CH410962A - Process for the preparation of phenylazopyrimidines - Google Patents
Process for the preparation of phenylazopyrimidinesInfo
- Publication number
- CH410962A CH410962A CH747860A CH747860A CH410962A CH 410962 A CH410962 A CH 410962A CH 747860 A CH747860 A CH 747860A CH 747860 A CH747860 A CH 747860A CH 410962 A CH410962 A CH 410962A
- Authority
- CH
- Switzerland
- Prior art keywords
- parts
- hydrazino
- mixture
- hydrogen
- alkyl
- Prior art date
Links
- ZMOHEJSEXHOUTG-UHFFFAOYSA-N (4-phenylpyrimidin-2-yl)-pyrimidin-2-yldiazene Chemical class C1=CC=CC=C1C1=CC=NC(N=NC=2N=CC=CN=2)=N1 ZMOHEJSEXHOUTG-UHFFFAOYSA-N 0.000 title claims description 10
- 238000000034 method Methods 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 6
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 12
- -1 alkyl radical Chemical group 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- ZHNIRIANAAPGDH-UHFFFAOYSA-N 6-hydrazinyl-1h-pyrimidine-2,4-dione Chemical compound NNC1=CC(=O)NC(=O)N1 ZHNIRIANAAPGDH-UHFFFAOYSA-N 0.000 claims description 8
- 229940005561 1,4-benzoquinone Drugs 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- LUWPFMIHXOPDBK-UHFFFAOYSA-N 2-amino-6-hydrazinyl-1h-pyrimidin-4-one Chemical compound NNC1=CC(=O)N=C(N)N1 LUWPFMIHXOPDBK-UHFFFAOYSA-N 0.000 claims description 5
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- RMRFFCXPLWYOOY-UHFFFAOYSA-N allyl radical Chemical compound [CH2]C=C RMRFFCXPLWYOOY-UHFFFAOYSA-N 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 239000003701 inert diluent Substances 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 229910052751 metal Chemical class 0.000 claims description 2
- 239000002184 metal Chemical class 0.000 claims description 2
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- QDGHXQFTWKRQTG-UHFFFAOYSA-N pyrimidin-2-ylhydrazine Chemical compound NNC1=NC=CC=N1 QDGHXQFTWKRQTG-UHFFFAOYSA-N 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 6
- 235000019253 formic acid Nutrition 0.000 description 6
- 239000007858 starting material Substances 0.000 description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 3
- HOCVPMXPWHBCSK-UHFFFAOYSA-N 6-chloro-5-methyl-1h-pyrimidine-2,4-dione Chemical compound CC1=C(Cl)NC(=O)NC1=O HOCVPMXPWHBCSK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- WFCXSZSLXQJFDD-UHFFFAOYSA-N chembl1742076 Chemical compound C1=CC(O)=CC=C1N=NC1=CC(=O)NC(=O)N1 WFCXSZSLXQJFDD-UHFFFAOYSA-N 0.000 description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 3
- WOGWYSWDBYCVDY-UHFFFAOYSA-N 2-chlorocyclohexa-2,5-diene-1,4-dione Chemical compound ClC1=CC(=O)C=CC1=O WOGWYSWDBYCVDY-UHFFFAOYSA-N 0.000 description 2
- KPSACJAXUZXHMO-UHFFFAOYSA-N 6-hydrazinyl-5-methyl-1H-pyrimidine-2,4-dione Chemical compound N(N)C1=NC(=NC(=C1C)O)O KPSACJAXUZXHMO-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- REZVRJZHTFIXDK-UHFFFAOYSA-N chembl1886015 Chemical compound N1C(N)=NC(=O)C=C1N=NC1=CC=C(O)C=C1 REZVRJZHTFIXDK-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- RAAWOIFHWPNICM-UHFFFAOYSA-N 2-amino-4-[(3-chloro-4-hydroxyphenyl)diazenyl]-1H-pyrimidin-6-one Chemical compound NC1=NC(=CC(=N1)N=NC1=CC(=C(C=C1)O)Cl)O RAAWOIFHWPNICM-UHFFFAOYSA-N 0.000 description 1
