DE1139505B - Process for the preparation of 4-chlorouracils substituted in the 1-position - Google Patents
Process for the preparation of 4-chlorouracils substituted in the 1-positionInfo
- Publication number
- DE1139505B DE1139505B DER29093A DER0029093A DE1139505B DE 1139505 B DE1139505 B DE 1139505B DE R29093 A DER29093 A DE R29093A DE R0029093 A DER0029093 A DE R0029093A DE 1139505 B DE1139505 B DE 1139505B
- Authority
- DE
- Germany
- Prior art keywords
- substituted
- chlorouracils
- water
- mol
- phosphorus oxychloride
- 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
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
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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 with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verfahren zur Herstellung von in l-Stellung substituierten 4-Chloruracilen Die Erfindung betrifft ein Verfahren zur Herstellung von in 1-Stellung substituierten 4-Chloruracilen. Es besteht darin, daß man in 1-Stellung durch Alkyl-, Aralkyl- oder Arylgruppen substituierte Barbitursäuren mit Phosphoroxychlorid im Überschuß in Gegenwart geringer Mengen Wasser unter Rückfluß kocht und die entstandenen, in 1-Stellung entsprechend substituierten 4-Chloruracile abtrennt. Process for the preparation of 4-chlorouracils substituted in the l-position The invention relates to a process for the preparation of substances substituted in the 1-position 4-chlorouracils. It consists in that in the 1-position by alkyl, aralkyl or aryl group-substituted barbituric acids with phosphorus oxychloride in excess boils under reflux in the presence of small amounts of water and the resulting, in 1-position separates correspondingly substituted 4-chlorouracils.
Die neuen 1-Alkyl-, 1-Aralkyl- oder Aryl-4-chloruracile sind wertvolle Ausgangsstoffe für weitere Synthesen; sie können zu Pteridinen, Purinen, Xanthinen und anderen pharmakologisch wertvollen Verbindungen dadurch umgesetzt werden, daß das Chloratom in der 4-Stellung substituiert wird. The new 1-alkyl-, 1-aralkyl- or aryl-4-chloruracils are valuable Starting materials for further syntheses; they can lead to pteridines, purines, xanthines and other pharmacologically valuable compounds are reacted in that the chlorine atom in the 4-position is substituted.
Es war bisher nicht bekannt, daß sich in 1-Stellung substituierte Barbitursäuren in die entsprechenden, nur in der 4-Stellung durch ein Chloratom substituierten Uracilderivate unmittelbar umwandeln lassen. It was not previously known that substituted in the 1-position Barbituric acids in the corresponding, only in the 4-position by a chlorine atom can convert substituted uracil derivatives immediately.
Diese Synthese ist um so überraschender, als man annehmen mußte, daß bei der Umsetzung von in 1-Stellung substituierten Barbitursäuren mit chlorierenden Mitteln zumindest drei isomere Monochlorderivate und drei isomere Dichlorderivate entstehen. Es ist daher überraschend, daß sich beim erfindungsgemäßen Verfahren ein einheitliches Produkt, nämlich die in 1-Stellung entsprechend substituierten 4-Chloruracile in hoher Ausbeute bilden. This synthesis is all the more surprising as one had to assume that in the reaction of barbituric acids substituted in the 1-position with chlorinating ones Mean at least three isomeric monochloro derivatives and three isomeric dichloro derivatives develop. It is therefore surprising that in the process according to the invention a uniform product, namely those correspondingly substituted in the 1-position Form 4-chloruracils in high yield.
Dem steht nicht entgegen, daß es bereits bekannt war, 1,3-Dimethylbarbitursäuren mit Phosphoroxychlorid in Gegenwart geringer Mengen Wasser zu 1,3-Dimethyl-4-chloruracil umzuwandeln und ferner in 3- und 5-Stellung trisubstituierte Barbitursäurederivate in 6-Stellung des Ringes mittels Phosphorhalogeniden zu chlorieren. This is not contradicted by the fact that 1,3-dimethylbarbituric acids were already known with phosphorus oxychloride in the presence of small amounts of water to form 1,3-dimethyl-4-chloruracil to convert and also in the 3- and 5-position trisubstituted barbituric acid derivatives to chlorinate in the 6-position of the ring by means of phosphorus halides.
Der Konstitutionsformel von 1,3-disubstituierter Barbitursäure ist zu entnehmen, daß einc Chlorierung nur an dem Kohlenstoffatom in 4- oder 6-Stellung erfolgen kann. 4- und 6-Chloruracil sind aber identisch, da es sich um ein symmetrisches Molekül handelt; es kann also nur ein einziges Chlorderivat entstehen. The constitutional formula of 1,3-disubstituted barbituric acid is it can be seen that a chlorination only at the carbon atom in the 4- or 6-position can be done. But 4- and 6-chlorouracil are identical because they are symmetrical Molecule acts; so only a single chlorine derivative can be produced.
