DE1543519C - Process for the preparation of p-aminobenzoic acid anilides - Google Patents
Process for the preparation of p-aminobenzoic acid anilidesInfo
- Publication number
- DE1543519C DE1543519C DE1543519C DE 1543519 C DE1543519 C DE 1543519C DE 1543519 C DE1543519 C DE 1543519C
- Authority
- DE
- Germany
- Prior art keywords
- general formula
- group
- aminobenzoic acid
- alkyl group
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims description 11
- QHWDUJPWCGEBTH-UHFFFAOYSA-N 4-amino-N-phenylbenzamide Chemical class C1=CC(N)=CC=C1C(=O)NC1=CC=CC=C1 QHWDUJPWCGEBTH-UHFFFAOYSA-N 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 4
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 150000002828 nitro derivatives Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 229960003893 Phenacetin Drugs 0.000 description 3
- 229960002895 Phenylbutazone Drugs 0.000 description 3
- 239000007868 Raney catalyst Substances 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- 230000003110 anti-inflammatory Effects 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 239000002904 solvent Substances 0.000 description 3
- MVPPADPHJFYWMZ-UHFFFAOYSA-N Chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- CPJSUEIXXCENMM-UHFFFAOYSA-N Phenacetin Chemical compound CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 230000000202 analgesic Effects 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 201000008125 pain agnosia Diseases 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- JYMVSZGJZRQOFY-UHFFFAOYSA-N (4-nitrobenzoyl) 4-nitrobenzoate Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(=O)OC(=O)C1=CC=C([N+]([O-])=O)C=C1 JYMVSZGJZRQOFY-UHFFFAOYSA-N 0.000 description 1
- QFEZYTBYDFNYMR-UHFFFAOYSA-N 4-amino-N-(2,3-dimethylphenyl)benzamide Chemical compound CC1=CC=CC(NC(=O)C=2C=CC(N)=CC=2)=C1C QFEZYTBYDFNYMR-UHFFFAOYSA-N 0.000 description 1
- XHGXSPTXAJXRGS-UHFFFAOYSA-N 4-amino-N-(2-ethylphenyl)benzamide Chemical compound CCC1=CC=CC=C1NC(=O)C1=CC=C(N)C=C1 XHGXSPTXAJXRGS-UHFFFAOYSA-N 0.000 description 1
- RUPHBOZLECXENU-UHFFFAOYSA-N 4-amino-N-(2-propan-2-ylphenyl)benzamide Chemical compound CC(C)C1=CC=CC=C1NC(=O)C1=CC=C(N)C=C1 RUPHBOZLECXENU-UHFFFAOYSA-N 0.000 description 1
- ZYKINIOHWRNMIC-UHFFFAOYSA-N 4-nitro-N-(2-propan-2-ylphenyl)benzamide Chemical compound CC(C)C1=CC=CC=C1NC(=O)C1=CC=C([N+]([O-])=O)C=C1 ZYKINIOHWRNMIC-UHFFFAOYSA-N 0.000 description 1
- 241000581650 Ivesia Species 0.000 description 1
- LEHVMGBGCKQTAN-UHFFFAOYSA-N N-(2,3-dimethylphenyl)-4-nitrobenzamide Chemical compound CC1=CC=CC(NC(=O)C=2C=CC(=CC=2)[N+]([O-])=O)=C1C LEHVMGBGCKQTAN-UHFFFAOYSA-N 0.000 description 1
- ICDCIUPEPWYOPN-UHFFFAOYSA-N N-(2-ethylphenyl)-4-nitrobenzamide Chemical compound CCC1=CC=CC=C1NC(=O)C1=CC=C([N+]([O-])=O)C=C1 ICDCIUPEPWYOPN-UHFFFAOYSA-N 0.000 description 1
- GMGQGZYFQSCZCW-UHFFFAOYSA-N N-(4-nitrophenyl)benzamide Chemical class C1=CC([N+](=O)[O-])=CC=C1NC(=O)C1=CC=CC=C1 GMGQGZYFQSCZCW-UHFFFAOYSA-N 0.000 description 1
- 210000004197 Pelvis Anatomy 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 230000001760 anti-analgesic Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Description
Die Erfindung betrifft ein Verfahren zur Herstellung von p-Aminobenzoesäureaniliden der allgemeinen FormelThe invention relates to a process for the preparation of p-aminobenzoic acid anilides in general formula
CO-NHCO-NH
