CH514554A - Quinazolinone derivs - with antiphlogistic props - Google Patents

Quinazolinone derivs - with antiphlogistic props

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Publication number
CH514554A
CH514554A CH1242671A CH1242671A CH514554A CH 514554 A CH514554 A CH 514554A CH 1242671 A CH1242671 A CH 1242671A CH 1242671 A CH1242671 A CH 1242671A CH 514554 A CH514554 A CH 514554A
Authority
CH
Switzerland
Prior art keywords
degrees
alkyl
inert solvent
alkoxy
formula
Prior art date
Application number
CH1242671A
Other languages
German (de)
Inventor
Ott Hans
Original Assignee
Sandoz Ag
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sandoz Ag filed Critical Sandoz Ag
Priority claimed from CH894669A external-priority patent/CH514597A/en
Publication of CH514554A publication Critical patent/CH514554A/en

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72Quinazolines; Hydrogenated quinazolines
    • C07D239/78Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/80Oxygen atoms
    • C07D239/82Oxygen atoms with an aryl radical attached in position 4
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00Carboxylic acid nitriles
    • GPHYSICS
    • G02OPTICS
    • G02BOPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B27/00Optical systems or apparatus not provided for by any of the groups G02B1/00 - G02B26/00, G02B30/00
    • G02B27/02Viewing or reading apparatus

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Quinazolinone derivs with antiphlogistic properties.. G3A. are of formula (I): (where R = H, F, Cl, Br, alkyl with 1 to 5C, alkoxy or alkylthio with 1 to 4C, NO2, CN or CF3; n = 1 or 2, and in the latter case, the two R's may be same or different; R1 = alkyl with 1 to 5C, allyl or propargyl; and R2 = phenyl opt. substd. with one or two F, Cl, Br, alkyl, or alkoxy gps. or by one CF3 group) and are prepared (a) from appropriate aminobenzophenoneimines, (esp. 2-isopropyl-amino-4-methylbenzophenonimine, II), provided that R1 is not tert-alkyl, by cyclisation with methyl or pref. ethyl chlorocarbonate at 60-100 degrees C in the presence of an inert solvent and a base; or with lower alkyl carbamates, particularly excess urethane, and a Lewis acid at 160-80 degrees; or with 1,1'-carbonyldiimidazole in an inert solvent at 60-90 degrees; or with phosgene in the presence of a base and an inert solvent at 10-30 degrees; or (b) corresp. 3,4-dihydroquinazolinones are oxidised with MnO2 or MnO4 at 15-30 degrees, or the analogous thiones are hydrolysed with aqueous alkali at 80-120 degrees; or 3,4-dihydroquinazoline-2-thiones are treated with MnO4 at 0-60 degrees. The products (I) have valuable pharmacological properties, and can be used orally or parenterally in pharmaceutical preparations to reduce inflammation; cpds. such as (II) are also excellent analgetics.

Description

  

  
 



  Verfahren zur Herstellung von 2-Nitrobenzonitrilen
Die Erfindung betrifft ein Verfahren zur Herstellung von 2-Nitrobenzonitrilen der Formel I,
EMI1.1     
 worin R Wasserstoff, Fluor, Chlor, Brom, Alkyl mit 1-5 Kohlenstoffatomen, Alkoxy oder Alkylthio mit je 14 Kohlenstoffatomen oder Trifluormethyl bedeutet und n für 1 oder 2 steht, wobei - falls n für 2 steht die Substituenten R gleich oder verschieden sein können und jeweils Wasserstoff, Halogen, Alkyl oder Alkoxy bedeuten.



   Das erfindungsgemässe Verfahren ist dadurch gekennzeichnet, dass man l-Halogen-2-nitrobenzole der Formel II,
EMI1.2     
 worin R und n obige Bedeutung besitzen und X für Fluor, Chlor oder Brom steht, mit Kupfer-I-cyanid umsetzt und den dabei erhaltenen Kupferkomplex zersetzt.



   Die Umsetzung von Verbindungen der Formel II mit Kupfer-I-cyanid wird zweckmässigerweise bei erhöhter Temperatur und in Gegenwart eines inerten organischen Lösungsmittels durchgeführt. Die Reaktionstemperatur kann beispielsweise 100 bis 2200 C, vorzugsweise 130 bis   1800    C, betragen. Als bevorzugte Lösungsmittel verwendet man solche, die innerhalb des bevorzugten Bereiches der Reaktionstemperaturen sieden, so dass man unter Rückfluss arbeiten kann, z. B.



