CH395998A - Process for the preparation of α-pyrrolidino-valerophenones - Google Patents
Process for the preparation of α-pyrrolidino-valerophenonesInfo
- Publication number
- CH395998A CH395998A CH286465A CH286465A CH395998A CH 395998 A CH395998 A CH 395998A CH 286465 A CH286465 A CH 286465A CH 286465 A CH286465 A CH 286465A CH 395998 A CH395998 A CH 395998A
- Authority
- CH
- Switzerland
- Prior art keywords
- pyrrolidino
- valerophenones
- acid
- preparation
- formula
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 4
- YDIIDRWHPFMLGR-UHFFFAOYSA-N α-pyrrolidinopentiophenone Chemical class C=1C=CC=CC=1C(=O)C(CCC)N1CCCC1 YDIIDRWHPFMLGR-UHFFFAOYSA-N 0.000 title claims description 3
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 150000002440 hydroxy compounds Chemical class 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 125000004043 oxo group Chemical group O=* 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 229910001868 water Inorganic materials 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- -1 B. the hydrohalides Chemical class 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000004936 stimulating effect Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- JHWIEAWILPSRMU-UHFFFAOYSA-N 2-methyl-3-pyrimidin-4-ylpropanoic acid Chemical compound OC(=O)C(C)CC1=CC=NC=N1 JHWIEAWILPSRMU-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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)
Description
Verfahren zur Herstellung von a-Pyrrolidino-valerophenonen
Gegenstand der Erfindung ist ein Verfahren zur Herstellung von neuen a-Pyrrolidino-valerophenonen der Formel :
EMI1.1
worin R Wasserstoff, ein Chloratom, eine Methyl- oder eine Methoxygruppe bedeutet, oder von Säure- Additionssalzen dieser Basen.
Substanzen der obigen Formel bzw. ihre Salze, z. B. die Hydrohalogenide, besitzen gute zentral, er- regende Wirkung ohne unerwünschte Nebenwirkun- gen, wie Kreislaufwirkungen.
Diese Wirkung ist für die erfindungsgemäss herstellbaren Verbindungen sehr spezifisch. Geringfügige Abweichungen von der angegebenen Formel (I) fü ren, wie sich gezeigt hat, zu einer Herabsetzung oder zum Verlust der zentral stimulierenden Wirkung oder zum Auftreten unerwünschter Nebenwirkungen. Zum Beispiel geht die zentral erregende Wirkung in folgenden Fällen teilweise oder ganz verloren : wenn ein Substituent R in einer andern Stellung als der p Stelluag ist oder, wenn er im Benzolkern mehrfach auftritt (z.
B. 3,4-Di-R- oder 3,4,5-Tri-R-Verbindungen) ; wenn im Substituenten R Alkyl-odr Alkoxygruppen mit mehr als einem GAtom auftreten ; wenn das Wasserstoffatom am tertiären C-Atom durch eine Alkylgruppe ersetzt wird ; oder wenn die Propylgruppe am tertiären C-Atom durch eine Alkylgruppe mit weniger als 3 C-Atomen ersetzt wird.
Die genannten neuen a-Pyrrolidino-valerophenone (I) werden erfindungsgemäss erhalten, indem man eine entsprechende Hydroxyverbindung der Formel :
EMI1.2
mit einem Oxydationsmittel, wie Chromsäure oder einem Alkalimetalldichromat, behandelt. Die Oxydation kann z. B. in einem eine Mineralsäure enthalten- den wässerigen Lösungsmitbel bei Zimmertemperatur durchgeführt werden, worauf das gebildete Keton mit einem organischen ; Lösungsmittel extrahiert und in üblicher Weise isoliert werden kann.
Die Säure-Additionssalze der Basen entsprechend Formel (I) kann man in üblicher Weise durch Umsetzen der Basen mit geeigneten anorganisohen oder organischen Säuren, wie
Chlorwasserstoffsäure, Bromwasserstoffsäure,
Schwefelsäure, Phosphorsäure, Essigsäure,
Weinsäure, Maleinsäure, Oxalsäure,
Citronensäure und dergleichen, erhalben.
Die erfindungsgemäss erhältlichen Produkte mit zentral stimulierender Wirkung können unter Verwendung der üblichen Träger-, Hilfs-und Füllstoffe in passenden Applikationsformen verabreicht werden, z. B. in Form von Tabletten oder Dragées mit etwa 5 bis 60 mg Wirkstoff oder von Suppositorien mit etwa 10 bis 60 mg Wirksboff.
Beispiel
19 g in einem Gemisch aus 50 ml Wasser und 6 ml konzentrierter Schwefelsäure gelös ; tes l-Phenyl- 2-pyrrolidino-n-pentanol-1 werden langsam unter Rühren mit einer Lösung von 10 g Natriumbichromat in einem Gemisch aus 50 ml Wasser und 15 ml kon zentrierter Schwefelsäure versetzt. Das Reaktions- gemisch wird während 3 Stunden bei Zimmertempe- ratur gerührt. Darauf wird es alkalisch gestellt und mit Benzol ausgeschütbelt. Die benzolische Lösung wird dreimal mit Wasser gewaschen, über Natriumsulfat getrocknet, mit 2n Salzsäure angesäuert und im Vakuum zur Trockne eingedampft.
