CS211346B1 - Method of epimerization of the stereoisomere acids d-9 esters,1%-dihydrolyserg and the derivatives thereof - Google Patents

Abstract

The invention relates to a novel process for epimerization at asymmetric center C, g. esters of stereoisomeric acids D-9,10-dihydrolysergic acid and derivatives thereof. According to the invention the epimerization is carried out such that ester in a polar aprotic environment Solvents with strong base to enolite which is decomposed without a salt a source of protons to form a mixture of epimers, from which the desired epimer is isolated by known methods ways

Description

(54) Method for the epimerization of stereoisomeric esters of D-9,10-dihydrolysergic acids and derivatives thereof

The invention relates to a novel method of epimerization at asymmetric center C, g. esters of stereoisomeric D-9,10-dihydrolysergic acids and derivatives thereof. According to the invention, epimerization is carried out by converting the ester in a polar aprotic solvent medium with a strong base into an enolet, which is decomposed without isolation by a suitable proton source to form a mixture of epimers from which the desired epimer is isolated by known methods.

The present invention relates to a novel process for epimerization at the asymmetric center of ^c (gy esters of stereoisomeric D-9,1O-dihydrolysergic acids and their derivatives of the general formula I),

(I) wherein R represents a straight or branched chain alkyl group of one to four carbon atoms, R ^ is hydrogen or a straight or branched chain alkyl group of one to four carbon atoms, R is hydrogen or bromine, R ^J is a hydrogen atom or a methyl group, and R. Is a hydrogen atom or a methoxy group.

In formula I, the wavy valency line (β) indicates that the substituent attached thereto may be either above the plane (beta position) or below the plane (alpha position) of the drawing. The epimerization process of the present invention relates exclusively to the asymmetric carbon at the 8-position and allows the conversion of the 8beta-alkoxycarbonylergolines of the formula Ia to the 8a-alkoxycarbonylergolines of the formula Ib and vice versa.

ROOC H

H COOR

la lb

It is known that by saturating the double bond at position 9,10 of lysergic acid and its derivatives, the possibility of epimerization on carbon is strongly suppressed, or the conjugation between the carboxyl group and the indole cycle is reduced due to the possibility of enolform formation (A. Stoli, A. Hofmann, T. Troxler, Helv., Chim. Acta., 2,506 (1949)). Epimerization occurs only in some cases in conjunction with a chemical reaction (for example, saponification of D-9,10-dihydroisolysergic acid methyl ester with methanolic potassium hydroxide solution produces irreversibly D-9,10-dihydrolysergic acid-I; see A. Stoli,

A. Hofmann, T. Petrzilka, Helv. Chim. Acta 29, 635 (1946)), or, using some bases in non-polar solvents, only in low yield (L. Bernardi, V. Barbieri, Gazz. Chim. Ital. 25, 375 (1965)); Bernardi, W. Barbieri. Gazz. Chim. Italian. 21, 9 (1964);

L. Bernardi, O. Goffredo, Tetrahedron 26, 2539 (1965); W. Barbieri, 1, Bernardi, G. Bosisio, A. Temperilli, Tetrahedron 25, 2401 (1961).

The present inventors have now surprisingly found that the esters of stereoisomeric D-9,10 dihydrolysergic acids and their derivatives can be converted, by treatment with strong bases in a suitable medium, into the corresponding enolytes which decompose under the action of protons to form both of the respective epimers. These epimerizations allow the reversible conversion of D-9,1O-dihydrolysergic acid esters to D-9,10-dihydroisolysergic acid esters and D-9,1O-dihydroisolysergic acid esters to D-9,1O-dihydrolysergic esters -II.

According to the invention, epimerization is carried out by reacting an ester of the formula I in a polar aprotic solvent with a strong base and decomposing the enolet without isolation with a suitable proton source to form a mixture of epimers from which the desired epimer is isolated by known methods .

Ethers such as vapor may be used as the polar aprotic solvent in the process of the invention. 1,2-dimethoxyethane, 1,2-diethoxyethene, tetrahydrofuran or dioxene, or dimethylformamide, dimethylsulfoxide and hexamethyltriophosphoric triamide, or mixtures of said solvents.

alkali metal alcoholates, preferably potassium tertiary butoxide, alkali metal amides, preferably lithium diisopropylamide, or alkali metal hydrides, preferably sodium hydride, can be used for eplmerization.