  Dimethylacetamid oder Dimethylformamid, vorzugsweise Dimethylacetamid. Das Molverhältnis von Kupfer-I-cyanid zu den Verbindungen der Formel II in dem Reaktionsgemisch ist nicht kritisch; normalerweise liegt es bei etwa der stöchiometrisch zur Bildung des gewünschten Produktes erforderlichen Menge bis hinauf zu einem schwachen   Überschuss.    Die Reaktionszeit beträgt etwa 1 bis 10 Stunden. Der Substituent X bei Verbindungen der Formel II ist vorzugsweise Chlor.



  Die Zersetzung des entstandenen Kupferkomplexes kann beispielsweise durch Zugabe von Methylenchlorid erfolgen.



   Die Verbindungen der Formel II sind entweder bekannt oder können in bekannter Weise hergestellt werden.



   Die Verbindungen der Formel I stellen Zwischenprodukte dar und können beispielsweise zur Herstellung wertvoller Pharmazeutika verwendet werden.



   Beispiel 4-Methyl-2 -nitrobenzonitril
Ein Gemisch aus 100 g 4-Chlor-3-nitrotoluol, 60 g Kupfer-I-cyanid und 150 ml Dimethylacetamid wird   4 t/2    Stunden unter Rückfluss erhitzt. Das dabei erhaltene braune Gemisch giesst man auf 1000 ml Eiswasser, filtriert es zur Abtrennung des ausgefallenen dunkelbraunen Kupferkomplexes und zersetzt diesen dann durch Behandlung mit 600 ml Methylenchlorid unter Rühren bei Zimmertemperatur. Das unlösliche anorganische Material wird abfiltriert, worauf man das Filtrat über wasserfreiem Natriumsulfat trocknet, mit 5 g Aktivkohle und 50 g Aluminiumoxyd behandelt und erneut zur   Entfemung    unlöslichen Materials abfiltriert.

 

  Das Filtrat wird im Vakuum zur Trockene eingedampft, und der dabei erhaltene rohe kristalline Rückstand ergibt nach Umkristallisieren aus Diäthyläther das 4 Methyl-2-nitrobenzonitril vom Smp.   96-97     C. 



  
 



  Process for the preparation of 2-nitrobenzonitriles
The invention relates to a process for the preparation of 2-nitrobenzonitriles of the formula I,
EMI1.1
 where R is hydrogen, fluorine, chlorine, bromine, alkyl with 1-5 carbon atoms, alkoxy or alkylthio with 14 carbon atoms each or trifluoromethyl and n is 1 or 2, where - if n is 2, the substituents R can be identical or different and each represent hydrogen, halogen, alkyl or alkoxy.



   The inventive method is characterized in that l-halo-2-nitrobenzenes of the formula II,
EMI1.2
 where R and n have the above meanings and X is fluorine, chlorine or bromine, reacts with copper-I-cyanide and decomposes the copper complex obtained in this way.



   The reaction of compounds of the formula II with copper (I) cyanide is expediently carried out at an elevated temperature and in the presence of an inert organic solvent. The reaction temperature can be, for example, 100 to 2200 C, preferably 130 to 1800 C. The preferred solvents used are those which boil within the preferred range of reaction temperatures so that reflux can be carried out, e.g. B.



  Dimethylacetamide or dimethylformamide, preferably dimethylacetamide. The molar ratio of copper (I) cyanide to the compounds of the formula II in the reaction mixture is not critical; normally it will be from about the stoichiometrically required amount to form the desired product up to a slight excess. The reaction time is about 1 to 10 hours. The substituent X in compounds of the formula II is preferably chlorine.



  The copper complex formed can be decomposed, for example, by adding methylene chloride.



   The compounds of the formula II are either known or can be prepared in a known manner.



   The compounds of the formula I are intermediates and can be used, for example, for the production of valuable pharmaceuticals.



