CH441377A - Process for the preparation of 1-phenyl-1- (o-chloro-phenyl) -3-tert-aminopropanolen- (1) - Google Patents
Process for the preparation of 1-phenyl-1- (o-chloro-phenyl) -3-tert-aminopropanolen- (1)Info
- Publication number
- CH441377A CH441377A CH745764A CH745764A CH441377A CH 441377 A CH441377 A CH 441377A CH 745764 A CH745764 A CH 745764A CH 745764 A CH745764 A CH 745764A CH 441377 A CH441377 A CH 441377A
- Authority
- CH
- Switzerland
- Prior art keywords
- phenyl
- tert
- chloro
- aminopropanolen
- preparation
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 8
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 title claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- BQRIIWKHNJGQFH-UHFFFAOYSA-M [Br-].[Mg+]C1=CC=CC=C1Cl Chemical compound [Br-].[Mg+]C1=CC=CC=C1Cl BQRIIWKHNJGQFH-UHFFFAOYSA-M 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- -1 phenyl anion Chemical class 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- PUAQLLVFLMYYJJ-UHFFFAOYSA-N 2-aminopropiophenone Chemical compound CC(N)C(=O)C1=CC=CC=C1 PUAQLLVFLMYYJJ-UHFFFAOYSA-N 0.000 claims 1
- 230000001419 dependent effect Effects 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 239000003929 acidic solution Substances 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- QBELEDRHMPMKHP-UHFFFAOYSA-N 1-bromo-2-chlorobenzene Chemical compound ClC1=CC=CC=C1Br QBELEDRHMPMKHP-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002253 acid Substances 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
- 238000004519 manufacturing process Methods 0.000 description 1
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 239000011734 sodium 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
- C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Hydrogenated Pyridines (AREA)
Description
Verfahren zur Herstellung von l-Phenyl-l-lo-chlor-phenyll-3-tert.-aminopropanolen-(1)
1-Phenyl-1- [o-chlorphenyl]-3-tert.-amino-propanole (1), insbesondere die Verbindungen der Formel
EMI1.1
worin R und R'geradkettige oder verzweigte Alkyl- gruppen mit 1-5 Kohlenstoffatomen bedeuten, wobei R und R' unter sich auch ringförmig, gegebenenfalls unter Zwischenschaltung eines Heteroatoms, wie Sauer- stoff, Schwefel oder Stickstoff, der seinerseits durch Alkylgruppen substituiert sein kann, verknüpft sein können, zeichnen sich durch eine hervorragende husten stillende Wirksamkeit aus.
Zur Herstellung der genannten Verbindungen wird erfindungsgemäss so verfahren, dass man entweder co- tert.-Amino-o-chlorpropiophenone mit das Phenylanion liefernden Stoffen der Formel Phenyl-Met., wobei Met., Na, Li oder Mg Halbgen bedeutet, reagieren lässt, oder dass man ?-tert.-Amino-propiophenone mit o-Chlor phenylmagnesiumbromid reagieren lässt.
Beispiel 1
Zu einer Atherlösung von ?-Dimethylamino-o-chlorpropiophenon (erhalten durch Freimachen der Base aus 25 g ihres Hydrochlorids) tropft man eine in blicher Weise bereitete Ïtherische L¯sung von Phenylmage siumbromid (aus 19 g Brombenzol und 2, 9 g Magnesium) langsam unter kräftigem Rühren und unter Kühlung des Reaktionsgemisches mit Eiswasser. Nach Beendi- gung der Zugabe wird das Reaktionsgemisch noch eine halbe Stunde auf dem Wasserbad gelinde erwÏrmt und auf eine Mischung von Eis und konzentrierter Salzsäure allmählich ausgetragen. Die ätherische Schicht wird abgetrennt.
Die klare, saure Lösung des Reaktionsproduktes wird nach Abdestillieren des Athers noch zwei Stunden unter Rühren auf 100 C erhitzt. Anschliessend wird die Mischung auf Eis gegossen und mit verdünnter Salzsäure kongosauer gesteNt. Nach dem Schmelzen des Eises wird die Toluolschicht abgetrennt, die wϯrige Lösung zur Entfernung der Nebenprodukte durch Ausschütteln mit ¯ther geklärt und aus der klar filtrierten, sauren wä6rigen Lösung durch Zusatz von Natronlauge die Base ausgefÏllt. Man erhält auf diese Weise ein 01, das durch kurzes Reiben kristallinisch erstarrt. Man saugt ab, wäscht mit Wasser und kristallisiert das rohe 1-Phenyl-l-[o-chlorphenyl]-3-dimethylamino- propanol-(1) aus verdünntem Methanol um.
