DE1079056B - Process for the preparation of 2,4-diamino-5- (4'-chlorophenyl) -6-aethylpyrimidine - Google Patents
Process for the preparation of 2,4-diamino-5- (4'-chlorophenyl) -6-aethylpyrimidineInfo
- Publication number
- DE1079056B DE1079056B DES28810A DES0028810A DE1079056B DE 1079056 B DE1079056 B DE 1079056B DE S28810 A DES28810 A DE S28810A DE S0028810 A DES0028810 A DE S0028810A DE 1079056 B DE1079056 B DE 1079056B
- Authority
- DE
- Germany
- Prior art keywords
- chlorophenyl
- ethylpyrimidine
- solvent
- diamino
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 title 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 20
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 12
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 229910021529 ammonia Inorganic materials 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 8
- 238000009835 boiling Methods 0.000 claims description 7
- 125000004494 ethyl ester group Chemical group 0.000 claims description 7
- 238000009833 condensation Methods 0.000 claims description 6
- 230000005494 condensation Effects 0.000 claims description 6
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 5
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 5
- WKSAUQYGYAYLPV-UHFFFAOYSA-N pyrimethamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1 WKSAUQYGYAYLPV-UHFFFAOYSA-N 0.000 claims description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000005660 chlorination reaction Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 2
- 230000021736 acetylation Effects 0.000 claims description 2
- 238000006640 acetylation reaction Methods 0.000 claims description 2
- 238000005576 amination reaction Methods 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000000155 melt Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 150000003230 pyrimidines Chemical class 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- OEVCQPRLPSNHFQ-UHFFFAOYSA-N N-[4-chloro-5-(4-chlorophenyl)-6-ethylpyrimidin-2-yl]acetamide Chemical compound C(C)(=O)NC1=NC(=C(C(=N1)Cl)C1=CC=C(C=C1)Cl)CC OEVCQPRLPSNHFQ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- -1 ethylimino ester Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- IVYMIRMKXZAHRV-UHFFFAOYSA-N 4-chlorophenylacetonitrile Chemical compound ClC1=CC=C(CC#N)C=C1 IVYMIRMKXZAHRV-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- STIAPHVBRDNOAJ-UHFFFAOYSA-N carbamimidoylazanium;carbonate Chemical compound NC(N)=N.NC(N)=N.OC(O)=O STIAPHVBRDNOAJ-UHFFFAOYSA-N 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- IQFVPQOLBLOTPF-HKXUKFGYSA-L congo red Chemical compound [Na+].[Na+].C1=CC=CC2=C(N)C(/N=N/C3=CC=C(C=C3)C3=CC=C(C=C3)/N=N/C3=C(C4=CC=CC=C4C(=C3)S([O-])(=O)=O)N)=CC(S([O-])(=O)=O)=C21 IQFVPQOLBLOTPF-HKXUKFGYSA-L 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- ZZTURJAZCMUWEP-UHFFFAOYSA-N diaminomethylideneazanium;hydrogen sulfate Chemical compound NC(N)=N.OS(O)(=O)=O ZZTURJAZCMUWEP-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 235000015243 ice cream Nutrition 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 235000021581 juice product Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012258 stirred mixture Substances 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
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- 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
- C07D239/48—Two nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Liquid Crystal Substances (AREA)
Description
Verfahren zur Herstellung von 2,4-Diamino-5-(4'-chlorphenyl)-6-äthylpyrimidin Kürzlich wurden die chemotherapeutischen Eigenschaften und insbesondere die Antimalariawirksamkeit eines Diaminoderivats des Pyrimidins, nämlich des 2,4-Diamino-5-(4'-chlorphenyl)-6-äthylpyrimidins, beschrieben. Process for the preparation of 2,4-diamino-5- (4'-chlorophenyl) -6-ethylpyrimidine Recently the chemotherapeutic properties and in particular the antimalarial activity have become a diamino derivative of pyrimidine, namely 2,4-diamino-5- (4'-chlorophenyl) -6-ethylpyrimidine, described.
Die vorliegende Erfindung betrifft ein neues Herstellungsverfahren für diese Substanz. Es besteht darin, daß man zuerst Guanidin mit 2-(4'-Chlorphenyl)-pentanon-(3)-säure-(1)-äthylester kondensiert. Das so erhaltene 2-Amino-4-oxy-5-(4'-chlorphenyl) -6-äthylpyrimidin wird anschließend, gegebenenfalls nach Acetylierung, der Einwirkung eines Chlorierungsmittels, z. B. The present invention relates to a new manufacturing method for this substance. It consists in first reacting guanidine with 2- (4'-chlorophenyl) pentanone (3) acid (1) ethyl ester condensed. The 2-amino-4-oxy-5- (4'-chlorophenyl) -6-ethylpyrimidine thus obtained is then, optionally after acetylation, the action of a chlorinating agent, z. B.