   Example 4-methyl-2-nitrobenzonitrile
A mixture of 100 g of 4-chloro-3-nitrotoluene, 60 g of copper (I) cyanide and 150 ml of dimethylacetamide is refluxed for 4 t / 2 hours. The brown mixture obtained is poured into 1000 ml of ice water, filtered to separate the precipitated dark brown copper complex and then decomposed by treatment with 600 ml of methylene chloride with stirring at room temperature. The insoluble inorganic material is filtered off, whereupon the filtrate is dried over anhydrous sodium sulfate, treated with 5 g of activated charcoal and 50 g of aluminum oxide and filtered again to remove the insoluble material.

 

  The filtrate is evaporated to dryness in vacuo, and the crude crystalline residue obtained after recrystallization from diethyl ether gives 4-methyl-2-nitrobenzonitrile with a melting point of 96-97 C.

 

Claims (1)

PATENTANSPRUCH PATENT CLAIM Verfahren zur Herstellung von 2-Nitrobenzonitrilen der Formel I, EMI2.1 worin R Wasserstoff, Fluor, Chlor, Brom, Alkyl mit 1-5 Kohlenstoffatomen, Alkoxy oder Alkylthio mit je 14 Kohlenstoffatomen oder Trifluormethyl bedeutet und n für 1 oder 2 steht, wobei - falls n für 2 steht die Substituenten R gleich oder verschieden sein können und jeweils Wasserstoff, Halogen, Alkyl oder Alkoxy bedeuten, dadurch gekennzeichnet, dass man 1 -Halogen-2-nitrobenzole der Formel II, EMI2.2 worin R und n obige Bedeutung besitzen und X für Fluor, Chlor oder Brom steht, mit Kupfer-I-cyanid umsetzt und den so erhaltenen Kupferkomplex zersetzt. Process for the preparation of 2-nitrobenzonitriles of the formula I, EMI2.1 where R is hydrogen, fluorine, chlorine, bromine, alkyl with 1-5 carbon atoms, alkoxy or alkylthio with 14 carbon atoms each or trifluoromethyl and n is 1 or 2, where - if n is 2, the substituents R can be identical or different and each is hydrogen, halogen, alkyl or alkoxy, characterized in that 1-halo-2-nitrobenzenes of the formula II, EMI2.2 where R and n have the above meanings and X is fluorine, chlorine or bromine, reacts with copper-I-cyanide and decomposes the copper complex thus obtained. UNTERANSPRUCH Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass man die Umsetzung in einem inerten organischen Lösungsmittel bei Temperaturen zwischen 130 und 1800 C durchführt und den dabei erhaltenen Kupferkomplex mit Methylenchlorid zersetzt. SUBClaim Process according to patent claim, characterized in that the reaction is carried out in an inert organic solvent at temperatures between 130 and 1800 C and the copper complex obtained is decomposed with methylene chloride.
CH1242671A 1968-07-01 1969-06-12 Quinazolinone derivs - with antiphlogistic props CH514554A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US74180768A 1968-07-01 1968-07-01
US74180668A 1968-07-01 1968-07-01
CH894669A CH514597A (en) 1968-07-01 1969-06-12 Quinazolinone derivs - with antiphlogistic props

Publications (1)

Publication Number Publication Date
CH514554A true CH514554A (en) 1971-10-31

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Application Number Title Priority Date Filing Date
CH1242671A CH514554A (en) 1968-07-01 1969-06-12 Quinazolinone derivs - with antiphlogistic props
CH1242071A CH514603A (en) 1968-07-01 1969-06-12 Process for the preparation of new 4-phenyl-2 (1H) -quinazolinones

Family Applications After (1)

Application Number Title Priority Date Filing Date
CH1242071A CH514603A (en) 1968-07-01 1969-06-12 Process for the preparation of new 4-phenyl-2 (1H) -quinazolinones

Country Status (1)

Country Link
CH (2) CH514554A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0110559A1 (en) * 1982-11-26 1984-06-13 Sanwa Kagaku Kenkyusho Co., Ltd. Process for the preparation of 4-chloro-2-nitrobenzonitrile

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0110559A1 (en) * 1982-11-26 1984-06-13 Sanwa Kagaku Kenkyusho Co., Ltd. Process for the preparation of 4-chloro-2-nitrobenzonitrile

Also Published As

Publication number Publication date
CH514603A (en) 1971-10-31

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