SI7910801A8 - Process for obtaining lysergol derivatives - Google Patents

Description

PROCEDURE FOR OBTAINING LIZERGOL DERIVATIVES

TECHNICAL AREAS

The invention relates to the field of production of lysergol, and in particular relates to a new process for the preparation of l-methyl-10-methoxy lumylisergol derivatives.

According to the International Patent Classification, the invention is classified in class C 07D 457/00; A 61K 31/33.

The compounds obtained by the process of the invention have interesting pharmacological properties, such as significant adrenolytic and antiserotonic activity and correspond to general formula (I):

wherein R is an organic carboxylic acid radical of the group consisting of aliphatic, cycloaliphatic, aromatic and heterocyclic carboxylic acids, containing up to 10 carbon atoms and may be substituted by halogen.

TECHNICAL_PROBLEM

The invention solves in a new and economical way the problem of obtaining a derivative of 1-methyl-10-methoxy-lumylisergol.

§TANE_TECHNICS

The lumilisergol derivatives of the general formula shown above are prepared according to known methods starting from commercially available lysergic acid monohydrate via the following reaction sequence:

A

According to phase (i), lysergic acid (II) is converted to the corresponding 10-methyl-methyl-ester (III) by irradiation with U.V. the brightness of a solution of compound (II) in methanol containing concentrated l- ^ SO ^.

Subsequently, 10-methoxy-1 or 1 isergol (IV) is obtained by reduction of ester (III) with LiAlH4 in tetrahydrofuran.

Alcohol (IV) is esterified by treatment with a carboxylic acid derivative R - C0X, such as acyl chloride (X = C1) or the corresponding anhydrides (X = O-CO-R), in the presence of a tertiary base, e.g., pyridine and triethylamine.

The esters (V) thus obtained are then alkylated in 1 position with methyl iodide in liquid ammonia and in the presence of NaNH _{2 or} KNH ₂ ', so that the desired compound (I) is obtained, (1-methylation is immediately possible even before the esterification phase is ( iii)).

- .4 -.)

The reaction scheme described above is described in Belgian xxxx patent 633430, in French patent 2084678 and in USP 3228943.

According to a modification of the general reaction scheme relating to phase (iii), the French patent protects an alternative esterification process, such as What. is illustrated by the following scheme:

Such modification is necessary when the R radical contains furan and pyrrole rings which, as is well known, are not stable in the presence of standard chlorinating agents, such as thionyl chloride and phosphoroxychioride. In this case, it is impossible to translate the acid RCOOH into the corresponding halides of RCOX (X = C1), alcohols (VI) are converted to alkyl chlorides (VII) by treatment with the same 1 chloride in pyridine and in the presence of pyridine chloride (phase V).

- φ

Compounds (VII) react with the metal salts of RCOO M suitable carboxylic acids to give compounds (VIII) (phase vi).

- 5 ·

DESCRIPTION OF A TECHNICAL PROBLEM WITH EXAMPLES

According to the present invention, it has been found that the new process for the preparation of compounds of formula (I) is efficient, simplified and generally applicable to the meaning of the substituents R.

The process of the present invention for the preparation of 1-methyl-tO-netoxy-lun11isergol derivatives having the general formula (I), wherein P iaa already has the meanings given, comprises the following steps:

a) translation of lysergol (IX) y 10-alpha-aetoxy-lumylisergol (X) atmosphere and V3n l era of lysergol solution;

b) loading of compound (X) onto indolovop nitrogen gas? the atom is assisted by a methylating agent to give a 1-mefcil derivative;

c) reacting the alcohol (XI) with the carboxylic acid R-CDOH, leaving R ins the above-mentioned meaning, in a rolled excess relative to the alcohol.

LizergGl is a starting reactant for synthetic reaction and it is a non-natural product that is easily obtained by seed extraction of some species of Ipoae.

The use of such crude naterifle and «some important advantage over the use of li3 acid, since lysergol is not subject to C-3 isorization and already has a heroic function to the ester fl ester.

The reaction scheme of the process of the invention is as follows:

.6 »

According to a preferred embodiment, 1 isergol (IX) is dissolved in methanol containing concentrated sulfuric acid, in a ratio of 5 to 20% v / v and subjected to mercury discharge type DV lamps or the like.

The reaction is carried out in an atmosphere of between 10 ° C and 50 ° C.

alpha-methoxy-1 umi 1 isergol yields after standard inert gas treatment at temp (X) is isolated in good reaction mixtures.

