CH370803A - Process for the preparation of dimethylaminopropyloxybenzenes - Google Patents
Process for the preparation of dimethylaminopropyloxybenzenesInfo
- Publication number
- CH370803A CH370803A CH1337962A CH1337962A CH370803A CH 370803 A CH370803 A CH 370803A CH 1337962 A CH1337962 A CH 1337962A CH 1337962 A CH1337962 A CH 1337962A CH 370803 A CH370803 A CH 370803A
- Authority
- CH
- Switzerland
- Prior art keywords
- group
- unsaturated
- preparation
- alkoxy
- benzenes
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 4
- XXSADNWJNBXHHF-UHFFFAOYSA-N n,n-dimethyl-3-phenoxypropan-1-amine Chemical class CN(C)CCCOC1=CC=CC=C1 XXSADNWJNBXHHF-UHFFFAOYSA-N 0.000 title description 3
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- -1 methoxy, ethoxy, isopropyloxy Chemical group 0.000 description 3
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- JYNZCQHQWDOOKH-UHFFFAOYSA-N 3-(3-chlorophenothiazin-10-yl)-n,n-dimethylpropan-1-amine Chemical compound ClC1=CC=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 JYNZCQHQWDOOKH-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 101100256191 Mus musculus Sbk1 gene Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000520330 Otomys irroratus Species 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 125000004984 dialkylaminoalkoxy group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- BJIOGJUNALELMI-UHFFFAOYSA-N isoeugenol Chemical compound COC1=CC(C=CC)=CC=C1O BJIOGJUNALELMI-UHFFFAOYSA-N 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000005394 methallyl group Chemical group 0.000 description 1
- 150000007522 mineralic acids Chemical group 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- BGBFVIKSTCLLDW-UHFFFAOYSA-N n,n-diethyl-2-(2-methoxy-6-prop-2-enylphenoxy)ethanamine Chemical compound CCN(CC)CCOC1=C(CC=C)C=CC=C1OC BGBFVIKSTCLLDW-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Verfahren zur Herstellung von Dimethylaminopropyloxybenzolen
Es wurde gefunden, dass man zu neuen therapeutisch wertvollen Stoffen gelangt, wenn man solche ,-Dimethylaminopropyloxybenzole herstellt, die in 2-Stellung des Benzolringes einen Alkoxy- oder Aralkoxyrest und ausserdem in 4-, 5- oder 6-Stellung einen ungesättigten, gegebenenfalls halogenierten Alkylrest enthalten. Als Beispiele für Alkoxy-oder Aralkoxyreste seien die Methoxy-, Athoxy-, Isopropyloxy-, N-Propyloxy- und Benzyloxygruppen, als Beispiele für ungesättigte, gegebenenfalls halogenierte Alkylreste die Allyl-, Propenyl-, Methallyl-, Crotyl-, ss-Bromallyl und y-Chlorallylgruppe genannt.
Es sind zwar aus den deutschen Patentschriften Nrn. 224160, 443182, 446606 und 563259 eine Reihe verwandter Stoffe bekannt, die anstelle der y Dimethylaminopropyloxygruppe eine andere Dialkylaminoalkoxygruppe, vorzugsweise die Diäthylamino äthoxygruppe, besitzen. Sie sind als Uterusmittel verwendbar. Demgegenüber zeigen die bisher noch nicht beschriebenen erfindungsgemäss hergestellten [y-Dimethylamino-propyloxy]-benzole eine zentraldämpfende Wirksamkeit ähnlich dem 3-Chlor-lO-[y-di- methylamino-propyl]-phenothiazin, besitzen jedoch gegenüber diesem eine erhöhte allgemeine Verträglichkeit.
Das erfindungsgemässe Verfahren zur Herstellung der [y-Dimethylamino-propyloxy]-benzole ist dadurch gekennzeichnet, dass man 1-Oxy-2-alkoxy (oder -aralkoxy)-benzole, die in 4-, 5- oder 6-Stellung einen ungesättigten, gegebenenfalls halogenierten Al- kylrest tragen, in Gegenwart säurebindender Mittel mit einem 1,3-Dihalogen-propan umsetzt und in dem so erhaltenen Produkt durch Umsetzung mit Dimethylamin das in der Propyloxygruppe y-ständige Halogen durch die Dimethylaminogmppe ersetzt.