Aus dem anderen obenerwähnten Verfahren zur Chlorierung der 6-Stellung des Ringes mittels Phosphorhalogeniden kann keine Voraussage getroffen werden, an welcher Stelle des Ringes das Chloratom bei dem erfindungsgemäßen Verfahren eintritt. Die bei dem bekannten Verfahren als Ausgangsstoff verwendeten Barbitursäurederivate müssen sowohl in 3-Stellung als auch in 5-Stellung substituiert sein; es bleibt somit gar keine andere Möglichkeit, als daß das Chlor in die 6-Stellung eintritt. From the other above-mentioned process for chlorinating the 6-position of the ring by means of phosphorus halides cannot be predicted which position of the ring the chlorine atom occurs in the process according to the invention. The barbituric acid derivatives used as starting materials in the known process must be substituted in both the 3-position and the 5-position; it stays thus no other possibility than that the chlorine enters the 6-position.
Beispiel 1 1 -Methyl-4-chloruracil 28,4 g 1-Methylbarbitursäure (0,2 Mol) wurden nach Zusatz von 27 ml Wasser (1,5 Mol) mit 200 ml Phosphoroxychlorid (etwa 2 Mol) versetzt, wobei sich nach wenigen Minuten eine klare, fast farblose Lösung bildete. Diese wurde 1 Stunde unter Rückfluß gekocht und anschließend das überschüssige Phosphoroxychlorid auf dem Wasserbad im Vakuum abdestilliert. Der hellgelbe sirupöse Rückstand wurde auf Eis gegossen, wobei l-Methyl-4-chloruracil in farblosen Kristallen ausschied. Die Kristalle wurden abgesaugt und einige Male mit destilliertem Wasser gewaschen, bis das Waschwasser neutral reagierte. Example 1 1-methyl-4-chloruracil 28.4 g of 1-methylbarbituric acid (0.2 Mol) were after addition of 27 ml of water (1.5 mol) with 200 ml of phosphorus oxychloride (about 2 mol) added, after a few minutes a clear, almost colorless Solution formed. This was refluxed for 1 hour and then the Excess phosphorus oxychloride is distilled off on a water bath in vacuo. Of the pale yellow syrupy residue was poured onto ice, l-methyl-4-chloruracil precipitated in colorless crystals. The crystals were sucked off and several times washed with distilled water until the wash water reacted neutrally.
F. 276 bis 277"C (nach 2stündigem Trocknen bei 1000C). F. 276 to 277 "C (after drying at 1000C for 2 hours).
Ausbeute: 24 g (760/0 der Theorie). Yield: 24 g (760/0 of theory).
Analyse: Gefunden C 37,38, H 3,23, N 17,44, Cl 2l,430/o; berechnet C 37,38, H 3,11, N 17,44, Cl 21,21010. Analysis: Found C 37.38, H 3.23, N 17.44, Cl 2l, 430 / o; calculated C 37.38, H 3.11, N 17.44, Cl 21.21010.
Beispiel 2 1 -Äthyl-4-chloruracil 31,2 g 1 -Äthylbarbitursäure (0,2 Mol) wurden nach Zusatz von 27 ml Wasser (1,5 Mol) mit 200 ml Phosphoroxychlorid (etwa 2 Mol) versetzt und die entstandene klare Lösung 1 Stunde unter Rückfluß gekocht, das überschüssige Phosphoroxychlorid im Vakuum abdestilliert und der hellgelbe viskose Rückstand auf Eis gegossen. Ein Teil des l-Äthyl-4-chloruracils fiel kristallin aus und wurde durch Filtration von der Flüssigkeit getrennt. Das Filtrat wurde mit 5 30 ml Chloroform extrahiert und das Chloroform abdestilliert. Example 2 1-ethyl-4-chloruracil 31.2 g 1-ethylbarbituric acid (0.2 Mol) were after addition of 27 ml of water (1.5 mol) with 200 ml of phosphorus oxychloride (about 2 mol) added and the resulting clear solution refluxed for 1 hour, the excess phosphorus oxychloride is distilled off in vacuo and the light yellow viscous Poured residue onto ice. Part of the 1-ethyl-4-chloruracil precipitated in crystalline form and was separated from the liquid by filtration. The filtrate was with 5 extracted 30 ml of chloroform and the chloroform was distilled off.
Aus dem Rückstand wurde das 1-Äthyl-4-chloruracil durch fraktionierte Kristallisation aus Wasser gewonnen. F. 215 bis 217"C. The 1-ethyl-4-chloruracil was fractionated from the residue Crystallization obtained from water. F. 215 to 217 "C.
Ausbeute: 21,8 g (600/0 der Theorie). Yield: 21.8 g (600/0 of theory).
Analyse: Gefunden C 42,60, H 4,00, N 16,03, Cl 19,980/0; berechnet C 41,38, H 4,02, N 16,09, Cl 20,100/0.Analysis: Found C 42.60, H 4.00, N 16.03, Cl 19.980 / 0; calculated C 41.38, H 4.02, N 16.09, Cl 20,100 / 0.