Beim Umkri stallisieren aus Aceton erhält man 15 g a-Pyrrolidino- n-valerophenonWmonohydirat-Hydrochlorid, Smp. 1W bis 106 C. a-Pyrrolidino-n-valerophenon-Hydrochlorid und sein Hydrat sind fast unlöslich in Aceton, leicht lös- lich in Wasser, Methanol und Alkohol. Sie lassen sich sehr gut umkristallisieren aus der 5fachen Menge Aceton unter Zusatz von etwa 1 Mol H20. Man er- hält direkt 91-94% des Rohproduktes an reiner Substanz und nach Aufarbeitung der Mutterlauge 98 %.
Die so erhaltene Substanz hat den Schmelzpunkt 104 bis 106 C, welcher sich nach Austreiben von 6% H2O auf 169-170 C (wasserfreie Form) erhöht.
Bei gleichem Vorgehen wie im vorerwähnben Beispiel erhält man aus entsprechenden Ausgangsmate- rialien ferner z. B. a-Pyrrolidino-p-methoxy-n-valerophenon-
Hydrochlorid, Smp. 177 C, a-Pyrrolidino-p-methyl-n-valerophenon-
Hydrochlorid, Smp. 178 C, sowie a-Pyrrolid'ino-p-chlor-ni-valerophenon-
Hydrochlorid, Smp. 203-208 C.
Process for the preparation of α-pyrrolidino-valerophenones
The invention relates to a process for the preparation of new a-pyrrolidino-valerophenones of the formula:
EMI1.1
wherein R denotes hydrogen, a chlorine atom, a methyl or a methoxy group, or of acid addition salts of these bases.
Substances of the above formula or their salts, e.g. B. the hydrohalides, have a good central, stimulating effect without undesirable side effects such as circulatory effects.
This effect is very specific for the compounds which can be prepared according to the invention. Slight deviations from the formula (I) given lead, as has been shown, to a reduction or loss of the centrally stimulating effect or to the occurrence of undesirable side effects. For example, the central excitatory effect is partially or completely lost in the following cases: if a substituent R is in a position other than the p position or if it occurs several times in the benzene nucleus (e.g.
B. 3,4-Di-R or 3,4,5-Tri-R compounds); if alkyl or alkoxy groups with more than one G atom occur in the substituent R; when the hydrogen atom on the tertiary carbon atom is replaced by an alkyl group; or if the propyl group on the tertiary carbon atom is replaced by an alkyl group with fewer than 3 carbon atoms.
The new a-pyrrolidino-valerophenones (I) mentioned are obtained according to the invention by adding a corresponding hydroxy compound of the formula:
EMI1.2
treated with an oxidizing agent such as chromic acid or an alkali metal dichromate. The oxidation can e.g. B. be carried out in an aqueous solvent containing a mineral acid at room temperature, whereupon the ketone formed with an organic; Solvent extracted and isolated in the usual way.
The acid addition salts of the bases corresponding to formula (I) can be prepared in a customary manner by reacting the bases with suitable inorganic or organic acids, such as
Hydrochloric acid, hydrobromic acid,
Sulfuric acid, phosphoric acid, acetic acid,
Tartaric acid, maleic acid, oxalic acid,
Citric acid and the like.
The products with a centrally stimulating effect obtainable according to the invention can be administered in suitable application forms using the usual carriers, auxiliaries and fillers, eg. B. 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.
example
19 g dissolved in a mixture of 50 ml water and 6 ml concentrated sulfuric acid; tes l-phenyl-2-pyrrolidino-n-pentanol-1 are slowly added with stirring with a solution of 10 g of sodium dichromate in a mixture of 50 ml of water and 15 ml of concentrated sulfuric acid. The reaction mixture is stirred for 3 hours at room temperature. It is then made alkaline and shaken out with benzene. The benzene solution is washed three times with water, dried over sodium sulfate, acidified with 2N hydrochloric acid and evaporated to dryness in vacuo.
When recrystallizing from acetone, 15 g of α-pyrrolidino-n-valerophenone monohydirate hydrochloride, melting point 1W to 106 C. α-Pyrrolidino-n-valerophenone hydrochloride and its hydrate are almost insoluble in acetone, easily soluble in water , Methanol and alcohol. They can be recrystallized very easily from 5 times the amount of acetone with the addition of about 1 mol of H20. 91-94% of the pure substance of the crude product is obtained directly, and 98% after working up the mother liquor.
The substance obtained in this way has a melting point of 104 to 106 C, which increases to 169-170 C (anhydrous form) after 6% H2O has been expelled.
Using the same procedure as in the example mentioned above, one also obtains z. B. a-pyrrolidino-p-methoxy-n-valerophenone-
Hydrochloride, m.p. 177 C, a-pyrrolidino-p-methyl-n-valerophenone
Hydrochloride, m.p. 178 C, and a-pyrrolid'ino-p-chloro-ni-valerophenone-
Hydrochloride, m.p. 203-208 C.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH286465A CH395998A (en) | 1961-05-05 | 1961-05-05 | Process for the preparation of α-pyrrolidino-valerophenones |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH286465A CH395998A (en) | 1961-05-05 | 1961-05-05 | Process for the preparation of α-pyrrolidino-valerophenones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH395998A true CH395998A (en) | 1965-07-31 |
Family
ID=4243297
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH286465A CH395998A (en) | 1961-05-05 | 1961-05-05 | Process for the preparation of α-pyrrolidino-valerophenones |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH395998A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1670755A4 (en) * | 2003-10-08 | 2007-02-28 | Harvard College | PYROVALERONE ANALOGUES AND THERAPEUTIC USES |
-
1961
- 1961-05-05 CH CH286465A patent/CH395998A/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1670755A4 (en) * | 2003-10-08 | 2007-02-28 | Harvard College | PYROVALERONE ANALOGUES AND THERAPEUTIC USES |
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