LU81714A1 - PROCESS FOR BROMINATING ALKALOIDS OF RYE ERGOT - Google Patents

Description

* D. 5o.799

δ "A" "J — 4 GftAND-DUCHÉ DE LUXEMBOURG

........ f ...... / * il · du o24 ... septsrnbDe .... l'9.79 ... 'Monsieur the Minister of National Economy and the Middle Classes

Book title: .........................................

Industrial Property Service

7 1 LUXEMBOURG

m ν /, ί ^ · * ii) s Application for an Invention Patent ................................. .................................................. .................................................. ............................

I. Request ..The ... company ,, di ta; ..... SANDOZ ..... SA, ..... A .... 4op2 BASEL, ..... Switzerland. «. .... represented (1) ... p.ar .... MQnsi.eur ..... a: acq.ues ...... üe.Muysei;. / ...... acting ... in ..... qualiM .... ae ... man -....................

... dated .............................................. .................................................. .................................................. .................................................. ................................................ (2 > drop off ........ this ... twenty-four ..... September ..... 19oo ..... sixty-ten ~ nine <$> at ....... 15 ............. .... hours, at the Ministry of National Economy and the Middle Classes, in Luxembourg: * 1. this request for obtaining a patent d invention relating to: .. ". Process ..... of ..... bromination, des, alkaloids ..... of ..... llergotde ..... rye", ".... ........ (4> d] ddckddèkhkÜiirl, / ÿ [Jl / (Is {/// nÏÜ {i) / Âd .................. .................................................. . (5) 2. the delegation of power, dated ...... ÈLE .............................. ................. on ... 21 ..... September ..... 197 9 3. description in French ........ language .................................... of the invention in two copies; 4 ........... U ............. drawing boards, in two copies; 5. the receipt of the taxes paid to the Luxembourg Registration Office on ..... 24 ..... September, .19 7 9 ................ .................................................. .................................................. .................................................. .........................

claims for the above patent application the priority of one (or more) application (s) of (6) .......................... patent ........................................... filed ^) in (7) . „XQugQsl & vle ............................................... ............................._ le ..... 2.6 ...... s.ep.t.eit ^ .re ..., l, 978 ........... (No ....... £,., 2.2,6.8. / 7.8.) ._____________________________________________________________________________________________________ (β) * in the name from ........ LKK ... LJUBLJANA. * „. ^^ ............................. .................................................. ........................................ (g) takes up residence for him / her and, if appointed, for its representative, in Luxembourg ....................................

..... 3.5., ..... bld ........ Royal ........................... .................................................. .......................................... do) requests the issue of a invention patent for the subject described and represented in the abovementioned appendices, - with postponement of this issue to ............... 6 ........... ...................month.

L · ..... agent ..................... l ....... r AJOOOdj.

II. Deposit Minutes

The above application for a patent for invention has been filed with the Ministry of National Economy and Medium-sized Companies, Industrial Property Service in Luxembourg, on: .. 2.4 ... se ptambre 1979 ..- · .. ......... · -. Pr. The Minister at ............. 15 ......... hours of the National Economy of the Middle Classes,

Mu 7 (“ft ~.“ I f} A 68007 __ \ ^ P. - ;. ÿ .ç: f! / _ D. 5ο.799

CLAIM OF PRIORITY

of the patent application / cfi / àéétÀéAi / uii / rfê / YOUGOSLAVIE * SEPTEMBER 26, 1978 Brief Description filed in support of a request for

PATENT

at

Luxembourg on behalf of: SANDOZ S.A.

> r »r» irr · "Bromination process for ergot alkaloids".

UUUI »i f

The subject of the present invention is a bromination process, in particular a process for the selective bromination of compounds such as ergot alkaloids, for example a-ergocryptine.