Phosphoroxychlorid, unterworfen, wodurch es in 2-Amino-bzw. 2-Acetylamino-4-ehlor-5-(4"-chlorphenyl) -li-äthylpyrimidin übergeführt wird; das so erhaltene Aminö-bzw. Acetylaminoderivat wird dann mit Ammoniak, vorzugsweise in einem organischen Lösungsmittel, behandelt, und man erhält das 2,SDiamino-5-(4'-chlorphenyl)-6-äthylpyrimidin in guter Ausbeute; wenn die Chlorierung an der acetylierten Verbindung durchgeführt wurde, so findet die Desacetylierung der Acetylaminogruppe gleichzeitig mit dem Ersatz des in 4-Stellung befindlichen Chlors durch einen Aminorest statt.Phosphorus oxychloride, which turns it into 2-amino or. 2-acetylamino-4-ehlor-5- (4 "-chlorphenyl) -li-ethylpyrimidine is converted; the amino or. Acetylamino derivative is then treated with ammonia, preferably in an organic solvent, and 2, SDiamino-5- (4'-chlorophenyl) -6-ethylpyrimidine is obtained in good yield; if the chlorination was carried out on the acetylated compound, then find the deacetylation of the acetylamino group simultaneously with the replacement of the 4-position existing chlorine is held by an amino residue.
Diese Umsetzungen können durch das folgende Schema wiedergegeben werden: (R = -II oderlCH3tCO) Die erste Reaktion, nämlich die Kondensation des Guanidins mit dem 2- (4'-Chlorphenyl)-pentanon- (3)-säure-(1)-äthylester, wurde bereits von Russell und Mitarbeitern (vgl. Journal of the American Chemical Society 73, S. 3763 [1951]) versucht, jedoch ohne Erfolg, Diese Autoren waren der Meinung, daß die Kondensation des Guanidins mit a-Phenyl-ß-ketocarbonsäureestern nicht durchzuführen sei. Es wurde jedoch gefunden, daß diese Kondensation in guter Ausbeute bewirkt werden kann, wenn man in 15- bis 40 0/0igem, vorzugsweise 20°/Oigem Oleum arbeitet.These conversions can be represented by the following scheme: (R = -II or 1CH3tCO) The first reaction, namely the condensation of guanidine with 2- (4'-chlorophenyl) pentanone (3) acid (1) ethyl ester, was already carried out by Russell and co-workers (see Journal of the American Chemical Society 73 , P. 3763 [1951]) tried, but without success. These authors were of the opinion that the condensation of guanidine with α-phenyl-β-ketocarboxylic acid esters could not be carried out. It has been found, however, that this condensation can be effected in good yield if one works in 15 to 40%, preferably 20%, oleum.
Das in der letzten Phase verwendete Lösungsmittel wird vorzugsweise aus den Lösungsmitteln mit hohem Siedepunkt ausgewählt (wenigstens 160 bis 180"C), z.B. Phenol, und in diesem Fall arbeitet man vorteilhaft bei Atmosphärendruck bei der Siedetemperatur dieses Lösungsmittels. Man kann jedoch auch unter Druck arbeiten, wobei man ein Lösungsmittel mit niedrigerem Siedepunkt verwendet, z. B. Alkohol. The solvent used in the final phase is preferred selected from the solvents with a high boiling point (at least 160 to 180 "C), e.g. phenol, and in this case it is advantageous to work at atmospheric pressure the boiling point of this solvent. However, you can also work under pressure, using a solvent with a lower boiling point, e.g. B. Alcohol.
Die folgenden Beispiele sollen die Erfindung näher erläutern. Die angegebenen Schmelzpunkte wurden im Koffer-Block bestimmt, wenn nichts anderes angegeben ist. Beispiel 1 Man gibt 10,8 g Guanidinsulfat, das mit einem halben Mol Kristallwasser kristallisiert ist, langsam zu 43 ccm 20 obigem Oleum, das auf 0° C gekühlt ist. Zu der erhaltenen Lösung gibt man nach und nach unter Kühlung 24g 2-(4'-Chlorphenyl)-pentanon-(3)-säure-(1)-äthylester. Man läßt die Masse sich auf gewöhnliche Temperatur erwärmen und erhitzt dann 1 Stunde auf dem Wasserbad auf 80"C. The following examples are intended to explain the invention in more detail. the The melting points given were determined in a suitcase block, unless otherwise stated is. EXAMPLE 1 10.8 g of guanidine sulfate are added, which is mixed with half a mole of water of crystallization is crystallized, slowly to 43 cc of 20 of the above oleum, which is cooled to 0 ° C. 24 g of 2- (4'-chlorophenyl) pentanone (3) acid (1) ethyl ester are gradually added to the resulting solution with cooling. The mass is allowed to warm to ordinary temperature and then heated for 1 hour on the water bath at 80 "C.
