Process for preparing xanthine derivatives, in particular 1,3-di

Details Process for preparing xanthine derivatives, in particular 1,3-di Process for preparing xanthine derivatives, in particular 1,3-di

1995-03-07

1997-10-07

Berch, Mark L.

Organic compounds -- part of the class 532-570 series

Organic compounds

Chalcogen bonded directly to ring carbon of the purine ring...

544267, 544268, 544272, 544273, 544311, 549333, C07D47306, C07D47308, C07D40512, C07D47304

Patent

active

056750056

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to an improved process for preparing xanthine derivatives substituted in the 8-position.
Xanthine derivatives have valuable pharmacological properties as adenosine antagonists. Synthesis processes which enable xanthine derivatives to be prepared in chemically and optically high yields are of particular interest. Xanthine derivatives are usually synthesised by a ring-closure reaction of the correspondingly substituted aminouracils under alkaline conditions--such as for example aqueous sodium hydroxide solution--at elevated temperatures. In many cases at least partial racemisation takes place under these reaction conditions.
It has been shown, surprisingly, that considerably improved yields and higher product quality is obtained if cyclisation of the amido-substituted aminouracils is carried out in an aqueous organic solvent using lithium hydroxide as a base.
The process of the invention is particularly suitable for preparing xanthine derivatives of the general formula ##STR3## wherein R.sub.1 denotes hydrogen, C.sub.1 -C.sub.6 alkyl, preferably C.sub.3 -alkyl, in particular n-propyl, C.sub.3 -C.sub.6 alkenyl, preferably allyl or C.sub.3 -C.sub.6 alkynyl; -C.sub.3 alkyl, in particular n-propyl, C.sub.3 -C.sub.8 alkenyl or C.sub.3 -C.sub.8 alkynyl group, C.sub.3 -alkyl, C.sub.3 -C.sub.8 alkenyl or C.sub.3 -C.sub.8 alkynyl group, which carries one of the following groups: --OR.sub.8, --NR.sub.6 R.sub.7, --NHCOR.sub.8, --NHCONR.sub.6 R.sub.7, halogen, --OCH.sub.2 COOH, --SO.sub.2 R.sub.5, --S--R.sub.5, --NHCONH phenyl, --OCH.sub.2 CH.sub.2 OH, --OCH.sub.2 --CH.sub.2 --NR.sub.6 R.sub.7, --SO.sub.2 --CH.sub.2 --CH.sub.2 --OH, --OCH.sub.2 CH.sub.2 OR.sub.8, --COOH, --SR.sub.8, --SOR.sub.8, --SO.sub.2 R.sub.8, --SO.sub.3 H, --SO.sub.2 NR.sub.6 R.sub.7, --CH.dbd.NOH, --COR.sub.9, --CH(OH)R.sub.9, --CH(OR.sub.8).sub.2, --CH.dbd.CH--R.sub.10, ##STR4## 1,3-dioxolane or 1,3-dioxane optionally mono- or poly-substituted--preferably mono--by methyl; phenyl-C.sub.1 -C.sub.4 -alkylene, phenyl-C.sub.2 -C.sub.6 -alkenylene or phenyl-C.sub.2 -C.sub.6 -alkynylene, the phenyl ring being optionally substituted either directly or via an alkylene group having 1 to 4 C atoms, by one or more, preferably one, of the following groups, --OR.sub.8, --CH.sub.2 --NH--SO.sub.2 --R.sub.8, --NHCONR.sub.6 R.sub.7, halogen, --OCH.sub.2 COOH, --SO.sub.2 R.sub.5, --OCH.sub.2 CH.sub.2 OH, --OCH.sub.2 --CH.sub.2 --NR.sub.6 R.sub.7, --OCH.sub.2 CH.sub.2 OR.sub.8, --COOH, --CF.sub.3, cyclopropyl, --CH.sub.2 OH, --CH.sub.2 OR.sub.8, --SR.sub.8, --SOR.sub.8, --SO.sub.2 R.sub.8, --SO.sub.3 H, --SO.sub.2 NR.sub.6 R.sub.7, --COR.sub.9, --CH(OH)R.sub.9, --CH(OR.sub.8).sub.2, --CH.dbd.CH--R.sub.10, ##STR5## 1,3-dioxolane or 1,3-dioxane optionally mono- or poly-substituted by methyl; alkylene group having 1 to 4 C atoms, by --CN, --CH.sub.2 NR.sub.6 R.sub.7, .dbd.O, --OH, --OR.sub.8, --NR.sub.6 R.sub.7, halogen, --OCH.sub.2 COOH, --SO.sub.2 R.sub.5, --OCH.sub.2 CH.sub.2 OH, --OCH.sub.2 --CH.sub.2 --NR.sub.6 R.sub.7, --OCH.sub.2 CH.sub.2 OR.sub.8, --COOH, --CH.sub.2 OH, --CH.sub.2 OR.sub.8, --SR.sub.8, --SOR.sub.8, --SO.sub.2 R.sub.8, --SO.sub.3 H, --SO.sub.2 NR.sub.6 R.sub.7, --COR.sub.9, --CH(OH) R.sub.9, --CH(OR.sub.8).sub.2, --CH.dbd.CH--R.sub.10, ##STR6## 1,3-dioxolane or 1,3-dioxane optionally mono- or poly-substituted by methyl; ring containing nitrogen, oxygen or sulphur as hetero atoms, and which may be optionally mono or poly-substituted by C.sub.1 -C.sub.4 alkyl, halogen, --OR.sub.8, --NO.sub.2, --NH.sub.2, --CH.sub.2 NR.sub.6 R.sub.7, --OH, .dbd.O, a ketal, --COOH, --SO.sub.3 H, --COR.sub.9, --SO.sub.2 --R.sub.8, or ##STR7## R.sub.3 denotes an optionally substituted C-linked saturated or unsaturated five, six or seven-membered heterocyclic ring containing one or more hetero atoms selected from the group oxygen or sulphur, by C.sub.2 to C.sub.4 alkenyl, -cycloalkanone, or a C.sub.4 to C.sub.8, preferably C.sub.5 and C.sub.6 -cycloalkanol, which may be substituted in the .alpha.-position by C.sub.2 to C.sub.6, preferably

REFERENCES:
patent: 4755517 (1988-07-01), Bruns
Coelho, Tet Letters 30, 565 (1989).
Venkatachalam, Tet. Letters 27, 4111 (1986).
Nguyen, Tetrahedron 43, 527 (1987).
Horiguchi, J.A.C.S. 111, 6257 (1989).

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