GB2031890A - Process for the preparation of brominated ergot alkaloids - Google Patents
Process for the preparation of brominated ergot alkaloids Download PDFInfo
- Publication number
- GB2031890A GB2031890A GB7932989A GB7932989A GB2031890A GB 2031890 A GB2031890 A GB 2031890A GB 7932989 A GB7932989 A GB 7932989A GB 7932989 A GB7932989 A GB 7932989A GB 2031890 A GB2031890 A GB 2031890A
- Authority
- GB
- United Kingdom
- Prior art keywords
- alkyl
- bromo
- amido
- formula
- chloro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
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
SPECIFICATION
Improvements in or relating to bromination processes
The present invention relates to brominating processes, especially for selectively brominating sensitive
Compounds such as ergot alkaloids, e.g. a-ergocryptine.
It is known to brominate a-ergocryptine with a mild brominating agent N-bromosuccinimide, N-bromocaprolactam, N-bromophthalamide and bromine/dioxane [see Swiss Patent No 507249]. It has also been recently proposed to brominate a-ergocryptine using pyrrolidone-(2)-hydrotribromide or N-bromosaccharin in the presence of a radical initiator (German Offenlegungsschrift 2752532).
The present invention provides an novel and advantageous process for the production of a compound of formula I
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
wherein R0 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, characterised in that a compound of formula Ill
wherein R1 to R4 are as defined above, is brominated with a bromine complex of 3-bromo-6-chloro-2-methylimidazo[1 ,2-b]pyridazine.
This brominating agent may for example 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 excess bromine. The product is believed to comprise 3-bromo-6-chloro-2-methyl-imidazo[l ,2-b]pyridazine dibromide of formula IV
The brominating agent possesses especially advantageous 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 solvents and is stable in solution; 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[1 ,2-b]pyridazine formed in the reaction.
In formulae I and Ill the side chain in the 8 position may have the a or preferably the p configuration. The brominating reaction proceeds stereospecifically in that epimerisation at the 8 position may be unexpectedly minimal.
For the above mentioned ergot alkaloids, it is 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(C13) as solvent. Suitable reaction temperatures are for example from about - 1 0 C to about 10000. At room temperature satisfactory yields may be surprisingly obtained, for example in a few minutes.
Any excess brominating agent in the reaction mixture may be deactivated by the addition, for example, of acetone and ammonium hydroxide. The isolation of the brominated product is then facilitated. Conventional isolation methods may be used, for example, liquid/liquid extraction and column chromatography, to obtain the brominated product in pure form.
From the reaction mixture 3-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine may be isolated. This may be converted back into the brominating agent by treatment with excess bromine in concentrated acetic acid.
The brominating agent may be initially 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 bromine in concentrated acetic acid, and collecting the resultant precipitate.
The bromination of 6-chloro-2-methyl-imidazo[1,2-bjpyridazine has been described by Kobe et al
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-b]pyridazine may be prepared as described in the above-mentioned Tetrahedron article and may be brominated in analogous manner to the bromination of 6-chloro-2-methyl-imidazo[1 ,2-b]pyridazine 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 30 centigrade in a vacuum. The complex may contain further bromine over that represented by structure IV. e.g. in the form of H.B.R.
In the following examples all temperatures are in degrees Centigrade and are uncorrected.
Example 1: 2-bromo-9, 10-dihydroergotamine 0.584 g (1 mMol) 9,10-dihydroergotamine are dissolved in 20 ml methylene chloride. The solution is stirred and 0.612 g (1.5 m Mol) 3-bromo-6-chloro-2-methyl-imidazo[1 ,2-bjpyridazine-dibromide in 180 ml methylene chloride are added. After the mixture has been stirred for 2 minutes at room temperature, 10 ml acetone and 100 mi 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 concentrated to give a dry residue.
This residue is applied to a column containing 50 g of silicagel. Using an eluant of methylene chloride containing 5% ethanol 0.23 g 3-bromo-6-chloro-2-methyl-imidazo[1 ,2-b]pyridazine are eluted.
Further elution yields pure 2-bromo-9,10-dihydroergotamine; 0.33 g, 50% yield. M.Pt. 1 98-200" and [ID20 -84" (c= 1, pyridine).