in der R2 eine gerade oder verzweigte gesättigte oder ungesättigte Alkylgruppe mit 2 bis 6 Kohlenstoffatomen und R3 ein Wasserstoffatom oder eine gerade oder verzweigte gesättigte oder ungesättigte Alkylgruppe mit 1 bis 6 Kohlenstoffatomen bedeutet, wobei R2 auch eine Methylgruppe sein kann, wenn R3 eine Alkylgruppe ist, und deren Salze, das dadurch gekennzeichnet ist, daß man in an sich bekannter Weisein which R 2 is a straight or branched saturated or unsaturated alkyl group with 2 to 6 carbon atoms and R 3 is a hydrogen atom or a straight or branched saturated or unsaturated alkyl group with 1 to 6 carbon atoms, where R 2 can also be a methyl group when R 3 is an alkyl group, and the salts thereof, which is characterized in that in a manner known per se
a) in einer Nitro verbindung der allgemeinen Formela) in a nitro compound of the general formula
-ΝΗ-/Λ-ΝΗ- / Λ
CO2HCO 2 H
IOIO
'5 89 g (0,329 Mol) 4-Nitrobenzoesäure-(2,3-dimethyl-anilid) werden in, 1 1 Methanol in Gegenwart von 15 g Raney-Nickel bei 20 atü und Zimmertemperatur hydriert. Nach 10 Minuten ist die berechnete Menge Wasserstoff aufgenommen und die Temperatur auf 45° C gestiegen. Der Katalysator wird abgetrennt und die Lösung mit 2 1 Wasser verdünnt, wobei das Produkt auskristaUisiert. Es wird aus,Äthanol umkristallisiert.' * .■■■■; . · '5 89 g (0.329 mol) of 4-nitrobenzoic acid (2,3-dimethyl anilide) are hydrogenated in 1 1 of methanol in the presence of 15 g of Raney nickel at 20 atmospheres and room temperature. After 10 minutes, the calculated amount of hydrogen has been absorbed and the temperature has risen to 45.degree. The catalyst is separated off and the solution is diluted with 2 liters of water, the product crystallizing out. It is recrystallized from "ethanol." *. ■■■■; . ·
Ausbeute: 78 g (98,6%); Fp. 170 bis 171°C.Yield: 78 g (98.6%); Mp 170-171 ° C.
: B e is ρ i e 1 2 : l- : B e is ρ ie 1 2 : l-
4-Aminobenzoesäure-(2-äthyl-anilid)4-aminobenzoic acid- (2-ethyl-anilide)
.. . ■ ■ I R3 ... ■ ■ IR 3
■ ■■...·■ ■:·. ; \ :■■ ':- - _ ·· R2 «■·■■ ■■ ... · ■ ■: ·. ; \: ■■ ' : - - _ ·· R 2 «■ · ■
die Nitrogruppe zur Aminogruppe reduziert oder - b) eine Benzoesäure der allgemeinen Formelthe nitro group is reduced to the amino group or - b) a benzoic acid of the general formula
worin Z eine Amino- oder eine acylierte Aminogruppe bedeutet bzw. ein Amid oder einen Ester dieser Säure mit einer Verbindung der allgemeinen Formel ...where Z denotes an amino or an acylated amino group or an amide or an ester this acid with a compound of the general formula ...
H7N-H 7 N-
CO-NHCO-NH
2020th
3535
umsetzt und gegebenenfalls entacyliert und die nach den Verfahren a) oder b) erhaltenen Verbindungen gegebenenfalls in ihre Salze überführt.reacted and optionally deacylated and the compounds obtained by process a) or b) optionally converted into their salts.
Die Reduktion des Verfahrensweges a) wird vorzugsweise mit Wasserstoff in Gegenwart eines Hy- drierungskatalysators, beispielsweise Raney-Nickel oder einem Edelmetallkatalysator in einem Lösungsmittel bei Temperaturen zwischen 20 und-60° C und einem Druck von 10 bis 60 atü durchgeführt.The reduction of process route a) is preferably carried out with hydrogen in the presence of a hy- dration catalyst, for example Raney nickel or a noble metal catalyst in a solvent carried out at temperatures between 20 and -60 ° C and a pressure of 10 to 60 atü.
Die hierbei als Ausgangsverbindungen benötigten p-Nitrobenzanilide, Tür deren Herstellung im Rahmen dieser Erfindung kein Schutz begehrt wird, werden in an sich bekannter Weise durch Umsetzung von p-Nitrobenzoesäureanhydrid mit dem entsprechenden Anilin gewonnen. , .., ,..;_.... „.The p-nitrobenzanilides required here as starting compounds, door their production within the framework This invention is not sought protection, are in a known manner by implementation of p-nitrobenzoic anhydride obtained with the corresponding aniline. , ..,, ..; _.... ".
