CS262581B1 - 2-Trifluoroacetylderfvits of ergoline and a process for their preparation - Google Patents

Abstract

2-trifluoroacetyl derivatives of ergoline of general formula I, in which R denotes a diethylureide group with an 8-alpha configuration (i.e. 8S) or a methoxycarbonyl group with an 8-beta configuration (i.e. 8R) and a method for their preparation by reaction of a 2-H-precursor with trifluoroacetic anhydride under Friedel-Crafts acylation conditions. The prepared compounds are valuable intermediates for the production of pharmaceuticals

Description

The invention relates to ergoline 2-trifluoroacetyl derivatives of the general formula I

in which

R represents a group diethylureidovou (-NHCON (C ₂ H ,.) ₂₎ Configuration 8-alpha (i.e. 8S) or methoxycarbonyl (COOCHj) Configuration 8-beta (i.e. 8R) and their preparation.

The ergoline 2-trifluoroacetyl derivatives of formula (I) are valuable intermediates of drugs having effects on prolactin secretion, dopamine receptors and antipsychotic effects.

The 2-trifluoroacetyl derivatives of ergoline of formula (I) have three chiral centers in the molecule, asymmetric carbons at the 5, 8 and 10 positions, the hydrogen atom on C (5) having a beta position (5R configuration). in accordance with formula (I), the alpha or beta position and the hydrogen atom on C (10) has the alpha position (10R configuration).

According to the invention, the ergoline derivatives of the formula I can be prepared by reacting the starting 2-H derivative of ergoline with trifluoroacetanhydride under Friedel-Crafts reaction conditions.

The reaction is preferably carried out by dissolving the starting ergoline precursor in trifluoroacetic anhydride without or preferably using a cosolvent which may be a non-polar solvent such as 1,2-dichloroethane, a polar aprotic solvent such as tetrahydrofuran, or a strong acid such as an acid. trifluoroacetic acid and acylation to the 2-position are catalyzed by the addition of a strong Lewis acid such as boron trifluoride etherate or a strong protic acid such as trifluoroacetic acid or a superacid such as trifluoromethanesulfonic acid. The reaction itself proceeds according to the nature of the solvent used, whose ratio to trifluoroacetanhydride can be 0 to 2, the catalyst used, the ratio to substrate being 0.1 to 5, the temperature, which can range from -5 ° C to 50 ° C and the nature 5 minutes to several days.

Thereafter, the reaction mixture is worked up by methods customary in ergoline derivative chemistry, for example by pouring into water, shaking it into a water-immiscible solvent, evaporating the solution and chromatography and / or crystallizing from a suitable solvent.

The compounds of formula (I) are yellowish, well crystallizing, of slightly basic character, providing acid addition salts with strong acids.

The process for the preparation of the 2-trifluoroacetyl derivatives of ergoline of formula (I) is illustrated in more detail by the following non-limiting examples. Melting points are determined on a Kofler block and are reported in ° C.

Structure of compounds was confirmed by infrared, ultraviolet and NMR spectra, composition by elemental analysis.

Example 1

Methyl 2-trifluoroacetyl-9,10-dihydrolysergate

2.84 g (10 mmol) of methyl 9,10-dihydrolysergate are dissolved in a mixture of 37.5 ml of trifluoroacetanhydride and 25 ml of absolute tetrahydrofuran and 4.0 ml (7.1 g) of ether are added dropwise over 5 minutes while cooling to room temperature. boron trifluoride. The mixture was allowed to stand without stirring for 3 days at room temperature, then quenched by pouring onto 100 g of ice and cautiously basified with conc. aqueous ammonia to pH 7.5. The product is then shaken with 3x200 ml of chloroform, the extracts are dried freely. sodium sulfate and evaporated in vacuo. The residue obtained (7.5 g) was crystallized from aqueous methanol. 2.40 g (63% of theory) of methyl 2-trifluoroacetyl-9,10-dihyrolysergate are obtained, m.p. 205 DEG C., [.alpha.] D @ ²⁰ -142.22 DEG (c = 0.2; pyridine).

Example 2

In the same manner as in Example 1, but using 680 mg (2 mmol) of terguride, 7.5 mL of trifluoroethane anhydride, 10 mL of absolute. 1,2-dichloroethane and 0.8 ml (1.43 g) of boron trifluoride etherate, after work-up and crystallization from ethanol, yield 535 mg (60%) of amorphous N- (5-beta, 10-alpha-2-trifluoroacetyl-). 6-methylergolin-8-alpha-yl) -N ', Ν'-diethylurea, IR (KBr): 3,422 (indole NH), 2,799 (N-Me), 1,661, 1,626 (> CO in NHCONEt ₂ + CF ₃ CO-), 1515 (NH in NHCONEt ₂ ), 1219, 1196 (-CF ₃ ), 1143 (CN), 757, 726 cm ^-1 (1,2,3-trisubstituted phenyl).

Claims (5)

SUBJECT OF THE INVENTION 1. The ergoline ergoline 2-trifluoroacetyl derivatives of the formula I R denotes an 8-alpha, i.e., 8S, diethylureide group, or an 8-beta, i.e., 8R, methoxycarbonyl group. A process for the preparation of ergoline 2-trifluoroacetyl derivatives of the general formula I, in which it has: R is as defined above, characterized in that the corresponding 2-H ergoline precursor is acylated with trifluoroacetanhydride under Friedel-Crafts acylation conditions. 3. A process according to claim 2, wherein the catalyst is a boron trifluoride-type Lewis acid, a trifluorotonic acid-type strong acid or a trifluoromethanesulfonic acid-type superacid. 4. A process according to claim 3, wherein a catalyst / substrate molar ratio of 0.1 to 5 is used. 5. Process according to claim 4, characterized in that a tetrahydrofuran or 1,2-chloroethane or trifluorotonic acid cosolvent is used to carry out the reaction.