temperatures, the formation of dark colored by-products increases rapidly with the increase in temperature and makes the isolation of the desired compounds much more difficult.

Example 10:

Preparation of 4-acetyl-9-cyano-7-methyl-.

The A1 "-ergolen.

To 300 ml of ice-cold, liquid hydrogen cyanide was added 40 g of dry, powdered sodium cyanide, and the mixture was stirred and cooled in ice while 7.5 g of amorphous 4-acetyl-9-chloro-7-methyl-A1"-ergolene hydrochloride was added . Stirring of the reaction mixture was continued for about 30 minutes. Hydrogen cyanide was then rapidly removed from the reaction mixture by distillation under reduced pressure at a temperature below 10° C. The residue from the distillation was treated with a mixture of chloroform and ice water, and the resulting mixture was filtered. The chloroform was separated from the aqueous layer and the filtrate, and the aqueous phase was extracted with 2 portions of chloroform, each of 100 ml. The combined chloroform extracts, which contained 4-acetyl-9-cyano-7-methyl-A10-ergolene, was dried over anhydrous magnesium sulfate, and then treated with decolorizing charcoal and filtered.

The chloroform was removed from the decolorized

filtrate by distillation in vacuum. The residue was crystallized from ethyl acetate to give 4-

and acetyl-9-cyano-7-methyl-A1 "-ergolene, which melted at about 180-181°C.

Other metal cyanides can be used for the reaction, such as potassium cyanide, lithium cyanide, calcium cyanide, copper cyanide and the like.

By following the procedure in this example but using the hydrogen halogen salts of 4-benzoyl-9-chloro-7-methyl-A1"-ergolene, 4-acetyl-9-bromo-7-ethyl-A1"-ergolene , and 4-acetyl-9-chloro-7-n-heptyl-A1 "-ergolene, the corresponding 4-benzoyl-9-cyano-7-methyl-A1 "-ergolene, 4-acetyl-9-cyano-7 -ethyl-A1 "-ergolene, and 4-acetyl-9-cyano-7-n-heptyl-A1 "-ergolene.

Example 11:

Alternative preparation of 4-acetyl-9-cyano-7-methyl-A1"-ergolene from 4-acetyl-9- hydroxy-7-methyl-A1"-ergolene.

To 25 ml of liquid hydrogen cyanide cooled in crushed ice was added 0.5 g of 4-acetyl-9-hydroxy-7-methyl-A>"-ergolene. A stream of gaseous boron trifluoride was bubbled into the cooled mixture until all the ergolene had dissolved . The reaction mixture was kept at about 0° C. for about 2 hours longer, and was then concentrated by distillation in vacuo to a gummy residue. About 5 ml of ethanol and a few drops of dilute hydrochloric acid were added to the residue, and the resulting mixture was neutralized with solid sodium bicarbonate. The neutral residue, containing the 4-acetyl-9-cyano-7-methyl-A10-ergolene formed by the reaction, was extracted with 3 portions of 25 ml chloroform, and the combined chloroform extracts were dried over anhydrous magnesium sulfate The chloroform was removed from the anhydrous solution by vacuum distillation. The residue from the distillation was dissolved in 25 ml of an anhydrous mixture of approximately equal parts methanol and ether, and anhydrous hydrogen chloride gas was bubbled through the solution in until no further precipitate appeared. The crude hydrochloric acid salt of 4-acetyl-9-cyano-7-methyl-A1"-ergol thus prepared was converted to the free base by treating the solid, crude substance with 15 ml of aqueous sodium bicarbonate solution. The alkaline aqueous solution was extracted with several 20 ml portions of chloroform, and the combined chloroform extracts were dried over anhydrous magnesium sulfate, concentrated to a volume of about 10 ml, and applied to a chromatographic column containing about

20 g of aluminum oxide. The free base 4-acetyl-9-cyano-7-methyl-A'"-ergol was eluted

pea from the column using a mixture of 4 parts chloroform to 1 part petroleum ether as eluent. The first 100 mL of eluate recovered was evaporated in vacuo to remove the solvents. The residue was an oil which crystallized after dissolution in hot methanol and subsequent cooling. The 4-acetyl-9-cyano-7-methyl-A1"-ergolene thus produced melted at about 180-181°C, and did not show any lowering of the melting point when it was mixed with the product obtained by the process in Example 10 .