Der.Verfahrensweg b) kann mit und ohne Lösungsmittel bei Temperaturen zwischen 50 und 300° C ausgeführt werden. Falls ein Lösungsmittel verwendet wird, so kommen beispielsweise in Betracht: Benzol, Chlorbenzol, Toluol, Dimethylsulfoxyd, Alkohole usw.Der.Verfahrenweg b) can with and without a solvent be carried out at temperatures between 50 and 300 ° C. If a solvent is used for example: benzene, chlorobenzene, toluene, dimethyl sulfoxide, alcohols, etc.
Beispiell
4-Aminobenzoesäure-(2,3-dimethyl-anilid)For example
4-aminobenzoic acid (2,3-dimethyl anilide)
H2N-^ V-CO-NHH 2 N- ^ V-CO-NH
85 g (0,314MoI) 4-Nitrobenzoesäure-(2-äthyl-anilid) werden analog Beispiel 1 hydriert und aufgearbeitet. Es wird aus Isopropanol umkristallisiert.85 g (0.314MoI) 4-nitrobenzoic acid (2-ethyl-anilide) are hydrogenated and worked up analogously to Example 1. It is recrystallized from isopropanol.
Ausbeute: 70 g (93%); Fp. 171 bis 172°C.Yield: 70 g (93%); Mp 171-172 ° C.
B e i s ρ i e 1 3 4-Aminobenzoesäure-(2-isopropyl-anilid)B e i s ρ i e 1 3 4-aminobenzoic acid (2-isopropyl anilide)
CO-NH*CO-NH *
115 g (0,405 Mol) 4-Nitro-benzoesäure-(2-isopropyl-anilid) werden in 1,21 Methanol mit 30 g Raney-Nickel im Autoklav bei 4O0C und 40 atü hydriert. Der Katalysator wird abgesaugt und das Filtrat eingedampft. Der kristalline Rückstand wird aus Äthanol umkristallisiert. ■115 g (0.405 mol) of 4-nitro-benzoic acid (2-isopropyl-anilide) are dissolved in 1.21 of methanol with 30 g of Raney nickel in an autoclave at 4O 0 C and hydrogenated atm 40th The catalyst is filtered off with suction and the filtrate is evaporated. The crystalline residue is recrystallized from ethanol. ■
Ausbeute: 80 g = 77,6%; Fp. 178 bis 179°C,Yield: 80 g = 77.6%; Mp. 178 to 179 ° C,
Die nach dem Verfahren der Erfindung hergestellten Verbindungen besitzen eine ausgezeichnete antiphlogistische und analgetische Wirkung. -The compounds prepared by the process of the invention are excellent in anti-inflammatory properties and analgesic effect. -
In der untenstehenden Tabelle werden die pharmakologischen Eigenschaften der Verfahrensprodukte mit dem bekannten Antiphlogistikum Phenylbutazon sowie dem bekannten Analgetikum Phenacetin verglichen. The table below shows the pharmacological properties of the products of the process compared with the well-known anti-inflammatory drug phenylbutazone and the well-known analgesic phenacetin.
Methodikmethodology
Die antiphlogistische Wirkung wurde am Eiweißödem der Rattenpfpte in Anlehnung an die Methode von Domenjoz und Mitarbeitern (Arch. exp. Pharm. Path., 230 [1957], 325) geprüft. Die analgetische Wirkung wurde mit der Mäuseschwanzmethode nach Haffner (Dtsch. Med. Wschr., 55 [1929], 731) untersucht. Die akute Toxizität wurde an der Maus nach Miller und Tainter (Prof. Soc. Exper. Biol. a. Med., 57 [1944], 261) bestimmt.The anti-inflammatory effect was demonstrated on the protein edema of the rat pelvis based on the method by Domenjoz et al. (Arch. exp. Pharm. Path., 230 [1957], 325). The analgesic Effect was determined with the mouse tail method according to Haffner (Dtsch. Med. Wschr., 55 [1929], 731) examined. The acute toxicity was determined on the mouse according to Miller and Tainter (Prof. Soc. Exper. Biol. A. Med., 57 [1944], 261).
IOIO
Die Versuchsdaten zeigen, daß die antiphlogistische Wirkung der Verfahrensprodukte etwa in der gleichen Größenordnung liegt wie die des Phenylbutazons. In der Analgesie sind die Verfahrensprodukte dem Phenacetin jedoch deutlich überlegen. Der besondere und überraschende Vorteil der erfindungsgemäßen Verbindungen liegt jedoch darin, daß beide Eigenschaften in einer Substanz vereinigt sind.The test data show that the anti-inflammatory effect of the products of the process is about the same It is of the same order of magnitude as that of phenylbutazone. In analgesia, the products of the process are dem However, clearly superior to phenacetin. The particular and surprising advantage of the invention Compounds lies in the fact that both properties are combined in one substance.
Claims (1)
Family
ID=
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