CH522641A - Cinnamic acid amide - Google Patents
Cinnamic acid amideInfo
- Publication number
- CH522641A CH522641A CH144372A CH144372A CH522641A CH 522641 A CH522641 A CH 522641A CH 144372 A CH144372 A CH 144372A CH 144372 A CH144372 A CH 144372A CH 522641 A CH522641 A CH 522641A
- Authority
- CH
- Switzerland
- Prior art keywords
- formula
- cinnamic acid
- compound
- lower alkyl
- hydroxypiperidide
- Prior art date
Links
- APEJMQOBVMLION-UHFFFAOYSA-N cinnamamide Chemical compound NC(=O)C=CC1=CC=CC=C1 APEJMQOBVMLION-UHFFFAOYSA-N 0.000 title claims description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- 125000003118 aryl group Chemical group 0.000 claims abstract description 3
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 3
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 13
- BSPFBABKJFAMJV-UHFFFAOYSA-N 3-(4-chlorophenyl)-1-(4-hydroxypiperidin-1-yl)prop-2-en-1-one Chemical compound C1CC(O)CCN1C(=O)C=CC1=CC=C(Cl)C=C1 BSPFBABKJFAMJV-UHFFFAOYSA-N 0.000 claims description 6
- QYNONMWWGFKWAC-UHFFFAOYSA-N 3-(4-bromophenyl)-1-(4-hydroxypiperidin-1-yl)prop-2-en-1-one Chemical compound C1CC(O)CCN1C(=O)C=CC1=CC=C(Br)C=C1 QYNONMWWGFKWAC-UHFFFAOYSA-N 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims 1
- 206010030113 Oedema Diseases 0.000 abstract description 5
- 230000001754 anti-pyretic effect Effects 0.000 abstract description 3
- -1 piperidino, 4-hydroxypiperidino Chemical group 0.000 abstract description 3
- 229960002895 phenylbutazone Drugs 0.000 abstract description 2
- 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 abstract description 2
- 125000000217 alkyl group Chemical group 0.000 abstract 4
- 230000001741 anti-phlogistic effect Effects 0.000 abstract 2
- 239000002221 antipyretic Substances 0.000 abstract 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 abstract 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 abstract 1
- 125000004423 acyloxy group Chemical group 0.000 abstract 1
- 125000003545 alkoxy group Chemical group 0.000 abstract 1
- 239000002260 anti-inflammatory agent Substances 0.000 abstract 1
- 229940125716 antipyretic agent Drugs 0.000 abstract 1
- 229930016911 cinnamic acid Natural products 0.000 abstract 1
- 235000013985 cinnamic acid Nutrition 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 abstract 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 239000000126 substance Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- GFPWIKRIKOOKOI-UHFFFAOYSA-N 2-chloro-1-(4-hydroxypiperidin-1-yl)ethanone Chemical compound OC1CCN(C(=O)CCl)CC1 GFPWIKRIKOOKOI-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 2
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 2
- 239000005995 Aluminium silicate Substances 0.000 description 2
- OUHVFCWKJVLEAM-UHFFFAOYSA-N CCOP(CC(N(CC1)CCC1O)=O)(OCC)=O Chemical compound CCOP(CC(N(CC1)CCC1O)=O)(OCC)=O OUHVFCWKJVLEAM-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 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 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- IFIZQPWVYOKQPK-UHFFFAOYSA-M [Cl-].C1(=CC=CC=C1)[P+](CC(=O)N1CCC(CC1)O)(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound [Cl-].C1(=CC=CC=C1)[P+](CC(=O)N1CCC(CC1)O)(C1=CC=CC=C1)C1=CC=CC=C1 IFIZQPWVYOKQPK-UHFFFAOYSA-M 0.000 description 2
- 235000012211 aluminium silicate Nutrition 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000002026 chloroform extract Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000000548 hind-foot Anatomy 0.000 description 2
- 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 2
- CPJSUEIXXCENMM-UHFFFAOYSA-N phenacetin Chemical group CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- RMMXTBMQSGEXHJ-UHFFFAOYSA-N Aminophenazone Chemical compound O=C1C(N(C)C)=C(C)N(C)N1C1=CC=CC=C1 RMMXTBMQSGEXHJ-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229960000212 aminophenazone Drugs 0.000 description 1
