Note: Descriptions are shown in the official language in which they were submitted.
28Q3~3
The present invention relates to brominating
processes, especially for selectively brominating sensi-
tive compounds such as ergot alkaloids, e.g. ~-ergocryp-
tine.
It is known to brominate ~-ergocryptine with a
mild brominating agent, e.g. N-bromosuccinimide,
N-bromo-caprolactam, N-bromophthalamide
and bromine/dioxane [see Swiss Patent No 507249]. It has
also been recently proposed to brominate ~-ergocryptine
using pyrrolidone-(2)-hydrotribromide or N-bromosaccharin
in the presence of a radical lnitiator (German Offenlegungs-
schrift 2752532).
The present invention provides an novel and advan-
tageous process for the production of a compound of formula
R ~
N-C~I I
N - ~r
t~2
~2t~Q3~
- 2 - 118-3377
wherein Rl is carboxyl, alkoxy(Cl 5)carbonyl, amido,
alkyl(Cl 5)amido, di(alkyl(Cl 5))amido or an
amido radical of formula II
R OH
-Co-NH - - ~ ~ J II
H
`~
wherein Ra is alkyl(Cl_4),
~ is alkyl(Cl 4) or benzyl, and
~2 is hydrogen or alkyl(Cl 4), and
either ~3 is hydrogen and R4 is hydrogen or alkoxy~Cl 4)
or R3 and R4 together are a single bond,
characterised in that a compound of formula III
~-C H3
N
R2
wherein Rl to R4 are as ~efin~fl ahove,
is brominatecl with a bromine complex of 3-bromo-6-chloro-
2-methyl-imiclazo[1,2-b]pyridazine.
.
:~
. .
,
~128~38
- - 3 - 118-3377
This brominating agent may for example be prepared
by reacting 3-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyrida--
zine or 6-chloro-2-methyl-imidazo~1,2-b]pyridazine with
excess bromine. The product is believed to comprise 3-bromo-
6-chloxo-2-methyl-imidazo[1,2-b]pyridazine dibromide of
formula IV
~ C1 ~ ,~ ~ Br ~ 2 IV
The brominating agent possesses especialls~ advan-
tageous properties. For example it is selective and does
not lead to large amounts of side products; it is soluble
in a wide range of organic solvents e.g. halogenated sol-
vents and is stable in solution jt excess brominating agent
may be easily destroyed and the brominated product can be
easily separated from the reaction mixture. The brominating
agent may be easily regenerated from 3-bromo-6-chloro-2-
methyl-imidazo[l~2-b~pyridazine formed in the reaction.
In formulae I and III the side chain in the 8 posi-
tion may have the ~ or preferably the ~ configuration. The
brominating reaction proceeds stereospecifically in that
epimerisation at the 8 position may be unexpec~edly minimal.
For the above mentioned ergot alkaloids, it is
,
.
r . : : .
_ 4 _ ~12`8~38
preferred to use a ratio of 1 mole of ergot alkaloid to 1.2 to
1.5 moles of brominating agent (based on structure IV). The
brominating reaction is preferably effected using methylene
chloride or another appropriate chlorinated alkane (Cl 3) as
solvent. Suitable reaction temperatures are for example from
about -10C to about 100C. At room temperature satisfactory
yields may be surprisingly obtained, for example in a
few minute 5 .
Any excess brominating agent in the reaction mix-
ture may be deactivated by the addition, for example, ofacetone and ammonium hydroxide. The isolation of the bromi-
nated product is then facilitated. Conventional isolation
methods may be used, for examFle, liquid/liquid extraction
and column chromatography, to obtaln the brominated pro-
duct in pure form.
From the reaction mixture 3-bromo-6-chloro-2-methyl-
imidazo[l,2-b3pyridazine may be isolated. This may be conver-
ted back into the brominating agent by treatment with excess
bromine in concentrated acetic acid.
The brominating ag~nt may be inltially produced by
reacting 3-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine
or 6-chloro-2-methyl-imidazo[1,2-b]pyridazine with excess
bro~ine in concentrated acetic acid, and collecting the re-
~ultant precipitate.