Reine weisse Nadeln, F. 117-119 C. Das in üblicher Weise dargestellte Hydrochlorid schmilzt bei 185-186¯ C ; das Phosphat bei 205-207 C ; das Maleinat bei 173 C.
Ersetzt man das < u-Dimethylamino-o-chlorpropio- phenon durch die äquivalente Menge co-Piperidino-o- chlorpropiophenon, so erhält man bei analoger Arbeitsweise das l-Phenyl-l-(o-chlorphenyl3-3-piperidino-pro- pan-l-0l vom F. 107 C. Die analog hergestellte Morpholinoverbindung schmilzt bei 142 C, die N'-Methyl piperazinoverbindung bei 131-132 C.
Beispiel 2
Zu einer Atherlösung von ?-Dimethylaminopropiophenon (erhalten durch Freimachen der Base aus 21 g [0, 1 Mol] ihres Hydrochlorids) tropft man eine in üblicher Weise bereitete ätherische Lösung von o-Chlorphenylmagnesiumbromid [aus 23 g (0, 12 Mol) o-Chlorbrombenzol und 2, 9 g (0, 12 Mol) Magnesium] langsam unter kräftigem Rühren und unter Kühlung des Reaktionsgemisches mit Eiswasser. Nach Beendigung der Zugabe wird das Reaktionsgemisch noch eine halbe Stunde auf dem Wasserbad gelinde erwärmt und auf eine Mischung von Eis und konzentrierter Salzsäure allmählich ausgetragen. Die Ïtherische Schicht wird abgetrennt.
Die klare, saure Lösung des Reaktionsprod'uktes wird nach Abdestillieren des Äthers noch zwei Stunden unter Rühren auf 100¯ C erhitzt. Anschlie¯end erhitzt. die Mischung auf Eis gegossen und mit t verdiinnter Sak- sÏure kongosauer gestellt. Nach dem Schmelzen des Eises wird die Toluolschicht abgetrennt, die wässrige Lösung zur Entfernung der Nebenprodukte durch Ausschütteln mit Ather geklärt und aus der klar filtrierten, sauren wässrigen Lösung durch Zusatz von Natronlauge die Base ausgefällt. Man erhält auf diese Weise ein 01, das durch kurzes Reiben kristallinisch erstarrt.
Man saugt ab, wäscht mit Wasser und kristallisiert das rohe 1-Phenyl-1-[o-chlorphenyl]-3-dimethylamino-propanol-(1) aus verdünntem Methanol um. Reine weisse Nadeln, F. 117-119 C.
Process for the production of l-phenyl-l-lo-chlorophenyll-3-tert.-aminopropanol- (1)
1-Phenyl-1- [o-chlorophenyl] -3-tert-aminopropanols (1), in particular the compounds of the formula
EMI1.1
where R and R 'are straight-chain or branched alkyl groups with 1-5 carbon atoms, where R and R' are also ring-shaped among themselves, optionally with the interposition of a hetero atom such as oxygen, sulfur or nitrogen, which in turn can be substituted by alkyl groups , can be linked, are characterized by an excellent cough suppressing effectiveness.
To prepare the compounds mentioned, the process according to the invention is such that either co-tert-amino-o-chloropropiophenone is allowed to react with substances of the formula phenyl-met., Where met., Na, Li or Mg denotes halogene, or that? -tert.-Amino-propiophenone is allowed to react with o-chloro phenylmagnesium bromide.
example 1
An ethereal solution of phenylmagnesium bromide (from 19 g of bromobenzene and 2.9 g of magnesium), prepared in the usual way, is slowly added dropwise to an ethereal solution of? -Dimethylamino-o-chloropropiophenone (obtained by liberating the base from 25 g of its hydrochloride) while stirring vigorously and cooling the reaction mixture with ice water. After the addition is complete, the reaction mixture is warmed gently on the water bath for a further half an hour and gradually poured out onto a mixture of ice and concentrated hydrochloric acid. The ethereal layer is separated.
After the ether has been distilled off, the clear, acidic solution of the reaction product is heated to 100 ° C. for a further two hours while stirring. The mixture is then poured onto ice and made Congo acidic with dilute hydrochloric acid. After the ice has melted, the toluene layer is separated off, the aqueous solution is clarified to remove the by-products by shaking with ether and the base is precipitated from the clear, filtered, acidic aqueous solution by adding sodium hydroxide solution. In this way, an oil is obtained which solidifies crystalline by brief rubbing. It is filtered off with suction, washed with water and the crude 1-phenyl-1- [o-chlorophenyl] -3-dimethylaminopropanol- (1) is recrystallized from dilute methanol.
