CH314567A - Process for the preparation of an anesthetic - Google Patents
Process for the preparation of an anestheticInfo
- Publication number
- CH314567A CH314567A CH314567DA CH314567A CH 314567 A CH314567 A CH 314567A CH 314567D A CH314567D A CH 314567DA CH 314567 A CH314567 A CH 314567A
- Authority
- CH
- Switzerland
- Prior art keywords
- acid
- preparation
- piperidino
- anesthetic
- ethyl ester
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 4
- 230000003444 anaesthetic effect Effects 0.000 title description 3
- 239000002253 acid Substances 0.000 claims description 7
- 238000002844 melting Methods 0.000 claims description 4
- 230000008018 melting Effects 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 6
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 150000004982 aromatic amines Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000003472 neutralizing effect Effects 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- -1 carbanilic acid ester Chemical class 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- PWXJULSLLONQHY-UHFFFAOYSA-N phenylcarbamic acid Chemical compound OC(=O)NC1=CC=CC=C1 PWXJULSLLONQHY-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- CREZIHDFCDXCBT-UHFFFAOYSA-N (2,6-dimethylphenyl)carbamic acid Chemical compound CC1=CC=CC(C)=C1NC(O)=O CREZIHDFCDXCBT-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 238000005406 washing 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
- 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
- C07D295/08—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 singly bound oxygen or sulfur atoms
- C07D295/084—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 singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—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 singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verfahren zur Herstellung eines Anästhetikums Von Aminoalkoholen abgeleitete Ester der Carbani'lsäure mit Alkyl- oder Alkoxygruppen in 2,6- oder 2,4,6=Stellung des Phenylrestes be sitzen ausgezeichnete anästhetische Eigenschaf ten, wie hohe Wirksamkeit, geringe Toxizität und gute Stabilität der Lösungen ihrer Salze, was sie sowohl für die Oberflächen- als auch für die Injektionsanästhesie geeignet macht.
Ein entscheidender Faktor für die Wirksam keit und Stabilität dieser Ester ist die sym metrische Anordnung der Subatituenten im Phenylkern der Carbanilsäure, und Unter suchungen haben ergeben, dass besonders die Carbanilsäureester von Alkoholen von der Art von Piperidinolalkanolen und Dialkjamino- alkanolen günstige Eigenschaften aufweisen.
Die Verbindungen entsprechen der Formel
EMI0001.0017
in der R, und R3 Alkyl- oder Alkoxygruppen, R2 Wasserstoff, A2kyl oder eine Alkoxy- gruppe, R4 eine verzweigte oder unverzweigte,
gesättigte oder ungesättigte Kohlenwasserstoff kette mit höchstens 6 Kohlenstoffatomen und R5 und R6 Alkylgruppen oder zusammen mit dem Stickstoff einen gesättigten heterocyeli- sehen Ring bedeuten. Diese Anästhetika lassen sich in der Weise herstellen, dass man ein aromatisches Amin der Formel
EMI0001.0035
mit einem Halogenameisensäureester der For mel
EMI0001.0037
umsetzt, wobei X Halogen bedeutet. An Stelle des Halogenameisensäureesters kann man auch ein Salz dieser Base verwenden.
Es empfiehlt sich, die Reaktion in einem indifferenten Lö sungsmittel durchzuführen.
Dabei kann man den Halogenameisensäure- aminoalkylester entweder als solchen oder in einem indifferenten Lösungsmittel gelöst in die Lösung des aromatischen Amins fliessen lassen. Für den Verlauf der Reaktion ist .es umerheblich, welche der Komponenten der andern zugesetzt wird.
Zur Neutralisation des bei der Reaktion entstehenden Halogenwasserstoffes kann man die Reaktion in Gegenwart von 2 Mol des be- treffenden aromatischen Amins oder eines andern geeigneten Neutralisiermittels durch führen; doch kann man auch ohne anderes Neutralisiermittel als den gebildeten Carbanil- säureester arbeiten.
Nach Beendigung der Reaktion kann der freie Carbanilsäureester nach Behandlung mit einem Neutralisiermittel durch mehrmaliges Waschen mit Wasser und nachheriges Abtrei ben des verwendeten Lösungsmittels isoliert werden. Er kann dann nach bekannten Me thoden, z. B. durch Behandlung mit Aktiv kohle und Umkristallisieren, gereinigt werden.
Gegenstand des vorliegenden Patentes ist nun ein Verfahren zur Herstellung von 2,6- Dimethyl-carbanilsäure -,8 - piperidino - äthyl- ester, welches dadurch gekennzeichnet ist, dass man 2,6-Dimethyl-anilin mit einem Halogen ameisensäure-ss-piperidino-äthylester umsetzt.
An Stelle des Halogenameisensäureesters kann man auch ein Salz dieser Base verwen den.
Beispiel 121 Teile 2,6-Dimethyl-anilin, in 700 Teilen Benzol gelöst, werden mit 80 Teilen feinpulve risiertem Soda, das durch kräftiges Rühren in Suspension gehalten wird, vermischt. Die ver wendeten Chemikalien müssen gut getrocknet sein. Dann lässt man eine Lösung von 193 Teilen Chlorameisensäure-ss-piperidino-äthyl- ester in 300 Teile Benzol unter Kühlung bei etwa 20 C in die Suspension einlaufen.
