FI66185C - NYTT FOERFARANDE FOER BROMERING AV FOERENINGAR - Google Patents

Description

--— 1 ri NOTICE OF PUBLICATION, „„ Λ _ JKi ™ ^ utlAcgningsskript 66185 W Patent ceddelat (51) K * ji / hta3 C 07 o 457/04, 519/02 FINLAND — FINLAND («) ....... .. »792957 (B) Η · Ιμ« Ι * Μ-ΑμΒΜ ** | 24.09.79 'Fl' (23) GHUfkatari ·! 24.09.79 (41) TMhcHUmM — Mmcq «iw« i 27.03 80

Patanttl. It rtHittrihilUtm

Matane · ech rfhUrttyfi — n ^ AwataT '^ d ^ «& aSStoiifct ·> JK 31.05.84 (32) (33) (31) ryyd * qretwHwt-SUN ^ lertw 26.09.78 Yugoslavia-Yugoslavia (YU) P 2268/78 ( (71) Sandoz AG, Basel, Switzerland-Switzerland (CH) (72) Milan Jurgec, Ljubljana, Rudolf Rucman, Ljubljana,

Branko Stanovnik, Vrhnika, Miha Tisler, Ljubljana,

Jugos1 av i a-Jugos1 av ien (YU) (74) Oy Kolster Ab (54) New method for bromination of compounds -N now for the bromination of compounds

The invention relates to a novel bromination process by which particularly sensitive compounds, such as ergot alkaloids, e.g. β-ergocryptine, can be selectively brominated.

Bromatao (-ergocryptine with a weak brominating agent is known, e.g. N-bromosuccinimide, N-bromo-caprolactam, N-bromophthalamide and bromine / dioxane / see Swiss patent CH 507 249 \ J. bromination of ergocryptine using pyrrolidone- (2) -hydrothribromide or N-bromosaccharin in the presence of a radical initiator (German application DE 2 752 532).

The present invention relates to a new process for the preparation of compounds of formula 661 85 2

Ri

* 3YS

n -C H 3 I

H-L. Br * 2 having a carboxyl, C 1-5 alkoxycarbonyl, amido, C 1-4 alkylamido, di-C 1-4 alkylamido or amido radical of formula

H ° H

, · <>: JtV

-CO-NH ---- Y XI

0 = J-N 1 = 0 R.

D

wherein R a is C 1-4 alkyl, is C 1-4 alkyl or benzyl, R 2 is hydrogen or C 1-4 alkyl, R 3 is hydrogen and R 4 is hydrogen or C 1-4 alkoxy or R 3 and together form a single bond. The process is characterized in that a compound of formula R1 # 111 -ch3 IV-R2 66185 3 wherein R1, R4 / R3 and R2 are as defined above is brominated with 3-bromo-6-chloro-2-methyl- imidazo [1,2-b] pyridazine bromine complex.

The brominating agent used in the process can be prepared, for example, by reacting 3-bromo-6-chloro-2-methylimidazo [1,2-b] pyridazine or 6-chloro-2-methylimidazo [1,2-b] pyridazine with an excess of bromine. The product is believed to comprise 3-bromo-6-chloro-2-methylimidazo [1,2-b] pyridazine dibromide of formula Γ j!

! CH

I H J Br »IV

Cl L N_J _ Br 2 i This brominating agent has particularly advantageous properties. For example, it is selective and does not result in large amounts of by-products; it is soluble in a large number of organic solvents, e.g. halogenated solvents, and is stable in solution; the excess brominating agent can be easily disposed of and the brominated product can be easily separated from the reaction mixture. The brominating agent can be easily regenerated from the 3-bromo-6-chloro-2-methylimidazo [1,2-b] pyridazine formed in the reaction.

In formulas I and III, the side chains at the 8-position may have the oC or preferably ft configuration. The bromination reaction proceeds stereospecifically, so that the epimerization at the 8-position is unexpectedly low.

For the above-mentioned ergot alkaloids, it is preferable to use a ratio of 1 mole of ergot alkaloid per 1.2 to 1.5 moles of brominating agent (of formula IV). The bromination reaction is preferably carried out using methylene chloride or another suitable chlorinated C 1-3 alkane as solvent. A suitable reaction temperature is, for example, between about -10 ° C and about 100 ° C. Surprisingly, satisfactory yields are obtained at room temperature, for example in a few minutes.

Any excess brominating agent in the reaction mixture can be deactivated by adding, for example, acetone and ammonium hydroxide. This makes it easier to isolate the brominated product. Conventional isolation methods can be used, for example, liquid / liquid extraction and column chromatography to obtain the brominated product in pure form.

3-Bromo-6-chloro-2-methylimidiazo [1,2-b] pyridazine is isolated from the reaction mixture. This can be converted back to a bro flavor by treating with excess bromine in concentrated acetic acid.

The brominating agent can be prepared initially by reacting 3-bromo-6-chloro-2-methylimidiazo [1,2-b] pyridazine or 6-chloro-2-methylimidiazo [1,2-b] pyridazine with an excess of bromine in concentrated form. in acetic acid and recovering the precipitate formed.