- 230000002322 anti-exudative effect Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- 150000001851 cinnamic acid derivatives Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003893 phenacetin Drugs 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- BYMVZHORNHZYPQ-UHFFFAOYSA-N sodium;diethyl phosphite Chemical compound [Na+].CCOP([O-])OCC BYMVZHORNHZYPQ-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
Classifications
-
- 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
- C07F9/28—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
-
- 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
-
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5407—Acyclic saturated phosphonium compounds
-
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5456—Arylalkanephosphonium compounds
-
- 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
- C07F9/547—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
-
- 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
- C07F9/547—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)
Abstract
ANTIPHLOGISTIC AND ANTIPYRETIC CINNAMIC ACID AMIDES G3A- Are new compounds of formula (I): (where R1 is Br or I and R2 is piperidino, 4-hydroxypiperidino or morpholino). Prepared by (a) reacting (II): (where X is OH, NH2, NH(lower alkyl) or N(lower alkyl)2 or a reactive residue, e.g. halogen, alkoxy or acyloxy) with H-R, or a reactive deriv. thereof or (b) olefinating (IV) with (V): (where A is (R3O)2P-CH2- in which R3 is lower alkyl, or (R4)3P=CH- in which R4 is aryl or alkyl), the reaction being carried out in the presence of a base when A is (R3O)2P-CH2-. Use is as antiphlogistics and antipyretics (better than phenylbutazone in kaolin- and carrageenin-oedema tests).
Description
Verfahren zur Herstellung von neuen Zimtsäureamiden
Die Erfindung betrifft ein Verfahren zur Herstellung neuer Zimtsäureamide der Formel 1
EMI1.1
in der Hal ein Chlor-, Brom oder Jodatom bedeutet, das dadurch gekennzeichnet ist, dass man ein Zimtsäurederivat der Formel 2
EMI1.2
mit einer Verbindung der Formel 3
EMI1.3
in der A eine
EMI1.4
in der R5 einen niederen Alkylrest darstellt, in Gegenwart einer Base oder in der A eine (R4)3P= CH-Gruppe, in der R einen Aryl- oder Alkylrest darstellt bedeutet, olefiniert.
Bedeutet A eine
EMI1.5
so wird zunächst eine Verbindung der Formel 3 vorteil hafterweise in einem Lösungsmittel, z.B. Dioxan, Äther oder Benzol, mit einer Base, z.B. einem Alkalihydrid,
Alkaliamid, Alkalialkoholat oder Alkalimetall, in ihr
Carbanion überführt, welches dann mit einer Verbin dung der Formel 2 vorzugsweise bei Temperaturen zwi schen 20 und 100 C zu einem Zimtsäureamid der For mel 1 umgesetzt wird. Die Umsetzung ist jedoch auch mit Alkali-Basen in einem wasserhaltigen Lösungsmit tel, z.B. mit einem Alkalicarbonat in einem wässrigen niederen Alkanol durchführbar. Ein Carbanion einer
Phosphorverbindung der Formel 3 kann auch in Gegen wart einer Verbindung der Formel 2 erzeugt werden.
Bedeutet A eine (R4)3P=CH-Gruppe, so wird ein
Ylid der Formel 3 gegebenenfalls ohne vorherige Isolie rung zweckmässigerweise in einem inerten wasserfreien
Lösungsmittel, z.B. Dioxan oder Benzol, und vorzugs weise bei 20 bis 1000C, z.B. bei der Siedetemperatur des verwendeten Lösungsmittels, mit einer Verbindung der
Formel 2 umgesetzt (Lit.: Organic Reactions, Vol. 14,
270 f1965]).
Die bei dem erfindungsgemässen Verfahren verwen deten Ausgangsstoffe lassen sich nach bekannten Methoden darstellen.
Die Herstellung einer Phosphorverbindung der Formel 3 erfolgt z.B. durch Umsetzung von Natrium-dialkyl-phosphit mit einem entsprechenden Halogenessigsäureamid.
