DE1169941B - Process for the preparation of new N-alkyl-piperidine-monocarboxylic acid and N-alkyl-pyrrolidine-ª-monocarboxylic acid arylides - Google Patents
Process for the preparation of new N-alkyl-piperidine-monocarboxylic acid and N-alkyl-pyrrolidine-ª-monocarboxylic acid arylidesInfo
- Publication number
- DE1169941B DE1169941B DEA23090A DEA0023090A DE1169941B DE 1169941 B DE1169941 B DE 1169941B DE A23090 A DEA23090 A DE A23090A DE A0023090 A DEA0023090 A DE A0023090A DE 1169941 B DE1169941 B DE 1169941B
- Authority
- DE
- Germany
- Prior art keywords
- monocarboxylic acid
- alkyl
- pyrrolidine
- acid ester
- parts
- 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.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- -1 pyridine monocarboxylic acid ester Chemical class 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 2
- 150000001735 carboxylic acids Chemical class 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- BPSLZWSRHTULGU-UHFFFAOYSA-N Methylpipecolic acid Chemical compound CN1CCCCC1C(O)=O BPSLZWSRHTULGU-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000003610 charcoal Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 description 2
- MLPVBIWIRCKMJV-UHFFFAOYSA-N 2-ethylaniline Chemical compound CCC1=CC=CC=C1N MLPVBIWIRCKMJV-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 2
- 150000003931 anilides Chemical class 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000003589 local anesthetic agent Substances 0.000 description 2
- 150000002681 magnesium compounds Chemical class 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- FCTZHFATVFONMW-UHFFFAOYSA-N n-phenylpyridine-4-carboxamide Chemical compound C=1C=NC=CC=1C(=O)NC1=CC=CC=C1 FCTZHFATVFONMW-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- JSHASCFKOSDFHY-UHFFFAOYSA-N 1-butylpyrrolidine Chemical compound CCCCN1CCCC1 JSHASCFKOSDFHY-UHFFFAOYSA-N 0.000 description 1
- CZZZAQIBVXXNRC-UHFFFAOYSA-N 1-methyl-n-phenylpiperidine-4-carboxamide Chemical compound C1CN(C)CCC1C(=O)NC1=CC=CC=C1 CZZZAQIBVXXNRC-UHFFFAOYSA-N 0.000 description 1
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 1
- WFNLHDJJZSJARK-UHFFFAOYSA-N 2-chloro-6-methylaniline Chemical compound CC1=CC=CC(Cl)=C1N WFNLHDJJZSJARK-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- XQMUEFDDYYIRPT-UHFFFAOYSA-L [Br-].[Mg+2].C(C)C1=C(N)C=CC=C1.[Br-] Chemical compound [Br-].[Mg+2].C(C)C1=C(N)C=CC=C1.[Br-] XQMUEFDDYYIRPT-UHFFFAOYSA-L 0.000 description 1
- BOYAEDAIOHNLKU-UHFFFAOYSA-L [Br-].[Mg+2].ClC1=C(N)C(=CC=C1)C.[Br-] Chemical compound [Br-].[Mg+2].ClC1=C(N)C(=CC=C1)C.[Br-] BOYAEDAIOHNLKU-UHFFFAOYSA-L 0.000 description 1
- HDHAIRSXHRAPHN-UHFFFAOYSA-L [Br-].[Mg+2].NC1=CC=CC=C1.[Br-] Chemical compound [Br-].[Mg+2].NC1=CC=CC=C1.[Br-] HDHAIRSXHRAPHN-UHFFFAOYSA-L 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- MCRPKBUFXAKDKI-UHFFFAOYSA-N ethyl pyridine-4-carboxylate Chemical compound CCOC(=O)C1=CC=NC=C1 MCRPKBUFXAKDKI-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 238000002690 local anesthesia Methods 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- ONXRNTKLIOTLCJ-UHFFFAOYSA-L magnesium 2,6-dimethylaniline dibromide Chemical compound [Br-].[Mg+2].CC1=C(N)C(=CC=C1)C.[Br-] ONXRNTKLIOTLCJ-UHFFFAOYSA-L 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- DNZSDACGXYHMOL-UHFFFAOYSA-N n-(2-ethylphenyl)piperidine-3-carboxamide Chemical compound CCC1=CC=CC=C1NC(=O)C1CNCCC1 DNZSDACGXYHMOL-UHFFFAOYSA-N 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000010802 sludge Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000008673 vomiting Effects 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
