CH584220A5 - 13-Bromo-lysergic acid derivs - with vigilance-increasing activity - Google Patents
13-Bromo-lysergic acid derivs - with vigilance-increasing activityInfo
- Publication number
- CH584220A5 CH584220A5 CH816076A CH816076A CH584220A5 CH 584220 A5 CH584220 A5 CH 584220A5 CH 816076 A CH816076 A CH 816076A CH 816076 A CH816076 A CH 816076A CH 584220 A5 CH584220 A5 CH 584220A5
- Authority
- CH
- Switzerland
- Prior art keywords
- acid
- bromo
- formula
- vigilance
- dihydrolysergic
- Prior art date
Links
- BINZJVHNWBJJNU-YMTOWFKASA-N (6ar,9r)-2-bromo-7-methyl-6,6a,8,9-tetrahydro-4h-indolo[4,3-fg]quinoline-9-carboxylic acid Chemical compound BrC1=CC(C2=C[C@H](CN([C@@H]2C2)C)C(O)=O)=C3C2=CNC3=C1 BINZJVHNWBJJNU-YMTOWFKASA-N 0.000 title 1
- 239000002253 acid Substances 0.000 claims abstract description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 5
- ORBSYPFBZQJNJE-MPKXVKKWSA-N (6ar,9r,10ar)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-carboxylic acid Chemical compound C1=CC([C@H]2C[C@H](CN([C@@H]2C2)C)C(O)=O)=C3C2=CNC3=C1 ORBSYPFBZQJNJE-MPKXVKKWSA-N 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 abstract 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 abstract 1
- 230000002490 cerebral effect Effects 0.000 abstract 1
- 239000012442 inert solvent Substances 0.000 abstract 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 239000002904 solvent Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 7
- 239000012362 glacial acetic acid Substances 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Derivs. of formula (I): (where R1 is methyl or isopropyl and R2 is isopropyl, sec. butyl, isobutyl or benzyl) and their acid addn. salts, which are indicated for the treatment of cerebral insufficiency, are prepd. by reacting a functional deriv. of the acid of formula (II): in an inert solvent or solvent mixt. in the presence of a tert. org. base.
Description
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von 13-Brom-9,10-dihydrolysergsäure der Formeln (siehe Formelblatt).
Erfindungsgemäss gelangt man zu 13-Broan-8,1 1 3-Brom-9,l0-dihydro- lysergsäure, indem man 9,10-Dihydrolysergsäure (Formel II) in einem organischen Lösungsmittel, wie Eisessig oder Propionsäure, in einem Temperaturbereich von 10 - 80 C mit einem Bromierungsmittel, das elementares Brom enthält, vorzugsweise Pyridinhydrobromid-perbromid, zu 2,13-Dibrom- -9,10-dihydrolysergsäure (Formel III) umsetzt. Dieses 2,13 -Dibrom-Derivat wird reduktiv, beispielsweise durch katalytische Hydrierung oder durch Zinkstaub-Reduktion, in die Verbindung der Formel I übergeführt.
Die Hydrierung wird bei Raumtemperatur unter Zusatz von Raney-Nickel durchgeführt und muss nach Aufnahme von 1 Äquivalent Wasserstoff abgebrochen werden. Aus dem Filtrat kann 13-Brom-9,10-dihydrolysergsäure auf an sich bekannte Weise isoliert werden.
Die Zinkstaub-Reduktion wird vorteilhaft in Eisessig vorgenommen. Nach Zugabe des Zinkstaubs in Gegenwart von Salzsäure wird 4 Stunden auf 80"C erhitzt und filtriert. Das eingeengte Filtrat wird alkalisch eingestellt, der Niederschlag abfiltriert und die Säure durch Zugabe von Eisessig ausgefällt, die anschliessend durch Umkristallisation gereinigt werden kann.
13-Brom-9,10-dihydrolysergsäure dient als Ausgangsprodukt zur Herstellung pharmakologisch interessanter Verbindungen.
In dem nachfolgenden Beispiel, welches die Erfindung näher erläutern, ihren Umfang aber in keiner Weise einschränken soll, erfolgen die Temperaturangaben in Celsiusgraden und sind nicht korrigiert.
EMI1.1
EMI1.2
Beispiel a) 2,13-Dibrom-9.10-dihydrolysergsäure
40,5 g 9,10-Dihydrolysergsäure werden unter leichtem Erwärmen in 1,15 1 Eisessig gelöst, die rotbraune Lösung auf 100 abgekühlt, mit 104,9 g Pyridinhydrobromid-perbromid versetzt und anschliessend bei Raumtemperatur gerührt.