Man gießt die erhaltene, dunkelgefärbte Lösung auf zerkleinertes Eis, dekantiert den ausgefällten festen Stoff und nimmt ihn in 200 ccm Wasser und 30 ccm Natronlauge von 36"Be auf. Durch Ansäuern dieser Lösung mit Essigsäure fällt man das rohe 2-Aminoloxy-5-(4'-chlorphenyl)-6-äthylpyrimidin vom F. 2100C aus. Durch Umkristallisieren aus siedendem Äthanol erhält man das reine Produkt vom F. 250"C.The dark-colored solution obtained is poured onto crushed ice, decant the precipitated solid matter and take it in 200 cc of water and 30 ccm sodium hydroxide solution of 36 "Be. Acidification of this solution with acetic acid precipitates the crude 2-aminoloxy-5- (4'-chlorophenyl) -6-ethylpyrimidine has a melting point of 2100C. By Recrystallization from boiling ethanol gives the pure product with a melting point of 250 ° C.
11,5 g dieses Pyrimidins werden 1 Stunde mit 80 ccm Phosphoroxychlorid am Rückflußkühler erhitzt. Man verjagt das überschüssige Phosphoroxychlorid durch Verdampfen unter vermindertem Druck. Der Rückstand wird in Eiswasser aufgenommen. Man neutralisiert mit Ammoniak und extrahiert mit Äther. Die ätherische Lösung vird über Natriumsulfat getrocknet und eingedampft. 11.5 g of this pyrimidine are mixed with 80 cc of phosphorus oxychloride for 1 hour heated on the reflux condenser. The excess phosphorus oxychloride is chased away Evaporation under reduced pressure. The residue is taken up in ice water. It is neutralized with ammonia and extracted with ether. The essential solution will be dried over sodium sulfate and evaporated.
Man erhält auf diese Weise das 2-Amino-4.chlor-5-(4'.chlor. phenyl)-6-äthylpyrimidin vom F. 1600C, das nach dem Umkristallisieren aus Alkohol bei 163"C schmilzt.In this way, 2-amino-4.chlor-5- (4'.chlor. Phenyl) -6-ethylpyrimidine is obtained from the F. 1600C, which melts at 163 "C after recrystallization from alcohol.
1,6 g dieses chlorierten Pyrimidins werden mit 10 ccm ruit Ammoniak gesättigtem Äthanol im geschlossenen Rohr 6 Stunden auf 1300C erhitzt. Durch Abkühlen kristallisiert das 2,4-Diamino-5-(4'-chlorphenyl)-6-äthylpyrimidin in reinem Zustand aus; man saugt es ab, wäscht mit Alkohol und trocknet im Trockenschrank. Es schmilzt bei 2410 C. Sein Monochlorhydrat schmilzt bei 270"C (Block Maquenne). 1.6 g of this chlorinated pyrimidine are ruit ammonia with 10 ccm saturated ethanol in a closed tube heated to 1300C for 6 hours. By cooling down 2,4-diamino-5- (4'-chlorophenyl) -6-ethylpyrimidine crystallizes in the pure state the end; it is vacuumed off, washed with alcohol and dried in a drying cabinet. It melts at 2410 C. Its monochlorohydrate melts at 270 "C (Block Maquenne).
Der als Ausgangsprodukt verwendete 2-(4'-Chlorphenyl) -pentanon-(3) -säure- (1) -äthylester (Kp.0,15 126 bis 130°C) wird durch vorsichtige Hydrolyse des Äthyliminoesters der 2- (4'-Chlorphenyl) -pentanon- (3)-säure- (1) erhalten. The 2- (4'-chlorophenyl) pentanone (3) used as the starting product Acid (1) ethyl ester (boiling point 0.15 126 to 130 ° C) is hydrolysed carefully of the ethylimino ester of 2- (4'-chlorophenyl) pentanone (3) acid (1) obtained.
Dieser wird seinerseits aus dem Nitril dieser Säure erhalten, und dieses Nitril (F. 52"C) wird durch Kondensation von Propionsäureäthylester mit 4-Chlorbenzylcyanid (Kp.14 138 bis 139"C) gewonnen. This in turn is obtained from the nitrile of this acid, and this nitrile (m.p. 52 "C) is obtained by condensation of ethyl propionate with 4-chlorobenzyl cyanide (Bp 14 138 to 139 "C) won.
