DE1620710A1 - Process for the production of compounds with a central excitatory effect - Google Patents
Process for the production of compounds with a central excitatory effectInfo
- Publication number
- DE1620710A1 DE1620710A1 DE19611620710 DE1620710A DE1620710A1 DE 1620710 A1 DE1620710 A1 DE 1620710A1 DE 19611620710 DE19611620710 DE 19611620710 DE 1620710 A DE1620710 A DE 1620710A DE 1620710 A1 DE1620710 A1 DE 1620710A1
- Authority
- DE
- Germany
- Prior art keywords
- compounds
- valerophenone
- formula
- production
- pyrrolidino
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
Description
Verfahren zur Herstellung von zentral erregend wirkenden Verbindungen Gegenstand der Erfindung ist ein Verfahren zur Herstellung von a-Pyrrolidino-valerophenonen der Formel 1: worin R Wasserstoff, ein Chloratom, eine Methyl- oder eine Methoxygruppe bedeutet, sowie von Salzen dieser Basen.Process for the preparation of compounds with a central excitatory action The invention relates to a process for the preparation of α-pyrrolidino-valerophenones of the formula 1: wherein R denotes hydrogen, a chlorine atom, a methyl or a methoxy group, and salts of these bases.
Substanzen der obigen Formel bzw. ihre Salze, die Halogenide, besitzen gute zentral erregende Wirkung ohne unerwünschte Nebenwirkungen, wie Kreislaufwirkungen.Substances of the above formula or their salts, the halides, have good centrally arousing effect without undesirable side effects such as circulatory effects.
Diese Wirkung ist fifr die erfindungsgemässen Verbindungen sehr spezifisch. Geringfügige Abweichungen von der angegebenen Formel (1) fuhren nach den Feststellungen der Anmelderin zu einer Herabsetzung oder zum Verlust der zentral stimulierenden Wirkung oder zum Auftreten unerwünschter Nebenwirkungen. Z. B. geht die zentral erregende Wirkung in folgenden Fällen teilweise-oder ganz verloren: a) wenn der Substituent R in einer andern Stellung als der p-Stellung ist oder wenn er im Benzolkern mehrfach auftritt (z.B, 3,4-Di-R- oder 3,4,5-Tri-R-Verbindungen); b) wenn im Substituenten R Alkyl- oder Alkoxygruppen mit mehr als einem C-Atom auftreten; c) wenn die Ketogruppe zur Hydroxygruppe reduziert wird; d) wenn das Wasserstoffatom am tertiären C-Atom durch eine Alkylgruppe ersetzt wird; oder e) wenn die Propylgruppe am tertiären C-Atom durch eine Alkylgruppe mit mehr oder weniger als 3 C-Atomen ersetzt wird.This effect is very specific for the compounds according to the invention. Slight deviations from the specified formula (1) lead to the findings the applicant to a reduction or lose the central stimulating effect or the occurrence of undesirable side effects. E.g. goes the central excitatory effect is partially or completely lost in the following cases: a) if the substituent R is in a position other than the p-position or if it occurs several times in the benzene nucleus (e.g. 3,4-di-R or 3,4,5-tri-R compounds); b) when alkyl or alkoxy groups with more than one carbon atom occur in the substituent R; c) when the keto group is reduced to the hydroxyl group; d) if the hydrogen atom is replaced on the tertiary carbon atom by an alkyl group; or e) when the propyl group on the tertiary carbon atom by an alkyl group with more or less than 3 carbon atoms is replaced.
Die anmeldungsgemassen a-Pyrrolidino-valerophenone (1) werden gemäss
der Erfindung hergestellt dadurch, dass ein a-Halogenvalerophenon der Formel
Als Ausgangsprodukt kann dabei ein kernsubstituiertes Valerophenon verwendet werden, das durch Halogenieren insbesondere Bromieren zu dem Produkt der Formel II umgewandelt wird.A nucleus-substituted valerophenone can be used as the starting product be used, which by halogenation in particular bromination to the product of Formula II is converted.
Die Bildung des Epoxy-äthers erfolgt vorzugsweise in einem organischen Lösungsmittel, wie Methanol, Aethanol, Aether, Tetrahydroruran u. dgl., vorzugsweise unter Erwärmen.The epoxy ether is preferably formed in an organic one Solvents such as methanol, ethanol, ether, tetrahydrofuran and the like, preferably under warming.
Die Umsetzung mit Pyrrolidin wird vorzugsweise in einem geschlossehen Gefäss bei erhöhter Temperatur durchgeführt; der Epoxy-äther braucht nicht isoliert zu werden.The reaction with pyrrolidine is preferably closed in one Vessel carried out at elevated temperature; the epoxy ether does not need to be isolated to become.
Die erfindungsgemässen Produkte mit zentral stiaiulierender Wirkung können unter Verwendung der üblichen Trager-, Hilfs- und Füllstoffe in passenden Applikationsformen verabreicht werden, zB. in Form von Tabletten oder Dragäes mit etwa 5 bis 60 mg Yirkstoff oder von Suppositorien mit etwa 10 bis 60 mg Wirkstoff.The products according to the invention with a centrally stimulating effect can using the usual carriers, auxiliaries and fillers in suitable Application forms are administered, eg. in the form of tablets or dragees with about 5 to 60 mg of active ingredient or of suppositories with about 10 to 60 mg of active ingredient.
