DE19517035A1 - Prepn. of 3-aryl-quinazolin-2,4-di:one derivs., useful as intermediates for pharmaceuticals and plant-protecting agents - Google Patents
Prepn. of 3-aryl-quinazolin-2,4-di:one derivs., useful as intermediates for pharmaceuticals and plant-protecting agentsInfo
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- DE19517035A1 DE19517035A1 DE1995117035 DE19517035A DE19517035A1 DE 19517035 A1 DE19517035 A1 DE 19517035A1 DE 1995117035 DE1995117035 DE 1995117035 DE 19517035 A DE19517035 A DE 19517035A DE 19517035 A1 DE19517035 A1 DE 19517035A1
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- acid
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- 239000003814 drug Substances 0.000 title description 2
- 239000000543 intermediate Substances 0.000 title description 2
- 239000003223 protective agent Substances 0.000 title 1
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003446 ligand Substances 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 239000000010 aprotic solvent Substances 0.000 claims abstract description 5
- 229910002091 carbon monoxide Inorganic materials 0.000 claims abstract description 5
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims abstract description 4
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000003118 aryl group Chemical group 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 9
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 8
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 7
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- -1 phenyloxy Chemical group 0.000 claims description 5
- 125000004642 (C1-C12) alkoxy group Chemical group 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 3
- WSABVXQKFNLRDA-UHFFFAOYSA-N 3-(2,4-dichlorophenyl)-6-fluoro-1h-quinazoline-2,4-dione Chemical compound O=C1C2=CC(F)=CC=C2NC(=O)N1C1=CC=C(Cl)C=C1Cl WSABVXQKFNLRDA-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 229940117389 dichlorobenzene Drugs 0.000 claims description 3
- 239000012442 inert solvent Substances 0.000 claims description 3
- 150000002828 nitro derivatives Chemical class 0.000 claims description 3
- 229910000510 noble metal Inorganic materials 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- LRLQQERNMXHASR-UHFFFAOYSA-N 2-diphenylphosphanylpropan-2-yl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)C(C)(C)P(C=1C=CC=CC=1)C1=CC=CC=C1 LRLQQERNMXHASR-UHFFFAOYSA-N 0.000 claims description 2
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 2
- CMIHWILCIPLTFO-UHFFFAOYSA-N [1-[2-(diphenylphosphanylmethyl)naphthalen-1-yl]naphthalen-2-yl]methyl-diphenylphosphane Chemical compound C=1C=C2C=CC=CC2=C(C=2C3=CC=CC=C3C=CC=2CP(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1CP(C=1C=CC=CC=1)C1=CC=CC=C1 CMIHWILCIPLTFO-UHFFFAOYSA-N 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 150000002736 metal compounds Chemical class 0.000 claims description 2
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 150000005622 tetraalkylammonium hydroxides Chemical class 0.000 claims description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims 4
- 229910052703 rhodium Inorganic materials 0.000 claims 3
- 229910052707 ruthenium Inorganic materials 0.000 claims 3
- 229910052763 palladium Inorganic materials 0.000 claims 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 2
- HDIJZFORGDBEKL-UHFFFAOYSA-N 2,3,4-trimethylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C(C)=C1C HDIJZFORGDBEKL-UHFFFAOYSA-N 0.000 claims 1
- FWXAUDSWDBGCMN-UHFFFAOYSA-N 3-diphenylphosphanylbutan-2-yl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)C(C)C(C)P(C=1C=CC=CC=1)C1=CC=CC=C1 FWXAUDSWDBGCMN-UHFFFAOYSA-N 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims 1
- 150000004679 hydroxides Chemical class 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 claims 1
- 239000002184 metal Substances 0.000 claims 1
