NO133198B - - Google Patents
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- NO133198B NO133198B NO3825/71A NO382571A NO133198B NO 133198 B NO133198 B NO 133198B NO 3825/71 A NO3825/71 A NO 3825/71A NO 382571 A NO382571 A NO 382571A NO 133198 B NO133198 B NO 133198B
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- 239000002253 acid Substances 0.000 claims description 10
- 238000005984 hydrogenation reaction Methods 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000000460 chlorine Chemical group 0.000 claims description 2
- 229910052801 chlorine Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 206010010904 Convulsion Diseases 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- RWZSFUHBNNZPJU-UHFFFAOYSA-N 2-(2-aminophenyl)-n-methylacetamide Chemical group CNC(=O)CC1=CC=CC=C1N RWZSFUHBNNZPJU-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- FAGCGLVYZVONBW-UHFFFAOYSA-N 2-(2-aminophenyl)-n-ethylacetamide Chemical compound CCNC(=O)CC1=CC=CC=C1N FAGCGLVYZVONBW-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000003929 acidic solution Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- WMUZDBZPDLHUMW-UHFFFAOYSA-N (2-nitrophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC=C1[N+]([O-])=O WMUZDBZPDLHUMW-UHFFFAOYSA-N 0.000 description 2
- VGAVDFWIHUETOY-UHFFFAOYSA-N 2-(2-amino-4-chlorophenyl)-n-methylacetamide Chemical compound CNC(=O)CC1=CC=C(Cl)C=C1N VGAVDFWIHUETOY-UHFFFAOYSA-N 0.000 description 2
- FLZUSUKBKOZJLG-UHFFFAOYSA-N 2-(4-chloro-2-nitrophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(Cl)C=C1[N+]([O-])=O FLZUSUKBKOZJLG-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 230000001914 calming effect Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 230000036461 convulsion Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 208000028329 epileptic seizure Diseases 0.000 description 2
- 206010022437 insomnia Diseases 0.000 description 2
- ONHWNARPSWLBLK-UHFFFAOYSA-N n-methyl-2-(2-nitrophenyl)acetamide Chemical compound CNC(=O)CC1=CC=CC=C1[N+]([O-])=O ONHWNARPSWLBLK-UHFFFAOYSA-N 0.000 description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229910003446 platinum oxide Inorganic materials 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- XODRHOWZEUKZFD-UHFFFAOYSA-N 2-(2-aminophenyl)-n-propan-2-ylacetamide Chemical compound CC(C)NC(=O)CC1=CC=CC=C1N XODRHOWZEUKZFD-UHFFFAOYSA-N 0.000 description 1
- JBQZJVJEAYXBAT-UHFFFAOYSA-N 2-(2-aminophenyl)-n-propylacetamide Chemical compound CCCNC(=O)CC1=CC=CC=C1N JBQZJVJEAYXBAT-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000010513 Stupor Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- AUPLPHUNRCIGDR-UHFFFAOYSA-N [N+](=O)([O-])C1=C(C=CC(=C1)Cl)CC(=O)NC Chemical compound [N+](=O)([O-])C1=C(C=CC(=C1)Cl)CC(=O)NC AUPLPHUNRCIGDR-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- UYXAWHWODHRRMR-UHFFFAOYSA-N hexobarbital Chemical compound O=C1N(C)C(=O)NC(=O)C1(C)C1=CCCCC1 UYXAWHWODHRRMR-UHFFFAOYSA-N 0.000 description 1
- 229960002456 hexobarbital Drugs 0.000 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- YYWFADAFBVXZNR-UHFFFAOYSA-N n-ethyl-2-(2-nitrophenyl)acetamide Chemical compound CCNC(=O)CC1=CC=CC=C1[N+]([O-])=O YYWFADAFBVXZNR-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 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
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/72—Hydrazones
Description
Fremgangsmåte for fremstilling av sedativt virksomme orthof-minofenylacetamider. Process for the production of sedative-active orthof-minophenylacetamides.
Foreliggende oppfinnelse vedrører fremstillingen av nye forbindelser som er i besittelse av beroligende (sedative) egen-skaper. The present invention relates to the production of new compounds which possess calming (sedative) properties.