Example 12:

Preparation of 9-carbomethoxy-7-methyl-A1"-ergolene.

A mixture of 1 g of 4-acetyl-9-cyano-7-methyl-A1"-ergolene, 15 ml of methanol and 0.25 water was cooled, and 2 ml of concentrated sulfuric acid was slowly added to it. The resulting solution was sealed in a glass tube under nitrogen and was heated to about 100° C. for about 24 hours. The sealed tube was cooled and opened, and the reaction mixture was treated with decolorizing charcoal, filtered and concentrated in vacuo to a volume of about 5 ml. The concentrated reaction mixture was poured into a mixture of about 30 ml of chloroform, 50 g of crushed ice, and 10 g (an excess) of sodium bicarbonate After the ice had melted, the chloroform was separated from the aqueous phase, and the aqueous phase was extracted with 3 portions of chloroform to 10 ml. The combined extracts containing 9-carbomethoxy-7-methyl-A'"-ergolene were made anhydrous over anhydrous magnesium sulfate, and the chloroform was removed by distillation in vacuo. The residue was crystallized from benzene. Crystalline 9-carbomethoxy-7-methyl-A1"-ergolene thus produced melted at about 160-161°C.

Any lower alkanol, such as methanol, isopropanol and the like can be used in the reaction to produce the corresponding 9-carbalkoxy-7-methyl-A1"-ergolene. Other strong mineral acids can likewise be used, such as hydrochloric acid, hydrobromic acid and the like. On the like way, 4-acyl-9-cyano-7-alkyl-A1 "-ergolenes, such as 4-acetyl-9-cyano-7-ethyl-A1 "-ergolene, 4-acetyl-9-cyano-7-propyl- The A1 "-ergolene, and 4-acetyl-9-cyano-7-7i-heptyl-A10-ergolene, are used as starting materials in this method step of this invention for the production of the corresponding 9-carbomethoxy-7-ethyl-,

9-carbomethoxy-7-propyl-, and 9-carbomethoxy-7-?i-heptyl-A1"-ergolene.

Other 4-acyl-9-cyano-7-methyl-A1°-ergolenes, such as 4-benzoyl-9-cyano-7-methyl-A10-ergolene, can also be used for the process. - The reaction can be carried out at atmospheric pressure at a temperature slightly above room temperature to produce the 9-carbaloco-sy-ergolenes; but a temperature in the area approx. 100° C and sealed containers are preferred, as thereby the time required for the completion of the reaction is shortened.

Example 13:

Preparation of cZZ-lysergic acid (9-carboxy- 7-methyl-A5'1 °-ergoladiene).

A mixture of 3.9 g of 9-carbomethoxy-7-methyl-A1"-ergolene and 78 ml of 1.5% aqueous potassium hydroxide was heated under reflux under nitrogen for about 1y2 hours. About 8.5 g of hydrated sodium arsenate was added to the reaction mixture. , and about 16 g of Raney nickel, which had just before been deactivated by boiling in a xylene suspension. The reaction mixture together with the catalyst was heated under reflux with stirring under a nitrogen atmosphere for about 20 hours. The reaction mixture was then treated with decolorizing charcoal and filtered . The decolored filtrate was adjusted to approximately pH 5.6 by the addition of aqueous 4% hydrochloric acid, after which coarse cZZ-lysergic acid precipitated. The precipitate was filtered off and washed with water. The coarse acid was quickly dissolved in glacial acetic acid, and was precipitated in crystalline form by adding several portions of water. The dl-lysergic acid thus produced melted during decomposition at about 241-242° C. The infrared absorption spectrum of the material, rubbed in a miner aloe oil, was indistinguishable from the equivalent of an authentic cZZ-lysergic acid rubbed in mineral oil prepared from ergot alkaloids.

