DE1113696B - Process for the preparation of 1,3-disubstituted or 1,3,8-trisubstituted 9-methylisoxanthines - Google Patents
Process for the preparation of 1,3-disubstituted or 1,3,8-trisubstituted 9-methylisoxanthinesInfo
- Publication number
- DE1113696B DE1113696B DEC19652A DEC0019652A DE1113696B DE 1113696 B DE1113696 B DE 1113696B DE C19652 A DEC19652 A DE C19652A DE C0019652 A DEC0019652 A DE C0019652A DE 1113696 B DE1113696 B DE 1113696B
- Authority
- DE
- Germany
- Prior art keywords
- xanthines
- compound
- general formula
- methylation
- methylisoxanthines
- 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 15
- 238000002360 preparation method Methods 0.000 title claims description 3
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 claims description 11
- 230000011987 methylation Effects 0.000 claims description 8
- 238000007069 methylation reaction Methods 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 229940065721 systemic for obstructive airway disease xanthines Drugs 0.000 claims description 5
- 230000004048 modification Effects 0.000 claims description 3
- 238000012986 modification Methods 0.000 claims description 3
- 150000003839 salts Chemical group 0.000 claims description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims 1
- 238000005984 hydrogenation reaction Methods 0.000 claims 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims 1
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 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
- 239000000047 product Substances 0.000 description 6
- -1 1-hexyl-3-methyl-8-ethylxanthine Chemical compound 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 2
- 229940073608 benzyl chloride Drugs 0.000 description 2
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- WZSPDGAUNTWDMP-UHFFFAOYSA-N 1-hexyl-3-methyl-7h-purine-2,6-dione Chemical compound O=C1N(CCCCCC)C(=O)N(C)C2=C1NC=N2 WZSPDGAUNTWDMP-UHFFFAOYSA-N 0.000 description 1
- WHZOIDLYAIURJP-UHFFFAOYSA-N 7-(methoxymethyl)-1,3-dimethylpurine-2,6-dione Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2COC WHZOIDLYAIURJP-UHFFFAOYSA-N 0.000 description 1
- 241000272525 Anas platyrhynchos Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000000944 Soxhlet extraction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- HRQGCQVOJVTVLU-UHFFFAOYSA-N bis(chloromethyl) ether Chemical compound ClCOCCl HRQGCQVOJVTVLU-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verfahren zur Herstellung i,3-disubstituierter oder 1,3,8-trisubstituierter 9-Methylisoxanthine In 9-Stellung alkylierte Xanthine (Isoxanthine) werden gemäß deutscher Patentschrift 120437 über die entsprechenden Thioharnsäuren hergestellt; auch F. Blicke und R. Schaaf (Journal of the American Chemical Society, Bd. 78 [1956], 5. 5857 bis 5863) arbeiten nach dem gleichen Verfahren und stellen z. B. das 1 ,3,9-Trimethylisoxanthin aus 1,3,8,9-Tetramethylthioisoxanthin her (a. a. O. S. 5863, rechte Spalte, Absatz 2). Abgesehen davon, daß die 9-Alkylthioharnsäuren erst aus Uramilen aufgebaut werden müssen, sind auch die Ausbeuten gering, z. B. im Falle des 1,3,9-Trimethylisoxanthins 25O/o. Process for the preparation of i, 3-disubstituted or 1,3,8-trisubstituted 9-Methylisoxanthines Xanthines (isoxanthines) alkylated in the 9-position are according to German Patent 120437 produced on the corresponding thiouric acids; also F. Blick and R. Schaaf (Journal of the American Chemical Society, Vol. 78 [1956], 5. 5857 to 5863) work according to the same procedure and provide e.g. B. the 1, 3,9-trimethylisoxanthine from 1,3,8,9-tetramethylthioisoxanthin (loc. cit. p. 5863, right column, paragraph 2). Apart from the fact that the 9-alkylthiouric acids are only built up from Uramils must, the yields are low, z. B. in the case of 1,3,9-trimethylisoxanthine 25O / o.
