DE1157628B - Process for the production of halogen-substituted orthanilic acid amides with a sedative effect - Google Patents
Process for the production of halogen-substituted orthanilic acid amides with a sedative effectInfo
- Publication number
- DE1157628B DE1157628B DEA35099A DEA0035099A DE1157628B DE 1157628 B DE1157628 B DE 1157628B DE A35099 A DEA35099 A DE A35099A DE A0035099 A DEA0035099 A DE A0035099A DE 1157628 B DE1157628 B DE 1157628B
- Authority
- DE
- Germany
- Prior art keywords
- substituted
- halogen
- acid amides
- production
- orthanilic acid
- 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
- ZMCHBSMFKQYNKA-UHFFFAOYSA-N 2-aminobenzenesulfonic acid Chemical class NC1=CC=CC=C1S(O)(=O)=O ZMCHBSMFKQYNKA-UHFFFAOYSA-N 0.000 title claims description 5
- 238000000034 method Methods 0.000 title claims description 3
- 230000001624 sedative effect Effects 0.000 title description 7
- 238000004519 manufacturing process Methods 0.000 title description 2
- 239000000460 chlorine Substances 0.000 claims description 9
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 2
- 230000000147 hypnotic effect Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 4
- 230000008018 melting Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 3
- 239000000932 sedative agent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- WJVMARQNXIKFPI-UHFFFAOYSA-N 2-amino-4,5-dichlorobenzenesulfonamide Chemical compound NC1=CC(Cl)=C(Cl)C=C1S(N)(=O)=O WJVMARQNXIKFPI-UHFFFAOYSA-N 0.000 description 2
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000001773 anti-convulsant effect Effects 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 229960003965 antiepileptics Drugs 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- QMGVPVSNSZLJIA-FVWCLLPLSA-N strychnine Chemical compound O([C@H]1CC(N([C@H]2[C@H]1[C@H]1C3)C=4C5=CC=CC=4)=O)CC=C1CN1[C@@H]3[C@]25CC1 QMGVPVSNSZLJIA-FVWCLLPLSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- YKQPZGMHAXHTJQ-UHFFFAOYSA-N 2-amino-5-fluorobenzenesulfonamide Chemical compound NC1=CC=C(F)C=C1S(N)(=O)=O YKQPZGMHAXHTJQ-UHFFFAOYSA-N 0.000 description 1
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- QMGVPVSNSZLJIA-UHFFFAOYSA-N Nux Vomica Natural products C1C2C3C4N(C=5C6=CC=CC=5)C(=O)CC3OCC=C2CN2C1C46CC2 QMGVPVSNSZLJIA-UHFFFAOYSA-N 0.000 description 1
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 1
- 241001279009 Strychnos toxifera Species 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002082 anti-convulsion Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960005453 strychnine Drugs 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
INTERNAT. KL. C 07 C INTERNAT. KL. C 07 C
DEUTSCHESGERMAN
PATENTAMTPATENT OFFICE
A 35099 IVb/12qA 35099 IVb / 12q
BEKANNTMACHUNG
DERANMELDUNG
UND AUSGABE DER
AUSLEGESCHRIFT: 21. NOVEMBER 1963 NOTICE
LOGIN
AND ISSUE OF THE
EDITORIAL: NOVEMBER 21, 1963
Die Erfindung betrifft die Herstellung halogensubstituierter Orthanilsäureamide der allgemeinen Formel IThe invention relates to the preparation of halogen-substituted orthanilic acid amides of the general Formula I.
worin A Chlor oder Fluor und B Chlor, Fluor oder Wasserstoff bezeichnen. Es hat sich erwiesen, daß diese Substanzen bei parenteraler Eingabe in Versuchstieren und Menschen eine antikonvulsivische und hypnotische, insbesondere aber sedative Wirkung ausüben und daß sie in therapeutischen Dosen nur geringe Toxizität aufweisen.where A denotes chlorine or fluorine and B denotes chlorine, fluorine or hydrogen. It has been shown that these substances, when administered parenterally in experimental animals and humans, have an anticonvulsive and exert hypnotic, but especially sedative effects and that they are only available in therapeutic doses have low toxicity.