- VTWDKFNVVLAELH-UHFFFAOYSA-N 2-methylcyclohexa-2,5-diene-1,4-dione Chemical compound CC1=CC(=O)C=CC1=O VTWDKFNVVLAELH-UHFFFAOYSA-N 0.000 description 1
- NBHAZVWKRHTWRW-UHFFFAOYSA-N 2-propylcyclohexa-2,5-diene-1,4-dione Chemical compound CCCC1=CC(=O)C=CC1=O NBHAZVWKRHTWRW-UHFFFAOYSA-N 0.000 description 1
- FHDGSYIDVKPQAY-UHFFFAOYSA-N 4-chloro-2,6-dimethoxy-5-methylpyrimidine Chemical compound COC1=NC(Cl)=C(C)C(OC)=N1 FHDGSYIDVKPQAY-UHFFFAOYSA-N 0.000 description 1
- PPECMSQKAVWRSP-UHFFFAOYSA-N 4-chloro-6-hydrazinylpyrimidin-2-amine Chemical compound NNC1=CC(Cl)=NC(N)=N1 PPECMSQKAVWRSP-UHFFFAOYSA-N 0.000 description 1
- VFKWOJAARMMQRW-UHFFFAOYSA-N 6-[(3-chloro-4-hydroxyphenyl)diazenyl]-1H-pyrimidine-2,4-dione Chemical compound OC1=NC(=CC(=N1)N=NC1=CC(=C(C=C1)O)Cl)O VFKWOJAARMMQRW-UHFFFAOYSA-N 0.000 description 1
- RJXOPDWDFGZZLB-UHFFFAOYSA-N 6-[(4-hydroxy-3-methylphenyl)diazenyl]-1H-pyrimidine-2,4-dione Chemical compound CC1=C(O)C=CC(=C1)N=NC1=CC(O)=NC(O)=N1 RJXOPDWDFGZZLB-UHFFFAOYSA-N 0.000 description 1
- UBLCFJXUFHOWLB-UHFFFAOYSA-N 6-[(4-hydroxy-3-propylphenyl)diazenyl]-1H-pyrimidine-2,4-dione Chemical compound OC1=NC(=CC(=N1)N=NC1=CC(=C(C=C1)O)CCC)O UBLCFJXUFHOWLB-UHFFFAOYSA-N 0.000 description 1
- PKUFNWPSFCOSLU-UHFFFAOYSA-N 6-chloro-1h-pyrimidine-2,4-dione Chemical compound ClC1=CC(=O)NC(=O)N1 PKUFNWPSFCOSLU-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- MRNRBQDGZFVHCB-UHFFFAOYSA-N OC1=NC(=C(C(=N1)N=NC1=CC=C(C=C1)O)C)O Chemical compound OC1=NC(=C(C(=N1)N=NC1=CC=C(C=C1)O)C)O MRNRBQDGZFVHCB-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- OCBFFGCSTGGPSQ-UHFFFAOYSA-N [CH2]CC Chemical compound [CH2]CC OCBFFGCSTGGPSQ-UHFFFAOYSA-N 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 159000000009 barium salts Chemical class 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000004396 mastitis Diseases 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- KMIOJWCYOHBUJS-HAKPAVFJSA-N vorolanib Chemical compound C1N(C(=O)N(C)C)CC[C@@H]1NC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C KMIOJWCYOHBUJS-HAKPAVFJSA-N 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
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verfahren zur Herstellung von Phenylazopyriniidinen
Die vorliegende Erfindung bezieht sich auf ein Verfahren zur Herstellung von Phenylazopyrimidinen, die wertvolle therapeutische Eigenschaften, beispielsweise als antibakterielle Mittel, besitzen.
Die erfindungsgemäss hergestellten Phenylazopyrimidine entsprechen der Formel:
EMI1.1
worin R1 eine Hydroxyl oder Aminogruppe, R2 Wasserstoff oder einen Alkylrest und R3, R4, R und Ro, die gleich oder verschieden sein können, Wasserstoff oder Alkyl- oder Alkenylreste oder Halogenatome bedeuten. Die erfindungsgemäss hergestellten Verbindungen können in ihre Salze übergeführt werden.
Zu bemerken wäre, dass der in Frage stehende Phenylazorest
EMI1.2
auch in der tautomeren Form
EMI1.3
wiedergegeben werden kann.
R2 kann vorzugsweise ein nicht mehr als 5 Kohlenstoffatome enthaltender Alkylrest, z. B. der Methylrest, sein.
Geeignete Bedeutungen von R3, R4, R6 und Rn sind beispielsweise nicht mehr als 5 Kohlenstoffatome enthaltende Alkylreste, z. B. der Methyl-oder n-Propylrest, oder nicht mehr als 5 Kohlenstoffatome enthaltende Alkenylreste, z. B. der Allylrest, oder Halogenatome, wie z. B. Chlor- und Bromatome.