The reaction can be carried out at temperatures ranging from -80 ° C to the boiling point of the reaction of the mixture, preferably ranging from -30 to +25 ° C.

For example, water, lower aliphatic alcohols or aqueous solutions of inorganic or organic acids may be used as proton sources to break down the enolate.

Conventional organic chemistry methods can be used to separate the obtained epimer mixtures Ia and Ib, for example fractional crystallization from a suitable solvent or solvent mixture, column chromatography, preparative thin layer chromatography, high performance liquid chromatography, or by fractional crystallization after conversion to suitable diastereomeric acid salts. After separation of the desired epimer, the remaining mixture, in which the starting isomer predominates, can be re-epimerized according to the invention.

The epimeric esters Ia and Ib are important intermediates in the production of pharmaceutically important ergoline derivatives, and some of them have so far been prepared only by lengthy multi-step syntheses (P.L. Stutz, P.A. Stadler, J. Hed. Chem. 21, 754 (1978)).

The process of epimerization of the stereoisomeric esters of D-9,1O-dihydrolyseric acids and their derivatives according to the invention is explained in detail in the following non-limiting examples.

He did

D-9,1O-Dihydroisolysergic acid methyl ester-I

To a solution of 0.16 mol of lithium diisopropylamide (prepared from 16.2 g (0.16 mol) of diisopropylamine and 106.6 ml (0.16 mol) of a 1.5 M hexane solution of butyllithium) in 200 ml of tetrahydrofuran, cooled to A solution of D-9,10-dihydrolysergic acid-I ester (11.4 g; 0.04 mol) in tetrahydrofuran was added dropwise at -20 ° C so that the temperature of the reaction mixture did not exceed -10 ° C.

The mixture was stirred at this temperature for 20 minutes, and after cooling to -50 ° C, a 10% (v / v) aqueous acetic acid solution was added until neutral (pH about 7). The reaction mixture was evaporated in a water pump vacuum at 40 ° C, the crystalline residue was poured over a saturated aqueous sodium bicarbonate solution and the product ea was taken up in chloroform. The organic extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was crystallized repeatedly from aqueous methanol. M.p. 85 DEG-187 DEG C. (.alpha.) .Alpha. = -82 DEG (c 0.2, pyridine).

Example 2

D-9,10-Dihydrolysergic acid methyl ester II

To a solution of 0.20 mL of lithium diisopropylamide (prepared analogously to Example 1) in 150 mL of tetrahydrofuran at -30 ° C was added a solution of 14 g (0.049 mol) of D-9,10-dihydroisolysergic-II-methyl ester in 100 mL. tetrahydrofuran, the reaction mixture is stirred at this temperature for 30 minutes, cooled to -70 ° C and a 10% (v / v) aqueous acetic acid solution is added until the reaction is neutral. The reaction mixture was evaporated at 40 ° C under a water pump vacuum, the residue was poured into a saturated aqueous solution of sodium bicarbonate and the product was taken up in chloroform.

The organic extract was dried over magnesium sulphate and the solvent was removed by rotary evaporation. The residue is chromatographed on a silica gel column using aeeton / benzene / conc. ammonium hydroxide (1000/1 500/1), the homogeneous fractions were combined and the residue was crystallized from aqueous methanol. 169 DEG-170 DEG C., [.alpha.] D @ 20 = + 75.3 DEG (c 0.2, pyridine).

Example 3

D-9,1O-Dihydroisolysergic acid methyl ester-I

To a solution of 2.84 g (0.01 mol) of methyl D-9,10-dihydrolysergic acid-X in 50 ml of hexamethylphosphoric triamide was added 1.2 g (0.05 mol) of sodium hydride at room temperature and stirred. 30 minutes, then poured into a large excess of water. The precipitate was filtered off, washed with water and crystallized from aqueous methanol after seeding with D-9,1O-dihydrolysergic acid-1 methyl ester. The starting crystallized ester is filtered off and the residue of the mother liquor is chromatographed on a silica gel column (aeeton / benzene / conc.). ammonium hydroxide (1000/1 500/1), the homogeneous fractions were combined and crystallized from aqueous methanol. 185 DEG-187 DEG C. (.alpha.) D @ 20 = -82 DEG (c 0.2; pyridine).