Als säurebindende Mittel lassen sich z. B. Alkalihydroxyde oder Alkalialkoholate verwenden. Die Umsetzung erfolgt zweckmässig in einem Lösungsmittel, wie z. B. einem Alkanol, unter Erwärmen.
Die erhaltenen Verbindungen sind in der Form der freien Basen unter vermindertem Druck gut destillierbare, bei Zimmertemperatur flüssige oder verhältnismässig niedrig schmelzende Stoffe, die mit zahlreichen organischen und anorganischen Säuren leicht wasserlösliche und grösstenteils gut kristallisierte Salze bilden.
Die nach vorliegendem Verfahren herstellbarcn Dialkylaminoalkyloxybenzole, die einen ungesättigten Alkylrest enthalten, sind den bekannten vergleichbaren Verbindungen in ihrer pharmakologischen Wirkung überlegen. Dies geht aus den folgenden Vergleichsversuchen hervor, für welche die nachstehenden Verbindungen herangezogen wurden: (I) Verfahrensprodukt von folgender Formel:
EMI1.1
(II) Gravitol:
EMI1.2
EMI2.1
Unsere Ergebnisse sind folgende:
Toxizität
In folgender Tabelle ist die Toxizität Dl o (= Dosis letalis, bei der 509/o der Tiere innerhalb von 4 Tagen sterben) angegeben.
Tabelle D1,, in mg/kg
Maus sbk. Maus i. v. Ratte p. o.
(1) 400 85 600 (11) 125 40 150 (III) 125 35 400 (IV) 85 25 100
In Tierversuchen über die sedative Wirkung der erfindungsgemäss erhältlichen Verbindungen auf das Zentralnervensystem (Test an der schiefen Ebene und Motilitätstest) sowie bei klinischen Versuchen mit der elektroenzephalographischen Methode zeigten die vorstehend genannten Verbindungen I bis IV hervorragende und den bisher verwendeten Produkten überlegene Eigenschaften. Versuche über die Uteruswirkung bei Kaninchen nach Magnus bestätigten ferner die vorteilhaften Eigenschaften der vorliegenden Produkte.
Beispiel
Zu einer Lösung von 2,8 g Natrium in 200 cm3 Alkohol gibt man 20 g 5-Propenyl-guajakol. Diese Lösung tropft man unter Rühren in eine auf 600 angewärmte Mischung aus 100 g 1,3-Dibrom-propan und 150 cm Alkohol und kocht sie anschliessend 12 Stunden am Rückflusskühler. Danach destilliert man den Alkohol und überschüssiges 1,3-Dibrom- propan im Vakuum ab und nimmt den Rückstand in Äther auf. Nach dem Abtrennen des Natriumbromids wäscht man die ätherische Lösung mit 100/auger Natronlauge und Wasser. Nach dem Verjagen des ethers destilliert man den Rückstand im Vakuum, wobei 22 g 1-(,-Brompropyloxy)-2-meth- oxy-5-propenyl-benzol mit KPS = 178-184 übergehen.
Diese Menge wird mit einem Überschuss an alkoholischer Dimethylaminlösung 2 Stunden rückfliessend gekocht, der Alkohol verjagt und der Rückstand mit verdünnter Natronlauge versetzt. Man nimmt die ausgeschiedene Base in Äther auf, trocknet die Ätherlösung mit Kaliumcarbonat und destilliert nach dem Verjagen des ethers den Rückstand im Vakuum, wobei 15,4 g l-(,-Dimethylamino-pro- pyloxy)-2-methoxy-5-propenyl-benzol mit Kp3 = 159 bis 162" übergehen; Hydrochlorid, F = 1660.
Process for the preparation of dimethylaminopropyloxybenzenes
It has been found that new therapeutically valuable substances are obtained if dimethylaminopropyloxybenzenes are prepared which contain an alkoxy or aralkoxy radical in the 2-position of the benzene ring and also an unsaturated, optionally halogenated, radical in the 4-, 5- or 6-position Contain alkyl radical. Examples of alkoxy or aralkoxy radicals are the methoxy, ethoxy, isopropyloxy, N-propyloxy and benzyloxy groups, and examples of unsaturated, optionally halogenated alkyl radicals are the allyl, propenyl, methallyl, crotyl, ss-bromoallyl and called y-chlorallyl group.