Biltz beschreibt die Bildung zweier 8-Methylisoxanthine, die er durch Methylierung von 9-Methylisoxanthin (Annalen der Chemie, Bd. 423 [1921], S. 211) und von 1,3,9-Trimethylisoxanthin (berichte der Deutschen Chemischen Gesellschaft«, Bd. 64 [1931], S. 765) erhielt. Die Ausbeute ist aber wenig befriedigend, im ersten Falle beträgt sie etwa 300/0, im zweiten sogar nur etwa 70/o. Höhere Alkylreste oder Arylgruppen in 8-Stellung lassen sich nach dieser Methode ebenfalls nicht einführen. Biltz describes the formation of two 8-methylisoxanthines, which he caused Methylation of 9-methylisoxanthine (Annalen der Chemie, Vol. 423 [1921], p. 211) and of 1,3,9-trimethylisoxanthine (reports of the German Chemical Society ", Vol. 64 [1931], p. 765). But the yield is not very satisfactory in the first one In the second case it is about 300/0, in the second even only about 70 / o. Higher alkyl radicals or aryl groups in the 8-position cannot be introduced by this method either.
In neuerer Zeit haben Bredereck und Mitarbeiter durch Methylieren des 4-Amino-5-acetaminouracils in 20 0/o Ausbeute das 4-Methyl-5-acetamino-l,3-dimethyluracil erhalten, das sich mit Acetamid in das schon von Biltz erhaltene 1 ,3,8,9-Tetramethylisoxanthin überführen läßt («Berichte der Deutschen Chemischen Gesellschaft«, Bd. 86 [1953], S. 334 bis 336). Wenn sich das Verfahren sicher auch auf andere Säureamide erweitern läßt und man auf diese Weise verschiedene Substituenten in 8-Stellung einführen kann, so verhindert die mangelhafte Ausbeute anAusgangssubstanz eine Auswertung für gewerbliche Zwecke. In more recent times, Bredereck and coworkers have made methylation through of 4-amino-5-acetaminouracil in 20% yield is 4-methyl-5-acetamino-1,3-dimethyluracil obtained, which is converted with acetamide into the 1, 3,8,9-tetramethylisoxanthine already obtained from Biltz can be transferred ("Reports of the German Chemical Society", Vol. 86 [1953], Pp. 334 to 336). If the process can certainly be extended to other acid amides as well and introducing various substituents in the 8-position in this way can, the inadequate yield of starting substance prevents an evaluation for commercial purposes.
Es wurde nun gefunden, daß man 1,3-disubstituierte oder I ,3,8-trisubstituierte 9-Methylisoxanthine dadurch herstellen kann, daß man 1,3-dialkylierte oder 1 ,3,8-trialkylierte Xanthine zunächst in der 7-Stellung mit einer Verbindung der allgemeinen Formel R-CH2-X in der R eine Phenylgruppe und X ein Halogenatom bedeutet, umsetzt, dann in an sich bekannter Weise in 9-Stellung zum quaternären Salz methyliert und anschließend die Benzylgruppe in 7-Stellung durch katalytische Hydrierung entfernt. It has now been found that 1,3-disubstituted or 1,3,8-trisubstituted 9-Methylisoxanthine can be prepared by 1,3-dialkylated or 1, 3,8-trialkylated Xanthines initially in the 7-position with a compound of the general formula R-CH2-X in which R is a phenyl group and X is a halogen atom, then methylated in a manner known per se in the 9-position to the quaternary salt and then the benzyl group in the 7-position is removed by catalytic hydrogenation.
In Abänderung dieses Verfahrens kann man die entsprechenden Xanthine in 7-Stellung mit einer Verbindung der oben angegebenen allgemeinen Formel, worin R eine Methoxygruppe darstellt und X die oben angegebene Bedeutung hat, umsetzen und nach der Methylierung in 9-Stellung die Methoxymethylgruppe in 7-Stellung durch saure Hydrolyse abspalten. In modification of this procedure one can use the corresponding xanthines in the 7-position with a compound of the general formula given above, in which R represents a methoxy group and X has the meaning given above and after the Methylation in the 9-position by the methoxymethyl group in the 7-position split off acid hydrolysis.