Ein Ylid der Formel 3 lässt sich beispielsweise durch Umsetzung eines Triaryl- oder Trialkylphosphins mit einem entsprechenden Halogenessigsäureamid und anschliessender Umsetzung mit einer Base herstellen.
Bei dem erfindungsgemässen Verfahren erhält man in überwiegendem Masse trans-Verbindungen der Formel 1.
Die erfindungsgemäss hergestellten neuen Zimtsäureamide der Formel 1 besitzen wertvolle pharmakologische Eigenschaften, insbesondere eine antiphlogistische und antipyretische Wirkung.
Die Substanzen A = 4-Chlor-zimtsäure-(4-hydroxypiperidid) und B = 4-Brom-zimtsäure-(4-hydroxypiperidid) wurden hinsichtlich ihrer antiphlogistischen Wir kung im Vergleich zu C = Phenylbutazon und hinsichtlich ihrer temperatursenkenden Wir kung im Vergleich zu D = Aminopyrin und E = Phenacetin untersucht
1. Die antiphlogistische Wirkung der zu untersuchenden Substanzen wurde als antiexsudative Wirkung gegenüber dem Carrageeninödem der Rattenhinterpfote nach der Methode von Winter et al. fProc. Soc. exper.
Biol. Med. 111, 544- 547 (1962)] und gegenüber dem Kaolinödem der Rattenhinterpfote nach der Methode von Hillebrecht (Arzneimittelforschung, 4, 607 - 614 [19541) nach oraler Gabe vom mindestens 3 Dosen an mindestens 14 Tieren pro Dosis getestet.
Die Messung erfolgte nach der Methode von Doepfner und Cerletti (Int. Arch. Allergy al appl. Immun. 12, 89-97 [19581), es wurde die Dosis graphisch ermittelt, welche eine 35%ige Abschwachung (ED35) der jeweiligen Schwellung bewirkt:
Carrngeenbi- Ödem Kaolin- ödem Substanz EDss mglkg ED95 mg/kg
A 31 55
B 51 73
C 74 62
2. Die Prüfung auf eine temperatursenkende Wirkung der zu untersuchenden Substanzen erfolgte an normothermen Ratten nach oraler Gabe von mindestens 4 Dosen an mindestens 10 Tieren pro Dosis.
Aus den mit den verschiedenen Dosen erzielten gemittelten Werten für maximale Temperaturerniedrigung des Einzeltieres wurde durch graphische Interpolation die Dosis bestimmt, die eine Senkung der Körpertemperatur um 1,50C (ED-,S.c) bewirkt:
Substanz ED I,5oa mg/kg
A 5,5
B 7,0
D 70
E 80
3. Die akute Toxizität der Substanzen A bis D wurde an Gruppen zu mindestens je 10 Ratten mit mindestens 3 Dosen pro Gruppe bestimmt.
Es wurde die Led55, die Dosis bei deren peroralen Verabreichung 50% der Tiere innerhalb 14 Tagen verstarben, graphisch bestimmt:
Substanz LD50 g/kg
A ,,,,,5,0
B ,,-,5,0
C 0,98
D 1,1
E 2,3
Die nachfolgenden Beispiele sollen die Erfindung näher erläutern:
Beispiel I 4-Chlor-zimtsäure-(4-hydroxy-piperidid)
2,5 g (8,9 m Mol) Diäthylphosphon-essigsäure-(4 -hydroxy-piperidid) [öliges Rohprodukt, hergestellt aus Chloressigsäure-(4-hydroxy-piperidid) und Natrium-di äthylphosprin] und 1,4 g (10 m Mol) 4-Chlorbenzaldehyd werden in 50 ml absolutem Dioxan gelöst. Man gibt 1,0 g (8,9 m Mol) Kalium-tert.-butylat hinzu und erwärmt 2 Stunden auf 60 C. Das Reaktionsgemisch wird mit Wasser versetzt und mit Chloroform extrahiert.
