SE433497B - SET TO BRROME ERGOTAL CALOIDS - Google Patents

Description

Wherein R 1 to R 4 have the meaning given above, is brominated with a bromine complex of B-bromo-S-chloro-Z-methyl-imidazo [la-b] pyridazine.

This brominating agent can e.g. prepared by reacting 3-bromo-6-chloro-Z-methyl-imidazo [1H-b] pyridazine or G-chloro-Z-methyl-imidazo [1H-b] -pyridazine with excess bromine. The product is believed to contain 3-bromo-6-chloro-2-methyl-imidazo [IJ-b] pyridazine dibromide of the formula IV IV / YN 'H3 _ i | Brz Cl \ / N Br The brominating agent has particularly advantageous properties. For example, it is selective and does not lead to large amounts of by-products. It is soluble in a large number of organic solvents, e.g. halogenated solvents, and is stable in solution. excess brominating agent can be easily destroyed, and the brominated product can be easily separated from the reaction mixture. The brominating agent can be easily regenerated from 3-bromo-6-chloro-2-methyl-imidazo [low-b] pyridazine formed in the reaction.

In formulas I and II, the side chain in the 8-position may have ot- or preferably β-configuration. The bromination reaction proceeds stereospecifically in that epimerization in the 8-position may be unexpectedly minimal. For the above-mentioned ergot alkaloids, it is preferred to use a ratio of 1 mole of ergot alkaloid per 1.2 to 1.5 moles of brominating agent based on structure IV. The bromination reaction is preferably carried out using methylene chloride or any other suitable chlorinated CLB alkane as solvent.

Suitable reaction temperatures are e.g. from about 100 ° C to about 100 ° C. At room temperature, satisfactory yields can be obtained quite surprisingly, e.g. in a few minutes.

Any excess brominating agent in the reaction mixture can be deactivated by adding e.g. acetone and ammonium hydroxide. the isolation of the brominated product is then facilitated. Conventional insulation methods can be used, e.g. liquid / liquid extraction and column chromatography, to obtain the brominated product in pure form.

3-Bromo-6-chloro-Z-methyl-imidazo - [IJ-b] pyridazine can be isolated from the reaction mixture. This can be converted back to the brominating agent by treatment with excess bromine in concentrated acetic acid.

The brominating agent can be initially prepared by reacting 3-bromo-6-chloro-2-methyl-imidazo [1H-b] pyridazine or β-chloro-Z-methyl-imidazo [1H-b] pyridazine with excess bromine in concentrated acetic acid, and collects the resulting precipitate.

Bromination of S-chloro-Z-methyl-imidazo [IJ-b] pyridazine has been described by Kobe et al, Tetrahedron, 2, 239 (1968), but there is no indication that the bromine complex formed could be used as a brominating agent. 3-Bromo-6-chloro-2-methyl-imidazo [IJ-b] pyridazine can be prepared as described in the above-mentioned Tetrahedron article and can be brominated analogously to the method of brominating 6-chloro-2-methyl-imidazo [1, 2-b] pyridazine, and the bromine complex can be purified in the usual manner. The yields of the brominating agent can be conveniently increased by brominating all the unreacted starting material in the bromine complex.

The complex can be further purified by recrystallization from acetic acid, washing the crystals with ether and drying, e.g. at 30 ° C in vacuo. The complex may contain additional bromine in addition to that represented by structure IV, e.g. in the form of HBr.

In the following examples, all temperatures are given in degrees Celsius and uncorrected.

Example I: 2-Bromo-9,10-dihydroergotamine 0.584 S (1 mmol) 9,10-dihydroergotamine is dissolved in 20 ml of methylene chloride.

The solution is stirred and 0.612 g (1.5 mmol) of B-bromo-G-chloro-Z-methyl-imidazo [1,2-b] pyridazine dibromide in 180 ml of methylene chloride are added. After the mixture is stirred for 4 minutes at room temperature, 10 ml of acetone and 100 ml of 296 g of aqueous ammonium hydroxide are added. The methylene chloride phase is separated, and the aqueous phase is extracted twice with 200 ml portions of methylene chloride. The combined methylene chloride extracts are concentrated to a dry residue.

