CS262148B1 - 2-bromo-13-nitro derivatives of ergoline; - Google Patents

Abstract

2-bromo-13-nitroderivatives of ergoline (of the general formula I, in which R denotes a diethylaminoureido group with the 8α configuration, i.e. '8S, or a methoxycarbonyl group with the 8β configuration, i.e. 8R, and a process for their preparation by nitration of the 2-bromo-13-H-precursor salt with aqueous nitric acid in the presence of urea.

Description

The invention relates to 2-bromo-13-nitroderivatives of ergoline of formula I,

in which

R denotes a diethylamino -reide group '(—NHC-ON / C2H5 / 2) with an 8' configuration (ie 8S) or a methoxycarbonyl group (COOCH3) having the configuration (ie 8Rj) and a process for their preparation.

The compounds of formula (I) are potential drugs with effects on the secretion of the prodrug and on dopamine receptors. Furthermore, they serve as valuable (intermediates for the manufacture of medicaments with such effects.

The 2-bromo-13-nitroderivatives of ergoline of formula I have three chiral centers in the molecule, asymmetric carbons at positions 5, 8 and 10, the hydrogen atom on C (5) having the β position (5R configuration), a C bonded group ( 8) is in accordance with the general formula I in position A or I and the hydrogen atom on C (10) has the position "(10R configuration).

According to the invention, the 2-bromo-13-nitroderivatives of ergoline of formula (I) may be prepared by starting the 2-bromo-13-H precursor of formula (II) in which ^: R is as defined above in the form of an aqueous salt solution with a suitable acid nitrates with aqueous nitric acid with the addition of urea, eliminating the presence of free nitrogen toxins. The starting 2-bromo derivatives of formula II are known.

The reaction is preferably carried out by adding urea and then concentrated acid with stirring to a solution of the precursor in an aqueous acid such as acetic, tartaric or methanesulfonic acid, i.e. the in situ formed precursor salt, while cooling to 0 ° C to 15 ° C. nitric acid in an amount such that its concentration in the resulting mixture was 15-50%. 1% to 20% by weight, calculated on the nitric acid used, is added to the urea. The resulting mixture was stirred for 1 minute to 30 minutes at the temperature given by the substrate used and the acid concentration in the reaction mixture.

After the reaction time has elapsed, the reaction mixture is worked up by conventional methods in the chemistry of ergoline derivatives, for example by alkalization, shaking the product into a suitable non-carrying solvent, evaporating the solution and chromatographing and / or crystallizing from a suitable solvent.

The compounds of formula (I) are yellow, crystalline substances, of slightly basic character, forming addition salts with strong inorganic and organic acids.

The following non-limiting Examples illustrate the preparation of 2-bromo-13-nitroderivatives of formula (I). Melting points are determined on a Kofler block and are reported in ° C.

Structure of substances was confirmed by infrared and mass spectra, composition by elemental analysis.

Example 1

Q6-3 mg (1 mmol) of methyl 2-bromo-9,10-dihydrolysergate is dissolved in a mixture of 18 ml of moda and 0.071 ml (1.1 mmol) of meithansulfonic acid, 1 g of urea is added and 15 ml of 68% nitric acid, cooled to 0 ° C, are added with stirring and cooling. The reaction mixture is then stirred for 4.5 minutes while cooling to 15 DEG C. and then poured into a mixture of 50 g of ice, 15 ml of concentrated aqueous ammonia and 50 ml of chloroform. The organic phase is separated, the aqueous is extracted with 2 X -X 50 ml of chloroform. The combined organic phases are dried freely. sodium sulfate and evaporated. The residue was crystallized from ethyl acetate and the precipitated material was purified by 2 x silica gel chromatography (eluent: chloroform, containing 0.2% triethylamine). Qualitatively identical fractions were combined, filtered and evaporated and the residue was crystallized from ethyl acetate. Ttk of 175 mig (43% of theory) of golden yellow methyl 2-broim-9,10-dihydro-13,11-nitrolysergate, m.p. -t. 255-258 ^Q C.

Example 2

To a solution of 690 mg (1.645 mmol) of 2-bromo-terburide and 250 mg (1.67 mmol) of tartaric acid in 75 ml of water was added 1.0 g of urea and the mixture was cooled to 5 ° C. 50 ml of 68% nitric acid, cooled to 5 DEG C., are then added with stirring and cooling, and the resulting reaction mixture is stirred for 4.5 minutes. Workup of the reaction mixture of Example 1 yielded 250 mg (33%) of yellow 2-bromo-13-nitroterguride after 3 fold chromatography and crystallization from ethanol. Mp 157-160 ° C.

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Claims (3)

SUBJECT 1. The 2-bromo-13-nitroderivatives of ergoline of formula (I) according to the invention, characterized in that the corresponding 2-ibromo-13-H precursor of formula (II): R denotes an 8 ' configuration, i.e., 8S, or an 8/3, 1j configuration, a diethyluminareide group. 8R. 2. A process for the preparation of the 2-bromo-13-nitroderivatives of ergoline of formula (I) according to claim 1, in which R is as defined above, nitrates in the form of an aqueous solution of a salt with a suitable acid, nitric acid. 3. A process according to claim 2, wherein urea is added to the reaction mixture, representing 1 to 20% by weight of the nitric acid used.