DE1445969C - Process for the preparation of basic 3,4,5 trimethoxybenzoic acid esters - Google Patents
Process for the preparation of basic 3,4,5 trimethoxybenzoic acid estersInfo
- Publication number
- DE1445969C DE1445969C DE1445969C DE 1445969 C DE1445969 C DE 1445969C DE 1445969 C DE1445969 C DE 1445969C
- Authority
- DE
- Germany
- Prior art keywords
- trimethoxybenzoic acid
- basic
- water
- general formula
- esters
- 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.)
- Expired
Links
- SJSOFNCYXJUNBT-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid Chemical class COC1=CC(C(O)=O)=CC(OC)=C1OC SJSOFNCYXJUNBT-UHFFFAOYSA-N 0.000 title claims description 11
- 238000000034 method Methods 0.000 title claims description 6
- -1 diethylamino, pyrrolidino, piperidino Chemical group 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- BUHYMJLFRZAFBF-UHFFFAOYSA-N 3,4,5-trimethoxybenzoyl chloride Chemical compound COC1=CC(C(Cl)=O)=CC(OC)=C1OC BUHYMJLFRZAFBF-UHFFFAOYSA-N 0.000 claims description 6
- IWPZKOJSYQZABD-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid Natural products COC1=CC(OC)=CC(C(O)=O)=C1 IWPZKOJSYQZABD-UHFFFAOYSA-N 0.000 claims description 4
- 230000001624 sedative effect Effects 0.000 claims description 4
- 231100001274 therapeutic index Toxicity 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 2
- 239000000932 sedative agent Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 4
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims 3
- CPEONABTMRSIKA-UHFFFAOYSA-N 1,4$l^{2}-oxazinane Chemical compound C1COCC[N]1 CPEONABTMRSIKA-UHFFFAOYSA-N 0.000 claims 2
- MXZROAOUCUVNHX-UHFFFAOYSA-N 2-Aminopropanol Chemical class CCC(N)O MXZROAOUCUVNHX-UHFFFAOYSA-N 0.000 claims 2
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims 2
- 230000003276 anti-hypertensive effect Effects 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 230000000694 effects Effects 0.000 claims 2
- 239000012442 inert solvent Substances 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 210000000653 nervous system Anatomy 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 2
- 230000001988 toxicity Effects 0.000 claims 2
- 231100000419 toxicity Toxicity 0.000 claims 2
- 241000252095 Congridae Species 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 150000001721 carbon Chemical group 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 238000011835 investigation Methods 0.000 claims 1
- 230000001962 neuropharmacologic effect Effects 0.000 claims 1
- 230000000144 pharmacologic effect Effects 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 230000036772 blood pressure Effects 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- UYXAWHWODHRRMR-UHFFFAOYSA-N hexobarbital Chemical compound O=C1N(C)C(=O)NC(=O)C1(C)C1=CCCCC1 UYXAWHWODHRRMR-UHFFFAOYSA-N 0.000 description 2
- 229960002456 hexobarbital Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- GAZNVVBKELWTBC-UHFFFAOYSA-N 2,3,4-trimethoxybenzoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C(OC)=C1OC GAZNVVBKELWTBC-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 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
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000001168 carotid artery common Anatomy 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- SQMCFUSVGSBKFK-UHFFFAOYSA-M sodium;5-(cyclohexen-1-yl)-1,5-dimethylpyrimidin-3-ide-2,4,6-trione Chemical compound [Na+].O=C1N(C)C(=O)[N-]C(=O)C1(C)C1=CCCCC1 SQMCFUSVGSBKFK-UHFFFAOYSA-M 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Description
N /
N
N /
N
Wirksamkeit
ED50/mg/kgSedatives
effectiveness
ED 50 / mg / kg
IndexMore therapeutic
index
CH, OCH, O
CH3O-/ S-CO-O-CH2-C-CH2-BCH 3 O- / S-CO-O-CH 2 -C-CH 2 -B
N /
N
senkende
Wirksamkeit
EDso/mg/kgBlood pressure
lowering
effectiveness
ED 50 / mg / kg
IndexTherapeutic,
index
Fortsetzungcontinuation
N /
N
senkende
Wirksamkeit
ED50 mg kgBlood pressure
lowering
effectiveness
ED 50 mg kg
IndexMore therapeutic
index
Die akute Toxizität ist in den Tabellen mit DL50 (mg/kg) angegeben. Es ist dies die Substanzmenge, die nach subcutaner Verabreichung den Tod von 50% der Versuchstiere (weiße Mäuse) innerhalb von 24 Stunden hervorruft.The acute toxicity is given in the tables with DL 50 (mg / kg). This is the amount of substance which, after subcutaneous administration, causes the death of 50% of the test animals (white mice) within 24 hours.