- QENJZWZWAWWESF-UHFFFAOYSA-N tri-methylbenzoic acid Natural products CC1=CC(C)=C(C(O)=O)C=C1C QENJZWZWAWWESF-UHFFFAOYSA-N 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 2
- 125000001475 halogen functional group Chemical group 0.000 abstract 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000012948 isocyanate Substances 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- FFFIRKXTFQCCKJ-UHFFFAOYSA-N 2,4,6-trimethylbenzoic acid Chemical compound CC1=CC(C)=C(C(O)=O)C(C)=C1 FFFIRKXTFQCCKJ-UHFFFAOYSA-N 0.000 description 2
- QUIMTLZDMCNYGY-UHFFFAOYSA-N 2,4-dichloro-1-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C=C1Cl QUIMTLZDMCNYGY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000006315 carbonylation Effects 0.000 description 2
- 238000005810 carbonylation reaction Methods 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 150000003003 phosphines Chemical class 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- PKORYTIUMAOPED-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinazoline Chemical compound C1=CC=C2NCNCC2=C1 PKORYTIUMAOPED-UHFFFAOYSA-N 0.000 description 1
- UAXNXOMKCGKNCI-UHFFFAOYSA-N 1-diphenylphosphanylethyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)C(C)P(C=1C=CC=CC=1)C1=CC=CC=C1 UAXNXOMKCGKNCI-UHFFFAOYSA-N 0.000 description 1
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
- NPAXPTHCUCUHPT-UHFFFAOYSA-N 3,4,7,8-tetramethyl-1,10-phenanthroline Chemical compound CC1=CN=C2C3=NC=C(C)C(C)=C3C=CC2=C1C NPAXPTHCUCUHPT-UHFFFAOYSA-N 0.000 description 1
- 239000007848 Bronsted acid Substances 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- NYKUZBVJIFJLLO-UHFFFAOYSA-N benzoic acid;4-methylbenzenesulfonic acid Chemical class OC(=O)C1=CC=CC=C1.CC1=CC=C(S(O)(=O)=O)C=C1 NYKUZBVJIFJLLO-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- GTCAXTIRRLKXRU-UHFFFAOYSA-N carbamic acid methyl ester Natural products COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 150000005041 phenanthrolines Chemical class 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
- C07D239/96—Two oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
Substituierte 3-Arylchinazolin-2,4-dione der allgemeinen Formel (I) sind interessante Zwischenprodukte für Pharmazeutika und Pflanzenschutzmittel (US 4.405.623; GB 1.059.271; EP 360.417).Substituted 3-arylquinazoline-2,4-diones of the general formula (I) are interesting intermediates for pharmaceuticals and pesticides (US 4,405,623; GB 1,059,271; EP 360,417).
Die Herstellung von (I) erfolgt üblicherweise durch Reaktion von Anthranilsäure oder eines Anthranilsäurealkylester mit einem Arylisocyanat in einem gegenüber Isocyanaten inerten Reaktionsmedium.(I) is usually prepared by reacting anthranilic acid or an anthranilic acid alkyl ester with an aryl isocyanate in one opposite Isocyanate inert reaction medium.
Im Falle von Antrhanilsäuren erhält man so N-Arylcarbamoylanthranilsäuren, die zwischenisoliert, gegebenenfalls durch Umkristallisation gereinigt werden und dann in einem zweiten Reaktionsschritt, z. B. in Polyphosphorsäure innerhalb von 5 Std. bei 150°C (EP 360 417) oder einem protischen, organischen Medium, wie z. B. Ethanol in Gegenwart überschüssiger, starker Mineralsäure, bevorzugt gasförmiger Salzsäure, zu 3-Arylchinazolin-2,4-dionen der Formel (I) ringgeschlossen werden (GB 1.059.271, Bsp. 3).In the case of antrhanilic acids, N-arylcarbamoylanthranilic acids are thus obtained intermediately isolated, if necessary cleaned by recrystallization and then in a second reaction step, e.g. B. in polyphosphoric acid within 5 hours at 150 ° C (EP 360 417) or a protic, organic medium, such as B. ethanol in the presence of excess, strong mineral acid, preferred gaseous hydrochloric acid, to 3-arylquinazoline-2,4-diones of the formula (I) be closed (GB 1.059.271, Ex. 3).