Replacing the 9,10-dihydroergotamine with an equivalent amount of: a) a-ergosine; b) 9,10-dihydro-a-ergosine; c) a-ergocryptine; d) a-ergosinine; e) (5R,8R) lysergic acid diethylamide; or f) 1 -methyl-9,1 0-dihydrolysergic acid methyl ester.
there are obtained respectively:a) 2-bromo-a-ergosine; 81% yield, M.pt. 183-185" (decomp) [a]i) = - 91.6 , (c = 1, chloroform); b) 2-bromo-9,10-dihydroergosine; 69% yield, M.pt. 186-188" (decomp) [a]D = - 40 (c = 1, methanol); c) 2-bromo-a-ergocryptine; 75% yield, M.pt. 215-218" [a]D = -98 ; (c = 1, pyridine); [a]D = -195 ; (c = 1, methylene chloride); d) 2-bromo-a-ergosinine; 70% yield, M.pt. 188-190"; [a]20 = + 403 ; (c = 1,chloroform); e) (5R, 8R) 2-bromo-lysergic acid diethyl amide; 73.4% yield after recrystallization from ether of the dry residue before chromatography, M.pt. 122-125"; [a]j, = + 17 (c = 1, pyridine); f) 2-bromo-1 -methyl-9,1 0-dihydrolysergic acid methyl ester; 65% yield after recrystallization of the dry residue before chromatography from methanol/water (85:15 by volume), M.pt. 166-168"; [a]D = - 94" (c = 0.5, chloroform).
Example 2: Regeneration of 3-bromo-6-chloro-2-methyl-imidazojl,2-b]pyridazine dibromide
0.23 g (0.93 mMol) 3-bromo-6-chloro-2-methyl-imidazo [1,2-b]pyridazine obtained from Example 1 is dissolved in 2 ml concentrated acetic acid and treated with 1.39 mMol elemental bromine. From the reaction mixture crystallizes out after a little while 3-bromo-6-chloro-2-methyl-imidazo[1 ,2-b]pyridazine dibromide.
This is filtered off and dried. Yield 0.38 g, (89.4%), M.pt 217-220 .
Claims (5)
1. A process for the production of a compound of formula I
wherein R is carboxyl, alkoxy(C1.5)carbonyl, amido, alkyl(C1 5)amido, di(alkyl(C1.5))amido or an amido radical of formula II
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(Cn 4) or R3 and R4 together are a single bond, characterised in that a compound of formula Ill
wherein R1 to R4 are as defined above, is brominated with a bromine complex of 3-bromo-6-chloro-2-methylimidazo[l,2-b]pyridazine.
