CS215027B2 - Method of preparation of 2-bromergot alcaloids - Google Patents

Abstract

A process for the production of a compound of formula I <IMAGE> wherein R1 is carboxyl, alkoxy- (C1-5)carbonyl, amido, alkyl(C1-5)amido, di(alkyl(C1-5))amido or an amido radical of formula II <IMAGE> wherein Ra is alkyl(C1-4), Rb is alkyl(C1-4) or benzyl, and R2 is hydrogen or alkyl(C1-4), and either R3 is hydrogen and R4 is hydrogen or alkoxy(C1-4> or R3 and R4 together are a single bond, is characterised in that a compound of formula III <IMAGE> wherein R1 to R4 are as defined above, is brominated with a bromine complex of 3-bromo-6-chloro-2-methyl- imidazo[1,2-b]pyridine having the formula IV: <IMAGE>

Description

The invention relates to a bromination process, in particular selective bromination of sensitive compounds such as ergot alkaloids, for example α-ergocryptin.

It is known in the literature to brominate α-ergocryptine with mild brominating agents such as N-bromosuccinimide, N-bromocaprolactam, N-bTOimphitalamide and bromine in dioxane (see Swiss Patent No. 507,249). Recently, bromination of α-ergocryptine with pyrroliden- (2) -hy drotribromide or N-bromosaccharin in the presence of a radical initiator has also been proposed (DOS 2,752,532).

SUMMARY OF THE INVENTION The present invention provides a novel and preferred process for the preparation of 2-bromoergotic alkaloids of formula (I) wherein:

R 1 is carboxyl, C 1 -C 5 alkoxycarbonyl, amido, C 1 -C 5 alkylamido, C 1 -C 5 dialkylamido, C 1 -C 5 dialkylamido, or a group of formula (II),

where

R _a is C 1 -C 4 alkyl,

R _b is C 1 -C 4 alkyl or benzyl a

R 2 is hydrogen or C 1 -C 4 alkyl and either R 3 is hydrogen and R 4 is hydrogen or C 1 -C 4 alkoxy, or R 5 and R 6 together form a bond, by reacting a compound of formula III,

wherein R 1 -R 1 are as defined above, with a brominating agent, characterized in that the brominating agent is a 3-bromo-6-chloro-2-methylimidazo [1,2- b] pyridazine complex with bromine.

This brominating agent can be prepared, for example, by reacting 3-bromo-6-chloro-2-methylimidazo-1,2-bpyridazine or 6-chloro-2-methylimidazo [1,2-b] pyridazine with an excess of bromine. The product of this reaction is believed to be the 3-bromo-6-chloro-2-methylimidazo [1,2-b] pyridazinedibromide of formula IV.

This brominating agent exhibits particularly advantageous properties. For example, it is selective and does not lead to large amounts of by-products, is soluble in a variety of organic solvents, for example halogenated solvents, and is stable in solution. The excess brominating agent can be readily decomposed and the brominating product can easily be separated from the reaction mixture. The brominating agent can be readily regenerated from the 3-bromo-6-chloro-2-methylimidazo [1,2- b] pyridazine formed in this reaction.

In the compounds of formulas I and III, the side chain may have an 8a- or preferably / configuration. Bromination occurs stereospecifically such that epimerization at position 8 is unexpectedly minimal.

For the above ergot alkaloids, it is preferable to use a ratio of 1 mole of ergot alkaloid to 1.2-1.5 mole of brominating agent (based on structure IV). The bromination reaction is preferably carried out using methylene chloride or other suitable chlorinated alkane having 1 to 3 carbon atoms as solvent. Suitable reaction temperatures are, for example, temperatures from -10 to about 100 ° C. Surprisingly, at room temperature, sufficient yields can be achieved, for example, within minutes.

Any excess brominating agent in the reaction mixture can be deactivated by the addition of, for example, acetone or ammonium hydroxide. Isolation of the accumulated product is then facilitated. Conventional isolation methods, such as liquid-liquid extraction and column chromatography, may also be used. The bromination product is thus obtained in pure form.

3-Bromo-6-chloro-2-methyl-imidazo [1,2-b] pyridazine can be isolated from the reaction mixture. This compound can be converted back to the brominating agent by reaction with an excess of bromine in concentrated acetic acid.

The brominating agent can first be prepared by reacting 3-bromo-6-chloro-2-methyl-imidazo [1,2-b] pyridazine or 6-chloro-2-methyl-imidazo [1,2-b] pyridazine with an excess of bromine in concentrated acetic acid and separating the resulting precipitate.

