CA1294956C - Production of 2-bromo-alpha-ergocryptine and its acid addition salts - Google Patents
Production of 2-bromo-alpha-ergocryptine and its acid addition saltsInfo
- Publication number
- CA1294956C CA1294956C CA000576777A CA576777A CA1294956C CA 1294956 C CA1294956 C CA 1294956C CA 000576777 A CA000576777 A CA 000576777A CA 576777 A CA576777 A CA 576777A CA 1294956 C CA1294956 C CA 1294956C
- Authority
- CA
- Canada
- Prior art keywords
- alpha
- ergocryptine
- bromo
- acid addition
- addition salts
- 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.)
- Expired - Fee Related
Links
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE:
2-Bromo-alpha-ergocryptine, the potent inhibitor of prolactin /luteotropic hormone/, is prepared in high yield and purity grade by the bromination of alpha-ergocryp-tine with elemental bromine in chlorinated aliphatic hydrocarbons and/or tetrahydrofuran in the presence of catalytic amounts of Lewis acids, preferably boron tri-fluoride, in the temperature range of from -40 to 0°C and optionally converted as known per se into its acid addition salt, preferably methanesulfonate.
2-Bromo-alpha-ergocryptine, the potent inhibitor of prolactin /luteotropic hormone/, is prepared in high yield and purity grade by the bromination of alpha-ergocryp-tine with elemental bromine in chlorinated aliphatic hydrocarbons and/or tetrahydrofuran in the presence of catalytic amounts of Lewis acids, preferably boron tri-fluoride, in the temperature range of from -40 to 0°C and optionally converted as known per se into its acid addition salt, preferably methanesulfonate.
Description
The present invention relates to a process for the production of 2-bromo-alpha-ergocryptine, the potent prolactin inhibitor, by the bromination of alpha-ergocryptine.
Known bromination methods for ergot alkaloids and their derivatives make predominantly use of N-brominated compounds as mild brominating agents in inert polar organic solvents. Thus, according to Swiss patent 507 249 /CA 953 720/, ergocryptine is reacted with N-brominated amides or imides of carboxylic or sulfonic acids such as N-bromophthalimide, N-bromosuccinimide or N-bromocaprolactam, or with a bromo-dioxane complex, in dioxane or acetonitrile at a temperature between 10 and 80C, preferably at 60C
with subsequent conventional isolation procedures.
Another bromination process uses pyrrolidone-hydrotribromide or N-bromosaccharin in dioxane in the presence of an initiator of radical reactions, e.g. 2,2-azo-bis-/2-methylpropionitrile/, at temperatures below 50C
/DE-OS 27 52 532/. These two known methods involve water-miscible reaction media which, on completion of the reaction, must first be removed by evaporation under reduced pressure prior to further processing of the reaction mixture. The evaporation in the presence of the unreacted brominating agent and especially rather drastic reaction conditions /elevated temperature for protracted reaction period/ result in partial epimerization in position 8 to the respective dextrorotatory isomers, i.e. alpha-ergocryptinine and predominantly 2-bromo-alpha-ergocryptinine, under simultaneous formation of dark coloured decomposition products due to the oxidative action of the employed brominating agents.
Alternatively, the bromination of alpha-ergocryp-tine with N-brominated amides or imides can be effected in reaction media predominantly consisting of a water-~;~9~9~6 immiscible solven-t, e.g. in dichloromethane containin~ from 10 to 25% of dioxane, in the presence of a minor quantity of dioxane peroxide at room or moderately elevated temperature /CS author certificate 250 972/.
Still alternatively, certain ergoline derivatives were bromina-ted with nascent bromine formed in situ from hydrogen bromide in dimethylsulfoxide /DE-OS 36 19 617/ or with elemental bromine in the presence of hydrogen bromide in halogenated hydrocarbons /EP 141 387/. Common disadvantage of the two last-mentioned procedures is comparatively large dilution of the reaction mixture /low concentration of the reactants/ due to low solubility of ergoline deriva-tives in organic solven-ts.
It has recently been found to surprise that the bromination of alpha-ergocryptine with elemental bromine in polar organic solvents is most beneficially influenced by the presence of Lewis acids, preferably boron trifluoride.
Therefore, according to the present invention, there is provided a process for the production of 2-bromo-alpha-ergocryptine and its acid addition salts, comprising the bromination of alpha-ergocryptine with elemental bromine in the presence of catalytic amounts of boron trifluoride in dichloromethane, tetrahydrofurane or their mixtures at a temperature in the range substantially of from -~0 to 0C
and, if required, subsequent neutralization of the resulting 2-bromo-alpha-ergocryptine ba.se with the corresponding pharmaceutically acceptable inorganic or organic acid.