De nye forbindelser i henhold til oppfinnelsen er ortho-aminofenylacetamider med formelen: The new compounds according to the invention are ortho-aminophenylacetamides with the formula:
og syreaddisjonssalter herav, hvor R er lavere alkyl og R, er hydrogen eller klor. Disse nye forbindelser har vist seg å utøve and acid addition salts thereof, where R is lower alkyl and R is hydrogen or chlorine. These new compounds have been shown to exert
en overraskende effekt ved bekjempelse av forstyrrelser i sentralnervesystemet og dessuten potensierer de virkningen av visse sentralvirkende legemidler når de admini-streres i mengder langt mindre enn de toksiske mengder. a surprising effect when combating disturbances in the central nervous system and furthermore they potentiate the effect of certain centrally acting drugs when they are administered in amounts far smaller than the toxic amounts.
For å danne et beroligende preparat To form a soothing preparation
av forbindelsene ifølge oppfinnelsen for-enes et aktivt middel omfattende et ortho-aminofenylacetamid tilsvarende den foran angitte formel, eller et syreaddisjonssalt herav, med et passende farmasøytisk bæremiddel. Et slikt bæremiddel kan være et fast bæremiddel, en suspensjon eller en ste-ril parenteral væske. Passende faste preparater omfatter tabletter, pulvere og kaps-ler, i hvilke det aktive middel er innført. Passende flytende preparater omfatter sus- of the compounds according to the invention, an active agent comprising an ortho-aminophenylacetamide corresponding to the above formula, or an acid addition salt thereof, is combined with a suitable pharmaceutical carrier. Such a carrier can be a solid carrier, a suspension or a sterile parenteral fluid. Suitable solid preparations include tablets, powders and capsules, in which the active agent has been introduced. Suitable liquid preparations include sus-
pensjoner og oppløsninger av det aktive middel. For parenteral administrering kan det aktive middel oppløses i sterilt destillert vann eller i en isotonisk saltoppløsning. pensions and dissolutions of the active agent. For parenteral administration, the active agent can be dissolved in sterile distilled water or in an isotonic saline solution.
Eksempler på preparater fremstilt av forbindelsene i henhold til oppfinnelsen omfatter følgende: Examples of preparations made from the compounds according to the invention include the following:
Formulering 1: Formulation 1:
(Tabletter) (Pills)
Formulering 2: Formulation 2:
(Tabletter) (Pills)
Formulering 3: Formulation 3:
(Suspensjon) (Suspension)
Det vil lett forstås av fagfolk på om-rådet at de anførte eksempler på preparater tilveiebringer midler for å gi varierende doser av den aktive bestanddel ved bruk av et antall av enhetsdoseringsformer eller brøkdeler herav, som f. eks. ved oppdelte tabletter og at slike preparateksempler ikke nødvendigvis representerer rigorøs eller i ethvert tilfelle en uforanderlig doserings-mengde. It will be readily understood by those skilled in the art that the listed examples of preparations provide means for providing varying doses of the active ingredient using a number of unit dosage forms or fractions thereof, such as e.g. in the case of divided tablets and that such preparation examples do not necessarily represent a rigorous or in any case an unchanging dosage amount.
Det har vist seg at administrering av preparatene bekjemper forstyrrelser som omfatter sentralnervesystemet, som f. eks. kramper, epileptiske anfall, insomnia, angstspenninger og hyperaktivitet. Kramper frembrakt i dyr ved elektrosjokk eller administrering av Metrazol nedsettes så-ledes ved administrering til dyrene av preparater som inneholder fra ca. 150 til ca. 350 mg/kg av den aktive bestanddel pr. kilo av dyrenes vekt. Det har vist seg at anfall av typen sterkt epileptisk anfall, lite epileptisk anfall og psykomotortypen kan bedres ved doser av ca. 1—2 g pr. dag. Det har vi-dere vist seg at beroligelse, befrielse eller lettelse av angstspenninger og tøyling eller forbedring av søvnløshet kan oppnåes ved anvendelse av daglige doser av størrelses-ordenen ca. 400 til ca. 1000 mg. It has been shown that administration of the preparations combats disorders involving the central nervous system, such as, for example, convulsions, epileptic seizures, insomnia, anxiety and hyperactivity. Convulsions produced in animals by electroshock or the administration of Metrazol are thus reduced by administering to the animals preparations containing from approx. 150 to approx. 350 mg/kg of the active ingredient per kilograms of the animal's weight. It has been shown that seizures of the severe epileptic seizure type, mild epileptic seizure and the psychomotor type can be improved with doses of approx. 1-2 g per day. It has also been shown that calming, relieving or alleviating anxiety and controlling or improving insomnia can be achieved by using daily doses of the order of magnitude approx. 400 to approx. 1000 mg.