Als weitere Ausbildung des beanspruchten Verfahrens kann man 2 Mol der entsprechenden Xanthine mit 1 Mol einer Verbindung der oben angegebenen allgemeinen Formel, worin R und X Halogenatome bedeuten, umsetzen und nach Methylierung in 9-Stellung der beiden in 7,7'-Stellung durch einen Methylenrest verknüpften Xanthinreste die Methylenbrücke hydrolytisch abspalten. As a further development of the claimed process can be 2 mol of the corresponding xanthines with 1 mole of a compound of the general above Formula in which R and X are halogen atoms, convert and after methylation in the 9-position of the two xanthine residues linked in the 7,7'-position by a methylene residue Split off the methylene bridge hydrolytically.
Das Verfahren verläuft somit über folgende Stufen: a) Blockierung der 7-Stellung, b) Methylierung in 9-Stellung, c) Entfernung des bei a) in 7-Stellung eingeführten Substituenten. The process thus proceeds through the following stages: a) Blocking the 7-position, b) methylation in the 9-position, c) removal of that in a) in the 7-position introduced substituents.
Wenn R und X Halogenatome sind, werden in Stufe a) zwei Xanthinreste durch eine Methylenbrücke in 7-Stellung verbunden, so daß beide Molekülhälften in 7-Stellung blockiert sind. Dieses dimolekulare Produkt wird bei der späteren Hydrolyse (Stufe c) zu den entsprechenden, in 9-Stellung substituierten Isoxanthinen aufgespalten. When R and X are halogen atoms, two xanthine residues are formed in step a) connected by a methylene bridge in the 7-position, so that both halves of the molecule in 7 position are blocked. This dimolecular product becomes during the later hydrolysis (Step c) split to the corresponding isoxanthines substituted in the 9-position.
Das Verfahren gemäß vorliegender Erfindung ergibt wesentlich höhere Ausbeuten (etwa 60 bis über 900/o der Theorie) als die bisher bekannten Methoden; es erlaubt auch, gleichfalls im Gegensatz zu den bekannten Verfahren, die Herstellung in 8-Stellung substituierter Isoxanthine. The method of the present invention yields much higher Yields (about 60 to over 900 / o of theory) than the previously known methods; it also allows production, likewise in contrast to the known processes Isoxanthines substituted in the 8-position.
Die erfindungsgemäß hergestellten Isoxanthinderivate sind therapeutisch verwertbar, z. B. als Diuretika; sie können auch als Zwischenprodukte für weitere pharmazeutische Präparate dienen. The isoxanthine derivatives prepared according to the invention are therapeutic usable, e.g. B. as diuretics; they can also be used as intermediates for further pharmaceutical preparations are used.