In entsprechender Weise liefern die Anthranilsäurealkylester bei der Umsetzung mit Arylisocyanaten N-Arylcarbamoylanthranilsäurealkylester, die zwischenisoliert werden und in analoger Weise wie die Säuren zu den 3- Arylchinazolin-2,4-dionen cyclisiert werden können. Es ist auch bekannt, die Cyclisierung zu (I), in protischen Medien wie z. B. Ethanol oder Methanol in Gegenwart von wäßrigem Natriumhydroxid durchzuführen (DOS 1.804.391, Bsp. 4; J. Heterocycl. Chem. 19(2), S. 269, 1982).The anthranilic acid alkyl esters deliver the reaction in a corresponding manner with aryl isocyanates N-arylcarbamoylanthranilic acid alkyl esters, the are isolated and in an analogous manner to the acids to the 3- Arylquinazoline-2,4-diones can be cyclized. It is also known that Cyclization to (I) in protic media such as e.g. B. ethanol or methanol in In the presence of aqueous sodium hydroxide (DOS 1.804.391, Ex. 4; J. Heterocycl. Chem. 19 (2), p. 269, 1982).
Die Arylisocyanate werden im allgemeinen durch Phosgenierung von den entsprechenden Anilinen dargestellt (Houben Weyl, Band E4, S. 741), welche wiederum aus den entsprechenden Nitroaromaten durch Reduktion gewonnen werden (Houben Weyl, Band 11/1, S. 360).The aryl isocyanates are generally phosgenated by the corresponding anilines (Houben Weyl, Volume E4, p. 741), which again obtained from the corresponding nitroaromatics by reduction (Houben Weyl, volume 11/1, p. 360).
Der Einsatz von hochgiftigem Phosgen und damit der von Chlor, das nicht im Endprodukt erscheint, verteuert diesen zweistufigen Prozeß zusätzlich und bringt Probleme mit sich hinsichtlich des Umweltschutzes und der Sicherheit.The use of highly toxic phosgene and thus of chlorine, which is not in the The end product appears, makes this two-step process more expensive and brings Problems with environmental protection and safety.
Insgesamt läuft die Synthese von (I) ausgehend von den entsprechenden Nitroaromaten über 4 Stufen und beinhaltet den Einsatz von giftigem Phosgen und Isocyanaten. Es bestand daher Bedarf, ein kürzeres, verbessertes Verfahren zur Herstellung von 3-Arylchinazolin-2,4-dionen zu entwickeln.Overall, the synthesis of (I) starts from the corresponding ones Nitroaromatics over 4 levels and includes the use of toxic phosgene and isocyanates. There was therefore a need for a shorter, improved process to develop 3-arylquinazoline-2,4-diones.
Diese Aufgabe wird gelöst durch ein Verfahren zur Herstellung von substituierten 3-Arylchinazolin-2,4-dionen der allgemeinen Formel (I)This object is achieved by a method for producing substituted 3-arylquinazoline-2,4-diones of the general formula (I)
worin R¹, R², R³ und R⁴ unabhängig voneinander Wasserstoff, Halogen, (C₁-C₁₂)Alkyl, (C₁-C₁₂)Alkoxy, Ar oder ArO bedeuten und Ar für wherein R¹, R², R³ and R⁴ independently of one another are hydrogen, halogen, (C₁-C₁₂) alkyl, (C₁-C₁₂) alkoxy, Ar or ArO and Ar for
steht, wobei R⁵ bis R⁹ unabhängig voneinander Wasserstoff, Halogen, (C₁- C₁-₂)Alkyl, (C₁-C₁₂)Alkoxy, Phenyl, Phenyloxy bedeuten, wobei R⁵ und R⁶, R⁶ und R⁷, R⁷ und R⁸ oder R⁸ und R⁹ auch einen weiteren aromatischen Ring bilden können, dadurch gekennzeichnet, daß eine Nitroverbindung der allgemeinen Formel (II)stands, where R⁵ to R⁹ independently of one another hydrogen, halogen, (C₁- C₁-₂) alkyl, (C₁-C₁₂) alkoxy, phenyl, phenyloxy, where R⁵ and R⁶, R⁶ and R⁷, R⁷ and R⁸ or R⁸ and R⁹ also a further aromatic ring can form, characterized in that a nitro compound of general formula (II)