Zur Feststellung der sedierenden Wirkung wurde die prozentuale Verlängerung des Hexobarbitalschlafes*) nach der Methode von Holten und L a r s e η (Acta Pharmakologica et Toxicologica 12 [1956], S. 346 bis 363) ermittelt, indem die Versuchssubstanzen in den Dosen von 1, 2 und 5% der DL50 jeweils 30 Minuten vor der subcutanen Applikation von 100 mg/kg Hexobarbitalnatrium verabreicht wurden und die Schlafverlängerung gegenüber nicht vorbehandelten Tieren gemessen wurde. Die ED50 (= effektive Dosis, die eine 50%ige Schlafverlängerung hervorruft) wurde an Hand der Dosiswirkungskurve graphisch bestimmt.To determine the sedative effect, the percentage prolongation of the hexobarbital sleep *) was determined by the method of Holten and L arse η (Acta Pharmakologica et Toxicologica 12 [1956], pp. 346 to 363) by adding the test substances in doses of 1, 2 and 5% of the DL 50 were administered 30 minutes before the subcutaneous application of 100 mg / kg hexobarbital sodium and the prolonged sleep was measured in relation to animals that had not been pretreated. The ED 50 (= effective dose that causes 50% sleep prolongation) was determined graphically on the basis of the dose-effect curve.
Die Blutdruckmessung erfolgte blutig am mit Urethan — 1 g/kg (25%ige Lösung) i.V. — narkotisierten Kaninchen an der Arteria carotis communis mittels Hg-Manometer. Die zu prüfenden Substanzen wurden intravenös in die Vena jugularis externa injiziert, wie in L. T h e r, »Pharmakologische Methoden« (1949), S. 212 bis 227, beschrieben. Die ED50 (= effektive Dosis, die eine 50%ige Blutdrucksenkung hervorruft) wurde aus der Dosiswirkungskurve graphisch ermittelt.The blood pressure was measured in blood on rabbits anesthetized with urethane - 1 g / kg (25% solution) iv - on the common carotid artery using a mercury manometer. The substances to be tested were injected intravenously into the external jugular vein, as described in L. T., "Pharmakologische Methode" (1949), pp. 212 to 227. The ED 50 (= effective dose which causes a 50% reduction in blood pressure) was determined graphically from the dose-effect curve.
Die nachfolgenden Beispiele sollen die Erfindung erläutern:The following examples are intended to explain the invention:
telt. Die Benzolphasen werden zusammengegeben, dreimal mit je 50 ml 15%iger Natronlauge ausgeschüttelt,
anschließend mit Wasser neutral gewaschen, mit Na2SO4 getrocknet und eingeengt. Der
Rückstand wird im Hochvakuum destilliert.
Ausbeute: 4Og = 70% der Theorie, n'i = 1,5103.telt. The benzene phases are combined, extracted three times with 50 ml of 15% sodium hydroxide solution each time, then washed neutral with water, dried with Na 2 SO 4 and concentrated. The residue is distilled in a high vacuum.
Yield: 40 g = 70% of theory, n'i = 1.5103.