2. A process according to claim 1 substantially as herein before described with reference to the Example 1.
3. A compound of formula I whenever produced according to the process of claim 1 or 2.
4. A process according to claim 1 wherein the compound of formula Ill is a-ergocryptine.
5. 2-bromo-a-ergocryptine whenever produced according to the process of claim 2 or 4.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YU2268/78A YU39849B (en) | 1978-09-26 | 1978-09-26 | Process for preparing 2-bromo-ergolene and 2-bromo-ergoline compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2031890A true GB2031890A (en) | 1980-04-30 |
| GB2031890B GB2031890B (en) | 1983-02-02 |
Family
ID=25557457
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7932989A Expired GB2031890B (en) | 1978-09-26 | 1979-09-24 | Process for the preparation of brominated ergot alkaloids |
Country Status (45)
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU196394B (en) * | 1986-06-27 | 1988-11-28 | Richter Gedeon Vegyeszet | Process for preparing 2-halogenated ergoline derivatives |
| CN104016982A (en) * | 2014-06-26 | 2014-09-03 | 华东理工大学 | Method for preparing fumigaclavine C by using macroporous resin |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH507249A (en) * | 1968-05-31 | 1971-05-15 | Sandoz Ag | Process for the preparation of 2-bromo-a-ergocryptine |
| YU39786B (en) * | 1976-12-23 | 1985-04-30 | Lek Tovarna Farmacevtskih | Process for preparing 2-bromo-alfa-ergocriptine |
| YU216177A (en) * | 1977-09-09 | 1984-02-29 | Rudolf Rucman | Process for preparing 2-bromo ergosine |
-
1978
- 1978-09-26 YU YU2268/78A patent/YU39849B/en unknown
-
1979
- 1979-09-19 IT IT7950300A patent/IT1206988B/en active
- 1979-09-20 CH CH8492/79A patent/CH649769A5/en not_active IP Right Cessation
- 1979-09-21 DE DE19792938313 patent/DE2938313A1/en active Granted
- 1979-09-24 NO NO793058A patent/NO153852C/en unknown
- 1979-09-24 AT AT0624379A patent/AT376439B/en not_active IP Right Cessation
- 1979-09-24 MX MX798393U patent/MX5864E/en unknown
- 1979-09-24 NZ NZ191643A patent/NZ191643A/en unknown
- 1979-09-24 DD DD79215747A patent/DD146048A5/en not_active IP Right Cessation
- 1979-09-24 IS IS2512A patent/IS2512A7/en unknown
- 1979-09-24 LU LU81714A patent/LU81714A1/en unknown
- 1979-09-24 HU HU79SA3200A patent/HU182576B/en unknown
- 1979-09-24 CY CY1240A patent/CY1240A/en unknown
- 1979-09-24 GR GR60103A patent/GR73015B/el unknown
- 1979-09-24 BE BE1/9540A patent/BE878953A/en not_active IP Right Cessation
- 1979-09-24 PT PT70216A patent/PT70216A/en unknown
- 1979-09-24 FI FI792957A patent/FI66185C/en not_active IP Right Cessation
- 1979-09-24 GB GB7932989A patent/GB2031890B/en not_active Expired
- 1979-09-24 AR AR278180A patent/AR223496A1/en active
- 1979-09-25 UA UA2818045A patent/UA7078A1/en unknown
- 1979-09-25 RO RO7998760A patent/RO78936A/en unknown
- 1979-09-25 SU SU792818045A patent/SU1178324A3/en active
- 1979-09-25 PH PH23062A patent/PH14986A/en unknown
- 1979-09-25 SE SE7907942A patent/SE433497B/en not_active IP Right Cessation
- 1979-09-25 PL PL1979218497A patent/PL120388B1/en unknown
- 1979-09-25 IL IL58318A patent/IL58318A/en unknown
- 1979-09-25 AU AU51172/79A patent/AU529462B2/en not_active Ceased
- 1979-09-25 FR FR7923816A patent/FR2437411A1/en active Granted
- 1979-09-25 CS CS796471A patent/CS215027B2/en unknown
- 1979-09-25 BG BG7944956A patent/BG32716A3/en unknown
- 1979-09-25 EG EG566/79A patent/EG14277A/en active
- 1979-09-25 DK DK401979A patent/DK149956C/en not_active IP Right Cessation
- 1979-09-25 NL NL7907122A patent/NL7907122A/en not_active Application Discontinuation
- 1979-09-25 ES ES484445A patent/ES484445A1/en not_active Expired
- 1979-09-25 MA MA18795A patent/MA18595A1/en unknown
- 1979-09-25 JP JP12373279A patent/JPS5545699A/en active Granted
- 1979-09-26 IE IE1832/79A patent/IE49076B1/en not_active IP Right Cessation
- 1979-09-26 CA CA336,448A patent/CA1128038A/en not_active Expired
- 1979-09-26 BR BR7906175A patent/BR7906175A/en unknown
- 1979-09-26 ZA ZA00795110A patent/ZA795110B/en unknown
-
1980
- 1980-09-23 IN IN1077/CAL/80A patent/IN154914B/en unknown
-
1984
- 1984-03-05 SG SG204/84A patent/SG20484G/en unknown
- 1984-04-12 KE KE3392A patent/KE3392A/en unknown
- 1984-06-14 HK HK491/84A patent/HK49184A/en not_active IP Right Cessation
-
1985
- 1985-12-30 MY MY131/85A patent/MY8500131A/en unknown
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 732E | Amendments to the register in respect of changes of name or changes affecting rights (sect. 32/1977) | ||
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19980924 |