worin R⁵ bis R⁹ die oben erwähnte Bedeutung besitzen mit Kohlenmonoxid und einem Alkohol der Formel (III)wherein R⁵ to R⁹ have the meaning mentioned above with carbon monoxide and an alcohol of formula (III)
R¹⁰oh (III)R¹⁰oh (III)
wobei R¹⁰ (C₁-C₁₂)Alkyl bedeutet, in Gegenwart eines Katalysators, eines Liganden und eines Lösungsmittels zu einem Carbamat der Formel (IV) umsetztwherein R¹⁰ is (C₁-C₁₂) alkyl, in the presence of a catalyst, one Ligands and a solvent to form a carbamate of the formula (IV)
und dieses anschließend mit einem Anthranilsäurederivat der Formel (V)and this then with an anthranilic acid derivative of the formula (V)
worin R¹ bis R⁴ die oben erwähnte Bedeutung besitzen und R für Wasserstoff oder (C₁-C₁₂)Alkyl steht, in Gegenwart einer Base und eines aprotischen Lösungsmittels umsetzt.wherein R¹ to R⁴ have the meaning mentioned above and R is hydrogen or (C₁-C₁₂) alkyl, in the presence of a base and an aprotic Implement solvent.
Von Bedeutung ist das erfindungsgemäße Verfahren zur Herstellung von Verbindungen der Formel (I), worin R¹ bis R⁹ für Wasserstoff, Halogen, (C₁- C₆)Alkyl oder (C₁-C₆)Alkoxy steht, insbesondere zur Herstellung von 3-(2,4- Dichlorphenyl)-6-fluor-2,4-(1H,3H)-chinozolindion.The process according to the invention for the production of Compounds of formula (I) in which R¹ to R⁹ represent hydrogen, halogen, (C₁- C₆) alkyl or (C₁-C₆) alkoxy, in particular for the preparation of 3- (2,4- Dichlorophenyl) -6-fluoro-2,4- (1H, 3H) -quinazolinedione.
Die reduktive Carbonylierung wird in Gegenwart von Edelmetallen der 8. Nebengruppe, bevorzugt in Gegenwart von Pd (J. Organomet. Chem. 291, 117- 27, 1985), Ru (J. Organomet. Chem. 451, 157-62, 1993) und Rh (J. Mol. Catal. 94, 195-206, 1994) und Liganden wie Pyridin, tert. Aminen oder Phosphinen und deren Derivaten, wobei zweizähnige Liganden, wie z. B. Bipyridin oder Phenanthrolinderivaten, bevorzugt sind, durchgeführt. Als Phosphine können z. B. Bisdiphenylphosphinoethan, Bisdiphenylphosphinopropan, Bisdiphenylphosphinomethan, Bisdiphenylphosphinobutan oder Naphos eingesetzt werden. Die Edelmetalle können in Form ihrer Salze, wie z. B. der Halogenide, Acetate, Sulphate etc., ihrer Oxide oder in Form von Komplexen, wie z. B. den Carbonylkomplexen, vorliegen. Es ist auch möglich, den Katalysator in metallischer Form auf einem inerten Träger wie Aktivkohle oder Aluminiumoxid einzusetzen.The reductive carbonylation is carried out in the presence of noble metals from the 8th Subgroup, preferably in the presence of Pd (J. Organomet. Chem. 291, 117- 27, 1985), Ru (J. Organomet. Chem. 451, 157-62, 1993) and Rh (J. Mol. Catal. 94, 195-206, 1994) and ligands such as pyridine, tert. Amines or Phosphines and their derivatives, with bidentate ligands, such as. B. Bipyridine or phenanthroline derivatives are preferred. As Phosphines can e.g. B. bisdiphenylphosphinoethane, Bisdiphenylphosphinopropane, bisdiphenylphosphinomethane, Bisdiphenylphosphinobutan or Naphos can be used. The precious metals can in the form of their salts, such as. B. the halides, acetates, sulphates etc., their oxides or in the form of complexes, such as. B. the carbonyl complexes, available. It is also possible to use the catalyst in metallic form use inert carriers such as activated carbon or aluminum oxide.