Det har også vist seg at potensiering av anestesi oppnåes ved hjelp av preparatene. En dose av ca. 220 mg/kg i dyr er til-strekkelig til å forlenge en utpreget nar-kose frembragt av hexobarbital. It has also been shown that potentiation of anesthesia is achieved with the help of the preparations. A dose of approx. 220 mg/kg in animals is sufficient to prolong a pronounced narcosis produced by hexobarbital.
Mens preparatene generelt utøver en lignende farmakologisk virkning, kan de variere noe med hensyn til aktivitetsgra-den alt etter den spesielt valgte aktive bestanddel. Preparater som nå for tiden an-sees å være å foretrekke, inneholder som den aktive bestanddel herav forbindelsen 2-(2-amino-4-klorfenyl)-N-methylacet-amid. En annen forbindelse som oppviser fremragende farmakologisk aktivitet er 2-(2-amino-fenyl)-N-methylacetamid. While the preparations generally exert a similar pharmacological effect, they can vary somewhat with regard to the degree of activity depending on the particularly chosen active ingredient. Preparations which are currently considered to be preferable contain as the active ingredient thereof the compound 2-(2-amino-4-chlorophenyl)-N-methylacet-amide. Another compound that exhibits outstanding pharmacological activity is 2-(2-amino-phenyl)-N-methylacetamide.
Preparatene er relativt ikke-giftige. Intet utslag av toksiske symptomer har vist seg ved deres administrering i tera-peutiske mengder. The preparations are relatively non-toxic. No rash of toxic symptoms has been shown when they are administered in therapeutic amounts.
I overensstemmelse med oppfinnelsen fremstilles ortho-aminofenylacetamider ved å redusere et ortho-nitrofenylacetamid med formelen: In accordance with the invention, ortho-aminophenylacetamides are prepared by reducing an ortho-nitrophenylacetamide with the formula:
og om ønskes bringes produktet til å reagere med en syre så at syreaddisjonssaltet dannes. Reduksjonen kan utføres ved hydrogenering i nærvær av en katalysator. Nevnte ortho-nitrofenylacetamid av formelen II fremstilles ved å la et syreklorid med formelen: reagere med et primært amin som inneholder R. Nevnte syreklorid som har formelen III fremstilles ved å klorere en ortho-nitrofenyleddiksyre av formelen: and if desired, the product is reacted with an acid so that the acid addition salt is formed. The reduction can be carried out by hydrogenation in the presence of a catalyst. Said ortho-nitrophenylacetamide of the formula II is prepared by reacting an acid chloride of the formula: with a primary amine containing R. Said acid chloride of the formula III is prepared by chlorinating an ortho-nitrophenylacetic acid of the formula:
Hvilke som helst av de på denne måten fremstilte ortho-aminofenylacetamider kan omdannes til det tilsvarende syreaddisjonssalt herav ved å oppløse en slik base i en vandig oppløsning som inneholder en stø-kiometrisk mengde av en syre, som f. eks. saltsyre, svovelsyre, vinsyre, fosforsyre eller sitronsyre. Et slikt salt kan lett utvinnes fra oppløsningen ved konsentrering på kjent måte. Any of the ortho-aminophenylacetamides prepared in this way can be converted into the corresponding acid addition salt thereof by dissolving such a base in an aqueous solution containing a stoichiometric amount of an acid, such as e.g. hydrochloric acid, sulfuric acid, tartaric acid, phosphoric acid or citric acid. Such a salt can be easily recovered from the solution by concentration in a known manner.