Erfindungsgemäß lassen sich solche 4,5-dihalogenierten oder 5-halogensubstituierten Orthanilsäureamide dadurch herstellen, daß man Anilin, welches durch Chlor oder Fluor oder sowohl Chlor als auch Fluor in der 4- oder 3- und 4-Stellung substituiert ist, in an sich bekannter Weise sulfoniert bzw. chlorsulfoniert und anschließend amidiert.According to the invention, such 4,5-dihalogenated or 5-halogen-substituted orthanilic acid amides by using aniline, which is substituted by chlorine or fluorine or both chlorine and fluorine in the 4- or 3- and 4-position, sulfonated or chlorosulfonated in a manner known per se and then amidated.
Die antikonvulsivischen, sedativen und hypnotischen Wirkungen der gemäß der Erfindung hergestellten Stoffe erhellen aus untenstehender Übersicht Verfahren zur HerstellungThe anticonvulsant, sedative and hypnotic effects of those made according to the invention Fabrics are shown in the overview below for manufacturing processes
von sedativ wirksamen halogensubstituiertenof halogen-substituted persons with sedative effects
OrthanilsäureatnidenOrthanilic acid atenides
Anmelder:
A/S Ferrosan, KopenhagenApplicant:
A / S Ferrosan, Copenhagen
Vertreter:Representative:
Dipl.-Ing. Dr.-Ing. R. Poschenrieder, Patentanwalt, München 8, Lucile-Grahn-Str. 38Dipl.-Ing. Dr.-Ing. R. Poschenrieder, patent attorney, Munich 8, Lucile-Grahn-Str. 38
Beanspruchte Priorität: Dänemark vom 11. Juli 1959Claimed priority: Denmark of July 11, 1959
J0rgen Anders Christensen, Virum (Dänemark), ist als Erfinder genannt wordenJ0rgen Anders Christensen, Virum (Denmark), has been named as the inventor
über experimentelle Bestimmungen der effektiven Dosen in Mäusen pro Kilo Körpergewicht.on experimental determinations of the effective doses in mice per kilo of body weight.
B^ -NH 2
B.
Toxizität
LD50 Acute
toxicity
LD 50
Antikonvulsive ED50 mg / kg mouse subcutE
Anticonvulsant ED 50
ED4)Hypnotic
ED 4 )
methylen-
tetrazol1)Penta
methylene
tetrazole 1 )
*) E. Swinyard, J. Am. Pharm. Assoc. Sei. Ed., 38,1949, S. 201.*) E. Swinyard, J. Am. Pharm. Assoc. May be. Ed., 38, 1949, p. 201.
*) F. Berger, J. Pharmacol., 112, 1954, S. 413.*) F. Berger, J. Pharmacol., 112, 1954, p. 413.
·) Sedative — Barbiturpotenzierende; F. Berger, J. Pharmacol., 112, 1954, S. 413.·) Sedative - barbiturepotentiating; F. Berger, J. Pharmacol., 112, 1954, p. 413.
*) Diejenige Dosis, die einen lstündigen, reflexlosen Schlaf bewirkt.*) The dose that causes an hour-long, reflex-free sleep.
Aus der vorstehenden Tabelle ist zu ersehen, daß die hypnotische ED höher liegt als die der Phenyläthylbarbitursäure, die Toxizität dieser Verfahrensprodukte In der folgenden Tabelle sind die Quotienten Sed. ED , Sed. EDFrom the table above it can be seen that the hypnotic ED is higher than that of phenylethylbarbituric acid, the toxicity of these process products. The following table shows the quotients Sed. ED, Sed. ED
undand
für die verschiedenen nachfor the different after
LD50 Hyp. EDLD 50 Hyp. ED
jedoch bedeutend niedriger liegt, da die Werte für 50 den Beispielen der vorliegenden Erfindung hergedie akute toxische letale Dosis um mehr als das stellten Substanzen aus der vorhergehenden Tabelle dreifache höher liegen. errechnet.however, is significantly lower as the values for 50 are used in the examples of the present invention acute toxic lethal dose by more than the substances listed in the previous table three times higher. calculated.
309 749/397309 749/397
5F
4-C1.5-F
4,5-di-F
Phenyläthylbarbitursäure4,5-di-Cl
5F
4-C1.5-F
4,5-di-F
Phenylethylbarbituric acid
0,4
0,17
0,17
0,230.3
0.4
0.17
0.17
0.23
0,19
0,580.24
0.19
0.58
punkt 173 bis 178° C. Durch Umkristallisation aus 50%igem Äthanol erhält man den reinen Stoff mit Schmelzpunkt 183 bis 185° C.point 173 to 178 ° C. The pure substance is obtained by recrystallization from 50% ethanol Melting point 183 to 185 ° C.