Es hat sich in vielen Fällen bewährt, einen Katalysator einzusetzen, der aus einer der erwähnten Metallverbindungen und einer Lewis- oder Brönstedtsäure besteht. Als Säure können beispielsweise p-Toluolsulfonsäure, substituierte Benzoesäuren wie z. B. 2,4,6-Trimethylbenzoesäure oder Pivalinsäure eingesetzt werden. Es hat sich als günstig erwiesen, 0,001 bis 10 mol-%, insbesondere 0,01 bis 1 mol-%, Katalysator bezogen auf Nitrogruppen in der Lösung einzusetzen. Für Ligand und Säure liegt die zweckmäßige Menge im Bereich von der 0,1 bis 100fachen Menge an eingesetztem Katalysator, muß aber nicht identisch sein. Die erste Stufe der Reaktion wird bei Temperaturen von 75-250°C, insbesondere von 100-180°C, und CO-Drücken von 20 bis 500 bar, insbesondere 50 bis 200 bar, durchgeführt. Als Lösungsmittel wird zweckmäßig der Alkohol R¹⁰OH verwendet, der jedoch auch durch inerte Lösungsmittel wie z. B. Xylol, Toluol oder Dichlorbenzol verdünnt werden kann.In many cases it has proven useful to use a catalyst which consists of a of the metal compounds mentioned and a Lewis or Bronsted acid consists. Examples of acids which can be substituted are p-toluenesulfonic acid Benzoic acids such as B. 2,4,6-trimethylbenzoic acid or pivalic acid will. It has proven to be convenient, 0.001 to 10 mol%, in particular 0.01 to 1 mol%, catalyst based on nitro groups in the solution to use. For ligand and acid, the appropriate amount is in the range of 0.1 to 100 times the amount of catalyst used, but need not be identical. The first stage of the reaction is carried out at temperatures of 75-250 ° C, in particular from 100-180 ° C, and CO pressures from 20 to 500 bar, in particular 50 to 200 bar. It is useful as a solvent the alcohol R¹⁰OH used, but also by inert solvents such as e.g. B. xylene, toluene or dichlorobenzene can be diluted.
Die erhaltenen Carbamate der Formel (IV) werden anschließend mit den Anthranilsäurederivaten der Formel (V) in Gegenwart einer Base und eines aprotischen Lösungsmittels cyclisiert. Hierbei hat es sich bewährt, die Verbindungen (IV) und (V) im Molverhältnis von 0,9 : 1 bis 1,1 : 1 einzusetzen.The carbamates of the formula (IV) obtained are then mixed with the Anthranilic acid derivatives of the formula (V) in the presence of a base and one aprotic solvent cyclized. It has proven itself here Use compounds (IV) and (V) in a molar ratio of 0.9: 1 to 1.1: 1.
Es hat sich als günstig erwiesen, als Base Alkali- oder Erdalkalimetallalkoholate, -amide, -hydride oder Tetraalkylammoniumhydroxide zu verwenden.It has proven to be cheap as a base alkali or Alkaline earth metal alcoholates, amides, hydrides or tetraalkylammonium hydroxides to use.
Als aprotisches Lösungsmittel kann z. B. ein aromatischer, aliphatischer oder cycloaliphatischer Kohlenwasserstoff, der auch inerte Substituenten wie z. B. Alkyl- oder Chlorsubstituenten tragen kann, eingesetzt. Gute Resultate liefern auch Heterocyclen oder Ketone, sofern sie gegenüber der Base inert sind, als Lösungsmittel. In vielen Fällen haben sich Toluol, Xylol oder Dichlorbenzol in reiner Form oder als Isomerengemisch bewährt.As an aprotic solvent z. B. an aromatic, aliphatic or cycloaliphatic hydrocarbon, which also contains inert substituents such. B. Can carry alkyl or chlorine substituents. Deliver good results also heterocycles or ketones, provided they are inert to the base, as Solvent. In many cases, toluene, xylene or dichlorobenzene have become proven in pure form or as a mixture of isomers.
