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Details for Patent: 7,820,815

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Details for Patent: 7,820,815

Title:Process for the preparation of chiral 8-(-3-aminopiperidin-1-yl) xanthines
Abstract: The invention relates to an improved process for preparing enantiomerically pure 8-(3-aminopiperidin-1-yl)-xanthines. The process involves reacting a compound of the formula (III) with 3-(phthalimido)piperidine or an enantiomer thereof ##STR00001## where X is a leaving group selected from halogens and sulphonic ester acid residues, and R.sup.1 to R.sup.3 are as defined herein, to obtain a compound of the formula (II) ##STR00002## and deprotecting the obtained compound of the formula (II) to obtain the product xanthines.
Inventor(s): Pfrengle; Waldemar (Biberach, DE), Pachur; Thorsten (Schwendi, DE), Nicola; Thomas (Ingelheim, DE), Duran; Adil (Rissegg, DE)
Assignee: Boehringer Ingelheim International GmbH (Ingelheim am Rhein, DE)
Filing Date:Nov 04, 2005
Application Number:11/267,235
Claims:1. A process for preparing a compound of the general formula (I) ##STR00017## or an enantiomer or salt thereof, wherein R.sup.1 is a phenylcarbonylmethyl, benzyl, naphthylmethyl, pyridinylmethyl, pyrimidinylmethyl, quinolinylmethyl, isoquinolinylmethyl, quinazolinylmethyl, quinoxalinylmethyl, naphthyridinylmethyl or phenanthridinylmethyl group in which the aromatic or heteroaromatic moiety is in each case mono- or disubstituted by R.sub.a, where the substituents may be the same or different and R.sub.a is a hydrogen, cyano, methyl, trifluoromethyl, ethyl, phenyl, methoxy, difluoromethoxy, trifluoromethoxy or ethoxy group, or two R.sub.a radicals that are bonded to adjacent carbon atoms, may also be an --O--CH.sub.2--O-- or --O--CH.sub.2--CH.sub.2--O-- group, R.sup.2 is a methyl, ethyl, propyl, isopropyl, cyclopropyl or phenyl group; and R.sup.3 is a 2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-butin-1-yl, 2-fluorobenzyl, 2-chlorobenzyl, 2-bromobenzyl, 2-iodobenzyl, 2-methylbenzyl, 2-(trifluoromethyl)benzyl or 2-cyanobenzyl group, the process comprising: reacting a compound of the general formula (III) with 3-(phthalimido)piperidine or an enantiomer thereof ##STR00018## wherein X is a leaving group selected from the group consisting of halogens phenylsulphonyloxy, p-toluenesulphonyloxy, methylsulphonyloxy and trifluoromethylsulphonyloxy, and R.sup.1 to R.sup.3 are as defined above to obtain a compound of the general formula (II) ##STR00019## wherein R.sup.1 to R.sup.3 are each defined as mentioned above; and deprotecting the obtained compound of the general formula (II) to obtain the compound of general formula (I).

2. The process according to claim 1, further comprising converting the compound of general formula (I) to a physiologically tolerated salt.

3. The process according to claim 1, wherein X is chlorine or bromine; R.sup.1 is a phenylcarbonylmethyl, benzyl, naphthylmethyl, pyridinylmethyl, pyrimidinylmethyl, quinolinylmethyl, isoquinolinylmethyl, quinazolinylmethyl, quinoxalinylmethyl, or naphthyridinylmethyl group, in which the aromatic or heteroaromatic moiety is in each case mono- or disubstituted by R.sub.a, where the substituents may be the same or different, and R.sub.a is a hydrogen, cyano, methyl, ethyl, methoxy, or ethoxy group; R.sup.2 is a methyl, ethyl, propyl, isopropyl, cyclopropyl or phenyl group; and R.sup.3 is a 2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-butin-1-yl, 2-fluorobenzyl, 2-chlorobenzyl, 2-bromobenzyl, 2-iodobenzyl, 2-methylbenzyl, 2-(trifluoromethyl)benzyl or 2-cyanobenzyl group.

4. The process according to claim 1, wherein X is chlorine or bromine, R.sup.1 is a cyanobenzyl, (cyanopyridinyl)methyl, quinolinylmethyl, (methylquinolinyl)methyl, isoquinolinylmethyl, (methylisoquinolinyl)methyl, quinazolinylmethyl, (methylquinazolinyl)methyl, quinoxazinylmethyl, (methylquinoxalinyl)methyl, (dimethylquinoxalinyl)methyl, or naphthyridinylmethyl group, and R.sup.2 is a methyl, cyclopropyl, or phenyl group; and R.sup.3 is a 2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-butin-1-yl, 2-chlorobenzyl, 2-bromobenzyl or 2-cyanobenzyl group.

5. The process according to claim 1, wherein X is bromine, R.sup.1 is a (4-methylquinazolin-2-yl)methyl, (3-methylisoquinolin-1-yl)methyl, or (3-cyanopyridin-2-yl)methyl group, R.sup.2 is a methyl group; and R.sup.3 is a 2-butin-1-yl group.

6. The process according to claim 1, wherein the compound of the formula (III) is reacted with (R)-3-(phthalimido)piperidine.

7. The process according to claim 1 wherein X is a leaving group selected from the group consisting of halogens.

8. The process according to claim 5, wherein said 3-(phthalimido)piperidine is (R)-3-(phthalimido)piperidine.

9. The process according to claim 1, wherein X is bromine, R.sup.1 is a (4-methylquinazolin-2-yl)methyl group, R.sup.2 is a methyl group, and R.sup.3 is a 2-butin-1-yl group.

10. The process according to claim 9, wherein said 3-(phthalimido)piperidine is (R)-3-(phthalimido)piperidine.

11. The process according to claim 10 further comprising crystallizing the compound of formula (I) from a methanol or ethanol solution.

12. The process according to claim 11 wherein the solution further comprises tert-butyl methyl ether.

13. The process according to claim 10 further comprising crystallizing the compound of formula (I) from ethanol.
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