NL7907122A - Bromination method. - Google Patents

Description

. 1 • **

V

SANDOZ AG, in Basel, Switzerland.

Bromination process.

The invention relates to bromination processes, in particular for the selective bromination of sensitive compounds, such as ergot alkaloids, for example α-ergocryptine.

It is known to bromine α-ergocryptine with a mild brominating agent, for example N-bromosuccinimide, N-bromo-caprolactam, N-bromophthalamide and bromo-dioxane (see Swiss Patent 507,249). It has also recently been proposed to bromine α-ergocryptine in the presence of a radical initiator with pyrrolidone- (2) -hydrotribromide or N-bromine saccharin (German Offenlegungsschrift 10 2,752,532).

The invention provides a new and advantageous process for the preparation of a compound of formula 1, wherein R 1 is a carboxyl, alkoxy (C 1 carbonyl, amido, alkyl (C 1) amido, di (alkyl (C .)) amido-JL-b 1-b Ib or an amido group of formula 2, wherein R represents an alkyl group with d 15 at most 4 carbon atoms and R 2 also represents an alkyl group with up to 4 carbon atoms or a benzyl group and R 4 represents a hydrogen atom or an alkyl group with up to 4 carbon atoms and either R 1 represents a hydrogen atom and R 1 represents a hydrogen atom or an alkoxy group with up to 4 carbon atoms, or R 1 and R 1 together form a single bond 20, by a compound of formula 3, wherein R ^ -R ^ have the meaning indicated above, to bromine with a bromine complex of 3-bromo-6-chloro-2-methyl-imidazo / 1,2-b-pyridazine.

This brominating agent can be prepared, for example, by reacting 3-bromo-6-chloro-2-methyl-imidazo / 1,2-b-pyridazine 25 or 6-chloro-2-methyl-imidazo / 1,2-b7-pyididazine with an excess of bromine.

This product is believed to contain 3-bromo-6-chloro-2-methyl-imidazo / 1,2-b7 pyridazine dibromide of formula IV. This brominating agent has particularly favorable properties. For example, it is selective and does not result in large amounts of by-products, further it is soluble in a wide variety of organic solvents, for example halogenated solvents, and is stable in solution. In addition, the excess of their brominating agent can be easily decomposed 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 / 1,2-b / -pyridazine formed in the reaction.

In formulas 1 and 3, the side chain at the 8 position may have the α configuration, but this side chain preferably has the 10α configuration. The bromination reaction is so stereo-specific that epimerization at the 8-position is surprisingly low.

It is recommended to use a molar ratio of 1 mol ergot alkaloid to 1.2-1.5 mol brominating agent (based on the compound of formula 4) of the aforementioned ergot alkalides. It is recommended to carry out the bromination reaction using methylene chloride or another suitable chlorinated alkane with up to 3 carbon atoms as the solvent. Reaction temperatures suitable for use lie, for example, between about -10 and 100 ° C. It is noteworthy that satisfactory yields can be obtained at room temperature, for example in just a few minutes.

Any excess of the brominating agent, if any. in the reaction mixture. can be deactivated by adding, for example, acetone and ammonium hydroxide. Separation of the brominated product is then facilitated. Conventional isolation methods such as, for example, liquid-liquid extraction and column chromatography can be used to obtain the brominated product in its pure form.

3-Bromo-6-chloro-2-methyl-30-imidazo / 1,2-b-pyridazine can be separated from the reaction mixture. This can be converted into the brominating agent by treatment with excess bromine in concentrated acetic acid.

The brominating agent can be prepared initially by reacting 3-bromo-6-chloro-2-methyl-imidazo / 1,2-b / pyridazine or 6-chloro-2-methyl-imidazo / 1,2-b / pyridazine collect with excess broth in 7907122 * v 3 concentrated acetic acid and the precipitate formed.

Bromination of 6-chloro-2-methyl-imidazo / 1,2-b / pyridazine has been described by Kobe and med. Tetrahedron, 24, 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-b7 pyridazine can. be prepared in the manner described in the aforementioned article in Tetrahedron and may also be brominated in a similar manner to the bromination of 6-chloro-2-methyl-imidazo / 1,2-b / pyridazine and the bromine complex obtained may be purified in the usual manner. The yield of the brominating agent can be appropriately increased by brominating any unreacted starting material to the bromine complex. The complex can be further purified by recrystallization from acetic acid, washing the crystals formed with diethyl ether and drying, for example under reduced pressure at about 30 ° C. The complex may further contain even more bromine than the amount corresponding to formula 4, for example in the form of hydrogen bromide.