Beispiel 1 l-Hexyl-3,9-dimethyl-8-äthylisoxanthin a) Ein Gemisch aus 56 g 1-Hexyl-3-methyl-8-äthylxanthin, 150 ccm Isopropanol und 60 ccm 4 n-Natronlauge wird unter Rückfluß erhitzt, bis sich eine klare Lösung ergeben hat. Dann gibt man 35 g Benzylchlorid hinzu und kocht 8 Stunden. Man entfernt das Isopropanol im Vakuum, versetzt mit 400 ccm 8 n-Sa1zsäure und vertreibt das überschüssige Benzylchlorid durch azeotrope Destillation bei einem Druck von 100 mm Quecksilbersäule. Das stark eingeengte Reaktionsgemisch wird in Wasser eingetragen und mit wenig Natronlauge alkalisch gestellt. Beim Antreiben kristallisiert das l-Hexyl-3-methyl-7-benzyl-8-äthylxanthin; es wird fein zerrieben und nach dem Absaugen mit Wasser gewaschen. Die Ausbeute beträgt 70 g = 95°/0 der Theorie. Der Schmelzpunkt von 60 bis 64"C steigt nach dem Umkristallisieren aus verdünntem Methanol auf 65 bis 66"C. b) 37 g 1-Hexyl-3-methyl-7-benzyl-8-äthylxanthin werden mit 20 ccm Dimethylsulfat 5 Stunden auf 1000 C erwärmt. Durch Zugabe von 200 ccm Methanol erhält man eine Lösung des l-Hexyl-3,9-dimethyl-7 - benzyl - 8 - äthylxanthinium-methylsulfats, das als solches nicht isoliert wird. c) Die so erhaltene Lösung wird mit Tierkohle und 10 ccm l00/0iger Palladiumchloridlösung versetzt und in der Schüttelente unter Überdruck hydriert; in 5 Stunden ist die theoretische Menge von 2,241 Wasserstoff aufgenommen. Nach Absaugen und Auswaschen des Katalysators mit Methanol wird das Filtrat stark eingeengt, mit Wasser verdünnt und mit Ammoniak gefällt. Nach Absaugen und Trocknen erhält man 27 g 1-Hexyl-3,9-dimethyl-8-äthylisoxanthin vom Schmelzpunkt 146 bis 148"C (92°/o der Theorie). Example 1 l-Hexyl-3,9-dimethyl-8-ethylisoxanthine a) A mixture from 56 g of 1-hexyl-3-methyl-8-ethylxanthine, 150 cc of isopropanol and 60 cc of 4N sodium hydroxide solution is refluxed until a clear solution has resulted. Then you give Add 35 g of benzyl chloride and cook for 8 hours. The isopropanol is removed in vacuo, mixed with 400 ccm of 8 n-hydrochloric acid and drives off the excess benzyl chloride by azeotropic distillation at a pressure of 100 mm of mercury. That strong The concentrated reaction mixture is poured into water and mixed with a little sodium hydroxide solution made alkaline. The l-hexyl-3-methyl-7-benzyl-8-ethylxanthine crystallizes on driving; it is finely ground and washed with water after suction. The yield is 70 g = 95% of theory. The melting point of 60 to 64 "C rises after the Recrystallization from dilute methanol to 65 to 66 ° C. b) 37 g of 1-hexyl-3-methyl-7-benzyl-8-ethylxanthine are heated to 1000 C for 5 hours with 20 cc of dimethyl sulfate. By adding A solution of 1-hexyl-3,9-dimethyl-7-benzyl-8 is obtained with 200 cc of methanol - ethylxanthinium methyl sulfate, which is not isolated as such. c) The so The solution obtained is mixed with animal charcoal and 10 ccm 100/0 palladium chloride solution added and hydrogenated in the shaking duck under excess pressure; in 5 hours it will be theoretical amount of 2.241 hydrogen added. After suctioning off and washing out of the catalyst with methanol, the filtrate is strongly concentrated and diluted with water and precipitated with ammonia. After filtering off with suction and drying, 27 g of 1-hexyl-3,9-dimethyl-8-ethylisoxanthine are obtained from the melting point 146 to 148 "C (92% of theory).
Durch Umkristallisieren aus Isopropanol steigt der Schmelzpunkt auf 149 bis 150"C. Die Gesamtausbeute beträgt 87 °/o der Theorie.The melting point rises through recrystallization from isopropanol 149 to 150 "C. The total yield is 87% of theory.
Beispiel 2 1,3,9-Trimethylisoxanthin a) Ein Gemisch aus 18 g Theophyllin, 27,6 g Kaliumcarbonat und 200 ccm Aceton wird unter Rühren 1 Stunde zum Sieden erhitzt. Danach tropft man in der Hitze innerhalb von 30 Minuten 16 ccm Chlormethyläther zu, läßt weitere 30 Minuten kochen und dann erkalten. Danach wird abgesaugt und der Filterrückstand im soxhletschen Extraktionsapparat mit Aceton extrahiert. Das aus dem Extrakt abgeschiedene Produkt wird abgesaugt und mit Aceton gewaschen. Example 2 1,3,9-Trimethylisoxanthine a) A mixture of 18 g of theophylline, 27.6 g of potassium carbonate and 200 cc of acetone are heated to boiling for 1 hour while stirring. Then 16 ccm of chloromethyl ether are added dropwise in the heat within 30 minutes let it cook for another 30 minutes and then cool. Then it is sucked off and the filter residue is extracted with acetone in the Soxhlet extraction apparatus. That Product separated from the extract is filtered off with suction and washed with acetone.