This residue is applied to a column containing 50 g of silica gel. Using a methylene chloride eluent containing 5% ethanol, 0.23 g of 3-bromo-6-chloro-Z-methyl-imidazo [1H-b] pyridazine is eluted.

Further elution gives pure 2-bromo-9,10-dihydroergotamine; 0.33 g; 5096 yield. m.p. read - zoo ° and [m] 1232-81? (<: = 1, pyfidin).

By replacing 9,10-dihydroergotamine with an equivalent amount of: a) OC-ergosine; b) 9,1 O-dihydro-oi-ergosine; c) OL ergocryptine; d) ot-ergosinin; e) (5R, SR) lysergic acid diethylamide; or f) 1-methyl-9,10-dihydrolysergic acid methyl ester is obtained: 'a) Z-bromo-oc-ergosine; 8196 yield, m.p. 183 DEG-185 DEG (sun = .alpha., D @ 20 = -91.6 °, (c = 1.7 chloroform); b) 2-bromo-9,10-dihydroergosine; 6996 yield, m.p. 186 - 1880 (Sun fl ßllšo: -400 (c = 1, methanoD; c) Z-bromo-oc-ergocryptine; 75% yield, mp 215 - 2l8 °, [NJÉO = -98 °; (c pyridinh lšflšo = -195 °; (c = 1, methylene chloride), d) z-bromo-e-ergosinine; 70% yield, mp las - 190 °; relay "= + 4o3 °; (c chloroform); e) (5R, SIU- Z-bromo-lysergic acid diethylamide; 73.1 + 96 yield after recrystallization from ether of the dry residue before chromatography 122, mp 122-125 °; Evlj1α: + 17 ° (c = 1.11, 1, 1, pyridine); f) 2-bromo-1-methyl-9,10-dihydrolysergic acid methyl ester, 6596 yield after recrystallization of the dry residue before chromatography from methanol / water (85: 15 by volume), mp read - 1es °; E> Example 2: Regeneration of B-bromo-G-chloro-Z-methyl-imidazo [b] pyrid-1-azin-dibformide 0.23 g (0.93 mmol) of B-bromo-6-chloro-Z-methyl-imidazo [ The IJ-b] pyridazine obtained from Example I is dissolved in 2 ml of concentrated acetic acid and treated with 1.39 mmol of elemental bromine. After a short time, B-bromo-G-chloro-Z-methylimidazo [ IJ-b] pyridazine dibromide from r the reaction mixture. This is filtered off and dried. yield 0.38 g, (seven), m.p. 217-222 °.

Claims (2)

1. 7907942-2 PATENTKRAV fl. A process for the preparation of a compound of formula I wherein R 1 is carboxyl, alkoxy (C 1-5) carbonyl, amido, alkyl (C 1-5) amido, di-alkyl (C 1 amido or an amido group of formula II a I i 0: p -co-ruu Where Ra is alkyl (C 14) and E-1b is alkyl (C 1%) or benzyl, R 2 is hydrogen or alkyl (C 1 +), and either R 3 is hydrogen and R 4 is hydrogen or alkoxy (C1-4) or RB and R4 together are a single bond, characterized by brominating a compound of formula III - III wherein R1 to Ra has the meaning given above, with a bromine complex of 3- bromo-G-chloro-Z-methyl-imidazo [1J-b] pyridazine. 2. A method according to claim 1, characterized in that the compound of formula III is ergo-ergocryptine. SUMMARY A method of preparing a compound of formula I wherein R 1 is carboxyl, alkoxy (C 1-5) carbonyl, amido, alkyl (C 1-5) amido, di-alkyl (C 1-5) -amido or an amido group of the formula II R 031 m 0. where R a is alkyl (C 14) and R b is alkyl (C 1-4) or benzyl, R 2 is hydrogen or alkyl (C 14), and either RB is hydrogen and RL, is hydrogen or alkoxy (C1-4) or Ra and Ru together are a single bond, by bromination of a compound of formula III - III N ... IR where R 1 to Ru has the meaning given above , with a bromine complex of 3-bromo-6-chloro-2-methyl-imidazo [L 2 -bylpyridazine.