Als geeignete Salze seien beispielsweise Säureadditionssalze, z. B. Salze mit anorganischen Säuren, wie z. B. mit Salzsäure, und Metallsalze, z. B. Salze mit Alkalimetallen, wie z. B. Natrium- oder Kaliumsalze, oder mit Erdalkalimetallen, wie z. B. Calciumoder Bariumsalze, genannt.
Bevorzugte erfindungsgemäss hergestellte Phenylazopyrimidine sind 2,6-Dihydroxy-4-(4'-hydroxy- phenylazo)-pyrimidin und 2-Amino-6-hydroxy-4 (4'-hydroxy-phenylazo)-pyrimidin.
Die Phenylazopyrimidine der obgenannten allgemeinen Formel werden erfindungsgemass dadurch erhalten, dass man ein Hydrazinopyrimidin der Formel
EMI1.4
mit einem Benzochinon der Formel
EMI1.5
umsetzt.
Die Umsetzung erfolgt vorzugsweise durch Vermischen oder Erhitzen der Reaktionsteilnehmer in Gegenwart eines inerten Verdünnungsmittels oder Lösungsmittels, wie z. B. Wasser, Alkohol, Tetrahydrofuran oder Dimethylformamid, und in Gegenwart eines sauren Katalysators, wie z. B. einer organischen Säure, wie z. B. Essigsäure oder Ameisensäure, oder einer anorganischen Säure, wie z. B.
Schwefelsäure oder Salzsäure, oder in Gegenwart von Bortrifluorid. Die Umsetzung kann auch in Gegenwart einer Substanz durchgeführt werden, welche nicht nur ein Verdünnungsmittel oder Lösungsmittel ist, sondern gleichzeitig auch als saurer Katalysator wirkt, wie z. B. Essigsäure oder Ameisensäure.
Die erfindungsgemäss erhältlichen Phenylazopyrimidine besitzen ausgezeichnete antibakterielle Eigenschaften sowohl in vitro als auch in vivo, wobei sie insbesondere gegen Staphylococcen, die eine Resistenz gegen gewisse Antibiotica entwickelt haben, wirksam sind.
Die genannten Phenylazopyrimidine können zu pharmazeutischen und veterinären Präparaten verarbeitet werden, die mindestens eines der besagten Phenylazopyrimidine oder ein Salz davon in Mischung mit einem nichtgiftigen, pharmazeutisch annehmbaren Verdünnungsmittel oder Trägerstoff enthalten.
Gewisse der oben erwähnten Präparate eignen sich insbesondere für die Behandlung von Mastitis bei Rindern.
In den folgenden Beispielen bedeuten die Teile Gewichtsteile.
Beispiel 1
Eine Mischung von 1 Teil 1,4-Benzochinon, 1 Teil 4-Hydrazino-2, 6-dihydroxy-pyrimidin und 20 Teilen 98 0/oiger Ameisensäure wird während 5 Minuten bei 25"C und hierauf während weiteren 5 Minuten bei 500 gerührt und dann abgekühlt. Das Gemisch wird filtriert und der feste Rückstand mit Ameisensäure, Wasser und Äthanol gewaschen und hierauf getrocknet. Auf diese Weise erhält man 2,6 Dihydroxy-4-(4'-hydroxy-phenylazo)-pyrimidin, das sich oberhalb 2500C allmählich zersetzt.
Das als Ausgangsmaterial verwendete 4-Hydra zino-2,6-dihydroxy-pyrimidin kann wie folgt erhalten werden:
Eine Lösung von 1 Teil 4-Chlor-2,6-dihydroxypyrimidin in einer Mischung von 1 Teil 100 0/obigem Hydrazinhydrat und 10 Teilen Wasser wird während 1 Stunde unter Rückfluss erhitzt und hierauf gekühlt und filtriert. Der feste Rückstand besteht aus 4-Hy drazino-2, 6-dihydroxy-pyrimidin, das sich bei 290 zersetzt.