He attaches

D-6-nor-9,1O-dihydroisolysergic acid methyl ester-I

A solution of 135 mg (0.5 mmol) of methyl D-6-nor-9,10-dihydrolysergic acid-I in 10 ml of tetrahydrofuran was added dropwise to a solution of 4 mmol of lithium diisopropylamide (prepared analogously to Example 1) in 10 ml of tetrahydrofuran. After stirring at this temperature for 30 minutes, the reaction mixture is cooled to -60 ° C, aqueous acetic acid is added until neutral, and the solvent is evaporated at 40 ° C under a water pump vacuum.

The residue was poured into a saturated aqueous solution of sodium bicarbonate and the product was taken up in dichloromethane. The organic extract was dried over magnesium sulphate and the solvent was removed by rotary evaporation at 40 ° C. The residue is dissolved in a minimum amount of CH 3 Cl 2 and loaded onto a high performance liquid chromatography column packed with MicroPak Si 5 adsorbent with 79% dichloromethane + 20% hexane + 0.5% isopropenol + + 0.5% triethylamine as the liquid phase. The detected homogeneous fraction with the corresponding retention time was collected by UV detection, evaporated and the residue crystallized from ethyl acetate.

88 DEG-90 DEG C. and [.alpha.] D @ 20 = -47 DEG (0.2; pyridine).

In an analogous manner to Examples 1-4, the following compounds were prepared by epimerization of the respective D-9,1O-dihydrolysergic acid esters:

D-9,1O-dihydroisolysergic acid ethyl ester-I, mp 159-161 ° C (o) = -55.7 ° (c 0.2 pyridine);

D-9,1O-dihydroisolysergic acid-1-isopropyl ester, mp 164-165 ° C (°) 10 ° (e 0.2, pyridine);

D-9,1O-dihydroisolysergic acid butyl ester, m.p. 87-88 ° C, [.alpha.] D = -75.5 DEG (c 0.2, pyridine);

D-6-nor-6-ethyl-9,1O-dihydroisolysergic acid-1-methyl ester, mp 184-186 ° C, (?) = -84 ° (c 0.2, pyridine);

methyl ester of D-6-nor-6-allyl-9,1O-dihydroisolysergové-I, mp 160-162 ° C, (A) * ⁰ = -83.5 ° (c 0.2, pryridin);

D-6-nor-6-propyl-9,1O-dihydroisolysergic acid methyl ester, mp 165-167 ° C, (α) P = -60 ° (c 0.2; pyridine);

D-2-bromo-9,1O-dihydroisolysergic acid-1-methyl ester, mp 185-186 ° C, (α) D = -69.1 ° (c 0.2; pyridine);

acid methyl ester, D-1-methyl-9,10-dihydroisolysergové-I, mp 160-162 ° C (o) * ⁰ = -74.2 ° (c 0.2, pyridine);

D-10alpha-9,10-dihydroisolysergic acid-1-methyl ester, m.p. 255 DEG-256 DEG C., (.alpha.) D @ 20 = -16.8 DEG (by 0.2; pyridine).

Claims (5)

SUBJECT OF THE INVENTION A process for epimerizing stereoisomeric esters of D-9,10-dihydrolysergic acids and derivatives thereof of the general formula I, COOR (I) wherein R represents a straight or branched alkyl chain of one to four carbon atoms, R ¹ is hydrogen or a straight or branched alkyl group o> carbon chain of one to four carbon atoms, R is hydrogen or bromine, R ^J is hydrogen or methyl and R is hydrogen or methoxy, characterized in that the ester of formula I is brought in a polar aprotlckého solvent to the reaction, with a strong base and the resulting enolet is decomposed by a proton source to form a mixture of epimers from which the desired epimer is isolated by known methods. 2. A process according to claim 1, wherein the polar aprotic solvent is an ether such as 1,2-dimethoxyethane, 1,2-diethoxyethane, tetrahydrofuran or dioxane, or dimethylformamide, dimethylsulfoxide and hexamethylphosphoric triamide, or mixtures thereof. solvents. ³ Method according to claim 1, characterized in that the base used is an alkali metal alcoholate, preferably potassium tertiary butoxide, alkali metal amide, preferably lithium diisopropylamide, or alkali metal hydride, preferably sodium hydride. between 4. Process according to claim 1, characterized in that from -80 ° C up to the boiling point of the reaction mixture, the reaction is carried out at temperatures preferably in the range of -30 to + 25 ° C. 5. A process according to claim 1, wherein water, lower aliphatic alcohols or aqueous inorganic acid solutions are used as proton sources to decompose the enolate.