In step (b) of the present process, methylation on the indole nitrogen atom is carried out by treating a solution of compound (X) in dimethylsulfoxide with methyl iodide, in the presence of a finely ground alkali hydroxide at a temperature between 10 ° C and 40 ° C.

At the end of the reaction, the reaction mixture is diluted with water and 1-methyl 1 -10-alpha-methoxy-1 umi 1 isergol (XI) is extracted with suitable organic solvents such as chloroform. In step (c), the alcohol (XI) is then dissolved in tetrahydrofuran and the resulting solution is supplemented with carboxylic acid, in an amount of 2 to 4 moles per mole of alcohol (XI), together with a slight excess of dicyclohexylcarbodiim as a condensing agent.

The reaction is carried out at a temperature between 20 and 40 [deg.] C. and finally esterified, dicyclohexylcarbamide is separated by filtration, excess unsaturated acid R-COOH is isolated and the reaction product (I) is obtained by evaporation of the solvent under reduced pressure.

The esterifier method of the invention enables carboxylic acids to be used directly without prior translation into functional derivatives, such as the corresponding acid chlorides, anhydrides and metal salts, thus eliminating problems and drawbacks of prior art. The following examples illustrate the experimental details of the process of the present invention, and are not intended to be limiting.

EXAMPLE 1

-metals Τ-ΊΟ-alpha-methoxy-Tumi Ti zergol-8 (^ - bromo) nicotinate:

/ I / R

Nr

a) 10-alpha-methoxy- Tumi 1i zergol (X)

50.35 g of lysergol was dissolved in 1500 ml of CH ₂ OH / H ₂ SO ₄ (40 / 7.5 v / v), with a possible heating of the mixture to 35-40 ° C. The solution is charged in a suitable reactor for photochemical reactions, and irradiation is started, keeping the temperature at 20 40 ° C and the atmosphere being an inert gas. Light Source- 8 -.............

With '', *. Ι _ '.', The Phillips lamp is an HPLR-N 250W.

The reaction behavior is controlled by thin layer chromatography (TLC), using silica gel θ ^ 254 ^ ^{ao ac} * sorbent, a mixture of CH ₃ OH / CH C1 ₃ / NH ₄ 0H = 20/80 / 0.2 as eluent, and UV light (λ = 254 nm) and Van Urk reagents (Stahl No. 73) as detection agents.

At the end of the reaction, the contents of the reactor were poured into 6 liters of ice water, the mixture was basified with NH 4 OH (650 ml) and extracted exhaustively with chloroform. The combined organic extracts were washed with water, dried over Na2 SO4 ·, filtered and concentrated to rest under reduced pressure and at 30-35 ° C.

The residue was recrystallized from acetonitrile to give 45 g (yield = 80%) of 10-alpha-methoxy-1 and 1 isergol, m.p. 183-185 ° C.

b) 1-meth T-10 aTfa-methoxy -1umi Tizergol (XI)

30.5 g of dry finely ground KOH and 250 ml of dimethylsulfoxide are charged into a reactor having a mechanical stirrer, thermometer and refrigerants.

The mixture was stirred for 10 minutes and then 39 g of 10 alfamethoxy-1 umi of 1 isergol (X) were added: stirring was continued at 15-20 ° C for 45 minutes and then was added dropwise with 9.8 ml of CH 2 J, controlling the temperature at 25 to 35 ° C.

When the addition is complete, the reaction mixture is stirred for about 45 minutes, whereby the reaction behavior is recorded by TLC under the same conditions as in step (a).

The contents of the reactor are poured into ice water, the precipitate is filtered off and the filtered liquids are extracted exhaustively with CHC1 ₃ The combined organic solutions are washed with water, and then g 'is dried over Na2SO4, filtered and concentrated to a residue under reduced pressure. 30 ° C. The crude residue was combined with a precipitate from water and crystallized again from acetone. It gets l

28-30 g (yield = about 70%) of 1-meth 1 -10-alpha-methoxy-1 um lysergol, m.p. 213-216 ° C.

c) targets 1-10 alpha-methoxy-1 do zergol-8 (5 '-bromo) angles nat

A solution containing 79.4 g of 5-bromo-nicotinic acid, 27.05 g of 1-methyl-10 alpha-methoxy-1 um 1 isergol (XI) and 900 ml of tetrahydrofuran was made in a reactor equipped with a thermometer, stirrer and refrigerator.

20.62 g of dicyclohexylcarbodiimide was added, keeping the temperature at about 30 ° C.

The reaction was monitored by TLC under the same conditions as described above.

The mixture was cooled to 0 ° C, the precipitated dicyclohexylcarbadide was separated by filtration and the filtrate was concentrated to a residue under reduced pressure at 35 ° C.