Beispiel 1 Zu 750 g n-Valerophenon in 2,5 1 Chloroform, die sich in einem 10 l-Porzellanbecher mit kräftigem Rührer befinden, lässt man 235 ml Brom in 590 ml Chloroform innerhalb 35 Min. zutropfen; es wird noch 15 Min. nachgerührt. Die hellgelbe Chloroformlösung wird mit Wasser und Bicarbonatlösung saurefrei gewaschen, über Natriumsulfat getrocknet und das Chloroform möglichst weitgehend abdestilliert. Man erhält 1104 g rohes α-Brom-valerophenon vom Kp. 22 159°C, entsprechend einer Ausbeute von 99 % der Theorie.Example 1 To 750 g of n-valerophenone in 2.5 1 of chloroform, which is in a 10 l porcelain beaker with a powerful stirrer, 235 ml of bromine are left in add dropwise in 590 ml of chloroform within 35 minutes; it is stirred for a further 15 minutes. The light yellow chloroform solution is washed acid-free with water and bicarbonate solution, dried over sodium sulfate and most of the chloroform was distilled off. 1104 g of crude α-bromo valerophenone with a boiling point of 22 159 ° C. are obtained, correspondingly a yield of 99% of theory.
275 g dieser Verbindung in 700 ml Benzol werden bei O°C mit 220 ml Pyrrolidin (2,3 Mol) versetzt, Nach wenigen Min. tritt Erwarmung ein, worauf man durch Einstellen in Eis kurz kühlt. Nach 3-stündigem Stehen bei Raumtemperatur wird 15 Min. rückgekocht. Die erkaltete Lösung wird 2 mal mit wenig Wasser durchgeschüttelt, die Benzollösung Uber Natriumsulfat getrocknet und das Benzol abdestilliert.275 g of this compound in 700 ml of benzene are mixed at 0 ° C. with 220 ml Pyrrolidine (2.3 mol) are added. After a few minutes, warming occurs, whereupon one briefly cools by placing in ice. After standing for 3 hours at room temperature Cooked back for 15 minutes. The cooled solution is shaken twice with a little water, the benzene solution dried over sodium sulfate and the benzene was distilled off.
Der Rückstand wird mit 525 ml 2-n Salzsäure schwach angesäuert und die Lösung zur Trockne eingedampft. Durch Behandeln mit Aceton erhält man 248 g und durch Aufarbeiten der Aceton-Mutterlaugen weitere 26 g rohes α-Pyrrolidino-n-valerophenon-Monohydrat-Hydrochlorid, entsprechend einer Ausbeute von 85 ffi der Theorie. a-Pyrrolidino-n-valerophenon Hydrochlorid und sein Hydrat sind fast unlöslich in Aceton, leicht löslich in Wasser, ethanol und Alkohol. Sie lassen sich sehr gut umkristallisieren aus der 5-fachen Menge Aceton unter Zusatz von ca. 1 Mol H20. tan erhalt direkt-91-94 % des Rohproduktes an reiner Substanz und nach Aufarbeitung der Mutterlauge 98 %. Die so erhaltene Substanz hat den Schmelzpunkt 104-106°C, welcher sich nach Austreiben von 6 % H2O auf 169-170°C (wasserfreie Form) erhöht.The residue is weakly acidified with 525 ml of 2N hydrochloric acid and the solution evaporated to dryness. Treatment with acetone gives 248 g and by working up the acetone mother liquors a further 26 g of crude α-pyrrolidino-n-valerophenone monohydrate hydrochloride, corresponding to a yield of 85 ffi of theory. α-pyrrolidino-n-valerophenone Hydrochloride and its hydrate are almost insoluble in acetone, easily soluble in water, ethanol and alcohol. They can be recrystallized very well from the 5-fold Amount of acetone with the addition of approx. 1 mol of H20. Tan directly receives 91-94% of the crude product of pure substance and 98% after working up the mother liquor. The thus obtained The substance has a melting point of 104-106 ° C, which is reached after 6% H2O has been expelled increased to 169-170 ° C (anhydrous form).
Beispiel 2 19 g des durch Umsetzen von a-Brom-valerophenon mit Natriummethylat erhaltenen Epoxy-methyläthers werden mit 35 g Pyrrolidin im Autoklaven während 7 Stunden auf 1800C erhitzt. Das Reaktionsgemisch wird mit Wasser versetzt und mit Benzol ausgeschüttelt.Example 2 19 g of the obtained by reacting α-bromo valerophenone with sodium methylate epoxymethyl ethers obtained are mixed with 35 g of pyrrolidine in an autoclave for 7 Heated to 1800C for hours. The reaction mixture is mixed with water and with Benzene shaken out.
Die organische Phase wird dreimal mit Wasser gewaschen, über Natriumsulfat getrocknet, mit 2-n Salzsaure angesauert und im Vakuum zur Trockne eingedampft.The organic phase is washed three times with water over sodium sulfate dried, acidified with 2N hydrochloric acid and evaporated to dryness in vacuo.
Beim Umkristallisieren aus Aceton erhält man 16 g α-Pyrrolidinovalerophenon-Monohydrat-Hydrochlorid, Schmelzpunkt 104 - 106°C.Recrystallization from acetone gives 16 g of α-pyrrolidinovalerophenone monohydrate hydrochloride, Melting point 104-106 ° C.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEW0039501 | 1961-04-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1620710A1 true DE1620710A1 (en) | 1970-04-30 |
Family
ID=7602133
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19611620710 Pending DE1620710A1 (en) | 1961-04-26 | 1961-04-26 | Process for the production of compounds with a central excitatory effect |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1620710A1 (en) |
-
1961
- 1961-04-26 DE DE19611620710 patent/DE1620710A1/en active Pending
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