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verfahren zur Herstellung von neuen N-Alkylpiperi(iin-monocarbonsäure- und N-Alkylpyrrolidin-a-monocarbonsäurearyliden Die Erfindung betrifft ein Verfahren zur Herstellung von neuen N-Alkyl-piperidin-monocarbonsäure- und N-Alkyl-pyrrolidin-a-Monocarbonsäurearyliden der allgemeinen Formeln: wobei Ri eine Alkylgruppe, R? eine niedere Alkylgruppe oder ein Chloratom, R3 ein Wasserstoffatom, eine Hydroxylgruppe, eine niedere Alkyl-oder Alkoxygruppe, R4 ein Wasserstoffatom, ein Chloratom, eine niedere Alkyl- oder Alkoxygruppe darstellt oder wobei R2, R3 und R4 gleichzeitig Wasserstoffatome darstellen.Process for the preparation of new N-alkylpiperi (iin-monocarboxylic acid and N-alkylpyrrolidine-α-monocarboxylic acid arylides Formulas: where Ri is an alkyl group, R? a lower alkyl group or a chlorine atom, R3 a hydrogen atom, a hydroxyl group, a lower alkyl or alkoxy group, R4 a hydrogen atom, a chlorine atom, a lower alkyl or alkoxy group or where R2, R3 and R4 simultaneously represent hydrogen atoms.
Die erfindungsgemäß herstellbaren Arylide haben sich als ausgezeichnete Lokalanästhetika mit im Vergleich zu ihrer Aktivität sehr geringer Toxizität erwiesen.The arylides which can be prepared according to the invention have proven to be excellent Local anesthetics shown to be very low in toxicity compared to their activity.
Durch Versuche wurde festgestellt, daß das erfindungsgemäß herstellbare 1-Methyl-piperidin-2-earbonsäure-2',6'-dimethyl-anilid dem bekannten Diäthylaminoessigsäure - 2,6 - dimethyl - anilid als Lokalanästhetikum überlegen ist. Es ist weniger toxisch und zeigt weniger Nebenwirkungen.Experiments have shown that the 1-methyl-piperidine-2-carboxylic acid-2 ', 6'-dimethyl-anilide which can be prepared according to the invention is superior to the known diethylaminoacetic acid -2,6- dimethyl - anilide as a local anesthetic. It is less toxic and has fewer side effects.
Die Versuche wurden mit Mäusen durchgeflüh-t. Der LD50-Wert des 1-Methyl-piperidin-2-carbonsäure-2',6'-dimethyl-anilids liegt bei 43,1 mg/kg Versuchstier, während der entsprechende Wert für Diäthylaminoessigsäure - 2,6 - dimethyl - anilid bei 27,7 mg/kg Versuchstier liegt.The experiments were carried out with mice. The LD50 value of 1-methyl-piperidine-2-carboxylic acid-2 ', 6'-dimethyl-anilide is 43.1 mg / kg test animal, while the corresponding value for diethylaminoacetic acid - 2,6 - dimethyl - anilide is 27 , 7 mg / kg test animal.
Auch ist die Subtoxizitätsdosis der ersteren Verbindung höher als die der bekannten, und zwar 7,2 mg/kg Versuchstier gegenüber 2,5 mg/kg Versuchstier. Dabei wird unter Subtoxizitätsdosis die Dosis verstanden, bei der das Versuchstier deutliche Spuren von Nebenwirkungen (besonders Übelkeit, Erbrechen, Gleichgewichtsstörungen) erkennen läßt. Diese Versuche wurden mit Hunden durchgeführt.The sub-toxicity dose of the former compound is also higher than that of the known, namely 7.2 mg / kg test animal compared to 2.5 mg / kg test animal. The subtoxicity dose is understood to mean the dose at which the test animal shows clear traces of side effects (especially nausea, vomiting, imbalance). These experiments were carried out with dogs.
