DK149956B - PROCEDURE FOR THE PREPARATION OF BROOM-CONTAINED ERGOTAL KALOIDS - Google Patents

Description

149956

The present invention relates to a particular process for the preparation of ergot alkaloids of general formula I

R1 R3 1

N "CH3 I

N-L Br L2

wherein R car represents carboxyl, C ^ _-alkoxycarbonyl, amido, C ^g am alkylamido, ido-dialkylamido or an amido group of the general formula II

OH

R *! Uh J

"-L-M

H '' Eb 1,2 where R a represents C 1-4 alkyl, R 4 represents C 1-4 alkyl or benzyl, R 2 represents hydrogen or C 1-6 alkyl and either R represents hydrogen, 4 3 4 10 and R represents hydrogen or C β-alkoxy, or R and R together represent a single bond which is peculiar

know that a compound of general formula III

Where R, R, R and R are as defined above, bromines with a bromine complex of 3-bromo-6-chloro-2-methyl-imidazo [ 1,2-b] py-pyridazine.

The bromine complex used as a brominating agent can e.g. is prepared by reacting 6-chloro-2-methyl-imidazo [1,2-b] pyridazine or, preferably, 3-bromo-6-chloro-2-methyl-imidazo [1,2-b] pyridazine with an excess of bromine. The product is believed to contain 3-bromo-6-chloro-

2-methyl-imidazo [1,2-b] pyridazine dibromide of formula IV

rrV1 * 3 CL-kii - ^ = * 2 in 10 It is known to brominate ergot alkaloids such as α-ergocryptin with a mild brominating agent, e.g. N-bromosuccinimide, N-bromine-caprolactam, N-bromophthalamide or bromine / dioxane (cf. Swiss patent no.

507,249). It has also recently been proposed to bromine α-ergocryptin using pyrrolidone (2) -hydrotribromide or N-bromosaccharin in the presence of a radical initiator (German Publication No. 2752532).

The brominating agent used herein has particularly advantageous properties. It is e.g. selectively and does not lead to any large amount of by-products; it is soluble in a wide variety of organic solvents, e.g. halogenated solvents, and is stable in solution; Excess brominating agent can be easily decomposed and the brominated product easily isolated from the reaction mixture. The brominating agent can be readily recovered from 3-bromo-6-chloro-2-methyl-imide-azo [1,2-b] pyridazine, which is formed by the reaction.

In formulas I and III, the side chain at the 8-position may have o- or preferably β-configuration. The bromination reaction proceeds stereospecifically, ie. that the epimerization in the 8-position can be surprisingly low.

For the above-mentioned ergot alkaloids, it is preferable to use a ratio of 1 mole of ergot alkaloids to 1.2-1.5 moles of brominating agent, calculated on structure IV. The bromination reaction is preferably carried out using methylene chloride or another suitably chlorinated alkane having 1-3 carbon atoms as the solvent. Suitable reaction temperatures are e.g. from approx. -10 ° C to approx. + 100 ° C. At room temperature, surprisingly, satisfactory results can be obtained, e.g. a few minutes.

Any excess brominating agent in the reaction mixture can be e.g. deactivated by the addition of acetone and ammonium hydroxide.

The isolation of the brominated product is then facilitated. Conventional insulation techniques may be used, e.g. liquid / liquid extraction and column chromatography to recover the brominated product in pure form.

From the reaction mixture, 3-bromo-6-chloro-2-methyl-imidazo [1,2-b] pyridazine can be isolated. This can be returned to the brominating agent 20 by treatment with excess bromine in concentrated acetic acid.

The brominating agent may be formed initially by reacting 3-bromo-6-chloro-2-methyl-imidazo [1,2-b] pyridazine or 6-chloro-2-methyl-imidazo [1,2-b] pyridazine with a excess bromine in concentrated acetic acid and isolation of the resulting precipitate.

The bromination of 6-chloro-2-methyl-imidazo [1,2-b] pyridazine is described by Kobe et al. in Tetrahedron, 24, 239 (1968), but there is no indication at this point that the bromine complex formed could be used as a brominating agent. 3-Bromo-6-chloro-2-methyl-imidazo- [1,2-b] pyridazine can be prepared as described in the above-mentioned article in Tetrahedron and can be brominated analogously to the bromination of 6-chloro-2-methyl -imidazo [1,2-b] pyridazine and the bromine complex can be purified by conventional means. The yield of brominating agents can conveniently be increased by brominating any unreacted starting material in the bromine complex. The complex can be further purified by recrystallization of acetic acid, washing the crystals with ether and drying, e.g. at 30 ° C in vacuo. The complex may contain more bromine than 5 given in Formula IV, e.g. in the form of hydrogen bromide.