In ähnlicher Weise lassen sich 4-Chlor- oder 4-Fluoranilin oder 3,4-dihalogensubstituiertes Anilin, worin einer der oder die beiden Substituenten Fluor und der Rest Chlor ist, mit Chlorsulfonsäure oder Sulfonierungsmitteln behandeln, und das gewonnene Produkt wird amddiert.In a similar way, 4-chloro- or 4-fluoroaniline or 3,4-dihalosubstituted aniline, wherein one of the or the two substituents is fluorine and the remainder is chlorine, with chlorosulfonic acid or Treat sulfonating agents and the product recovered is amddated.
IOIO
Aus dieser Zusammenstellung geht hervor, daß man bei Anwendung der erfindungsgemäßen Substanzen durchschnittlich eine geringere Toxizität und eine geringere hypnotische Wirkung erzielt, wenn man eine bestimmte sedative Wirkung erzielen will, als dies bei der Phenyläthylbarbitursäure der Fall ist.From this compilation it can be seen that when using the substances according to the invention on average has a lower toxicity and a lower hypnotic effect if one wants to achieve a certain sedative effect than is the case with phenylethylbarbituric acid.
2-Amino-4,5-dichlorbenzolsulfonamid2-amino-4,5-dichlorobenzenesulfonamide
150 ml Chlorsulfonsäure werden in einen dreihalsigen
Kolben von 11 gebracht, der mit Rührer versehen und in ein Ölbad mit einer Temperatur von etwa 700C
eingetaucht ist. Zur Chlorsulfonsäure werden zunächst 63 g 3,4-DichloraniJin und danach 130 g Natriumchlorid
gegeben, wonach die Temperatur bei stetigem Rühren der Mischung auf 130° C erhöht wird, auf
diesem Wert etwa 1 Stunde gehalten, dann auf 150°C erhöht und während etwa 2 Stunden auf 1500C
gehalten wird. Dann wird die Mischung auf Zimmertemperatur abgekühlt. Nun werden 500 g Eis hinzugesetzt,
und nach Schmelzen des Eises wird das gebildete Sulfonsäurechlorid abgeschieden und mit
Wasser ausgewaschen, wonach es sofort unter Erwärmen mit etwa 500 ml konzentriertem Ammoniakwasser
umgesetzt wird. Bei teilweisem Eindampfen und Neutralisation mit Salzsäure erhält man 37 g
2-Amino-4,5-dichlorbenzoIsulfonamid vom Schmelz-Beispiel 2
2-Amino-5-fluorbenzolsulfonamid150 ml of chlorosulfonic acid are placed in a three necked flask 11, which is provided with a stirrer and immersed in an oil bath at a temperature of about 70 0 C. To the chlorosulfonic acid, 63 g of 3,4-dichloraniJin and then 130 g of sodium chloride are added, after which the temperature is increased to 130 ° C. with constant stirring of the mixture, held at this value for about 1 hour, then increased to 150 ° C. and for about Is held at 150 0 C for 2 hours. Then the mixture is cooled to room temperature. 500 g of ice are then added, and after the ice has melted, the sulfonic acid chloride formed is separated off and washed out with water, after which it is immediately reacted with about 500 ml of concentrated ammonia water while heating. With partial evaporation and neutralization with hydrochloric acid, 37 g of 2-amino-4,5-dichlorobenzene sulfonamide from melting example 2 are obtained
2-amino-5-fluorobenzenesulfonamide
150 ml Chlorsulfonsäure werden in einen dreihalsigen Kolben angebracht, der mit Rührer versehen ist, und in ein Ölbad mit einer Temperatur von etwa 70° C eingetaucht. Man fügt 38 g 4-Fluoranilin hinzu und läßt das Gemisch während 3 Stunden unter Rühren bei 700C stehen, wonach 40 g Thionylchlorid zugesetzt werden, und die Reaktion während weiterer 3 Stunden bei derselben Temperatur fortgesetzt wird. Das entstandene Reaktionsgemisch wird gekühlt und einem Überschuß an Eis zugesetzt. Das dabei ausgeschiedene Sulfonsäurechlorid wird abgesaugt und mit wenig Wasser gewaschen, wonach es 100 ml eiskaltem Ammoniakwasser hinzugesetzt wird. Nach Lösung und Filtrieren wird die Flüssigkeit etwas eingeengt und danach mit Salzsäure neutralisiert. Das ausgeschiedene Produkt wird abgesaugt und mit Wasser gewaschen. Schmelzpunkt 104 bis 105°C.150 