Example 14:

Alternative production of cZZ-lysergic acid from 4-Acetyl-9-cyano-7-methyl-A1 «-ergolene.

1 g of 4-acetyl-9-cyano-7-methyl-A'°-ergolene was suspended in 20 ml of water containing 1 g of sodium hydroxide and refluxed under a nitrogen atmosphere until the insoluble material was completely dissolved. Subsequently, approx. 8 g of Raney nickel catalyst previously deactivated by boiling with xylene, and the mixture was refluxed for approx. 18 hours. reaction mixture

gen was treated with decolorizing charcoal and filtered. The clear filtrate was adjusted to approx. pH 5.6, after which dZ-lysergic acid precipitates. It was then recrystallized in accordance with the method in Example 13. The physical characteristics of dZ-lysergic acid thus produced corresponded to those corresponding to authentic dZ-lysergic acid.

Example 15:

Preparation of 4-acetyl-9-keto-7-methyl-A1 "-ergolene from 9-keto-7-methyl-A<1>"- the ergol.

To a solution of 0.5 g of -9-keto-7-methyl-A10-ergolene in 20 ml of anhydrous chloroform was added 10 ml of methanol and 1.0 ml of acetic anhydride. The solution was allowed to stand at room temperature for approx. 2 hours, and then the solvents were removed by distillation in vacuo. The residue, which consisted of 4-acetyl-9-keto-7-methyl-A1"-ergolene, was taken up in a minimal amount of hot acetone, and ether was added to induce crystallization. The resulting precipitate was filtered off. and recrystallized from a mixture of equal parts acetone and ethanol. The 4-acetyl-9-keto-7-methyl-A1"-ergolene thus prepared melted at approx. 169— 170° C.

To a solution of 0.25 ml of the acetylated ergolene base in 10 ml of ethanol, the theoretical amount of hydrochloric acid was added with stirring. A crystalline precipitate of the hydrochloric acid addition salt formed. It was filtered off and recrystallized from a minimum amount of hot aqueous ethanol.

4-acetyl-9-keto-7-methyl-A10-ergolene hydrochloride thus prepared melted at approx. 250° C during decomposition.

Example 16:

Preparation of 4-acetyl-9-hydroxy-7-methyl-A1"-ergolene from 4-acetyl-9-keto-7- methyl-A1 "-ergolene.

To a solution of 10 g of 4-acetyl-9-keto-7-methyl-A1"-ergolene in a mixture of 150 ml of methanol and 10 ml of water was added 1.5 g of sodium borohydride. The reaction mixture was allowed to stand at room temperature for approximately 2 hours. The solution was then concentrated by evaporation in vacuo to a volume of about 20 ml, and a solution of 15 ml of concentrated hydrochloric acid in 60 ml of water was added to it.After cooling the solution, a precipitate of the hydrochloric acid salt of 4-acetyl formed -9-Hydroxy-7-methyl-A1 "-ergolene. The precipitate was filtered off, washed with methanol and recrystallized from warm, dilute ethanol solution. The pure 4-acetyl-9-hydroxy-7-methyl-A10-ergolene hydrochloride melted at approx. 245-246° C.

A resolution of. 5 g of the hydrochloric acid salt in 25 ml of water was neutralized by the addition of sodium bicarbonate. The neutral solution was extracted with three 10 ml portions of chloroform. The combined chloroform extracts, which contained the free base, were dried over anhydrous magnesium sulfate, and the chloroform was removed by distillation in vacuo. The residue was crystallized by dissolving it in hot ethyl acetate and then cooling the solution. The 4-acetyl-9-hydroxy-7-methyl-A1"-ergolene thus produced melted at about 182-184° C.

The theoretical amount of aqueous 48% hydrobromic acid was added to a solution of 1 g of the above-mentioned base in 10 ml of ethanol, after which the crystalline hydrobromic acid salt precipitated. It was filtered off and recrystallized from dilute ethanol. The pure 4-acetyl-9-hydroxy-7-methyl-A1"-ergol melted with decomposition at about 243-244°C.