Den aus dem Chloroform-Extrakt erhaltenen Eindampfrückstand unterwirft man einer Säulenchromatographie an Kieselgel (Benzol/Aceton = 2/1). Man erhält 670 mg (28% d. Th.) 4-Chlor-zimtsäure-(4-hydroxy-piperidid) vom Schmelzpunkt 167-1690C.
Beispiel 2 4-Chloi-zimtsäure-(4-hydroxy-piperidid)
5,65 g (0,050 Mol) Kalium-tert.-butylat werden bei 200C in Portionen zu 3,6 g (0,025 Mol) 4-Chlorbenzaldehyd und 11,0 g (0,025 Mol) Triphenyl-(4-hydroxy - piperidino) - carbonylmethylphosphoniumchlorid öliges Rohprodukt, hergestellt aus Triphenylphosphin und Chloressigsäure-(4-hydroxy-piperidid)] in absolutem Dioxan gegeben. Man erhitzt 9 Stunden zum Sieden, filtriert den Niederschlag ab und dampft das Filtrat i. Vak.
ein. Der Eindampfrückstand wird in Chloroform gelöst. Man extrahiert die Chloroformlösung mit 2 n Salzsäure, 2 n Natronlauge und Wasser, trocknet über Natriumsulfat und dampft erneut i. Vak. ein. Durch Säulenchromatographie des Rückstands an Kieselgel (Benzol/ Aceton = 2/1) werden 460 mg (7% d.Th) 4-Chlor -zimtsäure-(4-hydroxy-piperidid) vom Schmelzpunkt 1671680C isoliert.
Beispiel 3
4-Brom-zimtsäure-(4-hydroxy-piperidid)
Eine Lösung von 1,20 g (4,31 m Mol) öligem Di äthylphosphonessigsäure-4-hydroxypiperidid [hergestellt aus Chloressigsäure-4-hydroxypiperidid (Schmp. 77-78 0C) und Natriumdiäthylphosphit] und 0,833 g (4,50 m Mol) 4-Brombenzaldehyd in 20 ml absolutem Dioxan wird mit 0,482 g (4,30 m Mol) Kalium-tert.-butylat versetzt und 2 Stunden im Bad von 600C gerührt. Die braungefärbte Lösung wird abgekühlt, mit 200 ml Wasser verdünnt und mit Chloroform extrahiert. Der Eindampf rückstand des Chloroform-Extraktes wird an 75 g Kieselgel mit Benzol/Aceton-l:l säulenchromatographiert. Aus dem Roheluat (0,70 g) werden durch Umkristallisation aus Chlorform/Methanol unter Zusatz von Äther 0,45 g (34% d.
Th.) farbloses 4-Brom-zimtsäure-(4-hydroxy-piperidid) vom Schmp. 159-1610C erhalten.
Beispiel 4 4-Brom-zimtsäure-(4-hydroxy-piperidid)
Zu 0,8 g (4,3 m Mol) 4-Brombenzaldehyd und 1,9 g (4,3 m Mol) Triphenyl-(4-hydroxy-piperidino)-carbonylmethyl-phosphoniumchlorid [hergestellt aus Triphenylphosphin und Chloressigsäure- 4 -hydroxypiperidid, Schmp. 57-590C] in 20 ml absolutem Dimethylformamid werden 1,1 g (9,9 m Mol) Kalium-tert.-butylat gegeben.
Man erwärmt 14 Stunden auf 500C, gibt nach dem Abkühlen Wasser zu und extrahiert mit Chloroform. Die Chloroform-Phase wird mit Natriumsulfat getrocknet und i. Vak. eingedampft. Durch Säulenchromatographie des Eindampfrückstandes an Kieselgel (Benzol/Aceton = 2/1) werden 0,4 g (30% d. Th.) des Produktes vom Schmp. 159-l610C isoliert.
Process for the preparation of new cinnamic acid amides
The invention relates to a process for the preparation of new cinnamic acid amides of the formula 1
EMI1.1
in which Hal denotes a chlorine, bromine or iodine atom, which is characterized in that a cinnamic acid derivative of the formula 2
EMI1.2
with a compound of formula 3
EMI1.3
in the A one
EMI1.4
in which R5 represents a lower alkyl radical, in the presence of a base or in which A represents an (R4) 3P = CH group, in which R represents an aryl or alkyl radical, olefinates.