Beispiel 3 1 -Phenyl-4-chloruracil 20,4 g l-Phenylbarbitursäure wurden nach Zusatz von 27 ml Wasser (1,5 Mol) mit 200 ml Phosphoroxychlorid (etwa 2 Mol) versetzt und 2 Stunden unter Rückfluß gekocht. Das überschüssigePhosphoroxychlorid wurde ab destilliert und der hellgelbe Rückstand auf Eis gegossen. Das 1-Phenyl-4-chloruracil schied sich dabei kristallin aus. Die Kristalle wurden abgesaugt und einige Male mit destilliertem Wasser gewaschen, bis das Wasser neutral reagierte. Example 3 1-phenyl-4-chloruracil 20.4 g of 1-phenylbarbituric acid were used after adding 27 ml of water (1.5 mol) with 200 ml of phosphorus oxychloride (about 2 mol) added and refluxed for 2 hours. The excess phosphorus oxychloride was distilled off and the pale yellow residue poured onto ice. The 1-phenyl-4-chloruracil precipitated in crystalline form. The crystals were sucked off and several times washed with distilled water until the water reacted neutral.
F. 214°C (nach 2stündigem Trocknen im Trockenschrank bei 100"C).Mp 214 ° C (after drying for 2 hours in a drying cabinet at 100 ° C).
Ausbeute: 17,0 g (830/0 der Theorie). Yield: 17.0 g (830/0 of theory).
Analyse: Molekulargewicht 222,5.Analysis: molecular weight 222.5.
Gefunden C 53,63, H 3,14, N 12,61, C1 lS,900/o; berechnet C 53,60, H 3,15, N 12,61, C1 15,850/0. Found C 53.63, H 3.14, N 12.61, C1 IS, 900 / o; calculated C 53.60, H 3.15, N 12.61, C1 15.850 / 0.
Beispiel 4 1-Benzyl-4-chloruracil 21,8 g 1-Benzylbarbitursäure (0,1 Mol) wurden nach Zusatz von 27 ml Wasser (1,5 Mol) mit 200 ml Phosphoroxychlorid (etwa 2 Mol) versetzt und die entstandene klare Lösung 11/2 Stunden unter Rückfluß gekocht. Nach Beendigung der Reaktion wurde das überschüssige Phosphoroxychlorid im Vakuum abdestilliert. Der hellgelbe sirupartige Rückstand wurde auf Eis gegossen, wobei 1-Benzyl-4-chloruracil als weiße Substanz kristallin ausschied. Die Kristalle wurden abgesaugt und so lange mit Wasser gewaschen, bis das Waschwasser neutral reagierte. Example 4 1-Benzyl-4-chloruracil 21.8 g of 1-benzylbarbituric acid (0.1 Mol) were after the addition of 27 ml of water (1.5 mol) with 200 ml Phosphorus oxychloride (about 2 mol) are added and the resulting clear solution is refluxed for 11/2 hours cooked. After the completion of the reaction, the excess phosphorus oxychloride became distilled off in vacuo. The light yellow syrupy residue was poured onto ice, 1-Benzyl-4-chloruracil precipitated as a white substance in crystalline form. The crystals were suctioned off and washed with water until the wash water was neutral responded.
Zwecks Reinigung wurde die Substanz aus Wasser umkristallisiert. F. 196 bis 198"C (nach 2stündigem Trocknen im Trockenschrank bei 100"C).For the purpose of purification, the substance was recrystallized from water. F. 196 to 198 "C (after drying in a drying cabinet at 100" C for 2 hours).
Ausbeute: 19,8 g. Yield: 19.8 g.
Analyse: Gefunden C 56,49, H 3,88, N 10,77, C1 l4,710/o; berechnet C 56,00, H 3,87, N 10,44, Cl 14,820/0.Analysis: Found C 56.49, H 3.88, N 10.77, Cl 14.710 / o; calculated C 56.00, H 3.87, N 10.44, Cl 14.820 / 0.
Claims (1)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DER29093A DE1139505B (en) | 1960-11-16 | 1960-11-16 | Process for the preparation of 4-chlorouracils substituted in the 1-position |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DER29093A DE1139505B (en) | 1960-11-16 | 1960-11-16 | Process for the preparation of 4-chlorouracils substituted in the 1-position |
Publications (1)
Publication Number | Publication Date |
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DE1139505B true DE1139505B (en) | 1962-11-15 |
Family
ID=7402906
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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DER29093A Pending DE1139505B (en) | 1960-11-16 | 1960-11-16 | Process for the preparation of 4-chlorouracils substituted in the 1-position |
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DE (1) | DE1139505B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1296636B (en) * | 1963-07-20 | 1969-06-04 | Robugen Gmbh | Process for the preparation of chloropyrimidines |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE543024C (en) * | 1930-12-04 | 1932-01-30 | Hoffmann La Roche & Co Akt Ges | Process for the preparation of derivatives of 6-halo-2, 4-diketotetrahydropyrimidine |
-
1960
- 1960-11-16 DE DER29093A patent/DE1139505B/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE543024C (en) * | 1930-12-04 | 1932-01-30 | Hoffmann La Roche & Co Akt Ges | Process for the preparation of derivatives of 6-halo-2, 4-diketotetrahydropyrimidine |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1296636B (en) * | 1963-07-20 | 1969-06-04 | Robugen Gmbh | Process for the preparation of chloropyrimidines |
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