B e i s ρ i e 1 2B e i s ρ i e 1 2
3,4,5-Trimethoxybenzoesäure-(2,2-diäthyl-3-pyrrolidino-propyl)-ester, 27,8 g 2,2-Diäthyl-3-pyrrolidinopropanol-1 und 6 g Ätznatron, in 80 ml Wasser gelöst, werden zusammen in einen 500-ml-Dreihalskolben gegeben. Unter Eiskühlung wird anschließend 34,5 g = 0,15 Mol Trimethoxybenzoesäurechlorid, in ;t'-absolutem Benzol gelöst, zugetropft. Nach vollendeter Eintragung wird das Reaktionsgemisch noch 2 Stunden unter Rückfluß gekocht. Anschließend wird die Benzolphase von der wäßrigen Phase getrennt. Die wäßrige Phase wird mehrfach mit Benzol ausgeschüttelt. Die beiden Benzolphasen werden zusammengegeben, dreimal mit je 50 ml 15%iger Natronlauge ausgeschüttelt, anschließend mit Wasser neutral gewaschen, mit Na2SO4 getrocknet und .eingeengt. Der Rückstand wird mit Alkohol aufgenommen und unter Zusatz von Aktivkohle umkristallisiert.3,4,5-trimethoxybenzoic acid (2,2-diethyl-3-pyrrolidino-propyl) ester, 27.8 g of 2,2-diethyl-3-pyrrolidinopropanol-1 and 6 g of caustic soda, dissolved in 80 ml of water, are placed together in a 500 ml three-necked flask. With ice cooling, 34.5 g = 0.15 mol of trimethoxybenzoic acid chloride, dissolved in 't ' - absolute benzene, are then added dropwise. When the entry is complete, the reaction mixture is refluxed for a further 2 hours. The benzene phase is then separated from the aqueous phase. The aqueous phase is extracted several times with benzene. The two benzene phases are combined, extracted three times with 50 ml of 15% sodium hydroxide solution each time, then washed neutral with water, dried with Na 2 SO 4 and concentrated. The residue is taken up in alcohol and recrystallized with the addition of activated charcoal.
Ausbeute: 22,5 g = 39,5% der Theorie, farblose Kristalle vom Fp. 680C.Yield: 22.5 g = 39.5% of theory, colorless crystals with a melting point of 68 ° C.
3,4,5 - Trimethoxybenzoesäure - (2,2 - diäthyl - 3 - diäthyl-amino-propyl-l)-ester, 28 g 2,2-Diäthyl-3-diäthyl-amino-propanol-1 und 6 g Ätznatron, in 80 ml Wasser gelöst, werden zusammen in einen 1 -1-Dreihalskolben gegeben. Unter Eiskühlung werden anschließend 34,5 g 3,4,5-Trimethoxybenzoesäurechlorid, in 200 ml absolutem Benzol gelöst, zugetropft. Anschließend wird das Reaktionsgemisch 2 Stunden unter Rückfluß gekocht. Nach dem Erkalten wird die Benzolphase von der wäßrigen Phase getrennt. Die wäßrige. Phase wird mehrfach mit Benzol ausgeschüt-3,4,5 - trimethoxybenzoic acid - (2,2 - diethyl - 3 - diethylamino-propyl-1) ester, 28 g of 2,2-diethyl-3-diethyl-aminopropanol-1 and 6 g of caustic soda, dissolved in 80 ml of water, are put together in a 1 -1 three-necked flask given. 34.5 g of 3,4,5-trimethoxybenzoic acid chloride, in 200 ml of absolute benzene dissolved, added dropwise. The reaction mixture is then taken for 2 hours Refluxed. After cooling, the benzene phase is separated from the aqueous phase. the aqueous. Phase is poured out several times with benzene
*) »Hexobarbital« = nicht schutzfähige internationale Kurzbezeichnung
für S-fCyclohexen-l-yH-S-methyl-N-methylbarbitursäure.
Der therapeutische Index = DL50 : ED50.*) "Hexobarbital" = international abbreviation for S-f-cyclohexen-1-yH-S-methyl-N-methylbarbituric acid that cannot be protected.
The therapeutic index = DL 50 : ED 50 .