Beispiel 2
Eine Lösung von 3,7 Teilen 1,4-Benzochinon in 20 Teilen Äthanol wird in eine Suspension von 4,3 Teilen 4-Hydrazino-2, 6-dihydroxy-pyrimidin in 100 Teilen 1n Salzsäure eingerührt. Das Gemisch wird dann während 30 Minuten bei 20 gerührt und filtriert und der feste Rückstand mit Wasser und Äthanol gewaschen und hierauf getrocknet. Dabei erhält man 2,6-Dihydroxy-4-(4'-hydroxy-phenylazo)pyrimidin, das sich oberhalb 250"C allmählich zersetzt.
Beispiel 3
Eine Lösung von 0,6 Teilen 1, 4-Benzochinon in 8 Teilen warmem Äthanol wird in eine Suspension von 0,8 Teilen 4-Hydrazino-2,6-dihydroxy-5-methyi- pyrimidin in 20 Teilen 1n Salzsäure eingerührt. Das Gemisch wird während 1 Stunde bei 20 gerührt und hierauf filtriert und der feste Rückstand mit Äthanol und Wasser gewaschen und getrocknet. Dabei erhält man 2, 6-Dihydroxy-4-(4'-hydroxy-phenylazo)-5 -me- thyl-pyrimidin, das sich oberhalb 255"C zersetzt.
Das als Ausgangsmaterial verwendete 4-Hydrazino-2, 6-dihydroxy-5 -methyl-pyrimidin kann wie folgt erhalten werden:
Eine Lösung von 1 Teil 4-Chlor-2,6-dihydroxy5-methyl-pyrimidin in 50 Teilen Wasser, die 1 Teil 100 /oiges Hydrazinhydrat enthält, wird während 18 Stunden in einer Stickstoffatmosphäre unter Rückfluss erhitzt. Das Gemisch wird dann gekühlt und filtriert und der kristalline Rückstand aus Wasser umkristallisiert. Dabei erhält man 4-Hydrazino-2,6- dihydroxy-5-methyl-pyrimidin in Form von farblosen Nadeln, welche bei 275-276 C unter Zersetzung schmelzen.
Das als Ausgangsmaterial verwendete 4-Chlor2, 6-dihydroxy-5-methyl-pyrimidin lässt sich wie folgt herstellen:
Eine Mischung von 1 Teil 4-Chlor-2,6-dimethoxy-5-methyl-pyrimidin, 1 Teil wässriger 36 0/oiger Salzsäure, 10 Teilen Wasser und 40 Teilen Essigsäure wird während 21/2 Stunden unter Rückfluss erhitzt und dann im Vakuum zur Trockne eingedampft. Durch Umkristallisieren des Rückstandes aus Wasser erhält man 4-Chlor-2, 6-dihydroxy-5methyl-pyrimidin vom Schmelzpunkt 266-267 C.
Beispiel 4
Eine Mischung von 1 Teil 4-Hydrazino-2,6-dihydroxy-pyrimidin, 0,84 Teilen 2, 5-Toluchinon, 145 Teilen Essigsäure und 145 Teilen Wasser wird während 5 Minuten unter Rückfluss zum Sieden erhitzt und dann gekühlt. Das Gemisch wird filtriert und der feste Rückstand aus Äthanol umkristallisiert.
Dabei erhält man 2,6-Dihydroxy-4-(4'-hydroxy-3'- methyl-phenylazo)-pyrimidin, das sich oberhalb 2500C zersetzt.
Beispiel 5
Eine Mischung von 1,1 Teilen 4-Hydrazino-2,6- dihydroxy-pyrimidin, 1,6 Teilen 2-Chlor-l,4-benzo- chinon und 40 Teilen 98 0/obiger Ameisensäure wird während 15 Minuten bei 20 gerührt. Das Gemisch wird filtriert und der feste Rückstand aus Essigsäure umkristallisiert, wobei man 2,6-Dihydroxy-4-(3'chlor-4'-hydroxy-phenylazo)-pyrimidin, das sich oberhalb 2700C zersetzt, erhält.
Beispiel 6
Eine Mischung von 1 Teil 4-Hydrazino-2,6-dihydroxy-pyrimidin, 1 Teil 2-Allyl- 1, 4-benzochinon und 50 Teilen 1n Salzsäure wird zusammen während 20 Minuten bei 20O gemahlen. Das Gemisch wird dann filtriert und der feste Rückstand aus 50 0/obiger wässriger Essigsäure kristallisiert. Dabei erhält man 2,6- 6-Dihydroxy-4-(3'-allyl-4'-hydroxy-pherLylazo)-py- rimidin, das sich bei 2300C zersetzt.