Man erhält 19,5 g 7-Methoxymethyltheophyllin (1,3-Dimethyl-7-methoxymethyl-xanthin) = 870/o derTheorie; der Schmelzpunkt beträgt 170 bis 173"C. b) 11,2 g dieses Produktes werden mit 20 ccm Dimethylsulfat versetzt und 5 Minuten auf 130"C gehalten. Man erhält eine Lösung des 1,3,9-Trimethyl-7-methoxymethyl-xanthiniummethylsulfats, das nicht isoliert wird. c) Die so erhaltene Reaktionslösung, die von der Methylierung her freie Säure erhält, wird unter Zusatz von 50 ccm Wasser 15 Minuten zu gelindem Sieden erhitzt und dann mit 50 ccm Ammoniak (Dichte 0,91) versetzt. Danach wird abgesaugt und der Rückstand mit wenig Wasser gewaschen. Man erhält 7,5 g 1,3,9-Trimethylisoxanthin = 770/ der Theorie. Der Schmelzpunkt liegt bei 278" C. Durch Umkristallisieren erhält man 670/o der theoretischen Ausbeute an reinem Produkt, dessen Schmelzpunkt 285 bis 287"C beträgt.19.5 g of 7-methoxymethyltheophylline (1,3-dimethyl-7-methoxymethyl-xanthine) are obtained = 870 / o of theory; the melting point is 170 to 173 "C. b) 11.2 g of this product 20 cc of dimethyl sulfate are added and the mixture is kept at 130 ° C. for 5 minutes receives a solution of 1,3,9-trimethyl-7-methoxymethyl-xanthinium methyl sulfate, that is not isolated. c) The reaction solution thus obtained from the methylation When free acid is obtained, it is mild with the addition of 50 cc of water for 15 minutes Heated to the boil and then mixed with 50 ccm of ammonia (density 0.91). After that, will suctioned off and the residue washed with a little water. 7.5 g of 1,3,9-trimethylisoxanthine are obtained = 770 / the theory. Of the Melting point is 278 "C. Obtained by recrystallization one 670 / o of the theoretical yield of pure product, the melting point of which is 285 to 287 "C.
Beispiel 3 l-Hexyl-3,9-dimethylisoxanthin a) 10 g l-Hexyl-3-methylxanthin werden mit 7 g Methylenbromid, 9 g Kaliumcarbonat und 30ccm Methyläthylketon 4 Stunden unter Rühren am Sieden gehalten. Das Reaktionsgemisch wird anschließend mit viel Wasser versetzt, daß die anorganischen Salze in Lösung gehen, dann wird weiter verdünnt. Beim Abdestillieren der überschüssigen Anteile Methyläthylketon und Methylenbromid kristallisiert l,l'-Dihexyl-3,3'-dimethyl-7,7'-methylendixanthin aus. Nach dem Waschen mit Wasser verbleiben 9,5 g (= 92 0/o der Theorie) gereinigtes Produkt mit dem Schmelzpunkt von 164 bis 168"C. b) 7 g des so erhaltenen Produktes werden mit 8 ccm Dimethylsulfat 5 Minuten auf 130"C erhitzt, wobei man eine klare Lösung des in 9,9'-Stellung methylierten Produktes erhält. c) Diese noch warme Lösung wird mit 50 ccm Wasser versetzt und 30 Minuten bei schwachem Sieden gehalten. Nach dem Erkalten wird mit Ammoniak schwach alkalisch gemacht; dabei fallen 6,5 g (= 90 °/0 der Theorie) l-Hexyl-3,9-dimethyl-isoxanthin mit dem Schmelzpunkt 143"C aus. Durch Umkristallisieren aus Isopropanol steigt der Schmelzpunkt auf 144 bis 146° C. Example 3 1-Hexyl-3,9-dimethylisoxanthine a) 10 g of 1-hexyl-3-methylxanthine are with 7 g of methylene bromide, 9 g of potassium carbonate and 30ccm of methyl ethyl ketone for 4 hours kept at the boil with stirring. The reaction mixture is then with a lot Water is added so that the inorganic salts go into solution, then the mixture is further diluted. When distilling off the excess methyl