Suitable solvents are dichloromethane, chloroform, dichloroethanes and tetrahydrofuran, advantageously mixtures of dichloromethane with tetrahydrofuran, in which most of ergoline derivatives are readily soluble even at low temperatures; the bromination is conveniently conducted in the temperature range substantially of from -40 to 0C.
The reaction of alpha-ergocryptine with elemental ~z~9~
bromine in such solvent mixtures proceeds at -20 to 0C even in the absence of Lewis acids but, due to the oxidative properties of bromine, results to a considerable extent in concurren-t formation of the corresponding 2-oxo compounds /30 to 60~/. If catalytic amount of a Lewis acid, preferably boron trifluoride, is present, the undesired oxidation is almost completely suppressed /to less than 5%
of the 2-oxo compound/ and the yield of 2-bromo-alpha-ergocryptine is considerably increased; similar effect is - 2a -~s .~ ~
1;~94~
achieved by further lowering of the reaction temperature.
Advantages of the subject procedure of the present invention are very mild reaction conditions, comparatively high concentration of the reaction mixture, slight formation of decomposition products, high yield /over 80% of theory/
of the desired compound and its smooth isolation in the pure state. If required, the resulting base is finally converted, by per se known procedure, into its acid addition salts, preferably methanesulfonate, suitable for the preparation of medical dosage forms.
Further particulars of the procedure are illustrated by the subsequent non-limitative example.
EXAMPLE
Hundred grams of alpha-ergocryptine substance containing 92.5~ of the pure compound is dissolved in 1200 ml of a mixture of dichloromethane and tetrahydrofuran /2 : 1/. To the formed solution there are added 20 ml of boron trifluoride etherate and the mixture is precooled to - 30C~ The precooled mixture is treated with 420 ml of a 8% solution of bromine in dichloromethane. After l minute of stirring, the reaction mixture is admixed with 700 ml of a 5% aqueous potassium carbonate solution and 300 ml of a 5~
aqueous sodium pyrosulfite /disulfite/ solution. After the separation of phases the aqueous layer is extracted with 200 ml of dichloromethane and the combined organic portions are evaporated to dryness. The residue is dissolved in the same solvent and chromatographed over 1 kg of silica gel; elution of the material is effected with dichloromethane - acetone /4 : 1/. F'ractions containing 2-bromo-alpha-ergocryptine are evaporated to dryness and the residue is crystallized from a chloroform - ether mixture to afford 92.2 g of crystalline 2-bromo-alpha-ergocryptine product with the conten-t of 91.5% of the pure compound, which corresponds to an overall yield of 80.3% of theory.
Known bromination methods for ergot alkaloids and their derivatives make predominantly use of N-brominated compounds as mild brominating agents in inert polar organic solvents. Thus, according to Swiss patent 507 249 /CA 953 720/, ergocryptine is reacted with N-brominated amides or imides of carboxylic or sulfonic acids such as N-bromophthalimide, N-bromosuccinimide or N-bromocaprolactam, or with a bromo-dioxane complex, in dioxane or acetonitrile at a temperature between 10 and 80C, preferably at 60C
with subsequent conventional isolation procedures.
Another bromination process uses pyrrolidone-hydrotribromide or N-bromosaccharin in dioxane in the presence of an initiator of radical reactions, e.g. 2,2-azo-bis-/2-methylpropionitrile/, at temperatures below 50C
/DE-OS 27 52 532/. These two known methods involve water-miscible reaction media which, on completion of the reaction, must first be removed by evaporation under reduced pressure prior to further processing of the reaction mixture. The evaporation in the presence of the unreacted brominating agent and especially rather drastic reaction conditions /elevated temperature for protracted reaction period/ result in partial epimerization in position 8 to the respective dextrorotatory isomers, i.e. alpha-ergocryptinine and predominantly 2-bromo-alpha-ergocryptinine, under simultaneous formation of dark coloured decomposition products due to the oxidative action of the employed brominating agents.
Alternatively, the bromination of alpha-ergocryp-tine with N-brominated amides or imides can be effected in reaction media predominantly consisting of a water-~;~9~9~6 immiscible solven-t, e.g. in dichloromethane containin~ from 10 to 25% of dioxane, in the presence of a minor quantity of dioxane peroxide at room or moderately elevated temperature /CS author certificate 250 972/.
Still alternatively, certain ergoline derivatives were bromina-ted with nascent bromine formed in situ from hydrogen bromide in dimethylsulfoxide /DE-OS 36 19 617/ or with elemental bromine in the presence of hydrogen bromide in halogenated hydrocarbons /EP 141 387/. Common disadvantage of the two last-mentioned procedures is comparatively large dilution of the reaction mixture /low concentration of the reactants/ due to low solubility of ergoline deriva-tives in organic solven-ts.