Does A mean a
EMI1.5
so first a compound of formula 3 is advantageously dissolved in a solvent, e.g. Dioxane, ether or benzene, with a base, e.g. an alkali hydride,
Alkali amide, alkali alcoholate or alkali metal, in it
Carbanion transferred, which is then reacted with a compound of the formula 2, preferably at temperatures between 20 and 100 ° C., to form a cinnamic acid amide of the formula 1. However, the reaction is also possible with alkali bases in a water-containing solvent, e.g. feasible with an alkali carbonate in an aqueous lower alkanol. A carbanion one
A phosphorus compound of the formula 3 can also be produced in the presence of a compound of the formula 2.
If A is a (R4) 3P = CH group, it becomes a
Ylide of the formula 3, if appropriate without prior isolation, expediently in an inert anhydrous
Solvents, e.g. Dioxane or benzene, and preferably at 20 to 1000C, e.g. at the boiling point of the solvent used, with a compound of
Formula 2 implemented (Lit .: Organic Reactions, Vol. 14,
270 f1965]).
The starting materials used in the process according to the invention can be prepared by known methods.
A phosphorus compound of formula 3 is prepared e.g. by reacting sodium dialkyl phosphite with a corresponding haloacetic acid amide.
An ylide of the formula 3 can be prepared, for example, by reacting a triaryl or trialkyl phosphine with a corresponding haloacetic acid amide and then reacting with a base.
In the process according to the invention, trans compounds of the formula 1 are predominantly obtained.
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.
The substances A = 4-chloro-cinnamic acid (4-hydroxypiperidide) and B = 4-bromo-cinnamic acid (4-hydroxypiperidide) were compared to C = phenylbutazone in terms of their anti-inflammatory effect and in terms of their temperature-lowering effect D = aminopyrine and E = phenacetin investigated
1. The anti-inflammatory effect of the substances to be examined was determined as an anti-exudative effect against the carrageenin edema of the rat hind paw by the method of Winter et al. fProc. Soc. exper.
Biol. Med. 111, 544-547 (1962)] and tested against kaolin edema of the rat hind paw by the method of Hillebrecht (Arzneimittelforschung, 4, 607-614 [19541) after oral administration of at least 3 doses to at least 14 animals per dose.
The measurement was carried out according to the method of Doepfner and Cerletti (Int. Arch. Allergy al appl. Immun. 12, 89-97 [19581); the dose was determined graphically, which causes a 35% reduction (ED35) of the respective swelling :
Carrngeenbi edema Kaolin edema Substance EDss mglkg ED95 mg / kg
A 31 55
B 51 73
C 74 62
2. The test for a temperature-lowering effect of the substances under investigation was carried out on normothermic rats after oral administration of at least 4 doses to at least 10 animals per dose.
From the averaged values achieved with the various doses for the maximum decrease in temperature of the individual animal, the dose was determined by graphic interpolation, which causes a decrease in body temperature by 1.50C (ED-, S.c):
Substance ED I, 50 mg / kg
A 5.5
B 7.0
D 70
E 80
3. The acute toxicity of substances A to D was determined in groups of at least 10 rats with at least 3 doses per group.
The Led55, the dose of which 50% of the animals died within 14 days of oral administration, was determined graphically:
Substance LD50 g / kg
A ,,,,, 5.0
B ,, -, 5.0
C 0.98
D 1.1
E 2.3
The following examples are intended to explain the invention in more detail:
Example I 4-chloro-cinnamic acid- (4-hydroxypiperidide)
2.5 g (8.9 mol) of diethylphosphonoacetic acid (4-hydroxy-piperidide) [oily crude product, prepared from chloroacetic acid (4-hydroxy-piperidide) and sodium diethylphosprin] and 1.4 g (10 m mol) of 4-chlorobenzaldehyde are dissolved in 50 ml of absolute dioxane. 1.0 g (8.9 mol) of potassium tert-butoxide are added and the mixture is heated to 60 ° C. for 2 hours. The reaction mixture is mixed with water and extracted with chloroform.