5 It is known to brominate oC-ergocryptine by means of a mild brominating agent, such as for example N-bromo-succinimide, N-bromo-caprolactarne, N-bromophthalimide or a mixture of bromine and dioxane (see Swiss patent 5072 ^ 9) · 3 German patent application No. 2 752 532 describes the bromination of oct-ergocryptine by 2-pyrrolidone trihydrobromide or by N-bromosaccharin, in presence of a radical initiator.

The new invention relates more particularly to a process for preparing the compounds of formula I

15 "J

vTVi (I) 20 N — iL Br R2 in which R .. represents a carboxy or carbamoyl group, a group

v X

25 alkoxycarbonyl of which the alkyl residue contains from 1 to

5 carbon atoms, an alkylcarbamoyl or dialkylcarbamoyl group in which the alkyl radicals each contain from 1 to 5 carbon atoms or a residue of formula II

30 P OH

1 0! ΡΠ

-CO-NH ---- K

TII (il 0 Ξ3 ___ Ν IrsO 1 2 where R ^ represents an alkyl group containing from 1 to 4 carbon atoms, and R ^ represents an alkyl group containing from 1 to 4 carbon atoms or a benzyl group, 5 1 * 2 represents a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms, and either represents a hydrogen atom and, in this case, R4 represents a hydrogen atom or an alkoxy group containing from 1 to 4 carbon atoms , t ÎO let R_ and R. together form a second bond, 3 4

characterized in that a compound of formula III is brominated

* 1 (III) 15 s 1? R2 20 in which R ^, R2 / R3 and R4 have the meanings already given, by reaction with a bromine complex of 3-bromo-6-chloro-2-methyl-imidazo [1,2-b] pyridazine.

%

To prepare this bromatization agent, it is possible, for example, to react 3-bromo-6-chloro-2-methyl-imidazo [1,2-b] pyridazine or 6-chloro “2-methyl-imidazo [1 , 2-b] pyridazine with excess bromine. The product obtained during this reaction probably contains 3-bromo-6-chloro-2-methyl-imidazo dibromide [1,2-b]

30 pyridazine corresponding to formula IV

A ^ / YH3 I I M ®r * ”(IV) cl“ —-— Br z 1 t “3 v This brominating agent has particularly advantageous properties. Thus, this compound is selective and does not give rise to the formation of large. quantities of secondary products; it is soluble in a large number of organic solvents, for example halogenated solvents and is stable in solution. The excess brominating agent can be easily removed and the brominated product obtained can be easily separated from the reaction mixture. The broating agent can be regenerated from the 3-bromo-6-chloro-2-methyl-imidazo „[1,2-b] pyridazine formed during the reaction.

In the compounds of formulas I and III, the # side chain in position 8 can have the configuration a or, preferably, the configuration ß. The bromination reaction is stereospecific, i.e. the epimerization at position 8 is weak.

For bromination of the rye ergot alkaloids specified above, it is preferable to operate in a ratio of 1 mole of rye ergot alkaloid to 1.2 to 1.5 mole of agent. bromination (based on formula Y). The bromination is carried out using, as solvent, methylene chloride or another suitable chlorinated alkane containing from 1 to 3 carbon atoms. The operation is advantageously carried out at a temperature between approximately -10 ° and approximately 100 °. When operating at room temperature, very satisfactory results are obtained, for example "! After a few minutes of reaction.

The excess of brominating agent present in the reaction mixture can be quenched by the addition, for example, of acetone and ammonia; this facilitates the isolation of the final brominated product. The reaction product can be isolated using known methods, for example by liquid / liquid extraction and by column chromatography; the brominated product thus obtained is pure.

3-Bromo-6-chloro-2-methyl-imidazo [1,2-b] if pyridazine can be isolated from the reaction mixture. This product can be transformed into a brominating agent by treatment with an excess of bromine in concentrated acetic acid.

To prepare the starting brominating agent, react 3-bromo-6-chloro-2-methyl-imidazo / 1,2-b_ / pyridazine or 6-chloro-2-methyl-imidazo / l , 2-b_7pyridazine with an excess of bromine in concentrated acetic acid, then the precipitate which has formed is collected.

