CS262200B1 - 1-tosyl derivatives of ergoline and a process for their preparation - Google Patents

Abstract

1-Tosyl derivatives of ergoline of general formula I, in which R denotes a diethylaminoureide group with configuration 8a, i.e. 8S, or a cyanomethyl group with configuration 8/3, i.e. 8R, and a method for their preparation by deprotonation of the 1H-precursor by the action of a strong base and reaction of the resulting salt with tosyl chloride.

Description

The invention relates to ergosin 1-tosyl derivatives of the general formula I

in which

R denotes an 8a (i.e. 8S) -dlethylamino -reide group [—NHCON (C2H5) 2] ”or the < -β (i.e. 8R) -cyanomethyl group (—CH2CN) and a process for their preparation.

The ergoline 1-tosylderivatives of formula I are valuable intermediates of drugs having effects on prolactin secretion, dopamine receptors and antipsychotic effects.

The ergoline 1-tosylderivatives of formula (I) have three chiral centers in the molecule, asymmetric carbons at the 5, 8 and 10 positions, with the hydrogen atom on C (5) having the β position (5R configuration); in accordance with formula (I), the α or β position and the hydrogen atom on C (10 j has the α position (10R configuration).

According to the invention, the ergoline derivatives of the formula (I) can be prepared by deprotonating the starting 1-H derivative of ergoline in a nonpolar or polar aprotic solvent with a sufficiently strong base and treating the resulting salt with tosyl chloride (p-toluenesulfochloride).

The reaction is preferably carried out by contacting the starting ergoline precursor in a polar aprotic solvent such as tetrahydrofuran, dioxam, 1,2-dimethoxyethane or dimethylsulfoxide at -15 ° C to + 50 ° C with powdered potassium hydroxide, sodium hydride sodium amide or lithium dialkylamide (such as lithium diisopropylamide with stirring, preferably under an inert gas atmosphere, such as nitrogen or argen), wherein the molar ratio of reagent / substrate deprotonation is 1-10 and after deprotonation lasting 10 minutes to 4 hours, add an excess of tosyl chloride (with a tosyl chloride / substrate molar ratio of 1.01 to 10.) After a reaction of 30 minutes to 20 hours and carried out at 0 ° C to the reflux temperature of the solvent used, the reaction mixture is worked up according to conventional methods of ergoline derivative chemistry. for example by pouring into water, shaking it into a water-immiscible solvent, evaporating r solution and chromatography and / or crystallization from a suitable solvent.

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

The following non-limiting examples illustrate the preparation of ergoline 1-tosyl derivatives of formula (I). 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

5 ', 10a-8/2-cyanomethyl-6-methyl-1-tosylergoline

To a suspension of 795 mg (3 mmol) of 5β, 10α-8β-cyanomethyl-6-methylergoline in 90 ml abs. tetrahydrofuran was added with stirring, under nitrogen, 840 mg (T5 mmol) of powdered potassium hydroxide, and the mixture was stirred for 30 minutes. 1320 mg (6.9 mmol) of tosyl chloride are then added, the mixture is stirred for 15 minutes and then gently refluxed for 7 hours. After cooling, it is poured into 200 ml of water acidified with 0.5 ml of acetic acid and the product is extracted with 4 x 50 ml of dichloromethane. The combined extracts were dried. sodium sulfate and evaporated. The residue obtained is crystallized from acetone. This gives 960 mg (76% of theory) of the product, mp 214 ° C to 215.5 ° C; specific rotation [.alpha.] D @ ²⁰ = -33.13 DEG (c = 0.2, chloroform). Example 2

Using the same procedure as in Example 1, but using 680 mg (2 mmol) of terguride, 560 mg (10 mmol) of powdered potassium hydroxide and 880 mg (4.6 mmol) of tosyl chloride in 15 ml of abs. 1,2-dimethoxyethane is obtained after work-up and chromatographic purification (silica gel chromatography, eluting with chloroform-1% ethanol-0.1% ethylmethylamine) by crystallization of a residue of united qualitatively identical fractions from ether (680 ml, 69%). 5 / 3,10a-6-: methyl-1-tosylergolin-8a-yl) -N ', N'-diethylurea, mp 108 ^and C to 110 ° C; specific rotation [a] D ^Z0 - 0 ° (c = 0.2, pyridine).

Claims (3)

1. ergolin-1-tosyl derivatives of the general formula I H R VYNALEZU R is an 8a-configuration diethylamino-ride group or a 83-configuration cyanomethyl group. 2. A process according to claim 1, wherein the corresponding 1-H ergoline precursor is deprotonated with a strong base in a non-polar or polar aprotic solvent and the resulting salt is introduced. in contact with tosyl chloride. 3. A process according to claim 2, wherein the deprotonation has a molar ratio of deprotonating agent / substrate of 1.0 to 10 and a molar ratio of toeyl chloride / substrate of 1.01 to 10.