CS272370B1 - Method of ergoline compounds preparation that are position-substituted by 2-bromine - Google Patents

Abstract

2-Bromo-alpha-ergocryptine, the potent inhibitor of prolactin /luteotropic hormone/, is prepared in high yield and purity grade by the bromination of alpha-ergocryp-tine with elemental bromine in chlorinated aliphatic hydrocarbons and/or tetrahydrofuran in the presence of catalytic amounts of Lewis acids, preferably boron trifluoride, in the temperature range of from -40 to 0.degree.C and optionally converted as known per se into its acid addition salt, preferably methanesulfonate.

Description

The present invention relates to a process for the preparation of bromine-substituted ergoline derivatives. These substances have significant pharmacological effects. Some of them are used as drugs (2-bromo -? - ergocryptine), others can be considered as potential drugs or precursors for the synthesis of new drugs. SUMMARY OF THE INVENTION The present invention provides a novel process for brominating ergot alkaloids of formula I to form compounds known per se.

(AND)

In the formula IR ^, Hg »^ 3 is hydrogen or R ^ is methoxy or R ^ and Rg or Rg or Rg and R ^ together form a chemical bond and R ^ is methyl, hydroxymethyl, methoxycarbonyl or CHg-OR where R ^ is an aliphatic acyl group having a maximum of 5 carbon atoms, or R ^ is a group of the formula CHg-NH-Rg, where Rg is a benzyloxycarbonyl group, or R ^ is a group of the formula CO-NH-Ry, wherein R ? represents a group

Hi í

// o

OH

N.

'W

R, wherein R 8 is methyl, ethyl or isopropyl, and R 6 is benzyl, isobutyl, isopropyl or sec, butyl.

Halogenation of ergot alkaloids was first described by P. Troxler and A, Hofmann (Helv. Chim. Acta 40, 2160 (1957)). They described the bromination of ergot alkaloids with various brominating agents. Bromination with bromine gave rise to chromium-plated and decomposition products. They also tested bromination with pyridine hydrobromide perbromide, N-bromosuccinimide, H-bromoacetamide, N-bromophthalimide and Ν, Ν-dibromohydantoin. The best results were obtained using N-bromosuccinimide in dioxane.

In Swiss Patent No. 507,249 to Sandoz, N-bromosuccinimide, N-bromophthalimide, N-bromocaprolactan and dioxane dibromide are used to prepare 2-bromo-α-ergocryptine. The bromination is carried out in dioxane or in a mixture of dioxane with other solvents.

The procedure of LEK (DE 27 52 532) uses pyrrolidone hydrotribromide or N-bromosaccharin in cyclic ether to brominate the erg-ergocryptine in the presence of radical initiators, e.g. 2,2-azobis (2-methylpropionitrile). bromination, suggesting that under the conditions described in the invention the reaction takes place by a radical mechanism.

Both methods have some common disadvantages. The first are relatively drastic reaction conditions (high temperature and long reaction time), resulting in bromination

CS 272370 B1 tt-ergocryptine formation of a non-negligible amount of 2-bromo- α, -ergocryptinine. A second disadvantage is the oxidizing properties of the brominating agents used. This results in the formation of tarry, undefined oxidation products - the reaction mixture is always very dark. A third disadvantage is the presence of a bromine carrier, which must be removed from the reaction mixture - usually by chromatography.

These disadvantages try to eliminate some other procedures. The patent of Gedeon Richter (DE 36 19 617) uses hydrogen bromide in the presence of dimethyl sulfoxide for bromination with an ergoline structure. It is actually bromination with bromine, which is formed by oxidation of hydrogen bromide with dimethylsulfoxide.

The Schering procedure (EP 141 387) protects the bromination of ergoline compounds with elemental bromine in the presence of hydrogen bromide in the environment of halogenated hydrocarbons. A common disadvantage of both processes is the necessity to work in a relatively large dilution - the addition compounds of ergoline substances with hydrogen bromide present in the reaction mixture are poorly soluble in organic solvents. The Bromaee processes of the last two inventions are carried out at low temperature and in the presence of protic acids. This practically eliminates the radical course of the reaction.

In studying bromaee ergot alkaloids with elemental bromine, we found that the reaction is influenced by typical electrophilic catalysts - Lewis acids.

This suggests that at low temperature bromine and ergot alkaloids run through an electrophilic mechanism.