ethyl ketone and methylene bromide l, l'-dihexyl-3,3'-dimethyl-7,7'-methylendixanthine crystallizes out. After washing with water, 9.5 g (= 92% of theory) of purified product with the melting point remain from 164 to 168 "C. b) 7 g of the product thus obtained are mixed with 8 cc of dimethyl sulfate Heated to 130 ° C. for 5 minutes, a clear solution of the methylated in the 9,9'-position Product. c) This still warm solution is mixed with 50 ccm of water and Maintained at a low boil for 30 minutes. After cooling, ammonia becomes weak made alkaline; 6.5 g (= 90 ° / 0 of theory) of 1-hexyl-3,9-dimethyl-isoxanthine fall in the process with a melting point of 143 ° C. Recrystallization from isopropanol increases the Melting point at 144 to 146 ° C.
Claims (3)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEC19652A DE1113696B (en) | 1959-08-21 | 1959-08-21 | Process for the preparation of 1,3-disubstituted or 1,3,8-trisubstituted 9-methylisoxanthines |
| DEC23775A DE1140581B (en) | 1959-08-21 | 1961-03-29 | Process for the preparation of 1,3,8-trisubstituted 9-methylisoxanthines |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEC19652A DE1113696B (en) | 1959-08-21 | 1959-08-21 | Process for the preparation of 1,3-disubstituted or 1,3,8-trisubstituted 9-methylisoxanthines |
| DEC23775A DE1140581B (en) | 1959-08-21 | 1961-03-29 | Process for the preparation of 1,3,8-trisubstituted 9-methylisoxanthines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1113696B true DE1113696B (en) | 1961-09-14 |
Family
ID=33098954
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEC19652A Pending DE1113696B (en) | 1959-08-21 | 1959-08-21 | Process for the preparation of 1,3-disubstituted or 1,3,8-trisubstituted 9-methylisoxanthines |
| DEC23775A Pending DE1140581B (en) | 1959-08-21 | 1961-03-29 | Process for the preparation of 1,3,8-trisubstituted 9-methylisoxanthines |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEC23775A Pending DE1140581B (en) | 1959-08-21 | 1961-03-29 | Process for the preparation of 1,3,8-trisubstituted 9-methylisoxanthines |
Country Status (1)
| Country | Link |
|---|---|
| DE (2) | DE1113696B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0077896B1 (en) * | 1981-08-27 | 1989-01-25 | Miles Inc. | Theophylline derivatives, antibodies and their preparation from theophylline immunogens, as well as an immuno assay method and reagent means for determining theophylline |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5032593A (en) * | 1988-07-01 | 1991-07-16 | Marion Merrell Dow Inc. | Method of treating bronchoconstriction with 1,3-unsymmetrical straight chain alkyl-substituted 8-phenylxanthines |
-
1959
- 1959-08-21 DE DEC19652A patent/DE1113696B/en active Pending
-
1961
- 1961-03-29 DE DEC23775A patent/DE1140581B/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| None * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0077896B1 (en) * | 1981-08-27 | 1989-01-25 | Miles Inc. | Theophylline derivatives, antibodies and their preparation from theophylline immunogens, as well as an immuno assay method and reagent means for determining theophylline |
Also Published As
| Publication number | Publication date |
|---|---|
| DE1140581B (en) | 1962-12-06 |
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