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

20

Example I

2-bromo-9,10-dihydroergotamine

Hen dissolved 0.584 g (1 mmol) of 9,10-dihydroergotamine in 20 ml of methylene chloride. This solution was stirred and 0.612 g (1.5 mole) of 3-bromo-6-chloro-2-methyl-imidazo / 1,2-b-7-pyridazine dibromide in 180 ml of methylene chloride were added thereto. After the reaction mixture was stirred for an additional 2 min at room temperature, 10 ml of acetone and 100 ml of 2% aqueous ammonium hydroxide were added. The methylene chloride phase was then separated and the water phase was extracted twice with 200 ml of 30 portions of methylene chloride. Then, the combined methylene chloride extracts were concentrated to give a dry residue.

This residue was applied to a column containing 50 g of silica gel. Using methylene chloride containing 5% ethanol as the eluent, 0.23 g of 3-bromo-6-chloro-2-methyl-imidazo / 1,2-b / 35 pyridazine were eluted.

7907122 4 '

Further elution gave 0.33 g (50% yield) of pure 2-bromo-9,10-dihydroergotamine, melting point: 198-200 ° C and / α7 ^ -84 ° (c = 1, pyridine).

By replacing the used 9,1O-dihydroergotamine 5 with an equivalent amount: a) α-ergosine; b) 9.1O-dihydro-α-ergosine; c) α-ergocryptine; d) α-ergosinine; 10 é) (5R, 8R) lysergic acid diethylamine or fi) the methyl ester of 1-methyl-9,10-dihydrolysergic acid, respectively: a) 2-bromo-a-ergosine, 81% yield, melting point: 183-185 ° C (dec.), / α7-7 ° = 91.6 °, (c = 1, chloroform).

B) 2-Bromo-9,10-dihydroergosine, 69% yield, mp 186-188 ° (dec.)

[alpha] 7β = -40 ° (c = 1, methanol), c) 2-bromo-a-ergocryptine; 75% yield, melting point: 215-218 ° C

/ a_7 ^ = * 98 °, (c = 1, pyridine), / a? ^ = -195 °, (c = 1, methyl chloride).

D) 2-bromo-a-ergosinine, 70% yield, melting point 188-190 °, -20 ° / op = 403, (c = 1, chloroform).

e) (5R, 8R) 2-bromo-lysergic acid diethylamine, 73.4% yield, after recrystallization of the dry residue from diethyl ether before carrying out the chromatographic purification, mp: 122-125 ° C, / a 7 ^ = + 17 ° 25 (c = 1, pyridine).

f) the methyl ester of 2-bromo-1-methyl-9,10-dihydrolysergic acid, 65% yield after recrystallization of the dry residue from a mixture of methanol and water (85:15 vol.) before carrying out the chromatographic purification, mp 166-168 ° / 7 ^ = -94 ° (c = 0.5 chloroform).

30

Example II

Regeneration of 3-bromo-6-chloro-2-methyl-imidazo / 1,2-b / pyridazine-dibro-amide.

0.23 g (0.93 mole) of 3-bromo-6-chloro-2-methyl-35-imidazo / 1,2-b-pyridazine obtained by the procedure of Example 1, 7907122, were dissolved in 2 ml of concentrated acetic acid and treat this solution with 1.39 in mol of elemental bromine. After some time, 3-bromo-6-chloro-2-methyl-imidazo / 1,2-b-pyridazine.dibromide crystallized from the reaction mixture. These crystals were filtered and dried. Yield: 0.38 g, (89.4%), melting point: 217-220 ° C.

% 7907122

Claims (6)

1. Compounds of formula 1, wherein R 1 is a carboxyl, alkoxy ((C 1 -5) carbonyl, amido, alkyl (C 1 -5) amido; di (alkyl (C 1 -6)) amido or an amido group of formula 2, wherein R represents an alkyl group with d up to 4 carbon atoms and R 1 also represents an alkyl group with up to 4 carbon atoms or a benzyl group and R 1 represents a hydrogen atom or an alkyl group having up to 4 carbon atoms and either R 1 represents a hydrogen atom and R 1 also represents a hydrogen atom or an alkoxy group having up to 4 carbon atoms or R 4 together form a single bond. 2. Process for the preparation of an aromatic compound, characterized in that a compound of formula 1, in which R 1 -R 1 has the meanings indicated in claim 1, is prepared by a compound of formula 3, in which R 1 -R 1 The meanings indicated above have to be brominated with a brominating agent which can 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. 3. Process according to claim 2, characterized in that bromination is carried out with a bromine complex of 3-bromo-6-chloro-2-methyl-imidazo 20 / 1,2-b7-pyridazine. Process according to claims 2 and 3, characterized in that α-ergocryptine is used as the compound of formula 3. 5. Method as described in the description and / or examples. 25 z / 7907122 1 R1 ¥ RV ', Η 1. λΧΓν — ch5 i — ί — er 1 h Ra OH —j ^ -r -CO —— NH ------ 0 ^ 0 = l —— N ^ J = 0 H ^ 'NRb 2 «1 r <sTu 1 ^ | A | / N- ch3 I 3 N-1 J rrr "] * W —- Ler J 4 7907122 SANDOZ AG, Basel, Switzerland