The process of our invention solves the preparation of bromine-substituted ergoline compounds by bromination of ergot alkaloids with elemental bromine in organic solvents in the presence of Lewis acids. Lewis acids may be aluminum chloride, aluminum bromide or boron tribromide. As the organic solvent, dichloromethane, chloroform, dichloroethane or tetrahydrofuran can be used, but preferably a mixture of dichloromethane and tetrahydrofuran, in which most ergoline compounds are well soluble at low temperature. Bromination can be carried out in the temperature range of -40 to 0 ° C.

The reaction of the ergoline compounds 8 with elemental bromine in a mixture of dichloromethane and tetrahydrofuran proceeds at temperatures of -20 to 0 ° C even in the absence of electrophilic catalysts. However, the oxidative effects of bromine predominate in the reaction, so the reaction product is a mixture of 20 to 50% 2-bromo derivative and 30 to 60% 2-oxo derivative. When an Lewis acid-type electrophilic catalyst is added to the reaction mixture, the 2-oxo compound content of the reaction mixture drops below 5% and the yield of the 2-bromo derivative is increased. The yield of the 2-bromo derivative can still be influenced by temperature - as the temperature decreases, the yield of the 2-bromo derivative increases and the content of undesirable minor products in the reaction mixture decreases. Then, according to the invention, a yield of the 2-bromo compound of greater than 90% for substances with an ergoline structure and greater than 80% for substances containing a double bond at positions can be achieved

8.9 or 9.10.

The process according to the invention has some advantages over the prior art methods of bromine and ergoline compounds

1. Mild reaction conditions and hence light color of the reaction mixture

2. High yield of 2-bromo derivative

3. Possibility to work in relatively concentrated solutions

4. Easy isolation of the product from the reaction mixture

The process according to the invention is explained in more detail by the following non-limiting examples.

CS 272370 Bl

EXAMPLE 1 g of 10-methoxy-dihydrolysergic acid methyl ester is dissolved in 60 ml of dichloromethane-tetrahydrofuran (3 L). 2 g of aluminum chloride are added and the solution is cooled to -10 ° C. Then, while stirring, 3.5 g of bromine dissolved in 30 ml of dichloromethane are added in one go. After stirring for 1 minute, 50 ml of 5% potassium carbonate solution and 20 ml of 5% sodium pyrosulfite solution were added to the reaction mixture. After stirring for 5 minutes, the organic phase is separated and concentrated to a residue. The light brown residue was crystallized from acetone. 7.5 g of product were obtained, which was determined to be 95.25 by titration. This corresponds to a yield of 92.8% of theory.

Example 2

100 g of α-ergocryptine containing 92.5% was dissolved in 1200 ml of dichloromethane-tetrahydrofuran 2: 1. To the solution was added 20 g of aluminum bromide and the solution was cooled to -30 ° C. 420 ml of a 8% solution of bromine in dichloromethane were added with stirring. After stirring for 1 minute, 700 ml of 5% aqueous potassium carbonate solution and 300 ml of 5% aqueous sodium pyrosulfite solution were added to the reaction mixture. After separation of the phases, the aqueous phase is extracted with an additional 200 ml of dichloromethane and the combined organic phases are concentrated to a residue. The residue was dissolved in dichloromethane and chromatographed over 1 kg of silica gel, eluting with 4: 1 dichloromethane-acetone. A total of 92.2 g of crystalline 2-bromo-4-ergocryptine having a content of 91.5% is obtained. corresponding to a yield of 80.3% of theory.

Claims (2)

1. A process for the preparation of ergoline compounds substituted at the 2-position with bromine bromination of ergoline compounds of formula I (I) wherein R p R g and R j are hydrogen or is methoxy or R 6 and R ₂ or R 6 and R 6 together form a chemical bond and R R znamená is methyl, hydroxymethyl, methoxycarbonyl or CH nebo-OR ^, where R z is an aliphatic acyl group of up to 5 carbon atoms, or R ^ is CHg-NH-Rg, where Rg is benyloxycarbonyl a or R ^ represents a group of the formula CO-NH-R?, where R? = R?; represents a group in which Ηθ represents a methyl, ethyl or isopropyl group and Rg represents a benzyl, isobutyl, isopropyl group or sec. Butyl elemental bromine in organic solvents, characterized in that the bromination is carried out in the presence of Lewis acids in the temperature range of -40 to 0 ° C, 2. 2. The process of claim 1 wherein the lewis acid is aluminum chloride, aluminum bromide or boron tribromide.