The evaporation residue obtained from the chloroform extract is subjected to column chromatography on silica gel (benzene / acetone = 2/1). 670 mg (28% of theory) of 4-chloro-cinnamic acid (4-hydroxypiperidide) with a melting point of 167-1690 ° C. are obtained.
Example 2 4-chlorocinnamic acid (4-hydroxypiperidide)
5.65 g (0.050 mol) of potassium tert-butoxide are added at 200C in portions of 3.6 g (0.025 mol) of 4-chlorobenzaldehyde and 11.0 g (0.025 mol) of triphenyl (4-hydroxypiperidino) - carbonylmethylphosphonium chloride oily crude product, prepared from triphenylphosphine and chloroacetic acid (4-hydroxy-piperidide)] in absolute dioxane. The mixture is heated to boiling for 9 hours, the precipitate is filtered off and the filtrate is evaporated i. Vac.
one. The evaporation residue is dissolved in chloroform. The chloroform solution is extracted with 2N hydrochloric acid, 2N sodium hydroxide solution and water, dried over sodium sulfate and evaporated again i. Vac. one. Column chromatography of the residue on silica gel (benzene / acetone = 2/1) is used to isolate 460 mg (7% of theory) of 4-chloro-cinnamic acid (4-hydroxypiperidide) with a melting point of 1671680C.
Example 3
4-bromo-cinnamic acid- (4-hydroxypiperidide)
A solution of 1.20 g (4.31 m mol) of oily diethylphosphonoacetic acid 4-hydroxypiperidide [prepared from chloroacetic acid 4-hydroxypiperidide (melting point 77-78 ° C.) and sodium diethyl phosphite] and 0.833 g (4.50 molar) 4-bromobenzaldehyde in 20 ml of absolute dioxane is mixed with 0.482 g (4.30 mol) of potassium tert-butoxide and stirred for 2 hours in a bath at 60.degree. The brown colored solution is cooled, diluted with 200 ml of water and extracted with chloroform. The evaporation residue of the chloroform extract is column chromatographed on 75 g of silica gel with benzene / acetone-1: 1. 0.45 g (34% of theory) are obtained from the crude oil (0.70 g) by recrystallization from chloroform / methanol with the addition of ether.
Th.) Colorless 4-bromo-cinnamic acid- (4-hydroxypiperidide) of melting point 159-1610C.
Example 4 4-Bromo-cinnamic acid- (4-hydroxypiperidide)
To 0.8 g (4.3 mol) of 4-bromobenzaldehyde and 1.9 g (4.3 mol) of triphenyl- (4-hydroxypiperidino) carbonylmethylphosphonium chloride [prepared from triphenylphosphine and chloroacetic acid-4-hydroxypiperidide , Melting point 57-590C] in 20 ml of absolute dimethylformamide, 1.1 g (9.9 mol) of potassium tert-butoxide are added.
The mixture is heated to 50 ° C. for 14 hours, water is added after cooling and the mixture is extracted with chloroform. The chloroform phase is dried with sodium sulfate and i. Vac. evaporated. Column chromatography of the evaporation residue on silica gel (benzene / acetone = 2/1) isolates 0.4 g (30% of theory) of the product with a melting point of 159-1610C.
Claims (1)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT1075668A AT281822B (en) | 1968-11-05 | 1968-11-05 | Process for the production of new cinnamic acid amides |
| AT494669A AT288388B (en) | 1969-05-23 | 1969-05-23 | Process for the preparation of a new cinnamic acid amide |
| CH1604469A CH522640A (en) | 1967-12-01 | 1969-10-28 | Cinnamic acid amide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH522641A true CH522641A (en) | 1972-06-30 |
Family
ID=27150194
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH144372A CH522641A (en) | 1968-11-05 | 1969-10-28 | Cinnamic acid amide |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH522641A (en) |
-
1969
- 1969-10-28 CH CH144372A patent/CH522641A/en not_active IP Right Cessation
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