For at de fremgangsmåter som nå fore-trekkes for fremstilling av de aktive be-standdeler i preparatene kan gjøres lett tilgjengelig, skal det i det følgende beskri-ves endel eksempler: Eksempel 1: N- methyl- 2- aminofenylacetamid A. N- methyl- 2- nitrofenylacetamid. I en 22 liters tre-halset kolbe utstyrt med en rører og en kondensator anbringes 4530 g (25 m) rå o-nitrofenyleddiksyre [Ann. 403:188, (1914)] og 4000 g (33,6 m) vanlig thionylklorid. Denne blanding om-røres og opphetes i et vannbad ved 35—40° . Etter at det faste stoff er stivnet, opphetes blandingen i 3 timer ved samme temperatur. I løpet av denne tid utvikles rikelige mengder hydrogenklorid og svoveldioxyd. Overskudd av thionylklorid fjernes under vannpumpevakuum i ca. V, time ved 35— So that the methods that are now preferred for the production of the active ingredients in the preparations can be made easily available, a few examples will be described in the following: Example 1: N-methyl-2-aminophenylacetamide A. N-methyl - 2-nitrophenylacetamide. Into a 22 liter three-necked flask equipped with a stirrer and a condenser is placed 4530 g (25 m) of crude o-nitrophenylacetic acid [Ann. 403:188, (1914)] and 4000 g (33.6 m) of ordinary thionyl chloride. This mixture is stirred and heated in a water bath at 35-40°. After the solid has solidified, the mixture is heated for 3 hours at the same temperature. During this time copious amounts of hydrogen chloride and sulfur dioxide are developed. Excess thionyl chloride is removed under a water pump vacuum for approx. V, hour at 35—
40° C. Halvparten av det mørke residuum (1950 ml) tilsettes gjennom en dryppe-trakt i 4 kg avkjølt 40 %'s monomethyl-aminoppløsning som befinner seg i en 12 liters tre-halset kolbe. Kolbens innhold om-røres og kjøles i et salt isbad. Tilsetningen tilendebringes i løpet av ca. 2 timer. Derpå anbringes blandingen i kjøleskap over natten. Utfellingen filtreres, vaskes med vann og tørkes ved 65° C. Den annen halvdel av materialet behandles som ovenfor angitt. Det rå amid veier ca. 4950 g. Amidet opp-løses i ca. 100 kg kokende vann, behandles med 1,36 kg aktivert benkull og filtreres gjennom en trakt under anvendelse av et filterhjelpemiddel. Filtratet kjøles til ca. 15° C over natten. Utfelningen filtreres derpå, vaskes med vann og tørkes i en ovn. Produktet veier ca. 1952 g (40 %). 40° C. Half of the dark residue (1950 ml) is added through a dropping funnel to 4 kg of cooled 40% monomethylamine solution in a 12 liter three-necked flask. The contents of the flask are stirred and cooled in a salted ice bath. The addition is completed within approx. 2 hours. The mixture is then placed in the refrigerator overnight. The precipitate is filtered, washed with water and dried at 65° C. The other half of the material is treated as indicated above. The raw amide weighs approx. 4950 g. The amide is dissolved in approx. 100 kg of boiling water is treated with 1.36 kg of activated charcoal and filtered through a funnel using a filter aid. The filtrate is cooled to approx. 15° C overnight. The precipitate is then filtered, washed with water and dried in an oven. The product weighs approx. 1952 g (40%).
B. N- methyl- o- aminofenylacetamid. B. N-methyl-o-aminophenylacetamide.
Hydrogeneringen av produktet fra A utføres i en 12 liters tre-halset kolbe utstyrt med rører, termometer, U-formet mano-meter, hydrogengassinnføringsrør og forbindelse til en vakuumpumpe. Kolben opphetes på et vannbad. Systemet undersøkes først for å sikre at det ikke foreligger noen lekkasje. N-methyl-2-nitrofenylacetamid (955 g) tilsettes til reaksjonskolben sam-men med 4500 ml isopropanol. Katalysatoren (200 g 5 % palladium-på-kull) fuktes med 1000 ml isopronanol og tilsettes derpå til kolben. Systemet evakueres to ganger og filtreres hver gang med nitrogen. Derpå evakueres tre ganger og fylles hver gang med hydrogengass. Systemet er nå ferdig for hydrogenering. Først går reaksjonen ganske langsomt, men når den indre temperatur når 40° C, løper hydrogeneringen ganske hurtig. Under reaksjonen holdes vannbadet ved 45—48° C og den indre temperatur under 56° C. Hydrogeneringen er fullstendig i løpet av 2 til 3V2 timer. Når reaksjonen er tilendebragt, hvilket viser seg ved at temperaturen synker og ved at hy-drogenabsorpsjonen blir langsommere, av-kjøles reaksjonsblandingen til romtemperatur og katalysatoren filtreres fra. The hydrogenation of the product from A is carried out in a 12 liter three-necked flask equipped with stirrer, thermometer, U-shaped manometer, hydrogen gas introduction pipe and connection to a vacuum pump. The flask is heated in a water bath. The system is first examined to ensure that there are no leaks. N-methyl-2-nitrophenylacetamide (955 g) is added to the reaction flask together with 4500 ml of isopropanol. The catalyst (200 g 5% palladium-on-charcoal) is moistened with 1000 ml of isopronanol and then added to the flask. The system is evacuated twice and filtered each time with nitrogen. It is then evacuated three times and each time filled with hydrogen gas. The system is now ready for hydrogenation. At first the reaction proceeds quite slowly, but when the internal temperature reaches 40° C, the hydrogenation proceeds quite quickly. During the reaction, the water bath is kept at 45-48° C. and the internal temperature below 56° C. The hydrogenation is complete within 2 to 3V2 hours. When the reaction is completed, which is shown by the temperature dropping and hydrogen absorption becoming slower, the reaction mixture is cooled to room temperature and the catalyst is filtered off.