Nach 2 Stunden engt man das Reaktionsgemisch am Rotationsverdampfer auf die Hälfte ein, stellt den Rückstand unter Eiskühlung mit konz. Ammoniak alkalisch und filtriert den ausgefallenen hellbraunen Niederschlag ab.
Zur weiteren Reinigung wird der feuchte Filterrückstand mit je 300 ml konz. Ammoniak und Methanol in der Wärme gelöst, mit Aktivkohle versetzt, klar filtriert und bis zur beginnenden Kristallisation am Rotationsverdampfer eingeengt.
Nach Stehen über Nacht bei 0 wird abfiltriert, mit wenig Methanol nachgewaschen und im Vakuum bei 80" getrocknet.
Man erhält blassgelbe Kristalle, Smp. ab 2900 (Zers.), [am20 = 910 + 30 (c = 0,5 Pyridin).
b) 13-Brom-9.1 O-dihydrolysergsäure
Eine Lösung von 2,2 g (5 Mol) 2,13-Dibrom-9,10-dihydrolysergsäure in 10 ml Triäthylamin und 50 ml Wasser wird unter Zusatz von 2,2 g feuchtem Raney-Nickel bei Raumtemperatur hydriert. Nach Aufnahme von 1 Äquivalent H2 wird die Hydrierung abgebrochen, vom Katalysator abfiltriert und das Filtrat unter Eiskühlung mit 2 N Salzsäure angesäuert (pH 4,5 - 5,0). Der ausgefallene Niederschlag wird abfiltriert über Phosphorpentoxid getrocknet und aus Methanol Methylenchlorid/konz. Ammoniak umkristallisiert. Man erhält die Titelverbindung als farblose Nadeln, Zers. ab 2900, ( ]n21 = -63 + 20 (c = 0,5 in Pyridin).
c) 13-Brom-9,1 0-dihydrolysergräure
5 g 2,13-Dibrom-9,10-dihydrolysergsäure werden in 75 ml Eisessig suspendiert und mit 30 ml 2 N Salzsäure und 30 g Zinkstaub versetzt. Das Reaktionsgemisch wird auf 800 erhitzt, nach 4 Stunden heiss abfiltriert und der Filterrückstand mit 25 ml 50-proz. Essigsäure gewaschen. Das Filtrat engt man im Vakuum ein und zieht den Rückstand dreimal mit Methanol im Vakuum hoch. Anschliessend löst man erneut in 30 ml Methanol und versetzt in der Wärme mit 2 N Natronlauge bis zur alkalischen Reaktion (pH 12). Der gebildete Niederschlag wird abfiltriert und die Säure durch Zugabe von Eisessig bis pH 4,6 ausgefällt. Das abfiltrierte Kristallisat wird mit Wasser, Methanol und Aceton gewaschen.
Zur Umkristallisation löst man in mit Ammoniak gesättigtem Methanol und engt im Vakuum sorgfältig bis zur Kristallisation ein, wobei 13-Brom-9,10-dihydrolysergsäure mit den unter b) angegebenen Charakteristika erhalten wird.
The present invention relates to a process for the preparation of 13-bromo-9,10-dihydrolysergic acid of the formulas (see formula sheet).
According to the invention, 13-broan-8.1 1 3-bromo-9, 10-dihydrolysergic acid is obtained by adding 9,10-dihydrolysergic acid (formula II) in an organic solvent such as glacial acetic acid or propionic acid in a temperature range of 10 - 80 C with a brominating agent containing elemental bromine, preferably pyridine hydrobromide perbromide, to 2,13-dibromo-9,10-dihydrolysergic acid (formula III). This 2,13 -dibromo derivative is converted into the compound of the formula I reductively, for example by catalytic hydrogenation or by zinc dust reduction.
The hydrogenation is carried out at room temperature with the addition of Raney nickel and has to be terminated after 1 equivalent of hydrogen has been absorbed. 13-Bromo-9,10-dihydrolysergic acid can be isolated from the filtrate in a manner known per se.
The zinc dust reduction is advantageously carried out in glacial acetic acid. After adding the zinc dust in the presence of hydrochloric acid, the mixture is heated to 80 ° C. for 4 hours and filtered. The concentrated filtrate is made alkaline, the precipitate is filtered off and the acid is precipitated by adding glacial acetic acid, which can then be purified by recrystallization.