Bromination of 6-chloro-2-methyl-imidazo / fl, 2-b_7 pyridazine has been described by Kobe et al. in Tetrahedron, 2k, f 239 (1968); however, this publication does not mention the use of the bromine complex as a brominating agent. To prepare 3-bromo-6-chloro-2-methyl-imidazo / “1,2-b7pyridazine, it is possible to proceed as described in the mentioned article of Tetrahedronj. This compound can be brominated by proceeding as for bromination of 6-chloro-2-methyl-imidazo / ~ l, 2-b_7pyridazine, then the bromine complex thus obtained is purified by known methods. The yield of brominating agent can advantageously be increased by brominating the starting material which has not reacted in the bromine complex. The complex can be purified by recrystallization from acetic acid, washing the crystals with ether and drying, for example at 30 ° C under reduced pressure. The complex may also contain bromine other than that represented by formula IV,. for example in the form of hydrobromic acid.

The following examples illustrate the present invention without in any way limiting its scope. The temperatures are all indicated in degrees Celsius and are given uncorrected.

Example 2-bromo-9,10-dihydroergotamine 3 ° 0.58 μg (1 mmol) of 9 × 10-dihydroergotamine is dissolved in 20 ml of methylene chloride. This solution is stirred and 0.612 g (1.5 mmol) of 3-bromo-6-chloro-2-methyl-imidazo / 1,2-b_ / pyridazine dibromide in 180 ml of methylene chloride is added. After stirring this mixture at room temperature for 52 minutes, add 10 ml of acetone and 100 ml of 2% ammonia. The methylene chloride phase is then separated, the aqueous phase is extracted twice with 200 ml of methylene chloride each time, the ex-5 traces of methylene chloride are combined and evaporated; a dry evaporation residue is thus obtained.

This residue is placed on a column of 50 g of silica gel and eluted with methylene chloride containing 5% ethanol. 0.23 g of 3-bromo-6-chloro-2-methyl-imidazo [1,2-b] pyridazine is thus obtained.

Continuing the elution, 0.33 g of pure 2-bromo-9,10-dihydro-ergotamine is obtained, which corresponds to a yield of 50%; it melts at 198-200 °; [cc] D - -84 ° (c = 1 in pyridine).

15 When 9.10-dihydroergotamine is replaced by an equivalent amount of a) a-ergosine, b) 9.10-dihydro-a-ergosine, c) a-ergocryptine, 20 d) a-ergosinine, e) diethylamide lysergic acid (5R, 8R), or f) methyl ester of l-methyl-9,10-dihydro-lysergic acid, h we obtain respectively 25 a) 2-bromo-a-ergosine with a yield of 81%; 20 ° F = 183-185 ° (with decomposition); [a] D = “91.6 ° (c = 1 in chloroform); b) 2-bromo-9,10-dihydroergosine with a yield of 69%; F = 186-188 ° (with decomposition); [ex] D = 30 -40 ° (c = 1 in methanol); c) 2-bromo-cc-ergocryptine with a yield of 75%; Mp 215-218 °; [α1 ^ ° = ~ 98 ° î (c = 1 in pyridine); [α] β = -195 °; (c = 1 in methylene chloride); d) 2-bromo-a-ergosinine with a yield of 70%; 20 35 F = 188-190 °; [cxl ^ = +403; (c - 1 in chloroform); 6 e) (5R, 8R) 2-bromo-lysergic acid diethylamide with a yield of 73.4% after recrystallization from the ether of the dry residue before chromatography; M = 122-125 °; [<x] £ = + 17 ° (c = 1 in pyridine); f) the methyl ester of 2-bromo-1-methyl-9,10-dihydrolysergic acid with a yield of 65% after recrystallizing the dry evaporation residue, before chromatography, from a mixture of methanol 10 and water (ratio 85:15 by volume); M = 166-168 °; 20 [α] ρ "“ 94 ° (c = 0.5 in chloroform).