Die als Base verwendeten Alkali- oder Erdalkalimetalle können in Substanz oder als Lösung in den entsprechenden Alkoholen eingesetzt werden. In vielen Fällen hat sich der Einsatz von Natriummethylat in Methanol bewährt. Verwendet man Alkali- oder Erdalkalimetallhydride oder -amide, so können diese ebenfalls in Substanz oder als Suspension in einem inerten Solvent eingesetzt werden. Die verwendeten Basen werden üblicherweise in Mengen von 0.5 bis 95 mol-% bezogen auf die Edukte eingesetzt. Es hat sich als günstig erwiesen, Mengen von 1 bis 20 mol-%, insbesondere 5 bis 10 mol-%, zu verwenden.The alkali or alkaline earth metals used as base can be in substance or can be used as a solution in the corresponding alcohols. In many cases the use of sodium methylate in methanol has proven itself. One uses Alkali or alkaline earth metal hydrides or amides, these can also in Substance or as a suspension in an inert solvent. The Bases used are usually in amounts of 0.5 to 95 mol% based on the starting materials. It has proven to be convenient, quantities from 1 to 20 mol%, in particular 5 to 10 mol%, to be used.
Die Reaktionstemperatur der Cyclisierung wird zweckmäßig so gewählt, daß der freiwerdende Alkohol aus dem Reaktionsmedium abdestilliert. Bevorzugt liegen die Temperaturen zwischen 100 und 200°C.The reaction temperature of the cyclization is advantageously chosen so that the Alcohol released is distilled off from the reaction medium. Preferably lie the temperatures between 100 and 200 ° C.
Der glatte Verlauf und die hohe Ausbeute des Cyclisierungsschrittes waren besonders überraschend, da bei der Umsetzung von N-Phenylalkylcarbamaten mit Anthranilsäure (Organic Preparations and Procedures Int. 10(1), 13-16, 1978) eine nur mäßige Ausbeute von bestenfalls 60% beschrieben ist, wenn man Anthranilsäure mit N-Phenylalkylcarbamaten auf 180°C erhitzt. Zudem mußte das Carbamat im Überschuß zugegeben werden.The smoothness and high yield of the cyclization step were Particularly surprising, since in the implementation of N-phenylalkyl carbamates with anthranilic acid (Organic Preparations and Procedures Int. 10 (1), 13-16, 1978) a moderate yield of 60% at best is described if one heats anthranilic acid to 180 ° C. with N-phenylalkyl carbamates. In addition the carbamate had to be added in excess.
22.4 Gew.-% 2,4-Dichlornitrobenzol, 2.0 Gew.-% Pd-C (5%), 1.3 Gew. % 2,4,6-Trimethylbenzoesäure und 0.4 Gew.-% 3,4,7,8-Tetramethyl- 1,10-phenanthrolin werden in 73.8 Gew.-% Methanol gelöst und in einem HC-4 Autoclaven gefüllt. Es wird ein Druck von 100 bar CO eingestellt und die Temperatur auf 180°C erhöht. Nach 2 Stunden wird der Versuch abgebrochen und die Lösung gaschromatographisch untersucht. Der Umsatz betrug 100% bei einer Selektivität zum N-2,4- Dichlorphenylmethylcarbamat von 85%.22.4% by weight 2,4-dichloronitrobenzene, 2.0% by weight Pd-C (5%), 1.3% by weight % 2,4,6-trimethylbenzoic acid and 0.4% by weight 3,4,7,8-tetramethyl- 1,10-phenanthroline are dissolved in 73.8% by weight of methanol and in one HC-4 autoclave filled. A pressure of 100 bar CO is set and raised the temperature to 180 ° C. After 2 hours, the trial will canceled and the solution examined by gas chromatography. Of the Conversion was 100% with a selectivity to N-2,4- Dichlorophenyl methyl carbamate of 85%.