Auch hinsichtlich der Dauer der örtlichen Betäubung ist die erfindungsgemäß
herstellbare Verbindung der bekannten überlegen, wie die folgende Tabelle zeigt:
Das erfindungsgemäße Verfahren wird durch die folgenden Beispiele erläutert.The process of the invention is illustrated by the following examples explained.
Beispiel 1 Es wird ein 2,6-Dimethyl-anilin-magnesiumbromid-schlamm angewendet, der hergestellt worden ist, indem einer ätherischen Lösung von Äthylmagnesiumbromid, die in üblicher Weise durch Reaktion von 185 Gewichtsteilen Äthylbromid in 800 Teilen wasserfreiem Äther mit 37 Teilen Magnesiumspänen erhalten worden ist, unter kräftigem Rühren 121 Teile 2,6-Dimethyl-anilin mit einer Geschwindigkeit zugefügt wurden, die von der Stärke der Gasentwicklung abhängt. Wenn die Gasentwicklung aufgehört hat, werden 85 Teile 1 - Methyl - piperidin - 2 - carbonsäure - äthylester zu dem 2,6 - Dimethyl,- anilin - magnesiumbromidschlamm zugefügt. Die Mischung wird 1/2 Stunde unter Rückfluß und fortgesetzter Rührung gekocht und wird dann abgekühlt. Verdünnte Salzsäure wird sorgfältig zugefügt, um die gebildeten Magnesiumverbindungen zu lösen und zu hydrolysieren. Der pH-Wert wird auf 5,5 eingestellt und die wäßrige Phase abgetrennt und mit zugesetztern Äther extrahiert, um das überschüssige Dimethylanilin zu entfernen. Nach Zusatz eines Überschusses an Ammoniak zu der Lösung des Reaktionsproduktes wird 1 - Methyl - piperidin - 2 - earbonsäure-2',6'-dimethyl-anilid durch Extraktion mit Isoamylalkohol gewonnen. Die Lösung von Isoamylalkohol wird zur Trockne eingedampft, das Produkt in verdünnter Salzsäure gelöst, mit Kohle behandelt und erneut mit Natronlauge gefällt. 1-Methyl-piperidin-2 - carbonsäure - 2',6' - dimethyl - anilid wird in kristalliner Form erhalten. Ausbeute: 550jo. EXAMPLE 1 A 2,6-dimethyl-aniline-magnesium bromide sludge is used, which has been prepared by adding an ethereal solution of ethyl magnesium bromide, which is obtained in the usual manner by reacting 185 parts by weight of ethyl bromide in 800 parts of anhydrous ether with 37 parts of magnesium shavings has been, 121 parts of 2,6-dimethylaniline were added with vigorous stirring at a rate which depends on the strength of the gas evolution. When gas evolution has ceased to be 85 parts of 1 - methyl - piperidin - 2 - carboxylic acid - dimethyl - - aniline - added to the ethyl ester magnesiumbromidschlamm 2.6. The mixture is refluxed for 1/2 hour with continued stirring and is then cooled. Dilute hydrochloric acid is carefully added to dissolve and hydrolyze the magnesium compounds formed. The pH is adjusted to 5.5 and the aqueous phase is separated off and extracted with added ether in order to remove the excess dimethylaniline. After an excess of ammonia has been added to the solution of the reaction product, 1- methyl - piperidine - 2 - carboxylic acid-2 ', 6'-dimethyl anilide is obtained by extraction with isoamyl alcohol. The isoamyl alcohol solution is evaporated to dryness, the product is dissolved in dilute hydrochloric acid, treated with charcoal and reprecipitated with sodium hydroxide solution. 1-Methyl-piperidine-2 - carboxylic acid - 2 ', 6' - dimethyl - anilide is obtained in crystalline form. Yield: 550jo.