Beispiel 7
Ein Gemisch von 1 Teil 4-Hydrazino-2,6-dihydroxy-pyrimidin, 1 Teil 2-(n-Propyl)- 1, 4-benzo- chinon und 30 Teilen 98 0/obiger Ameisensäure wird während 20 Minuten bei 20O gerührt. Dann gibt man dem Gemisch ein gleiches Volumen Wasser zu. Das Gemisch wird filtriert und der feste Rückstand mit Wasser und hierauf mit Äthanol gewaschen und dann getrocknet, wobei man 2, 6-Dihydroxy-4-[4'-hydroxy- 3 '-(n-propyl)-phenylazo] -pyrimidin, das sich bei 238-242"C zersetzt, erhält.
Beispiel8
Eine Lösung von 7,2 Teilen 1, 4-Benzochinon in 80 Teilen Äthanol wird in ein Gemisch von 10 Teilen 2-Amino-4-hydrazino-6-hydroxy-pyrimidin und 1000 Teilen 3n Salzsäure eingerührt. Das Gemisch wird während 15 Minuten bei 20O gerührt, filtriert und der feste Rückstand mit Wasser gewaschen und mit einer Lösung von 10 Teilen Natriumacetat in 100 Teilen Wasser gemahlen. Das Gemisch wird filtriert und der feste Rückstand mit Wasser gewaschen und getrocknet. Dabei erhält man 2-Amino-6-hydroxy-4 (4'-hydroxy-phenylazo)-pyrimidin, das sich oberhalb 250O zersetzt.
Das als Ausgangsmaterial verwendete 2-Amino4-hydrazino-6-hydroxy-pyrimidin kann wie folgt erhalten werden:
Ein Gemisch von 1 Teil 2-Amino-4-chlor-6hydrazino-pyrimidin, 1 Teil 1000/obigem Hydrazinhydrat und 50 Teilen Wasser wird während 1 Stunde unter Rückfluss erhitzt und hierauf gekühlt. Das Gemisch wird filtriert und der feste Rückstand mit Wasser gewaschen und getrocknet. Auf diese Weise erhält man 2-Amino-4-hydrazino-6-hydroxy-pyrimidin, das sich oberhalb 3000C zersetzt.
Beispiel 9
Ein Gemisch von 1,6 Teilen 2-Chlor-1 ,4-benzo- chinon, 1,1 Teilen 2-Amino-4-hydrazino-6-hydroxypyrimidin, 10 Teilen Äthanol und 30 Teilen 1n Salzsäure wird während 20 Minuten bei 20O gerührt. Das Gemisch wird filtriert und der feste Rückstand mit Wasser gewaschen und getrocknet. Dabei erhält man 2 -Amino- 6 -hydroxy-4-(3'-chlor-4'-hydroxy-phenyl- azo)-pyrimidin-hemihydrochlorid, das sich oberhalb 2500C zersetzt.
Process for the preparation of phenylazopyriniidines
The present invention relates to a process for the preparation of phenylazopyrimidines which have valuable therapeutic properties, for example as antibacterial agents.
The phenylazopyrimidines prepared according to the invention correspond to the formula:
EMI1.1
where R1 is a hydroxyl or amino group, R2 is hydrogen or an alkyl radical and R3, R4, R and Ro, which can be identical or different, are hydrogen or alkyl or alkenyl radicals or halogen atoms. The compounds prepared according to the invention can be converted into their salts.
It should be noted that the phenylazo radical in question
EMI1.2
also in the tautomeric form
EMI1.3
can be reproduced.
R2 can preferably be an alkyl radical containing not more than 5 carbon atoms, e.g. B. the methyl radical.
Suitable meanings of R3, R4, R6 and Rn are, for example, alkyl radicals containing no more than 5 carbon atoms, e.g. B. the methyl or n-propyl radical, or alkenyl radicals containing no more than 5 carbon atoms, e.g. B. the allyl radical, or halogen atoms, such as. B. chlorine and bromine atoms.
Suitable salts are, for example, acid addition salts, e.g. B. salts with inorganic acids, such as. B. with hydrochloric acid, and metal salts, e.g. B. salts with alkali metals, such as. B. sodium or potassium salts, or with alkaline earth metals, such as. B. calcium or barium salts called.
Preferred phenylazopyrimidines prepared according to the invention are 2,6-dihydroxy-4- (4'-hydroxyphenylazo) -pyrimidine and 2-amino-6-hydroxy-4 (4'-hydroxyphenylazo) -pyrimidine.