8.5 Gew.-% N-2,4-Dichlorphenylcarbamat, 6.5 Gew.-% 5- Fluoranthranilsäuremethylester, 0.1 Gew.-% Natriummethylat werden in 84.9 Gew.-% o-Dichlorbenzol gelöst und auf 170°C erhitzt. Das entstehende Methanol wird dabei abdestilliert. Nach 6 Std. Reaktionszeit läßt man abkühlen. Den dabei entstehenden Niederschlag trennt man ab und erhält so 91.3% Ausbeute an 3-(2,4-Dichlorphenyl)-6-fluor- 2,4(1H,3H)chinazolindion.8.5% by weight N-2,4-dichlorophenyl carbamate, 6.5% by weight 5- Fluoranthranilsäuremethylester, 0.1 wt .-% sodium methylate are in 84.9 wt .-% o-dichlorobenzene dissolved and heated to 170 ° C. The The resulting methanol is distilled off. After a reaction time of 6 hours let it cool. The resulting precipitate is separated off and thus receives 91.3% yield of 3- (2,4-dichlorophenyl) -6-fluoro- 2.4 (1H, 3H) quinazoline indione.
Claims (22)
23. Verfahren nach mindestens einem der Ansprüche 1 bis 22, dadurch gekennzeichnet, daß Verbindung (IV) zu (V) im Mol-Verhältnis von 0,9 : 1 bis 1,1 : 1 eingesetzt wird.22. The method according to at least one of claims 1 to 21, characterized in that the reaction temperature of the second stage is between 100 and 200 ° C.
23. The method according to at least one of claims 1 to 22, characterized in that compound (IV) to (V) is used in a molar ratio of 0.9: 1 to 1.1: 1.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1995117035 DE19517035A1 (en) | 1995-05-10 | 1995-05-10 | Prepn. of 3-aryl-quinazolin-2,4-di:one derivs., useful as intermediates for pharmaceuticals and plant-protecting agents |
| EP96107059A EP0742213A1 (en) | 1995-05-10 | 1996-05-06 | Process for the preparation of substituted 3-arylquinazolin-2,4-diones |
| JP8115124A JPH08325240A (en) | 1995-05-10 | 1996-05-09 | Production of substituted 3-arylquinazoline-2,4-dione |
| US08/646,678 US5719284A (en) | 1995-05-10 | 1996-05-10 | Process for the preparation of substituted 3-arylquinazoline-2,4-diones |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1995117035 DE19517035A1 (en) | 1995-05-10 | 1995-05-10 | Prepn. of 3-aryl-quinazolin-2,4-di:one derivs., useful as intermediates for pharmaceuticals and plant-protecting agents |
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| DE19517035A1 true DE19517035A1 (en) | 1996-11-14 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1059271A (en) * | 1964-02-05 | 1967-02-15 | Ici Ltd | Quinazolin-2,4-diones and pharmaceutical compositions thereof |
| EP0086281A1 (en) * | 1981-12-02 | 1983-08-24 | Shell Internationale Researchmaatschappij B.V. | Preparation of carbamates using a palladium-containing catalyst |
| US4405623A (en) * | 1980-05-15 | 1983-09-20 | Masayuki Ishikawa | Quinazolinde-dione compounds, process for production thereof and pharmaceutical use thereof |
-
1995
- 1995-05-10 DE DE1995117035 patent/DE19517035A1/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1059271A (en) * | 1964-02-05 | 1967-02-15 | Ici Ltd | Quinazolin-2,4-diones and pharmaceutical compositions thereof |
| US4405623A (en) * | 1980-05-15 | 1983-09-20 | Masayuki Ishikawa | Quinazolinde-dione compounds, process for production thereof and pharmaceutical use thereof |
| EP0086281A1 (en) * | 1981-12-02 | 1983-08-24 | Shell Internationale Researchmaatschappij B.V. | Preparation of carbamates using a palladium-containing catalyst |
Non-Patent Citations (3)
| Title |
|---|
| J. Am. Chem. Soc., (1992), 8933 * |
| J. Chem. Soc., Chem. Commun. (1990), 1616-1617 * |
| J. Org. Chem., (1988), 1243-1250 * |
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