The bromination of 6-chloro-2-methylimidazo [1,2-b] pyridazine has been described by Kobe-ai. in Tetrahedron 24, 239 (1968), but no mention was made 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 previously reported in Tetrahedron and can be accumulated in an analogous manner to 6-chloro-2-methyl- imidazo [1,2-b] pyridazine and complex with. . bromine is purified in a conventional manner. The yield of the brominating agent can be advantageously increased by bromination of unreacted starting material complexed with bromine. The complex can be further purified by recrystallization from acetic acid, washing the crystals with ether, and drying, for example, at 30 ° C under vacuum. The complex may further comprise additional bromine, for example in the form of HBr.

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

Example 1

2-bromo-9,10-dihydroergotamine

0.584 g (1 mmol) of 9,10-dihydroergotamine are dissolved in 20 ml of methylene chloride. The solution was stirred and 0.612 (1.5 mmol) of 3-bromo-6-chloro-2-methyl-imidazo [1,2-b] pyridazinedibromide in 180 ml of methylene chloride was added. The methylene chloride phase was separated and the aqueous phase was extracted twice with 200 ml portions of methylene chloride and the combined methylene chloride extracts were concentrated to give an anhydrous residue.

This residue is applied to a column containing 50 g of silica gel. Use of methylene chloride containing 5% ethanol as eluent gave 0.23 g of 3-bromo-6-chloro-2-methylimidazo [1,2-b] pyridazine.

Further elution gave 2-bromo-9,10-dihydroergotamine, 0.33 g, 50% yield, m.p.

200 DEG and [.alpha.] D @ ²⁰ -84 DEG (c = 1, pyridine).

Replacement of 9,10-dihydroergotamine for an equivalent amount

(a) α-ergosine; (b) 9,10. ^, -diby ^ (^ ^^ ^ - ^ a-erg ₎

(c) α-ergocryptin,

(d) α-ergosinin,

(e) lysergic acid [5R, 8R] diethylamine;

(f) 1-methylb9,10-dihydrolysergic acid methyl ester, obtained by:

a) 2-bromo-a-ergosine, 81% yield, mp 183-185 ° (dec.), [a] ^'2 0 = -91.6 ° (c = 1, chloroform;

b) 2-bromo-9,10-dihydroergyme, 69% yield, mp 186-188 ° (dec.), [α] _D 20 = -40 ° (c = 1, methanol);

c) 2-bromo-α-ergocryptine, 75% yield, mp 215-218 °.

I «] d ^{2 ()} = -98 ° (c = 1, pyridine);

[.Alpha.] D @ 20 = -195 DEG (c = 1, methylene chloride);

d) 2-bromo-1-ergosinium, 70% yield, mp 188-190 °, [α] _D 20 = + 403 ° (c = 1, chloroform);

(e) (5R, 8R) 2-Bromo-lysergic acid diethylamide, 73.4% yield after crystallization of an anhydrous residue from ether before chromatography, mp 122-125 °, [α] _D 20 = + 17 ° (c = 1, pyridine);

f) 2-bromo-1-methyl-9,10-dihydrolysergic acid methyl ester, 65% yield after crystallization of the anhydrous residue before chromatography from methanol / water (85: 15 by volume), mp 166-168 °, [α] _D ² [.Alpha.] D = 94 DEG (c = 0.5, chloroform).

Example 2

Regeneration of 3-bromo-6-chloro-2-methylimidazo 1,2-b] pyridazinedib omide

0.23 g (0.93 mmol) of 3-bromo-6-chloro-2-methyl-1-imidazo [1,2-b] pyridazine obtained from Example 1 is dissolved in 2 ml of concentrated acetic acid and treated with 1.39 mmol of bromine. After a short period of time, 3-bromo-6-chloro-2-methylimidazo [1,2-b] pyridazinedibromide crystallizes from the reaction mixture. The product was filtered off and dried. Yield 0.38 g (89.4%), mp 217-220 °.

Claims (2)

A process for the preparation of 2-bromoergotic alkaloids of formula I, wherein Ri is carboxy, alkoxycarbonyl of 1-5 carbon atoms ⁷ alkoxy, amido, alkylamido of 1 to 5 carbon atoms, dialkýlamidosk.upina having 1-5 carbon atoms in each alkyl or a group of formula II wherein R _a is C 1 -C 4 alkyl, R _b is C 1 -C 4 alkyl or benzyl, and R 2 is hydrogen or C 1 -C 4 alkyl and either R 3 is hydrogen and R 1 is hydrogen or C 1 -C 4 alkoxy, or R 3 and R 4 are taken together to form a bond, by reacting a compound of formula III, ^R 2 (III) wherein R 1 to R 1 are as defined above, with a brominating agent, characterized in that a 3-bromo-6-chloro-2-methylimidazo [1,2-b] pyridazine-bromine complex is used as the bulk reagent. 2. A process according to claim 1, wherein the starting compound of formula (III) is [alpha]-ergocryptine.