Process for the preparation of chiral 8-(-3-aminopiperidin-1-yl) xanthines

1. A process for preparing a compound of the general formula (I)

or an enantiomer or salt thereof, wherein

R 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 a , where the substituents may be the same or different and

R a is a hydrogen, cyano, methyl, trifluoromethyl, ethyl, phenyl, methoxy, difluoromethoxy, trifluoromethoxy or ethoxy group, or

two R a radicals that are bonded to adjacent carbon atoms, may also be an —O—CH 2 —O— or —O—CH 2 —CH 2 —O— group,

R 2 is a methyl, ethyl, propyl, isopropyl, cyclopropyl or phenyl group; and

R 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

wherein X is a leaving group selected from the group consisting of halogens phenylsulphonyloxy, p-toluenesulphonyloxy, methylsulphonyloxy and trifluoromethylsulphonyloxy, and R 1 to R 3 are as defined above to obtain a compound of the general formula (II)

wherein R 1 to R 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 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 a , where the substituents may be the same or different, and R a is a hydrogen, cyano, methyl, ethyl, methoxy, or ethoxy group;

R 2 is a methyl, ethyl, propyl, isopropyl, cyclopropyl or phenyl group; and

R 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 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 2 is a methyl, cyclopropyl, or phenyl group; and

R 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 1 is a (4-methylquinazolin-2-yl)methyl, (3-methylisoquinolin-1-yl)methyl, or (3-cyanopyridin-2-yl)methyl group,

R 2 is a methyl group; and

R 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 1 is a (4-methylquinazolin-2-yl)methyl group,

R 2 is a methyl group, and

R 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.