Alkoholen fjernes med en vannpumpe. Det gule faste stoff som fåes og som veier ca. 930 g oppløses i 2,5 liter 10 %'s HC1 oppløsning (for-kjølt). Den sure oppløs-ning behandles med Darco og ekstraheres med kloroform (2x1000 ml). Derpå over-føres den sure oppløsning til et rystebat-teri utstyrt med rører og avkjøles. Syren nøytraliseres med en mettet Na.2CO.,-opp-løsning (1,25 1). Den hvite utfeining filtreres, vaskes med en minimumsmengde av-kjølt vann og tørkes (475 g). The alcohol is removed with a water pump. The yellow solid that is obtained and which weighs approx. Dissolve 930 g in 2.5 liters of 10% HC1 solution (pre-cooled). The acidic solution is treated with Darco and extracted with chloroform (2x1000 ml). The acidic solution is then transferred to a shaking battery equipped with stirrers and cooled. The acid is neutralized with a saturated Na.2CO., solution (1.25 1). The white precipitate is filtered, washed with a minimum amount of chilled water and dried (475 g).
Filtratet fra det foran nevnte ekstraheres med kloroform (3x1000 ml) og kloro-formen avdampes. Residuet oppløses påny i 250 ml 10 %'s HCl-oppløsning, ekstraheres med kloroform og behandles med Darco. Mer produkt utf elles når den sure oppløs-ning nøytraliseres med 175 ml mettet Na2COrt-oppløsning. Utfelningen (104 g) filtreres, vaskes med vann og tørkes. The filtrate from the above is extracted with chloroform (3x1000 ml) and the chloroform is evaporated. The residue is redissolved in 250 ml of 10% HCl solution, extracted with chloroform and treated with Darco. More product is precipitated when the acidic solution is neutralized with 175 ml of saturated Na2COrt solution. The precipitate (104 g) is filtered, washed with water and dried.
En lignende fremgangsmåte anvendes påny med filtratet under anvendelse av mindre oppløsningsmidler og reagenser, 75 ml av en 10 %'s HCl-oppløsning og 60 ml av en mettet oppløsning for å gi en ytterligere produktmengde (36 g). A similar procedure is repeated with the filtrate using less solvents and reagents, 75 ml of a 10% HCl solution and 60 ml of a saturated solution to give a further amount of product (36 g).
Det totale utbytte er 615 g (74 %) N-methyl-2-aminofenylacetamid, smp. 89— 90° C. The total yield is 615 g (74%) of N-methyl-2-aminophenylacetamide, m.p. 89— 90° C.
Eksempel 2: N- ethyl- 2- aminofenylacetamid A. N.- ethyl- 2- nitrofenylacetamid. Example 2: N-ethyl-2-aminophenylacetamide A. N-ethyl-2-nitrophenylacetamide.
Denne forbindelse fremstilles analogt med forbindelsen etter eksempel 1, A, under anvendelse av ethylamin i stedenfor monomethylamin. This compound is prepared analogously to the compound according to example 1, A, using ethylamine instead of monomethylamine.