ml of chlorosulfonic acid are placed in a three-necked flask equipped with a stirrer and immersed in an oil bath at a temperature of about 70 ° C. Is added 38 g 4-fluoroaniline are added and the mixture is left for 3 hours under stirring at 70 0 C for, after which 40 g of thionyl chloride are added and the reaction is continued for a further 3 hours at the same temperature. The resulting reaction mixture is cooled and added to an excess of ice. The sulfonic acid chloride which separates out is filtered off with suction and washed with a little water, after which 100 ml of ice-cold ammonia water is added. After dissolving and filtering, the liquid is concentrated somewhat and then neutralized with hydrochloric acid. The precipitated product is filtered off with suction and washed with water. Melting point 104 to 105 ° C.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK1157628X | 1959-07-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1157628B true DE1157628B (en) | 1963-11-21 |
Family
ID=8157700
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEA35099A Pending DE1157628B (en) | 1959-07-11 | 1960-07-11 | Process for the production of halogen-substituted orthanilic acid amides with a sedative effect |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1157628B (en) |
-
1960
- 1960-07-11 DE DEA35099A patent/DE1157628B/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CH351791A (en) | Fungicidal agent | |
| DE2422243A1 (en) | CARBANILIDES AND THEIR PRODUCTION | |
| DE1157628B (en) | Process for the production of halogen-substituted orthanilic acid amides with a sedative effect | |
| DE1201008B (en) | Disinfectants | |
| DE1094737B (en) | Process for the preparation of aryl isocyanide dihalides | |
| DE1147951B (en) | Process for the preparation of 5-acetyl-6-methyl-4- [5-nitrofuryl- (2)] - 1, 2, 3, 4-tetrahydropyrimidin-2-one | |
| DE2654852C3 (en) | Process for the preparation of aromatic amines from α, ß-unsaturated cycloaliphatic ketoximes | |
| DE2414084A1 (en) | DINITROANILINE DERIVATIVES | |
| DE673521C (en) | Process for the production of liquid chlorine products from high molecular weight, aliphatic hydrocarbon mixtures | |
| DE1237560B (en) | Process for the preparation of cyanoformic acid ethiol esters | |
| DE951718C (en) | Process for removing chlorosulfur from dialkoxyphosphorus sulfochlorides containing chlorosulfur | |
| DE1229084B (en) | Process for the preparation of tetracycline cyclohexyl sulfamate | |
| DE2521905A1 (en) | FUMARIC SALT OF 1-DIAETHYLAMINO-AETHYL-3-(P-METHOXYBENZYL)-1,2-DIHYDRO-QUINOXALIN-2-ONE, PROCESS FOR ITS PREPARATION AND PHARMACEUTICALS CONTAINING THIS COMPOUND | |
| DE1215696B (en) | Process for the preparation of 3, 4, 5-trimethoxy-benzamides and 3, 4, 5-trimethoxy-cinnamic acid amides | |
| AT67205B (en) | Process for the production of a mercury preparation, in particular for therapeutic purposes. | |
| DE895672C (en) | Insecticides and fungicides crop protection product and process for its manufacture | |
| DE1620569B2 (en) | PROCESS FOR THE MANUFACTURING OF LAURINSAEURELACTAM | |
| DE1814334B2 (en) | FATTY ACID AMIDES AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS | |
| AT229322B (en) | Process for the preparation of the new 2-sec-butoxyphenyl-N-methylcarbamate | |
| DE749148C (en) | Process for the nitrosation of 4-aminouracil | |
| DE1593838C3 (en) | Rutin tri- (dihydroxypropyl) ether and process for its preparation | |
| DE604016C (en) | Process for the production of aliphatic aminosulfonic acids | |
| AT119480B (en) | Process for the preparation of addition compounds of sulfur dioxide with aromatic p-diamines. | |
| DE922102C (en) | Process for the preparation of the semicarbazones of triacetylbenzene | |
| DE1060857B (en) | Process for the production of stable, highly concentrated cyclohexanone peroxide solutions |