The bromination of 6-chloro-2-methylimidiazo [1,2-th] pyridazine has been described by Kobe et. et al., Tetrahedron, 24, 239 (1968), but there is no mention here that the bromine complex formed could be used as a brominating agent. 3-Bromo-6-chloro-2-methylimidiazole-1,2-b-pyridazine can be prepared as described and described in Tetrahedron, supra, in a manner analogous to 6-chloro-2-methyl-imidazo-1, The bromination and bromine complex of 2-thiopyridazine are purified in the usual manner. The yield of brominating agent can be suitably increased by bromination of any unreacted starting material in the bromine complex. · The complex can be further purified by crystallization from acetic acid-Posta, washing the crystals with ether and drying in vacuo at about 30 ° C. The complex may contain more bromine, e.g. as HBr, than the amount indicated by formula IV.

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 is stirred and 0.612 g (1.5 mmol) of 3-bromo-6-chloro-2-methylimidiazole-1,2-thipyridazine dibromide in 180 ml of methylene chloride are added.

After stirring 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 off and the aqueous phase is extracted twice with 200 ml portions of methylene chloride. The combined methylene chloride extracts are evaporated to give a dry residue.

5,6185 This residue is applied to a column containing 50 g of silicic acid gel. Using methylene chloride containing 5% ethanol as eluent, 0.23 g of 3-bromo-6-chloro-2-methylimidiazo [1,2-t] pyridazine are eluted.

Further elution gives pure 2-bromo-9,10-dihydro-ergotamine; 0.33 g; 50% catch. Melting points 198-200 ° and -84 ° (c = 1, pyridine).

By replacing 9,10-dihydroergotamine with an equivalent amount of: a) rergosin; b) 9,10-dihydro-N-ergosine; c) o6 * ergocryptine; d) oi.- ergo sini in ia; e) (5R, 8R) -licergic acid diethylamide; or f) 1-methyl-9,10-dihydrolysergic acid methyl ester, to give, respectively: a) 2-bromo-o-ergosine; 81% yield, m.p. 183-185 ° (decomposes), = -91.6 °, (c = 1, chloroform); b) 2-bromo-9,10-dihydroergosin; 69% yield, m.p. 186-188 ° (dec.) = -40 ° (c = 1, methanol); c) 2-bromo-> 6-ergocryptine; 75% yield, m.p. 215-218 °, ~ ~ 98 ° »(c = 1, pyridine); -195 °; (c = 1, methylene chloride); d) 2-bromo-? -ergosinine; 70% yield, m.p. 188-190; C ° ^ D ^ = + t + ° 3 °; = 1> chloroform); e) (5R, 8R) 2-bromo-lysergic acid diethylamide; 73.4% yield after recrystallization of the dry residue from ether before chromatography, m.p. 12 2-125 °; + 17 ° (c = 1, pyridine); f) 2-bromo-1-methyl-9,10-dihydrolysergic acid methyl ester; 65% yield after recrystallization of the dry residue before chromatography on a methanol / water mixture (85/15, v / v), m.p. 166-168 °; ~ 94 ° (c = 0.5, chloroform).

Example 2: Regeneration of 3-bromo-6-chloro-2-methylimidazo [1,2-b] pyridazine dibromide Q, 23 g (0.93 mmol) of 3-bromo-6-chloro-2-methylimidazo The 1,2-b-pyridazine obtained from Example 1 is dissolved in 2 ml of concentrated acetic acid and treated with 1.39 mmol of elemental bromine. After some time, 3-bromo-6-chloro-2-methylimidazole, 2-b, pyridazine dibrinide crystallizes out of the reaction mixture. This is filtered off and dried. Yield 0.38 g, (89.4%), m.p. 217-220 °.

Claims (3)

A process for the preparation of compounds of formula f1 in V-. Wherein H is carboxyl, C 1-6 alkoxecarbonyl, amido, C 1-6 alkylamido, di-C 1-4 alkyl amido or an amido radical of the formula OH -CO-NH --- f T | Where R a is C 1-4 alkyl, R 1 is C 1 -C 4 alkyl or benzyl, R 2 is hydrogen or C 1-4 alkyl, R 3 is hydrogen and R 4 is hydrogen or C 1-4 alkoxy or R 2 and R. together form a single bond, characterized in that a compound of the formula i1 * 3 yS, N-CH- ΓΎτ view N --- 1 wherein R,, R, R * and R with a 12,4-bromo complex of 3-bromo-6-chloro-2-methyl-imidazozyl, 2β] pyridazine. 2. A process according to claim 1, characterized in that the compound of formula III is 9,10-dihydroergotamine, ergosine, 9,10-dihydro-C + - ergosine, o-ergocryptin, θ , 8R) -lysergic acid diethylamide or 1-methyl-9,10-dihydrolysergic acid methyl ester. Method according to claim 1, characterized in that the compound of formula III is ergocryptin.