B. N- ethyl- 2- aminofenylacetamid. B. N-ethyl-2-aminophenylacetamide.
Produktet fra A (20,5 g) hydrogeneres i 150 ml ethanol i nærvær av 0,1 g platina-oxyd. Hydrogeneringen er tilendebragt i løpet av 32 minutter. Katalysatoren filtreres fra og oppløsningsmidlet fjernes ved hjelp av en vannpumpe. Det rå materiale, omkrystallisert fra isopropylether, gir 16,1 g N-ethyl-2-aminofenylacetamid, smp. 90— 91° C. The product from A (20.5 g) is hydrogenated in 150 ml of ethanol in the presence of 0.1 g of platinum oxide. The hydrogenation is completed within 32 minutes. The catalyst is filtered off and the solvent is removed using a water pump. The crude material, recrystallized from isopropyl ether, gives 16.1 g of N-ethyl-2-aminophenylacetamide, m.p. 90— 91° C.
På lignende måte fremstilles N-propyl-2-amino-fenylacetamid, smp. 69—70° C under anvendelse av propylamin og N-isopro-pyl-2-aminofenylacetamid, smp. 134—135° C under anvendelse av isopropylamin i trinn A. N-propyl-2-amino-phenylacetamide is prepared in a similar way, m.p. 69-70° C using propylamine and N-isopropyl-2-aminophenylacetamide, m.p. 134-135° C using isopropylamine in step A.
Eksempel 3: 2-( 2- amino- 4- klorfenyl) - Example 3: 2-(2-amino-4-chlorophenyl)-
N- methylacetamid N-methylacetamide
A. 2-( 2- nitro- 4- klorfenyl)-N- methylacetamid. A. 2-(2-nitro-4-chlorophenyl)-N-methylacetamide.
2-nitro-4-klorfenyleddiksyre (7200 g) 2-nitro-4-chlorophenylacetic acid (7200 g)
[J.A.C.S. 78:221 (1956)] og thionylklorid (10 650 g) blandes i en 22 liters, tre-halset kolbe utstyrt med rører, kondensator og termometer og oppvarmes på et vannbad ved 40—45° C i 3<1>/2 timer. Overskudd av thionylklorid fjernes ved hjelp av en vann- [J.A.C.S. 78:221 (1956)] and thionyl chloride (10,650 g) are mixed in a 22 liter three-necked flask fitted with a stirrer, condenser and thermometer and heated on a water bath at 40-45° C. for 3<1>/2 hours . Excess thionyl chloride is removed using a water
pumpe. Det mørke oljeaktige residuum tilsettes gjennom to dryppetrakter i to 22 liters kolber som inneholder like mengder av for-kjølt monomethylaminoppløsning (40 %). Den totale mengde methylamin som anvendes er 21 000 g. Salt-isbad anvendes under reaksjonen for kjøleøyemed. Blandingen omrøres i ytterligere 3 timer og filtreres derpå, vaskes med 2x4 liter koldt vann og tørkes. Det rå produkt veier 5850 g etter tørking ved 60° C. Dette omkrystalliseres fra methyialkohol (85 kg) og aktivert benkull (0,45 kg) i en 190 liters kjele. Totalutbyttet er 54,2 %, smp. 181— 182° C. pump. The dark oily residue is added through two dropping funnels into two 22 liter flasks containing equal amounts of pre-cooled monomethylamine solution (40%). The total amount of methylamine used is 21,000 g. A salt-ice bath is used during the reaction for cooling purposes. The mixture is stirred for a further 3 hours and then filtered, washed with 2x4 liters of cold water and dried. The crude product weighs 5850 g after drying at 60° C. This is recrystallized from methyl alcohol (85 kg) and activated charcoal (0.45 kg) in a 190 liter boiler. The total yield is 54.2%, m.p. 181— 182° C.
B, 2-( 2- amino- 4- klorfenyl)-N- methylacetamid. B, 2-(2-amino-4-chlorophenyl)-N-methylacetamide.