13-Bromo-9,10-dihydrolysergic acid is used as the starting material for the production of pharmacologically interesting compounds.
In the following example, which is intended to explain the invention in more detail, but in no way restrict its scope, the temperatures are given in degrees Celsius and are not corrected.
EMI1.1
EMI1.2
Example a) 2,13-dibromo-9.10-dihydrolysergic acid
40.5 g of 9,10-dihydrolysergic acid are dissolved in 1.15 l of glacial acetic acid with gentle warming, the red-brown solution is cooled to 100, 104.9 g of pyridine hydrobromide perbromide are added and the mixture is then stirred at room temperature.
After 2 hours, the reaction mixture is concentrated to half on a rotary evaporator, and the residue is concentrated with ice-cooling. Ammonia is alkaline and the light brown precipitate is filtered off.
For further cleaning, the moist filter residue is concentrated with 300 ml each. Ammonia and methanol dissolved in the heat, mixed with activated charcoal, filtered until clear and concentrated on a rotary evaporator until crystallization begins.
After standing overnight at 0, it is filtered off, washed with a little methanol and dried in vacuo at 80 ".
Pale yellow crystals are obtained, m.p. from 2900 (decomp.), [Am20 = 910 + 30 (c = 0.5 pyridine).
b) 13-Bromo-9.1 O-dihydrolysergic acid
A solution of 2.2 g (5 mol) of 2,13-dibromo-9,10-dihydrolysergic acid in 10 ml of triethylamine and 50 ml of water is hydrogenated at room temperature with the addition of 2.2 g of moist Raney nickel. After 1 equivalent of H2 has been taken up, the hydrogenation is terminated, the catalyst is filtered off and the filtrate is acidified with 2N hydrochloric acid (pH 4.5-5.0) while cooling with ice. The deposited precipitate is filtered off, dried over phosphorus pentoxide and methylene chloride / conc. From methanol. Ammonia recrystallized. The title compound is obtained as colorless needles, decomp. from 2900, (] n21 = -63 + 20 (c = 0.5 in pyridine).
c) 13-bromo-9,1 0-dihydrolyseric acid
5 g of 2,13-dibromo-9,10-dihydrolysergic acid are suspended in 75 ml of glacial acetic acid, and 30 ml of 2N hydrochloric acid and 30 g of zinc dust are added. The reaction mixture is heated to 800, filtered off hot after 4 hours and the filter residue with 25 ml of 50 percent. Acetic acid washed. The filtrate is concentrated in vacuo and the residue is drawn up three times with methanol in vacuo. It is then dissolved again in 30 ml of methanol and 2N sodium hydroxide solution is added while hot until an alkaline reaction (pH 12). The precipitate formed is filtered off and the acid is precipitated by adding glacial acetic acid to pH 4.6. The filtered crystals are washed with water, methanol and acetone.
For recrystallization, it is dissolved in methanol saturated with ammonia and carefully concentrated in vacuo until crystallization, 13-bromo-9,10-dihydrolysergic acid having the characteristics given under b) is obtained.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH816076A CH584220A5 (en) | 1972-09-26 | 1972-09-26 | 13-Bromo-lysergic acid derivs - with vigilance-increasing activity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH816076A CH584220A5 (en) | 1972-09-26 | 1972-09-26 | 13-Bromo-lysergic acid derivs - with vigilance-increasing activity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH584220A5 true CH584220A5 (en) | 1977-01-31 |
Family
ID=4336083
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH816076A CH584220A5 (en) | 1972-09-26 | 1972-09-26 | 13-Bromo-lysergic acid derivs - with vigilance-increasing activity |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH584220A5 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0217734A1 (en) * | 1985-09-19 | 1987-04-08 | Schering Aktiengesellschaft | 12- or 13-bromoergoline derivatives |
-
1972
- 1972-09-26 CH CH816076A patent/CH584220A5/en not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0217734A1 (en) * | 1985-09-19 | 1987-04-08 | Schering Aktiengesellschaft | 12- or 13-bromoergoline derivatives |
| US4740509A (en) * | 1985-09-19 | 1988-04-26 | Schering Aktiengesellschaft | 12- and 13-bromoergolines useful for treating hypertension |
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| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased | ||
| PL | Patent ceased |