A number of related substances are known from German Patent Nos. 224160, 443182, 446606 and 563259 which, instead of the y dimethylaminopropyloxy group, have another dialkylaminoalkoxy group, preferably the diethylamino ethoxy group. They can be used as uterine remedies. In contrast, the [γ-dimethylamino-propyloxy] -benzenes produced according to the invention, which have not yet been described, show a central damping activity similar to 3-chloro-10- [γ-dimethylamino-propyl] -phenothiazine, but have an increased general compatibility with this.
The process according to the invention for the preparation of the [y-dimethylamino-propyloxy] -benzenes is characterized in that 1-oxy-2-alkoxy (or -aralkoxy) -benzenes which in the 4-, 5- or 6-position are an unsaturated, Carry optionally halogenated alkyl radical, reacted in the presence of acid-binding agents with a 1,3-dihalopropane and in the product thus obtained, by reaction with dimethylamine, the halogen in the propyloxy group is replaced by the dimethylaminogmppe.
As acid-binding agents, for. B. use alkali hydroxides or alkali alcoholates. The reaction is conveniently carried out in a solvent, such as. B. an alkanol, with heating.
In the form of the free bases, the compounds obtained are readily distillable under reduced pressure, are liquid at room temperature or have a relatively low melting point and with numerous organic and inorganic acids form readily water-soluble and mostly well crystallized salts.
The dialkylaminoalkyloxybenzenes which can be prepared by the present process and which contain an unsaturated alkyl radical are superior to the known comparable compounds in their pharmacological action. This can be seen from the following comparative tests, for which the following compounds were used: (I) Process product of the following formula:
EMI1.1
(II) Gravitol:
EMI1.2
EMI2.1
Our results are as follows:
toxicity
The following table shows the toxicity Dl o (= lethal dose at which 509 / o of the animals die within 4 days).
Table D1 ,, in mg / kg
Mouse sbk. Mouse i. v. Rat p. O.
(1) 400 85 600 (11) 125 40 150 (III) 125 35 400 (IV) 85 25 100
In animal experiments on the sedative effect of the compounds obtainable according to the invention on the central nervous system (test on the inclined plane and motility test) as well as in clinical experiments with the electroencephalographic method, the abovementioned compounds I to IV showed excellent properties and superior properties to the products previously used. Tests on the uterine effect in rabbits according to Magnus also confirmed the advantageous properties of the present products.
example
20 g of 5-propenyl-guaiacol is added to a solution of 2.8 g of sodium in 200 cm3 of alcohol. This solution is added dropwise, with stirring, to a mixture of 100 g of 1,3-dibromopropane and 150 cm of alcohol, warmed to 600, and then boiled for 12 hours on the reflux condenser. The alcohol and excess 1,3-dibromopropane are then distilled off in vacuo and the residue is taken up in ether. After the sodium bromide has been separated off, the ethereal solution is washed with 100% sodium hydroxide solution and water. After the ether has been driven off, the residue is distilled in vacuo, with 22 g of 1 - (, - bromopropyloxy) -2-methoxy-5-propenylbenzene with KPS = 178-184 passing over.
This amount is refluxed for 2 hours with an excess of alcoholic dimethylamine solution, the alcohol is driven off and the residue is mixed with dilute sodium hydroxide solution. The precipitated base is taken up in ether, the ether solution is dried with potassium carbonate and, after the ether has been driven off, the residue is distilled in vacuo, with 15.4 g of l - (, - dimethylamino-propyloxy) -2-methoxy-5-propenyl -benzene with bp3 = 159 to 162 "pass over; hydrochloride, F = 1660.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1337962A CH370803A (en) | 1957-06-11 | 1957-06-11 | Process for the preparation of dimethylaminopropyloxybenzenes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1337962A CH370803A (en) | 1957-06-11 | 1957-06-11 | Process for the preparation of dimethylaminopropyloxybenzenes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH370803A true CH370803A (en) | 1963-07-31 |
Family
ID=4391901
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1337962A CH370803A (en) | 1957-06-11 | 1957-06-11 | Process for the preparation of dimethylaminopropyloxybenzenes |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH370803A (en) |
-
1957
- 1957-06-11 CH CH1337962A patent/CH370803A/en unknown
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