Example 17:

Preparation of 4-acetyl-9-epi hydroxy- 7-methyl-A1"-ergolene.

A solution of 0.5 g of 4-acetyl-9-hydroxy-7-methyl-A10-ergolene hydrochloride in 15 ml of concentrated hydrochloric acid was kept at acid was kept at 25° C for approx. 2 hours. The excess of hydrochloric acid was removed by distillation in vacuo, and the residue was neutralized with aqueous 5% sodium bicarbonate. The neutral solution was extracted with three portions of 10 ml chloroform, and the combined chloroform extracts were dried over magnesium sulfate. The chloroform was removed by distillation in vacuo, and the residue consisting of 4-acetyl-9-epihydroxy-7-methyl-A1"-ergolene was crystallized from hot ethyl acetate. The substance melted during decomposition at about 194-196° C.

To a solution of 0.25 g of 4-acetyl-9-epihydroxy-7-methyl-A1"-ergolene in 10 ml of ethanol was added a small excess of hydrochloric acid. The solution was cooled, and a precipitate of the hydrochloric acid addition salt of the base separated out . It was filtered off and was recrystallized from a minimum amount of hot dilute ethanol. 4-Acetyl-9-epihydroxy-7-methyl-A1"-ergolene hydrochloride thus prepared melted during decomposition at approx. 195°C.

Other non-oxidizing strong mineral acids can be used for the process of converting the normal 9-hydroxy ergolene to the 9-epihydroxy ergolene, such as e.g. sulfuric acid, hydrobromic acid, trichloroacetic acid, and the like.

Although the temperature at which the inversion from normal to epi-hydroxy ergolene takes place is not decisive, it is clear that increasing the temperature will act to speed up the reaction but also to increase the degree of by-product formation. Temperatures in the range from approx. 20° C to 100° C to carry out the conversion.

Other 4-acyl-9-hydroxy-A1"-ergolenes, as described in Example 8, can be epimerized according to the procedure in this example to prepare the corresponding 4-acyl-9-epz-hydroxy-A1"-ergolenes.

Example 18:

Preparation of 4-acetyl-9-chloro-7-methyl-A1"-ergolene hydrochloride from 4-acetyl-9-epi-hydroxy-7-methyl-A1"-ergolene hydrochloride. 1 g of 4-acetyl-9-epihydroxy-7-methyl-A1"-ergolene hydrochloride was dissolved in about 25 ml of liquid sulfur dioxide placed in a glass-lined autoclave. 1V2 nil thionyl chloride was added to it, and the vessel was sealed and kept at 25° C for about 5 hours. The autoclave was then cooled and opened, and the sulfur dioxide was allowed to evaporate from the reaction mixture while the volume of the solution was kept constant by slow addition of dry ether. An amorphous precipitate of, 4-acetyl-9-chloro -7-methyl-A1"-ergolene hydrochloride. It was filtered off, washed well with ether and dried in vacuo. The substance which melted during decomposition at 130— 135? C, was identical to the substance produced by the method in example 9.

Other 4-acyl-9-epi hydroxy-A1"-ergolenes, as described in Example 17, can be used as starting materials for the process in this example to prepare the corresponding 4-acyl-9-chloro-A10-ergolenes.

Example 19:

Preparation of 7-methyl-9-carboxy-A10- the ergol.

A solution of 1 g of 7-methyl-9-carbomethoxy-A1"-ergol in a mixture of 30 ml of 12 N HCl and 5 ml of water was heated under reflux for 3 hours. The ice-free reaction mixture was evaporated to dryness under reduced pressure on a steam bath. The white residue consisting of the dihydrochloride salt of 7-methyl-9-carboxy-A1"-ergolene was slurried with 25 ml of ethanol, and the ethanol distilled off to . remove excess hydrogen chloride. The 7-methyl-9-carboxy-ergolene dihydrochloride formed in the reaction was a white crystalline powder. It was dissolved in 20 mL of water and passed through a 10 inch column of quaternary ammonium cation exchange resin ("IR-45") to remove chloride ion. The resin was washed with several 30 ml portions of water, and the eluate was evaporated to dryness. The white residue after evaporation was slurried with 20 ml of methanol, filtered, washed with methanol and ether, and dried in vacuo. The white, crystalline 7-methyl-9-carboxy-A1"-ergolene obtained had no definite melting point, but slowly decomposed when heated above the range 250-350°C.