The residue was collected with 800 ml of CH2Cl2 and the mixture was treated with stirring with saturated aqueous NaHCO3 solution so that unreacted 5-bromo-nicotinic acid was isolated.

After separation of the phases, the organic phase is washed with water, dried over Na2SO4, filtered and concentrated to dryness under reduced pressure at 30 ° C.

The residue was crystallized again from ether.

40 g (yield = about 90%) of the bromo-nicotinic ester of 1-methyl 1 -10 alpha-methoxy-1 and 1 isergole are obtained, m.p. 1 35-1 36 ° C. The alkaline aqueous phase is acidified to pH 3 with HCl and unreacted

- B; 0. ~ Bromo-nicotinic acid is isolated by fi1 gossip (isolation yield = about 75%).

EXAMPLE 2 /

1-meth 1 -10 aTfa-methoxy-1 umi 1i zergol-8-angles nat

AJ

The starting 1-methyl-10 alpha-methoxy-1 umi 1 isergol was made as described in Example 1, stages (a) and (b), and the esterification was carried out under experimental conditions similar to those of stage (c). using 48.3 g of nicotinic acid, 27.04 g of compound (XI), 750 ml of tetrahydrofuran and 20.62 g of dicyclohexylcarbodiim.

At the end of the process, 32 g (yield = 88%) of pure ester are obtained, m.p. 124-126 ° C.

The isolation yield of unreacted nicotinic acid is about 73%.

EXAMPLE 3

1-Methyl Τ-Ί 0 Alpha-methoxy-1 Umi 1i Zergol-8- (2 * -furan) -carboxylate / I /

Also in this case, the desired ester was made according to the operating conditions of Example 1.

More specifically, the esterifier reaction is carried out by use

13.5 g of compound (XI), 10.3 g of dicyclohexylcarbodiimide,

250 ml of THF and 20.34 g of pyruvic acid (2-furoic acid). 16 g (yield = 90%) of the ester are obtained, mp 142-144 ° C. “ _N c. >. \\ /

The regeneration yield of unreacted furan-2-carboxylic acid is about 40%.

Dos.73201 05.07.1985. ...... Ρ-801/79

THE APPLICANT'S STATEMENT ON THE BEST KNOWLEDGE WAY FOR THE ECONOMIC USE OF THE APPLICATION FINDED

a) I0-alpha-methoxy-lumfl1zergol (X)

J '<. * ·

50.35 g of Hzergol is dissolved in 1500 El of CH2OH / mixture.

H-jSO ^ (40 / 7.5 v / v), with the feet warmed to 35-40 ° C.

s'.

The solution is mixed in a suitable reactor for photohermal reactions, 1 starting from the irradiation, whereby the temperature and

maintained at 20-40 ° C 1 the atmosphere is fnertnl gas. The light source is Phillips laapa HPLR-B 2501 /.

Behavioral reaction control have tanksolojnoa hroaatografljoa (TLC), using silica-gel GF ₂ 54 ^{as a "d} sorbent mixture CH ₃ 0H / CHC1 ₃ / NH ₄ 0H - 20 of / 80 / 0.2 as eluant, 1 UV brightness (λ · 254 nm) 1 Van Urk reagent (Stahl No. 73) as a deburring agent. --------------------------- i__________________________________________________ ________

At the end of the reaction, the contents of the reactor were poured into 6 liters of ice water, the mixture was alkalinized with NH4OH (650 acre) 1 extracted exhaustively with chloroform. The combined organic extracts are washed with water; they are dried over Na ₂ SO ₄ , filtered 1 are concentrated to a residue under reduced pressure 1 at 30-35 ° C.

The residue was crystallized again from Acetonltrl 1 so that »J · * · yields 45 g (80 prin yield) of I0-alpha-netox1-lum1l1zergo1a, m.p. 183-185 ° C.

b) 1-methyl-10-alpha-methoxy-1-yl11Ezerool (XI),

V- · * '

30.5 g of dry finely ground KOH 1 250 nor dlmethylsulfoxide was batched. into a reactor having a mechanical scale, a thermometer and means are applied.

Η'ήί

City ^J __ __ ________----- -----—

The mixture was stirred for 10 minutes 1 then 39 g of tungsten was added. «$ Ato.ksi-ium11 Isergol (X): stirring continued at 15-20 ° C • * minutes 1 then was added dropwise to 9.8 acre CHjJ, where $ © «controls the temperature at 25 to 35 ° C.

When the addition is corapletlrano, the reaction occurs

Eseiša eye 45 minutes' from what the reaction boast reglstruje · · * ^"1 poescioču TLC under the same" uslovlma as in step (a).