It has recently been found to surprise that the bromination of alpha-ergocryptine with elemental bromine in polar organic solvents is most beneficially influenced by the presence of Lewis acids, preferably boron trifluoride.
Therefore, according to the present invention, there is provided a process for the production of 2-bromo-alpha-ergocryptine and its acid addition salts, comprising the bromination of alpha-ergocryptine with elemental bromine in the presence of catalytic amounts of boron trifluoride in dichloromethane, tetrahydrofurane or their mixtures at a temperature in the range substantially of from -~0 to 0C
and, if required, subsequent neutralization of the resulting 2-bromo-alpha-ergocryptine ba.se with the corresponding pharmaceutically acceptable inorganic or organic acid.
Suitable solvents are dichloromethane, chloroform, dichloroethanes and tetrahydrofuran, advantageously mixtures of dichloromethane with tetrahydrofuran, in which most of ergoline derivatives are readily soluble even at low temperatures; the bromination is conveniently conducted in the temperature range substantially of from -40 to 0C.
The reaction of alpha-ergocryptine with elemental ~z~9~
bromine in such solvent mixtures proceeds at -20 to 0C even in the absence of Lewis acids but, due to the oxidative properties of bromine, results to a considerable extent in concurren-t formation of the corresponding 2-oxo compounds /30 to 60~/. If catalytic amount of a Lewis acid, preferably boron trifluoride, is present, the undesired oxidation is almost completely suppressed /to less than 5%
of the 2-oxo compound/ and the yield of 2-bromo-alpha-ergocryptine is considerably increased; similar effect is - 2a -~s .~ ~
1;~94~
achieved by further lowering of the reaction temperature.
Advantages of the subject procedure of the present invention are very mild reaction conditions, comparatively high concentration of the reaction mixture, slight formation of decomposition products, high yield /over 80% of theory/
of the desired compound and its smooth isolation in the pure state. If required, the resulting base is finally converted, by per se known procedure, into its acid addition salts, preferably methanesulfonate, suitable for the preparation of medical dosage forms.
Further particulars of the procedure are illustrated by the subsequent non-limitative example.
EXAMPLE
Hundred grams of alpha-ergocryptine substance containing 92.5~ of the pure compound is dissolved in 1200 ml of a mixture of dichloromethane and tetrahydrofuran /2 : 1/. To the formed solution there are added 20 ml of boron trifluoride etherate and the mixture is precooled to - 30C~ The precooled mixture is treated with 420 ml of a 8% solution of bromine in dichloromethane. After l minute of stirring, the reaction mixture is admixed with 700 ml of a 5% aqueous potassium carbonate solution and 300 ml of a 5~
aqueous sodium pyrosulfite /disulfite/ solution. After the separation of phases the aqueous layer is extracted with 200 ml of dichloromethane and the combined organic portions are evaporated to dryness. The residue is dissolved in the same solvent and chromatographed over 1 kg of silica gel; elution of the material is effected with dichloromethane - acetone /4 : 1/. F'ractions containing 2-bromo-alpha-ergocryptine are evaporated to dryness and the residue is crystallized from a chloroform - ether mixture to afford 92.2 g of crystalline 2-bromo-alpha-ergocryptine product with the conten-t of 91.5% of the pure compound, which corresponds to an overall yield of 80.3% of theory.
Claims (2)
1. A process for the production of 2-bromo-alpha-ergocryptine and its acid addition salts, comprising the bromination of alpha-ergocryptine with elemental bromine in the presence of catalytic amounts of boron trifluoride in dichloromethane, tetrahydrofurane or their mixtures at a temperature in the range substantially of from -40 to 0°C
and, if required, subsequent neutralization of the resulting
and, if required, subsequent neutralization of the resulting
2-bromo-alpha-ergocryptine base with the corresponding pharmaceutically acceptable inorganic or organic acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS881617A CS272370B1 (en) | 1988-03-11 | 1988-03-11 | Method of ergoline compounds preparation that are position-substituted by 2-bromine |
| CSPV1617-88 | 1988-03-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1294956C true CA1294956C (en) | 1992-01-28 |
Family
ID=5350976
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000576777A Expired - Fee Related CA1294956C (en) | 1988-03-11 | 1988-09-08 | Production of 2-bromo-alpha-ergocryptine and its acid addition salts |
Country Status (2)
| Country | Link |
|---|---|
| CA (1) | CA1294956C (en) |
| CS (1) | CS272370B1 (en) |
-
1988
- 1988-03-11 CS CS881617A patent/CS272370B1/en unknown
- 1988-09-08 CA CA000576777A patent/CA1294956C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CS161788A1 (en) | 1990-05-14 |
| CS272370B1 (en) | 1991-01-15 |
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| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |