CH516555A - Process for the production of new cinnamic acid amides - Google Patents
Process for the production of new cinnamic acid amidesInfo
- Publication number
- CH516555A CH516555A CH1442571A CH1442571A CH516555A CH 516555 A CH516555 A CH 516555A CH 1442571 A CH1442571 A CH 1442571A CH 1442571 A CH1442571 A CH 1442571A CH 516555 A CH516555 A CH 516555A
- Authority
- CH
- Switzerland
- Prior art keywords
- cinnamic acid
- formula
- produced
- piperidide
- acid amides
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 13
- APEJMQOBVMLION-UHFFFAOYSA-N cinnamamide Chemical class NC(=O)C=CC1=CC=CC=C1 APEJMQOBVMLION-UHFFFAOYSA-N 0.000 title claims description 7
- 238000004519 manufacturing process Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 8
- ZROGHFJYTNYOOQ-UHFFFAOYSA-N 3-(4-bromophenyl)-1-piperidin-1-ylprop-2-en-1-one Chemical compound C1=CC(Br)=CC=C1C=CC(=O)N1CCCCC1 ZROGHFJYTNYOOQ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- CPEONABTMRSIKA-UHFFFAOYSA-N 1,4$l^{2}-oxazinane Chemical group C1COCC[N]1 CPEONABTMRSIKA-UHFFFAOYSA-N 0.000 claims description 2
- KRTMKXWOJHDSHE-UHFFFAOYSA-N 3-(3-bromophenyl)-1-piperidin-1-ylprop-2-en-1-one Chemical compound BrC1=CC=CC(C=CC(=O)N2CCCCC2)=C1 KRTMKXWOJHDSHE-UHFFFAOYSA-N 0.000 claims description 2
- MCECGULZPWFNLB-UHFFFAOYSA-N 3-(4-iodophenyl)-1-morpholin-4-ylprop-2-en-1-one Chemical compound IC1=CC=C(C=CC(=O)N2CCOCC2)C=C1 MCECGULZPWFNLB-UHFFFAOYSA-N 0.000 claims description 2
- QIDNQWYDBMVLOU-UHFFFAOYSA-N 3-(4-iodophenyl)-1-piperidin-1-ylprop-2-en-1-one Chemical compound IC1=CC=C(C=CC(=O)N2CCCCC2)C=C1 QIDNQWYDBMVLOU-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- REJKLNFPNCDEQR-UHFFFAOYSA-N 3-(3-bromophenyl)-1-morpholin-4-ylprop-2-en-1-one Chemical compound BrC1=CC=CC(C=CC(=O)N2CCOCC2)=C1 REJKLNFPNCDEQR-UHFFFAOYSA-N 0.000 description 1
- QVNBHWCGNNVOLL-UHFFFAOYSA-N 3-(3-iodophenyl)-1-morpholin-4-ylprop-2-en-1-one Chemical compound IC=1C=C(C=CC(=O)N2CCOCC2)C=CC1 QVNBHWCGNNVOLL-UHFFFAOYSA-N 0.000 description 1
- HCVJBKSLBZHWJL-UHFFFAOYSA-N 3-(3-iodophenyl)-1-piperidin-1-ylprop-2-en-1-one Chemical compound IC1=CC=CC(C=CC(=O)N2CCCCC2)=C1 HCVJBKSLBZHWJL-UHFFFAOYSA-N 0.000 description 1
- QWQHHPOXLXYYOF-UHFFFAOYSA-N 3-(4-bromophenyl)-1-morpholin-4-ylprop-2-en-1-one Chemical compound C1=CC(Br)=CC=C1C=CC(=O)N1CCOCC1 QWQHHPOXLXYYOF-UHFFFAOYSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 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
- C07D295/16—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 acylated on ring nitrogen atoms
- C07D295/18—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 acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
- C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/64—Acyl halides
- C07C57/72—Acyl halides containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/56—Unsaturated compounds containing hydroxy or O-metal groups containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/224—Phosphorus triamides
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4056—Esters of arylalkanephosphonic acids
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/535—Organo-phosphoranes
- C07F9/5352—Phosphoranes containing the structure P=C-
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5407—Acyclic saturated phosphonium compounds
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5456—Arylalkanephosphonium compounds
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
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- C—CHEMISTRY; METALLURGY
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/59—Hydrogenated pyridine rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verfahren zur Herstellung neuer Zimtsäureamide
Die Erfindung betrifft ein Verfahren zur Herstellung neuer Zimtsäureamide der Formel 1
1,
EMI1.1
worin R1 ein Brom- oder Jodatom und R2 einen Piperidino- oder Morpholinorest bedeuten, das dadurch gekennzeichnet ist, dass man aus einer Verbindung der Formel 2
2,
EMI1.2
worin die Reste D und D1 Halogenatome bedeuten, diese Reste D und D1 abspaltet.
Dabei geht man zweckmässig so vor, dass man eine Verbindung der Formel 2 unter gleichzeitiger Bildung einer Doppelbindung mit halogenabspaltenden Mitteln in geeigneten Lösungsmitteln, z.B. mit Zinkstaub in Äthanol oder einem Alkalijodid in Methyläthylketon, zweckmässigerweise bei erhöhter Temperatur, beispielsweise bei der Siedetemperatur des verwendeten Lösungsmittels, enthalogeniert. Die Umsetzung kann auch in der Weise durchgeführt werden, dass man eine Verbindung der Formel 2 längere Zeit, z.B. 1 bis 2 Tage, zweckmässigerweise in einem Lösungsmittel, z.B. in Dioxan oder Xylol, z.B. auf die Siedetemperatur des verwendeten Lösungsmittels, erhitzt.
Die bei dem Verfahren verwendeten Ausgangsstoffe sind neu und lassen sich nach bekannten Methoden darstellen:
Ein oc,-Dihalogen-propionsäureamid der Formel 2 erhält man z.B. durch Anlagerung von Halogen an ein entsprechendes Zimtsäureamid.
Die erfindungsgemäss hergestellten neuen Zimtsäureamide der Formel 1 besitzen wertvolle pharmakologische Eigenschaften, insbesondere eine antiphlogistische und antipyretische Wirkung.
Im Kaolin- und Carrageenin-Oedem-Test an der Ratte sind die Verbindungen der Formel 1 dem Phenylbutazon bezüglich der therapeutischen Breite überlegen.
Die nachstehenden Beispiele dienen zur näheren Erläuterung der Erfindung:
Beispiel I 4-Brom-zimtsäurepiperidid
10,0 g (0,022 Mol) ,43-Dibrom-a-(4-bromphenyl)-pro- pionsäurepiperidid (Fp. 169 bis 1700C) in 100 ml Äthanol werden bei 600C unter Rühren portionsweise mit 25,0 g (0,382 Mol) Zinkstaub versetzt. Man erhitzt danach 5 Stunden zum Sieden, filtriert heiss, dampft das Filtrat im Vakuum ein und löst den Rückstand in Essigester. Die Lösung wird mit verdünnter Salzsäure, verdünnter Natronlauge und Wasser gewaschen, über Natriumsulfat getrocknet und erneut im Vakuum eingedampft. Durch Umkristallisation des Rohproduktes aus Methanol unter Verwendung von Aktivkohle erhält man 2,4 g (37% d.Th.) 4-Bromzimtsäurepiperidid vom Fp. 132 bis 1330C.
Beispiel 2 4-Brom-zimtsäurepiperidid
Eine Lösung von 3,6 g (0,01 Mol) vçip-Dichlor-iss-(4- -bromphenyl)-propionsäurepiperidid (Fp. 1 13,5cm) und 4,5 g (0,03 Mol) Natriumjodid in Methyläthylketon wird 28 Stunden unter Rückfluss erhitzt. Zur Entfernung von ausgeschiedenem Jod wird mit wässriger Natriumthiosulfatlösung geschüttelt. Man trennt die organische Phase ab, extrahiert die wässrige Schicht mit Chloroform, wäscht die vereinigten organischen Extrakte mit Wasser, trocknet über Natriumsulfat und dampft im Vakuum ein.
Aus dem Rückstand wird das 4-Brom-zimtsäurepiperidid vom Ausgangsprodukt durch Säulenchromatographie an Kieselgel (Benzol/Aceton = 9 :1) getrennt.
Ausbeute: 0,9 g (31% d.Th.), Fp. 133 C.
Beispiel 3 4-Brom -zimtsäurepiperidid
Eine Lösung von 5,0 g (0,011 Mol) a,p-Dibrom-P-(4- -bromphenyl)-propionsäurepiperidid (Fp. 169 bis 170ob) in 200 ml Dioxan und 50 ml Wasser wird 40 Stunden zum Sieden erhitzt. Man dampft im Vakuum ein und nimmt den Rückstand in Chloroform auf. Nach Waschen mit Wasser und Trocknen über Natriumsulfat wird das Chloroform im Vakuum entfernt. Der Rückstand wird einer Säulenchromatographie an Kieselgel (Benzol/Aceton = 9: 1) unterworfen.
Ausbeute: 0,8 g (25% d.Th.), Fp. 131 bis 133 C.
Analog wurden folgende Verbindungen hergestellt: 3-Brom-zimtsäurepiperidid, Fp. 95-990C 4-Brom-zimtsäuremorpholid, Fp. 142-1440C 3-Brom-zimtsäuremorpholid, Fp. 80-81 0C 4-Jod-zimtsäurepiperidid, Fp. 134-1350 3-Jod-zimtsäurepiperidid, Fp. 109-1 lO0C 4-Jod-zimtsäuremorpholid, Fp. 175-1770C 3-Jod-zimtsäuremorpholid, Fp. 100-1010C.
Die erfindungsgemäss hergestellten Verbindungen der Formel 1 lassen sich nach an sich bekannten Methoden in übliche pharmazeutische Anwendungsformen, gegebenenfalls in Kombination mit anderen Wirksubstanzen, einarbeiten. Die Einzeldosis beträgt bei Erwachsenen 200,00 mg - 600,00 mg, bevorzugt 300,00 mg - 400,00 mg und die Tagesdosis 400,00 mg - 1 200,00 mg, bevorzugt 600,00 mg - 800,00 mg.
Process for the production of new cinnamic acid amides
The invention relates to a process for the preparation of new cinnamic acid amides of the formula 1
1,
EMI1.1
where R1 is a bromine or iodine atom and R2 is a piperidino or morpholino radical, which is characterized in that a compound of the formula 2
2,
EMI1.2
wherein the radicals D and D1 represent halogen atoms, these radicals D and D1 are split off.
It is expedient to proceed in such a way that a compound of the formula 2 is formed with simultaneous formation of a double bond with halogen-releasing agents in suitable solvents, e.g. dehalogenated with zinc dust in ethanol or an alkali iodide in methyl ethyl ketone, advantageously at an elevated temperature, for example at the boiling point of the solvent used. The reaction can also be carried out in such a way that a compound of formula 2 is left on for a long time, e.g. 1 to 2 days, conveniently in a solvent, e.g. in dioxane or xylene, e.g. heated to the boiling point of the solvent used.
The starting materials used in the process are new and can be represented using known methods:
An oc, -dihalopropionic acid amide of the formula 2 is obtained e.g. by the addition of halogen to a corresponding cinnamic acid amide.
The new cinnamic acid amides of formula 1 prepared according to the invention have valuable pharmacological properties, in particular an anti-inflammatory and anti-pyretic effect.
In the kaolin and carrageenin edema test on rats, the compounds of formula 1 are superior to phenylbutazone with regard to the therapeutic range.
The following examples serve to explain the invention in more detail:
Example I 4-Bromo-cinnamic acid piperidide
10.0 g (0.022 mol) of 43-dibromo-a- (4-bromophenyl) propionic acid piperidide (melting point 169 to 1700C) in 100 ml of ethanol are added in portions at 600C with 25.0 g (0.382 mol) while stirring Zinc dust added. The mixture is then heated to boiling for 5 hours, filtered hot, the filtrate is evaporated in vacuo and the residue is dissolved in ethyl acetate. The solution is washed with dilute hydrochloric acid, dilute sodium hydroxide solution and water, dried over sodium sulfate and evaporated again in vacuo. Recrystallization of the crude product from methanol using activated charcoal gives 2.4 g (37% of theory) of 4-bromocinnamic acid piperidide with a melting point of 132 to 1330C.
Example 2 4-Bromo-cinnamic acid piperidide
A solution of 3.6 g (0.01 mol) of vçip-dichloro-iss- (4-bromophenyl) -propionic acid piperidide (mp. 1 13.5 cm) and 4.5 g (0.03 mol) of sodium iodide in methyl ethyl ketone is Heated under reflux for 28 hours. To remove excreted iodine, it is shaken with aqueous sodium thiosulfate solution. The organic phase is separated off, the aqueous layer is extracted with chloroform, the combined organic extracts are washed with water, dried over sodium sulfate and evaporated in vacuo.
The 4-bromocinnamic acid piperidide is separated from the residue from the starting product by column chromatography on silica gel (benzene / acetone = 9: 1).
Yield: 0.9 g (31% of theory), melting point 133 C.
Example 3 4-Bromo-cinnamic acid piperidide
A solution of 5.0 g (0.011 mol) of a, p-dibromo-P- (4-bromophenyl) propionic acid piperidide (melting point 169 to 170ob) in 200 ml of dioxane and 50 ml of water is heated to boiling for 40 hours. It is evaporated in vacuo and the residue is taken up in chloroform. After washing with water and drying over sodium sulfate, the chloroform is removed in vacuo. The residue is subjected to column chromatography on silica gel (benzene / acetone = 9: 1).
Yield: 0.8 g (25% of theory), melting point 131 to 133 C.
The following compounds were prepared analogously: 3-Bromo-cinnamic acid piperidide, melting point 95-990C 4-Bromo-cinnamic acid morpholide, melting point 142-1440C 3-Bromo-cinnamic acid morpholide, melting point 80-81 ° C 4-iodo-cinnamic acid piperidide, melting point 134- 1350 3-iodo-cinnamic acid piperidide, m.p. 109-110 ° C. 4-iodo-cinnamic acid morpholide, m.p. 175-1770C 3-iodo-cinnamic acid morpholide, melting point 100-1010C.
The compounds of formula 1 prepared according to the invention can be incorporated into customary pharmaceutical application forms by methods known per se, optionally in combination with other active substances. The single dose for adults is 200.00 mg - 600.00 mg, preferably 300.00 mg - 400.00 mg and the daily dose is 400.00 mg - 1200.00 mg, preferably 600.00 mg - 800.00 mg.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT1075768A AT285606B (en) | 1968-11-05 | 1968-11-05 | Process for the production of new cinnamic acid amides |
| CH343371 | 1968-11-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH516555A true CH516555A (en) | 1971-12-15 |
Family
ID=25606129
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1442571A CH516555A (en) | 1968-11-05 | 1968-11-29 | Process for the production of new cinnamic acid amides |
| CH718972A CH528508A (en) | 1968-11-05 | 1968-11-29 | Halo-cinnamamide derivs |
| CH1442671A CH516556A (en) | 1968-11-05 | 1968-11-29 | Process for the production of new cinnamic acid amides |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH718972A CH528508A (en) | 1968-11-05 | 1968-11-29 | Halo-cinnamamide derivs |
| CH1442671A CH516556A (en) | 1968-11-05 | 1968-11-29 | Process for the production of new cinnamic acid amides |
Country Status (1)
| Country | Link |
|---|---|
| CH (3) | CH516555A (en) |
-
1968
- 1968-11-29 CH CH1442571A patent/CH516555A/en not_active IP Right Cessation
- 1968-11-29 CH CH718972A patent/CH528508A/en not_active IP Right Cessation
- 1968-11-29 CH CH1442671A patent/CH516556A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CH516556A (en) | 1971-12-15 |
| CH528508A (en) | 1972-09-30 |
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