Beispiel 2 Es wird 2-Äthyl-anilin-magnesiumbromid, das in entsprechender Weise, wie im Beispiel 1 beschrieben ist, aus 121 Gewichtsteilen 2-Äthylanilin hergestellt worden ist, verwendet. Dieses wird mit 78 Teilen Nipecotiiisäure-äthylester umgesetzt. Unter Anwendung der gleichen Arbeitsmethode wie im Beispiel 1 wird Nipecotinsäure-2-äthyl-anilid erhalten. 10 Teile davon werden in 16 Teilen Isopropylalkohol gelöst, und 5,3 Teile Isopropylbromid sowie 5 Teile Kaliumcarbonat werden zugesetzt. Die Mischung wird 12 Stunden unter Rührung am Rückflußkühler gekocht, filtriert und zur Trockne eingedampft. Nach Lösung des Rückstandes in verdünnter Salzsäure und erneuter Fällung mit Natronlauge wird die freie Base N-Isopropyl-nipecotinsäure-2-äthylanilid erhalten. Ausbeute: 40()/0.EXAMPLE 2 2-ethyl-aniline-magnesium bromide, which has been prepared from 121 parts by weight of 2-ethylaniline in a manner corresponding to that described in Example 1, is used. This is reacted with 78 parts of ethyl nipecotiate. Using the same working method as in Example 1 , nipecotic acid-2-ethyl-anilide is obtained. 10 parts thereof are dissolved in 16 parts of isopropyl alcohol, and 5.3 parts of isopropyl bromide and 5 parts of potassium carbonate are added. The mixture is refluxed with stirring for 12 hours, filtered and evaporated to dryness. After the residue has been dissolved in dilute hydrochloric acid and repeated precipitation with sodium hydroxide solution, the free base N-isopropyl-nipecotinic acid-2-ethylanilide is obtained. Yield: 40 () / 0.
Beispiel 3 Es wird Anilin-magnesiumbromid, das in entsprechender Weise wie im Beispiel 1 aus 93 Teilen Anilin hergestellt worden ist, mit 75 Teilen Isonicotinsäure-äthylester umgesetzt. Die gebildete Magnesiumverbindung wird in verdünnter Salzsäure gelöst und hydrolysiert, danach der pH-Wert auf etwa 7 eingestellt und der Äther abgetrennt. Die zurückbleibende wäßrige Lösung wird zweimal mit Isoamylalkohol extrahiert, und die erhaltene alkoholische Lösung wird zusammen mit der ätherischen Lösung zur Trockne eingedampft. Der Verdampfungsrückstand wird einer Dampfdestillation unterworfen, bis er von sämtlichem Anilin befreit ist. Das zurückbleibende Isonicotinsäure-anilid wird in verdünnter Salzsäure gelöst, mit Kohle behandelt, erneut mit Natronlauge gefällt, abfiltriert und getrocknet. 99 Teile Isonicotinsäure-anilid werden in 240 Teilen Alkohol und 60 Teilen Eisessig gelöst. 2,5 Teile Platinoxyd werden der Lösung zugefügt und das Anilid bei 2,5 atm. Druck und 50 bis gO'C hydriert. Wenn kein Wasserstoff mehr aufgenommen wird, wird der Katalysator abfiltriert. 40 Teile Natriumhydroxyd, in Wasser zu einer 40 bis 50%igen Lösung gelöst, und 250 Teile Äther werden dem Filtrat zugefügt. Nach Abkühlung wird das ausgefallene Natriumacetat abfiltriert und das Filtrat bis zur Kristallisation oder zur Trockne eingedampft. 10 Teile des Verdampfungsrückstandes (oder des kristallinen Produktes) werden in 16 Teilen Methanol gelöst. 