>

Contents- Reactor «Pour s ^ into ice water, precipitate is filtered off 1 filtered liquids are extracted exhausted with CHCl3.

The combined organic solutions were washed with water, 1 then dried over Na2 SO4, filtered 1 was concentrated to the residue of p <RTI ID = 0.0> d </RTI> sanyane at 30 ° C. The crude residue was combined with the ®-precipitate from water 1 and crystallized again from acetone. It gets with? 28-30 g (yield · ca. 70S) of 1-ethyl-IO-alpha-raetoxyl-luffilli / zergola, m.p. 213-216 ° C.

cj 1-wet11-10 alpha-methoxy-luraillzergol-8 (5 ^- brorao) n 1cotinate

A solution containing 79.4 g of 5-brorco-nicotinic acid, 27..05 g of 1-aetyl-10-alpha-methoxy-1-yl-11-isergole (XI) 1 900 ml of tetrahydrofuran is made in a reactor equipped with a thermometer, stirrer 1 cooler.

r <

'f

20.62 g of dlcyclohexylcarbodiimide was added, keeping the temperature at about 30 ° C, '

The reaction is washed by @ TLC under the same, asses koji _t I su described mountains. ⁴ '

The mixture was cooled to 0 [deg.] C., the equilibrium dlcyclohexycarbonyl was separated by filtration. HL 1 the filtrate was concentrated to the residue under reduced pressure at 35 [deg.] C.

'·. '- / 3- - ---. _Λ z

. Z ·

The residue was collected with SCO or CH2Cl2 and the mixture was treated with dewaxing with saturated aqueous HaHCO3 solution so that unreacted 5-brono-nicotinic acid was isolated.

e · ·

After separation of the phases, the organic phase is washed with water, dried over liqSd ^, filtered and concentrated to dryness under reduced pressure at 30 ° C,

The residue was crystallized again from ether.

It does. 40 g (yield approx. 90S) of the 1-netyl-10 alpha-netoxy-luraylisergol bromo-nicotinic ester »m.p. 135 «135 ° C. The alkaline aqueous phase was acidified to pH 3 with HCl and unreacted brora-nicotinic acid was isolated by filtration (isolation yield about 751).

Claims (4)

PATENT REQUIREMENTS: 1. A process for preparing a lysergol derivative of the general formula: in which R is a radical of an organic carboxylic acid selected from the group consisting of aliphatic, cycloaliphatic, aromatic and heterocyclic acids containing up to 10 C atoms-- and may be substituted by halogen for the conversion of lysergol of the formula: in 10 alpha-methoxy-lumylisergol formulas: I - by irradiation with UV rays, then methylation of the compound of formula (X) thus formed on the indole nitrogen atom by a methylation fortification to give a 1-methyl derivative of the formula: which reacts with a carboxylic acid of formula R-COOH, in which R has the meanings given above, in molar excess with respect to an alcohol of formula (XI), so as to obtain a derivative of formula (I). 2. The process according to claim 1, wherein the photochemical reaction is carried out in a solution of lysergol in a mixture of methanol and sulfuric acid, containing 5-20% H ₂ SO ₄ v / v, in an inert gas atmosphere, using mercury-emitting UV lamps iii equivalent type, at a temperature of 10-50 ° C. The method of claim 1, characterized by t and m e> as> the methylcarbonate reaction in the 1-position of 10-alpha-methoxy-lumylisergole is carried out with - Remove with iodide, in the presence of dry, finely ground alkali hydroxides, wherein the dimethylsulfoxide is a solvent and the temperature is between 10 and 40 ° C. 4. The process of claim 1, wherein the esterifier reaction is 1-methyl-10 alpha-methoxy-1 or 1 isergol carried out in tetrahydrofuran, using a carboxylic acid excess of two to four times the stoichiometric amount, and in the presence of dicyclohexylcarbodiimide as a condensing agent. ENRICO CORVI SEA Italy S 67 8 t ' Dos.73201 05.07.1985. P * -8 01/7 9 -V ABSTRACT The invention relates to a novel process for the preparation of a lysergol derivative of the general formula in which R is a radical of an organic carboxylic acid selected from the group consisting of aliphatic, cycloaliphatic, aromatic and heterocyclic acids of up to 10 C atoms which may be substituted by halogen. Lysergol is used as the starting compound in the process according to the invention, then the corresponding 10-alpha-methoxy lumylzergol is methylated in position 1, the methylated compound is re-certified with the carboxylic acid R-COOH. wherein R has the meaning given above.