The bromination of 6-chloro-2-methyl-imidazo[1,2-b3
pyridazine has been described by Kohe et al Tetrahedron,2~,
~28~3~
-- 5 --
239 (1968), but there is no indication therein that the
bromine complex formed could be used as a brominating
agent. 3-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine
may be prepared as described in the above-mentioned Tetra-
hedron article and may be brominated in analogous manner tothe bromination of 6-chloro-2-methyl-imidazo[1,2-b]pyri-
dazine and the bromine complex purified in conventional
manner. The yield of brominating agent may be conveniently
increased by brominating any unreacted starting material
in the bromine complex. The complex may be purified
further by recrystallization from acetic acid, washing the
crystals with ether and drying, e.g., at 30C in a vacuum.
The complex may contain further bromine over that
represented by structure IV~ e.g., in the form of HBr.
In the following examples all temperatures are in
degrees Centigrade and are uncorrected.
112~3~38
- 6 - 118-3377
EXP~SPLE 1: ~
0.584 g (1 mMol) 9,10-dihydroergotamlne are dissol-
ved in 20 ml methylene chloride. The solution is stlrred
and 0.~12 g (l.S m Mol) 3-bromo-6-chloro-2-methyl-imida~o-
5 [1,2-b]pyrldazine-dibromlde in 180 ml methylene chloride
are added. After the mixture haR been stirred for 2 minutes
at room temperature, 10 ml acetone and lOo ml 2% aqueous
c~mmonlum hydroxide are added. The methylene chloride phase
i8 separate~ off and the aqueous phase is extracted twlce
with 200 ml portions ofmethylene chlorlde. ~he o~ned nethylene
chloride extracts are cDncentrated to give a dry residue.
Thls resldue ls applied to a column
contalning 50 g of slllcagel. Uslng an eluant of methylene
chlorlde contalnlng 5% ethanol 0.23 g 3-bromo-6-chloro-2-
methyl~lmidazo[l,2-b]pyrldazlne are eluted.
Further elutlon yield~ pure 2-bromo-9,10-dlhydro-
ergotamlner 0.33 g,So% yleld. M.Pt. 198-200 and []D
-84 (c= 1, pyridlne).
Replacing the 9,10-dlhydroergotamine wlth an equl-
2~ valent amount o~:a) a-ergosine;
b) 9,10-dihydro-a-ergoslne;
c) a-ergocryptine;
d) ~-ergoslnine;
e~ (5R, 8R) lysergic acld diethylc~mide; or
f) l-methyl-9,lo-dlhydrolysergic acid methyl ester,
r
- , ;
~ '.'' ''' ~ , ': .
112~3~3~
- 7 - 118-3377
there are obtained, respectively:~
a) 2-bromo-~-ergos~ne; 81% yield, M.pt. 183-185 (decomp)
[]D = ~ 91.6, (c = 1, chloroform);
b) 2-bromo-9,10-dihydroergosine; 69~ yield, M.pt. 186-188
(decomp) [a]20 = - 40 (c = 1, methanol~;
c) 2-bromo-~-ergocryptine; 75% yield, M.pt, 215-218
[~]20= _ 98; (c = 1, pyridine); [~]D = -195; (c = 1,
methylene chloride~;
d) 2-bromo-a-ergosinine; 70% yield, M.pt. 188-190; [~]D
= + 403i (c = 1, chloroform);
e) (5R, 8R) 2-bromo-lysergic acid diethyl amide; 73.4~ yield
after recrystallization from ether of the dry resid~le before
chromatography, M.pt. 122-125; ~a)20 = + 17 (c - 1, pyri-
dine);
15 f) 2-bromo-1-methyl-9,10-dihydrolysergic acid methyl ester;
65~ yield after recrystallization of the dry residue before
chromatography from methanol/water (85:15 by volume), ~.pt.
166-168; ~]20 = _ 94 (c = 0,5, chloro~orm).
EXAMPLE 2: Reqeneration of 3-hromo-6-chloro-2-~eth~l-imi-
.
_azo[1,2-b]pyrid~zlne dibromlde
0.23 g (0.93 mMol) 3-bromo-6-chloro-2-methyl-imidazo
[1,2-b]pyridazine obtained from Example 1 is clissolved in 2 ml
concentrated acetic acid and treated with 1.39 n~lol elemen-
tal bromine. Fromtthe reaction mixture crystallizes out
25 after a little while 3-bromo-6-chloro-2-methyl-imidaæo[1,2-b~
pyridazine dibromide. Thls is filtered off and dried~ Yield
- 0.38 g, (~9.4%), M.pt 217-220.
.