5 Teile Kaliumcarbonat und 5,2 Teile Dimethylsulfat werden der Lösung zugesetzt. Nachdem 6 Stunden unter Rührung am Rückflußkühler gekocht worden war, wird die Lösung filtriert und zur Trockne eingedampft. Der Rückstand wird in verdünnter Salzsäure gelöst, mit Kohle behandelt und erneut mit Natronlauge gefällt. Auf diese Weise wird kristallines 1-Methyl-isonipecotinsäure-anilid erhalten. Ausbeute: 30()io.EXAMPLE 3 Aniline magnesium bromide, which has been prepared from 93 parts of aniline in the same manner as in Example 1, is reacted with 75 parts of ethyl isonicotinate. The magnesium compound formed is dissolved in dilute hydrochloric acid and hydrolyzed, then the pH is adjusted to about 7 and the ether is separated off. The remaining aqueous solution is extracted twice with isoamyl alcohol, and the alcoholic solution obtained is evaporated to dryness together with the ethereal solution. The evaporation residue is subjected to steam distillation until all aniline has been removed from it. The remaining isonicotinic acid anilide is dissolved in dilute hydrochloric acid, treated with charcoal, precipitated again with sodium hydroxide solution, filtered off and dried. 99 parts of isonicotinic anilide are dissolved in 240 parts of alcohol and 60 parts of glacial acetic acid. 2.5 parts of platinum oxide are added to the solution and the anilide at 2.5 atm. Pressure and 50 to gO'C hydrogenated. When no more hydrogen is absorbed, the catalyst is filtered off. 40 parts of sodium hydroxide, dissolved in water to form a 40 to 50% solution, and 250 parts of ether are added to the filtrate. After cooling, the precipitated sodium acetate is filtered off and the filtrate is evaporated to crystallization or to dryness. 10 parts of the evaporation residue (or of the crystalline product) are dissolved in 16 parts of methanol. 5 parts of potassium carbonate and 5.2 parts of dimethyl sulfate are added to the solution. After 6 hours of boiling with stirring on the reflux condenser, the solution is filtered and evaporated to dryness. The residue is dissolved in dilute hydrochloric acid, treated with charcoal and reprecipitated with sodium hydroxide solution. In this way, crystalline 1-methyl-isonipecotic anilide is obtained. Yield: 30 () io.
Beispiel 4 Es wird 2-Chlor-6-methyl-anilin-magnesiumbromid, das in entsprechender Weise, wie im Beispiel 1 beschrieben wurde, aus 141,5 Teilen 2-Chlor-6-methyl-anilin hergestellt worden ist, mit 100 Teilen 1 - n - Butyl - pyrrolidin - a - earbonsäureäthylester umgesetzt. Durch Anwendung der gleichen Arbeitsmethode, wie im Beispiel 1 beschrieben, wird 1-n-Butyl - pyrrolidin - a - carbonsäure - 2' - chlor - 6' - methyl-anilid erhalten. Ausbeute: 55%.Example 4 2-chloro-6-methyl-aniline-magnesium bromide, which has been prepared in a manner corresponding to that described in Example 1 , from 141.5 parts of 2-chloro-6-methyl-aniline, with 100 parts of 1, is used - n - Butyl - pyrrolidine - a - carboxylic acid ethyl ester reacted. By using the same working method as described in Example 1, 1-n-butyl - pyrrolidin - a - carboxylic acid - 2 '- chloro - 6' - methyl-obtained anilide. Yield: 55%.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE1169941X | 1955-04-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1169941B true DE1169941B (en) | 1964-05-14 |
Family
ID=20421300
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEA23090A Pending DE1169941B (en) | 1955-04-28 | 1955-07-19 | Process for the preparation of new N-alkyl-piperidine-monocarboxylic acid and N-alkyl-pyrrolidine-ª-monocarboxylic acid arylides |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1169941B (en) |
-
1955
- 1955-07-19 DE DEA23090A patent/DE1169941B/en active Pending
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