3,4,5 - Trimethoxybenzoesäure- (2,2 - diäthyl - 3 - morpholino-propyl)-ester, 30,2 g 2,2-Diäthyl-3-morpholinopropanol-(l) und 16 g Triäthylamin werden in 200 ml getrocknetem Chloroform gelöst. In die eisgekühlte Mischung wird eine Lösung von 35 g 3,4,5-Trimethoxybenzoesäurechlorid in 100 ml getrocknetem Chloroform zugetropft. Anschließeradientfernt man die Eiskühlung und erwärmt 30 Minuten später 1 Stunde lang auf dem Dampfbad.3,4,5 - trimethoxybenzoic acid (2,2 - diethyl - 3 - morpholino-propyl) ester, 30.2 g of 2,2-diethyl-3-morpholinopropanol- (l) and 16 g of triethylamine are dissolved in 200 ml of dried chloroform. In the ice-cold Mixture is a solution of 35 g of 3,4,5-trimethoxybenzoic acid chloride in 100 ml of dried Chloroform was added dropwise. Connection radiusdistant one ice-cooler and warms 30 minutes later for 1 hour on the steam bath.
Das erkaltete Reaktionsgemisch wird nacheinander mit verdünnter Natronlauge und Wasser ausgeschüttelt. Die abgetrennte benzolische Phase wird über Natriumsulfat getrocknet. Nach Entfernen des Benzols durch Destillation kristallisiert der Rückstand nach Erkalten.The cooled reaction mixture is extracted successively with dilute sodium hydroxide solution and water. The separated benzene phase is dried over sodium sulfate. After removing the benzene the residue crystallizes by distillation after cooling.
Ausbeute: 35 g = 59% der Theorie, farblose Kristalle vom Fp. 560C aus Äther—Petroläther.Yield: 35 g = 59% of theory, colorless crystals, melting at 56 0 C from ether-petroleum ether..
Analog der im Beispiel 3 beschriebenen Verfahrensweise werden 36 g 2-Äthyl-2-benzyl-3-diäthylaminopropanol-(l) mit 35 g 3,4,5-Trimethoxybenzoylchlorid unter Zusatz von 15 g Triäthylamin umgesetzt, wobei 3,4,5-Trimethoxybenzoesäure-(2-benzyl-2-äthyl-3-diäthylaminopropyl)-ester erhalten wird.Analogously to the procedure described in Example 3, 36 g of 2-ethyl-2-benzyl-3-diethylaminopropanol (l) reacted with 35 g of 3,4,5-trimethoxybenzoyl chloride with the addition of 15 g of triethylamine, wherein 3,4,5-trimethoxybenzoic acid (2-benzyl-2-ethyl-3-diethylaminopropyl) ester is obtained.
Ausbeute: 35 g = 55% der Theorie, Flüssigkeit vom Kp. 0,2 21O0C, η J5 = 1,5406.Yield: 35 g = 55% of theory, a liquid, boiling 0.2 21O 0 C, η Y 5 = 1.5406..
Wie im Beispiel 3 beschrieben, erhält man durch Umsetzung von 2-Äthyl-2-pheny]-3-pyrrolidinopropanol-(l) mit 3,4,5-Trimethoxybenzoylchlorid und Triäthylamin 3,4,5 - Trimethoxybenzoesäure - (2 - äthyl-2-phenyl-3-pyrrolidino-propyl)-ester. As described in Example 3, by reacting 2-ethyl-2-pheny] -3-pyrrolidinopropanol- (l) with 3,4,5-trimethoxybenzoyl chloride and triethylamine 3,4,5-trimethoxybenzoic acid (2-ethyl-2-phenyl-3-pyrrolidino-propyl) ester.
Ausbeute: 54%
ίο Kp. 0,01 2040C, ηί Yield: 54%
ίο Kp. 0.01 204 0 C, ηί
der Theorie,
= 1,5530.the theory,
= 1.5530.
Flüssigkeit vomLiquid from
209 514/335209 514/335
Claims (2)
Family
ID=
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