The phenylazopyrimidines of the above general formula are obtained according to the invention by using a hydrazinopyrimidine of the formula
EMI1.4
with a benzoquinone of the formula
EMI1.5
implements.
The reaction is preferably carried out by mixing or heating the reactants in the presence of an inert diluent or solvent, such as. B. water, alcohol, tetrahydrofuran or dimethylformamide, and in the presence of an acidic catalyst, such as. B. an organic acid, such as. B. acetic acid or formic acid, or an inorganic acid, such as. B.
Sulfuric acid or hydrochloric acid, or in the presence of boron trifluoride. The reaction can also be carried out in the presence of a substance which is not only a diluent or solvent, but also acts as an acid catalyst at the same time, such as. B. acetic acid or formic acid.
The phenylazopyrimidines obtainable according to the invention have excellent antibacterial properties both in vitro and in vivo, and they are particularly effective against staphylococci, which have developed resistance to certain antibiotics.
Said phenylazopyrimidines can be processed into pharmaceutical and veterinary preparations which contain at least one of the said phenylazopyrimidines or a salt thereof in admixture with a non-toxic, pharmaceutically acceptable diluent or carrier.
Certain of the above-mentioned preparations are particularly useful in the treatment of mastitis in cattle.
In the following examples, the parts mean parts by weight.
example 1
A mixture of 1 part 1,4-benzoquinone, 1 part 4-hydrazino-2, 6-dihydroxypyrimidine and 20 parts 98% formic acid is stirred at 25 ° C. for 5 minutes and then at 500 ° C. for a further 5 minutes The mixture is filtered and the solid residue is washed with formic acid, water and ethanol and then dried to give 2,6 dihydroxy-4- (4'-hydroxyphenylazo) pyrimidine, which gradually dissolves above 2500C decomposed.
The 4-hydrazino-2,6-dihydroxy-pyrimidine used as starting material can be obtained as follows:
A solution of 1 part of 4-chloro-2,6-dihydroxypyrimidine in a mixture of 1 part of 100% of the above hydrazine hydrate and 10 parts of water is refluxed for 1 hour and then cooled and filtered. The solid residue consists of 4-Hy drazino-2,6-dihydroxypyrimidine, which decomposes at 290.
Example 2
A solution of 3.7 parts of 1,4-benzoquinone in 20 parts of ethanol is stirred into a suspension of 4.3 parts of 4-hydrazino-2,6-dihydroxypyrimidine in 100 parts of 1N hydrochloric acid. The mixture is then stirred for 30 minutes at 20 and filtered and the solid residue is washed with water and ethanol and then dried. This gives 2,6-dihydroxy-4- (4'-hydroxyphenylazo) pyrimidine, which gradually decomposes above 250.degree.
Example 3
A solution of 0.6 part of 1,4-benzoquinone in 8 parts of warm ethanol is stirred into a suspension of 0.8 part of 4-hydrazino-2,6-dihydroxy-5-methyipyrimidine in 20 parts of 1N hydrochloric acid. The mixture is stirred for 1 hour at 20 and then filtered and the solid residue is washed with ethanol and water and dried. This gives 2,6-dihydroxy-4- (4'-hydroxyphenylazo) -5-methyl-pyrimidine, which decomposes above 255.degree.
The 4-hydrazino-2,6-dihydroxy-5-methyl-pyrimidine used as starting material can be obtained as follows:
A solution of 1 part of 4-chloro-2,6-dihydroxy5-methyl-pyrimidine in 50 parts of water, which contains 1 part of 100% hydrazine hydrate, is refluxed for 18 hours in a nitrogen atmosphere. The mixture is then cooled and filtered and the crystalline residue is recrystallized from water. This gives 4-hydrazino-2,6-dihydroxy-5-methyl-pyrimidine in the form of colorless needles which melt at 275-276 ° C. with decomposition.
The 4-chloro2,6-dihydroxy-5-methyl-pyrimidine used as starting material can be prepared as follows:
A mixture of 1 part of 4-chloro-2,6-dimethoxy-5-methyl-pyrimidine, 1 part of aqueous 36% hydrochloric acid, 10 parts of water and 40 parts of acetic acid is refluxed for 21/2 hours and then in vacuo evaporated to dryness. Recrystallization of the residue from water gives 4-chloro-2,6-dihydroxy-5methyl-pyrimidine with a melting point of 266-267 C.