Beispiel 2 Man löst 55 g trockenes Guanidincarbonat in kleinen Anteilen und unter Kühlung auf etwa 0° C in 197 ccm 200/,dem Oleum. In die erhaltene Lösung gibt man langsam und unter Rühren 78,7 g 2-(4'-Chlorphenyl)-pentanon-(3)-säure-(l)-äthylester, wobei man die Temperatur durch ein Kühlbad bei etwa -10" C hält. Hierauf entfernt man das Kühlbad, und die Masse erwärmt sich von selbst auf etwa 500 C; man hält noch 2 Stunden bei dieser Temperatur. Dann gießt man die erhaltene Lösung in eine kräftig gerührte Mischung aus 54 g Natriumcarbonat, 3,71 Wasser und 1,7 kg zerkleinertem Eis. Example 2 55 g of dry guanidine carbonate are dissolved in small portions and with cooling to about 0 ° C in 197 ccm 200 /, the oleum. In the solution obtained are added slowly and with stirring 78.7 g of 2- (4'-chlorophenyl) pentanone (3) acid (l) ethyl ester, the temperature being kept at about -10 "C. by means of a cooling bath. Then removed the cooling bath, and the mass heats up by itself to about 500 C; one holds another 2 hours at this temperature. Then the resulting solution is poured into a vigorously stirred mixture of 54 g sodium carbonate, 3.71 water and 1.7 kg crushed Ice cream.
Man saugt die gebildete krümelige Ausfällung ab, wäscht sie mit Wasser und suspendiert sie dann in 225 ccm Methanol. Man neutralisiert die verbliebene Azidität mit 5 ccm Ammoniak von 22° Be. Man saugt ab, wäscht mit Methanol und mit Wasser und trocknet im Trockenschrank bei 100" C. Man erhält 53 g rohes 2-AminoXoxy-5-(4'-chlorphenyl)-6-äthylpyrimidin vom F. 2340 C.The crumbly precipitate formed is suctioned off and washed with water and then suspend them in 225 cc of methanol. You neutralize the remaining one Acidity with 5 cc ammonia of 22 ° Be. It is suctioned off, washed with methanol and with Water and dry in a drying cabinet at 100 ° C. 53 g of crude 2-AminoXoxy-5- (4'-chlorophenyl) -6-ethylpyrimidine are obtained from F. 2340 C.
50 g dieses Oxypyrimidins werden mit 150 ccm wasserfreiem Pyridin und 30,6 g Essigsäureanhydrid vermischt. Man erhitzt 1 I2 Stunden unter Rückfluß, destilliert das überschüssige Pyridin unter vermindertem Druck ab und nimmt in Wasser und Salzsäure bis zur sauren Reaktion gegen Kongorot auf. Man saugt die erhaltene Ausfällung ab, wäscht mit Wasser und trocknet im Trockenschrank bei 100" C. Man erhält 53 g 2-Acetylamino - 4 - oxy - 5 - (4'- chlorphenyl) - 6 - äthylpyrimidin vom F. 260° C, das nach dem Umkristallisieren aus Alkohol bei 2640 C schmilzt. 50 g of this oxypyrimidine are mixed with 150 cc of anhydrous pyridine and 30.6 g of acetic anhydride mixed. The mixture is refluxed for 11/2 hours, the excess pyridine is distilled off under reduced pressure and taken in water and hydrochloric acid to an acidic reaction against Congo red. One sucks the obtained Precipitation off, washed with water and dried in a drying cabinet at 100 ° C. Man receives 53 g of 2-acetylamino - 4 - oxy - 5 - (4'-chlorophenyl) - 6 - ethylpyrimidine has a mp of 260 ° C, which melts at 2640 C after recrystallization from alcohol.