Example 20: Alternative preparation of 7-methyl-9-carb oxy-A1"-ergolene. 2 g of 4-acetyl-7-methyl-9-cyano-A'"-ergolene was dissolved in 40 ml of concentrated hydrochloric acid and heated under reflux for approx. 16 hours. By following the isolation method described in Example 19, the 7-methyl-9,carboxy-A1"-ergolene was obtained.

Other strong, non-oxidizing mineral acids such as hydrobromic acid, sulfuric acid and the like can be used to effect the conversion of 4-acyl-7-alkyl-9-cyano-A'°-ergolenes to 7-alkyl-9-carboxy-cyano-ergolenes . Thus, 4-acyl-7-alkyl-9, cyano-A'°-ergolenes, described in Example 10, can be used for the process to prepare the corresponding 7-alkyl-9, carboxy-Ain-ergolenes and their acid addition salts.

Example 21: Preparation of dZ-lysergic acid from 9-carb oxy-7-methyl-A in the "-ergolene.

400.mg of 9-carboxy-7-methyl-A1"-ergolene was dissolved in 15 ml of water containing 124 mg of potassium hydroxide. 1.81 g of deactivated Raney nickel was added and the mixture was heated under reflux under nitrogen for about 20 hours. About 0.5 g of activated decolorizing carbon was added to the cooled reaction mixture, the mixture was shaken

and was filtered. The filtrate was acidified to approx. pH 5.8 with hydrochloric acid, whereupon cZZ-lysergic acid precipitated. The precipitate was dissolved in a minimum amount of dilute ammonia, and dry ice was added to the solution. The cZZ-lysergic acid that separated was filtered off and dried in a vacuum desiccator.

As explained in example 13, a certain amount of sodium arsenate can also be used in the above-mentioned method, whereby an increased yield of dZ-lysergic acid can be achieved. The sodium arsenate appears to act either to further deactivate the Raney nickel or as a hydrogen acceptor. Whatever the reason, a greater degree of dehydration of the starting dihydro compound is effected. Besides sodium arsenate, other agents known for their ability to deactivate Raney nickel or to act as hydrogen acceptors can be used. Such include halides, maleates, cinnamates and the like.

Claims (4)

1. Process for the production of lysergic acid and/or homoligers thereof, consisting in the introduction of a double bond in the 5-5a position of a compound of the formula: where R1 is an alkyl radical with from 1 to 8 carbon atoms, R2 is H or RCO, in which R is an alkyl radical with from 1 to 8 carbon atoms, a monocarbocyclic aromatic radical or a monocarbocyclic aromatic-substituted alkyl radical with from 1 to 8 carbon atoms in the alkyl chain , and R,, is COOH when R 2 is H, and R 3 is CN when R 2 is RCO, by reacting said compound with a dehydrogenating catalyst when R 2 is H, and successively exposing said compound to the action of a strong base and a dehydrogenating catalyst when R2 is RCO. 2. Method as stated in claim 1, consisting in that a 7-alkyl-9-carboxy-A1 "-ergolene or a metal salt thereof is treated with a dehydrogenating catalyst to form a 7-alkyl-9-carboxy-A5, '°-ergoladien or respectively a metal salt thereof. 3. Method as stated in claim 1 or 2, in which the 7-methyl-9-carboxy-A10-ergolene is dehydrogenated with a deactivated Raney nickel catalyst. 4. Process as stated in claim 1, consisting in that the 4-acetyl-7-methyl-9-cyano-A'°-ergolene is successively exposed to the action of a strong base and a deactivated Raney nickel catalyst.