Example 4
A mixture of 1 part of 4-hydrazino-2,6-dihydroxypyrimidine, 0.84 parts of 2,5-toluquinone, 145 parts of acetic acid and 145 parts of water is refluxed for 5 minutes and then cooled. The mixture is filtered and the solid residue is recrystallized from ethanol.
This gives 2,6-dihydroxy-4- (4'-hydroxy-3'-methyl-phenylazo) -pyrimidine, which decomposes above 2500C.
Example 5
A mixture of 1.1 parts of 4-hydrazino-2,6-dihydroxypyrimidine, 1.6 parts of 2-chloro-1,4-benzoquinone and 40 parts of 98% formic acid is stirred at 20 for 15 minutes. The mixture is filtered and the solid residue is recrystallized from acetic acid, 2,6-dihydroxy-4- (3'chlor-4'-hydroxyphenylazo) pyrimidine, which decomposes above 270 ° C., is obtained.
Example 6
A mixture of 1 part of 4-hydrazino-2,6-dihydroxypyrimidine, 1 part of 2-allyl-1,4-benzoquinone and 50 parts of 1N hydrochloric acid is ground together at 20O for 20 minutes. The mixture is then filtered and the solid residue is crystallized from 50% aqueous acetic acid. This gives 2,6- 6-dihydroxy-4- (3'-allyl-4'-hydroxy-pherLylazo) pyrimidine which decomposes at 2300C.
Example 7
A mixture of 1 part of 4-hydrazino-2,6-dihydroxypyrimidine, 1 part of 2- (n-propyl) -1, 4-benzoquinone and 30 parts of 98% formic acid is stirred at 20 ° for 20 minutes. An equal volume of water is then added to the mixture. The mixture is filtered and the solid residue is washed with water and then with ethanol and then dried, whereby 2,6-dihydroxy-4- [4'-hydroxy-3 '- (n-propyl) -phenylazo] -pyrimidine, the decomposes at 238-242 "C.
Example8
A solution of 7.2 parts of 1,4-benzoquinone in 80 parts of ethanol is stirred into a mixture of 10 parts of 2-amino-4-hydrazino-6-hydroxypyrimidine and 1000 parts of 3N hydrochloric acid. The mixture is stirred for 15 minutes at 20 °, filtered and the solid residue washed with water and ground with a solution of 10 parts of sodium acetate in 100 parts of water. The mixture is filtered and the solid residue is washed with water and dried. This gives 2-amino-6-hydroxy-4 (4'-hydroxyphenylazo) pyrimidine, which decomposes above 250 °.
The 2-amino-4-hydrazino-6-hydroxypyrimidine used as starting material can be obtained as follows:
A mixture of 1 part of 2-amino-4-chloro-6hydrazino-pyrimidine, 1 part of 1000 / above hydrazine hydrate and 50 parts of water is refluxed for 1 hour and then cooled. The mixture is filtered and the solid residue is washed with water and dried. In this way, 2-amino-4-hydrazino-6-hydroxypyrimidine is obtained, which decomposes above 3000C.
Example 9
A mixture of 1.6 parts of 2-chloro-1,4-benzoquinone, 1.1 parts of 2-amino-4-hydrazino-6-hydroxypyrimidine, 10 parts of ethanol and 30 parts of 1N hydrochloric acid is stirred at 20O for 20 minutes . The mixture is filtered and the solid residue is washed with water and dried. This gives 2-amino-6-hydroxy-4- (3'-chloro-4'-hydroxyphenyl-azo) -pyrimidine hemihydrochloride, which decomposes above 2500C.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB22904/59A GB876601A (en) | 1959-07-03 | 1959-07-03 | Pyrimidine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH410962A true CH410962A (en) | 1966-04-15 |
Family
ID=10186945
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH747860A CH410962A (en) | 1959-07-03 | 1960-07-01 | Process for the preparation of phenylazopyrimidines |
Country Status (3)
| Country | Link |
|---|---|
| CH (1) | CH410962A (en) |
| FR (1) | FR377M (en) |
| GB (1) | GB876601A (en) |
-
1959
- 1959-07-03 GB GB22904/59A patent/GB876601A/en not_active Expired
-
1960
- 1960-07-01 CH CH747860A patent/CH410962A/en unknown
- 1960-08-29 FR FR837072A patent/FR377M/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FR377M (en) | 1961-04-04 |
| GB876601A (en) | 1961-09-06 |
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