Produktet fra A (1000 g) hydrogeneres i 6500 ml methanol i nærvær av 6,8 g plati-naoxyd. I løpet av tre timer ble en total-mengde av ca. 67 kg hydrogen opptatt hvilket representerer 86,3 % av det teoretiske (77 kg). Den innvendige temperatur lar man spontant stige fra romtemperatur og holdes ved 50° C ved hjelp av en vannpumpe. Den anvendte katalysator filtreres og alkoholen fjernes fra filtratet ved vann-pumpetrykk. Det oransjefargete residuum (ca. 3 liter) behandles med aktivert benkull. Filtratet gir etter kjøling et hvitt krystallinsk produkt som filtreres og vaskes med en liten mengde methanol og ether. Filtratet gir etter ytterligere konsentrering mer produkt. Det rå utbytte som beløper seg til 600 g (70 %), omkrystalliseres fra en blanding av benzen og methylalkohol (4 til 1 og 1 g. 16,65 ml) og 563 g av produktet er-holdes, hvilket representerer et totalutbytte av 65 %. Smp. 145—147° C. The product from A (1000 g) is hydrogenated in 6500 ml of methanol in the presence of 6.8 g of platinum oxide. Within three hours, a total amount of approx. 67 kg of hydrogen occupied, which represents 86.3% of the theoretical (77 kg). The internal temperature is allowed to rise spontaneously from room temperature and is kept at 50° C using a water pump. The catalyst used is filtered and the alcohol is removed from the filtrate by water pump pressure. The orange colored residue (approx. 3 litres) is treated with activated charcoal. After cooling, the filtrate gives a white crystalline product which is filtered and washed with a small amount of methanol and ether. After further concentration, the filtrate gives more product. The crude yield amounting to 600 g (70%) is recrystallized from a mixture of benzene and methyl alcohol (4 to 1 and 1 g. 16.65 ml) and 563 g of the product is obtained, representing a total yield of 65 %. Temp. 145-147°C.
Claims (1)
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BE (1) | BE774033A (en) |
CA (1) | CA969953A (en) |
CH (1) | CH573410A5 (en) |
DE (1) | DE2151487A1 (en) |
DK (1) | DK131149B (en) |
ES (1) | ES396073A1 (en) |
FR (1) | FR2111670A1 (en) |
HU (1) | HU162813B (en) |
IE (1) | IE35662B1 (en) |
IL (1) | IL37839A (en) |
NL (1) | NL7114259A (en) |
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GB1474399A (en) * | 1974-08-19 | 1977-05-25 | Ici Ltd | Cinnolin-3-yl carboxylic acids and derivatives thereof |
GB1472766A (en) * | 1974-11-07 | 1977-05-04 | Ici Ltd | Hydroxycinnoline derivatives processes for their preparation and their use in pharmaceutical compositions |
US4379929A (en) | 1981-03-19 | 1983-04-12 | Eli Lilly And Company | 4(1H)-Oxocinnoline-3-carboxylic acid derivatives |
US4756740A (en) * | 1983-09-14 | 1988-07-12 | Lafarge Coppee | Pollen suppressant comprising a fused pyridazine |
JP2008531709A (en) | 2005-03-01 | 2008-08-14 | ワイス | Cinnoline compounds and their use as liver X receptor modulators |
-
1971
- 1971-09-24 IE IE1194/71A patent/IE35662B1/en unknown
- 1971-09-28 CA CA123,923A patent/CA969953A/en not_active Expired
- 1971-10-05 IL IL37839A patent/IL37839A/en unknown
- 1971-10-05 DK DK484171AA patent/DK131149B/en unknown
- 1971-10-14 CH CH1500071A patent/CH573410A5/xx not_active IP Right Cessation
- 1971-10-15 DE DE19712151487 patent/DE2151487A1/en active Pending
- 1971-10-15 BE BE774033A patent/BE774033A/en unknown
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- 1971-10-15 NO NO3825/71A patent/NO133198C/no unknown
- 1971-10-15 FR FR7137218A patent/FR2111670A1/en active Granted
- 1971-10-16 ES ES396073A patent/ES396073A1/en not_active Expired
- 1971-10-16 HU HUIE480A patent/HU162813B/hu unknown
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DK131149C (en) | 1975-11-10 |
DE2151487A1 (en) | 1972-04-20 |
IL37839A0 (en) | 1971-12-29 |
BE774033A (en) | 1972-04-17 |
AT310757B (en) | 1973-10-10 |
DK131149B (en) | 1975-06-02 |
NL7114259A (en) | 1972-04-18 |
ES396073A1 (en) | 1974-10-16 |
IL37839A (en) | 1974-12-31 |
CA969953A (en) | 1975-06-24 |
NO133198C (en) | 1976-03-24 |
IE35662L (en) | 1972-04-16 |
FR2111670B1 (en) | 1975-10-10 |
HU162813B (en) | 1973-04-28 |
FR2111670A1 (en) | 1972-06-09 |
SU493969A3 (en) | 1975-11-28 |
AU3454871A (en) | 1973-04-19 |
CH573410A5 (en) | 1976-03-15 |
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