52 g dieser Acetylverbindung werden in 100 ccm Phosphoroxychlorid gegeben. Man erhitzt 5 Minuten auf 700 C und destilliert dann das überschüssige Phosphoroxychlorid unter vermindertem Druck ab. Man nimmt den Rückstand in 400 g zerkleinertem Eis auf, neutralisiert mit Ammoniak, saugt das auskristallisierende Produkt ab, wäscht es mit Wasser und trocknet es im Vakuum. Man erhält 55 g 2-Acetylamino-4-chlor-5-(4'-chlorphenyl)-6-äthylpyrimidin vom F. 2320 C. Nach dem Umkristallisieren aus Äthanol schmilzt es bei 235° C. 50 g dieses chlorierten Pyrimidins werden mit 250 ccm Äthanol und 200 g Ammoniak in einen Autoklav gegeben. Man erhitzt 6 Stunden auf 155° C. Nach dem Abkühlen saugt man das auskristallisierende Produkt ab, wäscht es mit Alkohol und trocknet es im Trockenschrank. 52 g of this acetyl compound are dissolved in 100 cc of phosphorus oxychloride given. The mixture is heated to 700 ° C. for 5 minutes and the excess is then distilled off Phosphorus oxychloride under reduced pressure. The residue is taken in 400 g crushed ice, neutralized with ammonia, sucks the crystallizing ice Product off, wash it with water and dry it in a vacuum. 55 g of 2-acetylamino-4-chloro-5- (4'-chlorophenyl) -6-ethylpyrimidine are obtained of F. 2320 C. After recrystallization from ethanol, it melts at 235 ° C. 50 g of this chlorinated pyrimidine are mixed with 250 cc of ethanol and 200 g of ammonia in given an autoclave. The mixture is heated to 155 ° C. for 6 hours. After cooling, suction the product that crystallizes out is washed with alcohol and dried in the Drying cabinet.
Man erhält 34 g 2,4-Dianiiuo-5- (4'-chlorphenyl) -6-äthylpyrimidin vom F. 2400 C, das nach dem Umkristallisieren aus Äthanol bei 2410 C schmilzt. 34 g of 2,4-dianuo-5- (4'-chlorophenyl) -6-ethylpyrimidine are obtained with a temperature of 2400 C, which melts at 2410 C after recrystallization from ethanol.
Beispiel 3 Man erhitzt in einem mit einem Rückllußkühler versehenen Kolben eine Mischung von 93 g 2-Acetylaminochlor-5-(4'-chlorphenyl) -6-äthylpyrimidin (erhalten gemäß Beispiel 2) und 150 g Phenol auf 110° C und leitet in diese Mischung einen Ammoniakstrom. Man hält die Temperatur etwa 5 Minuten bei 110° C und erhöht dann innerhalb einer 3/4 Stunde die Temperatur fortschreitend, so daß das Phenol leicht siedet (etwa 180 bis 184" C); man setzt das Einleiten von Ammoniak und das Erhitzen noch 3 Stunden fort (Gewicht des verbrauchten Ammoniaks: etwaltOg). Example 3 Heating is carried out in a condenser equipped with a reflux condenser Flask a mixture of 93 g of 2-acetylaminochloro-5- (4'-chlorophenyl) -6-ethylpyrimidine (obtained according to Example 2) and 150 g of phenol at 110 ° C and passes into this mixture a stream of ammonia. The temperature is kept at 110 ° C. for about 5 minutes and increased then within 3/4 hour the temperature progressing so that the phenol boils gently (about 180 to 184 "C); the introduction of ammonia and the Continue heating for 3 hours (weight of ammonia consumed: about Og).
Man läßt abkühlen und gießt dann die Reaktionsmischung in 500 ccm Wasser und 150 ccm Natronlauge von 36° Be. Man rührt eine Viertelstunde, saugt über einen Büchner-Trichter ab, und wäscht mit 150 ccm Wasser. It is allowed to cool and then the reaction mixture is poured into 500 cc Water and 150 cc sodium hydroxide solution at 36 ° Be. One stirs for a quarter of an hour, sucks over off a Buchner funnel and wash with 150 cc of water.
Man suspendiert das Produkt in 150 ccm Äthanol und rührt kräftig eine Viertelstunde. Man saugt ab, wäscht mit 150 ccm Äthanol und trocknet im Trockenschrank bei 100" C bis zur Gewichtskonstanz. Auf diese Weise erhält man 61 g 2,4-Diamino-5- (4'-chlorphenyl) -6-äthylpyrimidin vom F. 241° C (Kofler-Block).The product is suspended in 150 cc of ethanol and vigorously stirred Quarter of an hour. It is filtered off with suction, washed with 150 cc of ethanol and dried in a drying cabinet at 100 "C to constant weight. In this way, 61 g of 2,4-diamino-5- (4'-chlorophenyl) -6-ethylpyrimidine, mp 241 ° C (Kofler block).
Claims (6)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR1079056X | 1951-06-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1079056B true DE1079056B (en) | 1960-04-07 |
Family
ID=9608990
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DES28810A Pending DE1079056B (en) | 1951-06-23 | 1952-06-04 | Process for the preparation of 2,4-diamino-5- (4'-chlorophenyl) -6-aethylpyrimidine |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1079056B (en) |
-
1952
- 1952-06-04 DE DES28810A patent/DE1079056B/en active Pending
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