Example 2 Regeneration of 3-bromo-6-chloro-2-methyl-imidazo [1,2-b] pyridazine dibromide The 0.23 g (0.93 mmol) of 3-bromo-6-chloro- is dissolved 2-methyl-imidazo [1,2-b) pyridazine obtained in Example 1, in 2 ml of concentrated acetic acid and this solution is treated with 1.39 mmol of bromine. After a short time, 3-bromo-6-chloro-2-methyl-20 imidazo [1,2-b] pyridazine dibromide crystallizes; this product is then filtered and dried. The yield is 0.38 g (89.4%); F = 217-220 °.

Example 3

Preparation of the brominating agent An excess of bromine is added dropwise at room temperature to a solution of 1.67 g of 6-chloro-2-methylimidazo [1,2-b] pyridazine [prepared as described by B. Stanovnik and M. Tisler in Tetrahedron, 23, 2739 (1969)] in 25 ml of glacial acetic acid. The precipitate which has formed is then filtered and washed with glacial acetic acid. The brominating agent obtained in the raw state is recrystallized from acetic acid, washed with ether to remove the acetic acid and dried under reduced pressure for 60 minutes at 30 °.

Claims (9)

10 N-Br "2 in which R ^ represents a carboxy or carbamoyl group, an alkoxycarbonyl group in which the alkyl residue contains from 1 to 5 carbon atoms, an alkylcarbamoyl or dialkylcarbamoyl group in which the alkyl residues each contain from 1 to 5 atoms of carbon or a residue of formula II. 20 n 011, a0! Jpn -CO-NH --- y (II) „0 = 1_N j = -rQ ΙΓ '' R. 25 ° where R represents an alkyl group containing from 1 to 4 cl carbon atoms, and R ^ represents an alkyl group containing from 1 to 4 carbon atoms or a benzyl group, R2 represents a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms, and either R ^ represents a hydrogen atom and in this case, R ^ represents a hydrogen atom or an alkoxy group containing from 1 to 4 carbon atoms, 8. · * * Either r3 and R4 together form a second bond, characterized in that bromine. a compound of formula III 5 (HD 10 R2 r in which R ^, R3 and have the meanings already given, by reaction with a bromine complex of 3-bromo-6-chloro-2-methyl-imidazo [1,2-b] pyridazine. 2. A process according to claim 1, characterized in that 1 mole of rye ergo alkaloid is used for 1.2 to 1.5 mole of brominating agent. 3. A process according to any one of re-vendications 1 and 2, characterized in that, as a compound of formula III, α-ergocryptine is involved. 4. The ergot alkaloids corresponding to the formula I R1 25 i "xS u) fx J 3 N-Br R2 'in which R ^ represents a carboxy or carbamoyl group, an alkoxycarbonyl group in which the alkyl residue contains from 1 to 35 carbon atoms, an alkylcarbamoyl or dialkylcarbamoyl group in which the alkyl residues contain "" <9, each from 1 to 5 carbon atoms or a residue of .--; - formula: 5 R __: J7 "1 111 -CO-HH --- Y 'p" / 0 = J-Nj = 0 H 10 "where R represents an alkyl group containing from 1 to 4 cl carbon atoms, and represents a group alkyl containing from 1 to 4 carbon atoms or a benzyl group, I? 2 represents a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms, and either R3 represents a hydrogen atom and, in this case, R ^ represents a hydrogen atom or an alkoxy group containing 1 to 4 carbon atoms, ie R-, and R. together form a second bond, 3 4 characterized in that they are obtained according to the process specified in any one of claims 1 to 3. "j * 5.- 2-Bromo-a-ergocryptine, characterized in that it is obtained according to the process specified in any one of claims 1 to 3 - 6. Products and processes in substance as described above with reference to the examples cited.