Pure white needles, F. 117-119 C. The hydrochloride, prepared in the usual way, melts at 185-186¯ C; the phosphate at 205-207 C; the maleate at 173 C.
If the u-dimethylamino-o-chloropropiophenone is replaced by the equivalent amount of co-piperidino-o-chloropropiophenone, then l-phenyl-l- (o-chlorophenyl3-3-piperidino-propane is obtained with an analogous procedure) -l-0l of 107 C. The morpholino compound prepared analogously melts at 142 C., the N'-methyl piperazino compound at 131-132 C.
Example 2
To an ether solution of? -Dimethylaminopropiophenone (obtained by liberating the base from 21 g [0.1 mol] of its hydrochloride) is added dropwise an ethereal solution of o-chlorophenylmagnesium bromide [from 23 g (0.1 mol) of o- Chlorobromobenzene and 2.9 g (0.12 mol) magnesium] slowly with vigorous stirring and while cooling the reaction mixture with ice water. When the addition is complete, the reaction mixture is warmed gently on the water bath for a further half an hour and gradually poured out onto a mixture of ice and concentrated hydrochloric acid. The ethereal layer is separated.
After the ether has been distilled off, the clear, acidic solution of the reaction product is heated to 100 ° C. for a further two hours while stirring. Then heated. the mixture is poured onto ice and made Congo-sour with diluted sac acid. After the ice has melted, the toluene layer is separated off, the aqueous solution is clarified to remove the by-products by shaking with ether and the base is precipitated from the clear, filtered, acidic aqueous solution by adding sodium hydroxide solution. In this way, an oil is obtained which solidifies crystalline by brief rubbing.
It is filtered off with suction, washed with water and the crude 1-phenyl-1- [o-chlorophenyl] -3-dimethylamino-propanol- (1) recrystallized from dilute methanol. Pure white needles, F. 117-119 C.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEF0025420 | 1958-04-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH441377A true CH441377A (en) | 1967-08-15 |
Family
ID=7091623
Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1676364A CH418353A (en) | 1958-04-05 | 1959-03-16 | Process for the preparation of 1-phenyl-1- (o-chlorophenyl) -3-tert.-aminopropanol- (1) |
| CH745764A CH441377A (en) | 1958-04-05 | 1959-03-16 | Process for the preparation of 1-phenyl-1- (o-chloro-phenyl) -3-tert-aminopropanolen- (1) |
| CH7080859A CH408053A (en) | 1958-04-05 | 1959-03-16 | Process for the preparation of 1-phenyl-1- (chlorophenyl) -3-tert-aminopropanol- (1) |
| CH745864A CH439327A (en) | 1958-04-05 | 1959-03-16 | Process for the preparation of 1-phenyl-1- (o-chlorophenyl) -3-tert.-amino-propanolen- (1) |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1676364A CH418353A (en) | 1958-04-05 | 1959-03-16 | Process for the preparation of 1-phenyl-1- (o-chlorophenyl) -3-tert.-aminopropanol- (1) |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH7080859A CH408053A (en) | 1958-04-05 | 1959-03-16 | Process for the preparation of 1-phenyl-1- (chlorophenyl) -3-tert-aminopropanol- (1) |
| CH745864A CH439327A (en) | 1958-04-05 | 1959-03-16 | Process for the preparation of 1-phenyl-1- (o-chlorophenyl) -3-tert.-amino-propanolen- (1) |
Country Status (3)
| Country | Link |
|---|---|
| BE (1) | BE577370A (en) |
| CH (4) | CH418353A (en) |
| FR (1) | FR451M (en) |
-
1959
- 1959-03-16 CH CH1676364A patent/CH418353A/en unknown
- 1959-03-16 CH CH745764A patent/CH441377A/en unknown
- 1959-03-16 CH CH7080859A patent/CH408053A/en unknown
- 1959-03-16 CH CH745864A patent/CH439327A/en unknown
- 1959-04-04 BE BE577370A patent/BE577370A/en unknown
-
1960
- 1960-08-30 FR FR837161A patent/FR451M/fr active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CH439327A (en) | 1967-07-15 |
| FR451M (en) | 1961-04-24 |
| CH418353A (en) | 1966-08-15 |
| CH408053A (en) | 1966-02-28 |
| BE577370A (en) | 1959-07-31 |
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