The process of the present invention is further illustrated by the following examples, in which all temperature indications are uncorrected: EXAMPLE 1 10 2-Bromo-9,10-dihydroergotamine 0.584 g (1 mmol) of 9,10-dihydroergotamine is dissolved in 20 ml of methylene chloride. The solution is stirred and 0.612 g (1.5 mmol) of 3-bromo-6-chloro-2-methyl-imidazo [1,2-b] pyridazine dibromide is added in 180 ml of methylene chloride. After the mixture is stirred for 2 minutes at room temperature, 10 ml of acetone and 100 ml of 2% aqueous ammonium hydroxide are added. The methylene chloride phase is separated and the aqueous phase is extracted twice with 200 ml of methylene chloride each time. The combined methylene chloride extracts are evaporated to dryness. The residue obtained is placed on a column containing 50 g of silica gel. Elute 20 using methylene chloride containing 5% ethanol as the eluant 0.23 g of 3-bromo-6-chloro-2-methyl-imidazo [1,2-b] pyridazine.

Further elution gives 0.33 g of 2-bromo-9,10-dihydroergotamine (yield 50% of theory), mp 198-200 ° C, [α] D = -84 ° (c 25 = 1 in pyridine) .

By substituting 9,10-hydroergotamine with an equivalent amount of: a) a-ergosine, b) 9,10-dihydro-a-ergosine, c) a-ergocryptin, d) α-ergosinin, e) ( 5R, 8R) -lysergic acid diethylamide or f) 1-methyl-9,10-dihydrolyseric acid methyl ester are obtained respectively 5a) 2-Bromo-ct-ergosine, yield 81% of theoretical, mp 183-185 ° C (decomposition), [a ] + = -91.6 ° (c = 1 in chloroform), b) 2-bromo-9,10-dihydroergosine, yield 69% of theory, m.p. 186-188 ° C (decomposition), [a] p ° = -40 ° (c = 1 in methanol), c) 2-bromo-α-ergocryptin, yield 75% of theory, m.p. 215-218 ° C, [a] p ° = -98 ° (c = 1 in pyridine), [a] p ° = -195 ° C (c = 1 in methylene chloride), d) 2-bromo-o-ergosinin, yield 70% of theoretical, melting point 188-190 ° C, [a] p ° = + 403 ° (c = 1 in chloroform), e) (5R, 8R) -2-bromoseric acid diethylamide, yield 73.4% of theory after recrystallization of ether from the dry residue before chromatography, melting point 122-125 ° C, [<x] p 2 = 17 ° (c = 1 in pyridine) and f) 2-bromo-1-methyl-9,10-dihydroxylic acid methyl ester, yield 65% of theory after recrystallization of dry residue before chromatography of methanol / water (85:15 (v / v)), m.p. 166-168 ° C, 20 [a] p 2 = "94 ° (c = 0.5 in chloroform).

EXAMPLE 2

Recovery of 3-bromo-6-chloro-2-methyl-imidazo [1,2-b] pyridazin dibromide 0.23 g (0.93 mmol) of 3-bromo-6-chloro-2-methyl-imidazo [1 The 2-b] pyridazine 25 obtained as described in Example 1 is dissolved in 2 ml of concentrated acetic acid and treated with 1.39 mmol of elemental bromine. After a short time, the reaction mixture crystallizes 3-bromo-6-chloro-2-methyl-imidazo [1,2-b] pyridazine dibromide. This is filtered off and dried.

Yield 0.38 g (89.4% of theory), mp 217-220 ° C.

Claims (2)

149956 1. A process for the preparation of ergot alkaloids of general formula I R1 R3 I R4V10 | (<3> nLN "CH3 N -J-Br J * i wherein R represents carboxyl, C1-6 alkoxycarbonyl, amido, C1-5 alkylamido, C1-6 dialkylamido or an amido group of general formula II a OH _ -co-NH _ 0 =! - N ^ j = 0 II IT V 3 b where R represents C 1-6 alkyl and R represents C 1-6 alkyl or benzyl, 2 3 10. represents hydrogen or C 1-4 alkyl, and either R represents hydrogen and R represents hydrogen or C 1-4 alkoxy, or R and R together represent a single bond, characterized in that a compound of the general formula III R 1 15