Wenn die exotherme Reaktion beendet ist, kocht man noch eine Stunde unter Rückflusskühlung. Dann kühlt man auf Zimmertemperatur ab und filtriert vom gebildeten Kochsalz und dem überschüssigen Soda ab. Der Rückstand wird auf dem Filter mit 100 Teilen Benzol ge waschen. Die vereinigten Filtrate, die den ge bildeten 2,6-Dimet.hyl-earbanilsäure-ss-pipei,- idino-äthylester enthalten, werden mit ver dünnter Salzsäure extrahiert.
Die Sälzsäure- lösung wird nach Einstellen des pH-Wertes auf etwa 6,5 mit 20 Teilen Aktivkohle und 1 Teil Natriumdithionit behandelt. Bei vorsieh- tigem Ausfällen mit Ammoniak wird der freie Ester als weisser, krist.alliniseher Nied'ersehlaa erhalten. Er schmilzt. bei 80-82 C.
Das Hydrochlorid ist. ein weisses Kristall pulver mit Schmelzpunkt zwischen <B>167</B> bi.-# 169 C.
Process for the preparation of an anesthetic. Esters of carbani'l acid derived from amino alcohols with alkyl or alkoxy groups in the 2,6- or 2,4,6 = position of the phenyl radical have excellent anesthetic properties, such as high effectiveness, low toxicity and good stability Solutions of their salts, which makes them suitable for both surface and injection anesthesia.
A decisive factor for the effectiveness and stability of these esters is the symmetrical arrangement of the subatituents in the phenyl nucleus of the carbanilic acid, and studies have shown that especially the carbanilic acid esters of alcohols such as piperidinolalkanols and dialkjaminoalkanols have favorable properties.
The compounds correspond to the formula
EMI0001.0017
in which R, and R3 are alkyl or alkoxy groups, R2 is hydrogen, A2kyl or an alkoxy group, R4 is a branched or unbranched,
Saturated or unsaturated hydrocarbon chain with a maximum of 6 carbon atoms and R5 and R6 alkyl groups or together with the nitrogen a saturated heterocyclic ring. These anesthetics can be prepared by using an aromatic amine of the formula
EMI0001.0035
with a haloformic acid ester of the formula
EMI0001.0037
converts, where X is halogen. A salt of this base can also be used instead of the haloformic acid ester.
It is advisable to carry out the reaction in an inert solvent.
The aminoalkyl haloformate can be allowed to flow into the solution of the aromatic amine either as such or dissolved in an inert solvent. For the course of the reaction it is of great importance which of the components is added to the other.
To neutralize the hydrogen halide formed during the reaction, the reaction can be carried out in the presence of 2 mol of the aromatic amine concerned or another suitable neutralizing agent; but you can also work without a neutralizing agent other than the carbanilic acid ester formed.
After the reaction has ended, the free carbanilic acid ester can be isolated after treatment with a neutralizing agent by washing several times with water and subsequently stripping off the solvent used. He can then methods according to known Me, for. B. by treatment with activated carbon and recrystallization, cleaned.
The present patent now relates to a process for the preparation of 2,6-dimethylcarbanilic acid, 8-piperidino-ethyl ester, which is characterized in that 2,6-dimethyl-aniline is mixed with a halogen-formic acid-s-piperidino converts ethyl ester.
Instead of the haloformic acid ester, a salt of this base can also be used.
Example 121 parts of 2,6-dimethylaniline, dissolved in 700 parts of benzene, are mixed with 80 parts of finely powdered soda, which is kept in suspension by vigorous stirring. The chemicals used must be well dried. A solution of 193 parts of ß-piperidino-ethyl chloroformate in 300 parts of benzene is then allowed to run into the suspension at about 20 ° C. with cooling.
When the exothermic reaction has ended, the mixture is refluxed for a further hour. It is then cooled to room temperature and the sodium chloride formed and the excess soda are filtered off. The residue is washed on the filter with 100 parts of benzene. The combined filtrates, which contain the 2,6-Dimet.hyl-earbanilsäure-ss-pipei, - idino-ethyl ester formed, are extracted with dilute hydrochloric acid.
After the pH has been adjusted to about 6.5, the salt acid solution is treated with 20 parts of activated charcoal and 1 part of sodium dithionite. If it is carefully precipitated with ammonia, the free ester is obtained as a white, crystalline Nied'ersehlaa. He's melting. at 80-82 C.
The hydrochloride is. a white crystal powder with a melting point between <B> 167 </B> to - # 169 C.
Claims (1)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE314567X | 1951-07-14 | ||
| SE281251X | 1951-12-28 | ||
| CH309716T | 1952-07-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH314567A true CH314567A (en) | 1956-06-15 |
Family
ID=27178327
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH314567D CH314567A (en) | 1951-07-14 | 1952-07-14 | Process for the preparation of an anesthetic |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH314567A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995031449A1 (en) * | 1994-05-17 | 1995-11-23 | Sanofi | Novel 3,5-dimethylpiperidin-1-ylalkyl esters |
-
1952
- 1952-07-14 CH CH314567D patent/CH314567A/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995031449A1 (en) * | 1994-05-17 | 1995-11-23 | Sanofi | Novel 3,5-dimethylpiperidin-1-ylalkyl esters |
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